US009072799B2

(12) United States Patent (10) Patent No.: US 9,072,799 B2 Boyden et al. (45) Date of Patent: Jul. 7, 2015

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US 9,072,799 B2 1. 2 COMPOSITIONS AND METHODS FOR ick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold, Eliza SURFACE ABRASION WITH FROZEN beth A. Sweeney and Lowell L. Wood, Jr. as inventors, filed PARTICLES 31 Oct. 2008. The present application is related to U.S. patent application CROSS-REFERENCE TO RELATED Ser. No. 12/290,685, entitled COMPOSITIONS AND APPLICATIONS METHODS FOR THERAPEUTIC DELIVERY WITH FROZEN PARTICLES, naming Edward S. Boyden, Roder The present application is related to U.S. patent application ick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold, Eliza Ser. No. 12/290,670, entitled COMPOSITIONS AND beth A. Sweeney and Lowell L. Wood, Jr. as inventors, filed METHODS FOR SURFACE ABRASION WITH FROZEN 10 31 Oct. 2008. PARTICLES, naming Edward S. Boyden, Daniel B. Cook, The present application is related to U.S. patent application Roderick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold, Ser. No. 12/290,686, entitled COMPOSITIONS AND Elizabeth A. Sweeney and Lowell L. Wood, Jr. as inventors, METHODS FOR THERAPEUTIC DELIVERY WITH filed 31 Oct. 2008. FROZEN PARTICLES, naming Edward S. Boyden, Roder The present application is related to U.S. patent application 15 ick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold, Eliza Ser. No. 12/290,659, entitled COMPOSITIONS AND beth A. Sweeney and Lowell L. Wood, Jr. as inventors, filed METHODS FOR SURFACE ABRASION WITH FROZEN 31 Oct. 2008. PARTICLES, naming Edward S. Boyden, Daniel B. Cook, The present application is related to U.S. patent application Roderick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold, Ser. No. 12/290,690, entitled COMPOSITIONS AND Elizabeth A. Sweeney and Lowell L. Wood, Jr. as inventors, METHODS FOR THERAPEUTIC DELIVERY WITH filed 31 Oct. 2008. FROZEN PARTICLES, naming Edward S. Boyden, Roder The present application is related to U.S. patent application ick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold, Eliza Ser. No. 12/290,658, entitled COMPOSITIONS AND beth A. Sweeney and Lowell L. Wood, Jr. as inventors, filed METHODS FOR SURFACE ABRASION WITH FROZEN 31 Oct. 2008. PARTICLES, naming Edward S. Boyden, Daniel B. Cook, 25 The present application is related to U.S. patent application Roderick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold, Ser. No. 12/290.691, entitled COMPOSITIONS AND Elizabeth A. Sweeney and Lowell L. Wood, Jr. as inventors, METHODS FOR THERAPEUTIC DELIVERY WITH filed 31 Oct. 2008. FROZEN PARTICLES, naming Edward S. Boyden, Roder The present application is related to U.S. patent application ick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold, Eliza Ser. No. 12/290,665, entitled COMPOSITIONS AND 30 beth A. Sweeney and Lowell L. Wood, Jr. as inventors, filed METHODS FOR SURFACE ABRASION WITH FROZEN 31 Oct. 2008. PARTICLES, naming Edward S. Boyden, Daniel B. Cook, The present application is related to U.S. patent application Roderick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold, Ser. No. 12/290,684, entitled COMPOSITIONS AND Elizabeth A. Sweeney and Lowell L. Wood, Jr. as inventors, METHODS FOR THERAPEUTIC DELIVERY WITH filed 31 Oct. 2008. 35 FROZEN PARTICLES, naming Edward S. Boyden, Roder The present application is related to U.S. patent application ick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold, Eliza Ser. No. 12/290,677, entitled COMPOSITIONS AND beth A. Sweeney and Lowell L. Wood, Jr. as inventors, filed METHODS FOR SURFACE ABRASION WITH FROZEN 31 Oct. 2008. PARTICLES, naming Edward S. Boyden, Daniel B. Cook, All subject matter of the Related Applications and of any Roderick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold, 40 and all parent, grandparent, great-grandparent, etc. applica Elizabeth A. Sweeney and Lowell L. Wood, Jr. as inventors, tions of the Related Applications is incorporated herein by filed 31 Oct. 2008. reference to the extent Such subject matter is not inconsistent The present application is related to U.S. patent application herewith. Ser. No. 12/290,687, entitled COMPOSITIONS AND METHODS FOR SURFACE ABRASION WITH FROZEN 45 SUMMARY PARTICLES, naming Edward S. Boyden, Daniel B. Cook, Roderick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold, In one aspect, a composition or therapeutic composition Elizabeth A. Sweeney and Lowell L. Wood, Jr. as inventors, includes but is not limited to, one or more frozen particles filed 31 Oct. 2008. including at least one of hydrogen oxide, helium, neon, kryp The present application is related to U.S. patent application 50 ton, argon, Xenon, nitrogen, chlorine, bromine, oxygen, air, Ser. No. 12/290,676, entitled COMPOSITIONS AND carbon dioxide, polyethylene glycol, acetone, ethyl acetate, METHODS FOR SURFACE ABRASION WITH FROZEN dimethyl sulfoxide, dimethyl formamide, dioxane, hexam PARTICLES, naming Edward S. Boyden, Daniel B. Cook, ethylphosphorotriamide, perfluorohydrocarbon, methanol, Roderick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold, ethanol, tert-butyl alcohol, formic acid, hydrogen fluoride, Elizabeth A. Sweeney and Lowell L. Wood, Jr. as inventors, 55 ammonia, acetic acid, benzene, carbon tetrachloride, aceto filed 31 Oct. 2008. nitrile, hexane, methylene chloride, carboxylic acid, Saline, The present application is related to U.S. patent application Ringer's solution, lactated Ringer's solution, Hartmann's Ser. No. 12/290,671, entitled COMPOSITIONS AND Solution, acetated Ringer's Solution, phosphate buffered solu METHODS FOR THERAPEUTIC DELIVERY WITH tion, TRIS-buffered saline solution, Hank's balanced salt FROZEN PARTICLES, naming Edward S. Boyden, Roder 60 Solution, Earle's balanced salt Solution, standard saline cit ick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold, Eliza rate, HEPES-buffered saline, dextrose, glucose, or diethyl beth A. Sweeney and Lowell L. Wood, Jr. as inventors, filed ether. In at least one embodiment, at least one of the constitu 31 Oct. 2008. ents of the one or more frozen particles is frozen. In at least The present application is related to U.S. patent application one embodiment, all of the constituents of the one or more Ser. No. 12/290,683, entitled COMPOSITIONS AND 65 frozen particles are frozen. In at least one embodiment, the at METHODS FOR THERAPEUTIC DELIVERY WITH least one composition or therapeutic composition includes FROZEN PARTICLES, naming Edward S. Boyden, Roder one or more frozen Solution particles. In at least one embodi US 9,072,799 B2 3 4 ment, the composition or therapeutic composition includes ceramic, fiberglass, cellulose, broad carbide, aromatic polya one or more frozen solution particles and the composition or mide, nylon, silk, rayon, acetate, modacrylic, olefin, acrylic, therapeutic composition is in at least one crystalline or amor polyester, aromatic polyester, poly-lactic acid, vinyon, Saran, phous phase. In at least one embodiment, the frozen Solution spandex, Vinalon, aromatic nylon, vinylidene chloride, particles include at least one of the constituents described 5 modal, polybenzimidazole, Sulfur, lyocell, orlon, Zylon, high herein. performance polyethylene, polypyridobenzimidazole, vect In at least one embodiment, the at least one composition or ran, acrylonitrile rubber, glass, copper, iron, steel, Sodium, therapeutic composition includes hydrogen oxide in the form potassium, calcium, Zinc, manganese, carbon, magnesium, of at least one of amorphous frozen water, low density amor silicon, silica, hydrogen oxide ice, plant matter (including phous ice, high density amorphous ice, crystalline ice, very 10 Vegetable matter), animal matter, or mineral matter. In at least high density amorphous ice, clathrate ice, or hyperquenched one embodiment, the one or more reinforcement agents are glassy water. In at least one embodiment, the one or more located at least on the surface or beneath the surface of the frozen particles include hydrogen oxide in the form of at least particle. In at least one embodiment, the one or more rein one of ice Ic, ice Ih, ice II, ice III, ice IV, ice V, ice VI, ice VII, forcement agents are located within the particle. ice VIII, ice IX, ice X, ice XI, ice XII, ice XIII, or ice XIV. In 15 In at least one embodiment, the composition ortherapeutic at least one embodiment, the one or more frozen particles composition includes at least one abrasive. In at least one include hydrogen oxide in the form of ice Ic. embodiment, the composition includes at least one therapeu In at least one embodiment, the one or more frozen par tic agent, such as a prodrug or precursor compound. In at least ticles have at least one major dimension of approximately one one embodiment, the composition ortherapeutic composition decimeter or less, approximately one centimeter or less, includes at least one pharmaceutically-acceptable carrier or approximately one millimeter or less, approximately one excipient. micrometer or less, approximately one nanometer or less, In at least one embodiment, the composition is formulated approximately one picometer or less, or any value therebe to be a therapeutic composition administered by one or more tween. In at least one embodiment, the one or more frozen of topical delivery, oral delivery, enteral delivery, mucosal particles have at least one major dimension of approximately 25 delivery, percutaneous delivery, or parenteral delivery. In at ten micrometers or less. In at least one embodiment, the at least one embodiment, parenteral delivery includes at least least one major dimension of the one or more frozen particles one of intravenous delivery, intra-arterial delivery, intracar includes at least one of radius, diameter, length, width, height, diac delivery, Subcutaneous delivery, intraperitoneal delivery, or perimeter of a particle. In at least one embodiment, the one or intramuscular delivery. In at least one embodiment, the or more frozen particles have a density greater than approxi 30 composition or therapeutic composition is formulated to be mately 0.92 g/cm. administered by high Velocity impact. In at least one embodi In at least on embodiment, the one or more frozen particles ment, the composition or therapeutic composition is formu approximate the shape of at least one of a sphere, bullet, lated to be administered by one or more devices. In certain flechette, cone, needle, arrow, spear, diamond, pyramid, cyl instances, an example of a device that may be used for admin inder, minie ball, shuttlecock, spiral, bell, pear, crystal, cube, 35 istering one or more of the compositions described herein spheroid, tetrahedron, crescent, or high aspect ratio shape. In includes a handheld device, such as a wand, a pen, a baton, a at least one embodiment, the one or more frozen particles hose, a sprayer, a gun (e.g., a pellet gun), or other handheld include a plurality of frozen particles that are approximately device. In certain instances, the device is at least part of a uniform with regard to size, shape, weight, or density. built-in delivery device, such as may be included in a wall, an In at least one embodiment, the one or more frozen par 40 overhead device, a corral, a gate, or a device that includes a ticles or the compositions exist at about 30°C., about 20°C., cavity into which a Subject may be placed for administration about 10°C., about 5°C., about 0°C., about -10° C. about or delivery of at least one composition described herein. In -20°C., about -30°C., about -40°C., about -50° C., about certain instances, the device has robotic action. In any of these -60° C., about -70° C., about -75° C., about -80° C., about instances, the device may be remotely controlled, for -85°C., about -90° C., about -95°C., about -100° C., about 45 example, by a human or computer program. -120° C., about -150° C., about -180° C., about -200° C., In at least one embodiment, the composition ortherapeutic about -220° C., about -250° C., or any value less than or composition includes at least one of a polymer, biopolymer, therebetween. In certain instances, the one or more frozen nanoparticle, or detection material. In certain instances, the particles are utilized at a very cold temperature so that effec detection material may be located on or in the one or more tive penetration of a biological tissue is achieved. In certain 50 frozen particles. In certain instances, the detection material instances, the one or more frozen particles are utilized at may be intermixed with the one or more frozen particles. In warmer temperatures, particularly if the contents of the one or certain instances, the detection material provides a “tracer” more frozen particles include agents that have warmer freez agent that allows for viewing one or more locations of admin ing temperatures. For example, the freezing point of nitrogen istration of the at least one composition or therapeutic com is approximately -210° C., whereas the freezing point of 55 position. Thus, in certain instances the detection material is dimethyl sulfoxide (DMSO) is approximately 18.45° C. located on the at least one therapeutic composition or the at Thus, frozen particles of DMSO can be utilized or adminis least one frozen particle. In other instances, the detection tered at a warmer temperature than frozen particles of nitro material is separate from the at least one therapeutic compo gen. sition or the at least one frozen particle and forms a mixture In at least one embodiment, the composition ortherapeutic 60 with the therapeutic composition or frozen particles or is composition includes one or more reinforcement agents. In at administered at approximately the same time, in approxi least one embodiment, the one or more reinforcement agents mately the same place, or in approximately the same manner include at least one of a natural, artificial, or synthetic agent. as the one or more therapeutic compositions or frozen par In at least one embodiment, the one or more reinforcement ticles. agents include at least one of a plate, fiber, or spheroid. In at 65 In at least one embodiment, the detection material includes least one embodiment, the one or more reinforcement agents at least one electronic identification device. In at least one include one or more of polyaramid, vinylester matrix, metal, embodiment, the at least one electronic identification device US 9,072,799 B2 5 6 includes at least one radio frequency identification device. In psi, at least about 1200 psi, at least about 1300 psi, at least at least one embodiment, the detection material includes at about 1400 psi, at least about 1500 psi, about 2000 psi, about least one radioactive element. In at least one embodiment, the 2500 psi, about 3000 psi, about 3500 psi, about 4000 psi, radioactive element includes one or more of 'P, S, 'C, about 5000 psi, about 6000 psi, about 7000 psi, about 8000 13 II, 19 Ir, 192Ir, 193Ir, 201T, or H. psi, about 9000 psi, about 10000 psi, or any value therebe In at least one embodiment, the detection material includes tWeen. at least one colorimetric Substance. In at least one embodi In at least one embodiment, the at least one composition or ment, the at least one colorimetric Substance includes one or therapeutic composition is propelled to or at a predetermined more of an inorganic, organic, biological, natural, artificial, or velocity for delivery or administration to a desired location of synthetic Substance. In at least one embodiment, the at least 10 the at least one biological tissue. In at least one embodiment, one colorimetric Substance includes one or more of a dye, the at least one composition or therapeutic composition is pigment, or a light-emitting Substance. In at least one embodi propelled to orata Velocity of approximately 10 m/s, approxi ment, the light-emitting Substance includes at least one of a mately 20 m/s, approximately 30 m/s, approximately 40 m/s, luminescent Substance, fluorescent Substance, phosphores approximately 50 m/s, approximately 60 m/s, approximately cent Substance, or quantum dot. In at least one embodiment, 15 70 m/s, approximately 80 m/s, approximately 90 m/s, the at least one colorimetric Substance is biocompatible. approximately 100 m/s, approximately 200 m/s, approxi In at least one embodiment, the detection material includes mately 300 m/s, approximately 400 m/s, approximately 500 at least one of a diamagnetic particle, ferromagnetic particle, m/s, approximately 600 m/s, approximately 700 m/s, paramagnetic particle, Super paramagnetic contrast agent, or approximately 800 m/s, approximately 900 m/s, approxi other magnetic particle. mately 1000 m/s, approximately 1500 m/s, approximately In at least one embodiment, the composition ortherapeutic 2000 m/s, or any value greater or therebetween. composition includes one or more explosive materials. In at In at least one embodiment, delivering or administering the least one embodiment, the one or more explosive materials at least one composition or therapeutic composition includes include at least one of a high explosive or a low explosive. In ejecting the at least one composition or therapeutic composi at least one embodiment, the one or more explosive materials 25 tion toward at least one biological tissue. In at least one include at least one of carbon dioxide, nitroglycerine, or a embodiment, delivering or administering the at least one reactive metal. composition or therapeutic composition includes accelerat In one particular non-limiting example, a composition ing the at least one composition or therapeutic composition includes one or more frozen hydrogen oxide particles, toward at least one biological tissue. In at least one embodi wherein the one or more frozen hydrogen oxide particles have 30 ment, delivering the at least one composition or therapeutic at least one major dimension of approximately one centimeter composition includes accelerating the at least one composi or less, or approximately ten micrometers or less; and one or tion or therapeutic composition to a predetermined velocity more reinforcement agents including at least one of polyara for delivery to a desired location of the at least one biological mid, vinylester matrix, metal, ceramic, fiberglass, cellulose, tissue. broad carbide, aromatic polyamide, nylon, silk, rayon, 35 In at least one embodiment, the at least one composition or acetate, modacrylic, olefin, acrylic, polyester, aromatic poly therapeutic composition is accelerated toward the at least one ester, poly-lactic acid, Vinyon, Saran, Spandex, Vinalon, aro biological tissue to a Velocity of approximately 10 m/s, matic nylon, vinylidene chloride, modal, polybenzimidazole, approximately 20 m/s, approximately 30 m/s, approximately Sulfur, lyocell, orlon, Zylon, high-performance polyethylene, 40 m/s, approximately 50 m/s, approximately 60 m/s, polypyridobenzimidazole, vectran, acrylonitrile rubber, 40 approximately 70 m/s, approximately 80 m/s, approximately glass, copper, iron, Steel, Sodium, potassium, calcium, Zinc, 90 m/s, approximately 100 m/s, approximately 200 m/s, manganese, carbon, magnesium, silicon, silica, hydrogen approximately 300 m/s, approximately 400 m/s, approxi oxide ice, plant matter, animal matter, or mineral matter. mately 500 m/s, approximately 600 m/s, approximately 700 In one aspect, a method for abrasion of at least one biologi m/s, approximately 800 m/s, approximately 900 m/s, cal tissue Surface of a subject includes, but is not limited to, 45 approximately 1000 m/s, approximately 1500 m/s, approxi delivering at least one composition or therapeutic composi mately 2000 m/s, or any value greater or therebetween. tion including one or more frozen particles, as described In at least one embodiment, delivering at least one compo herein, to at least one surface of at least one biological tissue sition or therapeutic composition includes propelling, eject of a Subject in a manner Sufficient to abrade the at least one ing, or accelerating multiple frozen particles, multiple com Surface of the at least one biological tissue. 50 positions or multiple therapeutic compositions toward the at In at least one embodiment, a method for abrasion of at least one biological tissue. In at least one embodiment, two or least one biological tissue surface of a subject includes deliv more multiple frozen particles include one or more similar ering at least one composition or therapeutic composition to therapeutic agents. In at least one embodiment, two or more at least one biological tissue by propelling the composition or multiple frozen particles include one or more dissimilar therapeutic composition toward the at least one biological 55 therapeutic agents. In at least one embodiment, a single fro tissue. In certain instances, at least one composition or thera Zen particle includes two or more therapeutic agents. In at peutic composition is propelled to or at a predetermined pres least one embodiment, a single frozen particle includes mul Sure for delivery or administration of the at least one compo tiple therapeutic agents that are capable of combining to form sition ortherapeutic composition to a desired location on or in another therapeutic agent, or an active therapeutic agent. the at least one biological tissue. In at least one embodiment, 60 A particular plurality of compositions or therapeutic com the at least one composition or therapeutic composition is positions may include multiple frozen particles where various propelled using a pressure set at least about 10 psi, about 20 multiple agents are associated with a single particle. Like psi, about 30 psi, about 40 psi, about 50 psi, at least about 100 wise, a particular plurality of compositions or therapeutic psi, at least about 200 psi, at least about 300 psi, at least about compositions may include various multiple agents, where 400 psi, at least about 450 psi, at least about 500 psi, at least 65 each individual agent is associated with a single frozen par about 600 psi, at least about 700 psi, at least about 800 psi, at ticle. In at least one embodiment, a plurality of compositions least about 900 psi, at least about 1000 psi, at least about 1100 or therapeutic compositions may include any number of Sub US 9,072,799 B2 7 8 sets of frozen particles associated with a particular therapeu cavity, otic cavity, connective tissue, muscle tissue, or adipose tic agent or other constituent. During the course of any par tissue. In at least one embodiment, methods and compositions ticular method described herein, one or more plurality of described herein relate to providing or removing reproductive compositions or therapeutic compositions, or any particular sterilization of a subject. Subset thereof, may be administered in a single treatment. In at least one embodiment, a method for abrasion of at One non-limiting example of multiple therapeutic agents least one biological tissue surface of a subject and the at least capable of combining to form another therapeutic agent one biological tissue includes at least one cell mass. In at least includes combining at least one prodrug and at least one one embodiment, the at least one cell mass includes at least enzyme with a single frozen particle, wherein the at least one one of a scar, pore, pit, eschar, granuloma, keloid, artheroma prodrug and at least one enzyme combine during administra 10 tous plaque, abscess, pustule, Scaling (e.g., psoriasis or tion to form at least one active therapeutic agent. In another non-limiting example, a single frozen particle includes at eczema), infected tissue, hair follicle, necrotic tissue, stratum least one adjuvant and at least one immunogen. corneum, wrinkle, wound, tumor, skin structure, nevus, cyst, In at least one embodiment, delivering or administering the lesion, callus, neoplastic tissue, gangrenous tissue, or cellular at least one composition or therapeutic composition includes 15 deposit. contacting the at least one Surface of at least one biological In at least one embodiment, the at least one cell mass tissue of a subject with at least one composition ortherapeutic includes at least one benignormalignant tumor. In at least one composition. In at least one embodiment, delivering or embodiment, the at least one benign or malignant tumor administering the at least one composition or therapeutic relates to one or more of a melanoma, lymphoma, leukemia, composition includes contacting the at least one Surface of at sarcoma, blastoma, or carcinoma. In at least one embodiment, least one biological tissue of a Subject with one or more frozen the at least one cell mass is related to at least one blood clot, particles. In at least one embodiment, delivering or adminis microorganism accumulation, blood vessel obstruction, duct tering the at least one composition ortherapeutic composition obstruction, bowel obstruction, infection, gangrene, connec includes rupturing one or more cells of at least one Surface of tive tissue destruction, tissue or organ damage, injury, white at least one biological tissue of a Subject. 25 blood cell accumulation, or cancer. In at least one embodiment, a method for abrasion of at In at least one embodiment, a method for abrasion of at least one biological tissue Surface of a subject with at least one least one biological tissue Surface of a subject includes deliv composition or therapeutic composition described herein ering to the at least one biological tissue at least one of a includes extracting or collecting material from the at least one polymer, biopolymer, nanoparticle, or detection material, abraded Surface of at least one biological tissue. In at least one 30 examples of each of which are described herein. embodiment, the extracted or collected material includes at In at least one embodiment, a method for abrasion of at least one organic or inorganic material. In at least one least one biological tissue surface of a subject includes at least embodiment, extracting or collecting material includes one invertebrate or vertebrate animal. In at least one embodi extracting or collecting one or more cells from the at least one ment, the Subject includes at least one insect, arachnid, micro abraded Surface of at least one biological tissue. In at least one 35 organism, reptile, mammal, amphibian, bird or fish. In at least embodiment, the at least one extracted or collected material one embodiment, the Subject includes at least one human. In includes at least part of one or more granuloma, eschar, callus, at least one embodiment, the Subject includes at least one atheromatous plaque, abscess, pustule, Scaling (e.g., psoriasis livestock, pet, undomesticated herd animal, wild animal or or eczema), infected tissue, microorganism accumulation, product animal. In at least one embodiment, the Subject blood clot, blood vessel obstruction, duct obstruction, bowel 40 includes at least one of a sheep, goat, frog, dog, cat, rat, obstruction, necrotic tissue, stratum corneum, hair follicle, mouse, Vermin, monkey, duck, horse, cow, pig, chicken, nevus, wrinkle, keloid, biofilm, calculus, plaque, tartar, dan shellfish, fish, turkey, llama, alpaca, bison, wolf, fox, coyote, druff, keratin, collagen, dust, dirt, metal, glass, hair or fur, deer, rabbit, guinea pig, yak, chinchilla, mink, reindeer, deer, cellular secretion, microorganism, blood cell, particulate elk, raccoon, camel, donkey, or mule. matter, or connective tissue. 45 In one particular non-limiting example, a method for abra In at least one embodiment, a method for abrasion of at sion of at least one biological tissue surface of a subject least one biological tissue surface of a subject includes at least includes delivering at least one composition to at least one one biological tissue located in at least one of in situ, in vitro, Surface of at least one biological tissue of a Subject in a in Vivo, in utero, in planta, in silico, or ex vivo. In certain manner sufficient to abrade the at least one surface of the at instances, the at least one biological tissue includes at least 50 least one biological tissue; wherein the at least one composi one tissue or organ that was artificially synthesized from tion includes one or more frozen particles, including at least biological or other sources. In at least one embodiment, the at one of hydrogen oxide, helium, neon, krypton, argon, Xenon, least one biological tissue is located in vivo. In at least one nitrogen, chlorine, bromine, oxygen, air, or carbon dioxide; embodiment, the at least one biological tissue is located in at wherein the one or more frozen particles have at least one least one tissue or organ related to transplantation. In at least 55 major dimension of approximately one centimeter or less; one embodiment, the at least one tissue or organ related to and wherein the at least one composition includes one or more transplantation includes at least one donor or recipient tissue explosive materials. or organ. In at least one embodiment, the at least one donor In one particular non-limiting example, a method for abra includes at least one cadaver. In at least one embodiment, the sion of at least one biological tissue Surface of a Subject, at least one biological tissue is ingested by at least one Sub 60 includes delivering at least one composition to at least one ject. In at least one embodiment, the at least one biological Surface of at least one biological tissue of a Subject in a tissue includes one or more of skin, Scalp, hair, nail, nail bed, manner sufficient to abrade the at least one surface of the at teeth, eye, ear, ovary, Oviduct, tongue, tonsil, adenoid, liver, least one biological tissue; wherein the at least one composi bone, pancreas, stomach, blood vessel, blood, lymph, heart, tion includes one or more frozen particles, including at least lung, brain, breast, kidney, bladder, urethra, ureter, gallblad 65 one of hydrogen oxide, helium, neon, krypton, argon, Xenon, der, uterus, prostate, testes, fallopian tubes, vas deferens, nitrogen, chlorine, bromine, oxygen, air, or carbon dioxide; large intestine, Small intestine, esophagus, oral cavity, nasal wherein the one or more frozen particles have at least one US 9,072,799 B2 10 major dimension of approximately one centimeter or less; Sulfoxide, dimethyl formamide, dioxane, hexamethylphos and wherein the at least one composition includes one or more phorotriamide, perfluorohydrocarbon, methanol, ethanol, reinforcement agents. tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia, In one particular non-limiting example, a method for abra acetic acid, benzene, carbon tetrachloride, acetonitrile, hex sion of at least one biological tissue surface of a subject ane, methylene chloride, carboxylic acid, Saline, Ringer's includes delivering at least one composition to at least one Solution, lactated Ringer's solution, Hartmann's solution, Surface of at least one biological tissue of a Subject in a acetated Ringer's solution, phosphate buffered solution, manner sufficient to abrade the at least one surface of the at TRIS-buffered saline solution, Hank's balanced salt solution, least one biological tissue; wherein the at least one composi Earle's balanced salt solution, standard saline citrate, tion includes one or more frozen hydrogen oxide particles, 10 HEPES-buffered saline, dextrose, glucose, or diethyl ether; wherein the one or more frozen hydrogen oxide particles have wherein the one or more frozen particles have at least one at least one major dimension of approximately one centimeter major dimension of approximately one centimeter or less; or less; and wherein the one or more frozen hydrogen oxide and wherein the at least one composition includes one or more particles are in one or more phases including amorphous Solid explosive materials. water, low density amorphous ice, high density amorphous 15 In at least one aspect, a method for debridement of at least ice, very high density amorphous ice, clathrate ice, hyper one biological tissue of a Subject includes delivering at least quenched glassy water, ice Ic, ice Ih, ice II, ice III, ice IV, ice one composition or therapeutic composition as described V, ice VI, ice VII, ice VIII, ice IX, ice X, ice XI, ice XII, ice herein, to at least one biological tissue of a Subject in a manner XIII, or ice XIV; and wherein the at least one composition Sufficient to remove dead, damaged or infected tissue of the at includes one or more reinforcement agents. least one biological tissue. As described herein, the biological In one particular non-limiting example, a method for abra tissue may include, but not be limited to at least one of a tooth, sion of at least one biological tissue surface of a subject bone, connective tissue, adipose tissue, skin, Scalp, hair, nail, includes delivering at least one composition to at least one nail bed, teeth, eye, tongue, tonsil, adenoid, liver, pancreas, Surface of at least one biological tissue of a Subject in a stomach, blood vessel, heart, lung, brain, breast, kidney, blad manner sufficient to abrade the at least one surface of the at 25 der, urethra, ureter, gallbladder, uterus, ovary, Oviduct, pros least one biological tissue; wherein the at least one composi tate, testes, Vas deferens, fallopian tubes, large intestine, Small tion includes one or more frozen hydrogen oxide particles, intestine, esophagus, oral cavity, nasal cavity, otic cavity, wherein the one or more frozen hydrogen oxide particles have tumor, neoplastic tissue, adipose tissue, or muscle tissue. In at at least one major dimension of approximately one centimeter least one embodiment, the connective tissue includes at least or less; and wherein the one or more frozen hydrogen oxide 30 one loose connective tissue, dense connective tissue, elastic particles are in one or more phases including amorphous Solid connective tissue, reticular connective tissue, cartilage, or water, low density amorphous ice, high density amorphous blood. In at least one embodiment, the at least one biological ice, very high density amorphous ice, clathrate ice, hyper tissue includes at least one ligament or tendon. In at least one quenched glassy water, ice Ic, ice Ih, ice II, ice III, ice IV, ice embodiment, the composition or therapeutic composition V, ice VI, ice VII, ice VIII, ice IX, ice X, ice XI, ice XII, ice 35 includes at least one chemical debridement agent, such as an XIII, or ice XIV; and wherein the at least one composition enzyme, enzymatic agent, or urea. In certain instances, the includes one or more explosive materials. enzyme includes at least one of papain, elastase, protease, In one particular non-limiting example, a method for abra peptidase, or collagenase. sion of at least one biological tissue surface of a subject As described herein, the at least one composition or thera includes delivering at least one composition to at least one 40 peutic composition may be delivered or administered by vari Surface of at least one biological tissue of a Subject in a ous means and in accordance with various formulations for manner sufficient to abrade the at least one surface of the at debridement of the at least one biological tissue. As described least one biological tissue; wherein the at least one composi herein, in at least one embodiment, the at least one biological tion includes one or more frozen particles, including at least tissue is located in at least one of in situ, in vitro, in Vivo, in one of polyethylene glycol, acetone, ethyl acetate, dimethyl 45 utero, in planta, in silico, or ex vivo. In at least one embodi Sulfoxide, dimethyl formamide, dioxane, hexamethylphos ment, the at least one biological tissue is located in vivo. In at phorotriamide, perfluorohydrocarbon, methanol, ethanol, least one embodiment, the at least one biological tissue is tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia, located in at least one tissue or organ related to transplanta acetic acid, benzene, carbon tetrachloride, acetonitrile, hex tion, and may include an artificial tissue or organ, or a tissue ane, methylene chloride, carboxylic acid, Saline, Ringer's 50 or organ that was synthesized from one or more exogenous Solution, lactated Ringer's solution, Hartmann's solution, Sources, including biological Sources. In at least one embodi acetated Ringer's solution, phosphate buffered solution, ment, the at least one tissue or organ related to transplantation TRIS-buffered saline solution, Hank's balanced salt solution, includes at least one donor or recipient tissue or organ. In at Earle's balanced salt solution, standard saline citrate, least one embodiment, the at least one donor includes at least HEPES-buffered saline, dextrose, glucose, or diethyl ether; 55 one cadaver. wherein the one or more frozen particles have at least one In at least one aspect, a method is described for removing major dimension of approximately one centimeter or less; one or more materials from at least one blood vessel of at least and wherein the at least one composition includes one or more one subject, and includes delivering at least one composition reinforcement agents. ortherapeutic composition as described herein, to at least one In one particular non-limiting example, a method for abra 60 blood vessel of a subject in a manner sufficient to remove one sion of at least one biological tissue surface of a subject or more materials. includes delivering at least one composition to at least one As described herein, the at least one composition or thera Surface of at least one biological tissue of a Subject in a peutic composition may be delivered or administered by vari manner sufficient to abrade the at least one surface of the at ous means and in accordance with various formulations for least one biological tissue; wherein the at least one composi 65 removal of one or more materials from at least one blood tion includes one or more frozen particles, including at least vessel of at least one Subject. In at least one embodiment, the one of polyethylene glycol, acetone, ethyl acetate, dimethyl at least one blood vessel includes at least one artery, vein, or US 9,072,799 B2 11 12 capillary. In at least one embodiment, the at least one blood one dimension of cellular or tissue removal or destruction, or vessel is located in one or more of a liver, brain, heart, pan the removal or destruction of other materials such as cellular creas, breast, uterus, gallbladder, prostate, testes, vas defer products, extracellular matrix, collagen, elastin, protein, or ens, fallopian tubes, kidney, ovary, Oviduct, stomach, bladder, other materials. In at least one embodiment the information intestine, tumor, or lung. regarding the at least one dimension of cellular removal or As described herein, in at least one embodiment, theat least destruction includes information regarding at least one of one blood vessel is located in at least one of in situ, in vitro, in depth, width, or breadth of cellular removal or destruction. Vivo, in utero, in planta, in silico, or ex vivo, or a tissue or In at least one embodiment, the information regarding at organ located therein. In at least one embodiment, the at least least one aspect of cellular or tissue abrasion or ablation one blood vessel is located in at least one tissue or organ 10 related to transplantation, and may include an artificial tissue includes information regarding two or more Subjects with one or organ, including an artificial blood vessel. In at least one or more common attributes. In at least one embodiment, the embodiment, the at least one blood vessel is located in at least one or more common attributes include genetic attributes, one tissue or organ that was synthesized from one or more mental attributes, or psychological attributes. In at least one exogenous or endogenous sources, including biological 15 embodiment, the one or more common attributes include Sources. In at least one embodiment, the at least one blood genotype attributes or phenotype attributes. In at least one vessel was synthesized from one or more exogenous or embodiment, the one or more common attributes include at endogenous sources, including biological sources. In at least least one of height; weight; medical diagnosis; familial back one embodiment, the at least one blood vessel is located in at ground; results on one or more medical tests; ethnic back least one tissue or organ related to transplantation and ground; body mass index, age; presence or absence of at least includes at least one donor or recipient tissue or organ. In at one disease or condition; species; ethnicity; race; allergies; least one embodiment, the at least one donor includes at least gender; thickness of epidermis; thickness of dermis; thick one cadaver. ness of Stratum corneum; keratin deposition; collagen depo In at least one aspect, a method for abrasion of at least one sition; blood vessel condition; skin condition; hair or fur biological tissue or organ Surface related to transplantation 25 condition; muscle condition, tissue condition; organ condi includes delivering at least one composition or therapeutic tion; nerve condition; brain condition; presence or absence of composition, as described herein, to at least one surface of at at least one biological, chemical, or therapeutic agent in the least one tissue or organ in a manner Sufficient to abrade the at Subject; pregnancy status; lactation status; genetic profile; least one Surface of the at least one biological tissue, certain proteomic profile; partial or whole genetic sequence; partial specific methods of administration of which are described 30 or whole proteomic sequence; medical history; lymph condi herein. tion, or blood condition. In at least one aspect, a method for cleaning one or more In at least on embodiment, the output information includes wounds of a Subject includes delivering at least one compo at least one of a response signal, a comparison code, a com sition ortherapeutic composition, as described herein, to one parison plot, a diagnostic code, a treatment code, a test code, or more wounds in a manner Sufficient to clean the one or 35 a code indicative of at least one treatment received, a code more wounds, certain specific methods of administration of indicative of at least one prescribed treatment step, a code which are described herein. In at least one embodiment, the indicative of at least one vaccination delivered; a code indica one or more wounds include at least one of an incision, tive of at least one therapeutic agent delivered; a code indica laceration, abrasion, puncture wound, penetration wound, tive of at least one diagnostic agent delivered; a code indica gunshot wound, iatrogenic wound, severing, infection, ulcer, 40 tive of at least one interaction of a delivered agent and at least pressure sore, lesion, chemical burn (including but not limited one biological or chemical agent in the Subject; a code indica to irritant exposure, or exposure to a plant or synthetic chemi tive of at least one dispersion or location of at least one cal), dental caries, first-degree burn, second-degree burn, delivered agent; a code indicative of at least one detection third-degree burn, fourth-degree burn, fifth-degree burn, or material delivered; a code indicative of the depth of penetra sixth-degree burn. In at least one embodiment, the one or 45 tion of a delivered agent, or a code indicative of the condition more wounds are located in at least one of skin tissue, muscle of at least one location of an administered frozen particle tissue, eye tissue, an organ, connective tissue, neoplastic tis composition. Sue, or bone tissue. In certain instances, the wound may be a In at least one embodiment, the at least one aspect of result of a bite, such as a bite from an animal, insect, or cellular or tissue abrasion or ablation includes information arachnid. 50 regarding at least one cellular or tissue source. In at least one In at least one aspect, a method includes comparing infor embodiment, the information regarding at least one tissue mation regarding at least one aspect of cellular or tissue Source includes information regarding at least one abnormal abrasion or ablation of at least one biological tissue of at least cellular or tissue source. In at least one embodiment, the one subject, and information regarding at least one clinical information regarding at least one cellular or tissue source outcome following receipt by the at least one subject of at 55 includes information regarding at least one type of cell or least one frozen particle composition; and providing output tissue. In at least one embodiment, the at least one frozen information that is optionally based on the comparison. In at particle composition includes at least one of nitrogen, carbon least one embodiment, the method includes determining at dioxide, hydrogen oxide, helium, neon, Xenon, krypton, chlo least one statistical correlation. In at least one embodiment, rine, bromine, oxygen, air, argon, polyethylene glycol, the method includes counting the occurrence of at least one 60 acetone, ethyl acetate, dimethyl sulfoxide, dimethyl forma clinical outcome. mide, dioxane, hexamethylphosphorotriamide, perfluorohy In at least one embodiment, the information regarding at drocarbon, methanol, ethanol, tert-butyl alcohol, formic acid, least one aspect of cellular or tissue abrasion or ablation hydrogen fluoride, ammonia, acetic acid, benzene, carbon includes information regarding quantity of cells or tissue tetrachloride, acetonitrile, hexane, methylene chloride, car removed or destroyed. In at least one embodiment, the infor 65 boxylic acid, Saline, Ringer's solution, lactated Ringer's mation regarding at least one aspect of cellular or tissue Solution, Hartmann's Solution, acetated Ringer's solution, abrasion or ablation includes information regarding at least phosphate buffered solution, TRIS-buffered saline solution, US 9,072,799 B2 13 14 Hank's balanced salt solution, Earle's balanced salt solution, In at least one embodiment, the information regarding at standard saline citrate, HEPES-buffered saline, dextrose, glu least one aspect of cellular or tissue abrasion or ablation cose, or diethyl ether. includes information regarding two or more Subjects with one In at least one embodiment, the at least one frozen particle or more common attributes. In at least one embodiment, the composition includes at least one major dimension of 5 one or more common attributes include genetic attributes, approximately one centimeter or less, approximately one mil mental attributes, or psychological attributes. In at least one limeter or less, approximately one micrometer or less, embodiment, the one or more common attributes include approximately one nanometer or less, or any value therebe genotype attributes or phenotype attributes. In at least one tween. In at least one embodiment, the at least one frozen embodiment, the one or more common attributes include at particle composition includes one or more reinforcement 10 agents, one or more abrasives, or one or more explosive least one of height; weight; medical diagnosis; familial back materials. In at least one embodiment, the receipt by the at ground; results on one or more medical tests; ethnic back least one Subject of at least one frozen particle composition is ground; body mass index, age; presence or absence of at least pursuant to at least one clinical trial. one disease or condition; species; ethnicity; race; allergies; In at least one embodiment, the method further comprises 15 gender; thickness of epidermis; thickness of dermis; thick determining at least one comparison or correlation before the ness of Stratum corneum; keratin deposition; collagen depo administration or delivery of the at least one frozen particle sition; blood vessel condition; skin condition; hair or fur composition to at least one Subject. In at least one embodi condition; muscle condition, tissue condition; organ condi ment, the at least one comparison or correlation is used to tion; nerve condition; brain condition; presence or absence of predict at least one clinical outcome regarding at least one at least one biological, chemical, or therapeutic agent in the other subject. Subject; pregnancy status; lactation status; genetic profile; In at least one embodiment, the method includes creating at proteomic profile; partial or whole genetic sequence; partial least one inclusion criterion and at least one exclusion crite or whole proteomic sequence; medical history; lymph condi rion for a clinical trial involving the at least one frozen particle tion, or blood condition. composition. In at least one embodiment, the method com 25 In at least one embodiment, the generated response prises Suggesting the inclusion of one or more of the at least includes at least one of a response signal, a comparison code, one subject in at least one clinical trial. In at least one embodi a comparison plot, a diagnostic code, a treatment code, a test ment, the method includes suggesting the exclusion of one or code, a code indicative of at least one treatment received, a more of the at least one subject in at least one clinical trial. In code indicative of at least one prescribed treatment step, a at least one embodiment, the method includes using one or 30 code indicative of at least one vaccination delivered; a code more of the at least one comparison or correlation to predictat indicative of at least one therapeutic agent delivered; a code least one clinical outcome regarding at least one second sub indicative of at least one diagnostic agent delivered; a code ject. In at least one embodiment, the at least one second indicative of at least one interaction of a delivered agent and Subject has not received the at least one frozen particle com at least one biological or chemical agent in the Subject; a code position. 35 indicative of at least one dispersion or location of at least one In at least one embodiment, the method includes that at delivered agent; a code indicative of at least one detection least one second Subject is a plurality of people; and further material delivered; a code indicative of the depth of penetra includes segregating Subject identifiers associated with the tion of a delivered agent, or a code indicative of the condition plurality of people in reference to the predicted at least one of at least one location of a delivered or administered frozen clinical outcome. In at least one embodiment, the method 40 particle composition. includes that at least one second Subject is a plurality of In at least one embodiment, the information regarding at people; and further includes determining the eligibility of the least one aspect of cellular or tissue abrasion or ablation at least one second Subject for the at least one clinical trial. includes information regarding at least one cellular or tissue In at least one embodiment, a method of predicting a clini Source. In at least one embodiment, the information regarding cal outcome of at least one frozen particle composition treat- 45 at least one tissue source includes information regarding at ment for at least one first Subject includes determining a least one abnormal cellular or tissue source. In at least one similarity or a dissimilarity in information regarding at least embodiment, the information regarding at least one cellular one aspect of cellular or tissue abrasion or ablation of at least or tissue source includes information regarding at least one one biological tissue of at least one first Subject to information type of cell or tissue. In at least one embodiment, the infor regarding at least one aspect of cellular or tissue abrasion or 50 mation regarding at least one aspect of cellular or tissue ablation of at least one biological tissue of at least one second abrasion or ablation includes information regarding at least Subject, wherein the at least one second subject attained a one type of cell or tissue. clinical outcome following receipt of the at least one frozen In at least one embodiment, the at least one frozen particle particle composition; and providing output information that composition includes at least one of polyethylene glycol, is optionally based on the determination. 55 acetone, ethyl acetate, dimethyl sulfoxide, dimethyl forma In at least one embodiment, the information regarding at mide, dioxane, hexamethylphosphorotriamide, perfluorohy least one aspect of cellular or tissue abrasion or ablation drocarbon, methanol, ethanol, tert-butyl alcohol, formic acid, includes information regarding the quantity of cells or tissues hydrogen fluoride, ammonia, acetic acid, benzene, carbon removed or destroyed. In at least one embodiment, the infor tetrachloride, acetonitrile, hexane, methylene chloride, car mation regarding at least one aspect of cellular or tissue 60 boxylic acid, Saline, Ringer's solution, lactated Ringer's abrasion or ablation includes information regarding at least Solution, Hartmann's Solution, acetated Ringer's solution, one dimension of cellular, tissue, or other material removal or phosphate buffered solution, TRIS-buffered saline solution, destruction. In at least one embodiment, the at least one Hank's balanced salt solution, Earle's balanced salt solution, dimension of cellular, tissue, or other material removal or standard saline citrate, HEPES-buffered saline, dextrose, glu destruction includes information regarding at least one of 65 cose, diethyl ether, nitrogen, carbon dioxide, hydrogen oxide, depth, width, or breadth of cellular, tissue, or other material helium, neon, Xenon, krypton, chlorine, bromine, oxygen, air removal or destruction. or argon. US 9,072,799 B2 15 16 In at least one embodiment, the at least one frozen particle device cause the computing device to access the first possible composition includes at least one major dimension of dataset in response to the first input. In at least one embodi approximately one centimeter or less, approximately one mil ment, the system includes one or more instructions that when limeter or less, approximately one micrometer or less, executed on the computing device cause the computing approximately one nanometer or less, or any value therebe device to generate the first possible dataset in response to the tween. In at least one embodiment, the at least one frozen first input. In at least one embodiment, the system includes particle composition includes one or more reinforcement one or more instructions that when executed on the comput agents, one or more abrasives, or one or more explosive ing device cause the computing device to determine a graphi materials. cal illustration of the first possible dataset. In at least one embodiment, the receipt by the at least one 10 In at least one embodiment, the system includes one or Subject of at least one frozen particle composition is pursuant more instructions that when executed on the computing to at least one clinical trial. In at least one embodiment, the device cause the computing device to determine a graphical method includes creating at least one inclusion criterion and illustration of the second possible dataset. In at least one at least one exclusion criterion for a clinical trial involving the embodiment, the computing device includes one or more at least one frozen particle composition. 15 desktop computer, workStation computer, computing system In at least one embodiment, the method includes Suggest including a cluster of processors, a networked computer, a ing the inclusion of one or more of the at least one Subject in tablet personal computer, a laptop computer, a mobile device, at least one clinical trial. In at least one embodiment, the a mobile telephone, or a personal digital assistant computer. method includes Suggesting the exclusion of one or more of In at least one embodiment, the computing device is con the at least one Subject in at least one clinical trial. In at least figured to communicate with a database to access the first one embodiment, the at least one second Subject is a plurality possible dataset. In at least one embodiment, the computing of people; and includes segregating Subject identifiers asso device is configured to communicate with a frozen particle ciated with the plurality of people in reference to the predicted composition selecting apparatus. In at least one embodiment, at least one clinical outcome. In at least one embodiment, the the computing device is configured to communicate with a method includes determining the eligibility of the at least one 25 frozen particle composition generating apparatus. second subject for the at least one clinical trial. In at least one aspect, a system includes circuitry for receiv In one aspect, a system includes at least one computing ing a first input associated with a first possible dataset, the first device; one or more instructions that when executed on the possible dataset including data representative of one or more computing device cause the computing device to receive a measurements relating to one or more physical attributes of a first input associated with a first possible dataset, the first 30 first Subject; circuitry for comparing a value associated with possible dataset including data representative of one or more the first possible dataset with a second dataset including val measurements relating to one or more physical attributes of a ues representative of predictive regimen parameters related to first Subject; one or more instructions that when executed on a second Subject with one or more similar or dissimilar physi a computing device cause the computing device to compare a cal attributes; circuitry for determining from the comparison value associated with the first possible dataset with a second 35 at least one frozen particle composition treatment regimen for dataset including values representative of predictive regimen the first Subject; and circuitry for providing output informa parameters related to a second Subject with one or more tion, wherein the output information is optionally based on similar or dissimilar physical attributes; one or more instruc the comparison. tions that when executed on the computing device cause the In at least one embodiment, the system includes the cir computing device to determine from the comparison at least 40 cuitry for receiving a first input associated with a first possible one frozen particle composition treatment regimen for the dataset and includes circuitry for receiving one or more mea first Subject; and output information. Surements relating to one or more physical attributes includ In at least one embodiment, the output information is based ing at least one of height; weight, body mass index; age; on the determination. In at least one embodiment, the treat presence or absence of at least one disease or condition; ment regimen includes at least one of cellular or tissue or 45 species; ethnicity; race; allergies; gender; thickness of epi other material removal, cellular or tissue or other material dermis; thickness of dermis; thickness of stratum corneum; ablation, debridement, delivery of at least one therapeutic keratin deposition; collagen deposition; blood vessel condi agent, cleaning one or more wounds, removing material from tion; skin condition; hair or fur condition; muscle condition; at least one biological tissue, or removing material from at tissue condition; organ condition; nerve condition; brain con least one blood vessel. 50 dition; presence or absence of at least one biological, chemi In at least one embodiment, the frozen particle composition cal, or therapeutic agent in the Subject; pregnancy status; includes at least one of polyethylene glycol, acetone, ethyl lactation status; genetic profile; proteomic profile; partial or acetate, dimethyl Sulfoxide, dimethyl formamide, dioxane, whole genetic sequence; partial or whole proteomic hexamethylphosphorotriamide, perfluorohydrocarbon, sequence; medical history; lymph condition, or blood condi methanol, ethanol, tert-butyl alcohol, formic acid, hydrogen 55 tion. fluoride, ammonia, acetic acid, benzene, carbon tetrachlo In at least one embodiment, the treatment regimen includes ride, acetonitrile, hexane, methylene chloride, carboxylic at least one of cellular or tissue or other material removal, acid, Saline, Ringer's solution, lactated Ringer's solution, cellular or tissue or other material ablation, debridement, Hartmann's solution, acetated Ringer's solution, phosphate delivery of at least one therapeutic agent, cleaning one or buffered solution, TRIS-buffered saline solution, Hank's bal 60 more wounds, removing material from at least one biological anced salt Solution, Earle's balanced salt solution, standard tissue, or removing material from at least one blood vessel. saline citrate, HEPES-buffered saline, dextrose, glucose, In at least one embodiment, the frozen particle composition diethyl ether, nitrogen, carbon dioxide, hydrogen oxide, includes at least one of polyethylene glycol, acetone, ethyl helium, neon, Xenon, krypton, chlorine, bromine, oxygen, air acetate, dimethyl Sulfoxide, dimethyl formamide, dioxane, or argon. 65 hexamethylphosphorotriamide, perfluorohydrocarbon, In at least one embodiment, the system includes one or methanol, ethanol, tert-butyl alcohol, formic acid, hydrogen more instructions that when executed on the computing fluoride, ammonia, acetic acid, benzene, carbon tetrachlo US 9,072,799 B2 17 18 ride, acetonitrile, hexane, methylene chloride, carboxylic embodiment, the one or more instructions further include one acid, Saline, Ringer's solution, lactated Ringer's solution, or more instructions for counting the occurrence of at least Hartmann's solution, acetated Ringer's solution, phosphate one clinical outcome. In at least one embodiment, the infor buffered solution, TRIS-buffered saline solution, Hank's bal mation regarding at least one aspect of cellular or tissue anced salt Solution, Earle's balanced salt solution, standard abrasion or ablation includes information regarding quantity saline citrate, HEPES-buffered saline, dextrose, glucose, of cells or tissues removed or destroyed. diethyl ether, nitrogen, carbon dioxide, hydrogen oxide, In at least one embodiment, the information regarding at helium, neon, Xenon, krypton, chlorine, bromine, oxygen, air least one aspect of cellular or tissue abrasion or ablation or argon. includes information regarding at least one dimension of In at least one embodiment, the circuitry for comparing a 10 value associated with a first possible dataset includes circuitry cellular or tissue removal or destruction, or removal or for comparing one or more predictive regimen parameters destruction of other materials such as extracellular matrix, including clinical outcome; secondary effects related to the collagen, elastin, protein, plaque, or other materials. In at least one embodiment, the information regarding at least one treatment; disease stage; longevity; or vaccination adminis dimension of cellular removal or destruction includes infor tration or delivery. In at least one embodiment, the circuitry 15 for comparing a value associated with the first possible mation regarding at least one of depth, width, or breadth of dataset with a second dataset includes circuitry for selecting cellular removal or destruction. at least one of quality or quantity related to one or more frozen In at least one embodiment, the information regarding at particle compositions, method of delivery or administration least one aspect of cellular or tissue abrasion or ablation of one or more frozen particle compositions, delivery location includes information regarding two or more Subjects with one of one or more frozen particle compositions, content of one or or more common attributes. In at least one embodiment, the more frozen particle compositions, timing of delivery or information regarding at least one aspect of cellular or tissue administration of one or more frozen particle compositions, abrasion or ablation includes information regarding at least decrease in a physical dimension of one or more frozen par one cellular or tissue source. In at least one embodiment, the ticle compositions, or time interval between at least two deliv 25 information regarding at least one tissue source includes eries or administrations with one or more frozen particle information regarding at least one abnormal cellular or tissue compositions. Source. In at least one embodiment, the information regarding In at least one embodiment, the circuitry for determining at least one cellular or tissue source includes information from the comparison of the delivery or administration to at regarding at least one type of cell or tissue. In at least one least one subject of at least one frozen particle composition 30 embodiment, the information regarding at least one aspect of treatment regimen includes circuitry for selecting the combi cellular or tissue abrasion or ablation includes information nation of at least two parameters selected from quality or regarding at least one type of cell or tissue. quantity related to one or more frozen particle compositions, In at least one embodiment, the at least one frozen particle method of delivery or administration of one or more frozen composition includes at least one of polyethylene glycol, particle compositions, delivery location of one or more frozen 35 acetone, ethyl acetate, dimethyl sulfoxide, dimethyl forma particle compositions, content of one or more frozen particle mide, dioxane, hexamethylphosphorotriamide, perfluorohy compositions, timing of administration of one or more frozen drocarbon, methanol, ethanol, tert-butyl alcohol, formic acid, particle compositions, decrease in a physical dimension of hydrogen fluoride, ammonia, acetic acid, benzene, carbon one or more frozen particle compositions, or time interval tetrachloride, acetonitrile, hexane, methylene chloride, car between at least two deliveries with one or more frozen par 40 boxylic acid, Saline, Ringer's solution, lactated Ringer's ticle compositions. Solution, Hartmann's Solution, acetated Ringer's solution, In at least one embodiment, the circuitry for comparing a phosphate buffered solution, TRIS-buffered saline solution, value associated with the first possible dataset with a second Hank's balanced salt solution, Earle's balanced salt solution, dataset including values representative of predictive regimen standard saline citrate, HEPES-buffered saline, dextrose, glu parameters includes circuitry for selecting at least one of a 45 cose, diethyl ether, nitrogen, carbon dioxide, hydrogen oxide, clinical outcome; secondary effects related to the treatment; helium, neon, Xenon, krypton, chlorine, bromine, oxygen, air, disease stage, longevity; or vaccination delivery or adminis or argon. In at least one embodiment, the at least one frozen tration. In at least one embodiment, the clinical outcome particle composition includes at least one major dimension of includes a positive clinical outcome or a negative clinical approximately one decimeter or less, approximately one cen outcome. In at least one embodiment, the clinical outcome 50 timeter or less, approximately one millimeter or less, approxi includes one or more adverse effect, failure to attain a clinical mately one micrometer or less, approximately one nanometer endpoint of a clinical trial, failing to attain a beneficial effect, or less, or any value therebetween. or measurement of at least one biochemical, biological or In at least one embodiment, the at least one frozen particle physiological parameter. composition includes one or more reinforcement agents, one In at least one aspect, a system includes at least one com 55 or more abrasives, or one or more explosive materials. In at puter program, configured with a computer-readable least one embodiment, the receipt by the at least one subject medium, for use with at least one computer system and of at least one frozen particle composition is pursuant to at wherein the computer program includes a plurality of instruc least one clinical trial. In at least one embodiment, the instruc tions including but not limited to one or more instructions for tions include determining at least one comparison or correla comparing information regarding at least one aspect of cel 60 tion before the delivery or administration of the at least one lular or tissue abrasion or ablation of at least one biological frozen particle composition to at last one subject. tissue of at least one Subject and information regarding at least In at least one embodiment, the system includes creating at one clinical outcome following receipt by the at least one least one inclusion criterion and at least one exclusion crite Subject of at least one frozen particle composition. rion for a clinical trial involving the at least one frozen particle In at least one embodiment, the one or more instructions for 65 composition. In at least one embodiment, the system includes comparing information include one or more instructions for Suggesting the inclusion of one or more of the at least one determining at least one statistical correlation. In at least one Subject in at least one clinical trial. In at least one embodi US 9,072,799 B2 19 20 ment, the system includes Suggesting the exclusion of one or FIG. 6 illustrates the strength of hydrogen oxide samples more of the at least one Subject in at least one clinical trial. reinforced with a reinforcement agent. In at least one embodiment, the system includes using one FIG. 7 illustrates a partial view of a method 700 that or more of the at least one correlation to predict at least one includes generating at least one response. clinical outcome regarding at last one second subject. In at 5 FIG. 8 illustrates a partial view and an embodiment of FIG. least one embodiment, the at least one second subject has not 7. received the at least one frozen particle composition. In at FIG. 9 illustrates a partial view and an embodiment of FIG. least one embodiment, the method further includes predicting 7. at least one clinical outcome involving the at least one second FIG. 10 illustrates a partial view of a method 1000 that Subject, wherein the at least one second Subject is a plurality 10 includes generating at least one response. of people; and segregating Subject identifiers associated with FIG. 11 illustrates a partial view and an embodiment of the plurality of people in reference to the predicted at least one FIG 10. clinical outcome. In at least one embodiment, the at least one FIG. 12 illustrates a partial view and an embodiment of second subject is a plurality of people; and the system FIG 10. includes determining the eligibility of the at least one second 15 FIG. 13 illustrates a partial view of a system 1300 that subject for the at least one clinical trial. includes a computer program for executing a computing pro In at least one embodiment, a system includes at least one cess on a computing device. computer program, configured with a computer-readable FIG. 14 illustrates a partial view and an embodiment of medium, for use with at least one computer system and FIG. 13. wherein the computer program includes a plurality of instruc- 20 FIG. 15 illustrates a partial view and an embodiment of tions including but not limited to one or more instructions for FIG. 13. comparing information regarding at least one aspect of cel FIG. 16 illustrates a partial view of a system 1600 that lular or tissue abrasion or ablation of at least one biological includes a computer program for executing a computing pro tissue of at least one Subject and information regarding at least cess on a computing device. one frozen particle composition involving the at least one, 25 FIG. 17 illustrates a partial view of a computer program biological tissue of at least one Subject; and one or more product 1700 for executing a computing process on a com instructions for applying one or more comparisons to infor puting device. mation regarding at least one aspect of cellular or tissue FIG. 18 illustrates a partial view of a computer program abrasion or ablation regarding of a plurality of people. product 1800 for executing a computing process on a com In at least one embodiment, the system includes one or 30 puting device. more instructions for segregating Subject identifiers associ FIG. 19 illustrates a partial view of a computer program ated with the plurality of people in reference to at least one of product 1900 for executing a computing process on a com the one or more applied comparisons. In at least one embodi puting device. ment, the information regarding at least one aspect of cellular FIG. 20 illustrates a partial view of a computer program or tissue abrasion or ablation includes information regarding 35 product 2000 for executing a computing process on a com the quantity of cells or tissue removed or destroyed. In at least puting device. one embodiment, the information regarding at least one FIG. 21 illustrates a partial view of a computer program aspect of cellular, tissue, or other material abrasion or abla product 2100 for executing a computing process on a com tion includes information regarding at least one dimension of puting device. cellular, tissue, or other material removal or destruction. In at 40 FIG. 22 illustrates a partial view of a computer program least one embodiment, the information regarding at least one product 2200 for executing a computing process on a com dimension of cellular, tissue, or other material removal or puting device. destruction includes information regarding at least one of FIG. 23 illustrates a partial view of a method 2300 that depth, width, or breadth of cellular removal or destruction. In includes generating at least one response. at least one embodiment, a system includes one or more 45 FIG. 24 illustrates a partial view and an embodiment of instructions for segregating individual identifiers associated FIG. 23. with the plurality of people in reference to at least one char FIG. 25 illustrates a partial view and an embodiment of acteristic shared by two or more subjects of the plurality of FIG. 23. people. FIG. 26 illustrates a partial view of a method 2600 that The foregoing Summary is illustrative only and is not 50 includes generating at least one response. intended to be in any way limiting. In addition to the illustra FIG. 27 illustrates a partial view and an embodiment of tive aspects, embodiments, and features described above, fur FIG. 26. ther aspects, embodiments, and features will become appar FIG. 28 illustrates a partial view and an embodiment of ent by reference to the drawings and the following detailed FIG. 26. description. 55 FIG. 29 illustrates a partial view of a system 2900 that includes a computer program for executing a computing pro BRIEF DESCRIPTION OF THE FIGURES cess on a computing device. FIG. 30 illustrates a partial view and an embodiment of FIG. 1 illustrates particular phases of hydrogen oxide. FIG. 29. FIG. 2 illustrates the density of hydrogen oxide at various 60 FIG. 31 illustrates a partial view of a system 3100 that pressure points. includes a computer program for executing a computing pro FIG. 3 illustrates particular phases of hydrogen oxide at cess on a computing device. various pressure and temperature points. FIG. 32 illustrates a partial view and an embodiment of FIG. 4 illustrates particular phases of hydrogen oxide at FIG. 31. various pressure and temperature points. 65 FIG. 33 illustrates a partial view of a system 3300 that FIG. 5 illustrates the strength of hydrogen oxide samples includes a computer program for executing a computing pro reinforced with fiberglass or kaolin. cess on a computing device. US 9,072,799 B2 21 22 FIG. 34 illustrates a partial view and an embodiment of ammonia, acetic acid, benzene, carbon tetrachloride, aceto FIG. 33. nitrile, hexane, methylene chloride, carboxylic acid, Saline, FIG. 35 illustrates a partial view and an embodiment of Ringer's solution, lactated Ringer's solution, Hartmann's FIG. 33. Solution, acetated Ringer's Solution, phosphate buffered solu FIG. 36 illustrates a partial view of a system 3600 that tion, TRIS-buffered saline solution, Hank's balanced salt includes a computer program for executing a computing pro Solution, Earle's balanced salt Solution, standard saline cit cess on a computing device. rate, HEPES-buffered saline, dextrose, glucose, or diethyl ether. In at least one embodiment, at least one of the constitu DETAILED DESCRIPTION ents of the one or more frozen particles is frozen. In at least 10 one embodiment, all of the constituents of the one or more In the following detailed description, reference is made to frozen particles are frozen. In at least one embodiment, the at the accompanying drawings, which form a parthereof. In the least one composition or therapeutic composition includes drawings, similar symbols typically identify similar compo one or more frozen Solution particles. In at least one embodi nents, unless context dictates otherwise. The illustrative ment, the composition or therapeutic composition includes embodiments described in the detailed description, drawings, 15 one or more frozen solution particles and the composition or and claims are not meant to be limiting. Other embodiments therapeutic composition is in at least one crystalline or amor may be utilized, and other changes may be made, without phous phase. In at least one embodiment, the frozen Solution departing from the spirit or scope of the Subject matter pre particles include at least one of the constituents described sented here. herein. In the following detailed description, reference is made to In at least one embodiment, the one or more frozen par the accompanying drawings, which form a parthereof. In the ticles include frozen hydrogen oxide particles. Frozen hydro drawings, similar symbols typically identify similar compo gen oxide, or typical water ice, exists in several non-crystal nents, unless context dictates otherwise. The illustrative line forms. Each of these forms has specific physical embodiments described in the detailed description, drawings, characteristics such as density and vibrational spectra. Some and claims are not meant to be limiting. Other embodiments 25 of the frozen hydrogen oxide phase transformations are may be utilized, and other changes may be made, without shown in FIG. 1. (See e.g., Chaplin, the worldwide web at departing from the spirit or scope of the Subject matter pre lsbu.ac.uk/water; Ivanov et al., Russian J. Gen. Chem. Vol. 75, sented here. pp. 1851-1856 (2005), each of which is incorporated herein In at least one embodiment, at least one composition, thera by reference). peutic composition, device, system, product, or method dis 30 Hydrogen oxide (water) has many frozen phases (ices), closed herein relates to utilizing one or more frozen particles including crystalline and non-crystalline phases. The crystal for various purposes. In at least one embodiment, the one or line phases generally have the common structure of having more frozen particles include at least one frozen constituent hydrogen bonds to four neighboring water molecules, such as including at least one of hydrogen oxide, helium, neon, kryp two hydrogen atoms near each oxygen atom. Structural data ton, argon, Xenon, nitrogen, chlorine, bromine, oxygen, air, 35 on the known frozen hydrogen oxide polymorphs are shown carbon dioxide, polyethylene glycol, acetone, ethyl acetate, in Table I, with two known phases of ice XI. (See, e.g., dimethyl sulfoxide, dimethyl formamide, dioxane, hexam Chaplin, Ibid; and Zheligovskaya, et al., Russian Chem. Rev. ethylphosphorotriamide, perfluorohydrocarbon, methanol, 75, pp. 57-76, 2006, each of which is incorporated herein by ethanol, tert-butyl alcohol, formic acid, hydrogen fluoride, reference). TABLE I Structural data on the ice polymorphs Dielectric Density, constant, Ice polymorph g/cm Protons Crystal Symmetry es Notes Hexagonal ice, Ih 0.92 disordered Hexagonal One C 97.5 Cubic ice, Ic 0.92 disordered Cubic four C. LDA, Ia 0.94 disordered Non- As prepared, crystalline may be mixtures of several types HAD .17 disordered Non- As prepared, crystalline may be mixtures of several types VHDA .25 disordered Non crystalline II .17 ordered Rhombohedral One C 3.66 III .14 disordered Tetragonal One C 117 protons may be partially ordered IV .27 disordered Rhombohedral One C metastable in ice V phase Space .23 disordered Monoclinic One C2 144 protons may be partially ordered VI .31 disordered Tetragonal One C 193 protons can be partly ordered US 9,072,799 B2 23 24 TABLE I-continued Structural data. On the ice polymorphs Dielectric Density, constant, Ice polymorph g/cm Protons Crystal Symmetry es Notes

VII 1.50 disordered Cubic four C. 150 WO interpenetrating ice Ic rameworks VIII 1.46 ordered Tetragonal One C OW emperature orm of ice VII IX 1.16 ordered Tetragonal One C 3.74 OW emperature orm of ice III, metastable in ice II space 2.51 symmetric Cubic four C. symmetric proton form of ice VII XI 0.92 ordered Orthorhombic three C2 OW emperature orm of ice Ih XI >2.51 symmetric Hexagonal distorted Found in close packed simulations only XII 1.29 disordered Tetragonal One C metastable in ice V phase Space XIII 1.23 ordered Monoclinic One C2 ordered form of ice V phase XIV 1.29 mostly Orthorhombic One C ordered form of ordered ice XII phase 1.31 (2) ordered ordered form of ice VI phase

Cooling liquid hydrogen oxide below its standard freezing Similarly, amorphous solid water is formed from the slow point typically results in the formation of frozen hexagonal 35 deposition of hydrogen oxide vapor on a cold metal crystal ice. However, if the hydrogen oxide is pure and cooled slowly, Surface (at less than approximately 2 mm/s), below the tem the liquid hydrogen oxide can be Supercooled to approxi perature of approximately -153°C. Amorphous solid water is mately -42°C. Amorphous solids harden without crystalliz a viscous semi-solid material that has a density of approxi ing, Such that if hydrogen oxide is cooled rapidly it results in mately 0.94 g/cm and harbors gaps and spaces in its struc formation of a glass-like state, for example, hyperquenched 40 ture, as well as reactive hydrogen bonds. These structures are glassy water. (See e.g., Debenedetti, J. Phys. Condens. Mat removed by annealing under vacuum pressure, which allows ter, vol. 15, pp. R1669-R1726 (2003), and as cited by Chaplin, the material to convert to a high density glassy water or low worldwideweb at lsbu.ac.uk/water; each of which is incorpo density amorphous ice, depending on the temperature. Typi rated herein by reference.) Generally, hyperquenched glassy cally, high density glassy water, which has a density of water is formed by rapidly spraying a fine mist of micrometer 45 approximately 1.1 g/cm, is formed by vapor deposition at sized hydrogen oxide droplets into very cold liquefied gas, approximately -263°C. Such as propane. Alternatively, a fine mist of hydrogen oxide Low-density amorphous (LDA) ice also occurs from heat can be sprayed onto a very cold frozen substrate, at or below ing high-density amorphous (HDA) ice to just above approxi approximately -193° C. Hyperquenched glassy water may mately -153° C. at atmospheric pressure, and transforms to also be formed by cooling capillary tubes containing bulk 50 cubic ice at approximately -113°C. to -123° C. Low-density liquid water (~100 um diameter) with liquid helium at amorphous ice is also prepared by Submitting low-pressure approximately -269°C. phases (Ih, Ic, XI, etc.) to high pressure (approximately 1.0 As shown in FIGS. 1-4, hydrogen oxide attains various GPa) at low temperatures (e.g., below approximately -148 structures and phases depending upon the temperature or C.). pressure of the environment. As indicated in FIG. 1, for 55 Very-high density amorphous (VHDA) ice is a viscous example, hydrogen oxide ice Ic is derived from high density water state with a density of approximately 1.25 g/cm, and is amorphous water or deeply Supercooled liquid water, when prepared by heating high-density amorphous ice to just above put under low temperature or higher pressure. Likewise, as approximately -113°C. and approximately 1.15 GPa. When indicated in FIG. 2, the hydrogen oxide has a greater density very-high density amorphous ice is heated at different pres as a liquid than as a solid under ambient conditions (ice Ih). 60 sures between 0.3 and 2 GPa, it re-crystallizes into only the However, at increasing pressure, at least ice stages III, V, VI, proton disordered ices III, IV, V, XII, VI and VII in order of and VII exhibit a greater density than liquid hydrogen oxide. increasing pressure, but does not typically re-crystallize into FIG. 3 indicates the phase diagram for hydrogen oxide based the proton ordered phases (e.g., ice II). on pressure and temperature variance, while FIG. 4 shows the Typically, the density of liquid water increases with specific Sub-categories of hydrogen oxide based on physical 65 increased pressure. When liquid water approaches the critical properties. Such as structure and density, among others, as the point in the liquid-vapor phase, water enters a Supercritical temperature and pressure vary. phase where it exists as Small but liquid-like hydrogen US 9,072,799 B2 25 26 bonded clusters dispersed within a gas-like phase and its mately -210° C., whereas the freezing point of dimethyl physical properties vary according to changing density. sulfoxide (DMSO) is approximately 18.45° C. Thus, frozen Supercritical water is an excellent solvent for non-polar mol particles of DMSO can be utilized or administered at a ecules, due to its low dielectric constant and poor hydrogen warmer temperature than can frozen particles of nitrogen. bonding. Due to these same properties, Supercritical water is Ice Ic is generally formed by condensation of water vapor, typically not a good solvent for electrolytes, which tend to at ambient pressure and low temperatures (less than approxi form ionic bonds. mately -80° C.), or below approximately -38°C. as a mist. As indicated in FIG. 2, hexagonal ice is less dense than (See e.g., Murray et al., Phys. Chem. Chem. Phys. Vol. 8, pp. liquid water, whereas the other ice phases are all denser and 186-192 (2006), which is incorporated herein by reference). phase changes occur near the liquid and Solid densities (See 10 Ice Ic is also prepared by reducing the pressure on high e.g., Loerting et al., J. Phys.: Condens. Matter vol. 18, R919 pressure hydrogen oxide ice at approximately -196° C. It R977 (2006), which is incorporated herein by reference). may be the preferred phase for ice formed from hydrogen Liquid water density varies with change in temperature or oxide droplets Smaller than about 15 nm in radius, particu pressure, whereas the density of amorphous ice varies only larly at low temperatures (e.g., -113°C. to -53°C.). (See e.g., with change in pressure, but not temperature. 15 Johari, J. Chem. Phys. Vol. 122 pp. 1945.04 (2005); Zhang, et Hydrogen oxide has a high heat of vaporization (approxi al., Chem. Phys. Lett. Vol. 421, pp. 251-255 (2006), each of mately 40.7 kJ/mol), and a high heat of sublimation (approxi which is incorporated herein by reference). mately 51.059 kJ/mol at 0°C.), which allows for the frozen Ice Ih constitutes a large portion of naturally-occurring particles to remain intact for a short time period during which Snow and ice. Since hexagonal ice exhibits changes in the the particles are delivered to one or more cells or tissues. hydrogen bonding, ice Ih shows anomalous reduction in ther These properties further enable the frozen particles to serve as mal conductivity with increasing pressure (as does cubic ice particles for delivery of at least one therapeutic composition and low-density amorphous ice). (See e.g., Andersson et al., to one or more cells or tissues. Phys. Rev. B vol. 65 pp. 1402011-14201.4 (2002), which is Hydrogen oxide becomes more viscous as the temperature incorporated herein by reference). is decreased to below approximately 33°C., or the pressure is 25 Ice II maintains a general rhombohedral unit shape, similar increased. Frozen particles may include a "solid. Such as true to ice I. The density of ice II is approximately 1.17 g/cm. Ice Solids, semi-solids, and Viscous fluid, Such as gels, hydrogels, III maintains a general tetragonal unit shape, with a density of or Sols. Frozen particles may include particles that are at least approximately 1.14 g/cm. Ice VI also maintains a general partially frozen, or are entirely frozen. Compositions includ tetragonal unit shape, with a density of approximately 1.31 ing one or more particles may include one or more Subset 30 g/cm. Ice VII is primarily composed of multiple intercalating groups of one or more particles, some of which may be ice Ic lattices, and has a density of approximately 1.66 g/cm. entirely frozen and some of which may be at least partially In at least one embodiment, the therapeutic composition frozen. Such compositions may include multiple different includes at least one of a solid, liquid, or gas. In at least one compositions, where the group of frozen particles includes at embodiment, the therapeutic composition includes one or least one Subset that includes multiple particles, wherein each 35 more of a suspension, mixture, Solution, Sol, clathrate, col particle has an individual therapeutic agent or unique com loid, emulsion, microemulsion, aerosol, ointment, capsule, position. The group of frozen particles may also include at powder, tablet, Suppository, cream, device, paste, liniment, least one Subset of multiple particles, wherein each particle lotion, ampule, elixir, spray, Suspension, syrup, tincture, includes multiple agents (including therapeutic agents). detection material, polymer, biopolymer, buffer, adjuvant, A particular plurality of compositions or therapeutic com 40 diluent, lubricant, disintegration agent, Suspending agent, positions may include multiple frozen particles where various Solvent, calorimetric agent, light-emitting agent, glidant, multiple agents are associated with a single particle. Like anti-adherent, anti-static agent, Surfactant, plasticizer, emul wise, a particular plurality of compositions or therapeutic Sifying agent, flavor, gum, Sweetener, coating, binder, filler, compositions may include various multiple agents, where compression aid, encapsulation aid, preservative, granulation each individual agent is associated with a single frozen par 45 agent, spheronization agent, stabilizer, adhesive, pigment, ticle. In at least one embodiment, a plurality of compositions sorbent, nanoparticle, or gel. or therapeutic compositions may include any number of Sub In at least one embodiment, the at least one adhesive is sets of frozen particles associated with a particular therapeu included in one or more frozen particles. In at least one tic agent or other constituent. During the course of any par embodiment, the one or more frozen particles provide a ticular method described herein, one or more plurality of 50 vehicle for the at least one adhesive. In certain instances, at compositions or therapeutic compositions, or any particular least one adhesive is provided to at least one biological tissue Subset thereof, may be administered in a single treatment. in an inactive form, wherein the at least one adhesive poly In at least one embodiment, the one or more frozen par merizes or activates upon contact with the at least one bio ticles exist at about 30°C., about 20°C., about 10°C., about logical tissue, or shortly thereafter. 5° C., about 0°C., about -10° C. about -20°C., about -30° 55 In at least one embodiment, at least one scaffold (e.g., C., about -40°C., about -50° C., about -60° C., about -70° collagen, elastin, protein, carbohydrate, nucleic acid, organic C., about -75° C., about -80°C., about -85°C., about -90° chemical, or other component) is provided with the at least C., about -95°C., about -100° C., about -120° C., about one composition or therapeutic composition for one or more -150° C., about -180° C., about -200° C., about -220° C., cells. In at least one embodiment, the scaffold provides a about -250° C., or any value less than or therebetween. 60 matrix for one or more cells. In at least one embodiment, the In certain instances, the one or more frozen particles are one or more cells are located in at least one biological tissue. utilized at a very cold temperature so that effective penetra In at least one embodiment, clathrate compositions are tion of a biological tissue is achieved. In certain instances, the included. Clathrate ice forms from water or other liquids, and one or more frozen particles are utilized at warmer tempera contains Small amounts of non-polar molecules (generally tures, particularly if the contents of the one or more frozen 65 gases) under moderate pressure of a few MPa, and tempera particles include agents that have warmer freezing tempera tures close to 0°C. Clathrate structures can vary, but generally tures. For example, the freezing point of nitrogen is approxi allow a minimum amount of Small molecules to fit into and US 9,072,799 B2 27 28 stabilize gaps without forming covalent or hydrogen bonds In at least one embodiment, the one or more frozen par with the hydrogen oxide molecules. Certain clathrates are ticles approximate the shape of at least one of a sphere, bullet, formed at the interface of the liquid phase, under atmospheric flechette, cone, needle, arrow, spear, diamond, pyramid, cyl pressure. Clathrates include but are not limited to the struc inder, mini ball, shuttlecock, spiral, bell, pear, crystal, cube, tural forms of SI, SII, and sh. In certain instances, noble gases spheroid, tetrahedron, crescent, or high aspect ratio shape. may be used to form clathrate compounds with hydrogen The size, shape, weight, or density, as well as other physical oxide or other molecules. Noble gases generally have low parameters of the one or more frozen particles may be polarizability, and tend to be spherically symmetrical, which adjusted according to a particular composition or therapeutic allows for solubility with the hydrogen oxide cage. In addi composition, or desired goal in utilizing the compositions. In tion, the solubility of the noble gases increases considerably 10 at least one embodiment, the one or more frozen particles as the temperature is lowered. The solubility of particular include a plurality of frozen hydrogen oxide particles that are noble gases as clathrates with hydrogen oxide are shown in approximately uniform with regard to size, shape, weight, or Table II. (See e.g., Dec et al., J. Solution Chem. Vol. 14, pp. density. In at least one embodiment, the one or more frozen 417-429 (1985); Ivanov, et al., J. Struct. Chem. Vol. 46, pp. particles include an array of different sizes, shapes, weights, 253-263 (2005): Fernandez-Prini, et al., Elsvier, pp. 73-98 15 or densities. (2004); Ivanov, et al., Russian J. Gen. Chem. Vol. 75, pp. In at least one embodiment disclosed herein, one or more 1851-1856 (2005), each of which is incorporated herein by reinforcement agents may be included in the compositions or reference.) therapeutic compositions described. Examples of some rein TABLE II Solubility properties of the noble gases Property He Ne Air Kr Xe Rn

Atomic number 2 10 18 36 S4 86 Atomic radius, A 1.08 1.21 1.64 1.78 1.96 2.11 AG of solution in H2O at 25°C., 29.41 29.03 26.25 24.8O 23.42 kJ/mol AH of solution in H2O at 25°C., -0.59 -3.80 -11.98 - 1529 -18.99 kJ/mol AS of solution in H2O at 25°C., -100.6 -110.1 -128.2 -134.5 -142.2 J/molK Solubility, mM, 5° C., 101,325 Pa. HO O41 O.S3 2.11 4.2O 8.21, 1883 DO O49 O.61 2.38 4.61 8.91 20:41 Solubility minima, C. HO 30 50 90 108 110 DO 53 53 98 108 116

35 Other materials are included in one or more compositions forcement agents include, but are not limited to, polyaramid, described herein. For example, liquid nitrogen is nontoxic vinylester matrix, metal, ceramic, fiberglass, cellulose, broad and inert, with a freezing point at 1 atm pressure of approxi carbide, aromatic polyamide, nylon, silk, rayon, acetate, mately -210°C. Liquid helium is nontoxic and inert, with a 40 modacrylic, olefin, acrylic, polyester, aromatic polyester, freezing point at 367 psi of approximately -272.2°C. Liquid poly-lactic acid, Vinyon, Saran, Spandex, Vinalon, aromatic argon is nontoxic and inert with a freezing point at 1 atm nylon, vinylidene chloride, modal, polybenzimidazole, Sul pressure of approximately -189.4° C. Liquid neon has a fur, lyocell, orlon, Zylon, high-performance polyethylene, freezing point of approximately -245.95 C., while liquid polypyridobenzimidazole, vectran, acrylonitrile rubber, xenon has a freezing point of approximately -111.9°C. The 45 glass, copper, iron, Steel, Sodium, potassium, calcium, Zinc, freezing point of liquid dimethyl sulfoxide (DMSO) is manganese, carbon, magnesium, alluvium, Sand, Sugar, cal approximately 18.45° C., and water or other co-solvents can cite, emery, diamond, noVaculite, pumice, rouge, borazon, decrease the freezing point. The freezing point of lactated corundum, Zirconia alumina, silicon, silica, frozen hydrogen Ringer's solution is approximately -45° C. These and other oxide ice, plant matter, animal matter, or mineral matter. In at materials can be utilized as described herein either alone, or in 50 least one embodiment, plant matter may include vegetable combination with other materials. matter, nuts or nut products or pieces (e.g., almonds), grains In at least one embodiment, the one or more frozen par (e.g., oatmeal), wood (e.g., wood fibers) or other stalk mate ticles have at least one major dimension of approximately one rial, leaf matter, fruit matter (including pits or seeds or parts decimeter or less, approximately one centimeter or less, thereof), and other plant material. approximately one millimeter or less, approximately one 55 In at least one embodiment, one or more reinforcement micrometer or less, approximately one nanometer or less, agents are made by spinning into a fiber, wire, or filament. approximately one picometer or less, or any value therebe Some non-limiting examples of reinforcement fibers can be tween. In at least one embodiment, a plurality of frozen par foundat, for example, U.S. Pat. No. 5,855,663: U.S. Pat. No. ticles is delivered or administered, and the plurality includes 5,652,058; KEVLAR(R) technical guide, Polymer Bulletin, at least two subsets of frozen particles which can be differen 60 vol. 16, pp. 167-174 (1986), and WO/2003/060002, each of tiated based on size. In at least one embodiment, a plurality of which is incorporated herein by reference. frozen particles includes at least one Subset of frozen particles In at least one embodiment, the one or more reinforcement that have at least one major dimension of approximately ten agents are manufactured into a plate or spheroid. In certain micrometers or less. In at least one embodiment, the at least instances, the one or more reinforcementagents are utilized in one major dimension of the one or more frozen particles 65 the form of a resin, powder, solution, flake, sheet, film, ribbon, includes at least one of radius, diameter, length, width, height, gel, ball, pellet, or bead. (See e.g., U.S. Pat. No. 5,534,584; or perimeter. U.S. Pat. No. 5,331,046; each of which is incorporated herein US 9,072,799 B2 29 30 by reference). The one or more reinforcement agents may be Administration website on the worldwide web at fla.gov, the in the form of a solid, liquid, or gas. information at which is incorporated herein by reference. The one or more reinforcement agents are positioned on or In certain instances, the one or more frozen particles them in the one or more frozen particles depending on a given selves provide at least one therapeutic benefit. In certain context. For example, the positioning of one or more rein instances, the one or more frozen particles act as vehicles for forcement agents may consider the particular goal of admin one or more therapeutic agents that provide at least one thera istering the one or more frozen particles, the components of peutic benefit. The frozen particles acting as vehicles for one the at least one composition or therapeutic composition, or or more therapeutic agents may be inert, or may provide the needs or desires of a particular outcome of treatment or additional therapeutic benefit in the overall composition. In at administration of the one or more frozen particles. In at least 10 one embodiment, the one or more reinforcement agents are least one embodiment, at least one therapeutic agent is acti located at least on the surface or beneath the surface of the one vated during administration of the at least one composition or or more frozen particles. In at least one embodiment, the one therapeutic composition to at least one biological tissue. In at or more reinforcement agents are located within the one or least one embodiment, at least one therapeutic agent is acti more frozen particles. 15 vated prior to or Subsequent to administration of the at least As shown in FIGS. 5 and 6, the strength of hydrogen oxide one composition or therapeutic composition to at least one ice samples increases when particular reinforcement agents biological tissue. In at least one embodiment, at least one are added. As indicated in FIG. 5, ice samples exhibit therapeutic agent is activated after a prolonged time Subse increased strength, as measured by beam deflection as an quent to administration of the at least one therapeutic com angle of shear when reinforced with fiberglass or kaolin. As position or composition to at least one biological tissue (e.g. indicated in FIG. 6, the maximum stress (in MPa) and strain in cases where the therapeutic agent is encased or associated rate increases when particular reinforcementagents are added with a polymer or other agent that may insulate one or more to the hydrogen oxide ice samples. reactant or retard the explosive or decomposition process). In In certain instances, the composition or therapeutic com at least one embodiment, the composition ortherapeutic com position described herein includes one or more abrasives may 25 position includes at least one activatable therapeutic agent. In include treated or untreated abrasives, coated abrasives, at least one embodiment, the composition ortherapeutic com bonded abrasives, powders, aggregates, composites, or other position includes at least one activating agent or at least one forms. In at least one embodiment, the one or more abrasives inactivating agent, or both. include, but are not limited to include, but are not limited to, In certain instances, the therapeutic agent includes at least polyaramid, vinylester matrix, metal, ceramic, fiberglass, cel 30 one of an organic or inorganic Small molecule, clathrate or lulose, broad carbide, aromatic polyamide, nylon, silk, rayon, caged compound, protocell, coacervate, microsphere, pro acetate, modacrylic, olefin, acrylic, polyester, aromatic poly teinoid, laminate, helical rod, liposome, macroscopic tube, ester, poly-lactic acid, Vinyon, Saran, Spandex, Vinalon, aro niosome, sphingosome, toroid, Vesicular tube, Vesicle, Small matic nylon, vinylidene chloride, modal, polybenzimidazole, unilamellar vesicle, large unilamellar vesicle, large multila Sulfur, lyocell, orlon, Zylon, high-performance polyethylene, 35 mellar vesicle, multivesicular vesicle, lipid layer, lipid polypyridobenzimidazole, vectran, acrylonitrile rubber, bilayer, micelle, organelle, cell, membrane, nucleic acid, pep glass, copper, iron, Steel, Sodium, potassium, calcium, Zinc, tide, polypeptide, protein, glycopeptide, glycolipid, glyco manganese, carbon, magnesium, alluvium, sand, Sugar, cal protein, Sphingolipid, glycosphingolipid, peptidoglycan, cite, emery, diamond, noVaculite, pumice, rouge, borazon, lipid, carbohydrate, metalloprotein, proteoglycan, chromo corundum, Zirconia alumina, silicon, silica, frozen hydrogen 40 Some, nucleus, acid, base, buffer, protic solvent, aprotic Sol oxide ice, plant matter, animal matter, or mineral matter. In at vent, nitric oxide, nitric oxide synthase, amino acid, micelle, least one embodiment, plant matter may include vegetable polymer, co-polymer, or piloxymer. matter, nuts or nut products or pieces (e.g., almonds), grains In at least one embodiment, the at least one therapeutic (e.g., oatmeal), wood (e.g., wood fibers) or other stalk mate agent includes at least one of an anti-tumor agent, antimicro rial, leaf matter, fruit matter (including pits or seeds or parts 45 bial agent, anti-viral agent, analgesic, antiseptic, anesthetic, thereof), or other plant material. diagnostic agent, anti-inflammatory agent, vaccine, cell In at least one embodiment, a therapeutic composition and growth inhibitor, cell growth promoter, chemical debride methods of delivery to at least one biological tissue include ment agent, immunogen, antigen, radioactive agent, apop one or more frozenhydrogen oxide particles including at least totic promoting factor, angiogenic factor, anti-angiogenic one therapeutic agent; wherein the one or more hydrogen 50 factor, hormone, enzymatic factor, enzyme, papain, collage oxide particles are in one or more phases including at least nase, protease, peptidase, elastase, urea, vitamin, mineral, one of amorphous solid water, low density amorphous ice, nutraceutical, cytokine, chemokine, probiotic, coagulant, high density amorphous ice, very high density amorphous anti-coagulant, phage, prodrug, prebiotic, blood Sugar stabi ice, clathrate ice, hyperquenched glassy water, ice Ic, ice II, lizer, Smooth muscle cell activator, epinephrine, adrenaline, ice III, ice IV, ice V, ice VI, ice VII, ice VIII, ice IX, ice X, ice 55 neurotoxin, neuro-muscular toxin, Botulinum toxin type A, XI, ice XII, ice XIII, ice XIV, or ice XV. microbial cell or component thereof, or virus or component In at least one embodiment, a therapeutic composition thereof. In at least one embodiment, the nutraceutical includes one or more frozen Solution particles and at least one includes one or more of a flavonoid, antioxidant, beta-caro therapeutic agent; wherein the therapeutic composition is in tene, anthocyanin, alpha-linolenic acid, omega-3 fatty acids, at least one crystalline or amorphous phase. 60 yeast, bacteria, algae, other microorganisms, plant products, In at least one embodiment, the at least one composition or or animal products. In at least one embodiment, the analgesic therapeutic composition includes at least one therapeutic or anesthetic includes one or more of any aminoamid or agent. (See, e.g., The Merck Index, 14" Ed. Merck & Co., aminoester local anesthetic, ibuprofen, morphine, codeine, Inc., Whitehouse Station, N.J. (2006), which is incorporated aspirin, acetaminophen, lidocaine/lignocaine, ropivacaine, herein by reference). Other agents that are approved for use in 65 mepivacaine, benzocaine, chloroprocaine, cocaine, cyclom humans may be utilized as at least one therapeutic agent ethycaine, dimethocaine/larocaine, propoxycaine, procaine/ described herein, and may be found at the U.S. Food and Drug novocaine, proparacaine, tetracaine/amethocaine, articaine, US 9,072,799 B2 31 32 bupivacaine, carticaine, cinchocaine/dibucaine, etidocaine, plicamycin, hydroxyurea, camptothecin, topotecan, irinote levobupivacaine, piperocaine, prilocaine, trimecaine, sax can, rubitecan, belotecan, altretamine, amsacrine, bexaro itoxin, or tetrodotoxin. tene, estramustine, irofulven, trabectedin, cetuximab, panitu In at least one embodiment, the therapeutic agent includes mumab, trastuzumab, rituximab, to situmomab, at least one anti-inflammatory agent, including but not limited alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, to steroids, non-steroidal anti-inflammatory drugs, topical axitinib. bosutinib, cediranib, dasatinib, erlotinib, gefitinib, anti-inflammatory agents, or Subcutaneously administered imatinib, lapatinib, lestaurtinib, nilotinib, Semaxanib, Sor non-steroidal anti-inflammatory drugs (e.g. diclofenac). afenib, Sunitinib, Vandetanib, alvocidib, seliciclib, afliber In at least one embodiment, the analgesic includes but is cept, denileukin diftitoX, aminolevulnic acid, efaproxiral, not limited to one or more of paracetamol(acetaminophen), 10 porfimer Sodium, talaporfin, temoporfin, Verteporfin, alitret non-steroidal anti-inflammatory drugs (NSAIDs), salicy inoin, tretinoin, anagrelide, arsenic trioxide, asparaginase/ lates, narcotics, or tramadol. In at least one embodiment, the pegaspergase, atrasentan, bortezomib, carmofur, celecoxib, analgesic includes but is not limited to aspirin, rofecoxib, demecolcine, elesclomol, elasamitrucin, etoglucid, celecoxib, morphine, codeine, oxycodone, hydrocodone, lonidamine, lucanthone, masoprocol, mitobronitol, diamorphine, pethidine, buprenorphine, amitriptyline, car 15 mitoguanZone, mitotane, oblimersen, omacetaxine, sitima bamazepine, bagapentin, pregabalin, ibuprofen, naproxen, gene ceradenovec, tegafur, testolactone, tiazofurine, tipi lidocaine, a psychotropic agent, orphenadrine, cyclobenza farnib, or vorinostat. prine, Scopolamine, atropine, gabapentin, methadone, keto In at least one embodiment, at least one nutraceutical is bemidone, or piritramide. included. At least one nutraceutical includes but is not limited In at least one embodiment, the at least one therapeutic to one or more of an extract of plant or animal matter (e.g., an agent includes one or more antiseptic, including but not lim oil, aqueous, or solid extract), a vitamin, a mineral, a mixture ited to one or more of an alcohol, a quaternary ammonium or Solution, a food Supplement, a food additive, a food forti compound, boric acid, hydrogen peroxide, chlorhexidine glu fication element, or other nutraceutical. In at least one conate, iodine, mercurochrome, octenidine dihydrochloride, embodiment, at least one nutraceutical includes but is not phenol (carbolic acid) compounds, Sodium chloride, or 25 limited to resveratrol, an antioxidant, psyllium, Sulforaphane, Sodium hypochlorite. isoflavonoid, alpha-linolenic acid, beta-carotene, anthocya In at least one embodiment, the antiseptic includes but is nins, phytoestrogens, polyphenols, polyphenons, catechins, not limited to one or more of povidone-iodine, iodine, etha benzenediols, tannins, phenylpropanoids, caffeine, alcohol, nol. 1-propanol. 2-propanol/isopropanol, benzalkonium or others. chloride, cetyl trimethylammonium bromide, cetylpyri 30 In at least one embodiment, at least one therapeutic agent dinium chloride, benzethonium chloride, chlorhexidine, includes one or more vaccine. In at least one embodiment, the octenidine dihydrochloride, or carbolic acid. therapeutic composition including at least one vaccine In at least one embodiment, the antimicrobial agent includes at least one prophylactic vaccine or therapeutic vac includes at least one of an anti-fungal agent, antibiotic agent, cine. In at least one embodiment, the at least one therapeutic anti-bacterial, anti-parasitic agent, or anti-worm agent. In 35 vaccine includes at least one anti-cancer vaccine. In at least certain instances, the antimicrobial agent may occur in one embodiment, the at least one vaccine includes at least one nature, or it may be synthetic. of an anti-tumor agent, antimicrobial agent, anti-viral agent, In at least one embodiment, the at least one therapeutic immunogen, antigen, live microbe, dead microbe, attenuated agent includes one or more anti-tumor agent, at least one of microbe, microbe or component thereof, live virus, recombi which may also be identified as a cytotoxic agent, or chemo 40 nant virus, killed virus, attenuated virus, virus component, therapy agent. Non-limiting examples of an anti-tumor agent plasmid DNA, nucleic acid, amino acid, peptide, protein, for use as described herein include at least one of an alkylat glycopeptide, proteoglycan, glycoprotein, glycolipid, Sphin ing agent, antimetabolite, anthracycline, plant alkaloid (Such golipid, glycosphingolipid, cancer cellor component thereof, as paclitaxel), topoisomerase inhibitor, monoclonal antibody, organic or inorganic Small molecule, or toxoid. or tyrosine kinase inhibitor. In at least one embodiment, the 45 One or more vaccine may include but not be limited to therapeutic agent includes one or more of imatinib, mechlo vaccines containing killed microorganisms (such as vaccines rethamine, cyclophosphamide, chlorambucil, azathioprine, for flu, cholera, bubonic plague, and hepatitis A), vaccines mercaptopurine, Vinca alkaloid, taxane, Vincristine, vinblas containing live, attenuated virus or other microorganisms tine, Vinorelbine, vindesine, podophyllotoxin, etoposide, (such as vaccines for yellow fever, measles, rubella, and teniposide, amsacrine, dactinomycin, trastuzumab, cetux 50 mumps), live vaccine (such as vaccines for tuberculosis), imab, rituximab, bevacizumab, dexamethasone, finasteride, toxoid (such as vaccines for tetanus, diphtheria, and crotalis tamoxifen, goserelin, telomerase inhibitor, dichloroacetate, atroX), Subunit of inactivated or attenuated microorganisms aminopterin, methotrexate, pemetrexed, raltitrexed, cladrib (such as vaccines for HBV. VLP, and HPV), conjugate vac ine, clofarabine, fludarabine, pentostatin, thioguanine, cyt cines (such as vaccines for H. influenzae type B), recombinant arabine, decitabine, fluorouracil/capecitabine, floXuridine, 55 vector, DNA vaccination. In at least one embodiment, the at gemcitabine, enocitabine, Sapacitabine, chloromethine, least one vaccine includes but is not limited to rubella, polio, cyclophosphamide, ifosfamide, melphalan, bendamustine, measles, mumps, chickenpox, typhoid, shingles, hepatitis A, trofosfamide, uramustine, carmustine, fotemustine, lomus hepatitis B, diphtheria, pertussis, rotavirus, influenza, men tine, nimustine, prednimustine, ranimustine, Semustine, ingococcal disease, pneumonia, tetanus, rattlesnake Venom, spretpoZocin, carboplatin, cisplatin, medaplatin, oxaliplatin, 60 virus-like particle, or human papillomavirus, or anti-cancer triplatin tetranitrate, satraplatin, buSulfan, mannosulfan, treo vaccine. Sulfan, procarbazine, decarbazine, temozolomide, carbo In at least one embodiment, the at least one therapeutic quone. ThioTEPA, triaziquone, triethylenemelamine, doc agent includes at least one adjuvant. The at least one adjuvant etaxel, larotaxel, ortataxel, tesetaxel, Vinflunine, ixabepilone, may include but not be limited to one or more organic or aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubi 65 inorganic compounds. The at least one adjuvant may include cin, amrubicin, pirarubicin, valrubicin, Zorubicin, metox but not be limited to at least one of a liposome, Virosome, antrone, pixantrone, actinomycin, bleomycin, mitomycin, lipid, phospholipid, mineral salt, single-stranded DNA, US 9,072,799 B2 33 34 double-stranded RNA, lipopolysaccharide, molecular anti device. In at least one embodiment, the at least one electronic gen cage, CpG motif, microbial cell wall or component identification device includes at least one radio frequency thereof, squalene, oil emulsion, Surfactant, Saponin, isolated identification device. microbial toxin, modified microbial toxin, endogenous In at least one embodiment, the at least one detection immunomodulator, or cytokine. material includes but is not limited to, at least one radioactive In one non-limiting example, a therapeutic composition element. In at least one embodiment, the radioactive element includes one or more frozen particles including paclitaxel and includes but is not limited to 'P, S, C, "'I, ''Ir, 'Ir, at least one other constituent including at least one of air, ''Ir, 'T1, or H. In at least one embodiment, the at least one oxygen, nitrogen, carbon dioxide, hydrogen oxide, helium, detection material includes at least one calorimetric Sub 10 stance. In at least one embodiment, the at least one calorimet neon, Xenon, krypton, chlorine, bromine, or argon. ric Substance includes one or more of an inorganic, organic, In one non-limiting embodiment, a therapeutic composi biological, natural, artificial, or synthetic Substance. The tion includes one or more frozen particles including one or colorimetric substance may include, but not be limited to a more pegylated cytokines or one or more anti-tumor com dye, pigment, or a light-emitting Substance. Such as a lumi pounds; wherein the one or more frozen particles include 15 nescent Substance, a fluorescent Substance, phosphorescent nitrogen, air, oxygen, carbon dioxide, hydrogen oxide, Substance, or quantum dot. In at least one embodiment, the at helium, Xenon, krypton, chlorine, bromine, or argon. least one calorimetric Substance is biocompatible. In at least one embodiment, the one or more frozen par Some examples of colorimetric Substances include, but are ticles provide a vehicle for delivery of the therapeutic agent. not limited to, colored agents that have an affinity to a Sub In at least one embodiment, the at least one therapeutic agent strate. Such as acid dyes (e.g., water-soluble anionic dyes), is located in at least one distinct region of the one or more basic dyes (e.g., water-soluble cationic dyes), direct or Sub frozen particles. In at least one embodiment, the at least one stantive dyes (e.g., stains for nucleic acids, proteins, lipids, therapeutic agent is located in a physically or chemically carbohydrates, cell populations, tissues, or organelles), mor separable compartment from at least one other region of the dant dyes, vat dyes, reactive dyes, disperse dyes, azo dyes, one or more frozen particles. In at least one embodiment, the 25 Sulfur dyes, food dyes, solvent dyes, carbene dyes, or others. at least one therapeutic agent is located on the Surface or Some examples of chromophores that may be utilized beneath the surface of the one or more frozen particles. In at include, but are not limited to, dyes that are based on or least one embodiment, the at least one therapeutic agent is derivatives of acridine, anthraquinone, arymethane (e.g., physically or chemically segregated from at least one other diphenyl methane, triphenyl methane), N—Nazo struc portion of the therapeutic composition. In at least one 30 ture, phthalocyanine, diazonium salts, —NO nitro func embodiment, the at least one distinct region of the particle is tional group, —N=O nitroso functional group, phthalocya segregated by at least one of an impermeable, permeable, or nine, quinine, azin, eurhodin, Safrainin, indamin, indophenol, semi-permeable partition. In certain instances, the therapeu oxazin, oxazone, thiazin, thiazole, Xanthene, fluorine, pyro tic agent separates from the rest of the frozen particle upon nin, fluorine, rhodamine, or others. In at least one embodi administration of the therapeutic agent to a biological tissue. 35 ment, the calorimetric Substance includes trypan blue. As described herein, at least one embodiment includes In at least one embodiment, the calorimetric Substance administering at least one of a polymer, biopolymer, nano includes one or more fluorescent tags, including but not lim particle, or detection material in addition to a composition or ited to fluorescein, phycobilin, phycoerythrin, phycourobilin, therapeutic composition (including at least one vaccine). chlorophyll, phycocyanin, allophycocyanin, green fluores Such polymer, biopolymer, nanoparticle, or detection mate 40 cent protein, or others. In at least one embodiment, the colo rial may allow for visualization of the administration process, rimeteric Substance includes at least one light-emitting Sub or provide other benefits (including therapeutic benefits). stance, including but not limited to luminescent Substances In certain instances, the detection material may be located (e.g. bioluminescent Substances, chemiluminescent Sub on or in the one or more frozen particles, or it may be inter stances, luciferin, isoluminol, luminescent minerals, etc.). mixed with the one or more frozen particles. In certain 45 In at least one embodiment, the at least one detection instances, the detection material provides a “tracer agent that material includes but is not limited to at least one of a dia allows for visualization of one or more locations of adminis magnetic particle, ferromagnetic particle, paramagnetic par tration of the at least one therapeutic composition, or the at ticle, Super paramagnetic contrast agent, or other magnetic least one frozen particle. Thus, in certain instances the detec particle. tion material is located on the at least one therapeutic com 50 In at least one embodiment, a method or composition position or the at least one frozen particle. In other instances, described herein includes one or more explosive materials. the detection material is separate from the at least one thera Explosive materials are typically chemically or energetically peutic composition or the at least one frozen particle and unstable or produce a Sudden expansion of the material with forms a mixture with the therapeutic composition or frozen a change in pressure. Such a Sudden expansion of the material particles or is administered at approximately the same time, in 55 under pressure changes is generally accompanied by the pro approximately the same place, or in approximately the same duction of heat. Explosive materials are generally differenti manner as the one or more therapeutic compositions or frozen ated according to their decomposition rates. Generally, a particles. chemical decomposition rate of an explosive material takes In at least one embodiment, detection material includes a years, days, hours, minutes, seconds, or a fraction of a second. detectable label including but not limited to, a colorimetric 60 Certain explosive materials are relatively stable, and may label, a radioactive label, a light-emitting label (such as a maintain their explosive ability for some amount of time. luminescent compound, a fluorescent compound, a phospho Other explosive materials have relatively high rates of rescent compound, or a quantum dot), a nucleic acid label, a decomposition and detonate rapidly. protein label, an antibody label, a ligand label, a receptor Explosive materials may contain at least one oxidizer that label, a magnetic label, or other detectable label. In at least 65 provides fuel for certain explosive materials. In certain one embodiment, the at least one detection material includes instances, the oxidizer may be an oxidizing element, Such as but is not limited to at least one electronic identification oxygen. In certain instances, the oxidizer reacts with a reac US 9,072,799 B2 35 36 tive metal; an example of such a compound includes reacting which is incorporated herein by reference, gasified ice prod fine metal powder (e.g., aluminum or magnesium) with an ucts are produced in a similar manner that contain other gases, oxidizer (e.g., potassium chlorate or perchlorate). Chemically Such as nitrous oxide, Sulfur-containing gases, chlorine-con pure compounds may have high decomposition rates and lead taining gases, inert gases, or carbon monoxide. to an explosion, including but not limited to nitroglycerin, In at least one embodiment, compositions described herein acetone peroxide, trinitrotoluene, nitrocellulose, carbon, car include one or more explosive materials that may include, for bon monoxide, chlorine, potassium nitrate, Sulfur, nitrogen example, at least one of a high explosive or a low explosive. In compounds (such as nitrite, nitrate, and azide), potassium at least one embodiment, the one or more explosive materials chlorate and potassium nitrate, hydrogen, ammonium nitrate, include at least one of carbon dioxide, nitroglycerine, or a phosphorus, dinitrogen tetroxide, or others. In at least one 10 reactive metal. In certain instances, one or more compositions embodiment, one or more mixtures of organic materials and disclosed herein, including therapeutic compositions, main oxidizers are included. In at least one embodiment, one or tain one or more explosive properties. In certain instances, the more mixtures of reactive metals and oxidizers or oils are one or more explosive properties are the result of activation of included. one or more explosive materials. In certain instances, the one In at least one embodiment, the one or more explosive 15 or more explosive properties are the result of inherent tenden materials include carbon dioxide gas. Carbon dioxide gas can cies of the compositions themselves. In certain instances, the be entrapped into various compositions or therapeutic com one or more explosive properties relate to an external event or positions described herein. One method of incorporating car stimulus, such as a change in temperature or pressure. In bon dioxide gas into at least one composition or therapeutic certain instances, the one or more explosive properties relate composition includes liquefying the composition or thera to a change in light intensity. In certain instances, the one or peutic composition and introducing carbon dioxide gas while more explosive properties relate to a change in the composi maintaining the mixture under pressure. (See e.g., U.S. Pat. tion upon administration or contact with at least one compo Nos. 4,289,794; 4,289,790; 4,262,029; 5,439,698, each of sition, cell, tissue, or Subject. In certain instances, the one or which is incorporated herein by reference). more explosive properties result from a temperature or pres In at least one embodiment, the one or more explosive 25 Sure increase relating to penetration of at least one cell, tissue, materials include Sodium bicarbonate. In at least one embodi or Subject. In certain instances, the one or more explosive ment, the one or more explosive materials include citric acid. properties result from contact with water or other moisture in In at least one embodiment, the one or more explosive mate a cell or tissue. In addition to the intensity of the one or more rials include Sodium bicarbonate and citric acid. In at least explosives, the one or more explosive materials may differ one embodiment, the one or more explosive materials include 30 with regard to the Volatility, density, toxicity, hygroscopicity, hydrogen peroxide. or brisance of a particular explosive material. In certain instances, the at least one composition or thera In at least one embodiment, at least one pharmaceutically peutic composition explodes during administration of the acceptable carrier or excipient is included in a therapeutic composition ortherapeutic composition. In certain instances, composition. The at least one pharmaceutically-acceptable the at least one composition or therapeutic composition 35 carrier or excipient may take the form of a solid, liquid, gas, explodes prior to or Subsequent to administration of the com or any combination thereof. In certain instances, the at least position or therapeutic composition to at least one biological one pharmaceutically-acceptable carrier or excipient tissue. In certain instances, the at least one composition or includes one or more of air, oxygen, nitrogen, carbon dioxide, therapeutic composition explodes after a prolonged time Sub hydrogen oxide, helium, neon, Xenon, krypton, chlorine, bro sequent to administration or delivery to at least one biological 40 mine, or argon. In at least one embodiment, the at least one tissue (e.g. in cases where the explosive material is encased or pharmaceutically-acceptable carrier or excipient includes but associated with a polymer or other agent that may insulate one is not limited to polyethylene glycol, acetone, ethyl acetate, or more reactant or retard the explosive or decomposition dimethyl sulfoxide, dimethyl formamide, dioxane, hexam process). ethylphosphorotriamide, perfluorohydrocarbon, methanol, In at least one embodiment, at least one gasified frozen 45 ethanol, tert-butyl alcohol, formic acid, hydrogen fluoride, particle is formed by contacting fluid with gas under high ammonia, acetic acid, benzene, carbon tetrachloride, aceto pressure for a sufficient time period to form a gas hydrate. nitrile, hexane, methylene chloride, carboxylic acid, Saline, This gas hydrate is then cooled to a lower temperature in order Ringer's solution, lactated Ringer's solution, Hartmann's to freeze the remaining unreacted fluid and entrap the gas Solution, acetated Ringer's Solution, phosphate buffered solu hydrate. As one non-limiting example, aqueous liquid and 50 tion, TRIS-buffered saline solution, Hank's balanced salt carbon dioxide were kept in contact at approximately 0°C. Solution, Earle's balanced salt Solution, standard saline cit for a time Sufficient under a pressure range including at least rate, HEPES-buffered saline, dextrose, glucose, or diethyl approximately 200 psig to approximately 600 psig, while ether. In at least one embodiment, the at least one pharma permitting absorption in the liquid of the gas in bound form ceutically-acceptable carrier or excipient functions as a and formation of the gasified ice. This process yields approxi 55 vehicle, or means to transport another agent. In at least one mately 25-27.5 milliliters of gas per gram of ice. (See e.g., embodiment, the at least one pharmaceutically-acceptable U.S. Pat. Nos. 4487,023; 2,975,603: 3,086,370; 3,217,503, carrier or excipient provides at least one clinical benefit. and 4,404.807, each of which is incorporated herein by ref As described herein, at least one composition or therapeu erence). tic composition described herein is useful in one or more Similarly, as described in U.S. Pat. No. 2,975,603, which is 60 methods, including one or more of a method for abrasion of at incorporated herein by reference, water contacted with car least one biological tissue surface of a subject by delivering at bon dioxide at a pressure of approximately 400 psig, in a least one composition to at least one Surface of at least one temperature bath of approximately 0° C., is subsequently biological tissue of a Subject in a manner Sufficient to abrade placed at -10° C. for 24 hours to effect degasification. As the at least one Surface of the at least one biological tissue; a described in U.S. Pat. No. 2,975,603, the resulting product 65 method of delivering at least one therapeutic agent to at least yields approximately 75 Volumes of carbon dioxide per gram one biological tissue; a method of vaccinating a subject; a of ice. Additionally, as described in U.S. Pat. No. 3,086,370, method of treating a tissue related to transplantation; a US 9,072,799 B2 37 38 method for cleaning one or more wounds; a method for debri insect cells, insects, bacteria, algae, plankton, or protozoa. In dement of tissue or cells; a method for removing material at least one embodiment, the at least one subject includes one from one or more blood vessel, and others. These and other or more of a reptile, mammal, amphibian, bird, or fish. In at methods include utilizing one or more composition or thera least one embodiment, the at least one Subject includes at least peutic composition described herein. one human. In at least one embodiment, the at least one In at least one embodiment, a method for abrasion of at Subject includes at least one of livestock, pet, undomesticated least one biological tissue surface of a subject includes deliv herd animal, wild animal, or product animal. In certain ering at least one composition to at least one Surface of at least instances, the vaccine compositions and methods relate to one biological tissue of a subject in a manner Sufficient to vaccinating wildlife animals (e.g. Vaccinating raccoons for abrade the at least one surface of the at least one biological 10 tissue. rabies, or bison for brucellosis). In certain instances, the As indicated herein, in at least one embodiment, a method vaccine compositions and methods described herein relate to for providing at least one therapeutic agent to at least one vaccinating domesticated animals (such as cattle, horses, biological tissue of a subject is included. In at least one sheep, or goats). In certain instances, vaccine compositions embodiment, the at least one therapeutic agent is delivered to 15 and methods described herein relate to vaccinating a group of at least one biological tissue prior to, during, or Subsequent to Subjects, such as a population, a herd, a pride, a gaggle, a Surgery. In certain instances, at least one therapeutic agent pack, flock, band, cluster, School, brood, troop, colony, or includes one or more therapeutic agents described herein. In other group. In certain instances, vaccinating a group of Sub at least one embodiment, a method of providing at least one jects is included as a route to regulate or control infection therapeutic agent to at least one biological tissue of a subject within a group of Subjects. includes delivering at least one therapeutic composition to at In at least one embodiment, the at least one Subject includes least one biological tissue, including one or more frozen at least one of a sheep,goat, frog, dog, cat, rat, mouse, Vermin, hydrogen oxide particles including at least one therapeutic monkey, duck, horse, cow, pig, chicken, shellfish, fish, turkey, agent; wherein the at least one therapeutic composition has at llama, alpaca, bison, wolf, fox, coyote, deer, rabbit, guinea least one crystalline or amorphous phase. 25 pig, yak, chinchilla, mink, reindeer, elk, deer, raccoon, camel, In certain aspects, a method relates to vaccinating a subject donkey, or mule. by administering at least one therapeutic composition that As discussed herein, particular methods are disclosed for includes at least one vaccine. The therapeutic composition abrading or ablating at least one surface of at least one bio can be administered singularly, or in conjunction with another logical tissue. Abrading at least one surface of at least one treatment, such as Surface abrasion therapy. In at least one 30 biological tissue may entail debridement of at least one bio embodiment, a method of vaccinating a subject includes logical tissue. In certain instances, debridement may include administering to a subject at least one therapeutic composi removal or destruction of dead, damaged, or infected cells or tion; wherein the at least one therapeutic composition tissues. In certain instances, debridement may be included as includes one or more frozen hydrogen oxide particles, and at part of an additional course of treatment (e.g., Surgery). In at least one vaccine; wherein the therapeutic composition has at 35 least one embodiment, debridement may include penetrating least one crystalline or amorphous phase. one or more healthy cells or tissues in order to facilitate In at least one embodiment, a method of vaccinating a healing. In at least one embodiment, debridement may Subject includes administering to a subject at least one thera include penetrating one or more healthy cells or tissues near peutic composition; wherein the at least one therapeutic com in proximity to one or more unhealthy cells or tissues of a position includes one or more frozen particles, including at 40 Subject. least one of polyethylene glycol, acetone, ethyl acetate, dim In at least one embodiment, one or more of the debridement ethyl sulfoxide, dimethyl formamide, dioxane, hexameth methods described herein include penetrating one or more ylphosphorotriamide, perfluorohydrocarbon, methanol, etha cells or biological tissues of a Subject with at least one com nol, tert-butyl alcohol, formic acid, hydrogen fluoride, position or therapeutic composition, wherein the one or more ammonia, acetic acid, benzene, carbon tetrachloride, aceto 45 cells or tissues are chemically or physically partitioned or nitrile, hexane, methylene chloride, carboxylic acid, Saline, segregated from at least one other part of the tissue or another Ringer's solution, lactated Ringer's solution, Hartmann's tissue. In at least one embodiment, a method for debridement Solution, acetated Ringer's solution, phosphate buffered solu of at least one biological tissue of a subject includes deliver tion, TRIS-buffered saline solution, Hank's balanced salt ing at least one composition or therapeutic composition to at Solution, Earle's balanced salt Solution, standard saline cit 50 least one biological tissue of a subject wherein the at least one rate, HEPES-buffered saline, dextrose, glucose, or diethyl biological tissue is partitioned from another biological tissue ether; and at least one vaccine. or part of another biological tissue, and at least one compo As disclosed herein for other embodiments, a method of sition or therapeutic composition penetrates the at last one vaccinating a Subject includes administering at least one biological tissue with or without removing any tissue. In therapeutic composition that includes one or more abrasives, 55 certain instances, a therapeutic agent is included with the at one or more reinforcement agents, or one or more explosive least one composition or therapeutic composition, as materials. In at least one embodiment, the vaccine described described herein. In certain instances, one or more reinforce herein relates to a therapeutic or prophylactic vaccine, and in ment agents or one or more explosive materials may be certain instances the vaccine relates to an anti-cancer Vaccine. included in the at least one composition or therapeutic com In at least one embodiment, the one or more abrasives are the 60 position. same as the one or more reinforcement agents, or the one or In at least one embodiment, the one or more frozen par more explosive materials. In at least one embodiment, the one ticles are delivered or administered to the at least one biologi or more abrasives are different than the one or more reinforce cal tissue in a directed manner Such that the tissue is etched, ment agents. In at least one embodiment, the one or more tattooed, shaped, carved, or otherwise modified in a directed abrasives are different than the one or more explosive mate 65 outcome. In at least one embodiment, the directed manner is rials. In at least one embodiment, the Subject receiving the predetermined based on information, such as from the at least vaccine includes one or more of a vertebrate or invertebrate, one biological tissue, the Subject, the at least one composition US 9,072,799 B2 39 40 or therapeutic composition, the context of the debridement, frozen particles that are delivered at approximately the same the health of the subject, or other information. time, with approximately the same Velocity, or to approxi In at least one embodiment, the at least one biological mately the same location. tissue includes one or more of skin, Scalp, hair, nail, nail bed, In certain instances, it is desirable to deliver the one or teeth, eye, ear, ovary, Oviduct, tongue, tonsil, adenoid, liver, more frozen particles to at least one cell or tissue, or admin bone, pancreas, stomach, blood vessel, blood, lymph, heart, ister the one or more frozen particles to at least one subject. In lung, brain, breast, kidney, bladder, urethra, ureter, gallblad at least one instance, the one or more frozen particles include der, uterus, prostate, testes, vas deferens, fallopian tubes, a plurality of frozen particles that include two or more subsets large intestine, Small intestine, esophagus, oral cavity, nasal of frozen particles that are delivered or administered in cavity, otic cavity, connective tissue, muscle tissue, or adipose 10 sequential order. In at least one embodiment, the sequential tissue. Other cells or tissues of a subject are described herein. order is predetermined, based on factors relating to, for In at least one embodiment, a method for removing one or example, the at least one cellor tissue, the at least one Subject, more materials from at least one biological tissue includes or the at least one composition ortherapeutic composition. In delivering at least one composition or therapeutic composi 15 at least one embodiment, the sequential order is determined tion to the at least one biological tissue. In at least one during the course of delivery or administration of at least one embodiment, the at least one biological tissue includes one or of the one or more frozen particles or at least one composition more tissues described herein. In at leastone embodiment, the or therapeutic composition. In at least one embodiment, the one or more materials may include one or more materials sequential order is determined by a Software program. In at described herein. least one embodiment, the sequential order of delivery is In at least one embodiment, a method for removing one or randomized. more materials from at least one blood vessel of at least one In at least one embodiment, the sequential order includes Subject includes delivering at least one composition to at least one or more Subsets of frozen particles that vary in size, shape, one blood vessel of a subject in a manner sufficient to remove weight, density, location of delivery or administration, time one or more materials. 25 of delivery or administration, or velocity of delivery or In certain instances, a method for abrasion of at least one administration. In at least one embodiment, one or more biological tissue or organ Surface related to transplantation is subsets of frozen particles are delivered or administered included. In at least one embodiment, the at least one biologi according to a course of treatment (e.g., at least one Subset of cal tissue or organ includes one or more of the biological relatively small frozen particles are administered first, fol tissues or organs described herein. 30 lowed by at least one subset of relatively larger frozen par In at least one embodiment, a method for abrasion of at ticles; at least one Subset of frozen particles are administered least one biological tissue or organ Surface related to trans in a relatively fast velocity, followed by at least one subset of plantation includes one or more of biological tissues or organs frozen particles administered by a relatively slow velocity; at described herein. least one Subset of frozen particles approximately shaped as 35 spheroids are administered followed by at least one subset of In at least one embodiment, a method for cleaning one or frozen particles approximately shaped as bullets, etc.). more wounds is included. In at least one embodiment, the one In at least one embodiment, one or more methods described or more wounds are located in at least one biological tissue or herein include delivering or administering one or more frozen organ described herein, including but not limited to skin particles by high velocity impact. In at least one embodiment, tissue, muscle tissue, eye tissue, an organ, connective tissue, 40 the one or more devices that utilize high Velocity impact neoplastic tissue, or bone tissue. In at least one embodiment, delivery provide at least one of localized delivery, targeted the one or more wounds are located in at least one subject delivery, sustained delivery, modulated delivery, feedback described herein. In at least one embodiment, at least one controlled delivery. In some instances, an example of a device therapeutic agent is included in at least one composition for that may be used for administering one or more of the com cleaning one or more wounds. The one or more wounds 45 positions described herein includes a handheld device, such include but are not limited to at least one of an incision, as a wand, a pen, a baton, a hose, a sprayer, a gun (e.g., a pellet laceration, abrasion, puncture wound, penetration wound, gun), or other handheld device. In certain instances, the gunshot wound, iatrogenic wound, severing, infection, ulcer, device is at least part of a built-in delivery device. Such as may pressure sore, lesion, chemical burn (including but not limited be included in a wall, an overhead device, a corral, a gate, or to exposure to an irritant, plant, or synthetic chemical), dental 50 a device that includes a cavity into which a Subject may be caries, first-degree burn, second-degree burn, third-degree placed for administration or delivery of at least one compo burn, fourth-degree burn, fifth-degree burn, or sixth-degree sition described herein. In certain instances, the device has burn. In certain instances, the wound may be a result of a bite, robotic action. In any of these instances, the device may be Such as a bite from an animal, insect, or arachnid. remotely controlled, for example, by a human or computer In at least one embodiment, a plurality of frozen particles is 55 program. administered for a particular treatment. In some instances, the In at least one embodiment, delivering the at least one plurality of frozen particles includes multiple different com composition, including at least one therapeutic composition, positions or therapeutic compositions. In some instances, the to at least one biological tissue includes at least one of accel plurality of frozen particles includes one or more subsets of erating, ejecting, or propelling, the composition or therapeu one or more frozen particles with common characteristics. In 60 tic composition toward the at least one biological tissue. In at Some instances, one or more Subsets of the plurality of frozen least one embodiment, the at least one composition is accel particles may include but not be limited to one or more frozen erated, ejected, or propelled to or at a predetermined pressure particles that have approximately the same size, shape, or velocity for delivery of the at least one composition to a weight, or density; one or more Subsets of the plurality of desired location on or in the at least one biological tissue. In frozen particles may include but not be limited to one or more 65 certain instances, the at least one composition or therapeutic frozen particles that include similar therapeutic agents; one or composition is accelerated, ejected, or propelled at a particu more subsets may include but not be limited to one or more lar pressure or Velocity. In certain instances, the at least one US 9,072,799 B2 41 42 composition or therapeutic composition is accelerated, Metered-dose transdermal sprays may also be used for ejected, or propelled at a predetermined pressure or Velocity. delivery of at least one therapeutic composition as described The velocity or pressure determined for delivery of the at herein. As described by Rathbone, et al., in one particular least one composition to at least one biological tissue depends example, a topical Solution containing a volatile then non on certain factors, including but not limited to, size and den Volatile vehicle including a therapeutic agent is administered sity of the particle, content of the particle, desired effect or as a single-phase solution. (See Rathbone, et al., Modified outcome of administration of the particle, density of the target Release of Drug Delivery Technology, NY, Marcel Dekker, tissue, density of Surrounding tissue, type of tissue, architec Inc. vol. 126, pp. 471-619 (2004), which is incorporated ture of the tissue, and other factors. In certain instances, the herein by reference). A finite metered-dose application of the desired Velocity or pressure for accelerating, ejecting, or pro 10 formulation to intact skin results in evaporation of the volatile pelling the at least one composition described herein will be component, leaving the remaining nonvolatile penetration the minimum velocity or pressure needed to achieve desired enhancer or therapeutic agent to partition into the stratum penetration of the tissue with the composition, whether for corneum and creating a reservoir of the therapeutic agent(s). Surface abrasion, therapeutic delivery, or other goal. 15 (See Rathbone, Ibid; and Kumar, et al., Trop.J. Pharm. Res., The means for accelerating, ejecting, or propelling the vol. 6, pp. 633-644 (2007), each of which is incorporated compositions described herein are non-limiting, and may herein by reference). include general methods for making, formulating, and deliv In addition to these particular examples of devices that can ering to at least one biological tissue by carrier gas under be utilized for administration of the therapeutic compositions pressure, mechanical or electrical impulse assistance, cen described herein, the therapeutic compositions can be admin tripetal or centrifugal force, or others. Some of which are istered in conjunction with other delivery devices or avenues. described herein. (See e.g., U.S. Pat. No. 4,945,050 and PCT Likewise, the compositions described herein for abrasion of application WO 92/01802, each of which is incorporated at least one biological tissue can be delivered to the at least herein by reference). In certain instances, the one or more one tissue by any means described herein. Some such means frozen particles are made, propelled, accelerated, or ejected 25 for delivery of the compositions described herein include, but simultaneously. Thus, the frozen particles may be made while are not limited to, ultrasound, iontophoresis (which involves propelled, the frozen particles may be made while acceler applying an electrical potential across skin or other tissue in ated, the frozen particles may be made while ejected, or any order to increase penetration of ionizable drugs), diffusion, combination thereof. electroporation, photomechanical waves (such as by produc In at least one embodiment, the one or more frozen par 30 ing pulses with Q-switched or mode-locked lasers to the skin ticles are delivered or administered by a piezoelectric-type or other tissue), needle-free injections, electro-osmosis, arti apparatus or device, by ultrasound-mediated transdermal ficial vesicles, laser radiation, magnetophoresis (utilizing a drug transport, or by other device. When a Voltage is applied, diamagnetic Substance for use with a magnetic field for a piezoelectric-type apparatus generates a pressure pulse by increased penetration of the composition into the biological change in shape or size of a chamber containing a fluid (or 35 tissue), microscissuining, controlled heat aided delivery solid), and the pressure pulse drives the contents from the (which involves heating the skin prior to or during therapeutic chamber. In one particular instance, a high Velocity device administration), or tattoos and etchings. (such as a powderject, air guns, or slingshot type devices) is Some non-limiting examples of particular diamagnetic utilized for injection of particles formulated with at least one Substances include wood, water, organic compounds (such as therapeutic agent, for example, for therapy or prevention of a 40 petroleum), metals (including copper, mercury, gold, bis disease or condition. muth), or benzoic acid. For example, a powderject system, as described by Kumar In one particular example, skin abrasion for Superficial and Philip (Trop. J. Pharm. Res., vol. 6, No. 1, pp. 633-644 resurfacing (e.g., microdermabrasion) can be used to treat (2007), which is incorporated herein by reference) propels acne, Scars, hyperpigmentation, and other skin blemishes, as frozen drug particles into the skin by means of high-speed gas 45 described herein. Microscissuining creates microchannels in flow (such as helium) that is usually painless and causes the skin by eroding the outer layers of skin with sharp micro minimal bleeding or damage to the skin. (See also e.g., Tang scopic metal granules (Carlisle Scientific, Carlisle, Mass.), et al., Pharm. Res., vol. 19, pp. 1160-69 (2002), which is and Med Pharm Ltd (Charlbury, UK) has developed a novel incorporated herein by reference). As described by Kumar dermal abrasion device (D3S) for the delivery of difficult to and Philip, particles contained in a cassette between two 50 formulate therapeutics ranging from hydrophilic low molecu polycarbonate membranes located at the end of a chamber lar weight compounds to other biopharmaceuticals, and can (Trop. J. Pharm. Res., vol. 6, No. 1, pp. 633-644 (2007), be utilized in conjunction with administration of at least one which is incorporated herein by reference). As described by therapeutic composition described herein. (See e.g., Roberts, Kumar and Philip, the polycarbonate membranes are ruptured et al., Clin. Exp. Pharmacol. Physiol. Vol. 24, pp. 874-9 when a carrier gas enters the chamber under high pressure, 55 (1997); Murthy, et al., J. Controlled Rel. Vol. 93, pp. 49-57 and the rapid expansion of the gas forms a shock wave that (2003); each of which is incorporated herein by reference). travels down the nozzle at a speed of approximately 600-900 In at least one embodiment, Rathbone et al. have described m/s. Kumar and Philip report drug particle velocities of up to artificial vesicles that mimic cell vesicles (such as TRANS about 800 m/s at the nozzle exit, and the momentum density FERSOMESR), from IDEA AG, Germany) can be utilized for of the particles within the gas flow can be optimized for 60 administration of one or more therapeutic composition desired depth of penetration upon delivery to a biological described herein. Artificial vesicles penetrate the skin barrier tissue. (Trop. J. Pharm. Res., Vol. 6, No. 1, pp. 633-644 along the transcutaneous moisture gradient and causes “vir (2007), which is incorporated herein by reference). In the tual pores between the cells in an organ without affecting its powderject system, particle Velocity is controlled by nozzle biological properties. (See, e.g., Modified Release Drug geometry, membrane burst strength, and gas pressure. (See 65 Delivery Technology, NY. Marcel Dekker, Inc., vol. 126, pp. e.g., U.S. Pat. Nos. 5,630,796; and 5,699,880, which are 471-619 (2004), which is incorporated herein by reference). incorporated herein by reference). In addition, liposomes, and niosomes also serve as carriers US 9,072,799 B2 43 44 and can be utilized in administration of at least one therapeu In at least one embodiment, delivering at least one compo tic composition described herein. sition to at least one biological tissue includes accelerating, In at least one embodiment, the one or more frozen par ejecting, or propelling a plurality of frozen particles toward ticles are generated by spraying a jet or mist of the composi the at least one biological tissue. Such a plurality of particles tion constituents into a low temperature environment (Solid, may include at least one embodiment wherein two or more liquid, gas, or any combination thereof) Such that the compo frozen particles of the plurality include one or more similar sitions freeze and form frozen particles. In at least one therapeutic agents. Likewise, a plurality of frozen particles embodiment, streams of frozen particles are extruded at low may include at least one embodiment wherein two or more temperatures through fine ducts and into a low temperature frozen particles include one or more dissimilar therapeutic environment. In at least one embodiment, the one or more 10 agents. frozen particles are propelled through a nozzle or other deliv As described herein, a plurality of compositions or frozen ery apparatus. In at least one embodiment, the one or more particles may include one or more Subsets, which may be frozen particles are delivered by utilizing flash boiling of a delivered or administered in an order of operations. In at least cold liquid. In one particular example, liquid nitrogen is flash 15 one embodiment, the order of operations includes delivery or boiled in order to accelerate, eject, or propel one or more administration in a pattern. In at least one embodiment, the frozen particles for delivery or administration to at least one order of operations includes delivery or administration in a cell, tissue, or Subject. In at least one embodiment, the flash predetermined pattern. In at least one embodiment, the order boiling is caused or enhanced by one or more laser pulses of operations includes delivery or administration in sequen (e.g., an infrared laser pulse). In at least one embodiment, the tial order. In at least one embodiment, the order of operations one or more frozen particles are prepared, delivered, or includes delivery or administration at random. administered by another means. In at least one embodiment, delivering at least one compo In at least one embodiment, the at least one composition is sition to at least one Surface of at least one biological tissue of propelled using a pressure set at least about 1 psi, about 5 psi, a subject includes contacting the at least one Surface of at least about 10psi, about 20 psi, about 30 psi, about 40 psi, about 50 25 one biological tissue of a subject with the composition. In at psi, at least about 100 psi, at least about 200 psi, at least about least one embodiment, delivering at least one composition to 300 psi, at least about 400 psi, at least about 450 psi, at least at least one surface of at least one biological tissue of a subject about 500 psi, at least about 600 psi, at least about 700 psi, at includes contacting the at least one surface of at least one least about 800 psi, at least about 900 psi, at least about 1000 biological tissue of a subject with the one or more frozen psi, at least about 1100 psi, at least about 1200 psi, at least 30 particles. In at least one embodiment, delivering at least one about 1300 psi, at least about 1400 psi, at least about 1500 psi, composition to at least one Surface of at least one biological about 2000 psi, about 2500 psi, about 3000 psi, about 3500 tissue of a subject includes rupturing one or more cells of at psi, about 4000 psi, about 5000 psi, about 6000 psi, about least one surface of at least one biological tissue of a subject 7000 psi, about 8000 psi, about 9000 psi, about 10000 psi, with the one or more frozen particles. about 20000 psi, about 30000 psi, about 40000 psi, about 35 In at least one embodiment, a method described herein 50000 psi, or any value therebetween. includes extracting or collecting material from the at least one In at least one embodiment, the at least one composition is abraded Surface of at least one biological tissue. Such extrac propelled to or at a predetermined velocity for delivery of the tion or collection may include the use of at least one vacuum, at least one composition to a desired location of the at least aspirator, container, instrument, tool, device, chemical, laser, one biological tissue. In at least one embodiment, the at least 40 stylet, cannula, light source, scope (e.g., laprascope), needle, one composition is propelled to or at a Velocity of approxi Scalpel, shunt, stent, bag, film, filter, Suction apparatus, tube, mately 1 m/s, approximately 5 m/s, approximately 10 m/s, compressed gas, fluid (e.g., fluid stream or mist), magnifying approximately 20 m/s, approximately 30 m/s, approximately apparatus, imaging device, computing device, or System. 40 m/s, approximately 50 m/s, approximately 60 m/s, In at least one embodiment, at least one of the needle, approximately 70 m/s, approximately 80 m/s, approximately 45 Scalpel, or other tools or instruments utilized in extracting or 90 m/s, approximately 100 m/s, approximately 200 m/s, collecting material from the at least one cell, tissue, or Sub approximately 300 m/s, approximately 400 m/s, approxi ject, includes one or more frozen particles (e.g., frozen hydro mately 500 m/s, approximately 600 m/s, approximately 700 gen oxide, or other agents as described herein). Thus, the one m/s, approximately 800 m/s, approximately 900 m/s, or more frozen particles are fashioned or molded for use as approximately 1000 m/s, approximately 1500 m/s, approxi 50 microneedles or other instruments (e.g., Scapels, blades, mately 2000 m/s, approximately 3000 m/s, approximately tools, etc.). In at least one embodiment, the one or more 4000 m/s, approximately 5000 m/s, or any value greater or frozen particles are utilized prior to, during, or Subsequent to therebetween. Surgery. In at least one embodiment, the at least one composition is In at least one embodiment, the extracted or collected accelerated or ejected toward the at least one biological tissue 55 material includes at least one organic or inorganic material. In to a Velocity of approximately 1 m/s, approximately 5 m/s, at least one embodiment, the material includes one or more approximately 10 m/s, approximately 20 m/s, approximately cells from the at least one abraded surface of at least one 30 m/s, approximately 40 m/s, approximately 50 m/s, biological tissue. In at least one embodiment, the at least one approximately 60 m/s, approximately 70 m/s, approximately material includes at least part of one or more granuloma, 80 m/s, approximately 90 m/s, approximately 100 m/s, 60 eschar, callus, atheromatous plaque, abscess, pustule, Scaling approximately 200 m/s, approximately 300 m/s, approxi (e.g., psoriasis or eczema), infected tissue, microorganism mately 400 m/s, approximately 500 m/s, approximately 600 accumulation, blood clot, blood vessel obstruction, duct m/s, approximately 700 m/s, approximately 800 m/s, obstruction, bowel obstruction, necrotic tissue, stratum cor approximately 900 m/s, approximately 1000 m/s, approxi neum, hair follicle, nevus, wrinkle, keloid, biofilm, calculus, mately 1500 m/s, approximately 2000 m/s, approximately 65 plaque, tartar, dandruff, keratin, collagen, dust, dirt, metal, 3000 m/s, approximately 4000 m/s, approximately 5000 m/s, glass, hair or fur, cellular secretion, microorganism, blood or any value greater or therebetween. cell, particulate matter, or connective tissue. US 9,072,799 B2 45 46 In at least one embodiment, the at least one biological ware, Software, and/or firmware implementations of aspects tissue is located in at least one of in situ, in vitro, in Vivo, in of systems; the use of hardware, software, and/or firmware is utero, in planta, in silico, or ex vivo. In at least one embodi generally (but not always, in that in certain contexts the ment, the at least one biological tissue is located in vivo. In at choice between hardware and Software can become signifi least one embodiment, the at least one biological tissue is cant) a design choice representing cost vs. efficiency located in at least one tissue or organ related to transplanta tradeoffs. Those having skill in the art will appreciate that tion. In at least one embodiment, transplantation includes there are various vehicles by which processes and/or systems extraction or implantation of the at least one tissue or organ. and/or other technologies described herein can be effected In at least one embodiment, the at least one tissue or organ (e.g., hardware, Software, and/or firmware), and that the pre related to transplantation is extracted from at least one first 10 biological source or Subject and implanted into at least one ferred vehicle will vary with the context in which the pro second biological source or Subject. In at least one embodi cesses and/or systems and/or other technologies are ment, the at least one tissue or organ related to transplantation deployed. For example, if an implementer determines that is cultured prior to implantation in a subject. In at least one speed and accuracy are paramount, the implementer may opt embodiment, the tissue or organ related to transplantation is 15 for a mainly hardware and/or firmware vehicle: alternatively, an artificial tissue or organ (e.g. a bladder, heart, kidney, liver, if flexibility is paramount, the implementer may opt for a pancreas, skin, eye, lung, nerve, blood vessel, and others). In mainly software implementation; or, yet again alternatively, at least one embodiment, the tissue or organ related to trans the implementer may opt for some combination of hardware, plantation involves at least two sources (i.e. multiple species, software, and/or firmware. Hence, there are several possible partially artificial or synthetic, multiple biological cells or vehicles by which the processes and/or devices and/or other tissues including stem cells). In at least one embodiment, the technologies described herein may be effected, none of which at least one tissue or organ related to transplantation includes is inherently superior to the other in that any vehicle to be at least one donor or recipient tissue or organ. In at least one utilized is a choice dependent upon the context in which the embodiment, the at least one donor includes at least one vehicle will be deployed and the specific concerns (e.g., cadaver. In at least one embodiment, the at least one biologi 25 speed, flexibility, or predictability) of the implementer, any of cal tissue is ingested by at least one Subject. which may vary. Those skilled in the art will recognize that In at least one embodiment, the at least one tissue or organ optical aspects of implementations will typically employ related to transplantation includes one or more cells. The one optically-oriented hardware, Software, and or firmware. or more cells may include endogenous or exogenous cells In some implementations described herein, logic and simi relative to a particular subject. In at least one embodiment, the 30 lar implementations may include Software or other control at least one tissue or organ related to transplantation relates to structures. Electronic circuitry, for example, may have one or one or more stem cells (e.g., hematopoietic stem cells, adi more paths of electrical current constructed and arranged to pocyte stem cells, neuronal stem cells, embryonic stem cells, implement various functions as described herein. In some hepatic stem cells, dermal stem cells, pancreatic stem cells, implementations, one or more media may be configured to stem cells related to bone, stem cells related to muscle, or 35 bear a device-detectable implementation when such media others). In at least one embodiment, the at least one tissue or hold or transmit device detectable instructions operable to organ related to transplantation includes one or more of skin, perform as described herein. In some variants, for example, Scalp, hair, nail, nail bed, teeth, eye, cornea, ear, ovary, ovi implementations may include an update or modification of duct, tongue, tonsil, adenoid, liver, bone, pancreas, stomach, existing Software or firmware, or of gate arrays or program blood vessel, blood, lymph, heart, heart valve, lung, brain, 40 mable hardware. Such as by performing a reception of or a breast, kidney, bladder, urethra, ureter, gallbladder, uterus, transmission of one or more instructions in relation to one or prostate, testes, vas deferens, fallopian tubes, large intestine, more operations described herein. Alternatively or addition Small intestine, esophagus, oral cavity, nasal cavity, otic cav ally, in Some variants, an implementation may include spe ity, tendon, vein (e.g., femoral or Saphenous vein), artery, cial-purpose hardware, Software, firmware components, and/ capillary, connective tissue, muscle tissue, or adipose tissue. 45 or general-purpose components executing or otherwise In at least one embodiment, the at least one biological invoking special-purpose components. Specifications or tissue includes at least one cell mass. In at least one embodi other implementations may be transmitted by one or more ment, the at least one cell mass includes at least one of a scar, instances of tangible transmission media as described herein, pore, pit, eschar, granuloma, keloid, artheromatous plaque, optionally by packet transmission or otherwise by passing abscess, pustule, Scaling (e.g., psoriasis or eczema), infected 50 through distributed media at various times. tissue, hair follicle, necrotic tissue, stratum corneum, Alternatively or additionally, implementations may wrinkle, wound, tumor, skin structure, nevus, cyst, lesion, include executing a special-purpose instruction sequence or callus, neoplastic tissue, gangrenous tissue, or cellular invoking circuitry for enabling, triggering, coordinating, deposit. In at least one embodiment, the at least one cell mass requesting, or otherwise causing one or more occurrences of includes at least one benignormalignant tumor. In at least one 55 virtually any functional operations described herein. In some embodiment, the at least one benign or malignant tumor variants, operational or other logical descriptions herein may relates to one or more of a melanoma, lymphoma, leukemia, be expressed as source code and compiled or otherwise sarcoma, blastoma, or carcinoma. invoked as an executable instruction sequence. In some con In at least one embodiment, the at least one cell mass is texts, for example, C++ or other code sequences can be com related to at least one blood clot, microorganism accumula 60 piled or implemented in high-level descriptor languages (e.g., tion, blood vessel obstruction, duct obstruction, bowel a logic-Synthesizable language, a hardware description lan obstruction, infection, gangrene, connective tissue destruc guage, a hardware design simulation, and/or other Such simi tion, tissue or organ damage, injury, white blood cell accu lar mode(s) of expression). For example, Some or all of the mulation, or cancer. logical expression may be manifested as a Verilog-type hard For embodiments described herein, those having skill in 65 ware description or other circuitry model before physical the art will recognize that the state of the art has progressed to implementation in hardware. Those skilled in the art will the point where there is little distinction left between hard recognize how to obtain, configure, and optimize Suitable US 9,072,799 B2 47 48 transmission or computational elements, material Supplies, delivered agent; a code indicative of at least one detection actuators, or other structures in light of these teachings. material delivered; a code indicative of the depth of penetra As indicated in FIGS. 7-9, at least one embodiment, a tion of a delivered agent, or a code indicative of the condition method 700 includes comparing 710 information regarding at of at least one location of an administered or delivered frozen least one aspect of administering at least one frozen particle particle composition. In at least one embodiment, the at least therapeutic composition to at least one subject and informa one aspect of cellular or tissue abrasion or ablation includes tion regarding at least one clinical outcome following receipt information regarding at least one cellular or tissue source by the at least one subject of at least one frozen particle 820. In at least one embodiment, the information regarding at therapeutic composition; and providing output information least one tissue source includes information regarding at least optionally based on the comparison. 10 one abnormal cellular or tissue source 830. In at least one In at least one embodiment, the method includes determin embodiment, the information regarding at least one cellular ing at least one statistical correlation 720. In at least one or tissue source includes information regarding at least one embodiment, the method includes counting the occurrence of type of cell or tissue 840. In at least one embodiment, the at least one clinical outcome 730. In at least one embodiment, cellular or tissue source includes at least one cell or biological the method includes determining at least one correlation 15 tissue described herein. before the administration of the at least one frozen particle In at least one embodiment, the at least one frozen particle therapeutic composition 735. In at least one embodiment, composition or therapeutic composition includes at least one information regarding at least one aspect of administering at of nitrogen, carbon dioxide, hydrogen oxide, helium, neon, least one frozen particle therapeutic composition includes Xenon, krypton, chlorine, bromine, oxygen, air, argon, poly information regarding the amount of at least one frozen par ethylene glycol, acetone, ethyl acetate, dimethyl Sulfoxide, ticle therapeutic composition or therapeutic agent adminis dimethyl formamide, dioxane, hexamethylphosphorotria tered to at least one biological tissue of a subject 740. In at mide, perfluorohydrocarbon, methanol, ethanol, tert-butyl least one embodiment, the information regarding at least one alcohol, formic acid, hydrogen fluoride, ammonia, acetic aspect of administering or delivering at least one frozen par acid, benzene, carbon tetrachloride, acetonitrile, hexane, ticle therapeutic composition includes information regarding 25 methylene chloride, carboxylic acid, saline, Ringer's solu at least one dimension of biological tissue penetration 750. In tion, lactated Ringer's solution, Hartmann's solution, at least one embodiment, information regarding the at least acetated Ringer's solution, phosphate buffered solution, one dimension of biological tissue penetration includes infor TRIS-buffered saline solution, Hank's balanced salt solution, mation regarding at least one of depth, width, or breadth of Earle's balanced salt solution, standard saline citrate, administration of at least one frozen particle therapeutic com 30 HEPES-buffered saline, dextrose, glucose, or diethyl ether position to at least one biological tissue of at least one subject 850. 760. In at least one embodiment, the at least one frozen particle In at least one embodiment, the information regarding at composition or therapeutic composition includes at least one least one aspect of administering at least one frozen particle major dimension of approximately one decimeter or less, or therapeutic composition includes information regarding two 35 approximately one centimeter or less, approximately one mil or more subjects with one or more common attributes 770. In limeter or less, approximately one micrometer or less, at least one embodiment, the one or more common attributes approximately one nanometer or less, or any value therebe include genetic attributes, mental attributes, or psychological tween 860. attributes 780. In at least on embodiment, the one or more In at least one embodiment, the at least one frozen particle common attributes include genotype attributes or phenotype 40 composition ortherapeutic composition includes one or more attributes 790. reinforcement agents 870. In at least one embodiment, the at In at least one embodiment, the one or more common least one frozen particle composition or therapeutic compo attributes 797 include at least one of height; weight; medical sition includes one or more explosive materials 880. In at least diagnosis; familial background; results on one or more medi one embodiment, the receipt by the at least one subject of at cal tests; ethnic background; body mass index; age; presence 45 least one frozen particle composition or therapeutic compo or absence of at least one disease or condition; species; eth sition is pursuant to at least one clinical trial 900. nicity; race; allergies; gender; thickness of epidermis; thick In at least one embodiment, the method includes creating at ness of dermis; thickness of stratum corneum, keratin depo least one inclusion criterion and at least one exclusion crite sition; collagen deposition; blood vessel condition; skin rion for a clinical trial involving the at least one frozen particle condition; hair or fur condition; muscle condition: tissue con 50 composition or therapeutic composition 910. In at least one dition; organ condition; nerve condition; brain condition; embodiment, the method further comprises suggesting the presence or absence of at least one biological, chemical, or inclusion of one or more of the at least one subject in at least therapeutic agent in the Subject; pregnancy status; lactation one clinical trial 920. In at least one embodiment, the method status; genetic profile; proteomic profile; partial or whole further comprises suggesting the exclusion of one or more of genetic sequence; partial or whole proteomic sequence; 55 the at least one subject in at least one clinical trial 930. In medical history; lymph condition, or blood condition. certain instances, multiple Subjects from multiple clinical In at least one embodiment, the output information 810 trials are included. In at least one embodiment, the method includes at least one of a response signal, a comparison code, further includes using one or more of the at least one com a comparison plot, a diagnostic code, a treatment code, a test parison to predict at least one clinical outcome regarding at code, a code indicative of at least one treatment received, a 60 least one second subject 940. In at least one embodiment, the code indicative of at least one prescribed treatment step, a at least one second subject has not received the at least one code indicative of at least one vaccination delivered; a code frozen particle composition or therapeutic composition 950. indicative of at least one therapeutic agent delivered; a code In at least one embodiment, the at least one second Subject is indicative of at least one diagnostic agent delivered; a code a plurality of people; and the method further comprises seg indicative of at least one interaction of a delivered agent and 65 regating Subject identifiers associated with the plurality of at least one biological or chemical agent in the Subject; a code people in reference to the predicted at least one clinical out indicative of at least one dispersion or location of at least one come 960. In at least one embodiment, the at least one second US 9,072,799 B2 49 50 subject is a plurality of people; and the method further com tion of a delivered agent, or a code indicative of the condition prises determining the eligibility of the at least one second of at least one location of an administered or delivered frozen subject for the at least one clinical trial 970. particle composition or therapeutic composition. In at least As indicated in FIGS. 10-12, at least one aspect includes a one embodiment, the at least one aspect of cellular or tissue method 1000 relating to predicting a clinical outcome of 5 abrasion or ablation includes information regarding at least administering at least one frozen particle therapeutic compo one cellular or tissue source 1110. In at leastone embodiment, sition to at least one biological tissue of at least one first the information regarding at least one tissue source includes Subject includes determining a similarity or a dissimilarity in information regarding at least one abnormal cellular or tissue information regarding at least one aspect of administering at source 1120. In at least one embodiment, the information least one therapeutic composition to the at least one biologi 10 regarding at least one cellular or tissue source includes infor cal tissue of the at least one first Subject to information regard mation regarding at least one type of cell or tissue 1130. In at ing at least one aspect of administering at least one therapeu least one embodiment, the cellular or tissue source includes at tic composition to the at least one biological tissue of the at least one cell or biological tissue described herein. least one second Subject, wherein the at least one second In at least one embodiment, the at least one frozen particle Subject attained a clinical outcome following receipt of the at 15 composition or therapeutic composition includes at least one least one frozen particle therapeutic composition; and provid of nitrogen, carbon dioxide, hydrogen oxide, helium, neon, ing output information optionally based on the determination Xenon, krypton, chlorine, bromine, oxygen, air, argon, poly 1010. ethylene glycol, acetone, ethyl acetate, dimethyl Sulfoxide, In at least one embodiment, the information regarding the dimethyl formamide, dioxane, hexamethylphosphorotria at least one aspect of administering at least one frozen particle mide, perfluorohydrocarbon, methanol, ethanol, tert-butyl therapeutic composition includes information 1020 regarding alcohol, formic acid, hydrogen fluoride, ammonia, acetic the amount of at least one frozen particle therapeutic compo acid, benzene, carbon tetrachloride, acetonitrile, hexane, sition ortherapeutic agent delivered to at least one biological methylene chloride, carboxylic acid, saline, Ringer's solu tissue of a Subject. In at least one embodiment, the informa tion, lactated Ringer's solution, Hartmann's solution, tion regarding the at least one aspect of administering at least 25 acetated Ringer's solution, phosphate buffered solution, one frozen particle therapeutic composition includes infor TRIS-buffered saline solution, Hank's balanced salt solution, mation 1030 regarding at least one dimension of biological Earle's balanced salt solution, standard saline citrate, tissue penetration. In at least one embodiment, the informa HEPES-buffered saline, dextrose, glucose, or diethyl ether tion regarding the at least one dimension of biological tissue 1140. penetration includes information 1040 regarding at least one 30 In at least one embodiment, the at least one frozen particle of depth, width, or breadth of delivery of at least one frozen composition or therapeutic composition includes at least one particle therapeutic composition to at least one biological major dimension of approximately one decimeter or less, or tissue of at least one subject; or information 1050 regarding approximately one centimeter or less, approximately one mil two or more subjects with common attributes. limeter or less, approximately one micrometer or less, In at least one embodiment, the one or more common 35 approximately one nanometer or less, or any value therebe attributes include genetic attributes, mental attributes, or psy tween 1150. chological attributes 1060. In at least on embodiment, the one In at least one embodiment, the at least one frozen particle or more common attributes include genotype attributes or composition ortherapeutic composition includes one or more phenotype attributes 1070. reinforcementagents 1160. In at least one embodiment, the at In at least one embodiment, the one or more common 40 least one frozen particle composition or therapeutic compo attributes 1080 include at least one of height; weight; medical sition includes one or more explosive materials 1170. diagnosis; familial background; results on one or more medi In at least one embodiment, the receipt by the at least one cal tests; ethnic background; body mass index; age; presence Subject of at least one frozen particle composition or thera or absence of at least one disease or condition; species; eth peutic composition is pursuant to at least one clinical trial nicity; race; allergies; gender; thickness of epidermis; thick 45 1200. In at least one embodiment, the method further com ness of dermis; thickness of stratum corneum, keratin depo prises determining at least one correlation before the admin sition; collagen deposition; blood vessel condition; skin istration or delivery of the at least one frozen particle com condition; hair or fur condition; muscle condition: tissue con position or therapeutic composition to at least one subject dition; organ condition; nerve condition; brain condition; 1210. The at least one subject includes, but is not limited to at presence or absence of at least one biological, chemical, or 50 least one subject described herein. therapeutic agent in the Subject; pregnancy status; lactation In at least one embodiment, the method includes creating at status; genetic profile; proteomic profile; partial or whole least one inclusion criterion and at least one exclusion crite genetic sequence; medical history; partial or whole proteomic rion for a clinical trial involving the at least one frozen particle sequence; lymph condition, or blood condition. composition or therapeutic composition 1220. In at least one In at least one embodiment, the output information 1100 55 embodiment, the method further comprises suggesting the includes at least one of a response signal, a comparison code, inclusion of one or more of the at least one subject in at least a comparison plot, a diagnostic code, a treatment code, a test one clinical trial 1230. In at least one embodiment, the code, a code indicative of at least one treatment received, a method further comprises suggesting the exclusion of one or code indicative of at least one prescribed treatment step, a more of the at least one subject in at least one clinical trial code indicative of at least one vaccination delivered; a code 60 1240. In certain instances, multiple subjects from multiple indicative of at least one therapeutic agent delivered; a code clinical trials are included. In at least one embodiment, the indicative of at least one diagnostic agent delivered; a code method further includes using one or more of the at least one indicative of at least one interaction of a delivered agent and comparison to predictat least one clinical outcome regarding at least one biological or chemical agent in the Subject; a code at least one second subject 1250. In at least one embodiment, indicative of at least one dispersion or location of at least one 65 the at least one second Subject has not received the at least one delivered agent; a code indicative of at least one detection frozen particle composition ortherapeutic composition 1260. material delivered; a code indicative of the depth of penetra In at least one embodiment, the method includes predicting at US 9,072,799 B2 51 52 least one clinical outcome involving the at least one second composition or therapeutic composition includes at least one Subject, and the at least one second Subject is a plurality of major dimension of approximately one decimeter or less, people; and the method further comprises segregating Subject approximately one centimeter or less, approximately one mil identifiers associated with the plurality of people in reference limeter or less, approximately one micrometer or less, to the predicted at least one clinical outcome 1270. approximately one nanometer or less, or any value therebe In at least one embodiment, the at least one second subject tween 1440. In at least one embodiment, the at least one is a plurality of people; and the method further comprises frozen particle composition or therapeutic composition determining the eligibility of the at least one second subject includes one or more reinforcement agents 1450 or one or for the at least one clinical trial 1280. more explosive materials 1460. As shown in FIGS. 13-15, at least one embodiment 10 In at least one embodiment, the receipt by the at least one includes a system 1300 including at least one computer pro Subject of at least one frozen particle composition or thera gram 1310, configured with a computer-readable medium, peutic composition is pursuant to at least one clinical trial for use with at least one computer system and wherein the 1500. In at least one embodiment, the system further com computer program includes a plurality of instructions includ prises determining at least one correlation before the delivery ing but not limited to one or more instructions 1320 for 15 or administration of the at least one frozen particle composi comparing information regarding at least one aspect of at tion or therapeutic composition to at least one subject 1510. least one therapeutic administration of at least one frozen In at least one embodiment, the method includes creating at particle composition or therapeutic composition to at least least one inclusion criterion and at least one exclusion crite one subject. In at least one embodiment, information 1330 rion for a clinical trial involving the at least one frozen particle regarding amount of the at least one frozen particle compo composition or therapeutic composition 1520. In at least one sition, therapeutic composition, or therapeutic agent admin embodiment, the instructions further comprise Suggesting the istered to at least one biological tissue of at least one subject. inclusion of one or more of the at least one subject in at least In at least one embodiment, information regarding at least one one clinical trial 1530. In certain instances, multiple subjects aspect of at least one therapeutic administration of at least one from multiple clinical trials are included. frozen particle composition or therapeutic composition 25 In at least one embodiment, the instructions include Sug includes information regarding at least one dimension of gesting the exclusion of one or more of the at least one subject biological tissue penetration 1340. In at least one embodi in at least one clinical trial 1540. ment, information regarding at least one aspect of at least one In at least one embodiment, a method includes using one or therapeutic administration of at least one frozen particle com more of the at least one comparison to predict at least one position or therapeutic composition includes information 30 clinical outcome regarding at least one second subject 1550. regarding at least one of depth, width, or breadth of adminis In at least one embodiment, the at least one second Subject has tration of at least one frozen particle composition or thera not received the at least one frozen particle composition or peutic composition to at least one biological tissue of at least therapeutic composition 1560. In at least one embodiment, one subject 1350. In at least one embodiment, information the at least one second Subject is a plurality of people; and regarding at least one aspect of at least one therapeutic admin 35 further comprising segregating Subject identifiers associated istration includes information regarding two or more Subjects with the plurality of people in reference to the predicted at with one or more common attributes 1360. In at least one least one clinical outcome 1570. embodiment, the computing device is configured to commu In at least one embodiment, the using one or more of the at nicate with at least one imaging device. In at least one least one comparison, wherein the at least one second subject embodiment, the computing device is configured to commu 40 is a plurality of people; and further comprising determining nicate with at least one printing device. In at least one embodi the eligibility of the at least one second subject for the at least ment, the computing device is configured to communicate one clinical trial 1580. with at least one input device 1370. As indicated in FIG.16, at least one embodiment relates to In at least one embodiment, the information regarding at a system 1600 including at least one computer program 1610 least one aspect of therapeutic administration of at least one 45 configured with a computer-readable medium, for use with at therapeutic composition includes information regarding at least one computer system and wherein the computer pro least one cellular or tissue source 1400; information regard gram includes a plurality of instructions including but not ing at least one abnormal cellular or tissue source 1410; or limited to one or more instructions 1620 for comparing infor information regarding at least one type of cell or tissue 1420. mation regarding at least one aspect of at least one therapeutic In at least one embodiment, at least one frozen particle com 50 administration of at least one frozen particle therapeutic com position or therapeutic composition includes at least one of position to at last one subject, and information regarding at nitrogen, carbon dioxide, hydrogen oxide, helium, neon, least one frozen particle therapeutic composition involving at Xenon, krypton, chlorine, bromine, oxygen, air or argon. In at least one biological tissue of at least one subject; and one or least one embodiment, the at least one frozen particle com more instructions for applying one or more comparisons to position or therapeutic composition includes at least one of 55 the information regarding the at least one aspect of therapeu polyethylene glycol, acetone, ethyl acetate, dimethyl sulfox tic administration of at least one frozen particle therapeutic ide, dimethyl formamide, dioxane, hexamethylphosphorot composition to a plurality of people. In at least one embodi riamide, perfluorohydrocarbon, methanol, ethanol, tert-butyl ment, the computer program includes one or more instruc alcohol, formic acid, hydrogen fluoride, ammonia, acetic tions 1630 for segregating subject identifiers associated with acid, benzene, carbon tetrachloride, acetonitrile, hexane, 60 the plurality of people in reference to at least one of the one or methylene chloride, carboxylic acid, saline, Ringer's solu more applied comparisons. In at least one embodiment, infor tion, lactated Ringer's solution, Hartmann's solution, mation regarding at least one aspect of at least one therapeutic acetated Ringer's solution, phosphate buffered solution, administration includes information 1640 regarding the TRIS-buffered saline solution, Hank's balanced salt solution, amount of at least one frozen particle composition, therapeu Earle's balanced salt solution, standard saline citrate, 65 tic composition or therapeutic agent administered to at least HEPES-buffered saline, dextrose, glucose, or diethyl ether one biological tissue of at least one subject; information 1650 1430. In at least one embodiment, at least one frozen particle regarding at least one dimension of biological tissue penetra US 9,072,799 B2 53 54 tion; information 1660 regarding at least one of depth, width, As shown in FIG. 20, at least one embodiment relates to a or breadth of administration of at least one frozen particle computer program product 2000 that includes a signal bear therapeutic composition to at least one biological tissue of at ing medium 2010 bearing at least one of one or more instruc least one subject. In at least one embodiment, the computer tions 2020 for receiving a first input associated with a first program includes one or more instructions 1670 for segregat possible dataset, the first possible dataset including data rep ing individual identifiers associated with the plurality of resentative of one or more measurements relating to one or people in reference to at least one characteristic shared by two more physical attributes of a Subject; one or more instructions or more Subjects in the plurality of people. 2030 for comparing a value associated with the first possible As shown in FIG. 17, at least one embodiment relates to a dataset with a second dataset including values representative computer program product 1700 that includes a signal bear 10 of parameters relating to one or more expected biological ing medium 1710 bearing at least one of one or more instruc changes following administration of one or more frozen par tions 1720 for receiving a first input associated with a first ticle compositions or therapeutic compositions; one or more possible dataset, the first possible dataset including data rep instructions 2040 for determining from the comparison at resentative of one or more measurements relating to one or least one biological change following administration of one more physical attributes of a first Subject; one or more instruc 15 or more frozen particle compositions or therapeutic compo tions 1730 for comparing a value associated with the first sitions to the Subject; at least one generated output optionally possible dataset with a second dataset including values rep based on the determination. resentative of predictive regimen parameters from a second In at least one embodiment, the computer program product Subject with one or more similar or dissimilar physical includes one or more instructions 2050 for accessing the first attributes; one or more instructions 1740 for determining possible dataset in response to the first input. In at least one from the comparison at least one frozen particle therapeutic embodiment, the computer program product includes one or composition regimen for the first Subject and output informa more instructions 2060 for generating the first possible tion; one or more instructions 1750 for accessing the first dataset in response to the first input. possible dataset in response to the first input; one or more In at least one embodiment, the computer program product instructions 1760 for generating the first possible dataset in 25 includes one or more instructions 2070 for determining a response to the first input; one or more instructions 1770 for graphical illustration of the first possible dataset. In at least determining a graphical illustration of the first possible one embodiment, the computer program product includes one dataset; one or more instructions 1780 for determining a or more instructions 2080 for determining a graphical illus graphical illustration of the second possible dataset; and at tration of the second possible dataset. In at least one embodi least one generated output optionally based on the determi 30 ment, the signal bearing medium includes a computer-read nation. able medium 2090. In at least one embodiment, the signal In at least one embodiment, the computer program product bearing medium includes a recordable medium 2092. In at includes a signal bearing medium that includes a computer least one embodiment, the signal bearing medium includes a readable medium 1790. In at least one embodiment, the signal communications medium 2094. bearing medium of the computer program product includes a 35 As indicated in FIG. 21, at least one embodiment a com recordable medium 1792. In at least one embodiment, the puter program product 2100 includes a signal bearing computer program product includes a signal bearing medium medium 2110 bearing at least one of one or more instructions that includes a communications medium 1794. 2120 for processing a first input associated with a first pos As indicated in FIG. 18, at least one embodiment relates to sible dataset, the first possible dataset including data repre a computer program product 1800 that includes a signal bear 40 sentative of one or more measurements relating to one or ing medium 1810 bearing at least one of one or more instruc more physical attributes of a Subject; one or more instructions tions 1820 for processing a first possible dataset, the first 2130 for comparing a value associated with the first possible possible dataset including data representative of one or more dataset with a second dataset including values representative measurements relating to one or more physical attributes of a of parameters relating to one or more expected biological first subject; one or more instructions 1830 for comparing a 45 changes following administration of one or more frozen par value associated with the first possible dataset with a second ticle compositions or therapeutic compositions; one or more dataset including values representative of predictive regimen instructions 2140 for determining from the comparison at parameters from a second subject with one or more similar or least one biological change following administration of one dissimilar physical attributes; one or more instructions 1840 or more frozen particle compositions or therapeutic compo for determining from the comparison at least one frozen par 50 sitions to the Subject; at least one generated output optionally ticle composition or therapeutic composition treatment regi based on the determination. men for the first Subject, and output information. As shown in FIG. 22, at least one embodiment relates to a As indicated in FIG. 19, at least one embodiment relates to computer program product 2200 includes a signal bearing a computer program product 1900 that includes a signal bear medium 2210 bearing at least one of one or more instructions ing medium 1910 bearing at least one of one or more instruc 55 2220 responsive to a first possible dataset, the first possible tions 1920 responsive to a first possible dataset, the first dataset including data representative of one or more measure possible dataset including data representative of one or more ments relating to one or more physical attributes of a Subject; measurements relating to one or more physical attributes of a one or more instructions 2230 for comparing a value associ first subject; one or more instructions 1930 for comparing a ated with the first possible dataset with a second dataset value associated with the first possible dataset with a second 60 including values representative of parameters relating to one dataset including values representative of predictive regimen or more expected biological changes following administra parameters for a second Subject with one or more similar or tion of one or more frozen particle compositions or therapeu dissimilar physical attributes; one or more instructions 1940 tic compositions; one or more instructions 2240 for determin for determining from the comparison at least one frozen par ing from the comparison at least one biological change ticle composition or therapeutic composition treatment regi 65 following administration of one or more frozen particle com men for the first Subject; and output information optionally positions or therapeutic compositions to the Subject; and out based on the determination. put information optionally based on the determination. US 9,072,799 B2 55 56 As indicated in FIGS. 23-25, at least one embodiment, a at least one tissue source includes information regarding at method 2300 includes comparing 2310 information regard least one abnormal cellular or tissue source 2430. In at least ing at least one aspect of cellular or tissue abrasion orablation one embodiment, the information regarding at least one cel of at least one biological tissue of at least one subject and lular or tissue source includes information regarding at least information regarding at least one clinical outcome following one type of cellor tissue 2440. In at least one embodiment, the receipt by the at least one subject of at least one frozen particle cellular or tissue source includes at least one cell or biological composition or therapeutic composition; and providing out tissue described herein. put information optionally based on the determination. In at In at least one embodiment, the at least one frozen particle least one embodiment, the method includes determining at composition or therapeutic composition includes at least one least one statistical correlation 2320. In at least one embodi 10 of nitrogen, carbon dioxide, hydrogen oxide, helium, neon, ment, the method includes counting the occurrence of at least Xenon, krypton, chlorine, bromine, oxygen, air, argon, poly one clinical outcome 2330. In at least one embodiment, the ethylene glycol, acetone, ethyl acetate, dimethyl Sulfoxide, information regarding at least one aspect of cellular or tissue dimethyl formamide, dioxane, hexamethylphosphorotria abrasion or ablation includes information regarding quantity mide, perfluorohydrocarbon, methanol, ethanol, tert-butyl of cells or tissue removed or destroyed 2340. In at least one 15 alcohol, formic acid, hydrogen fluoride, ammonia, acetic embodiment, the information regarding at least one aspect of acid, benzene, carbon tetrachloride, acetonitrile, hexane, cellular or tissue abrasion or ablation includes information methylene chloride, carboxylic acid, saline, Ringer's solu regarding at least one dimension of cellular or tissue removal tion, lactated Ringer's solution, Hartmann's solution, or destruction, or removal or destruction of other materials, acetated Ringer's solution, phosphate buffered solution, Such as plaque, extracellular matrix, collagen, elastin, pro TRIS-buffered saline solution, Hank's balanced salt solution, tein, or other materials 2350. In at least one embodiment, Earle's balanced salt solution, standard saline citrate, information regarding the at least one dimension of cellular HEPES-buffered saline, dextrose, glucose, or diethyl ether removal ordestruction includes information regarding at least 245O. one of depth, width, or breadth of cellular removal or destruc In at least one embodiment, the at least one frozen particle tion 2360. 25 composition includes at least one major dimension of In at least one embodiment, the information regarding at approximately one decimeter or less, or approximately one least one aspect of cellular or tissue abrasion or ablation centimeter or less, approximately one millimeter or less, includes information regarding two or more Subjects with one approximately one micrometer or less, approximately one or more common attributes 2370. In at least one embodiment, nanometer or less, or any value therebetween 2460. the one or more common attributes include genetic attributes, 30 In at least one embodiment, the at least one frozen particle mental attributes, or psychological attributes 2380. In at least composition includes one or more reinforcement agents on embodiment, the one or more common attributes include 2470. In at least one embodiment, the at least one frozen genotype attributes or phenotype attributes 2390. particle composition includes one or more explosive materi In at least one embodiment, the one or more common als 2480. In at least one embodiment, the receipt by the at least attributes 2397 include at least one of height; weight; medical 35 one subject of at least one frozen particle composition is diagnosis; familial background; results on one or more medi pursuant to at least one clinical trial 2500. In at least one cal tests; ethnic background; body mass index; age; presence embodiment, the method further comprises determining at or absence of at least one disease or condition; species; eth least one correlation 2510 before the delivery or administra nicity; race; allergies; gender; thickness of epidermis; thick tion of the at least one frozen particle composition to at least ness of dermis; thickness of stratum corneum, keratin depo 40 one subject. The at least one subject includes, but is not sition; collagen deposition; blood vessel condition; skin limited to at least one subject described herein. condition; hair or fur condition; muscle condition: tissue con In at least one embodiment, the method includes creating at dition; organ condition; nerve condition; brain condition; least one inclusion criterion and at least one exclusion crite presence or absence of at least one biological, chemical, or rion for a clinical trial involving the at least one frozen particle therapeutic agent in the Subject; pregnancy status; lactation 45 composition or therapeutic composition 2515. In at least one status; genetic profile; proteomic profile; partial or whole embodiment, the method further comprises suggesting the genetic sequence; medical history; partial or whole proteomic inclusion of one or more of the at least one subject in at least sequence; lymph condition, or blood condition. one clinical trial 2520. In at least one embodiment, the In at least one embodiment, the output information 2410 method further comprises suggesting the exclusion of one or includes at least one of a response signal, a comparison code, 50 more of the at least one subject in at least one clinical trial a comparison plot, a diagnostic code, a treatment code, a test 2530. In certain instances, multiple subjects from multiple code, a code indicative of at least one treatment received, a clinical trials are included. In at least one embodiment, the code indicative of at least one prescribed treatment step, a method further includes using one or more of the at least one code indicative of at least one vaccination delivered; a code correlation to predict at least one clinical outcome regarding indicative of at least one therapeutic agent delivered; a code 55 at least one second subject 2540. In at least one embodiment, indicative of at least one diagnostic agent delivered; a code the at least one second Subject has not received the at least one indicative of at least one interaction of a delivered agent and frozen particle composition ortherapeutic composition 2550. at least one biological or chemical agent in the Subject; a code In at least one embodiment, the method further comprises indicative of at least one dispersion or location of at least one predicting at least one clinical outcome involving the at least delivered agent; a code indicative of at least one detection 60 one second Subject, wherein the at least one second Subject is material delivered; a code indicative of the depth of penetra a plurality of people; and segregating Subject identifiers asso tion of a delivered agent, or a code indicative of the condition ciated with the plurality of people in reference to the predicted of at least one location of a delivered or administered frozen at least one clinical outcome 2560. In at least one embodi particle composition. In at least one embodiment, the at least ment, the at least one second Subject is a plurality of people; one aspect of cellular or tissue abrasion or ablation includes 65 and the method further comprises determining the eligibility information regarding at least one cellular or tissue source of the at least one second subject for the at least one clinical 2420. In at least one embodiment, the information regarding trial 25.70. US 9,072,799 B2 57 58 As indicated in FIGS. 26-28, at least one embodiment includes information regarding at least one cellular or tissue relates to a method 2600 of predicting a clinical outcome of at source 2710. In at least one embodiment, the cellular or tissue least one frozen particle composition treatment for at least Source includes but is not limited to at least one biological one first subject includes determining 2610 a similarity or a tissue or cell described herein. In at leastone embodiment, the dissimilarity in information regarding at least one aspect of 5 information regarding at least one tissue source includes cellular or tissue abrasion orablation of at least one biological information regarding at least one abnormal cellular or tissue tissue of at least one first Subject to information regarding at source 2720. In at least one embodiment, the information least one aspect of cellular or tissue abrasion or ablation of at regarding at least one cellular or tissue source includes infor least one biological tissue of at least one second subject, mation regarding at least one type of cell or tissue 2730. In at wherein the at least one second Subject attained a clinical 10 outcome following receipt of the at least one frozen particle least one embodiment, the information regarding at least one composition or therapeutic composition; and providing out aspect of cellular or tissue abrasion orablation includes infor put information optionally based on the determination. mation regarding at least one type of cell or tissue. In at least one embodiment, the information regarding at In at least one embodiment, the at least one frozen particle least one aspect of cellular or tissue abrasion or ablation 15 composition or therapeutic composition includes at least one includes information regarding the quantity of cells or tissue of nitrogen, carbon dioxide, hydrogen oxide, helium, neon, removed or destroyed 2620. In at least one embodiment, the Xenon, krypton, chlorine, bromine, oxygen, air or argon. In at information regarding at least one aspect of cellular or tissue least one embodiment, the at least one frozen particle com abrasion or ablation includes information regarding at least position or therapeutic composition includes at least one of one dimension of cellular, tissue, or other material removal or polyethylene glycol, acetone, ethyl acetate, dimethyl sulfox destruction 2630. In at least one embodiment, the at least one ide, dimethyl formamide, dioxane, hexamethylphosphorot dimension of cellular removal or destruction includes infor riamide, perfluorohydrocarbon, methanol, ethanol, tert-butyl mation regarding at least one of depth, width, or breadth of alcohol, formic acid, hydrogen fluoride, ammonia, acetic cellular removal or destruction 2640. In at least one embodi acid, benzene, carbon tetrachloride, acetonitrile, hexane, ment, the information regarding at least one aspect of cellular 25 methylene chloride, carboxylic acid, saline, Ringer's solu or tissue abrasion or ablation includes information regarding tion, lactated Ringer's solution, Hartmann's solution, two or more Subjects with one or more common attributes acetated Ringer's solution, phosphate buffered solution, 26SO. TRIS-buffered saline solution, Hank's balanced salt solution, In at least one embodiment, the one or more common Earle's balanced salt solution, standard saline citrate, attributes include but are not limited to genetic attributes, 30 HEPES-buffered saline, dextrose, glucose, or diethyl ether mental attributes, or psychological attributes 2660. In at least 2740. one embodiment, the one or more common attributes include In at least one embodiment, the at least one frozen particle genotype attributes or phenotype attributes 2670. composition or therapeutic composition includes at least one In at least one embodiment, the one or more common major dimension of approximately one decimeter or less, or attributes include at least one of height; weight; medical 35 approximately one centimeter or less, or approximately one diagnosis; familial background; results on one or more medi millimeter or less, or approximately one micrometer or less, cal tests; ethnic background; body mass index; age; presence or approximately one nanometer or less, or any value ther or absence of at least one disease or condition; species; eth ebetween 2750. nicity; race; allergies; gender; thickness of epidermis; thick In at least one embodiment, the at least one frozen particle ness of dermis; thickness of stratum corneum, keratin depo 40 composition ortherapeutic composition includes one or more sition; collagen deposition; blood vessel condition; skin reinforcementagents 2760. In at least one embodiment, the at condition; hair or fur condition; muscle condition: tissue con least one frozen particle composition or therapeutic compo dition; organ condition; nerve condition; brain condition; sition includes one or more explosive materials 2770. presence or absence of at least one biological, chemical, or In at least one embodiment, the receipt by the at least one therapeutic agent in the Subject; pregnancy status; lactation 45 Subject of at least one frozen particle composition or thera status; medical history; genetic profile; proteomic profile; peutic composition is pursuant to at least one clinical trial partial or whole genetic sequence; partial or whole proteomic 2800. In at least one embodiment, the method includes cre sequence; lymph condition, medical history, or blood condi ating at least one inclusion criterion and at least one exclusion tion 2680. criterion for a clinical trial involving the at least one frozen In at least one embodiment, the output information 50 particle composition or therapeutic composition 2810. In at includes at least one of a response signal, a comparison code, least one embodiment, the method further comprises Suggest a comparison plot, a diagnostic code, a treatment code, a test ing the inclusion of one or more of the at least one subject in code, a code indicative of at least one treatment received, a at least one clinical trial 2820. In certain instances, multiple code indicative of at least one prescribed treatment step, a subjects from multiple clinical trials are included. In at least code indicative of at least one vaccination delivered; a code 55 one embodiment, the method includes suggesting the exclu indicative of at least one therapeutic agent delivered; a code sion of one or more of the at least one Subject in at least one indicative of at least one diagnostic agent delivered; a code clinical trial 2830. indicative of at least one interaction of a delivered agent and In at least one embodiment, a method includes using one or at least one biological or chemical agent in the Subject; a code more of the at least one determination to predict at least one indicative of at least one dispersion or location of at least one 60 clinical outcome regarding at least one second Subject 2840. delivered agent; a code indicative of at least one detection In at least one embodiment, the at least one second Subject has material delivered; a code indicative of the depth of penetra not received the at least one frozen particle composition or tion of a delivered agent, or a code indicative of the condition therapeutic composition 2850. In at least one embodiment, of at least one location of a delivered or administered frozen the at least one second subject is a plurality of people; and the particle composition 2700. 65 method further comprises segregating Subject identifiers In at least one embodiment, the information regarding at associated with the plurality of people in reference to the least one aspect of cellular or tissue abrasion or ablation predicted at least one clinical outcome 2860. US 9,072,799 B2 59 60 In at least one embodiment, the using one or more of the at particle composition selecting apparatus, a frozen particle least one comparison, wherein the at least one second subject composition generating apparatus, or both 3030. is a plurality of people; and the method further comprises As shown in FIGS. 31-32, at least one aspect relates to a determining the eligibility of the at least one second subject system 3100 including circuitry 3110 for receiving a first for the at least one clinical trial 2870. input associated with a first possible dataset, the first possible As indicated in FIGS. 29-30, at least one aspect relates to a dataset including data representative of one or more measure system 2900 that includes at least one computing device ments relating to one or more physical attributes of a first 2910; one or more instructions 2920 that when executed on subject; circuitry 3120 for comparing a value associated with the at least one computing device cause the at least one the first possible dataset with a second dataset including val computing device to receive a first input associated with a first 10 ues representative of predictive regimen parameters related to possible dataset, the first possible dataset including data rep a second Subject with one or more similar or dissimilar physi resentative of one or more measurements relating to one or cal attributes; circuitry 3125 for determining from the com more physical attributes of a first Subject; one or more instruc parison at least one frozen particle composition treatment tions 2930 that when executed on the at least one computing 15 regimen for the first subject; circuitry 3128 for selecting at device cause the at least one computing device to compare a least one of quality or quantity related to one or more frozen value associated with the first possible dataset with a second particle compositions, method of administration of one or dataset including values representative of predictive regimen more frozen particle compositions, administration location of parameters related to a second Subject with one or more one or more frozen particle compositions, content of one or similar or dissimilar physical attributes; one or more instruc more frozen particle compositions, timing of administration tions 2940 that when executed on the at least one computing of one or more frozen particle compositions, decrease in device cause the at least one computing device to determine physical dimension of one or more frozen particle composi from the comparison at least one frozen particle composition tions or time interval between at least two deliveries with one treatment regimen for the first Subject; and at least one gen or more frozen particle compositions. erated output optionally based on the determination; one or 25 In at least one embodiment, the system includes circuitry more instructions 2950 that when executed on the at least one 3130 for determining from the comparison at least one frozen computing device cause the at least one computing device to particle composition treatment regimen for the first Subject; access the first possible dataset in response to the first input; and circuitry 3140 for providing output information option one or more instructions 2960 that when executed on the at ally based on the comparison. In at least one embodiment, the least one computing device cause the at least one computing 30 circuitry for receiving a first input associated with a first device to generate the first possible dataset in response to the possible dataset includes circuitry 3200 for receiving one or first input; one or more instructions 2970 that when executed more measurements relating to one or more physical on the at least one computing device cause the at least one attributes including at least one of height; weight, body mass computing device to determine a graphical illustration of the index; age; presence or absence of at least one disease or possible dataset; or one or more instructions 3000 that when 35 condition; species; ethnicity; race; allergies; gender; thick executed on the at least one computing device cause the at ness of epidermis; thickness of dermis; thickness of stratum least one computing device to determine a graphical illustra corneum; keratin deposition; collagen deposition; blood ves tion of the second possible dataset. In at least one embodi sel condition; skin condition; hair or fur condition; muscle ment, the treatment regimen includes at least one of cellular or condition, tissue condition; organ condition; nerve condition; tissue removal, cellular or tissue ablation, debridement, deliv 40 brain condition; presence or absence of at least one biologi ery of at least one therapeutic agent, cleaning one or more cal, chemical, or therapeutic agent in the Subject; pregnancy wounds, removing material from at least one biological tis status; lactation status; genetic profile; medical history; pro sue, or removing material from at least one blood vessel3005. teomic profile; partial or whole genetic sequence; partial or In at least one nitrogen, carbon dioxide, hydrogen oxide, whole proteomic sequence; medical history; lymph condi helium, neon, Xenon, krypton, chlorine, bromine, oxygen, air, 45 tion, or blood condition. argon, polyethylene glycol, acetone, ethyl acetate, dimethyl In at least one embodiment, the system includes circuitry Sulfoxide, dimethyl formamide, dioxane, hexamethylphos 3210 for selecting the combination of at least two parameters phorotriamide, perfluorohydrocarbon, methanol, ethanol, selected from quality or quantity related to one or more frozen tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia, particle compositions, method of administration of one or acetic acid, benzene, carbon tetrachloride, acetonitrile, hex 50 more frozen particle compositions, administration location of ane, methylene chloride, carboxylic acid, Saline, Ringer's one or more frozen particle compositions, content of one or Solution, lactated Ringer's solution, Hartmann's solution, more frozen particle compositions, timing of administration acetated Ringer's solution, phosphate buffered solution, of one or more frozen particle compositions, decrease in a TRIS-buffered saline solution, Hank's balanced salt solution, physical dimension of one or more frozen particle composi Earle's balanced salt solution, standard saline citrate, 55 tions, or time interval between at least two administrations or HEPES-buffered saline, dextrose, glucose, or diethyl ether deliveries with one or more frozen particle compositions. 3008. In at least one embodiment, the system includes circuitry In at least one embodiment, the at least one computing 3220 for selecting the combination of at least two parameters device includes one or more desktop computer, workstation selected from quality or quantity related to one or more frozen computer, computing system including a cluster of proces 60 particle compositions, method of administration of one or sors, a networked computer, a tablet personal computer, a more frozen particle compositions, administration location of laptop computer, a mobile device, a mobile telephone, or a one or more frozen particle compositions, content of one or personal digital assistant computer 3010. In at least one more frozen particle compositions, timing of administration embodiment, the at least one computing device is configured of one or more frozen particle compositions, decrease in a to communicate with a database to access the first possible 65 physical dimension of one or more frozen particle composi dataset 3020. In at least one embodiment, the at least one tions, or time interval between at least two administrations computing device is configured to communicate with a frozen with one or more frozen particle compositions. US 9,072,799 B2 61 62 In at least one embodiment, the system includes circuitry prises one or more instructions for determining at least one 3230 for selecting at least one of a clinical outcome; second comparison before the delivery or administration of the at ary effects related to the treatment; disease stage; longevity; least one frozen particle composition or therapeutic compo or vaccination administration. In at least one embodiment, the sition to at least one subject 3510. clinical outcome 3240 includes a positive clinical outcome or 5 In at least one embodiment, the system includes one or a negative clinical outcome. In at least one embodiment, the more instructions for creating at least one inclusion criterion clinical outcome includes one or more adverse effect, failure and at least one exclusion criterion for a clinical trial involv to attain a clinical endpoint of a clinical trial, failing to attain ing the at least one frozen particle composition or therapeutic a beneficial effect, or measurement of at least one biochemi composition 3520. In at least one embodiment, the system cal, biological or physiological parameter 3250. 10 further comprises one or more instructions for Suggesting the FIGS. 33-35 illustrate a partial view of a system 3300 inclusion of one or more of the at least one subject in at least including at least one computer program 3310 configured one clinical trial 3530. In certain instances, multiple subjects with a computer-readable medium, for use with at least one from multiple clinical trials are included. computer system and wherein the computer program includes In at least one embodiment, the system further includes one a plurality of instructions including but not limited to one or 15 or more instructions for Suggesting the exclusion of one or more instructions 3320 for determining at least one compari more of the at least one subject in at least one clinical trial son between information regarding at least one aspect of 3540. In at least one embodiment, the system includes one or cellular or tissue abrasion orablation of at least one biological more instructions for using one or more of the at least one tissue of at least one Subject and information regarding at least comparison to predictat least one clinical outcome regarding one clinical outcome following receipt by the at least one at least one second subject 3550. In at least one embodiment, Subject of at least one frozen particle composition. In at least the at least one second Subject has not received the at least one one embodiment, the system includes one or more instruc frozen particle composition ortherapeutic composition 3560. tions 3330 for determining at least one statistical correlation. In at least one embodiment, the system includes predicting at In at least one embodiment, the system includes one or more least one clinical outcome involving the at least one second instructions 3340 for counting the occurrence of at least one 25 Subject, wherein the at least one second Subject is a plurality clinical outcome. In at least one embodiment, information of people; and segregating Subject identifiers associated with regarding at least one aspect of cellular or tissue abrasion or the plurality of people in reference to the predicted at least one ablation includes information 3350 regarding quantity of clinical outcome 3570. In at least one embodiment, theat least cells or tissue removed or destroyed; information 3360 one second Subject is a plurality of people; and the system regarding at least one dimension of cellular, tissue or other 30 further comprises determining the eligibility of the at least material removal or destruction; information 3370 regarding one second subject for the at least one clinical trial 3580. at least one of depth, width, or breadth of cellular removal or As indicated in FIG. 36, at least one aspect relates to a destruction; or information 3380 regarding two or more sub system 3600 that includes at least one computer program jects with one or more common attributes. In at least one 3610, configured with a computer-readable medium, for use embodiment, the information regarding at least one aspect of 35 with at least one computer system and wherein the computer cellular or tissue abrasion or ablation includes information program includes a plurality of instructions including but not 3400 regarding at least one cellular or tissue source, including limited to one or more instructions 3620 for comparing infor information 3410 regarding at least one abnormal cellular or mation regarding at least one aspect of cellular or tissue tissue source or information 3420 regarding at least one type abrasion or ablation of at least one biological tissue of at least of cell or tissue. 40 one Subject and information regarding at least one frozen In at least one embodiment, the at least one frozen particle particle composition involving the at least one biological composition or therapeutic composition includes at least one tissue of at least one Subject; and one or more instructions of polyethylene glycol, acetone, ethyl acetate, dimethyl Sul 3630 for applying one or more comparisons to information foxide, dimethyl formamide, dioxane, hexamethylphospho regarding at least one aspect of cellular or tissue abrasion or rotriamide, perfluorohydrocarbon, methanol, ethanol, tert 45 ablation regarding a plurality of people. In at least one butyl alcohol, formic acid, hydrogen fluoride, ammonia, embodiment, one or more instructions 3640 for segregating acetic acid, benzene, carbon tetrachloride, acetonitrile, hex subject identifiers associated with the plurality of people in ane, methylene chloride, carboxylic acid, Saline, Ringer's reference to at least one of the one or more applied compari Solution, lactated Ringer's solution, Hartmann's solution, sons. In at least one embodiment, the information regarding at acetated Ringer's solution, phosphate buffered solution, 50 least one aspect of cellular or tissue abrasion or ablation TRIS-buffered saline solution, Hank's balanced salt solution, includes information 3650 regarding quantity of cells or tis Earle's balanced salt solution, standard saline citrate, Sue removed or destroyed; information 3660 regarding at HEPES-buffered saline, dextrose, glucose, or diethyl ether least one dimension of cellular, tissue or other material 3430. In at least one embodiment, at least one frozen particle removal or destruction; or information 3670 regarding at least composition includes at least one major dimension of 55 one of depth, width, or breadth of cellular removal or destruc approximately one decimeter or less, approximately one cen tion. In at least one embodiment, the system includes one or timeter or less, approximately one millimeter or less, approxi more instructions 3680 for segregating individual identifiers mately one micrometer or less, approximately one nanometer associated with the plurality of people in reference to at least or less, or any value therebetween 3440. In at least one one characteristic shared by two or more subjects of the embodiment, the at least one frozen particle composition 60 plurality of people. includes one or more reinforcement agents 3450. In at least The foregoing detailed description has set forth various one embodiment, the at least one frozen particle composition embodiments of the devices and/or processes via the use of includes one or more explosive materials 3460. block diagrams, flowcharts, and/or examples. Insofar as Such In at least one embodiment, the receipt by the at least one block diagrams, flowcharts, and/or examples contain one or Subject of at least one frozen particle composition or thera 65 more functions and/or operations, it will be understood by peutic composition is pursuant to at least one clinical trial those within the art that each function and/or operation within 3500. In at least one embodiment, the system further com Such block diagrams, flowcharts, or examples can be imple US 9,072,799 B2 63 64 mented, individually and/or collectively, by a wide range of approximately 80% frozen ice Ic and approximately 20% hardware, Software, firmware, or virtually any combination frozen ice Ih. Following the procedures of Murray et al. thereof. In one embodiment, several portions of the subject selective production of ice Ic in pellet form produces quanti matter described herein may be implemented via Application ties suitable for use in various embodiments described herein. Specific Integrated Circuits (ASICs), Field Programmable Frozen particles generated in this manner are utilized for Gate Arrays (FPGAs), digital signal processors (DSPs), or abrasion of at least one biological tissue, including but not other integrated formats. However, those skilled in the art will limited to skin. The frozen particle composition is adminis recognize that some aspects of the embodiments disclosed tered to at least one biological tissue by, for example, accel herein, in whole or in part, can be equivalently implemented erating, ejecting, or propelling the frozen particles by way of in integrated circuits, as one or more computer programs 10 a carrier gas under pressure (e.g., air, carbon dioxide, nitro running on one or more computers (e.g., as one or more gen) through a tube, or other device directed toward at least programs running on one or more computer systems), as one one biological tissue, such as skin. Microdermabrasion, or more programs running on one or more processors (e.g., as microscissuining, or other Surface abrasion techniques are one or more programs running on one or more microproces carried out in a similar fashion. sors), as firmware, or as virtually any combination thereof, 15 and that designing the circuitry and/or writing the code for the software and or firmware would be well within the skill of one Example 2 of skill in the art in light of this disclosure. In addition, those skilled in the art will appreciate that the mechanisms of the Compositions and Methods of Making Frozen subject matter described herein are capable of being distrib Particles uted as a program product in a variety of forms, and that an illustrative embodiment of the subject matter described Frozen particles, including frozen hydrogen oxide ice Ic, herein applies regardless of the particular type of signal bear are produced by depositing hydrogen oxide vapor onto a ing medium used to actually carry out the distribution. copper plate held at low temperatures in vacuo. Purified Examples of a signal bearing medium include, but are not 25 (deionized) hydrogen oxide is added to a vessel at approxi limited to, the following: a recordable type medium Such as a mately 25° C. and the hydrogen oxide vapor is condensed floppy disk, a hard disk drive, a Compact Disc (CD), a Digital onto a metal plate held at approximately -196°C. in vacuo. Video Disk (DVD), a digital tape, a computer memory, etc.; The deposited amorphous ice is heated (at 10° C./min) to and a transmission type medium Such as a digital and/or an approximately -93°C. and is converted to crystalline cubic analog communication medium (e.g., a fiber optic cable, a 30 ice (ice Ic). Ice Ic is stable when stored under liquid nitrogen waveguide, a wired communications link, a wireless commu (See e.g., Johari, et al., J. Phys. Chem, Vol. 94, pp. 1212-1214 nication link (e.g., transmitter, receiver, transmission logic, (1990), which is incorporated herein by reference). An reception logic, etc.), etc.). example of an apparatus that is used to produce frozen hydro For any of the various aspects and embodiments disclosed gen oxide ice Ic is described in Hallbrucker et al (J. Phys. herein, one or more kits may be developed with the compo 35 Chem., vol. 93, pp. 4986-4990 (1989), which is incorporated nents described herein. In at least one embodiment, a kit herein by reference). includes one or more frozen particles as described herein. In at least one embodiment, a kit includes one or more frozen Example 3 particles and at least one therapeutic agent as disclosed herein. In at least one embodiment, a kit includes one or more 40 Compositions and Methods of Making Frozen frozen particles and one or more reinforcement agents. In at Particles least one embodiment, a kit includes one or more frozen particles and one or more explosive materials. Frozen hydrogen oxide ice Ic particles are produced from small hydrogen oxide droplets in an example of a “pelletizer” EXAMPLES 45 apparatus similar to those described by, for example, U.S. Pat. No. 4,617,064; U.S. Pat. No. 6,306,119, which are incorpo Example 1 rated herein by reference. Frozen hydrogen oxide ice Ic par ticles are formed by spraying hydrogen oxide droplets of the Compositions and Methods of Making Frozen desired size into a cooling chamber filled with a cold inert gas Particles 50 maintained at the desired temperature, for example, nitrogen gas maintained at approximately -100° C. to promote forma Frozen particles suitable for various embodiments tion of ice Ic. Spray droplet size is maintained by variation of described herein may be produced by controlling the pressure nozzle/orifice size and hydrogen oxide pressure to yield drop and temperature of hydrogen oxide that is introduced as a let diameters ranging from nanometers to centimeters. Frozen liquid, gas or frozen. Frozen particles, including frozen 55 hydrogen oxide ice Ic, ice Ih, amorphous low density ice, hydrogen oxide ice Ic, are produced by cooling Small hydro amorphous high density ice, and otherforms are produced by gen oxide droplets (-6 um diameter) below -38°C. (See e.g., controlling the temperature and pressure of the cooling cham Murray, et al., Phys. Chem. Chem. Phys. Vol. 8, pp. 186-192 ber. Cubic hydrogen oxide ice Ic particles are formed in a (2006), which is incorporated herein by reference). Emul step-wise process, by maintaining the chamber at a very low sions of 30-40% by weight of distilled and de-ionized hydro 60 temperature (approximately -196° C.) with increased pres gen oxide in paraffin oil (Fisher Scientific) are agitated to Sure, which first promotes formation of amorphous hydrogen produce hydrogen oxide droplets of mean diameters ranging oxide ice. Next, the chamber is heated to approximately -93° from 5 to 35 um as determined by optical microscopy. The C., which results in transformation to cubic hydrogen oxide droplets are cooled to -100° C. at a rate of 10° C./min by ice (ice Ic) particles. using a cryostat cooled with liquid nitrogen and containing a 65 The hydrogen oxide ice particles are propelled into a deliv heater and temperature controller. Freezing liquid droplets ery system (Such as tubing and nozzle) by nitrogen gas under with a median diameter of 5.6 um or smaller can provide pressure. The delivery system is maintained at the appropriate US 9,072,799 B2 65 66 temperature for preservation of the hydrogen oxide particle the number of dark pixels in the dropletimage to the pixel area structure, (e.g., approximately -93°C. for ice Ic structure). of a calibration circle. Droplet diameters between approxi mately 100 um (+3.2%) and approximately 2000 um Example 4 (+0.03%) were measured with 95% confidence (See e.g., Ireland et al., 6th ASME-JSME Thermal Engineering Joint Compositions and Methods of Making Frozen Conference (2003), which is incorporated herein by refer Carbon Dioxide Particles ence). Instruments, computer programs and protocols for measuring particle and droplet size are available, for Carbon dioxide frozen particles are produced from small example, from Oxford Lasers, Shirley, Mass. (e.g., world carbon dioxide droplets in a “pelletizer similar to those 10 wide web at Oxfordlasers.com, which is incorporated herein described by, for example, U.S. Pat. No. 4,617,064; and U.S. by reference). Pat. No. 6,306,119; each of which is incorporated herein by reference. Carbon dioxide frozen particles are formed by Example 7 spraying liquid carbon dioxide droplets into a cooling cham ber maintained at low temperatures (e.g., approximately 15 Methods of Assessment or Selection of Frozen -100° C.). Droplet size is regulated by varying nozzle or Particles orifice size, and pressure. Carbon dioxide droplet diameters range, for example, from nanometers to centimeters. The According to various embodiments described herein, at frozen carbon dioxide particles are propelled into a delivery least one frozen particle is made by lowering the temperature System (e.g., tubing and noZZle) by carrier gas, (e.g., air or of liquid droplets of a selected material. Droplet and particle nitrogen) under pressure. The carbon dioxide particles are sizes are measured by laser diffraction. Laser diffraction maintained while in the delivery system at the appropriate based particle size analysis relies on particles passing through temperature, (e.g., approximately -100° C.). Frozen carbon a laser beam and scattering light at an angle that is directly dioxide particles Sublimate, or transition to a gas phase, at related to their size. As particle size decreases, the observed approximately -78.5° C. and 1 atm pressure. 25 scattering angle increases logarithmically. Scattering inten sity is also dependent on particle size, and decreases with Example 5 decreasing particle Volume. Thus, large particles scatter light at narrow angles with high intensity whereas Small particles Compositions and Methods of Making Frozen scatter at wider angles but with low intensity. Laser diffrac DMSO Particles 30 tion is used for the non-destructive analysis of wet or dry samples, to measure particles in the size range 0.02 to 2000 Dimethylsulfoxide (DMSO) frozen particles are produced micrometers (e.g., world wide web at chemie.de/articles/e/ from DMSO droplets, for example, in a “pelletizer apparatus 61205/, which is incorporated herein by reference). A laser similar to those described by, for example, U.S. Pat. No. diffraction instrument, protocols and analysis Software are 4,617,064; U.S. Pat. No. 6,306,119, which are incorporated 35 available, for example, from Malvern Instruments Ltd. (Mal herein by reference. DMSO frozen particles are formed from vern, Worcestershire, WR141XZ United Kingdom). spraying liquid DMSO droplets of the desired size into a cooling chamber that is maintained at low temperature, for Example 8 example, less than approximately 18.5° C. Droplet size is regulated by varying nozzle or orifice size, and pressure, with 40 Compositions and Methods of Making Frozen compressed air as a carrier gas. Droplet size can be regulated Particles Including a Reinforcement Agent by varying nozzle or orifice size, and DMSO pressure. DMSO droplet diameters range, for example, from nanometers to One or more reinforcement agents are added to the frozen centimeters. The DMSO frozen particles are propelled by a particles during the formation process. Among other things, carrier gas (e.g., air or nitrogen) under pressure to enter a 45 reinforcement agents can increase the strength of frozen par delivery system (e.g., tubing and nozzle). In order to preserve ticles (e.g., increase the modulus of rupture of ice) and DMSO particle structure, the delivery system is maintained at decrease the deformation of frozen particles (e.g., decrease low temperature (e.g., less than approximately 18.5° C.). the beam deflection of ice). As indicated in Table A below, glass fibers present at 9% (wt./vol.), for example, increase the Example 6 50 modulus of rupture of ice by approximately 7-fold relative to ice derived from unreinforced hydrogen oxide ice (See e.g., Methods of Assessment or Selection of Frozen Kingery, Science, vol. 134, pp. 164-168 (1960), which is Particles incorporated herein by reference).

According to various embodiments described herein, at 55 TABLE A least one frozen particle is made by lowering the temperature of liquid droplets of a selected material. Droplet and particle Strength of fresh ice with sawdust and Fiberglass, respectively, added. sizes are measured by imaging a spray or particle stream upon Additions were 96 wt.?vol. (Kingery, Ibid). a background screen. The background screen is illuminated Modulus of rupture (kg/cm with a short pulse of light, for example, from an infrared laser 60 beam (at approximately 805 nm), which is capable of pulsing Addition (%) Sawdust (-17 C.) Fiberglass (-20°C.) at frequencies of approximately 1000 Hz. O 22.5 24.1 A digital camera captures high resolution images of the O.8 22.7 24.0 2.5 35 65.4 droplets or particles. High-speed, real-time particle sizing 9.0 60 161 Software analyses the images to assess the diameter distribu 65 14.O 66.7 NA tion for the particles and to determine the shape. The diameter of each droplet is determined automatically by referencing US 9,072,799 B2 67 68 As indicated in FIG. 5, the beam deflection is less than TABLE B 0.005 inches for hydrogen oxide ice that is reinforced with approximately 9.0% glass fibers and increases over time for Frozen particles and reinforcement agents leading to increased hydrogen oxide ice that is reinforced with approximately particle strength 0.8% glass fibers (Kingery, Ibid). Furthermore, hydrogen 5 Particle Silica oxide ice with approximately 9% (w/v) of glass fibers is not Base Fiber Glass Saw Dust Beads PEG Kaolin deformed over 23 hours under an applied force of approxi Ice O.15% O.14 O.63 ND O.15 mately 24.5 in.lbs. As described in Kingery, et al., and as DMSO O.15 O.14 O.63 ND O.15 indicated in FIG. 5, beam deflection of hydrogen oxide ice carbon O.15 O.14 O.63 ND O.15 10 dioxide with approximately 0.8% glass fibers is approximately 0.16 gelatin O.15 O.14 O.63 ND O.15 inches after 23 hours under 25.3 in.lbs. of force. Likewise, as indicated in FIG. 5, and according to Kingery et al., hydrogen Volume fraction for reinforcement agents in frozen particle base materials is given, oxide ice without reinforcement agents is deformed approxi ND = Not Determined. (Yasui, et al.) mately 0.05 inches after 4 hours under approximately 26.6 15 in.lbs. of force. Additionally, aluminum and silica carbonate Example 10 particles can be mixed at various Volume fractions and co milled under an argon atmosphere to produce nanocrystalline Vaccine Compositions and Methods of Making composites as reinforcement agents for frozen particle com Frozen Particles positions. (See e.g., Kamrani, et al., Powder Met. Vol. 50, pp. 276-282(7) (2007), which is incorporated herein by refer As described herein, immunization of a Subject with a ence). vaccine is accomplished by way of introduction of the vac cine through, for example, Subcutaneous, transcutaneous or intramuscular administration. (See e.g., BerZofsky et al. Nat. 25 Rev. Immunol. Vol. 1, pp. 209-219, (2001), which is incorpo rated herein by reference). Non-limiting examples of frozen Example 9 particle Vaccines are described herein, and include one or more immunogens. The immunogen therapeutic composi tions are made, for example, in Solution or as a Solid in Compositions and Methods of Making Frozen 30 Particles Suspension created from buffered solutions (e.g., phosphate, citrate, lactate, pyruvate or an organic acid buffer) that opti mize the stability and immunogenicity of the vaccine. Frozen particles (e.g., carbon dioxide, DMSO, gelatin) are Storage stability of vaccines depends upon many factors, reinforced by incorporating one or more reinforcement including vaccine formulation and storage temperature. For agents, including but not limited to silica beads, fiberglass, 35 example, an influenza subunit vaccine formulated with treha polyethylene glycol, kaolin, or wood fibers. lose, and Hepes buffered saline, is stable at room temperature Silica beads approximately 1 micrometer in diameter are for approximately 26 weeks (See e.g., Amori et al., Pharm. mixed with hydrogen oxide at approximately 0°C. to make Volume fractions including the approximate ranges, but not Res. Vol. 25, pp. 1256-1273 (2008), which is incorporated limited to, 0, 0.004, 0.04, 0.15, 0.29, 0.49 and 0.63 volume 40 herein by reference). fraction. The Volume fractions, or one or more particular Vaccines with adjuvants such as: N-acetylmuramyl-l-ala Volume fraction, are frozen in, for example, a cylindrical nyl-d-isoglutamine, also called muramyl dipeptide (MDP) or mold, at low temperatures (e.g., approximately -10° C.). monophosphoryl lipid A (MPL) elicit enhanced cellular and Unconfined coaxial compression tests are used to determine humoral immunity (See e.g., Aguilar etal Vaccine Vol. 25, pp. 45 3752-62 (2007), which is incorporated herein by reference). the maximum stress (also known as the failure point) of the One or more hydrogen oxide frozen particle vaccine com one or more frozen particles at defined temperatures and positions, including, for example, one or more buffers, one or strain rates (See e.g., Yasui etal, Geophys. Res. Lett., Vol. 35, more immunogens (e.g., viral protein subunits) and one or L12206, (2008), which is incorporated herein by reference). more adjuvants, as a solution or Suspension, are made by As indicated in FIG. 6, maximum stress values (MPa) 50 spraying the compositions through an orifice or nozzle. Each increase for mixtures with an increased Volume fraction of vaccine composition is propelled by a pressurized gas (e.g., silica beads relative to the maximum stress for unreinforced compressed air) into a cooling chamber maintained at, for hydrogen oxide ice. (See e.g., Yasui et al., Ibid.) (p-silica example, approximately -40°C. Volume fraction The vaccine composition is delivered to at least one bio The strength of specific frozen particles is altered by vary 55 logical tissue of a subject, for example, by propelling the ing the composition of frozen particle mixtures containing particles via a carrier gas under pressure (e.g., air, carbon one or more reinforcement agents. For example, Table B dioxide, nitrogen) through a tube directed toward at least one indicates the frozen particle strength of frozen particles biological tissue (including but not limited to vascular, lym including hydrogen oxide, DMSO, carbon dioxide, and gela phatic, lymph node, epidermal, Subcutaneous, intramuscular, tin, which contain at least one reinforcement agent. As indi 60 oral, nasal, pulmonary, intraperitoneal or rectal tissue). cated, the reinforced frozen particles exhibited increased Alternatively, the vaccine composition is delivered to at strength compared to their unreinforced counterparts. As least one biological tissue of a Subject, for example, by first indicated in Table B, frozen particles containing at least one forming the frozen particle vaccine compositions through reinforcement agent at the Volume fractions shown in the spraying composition droplets into a cryogen bath (e.g., liq table displayed maximal strength in compression tests. (See 65 uid nitrogen). The frozen particle compositions are Subse also, FIGS. 5 and 6, as well as Table Aherein for hydrogen quently delivered to at least one biological tissue by flash oxide frozen particle strength). boiling liquid nitrogen, and propelling the frozen particle US 9,072,799 B2 69 70 compositions through a tube or barrel, for example, to at least Alternatively, the one or more frozen particle vaccine com one biological tissue of a Subject. positions are delivered to one or more pulmonary Surfaces of Frozen particle vaccine compositions containing one or the Subject via propulsion by way of a “pellet gun.” by using more reinforcement agents (e.g., silica beads) and of the flash boiled liquid nitrogen as a propellant, or by inhalation. appropriate size and shape (e.g., bullet, spheroid, high aspect Frozen particle influenza vaccine compositions administered ratio shape) penetrate the at least one biological tissue when to one or more pulmonary Surfaces of a Subject elicit mucosal propelled to high Velocity by a carriergas. In one non-limiting and systemic humoral, as well as cell-mediated immune example, a vaccine composition approximately 20-70 Lum in responses to influenza (See e.g., Amorietal Vaccine. Vol. 25. size penetrates the epidermis when the composition is accel pp. 8707-8717 (2007), which is incorporated herein by refer erated to high speed with a powder jet injector (PowerJect, 10 ence). PowerJect Pharmaceuticals) (Amorijet al., Ibid.). Example 12 Example 11 Compositions and Methods of Making Frozen Vaccine Compositions and Methods of Making 15 Particles Frozen Particles Frozen particle compositions of the appropriate size and shape, including botulinum toxin, an optimal buffer (e.g., Frozen particle vaccine compositions containing multiple Hepes buffer), one or more stabilizing agents, and one or immunogens, for example, toxoids (chemically modified tox more reinforcement agents are administered through the skin ins) from bacteria Such as Clostridium tetani, Corny bacte of a subject to neuromuscular junctions. Botulinum toxin rium diphtheriae or Bordetella pertussis, stimulate immunity inhibits acetylcholine release, which blocks synapse forma to multiple bacteria or toxins in a single vaccine composition. tion, and temporarily paralyzes the corresponding muscula Alternatively, multiple distinct immunogens, proteins, or ture. peptides that are derived from a single pathogenare combined 25 Frozen particle compositions containing a recommended in a single frozen particle vaccine composition that immu dose of botulinum toxin (See e.g., Borodic, U.S. Pat. No. nizes a Subject against a pathogenic virus or bacteria that 5,183,462, which is incorporated herein by reference), and at mutates frequently. For example, multiple hemagglutinin or least one reinforcement agent (e.g., polymer) are adminis neuraminidase proteins, (e.g., H1N1, H3N2) from different tered to skeletal muscles using a delivery system derived from viral strains (e.g., A/New Caledonia/H1N1, or A/Wellington/ 30 inkjet printer technology (See e.g., world wide web at H3N2) or viral species of influenza (e.g., influenza A or en.wikipedia.org/wiki/Inkjet Printer) that sprays picoliter influenza B) are combined in a single frozen particle vaccine quantities of the frozen particle compositions at high velocity composition and provides immunity to multiple strains or (e.g., 50 m/sec) toward the skin of the subject. Botulinum species. (See e.g., Kamps etal, Influenza Report, pp. 127-149 toxin is typically administered by Subcutaneous injection (2006); world wide web at influenzareport.com/ir/vaccines: 35 (generally with a 26 gauge hypodermic needle). Botulinum each of which is incorporated herein by reference). toxin is approved by the FDA for therapy of strabismus Alternatively, frozen particle vaccine compositions includ (crossed-eyes), blepharospasm (uncontrolled blinking), and ing one or more immunogens, antigens or proteins (e.g., other facial nerve disorders including hemifacial spasm. It is influenza A/New Caledonia/(H1N1)) are combined with one also approved for treatment of cervical dystonia and glabellar or more frozen particle vaccine compositions containing one 40 (frown) lines (See e.g., Jankovic, J. Neurol. Neurosurg. Psy or more different antigens (e.g., influenza B/Shanghai or chiatry vol. 75, pp. 951-957 (2004), which is incorporated influenza A/Wellington/(H3N2)). Such a frozen particle vac herein by reference). cine composition combination provides immunity against In addition, botulinum toxin is included in the treatment of seasonal variants of viral pathogens. focal or segmental dystonia (e.g., oromandibular-facial-lin In one non-limiting example, combinations of frozen par 45 gual dystonia, laryngeal dystonia, limb dystonia). Dystonias ticle vaccine compositions including specific antigens from are neurological disorders with repetitive and patterned con selected influenza variants or strains target a seasonal flu tractions of muscles that cause abnormal movements and epidemic. (Kamps etal, Ibid.) Combination of frozen particle postures. For example, cervical dystonia Subjects are injected compositions are made containing one or more different anti with, for example, approximately 100 I.U of botulinum toxin, gens or epitopes, wherein the one or more different antigens 50 distributed over 3-5 injection sites, spaced 5-15 mm apart, or epitopes are derived from mutant or variant HIV proteins across the length of the sternomastoid muscle. (Borodic, that evolve during HIV infection (See e.g., Berzofsky et al., J. Ibid.) Clin. Inv. Vol. 114, pp. 450-462 (2004)). Such combination Frozen particle vaccine compositions containing botuli compositions immunize a subject against existing HIV num toxin are administered to facial muscles that underlie mutants and anticipate the emergence of new HIV mutants or 55 frown lines, wrinkles, and “crow’s feet.” For example, botu variants. linum toxin is targeted to: 1) the corrugator and procerus Alternatively, one or more frozen particle Vaccine compo muscles to treat vertical glabellar eyebrow furrows; 2) to sitions are delivered to one or more mucosal tissues (e.g., multiple sites in the frontalis muscle to eliminate horizontal nasal, oral, rectal, pulmonary) via propulsion using a “pellet lines in the forehead; or 3) to the lateral orbicularis oculi to gun, via inhalation, or ingestion by a subject. For example, 60 treat crow’s feet. an influenza vaccine lyophilized and delivered nasally as Frozen particle compositions containing an optimal dose spherical particles, approximately 26.9 um (mean diameter), of botulinum toxin (e.g., 0.2-0.4 I.U./kg) are administered induces mucosal (e.g., nasal IgA response) and systemic over the length of a specific facial muscle (e.g., orbicularis immunity (e.g., serum antibody response) to influenza virus oculi) by use of a delivery system with an inkjet nozzle. As (See e.g., Garmise et al, AAPS PharmSciTech. vol. 8:E81 65 described herein, picoliter volumes of one or more frozen (2007); Huang et al. Vaccine. vol. 23(6), pp. 794-801 (2004); particle compositions are sprayed at a Velocity that achieves a each of which is incorporated herein by reference). desired or predetermined depth (for example, 5-8 mm; US 9,072,799 B2 71 72 Borodic, Ibid.). The velocity is also altered according to the Administration of at least one frozen particle hydrogen size, shape, and constituents of the frozen particle composi oxide therapeutic composition containing at least one thera tion. peutic antibody includes, for example, bevacizumab (an anti vascular endothelial growth factor) or cetuximab (an anti Example 13 epidermal growth factor receptor). Bevacizumab and cetuximab both target the tumor-associated vasculature and Methods of Administering Frozen Particle tumor cells in the remaining colon sections and the Surround Therapeutic Compositions ing tissues, mesentery and lymph nodes. Localized adminis tration of therapeutic antibodies provides Sustained protec Frozen hydrogen oxide particles of ice Ic form and at least 10 tion from recurrence of colon tumors at the site of tumor one therapeutic agent or at least one diagnostic agent are resection and in the Surrounding tissues. (Wolpinet al., Ibid.). formulated for treatment of hematological cancers (e.g., leu Following Surgery and adjuvant therapy with one or more kemia or lymphoma) or Solid tumors (e.g., carcinoma, Sar frozen particle hydrogen oxide therapeutic compositions, coma). For example, at least one of neo-adjuvant therapy, including at least one of one or more chemotherapy drugs, or adjuvant therapy, chemotherapy, antibody therapy, or immu 15 one or more antibodies, the remaining colon sections are notherapy are employed spliced together (i.e. anastomosis) or an artificial orifice (i.e. In one non-limiting embodiment, frozen hydrogen oxide stoma) is inserted to restore a functional colon. particles are used for adjuvant therapy of cancers treated with Example 14 Surgery such as colon cancer, lung cancer, and breast cancer. At least one frozen particle hydrogen oxide therapeutic com Methods of Administering Frozen Particle position containing one or more reinforcement agents (e.g., Therapeutic Compositions silica beads, Kevlar.R.), one or more buffers, one or more stabilizing agents (e.g., one or more saccharides), and one or Frozen particle hydrogen oxide therapeutic compositions more cancer therapeutic agents (such as one or more chemo 25 including one or more cancer therapeutics or one or more therapy drugs, antibodies, biological agents (e.g., antibodies, cancer diagnostics are used to treat cancers in distal locations cytokines or peptides), or one or more chemotherapeutic from the primary tumor or initial tumor site treated with agents) are administered to an area proximal to a region of at Surgery or radiation. For example, colon cancer cells often least one biological tissue where a tumor is present or metastasize to the liver ((Wolpin et al., Ibid.). At the time of believed to be present. Optionally, resection of at least a part 30 Surgical resection of colon cancer tumors, one or more frozen of a tumor may be performed, with or without additional particle hydrogen oxide therapeutic compositions including administration of the at least one frozen particle therapeutic at least one cancer therapeutic, such as one or more cytotoxic composition. drugs (e.g., fluouracil), antibodies (e.g., cetuximab), radio The at least one frozen particle therapeutic composition is isotopes conjugated to antibodies (e.g., ''I-cetuximab), or administered in Such a manner as described herein, that 35 one or more mixtures of at least one cytotoxic drug and at least allows for desired depth of penetration of the at least one one biological-based therapeutic agent are administered to biological tissue. In one embodiment, the at least one frozen the liver and Surrounding tissues. particle therapeutic composition is administered to a depth Administration of the at least one frozen particle hydrogen that allows for at least one of intracellular or intercellular oxide therapeutic composition is accomplished by traditional delivery. For example, the at least one frozen particle thera 40 Surgery or laparoscopic Surgery that allows access to the liver peutic composition is administered to a depth that allows for (or other organs to be treated). Administration of at least one delivery to at least one of epithelium, endothelium, Vascula frozen particle hydrogen oxide therapeutic composition ture, lymphatic vessels, lymph nodes or mucosa. directly to the liver and the surrounding vasculature allows for Specifically, if metastasis is present or believed to be intracellular or intercellular penetration and release of at least present in the Subject, administration of the at least one frozen 45 one anti-cancer therapeutic for treatment of any existing or particle therapeutic composition is delivered to Such region of Suspected colon cancer mestastases or micro-metastases. metastases or micro-metastases are believed to be present. As described herein, the at least one frozen particle hydro Frozen particle hydrogen oxide therapeutic compositions gen oxide therapeutic composition including one or more provide as an adjuvant therapy are administered by spraying cancer therapeutics are administered by way of a spraying at least one composition under pressure with a carrier gas 50 device. Such a spraying device includes an insulated tube and through a nozzle designed to uniformly distribute particles nozzle, as well as a valve that controls the flow of particles. In over at least one biological tissue at Sufficient Velocity to the case of traditional Surgery for tumor or tissue resection, penetrate the tissue exposed during tumor resection. the at least one frozen particle hydrogen oxide therapeutic Advanced colon cancer (e.g., stage II, III) is treated Surgi composition is sprayed directly onto the target tissue or tis cally by removal of sections of colon containing tumor with 55 Sues. Whereas in the case of laparoscopic Surgery for tumor or margins of “normal” colon tissue and often includes removal tissue resection, the at least one frozen particle hydrogen of associated lymph nodes and mesentery (collectomy). Stan oxide therapeutic composition is sprayed through a trocar (a dard adjuvant therapy following Surgery is systemic admin hollow tube approximately 10 millimeters in diameter). istration of a combination of chemotherapy drugs (e.g., In certain spraying devices, the at least one frozen particle 5-fluorouracil, leucovorin or oxaliplatin (FOLFOX)). (See 60 hydrogen oxide therapeutic composition is administered by e.g., Wolpin et al., CA Cancer J. Clin. Vol. 57, pp. 168-185 way of a carrier gas. The depth of penetration by the at least (2007)). Systemic FOLFOX adjuvant therapy is associated one therapeutic composition is controlled by regulating the with significant toxicities including gastrointestinal toxicity, carrier gas pressure as well as the consequent particle Veloc neutropenia and neurotoxicity (Wolpinetal, Ibid.). Localized ity. The at least one therapeutic composition optionally in situ delivery of FOLFOX by administration of frozen par 65 includes one or more tracer agents or is delivered simulta ticle therapeutic compositions permits delivery of a lower neously with one or more tracer agents. Some non-limiting dose. examples of tracer agents include dyes, stains or fluorescent US 9,072,799 B2 73 74 compounds that mark the tissue area sprayed. The one or tumumab, bevacizumab) are administered directly onto lung more tracer agents can optionally monitor or provide feed cancer tumors. Administration is conducted via endoluminal back as to the quantity or quality (in the case of multiple bronchoscopy or by video-assisted thoracoscopy by means of therapeutic compositions administered simultaneously or an insulated tube and noZZle integral to the endoscopic over time) of the at least one therapeutic composition admin 5 device. Frozen particle composition Velocities and spray rate istered to a specific site. are controlled by a valve between the spray head and the In at least one embodiment, the at least one frozen particle cooling chamber of the “pelletizer.” (See e.g., U.S. Pat. Nos. hydrogen oxide therapeutic composition including at least 6.306,119, or 6,764,493, each of which is incorporated herein one cancer therapeutic further includes hematoxylin and by reference). Precise localization and administration of the eosin stains mixed at a known ratio (e.g., 1:10). Alternatively, 10 frozen particle therapeutic compositions are accomplished by a batch of the at least one frozen particle hydrogen oxide bronchoscopy and endoscopy with fluoroscopy used to mark therapeutic composition is administered in a mixture or in the field(s) of interest. separate applications frozen particles including hematoxylin Methods for endoscopic targeting of tumors are described, and eosin stains. Staining of tissues is visualized by inspec for example, in Huber et al (Chest vol. 107, pp. 463-470 tion with a low power microscope (e.g., dissection micro 15 (1995); which is incorporated herein by reference). More Scope) or with a laparoscope, which allows for assessment of over, computed tomography, magnetic resonance imaging, the relative quantity or quality of the at least one therapeutic positron emission tomography or other techniques are used to composition administered to the tissue. Staining of the tissues locate lung cancer tumors. further provides a guide as to the region that received the at Frozen particle therapeutic composition administration by least one therapeutic composition. using endoscopic procedures or as an adjuvant therapy in conjunction with traditional Surgery is used for various Example 15 regions of existing or potential carcinogenesis, including mediastinal lymph nodes, vasculature, chest wall and other Methods of Administering Frozen Particle thoracic sites. Therapeutic Compositions 25 Alternatively, frozen particle therapeutic compositions are delivered during traditional Surgery for lung cancer and used Frozen particle hydrogen oxide therapeutic compositions to treat inoperable tumors remaining following lobectomy, including carbon dioxide and at least one cancer therapeutic wedge resection, and pneumonectomy, as well as to treat are administered to at least one tumor or tissue Suspected of margins of lobe, wedge or lung excisions to reduce recurrence being cancerous. Upon administration, the frozen particle 30 of lung cancer (See e.g., the worldwideweb at en.wikiped hydrogen oxide therapeutic compositions penetrate one or ia.org/wiki/Lung cancerHSurgery; which is incorporated more tumor cells, warm to ambient temperature, and undergo herein by reference). Without wishing to be bound by any rapid Sublimation and gaseous expansion of the carbon diox particular theory, frozen particle carbon dioxide therapeutic ide. This rapid reaction produces a small explosion that compositions maintained at approximately -80° C. while destroys at least one tumor cell as well as one or more adjacent 35 administered to tumors rapidly freeze the tumor cells leading cells. In addition, administration of the frozen particle thera to formation of ice crystals in tumor cells that destroy cell peutic compositions at low temperatures (e.g., lower than organelles (e.g., mitochondria) leading to death of the tumor approximately -78.5°C., which is the approximate sublima cells. (Vergnon et al., Ibid.) tion temperature for carbon dioxide at 1 atm pressure), Similarly, frozen particle therapeutic compositions con freezes cells and tissues, causing tumor cell death (See e.g., 40 taining at least one radioactive element deliver radiation to Vergnon et al., Eur. Respir. J. Vol. 28 pp. 200-218 (2006): lung cancer tumor cells. One non-limiting example utilizes incorporated herein by reference). frozen particle therapeutic compositions including 'Iri Alternatively, carbon dioxide gas is entrapped in frozen dium for irradiating lung tumors that obstruct major airways. particles by placing the liquid phase (e.g., hydrogen oxide) Administration of the frozen particle therapeutic composi under high pressure in the presence of carbon dioxide gas. 45 tions is conducted using an endoscope and a wire to place the (See e.g., U.S. Pat. Nos. 4,289,794; 4,289,790; 4,262,029: radioactive compositions in at least one lung tumor. Without 5.439,698, each of which is incorporated herein by refer wishing to be bound to any theory, tumor cell irradiation ence). Administration of the at least one therapeutic compo results in single-stranded DNA breaks that induce apoptosis sition is conducted as described herein. In at least one and reduce rates of cell division (Vergnonet, Ibid.). embodiment, the use of a tube and nozzle is used that sprays 50 While particular aspects of the present subject matter the frozen particle therapeutic compositions underpressure in described herein have been shown and described, it will be a carrier gas (e.g., carbon dioxide, nitrogen). Administration apparent to those skilled in the art that, based upon the teach of the at least one therapeutic composition is carried out as an ings herein, changes and modifications may be made without adjuvant therapy in conjunction with tumor resection, or as an departing from the subject matter described herein and its alternative when tumor resection is not favored. For example 55 broader aspects and, therefore, the appended claims are to lung cancer tumors are generally inoperable when Such encompass within their scope all Such changes and modifica tumors are adjacent to airways, or infiltrate central airways tions as are within the true spirit and scope of the Subject including the trachea, main stem bronchi or multiple lung matter described herein. It will be understood by those within lobes. Additionally, Subjects with compromised respiration the art that, in general, terms used herein, and especially in the (e.g., those with lung disease, heart disease or advanced age) 60 appended claims (e.g., bodies of the appended claims) are are generally not candidates for Surgery (See e.g., Spiro et al. generally intended as "open terms (e.g., the term “including Amer. J. Respir. Crit. Care Med., vol. 172, pp. 523-529 should be interpreted as “including but not limited to the (2005); which is incorporated herein by reference). term “having should be interpreted as “having at least the Carbon dioxide frozen particle therapeutic compositions term “includes should be interpreted as “includes but is not including one or more chemotherapeutic drugs (e.g., cispl 65 limited to.” etc.). It will be further understood by those within atin, docetaxel, Vinorelbine), targeted drugs (e.g., gefitnib, the art that if a specific number of an introduced claim reci erlotnib), or biological-based agents (e.g., cetuximab, pani tation is intended, such an intent will be explicitly recited in US 9,072,799 B2 75 76 the claim, and in the absence of such recitation no such intent wherein the one or more frozen particles have at least one is present. For example, as an aid to understanding, the fol major dimension of approximately one micrometer or lowing appended claims may contain usage of the introduc less, approximately one nanometer or less, or any value tory phrases “at least one' and “one or more' to introduce therebetween. claim recitations. However, the use of such phrases should not 5 2. The composition of claim 1, further including one or be construed to imply that the introduction of a claim recita more abrasives. tion by the indefinite articles “a” or “an limits any particular 3. The composition of claim 1, wherein the one or more claim containing Such introduced claim recitation to claims frozen particles include at least one of amorphous Solid water, containing only one such recitation, even when the same low density amorphous ice, high density amorphous ice, crys claim includes the introductory phrases “one or more' or “at 10 talline ice, very high density amorphous ice, clathrate ice, or least one' and indefinite articles such as “a” or “an' (e.g., “a” hyperquenched glassy water. and/or “an should typically be interpreted to mean “at least 4. The composition of claim 1, wherein the one or more one' or “one or more); the same holds true for the use of frozen particles include at least one of ice Ic, ice Ih, ice II, ice definite articles used to introduce claim recitations. In addi III, ice IV, ice V, ice VI, ice VII, ice VIII, ice IX, ice X, ice XI, tion, even if a specific number of an introduced claim recita 15 ice XII, ice XIII, or ice XIV. tion is explicitly recited, those skilled in the art will recognize 5. The composition of claim 1, wherein the one or more that such recitation should typically be interpreted to mean at frozen particles further include at least one of polyethylene least the recited number (e.g., the bare recitation of “two glycol, acetone, ethyl acetate, dimethyl sulfoxide, dimethyl recitations, without other modifiers, typically means all least formamide, dioxane, hexamethylphosphorotriamide, per two recitations, or two or more recitations). Furthermore, in fluorohydrocarbon, methanol, ethanol, tert-butyl alcohol, for those instances where a convention analogous to “at least one mic acid, hydrogen fluoride, ammonia, acetic acid, benzene, of A, B, and C, etc. is used, in general Such a construction is carbon tetrachloride, acetonitrile, hexane, methylene chlo intended in the sense one having skill in the art would under ride, carboxylic acid, Saline, Ringer's solution, lactated Ring stand the convention (e.g., “a system having at least one of A, er's solution, Hartmann's solution, acetated Ringer's solu B, and C would include but not be limited to systems that 25 tion, phosphate buffered solution, TRIS-buffered saline have A alone, B alone, C alone, A and B together, A and C solution, Hank's balanced salt solution, Earle's balanced salt together, B and C together, and/or A, B, and C together, etc.). solution, standard saline citrate, HEPES-buffered saline, dex In those instances where a convention analogous to “at least trose, glucose, or diethyl ether. one of A, B, or C, etc. is used, in general Such a construction 6. The composition of claim 1, further including at least is intended in the sense one having skill in the art would 30 one of a polymer, biopolymer, nanoparticle, or detection understand the convention (e.g., “a system having at least one material. of A, B, or C would includebut not belimited to systems that 7. The composition of claim 6, wherein the detection mate have A alone, B alone, C alone, A and B together, A and C rial includes at least one electronic identification device. together, B and C together, and/or A, B, and C together, etc.). 8. The composition of claim 7, wherein the at least one It will be further understood by those within the art that 35 electronic identification device includes at least one radio typically a disjunctive word and/or phrase presenting two or frequency identification device. more alternative terms, whether in the description, claims, or 9. The composition of claim 6, wherein the detection mate drawings, should be understood to contemplate the possibili rial includes at least one radioactive element. ties of including one of the terms, either of the terms, or both 10. The composition of claim 9, wherein the at least one terms unless context dictates otherwise. For example, the 40 radioactive element includes one or more of P, S, 'C, phrase “A or B will be typically understood to include the 13 II, 19 Ir, 192Ir, 193Ir, 201T, or H. possibilities of “A” or “B” or “A and B.” 11. The composition of claim 6, wherein the detection With respect to the appended claims, those skilled in the art material includes at least one colorimetric Substance. will appreciate that recited operations therein may generally 12. The composition of claim 11, wherein the at least one be performed in any order. Also, although various operational 45 colorimetric Substance includes one or more of an inorganic, flows are presented in a sequence(s), it should be understood organic, biological, natural, artificial, or synthetic Substance. that the various operations may be performed in other orders 13. The composition of claim 11, wherein the at least one than those which are illustrated, or may be performed con colorimetric Substance includes one or more of a dye, pig currently. Examples of such alternate orderings may include ment, or light-emitting Substance. overlapping, interleaved, interrupted, reordered, incremental, 50 14. The composition of claim 13, wherein the light-emit preparatory, Supplemental, simultaneous, reverse, or other ting Substance includes at least one of a fluorescent Substance, variant orderings, unless context dictates otherwise. Further phosphorescent Substance, or quantum dot. more, terms like “responsive to.” “related to,” or other past 15. The composition of claim 6, wherein the detection tense adjectives are generally not intended to exclude Such material includes at least one of a diamagnetic particle, fer variants, unless context dictates otherwise. 55 romagnetic particle, paramagnetic particle, Super paramag All publications and patent applications cited in this speci netic contrast agent, or other magnetic particle. fication are incorporated herein by reference to the extent not 16. The composition of claim 1, wherein the one or more inconsistent with the description herein and for all purposes frozen particles include a plurality of frozen particles that are as if each individual publication or patent application were approximately uniform with regard to size, shape, weight, or specifically and individually indicated to be incorporated by 60 density. reference for all purposes. 17. The composition of claim 1, further including at least What is claimed is: one pharmaceutically-acceptable carrier or excipient. 1. A composition, comprising: 18. The composition of claim 1, further including one or one or more frozen particles containing at least one antibi more explosive materials. otic, at least one anti-tumor agent, at least one cytokine, 65 19. The composition of claim 18, wherein the one or more and one or more reinforcement agents of metal or cellu explosive materials include at least one of a high explosive or lose; and a low explosive. US 9,072,799 B2 77 78 20. The composition of claim 18, wherein the one or more 30. The composition of claim 29, wherein the detection explosive materials include at least one of carbon dioxide, material includes at least one electronic identification device. nitroglycerine, or a reactive metal. 31. The composition of claim 30, wherein the at least one 21. A composition, comprising: one or more frozen dim electronic identification device includes at least one radio ethylsulfoxide Solution particles containing one or more anti bodies and one or more explosive materials, wherein the one frequency identification device. or more explosive materials do not include carbon dioxide; 32. The composition of claim 29, wherein the detection wherein the composition is in at least one crystalline or amor material includes at least one radioactive element. phous phase. 33. The composition of claim 32, wherein the at least one 22. The composition of claim 21, wherein the one or more radioactive element includes one or more of P, S, 'C, frozen particles have at least one major dimension of approxi 10 13 II, 19 Ir, 192Ir, 193Ir, 201T, or H. mately one micrometer or less, approximately one nanometer 34. The composition of claim 29, wherein the detection or less, or any value therebetween. material includes at least one colorimetric Substance. 23. The composition of claim 21, further including one or 35. The composition of claim 34, wherein the at least one more of fiberglass, silica beads, wood fibers, or kaolin. 24. The composition of claim 21, further including one or 15 colorimetric Substance includes one or more of an inorganic, more of Vectran, or silicon. organic, biological, natural, artificial, or synthetic Substance. 25. The composition of claim 21, wherein the one or more 36. The composition of claim 34, wherein the at least one frozen particles include at least one of amorphous Solid water, colorimetric Substance includes one or more of a dye, pig low density amorphous ice, high density amorphous ice, crys ment, or light-emitting Substance. talline ice, very high density amorphous ice, clathrate ice, or 37. The composition of claim 36, wherein the light-emit hyperquenched glassy water. ting Substance includes at least one of a fluorescent Substance, 26. The composition of claim 21, wherein the one or more phosphorescent Substance, or quantum dot. frozen particles include at least one of ice Ic, ice Ih, ice II, ice 38. The composition of claim 29, wherein the detection III, ice IV, ice V, ice VI, ice VII, ice VIII, ice IX, ice X, ice XI, material includes at least one of a diamagnetic particle, fer ice XII, ice XIII, or ice XIV. 25 romagnetic particle, paramagnetic particle, Super paramag 27. The composition of claim 21, wherein the one or more netic contrast agent, or other magnetic particle. frozen particles further include at least one of polyethylene 39. The composition of claim 21, wherein the one or more glycol, acetone, ethyl acetate, dimethyl sulfoxide, dimethyl frozen particles include a plurality of frozen hydrogen oxide formamide, dioxane, hexamethylphosphorotriamide, per particles that are approximately uniform with regard to size, fluorohydrocarbon, methanol, ethanol, tert-butyl alcohol, for 30 shape, weight, or density. mic acid, hydrogen fluoride, ammonia, acetic acid, benzene, 40. The composition of claim 21, formulated to be admin carbon tetrachloride, acetonitrile, hexane, methylene chlo istered by high velocity impact. ride, carboxylic acid, Saline, Ringer's solution, lactated Ring 41. The composition of claim 21, formulated to be admin er's solution, Hartmann's solution, acetated Ringer's Solu istered by one or more devices. tion, phosphate buffered solution, TRIS-buffered saline 35 42. The composition of claim 21, further including at least solution, Hank's balanced salt solution, Earle's balanced salt one pharmaceutically-acceptable carrier or excipient. solution, standard saline citrate, HEPES-buffered saline, dex 43. The composition of claim 21, wherein the one or more trose, glucose, or diethyl ether. explosive materials include at least one of a high explosive or 28. The composition of claim 21, further including at least a low explosive. one of an anesthetic, analgesic, or antimicrobial agent. 40 44. The composition of claim 21, wherein the one or more 29. The composition of claim 21, further including at least explosive materials include at least one of carbon dioxide, one of a polymer, biopolymer, nanoparticle, or detection nitroglycerine, or a reactive metal. material. k k k k k