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United States Patent (19) 11 Patent Number: 6,165,486 Marra Et Al

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United States Patent (19) 11 Patent Number: 6,165,486 Marra Et Al USOO6165486A United States Patent (19) 11 Patent Number: 6,165,486 Marra et al. (45) Date of Patent: Dec. 26, 2000 54) BIOCOMPATIBLE COMPOSITIONS AND 5,522,895 6/1996 Mikos ....................................... 623/16 METHODS OF USING SAME 5,679,723 10/1997 Cooper et al. .. 523/115 5,766,618 6/1998 Laurencin et al. ...................... 424/426 75 Inventors: Kacey G. Marra; Lee E. Weiss; Jay Primary Examiner Thurman K. Page Wynn Calvert; Prashant N. Kumta, ASSistant Examiner-Isis Ghali all of Pittsburg, Pa. Attorney, Agent, or Firm-Raymond A. Miller; Reed Smith 73 Assignees: Carnegie Mellon University; Shaw & McClay LLP University of Pittsburgh, both of 57 ABSTRACT Pittsburgh, Pa. Blends of biodegradable polymers, preferably poly 21 Appl. No.: 09/196,288 (caprolactone) and poly(D.L-lactic-co-glycolic) acid are dis 9 cussed as well as their applications in the medical field, 22 Filed: Nov. 19, 1998 particularly with regard to bone tissue engineering. 51 Int. Cl." ............................... A61F 200. A61F 1300 Preferably hydroxyapatite ("HA) granules are incorporated 5 U.S. C. 424/423: into the blends and the resulting blends have desirable 52) O X O -- O - - - - - - - - - - - - - - - - - - - - - - - - - - f423; 'EEE mechanical, physical, and biological characteristics. Even /425; f more preferably the compositions of the present invention 58 Field of Search ..................................... 424/423, 425; are utilized to form osteoconductive composites that Sup 606/230; 128/90 ported bone cell growth on the Surface as well as throughout th ffold. 56) References Cited C SCO U.S. PATENT DOCUMENTS 16 Claims, 8 Drawing Sheets 4,624,256 11/1986 Messier et al. ...................... 128/335.5 5,475,063 12/1995 Kaplan et al. ... ... 525/411 (3 of 8 Drawing Sheet(s) Filed in Color) 120 100 | 4O U.S. Patent Dec. 26, 2000 Sheet 1 of 8 6,165,486 | Figure 1 U.S. Patent Dec. 26, 2000 Sheet 2 of 8 6,165,486 Figure 2 U.S. Patent Dec. 26, 2000 Sheet 3 of 8 6,165,486 Figure 3 U.S. Patent Dec. 26, 2000 Sheet 4 of 8 6,165,486 S U.S. Patent Dec. 26, 2000 Sheet 5 of 8 6,165,486 S&S& S. U.S. Patent Dec. 26, 2000 Sheet 6 of 8 6,165,486 & Figure 6 U.S. Patent Dec. 26, 2000 Sheet 7 of 8 6,165,486 Figure 7 U.S. Patent Dec. 26, 2000 Sheet 8 of 8 6,165,486 6,165,486 1 2 BOCOMPATIBLE COMPOSITIONS AND patible copolymer and a biocompatible polyester. When METHODS OF USING SAME used as a bone Substitute the composition preferably includes a bioceramic material. The biocompatible copoly BACKGROUND OF THE INVENTION mer preferably is a copolymer of poly(lactic) acid and poly(glycolic) acid, the biocompatible polyester is prefer 1. Field of the Invention ably a polycaprolactone, and the bioceramic component is The present invention relates to a biocompatible material preferably exemplified by a coralline hydroxyapatite or which is useful as a tissue Substitute and as a material for Sintered calcium hydroxyapatite. The bioceramic materials forming or coating biomedical devices. are intended to mimic a mineralized bone component. 2. Background and Description of the Related Art Hydroxyapatite (“HA") is the preferred bioceramic material Biocompatible materials and/or compositions have many because it renders the composition Substantially Osteoinduc uses in the medical field. Orthopedic Surgeons, plastic Sur tive and/or osteoconductive. Most preferably, the biodegrad geons and neuroSurgeons, for example, frequently utilize able composition is comprised of a blend of copolymer, Substitute materials in their Surgical procedures to augment polyester and bioceramic material. AS used herein, a “blend’ or cement tissue. Bone Substitution or augmentation, for refers to a physical mix of polymers (e.g., a physical mix of example, is often required to repair or replace damaged, 15 copolymer, polyester, and bioceramic with little or no cova lent bonding between the respective constituents. It is pref diseased, or congenitally absent tissue. The types of cases erable that the concentration of the polyester be less than requiring bone augmentation range from and include about 50% with respect to the copolymer, even more pref trauma, congenital and degenerative diseases (i.e. spinal erably less than about 40% with respect to the copolymer, fusions), and cosmetic applications. Suitable materials for and most preferably the polyester is at a concentration of use as Synthetic Substitutes of muscular-skeletal tissue are about 10% with respect to the copolymer. preferably easy to apply, pliable, and shapeable, and are able An alternate embodiment of the present invention is a to withstand the Stresses, Strains and compressive forces composition comprised of a copolymer of poly(lactic) acid asSociated with the native tissue being replaced. and poly(glycolic) acid and polycaprolactone wherein the Biodegradable materials have been developed for use as 25 copolymer and the polycaprolactone are blended at a pre implantable prostheses, as pastes, and as templates around determined ratio to provide a desirable characteristic. It is which the body can regenerate various types of tissue. preferable that the predetermined ratio be in the range of Polymers which are both biocompatible and resorbable in about 10:90 polyester to copolymer to about 50:50 polyester Vivo are known in the art as alternatives to autogenic or to copolymer. If the tissue is to replace, augment or Serve as allogenic Substitutes. These resorbable biocompatible poly a Substitute for hard tissue Such as bone, the composition mers include both natural and Synthetic polymerS. Natural preferably includes bioceramic material Such as hypoxya polymers are typically absorbed by enzymatic degradation patite in the range of about 0-25 weight % hydroxyapatite in the body, while synthetic resorbable polymers typically to total polymer (copolymer and polyester) more preferably degrade by a hydrolytic mechanism. Synthetic resorbable in the range of about 1% to about 20%, even more polymers which are typically used to manufacture medical 35 preferably, about 5% to about 15% HA, and most preferably devices include homopolymerS Such as poly(glycolide), about 10% HA. Although the range of 10:90 polyester to poly(lactide), poly(e-caprolactone), poly(trimethylene copolymer to 50:50 polyester to copolymer is acceptable, it carbonate) and poly(p-dioxanone) and copolymerS Such as is preferable that the composition include more copolymer poly(lactide-co-glycolide), poly(e-caprolactone-co than polyester. glycolide), and poly(glycolide-co-trimethylene carbonate). 40 Some of the uses of the composition which include the The polymerS may be Statistically random copolymers, hydroxyapatite are: a bone Substitute; paste, or cement. The Segmented copolymers, block copolymers, or graft copoly present invention is particularly useful in treating patients merS or combinations of any of the above. having a major bone defect (e.g., cranio-facial). If the tissue The Substitutes or pastes preferably have properties which being replaced, augmented, or Substituted or the device allow them to be contoured into the defect site and are 45 being formed does not benefit from incorporation of a biodegradable. It is also preferable that they are capable of mineralized component, it is advisable to Substantially omit Sustaining the mechanical Stresses in the respective envi hydroxyapatite from the blend. This is because incorpora ronments in which the bone Substitute are placed. It is also tion of hydroxyapatite results in a more “brittle” device. preferable that the materials are able to integrate into Sur Minimal or no hydroxyapatite is desirable where a brittle rounding tissues and become Substantially vascularized. 50 characteristic renders the device or article leSS useful e.g., Inability to accept vascular ingrowth may increase the risk Sutures, anchors, fixation Systems. Such as Sutures, Suture for infection. If infected, the materials must be removed in anchors, Staples, Surgical tacks, clips, plates and Screws. It is order to avoid further Systemic infection. also advisable to avoid large concentrations (i.e., above 10% by weight) of hydroxyapatite Soft tissue applications Such as SUMMARY OF THE INVENTION 55 tissue used to Substitute or augment breast tissue. The present invention is directed to compositions useful Another embodiment of the present invention is a pros as delivery Systems, Substitute tissue, and in the manufacture thetic template comprised of a biodegradable polymer, a of biomedical articles. The term “tissue”, unless expressly bioceramic material, and a biodegradable polyester wherein otherwise noted herein, refers to an aggregation of Similarly the biodegradable polyester and the biodegradable polymer Specialized cells united in the performance of a particular 60 are chemically distinct. In this embodiment it is preferable function. AS used herein, the term “tissue’ Specifically that the biodegradable polymer be a copolymer of poly includes connective tissue (e.g., hard forms such as Osseous (lactic) acid and poly(glycolic acid), the polyester be tissue (bone)) as well as other muscular or skeletal tissue. polycaprolactone, and the bioceramic be hydroxyapatite. AS Preferably, the compositions of the present invention are above, it is preferable that the biodegradable polymer and Osteoconductive and/or Osteoinductive. 65 the biodegradable polyester be blended at a predetermined In a preferred embodiment, the present invention is ratio (i.e., about 10:90 to 50:50 biodegradeable polyester to directed to a composition which is comprised of a biocom biodegradable polymer). 6,165,486 3 4 Another embodiment of the present invention is a com FIG. 6 illustrates a schematic representation and a SEM of position which is comprised of biocompatible copolymer, an in Vivo implant according to the present invention; bioceramic material and biocompatible polyester. This FIG. 7 illustrates a TEM of (a) the seeded implant of FIG. embodiment has the preferred ranges of copolymer, bioce 6 at 8 weeks at 5,000 times magnification; (b) the unseeded ramic and polyester as described above and is most prefer scaffold at 8 weeks at 500 times magnification; and ably a blend of poly (lactic-co-glycolic) acid, FIG.
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