W ASM Handbook, Volume 23, Materials for Medical Devices Copyright # 2012 ASM International R. Narayan, editor All rights reserved www.asminternational.org

Fundamentals of Medical Implant Materials

Soumya Nag and Rajarshi Banerjee, University of North Texas

OVER THE LAST SEVERAL DECADES, astounding 90% of people above the age of 40 Implant Properties an increase in longevity and life expectancy suffer from such degenerative conditions. The has raised the average age of the world’s structure of a normal bone is distinctly different The property requirements of a modern-day population. Among the countries currently clas- when compared to a bone that is suffering from implant can broadly be categorized into three sified by the United Nations as more developed osteoporosis, with the bone cell density being equally important features (Ref 7): (with a total population of 1.2 billion in 2005), substantially lower for the osteoporotic bone the overall median age rose from 29.0 in 1950 as compared to the normal bone. Such prema- The human body must be compatible with to 37.3 in 2000 and is forecast to rise to 45.5 ture joint degeneration may arise mainly from the material used for the prosthesis. While by 2050 (Ref 1). This worldwide increase in three conditions: deficiencies in joint biomate- it is understandable that there is bound to the average age of the population has, in turn, rial properties, excessive loading conditions, be some amount of tissue reaction due to led to a rapidly increasing number of surgical and failure of normal repair processes (Ref 2). the introduction of a foreign substance, the procedures involving prosthesis implantation, Although minor surgical treatments are done resulting changes in mechanical, physical, because as the human body ages, the load-bear- to provide temporary relief to numerous and chemical properties within the localized ing joints become more prone to ailments. This patients, there is a consensus that the ultimate environment should not lead to local delete- has resulted in an urgent need for improved step is to replace the dysfunctional natural rious changes and harmful systemic effects. biomaterials and processing technologies for joints for prolonged pain relief and mobility. The implant should have the desired balance implants, more so for orthopaedic and dental Thus, the field of arthroplasty has become pop- of mechanical and physical properties neces- applications. ular in the surgical world and, according to the sary to perform as expected. The specific opti- medical term, means surgical repair of joints mization of properties such as elasticity, yield (Ref 2). Currently, one of the main achieve- stress, ductility, time-dependent deformation, Need for Prostheses ments in the field of arthroplasty is total joint ultimate strength, fatigue strength, hardness, replacement (TJR), where the entire load- and wear resistance really depends on the type The first question to ask while undertaking bearing joint (mainly in the knee, hip, or shoul- and functionality of the specific implant part. such a study is “What is the need for implants to der) is replaced surgically by ceramic, metal, or The device under question should be rela- replace or fix human joints during traumatic con- polymeric artificial materials. As stated earlier, tively easy to fabricate, being reproducible, ditions?” Human joints are complex and delicate the problem is that not all artificial materials consistent, and conforming to all technical structures capable of functioning under critical could be used for such purposes, only the ones and biological requirements. Some of the con- conditions, and it is a great challenge for doctors that fulfill certain broad specifications. straints could include the techniques to pro- as well as scientists to develop site-specific In comparison, the human tooth, consisting of duce excellent surface finish or texture, the implants that can be used in a human body to enamel, dentin, pulp, and cementum, is a highly capability of the material to achieve adequate serve a specific purpose for orthopaedic, dental, specialized calcified structure used to break sterilization, and the cost of production. The ophthalmological, cardiovascular, cochlear, and down food. It is a site where most surgical proce- repair of such implants in case of failure is also maxillofacial applications. dures in humans are performed, requiring very important. It has been noted that for any Synovial joints such as hips, knees, and implants of a subperiosteal (in contact with exte- dental prostheses or TJR surgery, the revision shoulders perform due to the combined efforts rior bone surface) or endosteal (extending into surgery of an implant is more difficult, has of articular cartilage, a load-bearing connective the bone tissue) nature (Ref 6). The fixtures can lower success rates, and may induce addi- tissue covering the bones involved in the joints, be either fixed or removable, which really tional damage to the surrounding tissues and synovial fluid, a nutrient fluid secreted depends on the type of employed prostheses, a (Ref 8). Unfortunately, in vivo degradation, within the joint area (Ref 2–4). However, these majority of which involve complete or partial primarily due to the higher wear rates asso- joints are more often than not prone to degener- dentures. In any case, the biomaterial interaction ciated with artificial implant materials and ative and inflammatory diseases that result in and tissue reaction of these implants, along with the consequent adverse biological effect of pain and joint stiffness (Ref 5). Apart from other intraoral devices, is critical for the stability the generated wear debris, results in a shorter the usual decay of articular cartilage due to and sustainability of dental prostheses. lifetime for these artificial implants when age, there are illnesses such as osteoarthritis The following section outlines some of the compared with their natural counterparts. (inflammation of bone), rheumatoid arthritis selection criteria that must be kept in mind Thus, it is imperative to account for the physi- (inflammation of synovial membrane), and when choosing an implant material for a spe- cal stability of the foreign material once it is chondromalacia (softening of cartilage). An cific purpose. placed inside a human body. Fundamentals of Medical Implant Materials / 7

Apart from these factors, the selection of extracellular matrix of connective tissue, such pacemaker cases, and heart valve cages the implant material itself is the principal crite- as tendons, ligaments, skin, blood vessels, and (Ref 18). To improve the strength for load- rion for proper functioning. No amount of bone. However, they are very difficult to pro- bearing applications such as total joint replace- design changes can help if the material is not cure and reproduce on a regular basis. Gener- ments, the alloy Ti-6Al-4V ELI (ASTM F136, biologically and mechanically compatible. ally, synthetic polymers are synthesized by the extra-low interstitial, or ELI, alloy com- That, along with the surgery location and polymerization and condensation techniques posed of titanium, 6 wt% Al, and 4 wt% V) desired functioning of the artificial joint, deter- to form long chains of the desired shape and was chosen. This Ti-6Al-4V alloy was origi- mines what material should be used. For exam- property (Ref 6). Other synthetic materials, nally developed for aerospace applications and ple, smaller implants used for cochlear and such as fibers and biotextiles, are prepared by had superior performance in the field of avia- dental prostheses are manufactured using a melt spinning and electrospinning, while hydro- tion, with an elastic modulus of approximately plastic or ceramic material. However, for gels are prepared by simply swelling cross- 110 GPa (16 106 psi) (Table 1), only half that making total hip replacements and total knee linked polymeric structures in water or other of 316L stainless steel. It was used for TJR sur- replacements, metals are considered the best biological fluids. gery with modular femoral heads and for long- candidate due to their higher tensile load- term devices such as pacemakers. However, it bearing capabilities. The various parts of hip was soon discovered that the presence of vana- and knee implants require different property char- Development of Implant Materials dium caused cytotoxicity and adverse tissue acteristics. Thus, it is understandable that for best reactions (Ref 19, 20). Thus, niobium and iron results, modern-day implants such as the Trape- Metallic Implants were introduced, replacing vanadium, to zoidal-28 (T-28) hip (Ref 9, 10), the Burstein- develop alloys such as Ti-6Al-7Nb (Ref 21) Lane (B-L) knee (Ref 11), or the Total Condylar In the early days of arthroplastic surgery, and Ti-5Al-2.5Fe (Ref 22). Other alloys with Prosthesis Knee (Ref 12) are assembled by joining stainless steel was considered a viable implant aluminum additions, such as Ti-15Mo-5Zr-3Al the various components made of metals, ceramics, material mainly because of its availability and (Ref 23) and Ti-15Mo-2.8Nb-3Al (Ref 2), were and/or polymers to form one unit. processing ease. Alloying additions of chro- tried. Further studies showed that the release of For metallic implants, casting and forging mium, nickel, and molybdenum were made to both vanadium and aluminum ions from the metallic components is still one of the most the ferrous matrix to prepare alloys such alloys may cause long-term health problems, accepted techniques in the implant fabrication 316L, also known as ASTM F138 (Ref 2). They such as peripheral neuropathy, osteomalacia, area, even though minuscule cracks and inho- were primarily used to make temporary devices and Alzheimer diseases (Ref 24, 25). Thus, mogeneous composition of parts provide major such as fracture plates, screws, and hip nails. Ti-6Al-4V somewhat lost its importance as the hurdles for the process (Ref 13). Along with However, as TJR surgery became popular, most viable orthopaedic alloy. that, the fabrication technique itself has some it was evident that the very high modulus of These circumstances led to an urgent need impact on implant performance. For example, stainless steel (200 GPa, or 29 106 psi) to develop newer and better orthopaedic alloys. preparing rough, serrated implant surfaces helps was a deterrent (Table 1). Also, researchers This required the researchers to first identify in better cell adhesion, differentiation, and pro- started looking for alloys that were more bio- those metallic elements that were completely liferation (Ref 14, 15). Having porous implants compatible and corrosion and wear resistant. biocompatible and could be alloyed with tita- has shown to help in the growth and attachment Cobalt-base alloys came into the picture where nium. The ideal recipe for an implanted alloy of bone cells. wrought alloys were used to fabricate prosthetic included excellent biocompatibility with no Ceramic devices are manufactured by a vari- stems and load-bearing components. Even adverse tissue reactions, excellent corrosion ety of techniques. Typical powder-metallurgy- though they offered excellent corrosion resis- resistance in body fluid, high mechanical based routes follow compaction and solid-state tance, wear resistance, and fatigue strength, strength and fatigue resistance, low modulus, sintering of powdered ceramics (alumina and these Co-Cr-Mo alloys (ASTM F75 and F799) low density, and good wear resistance. Unfortu- calcium phosphate) or metal-ceramic compo- still had higher modulus (210 GPa, or 30 nately, only a few of the alloying elements sites (CermeTi, Dynamet Technology, Inc.) 106 psi) (Table 1) and inferior biocompatibility do not cause harmful reactions when planted (Ref 16). Depending on the property require- than what was desired for implant materials inside the human body (Ref 26). These include ment, the heating schedules can be varied (Ref 2). After the early 1970s, titanium alloys titanium, molybdenum, niobium, tantalum, zir- to determine grain size and crystallinity. For started to gain much popularity due to their conium, iron, and tin. Of these, only tantalum example, sintering at a higher temperature excellent specific strength, lower modulus, showed an osseocompatibility similar to that (liquid-phase sintering or vitrification) is often superior tissue compatibility, and higher corro- of titanium. However, its high atomic weight done to produce a combination of fine-grained sion resistance (Ref 17). Commercially pure prevented tantalum from being used as a crystalline matrix with reduced porosity (Ref titanium (ASTM F67) was the first to be used primary alloying addition. In fact, the biocom- 6). Other materials, such as hydroxyapatite, because its oxide (titanium in atmosphere read- patibility of higher amounts of tantalum and are used as coatings on various biomaterials ily forms a nascent oxide layer) had excellent palladium additions was only tested for dental and are plasma sprayed onto the material. Con- osseointegration properties; that is, human bone and craniofacial prostheses where implant ventional casting routes are adopted to produce cells bonded and grew on the titanium oxide weight would not be of much concern bioceramic glasses. For this, one must ensure layer quite effectively. However, due to its lim- (Ref 27). For other types of load-bearing that the solidification process in this method is ited strength, the implants were confined to spe- implants, several molybdenum- and niobium- slow enough to prevent crystallization (other- cific parts, such as hip cup shells, dental crown base alloys were analyzed. Investigations on wise, polycrystalline products will form). This and bridges, endosseous dental implants, ternary Ti-Mo-Fe alloys were carried out, frustrated nucleation leads to the formation of glasses below the glass transition tempera- ture (Ref 6). If required, these glasses can Table 1 Comparison of mechanical properties of commonly used orthopaedic alloys be annealed at higher temperatures to nucleate and grow crystalline phases in the glassy Modulus Yield strength Ultimate tensile strength 6 matrix, commonly forming a new class of mate- Alloy GPa 10 psi MPa ksi MPa ksi rials called glass-ceramics. Stainless steel 200 29 170–750 25–110 465–950 (65–140) Polymeric implants can be divided into two Co-Cr-Mo 200–230 29–33 275–1585 40–230 600–1795 (90–260) Commercially pure Ti 105 15 692 100 785 115 broad categories: natural and synthetic poly- Ti-6Al-4V 110 16 850–900 120–130 960–970 140–141 mers. Natural polymers are made of an 8 / Introduction where the strengthening effect of the iron addi- b-type titanium alloys. This shift in the search the modulus of the implant alloys to match that tion was studied in a Ti-7.5Mo alloy (Ref 28, for better biomaterials from a/b-titanium to of the bone tissue, Ti-6Al-4V and related a/b 29). Guillermot et al. conducted tests on Ti- b-titanium alloys could be explained by the fact alloys were considered to be inferior. The Mo-Fe-Ta alloys with hafnium additions that the latter fit in very well with the tight b-titanium alloys have a microstructure pre- (Ref 30). The early works of Feeney et al. mechanical property requirements of orthopae- dominantly consisting of b-phase that exhibits focused on one of the most promising quater- dic alloys. Two of those important properties lower overall moduli. Table 2 shows that Ti- nary molybdenum-base b-titanium alloys, include yield strength and elastic modulus. 15Mo-5Zr-3Al, Ti-12Mo-6Zr-2Fe, Ti-15Mo- Ti-11.5Mo-6Zr-4.5Sn, also known as bIII Yield Strength. The yield strength deter- 3Nb-0.3O (21SRx), and Ti-13Nb-13Zr have (Ref 31). The phase transformations occurring mines the load-bearing capability of the elastic moduli ranging from 74 to 88 GPa in these alloys were found to be similar to implant. For example, in the case of TJR sur- (11 to 13 106 psi), which is approximately that of binary titanium-molybdenum alloys. geries where a high load-bearing capability of 2 to 7 times higher than the modulus of bones. At room temperature, the as-quenched bIII the implant is essential, one ideally needs an Fatigue. Variable fatigue resistance of the alloy showed low yield strength, high ductility, appropriately high yield strength value of the metallic implants is also a cause of concern and high toughness. The effects of iron in alloy. Thus, the orthopaedic alloys should have while developing an alloy. The orthopaedic titanium-molybdenum alloys (Ref 28) and the a sufficiently high yield strength value with implants undergo cyclic loading during body superior properties of bIII (Ref 31) were finally adequate ductility (defined by percentage elon- motion, resulting in alternating plastic deforma- combined together to develop Ti-12Mo-6Zr- gation or percentage reduction of area in a stan- tion of microscopically small zones of stress 2Fe (Ref 32, 33), which recorded superior yield dard tensile test). Table 2 lists the yield strength concentration produced by notches and micro- strength and modulus values. A parallel, if not and ultimate tensile strength values of some structural inhomogeneities. Standard fatigue better, effort was made to develop niobium- of the common titanium alloys. Interestingly, tests include tension/compression, bending, base b-titanium alloys. Karudo et al. (Ref 34) some of the metastable b-titanium alloys do torsion, and rotation-bending fatigue testing and Tang et al. (Ref 35) developed some alloys exhibit very high values in comparison to the (Ref 2). based on the Ti-Nb-Ta, Ti-Nb-Ta-Zr, Ti-Nb- a-ora/b-titanium alloys. There were several advantages and disadvan- Ta-Mo, and Ti-Nb-Ta-Sn systems. Of the Elastic Modulus. A number of experimental tages of the various alloys that were researched, different alloys that were chosen, the tensile techniques have been used to determine the and many more will probably be developed and strength and elongation of Ti-29Nb-13Ta- elastic properties of solids (Ref 43). There tested in the near future. Two of the most 4.6Zr alloy were found to be greater than or is always a concern for the relatively higher promising alloys appear to be the Ti-35Nb- equivalent to those of conventional titanium modulus of the implant compared to that of 7Zr-5Ta (often referred to as TNZT) and alloys for implant materials (Ref 36–38). the bone (10 to 40 GPa, or 1.5 to 6 106 Ti-29Nb-13Ta-4.6Zr (often referred to as On comparing the hardness values of the psi) (Ref 2). Long- term experiences indicate TNTZ) compositions, mainly because these quaternary alloys, it was evident that the homo- that insufficient load transfer from the artificial alloys exhibit the lowest modulus values genized samples had higher hardness than implant to the adjacent remodeling bone may reported to date—55 GPa (8 106 psi) in the air- or water-quenched samples. Finally, result in bone reabsorption and eventual loosen- the case of TNZT, almost 20 to 25% lower than the dynamic moduli were observed to be lowest ing of the prosthetic device (Ref 44, 45). It other available alloys (Ref 2, 42). While TNZT at 5 at.% Zr and a niobium/tantalum ratio of has been seen that when the tensile/compressive was developed at Clemson University by Rack 12.0, which was attributed to the preferred site load or the bending moment to which the et al. (Ref 42), TNTZ was developed at Tohuku occupancy of niobium, tantalum, and zirconium living bone is exposed is reduced, decreased University, Sendai, Japan, by Niinomi et al. within the body-centered cubic unit cell and its bone thickness, bone mass loss, and increased (Ref 34). TNZT is now commercially sold by effect on the nature of bonding (Ref 35, 39). osteoporosis occur. This is termed the stress- Allvac in the United States as TiOsteum and The alloys that possessed the lowest moduli shielding effect, caused by the difference in TiOstalloy. Its low yield strength value (547 were Ti-35.5Nb-5.0Ta-6.9Zr and Ti-35.3Nb- flexibility and stiffness, which is partly depen- MPa, or 79 ksi) was increased by adding inter- 5.7Ta-7.3Zr. dent on the elastic moduli difference between stitial oxygen; thus, Ti-35Nb-7Zr-5Ta-0.4O Based on this research, a number of contem- the natural bone and the implant material showed a strength of 976 MPa (142 ksi) and porary and prospective alloys were developed, (Ref 46). Any reduction in the stiffness of the a modulus of 66 GPa (9.6 106 psi) (Ref 42). such as Ti-12Mo-6Zr-2Fe (Ref 32, 33); Ti- implant by using a lower-modulus material 15Mo-3Nb-0.3O (Ref 40); interstitial oxygen, would definitely enhance the stress redistribu- Ceramic Implants also referred as TIMETAL 21 SRx; Ti-13Nb- tion to the adjacent bone tissues, thus minimiz- 13Zr (Ref 41); and Ti-35Nb-7Zr-5Ta (Ref 42). ing stress shielding and eventually prolonging Ceramics, including glasses and glass- Interestingly, all these alloys were primarily the device lifetime. In an attempt to reduce ceramics, are used for a variety of implant

Table 2 Mechanical properties of orthopaedic alloys developed and/or used as orthopaedic implants

Elastic modulus Yield strength Ultimate tensile strength Alloy designation Microstructure GPa 106 psi MPa ksi MPa ksi Commercially pure Ti {a} 105 15 692 100 785 115 Ti-6Al-4V {a/b} 110 16 850–900 125–130 960–970 140–141 Ti-6Al-7Nb {a/b} 105 15 921 135 1024 150 Ti-5Al-2.5Fe {a/b} 110 16 914 130 1033 150 Ti-12Mo-6Zr-2Fe {Metastable b} 74–85 10–12 1000–1060 145–155 1060–1100 155–160 Ti-15Mo-5Zr-3Al {Metastable b} 75 10 870–968 125–140 882–975 130–140 {Aged b + a} 88–113 13–16 1087–1284 160–190 1099–1312 160–190 Ti-15Mo-2.8Nb-3Al {Metastable b} 82 12 771 110 812 115 {Aged b + a} 100 14 1215 175 1310 190 Ti-13Nb-13Zr {a0/b} 79 11 900 130 1030 150 Ti-15Mo-3Nb-0.3O (21SRx) {Metastable b} + silicides 82 12 1020 150 1020 150 Ti-35Nb-7Zr-5Ta {Metastable b} 55 80 530 75 590 85 Ti-35Nb-7Zr-5Ta-0.4O {Metastable b} 66 9 976 140 1010 145 Source: Ref 2 Fundamentals of Medical Implant Materials / 9 applications in dental and orthopaedic pros- Among bioinert implant materials, alumina inflammation and risk of toxicity when intro- theses. Implanting ceramics in the body can (Al2O3) is the most commonly known ceramic, duced into the body. The natural set of poly- present a number of different scenarios. The used for load-bearing prostheses and dental mers perform a diverse set of functions bioceramic-tissue attachment can occur due to implants. It has excellent corrosion and wear in their native setting; for example, polysac- physical attachment or fitting of inert ceramic resistance and high strength. In fact, the coeffi- charides such as cellulose, chitin, and amylose to the tissue (morphological fixation), bone cient of friction of the alumina-alumina surface act as membrane support and intracellular com- ingrowth and mechanical attachment into is better than that of metal-polyethylene sur- munication; proteins such as collagen, actin, porous ceramic (biological fixation), chemical faces (Ref 6). It also has excellent biocompati- myocin, and elastin function as structural mate- bonding of bones with the dense, nonporous bility that enables cementless fixation of rials and catalysts; and lipids function as energy ceramic (bioactive fixation), or temporary implants. Purer forms of alumina with finer stores (Ref 51). Also, it is a great advantage attachment of resorbable ceramic that is finally grain sizes can be used to improve mechanical that these naturally occurring implants can replaced by bones (Ref 6). properties such as strength and fatigue resis- eventually degrade after their scheduled “task” One of the most commonly known groups of tance, as well as increase the longevity of the is complete, only to be replaced by the body’s bioactive ceramics is the calcium phosphates. prosthetic devices (Ref 6). Despite these advan- own metabolic process. This degradation rate They are naturally formed in minerals as well tages, the primary drawback of using alumina- can be controlled to allow for the completion as in the human body. These bioceramics can base ball-and-socket joints is the relatively high of the specific function for which the implant be further classified in terms of their calcium- elastic modulus of alumina (>300 GPa, or 44 was introduced. The main problem with these phosphorus ratios. For example dicalcium 106 psi), which can be responsible for stress- naturally formed polymers is their reproducibil- phosphate, tricalcium phosphate, and tetra cal- shielding effects. However, much of this is ity; the material is very specific to where and cium phosphate have calcium-phosphorus solved by using zirconia (ZrO2)-base products which species they are extracted. Also, due to ratios of 1, 1.5, and 2, respectively. In the case that have lower elastic modulus (200 GPa, their complex structural nature, synthetic prepa- 6 of hydroxyapatite (HA, or 3Ca3(PO4)2Ca or 29 10 psi). Again, while both alumina- ration of these materials is very difficult. (OH)2), which is considered a bioactive mate- or zirconia-ceramic femoral heads offer excel- The synthetic polymers can be prepared rial, the calcium-phosphorus ratio is 1.67, and lent wear resistance, these ceramics do not have by addition polymerization (e.g., PE, PVC, this ratio must be accurately maintained. Other- the same level of fracture toughness as their PMMA) or condensation polymerization (e.g., wise, during heat treatments the compound can metallic counterparts, leading to problems such PET, nylon). In the former process, the mono- decompose to more stable products such as a- as fracture of these heads in use. This has even mers go through the steps of initiation, propaga- or b-tricalcium phosphate. To prevent such an led to the recall of hip implants using zirconia tion, and termination to reach a desired length occurrence, many efforts have been directed femoral heads (Ref 49). Furthermore, the of polymeric chain. In contrast, the condensa- toward the development of fabrication routes use of a ceramic femoral head attached to a tion polymerization process usually involves a for HA that mainly involve compaction fol- metallic femoral stem also leads to an undesir- reaction of two monomers, resulting in elimina- lowed by sintering. Despite the enhanced able abrupt ceramic/metal interface in the hip tion of small molecules such as water, carbon efforts toward better processing routes, implant. These are outstanding issues in terms dioxide, or methanol. These materials exhibit abnormalities such as dehydration of HA and of optimized implant design and must be a range of hydrophobic to hydrophilic proper- formation of defects and impurities continue addressed. There are some efforts toward devel- ties and thus are used for specific applications to arise, and such defects can be characterized oping the concept of a unitized implant that only. For example, soft contact lenses that are by x-ray diffraction, infrared spectroscopy, uses a laser-based processing technique to fab- in constant contact with human eyes are prefer- and spectrochemical analyses. Calcium-phos- ricate a monolithic functionally-graded implant, ably made of materials that are hydrophilic, phate-base materials can be used for bioactive the details of which are discussed in the section such as poly 2-hydroxyethyl methacrylate as well as bioresorbable fixations in non-load- “Functionally-Graded Implants: Hybrid Proces- (polyHEMA). bearing parts and for coatings on metallic sing Techniques” in this article. Table 3 lists the applications of various bio- implants via sputtering techniques such as polymers (Ref 6).The mechanical and thermal plasma spraying. Other commonly known pro- properties of polymers are dictated by several cessing routes are based on electrophoresis, Polymeric Implants parameters, such as the composition of back- sol-gel, and electrochemical processing (Ref bone and sidegroups, structure of chains, and 47). Recently, laser-induced calcium-phos- Polymers are the most widely used materials molecular weight of molecules (Ref 50). In phate-base surface coatings have been success- for biomedical devices for orthopaedic, dental, the case of polymers, structural changes at high fully deposited to obtain desired biological soft-tissue, and cardiovascular applications, as temperature are determined by performing dif- properties in terms of cell adhesion, differentia- well as for drug delivery and tissue engineering. ferential scanning calorimetry experiments. tion, and proliferation (Ref 48). These coatings They consist of macromolecules having a large The deformation behavior of polymers can be are ideally expected to be of desired thickness, number of repeat units of covalently bonded analyzed by dynamic mechanical analyses as have excellent adhesion strength, and prevent chains of atoms (Ref 50). The polymers can well as via normal tensile testing of dog bone biodegradation. They are also used for making include a range of natural materials, such as samples. It should be noted here that, compared bone cements, a calcium-deficient HA-based cellulose, natural rubber, sutures, collagen, and to metals and ceramics, polymers have much product for anchoring artificial joints by filling deoxyribonucleic acid, as well as synthetically lower strength and modulus, but they can be in the space between prosthesis and bone. Such fabricated products, such as polyethylene (PE), deformed to a much greater extent before anchoring with soft tissues and bone can also polypropylene (PP), polyethylene terephthalate failure. be achieved by using glasses of certain propor- (PET), polyvinyl chloride (PVC), polyethylene A relatively new area of research has focused tions of SiO2,Na2O, CaO, and P2O5. Ideally, glycol (PEG), polycaprolactone (PCL), polyte- on biodegradable polymers that do not need to such glasses are processed so that they contain trafloroethylene (PTFE), polymethyl methacry- be surgically removed on completion of their less than 60 mol% of SiO2, a high Na2O and late (PMMA), and nylon (Ref 6). task. They are used for five main types of deg- CaO content, and a high CaO/P2O5 ratio (Ref Natural polymers are often pretty similar to radable implant applications: temporary support 6). Depending on the relative amount of the the biological environment in which they are device, temporary barrier, drug-delivery device, aforementioned oxides, they can be bioactive used, because they are basically an extracellular tissue scaffold, and multifunctional implants (form an adherent interface with tissues) or matrix of connective tissue such as tendons, (Ref 6). The additional concern while design- bioresorbable (disappear after a month of ligaments, skin, blood vessel, and bone ing this type of implant is the toxicity of the implantation). (Ref 6). Thus, there is a reduced chance of degradation products, along with the obvious 10 / Introduction

Table 3 Applications of various biopolymers always leads to the formation of chemically abrupt interfaces that are detrimental to the Polymer Application properties of the implant. For example, it Polyethylene (PE) Catheters, acetabular cup of hip joint was a standard convention of using titanium Polypropylene (PP) Sutures alloy stems for orthopaedic applications to Polyvinyl chloride (PVC) Tubing, blood storage bag Polyethylene terephthalate Tissue engineering, fabric tubes, cardiovascular implants be fitted with more wear-resistant cobalt (PET) alloy for the head. However, some of the Polyethylene glycol (PEG) Drug delivery designs showed significant fretting corrosion Polylactic and polyglycolic acid Tissue engineering effects due to micromotion between these Polytetrafloroethylene (PTFE) Vascular grafts Polymethyl methacrylate Hard contact lenses, bone cement for orthopaedic implants components (Ref 54). (PMMA) Polyacrylamide Swelling suppressant The current manufacturing route for implants Polyacryl acid Dental cement, drug delivery does not allow custom designing for specific Polydimethyl siloxane (PDMS) Heart valves; breast implants; catheters; insulation for pacemaker; ear, chin, and nose patients with rapid turnaround times. Conse- reconstruction Cellulose acetate Dialysis membrane, drug delivery quently, instead of custom designing the Nylon Surgical sutures implant, the surgeon is often forced to adapt Source: Ref 6 the pre-existing design to fit the patient’s requirements. This can become particularly challenging if the required physical dimensions of the implant differ substantially from those of biocompatibility issues of all implant materials. porous body and bioactive inorganic phase con- the standard manufactured ones, for example, The terms biodegradation, bioerosion, bioab- fined inside the pores. Again, PMMA/PCL implants to be used for children. sorption, and bioresorption are all loosely beads formulated with partially biodegradable To get around this problem, a novel proces- coined in the medical world to indicate that acrylic cements were used for delivery of drugs sing technique called Laser Engineered Net the implant device would eventually disappear such as antibiotics, analgesics, or antiinflamma- Shaping (LENS) (Sandia National Labora- after being introduced into the body (Ref 6). tories (Ref 53). tories) shows great promise. Similar to rapid The successful use of a degradable polymer- prototyping technologies such as stereolithogra- based device depends on understanding how phy, the LENS process (Ref 55, 56) begins with the material would lose its physicochemical a computer-aided design file of a three-dimen- properties, followed by structural disintegration Functionally Graded Implants— sional component, which is sliced into a series and ultimate resorption from the implant site. Hybrid Processing Techniques of layers electronically. The information about Despite their potential advantages, there are each of these layers is transmitted to the only a limited number of nontoxic materials As amply evident from the discussions in the manufacturing assembly. A metal or alloy sub- that have been successfully studied and preceding sections, the need for prosthesis strate is used as a base for depositing the approved by the U.S. Food and Drug Adminis- implants, ranging from dental to orthopaedic component. A high-power laser (capable of tration as degradable biopolymers. These applications, is increasing at an alarming rate. delivering several hundred watts of power) is include polylactic acid, polyglycolic acid, poly- While currently-existing implants function focused on the substrate to create a melt pool dioxanone, polycaprolactone, and poly(PCPP- appropriately, they do not represent the best into which the powder feedstock is delivered SA anhydride), along with the naturally occur- compromise of required properties. Further- via an inert gas flowing through a multinozzle ring collagen, gelatin, and hyaluronic acid more, the present manufacturing of implants is assembly. The powder-feeder system of the (Ref 6). largely via subtractive technologies involving LENS system consists of multiple hoppers. By Several totally or partially biodegradable substantial material waste, leading to increased controlling the deposition rates from individual self-polymerizing composites are being used costs and time of production. Therefore, an hoppers, it is possible to design composition- for orthopaedic surgery and dental applications. imperative need exists for functionally-graded ally-graded and, consequently, functionally- For fixation of endoprostheses, self-curing implants representing a better balance of prop- graded materials, as demonstrated in a number acrylic resins based on blends of PMMA parti- erties and manufactured via novel additive of previous papers on laser-processed composi- cles and MMA monomer or a copolymer of manufacturing technologies based on near-net tionally-graded titanium alloys (Ref 57–59). MMA with styrene are often used (Ref 52). shape processing. The nozzle is designed such that the powder The slurry containing the aforementioned Some specific problems associated with cur- streams converge at the same point on the blends can be introduced into the bone cavity. rently-used implant manufacturing processes focused laser beam. Subsequently, the substrate The use of biodegradable composites is greatly and the consequent compromise in properties is moved relative to the laser beam on a com- encouraged for making bone cements and beads are listed as follows: puter-controlled stage to deposit thin layers of for drug-delivery applications. This is primarily controlled width and thickness. There are four due to their minimal release of residual mono- The manufacturing is based on conventional primary components of the LENS assembly: mers along with their ability to control the casting and forging of components, followed the laser system, the powder-delivery system, resorption rates in conjunction with bone by material-removal steps via subtractive the controlled-environment glove box, and the ingrowth. Biodegradable antibiotic-loaded technologies such as precision machining. motion-control system. A 750 W neodymium: beads have the advantage of releasing the entire These technologies not only involve sub- yttrium-aluminum-garnet (Nd:YAG) laser, load of drug as they degrade (Ref 52). Compo- stantial material waste but are also limited which produces near-infrared laser radiation at sites based on polypropylene fumarate and to monolithic components without any com- a wavelength of 1.064 mm, is used for all the PMMA are being used extensively for these positional/functional changes within the depositions. The energy density is in the range purposes. For example, partially resorbable same component. of 30,000 to 100,000 W/cm2. The oxygen polymeric composites with bioactive properties Diverse property requirements at different content in the glove box is maintained below have been prepared by adding aqueous a- tri- locations on an implant are satisfied by join- 10 ppm during all the depositions. The powder calcium phosphate dispersions to PMMA bone ing different components (e.g., femoral stem flow rates are typically 2.5 g/min, while cement (Ref 53). The resulting composite was and femoral head) made of different materi- the argon volumetric flow rate is maintained a suitable bone substitute with a polymeric als in a total hip replacement system. This at 3 L/min. The LENS offers a unique Fundamentals of Medical Implant Materials / 11 combination of near-net shape manufacturing property requirements at different locations of materials. The tendency for high-impact frac- and rapid solidification processing that can be the monolithic implant are quite different. As ture makes these materials fragile. A more particularly useful for manufacturing orthopae- discussed earlier, the LENS technique with appropriate approach may be to manufacture dic implants. A schematic representation of multiple powder feeders is a viable tool to the core of the femoral stem and head assembly the LENS process is shown in Fig. 1. From produce a functionally graded implant in its in the form of a single monolithic component the viewpoint of making implants based on near-net shape form with site-specific proper- and use surface engineering to improve the metallic, ceramic, or even hybrid materials, ties. The basic core structure (hollow or similar wear resistance of the base titanium alloy compositional gradation can be particularly to the prototype shown in Fig. 2) of the femoral locally in the femoral head section. The LENS beneficial because it will enable the develop- stem and head assembly can be fabricated using process could be quite handy in implementing ment of custom-designed orthopaedic implants LENS. such an idea, where the core of the femoral with site-specific properties. Furthermore, engi- However, instead of conventional alloys such head could be made of tough b-titanium alloy neering functional gradation in these implants as Ti-6Al-4V, the material of choice for the (such as Ti-Nb-Zr-Ta), and there could be will allow for a single unitized component to core of the femoral stem and head assembly a radial gradation of optimal amounts of be manufactured without any chemically or could be based on one of the newer-generation boride (or carbide) precipitates dispersed within structurally abrupt interfaces, leading to low-modulus, biocompatible beta-titanium the matrix. This comes from the idea that enhanced properties and performance. alloys, such as those based on the Ti-Nb-Zr- hard titanium boride (or titanium carbide) pre- Surface engineering of the near-net shape Ta system. To achieve an optimal balance of cipitates within the soft beta-titanium matrix laser-processed implant can be carried out using mechanical properties, both solid geometries can enhance the wear resistance of these a number of related processing techniques. in terms of femoral head and stem, along with metal-matrix-based hybrids quite substantially Examples of these include the addition of bio- internal cavities, can be processed together. (Ref 60). ceramic surface layers via a different type of Because the surface of the femoral stem is The basic parts of the functionally-graded hip laser deposition to improve osseointegration of required to exhibit excellent osseointegration implant that can be manufactured by using the the implant, and the addition of wear-resistant properties, additional roughness can be intro- LENS process include: coatings via sputter deposition or other physical duced on the surface of the stem by laser vapor deposition techniques. depositing lines of the same alloy or even bio- Femoral stem: Made of beta-titanium-base compatible coatings such as calcium phosphate Ti-Nb-Zr-Ta alloys Functionally Graded Hip Implant in the form of a grid (Ref 48). The pattern of Femoral head: Made of metal-matrix-based these lines/grids can be optimized for achieving hybrid materials with radial gradations from Ti-Nb-Zr-Ta- to Ti-Nb-Zr-Ta-rein- Fabricating implants for total joint replace- the best potential of osseointegration based on forced borides (or carbides) ment surgeries such as total hip replacement trial in vitro studies. (THR) is rather challenging because the In contrast, the femoral head material must possess excellent wear resistance, especially in Subsequent to LENS processing of the femo- the regions that rub off against the internal sur- ral implant, surface engineering strategies can face of the acetabular cup made of ultrahigh- be used to enhance the osseointegration of the molecular-weight polyethylene (UHMWPE). femoral stem. For example, laser-based direct melting techniques may be used to simulta- Thus, ceramic-based materials (e.g., ZrO2) are generally preferred over titanium and its alloys. neously synthesize a physically textured surface As mentioned earlier, one drawback of using involving a substrate (such as Ti-6Al-4V) and a ceramic materials is that they exhibit poor frac- coating (such as calcium phosphate) (Ref 48). ture toughness, and thus, the joint between Such a process can help in systematic organiza- the head and the stem (made of titanium alloy) tion of the calcium-phosphorus coating by creates a weak interface between two dissimilar effectively controlling the thermophysical inter- actions. Furthermore a metallurgically-bonded interface can be obtained by controlling the laser processing parameters, because both the coating and substrate material are melted and solidified at very high cooling rates (104 to 108 K/s). Again, laser-induced surface modifi- cation techniques can be used to increase the wear resistance of the femoral head in hip implants. Reinforcing the soft matrix of metal- lic components (such as new-generation b- titanium alloys) with hard ceramic precipitates such as borides offers the possibility of substan- tially enhancing the wear resistance of these composites (Ref 61). The wear resistance seems to further improve when lubricious ZnO coating is sputter deposited on the surface of these boride-reinforced composites.

Host Response to Biomaterials

The first thing that happens to a living organ- ism after a foreign implant material is intro- Fig. 1 Schematic representation and image of the Fig. 2 Schematic diagram illustrating the functionally Laser Engineered Net Shaping (LENS) laser graded femoral head and stem of a hip duced into the body is its interaction with deposition system implant that can be fabricated using the LENS system proteins such as fibrinogen, albumin, losozyme, 12 / Introduction high- and low-density lipoprotein, and many blood. Fibrinogen, a protein present in blood, indications of infection is pus formation, which others. These proteins are present in large num- reacts with enzymes such as thrombin to form is a result of neutrophils and macrophages that bers within body fluids such as blood, saliva, polymerized fibrin threads or clots. die after killing the foreign parasites. To pre- and tears. Within seconds, the implant surface The cells, on the other hand, constantly adapt vent the spread of infection, fibrous tissues usu- becomes coated with these proteins that, in themselves to the changes in environments ally form around the pus. If these form at the turn, play a vital role in determining the tis- around them. Due to the presence of implants, surface of the skin, as in the case of superficial sue-implant interaction. In fact, the preferential the cells can face trauma by way of physical, immediate infection, the region stretches until it adsorption of proteins (at much higher concen- chemical, or biological agents, causing inflam- bursts open or is surgically drained (Ref 62). trations than the bulk) onto the biomaterial sur- mation. If the tissue injury is minimal or if it The second type of infection, called deep face makes it a biologically recognizable can regenerate (e.g., skin tissue forming due to immediate infection, is the primary effect of material. This not only affects subsequent blood proliferation and differentiation of stem cells), the implantation procedure and is caused by air- coagulation and inflammation, but it is what the then after complete healing, the normal func- borne or skin bacteria that are introduced into cells “see” and respond to. The type of protein tionalities can be achieved. However, scarring the body involuntarily. The biggest threat to as well as the nature of the biomaterial surface can occur, causing permanent loss of cell func- smooth surgery is deep late infection, which is responsible for the aforementioned factors. tionality if the injury is extensive or the tissue occurs several months after the procedure. For proteins to react more readily with the sur- cannot regenerate, for example, heart muscle It may be caused by a longer incubation period face, they must be larger in size and should be cells. Inflammation is an important part of the of the bacteria or even by slower development able to unfold at a faster rate. Surfaces, on the wound-healing process following implantation, of the infection. other hand, play their part depending on their often resulting in swelling and redness accom- As mentioned previously, tissue injury due to texture, nonuniformity, hydrophobicity, and panied by heat and pain. It involves the migra- implantation can affect the morphology, func- composition (Ref 50). Typically, proteins are tion of cells to the injury site via a process tion, and phenotype of the cells (Ref 50). The brought onto the surface of the foreign body called chemotaxis, removing the dead cellular change in environment due to the presence of via diffusion and/or convection. Variables such and tissue material from the site, destroying or implants can temporarily or permanently alter as concentration, velocity, and molecular size quarantining all the harmful biological and the functionality of surrounding tissues, for are important factors that determine such a chemical substances, and making sure that tis- example, bone loss due to the stress-shielding movement. At the surface, the protein mole- sue rebuilding can start. During inflammation, effect. When blood vessels are damaged, blood cules selectively bind with the substrate at dif- blood flow to the injury site is increased by clotting provides essential time for cell migra- ferent orientations (to minimize repulsive dilation of blood vessels (vasodilation) along tion and proliferation to start the rebuilding pro- interactions) via intramolecular forces such as with increased vascular permeability. Increase cess. This involves inflammation, which is also ionic bonding, hydrophobic interactions, and in blood circulation and metabolism rate causes a necessary step toward successful would heal- charge-transfer interactions (Ref 50). In terms the region to feel warm. Also, the endothelium ing. The cells, promoted by growth factors, syn- of kinetics of adsorption of proteins, the pro- becomes more adhesive, thus trapping and thesize extracellular matrix proteins from the teins initially attach quite rapidly to the largely retaining the leukocytes, present in eosinophil, point of the wound inward (Ref 50). Next open surface. However, at later stages, it is very neutrophil, and basophil, at the trauma site. comes the formation of new blood vessels that difficult for the arriving proteins to find and fit These cells are responsible for killing the are necessary to aid the newly formed tissues. into the empty spaces. This causes conforma- invading pathogens, such as viruses, bacteria, Due to the macrophages, endothelial cells, and tional changes so as to increase their contact and fungi, and consuming the foreign objects, several growth factors, the environment at the points with the surface, by molecular spreading such as debris from biomaterials, damaged tis- wound site is made suitable for development or by increasing the concentration of these sue, and dead cells (Ref 50). While basophils of endothelial cells to form capillaries. The molecules. Most adsorbed proteins are irrevers- and eosinophils are responsible for releasing newly formed tissue, called granulation tissue, ibly attached to the surface, meaning that once harmful chemicals to kill the attacking foreign consists of smaller blood vessels and is very they are attached, it is very difficult to detach parasites, the neutrophils help in phagocytosis delicate. At a later stage of wound healing, the them. In fact, desorption of protein molecules of foreign particles. Phagocytosis at all levels remodeling phase begins, where the newly would require a simultaneous dissociation of all involves identifying or marking the foreign formed tissue may have the structural and func- interactions between the molecule and the sur- objects, surrounding and engulfing them, and tional characteristics of the original tissue. Oth- face (Ref 50). Nevertheless, at longer times, the finally releasing harmful chemicals to destroy erwise, remodeling may cause scar tissue adsorbed molecules can eventually exchange them. Phagocytosis is also the primary function formation with reduced functionality. with other competing protein molecules that of macrophages that form during the phase of How long does it take for the entire wound have stronger interaction with the surface (Vro- chronic inflammation, leave the blood stream, healing to successfully take place? It depends man effect). For example, in blood, which has and attach themselves to tissues at the site of on several factors, from the proliferative capac- more than 150 proteins, albumin dominates the implantation (biomaterial surface). These take ity of cells to the type of tissue and from the initial interaction with the surface, primarily some time to form, unlike the neutrophils that severity of wounds to the health condition and due to its high concentration and mobility. How- result from an immediate response to injury age of the patient (Ref 50). Typically after sur- ever, in due course, other proteins such as immu- (active inflammation). The macrophage cells gery, the clotting of blood occurs almost instan- noglobulin G and fibrinogen, which have much usually span close to 50 to 100 mm, can live taneously. The migration of leukocyte cells less mobility but a higher affinity with the sur- from a couple of months to a year, and are con- takes place within a couple of days. In contrast, face, can exchange with the albumin molecules sidered the first line of defense. These macro- the macrophages migrate to the trauma site and form a stable coating (Ref 50). phages can also fuse together and form within a week. The tissue rebuilding and repair During implantation of a biomaterial, knowl- multinucleated foreign body giant cells that can last for several weeks, with the remodeling edge of the aforementioned processes is very can phagocytose even larger particles. phase extending for as much as a couple of important, because bleeding and injury of cells Along with inflammation, there may be years (Ref 50). is a part of the wound-healing process. (While undesired colonization of tissue by bacteria, blood is a mixture of plasma, red blood cells, fungi, or viruses during biomaterial implanta- white blood cells, and platelets, cells join tion. This is called infection, which is a serious Implant Failure together to form tissue, muscle, nerves, and cause of concern during surgery. It should be even the epithelium.) During injury, the endo- noted that infection can result in inflammation, From the time an implant is introduced into thelial cells and collagen fibers are exposed to but the reverse may not be true. One of the the body via invasive surgery, the biomaterial Fundamentals of Medical Implant Materials / 13 remains in prolonged contact with the cells and degradable and/or can be removed by existing culture medium. After the test, the cells are tissues. There are four different types of tissue metabolic pathways (Ref 50). Another compli- stained by hematoxylin blue, and the toxicity responses to the biomaterial: cation of implant surgery is the formation of is evaluated by the absence of stained cells, fibrous tissue around the surface. The thickness because dead cells do not stain. The main prob- The material is toxic, and the surrounding and texture of fibrous tissues formed around the lem with this type of test is cell trauma and tissue dies. implant can depend on the type of implant death due to movement of the sample or the The material is nontoxic and biologically material, size and shape of the implant, site of weight of highly dense materials. This is over- inactive, and a fibrous tissue forms. surgery in terms of functionality, and type of come by the agar diffusion test, where the agar The material is nontoxic and active, and the tissue that needs to be healed. The problem (colloidal polymer from red algae) forms a tissue bonds with it. occurs when such layering prevents the normal layer between the test sample and the cells. In The material is nontoxic and dissolves, and operation of the implant in terms of mechanical this assay, the healthy cells are stained red as the surrounding tissue replaces it (Ref 6). function and drug delivery (Ref 50). These compared to dead or affected cells. The main issues are further complicated if superficial problem with this type of test is the risk of the The implant material, its geometry, and the and deep infections occur due to the coloniza- sample absorbing water from the agar, thus environmental conditions around it play a very tion of bacteria, fungi, and viruses around the causing dehydration of the cells. The third type important role in governing how the proteins implant. Medications may not work due to the of test, elution, is conducted in two separate interact with the foreign substance, and the presence of an impervious fibrous layer, and steps: extraction of fluid (0.9% NaCl or ensuing cell adhesion occurs via receptors in the removal of the implant may be the only serum-free cultural medium) that is in contact the cell membrane. The various steps of the option. with the biomaterial, and biological testing of physiological wound-healing process, including To prevent such failures, several precautions the medium with cells. Although this type of the activation of neutrophils and macrophages, are usually taken before using an implant for a testing is time-consuming, it is very effective. and the differentiation and proliferation of the prosthesis. The first step is to evaluate the mate- It is universally observed and accepted that adhered cells in turn determine the structure rial itself, because it is known to be the most materials found to be nontoxic in vitro are non- and functionality of the neighboring tissues. In common reason for implant failure. Unsuitable toxic in in vivo assays as well (Ref 6). fact, evidence has shown that macrophages materials used for a prosthesis would mean that In Vivo Assessment of Tissue Compatibility. and foreign body giant cells can be present at its physical, chemical, and biological properties This type of test is conducted to determine the the implant-tissue interface throughout the are not suitable or compatible for the specific biocompatibility of a prosthetic device and also entire period of implantation, with all of this implant application. The design of the device to assess whether the device is performing being a part of foreign body reaction (Ref 50). is the next critical item. Information from past according to expectations without causing harm In an ideal situation, one would expect that failures as well as upcoming experimental and to the patient. It provides valuable data about the wound-healing process should be smoothly modeling results must be incorporated to arrive the initial tissue response to the biomaterial, completed and proper function of the tissues at better designs. For example, while designing which in turn helps in selection and design of around the implant should be restored. Also, orthopaedic load-bearing implants, data from the device. Some tests, such as toxicity, carci- one would hope that the implant should be finite-element analyses of stress-concentration nogenicity, sensitization, and irritation, deter- integrated with the body, with no short- or points as well as stress-strain results from walk mine if the leachable products of the medical long-term repercussions (failure of implant, simulators are taken into account. During fabri- device affect the tissues near or far from the infection, etc.). cation, the implant should be free of any defects implant site. Other tests, such as implantation However, in real life a number of processes and inclusions that may lead to implant failure. and biodegradation, study the postsurgery can delay and complicate the wound-healing In some cases, the sterilization process itself changes in the implant material itself and their process. Sometimes, the cells around the may cause changes in the structure and property ensuing effect on the body. Overall, there may implant completely reject it, leading to chronic of the prosthetic device. On the other hand, be an array of tests that must be conducted inflammation, which can lead to removal of incomplete sterilization can also lead to infec- and evaluated, depending on where and why a the biomaterial. This type of situation may arise tion, as with improper packaging and shipping. specific device is used, before certifying an for various reasons, such as inappropriate heal- After the implant is fabricated, both mechanical implant. For conducting the actual in vivo tests, ing (too little or overgrowth of the tissue) and (tensile, wear, fatigue) and biological (in vitro, animal models (sheep, pig, rat) are usually structural failure or migration of the implant in vivo) testing must be conducted to determine selected after weighing the advantages and dis- (wear, fracture, stress shielding) (Ref 6). Wear- its feasibility. While the mechanical testing pro- advantages for human clinical applications. ing or fracture of implants can cause debris for- cesses have been discussed in the section As evident from the previous discussions, a mation, which is more often observed in “Development of Implant Materials” in this variety of tests can be conducted before a pros- metallic materials. During dynamic loading/ article, a brief discussion of the biological tests thetic device is considered suitable for implan- unloading of load-bearing implants (hip, knee, follows. tation. The choice of test depends on the etc.), constant friction between two articulating In Vitro Assessment of Tissue Compatibility. specific application of the implant under con- parts can lead to the release of small particu- This usually involves performing cell cultures sideration. Sometimes, it is very difficult to rep- lates that are detrimental to the body. Stress for a wide variety of materials used in medical licate the exact test, even while performing in shielding is also a serious problem for load- devices. Three different cell culture assays are vivo tests. For example, there is no adequate bearing implants, where unequal distribution used for in vitro study: direct contact, agar dif- animal model to study the inflammatory reac- of the load between the implant and the bone fusion, and elution. In all the tests, experimen- tion to wear debris near hip joints (Ref 6). around it may lead to reabsorption. Other phys- tal variables such as cell type (usually L-929 After successful completion of all these iological reasons for implant rejection could be mouse fibroblast), number of cells, duration of steps, the implant is finally ready to be surgi- leaching out of ions (metals), degradation of exposure, and test sample size are kept constant cally inserted into a patient. The prosthetic material due to interaction with enzymes (poly- (Ref 6). Positive and negative controls are often device is chosen based on the patient and the mers), and inadequate encapsulation of the used during the assay test to determine the via- site of implantation. Each patient is different. implant surface via proteins and cells (Ref bility of the test. In all cases, the amount of He/she may have different allergic reactions 50). Although introduction of biodegradable affected or dead cells in each assay provides a to implant materials, may have previous polymers can minimize issues in this aspect, measure of the cytotoxicity and biocompatibil- health conditions unsuitable for the prosthesis, upon completion of their scheduled task, these ity of the biomaterials. In the direct contact test, or may even have different immunological materials degrade into by-products that are the material is placed directly on the cell responses to fighting infection. Failures can 14 / Introduction also be caused by the misuse of implants. For In the presence of various physical, chemical, calcium phosphate (Fig. 4) (Ref 48, 67). Laser- example, a patient who has undergone total and biological stimuli, the polymers exhibit dif- engineered textured materials can also promote hip replacement surgery can cause severe dam- ferent responses, such as gelation, surface directional growth and movement of cells. Other age and loosening of the implant by excessive adsorption, and collapse of hydrogel. All of these physicochemical methods are also being used to exercising before proper healing takes place responses are reversible processes, and, in the change the surface composition as well as the (Ref 6). All of these factors can single-handedly absence of the stimuli, the response is also biochemical properties of the surfaces. The latter or jointly contribute to improper functioning reversed (Ref 6). These smart polymers are even approach uses the organic components of bone to and eventual failure of implant devices. combined with biomolecules to enhance their affect tissue behavior by introducing peptides The implant structure should be carefully use beyond implant devices. These types of poly- and proteins. Many bone growth factors could analyzed postfailure to determine the exact mers, in combination with proteins and drugs, be used to influence the growth and differentia- cause and mechanism by which it failed. This can be used in solution, in surfaces, and as hydro- tion of osteoblasts (Ref 50). Even tissue engi- can lead to the improvement of processing tech- gels for applications such as drug delivery, neering approaches have been used to stimulate niques and materials used for fabricating removal of toxins, and enzyme processes (Ref precise reactions with proteins and cells at a the device, can help in bettering the design 6). To improve the osseointegration properties, molecular level. As mentioned previously, the and testing mechanisms used for these pro- the polymer matrices are filled with HAs. These cell and tissue response to implantation is greatly ducts, and can provide enough insight into materials contain approximately 50 vol% HA in dependent on what they “see” on the surface of adopting alternate surgery procedures and drug a polyethylene matrix and are used to make the foreign device. Even the interaction of cells therapy postimplantation (Ref 6). Thus, implant implants for ears (Ref 64). with the extracellular matrix (ECM) depends retrieval and evaluation is a vital study to Similarly, the osseointegration properties of on the rigidity of the substrate. Adhesive sur- determine the safety and biocompatibility of ceramics and metals can be improved by introdu- faces created by targeted use of proteins, pep- implants. Along with the implant material, cing porosity on those surfaces that are in direct tides, and other biomolecules help in examination of the tissue must be conducted contact with the bone. The growth of bones into mimicking the ECM environment (Ref 6). Even to assess the implant-tissue interface. At first, these pores would also ensure good mechanical chemically patterned surfaces, aided by techni- the overall implant and tissue specimen can be stability of both load-bearing and non-load-bear- ques such as photolithography, could be used to analyzed by light microscopy and cell culture, ing implants. Research has shown that optimal control cell adhesion at certain specific regions. respectively. Consequently, specific aspects of engineered porosity, fabricated by laser-deposi- In the future, several of the aforementioned sur- the material can be studied using techniques tion processes such as LENS with pore sizes in face-modification techniques could be combined such as scanning electron microscopy, trans- the range of 100 to 150 mm, can promote the to design devices with chemically engineered mission electron microscopy, energy-dispersive growth of osteoblast cells within these pores surfaces and controlled scaffold architecture that spectroscopy, contact-angle measurement, (Ref 65). Figure 3 shows one such study, where could manipulate specific cell growth, which in Fourier transform infrared spectroscopy, and Ti64 samples containing different sizes of engi- turn develops into specialized tissues. scanning ion mass spectroscopy. Similarly, neered porosity were fabricated by LENS. The Using this same concept has led to the design studies of proteins and genes can be conducted implant in this case acts as a scaffold for bone of multifunctional devices. Their application is on the tissue sample. Compilation of these data formation. For smaller pores, the fibrous tissue thought to be a combination of a variety of can aid in the development of next-generation occupies the void space, because an extensive functions that require the design of materials implants. A good example of the benefits of capillary network for osteogenesis does not with specific properties. For example, the implant evaluation is the modern use of occur (Ref 50). The degree of porosity of these development of biodegradable bone nail can UHMWPE as a polymeric cup instead of syn- materials has a big impact on bone integration provide mechanical support to fracture sites as thetic fluorine-containing resin, with which and modulus, with substantial reductions in well as ensure growth on new bone at implant some biological problems were encountered. modulus with increasing porosity. However, sites (Ref 6). As mentioned previously, biode- In the case of dental implants, the integration with increase in porosity, the strength of the gradable materials are used more and more for of bone with the metal was far better under- implant material reduces drastically, which this purpose, and the use of other functional stood after evaluation of failed fixtures. could be a big challenge for load-bearing combinations involving tissue-engineering scaf- implants. Other surface-modification techniques folds is also being actively considered. In the are currently being studied to promote bone future, these scaffolds could provide structural Summary growth, including increasing the surface rough- stability as well as serve as a means for drug ness of the device, using nanograined materials delivery (Ref 6). According to D.F. Williams in 1987, biocom- (Ref 66) to increase the surface area, and coating Similar to cell-biomaterial interaction, another patibility can be defined as the capability of a the implant with bioactive materials such as cause of concern is the blood- biomaterial medical device (implant) to perform with an appropriate host response in a specific applica- tion (Ref 63). Various parts of the device may be individually assessed, or every part may be considered separately. While the former is the biocompatibility of the device, the latter is the biocompatibility or bioresponse of indi- vidual materials (Ref 6). Either way, it is important to note that no material is suitable for all biomaterial applications. Nevertheless, implant science has been developing new tech- nologies for implant devices as well as improv- ing cell tissue interactions with biomaterials, some of which is discussed next. Over the years, the use of polymers as bioma- Fig. 3 Scanning electron microscopy backscattered electron images of Ti64 samples that were deposited via the terials has increased considerably. Scientists are LENS system using hatch widths of (a) 0.89 mm (0.035 in.), (b) 1.5 mm (0.06 in.), and (c) 2.0 mm (0.08 taking a very active interest in the development in.). The images show three different-sized scales of engineered porosities, resulting in different elastic moduli and of newer stimulus-responsive smart polymers. cell responses. Fundamentals of Medical Implant Materials / 15

been possible. First and foremost, the authors gratefully acknowledge the support, encourage- ment, and, guidance from Professor Hamish Fraser at The Ohio State University for his work on laser deposition of orthopaedic bioma- terials. The authors would also like to acknowl- edge Dr. Narendra Dahotre from the University of North Texas (UNT) for his guidance and support in the laser-deposited calcium phosphate work. The authors would also like to acknowledge the excellent work by graduate students, both past and present, working on this program over a period of time and at different institutions. These include Peeyush Nandwana and Antariksh Singh at UNT.

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