Originally Published January 2001
by Jon Katz
Like other important scientific concepts that change over time, the notion of biocompatibility has evolved in conjunction with the continuing development of materials used in medical devices. Until recently, a biocompatible material was essentially thought of as one that would "do no harm." The operative principle was that of inertness—as reflected, for example, in the definition of biocompatibility as "the quality of not having toxic or injurious effects on biological systems."1
A cartilage repair unit injection molded from biodegradable polylactide (PLA).
When more-recent devices began to be designed with materials that were more responsive to local biological conditions, the salient principle became one of interactivity, with biocompatibility regarded as "the ability of a material to perform with an appropriate host response in a specific application."1 Of course, this conceptual shift was predicated on the ability to determine just what constituted "an appropriate host response"—the result of insights gained through tremendous advances in molecular biology and biological surface sciences. Such progress also lies behind the current definition of biomaterial as "a material intended to interface with biological systems to evaluate, treat, augment, or replace any tissue, organ, or function of the body."2 In particular, the design approach regarding implantable devices—and especially long-term implants—has moved away from attempts to develop inert biomaterials in favor of biomaterials that interact with and in time are integrated into the biological environment.
The biocompatibility of a medical implant will be influenced by a number of factors, including the toxicity of the materials employed, the form and design of the implant, the skill of the surgeon inserting the device, the dynamics or movement of the device in situ, the resistance of the device to chemical or structural degradation (biostability), and the nature of the reactions that occur at the biological interface. These factors vary significantly depending on whether the implant is deployed, for example, in soft tissue, hard tissue, or the cardiovascular system—to the extent that "biocompatibility may have to be uniquely defined for each application."3 Among the prominent applications for biomaterials are:
- Orthopedics—joint replacements (hip, knee), bone cements, bone defect fillers, fracture fixation plates, and artificial tendons and ligaments.
- Cardiovascular—vascular grafts, heart valves, pacemakers, artificial heart and ventricular assist device components, stents, balloons, and blood substitutes.
- Ophthalmics—contact lenses, corneal implants and artificial corneas, and intraocular lenses.
- Other applications—dental implants, cochlear implants, tissue screws and tacks, burn and wound dressings and artificial skin, tissue adhesives and sealants, drug-delivery systems, matrices for cell encapsulation and tissue engineering, and sutures.
The types of materials featured in the above uses include metals (stainless steel, titanium, cobalt chrome, nitinol), ceramics and glasses (alumina, calcium phosphate, hydroxyapatite), and a wide range of synthetic and natural polymers. This article focuses on polymers, and presents a brief overview of some of the more exciting recent developments that are radically expanding the capabilities of polymeric biomaterials. These include:
- New approaches to biodegradable polymers.
- "Combinatorial" and "supramolecular" chemistry.
- So-called intelligent materials.
- Other new formulations, including phospholipids, polymers for gene therapy, enhanced polyurethanes, and protein-based polymers.
It should be kept in mind that the examples presented run the gamut from newly reported research to products in clinical trials or awaiting regulatory approval to devices that are commercially available.
NOVEL BIODEGRADABLE POLYMERS
As for other biomaterials, the basic design criteria for polymers used in the body call for compounds that are biocompatible (new definition), processable, sterilizable, and capable of controlled stability or degradation in response to biological conditions. The reasons for designing an implant that degrades over time often go beyond the obvious desire to eliminate the need for retrieval. For example, the very strength of a rigid metallic implant used in bone fixation can lead to problems with "stress shielding," whereas a bioabsorbable implant can increase ultimate bone strength by slowly transferring load to the bone as it heals. For drug delivery, the specific properties of various degradable systems can be precisely tailored to achieve optimal release kinetics of the drug or active agent.
An ideal biodegradable polymer for medical applications would have adequate mechanical properties to match the application (strong enough but not too strong), would not induce inflammation or other toxic response, would be fully metabolized once it degrades, and would be sterilizable and easily processed into a final end product with an acceptable shelf life. In general, polymer degradation is accelerated by greater hydrophilicity in the backbone or end groups, greater reactivity among hydrolytic groups in the backbone, less crystallinity, greater porosity, and smaller finished device size.
Beginning in the 1960s, a range of synthetic biodegradable polymers have been developed, including polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), poly(e-caprolactone), polydioxanone, polyanhydride, trimethylene carbonate, poly(ß-hydroxybutyrate), poly(g-ethyl glutamate), poly(DTH iminocarbonate), poly(bisphenol A iminocarbonate), poly(ortho ester), polycyanoacrylate, and polyphosphazene. There are also a number of biodegradable polymers derived from natural sources such as modified polysaccharides (cellulose, chitin, dextran) or modified proteins (fibrin, casein).
To date, the compounds that have been employed most widely in commercial applications are PGA and PLA, followed by PLGA, poly(e-caprolactone), polydioxanone, trimethylene carbonate, and polyanhydride. Some of the common PLA products include tissue screws, tacks, and suture anchors, as well as systems for meniscus and cartilage repair. The first FDA-cleared PLGA product was the Lupron Depot drug-delivery system (TAP Pharmaceutical Products Inc.; Lake Forest, IL), a controlled release device for the treatment of advanced prostate cancer that used biodegradable microspheres of 75:25 lactide/glycolide to administer leuprolide acetate over periods as long as 4 months (replacing daily injections). Another drug-delivery device, the Gliadel Wafer (Guilford Pharmaceuticals Inc.; Baltimore, MD), is used to prolong the life of patients suffering from a particularly deadly form of brain cancer, glioblastoma multiforme. In this case, dime-sized wafers of a biodegradable polyanhydride copolymer—poly[bis(p-carboxyphenoxy) propane:sebacic acid] in a 20:80 molar ratio—are implanted directly into the brain to deliver a powerful chemotherapeutic agent (BCNU) that has deleterious side effects when administered systemically.
BIODEGRADABLE POLYMERS FOR TISSUE ENGINEERING
One area of intense research activity is the use of biodegradable polymers for tissue engineering, which can be defined as "the application of engineering principles to create devices for the study, restoration, modification, and assembly of functional tissues from native or synthetic sources."4 Candidate materials include natural polymers (fibrin, collagen, gelatin, hyaluronan), synthetic polymers (e.g., PLA, PGA, PLGA, ethylene oxide block copolymers), and inorganic materials (tricalcium phosphate, calcium carbonate, nonsintered hydroxyapatite).
A recent project investigated the possibility of manufacturing biodegradable composites for use as bioactive matrices to guide and support tissue ingrowth.5 Composites were prepared using polyhydroxybutyrate (PHB), a naturally occurring ß-hydroxyacid linear polyester, and as much as 30% by volume of either hydroxyapatite (HA) or tricalcium phosphate (TCP) (Figure 1). One of the goals was to achieve a reasonably homogeneous distribution of the HA/TCP particles in the PHB matrix, as this uniformity would provide an anchoring mechanism when the materials would be employed as part of an implant. The composites were successfully manufactured through a compounding and compression molding process. It was observed that microhardness increased with an increase in bioceramic content for both the HA ad TCP compounds.
Figure 1. Polyhydroxybutyrate (PHB) typically requires the presence of enzymes for biodegradation. It is often copolymerized with polyhydroxyvalerate (PHV).
Another team of researchers has addressed the problem of fabricating open-pore, biodegradable polymer scaffolds for cell seeding or other tissue engineering applications.6 The material selected was the tyrosine-derived polycarbonate poly(DTE-co-DT carbonate), in which the pendant group via the tyrosine—an amino acid—is either an ethyl ester (DTE) or free carboxylate (DT). Through alteration of the ratio of DTE to DT, the material's hydrophobic/hydrophilic balance and rate of in vivo degradation can be manipulated. It was shown that, as DT content increases, pore size decreases, the polymers become more hydrophilic and anionic, and cells attach more readily. Previously encountered problems with maintaining sufficient interconnectivity between pores in the structure were avoided through a novel phase-separation technique. Tyrosine-derived polyarylates under study as resorbable coatings for other biomaterials have been reported to significantly decrease blood-coagulation activation and bacterial adhesion without modifying the structure of the substrate.7
Multiblock copolymers of poly(ethylene oxide) (PEO) and poly(butylene terephthalate) (PBT) are also under development as prosthetic devices and artificial skin and as scaffolds for tissue engineering.8 These materials are subject to both hydrolysis (via ester bonds) and oxidation (via ether bonds). Degradation rate is influenced by PEO molecular weight and content, and the copolymer with the highest water uptake degrades most rapidly.
Among the important series of physiological reactions or "cascades" is the fibrinolytic sequence, in which blood clots are removed from the circulation in part through the breakdown of the protein fibrin by the enzyme plasmin. Neurite-associated plasmin activity has also been shown to play a role in nerve growth, and a recent study describes the creation of a new biosynthetic material that imitates fibrin as a vehicle for promoting peripheral nerve regeneration.9 The material incorporates a recombinantly expressed fragment of human fibrin within a photo-cross-linked, polyethylene glycol (PEG)–based hydrogel matrix. According to the study, the resulting system degrades completely upon exposure to plasmin but is otherwise stable, demonstrating that it is possible to design biosynthetic materials with specific enzymatic degradability.
COMBINATORIAL AND SUPRAMOLECULAR CHEMISTRY
A product of revolutionary advances in molecular biology, microfabrication, and information technology, combinatorial chemistry is an emerging discipline of tremendous potential for pharmacological design, biomaterials development, and the entire realm of polymer science. This new approach to the synthesis of materials and characterization of their properties uses multicomponent screening, high-throughput chemical synthesis, and advanced computational techniques to produce and analyze a large number of novel monomeric and polymeric entities.
In a combinatorial synthesis, automated methods are used to process a relatively small number of "ingredients" in a parallel fashion so as to generate a large "library" of elemental combinations on a microscopic scale. Such incrementally controllable, permutationally designed systems hold out the promise of precise structure/property correlations to determine which specific materials will fulfill specific performance needs. One of the first reported examples of a combinatorially prepared library of biomaterials involved A-B type copolymers in which one monomer was a diphenol and the second a diacid.10,11 A total of 14 different diphenols were copolymerized in all combinations with eight different diacids to produce 112 (14 x 8) structurally related polyarylate copolymers. The characteristics of this series of new materials—properties such as wettability, glass-transition temperature, and cellular response—were then analyzed in a systematic manner to identify the relationship between polymer structure, properties, and performance.
Another intriguing new field of great promise is supramolecular chemistry, which is concerned with developing molecular assemblies for biological applications based on macromolecular architectures that mimic nanoscale systems or mechanisms in nature. Novel synthesis methods based on supramolecular chemistry have been used to create branched or graft, cyclic, cross-linked, star, and dendritic polymer structures.
An excellent example of the ability of supramolecular polymer systems to meet complex performance requirements and function like natural chemomechanical materials can be seen in two recent studies using polyrotaxanes—polymers comprising cyclic compounds that are threaded onto linear polymeric chains capped with bulky end groups (Figure 2).12 The first study prepared a series of biodegradable polyrotaxanes in which a-cyclodextrins (a-CDs) were threaded onto a PEG chain capped with amino acids. The resulting structure could be adapted to accomplish a two-stage, controlled release of drugs bonded to the a-CDs: hydrolytic enzymes could first attack the peptide bonds of the macrostructure, degrading the terminal moieties and releasing the drug-immobilized a-CDs, and a second enzyme could then attack the a-CDs and release the drugs. The very rapid and complete degradation of the polyrotaxane prevents problems like that posed by residual crystalline oligomers that can result from the incomplete hydrolysis of highly crystalline materials like PLA.
Figure 2. Polyrotaxanes and other supramolecular polymer structures can be designed to mimic nanoscale systems in nature.
Polyrotaxanes can also be designed to effect dynamic molecular functions similar to those of natural tissues through movement of the cyclic compounds along the polymer's linear chain. The second study used polyrotaxanes with b-cyclodextrins (b-CDs) threaded onto a triblock copolymer of PEG and poly(propylene glycol) (PPG) bounded by fluorescein-4-isothiocyanate end groups. It was observed that the majority of the b-CDs migrated toward the PPG segment with increasing temperature—a phenomenon that, with controlled temperature variation, could suggest the action of a molecular-scale piston. This stimulus response was seen to resemble the action of myosin molecules sliding along actin filaments in the muscle-contraction process.
The polyrotaxane polymers described above can be considered intelligent biomaterials insofar as they can function in a manner similar to molecular structures in the body. Other intelligent materials currently under development include hydrogels exhibiting critical behavior, anionic and cationic hydrogels, controlled porous structures, ultrapure biomaterials, tailored copolymers with desirable functional groups, biomimetic hydrogels, biodegradable polymers responding to specific biological conditions, and polymers precisely replicating selected properties.
One particularly fascinating model of an intelligent material has as its ultimate goal one of the most critical issues in modern medicine—the controlled delivery of insulin for the treatment of diabetes. This hydrogel system features an insulin-containing reservoir within a membrane of poly(methacrylic acid-g-poly[ethylene glycol]) copolymer in which glucose oxidase has been immobilized.13 The surface of the porous membrane contains a series of molecular "gates," which open and release insulin when the hydrogel shrinks at low pH values as a result of the interaction of glucose with glucose oxidase (Figure 3). In addition, the cross-linked polyethylene glycol graft in the decoupled state has the ability to adhere to a specific region in the upper intestine that is a preferred location for the delivery of insulin.
Figure 3. The porous surface of the P(MAA-g-EG) hydrogel system responds to the presence of glucose.
OTHER NEW FORMULATIONS
The tremendous range of current biomaterials research is proposing innovative new polymers for applications ranging from cardiovascular devices to gene therapy. Several of the more interesting formulations are highlighted below.
Phospholipids. Among the materials receiving a great deal of attention for its hemocompatible characteristics is 2-methacryloyloxyethyl phosphorylcholine, or MPC (Figure 4). Created in Japan in the mid-1970s, this polymer has been shown to inhibit to a significant degree the almost-instantaneous protein adsorption and subsequent denaturation that is the initial event affecting practically every material used in the body, and which can lead to thrombus formation. For example, it has been reported that a small-diameter (2-mm) vascular graft prepared from a blend of MPC polymer and segmented polyurethane (SPU) did not occlude for more than 8 months after implantation in a rabbit, whereas an identical SPU graft occluded within 90 minutes.14 The polymer has also been tested as a coating for implantable glucose sensors and hemodialyzer filters and as a rinsing agent to protect contact lenses from protein deposition.15
Figure 4. Molecular structure of the MPC polymer. The material has been shown to inhibit the absorption and denaturation of protein on the surface of an implant.
Polymers for Gene Therapy. Concerns about the potential risks associated with viral gene-delivery systems have led to the development of both degradable and nondegradable, targeted and nontargeted polymeric gene carriers. Examples include PLL-PEG-lactose as a carrier for the transfection of plasmid DNA at hepatocytes16; a biodegradable cationic polymer, poly(a-[4-aminobutyl]-L-glycolic acid), as a carrier for mouse plasmid DNA to prevent insulitis15; and biodegradable gelatin-alginate microspheres as a carrier of adenovirus (Ad5-p53) for intracranial delivery.17
Silicone-Urethane Copolymers. Novel families of silicone-urethane copolymers have been developed that, compared with traditional polyurethane biomaterials, offer advantages in biostability, thromboresistance, abrasion resistance, thermal stability, and surface lubricity, among other properties.18 Copolymer synthesis is performed via two methods: incorporation of silicone into the polymer backbone together with organic soft segments, and the use of surface-modifying end groups to terminate the copolymer chains. The organic soft block can be either polytetramethyleneoxide (PTMO) or an aliphatic polycarbonate used together with polydimethylsiloxane (PSX). Applications for the new materials include balloons, ventricular assist devices, vascular grafts, pacemaker leads, and orthopedic and urologic implants.
Protein-Based Polymers. A series of recently introduced casein- and soy-based biodegradable thermoplastics have recently joined collagen as a source of natural protein-based biomaterials.19 In comparison with collagen, however, these polymers are less susceptible to thermal degradation, can be easily processed via melt-based technologies, and can be reinforced with inert or bioactive ceramics. Temporary replacement implants, scaffolds for tissue engineering, and drug-delivery vehicles are among the potential biomaterials uses under investigation.
The discovery of novel polymeric biomaterials—and the refinement of traditional ones—is creating a thoroughly unprecedented excitement in the field as polymer chemists and other materials designers increasingly confront many of the fundamental challenges of medical science. As the biomaterials discipline itself evolves, the startling advances of the last few years in genomics and proteomics, in various high-throughput cell-processing techniques, in supramolecular and permutational chemistry, and in information technology and bioinformatics promise to support the quest for new materials with powerful analytic tools and insights of boundless energy and sophistication.
1. DF Williams, The Williams Dictionary of Biomaterials (Liverpool, UK: Liverpool University Press, 1999), 40.
2. DF Williams, The Williams Dictionary of Biomaterials (Liverpool, UK: Liverpool University Press, 1999), 42.
3. BD Ratner et al., Biomaterials Science (San Diego: Academic Press, 1996), 6.
4. DF Williams, The Williams Dictionary of Biomaterials (Liverpool, UK: Liverpool University Press, 1999), 318.
5. M Wang et al., Transactions of the Sixth World Biomaterials Congress, I (Minneapolis: Society for Biomaterials, 2000), 81.
6. B Wong et al., Transactions of the Sixth World Biomaterials Congress, I (Minneapolis: Society for Biomaterials, 2000), 363.
7. A Stemberger et al., Transactions of the Sixth World Biomaterials Congress, I (Minneapolis: Society for Biomaterials, 2000), 369.
8. A Deschamps et al., Transactions of the Sixth World Biomaterials Congress, I (Minneapolis: Society for Biomaterials, 2000), 364.
9. S Halstenberg et al., Transactions of the Sixth World Biomaterials Congress, I (Minneapolis: Society for Biomaterials, 2000), 427.
10. S Brocchini et al., Journal of Biomedical Materials Research 42 (1998): 66–75.
11. J Kohn, Transactions of the Sixth World Biomaterials Congress, I (Minneapolis: Society for Biomaterials, 2000), 84.
12. N Yiu, "Design of Polyrotaxanes Aiming at Intelligent Biomaterials," in Supramolecular Approach to Biological Function (Minneapolis: Society for Biomaterials, 2000).
13. N Peppas, Transactions of the Sixth World Biomaterials Congress, I (Minneapolis: Society for Biomaterials, 2000), 554.
14. T Yoneyama et al., Artificial Organs 24 (2000): 23–28.
15. K Ishihara et al., Polymer Journal 31 (1999): 1231–1236.
16. SW Kim, Transactions of the Sixth World Biomaterials Congress, I (Minneapolis: Society for Biomaterials, 2000), 250.
17. HQ Mao et al., Transactions of the Sixth World Biomaterials Congress, I (Minneapolis: Society for Biomaterials, 2000), 252.
18. RS Ward, "Thermoplastic Silicone-Urethane Copolymers: A New Class of Biomedical Elastomers," Medical Device & Diagnostic Industry 22, no. 4 (2000): 68–77.
19. CM Vaz et al., Transactions of the Sixth World Biomaterials Congress, I (Minneapolis: Society for Biomaterials, 2000), 429.
Jon Katz is editor of MD&DI.
Photo courtesy of TESco Associates Inc. and Matrix Biotechnologies Inc.
To the MDDI January 2001 table of contents | To the MDDI home page