Biomedical materials is an embryonic interdisciplinary science whose practitioners are scientists, engineers, biochemists, and clinicians who use synthetic polymers, metals, ceramics, inorganic, and natural polymers to fabricate artificial organs, medical devices, drug delivery systems, prosthetics, and packaging systems.

The intent of this special issue of the MRS Bulletin is to provide readers with insight into current biomaterials research and product development. This issue is not meant to be either conclusive or definitive, but rather a “sound bite” of the field.

For further information, please feel free to contact either the individual authors or the editors of this issue.

The Biomaterials Industry Subpanel was chartered by the National Research Council (on behalf of the National Academies of Sciences and Engineering) to address the needs and opportunities in materials science and engineering as perceived by the biomaterials industry. This report represents an initial overview and should not be considered definitive.

The Committee examined the short-term, intermediate, and long-term needs of the industry and how external factors such as regulations, lack of standards, and international competition influenced the industry. The industry is heterogeneous and was subsequently defined by the following market segments: artificial organs, biosensors, biotechnology, cardiovascular/blood products, drug delivery, equipment/devices, maxillofacial, ophthalmology, orthopedics, packaging, and wound management.

Each of these market segments then addressed the:

Role of materials in the industry,

Current materials and material needs,

Material opportunities and impact,

Industrial needs/issues,

International competition/foreign initiatives, and

Role of the U.S. government.

Biomedical materials are synthetic polymers, metals, ceramics, inorganics, and natural macromolecules (biopolymers), that are manufactured or processed to be suitable for use in or as medical devices or prostheses. These materials typically come in contact with cells, proteins, tissues, organs, and organ systems. They can be implanted for long-term use, e.g., an arrtificial hip, or for temporary use, e.g., an intravenous catheter. Except in isolated cases when a material is used by itself, such as collagen injections for filling soft tissue defects, biomedical materials are used as a component in a medical device. The form of the material (perhaps a textile) how it interfaces (blood contacting, for instance), and its time of use will determine its required properties. A material's use needs to be viewed in the context of the total device and its interface with the body. One material property alone is unlikely to lead to a successful and durable device, but the failure to address a key property can lead to device failure. Until recently, medical-grade polymers, ceramics, inorganics, and metals were purified versions of commercial-grade materials. A variety of polymers, biopolymers, and inorganics is now being specifically developed for medical applications. Table I summarizes the types of biomedical materials.

On May 28, 1976, President Gerald R. Ford signed into law the Medical Device Amendments to the Federal Food, Drug and Cosmetic Act. The purpose of the Amendments is to ensure that medical devices are safe and effective, and properly labelled for their intended use. In order to accomplish this mandate, the Amendments provide the Food and Drug Administration (FDA) with authority to regulate devices during most phases of their development, testing, and use. The FDA's approach to this regulation focuses heavily on both the pre- and post-market phases of a device's lifetime. During the pre-market phase, the FDA concentrates on providing a reasonable assurance that new devices are adequately evaluated for safety and effectiveness. Implicit in this assessment is the concept of balancing risk to benefit. If the benefits significantly outweigh the risks for the intended use, the device will most likely be approved for marketing in the United States. Since risk/benefit assessments for new technology involve considerable clinical judgment, the FDA utilizes expert panels composed of clinicians, engineers, toxicologists, and other experts familiar with the devices. These panels are often directed to review the data provided by the manufacturer to support claims for device safety and effectiveness. If the advisory panel believes the data support the manufacturer's claims, a recommendation for approval for marketing is made to the FDA. The Agency must ultimately decide whether the device is to receive approval for marketing.

Environmentally sensitive polymers and hydrogels exhibit sharp changes in behavior in response to relatively small changes in conditions such as temperature or pH. Typical changes include precipitation of the polymer in water or collapse of a hydrogel with expulsion of a large fraction of the gel pore water. These changes are depicted in Figure 1. If such a polymer is grafted or adsorbed on another polymer surface or within the pores of a porous membrane, then one observes sharp changes in wettability or permeability, respectively, when the polymer is environmentally stimulated. These changes are usually reversible, although the recdissolution or reswelling processes are often slower than the precipitation or deswelling steps. Other examples of environmental stimuli and polymer system responses are listed in Tables I and II.

A large number of polymers display sharp responses to such stimuli. Many are based on vinyl monomers, such as anionic and cationic monomers for pH, specificion, solvent, or electrically responsive systems, and N-alkyl substituted acrylamides (e.g., N-isopropyl acrylamide, or NIPAAm) for temperature-sensitive systems. Other copolymer compositions may contain the responsive moiety as a pendant group on one of the monomers. Photoresponsive groups have been incorporated in such a way.

The ratio in the responsive polymer of the responsive monomeric component to the “nonresponsive” comonomer (e.g., the pH-sensitive monomer, acrylic acid, versus acrylamide or the temperature-sensitive monomer, NIPAAm versus acrylamide) will control both the sharpness and intensity of the response as well as the specific environmental conditions where it begins.

For many years, drug delivery systems were composed of simple pills, eyedrops, ointments, or intravenous solutions. Recently, materials have begun to play a major role in improving drug delivery. Drugs are now chemically attached to polymers, entrapped in small vesicles that are injected into the bloodstream, or put in pumps or polymeric materials that are placed in the body. These new materials-based systems are beginning to change the way drugs can be administered and, in so doing, have improved human health. This article provides a brief review of the major classes of drug delivery systems; a recent paper discusses these issues in detail.

Chemically attaching a drug to a polymer may alter such properties as its distribution in the body, rate of appearance in certain tissues, solubility, or antigenicity. For example, drugs have been linked to soluble macromolecules such as proteins, polysaccharides, or synthetic polymers via degradable linkages. This alters the drug's size and other properties, resulting in a different bodily drug distribution pattern. One example involves coupling the antitumor agent neocarzinostatin to styrene-maleic acid copolymers. When this complex was injected intra-arterially in patients with liver cancer, tumor size decreased significantly. In animals, the antitumor agent, doxorubicin, bound to N(2-hydroxypropyl) methacrylamide copolymers reduced toxicity. The plasma half-life and the drug levels in the tumor increased while the concentrations in the rest of the body decreased.

The search for biocompatible cardiovascular materials has gone on for more a century, beginning with the metallic and glass blood vessel substitutes of Alexis Carrel. The quest has become more involved as the need for flexible polymeric materials became apparent, and as knowledge has been gained about the reactions of blood with artificial surfaces. Current materials in clinical practice are, for the most part, standard polymers that have been in incardiovascular materials is thrombosis, a combination of the coagulation of the blood proteins (which traps red cells, thus obstructing vessel channels) and the activation and deposition of blood platelets, cells that rapidly aggregate with other platelets to obstruct the channel. Coagulation and platelet aggregation are interdependent, highly volatile processes, acting like two positive feedback cascade amplification processes. Thrombosis is prevented in clinical practice by administering heparin, ity. The endothelial cell releases heparin and heparan sulfate, natural anticoagulants, in response to various external stimuli. Endothelial cells produce prostacyclin, which prevents platelet activation by surface contact and is also a powerful, shortacting vasodilator. Prostacyclin release is modulated by fluid shear stresses on the endothelial membrane, among other stimuli. Endothelial cells bind the coagulation enzyme thrombin to thrombomodulin, one of the endothelial membrane proteins, removing it from circulation but also enhancing the activation of protein C, another circulating protein which inhibits blood coagulation. Creation of a material that would precisely mimic all functions of the endothelial cell is a daunting task. Fortunately, more prosaic materials exist that may be purified or modified to elicit minimal biological responses. Progress in developing these materials will be discussed in the context of typical cardiovascular devices.

Bone-interfacing surgical implants used in orthopedics and dentistry must bear the forces of normal patient activity with minimal risk of mechanical failure of the implant. This requires using appropriate materials and designs for implant fabrication. Additionally, reliable long-term implant attachment to host bone must be assured so that effective force transfer between implant and bone occurs for the patient's lifetime without the implant loosening. With recent advances in implant designs and techniques for their placement, effective implant fixation to bone can last for years (decades) either directly or through an acceptable intermediate fibrous tissue layer at the bone-implant interface. With approximately 500,000 artificial hips implanted annually worldwide and the demand for other joint replacements approaching the same order of magnitude, as well as the recent major growth in the use of dental implants (300,300 projected for insertion in North America alone in 1991), the assurance of effective implant-to-bone fixation is extremely important.

Studies of implant biocompatibility have resulted from concerns over the cumulative effects of foreign element release through implant corrosion and wear. Accumulation of this debris in tissues both local and remote to implant sites over the long term is a concern. Of equal importance, for load-bearing implants, are studies to determine the important factors for successful long-term implant fixation. Current trends in design and use of both dental and orthopedic implants reflect the trial-and-error approach that has characterized this field for decades.

The innovative use of specially designed ceramics to repair and reconstruct diseased or damaged parts of the body has improved the quality of life, and in some cases the length of life, for thousands of people. Ceramics used for this purpose are termed “bioceramics” and can be single crystals (sapphire), polycrystalline (alumina or hydroxylapatite), glass (Bioglass®), glass-ceramics (Ceravital® or A/W glassceramic), or composites (stainless-steel fiber-reinforced Bioglass or polyethylene-hydroxylapatite).

Ceramics and glasses have long been used in the health care industry for eye glasses, diagnostic instruments, chemical ware, thermometers, tissue culture flasks, and fiber optics for endoscopy. Insoluble porous glasses have been used as carriers for enzymes, antibodies, and antigens. Ceramics are also widely used in dentistry as restorative materials, gold porcelain crowns, glass-filled ionomer cements, and dentures.

This review describes bioceramics used as implants to repair parts of the body, usually hard tissues such as bones or teeth, but also to replace heart valves. Dozens of ceramic compositions have been tested, but few have achieved human clinical application. Clinical success requires the simultaneous achievement of a stable interface with tissue and a match of the mechanical behavior of the implant with the tissue to be replaced.

The mechanism of tissue attachment depends on the type of tissue response at the implant interface (Table I).

The living body is an aggressive environment for almost all types of foreign materials, devices, prostheses, and artificial organs which are in contact with the tissues or body fluids of the living body. This aggressive environment can potentially produce changes in the chemical, physical, mechanical, and structural properties of biomaterials, i.e., biodegradation. The vast majority of biomedical polymers used today as biomaterials or in prostheses, devices, or artificial organs are considered biostable and are expected to resist the influence of the in vivo environment for the lifetime of the device or patient while retaining the necessary properties that fulfill the intended functions. In contrast, biodegradable or bioresorbable biomedical polymers are designed to be degraded and eliminated from the body by normal metabolic and physiological processes without adversely affecting body fluids, tissues, and organs.

The term “biostability” commonly refers to the relative stability of biomedical polymers in the physiological environment as a function of time. It is advantageous to discuss biostability and biodegradation of biomedical polymers together. In vivo physiological mechanisms leading to changes in the properties of biomedical polymers are considered to be biodegradation phenomena, while biostable materials are considered to be those materials where physiological interactions do not lead to material property changes and loss of function during the service life of the biomedical polymer.

Blood is a dispersion of formed elements in an aqueous colloid. The combined mass of the formed elements of blood measure on average 30 ml per kg body weight, or about the same weight as the liver. The colloidal phase of blood contains numerous organic factors that play important primary and supporting roles in homeostasis, including immune surveillance, coagulation, and nutrient transport.

Erythrocytes (red blood cells) are the principle formed elements and provide the life-sustaining function, in conjunction with the heart, lungs, blood vessels and kidneys, of transporting and protecting the oxygen-carrying pigment, hemoglobin, to the tissues. The oxygen-binding properties of hemoglobin are sensitive to factors such as the cooperative effects of O2 binding, pH and CO2 levels, and the presence of other metabolic intermediates such as 2,3-diphosphoglycerate. The synergistic effects of these factors produce a well-known sigmoidal curve plot of the relationship between oxygen affinity and the partial pressure of oxygen (pO2): there is high oxygen affinity in the lung where the pO2 is high, and a low oxygen affinity in the tissues, where the pO2 is low. Uptake and delivery of oxygen by hemoglobin is associated with considerable spatial rearrangement of the hemoglobin molecule.

Blood is a non-Newtonian suspension. Its viscosity is a function of both the vascular diameter and the concentration of erythrocytes. At a normal hematocrit of 40%, the viscosity of blood ranges between 2 and 4 Pa s as measured in tubes ranging 10–1,500 μm diameter. The osmolality of blood serum is 275–295 mOsm/1.

The National Science Foundation has estimated that 28% of the information processing products, 37% of the pharmaceutical processes, and 44% of the pharmaceuticals on the market today derive directly from university research. Single companies create annual research budgets in the hundreds of millions of dollars by allocating to research 2–10% of their revenues, a percentage identical to the typical royalty rate. Yet none of our great research institutions receives royalty income in excess of $15 million, and most receive under $1 million. Certainly, our universities and their faculty could enjoy greater benefit from the transfer of their technology to the private sector. Such expectations account for the explosive growth of university technology transfer programs.

We would define the mission of technology transfer as (1) to bring university inventions into public use with maximum integrity, effectiveness, and speed, and (2) to maximize the financial return to the university and the inventor. This article will describe “active licensing,” an approach to technology transfer that we have found to be more effective and that we feel is more rational than the paradigms in use at most institutions.

Figure 1 presents the commercial value of technology as a function of incremental time and cost investment in development of the technology.

In 1988 a biomaterials industry panel was chartered by the National Academy of Sciences and the National Academy of Engineering to address needs and opportunities in materials science and engineering as perceived by the biomaterials industry. This report was subsequently consolidated with similar reports from panels in the other materials science areas into a comprehensive National Research Council (NRC) report, Materials Science and Engineering for the 1990s: Maintaining Competitiveness in the Age of Materials, issued by the National Academy Press in late 1989.

After reading the NRC report, D. Alan Bromley, science adviser to President Bush, decided that materials science would be one of five priorities for research in the current aclministration. In a letter to Frank Press, January 1990, Bromley praised this report and encouraged the Academy to have regional meetings to stimulate action on the local level. It was felt that these regional meetings would offer materials scientists and engineers the opportunity to organize themselves and, cooperating with industry and federal laboratories, take the initiative to address the needs identified in the NRC report. Bromley encouraged structuring these meetings, to the extent possible, to produce items that could be considered for the Office of Science and Technology Policy (OSTP) agenda.