An Introduction to Biomaterials
Buddy D. Ratner
University of Washington Engineered Biomaterials
Biomaterials are materials (synthetic and natural; solid and sometimes liquid) that are used in medical devices or in contact with biological systems. Biomaterials as a field has seen steady growth over its approximately half century of existence and uses ideas from medicine, biology, chemistry, materials science and engineering. There is also a powerful human side to biomaterials that considers ethics, law and the health care delivery system. This brief introduction overviews some key characteristics of the field of biomaterials and outlines issues and major subdivisons.
Although biomaterials are primarily used for medical applications, they are also used to grow cells in culture, to assay for blood proteins in the clinical laboratory, in processing biomolecules in biotechnology, for fertility regulation implants in cattle, in diagnostic gene arrays, in the aquaculture of oysters and for investigational cell-silicon “biochips.” The commonality of these applications is the interaction between biological systems and synthetic or modified natural materials.
Biomaterials are rarely used on their own but are more commonly integrated into devices or implants. Thus, the subject cannot be explored without also considering biomedical devices and the biological response to them.
Some common medical devices comprised of biomaterials are illustrated here:
Biomaterials can be metals, ceramics, polymers, glasses, carbons, and composite materials. Such materials are used as molded or machined parts, coatings, fibers, films, foams and fabrics.
The numbers of medical devices used each year in humans is very large. The chart below estimates usage for common devices:
We’ve started a discussion of biomaterials without formally defining them. A commonly used definition of “biomaterial” is:
A biomaterial is a nonviable material used in a medical device, intended to interact with biological systems. (Williams, 1987)
If the word “medical” is removed, this definition becomes more general and still quite useful.
If the word “nonviable” is removed, the definition becomes even more general and can address new tissue engineering and hydrid artificial organ applications where living cells are used.
A complementary definition needed to understand an important aspect of biomaterials is that of “biocompatibility.”
Biocompatibility is the ability of a material to perform with an appropriate host response in a specific application. (Williams, 1987)
“Appropriate host responses” include lack of blood clotting, resistance to bacterial colonization and normal healing. Examples of specific applications include a hemodialysis (artificial kidney) membrane, a urinary catheter or a hip joint prosthesis. It is interesting that the hemodialysis membrane might be in contact with the patient’s blood for 3 hours, the catheter may be inserted for a week and the hip joint may be in place for the life of the patient.
The definitions introduce us to considerations that set biomaterials apart from most materials considered in materials science.
CHARACTERISTICS OF BIOMATERIALS AS A FIELD
We’ve defined some terms and reviewed a few specific examples. What are some characteristics of the field of biomaterials?
It’s Multidisciplinary
Biomaterials science brings together researchers from diverse academic backgrounds. They must communicate clearly. Some disciplines that intersect in the development, study and application of biomaterials include: bioengineer, chemist, chemical engineer, electrical engineer, mechanical engineer, materials scientist, biologist, microbiologist, physician, veterinarian, ethicist, nurse, lawyer, regulatory specialist and venture capitalist. This is only a partial list.
It Uses Many Diverse Materials
Biomaterials researchers and clinicians using biomaterials will have an appreciation of materials science and chemistry. Many different synthetic and modified natural materials are used in biomaterials and some understanding of the differing properties of these materials is important. A heart valve may be fabricated from polymers, metals, and carbons. A hip joint might be fabricated from metals and polymers (and sometimes ceramics) and will be interfaced to the body via a polymeric bone cement. In these examples, a single device uses many different materials, each with special properties and biological interactions.
The End product is the Development of Devices
Biomaterials by themselves do not make a useful clinical therapy. The materials have to be fabricated into devices. This is typically an engineer’s role, but the engineer might work closely with synthetic chemists to optimize materials properties and physicians to ensure that the device is useful in clinical applications.
The Magnitude of the Field is Generally Unappreciated
Lysaght and O’Laughlin (2000) have estimated that the magnitude and economic scope of the contemporary organ replacement enterprise are much larger than is generally recognized. In the year 2000, the lives of over 20 million patients will be sustained, supported or significantly improved by functional organ replacement. The impacted population grows at over 10% per year. Worldwide, first-year and follow-up costs of organ replacement and prostheses exceeds $300 billion US dollars per year and represents between 7% and 8% of total worldwide healthcare spending. In the United States, the costs of therapies enabled by organ replacement technology exceed 1% of the gross national product. The costs are also impressive when considering the needs of the individual patient. Thus, the cost of a substitute heart valve is roughly $4000. The surgery to implant the device costs approximately $60,000. Reoperation for replacing a failed valve will have these same costs and reoperations occur for 10% of all valve replacements.
Success and Failure are seen with Biomaterials and Medical Devices
Most biomaterials and medical devices perform satisfactorily, improving the quality of life for the recipient or saving lives. Still, manmade constructs are never perfect. Manufactured devices have a failure rate. Also, all humans differ in genetics, gender, body chemistries, living environment and physical activity. Furthermore, physicians also differ in their “talent” for implanting devices. The other side to the medical device success story is that there are problems, compromises and complications that occur with medical devices. Central issues for the biomaterials scientist, manufacturer, patient, physician and attorney are: (1) what represents good design; (2) who should be responsible when devices perform “with an inappropriate host response;” and (3) what are the cost/risk or cost/benefit ratios for the implant or therapy?
An example involving left ventricular assist devices (LVADs, sometimes incorrectly called artificial hearts) helps to clarify these issues. There are many complications with LVADs including clotting, strokes, blood damage and bacterial infection. A clinical trial called Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) led to following important statistics (Rose, et al, 2001). Patients with an implanted Heartmate® LVAD (Thoratec Laboratories) had a 52% chance of surviving for one year, compared with a 25% survival rate for patients who took medication (the common therapy for congestive heart failure). Survival for two years in patients with the Heartmate® was 23% versus 8% in the medication group. Also, the LVAD enhanced the quality of life for the patients – they felt better, were less depressed, and were mobile. Note that patients participating in the REMATCH trial were not eligible for a heart transplant. In the case of the LVAD, long-term clinical complications associated with imperfect performance of biomaterials does not preclude clinical success overall. The LVAD is better than the next best therapy.
These five characteristics of biomaterials science?multidisciplinary, multi-material, need-driven, substantial market and risk-benefit?color the field of biomaterials.
WHAT SUBJECTS ARE IMPORTANT TO BIOMATERIALS SCIENCE?
• Toxicology
A biomaterial should not be toxic, unless it is specifically engineered for such requirements (for example, a “smart bomb” drug delivery system that targets cancer cells and destroys them). Since the nontoxic requirement is the norm, toxicology for biomaterials has evolved into a sophisticated science. It deals with the substances that migrate out of biomaterials. For example, for polymers, many low-molecular-weight “leachables” exhibit some level of physiologic activity and cell toxicity. It is reasonable to say that a biomaterial should not give off anything from its mass unless it is specifically designed to do so. Toxicology also deals with methods to evaluate how well this design criterion is met when a new biomaterial is under development.
• Biocompatibility
The understanding and measurement of biocompatibility is unique to biomaterials science. Unfortunately, we do not have precise definitions or accurate measurements of biocompatibility. More often than not, biocompatibility is defined in terms of performance or success at a specific task. Thus, for a patient who is doing well with an implanted Dacron fabric vascular prosthesis, few would argue that this prosthesis is not “biocompatible.” However, the prosthesis probably did not re-cellularize (though it was designed to do so) and also can throw off blood clots (emboli), though the emboli in this case usually have little clinical consequence. This operational definition of biocompatible (“the patient is alive so it must be biocompatible”) offers us little insight in designing new or improved vascular prostheses. It is probable that biocompatibility may one day be defined for applications in soft tissue, hard tissue, and the cardiovascular system (blood compatibility).
• Functional Tissue Structure and Pathobiology
Biomaterials incorporated into medical devices are implanted into tissues and organs. Therefore, the key principles governing the structure of normal and abnormal cells, tissues and organs, the techniques by which the structure and function of normal and abnormal tissue are studied, and the fundamental mechanisms of disease processes are critical considerations to workers in the field.
• Healing
Special processes are invoked when a material or device heals in the body. Injury to tissue will stimulate the well-defined inflammatory reaction sequence that leads to healing. Where a foreign body (e.g., an implant) is present in the wound site (surgical incision), the reaction sequence is referred to as the “foreign body reaction.” The normal response of the body will be modulated because of the solid implant. Furthermore, this reaction will differ in intensity and duration depending upon the anatomical site involved. An understanding of how a foreign object alters the normal inflammatory reaction sequence is an important concern for the biomaterials scientist.
• Dependence on Specific Anatomical Sites of Implantation
Consideration of the anatomical site of an implant is essential. An intraocular lens may go into the lens capsule or the anterior chamber of the eye. A hip joint will be implanted in bone across an articulating joint space. A heart valve will be sutured into cardiac muscle and will contact both soft tissue and blood. A catheter may be placed in an artery, a vein or the urinary tract. Each of these sites challenges the biomedical device designer with special requirements for geometry, size, mechanical properties, and bioresponses.
• Mechanical and Performance Requirements
Biomaterials and devices have mechanical and performance requirements that originate from the physical (bulk) properties of the material. There are three categories of such requirements: mechanical performance, mechanical durability and physical properties. First, consider mechanical performance. A hip prosthesis must be strong and rigid. A tendon material must be strong and flexible. A heart valve leaflet must be flexible and tough. A dialysis membrane must be strong and flexible, but not elastomeric. An articular cartilage substitute must be soft and elastomeric. Then, we must address mechanical durability. A catheter may only have to perform for 3 days. A bone plate may fulfill its function in 6 months or longer. A leaflet in a heart valve must flex 60 times per minute without tearing for the lifetime of the patient (realistically, at least for 10 or more years). A hip joint must not fail under heavy loads for more than 10 years. The bulk physical properties will also address other aspects of performance. The dialysis membrane has a specified permeability, the articular cup of the hip joint must have high lubricity, and the intraocular lens has clarity and refraction requirements. To meet these requirements, design principles from physics, chemistry, mechanical engineering, chemical engineering, and materials science are invoked.
• Industrial Involvement
A significant basic research effort is now under way to understand how biomaterials function and how to optimize them. At the same time, companies are producing implants for use in humans and, appropriate to the mission of a company, earning profits on the sale of medical devices. Thus, although we are now only learning about the fundamentals of biointeraction, we manufacture and implant millions of devices in humans. How is this dichotomy explained? Basically, as a result of considerable experience we now have a set of materials that performs satisfactorily in the body. The medical practitioner can use them with reasonable confidence, and the performance in the patient is largely acceptable. Though the devices and materials are far from perfect, the complications associated with the devices are less than the complications of the original diseases.
The complex balance between the desire to alleviate suffering and death, the excitement of new scientific ideas, the corporate imperative to turn a profit, the risk/benefit relationship and the mandate of the regulatory agencies to protect the public forces us to consider the needs of many constituencies. Obviously, ethical concerns enter into the picture. Also, companies have large investments in the manufacture, quality control, clinical testing, regulatory clearance, and distribution of medical devices. How much of an advantage (for the company and the patient) will be realized in introducing an improved device? The improved device may indeed work better for the patient. However, the company will incur a large expense that will be perceived by the stockholders as reduced profits. Moreover, product liability issues are a major concern of manufacturers. The industrial side of the biomaterials field raises questions about the ethics of withholding improved devices from people who need them, the market share advantages of having a better product, and the gargantuan costs (possibly non-recoverable) of introducing a new product into the medical marketplace. If companies did not have the profit incentive, would there be any medical devices, let alone improved ones, available for clinical application?
When the industrial segment of the biomaterials field is examined, we see other essential contributions to our field. Industry deals well with technologies such as packaging, sterilization, storage, distribution and quality control and analysis. These subjects are specialized technologies, often ignored by academic researchers. Also, many companies support in-house basic research laboratories and contribute directly to the fundamental study of biomaterials.
• Ethics
A wide range of ethical considerations impact biomaterials science. Like most ethical questions, an absolute answer may be difficult to come by. Some articles have addressed ethical questions in biomaterials and debated the important points (Saha and Saha, 1987; Schiedermayer and Shapiro, 1989).
• Regulation
The consumer (the patient) demands safe medical devices. To prevent inadequately tested devices and materials from coming on the market, and to screen out individuals clearly unqualified to produce biomaterials, the United States government has evolved a complex regulatory system administered by the US Food and Drug Administration (FDA). Most nations of the world have similar medical device regulatory bodies. The International Standards Organization (ISO) has introduced international standards for the world community. Obviously, a substantial base of biomaterials knowledge went into establishing these standards. The costs to comply with the standards and to implement materials, biological, and clinical testing are enormous. Introducing a new biomedical device to the market requires a regulatory investment of tens of millions of dollars. Are the regulations and standards truly addressing the safety issues? Is the cost of regulation inflating the cost of health care and preventing improved devices from reaching those who need them? Under this regulation topic, we see the intersection of all the players in the biomaterials community: government, industry, ethics, and basic science. The answers are not simple, but the problems must be addressed every day.
BIOMATERIALS SOCIETIES
The evolution of the biomaterials field, from its roots with individual researchers and clinicians who intellectually associated their efforts with established disciplines such as medicine, chemistry, chemical engineering or mechanical engineering, to a modern field called “biomaterials,” parallels the formation of biomaterials societies. A few important biomaterials-related professional societies are: American Society for Artificial Internal Organs (ASAIO), founded in 1954; Society For Biomaterials USA, founded in 1975; The European Society for Biomaterials, founded in 1975; The Canadian Society For Biomaterials; the Japanese Society of Biomaterials; The Controlled Release Society, founded in 1978; The Biointerface Division of the AVS Science and Technology Society.
SUMMARY
Biomaterials may be the most multidisciplinary of all fields. The impact to people and to commerce is huge. Because of this impact and multidisciplinarity, biomaterials is always an exciting area for study and application.
References
Lysaght, MJ, O’Laughlin J. The demographic scope and economic magnitude of contemporary organ replacement therapies. ASAIO 2000; J46: 515-21.
Rose, EA, Gelijns AC, PhD, Moskowitz AJ, MD, Heitjan DF, PhD, Stevenson LW, MD, Dembitsky W, MD, Long JW, MD, PhD, Ascheim DD, MD, Tierney AR, MPH, Levitan RG, MSc, Watson JT, PhD, Ronan NS, RN, Shapiro PA, MD, Lazar RM, PhD, Miller LW, MD, Gupta L, RD, MPH, Frazier OH, MD, Desvigne-Nickens P, MD, Oz MC, MD, Poirier VL, MBA, Meier P. Long-term use of a left ventricular assist device for end-stage heart failure. New England Journal of Medicine 2001; 345:1435-1443.
Saha S, Saha P. Bioethics and applied biomaterials. J Biomed Mater Res: Appl Biomat 1987; 21: 181-190.
Schiedermayer, DL, Shapiro RS. The artificial heart as a bridge to transplant: Ethical and legal issues at the bedside. J. Heart Transplant 1989; 8: 471-473.
Society For Biomaterials Educational Directory (1992). Society For Biomaterials, Minneapolis, MN.
Williams, DF. Definitions in biomaterials. Proceedings of a consensus conference of the european society for biomaterials, Vol. 4. Chester, England, March 3-5 1986. New York: Elsevier, 1987.
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Acknowledgement: Parts of this overview of biomaterials have been taken from, or modified from, Biomaterials Science: An Introduction to Materials in Medicine, Elsevier Publishers, Amsterdam, 2004.
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