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Capturing the Full Power of Biomaterials for Military Medicine: Report of a Workshop 1 Biomaterials and Their Importance to Military Medicine Modern medicine is beginning to understand, realize, and utilize the benefits of biotechnology in health care and casualty care. Practical knowledge of the causes of human disease, biological targets for new drugs, genetic markers, and sophisticated diagnostic tests will all increase the effectiveness of medical professionals and the health and healing of everyone. Because of the highly specialized needs of military medicine,1 it may provide unique opportunities to absorb these advances at a rapid rate. The impacts of this may be profound, as observed by the Military Health Services System 2020 study:2 The study group’s overall assessment is that likely developments in biotechnology will transform every aspect of military medicine over the next ten to twenty years. These developments will significantly enhance our capabilities in warzone medicine. Beneficiary care will experience a paradigm change—a fundamental change in assumptions about how to go about the process of providing health care. And enormous new capabilities will emerge for carrying out health operations other than war. A key contributor to this revolution has been and will continue to be biomaterials. Biomaterials have been essential to such major medical breakthroughs as kidney dialysis, prosthetic heart valves, hip replacement implants, and cardiac pacemakers.3 A biomaterial is generally defined as any material that is used to replace or restore function to a body tissue and is continuously or intermittently in contact with body fluids.4 Medical applications of biomaterials fall into three broad categories: (1) extracorporeal uses, such as catheters, tubing, and fluid lines; dialysis membranes/artificial kidneys; ocular devices; and wound dressings and artificial skin; (2) permanently implanted devices, such as sensory devices; cardiovascular devices; orthopaedic devices, and dental devices; and (3) temporary implants, such as degradable sutures, implantable drug delivery systems, scaffolds for cell or tissue transplants, temporary vascular grafts and arterial stents, and temporary small bone fixation devices.5 Biomaterials have been used since the first bark bandage was pressed onto a wound. Today, physicians worldwide implant more than 200,000 pacemakers; 100,000 heart valves; 1 million orthopaedic devices; and 5 million intraocular lenses each year. The tremendous increase in medical 1 National Association of Emergency Medical Technicians. 2005. Basic and Advanced Prehospital Trauma Life Support, Military Version. 5th ed. Philadelphia, Pa.: Elsevier Health Sciences Division. Prepublication data available at http://www.phtls.net/datafiles/military5th2003sept04.pdf. Accessed July 2004. 2 SRA International. 1997. Military Health Services System 2020 Focused Study on Biotechnology and Nanotechnology. Prepared for the Deputy Under Secretary of Defense for Health Policy. Available at http://mhs2025.sra.com//study/images/focreport.pdf. Accessed July 2004. 3 P. Citron. 2004. Science-based testing: Balancing risk and reward. In Science-Based Assessment: Accelerating Product Development of Combination Medical Devices, pp. 4-5. Washington, D.C.: The National Academies Press, available at http://books.nap.edu/catalog/11035.html. Accessed July 2004. 4 J.B. Park. 1984. Biomaterials Science and Engineering. New York, N.Y.: Plenum Press, p. 1. 5 S. Dumitriu, ed. 2002. Polymeric Biomaterials, 2nd ed. New York, N.Y.: Marcel Dekker.
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Capturing the Full Power of Biomaterials for Military Medicine: Report of a Workshop applications means the demand for new biomaterials grows by 5 to 15 percent each year.6 The general categories of materials are as follows: Ceramic biomaterials, generally used for their hardness and wear-resistance in applications such as articulating surfaces in joints and in teeth as well as bonding bone surfaces in implants. They also show great promise for bone scaffolding with controlled degradation rates. Bioceramics are based on simple oxides, hydroxyapatite, calcium salts, silicate ceramics, silicate glasses, and glass ceramics, and also include ceramic-matrix composites. Metallic biomaterials, used for load-bearing applications, must have sufficient fatigue strength to endure the rigors of such daily activity as walking and chewing. The metals used in biological applications today are primarily titanium and stainless steel alloys for pins, plates, and bone stems. Polymeric materials, usually selected for their flexibility and stability, and also used for low-friction articulating surfaces. A range of synthetic biodegradable polymers has been developed, including polylactide, polyglycolide, poly(lactide-co-glycolide), 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. A number of biodegradable polymers can be derived from natural sources such as modified polysaccharides (cellulose, chitin, dextran) or modified proteins (fibrin, casein). Limitations to the use of biomaterials generally center on materials-body interactions such as immune response, inflammation, wound healing, blood-materials interactions, implant-associated infections, and tumor generation. More typical materials issues are also limiting factors. They include implant and tissue compatibility, biochemical and biophysical degradation, and calcification. Body chemistry remains a highly corrosive environment, and many parts of the human body undergo tens of thousands of loading and unloading cycles every day. Because of this unique array of challenges, the full potential of biomaterials has yet to be realized. To discuss strategies to capture the full power of biomaterials for military medical needs, a key workshop was held on February 2-4, 2004. During this time, representatives from academia, government, and industry engaged in intense and far-ranging discussions. The goal of the more than 70 attendees was to plan a way forward for the applications of biomaterials to military medicine. This report is intended to find ways to leapfrog current materials development and implementation processes. If these goals are targeted by the military and scientific communities, it is anticipated that time lines to implementation will be shortened dramatically. THE PROCESS OF BIOTECHNOLOGY ADAPTATION TO MILITARY NEEDS Advances in biomaterials technologies today are driven by the federally funded research of university faculty and by the commercial interests of biomedical companies.7 Although many of the discoveries and products emerging from these endeavors have some potential for military use, military needs are not typically a factor in research and development processes at an early enough stage to influence them. In particular, a large proportion of medical product research and development in the civilian sector is directed toward chronic diseases, whereas much of the military's unmet needs relates to trauma and acute diseases. Workshop attendees noted that in spite of the extremely large civilian biomaterials 6 Glacier Valley Medical Education. 2002. History of Medical Discovery. Available at http://www.glaciermedicaled.com/history/hxmed01c.html. Accessed July 2004. 7 H. Kelly. 2001. DARPA’s beachhead in biomedical research. Academic Medicine 76(12):1178-1180.
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Capturing the Full Power of Biomaterials for Military Medicine: Report of a Workshop research and development budget, the military's biomaterials needs have not been met in an optimum fashion. Recognizing that biotechnology advances would be as important in the twenty-first century as information technology advances were in the twentieth century, the Army commissioned the National Research Council (NRC) to help it plan in taking the fullest possible advantage of biotechnology developments. In 2001, the NRC issued the report Opportunities in Biotechnology for Future Army Applications.8 This report provided specific recommendations relating to biomaterials for tissue engineering and for therapeutics, including drug delivery systems. In addition, the report stated that the area of medical biomaterials had not been covered adequately there and that further assessment would be required to determine its importance to the military. That earlier report identified weaknesses in the Army’s research approach to providing biomaterial solutions to improve soldier well-being and made the following key recommendations: The Army should adopt new approaches toward commercial developers to accommodate cultural differences between the government and the biotechnology industry. The Army should develop a cadre of science and technology professionals capable of translating advances in the biosciences into engineering practice. The Army should conduct a study focusing on future biomedical applications, including biological implants, biocompatibility, and medical biomaterials and their implications for future military operations. Attendees at this workshop noted that current military support of biomaterials-related research is distributed over a variety of projects ranging from organic and inorganic prostheses to tissue banking. Within this decentralized structure, the rapidly expanding portfolio of military biomaterials-related projects may be missing important opportunities for interdisciplinary collaborations and industry-academia interactions. The military could therefore benefit from a coordinated vision for advancing its needs emerging biomaterials technologies. Tissue engineering technology is critical to combat casualty care and injuries suffered in terror attacks. Drug and vaccine delivery systems are also important for preventive care and soldier well-being. The design and development of such products for the military requires a full range of scientific expertise, clinical input, and technological capability. Specifically, the following research areas are centrally important and represent a starting point for the development of a comprehensive, coordinated resource: polymer science, biomaterials science, biocompatibility, self-assembly of materials, molecular recognition, extracellular matrix biology, cell biology, and developmental biology. In addition, the military must access a number of core competencies to successfully develop and deploy these new products. They include biomaterials design; advanced methods of synthesis, characterization, processing, and fabrication; drug delivery technologies; cell and stem cell technologies; and in vitro and in vivo model development for preclinical performance evaluations. THE STATUS OF BIOMATERIALS RESEARCH AND DEVELOPMENT Ongoing advances in our understanding of cell biology and wound healing are creating opportunities for the use of degradable, biocompatible materials in unprecedented ways. The biomedical research community is creating a paradigm shift in the treatment of trauma and aging-related tissue loss. Instead of using permanently implanted prostheses to replace damaged tissue, surgeons in the future may implant a regenerative, temporary scaffold that enables the body to heal itself. 8 National Research Council. 2001. Opportunities in Biotechnology for Future Army Applications. Washington, D.C.: National Academy Press.
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Capturing the Full Power of Biomaterials for Military Medicine: Report of a Workshop The selection of biomaterials is fundamental to the design and development of regenerative medicine and drug delivery therapies. Whereas the classical selection criterion for a safe, stable implant dictated choosing a passive, inert material, it is now understood that any such device will elicit a cellular response. Therefore, it is now widely accepted that a biomaterial must interact with tissue rather than act simply as a static implant. Thus, the principal criterion for biomaterials performance becomes a desirable, controlled cellular response. Consequently, a major focus of research on biomaterials centers on the control of cellular interactions with artificial material and the surrounding living tissue. The imagination of biomedical engineers and clinicians and advances in biology have outpaced the ability of materials scientists to provide the new generation of biomaterials that is critically needed for full clinical implementation of the tissue engineering approach. While biomedical engineers speak about resorbable polymer scaffolds that promote a variety of regenerative therapies, simple copolymers of lactic and glycolic acids remain the most commonly used scaffolding material in all tissue engineering research. Reviews of tissue engineering advocate the use of increasingly complex monomers, monomer combinations, polymer structures, and polymer blends that are meant to facilitate the design, synthesis, and fabrication of novel materials with properties tailored to specific biological needs and clinical applications. In reality, the widely used glycolic and lactic acids are the simplest of all hydroxy acids, there are very few polymers under consideration that have complex monomer structures, and current approaches to tailor the properties of polymers to specific applications are based mostly on trial and error. Similar challenges exist for the fabrication of bioceramics. Novel gelforming processing has the potential for rapid and cost-effective fabrication of net shape ceramics and ceramic microcomponents. Automated rapid fabrication of net shape ceramics via green machining shows promise, and the potential has also been proposed for desktop fabrication of bioceramics for orthopaedic and dental implants. Additional challenges for small-scale forming of materials include micropatterning and assembly of colloids and thin films, low temperature growth of one-dimensional oriented nanoscale arrays, development of nanofibers for structural and functional applications, and vapor deposition of bioactive coatings for metals and ceramics. Discussion of science related to biopolymers dominated the workshop discussion at times, because many attendees felt that the newest advances in polymers offer great promise for major advances in military medicine. The reasons for the slow progress toward an appropriate pool of candidate polymers are the scientific community’s limited abilities to (1) characterize and quantify the properties of structurally complex bio-relevant materials, (2) control cell-material interactions, and (3) fabricate in a cost-efficient way graded scaffolds with truly engineered and reproducible pore architecture and surface properties. While the application of biomaterials to military medical needs poses a number of similar technical challenges, the nontechnical aspects, especially regulatory requirements, of biomaterials may be more difficult to overcome. The 1976 medical device amendments to the Federal Food, Drug, and Cosmetic Act9 require that all new biomaterials used in applications (or existing biomaterials used in new applications) that are life-sustaining or involve significant risks to patients must undergo premarket approval to establish their safety and effectiveness. Materials must be biocompatible within the environment in which they are used, and a material must perform its intended function safely and effectively in that environment. Clinical trials involving both animals and humans are also part of the approval process.10 Clinical trials are costly and time-consuming, and are generally frustrating to materials scientists who have come to rely on accelerated testing and other science-based methods. While regulation has a clear role in ensuring patient safety, these regulatory and legal constraints are understood by many to inhibit innovation in biomaterials and medical devices. Many at the workshop observed the importance of optimizing the regulatory process so that an appropriate balance is achieved between innovations to improve patient health and avoiding risks to patient safety. However, progress has been slow. Although it is important for the biomedical community to have a wide range of biomaterials options available, over the last 40 years only five fundamentally new, 9 U.S. Code, Title 21, Chapter 9. Available at http://www.access.gpo.gov/uscode/title21/chapter9_.html. Accessed July 2004. 10 H.R. Piehler. 2000. The future of medicine: Biomaterials. Materials Research Society Bulletin (August):67-70.
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Capturing the Full Power of Biomaterials for Military Medicine: Report of a Workshop TABLE 1.1 Synthetic Degradable Polymers in Clinical Use Date of First Routine Clinical Use Polymer Chemical Structure of Polymer Backbone 1969 Poly(glycolic acid) Ester 1971 Lactide-glycolide copolymers Ester 1982 Polydioxanone Ester 1996 Polyanhydride Anhydride 1998 Acrylate-terminated poly(lactide)-poly(ethlene glycol) Ester synthetic, degradable polymers have reached wide clinical use in the United States. As shown in Table 1.1, the rate of entry of new, synthetic polymers into clinical use has historically been about one per decade. In fact, the data illustrate that development efforts for biomaterials in the past were not only too slow but also did not result in a sufficient diversity of chemical structures. A 1995 National Institutes of Health (NIH) workshop11 concluded that the slow rate of biomaterials development may be a bottleneck in the clinical implementation of (1) support devices for new tissue growth; (2) prevention of cellular activity (where tissue growth, such as in surgically induced adhesions, is undesirable); (3) guided tissue response (enhancing a particular cellular response while inhibiting others); (4) enhancement of cell attachment and subsequent cellular activation (e.g., fibroblast attachment, proliferation, and production of extracellular matrix for dermis repair); (5) inhibition of cellular attachment and/or activation (e.g., platelet attachment to a vascular graft); and (6) prevention of a biological response (e.g., blocking antibodies against homograft or xenograft cells used in organ replacement therapies). Several workshop presentations focused on the need for a more coordinated path for new technology development and application in this field. SCIENCE AND TECHNOLOGY ROADMAPS—PRECEDENTS Technology roadmaps provide an effective framework for focused product development by highlighting technology gaps that limit the translation of product concepts to market reality. The classic example of such a roadmapping effort is that used by the semiconductor industry to direct technical activities for the past 25 years. Roadmaps in this field have focused research and development efforts in the chip industry to stay on the predicted information density curve, allowing the computer hardware and software industries to develop products in anticipation of a technology's becoming available. The rapid growth of the computer industry over the past two decades bears witness to the utility of roadmaps. This strategy has demonstrated that the coupling of product vision to technical reality can be an effective tool to drive market development. Technology roadmaps can direct the application of technical resources to achieve defined market goals, providing a critical path time line to translate the current technological state of the art to needed future products. Over the past decade, many other industries have embraced the technology roadmap concept, leading to a proliferation of roadmap models available for study. Examples include the electricity technology roadmap,12 the national electronics manufacturing series of roadmaps,13 and the many technology roadmaps for energy-intensive industries developed under the auspices of the Department of Energy Office of Industrial Technology.14 The organization of its technology roadmap for the petroleum industry, published in 2000, is a particularly useful model for the construction of a technology roadmap for a complex, multiproduct industry. 11 National Institutes of Health. 1995. Workshop on biomaterials and medical implant science: Present and future perspectives. October 16-17. Available at http://odp.od.nih.gov/biomaterials/report.html. Accessed July 2004. 12 The Electric Power Research Institute sponsored this effort beginning in 1999; available at http://www.epri.com/corporate/discover_epri/roadmap/. Accessed July 2004. 13 The National Electronics Manufacturing Initiative roadmapping overview is available at http://www.nemi.org/roadmapping/index.html. Accessed July 2004. 14 Several industry roadmaps developed by the Department of Energy Industrial Technologies Program are available at http://www.eere.energy.gov/industry/technologies/industries.html. Accessed July 2004.
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Capturing the Full Power of Biomaterials for Military Medicine: Report of a Workshop The production of a useful technology roadmap requires an understanding of a range of technical and nontechnical issues, including the current science and technology; future performance targets; technical, institutional, and market barriers; and research and development needs. FINDING A PATH FORWARD This document is intended to aid the technology planning process undertaken by the new Center for Military Biomaterials Research and the National Research Council to begin closing the gap between available biomaterials-related technologies and the military’s needs. The technology development roadmap elements detailed in Figure 1.1 describe the first step in enabling the military to modify and enhance its existing research and development programs in order to take best advantage of academic-based and corporate advances in biomaterials technology. FIGURE 1.1 Schematic of the differences between a needs-driven process and a technology-driven process.
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Capturing the Full Power of Biomaterials for Military Medicine: Report of a Workshop A critical first step in this process was the workshop, held in Iselin, New Jersey, on February 2-4, 2004. To ensure that the directions taken would be aligned with the military’s needs, participants included 15 senior U.S. Army officers and scientists who are experts in the health care needs of the warfighter. Participants also included 27 industrial scientists and business leaders who provided knowledge of the state of the art in commercial biomaterial product developments. The third constituency was the 40 academicians who presented the most recent basic and applied research concepts in the field. A near-term benefit of implementing this roadmap will be advances in combat casualty care through focused attention on targeted modification of emerging industrial products to increase their suitability for use on the battlefield. Application areas addressed by workshop participants included wound care, hemostasis, and healing agents; prophylaxis for exposure to chemical and biological warfare agents; tissue regeneration applications in orthopaedic, vascular, and neural systems; agent and vaccine delivery; sensors; and diagnostics. All speakers at the workshop were in the plenary sessions and those are referenced throughout the report. Much of the focused discussion took place in the breakout sessions, which are referenced in their respective sections of Chapter 2. Each of the breakout sessions commented on its specific topic, but all also noted specific materials development issues. These had many commonalities and are described in Chapter 3. For the research area directorates (RADs) within the Army’s Medical Research and Materiel Command, the roadmap will be: Highly relevant to many efforts of the Combat Casualty Care Research Program (RAD2) in terms of delivery of immediate far-forward and en route care for soldiers; implants to address musculoskeletal and cardiovascular injuries; and techniques or technologies to improve the acquisition and availability of blood products; Relevant to the Military Infectious Diseases Research Program (RAD1) in terms of delivery systems for vaccines and drugs; and Relevant to the Medical Chemical and Biological Defense Research Program15 in terms of products to enhance a medical defensive posture, such as protective clothing or sprayable films based on biomaterials and delivery systems for vaccines and drugs against biological threat weapons. 15 Formerly RAD4, now overseen by the Defense Threat Reduction Agency.
Representative terms from entire chapter: