Capturing the Full Power of Biomaterials for Military Medicine: Report of a Workshop (2004)

The workshop began with a number of presentations on both the military needs and the state of the art in biomaterials research, development, and application. Workshop attendees then separated into groups to address the various aspects of biomaterials development. They looked at outcomes and goals and assessed the development steps needed to accomplish them. Finally, each group discussed barriers to success. The following sections summarize their discussions.

As the size of the U.S. armed forces decreases,¹ it becomes more important to allow wounded soldiers to remain functional on the battlefield and, if that is not possible, to treat wounded soldiers and return them to duty as quickly as possible. Products that will allow a soldier to complete his mission before the need for evacuation are becoming extremely important to today's fighting force.

A variety of wounds are incurred in battle, and they can be categorized as follows: Abrasions are generally caused by scraping of the skin's outer layers; incisions are cuts commonly caused by knives, metal edges, or other sharp objects; lacerations are jagged, irregular cuts or tears of the skin; punctures are caused by an object piercing the skin layers, creating a small hole; and burns cause damage to skin cells that may vary greatly in depth, size, and severity. Many wounds in the field include all of these forms of trauma, and many are severe to the point that tissue is torn away from the body or entire limbs are amputated.

Wounds have also been categorized by their severity, depth, and chronicity, and each category has its own standards of care. However, the principles of cleanliness, wound covering, tissue apposition, and protection from physical trauma while tissues return to their normal physiological state apply to all wounds.

Even minor wounds have the potential to incapacitate a soldier in battlefield conditions. Products for far-forward wound care have as their principal goal the rapid stabilization and return to function of wounded soldiers, thus enabling them to complete their mission. Members of the breakout session listed the characteristics of an ideal wound care product as follows:

• Can be self-administered or be easily applied by a medic or colleague;

• Can be rapidly applied;

• Acts rapidly and is functional from the moment of wound or tissue contact;

• Reduces blood loss;

• Reduces infection;

• Inhibits or reduces contamination;

• Provides pain control at the wound site only with no systemic effects; and

• Has minimum mass (load) and volume.

Ideal products would be multifunctional, in that they could simultaneously control bleeding, protect against bacterial infection or contamination, control pain at the wound site, and provide for adequate wound sealing or closure. Reducing the cube, or the volume of the product in the soldier's pack or in a shipping container, is also very important, meaning that spray- or paint-on products that can control and stop bleeding would be highly desirable. Finally, workshop participants added that the ideal product would be packaged in a durable, nonbreakable, sealed package or container that would permit easy access and application.

Current bandages are made of gauze and are often applied in conjunction with an elastic bandage. They allow the wound to breathe but are not good barriers to subsequent contamination. They also do not have any antimicrobial properties and cannot stop serious bleeding. New bandages have been developed recently made of natural chitosan and fibrin materials. Several presentations at the workshop discussed the benefits of these bandages in the field. Although both types of bandage are clearly more effective, they are relatively expensive, with the fibrin costing as much as $1,000 per bandage.² Members of this breakout session expressed the need for an improved bandage that is antimicrobial, is resistant to subsequent infection and contamination, and can stop massive hemorrhage. In addition, a bandage that can protect large surface area wounds from subsequent contamination and at the same time reduce pain and infection would be of great value. The aim of this product would be to allow soldiers to complete their mission before they have to be evacuated for further treatment.

Superficial wounds currently are closed primarily with sutures. Suturing requires a moderate level of training by the health care provider as well as suturing instruments, sutures, and local anesthesia. A way to glue these injuries closed such that sutures and anesthesia would not be required would be of great value. Workshop attendees pointed out that cyanoacrylate glues have received regulatory approval for limited use but are not used routinely for external wound closure.

Fracture care at the far-forward position offers unique challenges given the incapacitation of the wounded soldier. Currently if a limb is fractured, wooden splints are applied with cravats or aluminum splints are applied with elastic bandages. Neither technology leaves much functionality in the fractured limb, and often the soldier is not able to complete the mission. This is especially the case for leg fractures where the soldier not only is incapacitated but also becomes an evacuation burden to the unit. A limb stabilization system is needed that would allow a soldier to complete a mission or, at a minimum, reduce the impact of the injury on the unit's mission. To accomplish this, some workshop attendees suggested that the system should incorporate ultralightweight and strong materials and that an ideal product would weigh less than a pound and be able to be applied very quickly by a medic.

Currently, severe pain is controlled by morphine. Use of this drug results in complete incapacitation of the patient, which means that the patient is no longer able to help with his or her own care or defense. Morphine also depresses respiration and heart rate, which can be dangerous with some injuries and lethal if it is not administered properly. Breakout session members indicated the need for a safe, effective replacement for morphine that can both be easily and quickly applied and have immediate effect. It is

important that this drug have minimal psychoactive effects so that patients can continue to assist in their own care, evacuation, and defense. Preferably, this drug would act only at the wound site and not systemically.

Many synthetic and natural materials have been investigated for treating wounds.³ Such materials include biodegradable polymers or modified materials that slowly release such potentially beneficial medicines as blood-clotting agents, growth factors,⁴ or agents that induce blood vessel creation. Although there has certainly been progress, wound healing remains difficult for a number of reasons. This is especially true in the field, where conditions include dirt and other contaminants, sweat and other bodily fluids, and severe time constraints that may necessitate moving the injured soldier prior to stabilizing the wound. All of these things mean that traditional bandages are generally less than effective.

New materials are needed that can arrest blood loss, impede infection, counteract shock, and foster biological regeneration. Such materials will have to be multifunctional, providing structural support for large wounds, pressure on wounds that require compression, and the ability to carry medicines where and when they are needed.

A number of metrics were suggested by the wound care breakout session members, including the following:

• A wound care system that combines wound cleaning, wound closure, infection control, and pain management;

• Effective and cheap bandages that cost 10 percent of the cost of advanced bandages in current use; and

• Ultralightweight splints that weigh less than a pound and can be applied in less than a minute.

When a wound is very severe, much more than battlefield medicine is required. A critical need exists in the military for effective methods to repair injuries to muscle and bone structure. Army personnel at the workshop who had only recently returned from the field stated that more than 70 percent of combat-inflicted injuries damage muscles and bones in the limbs, head, or face. This heightened percentage was partially attributed to the efficacy of new ceramic body armor that prevented many immediately life-ending injuries.^5-8

Severe trauma may be only a small percentage of medical care dispensed in the United States, but it is typical of wounds encountered on the battlefield, and both present unique challenges to the medical community. To address the dual need to treat muscle and bone injuries, workshop participants cited the need for suitable biomaterials to replace the damaged tissue and bone, to restore structure and load-bearing capacity, and to facilitate healing. Breakout group members concluded that if the military can provide effective treatment for these potentially debilitating types of injuries, injured combat personnel will benefit from higher morale, will be able to return to duty more rapidly, and will retain greater physical function.

Although there are civilian applications for many types of medical biomaterials, the military has a particular interest in developing solutions to the problems posed by battlefield-induced trauma. This level of interest cannot exist in an entirely commercial or academic environment. The military makes excellent, civilian-quality health care facilities available to the injured warfighter, but to have treatment programs that match the military’s needs outside the civilian sector, some workshop attendees believed that the military must take an active role in their development. Tailoring treatment for injuries to the needs of a military environment means that newly developed technologies must address either the need to perform some operations in challenging conditions outside a sterile operating room or the need to treat the types of injuries military personnel, as opposed to civilian personnel, tend to encounter.

Currently, military medical personnel are skillfully transferring existing civilian technologies to therapies suitable for battlefield conditions. Breakout group participants cited a number of treatment methods including repairing skeletal structure by grafting pieces of living bone removed from other locations onto the patient (autografts) or by grafting dead bone from cadavers (allografts). Surgeons have also used bone substitutes such as various calcium phosphate materials, calcium sulfate, collagen, hyaluronan, chitosan, chondroitin sulfate, synthetic polymers (polylactides, polyglycolides, polyethylene glycol, etc.), and metal prostheses.

Both inside and outside the military, a common problem exists in the choice of the best treatment technology. That is, doctors have difficulty obtaining independent and objective advice about how to select the best materials for a particular medical procedure. Participants in the workshop recommend that a clearinghouse be quickly established to independently evaluate the merits and potential problems associated with each existing or proposed material and technology in the context of its likely applications. They suggested that the results of these evaluations, along with grades for each material in relevant applications, be published and available to surgeons. There exists a wide variety of materials that can be used to replace or repair bone in the body, and independent advice from such a clearinghouse can greatly aid surgeons in comparing the relative merits of available state-of-the-art technologies.

To provide an overview of possible future directions for biomaterials in tissue engineering, it is useful to consider three time frames:⁹

1. The past: removal of tissues

2. The present: replacement of tissues

3. The future: regeneration of tissues

Some workshop participants believed that the ultimate goal for military applications of tissue engineering is to have the capacity to routinely regenerate functional limbs, organs, and tissue that have been damaged by injuries sustained on the battlefield. The critical need for tissue, limb, and organ replacement technologies is illustrated by the fact that 71 percent of battlefield injuries cause damage to the muscular and skeletal systems and 13 percent cause damage to the head and face.¹⁰ The capacity to heal these types of injuries would improve the long-term quality of life for those warfighters who are injured and could better enable their return to duty. Current efforts have made some incremental steps toward providing the injured with prostheses that have some useful functions, but the present state of technology does not restore the former capacity of the body for physical performance or provide the appearance or structure of the natural limb or tissue.¹¹

Aside from the goal of developing techniques for the actual regeneration of damaged tissue, organs, or limbs, another goal would be to develop a way to attach or implant a rudimentary replacement structure at the location of the injury. The rudimentary structure could serve as scaffolding that would then gradually be modified or replaced by the body itself so the new tissue could take on its natural structure and function.¹² For example, a development of this proposed technique could include further progress on the use of resorbable materials that can degrade over time and be replaced with natural tissues. Workshop attendees pointed out that in practice, it would be desirable to ensure that the rate at which the body degrades this artificial material would match the rate at which the body manufactures its natural replacement.

Another approach mentioned was the use of biological self-replicating materials. These systems could quickly integrate living cells into synthetic scaffolds for generation of tissue (skin or muscle) at the wound site.¹³ A further alternative would be to develop permanent artificial replacements for injured limbs, organs, or tissue that, unlike current technologies, restore full function and integrate fully with existing bone, structure, and tissue.

There was agreement among breakout session members that achieving any or all of these solutions for the repair of severe tissue injuries will require the development and understanding of new biomaterials. It will also require better control of the properties of interfaces between natural and artificial materials. The success of a treatment method will depend on its ability to balance its interface requirements with surrounding material with its needs for structural function.

Although repair of large-scale injuries, even in the presence of complicating infections, is potentially the most significant, long-term goal for progress in this field, there is also a need to develop of treatments for smaller-scale, less devastating injuries. Finding effective treatment methods for small injuries will be an independently useful and incrementally necessary step. Development of small-scale treatments is a practical near-term problem. Breakout session members pointed out that understanding how to make

repairs on a small scale will improve our overall ability to repair larger areas of fractured bone, heal larger burns, and prevent scarring.

To achieve progress in biomedical materials for the military, members of the scientific and medical community will have to collaborate in a multidisciplinary environment. This was clear from a quick assessment of the backgrounds of breakout session members as well. Applying any new technologies and developing usable products will also require ongoing, active cooperation between members of commercial, academic, regulatory, and military organizations. Interactions with field surgeons and physicians will also be critical to success. Workshop participants expected that the example of the diverse organizations they represent would establish a precedent for future interorganizational collaborations in this field.

In addition to interorganizational collaboration, the process of developing the necessary technology to heal and repair battlefield injuries will require the participation of members of diverse scientific disciplines. Materials scientists; developmental and microbiologists; biochemists; and trauma, neural, vascular, and orthopaedic specialists can all contribute fundamental understanding to the task of improving existing technology and discovering new materials and methods. Some workshop attendees believed that only a team approach could realize the full potential of new technology for the warfighter.

Certain areas of potential development were identified by participants as crosscutting and enabling technologies. These technologies have applications in any of several possible solutions to the general problem of healing and repairing injuries, regardless of the ultimate choice of injury repair technology, whether it is regeneration, resorption and replacement, or an artificial prosthetic. Examples cited included wound-healing enhancement, scar mitigation, infection control and its elimination, and high-throughput assays. Even general methods and techniques for facilitating seamless interactions among academics, corporate developers, and clinical personnel were considered by some attendees to be a necessary enabling technology.

Several participants indicated that the end result of implementing this vision for the future must be the design and development of an effective and practical treatment method useful to military surgeons. The availability of a practical and functional suite of products could have a revolutionary impact on the care of injured warfighters, allowing military personnel to benefit from enhanced recovery, decreased infections, rapid return to duty, restoration of form and function, active participation in work and society, and an enhanced sense of well-being and confidence.

The tissue engineering group identified three necessary pathways for biomaterials technology development: neuronal, vascular, and orthopaedic. Each of these pathways has some goals in common with other pathways, along with some unique technological demands. The goal of the group's discussion was ultimately to integrate progress in all three of these pathways with progress in other enabling technologies to lead to the production of fully functional replacement tissue, limbs, or organs.

At the workshop, breakout group participants laid out a time line that recognizes the existing technological challenges, the current rapid rate of progress in this field, and the critical need of the military for improved treatment plans.

Discussion at the workshop on the topic of bone and muscle repair benefited from the presence of a large depth of experience in this field. The description by several presenters of the prevalence of combat-induced injuries that affect the bone and muscle system and the resulting need for orthopaedic treatment was also an important driving force behind the significant focus on this topic in the roadmap.

Workshop participants believed that there was potential for near-term success in the development of bone void-fillers. These are materials that can be injected into existing voids to replace bone structure, catalyze regeneration of missing bone, or deliver therapeutics to promote healing or prevent infection.

Participants viewed these types of treatment as relevant and practical to develop immediately, and early versions are likely to be available in the very near term, perhaps in less than a year.

In the next phase, workshop participants anticipated the development of a bone replacement material that has greater functional capabilities and load-bearing capacity in addition to being compatible with the surrounding bone and tissue environment. The breakout group anticipated that ensuring load-bearing capacity might be difficult for replacements not made of metal or a high-density ceramic. Up to this time, advances in materials technology have not resulted in materials that provide function in addition to biocompatibility. As a result, some members of the group cautioned it would probably take 7 to 10 years before a biomaterial that was both weight-bearing and biologically compatible could be developed to address the injuries that most commonly occur in combat.

A realistic near-term, biomaterials-based limb replacement therapy could separate the provisions for bone wound healing acceleration and infection control from the provisions for function. Compartmentalizing these technology challenges could enable the use of traditional metallic devices to restore function while adjoining, biologically compatible surfaces provide a suitable interface to the surrounding tissue and bone. Workshop participants observed that a strong interface between the different materials would be critical to the success of such a strategy.

The breakout group recognized the potential in 3 to 5 years for further development of bioactive materials that promote bone healing and decrease the incidence of nonunions. Nonunions arise when replacement material fails to bond properly with existing tissue and also can arise when adjacent tissues fail to generate an adequate healing response (atrophic nonunion) or attempt to heal in a mechanically unstable setting (hypertrophic nonunion). Tailoring the material to better facilitate recognition by bone could help prevent nonunions. Also, during this mid-term period, participants believed that bioactive biomaterials will be able to enhance the development of new blood vessels, promoting better healing and preventing infections during bone and muscle repair.

Workshop participants were aware of the long-term potential of cell therapies. They did not, however, see a near-term potential for simple applications of cell therapies on the battlefield or in hospitals near the battlefield. Instead, military applications of biomaterials containing bioactives (such as antibiotics or tailored reactive groups) will likely be significantly more practical and realistic. Further, even within the civilian sector, the technology for cell-based orthopaedic therapeutics has not yet matured, so participants anticipate a significant wait for military-ready versions.

A bone void-filler is one candidate for near-term (1 to 3 years) use in repairing the skeletal system. Discussion among workshop participants resulted in the following list of desired properties in a bone void-filler:

• Ease of use—for example, a paste-like consistency may be desirable because it could be introduced through an injection and would not be displaced by bleeding. If such a material were properly designed, it could surround the point of fracture outside the periosteum and then harden quickly in place without heating the surrounding area.

• Controlled X-ray imaging properties—the ability to see the bone void-filling material using X-ray imaging is desirable for many applications. However, participants also envisioned some applications in which transparency to X-rays was adequate or even preferable.

• Biodegradability—an ideal hardened bone filler material would degrade at a rate equal to the rate of bone healing and replacement in the body.

• Bioactivity—a bone filler material that could release wound-healing accelerant or an antibiotic in a controlled manner over a period of 1 to 3 weeks would be very desirable. A release that is timed to the biological action of therapeutics and the availability of responding cell populations would result in very rapid acceptance and healing.

• Regulatory approval—it is very important that such a product be designed for speedy regulatory approval so as to transition to the field quickly.

Depending on the outcome of bone void-filler therapies, their applications could be extended to ablative bone wounds and fractures. Goals for the 3- to 5-year period would include availability of biomaterials that decrease the incidence of fracture nonunions and accelerate the regeneration of destroyed bone. Biomaterial-based therapeutic goals for 5 years and beyond would include materials that enhance generation of new capillaries or blood vessels and have functional and weight-bearing capabilities consistent with complete replacement limb function.

All tissue is necessarily linked, so that it is impossible to repair bone and muscle without also repairing blood flow and, ultimately, neural function. However, the specific expertise of workshop participants limited the group's ability to address the significance and involvement of both circulatory and nervous system components of this task. The make up of the committee and the workshop attendees was chosen in part because of the perception that biomaterials will be more important in the near term to tissue and bone reconstruction than to blood vessel and nerve regeneration.

Some of the identified development goals in the field of repair and restoration of blood vessels included the following:

• Materials for artificial blood flow conduits;

• Methods to increase vessel patency;

• Capacity to extend, regenerate, and enhance circulatory structures; and

• Ways to prevent materials-induced blood clotting and adverse tissue responses.

For the near term (1 to 3 years), workshop participants emphasized that an increased knowledge of the healing process for inner surfaces of vessels or grafts by endothelial cells would guide therapy design. Specific requirements for blood vessel treatment methods during this period may include bioactives in implanted artificial blood vessels or in devices designed to help blood circulation and the development of extracellular matrix-derived materials that enhance vessel development.

For the mid-term (3 to 5 years), workshop participants anticipated readiness for the task of developing implantable small- and large-caliber blood vessels.

For the longer-term (5 years and beyond), workshop participants emphasized such tasks as improving blood flow through vessels by increasing patency, developing artificial blood vessels made of resorbable materials that are replaced over time by functional natural blood vessels, and making artificial blood vessels that do not induce blood clotting.

Breakout session members made a number of observations about nerve repair and regeneration, although there was general agreement that much of this progress is a long-term goal. Improving treatment of nerve damage will include making replacement conduits that are antifibrogenic, neuronal regeneration enhancers that promote proper joining of nerves to muscle fibers. Injury recovery will also improve with the introduction of seamless attachment of the nerve replacements to existing nerve and muscle structures that allow appropriate conduction properties.

Requirements for the development of better nerve repair methods would center on, in the near term, the development of artificial nerve conduits. In addition, new biomaterials that work as biomimetic extracellular matrices could be developed to promote nerve regeneration.

Mid-term goals (3 to 5 years) may include the improvement of nerve conduits to make them antifibrogenic and prevent the formation of scar tissue that might interfere with nerve regeneration. Long-term goals (5 years and beyond) include the development of biomaterial-based therapeutics for neuronal devices that are functional and can carry action potential signal. Finally, workshop participants identified technologies necessary to induce merging of cells between host and regenerated nerve areas.

Workshop attendees described the demanding constraints of military applications and emphasized that the design and development of biomaterials-based treatments must be responsive to them. There was also good agreement that simplicity of use is a virtue for any proposed treatment plan. Finally, participants added that therapeutics that successfully control infection would be particularly helpful.

The group chose not to list precise requirements either for the treatment of small injuries, such as the repair of fractures and localized wounds, or for the treatment of massive injuries requiring limb salvage.

A number of metrics were suggested by the tissue engineering breakout group members, including

• Implementation of bone void-fillers within 1 year;

• Incorporation of bioactives into implanted artificial blood vessels within 3 years;

• Development of load-bearing, biocompatible polymers and composites within 5 years; and

• Development of anti-fibrogenic nerve conduits within 7 years.

Workshop attendees assigned to assess drug delivery needs first focused on the current state of therapeutic areas and enabling biomaterial technologies that could enhance casualty prevention and management. Discussion ensued on the research and development possible within the next 3 to 7 years for three target areas: prophylaxis, infection control, and pain management. Prophylaxis was targeted at both vaccines against infectious diseases and attack from chemical or biological weapons. Target areas have unmet needs that, if satisfied, would benefit military medicine with respect to improved outcomes, cost-effectiveness, and better delivery of medicine and care for warfighters. Medical products with improved therapeutic delivery would be deployed to battlefield, field hospital, and recovery facilities. At the workshop, breakout group participants laid out a time line to give direction to the development of products within therapeutic and enabling biomaterials technology areas.

Challenges related to the prevention of endemic infectious diseases, control of infections, and management of pain in the hospital setting are magnified in the austere conditions of the battlefield.

Presenters at the workshop highlighted the dangers of infectious diseases, which have had the greatest role in casualty production, resulting in more hospitalizations than wounds and injuries do. More than 50 etiological agents were cited as having either historical or future impact on the health of service members on the modern battlefield. These infectious diseases can affect three different phases of military operations: training, deployment, and mission execution. Endemic diseases that affect training and deployment can be categorized as those that can be transmitted easily in the close quarters of military barracks and workspaces. Examples include influenza, adenoviral infections, and diarrheal diseases. These communicable diseases are usually transmitted by close personal contact or respiratory droplet spread.

Threats can come from naturally occurring endemic diseases or from etiologic agents intentionally delivered by an adversary as in the case of biological warfare. Vector-borne parasites and viruses dominate the diseases that commonly affect mission execution. Examples of the most serious arthropodborne diseases include malaria, yellow fever, dengue fever, and leishmaniasis.

Since the Revolutionary War and beginning with smallpox, vaccination has been the method of choice to counter infectious disease threats. Effective vaccines can decrease the amount of medical

resources required in a theater of operations. Approximately 20 federally licensed vaccines or antitoxin preparations are available for use in military populations.¹⁴ Presenters mentioned another approximately 11 preparations that are in investigational new drug status and could be used if an imminent threat were identified. However, breakout session members estimated that at least double the current number of vaccines may be required in the future. This large number of vaccines represents not only a significant number of inoculations for service members, but also an enormous logistical and medical administration challenge given that most vaccines require multiple booster immunizations to achieve full protection.

These problems are magnified by the need to immunize as many as 100,000 to 500,000 troops on short notice prior to an operation. In the case of anthrax protection, at least six immunizations are required over an 18-month period.¹⁵ This requirement has left the Department of Defense with various categories of service members in different stages of immunization. Lastly, many of the vaccines that are currently available must be kept cold during storage and transport, and the lack of reliable refrigeration throughout the logistics chain precludes their use in many areas. Breakout group members identified the need for advanced biomaterials to improve the thermal stability of vaccines, decrease the number of immunizations, and improve the effectiveness of delivery of vaccine antigens.

In addition to vaccinations, barrier methods to prevent infection have also been used by the military. In the case of vector-borne diseases, the most effective barrier used for more than 50 years has been N,N-diethyl-m-toluamide (DEET).¹⁶ Currently, repeated applications of insect repellents are required to maintain an effective dose, especially in hot and humid environmental conditions. However, repeated exposures to DEET have been cited as responsible for a variety of neurological or other medical effects.¹⁷ The lack of acceptance by soldiers of products containing DEET may decrease the effectiveness of these barriers. DEET has been incorporated into military clothing, sun protection creams, and camouflage face paints with limited success.

Barrier creams are designed to confer protection against toxic compounds. They may be applied to protect against a wide spectrum of compounds, or may confer particular protection against specific groups of compounds. For example, specific barrier creams have been developed against chemical warfare agents. Ongoing research includes the development of barrier creams that protect against heat.¹⁸ Barrier creams that offer wide protection are based on materials with high repellence to both oil and water. Creams against specific groups of toxic compounds contain reactive species that act to neutralize the compounds before they can penetrate through the skin into the circulation. Barrier creams offer a simple and direct approach that has the potential to confer protection from toxic chemicals. They may have broad commercial application, for example as a backup to protective clothing or as protection against such industrial chemicals as pesticides. Workshop attendees observed great potential for research and development in this area.

It is always preferable to prevent wound infections rather than treat them. Ballistic wounds on the battlefield are especially troublesome because of the amount of foreign material that may be carried into the wounds, including dirt, contaminated shrapnel, and clothing fragments. Wound infection from burns

and compound fractures has contributed often to the need for limb amputation.¹⁹ Workshop participants observed that no effective infection control or prevention tools currently exist for the battlefield medic, and many are not available for complex wounds.

Because of the number of bacterial species that can cause wound infections and also because of the emergence of antibiotic resistance, military care facilities are constantly challenged by the number and types of antibiotics required. The austere nature of battlefield facilities may also inhibit the use of complex treatment protocols.²⁰ In the case of biological warfare agents, therapeutic intervention should be started within hours to prevent morbidity and mortality. Workshop participants noted that advanced biomaterials research is required to improve prevention of wound infections, decrease the need for repeated dosing, and simplify administration.

Pain management in the context of mass casualties and austere treatment facilities is challenging. Often, the most powerful drugs, such as morphine, are used when lesser pain management formulations could be effective. Studies suggest that up to 50 percent of all patients do not have their pain managed effectively after trauma.²¹ Workshop participants observed that the need for repeated dosing and lack of targeted drug preparations may contribute to this problem. Logistics, drug pharmacology and safety, etiology of the pain, and the experience of the expected administrator may affect the availability of effective pain management in military theaters of operation. Advanced biomaterials are required that increase the effectiveness of analgesics, decrease the requirement for repeated dosing, and allow topical or regional application.²²

Enabling technologies are those that generally improve the development of biomaterials for many applications. Biomaterials are the underpinning of any method of drug delivery.²³ Relevant factors noted by breakout session members include the development of new biomaterial drug or vaccine carriers or other delivery systems, new methods of administration, new combinatorial approaches for materials design, and rapid effective screening methods. New approaches are required to shorten the current drug development cycle, which is typically 12 to 15 years,²⁴ and can be as long as 20 years according to some workshop participants.

Members of the breakout session proposed that a goal for the military should be to reduce the number of needed prophylactic administrations by 50 percent. This goal was intended to apply to vaccinations and boosters as well as to the application of topical barriers for protection against insect bites and chemical or biological agents.

Because the ultimate, and ultimately preferable, vaccine product would require only a single shot, attendees discussed a variety of strategies to accomplish this goal. One strategy is to enhance the immunogenicity of certain vaccine antigens by the development of more effective carriers. Another

approach to decrease the number of booster immunizations could be to develop materials that would enable the timed release of antigens over the course of several months. This technology could be tailored to individuals to release antigens at optimal times as required to stimulate the immune system. In other approaches, agent-specific DNA or antigens could be targeted directly to cellular components of the immune system. Lastly, large combinatorial libraries that contain essential information about the potential for antigenic molecules to produce antibodies could replace the need for individual vaccines.

Vaccine preparations for diseases of greater military importance could be formulated using epitopes, or smaller components of antigens, embedded in biomaterial substrates to improve their effectiveness. Workshop attendees noted that as an alternative to vaccines, effective barrier creams may be able to prevent vector-borne diseases.

Some additional suggestions by breakout group members were that vaccine preparations should be thermally stable and not require constant cold temperatures during storage or transportation. Finally, it was suggested that an alternative insect repellent to DEET with the same effectiveness but with less chance for neurological reactions is needed.

The breakout session attendees proposed that a goal for this area is reduce infections by 50 percent and increase return-to-duty rates by 50 percent without additional increases in current medical resources. Improving the formulation of antibiotics, anti-infectives, or disinfectants that could be applied directly to wounds were mentioned as tasks that could lead to accomplishing these goals. Attendees indicated that new formulations are required that decrease the requirement for multiple dosing. Products also should be directed for use at the first echelon of care, and requirements for extensive management, such as multiple boosters, should be minimized.

Breakout session members proposed that the goal of this area should be to reduce the pain management burden by 50 percent on the battlefield after trauma. Accomplishments that would reduce the burden might include the development of better analgesics that could (1) directly target the source of pain, (2) decrease the amount of pain medication needed, (3) decrease the number of times medication must be administered, and (4) decrease the deleterious effects suffered by the recipients of the medication. In some cases, pain management could be combined with infection control in appropriate wound coverings or bandages. Finally, spray-on applications were mentioned as warranting further investigation.

A goal identified by breakout session members was to decrease the time required to deliver new biomaterials to these applications by 50 percent. Incumbent in this is a need to develop better combinatorial libraries and screening methods for specific compounds. Investment in this area could shorten development times for all biomaterials and facilitate federal regulatory approval.

The roadmap delineates a series of tasks and requirements for research and development that will lead to the development of medical products with improved outcomes, cost-effectiveness, and better delivery of medicine and medical care for warfighters. The tasks and requirements needed to reach this vision can be broken down into three major elements: prophylaxis, infection control, and pain management. Elements of this development may include, first, analyzing the unmet needs of drug and drug delivery systems, the military medicines that are used in battlefield and postbattlefield situations, and the costs of medical management. Next, the potential for new therapeutic drug and biotechnology molecules and for potential drug delivery systems and biomaterials must be assessed. Finally, the

potential drug and delivery system can be assessed based on time of onset, duration of action, therapeutic blood level, pharmacokinetics, physical chemical properties, portal of entry to body, and other factors.

Other considerations mentioned by workshop attendees include the following:

• Drug, biomaterial, delivery platform, and selection process that meet the military performance requirements

• Drug and biomaterial production requirements

• Determining the best route of drug administration based on product requirements and better medical outcomes

• Ease of use under battlefield conditions as well as in hospital settings

• Prioritizing the product requirements based on improving recovery time or return to duty; ease of use; lighter weight; reduction of administration, infection, pain, and inflammation; introducing enabling materials technologies, and so forth

• Development of screening methods for enabling materials technologies

Once the need has been identified, a valuable step is to determine whether a drug delivery product already exists in the civilian market or whether the military, industrial, or academic sectors are currently developing a similar drug delivery product.

The following performance metrics were suggested by workshop participants for products developed for drug delivery in military applications: dressings.

• In the near term, implement methods to deliver bioactives to wounds using powders, films, and

• In the mid-term, reduce by 50 percent the pain management burden on the battlefield after trauma.

• In the long term, improve the efficacy and reduce the administration requirements of prophylactic vaccines and drugs by 50 percent.

• In the long term, reduce infections by 50 percent and thereby increase return-to-duty rates by 50 percent.

• In the long term, fully integrate drug delivery into wound care and tissue engineering products.

Workshop attendees assigned to assess physiologic sensors and diagnostic needs began with a discussion of the current state of development by the U.S. Army of a system to monitor the physiological status of the foot soldier.²⁵ The prototype system under development consists of an array of wearable sensors that monitor heart rate, respiratory rate, and skin temperature. Additional capabilities for situation-dependent missions may include measurement of core temperature, body orientation, and actigraphy, a measure of acceleration that can be used to infer whether a soldier is moving around and also the number of hours of sleep. Any one of these physiological parameters can be attained from a number of different technologies involving sensor location in different parts of the body. For example, actigraphy can be measured using a device similar to a wristwatch.

Workshop participants noted and emphasized that such devices are in the prototype and proof-of-principle phase. Soldiers involved in current conflicts in Iraq or Afghanistan are not wearing these systems.

Field monitoring of soldiers' physiological status is a very desirable tool and could be used for such beneficial activities as (1) sustenance of physical and mental performance, (2) prevention of such nonbattlefield injuries as heat stroke and hypothermia, and (3) improvement of casualty management. As a first step, the Army is developing a system employing the array of sensors noted above for remote life sign detection (that is, to automatically—based on the sensor measurements and computer-implemented algorithms—determine whether a soldier is dead or alive, or in an unknown state. The Department of Defense is also developing handheld systems for detecting and diagnosing soldier exposure to biological and infectious disease agents. However, these systems are not wearable.

In addition, the Army's Institute for Soldier Nanotechnologies is charged to pursue a long-range vision for how technology can make soldiers less vulnerable to enemy and environmental threats. The ultimate goal is to create a 21st century battle suit that combines high-performance sensor and diagnostic capabilities with light weight and comfort.²⁶

Monitoring today is limited to on-the-skin sensors that a soldier wears. The adhesives used in these sensors are problematic in that they can cause rashes, are not water resistant, and generate poor signal quality due to artifacts. These sensors are typically powered by alkaline batteries, which have a short useful life and are relatively heavy.

Periodic monitoring is done of the heart rate using commercially available electrocardiogram sensors. Respiration is currently monitored using inductance plethysmography to measure breathing rate and depth and also to assess stoppage of breathing in the case of sleep apnea. These are commercial products and sometimes have problems when deployed in battlefield conditions. In addition, workshop participants observed that algorithms specific to military needs may not be available. A specific example is the need to make a remote determination if a soldier is dead or alive, which is something not normally needed in the civilian world.

The Army is moving toward monitoring that can be done without contact with the skin or through clothing. This may include invasive implantation of sensors, but this strategy will depend strongly on acceptance by the soldier and must also have a long life to help amortize its generally high cost. For example, a pill that a soldier can ingest to measure core temperature has a useful life in the body of 24 to 48 hours. Workshop participants did not see this technology as cost-effective today.

Some workshop attendees proposed that the most important fact that a forward medic needs to know is the location of each of his charges. Global Positioning System (GPS) sensing is currently being used only with the radio soldier. Breakout group members noted that lightweight GPS sensors for the field soldier are near-term technology that should be implemented as soon as possible.

Much discussion ensued at the workshop on the parameters needed to accurately assess and treat soldiers in the field. This is a critical technology obstacle that must be addressed to identify the appropriate sensor, either a commercial product or one specifically developed for the Army's use, and to successfully develop and implement the necessary algorithms to interpret the sensed data. The current effort described by presenters is one of system integration of commercial sensors and development of decision algorithms. However, some workshop attendees cautioned that the potential for new sensor development must also be considered.

An important goal identified was to provide early remote assessment of the field soldier. If the forward medic could monitor the exact location of any soldier in his squad and the soldier's wearable sensors could measure heart rate, respiration, core and skin temperatures, blood pressure, cardiac output, fatigue, blood oxygen, total weight, and hydration, the overall effectiveness of the medic and the unit would be greatly improved. This goal could be accomplished using multifunctional, lightweight, off-the-skin, micromachine sensors that are integrated with the soldier's uniform or implanted.

Because field medics are typically young, inexperienced, or both, a major challenge is to develop an integrated physiological monitoring system that can provide the medic with real-time information presented as simple decision-making symbols. For example, if a soldier is injured but still alive, the integrated monitoring system would measure vital signs and then flash red or yellow depending on the severity of the soldier’s condition. In this way, the medic would be able to make quick decisions as to which soldiers require immediate evacuation or need lifesaving intervention. Such programs as the Virtual Soldier are investigating means of communicating these data in ways that are easy to interpret.²⁷

Another human factor need identified is to research which physiological parameters are key in predicting particular clinical outcomes in order to prioritize a need for lifesaving intervention. Ongoing research involving the mining of physiological data from trauma victims in the civilian environment could provide insights on what data should be monitored when a soldier becomes a casualty. Currently, the data needs for prevention of nonbattlefield injuries are known and include heart rate, core temperature, hydration, and metabolic rate. Research is ongoing for casualty management and for sustenance of performance. Currently the only tool available is actigraphy, used to estimate sleep time and predict soldier performance subject to sleep deprivation. A number of gaps have been identified for the development of biomathematical models for prediction of soldier performance subject to sleep deprivation.²⁸

Ultimately, sensors will be integrated with controls into systems to treat conditions remotely. This could include dispensing medications, providing hydration, warming boots, or cooling clothing. In the far future, nanosensors could circulate throughout the body, sending information and also controlling function. To this end, it is important that the biomaterials community work with the existing silicon-based devices to ensure compatibility for the next-generation biosensor.

Several presenters at the workshop noted that the threat of chemical or biological weapons attack is real in many locations where soldiers operate today. Such chemical agents as phosgene, chlorine, chloropicrin, and cholinesterase inhibitors may be categorized as blistering agents or toxins in the nervous, blood, and respiratory systems. Biological agents include bacteria, viruses, ricksettiae, and genetically engineered microorganisms. Biological agents can be more lethal than chemical agents but generally offer more time to respond to the threat. In either case, it is desirable to protect the soldier from exposure through early warning sensors that provide ample time to employ protective biomaterials for the skin and biofilters to protect respiration.

Workshop attendees noted that power is a limiting factor in many devices. For example, more than 75 percent of the weight of many devices is in the battery. The goal of many of the sensor systems discussed is to make them as small as possible in order to reduce the burden on the warfighter. This means that the power supply must also be made smaller. It could also allow the use of very low power sources that have previously been ignored, such as harvesting power from temperature differentials in the human body or using available insolation on clothing surfaces. Currently, there is little commercial demand for such specialized power sources.

Batteries present a variety of materials challenges in their electrodes, electrolytes, cases, and connections. These components are required to be physically robust while they maintain electrolytic function, meaning that the materials must exhibit mechanical stability during cycling and resistance to mechanical shock.²⁹ Commercial battery systems for small electronics have made great strides in recent years, and in theory, the military should be able to utilize this progress for its own purposes. However, a recent NRC report on advanced power systems describes some of these materials needs. For example, although thin-film, lithium-based batteries show tremendous promise in the laboratory, known challenges include (1) battery development on thinner, more flexible substrates, (2) stacking for creation of three-dimensional batteries, (3) improving yield (currently only 10 percent), and (4) packaging. At present, there is insufficient market pull to drive low-cost solutions to these problems. This implies that the military will have to make directed investments to achieve its specialized power goals for the future.

For many military applications, fuel cells were mentioned as attractive alternative to batteries. An interesting possibility is to use parts of the human body as components of the cell. For example, one could view the nervous system as an electrical system powered by glucose through oxidative phosphorylation. Although these technologies show promise in theory, there is currently little commercial demand for such innovations as energy harvesting. In addition, biomaterials have been shown to enable improved capabilities for future fuel cell configurations.³⁰

Predicted near-term advances encompass the transition of proven technology to the field. Achieving this will require validation over extended operational periods. Examples of near-term advances include the following:

• Equipping all soldiers with lightweight identification and location sensors.

• Improved adhesive materials to ensure that sensors remain on the skin under all battlefield conditions—an early implementation might include a wired system used to transmit data from the sensors to the soldier’s computer where data are processed. In the future, wireless technologies could be used, including magnetic induction, which is desirable because of its low signature level. From the soldier to the medic, data could be transmitted using radio-frequency signals.

• Determination of useful physiological data that the field medic may be able monitor with sensors for casualty management—respiration, heart rate, and the core and skin temperature of each field soldier are the first needs. Blood pressure is a useful parameter that is easy to measure, but cardiac output may be a better indicator. Other parameters may be useful only in combination with additional information.

Predicted mid-term advances include concepts that are currently in research and development. An example is sensors that do not require contact with the skin. Some potentially enabling technologies under investigation for this include micro-impulse radar technology that can detect respiratory rate and heart rate through clothing; range-finding radar that can operate with very low power, in the range of 1/1,000 of the power of a cell phone battery; and capacity-coupled noncontact electrocardiogram systems that have been shown to get good results through clothing.

Anticipated long-term advances are sensors that are integrated with soldiers' clothing and other equipment using micro- and nanotechnology. Another long-term goal is the development of algorithms that integrate physiological information for quick decision making and the availability of the multitude of data necessary to make these decisions reliably.

It is most important to determine what data are most useful to sense. Data collected will be used by soldiers in the field to make decisions, and these data must be useful and understandable. A number of other factors must be considered, including the following:

• Sensors should not add to the weight or cube of the soldier.

• Sensors must be robust to function in multiple environments and conditions.

• Sensors must provide precise and accurate data. It is tremendously important that sensors be reliable under strenuous environmental and operational conditions. The environment in which soldiers work, the things they do, and the notoriously poor connections between the sensors and the human body generally produce any number of artifacts that make data suspect and decisions unreliable.

• A long-term goal is the development of smart sensors that have self-diagnostics and are able to process information locally with minimal power consumption.

• Sensors should operate with low signature to avoid detection by enemy forces.

• Sensors embedded in clothing may fail when clothing tears.

• Ambulatory modalities are needed for monitoring blood pressure. This measurement currently requires either an electrocardiogram or a carbon monoxide monitor.

• The effects of high-altitude environments on monitoring blood oxygen and carbon monoxide levels must be considered.

• Implanted sensors may pose ethical questions in addition to questions of their impacts on health.

Finally, workshop attendees noted the importance of remembering that people will be using the technology. The forward medic operates in a difficult environment. Many times the environment is dark, dangerous, extremely hot or cold, and usually a high-stress situation. Medics are generally assigned 48 soldiers to monitor and must deal with a 3-day resupply cycle. Often, medics have little training and experience and, thus, need sensors that provide resolution and clear indicators of the situation.

Soldiers also operate in very high stress environments, and their comfort is always an issue. Some workshop attendees suggested that researchers should wear a MOPP³¹ to know what it feels like. Soldiers generally do not like the current adhesive electrodes. A major materials need for the soldier was identified as adhesives that stick to sweaty skin with no irritation and strong, light materials for packaging new sensors.

It is also important to remember that field soldiers are unique individuals with unique baseline vital signs for blood pressure and stress levels. This highlights the importance of access to a soldier's historical data during trauma in the field.

The following performance metrics were suggested by workshop participants for products developed for physiological sensors and diagnostics in military applications:

• In the near term, make lightweight location transmitters available for every field soldier.

• In the near term, develop a high-level system of diagnostic needs that will help to optimize sensor needs and facilitate the development of the most important combinations of sensors.

• In the mid-term, implement 50 percent smaller batteries using micro- and nanotechnology.

• In the long term, implement integrated, off-the-skin sensors for multiple diagnostic needs.

Success in this endeavor is intended to decrease the volume of the sensor system by 50 percent.

A final consideration comes from the realization that it is in many cases the same soldier who needs to be monitored remotely, treated on the battlefield, carefully medicated throughout these steps, and then reconstructed to original functionality. The integration of new technologies for acute care may present some interesting challenges that have implications for the therapeutics provided by the biomaterials-based devices. For example, wound care treatments need to be compatible with potential decontamination for biological and chemical warfare agents. Furthermore, treatments need to be optimized not only to stabilize the patient, but to have minimal impact on the reconstructive therapies to follow, particularly for potential regenerative therapies based on tissue engineering. For example, antimicrobial treatments from drug-eluting dressings should not damage or kill viable tissue.