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Mission
The mission of the Combat Casualty Care Research Program is to reduce the mortality and morbidity resulting from
injuries on the battlefield through the development of new life-saving strategies, new surgical techniques,
biological and mechanical products, and the timely use of remote physiological monitoring.
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Neuroprotection
Neurological Effects of Blast
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Extremity Trauma
The majority of battlefield wounds occur to the extremities (55%) and head/neck region (30%). In the
extremities, the wounds are predominantly penetrating soft tissue wounds and open fractures. Infection,
delayed/nonunion of bone, and impaired/loss of muscle function are common outcomes. The Extremity Trauma and
Regenerative Medicine team is addressing these problems several different ways with the goal of returning the
injured Warrior to full function.
First, injuries and their clinical outcomes are being defined. Until recently, there was not a good understanding of
the injuries sustained by our Soldiers in ongoing conflicts. To help direct research efforts, retrospective studies are
conducted to determine the incidence, rate, and qualitative outcomes of extremity injuries in the Iraq and
Afghanistan conflicts.
Second, pre-clinical studies are conducted to determine which therapies have the greatest clinical potential.
Various animal models that mimic traumatic injury are utilized to evaluate potential therapies for infection and
soft tissue and bone injury. We strive to evaluate the most advanced and promising technologies using the most
clinically relevant and stringent animal models possible.
Third, we conduct prospective clinical trials aimed at improving outcomes of extremity wounds.
Finally, we are actively involved in extramural research programs focused on repair of extremity injuries.
Pain Control
Pain, both acute and chronic, is recognized as a leading problem among US soldiers injured on active duty or
during deployments. Pain is experienced throughout the continuum of trauma care and within all ranks of the
military. Recent initiatives track pain scores from as early as time of admission to the Emergency Department (ED)
at Level 2 and Level 3 facilities. Preliminary results indicate that, of soldiers admitted to Level 2 and Level 3
facilities, 71% experience pain of 5 or greater on a scale of 0 to 10. Accepted clinical guidelines classify pain of 5
or greater as severe pain and recommend treating pain rated as 4 or greater. Treatment of acute pain is
particularly important because recent evidence suggests that uncontrolled acute pain leads to neuronal remodeling
and increased incidence of chronic pain.
The over-arching focus of this research area is the study of pain from the battlefield through recovery. Particular
attention is paid to identifying novel pain control techniques (including novel pain control targets) and molecular
mechanisms in the pain pathway. While the recognition of pain as a disease process rather than a symptom has
shed light onto the important role of pain, a more comprehensive understanding of pain has yet to be achieved.
Major hurdles include the unreliability of medical records when collected from austere environments with
inherently limited access and availability, and the lack of a consensus concerning the best tools to use for
validating pain research.
Although significant advancements have been made in the care of acute pain, we are just beginning to realize the
far-reaching impacts of suboptimal pain management on health processes; these include inflammation,
immunosuppression, longer hospital stays with slower recovery times, less effective physical rehabilitation,
neuropsychological pathology, and poor quality of life. As leaders in the management and research into pain
control, military pain specialists have established themselves as indispensable members of the combat casualty
team and the soldier's primary advocate in the treatment of pain.
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to apply this knowledge to the development of new technologies and devices that advance the medical monitoring
capabilities of combat medical personnel for triage, diagnosis and decision-making to improve the management of
combat casualties. An important research tool is a research effort focused on investigating the time course of
central hemodynamics, autonomic functions, and peripheral tissue metabolism during progressive reductions in
central blood volume induced by lower body negative pressure in healthy human subjects. Basic research efforts
are also used to investigate and describe the physiological signals that distinguish patients with low tolerance
(non-responders) to reductions in blood volume from those with high tolerance. Evolving technologies are applied
to assess physiological performance to reduction in blood volume. These include measures of early and continuous
alterations in central hemodynamics, autonomic functions and tissue perfusion including bioimpedance, real time
measures of cardiac beat-to-beat (R-R interval) performance and waveform analysis of arterial blood pressure for
stroke volume estimates and pressure oscillations, direct measurement of sympathetic nerve activity, linear and
non-linear frequency analysis of R-R interval captured from a standard ECG (heart rate variability indices to assess
autonomic oscillations; heart rate complexity indices), and near infrared spectroscopy (muscle oxygenation, pH,
lactate). Loss of the normal relationship between the circulatory system and nervous system sympathetic activity
is investigated as a potential mechanism of the poor blood pressure/tissue perfusion that occurs during progressive
reductions in central blood volume. The impact of other combat-related stressors such as heat, cold, exercise and
anxiety on physiological measures associated with monitoring patients with hemorrhage are investigated.
Learn more
Clinical Trials
The CCCRP Clinical Trials program is centered at the US Army Institute of Surgical Research (USAISR). The
USAISR is unique within the Medical Research and Materiel Command because both patients and research
scientists are present within the same Institute. This collaborative, integrated environment provides an
opportunity to translate science into improvements in combat casualty care and deliver these improvements to the
battlefield. The clinical trials program has two primary objectives. The first is to observe current combat casualties
to identify emergent challenges and opportunities for improved care. The USAISR serves as the only American
Burn Association verified burn center in the Department of Defense. Consequently, the USAISR receives all
significant burn injured service members evacuated from the wars in Iraq and Afghanistan. As a result, we have
the opportunity to observe patterns of injury and implement programs in order to prevent and better treat these
burns. Examples of our findings include identification of significant numbers of waste burning accidents and
implementation of an awareness program, identification of large numbers of debilitating hand burns and
implementation of a rapid equipping program for fire resistant gloves, identification of thermal injury to the
portions of the torso not covered by body armor and development of improved protective clothing, and
identification of over resuscitation injury and implementation of a burn resuscitation flow sheet to ensure
appropriate care. The second objective is to translate pre-clinical research from the other research areas at the
Institute into a clinical environment for validation. Examples of this type of translational effort include testing of
wound care dressings in donor sites, and assessment of damage control resuscitation strategies in the burn
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operating room.
The USAISR Clinical Research program prides itself on being responsive to clinical problems and striving for
excellence in burn care, critical care medicine, and the care of the multiply injured casualty. Critical advances in
burn care and trauma care developed and tested at the USAISR have significantly improved patient survival and
outcomes in combat casualties.
Craniomaxillofacial Injury
The United States Army Dental and Trauma Research Detachment (USADTRD) is the largest military dental
research organization in the Department of Defense and it is the only military research facility dedicated to the
study of injuries to the craniomaxillofacial (CMF) complex. Use of improvised explosive devices in Iraq and
Afghanistan and the capability of body armor to decrease fatal torso injuries have resulted in new wounding
patterns among survivors that includes ruinously destructive CMF trauma and burns. Wounds to the CMF are
usually associated with a poor prognosis because restoration of the specialized structures and cosmetics are
significantly challenging and impact functional outcomes, sense of self and social re-integration. The USADTRD's
research foci is established around three research areas; a) development of composite tissues for grafting and
implantation, b) ameliorating the effects of host healing processes and infection on trauma and burn wound repair,
and c) restoration of damaged or replacement of missing CMF tissues and structures.
Craniomaxillofacial Research at the USADTRD at USAISR will emphasize 3 challenges:
Craniomaxillofacial (CMF) Regenerative Medicine
Battle Injuries cause devastating deformities to the CMF area at a higher rate than previous wars. Current
treatment procedures for serious craniomaxillofacial battle injuries were developed during World War I. Using
the injured persons own tissue, a surgeon attempts to lessen one deformity while creating another. The end
point of these treatments is usually patient frustration, not successful outcome. The three research areas will
be fundamental in providing technologies to improve outcome in CMF battle injuries.
Biofilm-Impaired Wound Healing
The ultimate goal of this research is to mitigate the influence of infection on healing and regeneration.
Infections of the teeth (decay) and tooth-supporting tissues (periodontitis) are caused by plaque which is a
biofilm found in every mouth. Plaque, besides causing an enormous burden of disease on Soldiers and the
Military Healthcare System, is a perfect disease model to study and to develop therapeutic strategies to
prevent/treat biofilms of different bacterial species found in combat wounds.
Amelioration of Scar Formation in Injured Skin and Soft Tissues
Scar formation is currently the inevitable consequence of postnatal wound repair and is the means by which
the body expeditiously restores cutaneous barrier function following traumatic or burn injuries. Normal and
pathologic scarring (excessive collagen deposition beyond the borders of injury) of skin which includes
hypertrophic scars and keloids significantly reduce the function of injured skin and the underlying tissues.
Severe cases of hypertrophic scars can result in disfigurement, restriction of motion, and disabling pain in skin
and soft tissue wounds. The effects of pathologic scars on quality of life are significant and often
underappreciated. The impact is particularly magnified in oro-facial injuries where scarring can lead to
significant anatomical, functional and aesthetic facial degradation. This places a huge burden on the injured
warfighter for their re-integration into society. The pathophysiology underlying hypertrophic scar formation is
not well understood and is a subject for research.
Learn more
Blood Products
Recent efforts in blood products research have centered on finding suitable replacement compounds for use in
blood component therapy. That is, when fresh whole blood is not available, various components of blood (plasma,
platelets, red blood cells, etc.) are administered. Various methods to prepare such components including drying
and freezing components are being investigated. However, a requirement to identify and treat the underlying
causes of the lack of effective coagulation in severely injured patients has become apparent. Current efforts to
address the "coagulopathy of trauma" are largely focused on attempting to improve outcomes using treatment
regimens that incorporate available products in different ways, for example, more aggressive use of plasma
transfusion, earlier correction of pH, etc. These efforts provide incremental advances in care but are necessarily
limited by the existing products and knowledge. Major advances in patient care will require new products and
knowledge. Development of new diagnostics, therapeutic targets and drug candidates requires a more in-depth
knowledge of underlying mechanisms. This work is closely coordinated with the studies undertaken in the Damage
Control Resuscitation area. Research encompasses in vitro systems, animal models, and clinical studies to:
a. elucidate mechanisms relevant to coagulopathy,
b. to relate changes observed in blood with patient outcomes, and
c. to investigate potential diagnostic and therapeutic approaches.
An emphasis is that data collected is suitable for data integration and modeling efforts, such as systems biology or
other modeling approaches. Modeling efforts are incorporated into the research program to augment the
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conducted in animals. Other notable efforts include developing animal models for compartment syndrome, massive
contaminated defects, and large segmental muscle loss. The concept of a dual-purpose bone implant (promotes
regeneration and prevents infection) was developed and is being evaluated. The Brooke Army Medical Center
Department of Orthopedics has initiated several clinical trials in the areas of combat casualty care and several
more are planned in the near future.
The Combat Casualty Care Research Program (CCCRP) oversees a multi-center clinical trials consortium known as
the Orthopaedic Extremity Trauma Research Program (OETRP). The OETRP focuses on improving outcomes of
extremity injuries within the next 5 years. This is accomplished by funding translational research projects that
evaluate new and emerging therapies and by conducting clinical trials to evaluate current standards of care and
available treatments. In addition, the CCCRP provides technical oversight to more than 20 large research contracts
with universities and companies engaged in extremity trauma research. These relationships are used to advance
scientific inquiry in the areas of soft tissue and bone injury, infection, and tissue regeneration.
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A8. New vital signs to provide personnel with more sensitive and specific indicators of the true extent of trauma
injuries, in addition to providing more precise diagnosis at earlier stages of care. These new vital signs will allow
for better and earlier diagnosis of impending cardiovascular collapse and will provide personnel with a more
accurate indicator of the need for a life saving intervention. Part of this research involves the use of high
performance computing approaches for the extraction of informative features from high frequency and high
resolution waveform data digitized from different body sensors (i.e. EKG). Additionally, advanced information and
computer processing approaches will be used to develop systems that can process and implement these new vital
signs in smaller and lighter monitoring systems that can be carried by medics in the battlefield. To further
automate critical care procedures, open loop systems will also be developed that will provider personnel with
recommendations on treatment options in addition to providing the ability to execute the intervention
automatically. Finally, closed loop control systems will be developed to fully automate the care of the patient with
little or no intervention from the provider. Development of extracorporeal devices will be explored with capabilities
to augment and/or replace mechanical ventilation requirements for patients with severe ARDS.
Q9. What are some examples of clinical trials research?
A9. Clinical research in injured casualties is being conducted on a variety of combat-related medical issues.
Research includes resuscitation protocols and stabilization in local and far forward care, clothing issues and
protection from injury, continuous renal replacement therapy, antibiotic use, wound excision and closure
techniques, diagnosis and treatment of head injury including blast injury, pharmacokinetics of antibiotics in the
severely injured, topical wound treatments including silver products and vacuum assisted wound closure, wound
healing of the skin donor site, hemorrhage control in the burn OR, nutrition during ICU stay and during outpatient
recuperation, temperature control in the burned patient, hypotension control strategies, and heterotopic
ossification in the severely burned.
Q10. What are some examples of craniomaxillofacial research?
A10. Research to provide regenerated or genetically engineered tissue constructs to replace damaged or
destroyed face features through accelerated pre-clinical and clinical trials, development of biological therapies
combining tissue engineering and stem cell technologies to generate craniofacial structures at the USADTRD, and
accelerated research in collaboration with other institutions to leverage their resources to build our research
portfolio on craniomaxillofacial regenerative medicine. The deliverables will be a combination of a scientific process
and products such as angiogenic and/or osteogenic scaffolds, tissue-specific stem (progenitor) cells capable of local
repair and regeneration, vascularized soft tissue constructs conducive to the restoration of facial defects, and
bioactive bone construct to repair and regenerate facial bones.
Additional research is ongoing into algorithms to understand biofilm pathophysiology and test therapeutic agents
useful to treat not only dental plaque but biofilms which complicate healing of combat wounds. The deliverables
will be FDA approved anti-biofilm agents in the form of a wound gel consisting of antimicrobials which exhibit low
propensity to induce microbial resistance and biofilm dispersing agents. In addition, the research will produce
evidence-based treatment modalities to improve the outcome of infected combat wounds. This treatment
information will focus on being readily transferred into clinical testing.
Planned research includes development of a biological therapy comprised of cells (e.g., mixed-population of
progenitor cell types), matrix, growth factors, and other small molecules (e.g., Transformation Growth Factor-&#
946; antagonist). The intent of this biotherapeutic is to accelerate healing and reduce scarring by attenuating the
inflammatory response and by the recruitment of resident stem or progenitors cells and their secreted signaling
molecules to the injured site. It is now well-known that mesenchymal stem or progenitor cells have the ability to
modulate the inflammatory response. The deliverables include the identification of the most efficacious progenitor
cell types, growth factors, and small molecules to improve healing and scarring using the rabbit scar model. These
steps will provide information needed to achieve the next stage in the development of biological therapies to
improve disabling scarring and tissue regeneration therapeutics in the oro-facial region.
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inactivation are being studied. One promising study is trying to characterize the effects of a riboflavin-UV light
pathogen inactivation process upon whole blood. Because whole blood is perishable, efforts to increase its "life
span" research continues on extended storage solutions either to extend the storage or provide "fresher" quality
cells at time of transfusion and to evaluate the quality of frozen/deglycerolized blood versus liquid stored red cells
during storage (Days 0-42). Examples of blood research include determination of the underlying mechanisms and
clinical consequences (outcomes) of the coagulopathy that frequently occurs after trauma, ultimately leading to
development of diagnostics and therapeutics to effectively predict, diagnose, prevent, and treat trauma-induced
coagulopathy.
This effort includes studies of trauma-related changes in:
1. coagulation enzyme function
2. anticoagulant mechanisms
3. fibrinolytic enzyme function
4. antifibrinolytic mechanisms
5. platelet function
6. endothelial function
7. selected elements of inflammatory function involved in regulation of hemostatic mechanisms
Q14. Where can I find additional information about the combat casualty care research?
A14. Additional information about CCCRP can be found at https://ccc.amedd.army.mil
.
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