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Extremity Trauma Research
& Regenerative Medicine


BACKGROUND

The majority of battlefield wounds occur to the extremities. In fact, 82% of battlefield injured Warriors have at least one extremity injury; penetrating soft tissue wounds, burns, and open fractures account for most of these wounds.

Infection and nonunion of fractures, loss of muscle function, and the inability to achieve skin closure with vascularized skin are common complications and continues to be a significant source of morbidity and mortality.

The Extremity Trauma and Regenerative Medicine task area is addressing these problems several different ways with the ultimate goal of returning the injured Warrior to full function.

1. The Warriors' injuries and their clinical outcomes are being defined.

To help direct research efforts, retrospective studies were conducted to determine the incidence and qualitative outcomes of extremity injuries in the Iraq and Afghanistan conflicts. The wounds of a cohort of 1,566 battlefield injured Warriors are being fully characterized and followed throughout medical retirement.

It has become apparent that lack of effective treatment options for osteoarthritis, skeletal muscle conditions, back conditions, and nerve injury are the main reason why many injured Warriors never fully recover. A database of over 200 type 3 open tibia fractures is being used to determine what causes poor clinical outcomes. Infection and nonunions are the primary complications. Although this effort has provided significant insight into the clinical issues, it isn’t enough.

An orthopaedic registry that has data elements specific to extremity injuries has been created and will be used in conjunction with the Joint Theatre Trauma Registry.

2. Pre-clinical studies are conducted to determine which therapies have the greatest clinical potential.

We strive to evaluate the most advanced and promising technologies using the most clinically relevant and stringent animal models possible. Various pre-clinical animal models have been established and utilized to evaluate potential therapies for infection and soft tissue and bone injury, to include developing animal models for compartment syndrome, large contaminated musculoskeletal defects, large volumetric muscle loss and burn.

Relevant animal models have been created and collaborations with academic institutions have been established to develop innervated and vascularized muscle constructs to solve this skeletal muscle injury problem.

The ability to utilize stem cells as a therapy for skin, muscle, and bone injuries has been established. A vascularized skin substitute for early burn wound coverage is being developed from the adipose layer of discarded burn skin.

These stem cells are then used along with collagen and fibrin-based scaffolds to comprise the epithelial, dermal-vascular and hypodermal layers to develop a complete full thickness skin equivalent. Studies have been completed and are ongoing to improve the use of bone marrow-derived mesenchymal stem cells for bone regeneration.

Significant advances towards improving the effectiveness of stem cells following muscle injury have been made. Clinical practice guidelines for irrigation of contaminated wounds have been created from studies that we first conducted in animals.

The concept of a dual-purpose bone implant (i.e., promotes regeneration and prevents infection) was developed and is being evaluated by us. Outside collaborations are leveraged to make a wide variety of biomaterials readily available for evaluation in our animal models of soft tissue and bone defects.

We are also standing up a comprehensive biofilm research effort. Significant basic science discoveries have been made, and we will translate them to the clinic.

3. Prospective clinical trials aimed at improving outcomes of extremity wounds have been initiated.

We have partnered with the Department of Orthopaedics and Rehabilitation at Brooke Army Medical Center, and they are conducting several multi-center clinical trials in the areas of combat casualty care with seven more trials starting within a year.

A multi-center clinical trials consortium, Major Extremity Trauma Research (METRC), through a cooperative agreement with Orthopaedic Extremity Trauma Research Program (OETRP) has been created. Capable military orthopaedic departments (to include Brooke), and 24 very large civilian centers, will be members of this consortium; this will help develop needed infrastructure, allow military personnel to gain expertise, and will further solidify a research culture within the military orthopaedic departments.

Recently, a prospective study demonstrated that an energy-returning ankle brace substantially improves running speed of Warriors who had severe lower extremity injuries. A prospective study is underway to evaluate the effectiveness of a regenerative medicine based therapy on Warriors who have suffered a large amount of volumetric muscle loss.

4. Other research programs are being actively leveraged.

The USAISR manages the OETRP and is an active partner in the Armed Forces Institute of Regenerative Medicine (AFIRM). The OETRP focuses on improving outcomes of extremity injuries within the next 5 years.

This is accomplished by funding translational research projects that are evaluating new and emerging therapies and by conducting clinical trials that evaluate current standards of care and available treatments. To date, 26 preclinical and clinical studies have been funded, as well as the aforementioned consortium.

AFIRM is a collaboration between the military and two civilian research consortia; it is focused on utilizing regenerative medicine to improve outcomes of injured Warriors who have sustained extremity, craniomaxillofacial, and burn injuries.

Most of the immediate clinical efforts from AFIRM will be in skin replacement and scar mitigation along with composite tissue allografts.

The Dental Trauma Research Department is also at USAISR and is working on similar clinical problems; we partner and share resources and expertise whenever possible. Recently, we have begun collaborating with the Infectious Disease Department at BAMC, and our respective strengths complement each other well.

Summary

Great strides have been made in identifying the clinical challenges and barriers to optimum functional outcomes and addressing these challenges in a systematic fashion. Regenerative medicine therapies hold the key for complete recovery of severely injured Warriors. These therapies are emerging, but are not yet mature enough to make significant clinical improvements immediately. Pre-clinical work is required to determine what approaches are most effective; this work will serve as a pipeline for future clinicaltrials.

Our goal in the immediate future is to continue to make incremental progress by evaluating and improving currently available therapies. As new and promising advances in regenerative medicine emerge, we will be ready and capable to implement them into the clinic with the goal of returning the injured Warriors to full function.

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