SPARS Peer Review Facilitates Interdisciplinary Innovation with AFIRM

Proposals submitted to the Armed Forces Institute for Regenerative Medicine (AFIRM) describe an array of interdisciplinary research, including efforts to heal deep burn wounds by "printing" skin cells right into wound beds, engineer skin pre-matted with nano-sized grooves that guide nerve re-growth from amputated limbs and diseased spines, and trigger vein morphogenesis in pediatric patients with 90% body surface burns.

When biological tissue like skin, muscle, and bone - even complete organs - are lost or damaged by trauma, age, disease, or defect, the field of regenerative medicine works to create new, functioning tissue to repair or replace the damaged part.

Made possible by the late-20th century, computationally driven scientific revolution that has generated sweeping technical and conceptual breakthroughs in life sciences and engineering, regenerative medicine is a synergy of surgery, biochemistry, bioengineering, and biomechanics.

To harness - and fuel - these rapid-fire breakthroughs, the Armed Forces Institute of Regenerative Medicine (AFIRM) brought together more than one hundred investigators - 30% of them clinicians - to foster emerging innovations in five areas pertinent to both the warfighter and civilian populations:

• • cranio-facial reconstruction,
• • healing without scarring,
• • ameliorating compartment syndrome (the compression of nerves and blood vessels leading to muscle and nerve damage),
• • limb and digit salvage and reconstruction,
• • and burn repair

"This type of technology is changing the future of medicine in our world," said COL Robert Vandre, AFIRM's program director, and, in 2008, AFIRM requested that SPARS manage the independent peer review of 21 proposals submitted by consortia members.

To evaluate the widely interdisciplinary subjects, SPARS assembled a panel of experts in tissue engineering, periodontics, neurobiology, extremity injuries, and microvascular physiology.

This article notes recent progress in organizing the interdisciplinary forces that are essential to the process of regenerative medicine. In particular, it outlines SPARS-managed efforts to focus current research on one of the most difficult and deadly problems the medical community faces today: burn repair.

In 1970, only one out of two patients survived a 50 percent body surface burn. Today, most patients survive burns of greater than 75 percent.

But deep burns destroy tissue so completely that skin cannot repair itself. Its complex function as a barrier to microbial infection and moisture loss, as a tissue that is sensate, that sweats, and produces Vitamin D. Pigment too is destroyed, and springy texture is replaced with thin, disfiguring, sometime crippling, hypertrophic scar tissue.

Because deep burns (> 4cm) account for 10% of all casualties suffered by warfighters, and afflict 20,000 US civilians every year, many research projects submitted to AFIRM were designed to produce material, equipment, or techniques that attempt to restore or mimic the complexity of living, functional skin.

For example, to eliminate the problem of tissue rejection associated with cadaveric allografts, a burn victim's own healthy skin can be harvested to patch wounds; but, harvesting is painful, and sometimes there simply is not enough healthy skin left. Now, engineered substitute skin (ESS) can be cultured from a small sample of the patient's healthy skin, and grown into skin sheets that are patient-compatible.

But these are early days and, while ESS can act as a barrier, it cannot readily grow the vascular networks vital to reconnect the new skin to healthy veins and capillaries quickly, to carry nutrients, fluid, and gasses into the engineered tissue, speed healing, minimize scarring, and facilitate the body's acceptance of the new skin.

Working with pediatric patients with 90% surface area burns, the laboratory of Steven Boyce, PhD, at the University of Cincinnati is now developing an ESS that requires harvesting only a credit-card size piece of the patient's own skin - culturing, and then layering those skin cells onto a biodegradable membrane to dress the wound. Peer review evaluated novel research submitted by the Boyce group to AFIRM that adds dermal microvascular endothelial cells, the precursors of veins to the ESS skin cell dressing. Promising results in 2009 indicate that endothelial cells begin to self-organize into multicellular structures - some with lumina - and join with the engineered skin.

In addition to actually recreating living tissue, AFIRM supports device design. In battle and civilian emergencies, it is both critical and difficult to close and protect an extensive burn wound. At Wake Forest University, a co-leader of one of AFIRM's two consortia, the laboratory of James Yoo, MD, PhD, has developed a portable bio-printing device and software. The device is suitable for the treatment of battlefield burn injuries: a computer-controlled XYZ plotter and cell deposition system that is analogous to a dot-matrix printer that deploys a layer of fibroblasts followed by a layer of keratinocytes directly onto burn wounds. In studies last year, the printer-delivered cells self-organized into skin layers, stabilized the wound, and healed faster than controls.

Another major challenge, but often forgotten in the urgency to rebuild war-injured tissue, is nerve repair, but the loss of sensation and control means permanently poor function, serial re-injury, and a grim quality of life prognosis. Several nerve regeneration studies too are being pursued through AFIRM, including devising scaffolding - some imbedded with time-release growth factors to physically and physiologically support nerve growth. The Anderson laboratory at MIT is working on a system of bio-rubber conduits rifled with spiral nano-grooves designed not just to support nerves physically, but to guide nerve growth, stimulating them to grow from a person's healthy tissue, into the healing wound or ESS.

These are just a few examples of regenerative medicine in action - medicine that brings together surgery, biochemistry, bioengineering, and biomechanics in an interdisciplinary system that mimics the complexity of the biological systems it seeks to recreate, initially addressing the needs of soldiers, but designed to be directly and swiftly translatable to all populations. Regenerative medicine: truly changing the future of medicine in our world.