Finding a Permanent Solution for Vascular Repair
"Restoring blood flow is always the first step in dealing with a traumatic injury," said U.S. Army Lt. Col. David Saunders. "So it's our first step in this effort as well."
In the world of 21st century Army Medicine, the impossible is quickly becoming possible due to the innovative efforts of numerous men and women — including military, civilian and contract support — dedicated to the advancement of products and procedures that may have been lofty ideas only a few short years ago.
As the product manager for the Extremity Repair in the Tissue Injury and Regenerative Medicine Project Management Office of the U.S. Army Medical Materiel Development Activity, Saunders understands this unique area of vascular restoration. The TIRM PMO team's primary mission is to make wounded Service Members whole again by restoring form, function and appearance — and the group takes this responsibility quite seriously. Currently, it is driving the Department of Defense's investment to harness the potential of the rapidly growing field of regenerative medicine.
For this particular development effort, the team is focused on early limb salvage and currently working with industry partners to realize an organic, "human" product that will afford a more permanent solution for the repair of damaged vessels after traumatic injury on the battlefield.
"The lead product being developed is similar to currently available synthetic grafts in some ways, but considerably more sophisticated," said Saunders. "It is basically a tube of smooth muscle material — collagen, fibronectin — that has been derived from human blood vessels artificially grown in the lab. The implant is then decellularized to prevent an immune reaction in the recipient, which could lead to rejection by the body.
"Once implanted, however, the vessel recruits the patient's own stem cells and begins to resemble a native vessel within a month or two."
Saunders said the intent is to use the product as close as possible to the site of injury on the battlefield, providing a permanent vascular repair solution. Ideally, the graft would be usable at the first level where surgical care is provided to the injured (military Role of Care 2, e.g., the Forward Surgical Team). Addressing wounds at the earliest opportunity prior to evacuation provides the greatest chance to save the patient and salvage damaged limbs.
Said Saunders, "When we talk about permanent repair, we are aiming to develop an implant that remains functional for decades. This is particularly important for young Soldiers."
As a joint effort between the U.S. Army Medical Research and Materiel Command's Combat Casualty Care Research Program, the U.S. Army Institute of Surgical Research and industry partners, the project began under an Armed Forces Institute of Regenerative Medicine grant in 2008. With funding support from the DOD, it has since progressed to Phase 3 clinical trials for use as a hemodialysis shunt in end-stage renal disease.
"The approach to this initial development strategy [for hemodialysis]," explained Saunders, "is intended to obtain a primary indication in a relatively low-risk therapeutic area with a clear unmet need and a suboptimal current standard-of-care."
Saunders clarified that upon U.S. Food and Drug Administration approval of its use as a hemodialysis shunt, and with additional DOD funding, the product will be well positioned to secure a secondary, military-relevant indication for arterial reconstruction.
"Because trauma is (thankfully) a relatively small market from a commercial standpoint, a key part of our strategy is to repurpose regenerative medicine products being developed for widespread chronic diseases like stroke, heart attack, kidney failure and arthritis," he said.
As the product has progressed into the advanced development stage, management has been transferred to the USAMMDA's TIRM PMO. Serving as the DOD's advanced development activity for medical products designed to protect and preserve the lives of Warfighters, the USAMMDA develops new drugs, vaccines, blood products and medical support equipment that enhance readiness, maximizing survival of medical casualties on the battlefield.
Saunders reiterated that saving both life and limb remains the top priority for this effort.
"In the past decade," he said, "there have been approximately 2,000 amputees that have survived injury and surgery, and another 500 or so that have had a limb saved. If the new effort is successful, we expect that both more lives and limbs will be saved from fast restoration of the vascular supply."
Thus far, the bulk of research on the new vessel has been performed through the AFIRM consortium, spanning a number of laboratories at academic medical centers throughout the U.S. The Phase 3 clinical trials in hemodialysis patients are being conducted at more than 30 centers, and Phase 2 trauma trials are planned at six trauma centers across the country.
Saunders said that 20 to 40 vascular trauma patients will be enrolled into the study. However, due to the challenges of conducting regulated trials in trauma patients, enrollment is anticipated to begin late this year, with completion of the study not anticipated until 2019. As additional studies to support the arterial reconstruction indication may be required, the projected availability to the Warfighter is projected for 2025.
For the DOD and those in Army Medicine, however, this may be too late.
"The DOD is providing additional funding for this later effort because we need a trauma indication as soon as possible," said Saunders. "We are working to help accelerate the development for trauma use with an aim to obtain licensure as early as 2020."
"Based on the data we've seen so far," he continued, "we are optimistic that this product will be successful. The product is in Phase 3 clinical trials and has been progressing rapidly over the last few years."Once this product is fully approved for use, it will be made commercially available for hemodialysis and used also in the treatment of peripheral arterial disease, vascular trauma and vascular reconstruction, as well as for other potential civilian applications.
Saunders hopes that the successes from this early effort will be translated in short order to other extremity repair efforts in the TIRM portfolio.
"We're not going to rest on our laurels — just over the horizon, our sights are set on peripheral nerve and muscle repair, compartment syndrome, non-healing fractures and burns. We plan to roll out several new solutions that take advantage of these emerging technologies over the next decade, building a regenerative medicine tool kit for the military surgeon."