During the Vietnam War, only 75% of those injured in combat made it home alive; roll forward to the recent conflicts in Iraq and Afghanistan, and that number had risen to 92%. The combination of better body armour and advances in battlefield medicine means that today, wounds that once would have proved fatal, no longer do, but while wounded soldiers now enjoy better survival rates than at any time in history, there is a flip-side to the statistics. War-fighters lives are being saved, but they are increasingly being left with life-changing disabilities.
The rise of the improvised explosive device (IED) in particular has led to a huge upsurge in the number of major leg and arm injuries being sustained. In the course of Operations Iraqi Freedom and Enduring Freedom, some 1,700 amputations were required, 14% of those whose limbs were initially saved, subsequently lost them, and according to the US Army Medical Materiel Development Activity (USAMMDA), up to half of the service personnel affected will face severe impairment, long-term complications and poor recovery. Only a fifth of those suffering serious extremity damage return to active duty.
Implants, prosthetics, transplants – and now regenerative medicine?
For soldiers who do lose limbs, depending on the exact nature of the injury, the options currently available range from simple prosthetics, to advanced robotic limbs, osseo-integrated implants and now even entire hand transplants – but obviously none of these truly replaces the original.
However, that might change if regenerative medicine can deliver on the extraordinary potential that recent advances in the field seems to herald. The US Army’s specialist Tissue Injury and Regenerative Medicine Project Management Office (TIRM PMO) are working hard to make artificial limbs a thing of the past and, incredible though it may seem, enable wounded warriors to grow new arms and legs for themselves.
It sounds like the stuff of science fiction, but it is certainly not unknown in nature. Salamanders are especially adept at repairing themselves in this way, able to re-grow a perfect copy of a missing leg within a short time of losing the original, but sadly at the human end of the evolutionary tree, this trick has long since been lost. However, a recent study suggests that it may not have vanished entirely.
Scientists at the Kathryn W. Davis Center for Regenerative Biology and Medicine in Maine found that three unrelated species renowned for their regenerative powers – two fish and the axolotl, a kind of aquatic salamander – share 10 microRNAs in common. These are small pieces of RNA that regulate gene expression, and in all three cases, they seemed to be acting in exactly the same way to promote the re-growth of severed appendages.
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Since it was more than 400 million years ago that the animals involved last shared an ancestor in common, the researchers believe that the capacity for regeneration may well be a retained process, rather than something that individual groups evolve independently for themselves.
Opening the door: microRNAs and injury stabilisation
It is, of course, a big jump from this to soldiers actually re-growing the bones, muscles, blood vessels and nerve tissue of a brand new arm or leg. We are, as Lt. Col. David Saunders, USAMMDA’s extremity repair product manager, put it at a Military Health System Research Symposium last year, “not quite there yet,” but if such microRNAs could be programmed to behave the same way in humans, it might begin to open the door on the future possibility.
There are other aspects of regeneration, however, that are much more immediately within our reach and after carefully examining the current state of the science, TIRM PMO has identified some of the areas which hold particular promise for extremity repair today.
Bones that are simply broken will generally mend on their own accord, but the situation with those that have been shattered in explosions is very different, leaving surgeons with the hugely difficult task of trying to re-assemble a mosaic of pieces, some of which may be completely missing. These complex, traumatic injuries typically heal slowly, if at all, and pose a serious challenge for both repair and rehabilitation.
The immediate military focus in this area is to develop products that can stabilise these kinds of injuries, made from materials that can be assimilated into the patient’s body as the healing process takes place, while longer-term goals include dealing with post-traumatic joint damage and ultimately perhaps even moving closer to true limb regeneration itself.
Scaffolds and stem cells: muscle regeneration therapy enters early stages
Blast injuries can also involve large amounts of muscle being lost, which is particularly problematic since muscle does not regenerate well and the options available to repair the damage surgically are limited. In addition, infection or traumatic damage to the surrounding tissues can also make volumetric muscle loss (VML) more difficult to treat.
Current approaches tend to concentrate on preserving remaining muscle function, and although muscle-flap transfer procedures, using material taken from elsewhere on the patient’s body, can sometimes help restore missing tissue, the end result is not always entirely successful.
However, in recent years, advances in regenerative medicine have begun to suggest the possibility of new therapeutic options to treat VML, notably based on the use of extracellular matrix scaffolds and mesenchymal stem cells. Although their application is currently limited, and the research still at a relatively early stage, given the significant investment the Pentagon is channelling into research, the outlook for future generations of troops suffering from VML is likely to be considerably brighter.
Although the body’s peripheral nerves, which are responsible for sensation and controlling movement, are able to regenerate, they grow back very slowly and often suffer some months without function in the aftermath of injury, which can cause muscle deterioration and complicate recovery. As a consequence, it is impossible to predict with any certainty which nerves will successfully regenerate, and with a limited set of treatment options currently available, soldiers with significant nerve damage as a result of their wounds may be left with long-term problems.
Identifying products such as nerve growth factors that speed up nerve repair now forms a key target for the US military, along with developing the likes of bio-engineered scaffolding to help preserve, and prevent further loss of nerve and muscle function during the healing process.
Synthetic veins: bio-engineering blood vessels
Good healing needs good vascularisation to provide it with a healthy blood supply, and today’s standard of care for making permanent repairs to arteries and veins involves one of three kinds of grafting procedures. Most commonly used is the autograft, which involves a blood vessel being removed from one part of the patient’s body, often the leg, and grafted in to patch up the damage.
While this approach has a good record of success, finding a suitable donor vessel could obviously prove difficult for wounded warriors with extensive lower limb damage. In such cases synthetic vessels made from Teflon or Dacron are available, but they have problems of their own, including the risk of infection, while the third process, endovascular grafting, although effective on smaller injuries, requires both specialist equipment and training to perform.
Advances in regenerative medicine, however, have now led to the creation of grafts that model themselves after the patient’s own tissue, resist infection and mature into vessels that closely resemble the original. A bio-engineered blood vessel is reported to be in phase three of US Food and Drug Administration clinical trials which, if successful, could have significant applications in military medicine.
Lt. Col. Saunders told his audience at the Florida symposium that the goal was “to improve long-term outcomes in function and form of injured extremities.” Whether that will ultimately include a salamander-like ability to regenerate whole new limbs remains to be seen, but it is certainly an inspiring prospect.