Great advances have been made in prosthetics for amputees. These include the use of sensors, hydraulics and microprocessors in the prosthetics to provide the wearer with a more natural gait. Plastics, carbon fibre and other materials are used to make artificial limbs that are lighter and stronger. Specialized limbs have been developed for running, swimming and snow sports. But all prosthetics share a common weakness: the method by which they are attached. Custom sockets are moulded from the stump, a sock is fitted over the stump and the socket attached by belts, cuffs or suction. Any friction between the stump and the socket results in sores or abrasions that are extremely painful. These sores limit the use of any prosthetic and consequently impact the owner’s mobility. If the skin at the bottom of the limb could be made tougher, more resistant to mechanical stress, then these problems could be avoided. The skin on the palm of our hands or the bottom of our feet is known as palmo-plantar epidermis (PPE) and is far more capable of withstanding mechanical stress than normal epidermis. If there were a way of converting the skin at the end of a weight-bearing limb to PPE, many of the above mentioned problems would be alleviated.
In the immediate future a solution for this problem would be to graft PPE onto the bottom of the weight-bearing stump. Skin grafts are a relatively common medical procedure. Skin taken from the palm or bottom of the foot would continue to exhibit the characteristics of PPE after being placed on the new site. However there is not that much PPE available for use as donor skin for the grafts. Cultured epithelial autografts (CEA) is a technique developed for use on burn patients with only a small amount of skin available as donor skin. The ability to amplify a small amount of PPE into a larger surface area graft would be appropriate when used on an amputee given the small amount of PPE available as donor skin. Additionally scientists at the US Armed Forces Institute of Regenerative Medicine at Wake Forest, North Carolina, have recently developed a method of “printing” skin using an inkjet printer. This technology could used to create PPE skin grafts.
Ultimately the ideal solution would be a cream that one could rub on the stump causing the normal epidermis to transform into PPE. This is a very difficult task, as complicated as changing skin cells to heart cells, requiring one to alter the epigenetically set program of a differentiated cell. Is it possible to stimulate the expression of a protein in a cell where that protein is not normally expressed? Once a cell has differentiated the promoter sites are blocked by epigenetic modification of the DNA. Reprogramming cells has been done in vitro, (e.g. in stem cell research) but not in situ.
There are many factors that distinguish PPE from normal epidermis. The primary protein expressed by skin is keratin, which keratin is expressed being determined by cell type and degree of differentiation. Normal skin (interfollicular epidermis) predominantly expresses the K1-K10 pair, whereas in PPE K9 is prominently expressed in the thick epidermal ridges with K6, K16 and K17 in the thinner secondary ridges. Additionally PPE is thicker, does not have hair follicles, and is far more resistant to mechanical stress. Keratins clearly play a very important role in providing mechanical strength to skin. When there is a genetic defect in keratin the consequence is skin fragility. There is a good correlation between the severity of the genetic defect, how the function of the proteins is compromised, and the severity of the disease. Therefore increasing the level of K9 may increase the mechanical strength of skin, but this would have to be tested.
Another promising target to change the character of normal skin to make it more like PPE would be the HOXA13 gene. A paper by Rinn and co workers* examines the role that HOXA13 plays in maintaining the distal specific transcription program in PPE fibroblasts. The HOX gene family of homeodomain transcription factors act to specify cell positional identity during development. In adult fibroblast HOXA13 is required to maintain the expression of WNT5A and the induction of K9. To put this more simply, HOXA13 is necessary for K9 expression and is responsible for maintaining a part of PPE identity during homeostasis and regeneration. However, because the experiments were done on cultured cells it is not possible to say how much of the character of PPE is determined by HOXA13. Again this hypothesis would have to be tested.
Ultimately a cream that toughened skin would transform the lives of the millions of amputees who do not have access to skin grafts, sophisticated medical facilities or good quality prosthetics. I am speaking of the people who are the victims of senseless civil wars in Africa, of landmines laid in conflicts that are now over, of earthquakes (as in Haiti recently). It is worth pursuing.
I would like to thank Jonathan Jones and Pierre Coulombe for their insight, advice and support. I would also like to thank Choleton Senior (a personal trainer at LA Fitness on Moscow Road, London) for providing inspiration and insight into the life of an amputee.
*A dermal HOX transcriptional program regulates site-specific epidermal fate. Rinn JL, Wang JK, Allen N, Brugmann SA, Mikels AJ, Liu H, Ridky TW, Stadler HS, Nusse R, Helms JA, Chang HY. Genes Dev. 2008 Feb 1;22(3):303-7.
Pierre Coulombe http://web1.johnshopkins.edu/coulombelab/index.php/Main_Page
Jonathan Jones http://www.joneslab.northwestern.edu/Welcome.html