Typically ignored is the role nerves have in wound healing.
We always think that neuropathy has a role in the origin of wounds. That is not the whole story. It also has an influence on t5issue regeneration.
The best example of the importance of nerves on wound healing is in amphibians. Amphibians have the capacity for full regeneration. But only if the nerves are ok. No nerves, no limbs.(1)
In fetal wound care, you can observe another function of nerves. If you make a wound in an unborn lamb, the inflicted wound will be 14% smaller in a few days. But if you cut the nerve, the wound size will have increased by 60% in the same time. Somewhere this makes sense because you use muscle cells (myofibroblasts) for wound contraction. Muscle cells are guided by nerves.(2)
The myofibroblasts are not the only issues in a de-nerved wound. In these wounds you also have an increased amount of granulation tissue because both growth and death of new cells is not functioning properly. And all this tissue also leads to a larger scar.(3)
But this is not all, as most of you know, nails and fingertips regenerate perfectly, even in humans. That is depending on how much tissue is lost and the age of the patient. Mouse research discovered central in this process is the formation of a blastema. This functions like a growing nucleus of mesenchymal cells. This is a very common process in nature, both in plants and animals.(4)
The blastema only functions when innervated. Regeneration will fail if there is no proper nervature in the tissue. Both in mice and men.(5) The pure blastema seems lost in mammalian skin regeneration. It is not lost completely because mouse strains with almost full regeneration exist. This is why there is attention for mesenchymal cells in regeneration.
Nerve cells are also involved in producing all kinds of inflammatory mediators. In the diabetic neuropathic skin impaired nerves cause all kinds of regulatory problems and are one of the many causes for impaired “diabetic” healing.(6) Research took off when doctors realised that paraplegics had impaired wound healing beyond the lesion in their spine.(7)
This was a clear indication of the importance of functional nerves on wound healing.
All in all the so-called type C-nerve fibres (pain) appear to have a larger than expected influence on wound healing. They do not only directly control cells and vessels, but also play a role in the organisation of the wound healing process by means of narrow mediators. It influences on myofibroblast proliferation(8), mitosis and apoptosis, amount of granulation tissue
Leading to larger scars (l1), increased amount of granulation tissue (l2), is reduced re-epithelialisation (l2), reduced wound contraction (l3) reduced vasodilatation (l3) and reduced proliferation (l4). The good news is that new formation of these type of nerves can be stimulated with electricity.(9)
Before I started writing this little text I was not aware how much innovation influences wound healing. This is only a simple text, by no
This is only a simple text, by no means it is supposed to be the truth. Discussion is welcomed.
Nederlandse tekst op http://woundspecialist.eu/woundspecialist.eu/?p=550
- Cannata, S. M., Bagni, C., Bernardini, S., Christen, B. & Filoni, S. Nerve-independence of limb regeneration in larval Xenopus laevis is correlated to the level of fgf-2 mRNA expression in limb tissues. Dev. Biol. 231, 436–446 (2001).
- Stelnicki, E. J. et al. Nerve dependency in scarless fetal wound healing. Plast. Reconstr. Surg. 105, 140–7 (2000).
- Smith, P. G. & Liu, M. Impaired cutaneous wound healing after sensory denervation in developing rats: Effects on cell proliferation and apoptosis. Cell Tissue Res. 307, 281–291 (2002).
- Neufeld, D. A. Partial blastema formation after amputation in adult mice. J. Exp. Zool. 212, 31–36 (1980).
- Takeo, M. et al. Wnt activation in nail epithelium couples nail growth to digit regeneration. Nature 499, 228–232 (2013).
- Spenny, M. L. et al. Neutral endopeptidase inhibition in diabetic wound repair. Wound Repair Regen. 10, 295–301 (2002).
- Basson, M. D. & Burney, R. E. Defective wound healing in patients with paraplegia and quadriplegia. Surg. Gynecol. Obstet. 155, 9–12 (1982).
- Ashrafi, M., Baguneid, M. & Bayat, A. The Role of Neuromediators and Innervation in Cutaneous Wound Healing. Acta Derm. Venereol. (2014). doi:10.2340/00015555-2321
- Kao, C. H. et al. High-frequency electrical stimulation can be a complementary therapy to promote nerve regeneration in diabetic rats. PLoS One 8, (2013).