Skin grafting is not the only answer to severe burn injuries. If the burn is on a large area of the skin and affects both the epidermis and dermis, the new skin that grows is not “skin” - it's scar tissue. It is devoid of sweat glands, hair follicles, neural receptors and collagen structure. Chronic wounds, loss of motion, and permanently impaired sensation remain. Now stem cell therapy is being looked at as a means of altering that outcome.
Modern burn treatment has led to a significant improvement of survival. The surgical removal of the appendages in the first three days after injury, fluid therapy, infection control and skin grafts have all turned mortality rates in the right direction. However, tissue regeneration and wound closure are other issues. A skin graft is placed over the wound to close it but will not restore the function of the dermis.
This is exacerbated by the lack of available donor skin. Patients with burns that cover more than 20% of their total body surface area may not have enough unburned skin to be able to donate enough to receive enough grafts. Biological substitutes like cultured epithelial autografts are prone to contamination and require a high level of ongoing supervision and maintenance. Synthetic alternatives minimize pain but have a higher risk of infection and can cause hypertrophic scars. A current treatment fails to effectively regenerate functional skin tissue in a consistent manner.
The skin contains two important populations of stem cells for burn repair: namely, the mesenchymal stem cells (MSCs) present in the dermis and the epithelial stem cells (EpSCs) present in the epidermis.
MSCs have been identified in bone marrow, fat tissue, umbilical cord tissue and, importantly, burned skin tissue itself. They are not just cell replacement. MSCs secrete cytokines and growth factors that help to regulate the local inflammatory environment, promote the growth of new blood vessels, and stimulate fibroblasts to deposit organized collagen. Burn wounds can also lead to scarring and systemic complications caused by the uncontrolled inflammation. In preclinical studies, the MSC treatment has consistently decreased pro-inflammatory markers, increased vascularization and generated less fibrotic tissue than controls.
EpSCs are located in the basal layer of the epidermis and in the bulges of the hair follicles. Once injured, they move to the wound site, multiply and transform into keratinocytes that repair the skin barrier. In therapeutic applications, EpSCs provide an extra boost of reepithelialization and, most importantly, the ability to regenerate functional structures (sweat glands, hair follicles, and nerve-adjacent structures) that scar tissue does not contribute. It is also becoming apparent that eccrine sweat gland stem cells play a role in reepithelialization and can become incorporated into engineered skin substitutes, thus expanding sources of cells.
The human MSCs obtained from hair follicles (HF-MSCs) have also received a lot of interest because they are easily accessible, ethically less problematic and in initial comparisons seem to possess a superior quality. They rapidly differentiate into keratinocytes and other types of skin cells, and rapidly react to injury signals, and they may play a role in peripheral nerve repair, which is important for burn patients where affected areas are deprived of sensation.
The data are predominantly preclinical, as would be expected, and this is an honest limitation. In all 22 animal studies included in the meta-analysis, treatment with stem cells improved healing rates of burns compared to the control treatment, and these improvements were independent of treatment type, burn area and control treatment type. Another systematic review of 33 preclinical studies revealed that the MSC treatment groups exhibited greater cell proliferation, greater wound closure, decreased inflammation, enhanced vascularization, and higher collagen production.
In one phase I/II clinical trial, 100% wound closure with minimal fibrosis was achieved in patients with deep second-degree burns with allogeneic bone marrow MSCs. There were no reports of adverse effects. That's a small sample, with a favourable safety record in terms of it.
A noteworthy discovery: MSCs isolated from a patient's burned skin (burn-derived MSCs or BD-MSCs) stimulated wound healing when introduced into full-thickness excisional wounds in the same patient. This is a good practical benefit for patients with large burns with limited normal donor areas, as the tissue thrown away during debridement can be used as a cell source.
Currently, stem cell treatment for burns is not a substitute for grafting. There is no standardization in protocols for cell dosage, sourcing, and delivery. There's limited long-term safety data in humans. Cell survival in inflammatory environments such as a severe burn wound is still a challenge and costs and logistical issues limit the study of cell culture.
The current evidence is that the combination of MSCs and EpSCs may have synergistic effects that neither group of cells can achieve alone and technologies like biomaterial scaffolds and 3D bioprinting are starting to overcome the delivery issue. Field is early but on the move. That movement is important for burn patients who will have scaring and loss of function in the future.
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