Okay, I'm finally going to try and bite the bullet and blog about PATH3304, even though I probably won't do the researchers justice with my rambling, obnoxious blog posts. This lecture was delivered by Dr Fiona Wood, who is well known for her work in treating burn patients. She covered quite a lot in 45 minutes, and some of it went over my head a bit, but let's see how I go.
In order to design a treatment to heal skin, we need to figure out what healing of skin would entail. Some of the main requirements to heal skin (or anything really) are: 1) cells capable of differentiation (e.g. stem cells), 2) a framework for cell migration, and 3) mechanisms that the cells can use to organise themselves. We also need to ensure that the area has an adequate blood and nerve supply for regeneration. Now let's see how past and present treatments have been designed in order to meet these criteria!
One of the earlier cell therapies for burns was Cultured Epithelial Autograft (CEA) sheets. These sheets were made using the patient's own cells from the dermal-epidermal junction, obtained from a large, full-thickness biopsy. At first, it took 3-5 weeks to make one of these sheets, but as technology improved, this time was reduced to around 10 days. The cell sheets are around 3-10 cell layers thick and have polarity (i.e. the two sides are different). The sheets can be applied by first mounting to a dressing gauze and then applying to the patient.
Dr Wood and her team then investigated the ways that cells, and cell adhesion molecules such as integrins, behave when applied. They investigated what happens when the cells are applied in sheets, or as a suspension. Cells applied as a suspension turned out to be more active and caused fewer secondary problems, such as blistering. Furthermore, this method was quicker (initially took five days), as it was no longer necessary to wait for the cells to form sheets. Dr Wood and her team investigated the use of various aerosol sprays in order to spray on the cell suspensions.
Animal models were then employed to further investigate what exactly was going on. The cell suspensions did a better job at forming a dermal-epidermal junction as opposed to the sheets. Using cell sheets caused healing by secondary intention to occur, which is probably what caused some of the secondary problems. It was also found that cells that have been harvested maintain the characteristics of the original site: if you take cells from the dermal-epidermal junction, functional melanocytes may be transferred, and if you take cells from an area of thick skin, then CK9 (cytokeratin 9, a marker of thick skin) will remain. If you take cells from a scarred area, then the scar may re-form when the cells are sprayed on.
Even though cell suspensions only took five days to develop, Dr Wood and her team wanted to see if they could make healing even quicker. What if, for instance, we could prepare the wound bed (by cleaning it out etc.) so that cells could grow on it directly, rather than prepare the cells beforehand on some other substrate (used to be irradiated 3T3 fibroblasts)? This was the basis behind Dr Wood's "ReCell" technology, which only takes around 20 minutes. It is normally done between days 2 and 5, once the patient has stabilised. (Before this time, the wound is controlled by using nanocrystalline silver, which has anti-microbial and anti-inflammatory properties.) This therapy can also be modified to treat partial thickness burns, such as scalding.
While our current treatments are better than ever before, burns can still cause quite a bit of collateral damage, partly through apoptosis pathways. As such, topical inhibitors of apoptosis have been trialled in animal models. One such inhibitor is PYC35b, an inhibitor of C-Jun (a member of the AP-1 family of transcription factors that activates cell death and inflammation). In animal models, it can improve the healing potential, but more studies need to be done in humans. Apparently, even basic first aid like applying running water can also help to reduce the collateral cell damage and apoptotic pathways.
As mentioned at the beginning, cells are not the only important factors in wound healing. The scaffold that the cells attach to is also important. One scaffold that has been used is called Integra, which is a mix of collagen and glycosaminoglycans with a pseudo-epidermal surface made out of silicon. When placed on a wound, the cells on the wound grow into the scaffold. The pore size of Integra is important: if the pore size is too small or too large, then the cells will grow in a disordered fashion. Developing new scaffolds is a potential area for future research.
Back to the other impacts of burns! Apparently burns cause nerve damage, or at least a decrease in nerve density, even in areas that weren't scarred. And yes, that effect occurs over the whole body. Even patterns of brain activity are different in people who have been significantly burnt vs. controls.
The scar tissue itself is affected by burns not only at the visible level, but also on, well, less visible levels. Different methylation patterns have been detected between keloid scars (the worst kind of scars) and less severe burns. There are also differences in vascularisation patterns and collagen. Interestingly enough, using fractional laser ablation can make the vascular pattern more normal, but we're still not entirely sure why.
Burns, even "minor burns" (less than 20%), can also have more systemic effects, including raising the risk of cardiovascular problems and malignancies. We still don't know why- maybe it's related to the immune response to a burn, or to something else. Although we have made massive advances in treating burn scars, there's still a wide area for further research and improvements- which is where we come in, I guess...?
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