While doing research for my previous post, I very briefly mentioned the use of animal tissue as wound dressings. This partial-sentence represented a bit of a research rabbit hole I fell down regarding wound healing, how it works, and the medicine used to support it. So hopefully I can make this specific hyperfixation of mine interesting enough for other people to read about it.
How Skin Works
The integumentary system (the skin along with hair, nails, sweat glands, and everything else growing out of the skin) protects the body from the outside while also providing sensation and temperature regulation. As the body’s primary border with the outside world, it is perhaps the part of the body most susceptible to physical injury. As such, the skin and the tissues that support it have developed into a complex system of protection and ability to repair itself. The part of the skin you look at most often is the outermost layer, the epidermis. The epidermis starts between 0.05 and 1.5 millimeters from the surface (depending on the region of skin) with a layer of cells called the stratum basale. These cells are anchored in place to a basement membrane (more on that later) and reproduce constantly to produce another layer of cells directly above them. These cells attach themselves to each other with protein filaments and fill themselves up with the protein keratin (a strong, waterproof building block of skin) as well as other proteins. As more skin cells are produced by the stratum basale, these slightly-older cells are pushed up toward the surface. As they get further away from the skin’s blood supply, they lose access to nutrients and oxygen and start to die. These dying cells flatten themselves out into sheets and release keratin and fats into the space between themselves to further bind the cells together and to lock in moisture, respectively. Once skin cells reach this outermost layer, they typically last about two weeks before they fall away, being immediately replaced by the constantly replenishing skin cells beneath them.
Directly underneath the epidermis is the dermis, a layer of connective tissue that binds the epidermis to the body and provides it with support. The first bit of connective tissue we find is the basement membrane, a sheet of collagen and proteins that anchor epithelial tissue* to connective tissue and mediates cell signaling between them. Going down from the basement membrane, the dermis consists primarily of collagen and elastin proteins woven into bundles to form an extracellular matrix (ECM). ECM are complicated protein scaffolds that make up the body’s mechanical support structure, being constructed and maintained by cells but existing independently of them.. Most of the dermis’ mass is ECM with very few cells, but there are a few. The primary type of cell found in the dermis are fibroblasts, spindle-shaped cells found in all connective tissue that secrete individual collagen proteins and weave these proteins into the ECM, as well as immune cells** that regulate immune responses. Also within the dermis are the blood capillaries and nerve endings that feed the epidermis and communicate between the skin and brain, along with the active parts of hair follicles, nail beds, sweat glands, and oil glands. Below the dermis is the subcutaneous tissue, sometimes called the hypodermis. This layer contains more fibroblasts and collagen (connecting directly to the collagen in the dermis), but also fat cells that store energy and provide insulation and cushioning. The smaller blood vessels and nerves in the dermis connect to larger blood vessels and nerves in the subcutaneous tissue and immune cells populate both the dermis and the subcutaneous tissue. Below this final layer is the body’s musculature, with the collagen fibers in the hypodermis connecting directly with the rest of the body’s connective tissue.
Diagram of the layers of the skin. Notice how the border between the epidermis and the dermis is not perfectly flat. This increases the surface area of the border, so the connection between the two is stronger.
Repairing Skin
Because your skin is the most ‘forward-facing’ part of your body, it is the part that most often has to repair itself from unforeseen damage. Superficial injuries that only affect the epidermis, such as scrapes, scratches, and first-degree burns, are easy to fix; the damaged or missing skin cells are pushed out and replaced with new cells, just as would be done with undamaged skin. For less superficial injuries, i.e. those that draw blood, work must be done to repair the damage. The first step is to close the wound so blood can’t get out and pathogens can’t get in. Damaged cells at the site of injury secrete signal proteins that make nearby blood vessels constrict and attract immune cells to the site. When platelets in the blood detect collagen (which normally indicates they’re no longer inside the blood vessels), they begin adhering to whatever surface they come across and grow long protrusions to catch other platelets and blood cells. As more platelets and blood attach to this growing mass of adhered platelets, the hole gets plugged. Immune cells stationed in the skin secrete signal proteins that trigger inflammation, causing the tissue to retain water so immune cells can move around more easily in the wound environment. Within an hour, immune cells show up en masse to consume and destroy debris, as well as killing off any infectious agents that managed to slip in.
Once the site is clean and the immediate danger has passed, it’s time to begin rebuilding the tissue. Immune cells secrete signals that trigger angiogenesis; new blood vessels grow off from existing ones to restore oxygen supply to the construction site. Fibroblasts migrate in from surrounding tissues to weave together new collagen to rebuild the dermis. It’s also common for wound contraction to occur during this stage; specialized cells colonize the edges of the wound and pull the sides back together, reducing the amount of tissue that needs to be regrown. At the end of this stage, skin cells from around the site of the wound begin to recolonize the wound from the sides, replacing the epidermis. At this point, the wound will be largely healed, at least superficially.
At this point, the skin appears to have largely returned to normal, albeit slightly redder. But under the surface, the tissue is not identical to how it was before the injury. Collagen fibers are disorganized, not linked with each other, and made from different proteins than healthy collagen. As such, the tissue has as little as 20% of its pre-injury tensile strength and will be missing normal skin features such as hair and sweat glands. The body’s aim at first was to just fix the hole, but now that it is fixed, it has time to bring everything up to code. Tissue remodeling can last for weeks or months after the repair is finished and is the stage of wound healing that is still the most poorly understood. Even in healthy tissue, collagen fibers in connective tissue are constantly being broken down and rebuilt to fix small breaks and damage. These processes occur on a larger scale during tissue remodeling, as fibroblasts replace their hastily-built extracellular matrix with a more permanent structure. For smaller wounds, this remodeling can be done perfectly and restore the dermis to its pre-injury state. For larger or deeper wounds, the dermis will still be denser and less organized than healthy skin, becoming scar tissue.***
Structure of collagen in (A) normal dermal tissue and (B) scar tissue
Chronic Wounds
Finally, we’re approaching the topic that led me to this post in the first place. The steps above are how wound healing works under normal circumstances, but these steps can be disrupted. Chronic wounds are defined as any wound that remains unhealed for longer than three months. They can be caused by a number of factors that stall the healing process, such as certain illnesses and cancers, diabetes, aging, repeated injury to the same location, and certain genetic diseases. The most common types are venous ulcers (dysfunction of the valves in the circulatory system lead to poor circulation), pressure ulcers (consistent pressure on one spot pinches blood vessels in that spot, cutting off circulation), and diabetic ulcers (diabetes damages blood vessels and nerves, weakening circulation and causing paralysis which can result in repeated injuries to places where the patient can’t feel pain). Chronic wounds are prone to infection, can be extremely painful, and have a higher chance of necessitating amputation. The most common reason why a wound can’t heal is that the repair processes can itself cause tissue damage, at least enough to offset tissue repair. Immune cells can damage tissue when fighting infection, so a severe enough infection can result in an immune response powerful enough to cause significant collateral damage. Chronic inflammation also damages tissue, with the newly synthesized collagen made during wound repair being particularly vulnerable. Impaired blood flow can slow tissue regrowth and even cause the death of healthy cells, and blood vessels to fresh wounds to restrict blood loss. Inflammation and blood flow are also affected by other factors related to the injury, which is why these kinds of chronic wounds are less common, but the right combination of circumstances can create a vicious cycle where the body repeatedly destroys its own work.
Treatment for chronic wounds normally involves advanced wound care strategies. Bacterial load is reduced with topical antibiotics and removal of dead tissue that bacteria thrive in (fun fact: maggots are still used today to treat chronic wounds as they eat dead tissue but don’t affect live tissue). Keeping chronic wounds warm with heated dressings can help to restore blood flow and prevent infection. Negative-pressure wound therapy is a relatively recent development, using air-tight wound dressings connected to a suction pump to subject the wound to low air pressure. This removes pus from the wound and is shown to improve blood flow and reduce inflammation. Growth factors and hormones linked to tissue regrowth can be introduced to wounds and if the wound is caused by repeated injury, such as with bed sores, management strategies can be developed.
Finally, we get to the crossover with my previous entry, where I mentioned ‘wound dressings developed from samples of pig bladder or fish skin.’ This is a recent development in biotechnology, where skin or another epithelial tissue is taken from another source (usually an animal), the cells are killed off to leave behind only the extracellular matrix (the basement membrane and dermis, or equivalent if another tissue), and this ECM is used as a wound dressing. Instead of rebuilding the dermis from scratch, the body only has to connect this dressing into the existing dermis. Since these dressings would be made from healthy tissue, there would need to be minimal remodeling and likely comparatively little scarring. The ECM provides a scaffolding for new cells to adhere to and molecules in the ECM promote the growth of new blood vessels and regulate inflammation. There are currently multiple companies developing ECM wound dressings and they have been shown to significantly aid in wound repair, especially for chronic wounds.
Collagen wound dressing
Chronic wounds affect 13 million people worldwide a year and cause significant decline in quality of life for the patient. While the research I’ve discussed here is still relatively young, it represents a significant advancement for wound care with the potential to help a lot of people. ECM wound care also has the potential to treat severe burn victims and other difficult wounds. It’s a fascinating technology that comes from understanding the immense complexity of wound healing and our integumentary system. Hopefully, I’ve made this as interesting for you as it was for me.
For More Details
*Epithelial tissue is a category of tissue defined by semi-permeable membranes and/or secretory cells. Examples include the epidermis, the inner linings of blood vessels, the inner linings of the digestive tract, respiratory tract, and urinary tract, and the hormone-producing parts of each gland. All of these tissues are mounted on basement membranes to connect them to the body’s connective tissue.
**Specifically, these immune cells are a particular type of immune cell called macrophages. Macrophages are ‘border guards,’ being relatively stationary located in the dermis as other ‘border regions’ such as the lungs. When an infection begins, they are the first to begin attacking pathogens as well as sending signals to attract other immune cells and to tell surrounding tissue how to respond, such as restricting blood flow or becoming inflamed.
***Why the body can’t restore the dermis’ structure to its pre-injury state is still being researched, especially given that some species can regrow entire limbs without scarring. The likely explanation is that large-scale tissue growth and remodeling biochemically resembles tumor growth, so organisms with more complex immune systems (such as most mammals) deliberately restrict the amount of time and effort that can go into tissue repair and remodeling. Animals that can regrow whole body parts are likely more vulnerable to cancer, if they live long enough for that to become a risk.
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