BREAKING THE SKIN: Fundamentals of Epithelial Restoration

FOR INTERNAL USE ONLY- NOT PUBLISHED

Chapter 1:
SHAPING THE FRONTIER OF WOUND SCIENCE 

By José Ramirez-GarciaLuna, MD, PhD

Edited by: Roberta Kline, MD

A wound can be defined as an injury or a discontinuity in any tissue. Therefore, any part of the human body or any organ can have a wound. For example, fracture is a term describing a bone wound, and traumatic brain injury (TBI) is a term describing a brain wound. However, most conventionally the term wound refers to injuries to the skin and underlying soft tissue.

Wound healing is a very broad concept. The current definition of wound healing is the restoration of the structure of the tissue of the skin and the underlying tissue and the soft tissue below. At its core is the process of epithelialization of the skin. Skin has two layers. The upper layer is the epithelium or the epidermis. Whenever we have a breach in integrity of the tissue or the skin, the epidermis breaks. We can define wound healing as the restoration of that epithelium via epithelialization, often used interchangeably with re-epithelialization.

While this appears straightforward, it’s actually a long process that continues beyond the initial appearance of restoration of a new epithelial layer. For a normal, uncomplicated wound, it will take around two to three years for the wound to fully maturate and heal and restore its tensile strength to that of the skin that was before the injury. If there are any factors or conditions that affect the wound healing process, then this may take even longer for complete healing to occur.

Clinical assessment of wound healing is primarily visual, dependent on the clinician’s subjective assessment of it superficial appearance. This is not an uncommon problem in many areas of medicine, where lack of objective measurements leads to inconsistency in definitions and reproducible results. For wound healing, this contributes to important limitations in being able to objectively determine that the restored epithelium has fully regained its thickness and integrity that includes tissues below the visible skin layer. Developing objective measurement tools will enable research for better protocols and improved outcomes for patients.

DIFFERENCE IN MANAGING BURNS VS CUT OPEN WOUNDS

There are four phases of wound healing: hemostasis, inflammation, proliferation, and maturation.  Each has specific processes and functions involving complex coordination of many different biological systems. When these processes go smoothly, optimal wound healing occurs.

HEMOSTASIS is the body’s way of minimizing blood loss in response to an injury.  A good example of this is with an acute wound such as a surgical incision. When the surgeon cuts the skin, it bleeds because blood vessels have been severed. The first step that the body needs to take is to stop that bleeding, and it does this by creating small clots to “plug” the damaged blood vessels. Platelets are a key cell type in the blood that are necessary for this process are platelets. When the blood vessels are damaged, platelets become activated, and they release a number of cellular signaling molecules into the environment to mediate the entire process of clotting.

This triggers the second phase of wound healing, which is INFLAMMATION. The platelets release these mediators, which are recognized by the white blood cells in the blood and the resident immune cells in the tissue.  These cells alert the body that “there's a problem here… come and do your stuff!”. As such, these cells respond with a coordinated inflammatory response. The first cells that come are called NEUTROPHILS. They make up about 70% of the white blood cells that recruited to start clearing up the debris caused by the trauma and first phase process of hemostasis. They will clean up the wound bed, including removing bacteria if present.

Two to three days later, there is a new species of white blood cells that come in called MACROPHAGES. They are derived from precursor white blood cells in the blood called monocytes, and once they enter the tissue they become macrophages. Macrophages are a very interesting type of cell and are one of the key elements for wound healing. But, as with all phases of the wound healing response, they can also create problems when out of balance. This is why these cells can be termed the “Good, the Bad, or the Ugly” (referencing the classic western movie).

They can be the GOOD because they help clear everything, and they help restore the inflammation and inflammatory response in the wound bed. They can be the BAD, because if there's a lot of bacteria or contamination, or if for any reason patients cannot really mount an inflammatory response and they don't arrive into the wound bed, then the process can go awry.

They can be the UGLY because they are also tied to some diseases linked to chronic inflammation. Too much inflammation can be problematic, and this is where the proper balance is critical. We need some inflammation to kickstart the healing process. Without a little bit of inflammation, the healing process cannot proceed. That's one of the things that is often overlooked in clinical care. As clinicians, we like to think that inflammation is bad, and we do everything to avoid inflammation. But in the context of wound healing, inflammation is very important and needed to achieve proper healing.

Provided that inflammatory levels are kept within a normal range, the inflammatory phase of wound healing lasts for around one to two weeks. During this timeframe, the immune cells are also calling for stem cells. They are producing proteins that create blood vessels and trigger a process that's called NEOGENESIS, where new blood vessels sprout in the wound bed.

This then leads to the third phase of wound healing, which is called PROLIFERATION, or the proliferative phase. During proliferation, as the name implies, the cells start dividing in order to create new tissue. As they proliferate, they start depositing new extracellular matrix to provide the scaffolding fill up the defect and then create new tissue. This new tissue requires restoration of the blood supply through new blood vessels, which results in an integrated blood vessel network.

As a critical part of this process, we need stem cells to differentiate into different types of cells present in the tissue. Perhaps the most important ones are fibroblasts, which produce the dermis and extracellular matrix. And then finally, KERATINOCYTES, which are the cells in the epithelium or in the epidermis that produce a closed (or intact) epidermal layer and achieve wound healing.

But the wound still needs to undergo maturation and refinement, and this is done in the next phase called REMODELING. This is a much longer process, lasting for up to two years. As the name implies, the architecture of the tissue gets remodeled, so it represents a mature, functioning tissue layer. The protein content in its extracellular matrix gets changed over time and then the tissue reaches a maturity point that kind of resembles the old tissue. A visible effect of this process is the gradual smoothing out and fading of the scar where the skin was repaired.

The wound healing process typically lasts a total of 8 – 12 weeks. Most often, scars will remain visible and the extent to which they do is linked to how well the wound healing process was accomplished. Scars are a reminder that we had a wound healing process there, which was fully achieved, but the quality of the repaired tissue will never be the same as the original tissue. 

(To be continued)

THE CRITICAL ROLE OF DIAGNOSTICS IN HEALTH AND WELLNESS  By: Dr. Jess Sabrowsky DNP, RN, FNP-BC What I have learned over the years is the importance of listening to the patient, but equally, the importance of using data-driven diagnostics to make real-time decisions about care. This is not just about numbers on a chart—it is about understanding the full picture of your health, long before symptoms arise. We need to use technology, diagnostics, and assessment techniques to gather real data. Data that can guide each patient on their unique health journey. Diagnostics help us understand the true state of a person’s health, even when they may not feel “sick.” This is where the rubber meets the road: when you find a PCP who truly understands the importance of these tools and works with you to achieve your wellness goals and who also has skills beyond the transitional medical model to help you live your best life. Having difficult conversations is uncomfortable, but it is necessary for growth. If you want a healthcare provider who will partner with you—someone who creates a safe space, builds trust, and encourages honest dialogue to support long-term growth—then you must also be willing to put in the effort. Finding a provider who matches your commitment to your health, and one who uses diagnostics to empower you, is key to achieving your goals. WHY DIAGNOSTICS MATTER In short, diagnostics are essential because they offer concrete, actionable insights into your health that go beyond surface-level symptoms. They help uncover hidden health risks and enable early intervention, which can be the difference between preventing a chronic condition or managing it effectively. Diagnostics allow for personalized care tailoring interventions to meet the specific needs of the individual based on real, measurable data. I also would add that as a provider I prefer to reference functional lab ranges when reviewing results as I find that I can make small preventative recommendations and also challenge individuals and providers to think outside the box when looking to help resolve health conditions, like in the case of my daughter who otherwise would still be suffering. Let’s aim to stop the suffering and optimize wellness for all who seek it.