Why Some Wounds Get Stuck Instead of Healing

A small cut usually follows a familiar story. Bleeding stops. The area becomes red and tender. New tissue forms. The edges slowly pull together, and eventually the skin closes. But some wounds seem to lose the ending. Days become weeks. The wound remains open even though the body has already begun trying to repair it. From the surface, this can look like a simple failure to "heal properly." Underneath, something much more complicated is happening. Wound healing depends on coordinated inflammation, oxygen delivery, enzymes, immune cells, extracellular matrix, new blood vessels, and microorganisms. Research on chronic wounds shows that these systems can become trapped in an abnormal local environment marked by prolonged inflammation, excessive tissue-degrading enzymes, inadequate oxygen, and sometimes bacterial biofilms. The wound is not simply sitting there doing nothing. Its chemistry may be keeping normal repair from moving forward.

What Happens Inside a Normally Healing Wound?
The moment skin is injured, repair begins. A clot helps control bleeding, inflammatory cells enter the damaged area, and chemical signals coordinate the removal of damaged material and preparation for new tissue. The proliferative stage that follows includes re-epithelialization, fibroblast activity, and angiogenesis, while later remodeling reorganizes the repaired tissue. None of these stages operates like an independent switch. Cells communicate through signaling molecules, enzymes modify the extracellular environment, oxygen supports cellular activity, and proteins are continuously produced and broken down. That temporary inflammation and controlled tissue breakdown are useful. Trouble begins when processes meant to prepare the wound for rebuilding remain active for too long.

Why Can Inflammation Stop Being Helpful?
Inflammation is supposed to protect injured tissue and help begin repair. A chronic wound, however, can remain in a prolonged inflammatory state instead of progressing normally. Reviews of chronic wound biology describe persistent inflammation alongside defective re-epithelialization and disordered remodeling. That distinction matters because inflammation is not automatically harmful. The early inflammatory response is part of healing. The problem is failure to resolve it appropriately. An open wound can then contain inflammatory signals and enzymes for far longer than a normally progressing wound. In other words, the chemistry designed to clean up yesterday's damage can begin interfering with tomorrow's rebuilding.

Who Are the Matrix Metalloproteinases?
One of the most interesting chemical players is not a single molecule but a family of enzymes called matrix metalloproteinases, or MMPs. These zinc-dependent enzymes normally participate in remodeling the extracellular matrix, the network surrounding cells. Controlled protein breakdown is necessary because damaged material has to be removed and tissue has to be reorganized. But excessive proteolytic activity changes the situation. Reviews of clinical studies have found excessive expression or activation of certain MMPs in chronic wounds with delayed healing. If protein-degrading activity becomes too high, components needed for repair can also be damaged. The same chemistry that is useful in the correct amount can become destructive when its regulation is lost.

When Does Oxygen Become Part of the Problem?
A wound needs oxygen for far more than simply keeping cells alive. Oxygen participates in processes involved in cell proliferation, angiogenesis, and protein synthesis, all of which contribute to tissue restoration. Injury itself disrupts blood vessels, so some degree of reduced oxygen is expected. Cells can respond to low oxygen through hypoxia-related signaling that helps coordinate survival and angiogenesis. But severe or persistent oxygen deficiency is different. Chronic ischemic wounds can experience hypoxia severe enough to interfere with repair and cellular survival. A 2024 systematic review and meta-analysis of 31 randomized trials found that oxygen-based therapies improved several short-term chronic-wound outcomes, although the analysis did not find a statistically significant benefit for long-term wound healing. Oxygen matters, but wound healing is too complex to reduce to oxygen alone.

Where Do Reactive Oxygen Species Fit Into Healing?
Here is where wound chemistry becomes surprisingly delicate. Oxygen can be converted into reactive oxygen species, or ROS, including molecules such as hydrogen peroxide. The phrase "oxidative stress" often makes ROS sound entirely destructive, but biology is more complicated. At controlled concentrations, reactive oxygen species can act as signaling molecules during wound repair. Wound-healing research describes ROS as participating in cellular signaling needed by healing processes, while excessive oxidative activity can damage proteins, lipids, and DNA. So the goal is not simply more antioxidants or more oxygen. Normal repair depends on regulation. Too little of an important chemical signal can cause problems. Too much can cause different ones.

How Can Bacteria Change the Wound Environment?
Bacteria do not always exist as isolated cells floating freely in a wound. They can organize into communities called biofilms, surrounded by an extracellular matrix that helps protect them. Biofilms are particularly important in chronic wound research because they can tolerate antimicrobial agents and resist host immune defenses more effectively than freely living bacteria. A systematic review and meta-analysis examining 185 chronic wounds across nine studies estimated biofilm prevalence at 78.2%, although the authors noted the limited number and size of human studies available. Biofilm research helps explain why simply identifying bacteria does not capture the whole problem. Their organization and interaction with the wound environment matter too.

Real-Life Example
Imagine a wound on the lower leg that has remained open for weeks. It would be tempting to think of the problem as one missing ingredient. Perhaps the body needs more collagen, a stronger immune response, or simply more time. The biology does not support such a simple picture. Blood flow may be limiting oxygen delivery. Persistent inflammation may be altering the local environment. MMP activity may be excessively breaking down proteins. Microorganisms may be organized into biofilms. Underlying conditions may also be preventing normal repair. This is why a chronic wound cannot be understood just by looking at the opening in the skin. Clinicians need to consider the reason the wound developed and the biological conditions preventing it from progressing through repair.

Common Misconceptions
One misconception is that an open wound simply means the immune system is weak. Chronic wounds can actually contain persistent inflammatory activity rather than an absence of it. Another misconception is that bacteria automatically mean an obvious acute infection. Biofilm communities can behave differently from the classic picture people associate with infection, and reliable diagnosis of chronic-wound biofilms remains challenging. It is also misleading to assume that one chemical factor explains every chronic wound. Oxygen deficiency, excessive protease activity, biofilm, inflammation, vascular disease, diabetes, and other factors can interact differently depending on the wound. The chemistry is important precisely because it is part of a larger biological system.

What You Can Learn From This
The most interesting lesson may be that healing is not created by maximizing every "good" process. Inflammation is necessary, until it persists too long. Proteases are useful, until their activity becomes excessive. Reactive oxygen species can carry signals, yet high levels can contribute to molecular damage. Oxygen is required, but oxygen availability must exist within a much larger repair process. Chronic wounds show what happens when biological balance is lost. That is also why wounds that remain open, repeatedly reopen, become increasingly painful, develop drainage or odor, or show other concerning changes deserve medical assessment rather than endless home experimentation. Understanding the chemistry helps explain the problem, but it does not identify the cause of an individual wound.

Final Thoughts
A wound looks like an opening in the skin. Biologically, it is closer to a temporary construction site where immune cells, enzymes, proteins, blood vessels, chemical signals, and microorganisms are all interacting at once. Normal healing depends on those interactions changing at the right time. Chronic wounds reveal what can happen when the sequence becomes stuck. Research has identified persistent inflammation, excessive MMP activity, oxygen deficiency, and biofilms as important parts of that environment. This is why a wound that refuses to close is not simply taking longer. Beneath the surface, the chemistry of repair may have become the chemistry that prevents repair.

References
Lázaro JL, Izzo V, Meaume S, Davies AH, Lobmann R, Uccioli L. Elevated Levels of Matrix Metalloproteinases and Chronic Wound Healing: An Updated Review of Clinical Evidence. Journal of Wound Care. 2016. PMID: 27169343.
https://pubmed.ncbi.nlm.nih.gov/27169343/

Castilla DM, Liu ZJ, Velazquez OC. Oxygen: Implications for Wound Healing. Advances in Wound Care. 2012. PMID: 24527310. PMCID: PMC3625368. https://pubmed.ncbi.nlm.nih.gov/24527310/

Malone M, Bjarnsholt T, McBain AJ, et al. The Prevalence of Biofilms in Chronic Wounds: A Systematic Review and Meta-analysis of Published Data. Journal of Wound Care. 2017. PMID: 28103163.
https://pubmed.ncbi.nlm.nih.gov/28103163/

Wu YK, Cheng NC, Cheng CM. Biofilms in Chronic Wounds: Pathogenesis and Diagnosis. Trends in Biotechnology. 2019. PMID: 30497871. https://pubmed.ncbi.nlm.nih.gov/30497871/

Du X, et al. Effects of Oxygen Therapy on Patients with a Chronic Wound: A Systematic Review and Meta-analysis. Advances in Skin & Wound Care. 2024. PMID: 38648247. https://pubmed.ncbi.nlm.nih.gov/38648247/

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