Fibrosis in Wound Healing: From Repair to Scarring

Wound healing tips into fibrosis when the cells responsible for closing a wound refuse to stop working. In a healthy repair process, specialized cells called myofibroblasts build a temporary scaffold of collagen to seal the gap, then die off or revert to a quieter state. When that shutdown fails, collagen keeps piling up, tissue stiffens, and what should have been a resolved wound becomes a permanent, sometimes disabling scar. The difference between repair and scarring is largely a matter of timing and persistence, and research over the past decade has identified the key molecular switches, immune signals, and physical forces that push healing in one direction or the other.

The Three Phases and Where They Go Wrong

Wound repair unfolds in three overlapping stages: inflammation, proliferation, and remodeling. Each phase has its own cast of cells and signals, and fibrosis can be traced to disruptions in any of them.¹ During inflammation, immune cells flood the wound to fight infection and clear debris. In the proliferative phase, fibroblasts migrate in, transform into myofibroblasts, and begin weaving new collagen to physically contract and close the wound. Remodeling is the long cleanup: the body gradually replaces the hasty, disorganized collagen with better-organized fibers and breaks down what it no longer needs. A well-managed repair completes all three phases and yields a flat, faded scar that blends into the surrounding skin over months or years.

Fibrosis occurs when either inflammation drags on too long, feeding too many growth signals into the wound, or the proliferative machinery fails to wind down. The result is the same either way: myofibroblasts keep producing collagen, the tissue stiffens beyond what is needed for structural integrity, and the wound never fully enters the remodeling phase. Understanding why that shutdown fails requires looking at the cells driving the process, the signals they respond to, and the physical environment around them.

Myofibroblasts and the Persistence Problem

Myofibroblasts are the central players in both normal repair and pathological fibrosis. They are essentially construction workers that produce and organize collagen into scar tissue. In a normal wound, fibroblasts temporarily acquire a more muscular, contractile form, pull the wound edges together, deposit a collagen matrix, and then undergo programmed cell death once their job is done.² The critical distinction between healing and fibrosis hinges on whether that activation is transient or persistent. When myofibroblasts remain active longer than necessary, they overproduce collagen and create an inappropriately stiff mechanical environment that, ironically, further encourages their own survival.³

These cells do not all come from the same source, either. Resident skin fibroblasts are the most obvious origin, but myofibroblasts can also arise from the cells lining blood vessels through a process called endothelial-to-mesenchymal transition. In mouse wound tissue, researchers found that a substantial fraction of endothelial cells began co-expressing markers of both blood vessel cells and myofibroblasts, confirming that blood vessels themselves contribute to the myofibroblast population during scarring.⁴ This transition was also observed in fate-tracking experiments where wound vessels progressively shifted from an endothelial identity toward a mesenchymal, scar-producing one.⁵ Beyond this direct conversion, endothelial cells can also promote fibrosis indirectly by becoming senescent and secreting inflammatory signals that activate nearby fibroblasts.⁶

The variety of cellular origins helps explain why fibrosis can be so hard to prevent. Blocking one source of myofibroblasts may not be enough when several independent routes lead to the same outcome.

The TGF-β Signaling Axis

If myofibroblasts are the workers, transforming growth factor beta (TGF-β) is their foreman. TGF-β is the most studied molecular driver of fibrosis in virtually every organ, and the skin is no exception. It stimulates fibroblasts to convert into myofibroblasts, ramps up collagen production, and suppresses the enzymes that would normally break excess collagen down. Sustained activation of TGF-β signaling results in long-term overactivation of fibroblasts and myofibroblasts, which is what allows the excessive collagen buildup seen in pathological scars.⁷

There is a wrinkle, though. TGF-β is not one molecule but a family of closely related proteins, and they do not all push in the same direction. TGF-β1 is the isoform most associated with adult scarring, while TGF-β3 appears to promote scarless healing in fetal wounds and reduced scarring in adults.⁸ That distinction has driven significant drug development efforts, which we will return to later.

Mechanical Forces That Feed the Cycle

One of the less intuitive drivers of scarring is simple physical tension. Wounds in high-tension areas of the body, such as the chest, shoulders, and joints, are far more prone to pathological scarring than wounds on the scalp or eyelids, and the reason is mechanical. Increased mechanical stress in the wound environment activates signaling pathways inside cells that promote proliferation and collagen production, ultimately driving fibrosis.⁹ In rat models, mechanical tension applied to healing skin led to the formation of thicker scars along with increased nerve density and nerve growth factor in the scar tissue, which may partly explain why hypertrophic scars can be painful or itchy.¹⁰

The relationship between stiffness and fibrosis is self-reinforcing. Scar tissue is stiffer than normal skin. Myofibroblasts sense stiffness through their internal scaffolding and respond to a stiff environment by producing more collagen, making the tissue stiffer still. Signaling proteins like YAP and TAZ sit at the center of this feedback loop, translating mechanical cues into gene activation that sustains fibrotic behavior.¹¹ This positive feedback loop is one reason fibrosis, once established, is so difficult to reverse: the scar itself generates the signals that keep it growing.

How Immune Cells Tip the Balance

Macrophages, the immune system’s first responders, have an outsized role in deciding whether a wound heals cleanly or scars excessively. Early in healing, macrophages take on an inflammatory form that clears debris and fights pathogens. As the wound matures, they need to shift into a reparative form that supports tissue rebuilding and eventually scar resolution. If macrophages fail to make that transition, the result can be either chronic unresolved inflammation or fibrosis.¹²

These immune cells directly promote fibrosis by stimulating fibroblast proliferation, driving myofibroblast differentiation, and encouraging collagen deposition. Alterations in either macrophage numbers or their functional state can dictate the level of scar formation.¹³ There is also cross-talk between the skin’s surface cells, keratinocytes, and the fibroblasts beneath them. In fibrotic skin conditions including keloids and hypertrophic scars, keratinocytes appear to enhance extracellular matrix deposition by fibroblasts, adding another layer of regulation.¹⁴

Keloids Versus Hypertrophic Scars

Not all pathological scars are the same. The two main types, keloids and hypertrophic scars, look similar but behave differently. The defining difference is that keloids grow beyond the borders of the original wound while hypertrophic scars, however raised and thick, stay within the wound boundary.¹⁵ Under a microscope, keloids contain large, thick collagen fibers packed tightly together, while hypertrophic scars show a more modular structure with smaller vessels, fine disorganized collagen, and nodules populated by myofibroblasts.¹⁶

In practice, the line between the two is blurrier than textbook descriptions suggest. Many of the molecular abnormalities are shared, and the differences are often more a matter of degree than of kind. Hypertrophic scars sometimes flatten and soften over years, while keloids rarely regress on their own and tend to recur after surgical removal. This recurrence is one reason keloids are so frustrating for patients and clinicians alike.

Who Gets Pathological Scars and Why

Genetics matters a great deal. Keloid incidence is highest in people of African descent, with estimates ranging from about 4 to 6 percent in the general Black population and up to 16 percent in some survey samples of Black Africans.¹⁷ Asian populations also have elevated keloid risk. A recent single-cell meta-analysis of keloid tissue across Asian, Black, and White populations found that the cellular makeup of keloids differs by ethnicity: Asian and Black keloids showed expansion of endothelial (blood vessel) cell populations, whereas White keloids had greater fibroblast expansion, suggesting that the routes to keloid formation may not be identical across groups.¹⁸

Systemic health conditions also play a role. Type 2 diabetes appears to increase the risk of hypertrophic scarring. A Mendelian randomization study, which uses genetic variants to mimic a randomized trial, found a positive causal association between type 2 diabetes and hypertrophic scar formation, with odds ratios in the range of 1.2 to 1.3.¹⁹ High blood sugar disrupts the normal signaling pathways that control myofibroblast activity, alters fibroblast death timing, and damages the wound’s local environment in ways that can lead to either chronic non-healing wounds or excessive scarring.²⁰ Diabetes, in other words, disrupts the same cellular machinery that drives fibrosis, but the outcome is unpredictable: some diabetic wounds scar too much, others barely heal at all.

Why Fetuses Heal Without Scarring

One of the more striking observations in wound biology is that early-gestation fetal skin heals rapidly and without scar formation. Despite decades of investigation, the exact mechanisms remain only partly understood, but the differences are real and span the immune response, the extracellular matrix, and the signaling environment. Fetal wounds show less inflammation, different ratios of TGF-β isoforms (more TGF-β3, less TGF-β1), and a matrix composition that favors regeneration over fibrotic repair.²¹ This natural example of scarless healing has been a major source of inspiration for anti-scarring therapies, essentially guiding researchers to ask what adults are doing differently and whether those adult-specific responses can be dialed back.

MicroRNAs as Molecular Fine-Tuners

Beyond the well-known TGF-β pathway, small RNA molecules called microRNAs have emerged as important regulators of fibrosis. These molecules do not code for proteins themselves but instead fine-tune which genes get turned up or down in a cell. Several microRNAs are involved in skin fibrosis, with some acting as pro-fibrotic accelerators and others serving as brakes.²²

One example is miR-145, which is found at roughly three times the normal level in hypertrophic scar tissue. It works by suppressing a protein that normally keeps myofibroblast activation in check, which means more miR-145 translates to more collagen production and stronger contractile force. Blocking miR-145 in lab experiments reversed these effects, reducing collagen output and TGF-β1 secretion.²³ On the other side, miR-29b acts as a potent brake on collagen 1 production. When miR-29b levels drop, collagen shoots up, and forcing its expression back up dramatically reduces collagen output in skin fibroblasts.²⁴ These findings have fueled interest in microRNA-based therapies for scar prevention, though none have yet reached widespread clinical use.

Therapeutic Strategies That Target the Mechanism

Knowing the molecular and mechanical drivers of scarring has opened multiple therapeutic fronts. The approaches fall into a few broad categories, each aimed at a different part of the fibrotic machinery.

The most direct molecular strategy has been targeting TGF-β itself. Monoclonal antibodies, small molecules that block TGF-β receptor activity, and RNA-based therapies that silence TGF-β signaling have all been explored. Monoclonal antibodies targeting TGF-β were tested in a small clinical trial but produced disappointing results.²⁵ More promising was the approach of using TGF-β3 rather than blocking TGF-β1. A recombinant TGF-β3 product called avotermin (Juvista) showed in human trials that local administration at the wound site reduced dermal scarring in a dose-dependent manner and was safe and well tolerated.²⁶ However, avotermin ultimately failed to meet primary endpoints in larger Phase III trials and was not brought to market, illustrating how difficult it is to translate even biologically sound ideas into effective drugs for scarring.

Mechanical offloading has been more immediately successful. Because wound tension is a direct driver of fibrosis, devices that physically shield wounds from mechanical stress can reduce scar formation. In a combined animal and human study, a dynamic stress-shielding polymer device reduced histologic scar area by six-fold compared to control wounds in a pig model, and in human patients, it significantly improved scar appearance over eight months compared to within-patient control incisions.²⁷ Similar tension-offloading devices applied before and after surgery have shown better results in scar width and color compared to standard postoperative care.²⁸ The effectiveness of these devices tends to improve with longer application time after surgery.²⁹

Researchers are also exploring biomaterial-based scaffolds, including hydrogels and engineered wound dressings, that can modulate the mechanical and biochemical environment of a healing wound. The idea is to create a local environment that favors regeneration over fibrosis, potentially even supporting the regrowth of skin appendages like hair follicles and sweat glands that are normally lost in scar tissue.³⁰ Plant-derived compounds are another area of active investigation. Isorhamnetin, a flavonoid, was recently shown to suppress hypertrophic scar fibroblast activity by dampening TGF-β1 signaling in a dose-dependent manner in lab experiments.³¹

Fibrosis Beyond the Skin

Skin scarring is the most visible form of fibrosis, but the same fundamental process, excess collagen deposited by persistently activated myofibroblasts, drives organ damage in the heart, lungs, liver, kidneys, and gut. Fibrosis in these organs contributes to an estimated one-third of natural deaths worldwide.³² The shared molecular pathways across organs are the reason skin scar research attracts interest well beyond dermatology: a therapy that can tame fibrosis in skin wounds might, in principle, be adapted to prevent the progressive organ failure caused by fibrosis elsewhere. The overlap is not perfect, because each organ has tissue-specific quirks, but the core machinery is similar enough that insights travel between fields.

Monitoring Scars Without a Biopsy

Tracking how a scar is evolving has traditionally required removing a tissue sample, which is impractical for repeated monitoring and, somewhat ironically, risks creating more scar tissue. Non-invasive imaging is beginning to change that. Optical coherence tomography, or OCT, can produce cross-sectional images of the skin’s layers and visualize collagen content in real time. Research has shown that OCT has the potential to serve as an objective measure of collagen status and disease progression, potentially replacing serial biopsies in both clinical trials and day-to-day practice.³³

Even more detailed is two-photon microscopy, which can image individual collagen fibers and the junction between the skin’s outer and inner layers. A portable handheld version of this technology has been tested on pathological scars, where it found measurable differences in collagen depth, thickness, fiber orientation, and fiber density between scarred and normal skin. These objective measurements could help clinicians choose treatment strategies and track how well they are working without cutting into the patient.³⁴ As these tools become more affordable and widespread, they may shift scar management from subjective visual assessment toward quantifiable tracking of the underlying fibrotic process.