From Chronic Wounds to Scarring: The Growing Health Care Burden of Under- and Over-Healing Wounds

Abstract

Significance:

Wound healing is the largest medical market without an existing small molecule/drug treatment. Both “under-healing” (chronic wounds) and “over-healing” (scarring) cause a substantial biomedical burden and lifelong consequences for patients. These problems cost tens of billions of dollars per year in the United States alone, a number expected to grow as the population ages and the prevalence of common comorbidities (e.g., diabetes) rises. However, no therapies currently exist to produce the “ideal” healing outcome: efficient wound repair through regeneration of normal tissue.

Recent Advances:

Ongoing research continues to illuminate possible therapeutic avenues for wound healing. By identifying underlying mechanisms of wound repair—for instance, tissue mechanics' role in fibrosis or cell populations that modulate wound healing and scarring—novel molecular targets may be defined. This Advances in Wound Care Forum issue includes reviews of scientific literature and original research from the Hagey Laboratory for Pediatric Regenerative Medicine at Stanford and its alumni, including developing approaches for encouraging wound healing, minimizing fibrosis, and coaxing regeneration.

Critical Issues:

Wound healing problems reflect an enormous and rapidly expanding clinical burden. The issues of both under- and over-healing wound outcomes will continue to expand as their underlying causes (e.g., diabetes) grow. Targeted treatments are needed to enable wound repair with functional tissue restoration and decreased scarring.

Future Directions:

Basic scientists will continue to refine understanding of factors driving undesirable wound outcomes. These discoveries are beginning to be translated and, in the coming years, will hopefully form the foundation for antiscarring drugs and other wound therapeutics.

Michael T. Longaker, MD, MBA

SCOPE AND SIGNIFICANCE

Wound healing represents an enormous clinical field with a growing biomedical burden. Clinical wound healing problems broadly exist on the spectrum from “under-healing” (i.e., chronic/nonhealing wounds) to “over-healing” (i.e., scarring/fibrosis). Due to population-level factors such as increasing rates of diabetes and vascular dysfunction (which predispose individuals to poor wound healing), the prevalence of problematic wounds is increasing, and novel therapies to promote efficient wound healing without scarring are of significant interest. This review will discuss known pathophysiology, treatment options, and emerging research into both under- and over-healing wounds, including developing approaches for encouraging wound healing, minimizing fibrosis, and coaxing regeneration.

TRANSLATIONAL RELEVANCE

Current research, including original work presented in this Advances in Wound Care Forum issue, seeks to understand the molecular and cellular processes driving different aspects of wound repair, with the goal of informing novel therapies to improve wound healing. For chronic wounds, such work may include elucidating inflammatory cell subsets or vascular/endothelial cell pathologies that contribute to delayed healing, while for scarring, it includes defining the tissue-level factors (e.g., the role of tissue mechanics) and cell populations that drive a fibrotic versus regenerative injury response. The findings of these studies may facilitate development of new antiscarring and pro-repair therapeutic strategies.

CLINICAL RELEVANCE

Skin wounds are one of the most common clinical issues, with nonhealing/chronic wound care and scar treatment each representing multibillion-dollar industries. However, existing therapeutic options are largely restricted to conservative measures such as physical wound dressings; at best moderately effective; and often limited by poor patient compliance. Targeted molecular therapies, guided by novel basic science discoveries into the fundamental mechanisms of wound repair and scarring, may represent a promising and emerging future direction in the clinical management of wounds.

INTRODUCTION

The spectrum of wound healing

Wound repair is a complex biological process. As such, there is a broad range of possible outcomes from a skin wound, which depends on a wide range of patient and environmental factors.

Human wound healing can be thought of as a spectrum. The middle of the spectrum represents “normal” wound healing. This process canonically involves three overlapping phases:

• 1.Inflammation, which begins at the onset of injury and peaks within the first week of healing;
• 2.Proliferation, in which new, relatively tenuous provisional tissue known as granulation tissue (“proud flesh”) is formed and the epithelial barrier is restored, typically within 2–3 weeks of the initial injury; and
• 3.Remodeling, the process by which fibroblasts and other cells gradually alter granulation tissue into a mature scar, which can last for months or even years following injury.

While the above generalized timeline and stages reflect successful wound healing, this process can be dysregulated or interrupted, leading to healing outcomes outside of the normal range. Broadly, two possible pathologic healing outcomes exist that represent the two ends of the wound healing spectrum.

On one end of the spectrum is “under-healing.” When wound conditions are aberrant—for instance, in the setting of pressure/tissue ischemia, prolonged trauma, radiation therapy, or immune dysfunction, which often result from systemic causes such as diabetes or atherosclerosis—wounds may fail to heal at all. The resulting chronic wound remains open to its environment, as the body is unable to effectively restore the integrity of its skin barrier. As a result, chronic (otherwise known as nonhealing) wounds are highly prone to complications, which are an increasing risk as long as the wound remains unhealed. These include infections which can progress from skin to underlying structures and necessitate surgical intervention or even amputation.

On the other end of the spectrum is “over-healing.” As outlined above, even “normal” skin wound healing will result in the formation of permanent scar tissue, which, depending on the location and extent of injury, can cause lasting functional disruption. Beyond normal scarring, however, humans also suffer from “pathological scarring,” a term which generally encompasses the phenomena of hypertrophic scars and keloids. While the pathophysiology of these two processes is different, they share key characteristics, most notably a “hyperproliferative” aspect. Essentially, an overly-exuberant wound healing response can lead to the deposition of a supraphysiologic amount of scar tissue, resulting in an especially prominent scar. This heightened fibrotic response can cause an even greater burden to form and function than typical scars.

Impact of wound healing problems

Not every organism scars; in fact, scarring is a relatively late evolutionary event in the natural history of the animal kingdom. So, why did mammalian evolution converge on this process? Scarring represents a selective adaptation toward the ultimate evolutionary goal of survival and procreation. Despite the fact that scars compromise both form and function, they offer a key benefit: speed. The relatively rapid process of scarring allows for wounds to be closed and for the skin barrier to be restored quickly, thus preventing infections, blood loss, or other complications that would have meant the difference between life and death to early humans.

However, the demands of our times are not the same as those faced by early mammals. With modern medical advancements such as sterile dressings and antibiotics, most wounds heal in a relatively privileged environment. Life-threatening infections or bleeding are no longer likely dangers of simple wounds. But the fact remains that any injury to adult dermis will result in some degree of scarring. Furthermore, many wounds now occur in the context of obesity, diabetes, and/or aging. These comorbidities introduce a new level of complexity to the field of wound healing, as they create a suboptimal wound healing environment and impair critical components of the wound repair process.

Collectively, these factors have led to a unique challenge: how can we target wounds so that they heal effectively, but without producing lasting scars?

Between under- and over-healing problems, the United States and global markets for wound therapeutics are enormous. The global chronic wound care market has been valued at nearly $20 billion in recent years and is projected to exceed $30 billion in the next 5 years,¹ while the global scar treatment market was estimated at $20 billion in 2020 and is projected to reach over $60 billion in the next 10 years.² Beyond these direct costs, which take into account products such as wound dressings and biologics/grafts, wounds are responsible for substantial costs related to medical care and procedures, as well as lost productivity.

Understandably, the true costs of wound healing problems are notoriously difficult to pinpoint for several key reasons. Most calculations do not take into account secondary expenses such as the cost of amputations resulting from chronic wounds (and indeed, because the possible sequelae of wound complications are so broad, these expenses can be difficult to robustly identify or link to their wound etiology). Another possible explanation for underaccounting of wound costs is that there is not a single medical specialty specifically responsible for wound care.³ This is further complicated by the fact that wound care occurs at many different levels of the health care system, from hospitals to nursing homes.⁴

Regardless, the costs of wound healing problems to the U.S. medical system are undeniably massive and growing. One study estimated that in 2014, wound-related Medicare spending was at least $28.1 billion and as much as $96.8 billion.³ The prevalence of underlying conditions predisposing individuals to wound healing complications is rapidly growing. Advanced age is a major risk factor for chronic wounds. Chronic wounds are nearly 30 times more common in individuals over 60 years old than those under 20 years old.⁵ Three percent of the U.S. population aged 65 or older are estimated to have open wounds⁶; this sector of the population has grown by over one-third (34.2%) in the last decade.⁷ Diabetes is another common predisposing factor for nonhealing wounds. Currently, more than 1 in 10 Americans has diabetes,⁸ and the prevalence of diabetes is generally increasing over time,⁹ particularly in an aging population. Obesity is an independent risk factor for poor wound healing,⁶ as well as the leading risk factor for type 2 diabetes.¹⁰ It is well known that the prevalence of obesity has skyrocketed over the last few decades, and obesity currently affects almost half (>42%) of all adults in the United States, with nearly 1 in 10 adults having severe obesity (defined as a body mass index of 40 or higher).¹¹

In brief: clinical wound healing problems are not going anywhere any time soon.

But while there exist vast numbers of lotions, potions, and dressings claiming to aid wound healing or minimize scarring, there is a severe dearth of products that actually do what they claim to do. A large body of research has established basic principles of wound treatment and scar prevention; the most important is maintaining a hydrated and protected wound environment (e.g., through the use of occlusive/moist dressings^12–14; rather than gauze, which has been associated with increased infection rates¹⁵). Occlusive wound dressings have been associated with reduced pain, scar severity, infections, and time to healing compared with gauze dressings. However, targeted therapies remain elusive, and the wound healing market is arguably the largest medical market without any effective drug. Despite decades of research, none of the small molecules or drugs developed in the last 20 years in preclinical studies to target scarring has been borne out by clinical studies. Nearly 1,000 new drugs (930 total) were approved by the Food and Drug Administration (FDA) between 1985 and 2019¹⁶; of these, only 1 was for a wound healing indication. The drug, Regranex (approved 1997, generic, becaplermin; Johnson & Johnson), is a rhPDGF-BB protein indicated for advanced lower extremity diabetic neuropathic ulcers. However, early clinical trials showed only a modest improvement in healing with Regranex gel compared to vehicle control or good ulcer care alone, with a combined analysis of Regranex clinical trials suggesting that Regranex gel-treated ulcers of median size had a 50% chance of complete healing compared to 36% with placebo gel¹⁷ and similar rates of ulcer recurrence (∼30%) in all groups.¹⁸ And, while numerous topical products exist on the consumer market (for instance, silicone sheets to minimize scars), randomized controlled clinical trials have failed to demonstrate clear superiority of any one of these approaches.¹⁹

Toward novel therapies: drivers and obstacles of progress

Given both the exorbitant costs associated with wound healing problems and their sequelae, as well as the lack of effective treatments, it is easy to understand the impetus for developing and translating new therapies, particularly targeted small molecule and drug candidates. Yet we would argue that the wound care field suffers from a publicity problem: the potential market and demand for novel, effective wound therapies far overshadow the perceived need for new solutions. Perhaps this is due to the decentralized nature of wound care infrastructure, as mentioned above, which deprives the field of a unified advocate. Similarly, the fact that no single clinical specialty or scientific field “claims” wound healing as its own may pose a challenge to gathering momentum or funding for large-scale wound care research. This possibility underscores the importance of interdisciplinary, wound care-focused organizations, in promoting, supporting, and amplifying groundbreaking wound care research. Arguably, there is a lack of common knowledge of the sheer scope or impact of clinical wound healing problems, which may be compounded by the fact that wound problems are often a “secondary” clinical issue (given that they tend to occur in patients with serious comorbidities, such as uncontrolled diabetes, or postoperatively, in the case of scarring). In addition, there is a vast array of wound care products commercially available (most of whose efficacy is dubious, at best), whose development and popularity have been spurred by the extraordinarily high prevalence of scarring and other wound problems in combination with the lack of a clear “gold standard” treatment option. This glut of options may lead to the false perception—by both consumers and practitioners—that the market is already saturated, when in fact the vast majority of these products are either entirely unsupported by scientific evidence or have shown only very modest benefits. The enormous consumer market for wound and scar products may also dampen commercial interest in developing new therapies—regardless of their efficacy—in these spaces, by making market penetration substantially more challenging. Whatever the reason, the enormous (and growing) wound healing market is ripe for innovative disruption, from both a biomedical and a financial perspective. As a medical community and society, we devote disproportionate resources toward care in the last few months or weeks of life, care which often ultimately increases costs to the medical system. In contrast, any truly effective therapy that could be introduced into the wound healing market—for instance, a drug capable of preventing surgical incisions or burns from scarring, or one that could cause chronic skin wounds to heal—would be fundamentally and significantly cost-saving. Such a therapy could eliminate the sequelae of wound healing complications and the costly medical interventions they necessitate (such as amputation), which account for the lion's share of wound-related medical expenses.

While this article and issue will primarily discuss emerging research in the wound healing field, particularly basic science advancements in our understanding of scarring biology, it is worth acknowledging that limitations in scientific understanding are not the only barrier to developing effective new wound therapeutics. Clinical research in wound healing faces logistical challenges beyond those in most other fields. Wound healing trials are inherently more complex than other types of clinical studies, for multiple reasons. First, there often does not exist a clear, universally accepted/consistent “standard of care” for wound healing problems. Even where treatment approaches are generally agreed upon, the standard treatments themselves are often complicated. For instance, typical treatment of chronic wounds usually uses a multipronged approach involving debridement, off-loading/casting, and multiple types of wound dressings. Scar treatment is also enormously variable; there is a wide range of “standard” treatments used as controls in different clinical trials (e.g., no treatment vs. silicone sheeting/gels vs. nonsilicone occlusives), and other treatment factors—such as the precise location of wounds or individual variability in surgical technique—are impossible to standardize. These factors unavoidably introduce variability into clinical trials, making both conducting the study and analyzing its results more complex. Compounding this obstacle, the nature of clinical wound healing problems is such that patients are disproportionately likely to suffer one or multiple comorbidities, such as obesity or diabetes. Diabetic foot ulcers (DFUs) are one of the most studied examples of chronic wounds, likely due to their prevalence and the devastating impact they have on many patients. However, these trials are even more complex than a “standard” wound healing trial, given the additional patient factors (such as control of underlying disease) that must be taken into account. Finally, wound healing research—both clinical and basic science—suffer from a lack of objective outcome measures. Wound healing studies, for both nonhealing wounds and scarring, rely almost entirely on subjective metrics, such as patient-reported outcome measures and visual analog scales to assess scar or wound severity. The lack of consistent and objective metrics against which to gauge wound healing may at least partially explain why so many clinical trials fail to establish significant results, as well as inconsistencies between different studies' findings. The FDA historically only recognized complete wound closure as a clinical trial end point for wound healing; however, the Wound Care Experts/FDA Clinical Endpoint Project (WEF-CEP) is an ongoing initiative by the Association for the Advancement of Wound Care and the Wound Healing Society to expand FDA end points to include other important and clinically relevant metrics such as amputation reduction, pain, and social factors.²⁰ This collaboration, which was started in 2014, acknowledges that complete wound closure is not always the most relevant (or, even, achievable) end point for treating chronic wounds. Instead, the initiative emphasizes the development of reliable metrics that better reflect the factors most important to both clinicians and patients.^21,22 Ultimately, these changes could accelerate the development and approval of new wound healing therapeutics.

These challenges cannot be ignored, and it is equally important to consider how we can address the logistical obstacles inherent to clinical wound healing studies. New technologies such as image-processing algorithms have shown promise for improving diagnosis and classification in other fields. A notable example is the use of machine learning/artificial intelligence approaches to diagnose skin cancer.²³ Computational image analyses may similarly be developed to provide a more objective way to assess wounds and scars. By applying modern solutions to the age-old questions around wound healing, we may be able to accelerate progress in developing, evaluating, and refining new therapies for wound repair and scarring.

The articles in this Forum issue of Advances in Wound Care represent research performed in, or by alumni of, the Hagey Laboratory for Pediatric Regenerative Medicine at Stanford. The Hagey Laboratory is an interdisciplinary building with surgeon scientists in general surgery, pediatric surgery, and plastic surgery. A large focus of the research performed at Hagey is understanding the body's response to injury that yields fibrosis, or scarring, rather than regeneration and innovating new approaches to tackle this problem.

UNDER-HEALING ISSUES

There are many reasons why wounds may not heal. There is no consensus on what specific criteria define a “chronic wound,” such as time frame or patient comorbidities. However, generally speaking, chronic wounds (sometimes referred to as “nonhealing wounds”) are those that fail to progress through the typical stages of wound repair (see “The spectrum of wound healing” above) and remain open or incompletely healed in the long term. Chronic wounds are a huge problem, estimated to affect roughly 2% of the entire U.S. population⁶ and disproportionately impacting the elderly.

Causes of chronic wounds

In general, chronic wounds result from impaired blood flow and sustained inflammation, which lead to tissue damage that does not resolve and ultimately necrosis. Wound healing can also be compromised by factors such as radiation exposure or systemic disease (e.g., diabetes) that impairs the skin's ability to mount a normal response to injury. Over time, these unhealed wounds are prone to infection, which if not treated can progress to infection of the underlying bone or even systemic infection and sepsis.²⁴

While the specific etiology of chronic wounds varies, several key biomolecular factors have been identified as common drivers of impaired wound healing.²⁵ First, tissue ischemia significantly impedes normal healing by depriving the wound of both oxygen and circulating nutrients that are necessary for the survival and function of wound healing cells.²⁶ Ischemia is induced or worsened by clinical factors such as vascular dysfunction (including diabetic vasculopathy) and wound location. Due to regional differences in tissue circulation, the most common site of chronic wounds is the lower extremities, with chronic wounds of this region affecting over 6 million Americans.²⁷ Recent research has also shown that ischemia-reperfusion injury (which can occur in a cyclic manner; for instance, as patients must repeatedly transition from recumbent to ambulatory) contributes to prolonged tissue damage in chronic wounds.²⁵ Next, bacterial colonization, which generally occurs within 48 h of a wound being open to its environment,²⁵ infection leads to a persistent host immune response, dominated by neutrophils that secrete tissue-damaging substances such as proteases which further impede wound closure. Interestingly, it can be difficult to distinguish such harmful bacterial colonization from normal skin bacteria, and the role and regulation of the human skin microbiome in chronic wounds is a subject of research.²⁸ Finally, aging is a major risk factor for chronic wounds, with the average age of chronic wound patients being over 60 years.²⁵ Multiple factors related to aging can impair wound healing, including increased presence of reactive oxygen species, underlying ischemia, and an impaired cellular response to stress (including a heightened predisposition to pro-inflammatory behavior²⁹).²⁵ Cellular senescence has also been implicated in aging-related wound healing deficiency; the perpetually pro-inflammatory environment within a chronic wound leads to a prolonged demand for cellular proliferation/division, which overtime can lead to a senescent cellular phenotype and diminished healing capacity.³⁰ Given the greater degree of baseline cell senescence in aged individuals, wound cells' capacity to respond to their environment may be diminished and increase these individuals' predisposition to chronic wounds.²⁵

Specific etiology varies, but the vast majority of chronic wounds fall into one of three categories.³¹ The first, pressure injuries (commonly known as pressure ulcers or bedsores), result from compression of tissue, typically from weight bearing on a bony prominence (e.g., the sacrum) for extended periods, although these injuries are thought to develop within only a few hours of continuous loading.³² Compression of the overlying skin leads to tissue ischemia and ultimately necrosis.³³ Pressure injuries are most common among immobilized and insensate patients (e.g., secondary to spinal cord injury).³³

The second class of chronic wounds, vascular ulcers, can be further subdivided into arterial ulcers and venous ulcers. These can have similar clinical presentations but have distinct pathophysiologies. Venous ulcers are the most common type of leg ulcer,³⁴ comprising roughly 70% of all leg ulcers.³⁵ They are caused by impaired venous return of blood from the extremities due to venous valve incompetence and/or outflow obstruction. When severe, this can result in venous hypertension which, through an incompletely understood process, causes chronic inflammation resulting in tissue injury and necrosis.³⁴ Arterial ulcers, which represent roughly 20% of leg ulcers,³⁵ result from impaired blood flow to the extremities, most often caused by chronic atherosclerosis.³⁶ Overtime, this arterial insufficiency can lead to tissue ischemia and necrosis. Arterial and venous insufficiencies can occur simultaneously, and roughly one-quarter of patients with lower extremity ulcers exhibit mixed arterial/venous disease.³⁷

The final type diabetic ulcers are some of the most challenging chronic wounds to prevent and treat, as their etiology is complex and multifactorial. Multiple complications of diabetes predispose patients to wound healing problems, especially in the lower extremities. First, due to a combination of factors, including endothelial dysfunction and heightened inflammation, diabetic individuals have an increased risk of peripheral artery/vascular disease.³⁸ Second, peripheral neuropathy (combined with potential foot deformities related to altered nerve function) can both impair healing and lead to an increased risk of an inciting tissue trauma, as patients may not even be aware of injuries in affected tissues.³⁹ Lack of awareness of injury can lead to neglect and improper wound care, which further increases the likelihood of complications such as infections. Because of these factors, diabetic ulcers are most common on the plantar aspect of the foot,⁴⁰ and overall it is estimated that individuals with diabetes have a lifetime incidence of foot ulcers of 15–25%.³⁹

A final instance of under-healing is impaired wound healing in the setting of irradiated tissue. Radiotherapy is a component of treatment for over half of cancer patients.⁴¹ Because it damages not only cancerous cells but also the surrounding tissue, radiation can cause acute skin damage which, if severe, can lead to local necrosis and ulceration.⁴² Due to local tissue damage, the wound healing process is fundamentally impaired within the irradiated region.^43–45 Notably, while radiation acutely leads to compromised healing, in the long term, radiation injury/damage to skin cell populations can lead to substantial fibrosis which continues to develop over months or years.⁴⁵ Thus, radiation-induced skin complications include elements of both under- and over-healing, highlighting the complex nature of wound repair and related pathologies.

Focus study: DFUs

Chronic wounds—specifically chronic foot ulcers—are one of the most common complications faced by diabetic patients.⁴⁶ DFU can progress to gangrene, infection, and even death of the patient, with a 5-year mortality rate of 40% in patients who develop DFU.⁴⁷ One of the most devastating outcomes of DFU is amputation, which may become necessary if skin or bone infections cannot be controlled with more conservative management. Amputations are needed in 15–20% of diabetes patients within 5 years of DFU occurrence.⁴⁸ DFU is the most common cause of lower extremity amputation,⁴⁰ and chronic wounds such as diabetic ulcers precede 85% of all amputations.⁴⁹

Unfortunately, treatment options for DFU are limited. Most efforts to reduce the burden of DFU focus on prevention, as these wounds are notoriously difficult to treat. Treatment approaches are similar to those for other complicated wounds, including debridement, dressings, and off-loading of the affected limb, as well as improving nutrition and blood sugar control to target the underlying pathology.⁴⁶ More advanced methods such as hyperbaric oxygen therapy and bioengineered skin substitutes are emerging as possible adjunctive treatments.⁴⁶ However, given their limited availability outside of specialized wound centers and high costs—for example, a regimen of hyperbaric oxygen therapy consisting of 30 sessions costs around $20,000⁴⁸—these therapies are inaccessible to most diabetes patients. While more aggressive approaches such as full off-loading (using a plaster or fiberglass cast) are relatively effective, these treatments are onerous for the patient, and none is fully effective in healing DFU.

Basic science progress and developing therapies

The primary existing options for patients with chronic wounds are conservative wound treatment and strategies to resolve the underlying cause of tissue injury or dysfunction. For instance, one meta-analysis of patients with venous leg ulcers found evidence that progressive resistance exercise and physical activity were associated with increased rates of ulcer healing,⁵⁰ presumably due to improved venous return, although the effect size was moderate (for progressive resistance exercise or progressive resistance plus physical activity, 14 or 27 additional cases healed per 100 patients, respectively). Furthermore, patient compliance is often an issue for behavioral interventions such as those used for complicated wounds. Strategies to address this problem may include developing tools that can help to improve patient compliance with useful interventions; one meta-analysis showed that when diabetic patients with foot ulcers were treated with a nonremovable cast compared to a more easily removable one, rates of healing significantly increased.⁵¹ However, these studies highlight the challenges and limitations of existing treatment strategies: while they may be effective in an “ideal” setting, behavior-based interventions (such as weight off-loading or exercise) are often difficult for patients to consistently adhere to and may themselves (as with cast-wearing) interfere with patients' quality of life. While these obstacles by no means negate the possible positive impacts or utility of such approaches, they underscore the need for targeted/molecular treatments to improve healing of chronic wounds. Such therapies could serve as an additional tool available to wound care practitioners, as an adjunct to systemic and/or behavioral interventions focused on targeting the underlying causes of poor wound healing.

Unfortunately, no targeted local treatments exist to address the underlying causes of impaired wound healing in diabetic ulcers and other chronic wounds. A primary focus of scientific research in this area has been developing therapies that encourage improved blood supply and circulation at the affected site. Given that impaired/insufficient vascularization is a critical contributing factor to nearly all chronic wounds, a treatment targeting this underlying issue could have widespread applications for different types of poorly healing or chronic wounds. If such therapies could be developed, the expense of treating chronic wounds could be substantially reduced. The bulk of the cost of chronic wounds results from managing their sequelae; a treatment that could coax these wounds toward early healing could mitigate or eliminate the need for interventions such as amputation and would thus be fundamentally cost saving.

OVER-HEALING ISSUES

In essence, the entire process of human wound healing can be thought of as an “over-healing” problem. In humans, any injury involving the dermis inevitably results in some degree of scar formation. As a result, scars are incredibly common; nearly every adult has at least one scar. For some, scars are little more than an inconvenience. But for many individuals, scars can have lasting effects that impact both form and function.

What makes a scar a scar?

To understand the full burden of scarring, it is important to know what differentiates scarred/fibrotic skin from normal unwounded skin. Scar tissue fundamentally differs from normal skin in three key ways:

• 1.Scar tissue lacks any of the appendages/adnexa (such as hair follicles, sweat glands, and sebaceous glands) found in unwounded skin.
• 2.The fibrotic collagenous architecture of scar tissue is distinct from that of normal skin, with denser extracellular matrix (ECM) in an abnormal composition and spatial arrangement compared to skin.
• 3.Scars are mechanically weaker than skin and lack skin's usual tensile strength and pliability/elasticity. It is commonly estimated that scars will regain at most 80% of the strength of unwounded skin.⁵²

Scarring can cause devastating sequelae related to these three factors. Because scars lack any of the functional appendages found in skin, scar tissue lacks some of normal skin's key functionality. For example, sweat glands are critical for the body's ability to thermoregulate. In individuals with burns over a large percentage of their body's surface area, much of the ability to dissipate heat quickly is lost, which can cause or exacerbate hyperthermia.⁵³ The altered mechanical properties of scars can also be detrimental, particularly when scar tissue is situated over a joint such as on the neck or hand/forearm. Due to the stiff, dense, inelastic nature of scar tissue, as well as its propensity to contract overtime, contracture of scars across joints can lead to immobilization of the joint and, if not surgically treated, permanent functional loss.⁵⁴ These complications are especially prevalent and devastating in the developing world, where burn injuries are common and access to corrective surgery (often complex plastic surgical procedures) is limited.^54,55 Finally, scars are visually distinct from normal skin. In rare settings, this is a desirable outcome: since at least 60,000 B.C.E., cultures throughout the world (such as the Aboriginal peoples of Australia) have performed scarification, a practice in which skin is intentionally scarred for symbolic/ceremonial purposes and which continues to the present day.⁵⁶ However, for the large majority of individuals, scars are undesirable and can cause significant psychological trauma, particularly for children and/or those with highly visible (e.g., face) or prominent/extensive scars. For example, in children with cleft lip and/or palate (for whom early corrective craniofacial surgery is needed), their lifelong facial scar may lead to increased teasing, decreased self-esteem and psychosocial well-being, developmental issues, and depression.^57–59

Unfortunately, treatment options for scarring are extremely limited. The theoretical ideal healing outcome—often referred to as the “holy grail” of wound healing—is regeneration without scarring. Based on the characteristics of scars versus skin, a fully effective antiscarring therapeutic would therefore need to produce wound healing that fulfills three key criteria: regrowth of normal dermal appendages; restoration of skin's native extracellular matrix composition and structure; and healed wound strength comparable to that of unwounded skin. No current therapy meets all or even any one of these criteria.

Hypertrophic scars and keloids

In addition to the typical scarring outcome of all dermal injuries, humans may form two types of pathological or hyperproliferative scars: hypertrophic scars and keloids. Pathologic scarring is characterized by the deposition of excess scar tissue beyond that found in a normal scar. These scars thus tend to be more raised, may be abnormally pigmented, and are often associated with discomfort, pruritis, or pain at the site.⁶⁰ The exact cause of pathological scarring is unknown, and both types of hyperproliferative scar can result after any form of injury (e.g., burns, lacerations).

Hypertrophic scars and keloids both fall under the category of pathologic scarring but exhibit distinct pathophysiology and demographics. Unlike keloids, which are rare in the general population, hypertrophic scars are quite common and are estimated to affect as many as >90% of burn and surgery patients.^61,62 Hypertrophic scars are not believed to be genetically linked.⁶⁰ They occur more frequently on areas of high skin tension, such as the extensor surfaces of the body.⁶⁰ Aside from scar revision surgery and attempting to reduce tension on wounds to minimize the likelihood of hypertrophy (including, in the case of surgical incisions, placing incisions along the body's natural skin tension lines), no specific treatments have been validated to prevent or reduce hypertrophic scars.⁶¹ Hypertrophic scars may variably worsen and/or regress overtime, but by definition they do not extend beyond the borders of the original injury. Hypertrophic scarring should be thought of as an overly exuberant version of the “normal” scarring response, as these scars share key characteristics of typical scars (e.g., similar extracellular matrix composition and cellular properties^60,63) but are more prominent/severe.

In contrast, keloids are most accurately understood as benign fibrotic tumors that never stop growing. Unlike hypertrophic scars—which, while they may be raised/prominent, do not extend past the borders of the initial injury site—keloids continually expand and outgrow the borders of the original injury over time. They do not regress (again, in contrast to hypertrophic scars, which generally regress in the long term) but rather continue to grow in perpetuity, expanding into the surrounding normal skin.⁶⁰ This process is thought to occur through aberrant paracrine signaling from cells within the keloid leading to adoption of an abnormal, keloid cell-like phenotype by the surrounding normal skin cells (a process which does not occur in nonkeloid scars).⁶⁴ However, the pathophysiology of keloids remains largely unknown. In addition to typical injuries such as lacerations or burns, keloids can also occur after even extremely minor tissue trauma, such as ear piercing. While most keloids occur sporadically (i.e., do not have a strong family history of keloids), keloids do have a genetic component and are somewhat more common among darker-skinned individuals (highest in those of African descent and higher in people of Asian and Hispanic descent compared to white individuals).⁶⁵ However, the genetic basis of familial keloids has not been identified and is likely polygenic.⁶⁶ Keloids are challenging to treat, as surgical excision results in recurrence of the keloid in upwards of 70% of cases.^67,68 Local corticosteroid injection is a first-line treatment for keloids (either as a monotherapy or in combination with excision) and can induce keloid regression and help to prevent recurrence.⁶⁰ Intralesional injection of chemotherapeutic drugs 5-fluorouracil or bleomycin may also be used for keloid treatment, although these have been reported to have varying efficacy and side effect profiles.^62,69 Overall, treatment options for pathologic/hyperproliferative scars—like those for “normal” scars—are very limited, and there is a lack of robust evidence supporting the efficacy of many common existing therapies.^70,71

Focus study: burn injury

Burns are one of the most common causes of scarring worldwide. In 2016, nearly half a million Americans sought medical care for burns⁷²; worldwide, this number is over 10 million.⁷³ Burn injuries disproportionately impact those of lower socioeconomic status, and as many as 90% of burns affect people in low-/middle-income countries.⁷³ Young children are another vulnerable group, and infants and toddlers up to 4 years old account for nearly half of all childhood burns in some areas of the world.^74–76 Thanks to factors such as improved burn treatment, burn deaths in high-income countries such as the United States are generally trending downward.^77,78 However, survivors of severe burns must contend with a substantial burden of morbidity.

Long-term sequelae following burns are largely related to scarring, which can affect most or all of the body's surface area in the case of extensive burns. All second-degree or greater burns (i.e., those that extend any depth into the dermis) will result in scarring. While treatment options such as skin grafting can help achieve coverage of the burned area, these do not prevent scarring. Burn scars affect both form and function. Pruritis is incredibly common in healing burns,^79,80 and itching can lead to further skin injury and ulceration.⁵⁴ Burn scars can be visually disfiguring, particularly when they occur over large regions of skin and/or on the face, neck, and hands, which have significant and lasting negative impacts on patients' quality of life and mental health.^81,82 Joint contractures can occur in which progressive tightening of a scar across a joint causes loss of mobility and joint function. Often, a single patient can have multiple contractures resulting from a burn incident.⁵⁴ Contractures are usually preventable with high quality postburn care, and when they do occur can be treated by surgically releasing the contracted joint(s); as such, the burden of burn contractures in higher income countries is low.⁸³ However, in lower income countries where there may be fewer than one plastic surgeon per 1 million population, untreated contractures are very common.⁵⁴ If contractures remain untreated in the long term, patients may permanently lose function of the affected joints, at which point even surgical intervention cannot restore functionality.⁵⁴ This is one of the most devastating consequences of postburn scarring. Clearly, the formation of scar tissue following burns is responsible for much of the long-term damage suffered by burn patients, but there do not exist any treatments to enable healing of burn injuries without substantial scarring.

Basic science progress and developing therapies

Lessons from nature: mammalian regeneration

While most mammals (including humans) are not considered “regenerative,” there are certain contexts in which mammals exhibit the capacity for tissue regeneration. These have long interested researchers, who believe that by understanding the mechanisms of mammalian regeneration, we may unlock new directions for targeting regeneration in human patients. Multiple (although rare) instances of mammalian skin regeneration exist in the animal kingdom, such as wound healing in the Acomys genus of African spiny mice⁸⁴ or in the ears of the MRL/MpJ laboratory mouse strain.⁸⁵ However, arguably of greater interest are examples of wound regeneration within the human body, as these likely hold more direct translational relevance.

First, a “developmentally restricted” example of wound regeneration is mammalian fetal wound healing. In mammals (including humans), fetuses are capable of scarless wound repair in utero until roughly the third trimester of gestation.⁸⁶ The phenomenon of fetal scarless wound healing was experimentally explored starting in the 1990s, leading to studies that established early gestation fetuses as capable of rapid skin wound repair that resulted in regeneration of tissue indistinguishable from uninjured skin.⁸⁷ This regenerative ability is lost in the latter stages of fetal development, and late-gestation fetal and neonatal mammals heal through scarring similar to adults. Fetal regeneration was initially attributed to the unique intrauterine environment (a sterile environment in which the skin is constantly surrounded by amniotic fluid), but early studies strongly suggested that scarless healing is a property intrinsic to early fetal skin, rather than due to environmental factors.^88–90 More recent research has gradually revealed key factors that differentiate fetal scarless versus scarring wound repair, including differences in extracellular matrix composition/structure, reduced inflammation, and cytokines (e.g., TGF-β isoforms) that are differentially expressed.⁸⁶ However, the phenomenon of fetal scarless wound healing remains incompletely understood, and study of the process has not yet led to clinical advancements for adult wound healing. Still, this decade-old question continues to interest researchers as the only true example of skin regeneration in humans, and modern experimental methods such as single-cell sequencing and advanced imaging techniques may yield new, translationally relevant answers.

A second “tissue restricted” example of mammalian regeneration is healing of wounds to the oral mucosa. Minor injuries to the oral mucosa, such as aphthous ulcers (“canker sores”), bites, or lacerations, occur frequently in all humans, yet these do not generally result in a buildup of scar tissue. Instead, these wounds heal rapidly (compared to similar wounds to the skin) and result in deposition of tissue that is nearly identical to the native oral mucosa.⁹¹ Similar to fetal wound healing, inflammation is reduced in oral wounds, which is thought to be a key factor in the lack of fibrosis.⁹¹ The environment of oral mucosal healing is also markedly different from that of skin. Several environmental factors unique to the oral cavity, such as certain peptides present within saliva, have been proposed to contribute to accelerated wound repair and wound regeneration.^91–94 However, there are also clearly properties intrinsic to the oral mucosa that predispose it to regenerative healing, as demonstrated by transcriptional and phenotypic analysis of oral mucosal and skin cells.^95–98 Healing of the oral mucosa is explored in depth in a review article by Griffin et al. in this issue, “Understanding Scarring in the Oral Mucosa.”⁹⁹

Existing scar products: topicals and dressings

While a huge consumer market exists for products that claim to prevent or reduce scarring, robust clinical evidence supporting these claims is largely lacking, even for the most commonly used products. Topical products are understandably popular due to their ease of use and noninvasiveness. For example, onion extract products (such as Mederma^®; Merz Pharmaceuticals, Greensboro, NC)—one of the top selling “anti-scarring” products—claim to flatten and improve the appearance of surgical scars.¹⁰⁰ While onion extract does contain multiple components that reduce profibrotic cell activity in vitro, clinical trial results have been decidedly mixed, and there is limited evidence to support significant efficacy.¹⁹ Silicone gel sheeting is another product commonly recommended for flattening/reducing scars. While clinical studies do seem to agree that silicone sheeting helps in scar reduction, its primary mechanism seems to be preventing evaporative water loss and thus maintaining a more hydrated wound/scar environment, and multiple studies have shown that nonsilicone options (e.g., nonsilicone occlusive/gel dressings) are equally effective.¹⁰¹ While for many popular scar products individual studies can be identified that seem to support efficacy, literature reviews and meta-analyses agree that the large majority of scar treatment studies are flawed/of generally low quality, and thus, the level of evidence is low for most treatments.¹⁹

There are many possible reasons why treatments that seem promising in preclinical or early-stage clinical studies may ultimately be ineffective. An overarching issue is the complexity of the wound healing process. For instance, many attempted therapies are based on the premise that reducing inflammation will reduce scarring. This is consistent with the fact that multiple examples of regenerative healing—including both fetal and oral mucosal wound healing—exhibit minimal inflammation. But anti-inflammatory therapies such as local corticosteroids have inconsistent efficacy for typical scars, and in many cases have side effects (such as atrophy) that may outweigh their benefits.⁶⁹ However, while such drugs broadly inhibit the inflammatory response, not all immune cells are created equal. New basic science methods have allowed us to understand the heterogeneity of wound cells and their distinct functions at unprecedented depth. It is possible that a more precisely targeted approach could inhibit the specific factors that drive scarring, while allowing potentially beneficial wound processes to still function. Two articles in this issue— “Mechanical Strain Drives Myeloid Cell Differentiation Toward Proinflammatory Subpopulations (Ex Vivo Model),” by Chen et al., and “Deferoxamine to Minimize Fibrosis During Radiation Therapy,” by Tevlin et al. —explore the possibility of targeting specific wound cell populations or molecular processes toward encouraging effective tissue repair with minimal fibrosis.^102,103

Cell-based approaches

Autologous cell-based treatments, often marketed as “stem cell therapies,” are an emerging therapeutic approach for both under- and over-healing problems. Fat is most commonly used as a cell source, as it is readily accessible from most patients in large quantities and contains adipose-derived stem cells, a type of mesenchymal stem cell (MSC) with multipotent differentiation potential.¹⁰⁴ Interestingly, recent basic science studies have shown that fat cells (adipocytes) may also directly contribute to wound repair by differentiating into ECM-producing fibroblasts,¹⁰⁵ although it remains to be seen whether adipocytes within fat grafts also exhibit such behavior. Fat grafting and MSC-based therapies are being explored for their potential utility in both encouraging healing of challenging wounds (such as burns or diabetic ulcers)^106,107 and treating scars.^108–110 MSCs are thought to serve a therapeutic function primarily by acting as a source of trophic factors and immune-modulatory signals for wound-resident cells.¹¹⁰ While transplantation of MSCs seems to be a promising wound and scar treatment, there are difficulties inherent to autologous cell treatments, including the need to isolate cells from every individual patient. To circumvent this challenge, researchers have shown that MSC products, such as extracellular vesicles derived from MSCs, may have similar efficacy as the cells themselves.¹¹¹ In this issue, the original article “Decellularized Adipose Matrices Can Alleviate Radiation-Induced Skin Fibrosis” by Adem et al. explores a potential application of Renuva^® (MTF Biologics, Edison, NJ)—a decellularized adipose tissue allograft that contains proteins and growth factors found in fat—in encouraging regeneration in the setting of irradiated skin.¹¹²

Mechanically targeted approaches for fibrosis

Physical tension has long been known to contribute to scarring. For instance, surgeons will classically make their incisions along the skin's natural minimal tension lines (“Langer's lines”) to minimize mechanical strain on the resulting wound. Targeting mechanical tension has proven to be an effective strategy for reducing scarring. Paper tape has been used to reduce tension across healing wounds to prevent hypertrophic scarring.¹¹³ More recently, the embrace^® device (Neodyne Biosciences, Newark, CA), a dressing designed to actively off-load tension across incisions and other wounds, was shown in multiple clinical trials to significantly reduce postoperative scarring.^114–116

Cells sense and communicate their mechanical environment through cell surface proteins called integrins and key molecular signaling (“mechanotransduction”) pathways. Blocking mechanotransduction signaling through small molecule drugs may represent an effective approach for reducing scarring, as it could have a similar effect to physically reducing tension at the tissue level. In their article in this issue, “Modulating Cellular Responses to Mechanical Forces to Promote Wound Regeneration,” Mascharak et al. review current knowledge and approaches being investigated to target cellular mechanical signaling to prevent fibrosis and induce regeneration.¹¹⁷

Small molecule drug approaches are especially promising as, unlike dressings, they are not limited only to accessible regions of the skin. Fibrosis can affect not only the skin but also virtually every organ in the body and causes a substantial burden of disease, as fibrotic processes are collectively responsible for an estimated 45% of all deaths in the United States.¹¹⁸ A large body of evidence supports the concept that at least some underlying drivers and mechanisms of fibrosis are conserved between different tissues in the body.^119–121 Thus, developing targeted molecular therapies for scarring could have implications for treatment of fibroses in other organs. A mechanically-targeted approach for lung fibrosis is explored in this issue in the article by Trotsyuk et al., “Inhibiting Fibroblast Mechanotransduction Modulates Severity of Idiopathic Pulmonary Fibrosis.”¹²²

SUMMARY

Wound healing represents an enormous biomedical burden with a huge associated market for treatments. However, despite the fact that billions of dollars are spent every year on wound and scar treatments in the United States alone, no truly effective therapies exist for either chronic wounds or scar prevention. Both “under-healing” (chronic wounds) and “over-healing” (normal and pathological scarring) affect large segments of the population, often with devastating consequences: under-healing can lead to infection, amputation, and death, while over-healing leaves patients with lifelong scars that can impede form and function. An ideal therapy would result in effective wound regeneration with regeneration of skin's normal properties and without a fibrotic scar. In this review, we survey the current state of knowledge in both under- and over-healing wound problems, as well as emerging research directions. This article serves as an introduction to this Forum issue of Advances in Wound Care, in which original research and review articles will delve deeper into topics discussed here.

TAKE-HOME MESSAGES

• Wound healing is an enormous issue in the United States and worldwide.

• Both “under-healing” (i.e., chronic/nonhealing wounds) and “over-healing” (i.e., scarring, including hypertrophic scarring and keloids) are clinical problems with a massive biomedical and financial burden in the United States.

• An ideal wound therapy would promote effective wound healing through regeneration of normal skin, rather than scarring.

• Current therapies for both under- and over-healing wounds are largely conservative (e.g., occlusive dressings, physical off-loading for foot ulcers, exercise based therapy for venous ulcers). While these approaches may help to encourage favorable wound healing by resolving underlying issues (such as poor vascular supply), they are only moderately effective, and patient compliance is a significant obstacle.

• No targeted therapies currently exist that can produce regenerative healing outcomes. A molecular therapy capable of improving wound healing could theoretically save medical systems and patients billions of dollars in costs by preventing wound and scar complications.

• Ongoing basic science research focuses on understanding the fundamental mechanisms of wound repair and scarring, with the goal of identifying specific factors (such as cellular mechanical signaling or inflammatory cell populations) that contribute to problematic wound outcomes such as scarring or nonhealing.

• Better understanding the mechanistic drivers of wound healing problems may enable the development of more precisely targeted treatments to improve wound outcomes.

Abbreviations and Acronyms

DFU

diabetic foot ulcer

ECM

extracellular matrix

FDA

Food and Drug Administration

MSC

mesenchymal stem cell

rhPDGF-BB

recombinant human platelet-derived growth factor, BB homodimer

TGF-β

transforming growth factor beta

WEF-CEP

Wound Care Experts/FDA Clinical Endpoint Project

AUTHORS' CONTRIBUTIONS

H.E.d.J.-P. wrote the article. G.G., D.C.W., and M.T.L. edited the article.

ACKNOWLEDGMENTS AND FUNDING SOURCES

None declared. This work was supported by the Hagey Laboratory for Pediatric Regenerative Medicine (to Geoffrey C. Gurtner, Derrick C. Wan, Michael T. Longaker).

AUTHOR DISCLOSURE STATEMENT

M.T.L. and G.G. are cofounders of, have equity positions in, and are on the Board of Directors of Neodyne Biosciences, Inc., which developed the embrace device. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in this article. The content of this article was written entirely by the authors listed. No ghostwriters were involved in the writing of this article.

ABOUT THE AUTHORS

Heather E. desJardins-Park, AB is an MD/PhD student at the Stanford School of Medicine in the Stem Cell Biology and Regenerative Medicine graduate program. Geoffrey C. Gurtner, MD is the Johnson & Johnson Professor of Surgery and Inaugural Vice Chairman of Surgery for Innovation at Stanford. Derrick C. Wan, MD is Professor of Surgery (Plastic and Reconstructive Surgery) at Stanford. Michael T. Longaker, MD, MBA is Deane P. and Louise Mitchell Professor of Surgery and Co-Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford.