Chronic Skin Wounds
ICD-10 Code E11.621, E11.622, E10.621, E10.622, L89.154, L89.314, L89.622, L89.94, I70.231, I70.261, and L91.0
What is the clinical spectrum of chronic skin wounds?
Chronic skin wounds, such as ulcers and non-healing surgical wounds, are defined as persistent tissue injuries that cannot be treated with conventional methods.
Common features of chronic wounds include tissue degradation, excessive inflammation, fibrosis, necrosis, and persistent infections. Marked by local inflammation, swelling, erythema, or pain, the course of skin infection can range from microbial colonization without affecting healing to sepsis and organ dysfunction.
Skin ulcers are lesions involving loss of epidermal, and often dermal tissue, due to pressure, ischemia/venous disease or neuropathy. An example of chronic skin ulcer with debilitating consequences is diabetic foot ulcer, that poses an estimated lifetime risk of up to 30% for type 1 and 2 diabetes patients. Frequently recurring after initial healing, diabetic foot ulcers precede the majority of amputations in this patient population.
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What do we know about the etiology of chronic skin wounds?
Skin ulcers are often distinguished as vascular, diabetic neuropathy, and pressure ulcers. This executive summary focuses on diabetic skin ulcers. For a full analysis, including other chronic skin wound types, explore your access options.
Impaired wound healing in diabetes is driven by hyperglycemia, chronic inflammation, circulatory dysfunction, hypoxia, autonomic and sensory neuropathy, and impaired neuropeptide signaling.
Alongside other mechanisms of actions, hyperglycemia thickens capillary basement membranes through glycation of structural proteins, excessive ECM deposition, and reduced ECM degradation, thus impairing the delivery of oxygen, nutrients, macrophages, and neutrophils to skin repair cells. Additionally, hyperglycemia increases nerve-damaging sorbitol accumulation and ROS, driving nerve damage that produces loss of pain sensation and pressure detection in diabetic neuropathy patients.
Hyperglycemia-induced ischemia–reperfusion injury further worsens tissue damage by facilitating ROS production, inflammation, vascular leakage and capillary obstruction. The hyperglycemic milieu promotes biofilm formation, which enhance bacterial resistance to antimicrobial agents and to immune clearance, leading to chronic inflammation, and impaired wound healing.
Patient-specific genetic background, immune status, lifestyle and burden of comorbidities, all play a part in heterogeneity of chronic skin wound phenotype and pathomechanisms, underscoring the need for a personalized approach to therapy.
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How similar are human and animal skins?
Below are some of the examples of inter-species differences that negatively affect the face, construct, and predictive validity of animal models of chronic skin wounds.
Species-specific differences in skin anatomy and physiology
The human skin differs anatomically, physiologically, and biochemically from skin in other mammals, producing inter-species differences in wound healing features and mechanisms. For instance, contrarily to mice, rats, and rabbits, humans and pigs are tight-skinned. Compared to the human skin, the pig skin shows poor vascularization of cutaneous glands, extensive deposition of adipose tissue below the hypodermis, high levels of alkaline phosphatase in its supra-basal layers and a denser stratum corneum.
Species-specific differences in skin repair
Wound healing characteristics differ dramatically between humans and model organisms, producing inter-species differences in healing kinetics and functional restoration. For example, the human skin repair relies primarily on re‑epithelialization and granulation. By contrast, many other commonly employed model organisms, including rats, mice, rabbits, cats, dogs, macaques, and marmosets, rely on contraction.
Species-specific differences in skin regeneration
Due to inter-species differences in cell cycle kinetics, migration and differentiation rates, and regulatory signals, the epidermal renewal cycle is about three times faster in rodents than in humans. The density of epidermal stem cells in the basal layer is higher in rodents compared to humans, which can influence niche signaling and thereby the frequency of mitotic divisions. These rodent features are likely to contribute to a higher rate and quality of skin regeneration compared to humans.
Species-specific differences in skin immunity
The human immune system possesses species-specific features that cannot be faithfully recapitulated in animal models. For instance, in humans, the vast majority of epidermal CD4 and CD8 T cells are αβ T cells that carry a T cell receptor made of α and β chains. In contrast, mouse and rat epidermal T cells almost all have γδ chains. As for pigs, the percentage of resident γδ T cells is about five-fold higher than in humans. This inter-species difference has functional consequences, since αβ T cells require classical antigen presentation, whereas γδ T cells have a rapid innate-like activation enabling a faster re-epithelialization.
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Face validity - How well do animal models replicate the human disease phenotype?
Animal models tend to mimic acute healing wounds but are not representative of human chronic non-healing skin wounds. The most commonly used model organisms in wound healing impairment studies are mice, rats, rabbits, and pigs.
Diabetic wound models - In animal models of diabetic wounds, type 1 (T1DM) or type 2 diabetes (T2DM) are induced through chemical, spontaneous/selective breeding, diet, and genetic methods, followed by excisional founds or ischemic flaps. Typically, T1DM is chemically induced in rats, mice or pigs by single or multiple administration of streptozotocin (STZ). NOD mice and BB rats were frequently employed to model T1DM, while db/db mice, ob/ob mice, and Zucker diabetic fatty rats were routinely used in the context of T2DM studies.
However, in contrast to diabetic patients who develop chronic skin ulcers, the experimentally-induced skin wounds healed in mouse models of diabetes. Moreover, none of these models recapitulated the processes of segmental demyelination, axon loss and fiber loss related to diabetic ulcers. Degenerative neuropathy was minimal even in diabetic dogs and NHP. In the STZ-induced pig model of diabetic ulcer, a delay in healing was noted, nevertheless, the wounds healed after 18 days, which is not consistent with the persistence of diabetic wounds in humans.
Ischemic wound models - To study vascular occlusion and diabetic angiopathy, an ischemic foot rat model was created by hyperglycemia induction through STZ, followed by ischemia in the limb induction through resection of the external iliac, femoral, and saphenous arteries. This approach produced acute ischemic necrosis but without chronic non-healing ulcers typical of diabetic foot ulcers. A systematic review of animal studies in which ischemia was induced through ligation of the femoral/iliac/saphenous arteries suggested that the majority of hindlimb ischemia animal studies was not clinically relevant.
Biofilm-infected wound models - In a combined infected-diabetic wound pig model, STZ injection was followed by full-thickness excisional wounding and wound inoculation with Staphylococcus aureus. While the degree of epithelialization was significantly delayed compared to non-inoculated diabetic wounds, in contrast to human non-healing diabetic ulcers, inoculated wounds showed substantial re-epithelialization.
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Construct validity - How well do the mechanisms of disease induction in animals reflect the currently understood etiology of the human disease?
Animal models of chronic skin wounds do not recapitulate the complex mechanisms of chronic skin wound pathogenesis in humans, further diminishing their translational value.
Diabetic wound models - The existence of significant inter-species differences in genetics, pancreatic islets structure and function, glucose regulation, metabolic rates, feeding patterns, diet, immunity, and microbiome makes it very difficult to recapitulate in animal models of diabetes the complex processes responsible for human diabetic ulcer chronicity. For example, the mutations that cause diabetes-like symptoms in ob/ob and db/db mice are not representative of the genetic causes of human diabetes. In the same manner, unlike in human T1DM, the Akita mouse pathophysiology is not related to an autoimmune process, hindering investigation of the effect of dysregulated immune response in diabetic ulcers. While the BB rat displays spontaneous autoimmune destruction of beta cells, it is also associated with T-lymphopenia, which is not a hallmark of diabetic skin ulcers in humans. In addition, chemical induction of diabetes through direct cytotoxic action of glucose analogue STZ does not replicate the underlying pathophysiology of either T1DM (autoimmunity) or T2DM (insulin resistance).
Ischemic wound models - In humans, chronicity of wounds arises from a complex interplay of chronic low-grade ischemia, peripheral arterial disease, microvascular dysfunction, neuropathy, repeated trauma, biofilm-dominated infection, and systemic diseases. These factors cannot be simultaneously reproduced in model organisms and not in a manner that faithfully recapitulates human-relevant mechanisms of each systemic condition.
Biofilm-infected wound models - Animal models of bacterial infection often rely on monomicrobial inoculations that do not mimic human-relevant polymicrobial synergy and pathogen-host interactions. The mechanisms of human chronic conditions that can influence biofilm formation, whether it is through poor oxygenation, impaired immune cell function, or chronic inflammation, are not faithfully recapitulated in animal models.
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Predictive validity - How well do animal models predict safety and efficacy of therapies in patients?
To date, the standard of care for chronic wounds typically comprises debridement, wound dressings, pressure relief and managing underlying comorbidities. Based on meta-analyses and systemic reviews of randomized control trials, supplementary treatment options, such as advanced impregnated dressings, drugs, negative pressure wound therapy, and skin substitutes, enable in average 10-30% absolute increase in complete healing rates compared to standard of care alone.
Because animal models do not reproduce the complex pathophysiology of human chronic skin wounds, drugs that perform well preclinically have extremely rarely translated into clinical efficacy. In the past three decades of research, only one drug for this indication, Regranex, was clinically approved by the FDA. Indicated for lower‑extremity diabetic neuropathic ulcers, it is a topical gel containing recombinant human platelet‑derived growth factor‑BB (rhPDGF‑BB). By promoting the chemotactic recruitment and proliferation of cells involved in wound repair, rhPDGF‑BB enhanced the formation of granulation tissue in several animal wound‑healing models, including in db/db mouse, pig, and rabbit ear skin excision models.
Nonetheless, Regranex does not address the underlying disease mechanisms and recurrences remain high in a significant portion of patients. Notably, 40% of patients diabetic ulcers have a recurrence within 1 year, almost 60% within 3 years, and 65% within 5 years. Novel, effective medication remains badly needed to improve the quality of life of patients with ulcers, prevent amputations and reduce mortality.
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Ethical validity - How well do animal experiments align with human ethical principles?
Preclinical - Animal research is unethical in essence by human standards, since it involves physical constraint, psychological suffering and deprivation of freedom, social interactions, natural environment, and life purpose. In addition to this baseline, experiments inflict severe clinical harm in animals.
Clinical - Statistics consistently show that clinical success rates of drugs developed and tested in animals is very low, raising the question of whether it is ethical to put the health of patients at risk.
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Intrinsic validity - How well do animal models capture the clinical heterogeneity of the human disease?
Animal models do not capture the inter‑individual variability in comorbidities, age, disease duration, immune status nor do they recapitulate the heterogeneity of human chronic skin wounds phenotype, pathophysiology and responses to therapies.
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Extrinsic validity - How well does animal experimentation generate reliable and reproducible outcomes?
Contributing factors include flawed experimental design, variation in animal strains and experimental conditions, and lack of transparency on methodology and results of animal studies. In spite of significant investment in dissemination, various incentives and training of animal researchers, the ARRIVE - Animal Research: Reporting of In Vivo Experiments - guidelines remain poorly implemented and the majority of animal experiments is irreproducible. While in vitro methods are not immune to issues of reproducibility, the moral weight of irreproducible animal studies is not the same.
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Key takeaways
Chronic skin wound is a debilitating condition with potentially severe long-term consequences, ranging from amputation to mortality. Its heterogeneity in etiology and pathophysiology is linked to a multitude of intrinsic and extrinsic contributing factors that play a part in impairment of normal wound healing processes.
Modelling of persistent wounds in vivo produces particularly severe symptoms in model organisms. Yet, animal models of chronic skin wounds are widely recognized as inadequate and have rarely translated to effective therapies for humans. This result can be explained by numerous human-specific features of skin physiology that underly wound healing impairment.
Novel pharmaceutical agents are needed to enhance wound healing and prevent relapse in patients with diabetic ulcers. Research using advanced human-based in vitro systems will allow to more faithfully recapitulate the molecular and cellular drivers of chronic wounds, better understand its heterogenous pathophysiology, and develop personalized therapies.
How is Human-Based In Vitro the Answer to Advance Biomedical Research into Chronic Skin Wounds
The following section explores how advanced human-based in vitro technologies can be leveraged to develop effective therapies for patients suffering from diabetic skin ulcers. It features 20 suggestions and examples of in vitro approaches, including employing human ex vivo skin models to investigate the mechanisms of chronic skin wound healing dynamics and kinetics, employing hiPSC-derived hair-bearing skin organoids to determine the role of hair‑follicle stem cells in regeneration, simulating hyperglycemic conditions in a human immunocompetent microvascularized peripheral nervous system microfluidic device to study the mechanisms of diabetic peripheral neuropathy, and mapping transcriptional signatures of human skin fibroblast populations to develop targeted therapies.
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