Multi‐dimensional models for functional testing of keloid scars: In silico,in vitro,organoid, organotypic,ex vivo organ culture,and in vivo models

Keloid scars are described as benign fibro‐proliferative dermal outgrowths that commonly occur in pigmented skin post cutaneous injury, and continue to grow beyond the boundary of the original wound margin. There is a lack of thorough understanding of keloid pathogenesis and thus keloid therapeutic options remain ill‐defined. In view of the poor response to current therapy and high recurrence rates, there is an unmet need in improving our knowledge and therefore in identifying targeted and effective treatment strategies in management of keloids. Keloid research however, is hampered by a lack of relevant animal models as keloids do not spontaneously occur in animals and are unique to human skin. Therefore, developing novel animal models and nonanimal models for functional evaluation of keloid cells and tissue for better understanding their pathobiology and response to putative candidate therapies are essential. Here, we present the key concepts and relevant emerging research on two‐dimensional and three‐dimensional cell and tissue models for functional testing of keloid scars. We will describe in detail current models including in vitro mono‐ and co‐cultures, multi‐cellular spheroids (organoids) and organotyopic cultures, ex vivo whole skin keloid tissue organ culture models as well as in vivo human patient models. Finally, we discuss the role played by time as the fourth dimension in a novel model that involves sequential temporal biopsies of human patients with keloids (a so called 4D in vivo human model). The use of these unique models will no doubt prove pivotal in identification of new drug targets as well as biomarkers, in functional testing of emerging novel therapeutics, and in enhancing our understanding of keloid disease biology.     

Experimental models for cutaneous hypertrophic scar research

Human skin wound repair may result in various outcomes with most of them leading to scar formation. Commonly seen in many cutaneous wound healing cases, hypertrophic scars are considered as phenotypes of abnormal wound repair. To prevent the formation of hypertrophic scars, efforts have been made to understand the mechanism of scarring following wound closure. Numerous in vivo and in vitro models have been created to facilitate investigations into cutaneous scarring and the development of antiscarring treatments. To select the best model for a specific study, background knowledge of the current models of hypertrophic scars is necessary. In this review, we describe in vivo and in vitro models for studying hypertrophic scars, as well as the distinct characteristics of these models. The choice of models for a specific study should be based on the characteristics of the model and the goal of the study. In general, in vivo animal models are often used in phenotypical scar formation analysis, development of antiscarring treatment, and functional analyses of individual genes. In contrast, in vitro models are chosen to pathway identification during scar formation as well as in high‐throughput analysis in drug development. Besides helping investigators choose the best scarring model for their research, the goal of this review is to provide knowledge for improving the existing models and development of new models. These will contribute to the progress of scarring studies.     

Optical coherence tomography for assessment of epithelialization in a human ex vivo wound model

The ex vivo human skin wound model is a widely accepted model to study wound epithelialization. Due to a lack of animal models that fully replicate human conditions, the ex vivo model is a valuable tool to study mechanisms of wound reepithelialization, as well as for preclinical testing of novel therapeutics. The current standard for assessment of wound healing in this model is histomorphometric analysis, which is labor intensive, time consuming, and requires multiple biological and technical replicates in addition to assessment of different time points. Optical coherence tomography (OCT) is an emerging noninvasive imaging technology originally developed for noninvasive retinal scans that avoids the deleterious effects of tissue processing. This study investigated OCT as a novel method for assessing reepithelialization in the human ex vivo wound model. Excisional ex vivo wounds were created, maintained at air‐liquid interface, and healing progression was assessed at days 4 and 7 with OCT and histology. OCT provided adequate resolution to identify the epidermis, the papillary and reticular dermis, and importantly, migrating epithelium in the wound bed. We have deployed OCT as a noninvasive tool to produce, longitudinal “optical biopsies” of ex vivo human wound healing process, and we established an optimal quantification method of re‐epithelialization based on en face OCT images of the total wound area. Pairwise statistical analysis of OCT and histology based quantifications for the rate of epithelialization have shown the feasibility and superiority of OCT technology for noninvasive monitoring of human wound epithelialization. Furthermore, we have utilized OCT to evaluate therapeutic potential of allogeneic adipose stem cells revealing their ability to promote reepithelialization in human ex vivo wounds. OCT technology is promising for its applications in wound healing and evaluation of novel therapeutics in both the laboratory and the clinical settings.     

Optimization of an ex vivo wound healing model in the adult human skin: Functional evaluation using photodynamic therapy

Limited utility of in vitro tests and animal models of human repair, create a demand for alternative models of cutaneous healing capable of functional testing. The adult human skin Wound Healing Organ Culture (WHOC) provides a useful model, to study repair and enable evaluation of therapies such as the photodynamic therapy (PDT). Thus, the aim here was to identify the optimal WHOC model and to evaluate the role of PDT in repair. Wound geometry, system of support, and growth media, cellular and matrix biomarkers were investigated in WHOC models. Subsequently, cellular activity, extracellular matrix remodeling, and oxidative stress plus gene and protein levels of makers of wound repair measured the effect of PDT on the optimized WHOC. WHOCs embedded in collagen and supplemented DMEM were better organized showing stratified epidermis and compact dermis with developing neo‐epidermis. Post‐PDT, the advancing reepithelialization tongue was 3.5 folds longer, and was highly proliferative with CK‐14 plus p16 increased (p < 0.05) compared to controls. The neo‐epidermis was fully differentiated forming neo‐collagen. Proliferating nuclear antigen, p16, COLI, COLIII, MMP3, MMP19, and α‐SMA were significantly more expressed (p < 0.05) in dermis surrounding the healing wound. In conclusion, an optimal model of WHOC treated with PDT shows increased reepithelialization and extracellular matrix reconstruction and remodeling, supporting evidence toward development of an optimal ex vivo wound healing model.     

Utility of a human–mouse xenograft model and in vivo near‐infrared fluorescent imaging for studying wound healing

To study the complex cellular interactions involved in wound healing, it is essential to have an animal model that adequately mimics the human wound microenvironment. Currently available murine models are limited because wound contraction introduces bias into wound surface area measurements. The purpose of this study was to demonstrate utility of a human–mouse xenograft model for studying human wound healing. Normal human skin was harvested from elective abdominoplasty surgery, xenografted onto athymic nude (nu/nu) mice, and allowed to engraft for 3 months. The graft was then wounded using a 2‐mm punch biopsy. Wounds were harvested on sequential days to allow tissue‐based markers of wound healing to be followed sequentially. On the day of wound harvest, mice were injected with XenoLight RediJect cyclooxygenase‐2 (COX‐2) probe and imaged according to package instructions. Immunohistochemistry confirms that this human–mouse xenograft model is effective for studying human wound healing in vivo. Additionally, in vivo fluorescent imaging for inducible COX‐2 demonstrated upregulation from baseline to day 4 (P = 0·03) with return to baseline levels by day 10, paralleling the reepithelialisation of the wound. This human–mouse xenograft model, combined with in vivo fluorescent imaging provides a useful mechanism for studying molecular pathways of human wound healing.     

Treatment of aged wound healing models with FGF2 and ABT-737 reduces the senescent cell population and increases wound closure rate

Delayed tissue repair in the aged presents a major socio-economic and clinical problem. Age-associated delay in wound healing can be attributed to multiple factors, including an increased presence of senescent cells persisting in the wound. Although the transient presence of senescent cells is physiologic during the resolution phase of normal healing, increased senescent cell accumulation with age can negatively impact tissue repair. The objective of the study was to test interventional strategies that could mitigate the negative effect of senescent cell accumulation and possibly improve the age-associated delay in wound healing. We utilised a 3D in vitro senescent fibroblast populated collagen matrix (FPCM) to study cellular events associated with senescence and delayed healing. Senescent fibroblasts showed an increase in anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins. We hypothesized that reducing the senescent cell population and promoting non-senescent cell functionality would mitigate the negative effect of senescence and improve healing kinetics. BCL-2 inhibition and mitogen stimulation (FGF2) improved healing in the in vitro senescent models. These results were confirmed with an ex vivo human skin biopsy model. These data suggested that modulation of the senescent cell population with soluble factors improved the healing outcome in our in vitro and ex vivo healing models.     

The effect of pH on cell viability,cell migration,cell proliferation,wound closure,and wound reepithelialization: In vitro and in vivo study

Wound microenvironment plays a major role in the process of wound healing. It contains various external and internal factors that participate in wound pathophysiology. The pH is an important factor that influences wound healing by changing throughout the healing process. Several previous studies have investigated the role of pH in relation to pathogens but studies concentrating on the effects of pH on wound healing itself are inconclusive. The purpose of this study was to comprehensively and in a controlled fashion investigate the effect of pH on wound healing by studying its effect on human primary keratinocyte and fibroblast function in vitro and on wound healing in vivo. In vitro, primary human keratinocytes and fibroblasts were cultured in different levels of pH (5.5–12.5) and the effect on cell viability, proliferation, and migration was studied. A rat full‐thickness wound model was used to investigate the effect of pH (5.5–9.5) on wound healing in vivo. The effect of pH on inflammation was monitored by measuring IL‐1 concentrations from wounds and cell cultures exposed to different pH environments. Our results showed that both skin cell types tolerated wide range of pH very well. They further demonstrated that both acidic and alkaline environments decelerated cell migration in comparison to neutral environments and interestingly alkaline conditions significantly enhanced cell proliferation. Results from the in vivo experiments indicated that a prolonged, strongly acidic wound environment prevents both wound closure and reepithelialization while a prolonged alkaline environment did not have any negative impact on wound closure or reepithelialization. Separately, both in vitro and in vivo studies showed that prolonged acidic conditions significantly increased the expression of IL‐1 in fibroblast cultures and in wound fluid, whereas prolonged alkaline conditions did not result in elevated amounts of IL‐1 .     

Cadexomer iodine effectively reduces bacterial biofilm in porcine wounds ex vivo and in vivo

Biofilms are prevalent in non‐healing chronic wounds and implicated in delayed healing. Tolerance to antimicrobial treatments and the host's immune system leave clinicians with limited interventions against biofilm populations. It is therefore essential that effective treatments be rigorously tested and demonstrate an impact on biofilm across multiple experimental models to guide clinical investigations and protocols. Cadexomer iodine has previously been shown to be effective against biofilm in various in vitro models, against methicillin‐resistant Staphylococcus aureus biofilm in mouse wounds, and clinically in diabetic foot ulcers complicated by biofilm. Similarities between porcine and human skin make the pig a favoured model for cutaneous wound studies. Two antiseptic dressings and a gauze control were assessed against mature biofilm grown on ex vivo pig skin and in a pig wound model. Significant reductions in biofilm were observed following treatment with cadexomer iodine across both biofilm models. In contrast, silver carboxymethylcellulose dressings had minimal impact on biofilm in the models, with similar results to the control in the ex vivo model. Microscopy and histopathology indicate that the depth of organisms in wound tissue may impact treatment effectiveness. Further work on the promising biofilm efficacy of cadexomer iodine is needed to determine optimal treatment durations against biofilm.     

Exogenous CLASP2 protein treatment enhances wound healing in vitro and in vivo

Proliferative and migratory abilities of fibroblasts are essential for wound healing at the skin surface. Cytoplasmic linker‐associated protein‐2 (CLASP2) was originally found to interact with cytoplasmic linker protein (CLIP)‐170. CLASP2 plays an important role in microtubule stabilization and the microtubule‐stabilizing activity of CLASP2 depends on its interactions with end binding (EB)‐1 and CLIP‐170. Although the microtubule‐stabilizing role of CLASP2 is well established, the effects of CLASP2 on the migration and proliferation of fibroblasts remain unclear in the context of wound healing. Therefore, we tested the utilization of CLASP2 as a directly applied protein drug to improve wound healing by promoting the migration of effector cells, including skin fibroblasts, to the site of repair or injury using an in vivo excisional wound mouse model and in vitro Hs27 skin fibroblast model. Epidermal growth factor, which is a recognized contributor to cell proliferation and migration, was used as positive control. In vitro and in vivo, CLASP2 treatment significantly enhanced cell migration and accelerated wound closure. Furthermore, in vivo, the CLASP2‐treated animal group displayed enhanced epidermal repair and collagen deposition. Next, we studied the mechanism of CLASP2 for wound healing. Increasing the abundance of intracellular free CLASP2 in skin fibroblasts by supplying exogenous CLASP2 seemed to stabilize microtubules through an interaction between CLASP2 and CLIP‐170, as well as EB1. Exogenous CLASP2 also showed direct binding with IQGAP1, increasing both cyclic adenosine monophosphate activity and phosphorylation of glycogen synthase kinase 3β, which in turn reinstated the binding between free CLASP2 and IQGAP1. In summary, exogenous CLASP2 increased Hs27 skin fibroblast migration by interacting with IQGAP1 and other cytoskeletal linker proteins, such as CLIP‐170 and EB1. Our results strongly suggest that CLASP2 can be developed in wound healing drugs for skin repair and/or regenerating cosmetic products.     

Fluorescent cell tracer dye permits real‐time assessment of re‐epithelialization in a serum‐free ex vivo human skin wound assay

Ex vivo wounded human skin organ culture is an invaluable tool for translationally relevant preclinical wound healing research. However, studies incorporating this system are still underutilized within the field because of the low throughput of histological analysis required for downstream assessment. In this study, we use intravital fluorescent dye to lineage trace epidermal cells, demonstrating that wound re‐epithelialization of human ex vivo wounds occurs consistent with an extending shield mechanism of collective migration. Moreover, we also report a relatively simple method to investigate global epithelial closure of explants in culture using daily fluorescent dye treatment and en face imaging. This study is the first to quantify healing of ex vivo wounds in a longitudinal manner, providing global assessments for re‐epithelialization and tissue contraction. We show that this approach can identify alterations to healing with a known healing promoter. This methodological study highlights the utility of human ex vivo wounds in enhancing our understanding of mechanisms of human skin repair and in evaluating novel therapies to improve healing outcome.     

Cutaneous wound healing: myofibroblastic differentiation and in vitro models

Wound healing is an interactive, dynamic 3-phased process. During the formation of granulation tissue, many fibroblastic cells acquire some morphological and biochemical smooth muscle features and are called myofibroblasts. Myofibroblasts participate in both granulation tissue formation and remodeling phases. Excessive scarring, which is a feature of impaired healing, is a serious health problem that may affect the patient's quality of life. The treatment costs of such lesions are high, and often, the results are unsatisfactory. To understand the wound healing process better and to promote improvement in human healing, models are needed that can predict the in vivo situation in humans. In vitro models allow the study of cell behavior in a controlled environment. Such modeling partitions and reduces to small scales behavior perceived in vivo. This article is focused on "fibroblasts". In vitro models to study wound healing, the role of (myo)fibroblasts, and skin reconstruction in tissue replacement and promotion of wound healing are discussed.     

Fetal mouse skin heals scarlessly in a chick chorioallantoic membrane model system

In mammals, the early-gestation fetus has the regenerative ability to heal skin wounds without scar formation. This observation was first reported more than 3 decades ago, and has been confirmed in a number of in vivo animal models. Although an intensive research effort has focused on unraveling the mechanisms underlying scarless fetal wound repair, no suitable model of in vitro fetal skin healing has been developed. In this article, we report a novel model for the study of fetal wound healing. Fetal skin from gestational day 16.5 Balb/c mice (total gestation, 20 days) was grafted onto the chorioallantoic membrane of 12-day-old chicken embryos and cultured for up to 7 days. At 48 hours postengraftment, circular wounds (diameter = 1 mm) were made in the fetal skin using a rotating titanium sapphire laser (N = 45). The tissue was examined daily by visual inspection to look for signs of infection and ischemia. The grafts and the surrounding host tissue were examined histologically. In all fetal skin grafts, the wounds completely reepithelialized by postinjury day 7, with regeneration of the dermis. Fetal mouse skin xenografts transplanted onto the chorioallantoic membrane of fertilized chicken eggs provides a useful model for the study of fetal wound healing. This model can be used as an adjunct to traditional in vivo mammalian models of fetal repair.     

Inhibition of bone morphogenetic protein signalling promotes wound healing in a human ex vivo model

Background

Bone morphogenetic proteins (BMPs) and their receptors (BMPRs) play roles in embryonic development and postnatal remodelling of the skin. Many indications suggest that BMP signalling regulates keratinocyte proliferation and differentiation. Chronic wounds have been shown to exhibit high levels of BMP ligands; however, the effect of BMP pathway modulation on human skin healing remains undefined.

Methods

A human ex vivo skin wound healing model was used to analyse the expression of BMP signalling pathway components during healing and to investigate the effects of BMPs and the BMP antagonist Noggin on skin repair. Additionally, the effects of BMP signalling on keratinocyte proliferation, apoptosis and migration were tested using in vitro flow cytometry and ‘scratch’ migration assays, respectively.

Results

BMP receptor-1B (BMPR-1B) and downstream signalling protein phosphorylated-Smad-1/5/8 were highly expressed in healing epidermis. Treatment of human skin with exogenous BMPs impaired wound closure by reducing keratinocyte proliferation and increasing apoptosis. The BMP antagonist Noggin negated the inhibitory effects of BMP ligands, and when used alone, Noggin reduced keratinocyte apoptosis in the wound bed. In vitro, BMP ligands suppressed keratinocyte proliferation whilst Noggin stimulated proliferation. Keratinocyte migration was slowed following BMP treatment; in contrast, migration was significantly accelerated due to inhibition of BMP activity by either Noggin or BMPR-1B silencing.

Conclusions

BMP signalling is inherently involved in wound healing. BMPs slow skin repair by suppressing keratinocyte proliferation and migration. Thus, modulation of BMP signalling using BMP inhibitors such as Noggin may serve as a new approach to promote cutaneous wound repair.Level of evidence: Not ratable.

     

Green light emitting diodes accelerate wound healing: Characterization of the effect and its molecular basis in vitro and in vivo

Because light‐emitting diodes (LEDs) are low‐coherent, quasimonochromatic, and nonthermal, they are an alternative for low level laser therapy, and have photobiostimulative effects on tissue repair. However, the molecular mechanism(s) are unclear, and potential effects of blue and/or green LEDs on wound healing are still unknown. Here, we investigated the effects of red (638 nm), blue (456 nm), and green (518 nm) LEDs on wound healing. In an in vivo study, wound sizes in the skin of ob/ob mice were significantly decreased on day 7 following exposure to green LEDs, and complete reepithelialization was accelerated by red and green LEDs compared with the control mice. To better understand the molecular mechanism(s) involved, we investigated the effects of LEDs on human fibroblasts in vitro by measuring mRNA and protein levels of cytokines secreted by fibroblasts during the process of wound healing and on the migration of HaCat keratinocytes. The results suggest that some cytokines are significantly increased by exposure to LEDs, especially leptin, IL‐8, and VEGF, but only by green LEDs. The migration of HaCat keratinocytes was significantly promoted by red or green LEDs. In conclusion, we demonstrate that green LEDs promote wound healing by inducing migratory and proliferative mediators, which suggests that not only red LEDs but also green LEDs can be a new powerful therapeutic strategy for wound healing.     

Effects of an epidermal growth factor receptor‐based cancer vaccine on wound healing and inflammation processes in murine experimental models

Anti‐epidermal growth factor receptor (EGFR) therapies have been proven clinically effective for a variety of epithelial tumours. Vaccination of mice with the extracellular domain (ECD) of autologous EGFR overcomes the tolerance to self‐EGFR and has antimetastatic effect on EGFR+ tumour. Because EGF/EGFR‐signalling plays an important role in the inflammation stage of wound healing, the main objective of this study was to explore the possible role of murine (m) EGFR‐ECD vaccine in the croton‐oil‐induced ear oedema and wound healing process in mice as autologous experimental models, mimicking the possible post‐surgical wound complication in patients treated with human EGFR‐ECD/VSSP vaccine. Mice were intramuscularly immunised four times; biweekly with the mEGFR‐ECD/VSSP/Mont. Seven days later, an 8 mm diameter, full‐thickness skin wound was created on the back of each animal. Immunisation induced a strong specific humoral response against the mEGFR‐ECD protein and a DTH dose–response curve but interestingly, animals treated with mEGFR‐ECD/VSSP/Mont had similar inflammatory and healing speed responses compared to control ones. These data suggest that application of mEGFR‐ECD/VSSP vaccine as a therapeutic approach in cancer patients could not elicit a poor healing process after surgery.     

Characterization of a novel standardized human three‐dimensional skin wound healing model using non‐sequential fractional ultrapulsed CO2 laser treatments

Background and Objective

At present, there is no standardized in vitro human skin model for wound healing. Therefore, our aim was to establish and characterize an in vitro/ex vivo three‐dimensional (3D) wound healing model, which we employed to analyze the effects of dexpanthenol on wound healing and gene regulation.

Materials and Methods

The novel human 3D skin wound healing model using scaffold and collagen 3D organotypic skin equivalents was irradiated with a non‐sequential fractional ultrapulsed CO₂ laser. These standardized injured full‐thickness skin equivalents enable qRT–PCR, microarray, and histological studies analyzing the effect of topically or systemically applied compounds on skin wound healing.

Results

These human laser‐irradiated skin models were found to be appropriate for in vitro wound healing analysis. Topical treatment of skin wounds with a 5% dexpanthenol water‐in‐oil emulsion or two different 5% dexpanthenol oil‐in‐water emulsions clearly enhanced wound closure compared to laser‐irradiated untreated control models. To find out whether this positive effect is caused by the active substance dexpanthenol, laser‐irradiated skin models were cultured in calciumpantothenate containing medium (20 μg/ml) compared to skin equivalents cultured without calciumpantothenate. 3D models cultured in calciumpantothenate revealed considerably faster wound closure compared to the control models. Quantitative RT–PCR studies showed enhanced mRNA expression of MMP3, IL1α, keratin‐associated protein 4–12 (KRTAP4–12), and decreased expression of S100A7 in laser‐irradiated skin models cultured in medium containing calciumpantothenate.

Conclusion

This novel standardized human 3D skin wound healing model proves useful for topical pharmacological studies on wound healing and reveals new insights into molecular mechanisms of dexpanthenol‐mediated effects on wound healing. In addition, these novel 3D model systems can be used to monitor ex vivo effects of various laser systems on gene expression and morphology of human skin. Lasers Surg. Med. 47:257–265, 2015. © 2015 Wiley Periodicals, Inc.     

THE PIG AS A MODEL FOR HUMAN WOUND HEALING

The medical literature describes numerous in vitro and in vivo wound-healing models. The selection of an animal model depends on a number of factors including availability, cost, ease of handling, investigator familiarity, and anatomical/functional similarity to humans. Small mammals are frequently used for wound healing studies, however, these mammals differ from humans in a number of anatomical and physiological ways. Anatomically and physiologically, pig skin is more similar to human skin. The many similarities between man and pig would lead one to believe that the pig should make an excellent animal model for human wound healing. The purpose of this paper is to review the existing literature for evidence of this supposition and determine how well the various models correlate to human wound healing. Studies of wound dressings, topical antimicrobials, and growth factors are examined. Over 180 articles were utilized for this comparative review. Our conclusion is that the porcine model is an excellent tool for the evaluation of therapeutic agents destined for use in human wounds.     

Topical application of ex vivo expanded endothelial progenitor cells promotes vascularisation and wound healing in diabetic mice

Impaired wound healing leading to skin ulceration is a serious complication of diabetes and may be caused by defective angiogenesis. Endothelial progenitor cells (EPCs) can augment neovascularisation in the ischaemic tissue. Experiments were performed to test the hypothesis that locally administered EPCs can promote wound healing in diabetes. Full‐thickness skin wounds were created on the dorsum of diabetic mice. EPCs were obtained from bone marrow mononuclear cells (BMMNCs) and applied topically to the wound immediately after surgery. Vehicle and non‐selective BMMNCs were used as controls. Wound size was measured on days 5, 10 and 14 after treatment, followed by resection, histological analysis and quantification of vascularity. Topical application of EPCs significantly promoted wound healing, as assessed by closure rate and wound vascularity. Immunostaining revealed that transplanted EPCs induced increased expression of vascular endothelial growth factor and basic fibroblast growth factor. Few EPCs were observed in the neovasculature based on in vivo staining of the functional vasculature. Ex vivo expanded EPCs promote wound healing in diabetic mice via mechanisms involving increased local cytokine expression and enhanced neovascularisation of the wound. This strategy exploiting the therapeutic capacity of autologously derived EPCs may be a novel approach to skin repair in diabetes.     

Comparative wound healing—Are the small animal veterinarian's clinical patients an improved translational model for human wound healing research?

Despite intensive research efforts into understanding the pathophysiology of both chronic wounds and scar formation, and the development of wound care strategies to target both healing extremes, problematic wounds in human health care remain a formidable challenge. Although valuable fundamental information regarding the pathophysiology of problematic wounds can be gained from in vitro investigations and in vivo studies performed in laboratory animal models, the lack of concordance with human pathophysiology has been cited as a major impediment to translational research in human wound care. Therefore, the identification of superior clinical models for both chronic wounds and scarring disorders should be a high priority for scientists who work in the field of human wound healing research. To be successful, translational wound healing research should function as an intellectual ecosystem in which information flows from basic science researchers using in vitro and in vivo models to clinicians and back again from the clinical investigators to the basic scientists. Integral to the efficiency of this process is the incorporation of models which can accurately predict clinical success. The aim of this review is to describe the potential advantages and limitations of using clinical companion animals (primarily dogs and cats) as translational models for cutaneous wound healing research by describing comparative aspects of wound healing in these species, common acute and chronic cutaneous wounds in clinical canine and feline patients, and the infrastructure that currently exists in veterinary medicine which may facilitate translational studies and simultaneously benefit both veterinary and human wound care patients.