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Wound healing: an update

Wounds, both chronic and acute, continue to be a tremendous socioeconomic burden. As such, technologies drawn from many disciplines within science and engineering are constantly being incorporated into innovative wound healing therapies. While many of these therapies are experimental, they have resulted in new insights into the pathophysiology of wound healing, and in turn the development of more specialized treatments for both normal and abnormal wound healing states. Herein, we review some of the emerging technologies that are currently being developed to aid and improve wound healing after cutaneous injury. Keywords: biomaterials • stem cells • tissue engineering • wound healing

Wound healing pathophysiology Since the advent of mammalian cell culture in the early 1900s, scientists have been attempting to elucidate the complex molecular and cellular events responsible for scar tissue formation [1] . The goal of such research is an ancient one, described in the Greek myth of Prometheus: to change wound healing from a process of imperfect repair to complete regeneration. Yet the concept of regeneration is no myth, and can be seen not only in the adult liver, but also in early-gestation fetal wounds and among certain amphibian species [2,3] . Cutaneous injury in the adult human, however, elicits a fibroproliferative response, producing a scar in every case. Scar tissue, although providing restoration of the epithelial barrier, is structurally and functionally distinct from normal skin. In some cases, dysfunctional healing results in either a persistent open wound, or excessive, disorganized cellular proliferation leading to a hypertrophic or keloid scar. Both of these extremes of wound healing can lead to significant functional impairment, psychosocial morbidity and overall increased healthcare costs. Combining our increasing understanding of the pathophysiologic basis of wound

10.2217/RME.14.54 © 2014 Future Medicine Ltd

healing with advances in bio- and chemical engineering has resulted in improved clinical care over the years. While we cannot yet completely replicate lost or damaged tissues, the rapidly evolving field of regenerative medicine promises continued developments towards that goal. Keeping in mind the tremendous body of research that forms the scope of the relevant literature, we have attempted to provide an overview of the pathophysiology of cutaneous wound healing, and present some of the current technologies being developed and employed to improve the process.

Elizabeth R Zielins1, David A Atashroo1, Zeshaan N Maan1, Dominik Duscher1, Graham G Walmsley1, Owen Marecic1, Michael Hu1,2, Kshemendra Senarath-Yapa1, Adrian McArdle1, Ruth Tevlin1, Taylor Wearda1, Kevin J Paik1, Christopher Duldulao1, Wan Xing Hong1,3, Geoffrey C Gurtner1 & Michael T Longaker*,1 1 Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Division of Plastic Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA 94305–5148, USA 2 Department of Surgery, John A Burns School of Medicine, University of Hawai’i, Honolulu, HI, USA 3 University of Central Florida College of Medicine, Orlando, FL, USA *Author for correspondence: Tel.: +1 650 736 1707 Fax: +1 650 736 1705 longaker@

Stages of wound healing

Traditionally, mammalian wound healing is described as occurring in three overlapping stages: inflammation, proliferation and remodeling [3] . The process of wound healing technically begins at the moment of injury – with inflammation. The body’s initial response, formation of a fibrin clot, provides hemostasis and recruits several types of cells to the wound [4] . Neutrophils are the first circulating immune cells to arrive, with highest concentrations found 1 to 2 days postinjury. They function in preventing bacterial infection (given the disrupted epithelial barrier) as well as in activation of keratinocytes,

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part of

ISSN 1746-0751


Review  Zielins, Atashroo, Maan et al. fibroblasts and immune cells [4,5] . Early migration of keratinocytes along the temporary fibrin extracellular matrix (ECM) is seen within hours of wounding [6] . Circulating monocytes arrive 2–3 days after injury and differentiate into macrophages. During the early inflammatory phase of wound healing, macrophages function alongside neutrophils in preventing infection and serve to debride the wound of necrotic tissue [3,7] . As the inflammatory stage of wound healing ends and the second stage, proliferation, begins, macrophages adopt an anti-inflammatory, profibrotic phenotype. The growth factors they produce, such as TGF-β, recruit fibroblasts from the surrounding uninjured tissue [4,7] . These and other cells stimulate the migration of endothelial cells into the wound via production of VEGF, among other factors, resulting in the formation of new blood vessels and, thus, the hypervascular character of granulation tissue [8] . Completion of re-epithelialization is also achieved during the proliferative stage of wound healing. This process involves migration, proliferation and differentiation of keratinocytes drawn from both the wound edges and stem cell populations found in the hair follicle bulge region [9] . Despite the participation of stem cells, epidermal appendages are not regenerated during wound healing [4] . Re-epithelialization is aided by the production of a replacement ECM by fibroblasts. Components of the ECM such as fibronectin, along with cytokines such as TGF-β1 and certain inflammatory mediators produced during the immune response to injury, induce fibroblast activation [10–12] . Activated fibroblasts, or myofibroblasts, so named due to the contractile ability provided by their expression of α-SMA, respond physically and biochemically to the mechanical environment of the wound. Physically they contract, serving to bring the edges of the wound together, decreasing its overall size [3,13] . They are also responsible for the secretion of the abnormal ECM-characterizing scar tissue [14] . This ECM primarily differs from that of unwounded skin and mature scars in its collagen content, containing increased levels of immature type III collagen (relative to the mature type I collagen that predominates in normal skin and mature scar) [4] . Approximately 3 weeks after the initial injury, collagen levels in the wound have peaked, and the weeksto years-long process of remodeling begins. Heralding this change is a decrease in the cellular content of the wound, accomplished via both migration and apoptosis. With the apoptosis of myofibroblasts and an overall decrease in fibroblast collagen production, the structure of the ECM changes [11] . The ratio of type III to type I collagen decreases. MMPs and their inhibitors, TIMPs, work in harmony to reorganize collagen fibers


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into a stronger network. In spite of this, the maximum strength the mature scar reaches will be only 80% that of unwounded skin [4] . Pathologic wound healing

Although the mature scar formed through the process of normal wound healing is by no means equivalent to normal skin, it accomplishes the goal of restoring continuity to the integument. In fact, ‘normotrophic’ scars represent the midpoint in a spectrum of wound healing responses. The fibroproliferative disorders of hypertrophic scar and keloid formation represent an ‘over-healing’ response; conversely, patients with chronic wounds show evidence of an ‘under-healing’ response, as do those with atrophic scars [13] . Although the pathogenesis of over- and under-healing is not completely understood, the consequent patient morbidity and socioeconomic costs of abnormal healing make advances in knowledge a necessary and desirable goal. Chronic wounds

Chronic wounds, or ulcers, are non-healing wounds that persist for over 6 weeks [15] . They tend to develop after minor injuries, in the setting of advanced age and medical comorbidities such as atherosclerosis and diabetes [13] . In the USA alone, ulcers account for US$6–15 billion in annual healthcare costs [15] . Aging and diabetes are associated with delayed wound healing secondary to alterations in the structure and proliferative capacity of the epidermis and dermis, as well as impaired neovascularization [16–18] . Chronic wounds may be broadly classified into three groups: vascular, diabetic and pressure ulcers [13,19] . Although resulting from a diverse array of medical conditions, all share the presence of increased inflammation of the wound, hypoxia and, to some degree, microbial colonization and infection. Consequently, all share common features of increased proteolysis, and impairments in cell proliferation and migration [13,20] . Due to underlying systemic disease and/or wound infection, high numbers of immune cells are recruited during the inflammatory stage of healing. These cells produce reactive oxygen species (ROS) that damage the ECM and surrounding cells [13] . ROS and other inflammatory mediators induce production of proteolytic enzymes by multiple cell types in the wound, ranging from keratinocytes to endothelial cells. This creates a microenvironment where MMPs and other proteases degrade TIMPs, growth factors (e.g., VEGF), and components of the ECM [20,21] . Abnormal expression of matrix glycoproteins results in further instability of the ECM, impeding migration of keratinocytes and reepithelialization [9,13] . Myofibroblasts are also affected by the conditions of chronic wounds, particularly by

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Wound healing: an update 

hypoxia resulting from infection and/or insufficient angiogenesis in cases of diabetes or vascular insufficiency. Decreased numbers of myofibroblasts further contribute to the paucity of granulation tissue formed, and, thus, to delayed wound healing [22] . Fibroproliferative disorders

Dysfunctional inflammation has also been implicated in hypertrophic scarring. Specifically, hypertrophic scars (HTS) are associated with a prolonged inflammatory phase of wound healing. This may be related to mechanism of injury, as they typically occur after burn injury or other trauma to the deep dermis [23] . Keloid formation, on the other hand, is determined by both genetic and environmental factors: they are predominantly seen in darker skinned individuals and the propensity to form them can be inherited [24,25] . Clinically, both HTS and keloids present as pruritic, raised, reddened and firm masses, although a keloid will extend beyond the borders of the original wound [26] . They may be both cosmetically distressing and, due to scar contractures, functionally debilitating [27,28] . While a HTS will partially regress (undergo a remodeling phase), a keloid will not [25] . Although a number of therapeutic modalities exist for both hypertrophic scars and keloids, effective treatment is limited, in part by an incomplete understanding of the pathophysiology of these disorders [25,29] . What is known about the pathogenesis of abnormal scarring centers on the fact that fibroblasts from keloid and hypertrophic scars are phenotypically different from those of normal skin and mature scars [30] . Instead of undergoing apoptosis or decreasing their collagen production (senescence), fibroblasts in fibrotic lesions remain activated for a prolonged period of time, continuing to deposit high levels of ECM in the wound [22] . Although the precise relationships between cell intrinsic and extrinsic factors remain to be determined, reasons for this are undoubtedly linked to the mechanical forces acting on the wound [31,32] . HTS fibroblasts have been shown to express higher levels of the profibrotic cytokine TGF-β1 and lower levels of collagenases, resulting in excessive collagen production. The abnormal ECM of a HTS is further characterized by irregular proteoglycan content, particularly decreased decorin, which itself inhibits TGF-β [23,30] . TGF-β-related fibroblast dysfunction and an abnormal ECM also characterize keloids. Keloid fibroblasts are hyper-proliferative compared with HTS fibroblasts and manufacture increased levels of type I collagen. The resultant increase in the type I to type III collagen ratio is unique to keloids [25] . Emerging therapeutic concepts

Advances in understanding the cellular and molecular basis of both normal and pathological wound healing

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have made possible the development of more targeted, efficacious therapies (Figure 1). This is perhaps most obvious when considering attempts to correct pathologic wound healing via the application of growth factors and cytokines implicated in normal wound healing. Although the use of growth factors has seen some success in clinical trials, the extent to which a single growth factor can modify the complex dynamics of a healing wound is questionable. The ultimate bioavailability of protein directly applied to damaged tissue is also questionable, and has led to the development of scaffolds, and even cells, as drug-delivery vehicles. Scaffolds may act purely as devices for drug or growth factor delivery, or they may be seeded with cells thought to promote wound healing. Alternatively, cells themselves may be transfected or transduced with nucleic acids encoding genes to promote cell survival and wound healing. Traditionally, wound healing therapies have centered on dressings. Originally made of gauze or various fabric materials, practitioners now have a wide variety of substances to choose from based on the ‘goal’ of the dressing (e.g., absorption of wound exudate and debridement, among others). Dressing types range from materials such as hydrogels and alginates, suitable for lightly and heavily exudative wounds, respectively, to biological dressings that actively participate in healing [34] . Biological dressings encompass the scaffolds mentioned above, and when seeded with various cell types in a structured, 3D fashion, may serve as complete ‘skin substitutes’. Increased understanding of how cells are affected by the physical and chemical microenvironment in which they reside has led to further modifications of the composition of these skin substitutes. Leveraging a variety of technologies from the fields of biochemistry, cellular and molecular biology, and engineering, wound-healing therapies are rapidly developing. While a comprehensive review of each type of therapy is beyond the scope of this article, we will attempt to summarize some recent trends within each major area. Growth factors & cytokines The use of growth factors and cytokines to augment wound healing has technically existed since the early 1940s, when clinicians began the bench-to-bedside transition of applying embryonic ‘extracts’ shown to promote in vitro cell growth, to healing wounds [35] . Backed by a substantial body of research describing the major molecular players in wound healing, today’s scientists are able to make more refined choices in their attempts to improve the process. Growth factors may be applied to wounds in a variety of ways, from traditional topical or intralesional administration, to more complex methods utilizing specially fabricated scaffolds or gene therapy. Ostensibly, ideal candidates for manipulation are growth


Review  Zielins, Atashroo, Maan et al.

Epithelial sheets

Dermal matrices

Control release systems

Acute or chronic wound

Skin stem cells

Regenerated skin

Engineered grafts Figure 1. Multiple technologies have been developed to improve both normal and abnormal wound healing, all with the goal of regenerating lost tissue. Reproduced with permission from [33] © Elsevier (2013).


factors known to play key roles in wound healing, a selection of which we describe here. Scaffolds/dressings and cell-based therapies are covered in more detail later in this review, although we will touch on some of these technologies in the following section.

approved iron-chelating agent that stabilizes HIF-1 by both inhibiting PHDs and depleting iron; depletion of iron also serves to decrease oxidative stress [18,50–51] . These effects synergistically promote wound healing while decreasing tissue necrosis [52,53] .

HIF-1–VEGF/SDF-1 sxis


The hypoxic response is largely regulated by the canonical transcription factor, HIF-1 [36] . The structure of HIF-1 includes an α-subunit that, with the help of prolyl hydroxylases (PHDs), is degraded in the presence of oxygen and iron (Fe2+) [37,38] . Hypoxia impairs HIF-1 degradation, allowing it to promote the expression of a variety of proteins, including VEGF and SDF-1 [39,40] . The benefits of modulating HIF-1 signaling appear to be largely realized through the positive effects of VEGF on angiogenesis, and SDF-1 on the homing of circulating progenitor cells [41,42] . Wounds treated with SDF-1 show increased recruitment and engraftment of bone marrow progenitor cells [43] . In fact, overexpression of SDF-1 by stem cells delivered to wounds further enhances their efficacy in promoting healing [44–46] . A number of animal studies targeting this pathway have shown improvements in diabetic wound healing due to enhanced neovascularization [47–49] . One of the more recent approaches to modulating HIF-1 signaling involves the use of deferoxamine (DFO), a US FDA-

bFGF or FGF-2 is a potent cytokine for the stimulation of neovascularization. The provascular effects of FGF-2 are typically mediated via interactions with tyrosine kinase receptors, which activate signaling pathways regulating endothelial cell proliferation and migration [54] . FGF-2 is typically upregulated in the setting of ischemia; impaired neovascularization in the setting of diabetes has been associated with deficiencies in FGF-2 [55] . Therapeutic strategies seeking to upregulate FGF-2 in the wound environment have demonstrated efficacy in animal studies, increasing cell proliferation and angiogenesis, and accelerating wound closure in both diabetic and wild-type mice [56] . Human trials have shown improved healing of chronic wounds treated with recombinant FGF [57,58] .

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PDGF was originally isolated from platelets, but has since been shown to be expressed by a variety of cell

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Wound healing: an update 

types, including fibroblasts and endothelial cells [59] . It binds to PDGF receptors on endothelial cells, thereby exerting angiogenic effects. Similarly to FGF-2, PDGF signaling influences endothelial cell proliferation and migration [59] . PDGF-based therapies for wound healing have been examined in animal models of diabetes: application of recombinant PDGF resulted in increased fibroblast proliferation and vascular density with accelerated wound closure [60] . Viral-mediated gene delivery to diabetic wounds has seen similar success, with notable improvements in vascularization, as well as in collagen deposition and organization [61] . Recombinant human PDGF has been successful in the treatment of diabetic foot ulcers, although only one topical therapy has been FDA-approved for patient use: REGRANEX® Gel (Smith & Nephew, Inc., London, UK) [62] . TGF-β

TGF-β is a multifunctional protein with three isoforms: TGF-β1, -β2 and -β3. Activated TGF-β binds to three receptors (TβR1, 2 and 3). While TβR3 is believed to be linked to angiogenesis, TβR1 and TβR2 activity is associated with TGF-β-mediated scarring and fibrosis [63,64] . As previously described, dysregulated TGF-β1 signaling has been implicated in the fibroproliferative disorders of hypertrophic scarring and keloid formation. The importance of this growth factor is further evidenced by differences in the levels of the three isoforms between fetal (scarless healing) and adult skin [64] . Given its prominent role in fibrosis, it is not surprising that a number of studies have investigated the effects of modulating TGF-β activity in the wound environment. Le et al. found that TGF-β3 is necessary for re-epithelialization of excisional wounds, likely affecting keratinocyte activity via paracrine effects [65] . However, the most recent form of TGF-β with potential for clinical use failed to pass Phase III clinical trials. Juvista (Renovo, Bristol, UK), a recombinant TGF-β3 formulation for intradermal injection, was unable to demonstrate a substantial improvement in scar quality [66] . Biological dressings Biological dressings may be composed of materials naturally found in skin, such as hyaluronic acid and collagen, or of polymers that have been engineered to mimic the structure of human ECM. Some materials, such as chitosan, fall in between these categories. Derived from chitin, a component of fungal cell walls and invertebrate exoskeletons, chitosan has been found to prevent local infections and promote wound healing [34,67] . These dressings can serve as building blocks

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for more complex dressings incorporating antibacterial nanoparticles or growth factors (Figure 2) . The original use of biological dressings was simply to serve as matrix replacements for deep dermal or fullthickness wounds. Widely used for both reconstructive and cosmetic procedures, dermal matrix substitutes are traditionally indicated in cases where the native ECM has been damaged or destroyed [34] . Examples of matrix replacements include AlloDerm (LifeCell Corp., NJ, USA) an acellular dermal matrix (ADM) composed of devitalized human dermis, and Integra (Integra LifeSciences Corp., NJ, USA), a dermal substitute made from type I collagen (bovine) [34,68] . Integra is commonly used as a skin substitute in cases of burns or other trauma resulting in full thickness skin loss, sometimes in conjunction with split-thickness skin grafting [69,70] . Different types of artificial matrices are capable of inducing different cellular responses within wounds [68,71] . They share the common property, however, of aiding cell migration into the wound and, thus, promoting wound healing [71–73] . Negative pressure wound therapy

Negative pressure wound therapy (NPWT) is a dressing that exerts mechanical force on a healing wound, and has multiple indications for use. While the mechanical force exerted by NPWT primarily serves to remove exudate, it has also been shown in preclinical and numerous clinical studies to promote healing by stimulating wound contraction and, at the cellular level, enhancing neovascularization and proliferation [74] . Although first described over a decade ago and now used worldwide for many clinical indications, the exact mechanism of action of NPWT has yet to be elucidated [75] . However, research suggests that its proangiogenic effects are due to modulation of several factors: wound oxygen levels, growth factors (e.g., VEGF), and endothelial cells and their circulating progenitors [74,76,77] . While widely used, recent Cochrane reviews examining the efficacy of NPWT in primarily closed wounds and skin grafts, as well as in the treatment of diabetic foot wounds, have been cautious in fully endorsing the therapy, citing the need for further studies [78,79] . In an attempt to further refine its efficacy, research is being done into modifications of the foam dressing used in NPWT. For example, Wagstaff et al. recently evaluated a biocompatible foam designed to avoid retained foam fragments and disruption of granulation tissue during dressing changes [80] . VAC GranuFoam Silver Dressing (KCI, TX, USA), a silvercoated foam designed for use with NPWT, has the advantage of delivering high-doses of antimicrobial silver to wounds while (via negative pressure) removing enough of the ion to prevent systemic toxicity [81] .


Review  Zielins, Atashroo, Maan et al.

C Silicon membrane

B Nanoparticles

Synthetic scaffold D

Donor skin

Keratinocytes Fibroblasts Biosynthetic template Acellular dermal scaffold Dermal scaffold


Living skin equivalent Donor skin (skin graft)


Figure 2. Although intrinsically designed to improve wound healing through mimicry of the physical and biological nature of human skin, biological dressings may undergo further modifications to improve wound healing. (A) Skin grafts may be used for wound coverage, although donor site availability is limited. (B) Acellular dermal matrices. (C) Synthetic biological dressings may be modified with the addition of growth factors or antibacterial nanoparticles. (D) The addition of cells to dermal replacement scaffolds enables them to serve as skin substitutes.

Enhanced biological dressings

In some cases, such as hypertrophic scar formation, an attenuated cellular response to wound healing may be desired. Cui et al. used a poly(l-lactide) (PLLA) scaffold as a delivery vehicle for ginsenoside Rg3 (G-Rg3), a molecule shown to induce apoptosis of hypertrophic scar fibroblasts. They found attenuated scar formation in a rabbit ear model of HTS [82] . Decreased scar formation has also recently been seen in a new class of dressing: one that acts as a splint to shield closed, post-operative wounds from some of the mechanical forces acting on them. The embrace device (Neodyne Biosciences, Inc., CA, USA), a silicone-based dressing, resulted in improved aesthetic scar quality in a randomized, controlled scar revision trial [83] . Nanotechnology has emerged as an effective avenue through which to further modify and enhance biological dressings. For example, bacterial cellulose is a dressing material suitable for maintaining a moist wound environment, although with a concerning potential for


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infection. Wu et al. were able to mitigate this by depositing silver nanoparticles onto the dressing, showing in vitro antibacterial activity with preserved biocompatibility [84] . The use of biological dressings as drugdelivery vehicles continues to expand, with Shemesh et al. demonstrating sustained release of analgesic drugs (bupivacaine and ibuprofen) from a custom scaffold for up to 100 days [85] . Randomized, controlled clinical trials of a lipido-colloid matrix dressing incorporating an MMP inhibitor (nano-oligosaccharaide factor) have demonstrated superiority to dressings alone in healing in venous leg ulcers [86] . In an attempt to further recapitulate the structure and function of the missing tissue, matrix substitutes may serve as scaffolds and be pre-loaded with cells before placement into a wound. Combinations of cell types and scaffolds being assessed range from keratinocytes with acellular amniotic membrane (yet another type of matrix substitute), to embryonic stem cells (murine) with Integra [87,88] . These skin substitutes may also be

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Wound healing: an update 

modified by the addition of growth factors and cytokines to the matrix substitute. Jin et al. demonstrated successful differentiation of adipose-derived stem cells along an epidermal lineage by incorporating several epidermal induction factors (e.g., EGF) into a nanofiber scaffold [89] . The search for the most effective type of cellularized skin substitute represents a particularly active area of research in tissue engineering today. Cell-based therapies Cell-based wound therapies have existed for decades: cultured epithelial autografts (CEA) – application of a patient’s own in vitro-expanded keratinocytes to a burn injury – were first described in 1981 [90] . CEA is still commonly used in burn units, with much research focusing on the best mechanism of applying cells to the wound (e.g., cell sprays vs sheets), as well as on optimization for treatment of wounds lacking a suitable dermal recipient bed. Although advantageous in many ways, especially in the setting of major burn injuries where skin graft donor sites are limited, CEA also illustrates some of the drawbacks to using differentiated cells in wound healing therapies. As epidermal survival relies on the microenvironment provided by the underlying dermis and its microvasculature, keratinocytes alone are unable to compensate for the significant dermal destruction seen in some wounds, resulting in poor CEA take [91] . To that end, the use of CEA in combination with biological dressings and ADMs has been assayed, showing promise in improving the ease of CEA delivery and take, respectively [91,92] . Skin substitutes incorporating both keratinocytes and fibroblasts along with a replacement ECM do exist commercially, and are used clinically in the treatment of lower extremity ulcers [93] . Even so, while bilayered skin substitutes such as Apligraf (Organogenesis, Inc., MA, USA) replace the major components of injured tissue, it is important to remember that wound healing is a complex process involving interactions between many different cell types.


Stem cell therapies

Given the multipotent and self-renewing nature of stem cells, along with their low immunogenicity, it is not surprising that stem cell application is another emerging paradigm for the treatment of acute and chronic wounds. Stem cells from a variety of sources have proven successful in experimental wound healing applications, and are currently being tested in preclinical and clinical trials (Table 1) [94] . Populations of stem cells include: embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs). While the pluripotent nature of ESCs is attractive, both practical and ethical concerns surround their use. As such, the relative ease of accessibility of MSCs, especially adipose-derived stem (or stromal) cells (ASCs), mitigates their decreased differentiation capacity. iPSCs provide the pluripotency of ESCs without the ethical and moral controversy, and may be derived from autologous sources; however, their potential in wound healing therapies has been relatively less investigated. Mesenchymal stromal or stem cells

The terms ‘mesenchymal stem cell’, or ‘mesenchymal stromal cell’, refer to a population of self-renewing cells capable of giving rise to various cell types derived from the embryonic mesoderm, including bone, cartilage, muscle and fat [95] . MSCs may be obtained from different areas in the body, with the most common sources being bone marrow (BM-MSCs) and adipose tissue (ASCs). While differences in the phenotype of BM-MSCs and ASCs have been observed, both have proven to be efficacious in wound healing therapies [96] . Although both BM-MSCs and ASCs are mesenchymal stromal/stem cells, we will hereafter refer to ‘BM-MSCs’ as ‘MSCs’ in accordance with most published literature. Despite one of the key properties of stem cells being the potential for differentiation, the contribution of transdifferentiated MSCs to the healing wound remains unclear. Yu et al. saw signs of epithelial and endothelial

Table 1. Active clinical trials for stem cell-based wound therapies†. Topic

Study #

Treatment of hypertensive leg ulcer by adipose tissue grafting (Angiolipo)


Cell therapy for venous leg ulcers pilot study


Allogeneic stem cell therapy in patients with acute burn


Safety study of stem cells treatment in diabetic foot ulcers


Endogenous progenitors cell therapy for diabetic foot ulcers (AMD3100)


Safety and efficacy of autologous bone marrow stem cells for lower extremity ischemia treating


Information retrieved from:

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Review  Zielins, Atashroo, Maan et al. lineage specification in an in vivo assay of ascorbic acidtreated ASC sheets applied to full-thickness excisional wounds [97] . Conversely, Ojeh et al. observed a lack of epithelial transdifferentiation when MSCs were substituted for fibroblasts in a standard in vitro skin equivalent model [98] . These disparate findings may be attributable to differences in the artificial MSC microenvironments, or niches, created by each experiment. Interestingly, the natural role of MSCs in wound healing is thought to be regulatory rather than as direct rebuilders. Likely arising from perivascular cells (pericytes), local MSCs modulate both the immune response to injury and the tissue repair process by the secretion of various growth factors and cytokines [95] . In addition to their observations regarding the transdifferentation potential of MSCs, Ojeh et al. were the first to demonstrate that substituting MSCs for fibroblasts in an in vitro skin equivalent model preserves the differentiation and proliferative capacity of keratinocytes [98] . Shin and Peterson noted that, unlike MSCs, injection of isolated fibroblasts into murine excisional wounds did not improve the speed of wound healing. Wounds treated with MSCs showed improved healing seemingly due to the ability of the injected MSCs to recruit endogenous stem cells to the wound site [99] . The regulatory effects of MSCs may also hold promise for the treatment of abnormal wound healing states, such as fibroproliferative disorders, although more investigation in this area is needed. MSCs would appear to promote anti-fibrotic wound healing by modulating leukocyte activity (promotion of anti-inflammatory cytokine expression) and directly secreting anti-fibrotic cytokines and growth factors (e.g., HGF, IL-10 and MMP-9) [100] . However, recent findings reported by Ding et al. challenge this as co-culture with MSCs enhanced the fibrotic tendencies of human deep dermal fibroblasts [101] . While much has been done to characterize the wound healing potential of MSCs, ASCs are gaining popularity as an alternative for cell-based therapies. The ease of obtaining ample amounts of tissue (i.e., lipoaspirate) from which to harvest cells makes ASCs an attractive choice, especially when compared with MSCs extracted from a painfully-collected bone marrow sample [102] . The suggestion of a pluripotent nature further adds to allure of ASCs in regenerative medicine [103] . Unpublished findings from our laboratory suggest that ASCsupplemented fat grafts may reduce radiation-induced fibrosis while improving dermal angiogenesis, and that ASCs applied within a biomimetic hydrogel scaffold accelerate wound healing by releasing proangiogenic cytokines. As ASC- and MSC-based therapies move from experimental to translational, it is important to carefully


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consider both method of delivery and cell seeding density (Figure 3) . Our laboratory has previously shown decreased scar formation in excisional wounds treated with an ASC-loaded ECM replacement, compared with ASCs alone [104] . O’Loughlin et al. used a rabbit diabetic ulcer model to demonstrate a dose response to the delivery of MSCs on collagen scaffolds: increased epithelialization and wound closure were seen with larger numbers of MSCs [105] . However, clinical use of ASCs in wound healing therapies remains limited. Only recently, the ACellDREAM study, the first Phase I clinical trial of its kind, demonstrated that the intramuscular injection of human ASCs for the treatment of severe chronic limb ischemia (CLI) is possible, safe and effective [106] . iPSCs

Takahashi and Yamanaka created the iPSC by reprogramming adult fibroblasts into an immature, pluripotent state [108] . Autologous iPSCs effectively bypass the ethical constraints of human embryonic stem cells and are non-immunogenic. As such, they hold enormous potential for wound healing applications. However, establishing iPSC-based therapies for skin disease and wound healing requires the development of efficient and cost-effective methodologies for their differentiation into fibroblasts, keratinocytes and associated cells. Progress has been made on this front. Yang et al. differentiated folliculogenic human epithelial stem cells from iPSCs; all components of the hair follicle were regenerated in skin reconstitution assays [109] . Given the loss of epithelial appendages in scars, transplantation of iPSC-derived folliculogenic epithelial stem cells holds promise for the regeneration of normal skin architecture following wounding. Itoh and colleagues developed a protocol for differentiating iPSCs into dermal fibroblasts, generating in vitro 3D skin equivalents composed exclusively of human iPSC-derived keratinocytes and fibroblasts [110] . Others have shown that iPSCderived fibroblasts demonstrate augmented production and assembly of ECM proteins [111] . This is promising as a potential means to enhance the speed of wound repair, although it may result in increased scar tissue formation; in circumstances necessitating rapid healing or in the case of chronic wounds, such a compromise might be acceptable. Proof-of-principle iPSC-based therapies for the enhancement of wound healing have been slow to emerge. Chien et al. improved corneal healing after surgical abrasion using human corneal keratocyte-reprogrammed iPSCs seeded on a chitosan-based hydrogel. The hydrogel increased the viability and proportion of CD44 + (differentiated) iPSCs while maintaining stem cell-like gene expression [112] . The generation of

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Wound healing: an update 


Stem cell delivery options





Cutaneous wounds or surgical access

High pressure and density

Precise homing and egress

Mimic niche and protect

Figure 3. Stem cells may be delivered to a wound using a variety of methods, each with its own advantages and disadvantages. Reproduced with permission from [107] © Elsevier (2013).

genetically corrected iPSCs holds great potential for the treatment of dermatological conditions with a genetic component [113] . A relatively unexplored avenue of treatment, iPSCs may also prove useful for the treatment of burns and chronic wounds via their ability to attenuate the inflammatory response; however, few studies have investigated this possibility [114] . Alternatively, iPSCs may serve as resources from which to derive differentiated cells for implantation into the wound environment. Kim et al. observed that co-transplantation of iPSCderived endothelial and smooth muscle cells resulted in improved neovascularization of excisional wounds [115] . Conclusion Wound healing therapies continue to rapidly evolve, with advances in basic science and engineering research heralding the development of new therapies, as well as ways to modify existing treatments. This process can be observed in the changing nature of growth factor-based therapies and dressings. Growth factors are less commonly being investigated as single therapeutic agents. Rather, advances in chemical engineering have allowed nanofabrication of dressings able to provide more

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physio­logically relevant growth factor release kinetics. Dressings themselves must serve a dual purpose, even if it is simply to provide the right amount of moisture to a healing wound. Their role in aiding wound healing is becoming increasingly complex, as the importance of modulating the mechanical environment of the wound continues to emerge [31] .  Future perspective One of the most promising therapeutic concepts for wound healing is stem cell-based therapy. Advances in stem cell biology have provided researchers and clinicians alike with access to cells capable of actively modulating the healing response. iPSC-based therapies are especially exciting, due to the iPSC’s increased capacity for differentiation into cells derived from all three germ layers, compared with traditionally used MSCs. Currently, the precise effects of transplanting stem cells into a wound vary from experiment-to-experiment, and one of the hazards of culturing cells for any period of time is the risk of malignant transformation. In the case of CEA, guidelines have been developed to allow for effective monitoring, suggesting this too can be


Review  Zielins, Atashroo, Maan et al. accomplished for stem cell cultures [91] . As MSCs/ASCs appear to have a complex role in the tumor microenvironment – both pro- and anti-neoplastic effects have been reported – more studies must be carried out before they become widely used in wound-healing therapies [116–118] . The use of iPSCs carries the addition concern for teratoma formation [119] . Yet, these obstacles are being gradually overcome. ‘Footprint-free’ methods of deriving iPSCs, using temporally restricted reprogramming, have shown promise as effective methods for generating cells [120] . As our knowledge continues to grow, emerging technologies will allow for the development of safe, specialized wound therapies recreating the physical and chemical properties of the stem cell niche, potentially allowing for tissue regeneration as opposed to repair.

Acknowledgements The authors thank Dominik Andrzejczuk (Bitcraft Inc., Fremont, CA, USA) for the production of Figure 2 for this review.

Financial & competing interests disclosure MT Longaker and GC Gurtner have equity positions in and are on the Board of Directors of Neodyne Biosciences, Inc., a startup company developing a device to shield wounds from mechanical tension to minimize post-operative scarring. 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 the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Executive summary Wound healing pathophysiology • Wound healing is a dynamic process involving intricate interactions between multiple cell types, molecules and the extracellular matrix. • An incomplete understanding of the pathophysiology of both normal and abnormal wound healing responses has limited the development of effective treatments.

Growth factors & cytokines • Addition of certain growth factors and cytokines to wounds has resulted in improved wound healing, both in experimental models and clinically.

Biological dressings • Specialized dressings exist to modulate both the physical and molecular environment of the wound. • Dressings may serve as scaffolds for delivery of growth factors and/or cells to wounds.

Cell-based therapies • An increasing understanding of stem cell biology has led to the development of cell-based therapies able to affect multiple aspects of wound healing. • Stem cell therapies hold great promise as we continue to search for ways to regenerate damaged tissues.

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Wound healing: an update.

Wounds, both chronic and acute, continue to be a tremendous socioeconomic burden. As such, technologies drawn from many disciplines within science and...
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