Rapid Wound Repair Research Articles

Integrating Bioactive Graded Hydrogel with Radially Aligned Nanofibers to Dynamically Manipulate Wound Healing Process.

Skin wound healing is a complex process that requires appropriate treatment and management. Using a single scaffold to dynamically manipulate angiogenesis, cell migration and proliferation, and tissue reconstruction during skin wound healing is a great challenge. We developed a hybrid scaffold platform that integrates the spatiotemporal delivery of bioactive cues with topographical cues to dynamically manipulate the wound-healing process. The scaffold comprised gelatin methacryloyl hydrogels and electrospun poly(ε-caprolactone)/gelatin nanofibers. The hydrogels had graded cross-linking densities and were loaded with two different functional bioactive peptides. The nanofibers comprised a radially aligned nanofiber array layer and a layer of random fibers. During the early stages of wound healing, the KLTWQELYQLKYKGI peptide, which mimics vascular endothelial growth factor, was released from the inner layer of the hydrogel to accelerate angiogenesis. During the later stages of wound healing, the IKVAVS peptide, which promotes cell migration, synergized with the radially aligned nanofiber membrane to promote cell migration, while the nanofiber membrane also supported further cell proliferation. In an in vivo rat skin wound-healing model, the hybrid scaffold significantly accelerated wound healing and collagen deposition, and the ratio of type I to type III collagen at the wound site resembled that of normal skin. The prepared scaffold dynamically regulated the skin tissue regeneration process in stages to achieve rapid wound repair with clinical application potential, providing a strategy for skin wound repair.

Multifunctional Dual Network Hydrogel Loaded with Novel Tea Polyphenol Magnesium Nanoparticles Accelerates Wound Repair of MRSA Infected Diabetes

AbstractMethicillin‐resistant Staphylococcus aureus (MRSA) biofilm infection, caused by impaired glucose metabolism in diabetic foot patients, poses a significant obstacle to the healing process and carries a high risk of being life‐threatening. Due to microvascular occlusion and the entrenchment of MRSA biofilms in diabetic foot, controlling and effectively treating MRSA infection remains challenging. Traditional hydrogels suffer from swelling‐related mechanical issues and inadequate drug release control, limiting their applications as biomimetic extracellular matrices for wound healing. Herein, a double‐network hydrogel composed of polyvinyl alcohol, sodium alginate, and gelatin (PSG) loaded with tea polyphenol self‐assembled magnesium nanoparticles (TP‐Mg NPs) with antibacterial and angiogenic properties for treating MRSA‐infected diabetic foot wounds under hyperglycemic conditions is constructed. TP‐Mg@PSG exhibits enhanced mechanical strength and toughness for wound attachment and recovery movement torsion. In the acidic infection microenvironment representative of MRSA‐infected wounds, the TP‐Mg@PSG hydrogel degrades to release TP‐Mg NPs, showing excellent anti‐MRSA biofilm effect and high biocompatibility. Such localized controlled release enhances the inhibition of MRSA infection and reduces the inflammatory response in rats, promoting cell proliferation and rapid wound repair. Therefore, this study presents a multifunctional biomaterial system for managing diabetic foot conditions, highlighting its potential for clinical applications.

Successful treatment of a severe open wound in a raccoon dog (Nyctereutes procyonoides): antibiotic susceptibility testing supported

An adult raccoon dog with extensive, deep, and contaminated wounds on the right hip and multiple fractures was rescued. The open wound was managed daily by debridement and flushing for 3 weeks. Modified active drainage was then performed, and antibiotics administered according to the antibiotic susceptibility test. After 2 weeks, the exudate disappeared and the drain was removed. After monitoring for 1 month, the animal was released in to the wild. This case shows that even if infection remains, rapid wound repair is possible if appropriate antibiotic selection through regular examination and active drainage are combined.

Wound healing effects of Asparagus lucidus Lindl extract through the phosphorylation of ERK1/2

BackgroundSkin is the outermost part of the human body and is essential in maintaining body homeostasis. In the event of skin injury, rapid wound repair is crucial to protect the body. In this study, we investigated the wound-healing properties of Asparagus lucidus Lindl extract by promoting keratinocyte proliferation.MethodsTo evaluate the effect of Asparagus lucidus Lindl extract on skin regeneration, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to measure keratinocyte proliferation, while an in vitro wound-healing assay was performed to evaluate wound closure through keratinocyte re-epithelialization. The intracellular mechanisms of the extract were studied using Western blot analysis to measure the phosphorylated forms of mitogen-activated protein kinases and protein kinase B. The mRNA expression of cell cycle-related genes was analyzed using quantitative real time-PCR analysis. A murine in vivo wound-healing assay was also conducted to observe the effect of the extract on wound closure.ResultsAsparagus lucidus Lindl extract induced 131.15% keratinocyte proliferation compared to the control in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The in vitro wound-healing assay showed that the extract improved wound closure by 216.94% through keratinocyte re-epithelialization. Western blot analysis revealed that the phosphorylated form of extracellular signal-regulated kinase 1/2 was increased by extract treatment. Quantitative real time-PCR analysis showed a dose-dependent increase in the mRNA expression of c-fos, c-jun, and VEGF. The in vivo wound-healing assay showed a significant increase (22.13%) of wound closure compared to the control on day 5.ConclusionAsparagus lucidus Lindl extract promotes keratinocyte proliferation by activating the extracellular signal-regulated kinase 1/2 pathway and up-regulating the mRNA expression of c-fos, c-jun, and vascular endothelial growth factor.

Rap1 coordinates cell-cell adhesion and cytoskeletal reorganization to drive collective cell migration in vivo

Collective cell movements contribute to tissue development and repair and spread metastatic disease. In epithelia, cohesive cell movements require reorganization of adherens junctions and the actomyosin cytoskeleton. However, the mechanisms that coordinate cell-cell adhesion and cytoskeletal remodeling during collective cell migration invivo are unclear. We investigated the mechanisms of collective cell migration during epidermal wound healing in Drosophila embryos. Upon wounding, the cells adjacent to the wound internalize cell-cell adhesion molecules and polarize actin and the motor protein non-muscle myosin II to form a supracellular cable around the wound that coordinates cell movements. The cable anchors at former tricellular junctions (TCJs) along the wound edge, and TCJs are reinforced during wound closure. We found that the small GTPase Rap1 was necessary and sufficient for rapid wound repair. Rap1 promoted myosin polarization to the wound edge and E-cadherin accumulation at TCJs. Using embryos expressing a mutant form of the Rap1 effector Canoe/Afadin that cannot bind Rap1, we found that Rap1 signals through Canoe for adherens junction remodeling, but not for actomyosin cable assembly. Instead, Rap1 was necessary and sufficient for RhoA/Rho1 activation at the wound edge. The RhoGEF Ephexin localized to the wound edge in a Rap1-dependent manner, and Ephexin was necessary for myosin polarization and rapid wound repair, but not for E-cadherin redistribution. Together, our data show that Rap1 coordinates the molecular rearrangements that drive embryonic wound healing, promoting actomyosin cable assembly through Ephexin-Rho1, and E-cadherin redistribution through Canoe, thus enabling rapid collective cell migration invivo.

Promoting oral mucosal wound healing using a DCS-RuB2A2 hydrogel based on a photoreactive antibacterial and sustained release of BMSCs.

The high occurrence rate and difficulties in symptom control are listed as the major problems of oral mucosal disease by medical professionals. Following the development of oral mucosal lesions, the oral microenvironment changes, immunity declines, and continuous bacterial stimulation causes wound infection. Traditional antibacterial drugs are ineffective for oral mucosal lesions. To overcome this problem, a light-responsive antibacterial hydrogel containing sustained-release BMSCs was inspired by the trauma environment in the oral cavity, which is different from that on the body surface since it mostly remains under dark conditions. In the absence of light, the hydrogel seals the wound to form a barrier, exerts a natural bacteriostatic effect, and prevents invasion by foreign bacteria. Simultaneously, mesenchymal stem cells are presented, and the released growth factors and other substances have excellent anti-inflammatory and angiogenic effects, which result in rapid repair of the damaged site. Under light conditions, after photo-induced shedding of the hydrogel, RuB2A exerts an antibacterial effect accompanied by degradation of the hydrogel. Results in a rat oral mucosal repair model demonstrate that DCS-RuB2A2-BMSCs could rapidly repair the oral mucosa within 4 days. Sequencing data provide ideas for further analysis of the intrinsic molecular mechanisms and signaling pathways. Taken together, our results suggest that this light-responsive antibacterial hydrogel loaded with BMSCs can be used for rapid wound repair and may advance the development of therapeutic strategies for the treatment of clinical oral mucosal defects.

Coordinated efforts of different actin filament populations are needed for optimal cell wound repair.

Cells are subjected to a barrage of daily insults that often lead to their cortices being ripped open and requiring immediate repair. An important component of the cell's repair response is the formation of an actomyosin ring at the wound periphery to mediate its closure. Here we show that inhibition of myosin or the linear actin nucleation factors Diaphanous and/or dishevelled associated activator of morphogenesis results in a disrupted contractile apparatus and delayed wound closure. We also show that the branched actin nucleators WASp and SCAR function nonredundantly as scaffolds to assemble and maintain this contractile actomyosin cable. Removing branched actin leads to the formation of smaller circular actin-myosin structures at the cell cortex and to slow wound closure. Removing linear and branched actin simultaneously results in failed wound closure. Surprisingly, removal of branched actin and myosin results in the formation of parallel linear F-actin filaments that undergo a chiral swirling movement to close the wound, uncovering a new mechanism of cell wound closure. Taken together, we demonstrate the roles of different actin substructures that are required for optimal actomyosin ring formation and the extraordinary resilience of the cell to undergo wound repair when it is unable to form different subsets of these substructures.

A pH-responsive ZC-QPP hydrogel for synergistic antibacterial and antioxidant treatment to enhance wound healing.

The problems of bacterial resistance and high oxidation level severely limit wound healing. Therefore, we constructed a multifunctional platform of chitosan quaternary ammonium salts (QCS)/polyvinyl alcohol (PVA)/polyethylene glycol (PEG) hydrogels (QPP) loaded with ZnO@CeO2 (ZC-QPP). Firstly, the hydrogel was co-cross-linked by hydrogen and borate ester bonds, which allows easy adherence to a tissue surface for offering a protective barrier and moist environment for wounds. The chitosan quaternary ammonium salts due to their amino groups have inherent antibacterial properties to induce bacterial death. In response to the acidic conditions of the bacterial infection microenvironment, the borate ester bonds in the QPP hydrogel break and the ZC NCs dispersed in the hydrogel are released. The gradual dissociation of Zn2+ under acidic conditions can directly damage bacterial membranes. The wound site of bacterial infection always causes overexpression of reactive oxygen species (ROS) levels, often leading to inflammation and preventing rapid wound repair. CeO2 can eliminate excess ROS to reduce the inflammatory response. From in vitro and in vivo results, the high biosafety of the ZC-QPP hydrogel has demonstrated excellent antibacterial and antioxidant performance to enhance wound healing. Therefore, the ZC-QPP hydrogel opens a method to develop multifunctional synergistic therapeutic platforms combining enzyme-like nanomaterials with hydrogels for synergistic antibacterial and antioxidant treatment to promote wound healing.

Keratin 75 Is a Component of the LINC Complex and Has an Essential Role in Mediating the SOX2 Rapid Healing Response during Wound Repair

Keratin 75 Is a Component of the LINC Complex and Has an Essential Role in Mediating the SOX2 Rapid Healing Response during Wound Repair

770 Reprogramming of diabetic wounds by SOX2 triggers a pro-healing transcriptional signature

Diabetic foot ulcers (DFUs) are a severe complication of diabetes and a common cause of lower limb amputations and are associated with a high mortality rate. We previously demonstrated that the transcription factor SOX2 establishes a transcriptional network that primes the oral epithelium for rapid wound repair and reprogrammed cutaneous keratinocytes to present accelerated wound resolution both in vitro and in vivo. However, the mechanisms by which SOX2 reverses effects of diabetes during wound healing are not known.

Combined Effect of Low-Level LASER and Kinetic Chain Activation on Wound Healing

The management of chronic and nonhealing wounds involves the use of electrotherapy including low-level LASER therapy (LLLT), ultraviolet rays, infrared radiation, and transcutaneous electrical nerve stimulation (TENS). Evidence suggests that kinetic chain activation results in fascial mobilization needed for rapid wound repair. However, the combined effect of electrotherapy and fascial mobilization by kinetic chain activation on wound healing is not known. This case report highlights the effect of a novel rehabilitation model integrating LLLT, TENS, and kinetic chain activation on wound healing. This study was conducted on a 46-year-old female who presented with a nonhealing wound on the plantar aspect of the foot. A positive outcome was observed in terms of pain reduction, improvement in wound size, and functional independence

P38-mediated cell growth and survival drive rapid embryonic wound repair.

Embryos repair wounds rapidly, with no inflammation or scarring, in a process that involves polarization of the actomyosin cytoskeleton. Actomyosin polarization results in the assembly of a contractile cable around the wound that drives wound closure. Here, we demonstrate that a contractile actomyosin cable is not sufficient for rapid wound repair in Drosophila embryos. We show that wounding causes activation of the serine/threonine kinase p38 mitogen-activated protein kinase (MAPK) in the cells adjacent to the wound. p38 activation reduces the levels of wound-induced reactive oxygen species in the cells around the wound, limiting wound size. In addition, p38 promotes an increase in volume in the cells around the wound, thus facilitating the collective cell movements that drive rapid wound healing. Our data indicate that p38 regulates cell volumes through the sodium-potassium-chloride cotransporter NKCC1. Our work reveals cell growth and cell survival as cell behaviors critical for embryonic wound repair.

Furnishing Wound Repair by the Subcutaneous Fascia.

Mammals rapidly heal wounds through fibrous connective tissue build up and tissue contraction. Recent findings from mouse attribute wound healing to physical mobilization of a fibroelastic connective tissue layer that resides beneath the skin, termed subcutaneous fascia or superficial fascia, into sites of injury. Fascial mobilization assembles diverse cell types and matrix components needed for rapid wound repair. These observations suggest that the factors directly affecting fascial mobility are responsible for chronic skin wounds and excessive skin scarring. In this review, we discuss the link between the fascia’s unique tissue anatomy, composition, biomechanical, and rheologic properties to its ability to mobilize its tissue assemblage. Fascia is thus at the forefront of tissue pathology and a better understanding of how it is mobilized may crystallize our view of wound healing alterations during aging, diabetes, and fibrous disease and create novel therapeutic strategies for wound repair.

Beneficial effect on rapid skin wound healing through carboxylic acid-treated chicken eggshell membrane

At the initial stage of wound healing, growth factors stimulate tissue regeneration by interacting with the extracellular matrix (ECM), leading to rapid wound repair and structural support. Chicken eggshell membrane (ESM) is a low-cost and highly functional ECM biomaterial for tissue regeneration. However, natural ESM has limitations for tissue engineering purposes because it is difficult to control the size, shape, and biocompatibility of the surfaces. To overcome this, blends of synthetic materials and natural ESMs, such as soluble eggshell membrane protein, are combined for biomaterial applications. Unfortunately, it is difficult to pattern fibrous structure. Here, we modified the natural chicken ESM through weak acid treatment to promote wound healing and skin regeneration without loss of fibrous structure. Treatment of citric acid and acetic acid reacted the amine or amide group with carboxyl groups (R-COOH) and achieved hydrophilicity for adherence of proliferating regenerative cells. Our in vitro study revealed that the modified ESM scaffolds significantly promoted human dermal fibroblasts adhesion, viability, proliferation, and cytokine secretion, compared with natural ESM. In addition, the modified ESM accelerated skin regeneration and enhanced the wound healing process even at early stages in an in vivo rat wound model. Collectively, the modified ESM performed best for promoting skin regeneration, cytokine secretion, epidermal cell proliferation, and controlling the inflammatory response both in vitro and in vivo.

Therapeutic NKG2D Ligation Facilitates Improved Wound Healing

Abstract NKG2D is a C-type lectin-like receptor in the CD94/NKG2 family and is expressed by a variety of leukocyte populations including natural killer (NK) cells, γδ T cells, CD8+ T cells and certain innate lymphoid cell (ILC) subsets. NKG2D can bind proteins in two protein families – MIC and RAET1/ULBP. Expression of NKG2D ligands is low/absent under homeostatic conditions, but these proteins are upregulated in several contexts, including infection, cancer, physiologic stress, and senescence. NKG2D-driven activation of NK and CD8+ T cells has previously been shown to result in augmented control of infections and tumor growth. However, the role of NKG2D in the context of tissue injury and repair has not been established. Here we tested the effects of augmented NKG2D ligation in the context of a skin injury model. Biopsy punches were used to generate six 3- mm wounds on the dorsal surface of C57BL/6 mice. On days 0 and 1, NKG2D stimulating antibodies or isotype controls were injected into the peritoneal cavity and wound healing was assessed daily. Mice treated with NKG2D activating antibodies had more rapid wound repair than controls – wounds were healed by day 5 in NKG2D-treated mice as compared to day 7 in controls. Analogous results were observed in an ex vivo human skin model. Using a biolistic particle delivery system to induce upregulation of RAE (an NKG2D ligand), we observed more rapid wound repair compared to controls. Genetic ablation of NKG2D resulted in a 40% delay in wound healing. Moreover, depletion of NK1.1+ or CD8+ leukocytes blunted the benefit of NKG2D ligation, suggesting that T cells, NK cells, and/or ILCs may play a role in driving tissue repair. Thus, we demonstrate a potential therapeutic function of NKG2D engagement in tissue regeneration.

Dynamic Force Patterns Promote Collective Cell Migration

Embryonic wound repair is driven by collective cell migration into the wounded region. Contraction of a supracellular cable formed by actin and the motor protein non-muscle myosin II coordinates the cell movements that drive wound closure. We showed that, in Drosophila embryos, the actomyosin cable displays a heterogeneous pattern, with regions of high and low actin density. Mutants in which the distribution of actin is uniform around the wound display significantly slower wound healing. However, the mechanisms by which a non-uniform distribution of actin favors rapid wound repair are unknown. We used quantitative microscopy to investigate how the distribution of cytoskeletal molecules affects wound healing. We found that actin and myosin displayed matching heterogeneous distributions at the wound margin. Using laser ablation, we demonstrated that tension along the cable was correlated with actomyosin levels, indicating that contraction of the cable is non-uniform. A force balance showed that closure forces resulting at the interface between regions of high and low actomyosin contractility are greater than in regions of uniform contractility, suggesting that a non-uniform distribution of tension at the wound margin favors rapid wound repair. We developed an in silico model of wound repair, and we found that healing was faster when the pattern of tension along the wound margin was heterogeneous. Our model predicted that, to maintain a heterogeneous distribution of tension around the wound over time, the actomyosin pattern must change as cell boundaries deform. Consistent with this, we found that in vivo, myosin accumulates in segments of the wound margin that are stretched as a consequence of the contraction of adjacent, myosin-rich segments. Our results suggest that a non-uniform distribution of contractile forces along multicellular actomyosin networks generates mechanical signals that facilitate rapid network remodeling, and efficient collective cell movements.

Regenerative potential of characterised honey in wound healing

Event Abstract Back to Event Regenerative potential of characterised honey in wound healing Satarupa Sarkar1, Amrita Chaudhary1, Swarnendu Bag1, Bhuvaneshwaran Subramanian1, Amit K. Das2, Provas Banerjee3 and Jyotirmoy Chatterjee1 1 Indian Institute of Technology, Kharagpur, School of Medical Science & Technology, India 2 Indian Institute of Technology, Kharagpur, Department of Biotechnology, India 3 Banerjee's Biomedical Research Foundation, India Introduction: Outright harmonization amongst the events such as infiltration of inflammatory cells, granulation tissues constitution along with angiogenesis, proliferation and migration of fibroblasts and keratinocytes maintains dynamicity of ideal and rapid wound repair. Treatment with honey has regained popularity in recent times as because a number of small clinical trials have been completed which corroborate clinical improvement with regenerative potentiality on topical application of honey on wound. Honey is thought to be providing regenerative ambience in wound bed leading to the development of an embryonic environment with its own system intelligence. In this context present study performs exhaustive estimation of honey’s regenerative potential on topical application in wound model with a special emphasis on elucidation based on histopathological study. Materials and Methods: 10 male swiss albino mice (Mus musculus) were housed individually in a pathogen free environment and the study was performed under the Guidelines of the Institutional Animal Care and Use Committee. Two full thickness wounds were created on each animal after anaesthetizing with xylazine and ketamine hydrochloride and subsequent shaving of the dorsal part. One wound was regarded as control (povidone-iodine treated) and another was treated with physico-chemically characterized honey. The wounds were examined clinically at specific time points along with the collection of biopsy samples followed by Hematoxylin-Eosin (H and E), Periodic Acid–Schiff (PAS) and Van Gieson’s (VG) staining. Results and Discussion: As shown in figure 1, the total wound area (pixel value) for honey treated wound as calculated by ImageJ software was found to be significantly reduced when compared to control. Higher level of significance ( p= 5.6*E-05) is noted in case of honey treated wound as an indicator of wound contraction. The long lasting effect of honey on the release of TNF-α and IL-1β and IL-6 production may explain its therapeutic interface in the harmonized process of wound healing. On clinical evaluation, the honey treated wounds were found to show accelertaed healing comparitively with respect to control. The healing progression of skin biopsies were observed by histopathological techniques On 10th and 20th days after treatment, the microscopic observations under H and E staining explored remarkably improved histological features with progressive maturation of epithelial and connective tissues. The VG staining illustrated upgraded collagen density and formation of normal skin orientation. Conclusion: Topical application of honey escalates wound healing with exquisite dynamicity via apposite wound contraction and re-epithilialization in wound model. Results of this study may serve as a crucial step for exploration of honey in varied regenerative applications. This work is carried out under the project "Noninvasive Characterization Of Healing And Nonhealing Wounds And Development Of Honey-Biomaterial And Stem Cell Based Wound Therapy" (NIC), sponsored by MHRD, Department of higher Education, New Delhi, Government of India. IIT Kharagpur has been acknowledged for providing infrastructural facility

Regenerative healing, scar-free healing and scar formation across the species: current concepts and future perspectives.

All species have evolved mechanisms of repair to restore tissue function following injury. Skin scarring is an inevitable and permanent endpoint for many postnatal organisms except for non-amniote vertebrates such as amphibians, which are capable of tissue regeneration. Furthermore, mammalian foetuses through mid-gestation are capable of rapid wound repair in the absence of scar formation. Notably, excessive cutaneous scar formation, such as hypertrophic and keloid scars, is a species limited clinical entity as it occurs only in humans, although wounds on the distal limbs of horses are also prone to heal with fibroproliferative pathology known as equine exuberant granulation tissue. Currently, there are no reliable treatment options to eradicate or prevent scarring in humans and vertebrates. The limited number of vertebrate models for either hypertrophic or keloid scarring has been an impediment to mechanistic studies of these diseases and the development of therapies. In this viewpoint essay, we highlight the current concepts of regenerative, scar-free and scar-forming healing compared across a number of species and speculate on areas for future research. Furthermore, in-depth investigative research into the mechanisms of scarless repair may allow for the development of improved animal models and novel targets for scar prevention. As the ability to heal in both a scarless manner and propensity for healing with excessive scar formation is highly species dependent, understanding similarities and differences in healing across species as it relates to the regenerative process may hold the key to improve scarring and guide translational wound-healing studies.

Wounded cells drive rapid epidermal repair in the earlyDrosophilaembryo

Epithelial tissues are protective barriers that display a remarkable ability to repair wounds. Wound repair is often associated with an accumulation of actin and nonmuscle myosin II around the wound, forming a purse string. The role of actomyosin networks in generating mechanical force during wound repair is not well understood. Here we investigate the mechanisms of force generation during wound repair in the epidermis of early and late Drosophila embryos. We find that wound closure is faster in early embryos, where, in addition to a purse string around the wound, actomyosin networks at the medial cortex of the wounded cells contribute to rapid wound repair. Laser ablation demonstrates that both medial and purse-string actomyosin networks generate contractile force. Quantitative analysis of protein localization dynamics during wound closure indicates that the rapid contraction of medial actomyosin structures during wound repair in early embryos involves disassembly of the actomyosin network. By contrast, actomyosin purse strings in late embryos contract more slowly in a mechanism that involves network condensation. We propose that the combined action of two force-generating structures--a medial actomyosin network and an actomyosin purse string--contributes to the increased efficiency of wound repair in the early embryo.

Exogenous metallothionein‐IIA promotes accelerated healing after a burn wound

Severe injury to the epidermal barrier often results in scarring and life-long functional deficits, the outcome worsening with a number of factors including time taken to heal. We have investigated the potential of exogenous metallothionein IIA (Zn(7)-MT-IIA), a naturally occurring small cysteine-rich protein, to accelerate healing of burn wounds in a mouse model. Endogenous MT-I/II expression increased in basal keratinocytes concurrent with reepithelialization after a burn injury, indicating a role for MT-I/II in wound healing. In vitro assays of a human keratinocyte cell line indicated that, compared with saline controls, exogenous Zn(7)-MT-IIA significantly increased cell viability by up to 30% (p<0.05), decreased apoptosis by 13% (p<0.05) and promoted keratinocyte migration by up to 14% (p<0.05), all properties that may be desirable to promote rapid wound repair. Further in vitro assays using immortalized and primary fibroblasts indicated that Zn7-MT-IIA did not affect fibroblast motility or contraction (p>0.05). Topical administration of exogenous Zn(7)-MT-IIA (2 microg/mL) in vivo, immediately postburn accelerated healing, promoted faster reepithelialization (3 days: phosphate-buffered saline (PBS), 8.9+/-0.3 mm diameter vs. MT-I/II, 7.1+/-0.7 mm; 7 days: PBS 5.8+/-0.98 mm vs. MT-I/II, 3.6+/-1.0 mm, p<0.05) and reduced epidermal thickness (MT-I/II: 45+/-4 microm vs. PBS: 101+/-19 microm, p<0.05) compared with controls. Our data suggest that exogenous Zn(7)-MT-IIA may prove a valuable therapeutic for patients with burns and other skin injuries.