The uni-directional association of atopic dermatitis and rheumatoid arthritis: a systematic review and meta-analysis.

Atopic dermatitis (AD) is a highly pruritic, inflammatory skin disease with a strong immune component. Rheumatoid arthritis (RA) is a systemic autoimmune disease that causes synovitis and destruction of small joints. Researchers have attempted to quantify an association between both diseases with mixed conclusions. This systematic review and meta-analysis will study the association between AD and RA. Additionally, we conducted a systematic review between AD and other arthritic conditions including osteoarthritis (OA), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA). Medline, Web of Science, Cochrane, and EMBASE databases were searched for relevant studies from inception to March 2021. Observational studies examining relationships between AD and arthritic conditions were selected. 2539 studies were screened; nine were found suitable for quantitative analysis, all of which examined AD and RA. All studies had low risk of bias as determined by the Newcastle-Ottawa Scale. Patients with RA did not have significantly increased odds of comorbid AD. These findings were consistent across multiple study designs. However, patients with AD had significantly increased odds of comorbid RA. There were not enough studies identified to perform quantitative analysis between AD and other arthritic conditions. Two studies, one on JIA and one PsA, found no association with AD. Two studies on AD and OA had conflicting results. The present study provides definitive evidence of increased odds of comorbid RA in AD patients. There were no such increased odds of comorbid AD in RA patients. No such association was found between AD and PsA, OA or JIA.

Fibronectin-derived Epiviosamines enhance PDGF-BB-stimulated human dermal fibroblast migration in vitro and granulation tissue formation in vivo.

Fibronectin (FN) is a multimodular glycoprotein that is a critical component of the extracellular matrix (ECM) anlage during embryogenesis, morphogenesis, and wound repair. Our laboratory has previously described a family of FN-derived peptides collectively called "epiviosamines" that enhance platelet-derived growth factor-BB (PDGF-BB)-driven tissue cell survival, speed burn healing, and reduce scarring. In this study, we used an agarose drop outmigration assay to report that epiviosamines can enhance PDGF-BB-stimulated adult human dermal fibroblast (AHDF) outmigration in a dose-dependent manner. Furthermore, these peptides can, when delivered topically, stimulate granulation tissue formation in vivo. A thiol-derivatized hyaluronan hydrogel cross-linked with polyethyleneglycol diacrylate (PEGDA) was used to topically deliver a cyclized epiviosamine: cP12 and a cyclized engineered variant of cP12 termed cNP8 to porcine, full-thickness, excisional wounds. Both cP12 and cNP8 exhibited dose-dependent increases in granulation tissue formation at day 4, with 600 µM cNP8 significantly enhancing new granulation tissue compared to vehicle alone. In contrast to previous studies, this study suggests that epiviosamines can be used to increase granulation tissue formation without an exogenous supply of PDGF-BB or any cell-binding peptides. Thus, epiviosamine may be useful topically to increase granulation tissue formation in acute wounds.

Development of a contaminated ischemic porcine wound model and the evaluation of bromelain based enzymatic debridement.

OBJECTIVES: There are no well accepted animal models of chronic wounds, limiting advances in understanding and treatment of chronic ulcers. We developed a porcine wound model which combines multiple factors involved in chronic wounds to create a contaminated necrotic eschar and evaluated the debriding efficacy of a novel bromelain based enzymatic debriding agent (EscharEx). METHODS: Contaminated ischemic wounds were created on the flanks of domestic pigs by 'sandwiching' the skin between 2 'O' rings (1 placed on the surface of the skin and the other underneath the skin) for 24h prior to dermatomal excision of the necrotic eschar and its contamination with Staphylococcus aureus and Candida albicans. After confirming the development of infected eschars, additional animals were used to compare the effects of daily application of topical EscharEx or its hydrating vehicle on eschar debridement as a control. RESULTS: In all cases, application of the 'O' rings resulted in full thickness necrotic ecshars with invasive infections, which did not reepithelialize and sloughed off spontaneously within 14-21 days. All wounds reepithelialized within 28-42 days forming contracted scars. All EscharEx treated eschars were completely debrided within 7-9 days, while no debridement was evident in eschars treated with the control gel. CONCLUSIONS: Our model simulates the initial phase of chronic wounds characterized by a contaminated necrotic eschar allowing evaluation of wound debriding agents, and that a bromelain-based debriding agent completely debrides the contaminated necrotic eschars within one week in this model.

ArF excimer laser debrides burns without destruction of viable tissue: A pilot study.

INTRODUCTION: Recent evidence indicates that early removal of eschar by tangential debridement can promote healing. Laser debridement can be used for debridement of areas that prove challenging for debridement using tangential excision. In particular, irradiation with an ArF excimer laser ablates desiccated eschar and is self-terminating, preserving hydrated or viable tissue. METHODS: Thermal burns were created on the flanks of two outbred, female Yorkshire pigs using aluminum bars heated to 70°C and applied for different lengths of time. Three days after injury, burns were debrided using an ArF excimer laser (193nm). Tissue was harvested immediately after debridement and 7days after debridement (10days after burn). RESULTS: Data from a pilot study demonstrates that ArF excimer laser irradiation removes burn eschar and promotes healing at 10days after burn. ArF excimer laser debridement is self-terminating and preserves underlying and adjacent perfused tissue. Potentially, this modality would be ideal for the complex curvilinear structures of the body.

Blood vessel occlusion with erythrocyte aggregates causes burn injury progression-microvasculature dilation as a possible therapy.

Burns are dynamic injuries characterized by progressive tissue death and continuous severe pain over the course of several days. The extent of burn injury progression determines the ultimate patient outcome. Initial burns result in a central zone of necrosis surrounded by a potentially viable zone of ischemia. Several mechanisms have been proposed to explain injury progression, including oxidant and cytokine stress resulting from either ischemia/reperfusion and/or inflammation, but no proven therapy has emerged. To address the unmet need to limit burn injury progression, the root cause of this process must be delineated. For this reason, we have recently focused on post-burn blood vessel occlusion, currently ascribed to microthrombi. We have found that blood vessel occlusion is initially, mainly and persistently caused by erythrocyte aggregation. Although thermal-induced cell necrosis is the immediate cause of cell death, apoptotic cells from persistent ischemia/anoxia, admixed with inflammatory cells, form a band between viable and nonviable tissue 24 hours later. The delayed cell death by apoptosis appears to be the main attractant for inflammatory cells. Finally, we posit that fibrinogen elevation arising from inflammation provides stimulus for additional erythrocyte aggregation, further extending blood vessel occlusion. In our view this persistent occlusion with resultant prolonged tissue ischemia/anoxia, not ischemia/reperfusion, is the root cause of burn injury progression concomitant with associated severe and persistent pain. Epiviosamines, a new class of peptides, appear to selectively dilate microvasculature, and may provide therapy for burn injury progression.

Vasoactive effect of fibronectin-derived epiviosamine-1 and related peptides in quiescent and stress models.

OBJECTIVE: Following thermal burn injury, plasma fibronectin degrades within the interstitium; one possible product is EVA-1, PSHISKYILRWRPK found within the FNIII1 . EVA-1 ameliorates thermal burn injury progression, and binds to and enhances PDGF-BB in promoting cell metabolism, growth and survival; shorter related peptides lose these abilities. Here we study the effect of EVA-1 and shorter peptides for their vasoactivity under quiescent and stress conditions. METHODS: Using the hamster cheek pouch intravital microscopy model, five EVA-1 related peptides were applied to small arterioles via micropipette (10-16 -10-4 mol L-1 ) in quiescent tissue and after defined stress: nitric oxide or heat. RESULTS: Peak dilation occurred with nanomolar doses (longer peptides) or below (shorter peptides), blocked by propranolol (beta-adrenergic receptor antagonist). Micromolar doses of the same peptides induced only constriction, not antagonized by phentolamine (alpha-adrenergic receptor antagonist). Scrambled variants of two peptides yielded only constriction, suggesting constriction might be due peptide charge. Each stressor caused a left shift in dilation response, blocked by carazolol. CONCLUSIONS: Thus, this important region of FNIII1 contains sequences that have a gradation of biological functions dependent on the length of the peptide sequence, with increased efficacy for dilation following stressors.

Blood vessel occlusion in peri-burn tissue is secondary to erythrocyte aggregation and mitigated by a fibronectin-derived peptide that limits burn injury progression.

Although vascular occlusion has long been noted in peri-burn tissue, the literature is inconsistent regarding the nature of the occlusion, with articles in the 1940s claiming that erythrocytes were the culprit and in the 1980s-1990s that microthrombi were responsible. To better define the nature of vessel occlusion, we studied two porcine burn models, a hot comb horizontal injury model and a vertical injury progression model. In both cases, tissue from the first two days after burn were stained with hemotoxylin and eosin, or probed for platelets or for fibrinogen/fibrin. Erythrocytes, identified as nonstained, clumped, anuclear, 5 µm cells, occluded most blood vessels (BVs) in both burn models. In contrast, platelet or fibrinogen/fibrin antibodies stained BV occlusions minimally at early time points, and only up to 16% of deep dermal BVs at 48 hours in the hot comb model and up to 7% at 24 hours in the vertical injury progression model. Treatment of animals with a fibronectin-derived peptide (P12), which limits burn injury progression and can dilate peripheral microvasculature, reduced erythrocyte occlusion by at least 50%, speeded healing and reduced scarring. Early erythrocyte aggregation, rather than thrombosis, explains the ineffectiveness of anticoagulants to prevent burn injury progression.

Infrared Thermal Imaging Has the Potential to Reduce Unnecessary Surgery and Delays to Necessary Surgery in Burn Patients.

Clinical distinction between superficial and deep burns is problematic. The authors determined whether an infrared thermal imaging (IRTI) camera could predict burn depth. Burn depth was assessed by an experienced surgeon, and the burns were imaged with a portable, lightweight IRTI camera that measures heat emission from the skin using long infrared wavelengths (7.5-13 µm). Burns were considered "deep" if they were surgically excised and confirmed to be of full thickness on microscopic evaluation or if they did not heal spontaneously within 21 days of injury. All other burns were considered "nondeep." There were 39 burns that had both days 1 and 2 IRTI measurements and available outcome. Of these, 16 were "deep" burns and 23 were "nondeep." The mean temperatures of "nondeep" burns between days 1 and 2 increased from 30.6 ± 2.7 to 32.1 ± 3.0°C (difference of 1.5 ± 2.3°C). The mean temperatures of "deep" burns decreased from 32.3 ± 2.0 to 30.8 ± 1.3°C (difference of -1.5 ± 2.0°C) between days 1 and 2. Any decrease in temperatures between days 1 and 2 was predictive of a deep wound, and any increase between days 1 and 2 was predictive of a nondeep burn. Using the ultimate burn depth as the criterion standard, the overall accuracy of IRTI was considerably higher than that of clinical assessment; 87.2% (95% CI: 71.8-95.2) vs 54.1% (95% CI: 37.1-70.2). Any decrease in temperatures between days 1 and 2 was predictive of a deep wound. Our results suggest that thermography using IRTI is more accurate than clinical examination in predicting burn depth and could potentially reduce unnecessary surgery as well as reduce delays to surgery when necessary.

Forward-looking infrared imaging predicts ultimate burn depth in a porcine vertical injury progression model.

INTRODUCTION: Current methods of assessing burn depth are limited and are primarily based on visual assessments by burn surgeons. This technique has been shown to have only 60% accuracy and a more accurate, simple, noninvasive method is needed to determine burn wound depth. Forward-looking infrared (FLIR) thermography is both noninvasive and user-friendly with the potential to rapidly assess burn depth. The purpose of this paper is to determine if early changes in burn temperature (first 3 days) can be a predictor of burn depth as assessed by vertical scarring 28 days after injury. METHODS: While under general anesthesia, 20 burns were created on the backs of two female Yorkshire swine using a 2.5cm×2.5cm×7.5cm, 150g aluminum bar, for a total of 40 burns. FLIR imaging was performed at both early (1, 2 and 3 days) and late (7, 10, 14, 17, 21, 24 and 28 days) time points. Burns were imaged from a height of 12 inches from the skin surface. FLIR ExaminIR(©) software was used to examine the infrared thermographs. One hundred temperature points from burn edge to edge across the center of the burn were collected for each burn at all time points and were exported as a comma-separated values (CSV) file. The CSV file was processed and analyzed using a MATLAB program. The temperature profiles through the center of the burns generated parabola-like curves. The lowest temperature (temperature minimum) and a line midway between the temperature minimum and ambient skin temperature at the burn edges was defined and the area of the curve calculated (the "temperature half-area"). RESULTS: Half-area values 2 days after burn had higher correlations with scar depth than did the minimum temperatures. However, burns that became warmer from 1 day to 2 days after injury had a lower scar depth then burns that became cooler and this trend was best predicted by temperature minima. When data were analyzed as a diagnostic test for sensitivity and specificity using >3mm scarring, i.e. a full-thickness burn, as a clinically relevant criterion standard, temperature minima at 2 days after burn was found to be the most sensitive and specific test. CONCLUSIONS: FLIR imaging is a fast and simple tool that has been shown to predict burn wound outcome in a porcine vertical injury progression model. Data showed that more severe burn wounds get cooler between 1 and 2 days after burn. We found four analytic methods of FLIR images that were predictive of burn progression at 1 and 2 days after burn; however, temperature minima 2 days after burn appeared to be the best predictive test for injury progression to a full-thickness burn. Although these results must be validated in clinical studies, FLIR imaging has the potential to aid clinicians in assessing burn severity and thereby assisting in burn wound management.

The Role of Necroptosis in Burn Injury Progression in a Rat Comb Burn Model.

OBJECTIVES: Progression of cell death after burn injury may occur by one of three mechanisms: passive necrosis, apoptosis, and programmed necroptosis that requires the receptor-interacting protein kinase-3 (RIP-3). The hypothesis was that RIP-3 is present in normal and burned skin; that necroptosis plays a role in burn injury progression; and that treatment with necrostatin-1, an inhibitor of necroptosis, would reduce burn progression. METHODS: Skin specimens from rats were examined for the presence of RIP-3. Using a 150-g brass comb preheated to 100°C, we created two comb burns (one on each side) consisting of four rectangular burns, separated by three unburned interspaces, on both sides of the backs of anesthetized male Sprague-Dawley rats (240 to 300 g). The interspaces represent the ischemic zones surrounding the central necrotic core. Left untreated, these areas undergo necrosis. In the first experiment, 10 rats each were randomized to 1.65 mg/kg necrostatin-1 or control given by intraperitoneal injection 1 hour after injury. In the second experiment, 10 rats each were randomized to two intravenous injections of 1.65 mg/kg necrostatin-1 or its vehicle at 1 and 4 hours after injury. The primary outcome was the percentage of interspaces undergoing necrosis within 7 days of injury. Binary data were compared with chi-square or Fishers' exact tests. RESULTS: All normal and burned skin specimens from rats stained positive for RIP-3. In the first experiment, nearly all unburned interspaces in both the experimental and the control rats underwent necrosis (47 of 48, 97.9% vs. 48 of 48, 100%; p = not significant [NS]). Similarly, in the second experiment, there was no difference in the percentage of unburned interspaces undergoing necrosis within 7 days of injury in rats treated with two doses of necrostatin-1 or the control vehicle (46 of 48, 95.8% vs. 48 of 48, 100%; p = NS). There were no wound infections noted in rats injected with necrostatin-1. CONCLUSIONS: The skin of rats contains RIP-3 necessary for necroptosis. Injection of rats with either a single intraperitoneal dose or two intravenous doses of necrostatin-1 failed to reduce burn injury progression in a rat comb burn model. This may be due to inactivity of necrostatin-1 or the lack of a role of necroptosis in burn injury progression in the rat comb burn model.

Fibronectin Interaction and Enhancement of Growth Factors: Importance for Wound Healing.

Significance: This critical review focuses on interactions between cells, fibronectin (FN), and growth factors (GF). Recent Advances: Initially, the extracellular matrix (ECM) was thought to serve simply as a reservoir for GFs that would be released as soluble ligands during proteolytic degradation of ECM. This view was rather quickly extended by the observation that ECM could concentrate GFs to the pericellular matrix for more efficient presentation to cell surface receptors. However, recent reports support much more complex interactions among GFs and ECM molecules, particularly FN, and the way these interactions can fine-tune cell responses to the microenvironment. Critical Issues: Wounds that are unable to synthesize and sustain a functional ECM cannot optimally benefit from endogenous or exogenous GFs. Therefore, GF treatments have recently focused on utilizing ECM molecules as delivery vehicles. Thus, ECM can influence GF stability and activity, and GFs can modulate the ECM activity. Hence, both individually and together, ECM and GFs modulate cells that in turn control the type and level of GFs and ECM in the pericellular environment that ultimately results in new tissue generation. Although many ECM components are important for optimal tissue regeneration and wound healing, FN stands out as absolutely critical not only for wound healing and tissue regeneration but also for embryogenesis and morphogenesis. Future Directions: Understanding ECM/GF interactions will greatly facilitate our understanding of normal wound repair and regeneration, the failure of wounds to heal, and how the latter can be salvaged with proper ECM/GF combinations.

EDA Fibronectin in Keloids Create a Vicious Cycle of Fibrotic Tumor Formation.

During the early phase of wound healing, first plasma fibronectin (FN) and then in situ FN are deposited at the site of injury. In situ FN--FN made by tissue cells at the injury site--often contains an extra domain A (EDA) insert. Multiple wound-related signal transduction pathways control the deposition of EDA FN, and the EDA insert can in turn trigger pathways that induce inflammation, increased extracellular matrix molecule deposition including FN and collagen, and activation of fibroblasts. Together these pathways can create a vicious cycle that leads to fibrosis or keloid formation.

Establishing correlations in the en-mass migration of dermal fibroblasts on oriented fibrillar scaffolds.

Wound healing proceeds via fibroblast migration along three dimensional fibrillar substrates with multiple angles between fibers. We have developed a technique for preparation of three dimensional fibrillar scaffolds with where the fiber diameters and the angles between adjacent fiber layers could be precisely controlled. Using the agarose droplet method we were able to make accurate determinations of the dependence of the migration speed, focal adhesion distribution, and nuclear deformation on the fiber diameter, fiber spacing, and angle between adjacent fiber layers. We found that on oriented single fiber layers, whose diameters exceeded 1 µm, large focal adhesion complexes formed in a linear arrangement along the fiber axis and cell motion was highly correlated. On multi layered scaffolds most of the focal adhesion sites reformed at the junction points and the migration speed was determined by the angle between adjacent fiber layers, which followed a parabolic function with a minimum at 30°. On these surfaces we observed a 25% increase in the number of focal adhesion points and a similar decrease in the degree of nuclear deformation, both phenomena associated with decreased mobility. These results underscore the importance of substrate morphology on the en-mass migration dynamics. STATEMENT OF SIGNIFICANCE: En-mass fibroblast migration is an essential component of the wound healing process which can determine rate and scar formation. Yet, most publications on this topic have focused on single cell functions. Here we describe a new apparatus where we designed three dimensional fibrillar scaffolds with well controlled angles between junction points and highly oriented fiber geometries. We show that the motion of fibroblasts undergoing en-mass migration on these scaffolds can be controlled by the substrate topography. Significant differences in cell morphology and focal adhesions was found to exist between cells migrating on flat versus fibrillar scaffolds where the migration speed was found to be a function of the angle between fibers, the fiber diameter, and the distance between fibers.

Cutaneous wound healing in aging small mammals: a systematic review.

As the elderly population grows, so do the clinical and socioeconomic burdens of nonhealing cutaneous wounds, the majority of which are seen among persons over 60 years of age. Human studies on how aging effects wound healing will always be the gold standard, but studies have ethical and practical hurdles. Choosing an animal model is dictated by costs and animal lifespan that preclude large animal use. Here, we review the current literature on how aging effects cutaneous wound healing in small animal models and, when possible, compare healing across studies. Using a literature search of MEDLINE/PubMed databases, studies were limited to those that utilized full-thickness wounds and compared the wound-healing parameters of wound closure, reepithelialization, granulation tissue fill, and tensile strength between young and aged cohorts. Overall, wound closure, reepithelialization, and granulation tissue fill were delayed or decreased with aging across different strains of mice and rats. Aging in mice was associated with lower tensile strength early in the wound healing process, but greater tensile strength later in the wound healing process. Similarly, aging in rats was associated with lower tensile strength early in the wound healing process, but no significant tensile strength difference between young and old rats later in healing wounds. From studies in New Zealand White rabbits, we found that reepithelialization and granulation tissue fill were delayed or decreased overall with aging. While similarities and differences in key wound healing parameters were noted between different strains and species, the comparability across the studies was highly questionable, highlighted by wide variability in experimental design and reporting. In future studies, standardized experimental design and reporting would help to establish comparable study groups, and advance the overall knowledge base, facilitating the translatability of animal data to the human clinical condition.

Continual cell deformation induced via attachment to oriented fibers enhances fibroblast cell migration.

Fibroblast migration is critical to the wound healing process. In vivo, migration occurs on fibrillar substrates, and previous observations have shown that a significant time lag exists before the onset of granulation tissue. We therefore conducted a series of experiments to understand the impact of both fibrillar morphology and migration time. Substrate topography was first shown to have a profound influence. Fibroblasts preferentially attach to fibrillar surfaces, and orient their cytoplasm for maximal contact with the fiber edge. In the case of en-mass cell migration out of an agarose droplet, fibroblasts on flat surfaces emerged with an enhanced velocity, v = 52µm/h, that decreases to the single cell value, v = 28µm/h within 24 hours and remained constant for at least four days. Fibroblasts emerging on fibrillar surfaces emerged with the single cell velocity, which remained constant for the first 24 hours and then increased reaching a plateau with more than twice the initial velocity within the next three days. The focal adhesions were distributed uniformly in cells on flat surfaces, while on the fibrillar surface they were clustered along the cell periphery. Furthermore, the number of focal adhesions for the cells on the flat surfaces remained constant, while it decreased on the fibrillar surface during the next three days. The deformation of the cell nuclei was found to be 50% larger on the fiber surfaces for the first 24 hours. While the mean deformation remained constant on the flat surface, it increased for the next three days by 24% in cells on fibers. On the fourth day, large actin/myosin fibers formed in cells on fibrillar surfaces only and coincided with a change from the standard migration mechanism involving extension of lamellipodia, and retraction of the rear, to one involving strong contractions oriented along the fibers and centered about the nucleus.

ICG angiography predicts burn scarring within 48 h of injury in a porcine vertical progression burn model.

The current standard of care in determining the need to excise and graft a burn remains with the burn surgeon, whose clinical judgment is often variable. Prior work suggests that minimally invasive perfusion technologies are useful in burn prognostication. Here we test the predictive capabilities of Laser Doppler Imaging (LDI) and indocyanine green dye (ICG) angiography in the prediction of burn scarring 28 days after injury using a previously validated porcine burn model that shows vertical progression injury. Twelve female Yorkshire swine were burned using a 2.5 × 2.5 cm metal bar at variable temperature and application times to create distinct burn depths. Six animals (48 injuries total) each were analyzed with LDI or ICG angiography at 1, 24, 48, and 72 h following injury. A linear regression was then performed correlating perfusion measurements against wound contraction at 28 days after injury. ICG angiography showed a peak linear correlate (r(2)) of .63 (95% CI .34 to .92) at 48 h after burn. This was significantly different from the LDI linear regression (p < .05), which was measured at r(2) of .20 (95% CI .02 to .39). ICG angiography linear regression was superior to LDI at all timepoints. Findings suggest that ICG angiography may have significant potential in the prediction of long-term burn outcomes.

Intravenous curcumin efficacy on healing and scar formation in rabbit ear wounds under nonischemic, ischemic, and ischemia-reperfusion conditions.

Curcumin, a spice found in turmeric, is widely used in alternative medicine for its purported anti-inflammatory and antioxidant activities. The goal of this study was to test the curcumin efficacy on rabbit ear wounds under nonischemic, ischemic, and ischemia-reperfusion conditions. Previously described models were utilized in 58 New Zealand White rabbits. Immediately before wounding, rabbits were given intravenous crude or pure curcumin (6 µg/kg, 30 µg/kg, or 60 µg/kg) dissolved in 1% ethanol. Specimens were collected at 7-8 days to evaluate the effects on wound healing and at 28 days to evaluate the effects on hypertrophic scarring. Student's t test was applied to screen difference between any treatment and control group, whereas analysis of variance was applied to further analyze for all treatment groups in aggregate in some specific experiments. Treatment with crude curcumin suggested accelerated wound healing that reached significance for reepithelialization in lower and medium doses and granulation tissue formation in lower dose. Purified curcumin became available and was used for all later experiments. Treatment with pure curcumin suggested accelerated wound healing that reached significance for reepithelialization in lower and medium doses and granulation tissue formation in lower dose. Treatment with pure curcumin significantly promoted nonischemic wound healing in a dose-response fashion compared with controls as judged by increased reepithelialization and granulation tissue formation. Improved wound healing was associated with significant decreases in pro-inflammatory cytokines interleukin (IL)-1 and IL-6 as well as the chemokine IL-8. Curcumin also significantly reduced hypertrophic scarring. The effects of curcumin were examined under conditions of impaired healing including ischemic and ischemia-reperfusion wound healing, and beneficial effects were also seen, although the dose response was less clear. Systemically administrated pure curcumin significantly promotes nonischemic wound healing and reduces hypertrophic scarring. Improvements in wound healing were associated with decreased inflammatory markers in wounds. Further study is needed to optimize dosing in ischemic and ischemia-reperfusion wound healing. In aggregate, the studies strongly support the systemic administration of curcumin to improve wound healing.