Transcriptional changes in human palate and skin healing.

Most human tissue injuries lead to the formation of a fibrous scar and result in the loss of functional tissue. One adult tissue that exhibits a more regenerative response to injury with minimal scarring is the oral mucosa. We generated a microarray gene expression dataset to examine the response to injury in human palate and skin excisional biopsies spanning the first 7 days after wounding. Differential expression analyses were performed in each tissue to identify genes overexpressed or underexpressed over time when compared to baseline unwounded tissue gene expression levels. To attribute biological processes of interest to these gene expression changes, gene set enrichment analysis was used to identify core gene sets that are enriched over the time-course of the wound healing process with respect to unwounded tissue. This analysis identified gene sets uniquely enriched in either palate or skin wounds and gene sets that are enriched in both tissues in at least one time point after injury. Finally, a cell type enrichment analysis was performed to better understand the cell type distribution in these tissues and how it changes over the time course of wound healing. This work provides a source of human wound gene expression data that includes two tissue types with distinct regenerative and scarring phenotypes.

Differential microRNA profile underlies the divergent healing responses in skin and oral mucosal wounds.

Oral mucosal wounds heal faster than skin wounds, yet the role of microRNAs in this differential healing has never been examined. To delineate the role of microRNAs in this site-specific injury response, we first compared the microRNAome of uninjured skin and oral mucosa in mice. A total of 53 tissue-specific microRNAs for skin and oral mucosa epithelium were identified. The most striking difference was the high abundance of miR-10a/b in skin (accounting for 21.10% of the skin microRNAome) as compared to their low expression in oral mucosa (2.87%). We further examined the dynamic changes of microRNAome throughout the time course of skin and oral mucosal wound healing. More differentially expressed microRNAs were identified in skin wounds than oral wounds (200 and 33, respectively). More specifically, miR-10a/b was significantly down-regulated in skin but not oral wounds. In contrast, up-regulation of miR-21 was observed in both skin and oral wounds. The therapeutic potential of miR-10b and miR-21 in accelerating wound closure was demonstrated in in vitro assays and in a murine skin wound model. Thus, we provided the first site-specific microRNA profile of skin and oral mucosal wound healing, and demonstrate the feasibility of a microRNA-based therapy for promoting wound closure.

Effects of dermal wounding on distal primary tumor immunobiology in mice.

BACKGROUND: Before primary oral tumors are treated, various prophylactic procedures that require tissue repair are often necessary (e.g. biopsies, tooth extractions, radiation, and tracheotomies). Wound healing and tumor growth harness similar immune/inflammatory mechanisms. Our previous work indicates that tumors impair wound healing, although the extent to which tissue repair conversely influences tumor growth is poorly understood. Here, we test the hypothesis that dermal wound healing exacerbates primary tumor growth and influences tumor immunobiology. MATERIALS AND METHODS: Female, immunocompetent mice were inoculated subcutaneously with murine oral cancer cells (AT-84) to induce flank tumors. Half of the mice received dermal excisional wounds (4 × 3.5 mm diameter) on their dorsum 16 days later, whereas the skin of controls remained intact. Tumor and blood tissues were harvested 1 and 5 days post wounding, and tumor myeloid cell populations and inflammatory gene expression were measured. Circulating myeloid cells, cytokines, and corticosterone were also quantified. RESULTS: Wounding increased tumor mass, early tumor infiltration of macrophages, and tumor inflammatory gene expression. While wounding attenuated tumor growth-induced increases in circulating myeloid cells, no effects of wounding on circulating cytokine/endocrine measures were observed. CONCLUSIONS: These results indicate that modest skin immune/inflammatory processes can enhance distal tumor growth and alter innate tumor immunity. The implication for this work is that, in the presence of a tumor, the benefits of tissue-damaging procedures that occur clinically must be weighed against the potential consequences for tumor biology.

Tumors Alter Inflammation and Impair Dermal Wound Healing in Female Mice.

Tissue repair is an integral component of cancer treatment (e.g., due to surgery, chemotherapy, radiation). Previous work has emphasized the immunosuppressive effects of tumors on adaptive immunity and has shown that surgery incites cancer metastases. However, the extent to which and how tumors may alter the clinically-relevant innate immune process of wound healing remains an untapped potential area of improvement for treatment, quality of life, and ultimately, mortality of cancer patients. In this study, 3.5 mm full-thickness dermal excisional wounds were placed on the dorsum of immunocompetent female mice with and without non-malignant flank AT-84 murine oral squamous cell carcinomas. Wound closure rate, inflammatory cell number and inflammatory signaling in wounds, and circulating myeloid cell concentrations were compared between tumor-bearing and tumor-free mice. Tumors delayed wound closure, suppressed inflammatory signaling, and altered myeloid cell trafficking in wounds. An in vitro scratch "wounding" assay of adult dermal fibroblasts treated with tumor cell-conditioned media supported the in vivo findings. This study demonstrates that tumors are sufficient to disrupt fundamental and clinically-relevant innate immune functions. The understanding of these underlying mechanisms provides potential for therapeutic interventions capable of improving the treatment of cancer while reducing morbidities and mortality.

Intrinsic differences between oral and skin keratinocytes.

Keratinocytes cover both the skin and some oral mucosa, but the morphology of each tissue and the behavior of the keratinocytes from these two sites are different. One significant dissimilarity between the two sites is the response to injury. Oral mucosal wounds heal faster and with less inflammation than equivalent cutaneous wounds. We hypothesized that oral and skin keratinocytes might have intrinsic differences at baseline as well as in the response to injury, and that such differences would be reflected in gene expression profiles.

MicroRNA-99 family targets AKT/mTOR signaling pathway in dermal wound healing.

Recent studies suggest that microRNAs play important roles in dermal wound healing and microRNA deregulation has been linked with impaired wound repair. Here, using a mouse experimental wound healing model, we identified a panel of 63 differentially expressed microRNAs during dermal wound healing, including members of miR-99 family (miR-99a, miR-99b, miR-100). We further demonstrated that miR-99 family members regulate cell proliferation, cell migration, and AKT/mTOR signaling. Combined experimental and bioinformatics analyses revealed that miR-99 family members regulate AKT/mTOR signaling by targeting multiple genes, including known target genes (e.g., IGF1R, mTOR) and a new target (AKT1). The effects of miR-99 family members on the expression of IGF1R, mTOR and AKT1 were validated at both the mRNA and protein levels. Two adjacent miR-99 family targeting sites were identified in the 3'-UTR of the AKT1 mRNA. The direct interaction of miR-100 with these targeting sites was confirmed using luciferase reporter assays. The microRNA-100-directed recruitment of AKT1 mRNA to the RNAi-induced silencing complex (RISC) was confirmed by a ribonucleoprotein-IP assay. In summary, we identified a panel of differentially expressed microRNAs which may play important roles in wound healing. We provide evidence that miR-99 family members contribute to wound healing by regulating the AKT/mTOR signaling.

Restraint stress alters neutrophil and macrophage phenotypes during wound healing.

Previous studies reported that stress delays wound healing, impairs bacterial clearance, and elevates the risk for opportunistic infection. Neutrophils and macrophages are responsible for the removal of bacteria present at the wound site. The appropriate recruitment and functions of these cells are necessary for efficient bacterial clearance. In our current study we found that restraint stress induced an excessive recruitment of neutrophils extending the inflammatory phase of healing, and the gene expression of neutrophil attracting chemokines MIP-2 and KC. However, restraint stress did not affect macrophage infiltration. Stress decreased the phagocytic abilities of phagocytic cells ex vivo, yet it did not affect superoxide production. The cell surface expression of adhesion molecules CD11b and TLR4 were decreased in peripheral blood monocytes in stressed mice. The phenotype of macrophages present at the wound site was also altered. Gene expression of markers of pro-inflammatory classically activated macrophages, CXCL10 and CCL5, were down-regulated; as were markers associated with wound healing macrophages, CCL22, IGF-1, RELMα; and the regulatory macrophage marker, chemokine CCL1. Restraint stress also induced up-regulation of IL10 gene expression. In summary, our study has shown that restraint stress suppresses the phenotype shift of the macrophage population, as compared to the changes observed during normal wound healing, while the number of macrophages remains constant. We also observed a general suppression of chemokine gene expression. Modulation of the macrophage phenotype could provide a new therapeutic approach in the treatment of wounds under stress conditions in the clinical setting.

MMP-8 overexpression and persistence of neutrophils relate to stress-impaired healing and poor collagen architecture in mice.

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) are critical for tissue remodeling during wound repair. Psychological stress has been found to impair wound healing in humans and animals. The objective of this study was to assess MMP and TIMP gene expression during stress-impaired healing. Female SKH-1 mice (n=299) were divided into control and stress groups (13h restraint/day for 3days prior to and 5days post-wounding). Two 3.5mm cutaneous full-thickness wounds were placed on the dorsum of each mouse and wound measurements were performed daily. RT-PCR for gene expression of MMP-2, MMP-8, MMP-9, TIMP-1 and TIMP-2 was performed at days 1, 3 and 5. Immunohistochemical analyses of the healed wounds were performed at days 15 and 28. As expected, wounds healed more slowly in restraint-stressed mice compared to controls. Stressed mice exhibited MMP-8 overexpression and lower TIMP-1 levels during healing, and poorer collagen organization once healed. MMP-8 overexpression may have stemmed from a higher level of neutrophils, observed in wound tissue on days 3 and 5. These findings implicate higher neutrophil numbers, MMP-8 overexpression, and TIMP-1 under-expression, as mechanisms that may compromise wound outcomes such as scarring under conditions of stress.

Synthetic decapeptide reduces bacterial load and accelerates healing in the wounds of restraint-stressed mice.

Wound healing is a complex process involving four transitional yet concurrent stages: coagulation, inflammation, cell proliferation/epithelialization and remodeling. These overlapping stages occur uneventfully in normal physiology. However, during psychological stress, the inflammatory response can become dysregulated and result in increased susceptibility to bacterial infection and delayed wound closure. In our restraint stress model, cutaneous wounds of stressed SKH-1 mice demonstrate significantly higher levels of bacterial load, and healing progresses at a rate 30% slower, than in non-stressed mice. The purpose of this study was to test the hypothesis that a synthetic antimicrobial decapeptide (KSLW) enhances bacterial clearance during stress-impaired healing in mice. Here, using a Pluronic block copolymer nanocarrier, we endeavored to identify an efficient drug delivery system for KSLW, which would enhance the stability, substantivity and function of the cationic peptide in delayed-healing wounds. In this study, intradermal treatment of excisional wounds of stressed mice with 2mg/ml KSLW loaded in Pluronic F68, resulted in a sustained antimicrobial effect through post-operative day 5, with a 2-log (p<0.01) reduction in bacterial load compared with other stressed mice. The demonstrated bacterial reduction in KSLW-treated stressed mice did not approach the levels observed among control mice. Furthermore, treatment of stressed mice with KSLW improved healing, resulting in significantly faster (p<0.05) wound closure from days 2 to 5 post-wounding, relative to untreated stressed mice and stressed mice treated with Pluronic alone. These findings suggest that Pluronic F68 is an efficient carrier for KSLW, which improves its stability and activity in impaired dermal wounds.

Antimicrobial decapeptide KSL-W enhances neutrophil chemotaxis and function.

Mammalian cationic antimicrobial peptides have received increased attention over the last decade, due to their prokaryotic selectivity and decreased risk of microbial resistance. In addition, antimicrobial peptides display differential biological effects on mammalian immune cell function, such as migration, adhesion, and modulation of respiratory burst, which make them even more attractive as therapeutic agents. Synthetic combinatorial libraries provide a time-efficient and cost-effective source for these diverse molecules. The novel synthetic antimicrobial peptide, KSLW (KKVVFWVKFK-NH(2)), has been shown to display a broad spectrum of antimicrobial activity against Gram (+) and Gram (-) bacteria, fungi and viruses. In this study, we evaluated the alternative biological activity of the decapeptide on neutrophil migration and function. KSLW was demonstrated to be chemotactic for neutrophils in micromolar amounts, and neutrophil treatment with KSLW, after 1 min, resulted in significant increases in F-actin polymerization. KSLW was shown to inhibit oxygen radical production in PMA- and LPS-stimulated neutrophils. Future studies, to determine if KSLW regulates neutrophil phagocytosis, adhesion, and apoptosis, or examining the effect of KSLW on other mammalian cell types, such as cell populations of healing-impaired wounds, would provide significant insight for the potential therapeutic strategies offered by antimicrobial peptides.

Positional differences in the wound transcriptome of skin and oral mucosa.

BACKGROUND: When compared to skin, oral mucosal wounds heal rapidly and with reduced scar formation. Recent studies suggest that intrinsic differences in inflammation, growth factor production, levels of stem cells, and cellular proliferation capacity may underlie the exceptional healing that occurs in oral mucosa. The current study was designed to compare the transcriptomes of oral mucosal and skin wounds in order to identify critical differences in the healing response at these two sites using an unbiased approach. RESULTS: Using microarray analysis, we explored the differences in gene expression in skin and oral mucosal wound healing in a murine model of paired equivalent sized wounds. Samples were examined from days 0 to 10 and spanned all stages of the wound healing process. Using unwounded matched tissue as a control, filtering identified 1,479 probe sets in skin wounds yet only 502 probe sets in mucosal wounds that were significantly differentially expressed over time. Clusters of genes that showed similar patterns of expression were also identified in each wound type. Analysis of functionally related gene expression demonstrated dramatically different reactions to injury between skin and mucosal wounds. To explore whether site-specific differences might be derived from intrinsic differences in cellular responses at each site, we compared the response of isolated epithelial cells from skin and oral mucosa to a defined in vitro stimulus. When cytokine levels were measured, epithelial cells from skin produced significantly higher amounts of proinflammatory cytokines than cells from oral mucosa. CONCLUSIONS: The results provide the first detailed molecular profile of the site-specific differences in the genetic response to injury in mucosa and skin, and suggest the divergent reactions to injury may derive from intrinsic differences in the cellular responses at each site.

Elevated macrophage migration inhibitory factor (MIF) is associated with depressive symptoms, blunted cortisol reactivity to acute stress, and lowered morning cortisol.

Macrophage Migration Inhibitory Factor (MIF) is a proinflammatory cytokine produced by leukocytes and the secretory cells of the HPA axis. Remarkably, glucocorticoids (GC) induce leukocyte MIF secretion, while MIF renders leukocytes insensitive to the anti-inflammatory effects of glucocorticoids. In light of reported associations between dysphoric states, increased inflammatory activity, and reduced GC sensitivity, the current study investigated the association between MIF, loneliness and depressive symptoms. The study further investigated the relation between plasma MIF and markers of HPA function, i.e., diurnal cortisol and the cortisol response to acute stress. Healthy university undergraduates (N=126; 64 women) were invited to participate if their scores on the Beck Depression Inventory or UCLA loneliness scale were in the upper or lower quintile of their peer group. Plasma MIF and salivary cortisol were measured in response to a public speaking task. Ambulatory diurnal cortisol was assessed for 5 consecutive days. MIF levels were 40% higher in the high-depressive symptoms group compared to the low depressive symptoms group. Elevated MIF was also associated with a smaller cortisol response to acute stress and lower diurnal morning cortisol values. The observed association between HPA function and MIF remained robust after adjustment for depressive symptoms, and demographic, anthropomorphic, and behavioural factors. High levels of depressive symptoms were likewise associated with lower morning cortisol, but this association became non-significant after adjustment for MIF. MIF may be an important neuro-immune mediator linking depressive symptoms with inflammation and HPA dysregulation.

S100A8 and S100A9 inhibit neutrophil oxidative metabolism in-vitro: involvement of adenosine metabolites.

Neutrophils are short-lived granulocytic cells of the innate immune system specialized in the production of reactive oxygen species. S100A8 and S100A9 and their heterocomplex calprotectin play a role in neutrophil recruitment and represent 40% of neutrophil cytosolic protein weight. The present study was designed to test the effect of S100A8 and S100A9 on the rate of neutrophil oxidative metabolism. It is hypothesized that the two S100 proteins inhibit neutrophil associated oxidation. Granulocytes freshly isolated from healthy volunteers were tested for their ability to oxidize dichlorofluorescindiacetate (DCFH-DA) in-vitro. The data showed that S100A8 and S100A9 inhibited spontaneous and stimulated oxidation of the DCFH-DA probe by neutrophils. The inhibition of neutrophil oxidative metabolism by S100A8 and S100A9 was markedly reduced by the enzymatic activity of adenosine deaminase. Inhibitors of the P1 adenosine receptors also reduced the anti-oxidative effect of S100A8/A9 providing further support for the involvement of adenosine metabolites in S100A8/ A9 anti-oxidative effect.

Academic integrity in dental school: a call to action.

Recently there has been much discussion in the media and literature pertaining to academic misconduct in higher education. Dentistry has not been immune to this discussion. Recent "scandals" involving student misconduct in U.S. dental schools have sparked dialogue within dentistry's premier professional organizations. The authors of this position paper recognize that academic misconduct can be a serious threat to dental education and the profession of dentistry as a whole. This paper addresses academic misconduct in dental school, the impact it may have on our profession, and how educators can begin to develop strategies to curtail cheating in their institutions.

Ala42S100A8 ameliorates psychological-stress impaired cutaneous wound healing.

Although wound healing is generally a successful, carefully orchestrated and evolutionary sound process, it can be disregulated by extrinsic factors such as psychological-stress. In the SKH-1 restraint stress model of cutaneous wound healing, the rate of wound closure is approximately 30% slower in stressed mice. Delay in healing is associated with exaggerated acute inflammation and deficient bacterial clearance at the wound site. It has been suggested that wound hypoxia may contribute to the mechanisms of impaired cutaneous wound healing in the mouse SKH-1 model. Optimal healing of a cutaneous wound is a stepwise repair program. In its early phase, an inflammatory oxidative burst generated by neutrophils is observed. About 40% of neutrophils cytosolic protein weight is comprised of two calcium binding proteins S100A8 and S100A9. Our previous work has shown that S100A8 act as an oxidation-sensitive repellent of human neutrophils in-vitro. Ala(42)S100A8, a site-directed mutant protein is resistant to oxidative inhibition and inhibits neutrophil recruitment in-vivo. Accordingly, we tested the hypothesis that S100A8 may ameliorate wound healing in this model. We examined the effect of wild-type and ala(42)S100A8 for their ability to ameliorate wound closure rates. The data indicated that a single local application of ala(42)S100A8 ameliorated the decreased rate of wound closure resulting from stress. This occurred without significantly affecting wound bacterial clearance. Wild-type S100A8 only had a partial beneficial effect on the rate of wound closure. Those findings support further translational studies of S100 based intervention to ameliorate impaired wound healing.

Sex hormones and mucosal wound healing.

Wound healing studies, which have chiefly examined dermal tissues, have reported a female advantage in healing rates. In contrast, our laboratory recently demonstrated women heal mucosal wounds more slowly than men. We hypothesized sex hormones influence wound healing rates, possibly through their modulating effects on inflammation. This study involved 329 younger subjects aged 18-43 (165 women, 164 men) and 93 older subjects aged 50-88 (60 women, 33 men). A 3.5mm diameter wound was created on the hard oral palate and videographed daily to assess wound closure. Blood collected at the time of wounding was used to assess circulating testosterone, progesterone and estradiol levels, and in vitro cytokine production in response to LPS. No strong associations were observed between healing times and estradiol or progesterone levels. However, in younger subjects, lower testosterone levels related to faster wound closure. Conversely, in older women higher testosterone levels related to (1) lower inflammatory responses; and (2) faster healing times. No such relationships were seen in older men, or in women taking oral contraceptives or hormone replacement therapy [HRT]. Older women (50-54 years) not yet experiencing menopause healed similarly to younger women and dissimilarly from age-matched post-menopausal women. This suggests that the deleterious effects of aging on wound healing occur secondary to the effects of menopause. Supporting this, there was evidence in post-menopausal women that HRT augmented wound closure. Overall, this study suggests that human mucosal healing rates are modulated by testosterone levels. Based upon when between-group differences were observed, testosterone may impact upon the proliferative phase of healing which involves immune processes such as re-epithelialization and angiogenesis.

HIV infection and tooth loss.

OBJECTIVES: The objective of this study was to determine the relationship between HIV infection and tooth loss. Based on periodontal reports, we hypothesize HIV+ patients experience greater tooth loss than systemically healthy patients. STUDY DESIGN: This was a retrospective cross-sectional chart study involving 193 HIV+ patients and 192 controls matched on age, race, gender, and smoking status. The relationships between tooth loss and age, race, gender, smoking, CD4+ cell count, and viral load were determined. This study used a 2-year follow-up/maintenance period and was conducted during the era of highly active antiretroviral therapy (HAART). RESULTS: Tooth loss between groups was not significantly different at any time point: (1) before dental treatment; (2) after initial periodontal and restorative treatment; and (3) following a 2-year maintenance period. Age, race, and smoking were risk factors for tooth loss. Among HIV+ individuals, CD4+ cell count and viral load did not influence tooth loss. CONCLUSIONS: HIV infection, in the era of HAART, does not appear to be a risk factor for tooth loss. We also did not find any association between tooth loss and indices of HIV disease progression.

Depressive symptoms predict mucosal wound healing.

OBJECTIVE: There is mounting evidence that psychosocial stress can delay wound healing, but this literature almost exclusively pertains to dermal wound healing. Many surgical procedures involve damage to mucosal tissues and the time course and the role of repair processes, such as inflammation, in the healing of these tissues are markedly different from those in dermal healing. Feelings of depression and social isolation are common among surgical patients, and the present study therefore investigated if these factors predict the rate of mucosal wound healing. METHODS: Undergraduate students were invited to participate in the study if they reported high or low levels of loneliness or depressive symptoms, corresponding to the upper or lower quintile of their peer group. The UCLA loneliness scale and the Beck Depression Inventory [short form] were used for this screening. A sample of 193 healthy young adults (age range 18-31 years) received a 3.5-mm circular wound on the oral hard palate, under local anesthesia. Healing was monitored by daily videographs of the wound. RESULTS: The median healing rate was 7 days. High dysphoric participants were, however, more likely to heal slower than this median healing rate (odds ratio 3.57 (1.58-8.07); p < .001). This association remained robust after correction for a broad range of demographic and behavioral variables, including gender, age, ethnicity, and health behaviors. High dysphoric individuals also exhibited significantly larger average wound sizes from day 2 post wounding onward. Loneliness and diurnal cortisol secretion (measured over 5 days) were unrelated to healing. CONCLUSION: Depressive symptoms predict the rate of mucosal wound healing in healthy young adults. We discuss potential pathways that warrant further investigation.

Restraint stress impairs early wound healing in mice via alpha-adrenergic but not beta-adrenergic receptors.

Stress negatively influences wound healing in a clinically relevant manner. In an animal model, repeated restraint stress (RST) impairs wound healing in mice, partially through stress-induced glucocorticoid (GC) release. However, the role of stress-induced catecholamines (i.e., (nor)epinephrine) in healing has not been elucidated. In the present study, two 3.5mm round dermal wounds were placed on the backs of mice. Animals were restrained overnight for 3 days prior to and 5 days post-wounding. Prior to RST, mice were injected with either phentolamine or nadolol: non-specific alpha- and beta-adrenergic receptor antagonists, respectively. Pictures were taken daily to measure the rates of wound closure and contraction. Blockade of alpha-adrenergic, but not beta-adrenergic receptors, attenuated impairments in wound closure and contraction, and normalized edema, in RST mice. Thus, although stress impairment in wound healing clearly involves GCs, catecholamines play an important role via alpha-adrenergic receptor stimulation.

Mucosal wound healing: the roles of age and sex.

HYPOTHESIS: It remains unclear whether aging delays wound healing, as past human studies have not adequately controlled for confounding factors such as morbidity and medications. Furthermore, although dermal wounds heal more quickly in women than in men, clinical observations suggest that the opposite may be true for mucosal healing. We assessed age and sex differences in mucosal wound healing, and we hypothesized that aging delays healing and sex modulates healing independent of age. DESIGN AND SETTING: Clinical experimental study performed from June 2000 to August 2003 involving younger and older adult volunteers from the general community. PARTICIPANTS: Two hundred twelve male and female volunteers aged 18 to 35 years (n = 119) or 50 to 88 years (n = 93). INTERVENTION: Standardized 3.5-mm circular wounds were placed on the oral hard palates of volunteers. MAIN OUTCOME MEASURE: Wound videographs were taken daily for 7 days after wounding to assess wound closure. RESULTS: Wounds healed significantly more slowly in older adults compared with younger adults (P<.001) regardless of sex. This remained true even when individuals receiving medication and/or having a coexisting medical condition were excluded. Mucosal wounds healed more slowly in women than in men (P = .008) regardless of age. These effects were independent of demographic factors such as ethnicity, alcohol or nicotine use, or body mass index. CONCLUSIONS: Wound closure in older individuals was clearly delayed even when eliminating potential age-related confounds, indicating that aging does slow wound healing. Wound closure in women was also delayed, suggesting that wound healing is modulated by different mechanisms depending on tissue type. These findings may help target patients with increased surgical risks and greater need for postsurgical care.