Impaired healing following implant placement surgery: A case report of a modern-day manifestation of scurvy.

Simultaneous ablation of the two known activators of plasminogen (Plg), urokinase-type (uPA) and the tissue-type (tPA), results in a substantial delay in skin wound healing. However, wound closure and epidermal re-epithelialization are significantly less impaired in uPA;tPA double-deficient mice than in Plg-deficient mice. Skin wounds in uPA;tPA-deficient mice treated with the broad-spectrum matrix metalloproteinase (MMP) inhibitor galardin (N-[(2R)-2-(hydroxamido-carbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide) eventually heal, whereas skin wounds in galardin-treated Plg-deficient mice do not heal. Furthermore, plasmin is biochemically detectable in wound extracts from uPA;tPA double-deficient mice. In vivo administration of a plasma kallikrein (pKal)-selective form of the serine protease inhibitor ecotin exacerbates the healing impairment of uPA;tPA double-deficient wounds to a degree indistinguishable from that observed in Plg-deficient mice, and completely blocks the activity of pKal, but not uPA and tPA in wound extracts. These findings demonstrate that an additional plasminogen activator provides sufficient plasmin activity to sustain the healing process albeit at decreased speed in the absence of uPA, tPA and galardin-sensitive MMPs and suggest that pKal plays a role in plasmin generation.

Cold temperatures have been shown to slow skin wound healing. However, the specific mechanisms underlying cold-induced impairment of wound healing remain unclear. Here, we demonstrate that small extracellular vesicles derived from cold-exposed mouse plasma (CT-sEVs) decelerate re-epithelialization, increase scar width, and weaken angiogenesis. CT-sEVs are enriched with miRNAs involved in the regulation of wound healing-related biological processes. Functional assays revealed that miR-423-3p, enriched in CT-sEVs, acts as a critical mediator in cold-induced impairment of angiogenic responses and poor wound healing by inhibiting phosphatase and poly(A) binding protein cytoplasmic 1 (PABPC1). These findings indicate that cold delays wound healing via miR-423-3p in plasma-derived sEVs through the inhibition of the ERK or AKT phosphorylation pathways. Our results enhance understanding of the molecular mechanisms by which cold exposure delays soft tissue wound healing.

BACKGROUND: Wound Healing is the summation of a number of processes that follow injury. Despite immense advances in the technique of wound creation and closure, there continues to be an important percentage of patients undergoing abdominal operations, suffering from delayed wound healing and partial wound failure. Apart from increasing patient morbidity and hospital stay, it also is a psychological blow to both the surgeon and patient alike. The incidence of post-operative wound dehiscence was investigated in patients in several studies (e.g., 1.25 per 1,000 discharges at 0 to 17 years, 1.74 at 18 to 44 years, 2.65 at 45 to 65 years, and 3.77 at 65 or more years. Additionally, it was found that this complication resulted in an increased mean length of stay (by 21.1 days) and a tremendous increase in charges for affected patients, with 5.7 times higher odds of in-hospital mortality.Wound Infection rate varies from 6.8 percent to 21.4 percent depending on the procedure and other patient factors. The aim of this study is to assess the various factors inuencing post laparotomy wound healing. To identify the pre-operative, operative and post operative risk factors in patients having poor wound healing. RESULTS This prospective study was conducted in Government General Hospital, kurnool. A total of 100 patients undergoing laparotomies were studied .40 patients were found to have delayed wound healing. The strongest association for delayed healing was found to be wound infection, followed by chronic cough,steroids and poorly controlled diabetes. CONCLUSIONS The incidence of delayed healing was found to be higher in our study with increased incidence of wound infection. It was found that emergency laparotomies were associated with an increased incidence of wound infection and thereby delayed healing. Poor wound healing is also associated strongly with poor nutrition and uncontrolled diabetes. These factors should be taken into account and efforts have to be made to correct the risk factors pre or post-operatively.

Stress slows cutaneous wound healing (WH) in an endogenous glucocorticoid (GC)-dependent fashion. We investigated whether stress/GC-induced delays in WH require further intracutaneous activation of endogenous GC; and whether blockade or down-regulation of peripheral activation normalizes WH in the face of stress. Delayed WH in our motion-restricted murine model of stress could be attributed to elevated systemic GC, because blockade of GC production (using corticotropin-releasing factor inhibitor, antalarmin), or of peripheral binding to the GC receptor [GCr], with an antagonist, Ru-486, normalized WH. We next investigated whether local blockade or down-regulation of the peripheral GC-activating enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), accelerates cutaneous WH. Topical applications of nonspecific (carbenoxolone) as well as an isoform-specific 11β-HSD1 inhibitor overcame stress and exogenous GC-induced delays in WH. Moreover, two liver X receptor ligands, TO901317 and GW3695, down-regulated expression of 11β-HSD1, attenuating stress-induced delays in WH. Combined inhibitor and liver X receptor ligand applications accelerated WH in the face of stress/systemic GC. Thus: (1) intracutaneous conversion of inactive-to-active GC accounts for stress (GC)-induced delays in WH; and (2) blockade or down-regulation of 11β-HSD1 and/or GCr normalize cutaneous WH in the face of stress/GC. Local blockade or down-regulation of cutaneous GC activation could help enhance WH in various clinical settings.

Chronic non-healing wounds are characterized by persistent inflammation, excessive matrix-degrading proteolytic activity and compromised extracellular matrix (ECM) synthesis. Previous studies showed that S100A8/A9 are strongly dysregulated in delayed wound healing and impair the proper function of immune cells. Here, we demonstrate an unrecognized pathological function of S100A9 overexpression in wounds with impaired healing that directly affects ECM functions in fibroblasts. S100A9 was analyzed in two different mouse models mimicking the features of the two most prominent types of non-healing wounds in humans. Db/db mice were used as a model for diabetes-associated impaired wound healing. Iron-overloaded mice were used to mimic the conditions of impaired wound healing in chronic venous leg ulcers. The skin wounds of both mouse models are characterized by delayed wound closure, high and sustained expression of pro-inflammatory mediators and a substantially decreased ECM deposition, all together the hallmarks of non-healing wounds in humans. The wounds of both mouse models also present a solid and prolonged expression of S100A8 and S100A9 that coincides with a compromised ECM deposition and that was confirmed in chronic wounds in humans. Mechanistically, we reveal that S100A9 directly affects ECM deposition by shifting the balance of expression of ECM proteins and ECM degrading enzymes in fibroblasts via toll-like-receptor 4-dependent signaling. Consequently, blocking S100A9 during delayed wound healing in db/db mice restores fibroblast ECM functions eliciting increased matrix deposition. Our data indicate that the dysregulation of S100A9 directly contributes to a compromised ECM deposition in chronic wounds and further suggests S100A9 as a promising therapeutic target to improve tissue repair in chronic wounds.

Decreased Macrophage Number and Activation Lead to Reduced Lymphatic Vessel Formation and Contribute to Impaired Diabetic Wound Healing

Women with inflammatory bowel disease (IBD) face complexities of disease management during pregnancy and childbirth. Apprehension regarding vaginal delivery in pregnant individuals with IBD persists due to concern for perianal disease and perineal trauma. The incidence of poor wound healing after obstetric anal sphincter injury is approximately 4% in the general population. In an IBD population, risk of developing and difficulty healing perineal tears and episiotomy is not well described. In a multicenter prospective cohort of pregnant individuals with IBD, we collected demographic information, IBD disease and treatment history, pregnancy and labor history, and reports of delayed wound healing >1 month from episiotomy, vaginal tear, or Cesarean (C-) section. Prospective data were collected using questionnaires that were administered each trimester of pregnancy, at delivery, and in the year postpartum. There were 743 patients in the PIANO registry who answered questions pertaining to postpartum wound healing, with 330 (44%) reporting a C-section and 413 (56%) reporting a vaginal delivery. Of 119 C-section deliveries assessed for delayed wound healing, only 1 (0.8%) patient reported this complication. Episiotomies were reported in 59 (14%) patients, with 9 (15%) reporting delayed wound healing. Vaginal tears were reported in 252 (64%) patients. Delayed wound healing from vaginal tear was reported in 9% of patients. Use of immunomodulators was associated with delayed wound healing from episiotomy (33% vs 0% for those on no medications, P = .024). No difference was seen in wound healing time for episiotomy with other medications, including corticosteroids, anti-tumor necrosis factor, or anti-integrin use. Delayed wound healing from vaginal tear was not associated with any class of IBD medication. Episiotomy was a common occurrence in patients with IBD. Immunomodulator, but not biologic, use was found to be associated with delayed wound healing. This association could reflect a direct medication effect on episiotomy wound healing or inadequate treatment of underlying active disease prior to delivery. Vaginal tears were also common but delayed wound healing was not associated with IBD therapy. C-section occurred at high rates, particularly in Crohn's disease patients, with no reported delays in postpartum wound healing.

Impaired wound healing often occurs in patients with diabetes and causes great inconvenience to them. Aside from the presence of prolonged inflammation, the accumulation of oxidative stress is also implicated in the delayed wound healing. In the present study, we tested the effect of verbascoside, a caffeoyl phenylethanoid glycoside, on the improvement of cell viability and wound healing capacity of gingival epithelial cells under high glucose condition. We showed that verbascoside attenuated the high glucose-induced cytotoxicity and impaired healing, which may be associated with the downregulation of oxidative stress. Our results demonstrated that verbascoside increased the activity of the antioxidant enzyme SOD and reduced the oxidative stress indicator, 8-OHdG, as well as apoptosis. Moreover, verbascoside upregulated the PGC1-α and NRF1 expression and promoted mitochondrial biogenesis, which was mediated by suppression of PKC/HMGB1/RAGE/NFκB signaling. Likewise, we showed the inhibitory effect of verbascoside on oxidative stress was via repression of PKC/HMGB1/RAGE/NFκB activation. Also, our data suggested that the PKC-mediated oxidative stress may lead to the elevated production of inflammatory cytokines, IL-6 and IL-1β. Collectively, we demonstrated that verbascoside may be beneficial to ameliorate impaired oral wound healing for diabetic patients.

Retrospective cohort study. Malnutrition has been found to have negative effects on the immune system and inflammatory responses, impairing the wound healing process. Free flap failure is a serious complication in patients undergoing microvascular reconstruction, as it increases patient morbidity, length of stay in the hospital, patient, and hospital costs, as well as causes the need for further surgical interventions1. Malnutrition is estimated to be present in 35-50% of head and neck cancer patients with higher rates in those experiencing hypo-oropharyngeal disease. This is often caused by functional and pain limitations from due to disease burden causing odynophagia and dysphagia. The Malnutrition Universal Screening Tool (MUST) is recommended for risk screening and provides three scores for risk classification: high, intermediate, and low2. We argue that the use of MUST as a preoperative assessment tool is useful to predict postoperative surgical site infection and delayed wound healing in patients that will undergo reconstruction with free flaps for head and neck defects. A retrospective cohort study was designed to include all subjects who underwent head and neck microvascular free tissue transfer at a single institution between 2013 and 2019. Primary and secondary reconstructions were included, for benign or malignant pathology, osteonecrosis, osteomyelitis, congenital defects, and trauma. The nutritional risk was evaluated using MUST, which analyzes body mass index, weight loss, and acute disease effect, to classify patients as low, intermediate, and high risk. We further divided the subjects into two comparison groups- low-intermediate and high risk. The primary outcome was surgical site complications and delayed wound healing. Data was analyzed as frequencies and means with standard deviations, as well as Fisher's exact test and t-test. P-values <0.05 were considered statistically significant. Analyses were done utilizing IBM SPSS Statistics Version 29. 131 subjects were included for data analysis, with 54 being considered low MUST risk, 12 intermediate risk (66 low-intermediate), and 65 were high risk. The mean BMI overall was 25.5 ±5.3, and 27.2 in the low-intermediate group, and 23.7 in the high-risk group. Eighty-two subjects experienced <5-pound weight loss in the preceding 6 months to surgery, while 17 lost between 5-10 pounds, and 23 lost 10< pounds. Cancer/osteonecrosis was the etiology for 54 (82%) subjects of the low-intermediate group, and 61 (92%) of the high-risk group (P = .089). The subjects classified in High-risk group according to the MUST score had 11% more surgical site complications (P = .120) and 13.7% more delayed wound healing and dehiscence(P = .09); only 3 subjects in the study presented total flap loss and they were all in the High-risk group. Surgical site complication, delayed wound healing rates and partial or total flap loss were not increased by any specific medical comorbidity or history such as radiation or chemotherapy. In conclusion, Subjects with high MUST score had increased complications and poor wound healing, and subjects with acute disease effect that induces a phase of nil per os for > 5 day have higher risk of total flap loss and surgical site complication.

Angiogenesis and vasculogenesis: Inducing the growth of new blood vessels and wound healing by stimulation of bone marrow–derived progenitor cell mobilization and homing

EFFECTS OF UNLOADING CONDITION ON WOUND HEALING PROCESS: EXPERIMENTS WITH HIRUDO MEDICINALIS

Hypoxia/reoxygenation conditions can generate oxidative stresses resulting in the suppression of cell proliferation and the delay of corneal epithelial wound healing. The purpose of this study was to investigate the cellular mechanism involving the role of the stress-responsive Polo-like kinase 3 (Plk3) in hypoxic stress-induced delay of corneal epithelial wound healing. Plk3 activities were determined by immunochemistry and immunocomplex kinase assay approaches. Corneal epithelial wound healing was evaluated by a whole-eye organ culture model and by scratch-induced wound closure assay. Corneal epithelial layer was removed by using a corneal rust-ring-remover in wild-type and Plk3(-/-) mice. Wound healing was analyzed using a confocal imaging system. Cell growth was measured by MTT assays. The effect of hypoxic stress on early stages of corneal epithelial wound healing was compared with other oxidative stresses, including UV, CoCl(2), and H(2)O(2) treatments. Hypoxic stress-induced delay of corneal epithelial wound healing was further evaluated in human corneal epithelial cells and in the corneas of wild-type and Plk3 knockout (Plk3(-/-)) mice. Hypoxic stress-induced Plk3 activation resulted in growth attenuation and delay of wound healing. Further evidence demonstrated that the increase in Plk3 activity in constitutively active Plk3-expressed cells significantly enhanced stress-induced delay of wound healing. In contrast, hypoxic stress-induced delay of wound healing was markedly diminished in the corneas of Plk3 deficient Plk3(-/-) mice. These results provide for the first time important evidence that Plk3 plays a significant role in hypoxic stress-induced attenuation of cell growth and delay of corneal epithelial wound healing.

Diabetic wounds result in significant morbidity, prolonged hospitalization, and enormous health-care expenses. Pigs have been shown to have wound healing resembling that in humans. The aim of this study was to develop a large-animal model for diabetic wound healing. Diabetes was induced by streptozotocin injection in Yorkshire pigs. Full-thickness wounds were created and dressed with a sealed chamber. Nondiabetic pigs with or without high glucose wound fluid concentration served as controls. Glucose concentration in serum and wound fluid was measured and collected. Wound contraction was monitored, and biopsies were obtained for measurement of reepithelialization. Wound fluid was analyzed for insulin-like growth factor-1 (IGF-1), platelet-derived growth factor, and transforming growth factor. Glucose concentration in wound fluid initially followed serum levels and then decreased to undetectable on day 9. Reepithelialization was significantly delayed in diabetic pigs. In nondiabetic pigs, wounds treated in a local hyperglycemic environment, and thus excluding the effects of systemic hyperglycemia, showed no difference in wound closure compared with controls. This suggests that delayed wound healing in diabetes is not induced by local high-glucose concentration itself. Analysis of growth factor expression showed a marked reduction in IGF-1 in the diabetic wounds. Diabetic pigs have impaired healing that is accompanied by a reduction of IGF-1 in the healing wound and is not due to the local hyperglycemia condition itself.

Poor wound healing is one of the most common complications after laparotomy, especially in lower abdominal midline incisions. The aims of this trial are to assess the value of subcutaneous suture and identify risk factors to prevent poor wound healing. From October 2010 to October 2011, a total of 180 patients were randomized to the subcutaneous suture group (n = 89) or control group (n = 91) after laparotomy with a lower midline incision. Univariate and multivariate analyses were performed to determine the predictive significance of variables of poor wound healing. Patients' demographics, preoperative laboratory values, and operative details were comparable between the two groups. The overall rate of poor wound healing was 16.7 per cent (30 of 180). Patients randomized to subcutaneous suture group (n = 89) had poor healing in 10.1 per cent (nine of 89) and those without suture (n = 91) in 23.1 per cent (21 of 91) (P = 0.020). Multivariate logistic regression analysis revealed that American Society of Anesthesiologists (ASA) score (3 to 4) (odds ratio [OR], 2.933), subcutaneous suture (OR, 0.323), and blood loss (greater than 200 mL) (OR, 5.995) were independent risk factors for poor wound healing. Subcutaneous suture can effectively accelerate wound healing. Nonsubcutaneous suture, ASA score (3 to 4), and blood loss (greater than 200 mL) are independent risk factors for poor would healing.

Objective: To analyze the association between postoperative hypoalbuminemia and poor wound healing, and to evaluate whether postoperative supplementation of human serum albumin can improve postoperative wound healing after lumbar internal fixation surgery. Methods: From January 2014 to December 2018, 602 patients who underwent lumbar internal fixation surgery in the Department of Orthopedics, Zhujiang Hostiptal of Southern Medical University were identified. There were 250 males (41.5%) and 352 females (58.5%), with an average age of (60±12) years. All patients' clinical records were reviewed, including demographics data, comorbidity data, preoperative serum laboratory values, intraoperative factor, postoperative serum laboratory values and wound healing, and the incidence rate of poor wound healing was calculated. The statistical analyses were performed with R software and Empower(R) to analyze the factors related to poor wound healing. Multiple logistic regression models were performed with adjustment for the potential confounders to evaluate the effect of postoperative hypoalbuminemia and supplementation of human serum albumin on the development of poor wound healing. Results: Poor wound healing occurred in 51(8.47%) patients. After adjusting for the confounding factors, multiple regression analysis showed that there was no correlation between postoperative albumin levels and poor wound healing(OR=1.00, 95%CI: 0.91-1.10, P=1.000). Compared with patients with postoperative normal albumin level, postoperative hypoalbuminemia would increase the risk of poor wound healing by 13% (OR=1.13, 95%CI: 0.47-2.70, P=0.787). There was no correlation between supplementation of human serum albumin and poor wound healing in patients with normal albumin levels or postoperative hypoalbuminemia (P>0.05). Conclusions: There is no correlation between postoperative hypoalbuminemia and poor wound healing after lumbar internal fixation surgery. Postoperative supplementation of human serum albumin can't improve wound healing.