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General Purpose: To review the role of nutrition and high-quality dietary protein intake in creating healthy granulation tissue and optimize wound healing in patients with chronic wounds., Target Audience: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and registered nurses with an interest in skin and wound care., Learning Objectives/outcomes: After participating in this educational activity, the participant will:1. Summarize the structure and composition of proteins. 2. Specify the role of proteins in generating healthy granulation tissue and wound healing. 3. Explain the physiologic pathways involved in the wound healing process. 4. Describe evidence-based interventions to support nutrition in wound healing., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The management of chronic wounds presents a challenge for surgeons. In this pilot study, the authors established a novel auto-grafting approach for chronic wounds and evaluated its efficacy., Purpose: The objective of this pilot study was to observe the clinical efficacy of granulation-embedded skin grafting for the treatment of chronic wounds at high altitudes., Methods: The data of 45 patients with chronic wounds were obtained from the medical records of the Yushu People's Hospital. Patients were divided into stamp skin-grafting and granulation-embedded skin-grafting groups. Skin graft survival rate, wound coverage rate, and wound-healing time were observed and recorded. The length of hospital stay and 1% total body surface area (TBSA) treatment cost were compared., Results: Significant differences were noted in skin graft survival rate (94% ± 3% vs 86% ± 3%, P < .01), wound coverage rate on postoperative day 7 (61% ± 16% vs 54% ± 18%, P < .01), and wound-healing times (23 ± 2.52 days vs 31 ± 3.61 days, P < .05). The length of hospital stay and 1% TBSA treatment cost were significantly reduced in the granulation-embedded skin grafting group (P < .05)., Conclusions: Granulation-embedded skin grafting can improve the healing of chronic wounds at high altitudes. These findings provide a new approach to the clinical treatment of chronic wounds.

Objective: Skull baseosteomyelitis (SBO) is a rare phenomenon that typically occurs in diabetic or immunocompromised patients, causing significant morbidity and mortality. This study aimed to analyze a single institution's treatment results in SBO patients and propose anew integrated clinicoradiological classification system., Methods: The medical records of 32 SBO patients that were treated at a tertiary care center between 2006 and 2017 were retrospectively reviewed. A scoring system based on anatomical involvement according to MRI was created. Subsequently, the scoring system was integrated with cranial nerve dysfunction status and a clinical grading system (CGS) was proposed., Results: Among the 32 patients, 78.1% were diabetic and 63% had cranial nerve dysfunction at presentation. Bone erosion based on CT was greater in the patients without regression (P = 0.046). The regression rate decreased from clinical grade (CG)1 to CG3 (P = 0.029). Duration of hospitalization increased as CG increased (P = 0.047). Surgery had no effect on regression status at the time of discharge (P = 0.41). The 1-year, 2-year, and 5-year overall survival rates were 82.2%, 70.8%, and 45.8%, respectively. CG was significantly correlated with overall survival but not with disease-specific survival (log-rank; P = 0.017, P = 0.362, respectively)., Conclusion: SBO continues to pose a challenge to clinicians, and causes significant morbidity and mortality. The proposed new classification system can be an option for grouping SBO patients according to clinical and radiological findings, helping clinicians estimate prognosis., Competing Interests: Declaration of Competing Interest Authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

This study explored the clinical effectiveness of antibiotic-loaded bone cement on primary treatment of diabetic foot infection. This is a randomized controlled study, including thirty-six patients with diabetic foot ulcer complicated by osteomyelitis who had undergone treatment between May 2018 and December 2019. Patients were randomly divided into control group (group A) and study group (group B). Patients in the intervention group received antibiotic-loaded bone cement repair as primary treatment, while patients in the control group received conventional vacuum sealing draining treatment. Clinical endpoints were assessed and compared between the two groups, including wound healing time, wound bacterial conversion, NRS pain score, number of wound dressing changes, and average hospitalization time. All patients were followed up for a period of 12 months after discharge. Results show that compared with the control group, patients in the study group had significant difference in the number of patients for baseline pathogens eradication, short NRS pain score, hospital length of stay and cost, wound surface reduction, healing time, low rate of complications, and infection recurrence. Based on the findings, we conclude that antibiotic-loaded bone cement can be used for treatment of wound in patient with diabetic foot infection. It can help to control wound infections, shorten hospital length of stay, reduce medical cost, and relieve both doctors' and patients' burden. The application of antibiotic-loaded bone cement is suitable for diabetic wound with soft tissue infection or osteomyelitis., Competing Interests: All authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2021 Regis Ernest Mendame Ehya et al.)

Cutaneous wound pain causes physical and psychological stress for patients with wounds. Previous studies reported that stress induces hyperalgesia and deteriorates wound healing. However, the effect of the stress response such as in hypothalamic-pituitary-adrenal (HPA) axis on local wound area is unclear. We aimed to investigate the effects of a stress response on the mechanical withdrawal threshold in the local wound area and describe the identification of a wound pain exacerbation. We topically injected adrenocorticotropic hormone (ACTH) into the granulation tissue of full-thickness cutaneous wound model rats on the fifth day postwounding and measured the mechanical withdrawal thresholds, cytochrome P450 2Bs levels and concentration of 5,6-epoxyeicosatrienoic acid in wound exudate. We found that ACTH induced mechanical hypersensitivity at 4 and 6 hours after injection (P = .004 and .021, respectively), and increased gene expression of cytochrome P450 2B12 expression (P = .046). Concentration of 5,6-EET in the wound exudate was moderately correlated with the mechanical withdrawal threshold (r = -.630). Finally, the mechanical withdrawal threshold in the 5,6-EET group was significantly lower than that in the control group at 2 hours after the injection (P = .015). We propose that 5,6-EET is one of the most promising contributors to the wound pain exacerbation. These findings could guide clinical wound and pain management., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hypergranulation tissue formation is a common complication after gastrostomy tube (G-tube) placement, occurring in 44%-68% of children. Hydrocolloid dressings are often used in the treatment of hypergranulation tissue but have not been studied for the prevention of postoperative hypergranulation tissue. An institutional review board (IRB)-approved, prospective, randomised study was performed in paediatric patients who underwent G-tube placement at a single, large children's hospital from January 2011 to November 2016. After placement, patients were randomly assigned to (1) standard postoperative G-tube care, (2) standard hydrocolloid G-tube dressing, or (3) silver-impregnated hydrocolloid G-tube dressing, and the incidences of postoperative hypergranulation tissue formation, tube dislodgement, infection, and emergency department use were compared. A total of 171 patients were enrolled; 128 patients (75%) had at least 4 months of follow up and were included in the analyses. Eighty-nine patients (69.5%) developed hypergranulation tissue during the postoperative period, with no significant differences in incidence among the three treatment arms. Of those who developed hypergranulation tissue, 46 (56%) visited the emergency department, compared with 6 of the 39 patients (19%) who did not develop hypergranulation tissue. Hydrocolloid dressings (standard or silver-impregnated) do not prevent the development of hypergranulation tissue or other complications after G-tube placement in paediatric patients., (© 2018 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Background: Chronic kidney disease affects more than 500 million people worldwide. In this context, the uremic toxins present are related to worsening in tissue healing., Aim: Evaluate on healing of colonic anastomosis in uremic rats, serum and anatomopathological indicators, which may be related to the change tissue repair process., Methods: Twenty Wistar rats, were randomly separated into two groups. In the sham group they were submitted to 5/6 nephrectomy simulation in left kidney, simulation right nephrectomy, median laparotomy, colotomy and colorraphy. In the uremia group, they were submitted to 5/6 nephrectomy of the left kidney, total nephrectomy of the right kidney and median laparotomy, colotomy and colorraphy. Were collected for serum urea, creatinine and CRP dosages and the colonic segments were studied for evaluation of granulation tissue, collagen maturation, microvascular and myofibroblasts density, and cell viability. Through histochemical processing, microvascular density was evaluated by anti-CD34 monoclonal antibody marking, cell viability by cell proliferation nuclear antigen screening and myofibroblasts density with monoclonal anti-α-actin antibody. Computerized histometry was used for evaluations of collagens type I and III by the coloration of picrosirius., Results: The group submitted to nephrectomy 5/6, compared to the sham group, show urea increase (p<0.0000) and higher C reactive protein (p=0.0142). Decrease of granulation tissue formation (border reepithelialization p=0,0196, angiofibroblast proliferation p=0.0379), mean collagen I (p=0,0009) and collagen III (p=0,016), microvascular density (p=0,0074), cell proliferation nuclear antigen (p<0,0000) and myofibroblasts (p<0,0001)., Conclusion: The uremia induced by nephrectomy 5/6 model establishes negative impact in the colonic wound healing.

Chronic wounds complicated by diabetes are a significant clinical issue, and their occurrence is expected to continue to rise due to an increased prevalence of diabetes mellitus, especially type 2 diabetes. Diabetic wounds frequently lead to nonhealing ulcers, and often eventually result in limb amputation due to the high risk of infection of the chronic wound. Here, we present a tissue-engineered treatment that combines a novel electrochemically deposited collagen wound matrix and human adipose-derived stem cells. The matrix fabrication process is optimized for voltage and time, and the final collagen biomaterial is thoroughly characterized. This collagen material possesses high tensile strength, high porosity, and excellent biocompatibility and cellular proliferation capabilities. Human adipose-derived stem cells were seeded onto the collagen wound matrix and this construct is investigated in a full thickness excisional wound in a mouse model of type 2 diabetes. This novel treatment is shown to stimulate excellent healing and tissue regeneration, resulting in increased granulation tissue formation, epidermal thickness, and overall higher quality tissue reformation. Both the collagen wound matrix alone and collagen wound matrix in combination with adipose derived stem cells appeared to be excellent treatments for diabetic skin wounds, and in the future can also be optimized to treat other injuries such as burns, blast injuries, surgical incisions, and other traumatic injuries.

Objectives: Magnetic resonance imaging (MRI) and in particular diffusion-weighted imaging (DWI) have been broadly proven to be the reference imaging method to discriminate between cholesteatoma and noncholesteatomatous middle ear lesions, especially when high tissue specificity is required. The aim of this study is to define a range of apparent diffusion coefficient (ADC) values within which the diagnosis of cholesteatoma is almost certain., Methods: The study was retrospectively conducted on a cohort of 124 patients. All patients underwent first- or second-look surgery because primary or secondary acquired cholesteatoma was clinically suspected; they all had preoperative MRI examination 15 days before surgery, including DWI from which the ADC maps were calculated., Results: Average ADC value for cholesteatomas was 859,4 × 10 -6  mm 2 /s (range 1545 × 10 -6  mm 2 /s; IQR = 362 × 10 -6  mm 2 /s; σ = 276,3 × 10 -6  mm 2 /s), while for noncholesteatomatous inflammatory lesions, it was 2216,3 × 10 -6  mm 2 /s (range 1015 × 10 -6  mm 2 /s; IQR = 372,75 × 10 -6  mm 2 /s; σ = 225,6 × 10 -6  mm 2 /s). Interobserver agreement with Fleiss' Kappa statistics was 0,96. No overlap between two groups' range of values was found and the difference was statistically significant for p < 0.0001., Conclusions: We propose an interval of ADC values that should represent an appropriate benchmark range for a correct differentiation between cholesteatoma and granulation tissue or fibrosis of noncholesteatomatous inflammatory lesions.

Hypoxia in skin wounds is thought to contribute to healing through the induction of hypoxia inducible factor-1 (HIF-1). Although HIF-1 can regulate the expression of vascular endothelial growth factor A (Vegfa), whether hypoxia and HIF-1 are required to induce Vegfa expression in the context of wound healing is unknown. To test this hypothesis, we evaluated Vegfa expression and wound healing in mutant mice that lack a functional HIF-1 binding site in the Vegfa promoter. Full-thickness excisional wounds were made using a biopsy punch, left to heal by second intention, and granulation tissue isolated on a time course during healing. mRNA levels of Vegfa and its target genes platelet-derived growth factors B (Pdgfb) and stromal cell-derived factor-1 (Sdf1) were measured by RT-qPCR, and HIF-1alpha and VEGFA protein levels measured by immunoblotting. Lower levels of Vegfa, Pdgf1 and Sdf1 mRNA were found in intact skin of mutant mice relative to wild-type controls (n = 6 mice/genotype), whereas levels in granulation tissue during wound healing were unaltered. VEGFA protein levels were also lower in intact skin of the mutant versus the wild-type mice. Decreased Vegfa mRNA levels in skin of mutant mice could not be attributed to decreased HIF-1alpha protein expression, and were therefore a consequence of the loss of HIF-1 responsiveness of the Vegfa promoter. Comparative histologic analyses of healing wounds in mutant and wild-type mice (n = 8 mice/genotype) revealed significant defects in granulation tissue in the mutant mice, both in terms of quantity and capillary density, although epithelialization and healing rates were unaltered. We conclude that HIF-1 is not a major regulator of Vegfa expression during wound healing; rather, it serves to maintain basal levels of expression of Vegfa and its target genes in intact skin, which are required for optimal granulation tissue formation in response to wounding.

Background: Damage to the peripheral nervous system influences wound healing and, after a deep burn, imperfect cutaneous nerve regeneration occurs. A third-degree burn model was developed in rats combined with the use of resiniferatoxin (RTX), known to promote sensory neuropathy., Methods: Rats were injected intraperitoneally either with RTX or vehicle. A mechanical sensory assay and the hot plate thermal sensory test were performed. The structural integrity of the sciatic nerve was assessed using transmission electron microcopy. After RTX injection, third-degree thermal burns were performed. Wound closure was monitored and samples were collected for histological analysis, immunohistochemistry and immunoblotting for neuronal markers., Results: RTX promoted both mechanical and thermal hypoalgesia. This transient RTX-mediated sensory deficit occurred without damaging the integrity of nerve fibers and induced a significant depletion of neuropeptides in both neuronal bodies and intraepidermal nerve fibers. Although wound closure rates were similar in both groups, the kinetic of granulation tissue remodeling was delayed in the RTX group compared with control group. A significant reduction of the peripherin expression in the RTX group was observed indicating impaired axonal regrowth of small fibers within the wound., Conclusion: Our study confirms the important roles of innervation during skin healing and the defect of nerve regeneration after burn., (Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.)

Chronic wounds have a high prevalence and wound care, treatment, and prevention consume large quantities of resources. Chronic wounds are a growing challenge for clinicians. A prospective randomized pilot study was conducted to assess the effectiveness in terms of reduction in area and safety of the combined use of negative-pressure wound therapy and nanocrystalline silver dressings as compared to negative pressure wound therapy (NPWT) alone in the management of outpatients with chronic wounds. A total of 17 patients were included in the study, 10 were treated with the combined method and 7 with NPWT. Patients were followed for 6 weeks, with a final assessment at 3 months. Clinical improvement, microbiologic data, and toxicity of silver were evaluated. The antibacterial effects of ionic silver together with the development of granulation tissue promoted by NPWT reduced significantly the median extension of the wound between weeks 3 and 6 of treatment. The combination with silver also reduced bacterial colonization with Pseudomonas aeruginosa and the bacterial load on the surface of the wound. The silver levels correlated positively with the extension of the wound, although in none of the patients' toxic levels were reached. The combination of NPWT with nanocrystalline silver dressings was safe and as effective as NPWT alone., (© 2015 by the Wound Healing Society.)

Delayed wound healing is one of the major complications in diabetes and is characterized by chronic proinflammatory response, and abnormalities in angiogenesis and collagen deposition. Sirtuin family proteins regulate numerous pathophysiological processes, including those involved in promotion of longevity, DNA repair, glycolysis and inflammation. However, the role of sirtuin 6 (SIRT6), a NAD+-dependent nuclear deacetylase, in wound healing specifically under diabetic condition remains unclear. To analyse the role of SIRT6 in cutaneous wound healing, paired 6-mm stented wound was created in diabetic db/db mice and injected siRNA against SIRT6 in the wound margins (transfection agent alone and nonsense siRNA served as controls). Wound time to closure was assessed by digital planimetry, and wounds were harvested for histology, immunohistochemistry and Western blotting. SIRT6-siRNA-treated diabetic wound showed impaired healing, which was associated with reduced capillary density (CD31-staining vessels) when compared to control treatment. Interestingly, SIRT6 deficiency decreased vascular endothelial growth factor expression and proliferation markers in the wounds. Furthermore, SIRT6 ablation in diabetic wound promotes nuclear factor-κB (NF-κB) activation resulting in increased expression of proinflammatory markers (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumor necrosis factor-α and interleukin-1β) and increased oxidative stress. Collectively, our findings demonstrate that loss of SIRT6 in cutaneous wound aggravates proinflammatory response by increasing NF-κB activation, oxidative stress and decrease in angiogenesis in the diabetic mice. Based on these findings, we speculate that the activation of SIRT6 signalling might be a potential therapeutic approach for promoting wound healing in diabetics., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Middle ear surgery aims to eliminate pathology from the middle ear, improve drainage and ventilation of the postoperative cavity, and reconstruct the tympanic membrane and ossicles. The aim of this work is to define the factors that affect ABG (air-bone gap) and bone conduction in the patients operated on due to chronic otitis media., Material and Methods: A prospective analysis of patients operated on due to diseases of the middle ear during 2009-2012 was carried out. The cases of patients operated on for the first time due to chronic otitis media were analyzed. The analysis encompassed patients who had undergone middle ear surgery. The patients were divided into several groups taking into account the abnormalities of the middle ear mucous and damage of the ossicular chain observed during otosurgery., Results: A significant hearing improvement was observed in patients with type 2 tympanoplasty in the course of chronic cholesteatoma otitis media and in patients with simple chronic inflammatory process in whom a PORP was used in the reconstruction. Granulation tissue was an unfavorable factor of hearing improvement following tympanoplasty. A significant improvement of bone conduction was observed in the patients with dry perforation without other lesions in the middle ear. The elimination of granulation lesions was a positive factor for the future improvement of the function of the inner ear., Conclusions: The presence of granuloma-related lesions in the middle ear spaces is likely to impede hearing improvement. Damage to the ossicular chain rules out the possibility of bone conduction improvement after surgery. The prognosis on tube-related simple chronic otitis media after myringoplasty, with the preserved continuity of the ossicular chain, consists of closing the ABG and leads to significant improvement of bone conduction.

Background: Pathologic cutaneous scarring affects over 40 million people worldwide and costs billions of dollars annually. Understanding mechanisms of fibroblast activation and granulation tissue contraction is the first step toward preventing pathologic scarring. The authors hypothesize that nucleic acids increase fibroblast activation and cause granulation tissue contraction and that sequestration of nucleic acids by application of a nucleic acid scavenger dendrimer, polyamidoamine third-generation dendrimer, will decrease pathologic scarring., Methods: In vitro experiments were performed to assess the effect of nucleic acids on pathologic scar-associated fibroblast activity. The effect of nucleic acids on cytokine production and migration on mouse fibroblasts was evaluated. Immunofluorescence microscopy was used to determine the effect of nucleic acids on the differentiation of human primary fibroblasts into myofibroblasts. Using a murine model, the effect of polyamidoamine third-generation dendrimer on granulation tissue contraction was evaluated by gross and histologic parameters., Results: Mouse fibroblasts stimulated with nucleic acids had increased cytokine production (i.e., transforming growth factor-β, monocyte chemotactic protein 1, interleukin-10, tumor necrosis factor-α, and interferon-γ), migration, and differentiation into myofibroblasts. Polyamidoamine third-generation dendrimer blocked cytokine production, migration, and differentiation into myofibroblasts. Using a murine model of granulation tissue contraction, polyamidoamine third-generation dendrimer decreased wound contraction and angiogenesis. Collagen deposition in polyamidoamine third-generation dendrimer-treated tissues was aligned more randomly and whorl-like compared with control tissue., Conclusions: The data demonstrate that nucleic acid-stimulated fibroblast activation and granulation tissue contraction are blocked by polyamidoamine third-generation dendrimer. Sequestration of pathogen-associated molecular patterns may be an approach for preventing pathologic scarring.

Purpose: To investigate amniotic membrane as a biological dressing in infected wound healing in rabbits., Methods: The use of preserved amniotic membranes (AMs) was examined using 15 rabbits with experimentally induced wound infections on their backs. Healing was histologically evaluated during different phases including inflammation, granulation, epithelialization, and fibroplasia. The animals were distributed into three groups for histological study at seven, 14, 21, and 28 days post-wound induction. Group A did not receive treatment: the wound was left exposed and dry; Group B received a daily exposure treatment with collagenase; and Group C received one AM, which also remained exposed., Results: A marked reduction of the inflammatory phase was observed in Group C at 21 days, and the granulation phase of this healing increased at 14 days. Epithelialization was similar among the three groups, and fibroplasia was more pronounced in Group C at 14 days. Furthermore, gradual collagen organization also began for the animals in Group B at 14 days., Conclusion: The amniotic membrane did not significantly alter the inflammation, epithelialization, or fibroplasia phases but did increase angiogenesis up to Day 14 compared with the dry dressing and collagenase treatments.

The treatment of wounds by negative pressure requires the use of a foam or gauze interface. The study of scientific articles on the subject shows that the quality of the formation of granulation tissue and the pain during dressing removal differ depending on the technique, in favour of the use of the compress. On the other hand, no difference is found in terms of drainage capacity or the intensity of vascularisation.

The purpose of this study was to compare two negative-pressure wound healing systems (NPWT), -75 mmHg with a silicone-coated (SC) dressing and -125 mmHg with polyurethane foam dressing (standard of care). In addition, this study compared the effects of two different dressing interfaces, SC dressing and gauze, with -75 mmHg pressure. For both comparisons, two groups of five pigs were evaluated over a 21-day time course. Two excisional wounds were made on each animal and NPWT dressings were applied. A canvas saddle was constructed to hold the NPWT device so the animal had free range of the pen. Dressings were changed twice a week and wound measurements were taken. Specimens for histology and gene expression analyses were taken on day 7 and 21. These data show that there is increased expression in a few genes associated with remodeling and inflammatory processes in the NPWT-125 with polyurethane foam as compared with the NPWT-75 with SC dressing. These two systems, however, are equivalent with respect to wound healing, histology, and gene expression over 21 days of healing. Further, we demonstrate that there is no difference in measure of healing between the SC dressing and a basic gauze dressing., (© 2013 by the Wound Healing Society.)

Objective: The goal of this study was to evaluate the effects of crust formation on the healing of traumatic, dry, and minor-sized tympanic membrane perforations (TMPs) in humans., Study Design: Case series with a chart review., Setting: Tertiary university hospital., Materials and Methods: The clinical records of patients with traumatic TMPs who met the case selection criteria were retrieved and categorized according to the presence of a crust and the timing of crust formation into three groups: no crust, early crust formation, and late crust formation. Healing outcomes (i.e., healing rate and time) in the three groups were analyzed., Results: In total, 83 patients were analyzed. The perforation closure rates were 92%, 100%, and 78% in the groups with no-crust, early crust formation, and late crust formation, respectively. No significant difference was seen between the groups with no-crust and with late crust formation (p>0.05). By contrast, closure rates differed significantly between the early and late crust formation groups (p<0.05). Overall, the no-crust and early crust formation groups showed shorter healing times compared with the late crust formation group (p<0.05). However, closure times did not differ significantly between groups with early crust formation and no crust (p>0.05)., Conclusions: Crust formation at the margin of a traumatic TMP may serve as a predictor of healing outcome. Compared with perforations with early crust formation or no crust, late crust formation can result in delayed healing and failure to close completely., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Wound healing is a highly regulated process starting from coagulation and ending in tissue remodeling. The end result varies from perfectly restored tissue, such as in early fetal skin, to scars in adults. The balanced repair process is frequently disturbed by local or systemic factors, like infections and diabetes. A rapid increase of hyaluronan is an inherent feature of wounds and is associated with tissue swelling, epithelial and mesenchymal cell migration and proliferation, and induction of cytokine signaling. Hyaluronan extending from cell surface into structures called cables can trap leukocytes and platelets and change their functions. All these features of hyaluronan modulate inflammation. The present data show that mannose, a recently described inhibitor of hyaluronan synthesis, inhibits dermal fibroblast invasion and prevents the enhanced leukocyte binding to hyaluronan that takes place in cells treated with an inflammatory mediator interleukin-1β. Mannose also reduced hyaluronan in subcutaneous sponge granulation tissue, a model of skin wound, and suppressed its leukocyte recruitment and tissue growth. Mannose thus seems to suppress wounding-induced inflammation in skin by attenuating hyaluronan synthesis., (© 2013 by the Wound Healing Society.)

Transforming growth factor-β (TGF-β) is a multifunctional growth factor involved in all aspects of wound healing. TGF-β accelerates wound healing, but an excess of its presence at the wound site has been implicated in pathological scar formation. Our group has recently identified CD109, a glycophosphatidylinositol-anchored protein, as a novel TGF-β coreceptor and inhibitor of TGF-β signaling in vitro. To determine the effects of CD109 in vivo on wound healing, we generated transgenic mice overexpressing CD109 in the epidermis. In excisional wounds, we show that CD109 transgenic mice display markedly reduced macrophage and neutrophil recruitment, granulation tissue area, and decreased Smad2 and Smad3 phosphorylation, whereas wound closure remains unaffected as compared with wild-type littermates. Futhermore, we demonstrate that the expression of the proinflammatory cytokines interleukin-1α and monocyte chemoattractant protein-1, and extracellular matrix components is markedly decreased during wound healing in CD109 transgenic mice. In incisional wounds, CD109 transgenic mice show improved dermal architecture, whereas the tensile strength of the wound remains unchanged. Taken together, our findings demonstrate that CD109 overexpression in the epidermis reduces inflammation and granulation tissue area and improves collagen organization in vivo., (© 2013 by the Wound Healing Society.)

Objective: To map skin temperature kinetics, and by extension skin blood flow throughout normal or abnormal repair of full-thickness cutaneous wounds created on the horse body and limb, using infrared thermography., Study Design: Experimental., Animals: Standardbreds (n = 6), aged 3-4 years., Methods: Three cutaneous wounds were created on the dorsolateral surface of each metacarpus and on the lateral thoracic wall. Thoracic skin wounds and those on 1 randomly chosen forelimb healed by second intention without a bandage, whereas contralateral limb wounds were bandaged to induce formation of exuberant granulation tissue (EGT). Thermal data were collected from all planned wound sites before the surgical procedure (baseline), and at 24, 48, 96 hours, 1, 2, and 4 weeks after wounding. Data were analyzed using repeated measures ANOVA and a priori contrasts submitted to Bonferroni sequential correction. Level of significance was P < .05., Results: Cutaneous wound temperature (CWT) increased temporally from preoperative period to week 1 postwounding, independently of anatomic location (P < .0001). CWT of limb wounds was significantly less than that of body wounds throughout healing (P < .01). CWT of limb wounds managed with bandages and developing EGT was significantly less than that of unbandaged limb wounds, which did not develop EGT (P ≤ .01)., Conclusions: CWT varied with anatomic location and throughout healing. CWT of wounds developing EGT was significantly less than that of wounds without EGT., (© Copyright 2012 by The American College of Veterinary Surgeons.)

The indices of Doppler laser flowmetery are proposed to be used for determination of the readiness of a granulating wound for free autoplasty. An analysis of capillary blood flow in the groups under test showed the information value of indicators of microcirculation obtained by Doppler laser flowmetery for determination of the granulating wound condition before autotransplantation and prediction of the results of skin engraftment. It is stated, that the disorder of microcirculation has been developed against the background of progression of wound invasive infection. The obtained data can allow the development of an algorithm of treatment and the preparation of the patients to surgery, determination of the terms of operation, the development the strategy of postoperative management of the patients, which can reduce unfavorable results of operations.

Type 2 diabetes mellitus is a metabolic noncommunicable disease with an expanding pandemic magnitude. Diabetes predisposes to lower extremities ulceration and impairs the healing process leading to wound chronification. Diabetes also dismantles innate immunity favoring wound infection. Amputation is therefore acknowledged as one of the disease's complications. Hyperglycemia is the proximal detonator of systemic and local toxic effectors including proinflammation, acute-phase proteins elevation, and spillover of reactive oxygen and nitrogen species. Insulin axis deficiency weakens wounds' anabolism and predisposes to inflammation. The systemic accumulation of advanced glycation end-products irreversibly impairs the entire physiology from cells-to-organs. These factors in concert hamper fibroblasts and endothelial cells proliferation, migration, homing, secretion, and organization of a productive granulation tissue. Diabetic wound bed may turn chronically inflammed, procatabolic, and an additional source of circulating pro-inflammatory cytokines, establishing a self-perpetuating loop. Diabetic fibroblasts and endothelial cells may bear mitochondrial damages becoming prone to apoptosis, which impairs granulation tissue cellularity and perfusion. Endothelial progenitor cells recruitment and tubulogenesis are also impaired. Failure of wound reepithelialization remains a clinical challenge while it appears to be biologically multifactorial. Ulcer prevention by primary care surveillance, education, and attention programs is of outmost importance to reduce worldwide amputation figures.

Microdeformational Wound Therapy (MDWT) is a class of medical devices that have revolutionized the treatment of complex wounds over the last 20 years. These devices, are a subset of Negative Pressure Wound Therapy (NPWT), in which there is a highly porous interface material placed between the wound and a semi-occlussive dressing and connected to suction. The porous interface material acts to deform the wound on a micro scale promoting cellular proliferation. These devices appear to significantly improve the speed of healing in many wounds, facilitate granulation tissue formation and reduce the complexity of subsequent reconstructive operations. The mechanisms through which such effects are obtained are beginning to be better understood through basic research and clinical trials. Further work in this field is likely to yield devices that are designed to treat specific wound types., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The purpose of this study was to analyze tooth mobility changes in root-fractured permanent teeth and relate this to type of interfragment healing (hard tissue healing (HT), interfragment healing with periodontal ligament (PDL) and nonhealing with interposition of granulation tissue (GT) because of pulp necrosis in the coronal fragment. Furthermore, the effect of age, location of the fracture on the root, and observation period on mobility values was analyzed. Mobility values were measured for 44 of 95 previous reported root-fractured permanent incisors. Mobility changes were measured with a Mühlemanns periodontometer and noninjured incisors served as controls. The mobility values represented the labial-lingual excursion of the root measured in μm when the tooth received a frontal and a palatal impact of 100 g force. In 18 cases of hard tissue healing (HT), a slightly increased mobility was seen after 3 months and 1 year, and a normalization of mobility value was usually found after 5 and 10 years. In 17 cases of PDL healing, generally a higher mobility was found in comparison with root fractures healing with hard tissue, and a consistent decrease in mobility value was found in the course of the 10 year observation period. A tendency for reduced mobility over time was found, a relation that could possibly be explained by the known general decrease in tooth mobility with increasing age. Finally, nine cases of nonhealing with initial interposition of granulation tissue (GT) because of pulp necrosis in the coronal fragment resulted in increasing mobility values possibly related to a lateral breakdown of the PDL in relation to the fracture line. In control teeth, a lowering of mobility was found over the course of a 10-year observation period. In conclusion, mobility changes appeared to reflect the radiographic healing stages and known age effects upon tooth mobility., (© 2012 John Wiley & Sons A/S.)

Aim: The purpose of this study was to analyze tooth loss after root fractures and to assess the influence of the type of healing and the location of the root fracture. Furthermore, the actual cause of tooth loss was analyzed., Material and Methods: Long-term survival rates were calculated using data from 492 root-fractured teeth in 432 patients. The cause of tooth loss was assessed as being the result of either pulp necrosis (including endodontic failures), new traumas or excessive mobility. The statistics used were Kaplan-Meier and the log rank method., Results and Conclusions: The location of the root fracture had a strong significant effect on tooth survival (P = 0.0001). The 10-year tooth survival of apical root fractures was 89% [95% confidence interval (CI), 78-99%], of mid-root fractures 78% (CI, 64-92%), of cervical-mid-root fractures 67% (CI, 50-85%), and of cervical fractures 33% (CI, 17-49%). The fracture-healing type offered further prognostic information. No tooth loss was observed in teeth with hard tissue fracture healing regardless of the position of the fracture. For teeth with interposition of connective tissue, the location of the fracture had a significant influence on tooth loss (P = 0.0001). For teeth with connective tissue healing, the estimated 8-year survival of apical, mid-root, and cervical-mid-root fractures were all more than 80%, whereas the estimated 8-year survival of cervical fractures was 25% (CI, 7-43%). For teeth with non-healing with interposition of granulation tissue, the location of the fracture showed a significant influence on tooth loss (P = 0.0001). The cause of tooth loss was found to be very dependent upon the location of the fracture. In conclusion, the long-term tooth survival of root fractures was strongly influenced by the type of healing and the location of the fracture., (© 2012 John Wiley & Sons A/S.)

Purpose: The objective of the present study was to assess the effects of oriental sweet gum (Liquidambar orientalis Mill.) storax on partial-thickness and full-thickness wounds compared to conventional wound dressings in a porcine model., Methods: Six young Yorkshire pigs were used. Sixteen square excisional wounds measuring 3 × 3 cm were performed per animal. The wounds were allocated to one of the four treatment modalities: storax, hydrocolloid dressing, silver sulfadiazine, and control groups. Partial-thickness wounds were created in two pigs, and tissue samples were harvested on days 4 and 8, respectively. Full-thickness wounds were created in four pigs, and tissue samples were taken on days 4, 8, 14, and 21, respectively. Histologically, all wounds were examined for re-epithelialization and granulation tissue formation. Tissue hydroxyproline content and wound contraction areas were measured., Results: In storax-applied group, there was a greater depth of granulation tissue at 4 and 8 days compared to all other groups (p < .0125), and there was a faster re-epithelialization at 21 days compared to both hydrocolloid dressing and control groups in full-thickness wounds (p < .0125). Tissue hydroxyproline content and wound contraction did not differ significantly between the groups., Conclusion: The results of this study indicate that topical application of storax enhanced both re-epithelialization and granulation tissue formation in full-thickness wounds. Further studies are indicated in this important area of wound healing research to evaluate the clinical efficacy of this storax and search for the mechanisms that explain its effects.

Type 2 diabetes mellitus affects 6% of western populations and represents a major risk factor for the development of skin complications, of which impaired wound healing, manifested in e.g. "diabetic foot ulcer", is most prominent. Impaired angiogenesis is considered a major contributing factor to these non-healing wounds. At present it is still unclear whether diabetes-associated wound healing and skin vascular dysfunction are direct consequences of impaired insulin/IGF-1 signaling, or secondary due to e.g. hyperglycemia. To directly test the role of vascular endothelial insulin signaling in the development of diabetes-associated skin complications and vascular function, we inactivated the insulin receptor and its highly related receptor, the IGF-1 receptor, specifically in the endothelial compartment of postnatal mice, using the inducible Tie-2CreERT (DKO(IVE)) deleter. Impaired endothelial insulin/IGF-1 signaling did not have a significant impact on endothelial homeostasis in the skin, as judged by number of vessels, vessel basement membrane staining intensity and barrier function. In contrast, challenging the skin through wounding strongly reduced neo-angiogenesis in DKO(IVE) mice, accompanied by reduced granulation tissue formation reduced. These results show that endothelial insulin/IGF signaling is essential for neo-angiogenesis upon wounding, and imply that reduced endothelial insulin/IGF signaling directly contributes to diabetes-associated impaired healing., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Cutaneous scarring is often the epicenter of patient-related concerns, and the question "Will there be a scar?" is one that is all too familiar to the everyday clinician. In approaching this topic, we have reviewed the pathology, the embryology, and the molecular biology of cutaneous scarring., (Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Background: Mast cells are important in numerous inflammatory processes. They are also mechanosensitive and likely play an important role in wound healing. The authors hypothesized that mechanical alteration of the wound environment with a distributed suction device could link mast cells to the healing cascade., Methods: Controlled uniform full-thickness wound surface microdeformations were induced by suction combined with an open-pore polyurethane foam (microdeformational wound therapy) in mast cell-deficient WWv mice and their mast cell-sufficient littermates. Wound healing parameters were assessed in the inflammatory, proliferative, and remodeling phases of healing., Results: Wound tissue granulation, cell proliferation, blood vessel sprouting, and collagen maturation were found to be mast cell-dependent throughout the proliferating and remodeling stages of healing., Conclusion: Mast cells are critical in the robust granulation tissue response seen in microdeformational wound therapy and in the modulation of the remodeling phase of wound healing.

Negative pressure wound therapy (NPWT) contracts the wound and alters the pressure in the tissue of the wound edge, which accelerates wound healing. The aim of this study was to examine the effect of the type (foam or gauze) and size (small or large) of wound filler for NPWT on wound contraction and tissue pressure. Negative pressures between --20 and --160 mmHg were applied to a peripheral porcine wound (n = 8). The pressure in the wound edge tissue was measured at distances of 0·1, 0·5, 1·0 and 2·0 cm from the wound edge and the wound diameter was determined. At 0·1 cm from the wound edge, the tissue pressure decreased when NPWT was applied, whereas at 0·5 cm it increased. Tissue pressure was not affected at 1·0 or 2·0 cm from the wound edge. The tissue pressure, at 0·5 cm from the wound edge, was greater when using a small foam than when using than a large foam. Wound contraction was greater when using a small foam than when using a large foam during NPWT. Gauze resulted in an intermediate wound contraction that was not affected by the size of the gauze filler. The use of a small foam to fill the wound causes considerable wound contraction and may thus be used when maximal mechanical stress and granulation tissue formation are desirable. Gauze or large amounts of foam result in less wound contraction which may be beneficial, for example when NPWT causes pain to the patient., (© 2011 The Authors. © 2011 Blackwell Publishing Ltd and Medicalhelplines.com Inc.)

Background: Impaired healing is a problematic and common complication of chronic wounds. Although pulsed radiofrequency energy has been used in the treatment of chronic wounds with promising efficacy, its mechanism is still poorly characterized. In this study, the authors used a diabetic mouse model to illustrate the action of pulsed radiofrequency energy on cutaneous wounds and set the stage to begin to understand its mechanism., Methods: Full-thickness cutaneous wounds were created in diabetic mice (n = 26). The experimental group (n = 13) was subject to pulsed radiofrequency energy treatment two times per day, whereas the sham group (n = 13) was subjected to sham devices. The rate of wound closure was evaluated by digital analysis of surface area of the wound bed, zone of reepithelialization, and rate of contraction. Mice were euthanized on days 7, 10, 22, and 42 and wounds were evaluated qualitatively and quantitatively by hematoxylin and eosin, Masson's trichrome, and Ki-67 assay for cell proliferation., Results: In the experimental group, the rate of wound closure was significantly accelerated, particularly beyond day 17. Contraction contributed to the wound healing process rather than reepithelialization. This was also associated with increased granulation tissue that was most prominent by day 22 and with enhanced dermal cell proliferation, with 25 percent and 45 percent Ki-67-positive nuclei on days 10 and 22, respectively, as compared with control animals., Conclusion: These results indicate that pulsed radiofrequency energy accelerates impaired wound healing mainly through wound contraction by means of stimulating cell proliferation, granulation tissue formation, and collagen deposition.

Objective: One of the hallmarks of inflammation is lymphangiogesis that drains the interstitial fluids. During chronic inflammation, angiogenesis is induced by a variety of inflammatory mediators, such as prostaglandins (PGs). However, it remains unknown whether they enhance lymphangiogenesis. We examined the roles of cyclooxygenase-2 (COX-2) and PGE2 receptor signaling in enhancement of lymphangiogenesis during proliferative inflammation., Methods and Results: Lymphangiogenesis estimated by podoplanin/vascular endothelial growth factor (VEGF) receptor-3/LYVE-1 expression was upregulated during proliferative inflammation seen around and into subcutaneous Matrigel plugs containing fibroblast growth factor-2 (125 ng/site). A COX-2 inhibitor (celecoxib) significantly reduced lymphangiogenesis in a dose-dependent manner, whereas topical PGE2 enhanced lymphangiogenesis. Topical injection of fluorescein isothiocyanate-dextran into the Matrigel revealed that lymphatic flow from the Matrigels was COX-2 dependent. Lymphangiogenesis was suppressed in the granulation tissues of mice lacking either EP3 or EP4, suggesting that these molecules are receptors in response to endogenous PGE2. An EP3-selective agonist (ONO-AE-248) increased the expression of VEGF-C and VEGF-D in cultured macrophages, whereas an EP4-selective agonist (ONO-AE1-329) increased VEGF-C expression in cultured macrophages and increased VEGF-D expression in cultured fibroblasts., Conclusions: Our findings suggest that COX-2 and EP3/EP4 signaling contributes to lymphangiogenesis in proliferative inflammation, possibly via induction of VEGF-C and VEGF-D, and may become a therapeutic target for controlling lymphangiogenesis.

Background: Although tissue adhesives and traditional sutures were compared in numerous studies during the early stages of healing, it has to be clarified, from the histological and biomechanical point of view, how the differences develop during the later phases., Methods: Twenty-four male Sprague-Dawley rats were used and divided into 2 groups: the IRS (intradermal running suture) and G (glue) groups. Two parallel full-thickness skin incisions were made on the back of each rat. Wounds in the IRS group were closed by an IRS, whereas wounds in the G group were closed using tissue adhesive (n-butylcyanoacrylate). Rats were sacrificed 7 and 22 days after surgery., Results: Similar wound tensile strengths of glued and sutured wounds were measured on days 7 (IRS = 10.3 ± 1.7 g/mm(2) vs. G = 12.9 ± 4.0 g/mm(2), p = 0.9612) and 22 (IRS = 95.6 ± 15.7 g/mm(2) vs. G = 85.6 ± 16.4 g/mm(2), p = 0.2502) after surgery. Histology revealed a significantly increased amount of granulation tissue formation in glued wounds on day 7. The difference in granulation tissue formation was reduced until day 22., Conclusions: Tissue adhesive based on n-butylcyanoacrylate presents a fair alternative to traditional suture wound closure techniques., (Copyright © 2010 S. Karger AG, Basel.)

Malnutrition remains a significant problem, not only in developing countries, but also in the developed world. The aim of this study was to investigate the effects of protein restriction on rat excisional cutaneous healing. Male and female rats (12 weeks old) were exposed to different degrees of protein restriction (23%, 12% (slight restriction), and 0% (severe restriction)) for 12 weeks. On week 9, a full-thickness excisional skin lesion was performed, and the lesion area was measured to evaluate wound contraction and re-epithelialization. Euthanasia was performed after 12 weeks, and the lesion and adjacent skin were removed, fixed in formalin, and embedded in paraffin. Sections were stained with hematoxylin-eosin, toluidine blue, picro-mallory, and sirius red, and were immunostained for alpha-smooth muscle actin. Animals (males and females) exposed to severe protein restriction (0% protein) presented impairment of wound contraction. Inflammatory cells were present in higher amounts in the protein-restricted groups than in the 23% group. Extracellular matrix was poorly deposited in the severely restricted group (0%), but only mildly disturbed in the slightly restricted group (12%). Neovascularization was disturbed in both restricted groups. Our study demonstrates that animals exposed to slight protein restriction present disturbed wound healing, but animals exposed to severe protein restriction present impaired wound healing.

Impaired repair of skin defects is a major complication of diabetes; yet, the pathophysiology of diabetic (db) wound healing remains largely opaque. Here, we investigate the role of humoral factors in modulating db wound repair by generating chimeric animals through parabiotic joining of wild-type (wt) and diabetic (db/db) mice. This strategy allows wounds on healing-deficient db/db mice to be exposed to factors derived from the wt circulation at physiologically appropriate concentrations. When compared with db controls, chimeric db/db animals showed significantly improved healing of full-thickness, cutaneous wounds, with enhanced granulation tissue formation, angiogenesis, cell proliferation, and collagen deposition. Glycemic control was unaffected by parabiosis; however, the distribution of circulating leukocytes, altered in db controls, normalized in db-chimeras. Both wt and db cells were recruited from circulation into db wounds, but wt cells never exceeded 20% of total cells. Improved angiogenesis persisted in db-chimeras separated 24 hours after wounding, suggesting the existence of long-term normalizing factors. This study establishes a new model for studying db wound healing, and shows a key role for circulating factors in normalizing wound repair in diabetes.

Background: In rare cases, adults with normal or almost normal cognition may have giant brain ventricles surrounded by a sliver of brain. Because the usual flow of cerebrospinal fluid (CSF) is interrupted in these individuals, they may develop alternative CSF pathways to preserve brain function., Objective: To describe novel morphologic autopsy findings in a patient with chronic giant hydrocephalus that suggest the existence of alternative CSF draining pathways., Design: Case report., Setting: Autopsy study., Patient: A 48-year-old man with chronic compensated hydrocephalus associated with a Dandy-Walker malformation., Main Outcome Measure: Autopsy findings., Results: We observed microscopic structures on the ventricular wall that may facilitate CSF resorption. Their histologic appearance, reminiscent of pacchionian granulations, showed the opposite relation in regard to CSF/blood compartments: whereas the core of a pacchionian granulation contains CSF and the granulation is bathed in blood of the venous sinus, the core of the ventricular granulation in our patient contained venules, with the granulation bathed in ventricular CSF., Conclusions: These previously unreported (to our knowledge) ventricular wall granulations may facilitate draining of CSF into the venous system when CSF outflow from the ventricular system is occluded. The presence of these ventricular structures illustrates biologic adaptation to anomalous conditions and successful compensation.

We describe a new animal model designed to assess the impact of ischemia on wound healing. Eight patterns of arterial lesion in the limb were first tested in 24 Wistar rats. Resection of the external iliac artery down to the femoral artery at the level of the knee was chosen as the reference model and performed on the left limb of 45 rats; the right limb was used as the control. Skin wounds measuring 1.2 x 0.8 cm were created on both feet. Ischemia was assessed by blood flow measurement, which decreases dramatically in the ischemic limb. A significant delay in wound closure with a decrease in wound contraction was observed in the ischemic limb. Myofibroblast quantification showed a significant delay in appearance as well as a decrease in the number of these cells in the ischemic wound. Vascular endothelial growth factor-A appearance and evolution were qualitatively similar in both situations. However, collagen type I mRNA was markedly decreased in ischemic granulation tissue 10 days after wounding. These findings suggest that decreased wound contraction plays an important role in delayed ischemic wound healing, probably due to reduced myofibroblast development and activity.