Use of a novel human keratin matrix improves healing rates in diabetic lower extremity wounds.

BACKGROUND: Lower extremity wounds in patients with diabetes are difficult to heal due to an overabundance of pro-inflammatory M1 macrophages, reduced phagocytosis of necrosed cells, and circulatory issues. Keratin biomaterials have been shown to address some of these concerns by encouraging the proliferation of anti-inflammatory M2 macrophages, thereby creating more favorable conditions for wound healing resembling those of patients without diabetes. OBJECTIVE: To investigate the effect of a novel human keratin matrix (HKM) on wound healing. MATERIALS AND METHODS: Ten patients with diabetes with lower extremity wounds at risk for delayed healing underwent wound debridement and application of HKM. Patients received weekly follow-up care and reapplication of HKM until healing occurred; wound size at each visit was used to calculate healing rate. RESULTS: Increased healing rates were noted with HKM compared with standard of care (SOC), including debridement and collagen treatment in all 8 patients who had received SOC prior to HKM treatment. When HKM treatment was alternated with SOC in 2 patients due to other medical conditions, healing rates decreased with SOC and then increased after reintroduction of HKM applications. CONCLUSIONS: These results suggest that HKM may help regulate the pathological processes that contribute to wound chronicity to "kick-start" wound healing. This case series demonstrates that HKM is a promising technology to improve healing rates in nonhealing lower extremity wounds in patients with diabetes.

Mesenchymal stem cell-derived extracellular vesicles accelerate diabetic wound healing by inhibiting NET-induced ferroptosis of endothelial cells.

Impaired angiogenesis is a major factor contributing to delayed wound healing in diabetes. Dysfunctional mitochondria promote the formation of neutrophil extracellular traps (NETs), obstructing angiogenesis during wound healing. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown promise in promoting tissue repair and regeneration in diabetes; however, the precise pathways involved in this process remain unclear. In this study, NET-induced ferroptosis of endothelial cells (ECs) and angiogenesis were assessed in diabetic wound samples from both patients and animal models. In vitro and in vivo experiments were performed to examine the regulatory mechanisms of NETs in ECs using specific inhibitors and gene-knockout mice. MSC-EVs encapsulating dysfunctional mitochondria were used to trigger mitochondrial fusion and restore mitochondrial function in neutrophils to suppress NET formation. Angiogenesis in wound tissue was evaluated using color laser Doppler imaging and vascular density analysis. Wound healing was evaluated via macroscopic analysis and histological evaluation of the epithelial gap. NET-induced ferroptosis of ECs was validated as a crucial factor contributing to the impairment of angiogenesis in diabetic wounds. Mechanistically, NETs regulated ferroptosis by suppressing the PI3K/AKT pathway. Furthermore, MSC-EVs transferred functional mitochondria to neutrophils in wound tissue, triggered mitochondrial fusion, and restored mitochondrial function, thereby reducing NET formation. These results suggest that inhibiting NET formation and EC ferroptosis or activating the PI3K/AKT pathway can remarkably improve wound healing. In conclusion, this study reveals a novel NET-mediated pathway involved in wound healing in diabetes and suggests an effective therapeutic strategy for accelerating wound healing.

Exploring the effect of wound related pain on psychological stress, inflammatory response, and wound healing.

AIMS AND OBJECTIVES: The relationship between pain and poor healing is intricate, potentially mediated by psychological stress and aberrations in inflammatory response. The purpose of this study was to examine the biopsychosocial model of pain by assessing the relationships between pain, stress, inflammation and healing in people with chronic wounds. DESIGN: This was a 4-week prospective observational study to explore the relationship of pain, stress, inflammation and wound healing in a convenience sample of patients with chronic wounds in a chronic care hospital in Canada. METHODS: Only subjects over 18 with chronic wounds were recruited into the study. Chronic wounds were defined by the duration of wounds for more than 4 weeks of various aetiologies including wounds caused by pressure injuries, venous disease, arterial insufficiency, surgery or trauma and diabetic neuropathy. Participants were evaluated for pain by responding to the Brief Pain Inventory-Short Form, the McGill Pain Questionnaire-Short Form and the Leeds Assessment of Neuropathic Symptoms and Signs scale. Stress was measured by the Perceived Stress Scale (PSS). All wounds were assessed with the Pressure Ulcer Scale for Healing tool. The levels of matrix metalloproteinases were analysis by obtaining wound fluid from all participants. RESULTS: A total of 32 individuals with chronic wounds participated in the study. Correlation analysis indicated pain severity was positively and significantly related to pain interference, McGill Pain Questionnaire scores, neuropathic pain and matrix metalloproteinase levels. Logistic regression was used to determine the predictors for high or low perceived stress. The only significant variable that contributed to the stress levels was BPI-I. Results suggested that participants who experienced higher levels of pain interference also had an increased odds to report high level of stress by 1.6 times controlling for all other factor in the model. CONCLUSION: Pain is a complex biopsychosocial phenomenon affecting quality of life in people with chronic wounds. Results of this study identified a significant relationship between pain, stress and wound healing.

Repair of facial dog bite wound utilizing cryopreserved umbilical cord allograft.

BACKGROUND: In the United States, craniofacial injuries are the most frequently observed traumas in the pediatric population. Human birth tissue products contain growth factors, cytokines, and signaling molecules that can be potentially harnessed for tissue regeneration and wound healing. PURPOSE: A cryopreserved ultra-thick amniotic membrane (AM) allograft wound dressing was used in a patient with significant facial soft tissue loss due to a dog bite injury. METHODS: This is a single case report of a pediatric patient. After obtaining IRB exemption, operative and postoperative clinic notes were reviewed. RESULTS: A 10-year-old female presented to the emergency department after suffering a dog bite to her left cheek and upper lip, resulting in tissue loss. A cryopreserved ultra-thick AM allograft was used to cover the area of tissue loss as part of surgical reconstruction. The patient was followed up at 1 week, 3 weeks, 4 months, and 1 year after the graft was placed, and rapid healing and full epithelialization were achieved in addition to scar contracture due to wound location. CONCLUSION: In the setting of acute trauma and tissue loss, human birth tissue was found to promote epithelialization and regenerative healing of facial tissues.

Granulation-embedded autologous skin grafting improves healing chronic wounds at high altitudes: a pilot study.

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.

Extracorporeal shockwave therapy (ESWT) in an outpatient wound care clinic: case series analysis of a non-invasive technology in the management of chronic wounds for wound bed preparation.

BACKGROUND: Extracorporeal shockwave therapy (ESWT) has been shown to reduce wound dimensions and healing time in chronic wounds and should be considered a valuable tool in the healing of chronic complex lower extremity wounds. PURPOSE: The aim of this small case series was to evaluate the effect of ESWT on complex chronic wounds in patients with multiple comorbidities in a medically underserved outpatient wound care clinic setting. METHODS: All patients had baseline wound measurements taken. Pictures of the wounds were also taken at the time of the initial visit. Patients selected for ESWT received weekly treatments for a maximum recorded duration of 12 weeks in the form of focused electro-hydraulic acoustic pulses. Wound beds were cleansed according to standard of care. RESULTS: Thirteen patients were followed with a total of 18 wounds treated. After retrospectively analyzing the data, 3 subjects and a total of 5 wounds were excluded, leaving 10 total subjects and 13 wounds. Out of these wounds, 12 healed completely by or before week 12 of ESWT. All wounds demonstrated significant wound dimension reduction during the first 12 weeks of treatment. CONCLUSION: ESWT could offer accessible, fast, safe, and cost-effective management of some complex chronic wounds. Further research is needed to validate these findings.

The Challenge of Chronic Wounds in Older Adults.

Care for the older patient living with a chronic wound comes with challenges not seen in younger patients. The aging skin, impacted by the environment and intrinsic physiologic changes, makes it susceptible to injury and poor healing. Likewise, older adults' goals with regards to wound healing may vary depending on their functional abilities and quality of life. The clinician must pay attention to these nuances and collaborate with the older patient in developing a treatment plan. Careful systematic description, documentation, and communication with the patient/caregiver aids the clinician in tracking the treatment goals and potentially reducing medical liability risk.

Wound Bed Preparation and Treatment Modalities.

Wound healing is a highly complex natural process, and its failure results in chronic wounds. The causes of delayed wound healing include patient-related and local wound factors. The main local impediments to delayed healing are the presence of nonviable tissue, excessive inflammation, infection, and moisture imbalance. For wounds that can be healed with adequate blood supply, a stepwise approach to identify and treat these barriers is termed wound bed preparation. Currently, a combination of patient-related and local factors, including wound debridement, specialty dressings, and advanced technologies, is available and successfully used to facilitate the healing process.

Pressure Injuries and Skin Failure.

Pressure injuries are a common chronic wound in the older adult. Care of pressure injuries is an interprofessional effort and involves physicians, nurses, registered dieticians, rehabilitation therapists, and surgical subspecialties. Numerous treatment modalities exist but have varying evidence to substantiate their efficacy. All primary and other care providers, particularly geriatricians, need to be aware of current evidence-based prevention and treatment standards. When healing is not expected, palliative care should be considered to avoid futile procedures and preserve dignity and quality of life.

Nutritional Aspects of Wound Care.

Malnutrition is a collective term that includes both undernutrition and malnutrition. Malnutrition presents with and without inflammation, is reported in underweight, normal weight, and overweight individuals, and is associated with undesirable alterations in body composition, and diminished functional status. Older adults commonly experience dwindling nutritional status as evidenced by insidious weight loss, insufficient dietary intake, loss of muscle mass, quality, and strength, declining functional status, and other physical and emotional decline indicators. Sustained pressure, acute trauma, malnutrition, and inflammatory-driven chronic conditions increase the risk for skin integrity issues.

Diabetic Foot Ulcers in Geriatric Patients.

Care for the patient with diabetic foot ulcers (DFUs) entails understanding the epidemiology, pathophysiology, and a systematic approach to diagnosis and treatment. The authors will review elements of DFU in geriatric patients including the pathophysiology of diabetes, epidemiology and management of DFU in the context of developing a Plan for Healing. The authors will discuss comprehensive principles of a Plan for Healing, which applies to all aspects of chronic wounds.

Infectious Aspects of Chronic Wounds.

The treatment, maintenance, and suppression of infection in chronic wounds remain a challenge to all practitioners. From an infectious disease standpoint, knowing when a chronic wound has progressed from colonized to infected, when to use systemic antimicrobial therapy and when and how to culture such wounds can be daunting. With few standardized clinical guidelines for infections in chronic wounds, caring for them is an art form. However, there have been notable advances in the diagnosis, treatment, and management of infected wounds. This article will discuss the pathophysiology of infection in older adults, including specific infections such as cutaneous candidiasis, necrotizing soft tissue infection, osteomyelitis, and infections involving hardware.

"What really matters to the patients?": assessing the impact of wound healing on the quality of life in patients undergoing incisional hernia repair.

PURPOSE: We aim to evaluate the impact of surgical wound complications in the first 30 postoperative days after incisional hernia repair on the long-term quality of life of patients. In addition, the impact of the surgical technique and preoperative comorbidities on the quality of life of patients will also be evaluated. METHOD: Prospective cohort study, which evaluates 115 patients who underwent incisional hernioplasty between 2019 and 2020, using the onlay and retromuscular techniques. These patients were initially assessed with regard to surgical wound outcomes in the first 30 postoperative days (surgical site infection (SSI) or surgical site occurrence (SSO)), and then, assessed after three years, through a specific quality of life questionnaire, the Hernia Related Quality of Life Survey (HerQLes). RESULTS: After some patients were lost to follow-up during the study period, due to death, difficulty in contact, refusal to respond to the questionnaire, eighty patients were evaluated. Of these, 11 patients (13.8%) had SSI in the first 30 postoperative days and 37 (46.3%) had some type of SSO. The impact of both SSI and SSO on quality of life indices was not identified. When analyzing others variables, we observed that the Body Mass Index (BMI) had a significant impact on the patients' quality of life. Likewise, hernia size and mesh size were identified as variables related to a worse quality of life outcome. No difference was observed regarding the surgical techniques used. CONCLUSION: In the present study, no relationship was identified between surgical wound outcomes (SSO and SSI) and worse quality of life results using the HerQLes score. We observed that both BMI and the size of meshes and hernias showed an inversely proportional relationship with quality of life indices. However, more studies evaluating preoperative quality of life indices and comparing them with postoperative indices should be carried out to evaluate these correlations.

Management of Diabetic Foot Ulcers with Two Forefoot Offloading Techniques: Case Series.

ABSTRACT: Offloading is a key principle to healing diabetic foot ulcers. Nonremovable knee-high offloading devices are considered the criterion standard for offloading plantar forefoot ulcers. However, patients exhibit a limited tolerance for these devices, which contributes to a lack of use. In this case series describing two patients, the authors share two alternative offloading modalities for the treatment of diabetic plantar forefoot ulcers. One patient was managed using a football offloading dressing, and the other was managed with a modified felted football dressing. The football and modified felted football offloading dressings provide a cost-effective, less time-consuming application and often are a better-tolerated alternative to nonremovable knee-high offloading devices. Clinical findings support further investigation into dressing options tolerated by patients with improved adherence and optimal healing outcomes.

Continuous negative-pressure wound therapy improves the survival rate of skin grafts and shortens the time required for skin graft survival.

BACKGROUND: The effectiveness of negative-pressure wound therapy (NPWT) in skin graft fixation has been demonstrated in several clinical studies. However, in vitro and in vivo studies on skin graft fixation with NPWT have been scarce. In this in vivo study, we aimed to determine whether NPWT fixation enhances skin graft survival and how it contributes to improving skin graft survival biologically. MATERIALS AND METHODS: We harvested skin from the bilateral abdominal wall of 88 mice after anesthetizing them. Full-thickness skin grafts (FTSGs) were performed on contralateral harvest sites, and grafts were fixed using NPWT (continuous and intermittent modes), conventional compression methods, and wrapping with polyurethane foam as a control group. On days 5 and 10 of grafting, the survival rates of the FTSGs were evaluated. Immunohistopathological analysis and measurement of the expression levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2), and epidermal growth factor (EGF) were performed. RESULTS: The survival rates of FTSG in the continuous NPWT group were significantly higher than those in the other groups. The number of capillaries in the dermis was significantly higher in the continuous NPWT group than in the other groups. In the wound bed, VEGF levels were significantly higher in both NPWT groups than in the other groups. CONCLUSION: Continuous NPWT increases the survival rate of FTSGs and shortens the duration of skin graft survival.

Rab10-CAV1 mediated intraluminal vesicle transport to migrasomes.

Migrasomes, vesicular organelles generated on the retraction fibers of migrating cells, play a crucial role in migracytosis, mediating intercellular communication. The cargoes determine the functional specificity of migrasomes. Migrasomes harbor numerous intraluminal vesicles, a pivotal component of their cargoes. The mechanism underlying the transportation of these intraluminal vesicles to the migrasomes remains enigmatic. In this study, we identified that Rab10 and Caveolin-1 (CAV1) mark the intraluminal vesicles in migrasomes. Transport of Rab10-CAV1 vesicles to migrasomes required the motor protein Myosin Va and adaptor proteins RILPL2. Notably, the phosphorylation of Rab10 by the kinase LRRK2 regulated this process. Moreover, CSF-1 can be transported to migrasomes through this mechanism, subsequently fostering monocyte-macrophage differentiation in skin wound healing, which served as a proof of the physiological importance of this transporting mechanism.

The Optimal Effective Dose of Adipose-Derived Stem Cell Exosomes in Wound Healing.

INTRODUCTION: Although the effect of adipose-derived mesenchymal stem cell exosomes (ADSC-exos) on wound healing with different doses are shown in various studies, efficient and sufficient doses of ADSC-exos are still unknown. The study aimed to determine the optimal dose of ADSC-exos in wound healing. METHODS: The 45 Sprague-Dawley rats were randomly divided into five groups, with seven animals in each. After dorsal circular defects were created, each wound was injected as follows: group 1: saline, group 2: 10 µg/mL of ADSC-exos, group 3: 100 µg/mL of ADSC-exos, group 4: 200 µg/mL of ADSC-exos, and group 5: 400 µg/mL of ADSC-exos. The effects of ADSC-exos on epithelization, angiogenesis, and collagen formation were analyzed macroscopically, histopathologically, and immunohistochemically on day 14. RESULTS: A total of 200 µg/mL and 400 µg/mL ADSC-exos groups had higher epithelial tongue length, epithelial tongue area, and angiogenesis scores than the other groups. Although there was no statistical difference in fibrosis scores among groups, collagen fibers were becoming well-organized as the ADSC-exos doses increased. While the wound area was clinically smaller in the 200 µg/mL ADSC-exos group, there was no statistically significant difference among groups on day 14. CONCLUSIONS: A total of 200 µg/mL of ADSC-exos was found to be the adequate and effective dose for re-epithelialization and angiogenesis in cutaneous wound healing. Moreover, the collagen density increased with a more regular pattern in the 200 µg/mL group, which can be important in scar regulation.

Effects of Ziziphus Honey on Bone Healing of the Extracted Tooth Socket by Evaluating Osteopontin Levels.

OBJECTIVE: To evaluate the effect of Ziziphus honey on the healing of post-extraction alveolar sockets by estimating the levels of osteopontin (OPN) in humans. STUDY DESIGN: Randomised controlled trial. Place and Duration of the Study: Dental section of the Lahore General Hospital, Lahore, Pakistan, from March 2020 to February 2021. METHODOLOGY: A total of 30 patients were included in the study. The mean age was 35 ± 0.28 years. The participants were adults undergoing permanent molar extraction, randomly divided into two groups, a control group and an experimental group. After tooth extractions in both groups, 1ml of Ziziphus honey was administered into the extracted tooth socket of the experimental group while no intervention was done to the control group. Saliva samples were collected on day 0 before tooth extraction and on days 3 and 7 after tooth extractions. Enzyme-linked immunosorbent assay (ELISA) technique was used to measure the levels of OPN in the saliva sample. Radiographic evaluation was also done with the help of periapical radiographs using Image J® software. To find out the significance of the outcome in experimental and control groups, an unpaired t-test was applied. A p-value <0.05 was considered statistically significant. RESULTS: A total of 30 participants were selected for the study, of which 16 were females and 14 were males. The OPN levels between the control vs. experimental groups were (22.55 ± 2.45 vs. 23.31 ± 2.38; p = 0.4) on day 0, (30.95 ± 2.96 vs. 53.29 ± 4.69; p = 0.001) on day 3, and (55.33 ± 4.52 vs. 81.90 ± 4.49; p = 0.001) on day 7. CONCLUSION: Increased salivary levels of the OPN in the experimental group with the use of Ziziphus honey suggests better bone healing as compared to the control group. KEY WORDS: Extraction tooth, Honey, Osteopontin, Ziziphus, Bone healing.