Search

Introduction: Immediate evacuation of burn casualties can be challenging in austere environments, and it is predicted to be even more difficult in future multi-domain battlespaces against near-peer foes. Therefore, a need exists to treat burn wounds at the point of injury to protect the exposed injury for an extended period. In this study, we compare two commercially available FDA-approved therapies to the current gold standard of care (GSOC), excisional debridement followed by the application of split-thickness skin graft, and the standard for prolonged field care, silver sulfadiazine (SSD) cream. The shelf-stable therapies evaluated were irradiated human skin (IHS) allograft and polylactic acid (PLA). Our objective was to study whether they have the potential capability to reduce the need for evacuation to a burn center for surgical intervention so that the combat power can be preserved in the field., Materials and Methods: Sixteen burns (50 cm2) were created on the dorsum of four anesthetized swine. All materials were sterile, but a sterile field was not utilized in order to simulate the prolonged field care setting. The wounds were then treated with PLA, IHS, and SSD cream, and the remaining wounds (designated GSOC) were also treated with SSD cream. On post-operative day (POD) 3, sterile surgical debridement and skin grafting (1:4) were performed on the GSOC wounds. Burn healing was followed for either PODs 10, 14, 21, or 28, wherein one animal was humanely euthanized at each time point; each represented a time point of the healing process. A full-thickness excisional biopsy was taken from each wound immediately after euthanasia to give a cross-section view of the wound edge to edge. Wound healing was determined by the histological analysis of wound re-epithelialization, epidermal thickness, rete ridges, and scar elevation index and macroscopically using noninvasive imaging systems., Results: The PLA and IHS treatments did not need to be reapplied to the wounds during the course of the experiment, unlike SSD, which was reapplied at each assessment time point. In terms of re-epithelialization, on POD 10, IHS and SSD were similar to the GSOC; on POD 14, all treatments were similar; on POD 21, PLA and IHS were similar to SSD; finally, on POD 28, re-epithelialization was similar in all groups. On POD 28, scar elevation index and rete ridges/mm were similar to all groups, and epidermal and dermal thickness for PLA and IHS were similar to GSOC., Conclusions: This preclinical study demonstrated that the use of the PLA and the IHS dressings resulted in similar outcomes to the GSOC-treated burns in several key metrics of wound healing. These therapies represent a potentially useful tool in current and future battlespaces, where surgical intervention is not possible. The products are lightweight and, more importantly, stable at room temperature for their entire shelf lives. This would allow for easy storage and transport by medical practitioners in the field., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Sustained inflammation can halt or delay wound healing, and macrophages play a central role in wound healing. Inflammatory macrophages are responsible for the removal of pathogens, debris, and neutrophils, while anti-inflammatory macrophages stimulate various regenerative processes. Recombinant human Proteoglycan 4 (rhPRG4) is shown to modulate macrophage polarization and to prevent fibrosis and scarring in ear wound healing. Here, dissolvable microneedle arrays (MNAs) carrying rhPRG4 are engineered for the treatment of skin wounds. The in vitro experiments suggest that rhPRG4 modulates the inflammatory function of bone marrow-derived macrophages. Degradable and detachable microneedles are developed from gelatin methacryloyl (GelMA) attach to a dissolvable gelatin backing. The developed MNAs are able to deliver a high dose of rhPRG4 through the dissolution of the gelatin backing post-injury, while the GelMA microneedles sustain rhPRG4 bioavailability over the course of treatment. In vivo results in a murine model of full-thickness wounds with impaired healing confirm a decrease in inflammatory biomarkers such as TNF-α and IL-6, and an increase in angiogenesis and collagen deposition. Collectively, these results demonstrate rhPRG4-incorporating MNA is a promising platform in skin wound healing applications., (© 2024 Wiley‐VCH GmbH.)

Objective: To develop an efficacious and efficient method for treating chronic wounds using "nanosheet" that improves the survival and localization of transplanted cells without prior seeding to optimally derive the regenerative potentials of uncultured stromal vascular fraction (SVF) cells. Approach: We propose a method whereby the wound is covered by uncultured SVF cells using the nanosheet [porous poly(d, l,-lactic acid)] (PDLLA) films) designed to hold cells in a single-cell layer. A chronic wound model was created on 12-month-old db/db mice by inflecting a full-thickness skin excision on their dorsum and was subsequently given either no treatment or a treatment with SVF cells alone (with Tegaderm dressing), nanosheet alone, or nanosheet with SVF cells. Results: The placement of the nanosheet improved the grafted cell retention rate at day 10 timepoint by 5 folds, and the wound area was the smallest in the wounds treated with SVF cells plus nanosheet in comparison to the other groups. Collagen deposition and epidermal growth factor were significantly higher in the wound beds treated with SVF cells with the nanosheet, offering some mechanistic insights. Innovation: Porous poly(d, l,-lactic acid acid) (PDLLA) films or "nanosheet" printed on the nanoscale (1-100 nm in thickness) as a cellular scaffold for cytotherapy for the treatment of chronic wounds. Conclusion: The use of the nanosheet is an effective way to improve the transplanted SVF cell retention and accelerate the overall wound closure.

Introduction: Thermal injuries are caused by exposure to a wide variety of agents including heat, electricity, radiation, chemicals, and friction. Early intervention can decrease injury severity by preventing excess inflammation and mitigating burn wound progression for improved healing outcomes. Previous studies have demonstrated that cannabinoids can trigger anti-inflammatory responses and promote wound closure. Therefore, the purpose of this study was to investigate whether a topical application of Noneuphoric Phytocannabinoid Elixir 14 (NEPE14) containing a full complement of phytocannabinoids (< 0.3% delta-9-tetrahydrocannabinol or cannabidiol) and other phytochemicals would mitigate burn wound progression in the treatment of deep partial-thickness burn wounds., Methods: Deep partial-thickness burns were created on the dorsum of four anesthetized pigs and treated with NEPE14, Vehicle control, Silverlon, or gauze. The burns were assessed on postburn days 4, 7, and 14. Assessments consisted of digital photographs, Laser-Speckle imagery (blood perfusion), MolecuLight imagery (qualitative bacterial load), and biopsies for histology and immunohistochemistry (interleukin six and tumor necrosis factor-α)., Results: Topical treatment with NEPE14 significantly (P < 0.001) decreased inflammation (interleukin six and tumor necrosis factor-α) in comparison to control groups. It was also demonstrated that the reduction in inflammation led to mitigation of burn wound progression. In terms of wound healing and presence of bacteria, no statistically significant differences were observed., Conclusions: Topical treatment of deep partial-thickness burns with NEPE14 decreased wound inflammation and mitigated burn wound progression in comparison to control treatments., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Autologous skin transplantation is limited by donor site availability for patients with extensive burns. The objective of this study was to demonstrate the feasibility and efficacy of split-thickness skin (STS) and dermal pixel grafts (PG) in the treatment of burns. Approach: The study was divided into three arms of validation, expansion, and combination that all followed the same study design. Sixteen deep partial-thickness burns were created on the dorsum of anesthetized pigs. Three days postinjury the burns were debrided and grafted with STS and dermal PGs. The PGs were prepared by harvesting two skin grafts (split-thickness skin graft [STSG] and dermal graft) from the same donor site going down in depth. The grafts were minced to 0.3 × 0.3 × 0.3 mm PGs and suspended in a small volume of hydrogel. Healing was monitored for 6, 10, 14, or 28 days. In the validation study the PGs at 1:2 expansion ratio were transplanted and compared with STSG and untreated controls. The expansion study investigated the maximum expansion potential of the PGs and the combination of the benefits of transplanting STS and dermal PGs together. Results: The validation study showed that when STS and dermal PGs were transplanted in a 1:2 ratio they fully re-epithelialized the wounds in 14 days. The expansion study demonstrated that using expansion ratios up to 1:500 the wounds were re-epithelialized by day 28. The combination study showed that there was no additional benefit to use STS and dermal PGs together. Innovation: Pixel grafting provides expansion ratios greater than conventional STSG. The possibility to harvest both STS and dermal PGs from the same donor area further reduces the need for healthy skin. Conclusion: STSG and dermal grafts can be minced to PGs with preserved viability and expanded up to 500 times to re-epithelialize a wound.

Significance: Negative pressure wound therapy (NPWT) has been in practice for decades, proving its utility in many applications, ranging from acutely infected wounds to complex combat wounds and skin grafting. It has been routinely demonstrated that NPWT has superior wound healing outcomes compared with previous standard-of-care therapies. However, the technique involves some challenges related to each of the components that comprise the therapy. The purpose of this article is to highlight the challenges, introduce the recent advancements, and discuss about the future directions in NPWT systems. Recent Advances: New techniques and materials have been developed to improve the currently used NPWT systems with promising results when utilized with appropriate indications. Many advancements have been introduced in modes of negative pressure delivery, pumps, interface dressings, adhesive dressings, and tubing technology. Critical Issues: An optimal NPWT system would avoid the common problems such as failure to deliver negative pressure due to loss of an airtight seal or tissue ingrowth into the interface dressing causing painful dressing changes and bleeding. Other challenges include infection control and patient pain and discomfort that may contribute to noncompliance. Future Directions: Many studies have been performed to evaluate the optimal combination of settings and components in various wounds; however, there is still no clear "best" answer for many specific patient-wound scenarios. Novel and emerging tissue engineering and regenerative medicine approaches could potentially be utilized in the future NPWT systems and thus, this review will discuss some novel ideas for future considerations.

Objective: Despite advances in the use of topical and parenteral antimicrobial therapy and the practice of early tangential burn wound excision to manage bacterial load, 60% of the mortality from burns is attributed to bacterial biofilm infection. A low electric field (∼1 V) generated by the novel FDA-cleared wireless electroceutical dressing (WED) was previously shown to significantly prevent and disrupt burn biofilm infection in preclinical studies. Based on this observation, the purpose of this clinical trial was to evaluate the efficacy of the WED dressing powered by a silver-zinc electrocouple in the prevention and disruption of biofilm infection. Approach : A prospective, randomized, controlled, single-center clinical trial was performed to evaluate the efficacy of the WED compared with standard-of-care (SoC) dressing to treat biofilms. Burn wounds were randomized to receive either SoC or WED. Biopsies were collected on days 0 and 7 for histology, scanning electron microscopy (SEM) examination of biofilm, and for quantitative bacteriological analyses. Results: In total, 38 subjects were enrolled in the study. In 52% of the WED-treated wounds, little to no biofilm could be detected by SEM. WED significantly lowered or prevented increase of biofilm in all wounds compared with the pair-matched SoC-treated wounds. Innovation: WED is a simple, easy, and rapid method to protect the wound while also inhibiting infection. It is activated by a moist environment and the electrical field induces transient and micromolar amounts of superoxide anion radicals that will prevent bacterial growth. Conclusion: WED decreased biofilm infection better compared with SoC. The study was registered in clinicaltrials.gov as NCT04079998.

Introduction: Prolonged inflammation and infection in burns may cause inadequate healing. Platelet granules contain anti-inflammatory mediators that impact wound healing. Synthetic platelets (SPs) avoid portability and storage difficulties of natural platelets and can be loaded with bioactive agents. We evaluated wound healing outcomes in deep partial-thickness (DPT) burns treated topically with SP loaded with antibiotics., Materials and Methods: Thirty DPT burns were created on the dorsum of two Red Duroc hybrid pigs. Six wounds were randomized into five groups: SP alone, SP loaded with gentamicin vesicles, SP with gentamicin mixture, vehicle control (saline), or dry gauze. Wounds were assessed from postburn days 3-90. Primary outcome was re-epithelialization percentage at postburn day 28. Secondary outcomes included wound contraction percentage, superficial blood flow relative to normal skin controls, and bacterial load score., Results: Results showed that re-epithelialization with the standard of care (SOC) was 98%, SP alone measured 100%, SP loaded with gentamicin vesicles was 100%, and SP with gentamicin mixture was 100%. Wound contraction was 5.7% in the SOC and was ∼10% in both the SP loaded with gentamicin vesicles and SP with gentamicin mixture groups. Superficial blood flow in the SOC was 102.5%, SP alone was 170%, the SP loaded was 155%, and gentamicin mixture 162.5%. Bacterial load score in the SOC was 2.2/5.0 and was significantly less at 0.8/5.0 in SP loaded with gentamicin vesicles (P > 0.05). SP and gentamicin mixture scored 2.7 and 2.3/5.0., Conclusions: Topical SP treatment did not significantly improve outcomes. However, SP loaded with gentamicin-infused vesicles decreased bacterial load., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The current standard of care for the coverage of large wounds often involves split thickness skin grafts (STSGs) which have numerous limitations. One promising technique that has gained traction is fractional autologous skin grafting using full-thickness skin columns (FTSC). Harvesting occurs orthogonally by taking numerous individual skin columns containing the epidermis down through the dermis and transferring them to the wound bed. The purpose of this porcine study was to investigate the efficacy of implanting FTSCs directly into deep partial-thickness burn wounds, as well as examining donor site healing at the maximal harvest density. It was hypothesised that by utilising FTSCs, the rate of healing in deep partial thickness burns can be improved without incurring the donor morbidity seen in other methods of skin grafting. Deep partial-thickness burns were created on the dorsum of female red duroc swine, debrided 3 days later and FTSCs were implanted at varying expansion ratios directly into the burn wounds. At day 14, 1:50 expansion ratio showed significantly faster re-epithelialisation compared to the debrided burn control and 1:200. Donor sites (at 7%-10% harvest density) were 100% re-epithelialised by day 7. Additionally, the maximal harvest density was determined to be 28% in an ex vivo model, which then five donor sites were harvested at 28% density on a red duroc swine and compared to five STSG donor sites. At maximal harvest density, FTSC donor sites were significantly less hypopigmented compared to STSGs, but no significant differences were observed in re-epithelialisation, contraction, blood flow or dermal thickness. In conclusion, implantation directly into deep partial-thickness burns is a viable option for the application of FTSCs, favouring lower expansion ratios like 1:50 or lower. Little difference in donor site morbidity was observed between FTSC at a maximal harvest density of 28% and STSGs, exceeding the optimal harvest density., (© 2023 The Authors. Wound Repair and Regeneration published by Wiley Periodicals LLC on behalf of The Wound Healing Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Autologous split-thickness skin grafts (STSGs) are the standard of care for closure of deep and large burns. However, perforation and extensive fishnet-like expansion of the grafts to achieve greater area wound coverage can lead to treatment failures or esthetically poor healing outcomes and scarring. The purpose of this study was to validate an autologous advanced therapy medicinal product (ATMP)-compliant skin cell suspension and evaluate its efficacy to promote epithelialization., Methods: Cells isolated from a piece of STSG according to ATMP classification requirements were sprayed onto 20 patients during a single operation in a validation study. Comparative evaluation of treatment efficacy was carried out using side-by-side skin graft donor site wounds that were standardized in depth. Firstly, we characterized wound healing transcriptomes at 14 and 21 days from serial wound biopsies in seven patients. Then, side-by-side wounds in four patients were treated with or without the skin cells. The wounds were photographed, clinical outcomes assessed, and the treatment and control wound transcriptomes at 14 days were compared to the untreated wounds' healing transcriptomes., Results: The average cell yield after isolation from the STSG was 2.4 × 10 6 cells/cm 2 with 96 % viability. The product contained mainly keratinocytes and their precursors but also other skin cells such as fibroblasts were present. As compared to vehicle-treated donor site wounds, the wounds treated with cells demonstrated improved epithelialization by both direct comparison and machine learning analysis of the transcriptomes., Conclusions: We showed that rapid and scalable ATMP-classified processing of skin cells is feasible, and application of the skin cells effectively promotes healing and epithelization of donor site wounds., Competing Interests: Conflict of interest The views expressed in this article are those of the authors and do not reflect the official policy or position of the U.S. Army Medical Department, Department of the Army, DOD, or the U.S. Government. All the authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The platform wound device (PWD) is a wound coverage system that is designed to decrease wound infection rates by allowing for direct delivery of topical antibiotics and antimicrobials while creating a sealed, protective barrier around the area of injury. This study evaluated the safety and efficacy of the PWD as a protective dressing and a delivery system for topical antibiotics compared to the current standard of care (SoC). This was a multi-center, prospective, randomised, controlled clinical trial. The wounds were treated with the PWD with gentamicin cream or SoC dressings. The wounds were evaluated before the start of treatment and after 48-96 hours via clinical assessment, photographs, and qualitative bacterial swabs for bacterial analysis. The delivery of gentamicin via the PWD was safe and did not cause any adverse effects. The treatment decreased both inflammation and bacterial growth during the study period. No significant differences in the SoC were observed. The PWD is a transparent and impermeable polyurethane chamber that encloses and protects the injured area. The delivery of topical gentamicin via the PWD was safe and effective. Clinical assessment for infection found the PWD to be non-inferior to the current SoC treatment options., (© 2022 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Topical treatment of injuries such as skin wounds and ocular trauma is the favored route of administration. Local drug delivery systems can be applied directly to the injured area, and their properties for releasing therapeutics can be tailored. Topical treatment also reduces the risk of adverse systemic effects while providing very high therapeutic concentrations at the target site. This review article highlights the Platform Wound Device (PWD) (Applied Tissue Technologies LLC, Hingham, MA, USA) for topical drug delivery in the treatment of skin wounds and eye injuries. The PWD is a unique, single-component, impermeable, polyurethane dressing that can be applied immediately after injury to provide a protective dressing and a tool for precise topical delivery of drugs such as analgesics and antibiotics. The use of the PWD as a topical drug delivery platform has been extensively validated in the treatment of skin and eye injuries. The purpose of this article is to summarize the findings from these preclinical and clinical studies.

Burn are diverse and complex injuries that not only have local effects but also serious systemic consequences through severe and prolonged inflammatory response. They are caused by heat, electricity, friction, chemicals, or radiation and are commonly divided into superficial, superficial partial-, deep partial- and full-thickness injuries. The severity of the burn depends mainly on the size and depth of the injury but also on location, age, and underlying systemic diseases. A prolonged and strong immune response makes major burns even worse by causing multiple systemic effects including damage to the heart, lungs, blood vessels, kidneys, and other organs. Burns that do not require surgical excision, superficial and superficial partial-thickness, follow the known progression of wound healing (inflammation, proliferation, remodeling), whilst deep partial- and full thickness injuries requiring excision and grafting do not. For these burns, intervention is required for optimal coverage, function, and cosmesis. Annually millions of people worldwide suffer from burns associated with high morbidity and mortality. Fortunately, over the past decades, burn care has significantly improved. The improvement in understanding the pathophysiology of burn injury and burn wound progression has led to developments in skin grafting, fluid resuscitation, infection control and nutrition This review article focuses on the immune and regenerative responses following burn injury. In the Introduction, we describe the epidemiology of burns and burn pathophysiology. The focus of the following chapter is on systemic responses to burn injury. Next, we define the immune response to burns introducing all the different cell types involved. Subsequently, we discuss the regenerative cell response to burns as well as some of the emerging novel treatments in the battle against burns.

Introduction: Hypertrophic burn scars (HTBSs) remain a significant source of morbidity. Contemporary treatment has evolved to use CO2 lasers and/or pulse-dye lasers (PDLs) to reduce scar thickness (ST) and erythema. This study seeks to compare treatment efficacy with CO2 or PDL individually and in combination., Methods: Patients undergoing laser treatments for HTBSs were enrolled. Three 3 × 3 cm squares of HTBSs were randomized to receive treatment with CO2 laser, PDL or CO2 + PDL. Patients underwent 3 treatments, 4 to 6 weeks apart and were followed up over 3 to 6 months. Scar assessments occurred at each visit before treatment and consisted of photographs, ultrasound, colorimetry, and the Patient and Observer Scar Assessment Score., Results: Twenty-five patients were enrolled. Twenty completed 2 treatments (80%) and 11 completed all 3 treatments (44%). Median initial ST was 0.3 cm. Median time since injury was 8 months. Hypertrophic burn scars treated with CO2 or PDL showed a significant decrease in Patient and Observer Scar Assessment Scale score from visit 1 to 3 (P = 0.01 and 0.01, respectively). When separated by ST, thick scars (≥0.3 cm) showed a significant decrease in thickness between visit 1 and 2 using all laser modalities (CO2 + PDL, P = 0.01; CO2, P = 0.02; PDL, P = 0.03). Thin scars (<0.3 cm) showed a reduction in thickness by visit 3 after CO2 + PDL or PDL alone (P = 0.01 and 0.04, respectively). Separating scars by age, younger scars (<9 months) showed a significant reduction in thickness between visit 1 and 2 for CO2 treatment (P = 0.04), and between visit 2 and 3 for CO2 + PDL treatment (P = 0.04). Hypertrophic burn scars treated with PDL did not demonstrate a significant reduction in thickness until visit 3 (P = 0.002). Older scars (≥9 months) showed a significant reduction in thickness between visit 1 and 2 only after CO2 + PDL (P = 0.01)., Conclusions: Hypertrophic burn scars of varying ages, etiologies, and thicknesses were examined in this study with greater degree of early reduction seen in thicker scars using all laser modalities of CO2, PDL or in combination. However, there was no clinically meaningful benefit found with combination as compared with individual treatment. These data support the use of laser to improve HTBS but does not support one modality or combination of modalities over another., Competing Interests: Conflicts of interest: The views expressed in this article are those of the author(s) and do not reflect the official policy or position of the U.S. Army Medical Department, Department of the Army, DOD, or the U.S. Government., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Significance: A moist wound environment has several benefits that result in faster and better quality of healing. It facilitates autolytic debridement, reduces pain, reduces scarring, activates collagen synthesis, facilitates and promotes keratinocyte migration over the wound surface, and supports the presence and function of nutrients, growth factors, and other soluble mediators in the wound microenvironment. Recent Advances: Wound dressings can be utilized to create, maintain, and control a moist environment for healing. Moist wound dressings can be divided into films, foams, hydrocolloids, hydrogels, and alginates. We are also including negative pressure wound therapy systems in the moist dressings. Critical Issues: An optimal wound dressing should provide a moist environment and have an optimal water vapor transmission rate (WVTR) and absorptive capacity. It should also protect the wound against trauma and contamination and be easy to apply, painless to remove, and esthetically acceptable or even pleasing. Future Directions: Interventions, particularly dressing changes, by medical caregivers are labor intensive and expensive and there should be a continuous effort to reduce their number per week. Smart dressings with integrated microsensors and delivery capabilities that would allow wireless real-time monitoring and treatment of the wound would be very advantageous. This way the state of the wound as well as the wear time of the dressing could be assessed without dressing removal or visit to the wound care center. In addition, an ability to adjust the WVTRs to the exudate level of the wound (or having a large absorptive capacity without changing the WVTR) would be useful. This feature would guarantee an optimal level of hydration of the wound surface throughout the treatment.

Acute and chronic wounds affect millions of people around the world, imposing a growing financial burden on patients and hospitals. Despite the application of current wound management strategies, the physiological healing process is disrupted in many cases, resulting in impaired wound healing. Therefore, more efficient and easy-to-use treatment modalities are needed. In this study, we demonstrate the benefit of in vivo printed, growth factor-eluting adhesive scaffolds for the treatment of full-thickness wounds in a porcine model. A custom-made handheld printer is implemented to finely print gelatin-methacryloyl (GelMA) hydrogel containing vascular endothelial growth factor (VEGF) into the wounds. In vitro and in vivo results show that the in situ GelMA crosslinking induces a strong scaffold adhesion and enables printing on curved surfaces of wet tissues, without the need for any sutures. The scaffold is further shown to offer a sustained release of VEGF, enhancing the migration of endothelial cells in vitro . Histological analyses demonstrate that the administration of the VEGF-eluting GelMA scaffolds that remain adherent to the wound bed significantly improves the quality of healing in porcine wounds. The introduced in vivo printing strategy for wound healing applications is translational and convenient to use in any place, such as an operating room, and does not require expensive bioprinters or imaging modalities., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Extremity skeletal muscle injuries result in substantial disability. Current treatments fail to recoup muscle function, but properly designed and implemented tissue engineering and regenerative medicine techniques can overcome this challenge. In this study, a nanoengineered, growth factor-eluting bioink that utilizes Laponite nanoclay for the controlled release of vascular endothelial growth factor (VEGF) and a GelMA hydrogel for a supportive and adhesive scaffold that can be crosslinked in vivo is presented. The bioink is delivered with a partially automated handheld printer for the in vivo formation of an adhesive and 3D scaffold. The effect of the controlled delivery of VEGF alone or paired with adhesive, supportive, and fibrilar architecture has not been studied in volumetric muscle loss (VML) injuries. Upon direct in vivo printing, the constructs are adherent to skeletal muscle and sustained release of VEGF. The in vivo printing of muscle ink in a murine model of VML injury promotes functional muscle recovery, reduced fibrosis, and increased anabolic response compared to untreated mice. The in vivo construction of a therapeutic-eluting 3D scaffold paves the way for the immediate treatment of a variety of soft tissue traumas., (© 2021 Wiley-VCH GmbH.)

A major impediment preventing normal wound healing is insufficient vascularization, which causes hypoxia, poor metabolic support, and dysregulated physiological responses to injury. To combat this, the delivery of angiogenic factors, such as vascular endothelial growth factor (VEGF), has been shown to provide modest improvement in wound healing. Here, the importance of specialty delivery systems is explored in controlling wound bed drug distribution and consequently improving healing rate and quality. Two intradermal drug delivery systems, miniaturized needle arrays (MNAs) and liquid jet injectors (LJIs), are evaluated to compare effective VEGF delivery into the wound bed. The administered drug's penetration depth and distribution in tissue are significantly different between the two technologies. These systems' capability for efficient drug delivery is first confirmed in vitro and then assessed in vivo. While topical administration of VEGF shows limited effectiveness, intradermal delivery of VEGF in a diabetic murine model accelerates wound healing. To evaluate the translational feasibility of the strategy, the benefits of VEGF delivery using MNAs are assessed in a porcine model. The results demonstrate enhanced angiogenesis, reduced wound contraction, and increased regeneration. These findings show the importance of both therapeutics and delivery strategy in wound healing., (© 2021 Wiley-VCH GmbH.)

Significance: Hair follicles are complex miniorgans that reside in the dermal layer of the skin. When the skin is wounded, epidermal stem cells in the hair follicle activate and start migrating into the wound site, differentiating into epidermal cells. and contributing to the reepithelialization of the wound. The hair follicles represent the deepest epidermal elements in the skin, which are extremely beneficial in partial-thickness burns and abrasions where the skin can regenerate from the hair follicles. Recent Advances: Advanced animal models have demonstrated that the contribution of epidermal stem cells in the hair follicle bulge and isthmus regions is important for wound healing. In addition, several clinical studies have shown successful harvesting and transplantation of hair follicles as a treatment modality to accelerate wound healing. Critical Issues: Deep and large wounds require hospitalization and, without exception, surgical treatment. Harvesting and direct transplantation of hair follicles could provide a great source of autologous epidermal stem cells for wound healing. The procedure can be done in an outpatient setting, quickly and without creating a large donor site wound. Future Directions: Transplantation of hair follicles in a combination with novel biomaterials could provide advantageous treatment possibilities for both chronic wounds and burns. There is a substantial amount of molecular signaling data available on the role of hair follicles during wound repair, but almost all the data are derived from rodent models, and thus, more information from large animals and most importantly from humans would be beneficial and help to advance this promising treatment further.

Background: All common negative-pressure wound therapy systems include a material, usually foam or gauze, at the wound/device interface. In this preclinical study, the authors have compared the effects on different wound healing parameters in the three most common negative-pressure wound therapy systems (i.e., V.A.C.VIA, PREVENA, and PICO) with a new device without foam or gauze (i.e., Platform Wound Dressing). A strong effort was made to avoid bias. The study was conducted under good laboratory practice conditions, with the presence of an independent observer., Methods: In pigs, three types of wounds were studied: full-thickness excisions, open incisions, and sutured closed incisions. Several macroscopic and microscopic parameters were studied. The pigs were euthanized on day 9 and all wounds were processed for histology and excisions for immunohistochemistry., Results: In general, the devices produced similar results, with only a few significant differences. In the excisions, the Platform Wound Dressing reduced wound area more than the V.A.C.VIA and the PICO. In the excisional wounds, reepithelialization was the same. In open incisions, PREVENA was better than the Platform Wound Dressing. Histologic examination showed that, in open incisions, there was less inflammation in the PREVENA-treated in comparison with the Platform Wound Dressing- and the PICO-treated wounds. Immunohistochemical analyses showed that the Platform Wound Dressing-treated excisions had significantly more blood vessels (von Willebrand factor) than the V.A.C.VIA-treated ones and that the PICO caused less T-cell activation (CD3) than the other two., Conclusion: The devices-with foam, with gauze, or without either and just an embossed membrane-performed equally in general., (Copyright © 2020 by the American Society of Plastic Surgeons.)

The ability of skeletal muscle to regenerate declines significantly with aging. The expression of aryl hydrocarbon receptor nuclear translocator (ARNT), a critical component of the hypoxia signaling pathway, was less abundant in skeletal muscle of old (23-25 months old) mice. This loss of ARNT was associated with decreased levels of Notch1 intracellular domain (N1ICD) and impaired regenerative response to injury in comparison to young (2-3 months old) mice. Knockdown of ARNT in a primary muscle cell line impaired differentiation in vitro. Skeletal muscle-specific ARNT deletion in young mice resulted in decreased levels of whole muscle N1ICD and limited muscle regeneration. Administration of a systemic hypoxia pathway activator (ML228), which simulates the actions of ARNT, rescued skeletal muscle regeneration in both old and ARNT-deleted mice. These results suggest that the loss of ARNT in skeletal muscle is partially responsible for diminished myogenic potential in aging and activation of hypoxia signaling holds promise for rescuing regenerative activity in old muscle., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Objective: There is an unmet need to improve immediate burn care, particularly when definitive treatment is delayed. Therefore, the purpose of this project was to formulate a hydrogel that contains very high concentrations of antibiotics and validate its use together with a platform wound device (PWD) for the immediate care of burns. Approach: The hydrogel properties were optimized by using a rheometer, differential scanning calorimetry, and liquid chromatography-mass spectrometry and were tested in an infected porcine burn model. Immediately, after burn creation, the burns were infected with different bacteria. Subsequently, the burns infected with Staphylococcus aureus , Pseudomonas aeruginosa , and Acinetobacter baumannii were covered with the PWD and treated with a single dose of hydrogel containing 1000 × minimum inhibitory concentration of vancomycin, gentamicin, and minocycline, respectively. On day 7 or 45, the animals were euthanized, and the burns were harvested for histology and quantitative bacteriology. Results: 0.625% was the best alginate concentration for the hydrogel in terms of viscosity, stability, and drug release. The porcine studies demonstrated that vancomycin-, gentamicin-, and minocycline-treated tissues contained significantly less bacteria and reduced depth of tissue necrosis in comparison to controls. Innovation: The PWD represents a platform technology that begins at the point of the first treatment by protecting the wound and allowing administration of topical therapeutics. The device can be adapted to enclose any size burn over any contour of the body. Conclusion: Antibiotics can be delivered safely in very high concentrations in a hydrogel using the PWD, and burn infections can be treated successfully with this method., Competing Interests: K.N., L.Y., M.B., and E.E. are employees of Applied Tissue Technologies that manufactures the PWDs. All the other authors declare no conflict of interest. No ghostwriters were used to write this article., (Copyright 2020, Mary Ann Liebert, Inc., publishers.)

Volumetric muscle loss (VML) is a segmental loss of skeletal muscle which commonly heals with fibrosis, minimal muscle regeneration, and loss of muscle strength. Treatment options for these wounds which promote functional recovery are currently lacking. This study was designed to investigate whether the collagen-GAG scaffold (CGS) promotes functional muscle recovery following VML. A total of 66 C57/Bl6 mice were used in a three-stage experiment. First, 24 animals were split into three groups which underwent sham injury or unilateral quadriceps VML injury with or without CGS implantation. Two weeks post-surgery, muscle was harvested for histological and gene expression analysis. In the second stage, 18 mice underwent bilateral quadriceps VML injury, followed by weekly functional testing using a treadmill. In the third stage, 24 mice underwent sham or bilateral quadriceps VML injury with or without CGS implantation, with tissue harvested six weeks post-surgery for histological and gene expression analysis. VML mice treated with CGS demonstrated increased remnant fiber hypertrophy versus both the VML with no CGS and uninjured groups. Both VML groups showed greater muscle fiber hypertrophy than non-injured muscle. This phenomenon was still evident in the longer-term experiment. The gene array indicated that the CGS promoted upregulation of factors involved in promoting wound healing and regeneration. In terms of functional improvement, the VML mice treated with CGS ran at higher maximum speeds than VML without CGS. A CGS was shown to enhance muscle hypertrophy in response to VML injury with a resultant improvement in functional performance. A gene array highlighted increased gene expression of multiple growth factors following CGS implantation. This suggests that implantation of a CGS could be a promising treatment for VML wounds., (© 2019 by the Wound Healing Society.)

Wound infections cause inflammation, tissue damage, and delayed healing that can lead to invasive infection and even death. The efficacy of systemic antibiotics is limited due to poor tissue penetration that is especially a problem in burn and blast wounds where the microcirculation is disrupted. Topical administration of antimicrobials is an attractive approach because it prevents infection and avoids systemic toxicity, while hydrogels are an appealing vehicle for topical drug delivery. They are easy to apply to the wound site by being injectable, the drug release properties can be controlled, and their many characteristics, such as biodegradation, mechanical strength, and chemical and biological response to stimuli can be tailored. Hydrogels also create a moist wound environment that is beneficial for healing. The purpose of this study was to formulate an agarose hydrogel that contains high concentrations of minocycline or gentamicin and study its characteristics. Subsequently, the minocycline agarose hydrogel was tested in a porcine burn model and its effect as a prophylactic treatment was studied. The results demonstrated that 0.5% agarose in water was the optimal concentration in terms of viscosity and pH. Bench testing at room temperature demonstrated that both antibiotics remained stable in the hydrogel for at least 7 days and both antibiotics demonstrated sustained release over the time of the experiment. The porcine burn experiment showed that prophylactic treatment with the agarose minocycline hydrogel decreased the burn depth and reduced the number of bacteria as efficiently as the commonly used silver sulfadiazine cream., (© American Burn Association 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Burns are a very frequent injury type in the battlefield, comprising 5-20% of combat casualties in the recent conflicts. Almost 80% of the burns occur to the face, in part because the face is often not protected. Immediate treatment is critical in the first hours after severe burn injury in order to prevent infection and wound progression. Immediate treatment in the battlefield can be a serious challenge especially if the injury occurs in a remote area with limited transport options. Therefore, novel treatment modalities for prolonged field care when transport to the definitive care is delayed are needed. The purpose of this study was to utilize the platform wound device (PWD) with negative pressure capabilities for the immediate and definitive treatment of porcine full-thickness head burns., Materials and Methods: Full-thickness burn wounds were created on foreheads of seven Yorkshire pigs. Burns were created on day 0, immediately enclosed with the PWD and treated topically with minocycline and lidocaine. On day 3, the burns were surgically debrided. Subsequently, new PWDs were placed on the wounds and continuous negative pressure wound therapy was initiated with either -50 mmHg or -80 mmHg. On day 7, the animals were euthanized and wounds were harvested for analyses. Control wounds were treated with silver sulfadiazine cream., Results: The PWD treatment with negative pressure significantly reduced erythema and edema in the injured tissue and promoted granulation tissue and neocollagen formation by day 7 in comparison to control wounds. In addition, the PWD with both topical minocycline and negative pressure (-80 mmHg or -50 mmHg) reduced bacterial counts in the wounds similar to the current standard of care., Conclusion: This study demonstrates that the PWD is an effective platform for delivery of antibiotics and negative pressure wound therapy for the treatment of full-thickness burns. Therefore, the PWD may be utilized for both prolonged field care and definitive treatment of burn- and blast-injured warfighters., (© Association of Military Surgeons of the United States 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Negative pressure wound therapy (NPWT) promotes healing in acute or chronic wounds. Conventional NPWT devices consist of a filler (such as foam or gauze) that covers the wound and of a permeable membrane and tubing that connects the space under the membrane to a suction pump. The permeable membrane increases airflow and thus increases the required pump capacity that can cause patient discomfort or even ischemia in wounds with compromised vascularity. In addition, foam or gauze may fragment and become colonized with bacteria over time. To mitigate these, negative aspects, we have developed a new impermeable single layer component membrane dressing to deliver NPWT that does not need a foam or gauze to function. Therefore, the purpose of this study was to introduce this novel NPWT system (platform wound device, PWD) and evaluate its usability and effectiveness in the treatment of porcine full-thickness burns. A total of 48 burn wounds were created across four Yorkshire pigs on the dorsum. Wounds were created on day 0 and continuous NPWT with -50 mmHg and - 80 mmHg was initiated immediately. Subsequently, the burns were debrided on day 3 and animals were euthanized on day 7. The efficacy of the PWD on wound healing and reduction of bacterial burden was measured and compared to wounds that did not receive NPWT. The results showed that PWD promoted wound healing by outperforming the wounds that did not receive NPWT and that PWD was efficient at reducing bacteria from the burn eschar and from the wound bed. In conclusion, this study demonstrated that PWD promoted wound healing with a negative pressure as low as -50 mmHg, which likely benefits healing and avoids potential safety issues., (© 2018 by the Wound Healing Society.)

Cutaneous injury causes underlying tissue damage that must be quickly repaired to minimize exposure to pathogens and to restore barrier function. While the role of growth factors in tissue repair is established, the role of lipid mediators in skin repair has not been investigated extensively. Using a mass spectrometry-based lipid mediator metabolomics approach, we identified D-series resolvins and related pro-resolving lipid mediators during skin injury in mice and pigs. Differentiation of human epidermal keratinocytes increased expression of 15-lipoxygenase and stereospecific production of 17S-hydroxydocosahexaenoic acid, the common upstream biosynthetic marker and precursor of D-series resolvins. In human and pig skin, specific receptors for D-series resolvins were expressed in the epidermal layer and mice deficient in RvD1 receptor Alx/Fpr2 showed an endogenous defect in re-epithelialization. Topical application of D-series resolvins expedited re-epithelialization during skin injury and they enhanced migration of human epidermal keratinocytes in a receptor-dependent manner. The enhancement of re-epithelialization by RvD2 was lost in mice genetically deficient in its receptor and migration of keratinocytes stimulated with RvD2 was associated with activation of the PI3K-AKT-mTOR-S6 pathway, blockade of which prevented its pro-migratory actions. Collectively, these results demonstrate that resolvins have direct roles in the tissue repair program., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Injuries to the skin are often complicated by invasive infections. Standard treatment with intravenous antibiotics has limited tissue penetration and sometimes, major systemic toxicity. Traditional topical delivery of antimicrobials also has limited effectiveness and duration of action. We demonstrate the use of a new Platform Wound Device (PWD) for delivery of topical, ultrahigh concentrations of minocycline as well as lidocaine onto the burn eschar and on the surface of excisional wounds in a total of 56 burn wounds and 24 excisional wounds in a porcine model. Wounds were created on day 0, debrided on day 3, and pigs were killed on day 7. After 3 days of PWD with minocycline treatment, bacterial count was 5.44 log CFU/g in dorsal wound tissue inoculated with methicillin-resistant Staphylococcus aureus, less than that after treatment with silver sulfadiazine cream (7.64 log CFU/g). Pain was also relieved or eliminated in burn wounds and full-thickness excisional wounds when lidocaine was delivered by the PWD. The results demonstrate that ultrahigh concentrations of antibiotics can be delivered effectively by the PWD, and will accelerate wound bed preparation.

Background: Skin grafting is the current standard of care in the treatment of full-thickness burns and other wounds. It is sometimes associated with substantial problems, such as poor quality of the healed skin, scarring, and lack of donor-site skin in large burns. To overcome these problems, alternative techniques that could provide larger expansion of a skin graft have been introduced over the years. Particularly, different cell therapies and methods to further expand skin grafts to minimize the need for donor skin have been attempted. The purpose of this study was to objectively evaluate the efficacy of cell and micrograft transplantation in the healing of full-thickness wounds., Materials and Methods: Allogeneic cultured keratinocytes and fibroblasts, separately and together, as well as autologous and allogeneic skin micrografts were transplanted to full-thickness rat wounds, and healing was studied over time. In addition, wound fluid was collected, and the level of various cytokines and growth factors in the wound after transplantation was measured., Results: Our results showed that both autologous and allogeneic micrografts were efficient treatment modalities for full-thickness wound healing. Allogeneic skin cell transplantation did not result in wound closure, and no viable cells were found in the wound 10 d after transplantation., Conclusions: Our study demonstrated that allogeneic micrografting is a possible treatment modality for full-thickness wound healing. The allografts stayed viable in the wound and contributed to both re-epithelialization and formation of dermis, whereas allogeneic skin cell transplantation did not result in wound closure., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Split-thickness skin graft (STSG) donor site dressings can play an integral role in reducing donor site morbidity. This study tested a novel, chitosan-based wound dressing, Opticell Ag, as an STSG donor site dressing for wounds <10% total body surface area (TBSA)., Method: Between January and December 2016, the chitosan-based dressing was placed on participating patients' donor sites immediately following graft harvest and covered with a transparent occlusive dressing. Pain was evaluated on postoperative day one, before dressing change between days 5-7, and before and after dressing removal between days 10-14 using the Visual Analog Scale (VAS). The extent of re-epithelialisation was determined between day 10-14 and at one month, and healing quality was also evaluated at one month post-operatively using the Vancouver Scar Scale (VSS)., Results: A total of 19 patients were recruited, of which 16 completed the study. Patients experienced mild-to-moderate pain in their donor sites when the chitosan-based dressing was used. Pain decreased significantly between postoperative day one and days 10-14, as well as between days 5-7 and 10-14. The mean percentage of re-epithelialisation on days 10-14 was 92% and by one month was 99%. The mean VSS at one month was 3.2±1.4. There were no statistically significant differences between patients' re-epithelialisation rates or VSS scores. There were unplanned dressing changes in four patients. No donor site infections or other adverse events were identified., Conclusion: The chitosan-based dressing tested in this study is safe, effective, and associated with reasonable pain control and acceptable healing quality. The results suggest that it is a promising STSG donor site dressing.

Background: CCHCR1 (Coiled-Coil α-Helical Rod protein 1) is a putative psoriasis candidate gene with the risk alleles CCHCR1*WWCC and *Iso3, the latter inhibiting the translation of isoform 1. CCHCR1 was recently shown to be a centrosomal protein, as well as a component of cytoplasmic processing bodies (P-bodies) that regulate mRNA turnover. The function of CCHCR1 has remained unsettled, partly because of the inconsistent findings; it has been shown to play a wide variety of roles in divergent processes, e.g., cell proliferation and steroidogenesis. Here we utilized RNA sequencing (RNAseq) using HEK293 cells overexpressing isoforms 1 or 3 (Iso1, Iso3 cells), in combination with the coding non-risk or risk (*WWCC) haplotype of CCHCR1. Our aim was to study the overall role of CCHCR1 and the effects of its variants., Results: The overexpression of CCHCR1 variants in HEK293 cells resulted in cell line-specific expression profiles though several similarities were observable. Overall the Iso1 and Iso3 cells showed a clear isoform-specific clustering as two separate groups, and the Non-risk and Risk cells often exhibited opposite effects. The RNAseq supported a role for CCHCR1 in the centrosomes and P-bodies; the most highlighted pathways included regulation of cytoskeleton, adherens and tight junctions, mRNA surveillance and RNA transport. Interestingly, both the RNAseq and immunofluorescent localization revealed variant-specific differences for CCHCR1 within the P-bodies., Conclusions: CCHCR1 influenced a wide variety of signaling pathways, which could reflect its active role in the P-bodies and centrosomes that both are linked to the cytoskeleton; as a centrosomal P-body protein CCHCR1 may regulate diverse cytoskeleton-mediated functions, such as cell adhesion and -division. The present findings may explain the previous inconsistent observations about the functions of CCHCR1.

Background: Cellular grafts used for skin repair require rapid integration with the host tissue to remain viable and especially to nourish the epidermal cells. Here, we evaluated the responses in the split-thickness skin grafts (STSGs) grafted on three differently treated wound beds: directly on excised wound bed (EX), on an artificial dermal template (DT) and on granulation tissue (GT) induced by cellulose sponge., Methods: In ten burn patients, after excision, a test area was divided into three sections: One transplanted with STSG instantaneously and two sections had a pre-treatment for 2 weeks with either DT or a cellulose sponge inducing granulation tissue formation and thereafter grafted with STSGs., Results: One week after grafting, the STSGs on GT demonstrated most endothelial CD31 + staining, largest average vessel diameters as well as most CD163 + staining of M2-like macrophages and most MIB1 + proliferating epidermal cells, suggesting an active regenerative environment. STSGs on DT had smallest vessel diameters and the least CD163 + macrophages. STSGs on EX had the least CD31 + cells and the least MIB1 + proliferating cells. After 3 months, this reactivity in STSGs had subsided, except increased dermal cell proliferation was observed in STSGs on EX., Conclusions: Results show that pre-treatment of wound bed and induction of granulation tissue formation can accelerate host-graft interaction by stimulating graft vasculature and inducing cell proliferation.

Background: Although wound contraction is an essential part of healing, excessive contraction can compromise healing through induction of scarring and fibrosis. This in turn leads to development of wound contractures that limit elasticity and function. Major research efforts have focused on development of novel therapeutic approaches to gain inhibitory control over wound contraction. Despite these efforts, the need for cost-effective, clinically feasible, and effective agents to inhibit wound contraction remains., Methods: In this study, the authors investigated the effect of nanofibrillar cellulose hydrogel on wound contraction both in vitro and in vivo. Two different porcine full-thickness wounds (8-mm punch-biopsy wounds and 4 × 4-cm wounds covered with a 1:3-meshed split-thickness skin graft) were treated with or without nanofibrillar cellulose or carboxymethylcellulose (Purilon hydrogel), which was used as a reference treatment. Wound contraction was observed macroscopically, and histologic sections were taken at 14-day follow-up., Results: Nanofibrillar cellulose hydrogel inhibited 70 percent of punch-biopsy wound contraction, whereas the carboxymethylcellulose hydrogel was ineffective. Importantly, application of nanofibrillar cellulose on split-thickness skin grafts did not inhibit epithelialization of the interstices or cell migration from the graft., Conclusion: The authors' results, although preliminary, indicate a potential for nanofibrillar cellulose hydrogel as a novel material for controlling excessive wound contraction.

Chronic, non-healing wounds place a significant burden on patients and healthcare systems, resulting in impaired mobility, limb amputation, or even death. Chronic wounds result from a disruption in the highly orchestrated cascade of events involved in wound closure. Significant advances in our understanding of the pathophysiology of chronic wounds have resulted in the development of drugs designed to target different aspects of the impaired processes. However, the hostility of the wound environment rich in degradative enzymes and its elevated pH, combined with differences in the time scales of different physiological processes involved in tissue regeneration require the use of effective drug delivery systems. In this review, we will first discuss the pathophysiology of chronic wounds and then the materials used for engineering drug delivery systems. Different passive and active drug delivery systems used in wound care will be reviewed. In addition, the architecture of the delivery platform and its ability to modulate drug delivery are discussed. Emerging technologies and the opportunities for engineering more effective wound care devices are also highlighted., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Skin grafting is the current standard care in the treatment of full thickness burns. It was first described around 1500 BC but the vast majority of advancements have been achieved over the past 200 years., Methods: An extensive literature review was conducted on Pubmed, Medline and Google Scholar researching the evolution of skin grafting techniques. The authors concentrated on the major landmarks of skin grafting and also provide an overview of ongoing research efforts in this field., Results: The major innovations of skin grafting include Reverdin pinch grafting, Ollier grafting, Thiersch grafting, Wolfe grafting, Padgett dermatome and modifications, Meek-wall microdermatome and Tanner mesh grafting. A brief description of the usage, advantages and limitations of each technique is included in the manuscript., Conclusions: Skin grafting technique have evolved significantly over past 200 years from Reverdin pinch grafting to modern day meshed skin grafts using powered dermatome. Increasing the expansion ratio and improving the cosmetic and functional outcome are the main focus of ongoing skin grafting research and emerging techniques (such as Integra ® , Recell ® , Xpansion ® ) are showing promise., (Copyright © 2017 Elsevier Ltd and ISBI. All rights reserved.)

Background: Epidermal stem cells present in the skin appendages of the dermis might be crucial in wound healing. In this study, the authors located these cells in the dermis and evaluated their contribution to full-thickness wound healing in a porcine model., Methods: Four sequentially deeper 0.35-mm-thick skin grafts were harvested from the same donor site going down to 1.4 mm in depth (layers 1 through 4). The layers were minced to 0.8 × 0.8 × 0.35-mm micrografts and transplanted (1:2) onto full-thickness porcine wounds. Healing was monitored up to 28 days and biopsy specimens were collected on days 6 and 10. Multiple wound healing parameters were used to assess the quality of healing., Results: The authors' results showed that wounds transplanted with layer 2 (0.35 to 0.7 mm) and layer 3 (0.7 to 1.05 mm) micrografts demonstrated reepithelialization rates comparable to that of split-thickness skin graft (layer 1, 0.00 to 0.35 mm; split-thickness skin graft) at day 10. At day 28, dermal micrografts (layers 2 and 3) showed quality of healing comparable to that of split-thickness skin grafts (layer 1) in terms of wound contraction and scar elevation index. The amounts of epidermal stem cells [cluster of differentiation (CD) 34] and basal keratinocytes (KRT14) at each layer were quantified by immunohistochemistry., Conclusions: The analysis showed that layers 2 and 3 contained the most CD34 cells and layer 1 was the richest in KRT14 cells. The immunohistochemistry also indicated that, by day 6, CD34 cells had differentiated into KRT14 cells, which migrated from the grafts and contributed to the reepithelialization of the wound.

Obesity leads to a loss of muscle mass and impaired muscle regeneration. In obese individuals, pathologically elevated levels of prolyl hydroxylase domain enzyme 2 (PHD2) limit skeletal muscle hypoxia-inducible factor-1 alpha and vascular endothelial growth factor (VEGF) expression. Loss of local VEGF may further impair skeletal muscle regeneration. We hypothesized that PHD2 inhibition would restore vigorous muscle regeneration in a murine model of obesity. Adult (22-week-old) male mice were fed either a high-fat diet (HFD), with 60% of calories derived from fat, or a regular diet (RD), with 10% of calories derived from fat, for 16 weeks. On day 5 following cryoinjury to the tibialis anterior muscle, newly regenerated muscle fiber cross-sectional areas were significantly smaller in mice fed an HFD as compared to RD, indicating an impaired regenerative response. Cryoinjured gastrocnemius muscles of HFD mice also showed elevated PHD2 levels (twofold higher) and reduced VEGF levels (twofold lower) as compared to RD. Dimethyloxalylglycine, a cell permeable competitive inhibitor of PHD2, restored VEGF levels and significantly improved regenerating myofiber size in cryoinjured mice fed an HFD. We conclude that pathologically increased PHD2 in the obese state drives impairments in muscle regeneration, in part by blunting VEGF production. Inhibition of PHD2 over activity in the obese state normalizes VEGF levels and restores muscle regenerative potential.

Volumetric muscle loss (VML), usually occurring following traumatic injury, results in a composite loss of muscle mass. These injuries manifest as decreased strength and functional impairments. Clinically, these injuries often heal with fibrosis, as opposed to skeletal muscle regeneration. This study examines the healing patterns of a skeletal muscle following VML in a murine model. Eight-week old male C57BL/6J mice used in the study underwent either bilateral VML injury or cryoinjury, a widely used model known to induce skeletal muscle regeneration. Skeletal muscle was harvested at 2 and 4 weeks following injury and subjected to histological analysis. H&E staining demonstrated skeletal muscle regeneration following cryoinjury, but not VML, at either timepoint post-injury. Additionally, samples were analyzed using a wound-healing PCR array to identify differentially regulated genes of interest in VML and cryoinjury, as compared to noninjured controls. The gene array data further demonstrated prolonged inflammation and increased pro-fibrotic activity in the VML injured muscles, as compared to cryoinjury. In addition, IGF1, a known myogenic factor, was significantly decreased following VML, as compared to cryoinjury, in both ELISA and PCR. This study offers an insight into the pathophysiology of VML injury and reveals a gene profile of a nonregenerating skeletal muscle., (© 2017 by the Wound Healing Society.)

Concurrent injuries to multiple extremities present unique challenges to the reconstructive surgeon. The primary goal in such scenarios is to optimize functional outcomes. The goal of this article is to present an overview of various techniques necessary to provide sufficient soft tissue and preserve amputation limb lengths and function. The concept of innovative techniques for maximizing limb savage and function is presented using an index patient with multiple extremity third- and fourth-degree burn injuries resulting in nonsalvageable lower extremities and severe left-hand wounds. A review of other potential innovative techniques is discussed. The burn injury resulted in a need for bilateral guillotine below-knee amputations. Above-knee amputation was avoided in the left leg using a parascapular free fasciocutaneous flap, while through-knee amputation was preferred to above-knee amputation in the right leg. The preservation of areas with questionable viability resulted in salvaging the left hand of the patient using digital palmar flaps to resurface the dorsum with creation of a first web-space. Maintenance of maximal viable length of limbs and any residual function in the limbs can be of significant functional benefit to multiple limb amputation patients. Maximizing the limb length in such patients is critical, and typical "rules" that have traditionally been utilized to minimize numbers of operations and optimize prosthetic fit may not apply.

Wound microenvironment plays a major role in the process of wound healing. It contains various external and internal factors that participate in wound pathophysiology. The pH is an important factor that influences wound healing by changing throughout the healing process. Several previous studies have investigated the role of pH in relation to pathogens but studies concentrating on the effects of pH on wound healing itself are inconclusive. The purpose of this study was to comprehensively and in a controlled fashion investigate the effect of pH on wound healing by studying its effect on human primary keratinocyte and fibroblast function in vitro and on wound healing in vivo. In vitro, primary human keratinocytes and fibroblasts were cultured in different levels of pH (5.5-12.5) and the effect on cell viability, proliferation, and migration was studied. A rat full-thickness wound model was used to investigate the effect of pH (5.5-9.5) on wound healing in vivo. The effect of pH on inflammation was monitored by measuring IL-1 α concentrations from wounds and cell cultures exposed to different pH environments. Our results showed that both skin cell types tolerated wide range of pH very well. They further demonstrated that both acidic and alkaline environments decelerated cell migration in comparison to neutral environments and interestingly alkaline conditions significantly enhanced cell proliferation. Results from the in vivo experiments indicated that a prolonged, strongly acidic wound environment prevents both wound closure and reepithelialization while a prolonged alkaline environment did not have any negative impact on wound closure or reepithelialization. Separately, both in vitro and in vivo studies showed that prolonged acidic conditions significantly increased the expression of IL-1 α in fibroblast cultures and in wound fluid, whereas prolonged alkaline conditions did not result in elevated amounts of IL-1 α., (© 2017 by the Wound Healing Society.)

Background: Multiple previous studies have established that high systemic blood glucose concentration impairs skin wound healing. However, the effects of local hyperglycemia on wound healing are not well defined. Comprehensive animal studies and in vitro studies using both fibroblasts and keratinocytes are lacking., Materials and Methods: Primary keratinocytes and fibroblasts were isolated from discarded human tissue, cultured under different concentrations of glucose, and the effect on cell function was examined. In addition, a rat full-thickness wound model was used to topically treat the wounds with different glucose concentrations and the effect on wound closure and re-epithelialization was investigated over time., Results: The cell viability experiments indicated that both keratinocytes and fibroblasts endure high glucose well and concentrations under 26 mM did not have a remarkable effect on their viability over time. Moderate addition of glucose (10 mM) boosted fibroblast proliferation (6-fold) but did not have an effect on keratinocyte proliferation. In both keratinocytes and fibroblasts, glucose inhibited their migration and already the addition of 5.6-mM glucose had an inhibitory effect. In vivo experiments showed that full-thickness wounds treated with topical glucose had impaired wound closure and lower re-epithelialization rate in comparison to nontreated control wounds. The results also showed that higher glucose concentrations inhibited wound healing more efficiently., Conclusions: In conclusion, our study indicates that high glucose inhibits both keratinocyte and fibroblast migration as well as wound healing in vivo in a concentration dependent manner., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Wound infection can impair postoperative healing. Topical antibiotics have potential to treat wound infection and inflammation and minimize the adverse effects associated with systemic antibiotics., Methods: Full-thickness porcine wounds were infected with Staphylococcus aureus. Using polyurethane wound enclosure devices, wounds were treated with topical 100 μg/ml minocycline, topical 1000 μg/ml minocycline, topical saline control, or 4 mg/kg intravenous minocycline. Bacteria were quantified in wound tissue and fluid obtained over 9 hours. Immunosorbent assays were used to analyze inflammatory marker concentrations. Minocycline's effect on in vitro migration and proliferation of human keratinocytes and fibroblasts was tested using scratch assays and metabolic assays, respectively., Results: After 6 hours, 100 and 1000 μg/ml topical minocycline decreased bacteria in wound tissue to 3.5 ± 0.87 and 2.9 ± 2.3 log colony-forming units/g respectively, compared to 8.3 ± 0.9 log colony-forming units/g in control wounds (p < 0.001) and 6.9 ± 0.2 log colony-forming units/g in wounds treated with 4 mg/kg intravenous minocycline (p < 0.01). After 2 hours, topical minocycline reduced concentrations of the inflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α (p < 0.01), and inflammatory cell counts in wound tissue (p < 0.05). In noninfected wounds, topical minocycline significantly reduced interleukin-1β, interleukin-6, and inflammatory cell counts after 4 hours (p < 0.01). Matrix metalloproteinase-9 concentrations decreased after 1-hour treatment (p < 0.05). Keratinocyte and fibroblast in vitro functions were not adversely affected by 10 μg/ml minocycline or less., Conclusions: Topical minocycline significantly reduces bacterial burden and inflammation in infected wounds compared with wounds treated with intravenous minocycline or control wounds. Minocycline also decreases local inflammation independently of its antimicrobial effect.