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All organisms from single-cell amoebae through toiHomo sapiens/ihave evolved strategies for repairing wounds as an essential homeostatic mechanism for rebuilding their outer barrier layers after damage. In multicellular animals, this outer barrier layer is the skin, and, for more than a century, scientists have been attempting to unravel the mechanisms underpinning skin repair because of its clear clinical relevance to pathologies that range from chronic nonhealing wounds, through to excessive scarring. Most of these studies have been in rabbits and rodents, or in in vitro scratch wound models, but in the last decades, two newcomer model organisms to wound healing studies-flies and fish-have brought genetic tractability and unparalleled opportunities for live imaging to the field. These two models are complementary to one another, and to mouse and in vitro approaches, and thus offer different insights into various aspects of the wound repair process.

Wound repair is a systematic biological program characterized by four overlapping phases: hemostasis, inflammation, proliferation, and remodeling. Notwithstanding differences between species and distinct anatomical sites, the fundamental phases in the wound healing process are conserved among mammalian species. Oral wound healing is defined as an ideal wound healing model because it resolves rapidly and without scar formation. Understanding the regulation and contribution of the different molecular events that drive rapid wound healing in oral mucosa compared with those of the skin will help us define how these lesions heal more efficiently and may provide new therapeutic strategies that can be translated to the clinical settings for patients with chronic nonhealing wounds. Although all epithelial tissues have remarkable ability for tissue repair, the efficiency of such repair differs between epithelia (oral mucosa vs. cutaneous). This prompts the long-standing, fundamental biological and clinically relevant questions as to why and how does the oral mucosa achieve its enhanced wound healing capacity. In this review, we focus on (1) distinct innate wound healing capabilities of the oral mucosa, (2) lessons learned from comparative transcriptomic studies of oral mucosa versus skin, and (3) translation of findings to therapeutics for enhanced wound healing.

Wound healing requires a complex cascade of highly controlled and conserved cellular and molecular processes. These involve numerous cell types and extracellular matrix molecules regulated by the actin cytoskeleton. This microscopic network of filaments is present within the cytoplasm of all cells and provides the shape and mechanical support required for cell movement and proliferation. Here, an overview of the processes of wound healing are described from the perspective of the cell in relation to the actin cytoskeleton. Key points of discussion include the role of actin, its binding proteins, signaling pathways, and events that play significant roles in the phases of wound healing. The identification of cytoskeletal targets that can be used to manipulate and improve wound healing is included as an emerging area of focus that may inform future therapeutic approaches to improve healing of complex wounds. Refereed/Peer-reviewed

BACKGROUND: Epidermolysis bullosa (EB) is a rare, genetically and clinically heterogeneous group of skin fragility disorders. No cure is currently available, but many novel and repurposed treatments are upcoming. For adequate evaluation and comparison of clinical studies in EB, well-defined and consistent consensus-endorsed outcomes and outcome measurement instruments are necessary.OBJECTIVES: To identify previously reported outcomes in EB clinical research, group these outcomes by outcome domains and areas and summarize respective outcome measurement instruments.METHODS: A systematic literature search was performed in the databases MEDLINE, Embase, Scopus, Cochrane CENTRAL, CINAHL, PsycINFO and trial registries covering the period between January 1991 and September 2021. Studies were included if they evaluated a treatment in a minimum of three patients with EB. Two reviewers independently performed the study selection and data extraction. All identified outcomes and their respective instruments were mapped onto overarching outcome domains. The outcome domains were stratified according to subgroups of EB type, age group, intervention, decade and phase of clinical trial.RESULTS: The included studies (n = 207) covered a range of study designs and geographical settings. A total of 1280 outcomes were extracted verbatim and inductively mapped onto 80 outcome domains and 14 outcome areas. We found a steady increase in the number of published clinical trials and outcomes reported over the past 30 years. The included studies mainly focused on recessive dystrophic EB (43%). Wound healing was reported most frequently across all studies and referred to as a primary outcome in 31% of trials. Great heterogeneity of reported outcomes was observed within all stratified subgroups. Moreover, a diverse range of outcome measurement instruments (n = 200) was identified.CONCLUSIONS: We show substantial heterogeneity in reported outcomes and outcome measurement instruments in EB clinical research over the past 30 years. This review is the first step towards harmonization of outcomes in EB, which is necessary to expedite the clinical translation of novel treatments for patients with EB.

The present study aimed to evaluate the in vitro antibacterial and antioxidant activities and the in vivo wound healing performance of a polysaccharide isolated from Glycyrrhiza glabra named PSG. It was structurally characterized by Fourier transformed infrared (FT-IR) spectroscopy, which confirmed the presence of different polysaccharides functional bands. The antioxidant capacity of PSG was determined in vitro and evaluated in vivo through the examination of wound healing capacity. Thirty two rats were randomly divided into four groups: group I was treated with physiological serum (negative control); group II was treated with “CYTOL CENTELLA®”; group III was treated with glycerol and group IV was treated with polysaccharide. The response to treatments was assessed by macroscopic, histologic, and biochemical parameters. Data revealed that our sample exhibited potential antioxidant activities and accelerated significantly the wound healing process, after ten days of treatment, proved by the higher wound appearance scores and a higher content of collagen confirmed by histological examination, when compared with control and “CYTOL CENTELLA®”. Overall, these findings proved that this polysaccharide isolated from Glycyrrhiza glabra could be considered as a natural bioactive polymer for therapeutic process in wound healing applications. Resumo O presente estudo teve como objetivo avaliar as atividades antibacteriana e antioxidante in vitro e o desempenho cicatricial in vivo de um polissacarídeo isolado de Glycyrrhiza glabra denominado PSG. Foi caracterizado estruturalmente por espectroscopia no infravermelho com transformada de Fourier (FT-IR), que confirmou a presença de diferentes bandas funcionais de polissacarídeos. A capacidade antioxidante da PSG foi determinada in vitro e avaliada in vivo através do exame da capacidade de cicatrização de feridas. Trinta e dois ratos foram divididos aleatoriamente em quatro grupos: o grupo I foi tratado com soro fisiológico (controle negativo); o grupo II foi tratado com “CYTOL CENTELLA®”; o grupo III foi tratado com glicerol e o grupo IV foi tratado com polissacarídeo. A resposta aos tratamentos foi avaliada por parâmetros macroscópicos, histológicos e bioquímicos. Os dados revelaram que nossa amostra apresentou atividades antioxidantes potenciais e acelerou significativamente o processo de cicatrização da ferida, após dez dias de tratamento, comprovado pelos maiores escores de aparência da ferida e maior teor de colágeno confirmado pelo exame histológico, quando comparado ao controle e “CYTOL CENTELLA® ”. No geral, esses achados provaram que esse polissacarídeo isolado de Glycyrrhiza glabra pode ser considerado um polímero bioativo natural para processos terapêuticos em aplicações de cicatrização de feridas.

Juvenile Ossifying Fibroma (JOF) represents a disfiguring disease of humans and animals and has been reported to preferentially affect the rostral mandible of young horses. Currently, the inciting cause of JOF remains to be elucidated. However, previous oral trauma has been identified historically in several cases presented in the literature and anecdotally by attending clinicians. Oral trauma and the subsequent second intention wound healing’s effect on the development of JOF was investigated prospectively over eight weeks utilizing four weaning aged Thoroughbred Cross fillies. Histopathologic evaluation of the healing rostral mandibular incisive bone wounds revealed tissue architecture consistent with JOF in one out of four fillies (25%). These findings support oral trauma as one of the inciting causes of the condition currently characterized as JOF and offer a model for further investigation into JOF and other fibro-osseous conditions of the rostral mandible in juvenile horses.

Objective Chronic skin wounds are one of the most devastating complications in diabetic patients due to the formation of advanced glycation end products (AGEs) resulting from non-enzymatic glycation of proteins and lipids in hyperglycemia. AGEs, upon binding their receptors (RAGEs), trigger pro-inflammatory signals that impair wound healing in diabetes and contribute to the pathology of chronic skin wounds. Approach We previously developed a recombinant fusion protein containing the binding domain of RAGE (vRAGE) linked to elastin-like polypeptides (ELPs) that acts as a competitive inhibitor of AGEs, and another ELP fusion protein containing stromal cell-derived factor 1 (SDF1) that promotes revascularization. Herein, we report the effects of protein coacervates incorporating both vRAGE-ELP and SDF1-ELP on wound healing in an in vitro diabetes-mimicking cell culture system, and in in vivo in full-thickness wounds on diabetic mice. Results The combination of vRAGE-ELP and SDF1-ELP increased cell metabolic activity in AGE-stimulated endothelial cells, promoted in vitro tube formation and accelerated healing in an in vitro cell migration assay. When used in a single topical application on full-thickness excisional skin wounds in diabetic mice, wound closure in the combination groups reached almost 100% on post-wounding day 35, compared to 62% and 85% on the same days in animals treated with fibrin gel control and vehicle control consisting of ELP alone. Innovation To our knowledge, this is the first study that attempts to reverse the AGE-RAGE-mediated signaling as well as to promote cell proliferation and vascularization in one single treatment. Conclusion The co-delivery of vRAGE-ELP and SDF1-ELP has potential for the treatment of diabetic wounds.

Healing wounds and cancers present remarkable cellular and molecular parallels, but the specific roles of the healing phases are largely unknown. We developed a bioinformatics pipeline to identify genes and pathways that define distinct phases across the time-course of healing. Their comparison to cancer transcriptomes revealed that a resolution phase wound signature is associated with increased severity in skin cancer and enriches for extracellular matrix-related pathways. Comparisons of transcriptomes of early- and late-phase wound fibroblasts vs skin cancer-associated fibroblasts (CAFs) identified an "early wound" CAF subtype, which localizes to the inner tumor stroma and expresses collagen-related genes that are controlled by the RUNX2 transcription factor. A "late wound" CAF subtype localizes to the outer tumor stroma and expresses elastin-related genes. Matrix imaging of primary melanoma tissue microarrays validated these matrix signatures and identified collagen- vs elastin-rich niches within the tumor microenvironment, whose spatial organization predicts survival and recurrence. These results identify wound-regulated genes and matrix patterns with prognostic potential in skin cancer., Matrix Biology, 119, ISSN:0945-053X, ISSN:1569-1802

ZusammenfassungLokale Wundinfektionen sind ein multidisziplinär relevantes Problem und sollten möglichst frühzeitig diagnostiziert und adäquat therapiert werden. Neben einer Stagnation der Wundheilung sind es insbesondere die drohende Weiterentwicklung zu systemischen Infektionen bis hin zur Sepsis, die gefürchtete, potenziell lebensbedrohliche Komplikationen darstellen. Einen besonders hohen und multidisziplinären Stellenwert hat diese Thematik bei der Behandlung von Patienten mit chronischen Wunden. Bislang gab es für die Diagnostik keine einheitlich akzeptierten Kriterien. Hier ermöglicht jetzt der neu entwickelte und validierte TILI-Score als Ergänzung zu den Vitalparametern und serologischen Werten die rasche Objektivierung lokaler Wundinfektionen. Ergänzend können mit dem W.A.R.-Score zudem Patienten mit erhöhtem Infektionsrisiko identifiziert werden. Durch diese einfach einzusetzenden Hilfsmittel kann die Indikation einer antiseptischen Wundtherapie individuell, schnell und unproblematisch eingeschätzt werden. Für viele Patienten mit chronischen Wunden ist dann Polihexanid das Wundantiseptikum der ersten Wahl. Die Indikation von Wundantiseptika sollte aber spätestens nach einer Therapiedauer von 14 Tagen kritisch überprüft werden.

Objective: In this study, the antioxidant properties of Arum maculatum plant were evaluated. This study reported for the first time the wound healing activity of the methanol extract of A. maculatum fruits. This study aimed to assess and determine the possible pharmacological activities of A. maculatum and evaluate its potential to act as a wound care plant. Methods: The antioxidant and antimicrobial activities of A. maculatum were investigated using excisional in vivo and in vitro wound healing mouse models. A total of 32 Balb-c mice were used, which were equally, divided into four groups: saline control group, control group, A. maculatum group, and Centella asiatica extract group. Treatment applications were performed topically once per day. Wound area narrowing, wound healing percentage, and epithelialization time were analyzed. Results: A. maculatum application supported the healing process in in vivo and in vitro wound models. A. maculatum contributed to the healing process by promoting granulation tissue formation, epidermal regeneration, and angiogenesis. Conclusions: Wound healing is a complex and well-organized process that requires communication between cells. The antioxidant and antimicrobial activities of A. maculatum extract have been determined by current studies. A. maculatum extract may provide significant benefits in promoting the wound healing process. Amaç: Bu araştırmada antioksidan özelliklerini değerlendirmek için Arum maculatum bitkisi seçilmiştir. Bildiğimiz kadarıyla A. maculatum meyvelerinin metanol özünün yara iyileştirici aktivitesi ilk kez bu çalışmada rapor edilmiştir. Bu çalışma, A. maculatum’un olası farmakolojik aktivitelerini belirlemek, değerlendirmek ve bir yara tedavi edici bitki olarak etki gösterme potansiyelini değerlendirmek içindi. Yöntemler: A. maculatum’un antioksidan ve antimikrobiyal aktiviteleri, farelerde eksizyonel in vivo ve in vitro yara iyileşme modelleri kulanılarak araştırılmıştır. Toplamda 32 Balb-c fare kullanılmış olup salin kontrol grubu, kontrol grubu, A. maculatum uygulanan grup ve Centella asiatica özütü uygulanan grup olmak üzere 4 gruba ayrılmıştır. Tedavi uygulamaları günde bir kez topikal olarak gerçekleştirilmiştir. Skar alanı hacminde gerçekleşen değişim, yara iyileşme yüzdesi ve epitelizasyon süresi analiz edilmiştir. Bulgular: A. maculatum uygulaması in vivo ve in vitro yara modelinde iyileşme sürecini desteklemiştir. A. maculatum, granülasyon dokusunu artırarak iyileşme sürecine katkıda bulunmuş, epidermal rejenerasyonu ve anjiyogenezi artırmıştır. Sonuçlar: Yara iyileşmesi, hücreler arası iletişimi gerektiren karmaşık ve iyi organize edilmiş bir süreçtir. Mevcut çalışmalar doğrultusunda antioksidan ve antimikrobiyal aktivitesi belirlenmiş olan A. maculatum özü, yara iyileşme sürecinin desteklenmesinde önemli bir fayda sağlayabilir.

Burn areas are susceptible to bacterial growth and infections, particularly in cases with lengthy periods of hospital stay. Burn wound healing, which involves various molecular and cellular mechanisms, continues to be a significant problem. Growth factors and cytokines play an active and vital role in wound healing. In the present study, the effects of kefir on wound healing in a 2nd-degree mouse burn model infected with e.coli, s.aureus and p.aeruginosa were investigated in vitro. In order to clarify the effects of kefir in the wound healing process, the macroscopic changes in kefir-applied scar tissue as well as wound depth and width were examined and IL-1α, IL-1β, IL-6, IL-8, IL-10 and TNF-α, VEGF, TGF-β protein levels were determined using the qRT-PCR method. The findings of the present study show that kefir has a positive impact on the factors playing a role in wound healing and accelerates the healing process.

Diabetic foot ulcers (DFUs) are a crucial complication of diabetes, as in a diabetic wound, each step of the physiological healing process is affected. This entails a more easily infectable wound, and delayed tissue regeneration due to the inflammation that occurs, leading to a drastic decrease in the overall patient's quality of life. As a strategy to manage DFUs, skin alternatives and wound dressings are currently receiving a lot of attention as they keep the wound environment “under control”, while providing bioactive compounds that help to manage infection and inflammation and promote tissue repair. This has been made possible thanks to the advent of emerging technologies such as 3D Bioprinting to produce skin resembling constructs or microfluidics (MFs) that allows the manufacture of nanoparticles (NPs) that act as drug carriers, in a prompt and less expensive way.In the present proof-of-concept study, the possibility of combining two novel and appealing techniques in the manufacturing of wound dressings has been demonstrated for first time. The novelty of this work consists in the combination of liposomes (LPs) encapsulating the active pharmaceutical ingredient (API) into a hydrogel that is further printed into a three-dimensional scaffold for wound dressing; to the knowledge of the authors this has never been done before.A grid-shaped scaffold has been produced through the coaxial 3D bioprinting technique which has allowed to combine, in one single filament, two different bioinks. The inner core of the filament is a nanocomposite hydrogel consisting of hydroxyethyl cellulose (HEC) and PEGylated LPs encapsulated with thyme oil (TO) manufactured via MFs for the first time. The outer shell of the filament, instead, is represented by a hybrid hydrogel composed of sodium alginate/cellulose nanocrystals (SA/CNC) and enriched with free TO. This provides a combination of two different release ratios of the API, a bulk release for the first 24 h thanks to the free TO in the shell of the filament and a sustained release for up to 10 days provided from the API inside the LPs. Confocal Microscopy verified the actual presence of the LPs inside the scaffold after printing and evaluation using the zone of inhibition test proved the antibacterial activity of the manufactured scaffolds against both Gram-positive and Gram-negative bacteria.

Current cellular hydrogel-based skin grafts composed of human dermal fibroblasts and a hydrogel scaffold tend to minimize contraction of full-thickness skin wounds and support skin regeneration. However, there has been no comparison between the sources of the dermal fibroblast used. Products using human adult or neonatal foreskin dermal fibroblasts are often expandediin vitro/iand used after multiple passages without a clear understanding of the effects of this initial production step on the quality and reproducibility of the cellular behavior. Based on the known effects of 2D tissue culture expansion on cellular proliferation and gene expression, we hypothesized that differences in donor age and time in culture may influence cellular properties and contractile behavior in a fibroblast-populated collagen matrix. Using porcine skin as a model based on its similarity to human skin in structure and wound healing properties, we isolated porcine dermal fibroblasts of three different donor ages for use in a 2D proliferation assay and in a 3D cell-populated collagen matrix contractility assay. In 2D cell culture, doubling time remained relatively consistent between all age groups from passage 1 to 6. In the contractility assays, fetal and neonatal groups contracted faster and generated more contractile force than the adult group at passage 1iin vitro/i. However, after five passages in culture, there was no difference in contractility between ages. These results show how cellular responses in a hydrogel scaffold differ based on donor age and time in cultureiin vitro/i, and suggest that consistency in the cellular component of bioengineered skin products could be beneficial in the biomanufacturing of consistent, reliable skin grafts and graftiin vivo/imodels. Future research and therapies using bioengineered skin grafts should consider how results may vary based on donor age and time in culture before seeding. Impact statement Little is known about the impact of donor cell age and time in culture on the contraction of cellular, hydrogel-based skin grafts. These results show how cellular phenotypes of porcine fibroblasts differ based on donor age and time in culture. This information is beneficial when addressing important inconsistencies in biomanufacturing of bioengineered skin grafts andiin vitro/imodels. These findings are relevant to research and therapies using bioengineered skin graft models and the results can be used to increase reproducibility and consistency during the production of bioengineered skin constructs. The information from this study can be extrapolated to futureiin vivo/istudies using human dermal fibroblasts in aniin vivo/imodel to help determine the best donor age and time in culture for optimal wound healing outcomes or more reproducibleiin vitro/itesting constructs.

Significance: Skin inevitably heals with the formation of a fibrotic scar. Patients affected by skin scarring suffer from long-term psychological and physical burdens. Recent Advances: Since the di...

Hypertrophic and keloid scars are common skin conditions resulting from abnormal wound healing. They can cause itching, pain and have a negative physical and psychological impact on patients' lives. Different approaches are used aiming to improve these scars, including intralesional corticosteroids, surgery and more recently, laser therapy. Since laser therapy is expensive and may have adverse effects, it is critical to evaluate the potential benefits and harms of this therapy for treating hypertrophic and keloid scars.To assess the effects of laser therapy for treating hypertrophic and keloid scars.In March 2021 we searched the Cochrane Wounds Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL EBSCO Plus and LILACS. To identify additional studies, we also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses, and health technology reports. There were no restrictions with respect to language, date of publication, or study setting.We included randomised controlled trials (RCTs) for treating hypertrophic or keloid scars (or both), comparing laser therapy with placebo, no intervention or another intervention.Two review authors independently selected studies, extracted the data, assessed the risk of bias of included studies and carried out GRADE assessments to assess the certainty of evidence. A third review author arbitrated if there were disagreements.We included 15 RCTs, involving 604 participants (children and adults) with study sample sizes ranging from 10 to 120 participants (mean 40.27). Where studies randomised different parts of the same scar, each scar segment was the unit of analysis (906 scar segments). The length of participant follow-up varied from 12 weeks to 12 months. All included trials had a high risk of bias for at least one domain: all studies were deemed at high risk of bias due to lack of blinding of participants and personnel. The variability of intervention types, controls, follow-up periods and limitations with report data meant we pooled data for one comparison (and only two outcomes within this). Several review secondary outcomes - cosmesis, tolerance, preference for different modes of treatment, adherence, and change in quality of life - were not reported in any of the included studies. Laser versus no treatment: We found low-certainty evidence suggesting there may be more hypertrophic and keloid scar improvement (that is scars are less severe) in 585-nm pulsed-dye laser (PDL) -treated scars compared with no treatment (risk ratio (RR) 1.96; 95% confidence interval (CI): 1.11 to 3.45; two studies, 60 scar segments). It is unclear whether non-ablative fractional laser (NAFL) impacts on hypertrophic scar severity when compared with no treatment (very low-certainty evidence). It is unclear whether fractional carbon dioxide (CO

The fundamental reasons for delayed wound healing in diabetic animals include inadequate production of growth factors or their increased devastation. Vascular Growth Factor (VEGF) has a biological role in the healing process of mucosal and skin wounds, especially in the process of new vessel formation. We planned to examine the oxidant-antioxidant events that occur during healing with topical VEGF application in diabetic rats. Experiments were performed 36 adults female Wistar albino rat diabetes induced by streptozotocin. The incisional wounds were made on the dorsal region in the rats. Rats were separated to 3 groups: the untreated (negative control) group (n=12), the chitosan group (n=12), the chitosan + VEGF group (n=12). The treatments were continued for 3 and 7 days, excluding the control and negative control groups. Then, the animals were sacrificed on the 3rd and 7th days of wound healing. Antioxidant and oxidant parameters in skin tissue were measured using biochemical methods. Topical VEGF application was decreased the NOx levels on the 3rd day compared to other groups. Moreover, it increased wound tissue GSH and AA levels, subsequently contributing to the enhance tissue antioxidant capacity. In conclusion, VEGF application increases the antioxidant capacity of the tissue and simultaneously reduces the oxidative stress and thus gives a positive acceleration to the wound healing process.

Periodontal disease is a significant public health problem worldwide. Excess unresolved chronic inflammation destroys the periodontal tissues that surround and support the teeth, and efforts to control inflammation by removal of bacterial deposits on the teeth have limited long-term impact. Likewise, procedures aimed at regeneration of the periodontal tissues have shown limited success. Recent advances in stem cell research have shown promising novel prospects for the use of periodontal ligament stem cells (PDLSCs) in tissue regeneration; however, control of inflammation remains a barrier. Human PDLSCs have been shown to release specialized proresolving lipid mediators (SPMs) that modulate the immune response and promote resolution of inflammation, tissue repair, and regeneration. Studies on stem cell biology in periodontology have also been limited by the lack of a good large animal model. Herein, we describe PDLSC biology of the Yorkshire pig (pPDLSCs). pPDLSCs were isolated and characterized. Using lipid mediator profiling, we demonstrate for the first time that pPDLSCs biosynthesize cysteinyl-containing SPMs (cys-SPMs), specifically, maresin conjugates in tissue regeneration 3 (MCTR3) and its authentication using liquid chromatography/tandem mass spectrometry. The exogenous addition of the n-3 precursor docosahexaenoic acid enhances MCTR3 biosynthesis. Using immunocytochemistry, we show that pPDLSCs express 4 of the SPM biosynthetic pathway enzymes necessary for SPM biosynthesis, including 5-lipoxygenase, 12-lipoxygenase, and 15-lipoxygenase-1. In addition, we identified and quantified the cytokine/chemokine profile of pPDLSCs using a 13-plex immunology multiplex assay and found that the pretreatment of pPDLSCs with MCTR3 in an inflammatory environment reduced the production of acute and chronic proinflammatory cytokines/chemokines. Together, these results suggest that enhancing resolution of inflammation pathways and mediators may be a possible key early event in predictable periodontal regeneration.

The transcription factor NRF2 is well known as a master regulator of the cellular stress response. As such, activation of NRF2 has gained widespread attention for its potential to prevent tissue injury, but also as a possible therapeutic approach to promote repair processes. While NRF2 activation affects most or even all cell types, its effect on epithelial cells during repair processes has been particularly well studied. In response to tissue injury, these cells proliferate, migrate and/or spread to effectively repair the damage. In this review, we discuss how NRF2 governs repair of epithelial tissues, and we highlight the increasing number of NRF2 targets with diverse roles in regulating epithelial repair., Biochemical Society transactions, 51 (1), ISSN:0300-5127, ISSN:1470-8752

General awareness and clinical utilization of orthobiologic therapy has increased sharply in the recent years. Orthobiologics can be defined as "biological materials and substrates that promote bone, ligament, muscle, and tendon healing." There are 3 major strategies by which orthobiologics are thought to augment tissue repair or native biologic potential: factor-based, cell-based, and biomechanical augmentation. The purpose of this review is to synthesize the recent literature on orthobiologic techniques for surgical augmentation, with focus on several key areas including meniscus repair, osteochondral grafting, and rotator cuff repair.

Osteoarthritis and cartilage lesions are a major cause of functional limitations which is why the goal of biological treatment is to preserve the native joint to delay the onset of OA. As a result of improvements in surgical techniques and technology, treatment options are more and more available, allowing the treatment of a whole range of injuries, from minor to extensive lesions both acute and chronic. In chondral lesion treatment, restoring hyaline-like cartilage provides improved durability of repaired tissue and desirable wear characteristics. Biological cell-based cartilage restoration treatment was developed to address the need for the long-term viability of repaired tissue. These procedures provide a reliable source of chondrocytes, whether directly or through the differentiation of multipotent precursor cells, capable of producing hyaline-like cartilage, with the minimal formation of fibrocartilage tissue. However, if arthritic changes begin biological therapies offer possibilities to delay. This chapter aims to discuss and give insights into these regenerative, joint preservation techniques for cartilage treatment and possible biological treatment in OA.

Severe septal deviations are a constant challenge for rhinosurgeons. As the septum is the most important pillar of the nasal framework, septal deformities require correction to insure a straight nose. The septum should be on the midline without any tension to ensure a correct healing of the external nasal pyramid. In certain cases, the association of a correct septoplasty and dorsal preservation allows the treatment of the crooked nose and at the same time gives natural results with rapid postoperative recovery. The aim of this article was to underline the versatility of the dorsal preservation technique for the correction of severe septal deviation.

Biopolymer-based thermoresponsive injectable hydrogels with multifunctional tunable characteristics containing anti-oxidative, biocompatibility, anti-infection, tissue regeneration, and/or anti-bacterial are of abundant interest to proficiently stimulate diabetic wound regeneration and are considered as a potential candidate for diversified biomedical application but the development of such hydrogels remains a challenge. In this study, the Chitosan-CMC-g-PF127 injectable hydrogels are developed using solvent casting. The Curcumin (Cur) Chitosan-CMC-g-PF127 injectable hydrogels possess viscoelastic behavior, good swelling properties, and a controlled release profile. The degree of substitution (% DS), thermal stability, morphological behavior, and crystalline characteristics of the developed injectable hydrogels is confirmed using nuclear magnetic resonance (1H NMR), thermogravimetric analysis, scanning electron microscopy (SEM), and x-ray diffraction analysis (XRD), respectively. The controlled release of cur-micelles from the hydrogel is evaluated by drug release studies and pharmacokinetic profile (PK) using high-performance liquid chromatography (HPLC). Furthermore, compared to cur micelles the Cur-laden injectable hydrogel shows a significant increase in half-life (t1/2) up to 5.92 ± 0.7 h, mean residence time (MRT) was 15.75 ± 0.76 h, and area under the first moment curve (AUMC) is 3195.62 ± 547.99 μg/mL*(h)2 which reveals the controlled release behavior. Cytocompatibility analysis of Chitosan-CMC-g-PF127 hydrogels using 3T3-L1 fibroblasts cells and in vivo toxicity by subcutaneous injection followed by histological examination confirmed good biocompatibility of Cur-micelles loaded hydrogels. The histological results revealed the promising tissue regenerative ability and shows enhancement of fibroblasts, keratinocytes, and collagen deposition, which stimulates the epidermal junction. Interestingly, the Chitosan-CMC-g-PF127 injectable hydrogels ladened Cur exhibited a swift wound repair potential by up-surging the cell migration and proliferation at the site of injury and providing a sustained drug delivery platform for hydrophobic moieties.

Orthobiologic procedures are based on altering the microenvironment of musculoskeletal tissues to induce an anti-inflammatory effect and reduce pain, promote healing of these tissues, or provide mechanical support. Allograft tissues have these inherent qualities and can be used as such. This could provide patients whose own autologous tissues may be compromised or have contraindications to harvesting an alternative to treat their orthopedic conditions. Although these allograft therapies are promising, they lack high-quality clinical studies and regulatory guidelines currently limit their use.

In recent years, it has become clear that the burn eschar in deep burns can be selectively removed using the enzymatically debriding agent NexoBrid® (EDNX). In deep partial-thickness burns, such selective debridement preserves all non-injured dermis, which is sometimes sufficient for spontaneous re-epithelization. Nevertheless, it can be extremely challenging to determine exactly what and when to operate after an EDNX procedure. In this manuscript, we sought to investigate the clinical aspect of the enzymatically debrided wound bed of laser Doppler imaging (LDI)-confirmed deep dermal and full-thickness burns after NexoBrid® application. This to evaluate the residual wound healing capacity and implement specific indications for surgical therapy after enzymatic debridement.Mainly LDI-blue areas, determined between 48 h and 5d after burn and afterwards treated with EDNX were selected. Six practical and three expert EDNX users evaluated the high-quality digital images of the wound beds immediately post NexoBrid® removal and after a 2 h wet-to-dry (WTD) dressing period.One hundred and two mainly LDI-blue areas in 32 patients were analyzed. Regarding the early decision-making, there were no significant differences in the wound bed evaluations, wound healing assessment and treatment decision of all 9 EDNX users post EDNX removal versus post WTD. Moreover, there was a good to excellent consensus between the practical and expert EDNX users in the individual wound bed evaluations. Even in the evaluation of a newly developed wound bed color code, with 7 different colors/patterns to choose from, the consensus was 80%. There was also an 84% consensus on the decision whether or not to operate. All mainly LDI-blue areas with incomplete enzymatic debridement, determined during clinical investigation by expert EDNX users, required surgery. Additionally, the expert investigators demonstrated that the following wound bed characteristics were independent predictors of the need for surgical treatment: visible fat lobules (p = 0.028), translucent fat lobules (p 0.001), dermal step-off in the wound bed (p 0.001), visible blood vessels (p 0.001) and coagulated blood vessels (p = 0.023). Also, higher color code ranges on our own developed wound bed classification were significantly related to a surgical intervention (p = 0.006). When including the LDI flux values, the perfusion units were significantly different (p 0.001) between the exclusively LDI-blue areas treated conservatively (mean 145.7) and the areas ultimately treated with autografts (mean 119.5).To the best of our knowledge, this study is the first to address the clinical wound bed evaluation of LDI-confirmed deep burns after NexoBrid® application. Based on our results, it is recommended to evaluate the wound bed twice: immediately after removing NexoBrid® to assess the viability of the wound bed and after the WTD period to reach a more complete decision. During these evaluations, wound bed characteristics such as incomplete debridement, visible and/or translucent fat lobules, visible and/or coagulated blood vessels and a dermal step-off in the wound bed combined with a higher range (4-5) in the newly developed wound bed color code should lead to an early and reliable decision for skin grafting. For burn centers using LDI, mean flux values below 119.5PU - in addition to the above-mentioned wound bed evaluation - are a clear indicator for surgical therapy.

Eradication of infectious biofilms is becoming increasingly difficult due to the growing number of antibiotic-resistant strains. This necessitates development of nonantibiotic-based, antimicrobial approaches. To this end, we designed a heterocatalytic metal-organic framework composed of zirconium 1,4-dicarboxybenzene (UiO-66) with immobilized Pt nanoparticles (Pt-NP/UiO-66). Pt-NP/UiO-66 enhanced singlet-oxygen generation compared with Pt nanoparticles or UiO-66, particularly in an acidic environment. Singlet-oxygen generation degraded phosphodiester bonds present in eDNA gluing biofilms together and therewith dispersed biofilms. Remaining biofilms possessed a more open structure. Concurrently, Pt-NP/UiO-66 stimulated macrophages to adapt a more M1-like, "fighting"phenotype, moving faster toward their target bacteria and showing increased bacterial killing. As a combined effect of biofilm dispersal and macrophage polarization, a subcutaneous Staphylococcus aureus biofilm in mice was more readily eradicated by Pt-NP/UiO-66 than by Pt nanoparticles or UiO-66. Therewith, heterocatalytic Pt-NP/UiO-66 metal-organic frameworks constitute a nonantibiotic-based strategy to weaken protective matrices and disperse infectious biofilms, while strengthening macrophages in bacterial killing.

Orthobiologics have gained much popularity in recent years but there has not been a large amount of clinical evidence to support their use. In the limited research that has been published, they have been shown to be effective and safe. They can assist in earlier return to activity with the avoidance of surgery. They can also augment current surgical practice to aid in healing and return to sport with few complications. With new medical innovation, there is unfortunately a higher cost for these products. The use of orthobiologics will only grow and so will the need for high-level clinical evidence.

Rete ridges (RRs) are distinct undulating microstructures at the junction of the dermis and epidermis in the skin of humans and certain animals. This structure is essential for enhancing the mechanical characteristics of skin and preserving homeostasis. With the development of tissue engineering and regenerative medicine, artificial skin grafts have made great progress in the field of skin healing. However, the restoration of RRs has been often disregarded or absent in artificial skin grafts, which potentially compromise the efficacy of tissue repair and regeneration. Therefore, this review collates recent research advances in understanding the structural features, function, morphogenesis, influencing factors, and reconstruction strategies pertaining to RRs. In addition, the preparation methods and limitations of tissue-engineered skin with RRs are discussed. STATEMENT OF SIGNIFICANCE: The technology for the development of tissue-engineered skin (TES) is widely studied and reported; however, the preparation of TES containing rete ridges (RRs) is often ignored, with no literature reviews on the structural reconstruction of RRs. This review focuses on the progress pertaining to RRs and focuses on the reconstruction methods for RRs. In addition, it discusses the limitations of existing reconstruction methods. Therefore, this review could be a valuable reference for transferring TES with RR structure from the laboratory to clinical applications in skin repair.

Hemostasis and anti-infection are crucial for emergency treatment of severe trauma. Developing functional biomaterial with efficient hemostasis, antibacterial activity and wound healing is of great social significance and clinical value to fast stop bleeding and save lives, but it is still challenged. Here we designed a series of multifunctionalized SA/PDA cryogels by using two-step cross-linking of dopamine and sodium alginate. The resulting interpenetrating network structure had good swelling ratio, excellent mechanical and shape memory properties. Compared with cotton gauze and gelatin sponge, the cryogels exhibited excellent activation of coagulation cascade, more blood cells and platelet adhesion. Due to the action of polydopamine, the cryogel also showed good antioxidant activity and photothermal antibacterial ability assisted by near-infrared radiation, as well as better wound healing performance than gelatin sponge and Tegaderm™ film. Moreover, in the tests of mouse tail docking model, rat femoral artery hemostasis model and non-compressible rabbit liver defect model, the treatment by SA/PDA cryogels presented less blood loss and shorter hemostasis time than cotton gauze and gelatin sponge. Therefore, SA/PDA cryogels with simple preparation process, low cost, and good biocompatibility would be applied in the variety of great clinical applications in bleeding control, anti-infection and wound healing, etc.

The introduction of antibacterial and hemostatic hydrogels with good mechanical properties that display desirable impacts on wound healing process is still an unmet essential for clinical wound dressings. Herein, a multifunctional hydrogel PEG-CMC-THB-PRTM was fabricated via a one-pot method combining carboxymethyl chitosan (CMC), 2,3,4-trihydroxybenzaldehyde (THB), protamine (PRTM) and 4-arm polyethylene glycol aldehyde (PEG). The hydrogel was formed by the dynamic Schiff base reaction between amino groups of carboxymethyl chitosan and aldehyde groups of 4-arm polyethylene glycol aldehyde and exhibited excellent mechanical properties. The developed hydrogel also showed outstanding effects on anti-bacteria and hemostasis through the release of PRTM. Moreover, the hydrogel could promote extracellular matrix formation and wound closure in vivo, thereby accelerating the healing of skin wound. These results suggested that the multifunctional PEG-CMC-THB-PRTM hydrogel is a promising candidate for the clinical treatment of full-thickness wounds.

Chronic wounds are debilitating complications of diabetes mellitus. The present study was conducted to investigate the effect of the hair follicle stem cells (HFSCs) by polycaprolactone scaffold on the healing of incisional cutaneous wounds on streptozotocin-induced diabetic male rats.The wound model was obtained by a biopsy punch of the skin of the animals' back. The animals were randomly divided into five groups as follows: (1) Sham (nondiabetic, not treated), (2) Control (diabetic, not treated), (3) Scaffold (diabetic, treated with polycaprolactone nanofiber scaffold), (4) HFSCs (diabetic, treated with HFSCs), and (5) Scaffold + HFSCs (diabetic, treated with combination of Scaffold and HFSCs). The wounds were photographed in the course of the treatment and their healing rate was assessed. The samples were collected from the wound sites 7, 14, and 28 d after their development. Angiogenesis was surveyed by examining messenger RNA expression and the protein synthesis levels of vascular endothelial growth factor receptor 2 (VEGFR2) and platelet/endothelial cell adhesion molecule-1/cluster of differentiation 31. The histological changes were investigated using hematoxylin and eosin and Masson's trichrome staining. Furthermore, the wound breaking strength was measured on the 28th day by tensiometry.The application of the VEGFR2 as a substrate promotes the expression of CD31 in HFSCs and Scaffold + HFSCs groups compared to controls (P 0.0001). HFSCs and scaffold also rescue the diabetes-induced dysfunction as assessed based on the parameters, such as viability, proliferation, colony formation, cellular adhesion, and chemotactic migration. HFSCs augment the levels of VEGFR2 and promote the restoration of the wound healing in diabetic groups. Furthermore, the maximum biomechanical stress significantly increased in the experimental diabetic groups (Scaffold: 1.38 ± 0.09, HFSCs: 2.13 ± 0.8, Scaffold + HFSCs: 2.38 ± 0.11) compared to the diabetes control group (1.16 ± 0.12). Using of HFSCs and scaffold on diabetic wounds leads to an accelerated wound closure, notably.Thus, the current data showed that HFSCs and scaffold form excellent biomaterial in the treatment of diabetic wounds.

There are an estimated 500,000 patients treated with full-thickness wounds in the United States every year. Fire-related burn injuries are among the most common and devastating types of wounds that require advanced clinical treatment. Autologous split-thickness skin grafting is the clinical gold standard for the treatment of large burn wounds. However, skin grafting has several limitations, particularly in large burn wounds, where there may be a limited area of non-wounded skin to use for grafting. Non-cellular dermal substitutes have been developed but have their own challenges; they are expensive to produce, may require immunosuppression depending on design and allogenic cell inclusion. There is a need for more advanced treatments for devastating burns and wounds. This manuscript provides a brief overview of some recent advances in wound care, including the use of advanced biomaterials, cell-based therapies for wound healing, biological skin substitutes, biological scaffolds, spray on skin and skin bioprinting. Finally, we provide insight into the future of wound care and technological areas that need to be addressed to support the development and incorporation of these technologies.

Autologous skin grafting has permitted survival and restoration of function in burn injuries of ever larger total body surface area (TBSA) sizes. However, the goal of replacing “like with like” skin structures is often impossible because full-thickness donor harvesting requires primary closure at the donor site for it to heal. Split-thickness skin grafting (STSG), on the other hand, only harvests part of the dermis at the donor site, allowing it to re-epithelialize on its own. The development of the first dermal regenerative template (DRT) in the late 1970s represented a major advance in tissue engineering that addresses the issue of insufficient dermal replacement when STSGs are applied to the full-thickness defect. This review aims to provide an overview of currently available DRTs in burn management from a clinician’s perspective. It focuses on the main strengths and pitfalls of each product and provides clinical pearls based on clinical experience and evidence.

Wound healing is the restorative process of skin or tissue injury, composed of the inflammatory, proliferative, maturation, and remodeling phases. The current study aimed to examine the efficacy of ASPP 092 (a well-characterized diarylheptanoid from Curcuma comosa Roxb) in modulating wound healing. Full-thickness excision wounds were made in rats and treated with either ASPP 092 (dose: 1 mg/mL and 2 mg/mL) or mupirocin (bioequivalent formulation). A control group treated with the vehicle (gel base) was also maintained. The healing efficacy of ASPP 092 was evaluated based on gross appearance, wound closure, and histopathology on days 3, 7, and 12 post-wounding. The expression of cyclooxygenase-2 (COX-2) among the groups was also determined on day 3 post-wounding. Our results suggest that ASPP 092 treatment accelerated wound healing, as evidenced by rapid wound closure, re-epithelialization, and granulation of tissue formation with fewer inflammatory cells. More fibroblasts, collagen fibers, and blood vessels originated with reduced COX-2 expression in the wounds, demonstrating the anti-inflammatory potential of ASPP 092 in experimental wounds. In conclusion, our findings, for the first time, preliminarily identified the potential of ASPP 092 in accelerating wound healing; however, more detailed studies on its mechanism of action in wound healing are required.

Diabetic foot ulcers (DFUs) are one of the most common complications of diabetes. DFUs impede patients’ quality of life and are known to be unresponsive to conventional therapy. Photobiomodulation (PBM) is a pain-free, noninvasive treatment method that has been shown to promote chronic wound healing and has been successfully used for the treatment of DFUs. Since skin tone and color can affect the way light interacts with tissue, studies should take this into consideration when determining protocols for the use of PBM. This review is aimed at critically evaluating data of existing studies conducted to evaluate the clinical effect of PBM on DFUs, taking skin color into consideration. A literature search was conducted and resulted in articles on cell studies, animal studies, and clinical trials. Only 13 clinical trials and 2 clinical case studies were adopted and used in this review. All the clinical trials adopted for this review show evidence that PBM together with conventional treatment results in an increased healing rate of DFUs; however, only one study adjusted their protocol according to skin color. There are not enough studies conducted on people of color to determine the safety and efficacy of PBM therapy in such ethnic groups. Future randomized, placebo-controlled clinical trials are necessary on PBM and DFUs and should take skin color into consideration.

Dystrophic epidermolysis bullosa is a rare genetic blistering skin disease caused by mutations inWe conducted a phase 3, double-blind, intrapatient randomized, placebo-controlled trial involving patients 6 months of age or older with genetically confirmed dystrophic epidermolysis bullosa. For each patient, a primary wound pair was selected, with the wounds matched according to size, region, and appearance. The wounds within each pair were randomly assigned in a 1:1 ratio to receive weekly application of either B-VEC or placebo for 26 weeks. The primary end point was complete wound healing of treated as compared with untreated wounds at 6 months. Secondary end points included complete wound healing at 3 months and the change from baseline to weeks 22, 24, and 26 in pain severity during changes in wound dressing, assessed with the use of a visual analogue scale (scores range from 0 to 10, with higher scores indicating greater pain).Primary wound pairs were exposed to B-VEC and placebo in 31 patients. At 6 months, complete wound healing occurred in 67% of the wounds exposed to B-VEC as compared with 22% of those exposed to placebo (difference, 46 percentage points; 95% confidence interval [CI], 24 to 68; P = 0.002). Complete wound healing at 3 months occurred in 71% of the wounds exposed to B-VEC as compared with 20% of those exposed to placebo (difference, 51 percentage points; 95% CI, 29 to 73; P0.001). The mean change from baseline to week 22 in pain severity during wound-dressing changes was -0.88 with B-VEC and -0.71 with placebo (adjusted least-squares mean difference, -0.61; 95% CI, -1.10 to -0.13); similar mean changes were observed at weeks 24 and 26. Adverse events with B-VEC and placebo included pruritus and chills.Complete wound healing at 3 and 6 months in patients with dystrophic epidermolysis bullosa was more likely with topical administration of B-VEC than with placebo. Pruritus and mild systemic side effects were observed in patients treated with B-VEC. Longer and larger trials are warranted to determine the durability and side effects of B-VEC for this disease. (Funded by Krystal Biotech; GEM-3 ClinicalTrials.gov number, NCT04491604.).

OBJECTIVE To investigate the clinical and radiographic significance of using a mixture of mineralized and demineralized allografts in combination (M) or not (NM) with a resorbable cross-linked barrier membrane in the reconstructive therapy of peri-implantitis defects. METHODS A two-arm randomized clinical trial was performed in patients diagnosed with peri-implantitis that exhibited contained defects. Clinical parameters were recorded at baseline (T0 ), 6 months (T1 ) and 12 months (T2 ). Radiographic parameters were recorded at T0 and T2 . A composite criteria for disease resolution was defined a priori. A generalized linear model (GLM) of repeated measures with generalized estimation equations (GEE) statistical methods were used. RESULTS Overall, 33 patients (nimplants = 48) completed the study. At T2 , mean disease resolution was 77.1%. The use of a barrier membrane did not enhance the probability of disease resolution at T2 (OR = 1.55, p = 0.737). Conversely, the odds of disease resolution were statistically associated with modified plaque index (mPI) recorded at T0 (OR = 0.13, p = 0.006) and keratinized mucosa (KM) width (OR = 2.10, p = 0.035). Moreover, women exhibited greater odds to show disease resolution (OR = 5.56, p = 0.02). CONCLUSION Reconstructive therapy by means of a mixture of mineralized and demineralized allografts is effective in clinically resolving peri-implantitis and in gaining radiographic marginal bone level. The addition of a barrier membrane to reconstructive therapy of peri-implantitis does not seem to enhance the outcomes of contained bone defects (NCT05282667). This article is protected by copyright. All rights reserved.

It is highly desired yet challenging to fabricate biocompatible injectable self-healing hydrogels with anti-bacterial adhesion properties for complex wounds that can autonomously adapt to different shapes and depths and can promote angiogenesis and dermal collagen synthesis for rapid wound healing. Herein, an injectable zwitterionic hydrogel with excellent self-healing property, good cytocompatibility, and antibacterial adhesion was developed from a thermoresponsive ABA triblock copolymer poly[(

To determine pressure injury (PI) healing rate and time and identify influencing factors.A prospective cohort research design was used. Data collection was performed between May 2015 and August 2018. The study participants were 77 inpatients who developed at least one PI during their stay in a university hospital. Researchers assessed participants' demographic (age, sex); physical (incontinence, activity of daily living, and nutrition status); physiologic (serum total protein, albumin, and creatinine, blood glucose, and hemoglobin levels); and disease- (diagnosis, number of comorbidities, and cardiovascular comorbidity), wound- (PI stage and size at first detection, and Pressure Ulcer Scale for Healing score), and treatment-related (IV nutrition supply and albumin infusion) factors.Across the 77 patients, 91 PIs developed. Of these, 54 (59.3%) healed with a mean healing time of 17.63 days. The healing rate was better, and the healing time was shorter for stage 2 PIs compared with unstageable or deep-tissue PIs. Factors influencing PI healing rate were number of comorbidities, cardiovascular comorbidity, incontinence, PI stage at first detection, IV nutrition supply, and mean serum creatinine level. Factors influencing PI healing time were number of comorbidities, cardiovascular comorbidity, and PI stage at first detection.To reduce hospital stays, PI-related complications, and mortality, evidence-based management strategies for PIs are needed. The findings of the present study may contribute to the development of such strategies.

Delays in treatment of burn injuries can lead to significant morbidity, loss of function, and poor aesthetic appearance. Preventing conversion from partial- to full-thickness burns may help mitigate these sequelae. The pathophysiology of burn wound conversion remains unknown, but an overactive immune response is thought to be implicated. The purpose of this study was to determine whether downregulating the immune response via tacrolimus can decrease burn wound conversion.Assembly of the microfluidic hydrogels was achieved by embedding microfibers within a hydrogel scaffold composed of a gelatin-alginate blend. Tacrolimus stock solution for intraperitoneal injection was made by re-suspending powdered tacrolimus in DMSO at 10 mg/mL. 24 young (2-4 months) and 24 old (16 months) mice were given partial thickness burns. The treatment cohort received either tacrolimus ointment with a hydrogel dressing (6 young and 6 old) or an intraperitoneal injection of a tacrolimus solution (6 young and 6 old), while the control cohort only received either only the microcapillary hydrogel dressing or an intraperitoneal injection of saline. Mice were euthanized at day 3 after injury and skin samples were taken. Burn depth was evaluated using Vimentin immunostaining.In old mice, intraperitoneal injection of tacrolimus was able to significantly reduce burn wound depth compared to intraperitoneal injection of saline (p = 0.011). Similarly in old mice, topical hydrogel with tacrolimus was able to significantly reduce burn wound depth compared to hydrogel alone (p 0.001). Topical hydrogel with tacrolimus was able to mitigate the detrimental effects of older age on wound conversion, such that burn wounds of older mice treated with tacrolimus hydrogel dressing had similar burn depths as younger mice (p = 0.240).Utilizing a combination treatment of tacrolimus and microcapillary hydrogel is able to rescue the negative effects of aging and prevent partial- to full-thickness burn wound conversion. Hopefully these findings will encourage deeper investigation into the possible therapeutic advantages of utilizing immunosuppressive agents to decrease morbidity after burn injuries. Future research will need to specifically investigate IL-2 as an inhibitory target in the acute inflammatory cascade of burn injury.

Surgical repair of supraspinatus tendons (SSTs) has a high failure rate at the insertion site. A significant hurdle to therapeutic development is that effective intrinsic healing mechanisms are unknown. The MRL/MpJ (MRL) mouse exhibits tissue-specific enhanced healing; however, these tissues exhibit disparate properties from the complex SST. The extent of SST healing in the complex environment of the rotator cuff is unknown. We hypothesized that MRL mice would exhibit enhanced restoration of the structurally complex insertion site, resulting in functional improvements.B6 and MRL mice underwent SST detachment and immediate surgical repair. Mice were analyzed for gait assessment after either 2 or 6 weeks and were then killed humanely for immunohistologic analysis.MRL SSTs demonstrated enhanced recovery of zonal architecture and bone structure compared with B6 SSTs. MRL SSTs exhibited decreased levels of type III collagen at 2 weeks and increased levels of type I procollagen at 6 weeks compared with B6 SSTs. MRL mice experienced initial gait deficits at 2 weeks that had recovered by 6 weeks.The temporal balance of collagen in MRL mice suggests recovery toward naive composition. Initial gait deficits in MRL mice may provide a protective loading environment that is ultimately beneficial. The mechanisms of enhanced healing observed previously in MRL mice may be conserved in the complex SST, providing a platform to interrogate specific aspects of improved healing.

Genistein is a natural isoflavonoid and has several pharmacological effects, such as antioxidant, antitumor activity, and improvement of glucose metabolism. The safety of intestinal anastomosis after ischemia-reperfusion (I/R) injury is a critical issue for surgeons. This experimental study aimed to investigate the effects of genistein on anastomotic healing after intestinal I/R injury.A total of 36 male Wistar Albino rats were divided into four groups: control, I/R, genistein, and genistein + I/R. The control group received segmental ileal resection and ileoileal anastomosis. The I/R group received resection + anastomosis after intestinal I/R. The genistein group was administered subcutaneous injection of 1 mg/kg genistein 12 h and 1 h before the procedure and received ileal resection + anastomosis. The genistein + I/R group received I/R + ileal resection + anastomosis after genistein injection. Anastomotic bursting pressure, hydroxyproline, superoxide dismutase, and glutathione peroxidase levels and histopathological wound healing scores of all rats were measured on postoperative day 5.The anastomotic bursting pressure was significantly higher in the genistein and genistein + I/R groups (P 0.001). Genistein increased the hydroxyproline concentration and the superoxide dismutase and glutathione peroxidase levels in the intestinal anastomosis (P 0.001). In histopathological assessment, the mean wound healing score was significantly higher in the genistein group than in the other groups (P 0.001).Genistein, with its anti-inflammatory and antioxidant properties, shows protective effects against increased oxidative stress after intestinal I/R injury and contributes positively to intestinal anastomotic healing.

The complex process of wound healing depends on the coordinated interaction between various immunological and biological systems, which can be aided by technology. This present review provides a broad overview of the medical applications of piezoelectric and triboelectric nanogenerators, focusing on their role in the development of wound healing technology. Based on the finding that the damaged epithelial layer of the wound generates an endogenous bioelectric field to regulate the wound healing process, development of technological device for providing an exogenous electric field has therefore been paid attention. Authors of this review focus on the design and application of piezoelectric and triboelectric materials to manufacture self-powered nanogenerators, and conclude with an outlook on the current challenges and future potential in meeting medical needs and commercialization., Grpahical Abstract

OBJECTIVES: Escalation of the ustekinumab (UST) maintenance dosage was effective in adults with Crohn disease (CD), but no data are available for children. We evaluated the effectiveness and safety of dose escalation of UST in pediatric CD. METHODS: This was a retrospective multicenter study from 25 centers affiliated with the IBD Interest and Porto groups of ESPGHAN. We included children with CD who initiated UST at a standard dosing and underwent either dose escalation to intervals shorter than 8 weeks or re-induction of UST due to active disease. Demographic, clinical, laboratory, endoscopic, imaging, and safety data were collected up to 12 months of follow-up. RESULTS: Sixty-nine children were included (median age 15.8 years, interquartile range 13.8-16.9) with median disease duration of 4.3 years (2.9-6.3). Most children were biologic (98.6%)- and immunomodulator (86.8%)- experienced. Clinical response and remission were observed at 3 months after UST escalation in 46 (67%) and 29 (42%) children, respectively. The strongest predictor for clinical remission was lower weighted Pediatric Crohn Disease Activity Index (wPCDAI) at escalation ( P = 0.001). The median C-reactive protein level decreased from 14 (3-28.03) to 5 (1.1-20.5) mg/L ( P = 0.012), and the fecal calprotectin level from 1100 (500-2300) to 515 (250-1469) µg/g ( P = 0.012) 3 months post-escalation. Endoscopic and transmural healing were achieved in 3 of 19 (16%) and 2 of 15 (13%) patients, respectively. Thirteen patients (18.8%) discontinued therapy due to active disease. No serious adverse events were reported. CONCLUSIONS: Two-thirds of children with active CD responded to dose escalation of UST. Milder disease activity may predict a favorable outcome following UST dose escalation.

Skeletal muscle has a robust, inherent ability to regenerate in response to injury from acute to chronic. In severe trauma, however, complete regeneration is not possible, resulting in a permanent loss of skeletal muscle tissue referred to as volumetric muscle loss (VML). There are few consistently reliable therapeutic or surgical options to address VML. A major limitation in investigation of possible therapies is the absence of a well-characterized large animal model. In this study, we present results of a comprehensive transcriptomic, proteomic, and morphologic characterization of wound healing following VML in a novel canine model of VML which we compare to a nine-patient cohort of combat-associated VML. The canine model is translationally relevant as it provides both a regional (spatial) and temporal map of the wound healing processes that occur in human VML. Collectively, these data show the spatiotemporal transcriptomic, proteomic, and morphologic properties of canine VML healing as a framework and model system applicable to future studies investigating novel therapies for human VML. Impact Statement The spatiotemporal transcriptomic, proteomic, and morphologic properties of canine volumetric muscle loss (VML) healing is a translational framework and model system applicable to future studies investigating novel therapies for human VML.

Poor wound healing is a very common clinical problem, so far there is no completely satisfactory treatment. Electropsun nanofibrous wound dressings may provide an ideal structure to improve wound healing. Therefore, development of nanofibrous wound dressings with rapid hemostasis, antibacterial and tissue regenerative multi-functions has been a hotspot in the field of skin tissue engineering. In this work, polydopamine (PDA) and polypyrrole (PPy) were uniformly coated onto the surface of poly(l-lactide) (PLLA) nanofibers by in-situ polymerization, forming a novel PPy/PDA/PLLA three-layer core-shell structure. The homogeneously coated PPy and PDA two layers could significantly increase the hydrophilicity, conductivity, near-infrared photothermal antibacterial property, the speed of wound hemostasis, antioxidant capacity and reactive oxygen species (ROS) scavenging capacity, respectively. In addition, PPy/PDA/PLLA nanofibers showed good biocompatibility. Rat wound healing model confirmed that PPy/PDA/PLLA nanofibers could significantly accelerate wound repair in vivo. Thus, this novel nanofibrous wound dressing is a promising candidate for clinical wound healing.

Diabetic Foot ulcerations have devastating complications including amputations, poor quality of life, and serious infections. Diabetic wounds can be protracted, take significant time to heal, and can recur after healing. They are costly and consume healthcare resources. These consequences have serious public health and clinical implications. Debridement is often used as a standard of care. Debridement consists of both non-mechanical (autolytic, enzymatic) and mechanical methods (sharp/surgical, wet to dry debridement, aqueous high-pressure lavage, ultrasound, and biosurgery/maggot debridement therapy). Debridement is used to remove nonviable tissue, to facilitate wound healing, and help prevent these serious outcomes. What are the various forms, rationale, and evidence pertaining to debridement? This article comprehensively reviews the science of diabetic foot ulcers, and the science and methods behind the debridement of diabetic foot ulcers.

Normal myofibroblast differentiation is critical for proper skin wound healing. Neoexpression of α-smooth muscle actin (α-SMA), a marker for myofibroblast differentiation, is driven by transforming growth factor (TGF)-β receptor-mediated signaling. Hyaluronan and its three synthesizing enzymes, hyaluronan synthases (Has 1, 2, and 3), also participate in this process. Closure of skin wounds is significantly accelerated in Has1/3 double-knockout (Has1/3-null) mice. Herein, TGF-β activity and dermal collagen maturation were increased in Has1/3-null healing skin. Cultures of primary skin fibroblasts isolated from Has1/3-null mice had higher levels of TGF-β activity, α-SMA expression, and phosphorylation of p38 mitogen-activated protein kinase at Thr180/Tyr182, compared with wild-type fibroblasts. p38α mitogen-activated protein kinase was a necessary element in a noncanonical TGF-β receptor signaling pathway driving α-SMA expression in Has1/3-null fibroblasts. Myocardin-related transcription factor (MRTF), a cofactor that binds to the transcription factor serum response factor (SRF), was also critical. Nuclear localization of MRTF was increased, and MRTF binding to SRF was enhanced in Has1/3-null fibroblasts. Inhibition of MRTF or SRF expression by RNA interference suppresses α-SMA expression at baseline and diminished its overexpression in Has1/3-null fibroblasts. Interestingly, total matrix metalloproteinase activity was increased in healing skin and fibroblasts from Has1/3-null mice, possibly explaining the increased TGF-β activation.

Reactive oxygen species (ROS) are overproduced in diabetic wounds and retard the healing response. Considering the antioxidative function of idebenone, its exogenous administration may quench excessive ROS and promote diabetic wound healing. In the current study, idebenone was loaded into polyvinyl alcohol (PVA) /calcium alginate scaffolds at three different concentrations of 1 w/w%, 2 w/w%, and 3 w/w%. Various in vitro experiments were performed to characterize the developed wound dressings. Cell viability assay showed that scaffolds loaded with 1 w/w% idebenone had significantly better protection under oxidative stress and exhibited higher cell viability. Therefore, the dressings containing 1% drug was chosen to treat diabetic wounds in rat model. Wound healing assay showed that the dressings loaded with 1% drug had significantly higher rate of wound size reduction, collagen deposition, and epithelial thickness. Gene expression study showed that wound healing was accompanied by modulation of inflammatory response, protection against oxidative stress, and increasing angiogenesis-related genes. This preliminary research suggests that PVA/calcium alginate/1% idebenone scaffolds can be considered as a potential treatment modality to treat diabetic wounds in the clinic. However, more extensive studies at gene and protein expression levels are required to understand its exact mechanism of healing effects.