Search Results (47)

Epicardial mesothelium plays a pivotal role in postinfarction cardiac repair by generating fibroblasts, producing extracellular matrix, and releasing paracrine mechanisms. However, interspecies differences have not been sufficiently studied, particularly in in vivo models of scar-free healing such as the African spiny mouse (Acomys cahirinus). This study aimed to compare the profibrotic response of epicardial mesothelial cells (MCs) from Acomys and C57BL/6 mice to hypoxic stress, a key factor in postinfarction recovery. We isolated epicardial MCs from the African spiny mouse (Acomys cahirinus), a species with documented cardiac regenerative capabilities, and from C57BL/6 laboratory mice. Using a CoCl₂-induced hypoxia model in vitro, we assessed cell viability, morphological changes, and expression of epithelial and fibroblast markers. In vivo, following experimental myocardial infarction (MI), we evaluated tissue hypoxia (pimonidazole adducts), epicardial activation (layer thickness, Wt1⁺ and TBX18⁺ progenitor cells), and collagen accumulation. The study was conducted using real-time PCR, Western blotting, immunohistochemical analysis and microscopic examination. In vitro, MCs from both species exhibited an epithelial-like phenotype under normoxic conditions, expressing E-cadherin and cytokeratin 18. Hypoxia (200 µM CoCl₂) induced a comparable response in both Acomys and C57BL/6 cells, characterized by a shift to a spindle-shaped, fibroblast-like morphology, decreased E-cadherin expression, and increased pro-collagen 1 and α-SMA expression. Following MI, both species exhibited similarly extensive hypoxic areas affecting the epicardial zone. Epicardial activation dynamics were comparable: from day 3 post-MI, epicardial thickness increased significantly, and Wt1⁺ and TBX18⁺ progenitor cells accumulated, peaking during the first week. Collagen accumulation in the epicardial region was similar between species, although the number of Wt1⁺ cells was higher in C57BL/6 on day 7. Despite the well-known superior regenerative capacity of spiny mice, epicardial MCs from Acomys and C57BL/6 demonstrated similar signs of profibrotic responses to hypoxic stimulation both in vitro and following MI. These findings suggest that species-specific regenerative outcomes may not be attributable to differential acute epicardial sensitivity to hypoxia, but rather to downstream mechanisms or additional factors influencing the cardiac repair process. This study provides the first characterization of Acomys epicardial MCs and establishes a foundation for further investigation of evolutionarily conserved and species-specific mechanisms of cardiac regeneration. Full article

Background: Complex elbow soft-tissue defects often combine exposed critical structures, unstable scars, and high mechanical stress, making durable coverage and early mobilization challenging. Among regional options, the reverse lateral arm flap provides thin fasciocutaneous tissue based on a reliable collateral circulation and preserves major forearm vessels. The aim of this study was to report our single-center experience with the pedicled reverse lateral arm flap for elbow soft-tissue reconstruction, focusing on stable coverage, donor-site morbidity, and functional recovery. Methods: A retrospective single-center case series was conducted at the Division of Plastic Surgery, University Hospital of Padua, Italy. All consecutive patients treated between 2013 and 2023 with a pedicled reverse lateral arm flap for elbow soft-tissue defects were included. Recorded variables included defect etiology, donor-site management, complications, range of motion, and follow-up. Elbow flexion–extension was recorded clinically preoperatively and at last follow-up. Minimum follow-up was 12 months in all patients. Results: Seven patients underwent reconstruction. Defect etiology was burn-related in four cases, shotgun trauma in one, crush injury in one, and melanoma resection in one. All defects were covered with a pedicled reverse lateral arm flap. All flaps survived completely without partial necrosis or flap-related reoperation. Donor-site closure was primary in four patients and required split-thickness skin grafting in three. One patient developed donor-site keloid, and one had donor-site skin-graft partial loss with delayed healing. Elbow flexion–extension improved in all seven cases, with a median gain in arc of motion of 25° (range 15–41°). Conclusions: In this series, the reverse lateral arm flap provided complete coverage of selected elbow defects with preserved motion and limited donor-site morbidity at a minimum follow-up of 12 months. Our findings suggest that it may represent a useful regional option in selected posterior and lateral elbow defects, particularly in post-burn and traumatic settings where thin vascularized tissue is needed, and free-flap reconstruction may be avoidable. Full article

Chronic cutaneous wounds and traumatic skin injuries remain a major clinical challenge, characterized by dysregulated healing phases, high susceptibility to microbial infection, and suboptimal response to conventional therapies. Stem cell-derived exosomes (SC-Exos) have emerged as a paradigm-shifting, cell-free nanotherapeutic platform that harnesses the paracrine secretome of stem cells while avoiding the immunological and proliferative complications inherent to direct cell transplantation. Exosomes derived from diverse stem cell sources orchestrate multifactorial wound repair by modulating key cellular signaling cascades and transcriptomic programs that collectively regulate inflammation, angiogenesis, re-epithelialization, extracellular matrix (ECM) remodeling, and scar formation. Beyond their intrinsic regenerative capacity, SC Exos can be engineered using direct strategies (cargo loading, surface modification, biomaterial integration, and conjugation) and indirect approaches (genetic engineering, pretreatment, and preconditioning of parental cells), thereby enabling spatially controlled and temporally sustained exosome release at wound sites with enhanced bioavailability and therapeutic efficacy. In parallel, biomaterial-assisted delivery platforms, including hydrogels, scaffolds, and nanofibers, enhance exosome retention, stability, and controlled-release profiles within the wound microenvironment, thereby further potentiating tissue repair. This review provides a comprehensive overview of recent advances in SC Exos for wound healing and skin regeneration. We first summarize exosome biogenesis, molecular composition, and the distinctive characteristics of exosomes derived from different stem cell sources, along with preclinical evidence supporting their efficacy in cutaneous repair. We then critically examine exosome engineering strategies and biomaterial-integrated delivery systems that augment and fine-tune therapeutic outcomes. Finally, we discuss the current status of clinical trials of SC Exo-based therapies, key manufacturing and regulatory challenges, and future directions for translating these nanoscale, cell-free therapeutics into advanced, personalized wound management. Full article

Background/Objectives: Thermal injuries represent a significant global health burden, often complicated by hypertrophic scarring, chronic inflammation, and delayed re-epithelialization. While Mesenchymal Stem Cell (MSC) transplantation has shown promise, its clinical translation is hindered by risks of tumorigenicity and immunological concerns. This study evaluates the efficacy of cell-free Extracellular Vesicle (EV) therapy—derived from both mammalian MSCs and plant sources (PDNVs)—as standardized, off-the-shelf alternatives. This study synthesizes evidence focusing on re-epithelialization velocity, angiogenic activity, and anti-fibrotic outcomes, while assessing the impact of second-generation delivery scaffolds on therapeutic durability. Methods: Conducted in accordance with PRISMA 2020 guidelines and registered in PROSPERO (CRD420261305379), this review interrogated PubMed, Scopus, Embase, and Web of Science for studies published between 2015 and 2026. Eligible studies included in vivo animal models of thermal injury using purified vesicles from mammalian MSC sources or plant-derived nanovesicles compared with placebo, standard care, or untreated controls. Data were synthesized narratively; methodological quality was appraised using the SYRCLE risk of bias tool and compliance with MISEV guidelines. Results: Synthesis of 50 studies revealed that vesicle-based interventions consistently accelerate wound closure and improve histological healing. Mammalian ADSC-derived vesicles demonstrated superior anti-fibrotic effects via the miR-192-5p and miR-125b-5p axes, while hUC-MSC vesicles attenuated systemic inflammatory signaling via miR-181c. Plant-derived nanovesicles (PDNVs) showed potent antioxidant and re-epithelialization effects, with emerging potential as engineered genetic carriers. Crucially, advanced delivery systems, including bioactive hydrogels and microneedle patches, were repeatedly associated with improved local retention and more durable effects than bolus injections. Conclusions: Vesicle-based therapies show consistent pro-healing signals in preclinical models, suggesting source-dependent profiles: MSC-derived vesicles excel in immunomodulation and anti-fibrotic remodeling, while PDNVs provide a scalable, low-immunogenicity platform. As a cell-free strategy, these therapies circumvent the safety risks of live cell transplantation. This review identifies a critical shift toward second-generation delivery scaffolds to overcome the clearance crisis of topical applications, emphasizing the need for harmonized MISEV-aligned characterization in future clinical translation. Full article

Background: Defects following total parotidectomy represent a distinctive reconstructive challenge. Restoration of facial volume and contour must be balanced with protection of the preserved facial nerve and reliable healing, particularly after extensive dissection and when adjuvant radiotherapy is anticipated. Multiple reconstructive options exist, each involving trade-offs regarding volume, pliability, long-term stability, and donor-site morbidity. We report our early clinical experience using the adipofascial infragluteal perforator (AIGP) free flap for reconstruction after total parotidectomy with skin and facial nerve preservation. Methods: We retrospectively reviewed the results of three consecutive patients undergoing total parotidectomy for parotid tumors, receiving immediate reconstruction with an AIGP free flap, operated between June and July 2025. The flap, based on terminal branches of the infragluteal vessels, was anastomosed to cervical recipient vessels. To address the two-compartment defect created by facial nerve preservation, the adipofascial tissue was tailored in a chimeric configuration to separately restore the superficial and deep parotid spaces. Results: All flaps survived. One patient developed a postoperative hematoma managed conservatively. Two patients developed minor donor-site seromas after drain removal, which resolved without intervention. Facial contour was satisfactorily restored in all cases, with mild overcorrection in one patient. Facial nerve function improved during follow-up. Donor-site scars were concealed within the infragluteal crease. Conclusions: In this preliminary case series, the AIGP free flap proved to be a feasible option for reconstruction after total parotidectomy with skin and facial nerve preservation, offering satisfactory contour restoration and low donor-site morbidity. Larger studies with longer follow-up are required to define indications and long-term outcomes. Full article

Responses to cutaneous injury differ fundamentally across developmental stages in several mammal species. During early human gestation, when the fetus is less than 24 weeks old, wounds are capable of restoring normal tissue architecture without forming fibrotic scars. In contrast, postnatal and adult injuries typically resolve through the process of fibrosis. This divergence reflects coordinated differences in epidermal and dermal compartments, inflammatory signaling, extracellular matrix (ECM) composition, mechanical cues, and gene regulation. Recent studies have demonstrated that dermal fibroblasts are no longer considered a uniform population but instead arise from distinct developmental lineages with stable functional identities. Engrailed-1-negative fibroblasts (ENFs) predominate in early fetal skin in mice and support regenerative repair, while Engrailed-1-positive fibroblasts (EPFs) emerge later in development and are the principal contributors to fibrotic matrix deposition following injury. The developmental shift between these fibroblast populations coincides with the loss of scar-free healing capacity. This review examines the current understanding of fibroblast lineage specification, with particular emphasis on the roles of mechanotransduction, extracellular matrix cues, and epigenetic regulation. Elucidating how these lineage-encoded programs are established and maintained may enable strategies to reprogram adult fibroblasts toward a fetal-like regenerative state and thereby promote scar-free tissue repair. Full article

Background: Perforator flaps improved the reconstruction paradigm in the lower extremity, increasing coverage possibilities. This study aims to quantify how added perforators could enhance standard geometrical patterns (compared to random flaps). Methods: A total of 29 cases of lower limb soft tissue reconstruction (STR)—52% trauma, 21% osteomyelitis with skin fistulas, 21% healing disorders with unstable scarring and 6% cancer-related surgery—were performed in our institution between 2012 to 2023 with geometric random (GR) local flaps (34%), geometric perforator-enhanced (GP) flaps (32%) or pure propeller perforator (PP) flaps (34%), were retrospectively analysed. Patients with proximal thigh defects, a follow up of less than 3 months and those who received an axial, muscle or free flap were excluded. Geometric patterns (as length:width ratio (L:W)) were compared among groups, analysing healing outcomes and complications. Results: Leg defects were categorized into 62% distal, 14% middle, 14% proximal third and 10% distal thigh. No significant difference in defect size was detected among groups. Mean flap size was significantly larger for GP (70.5 cm², (p < 0.05)) and PP (74.4 cm², (p < 0.01)) than GR (53.7 cm²). The L:W ratio was significantly higher in GP (L:W 2.2:1, (p < 0.05)) and PP (L:W 2.8:1, (p < 0.01)) than in GR (1.5:1), but no significant difference was found between GP and PP. A reduced complications rate (partial flap loss, infection, healing, revision surgery, etc.) was observed in the GP group, when compared to GR. Conclusions: Flap geometric design can be significantly improved by the inclusion of perforators, maintaining spatial advantages with larger ductility and improved vascular solidity. Full article

Wound healing has been studied extensively in humans and lab animals, but not in dolphins. Severe human wounds require extensive medical intervention to avoid infection. Yet severe wounds on free-ranging dolphins heal without infection in microbial-infested seas, a compelling distinction. An eye-witnessed shark attack on a yearling bottlenose dolphin yielded 8 years of macroscopic markers on a live recuperating dolphin by known days of healing. In total, 106 healing histories were generated from the author’s 20-year ethological study of free-ranging bottlenose dolphins (Tursiops truncatus) in St. Petersburg, FL, USA. Results show that unaided wound healing at sea involves two consecutive macroscopic pigment patterns, wounds form preliminary seals by 4–8 weeks, and most heal to atrophic scars that remodel for years. Macroscopic markers in live recuperating dolphins show strong matches with macroscopic wound patterns in stranded Fraser’s dolphins (Lagenodelphis hosei), demonstrating links between macroscopic markers and immune activities. This is the first study to link macroscopic markers visible as healing-related pigment patterns to immunity. Macroscopic markers are conservation tools for tracking anthropogenic impacts on increased susceptibility to infection at sea and could lead to novel therapies in veterinary and human regenerative medicine. Full article

Segment regeneration in earthworms is a remarkable example of postembryonic morphogenesis, yet its fidelity and cellular mechanisms remain incompletely understood. The present study investigated posterior segment regeneration in adult specimens of the earthworm model Eisenia andrei from wound closure to the 5th postoperative week using anatomical, histological, and ultrastructural approaches. Rapid wound closure occurred through fusion of the cut edges of the body wall and midgut without direct involvement of coelomocytes. The regeneration blastema consisted of dedifferentiated epithelial and muscle cells, innervated by fibers from the last intact ventral nerve cord ganglion. Coelomocytes accumulated in the last intact segments and were primarily involved in debris clearance. Notably, early regenerating tissues lacked collagen fibers, which appeared only after the third postoperative week and remained sparse until the fifth week, whereas original segments exhibited intense, region-specific collagen deposition. Transmission electron microscopy revealed characteristic cytological changes in distinct stages of body wall regeneration, including muscle dedifferentiation and the emergence of collagen-producing fibroblasts. These findings indicate that early cell migration, proliferation, and orientation in the blastema proceed independently of collagen and that collagen functions as a delayed structural scaffold, supporting tissue integrity without impeding regeneration. Importantly, no scar formation was observed between old and new tissues, resembling scarless fetal wound healing. Overall, we clarified previously controversial cellular mechanisms and propose a new, comprehensive model for the early stages of segment regeneration. Our results highlight that coordinated dedifferentiation, spatiotemporal extracellular remodeling, and delayed collagen deposition underlie effective, scar-free regeneration in earthworms, offering insights into conserved mechanisms of regenerative repair across metazoans and potential strategies for enhancing tissue regeneration in mammals. Full article

Wound coatings in the form of sponge plates were obtained based on hydrogels of cod collagen (CC) copolymers. The synthesis of CC copolymers with pectin was carried out in the presence of a triethylbor–hexamethylenediamine (TEB-HMDA) complex, which forms free radicals under reaction conditions, and with polyethylene glycol (PEG) during photocatalysis in the presence of RbTe_1.5W_0.5O₆ oxide under visible-light irradiation with a LED lamp. Evaluation of their effectiveness and safety for rapid healing of wounds and burn surfaces has been conducted on small animals (rats). It has shown significantly higher efficiency in comparison with commercial collagen sponges based on bovine collagen. Coatings based on cod collagen contributed to the normalization of microcirculation levels according to the results of laser Doppler flowmetry and a high rate of reduction in the area of the scalped burn wound according to planimetry. The morphological studies indicate complete epithelialization with the formation of scar tissue in all studied groups of animals. The dynamics of microcirculation parameters indicate the repair of thermal burns during local treatment with wound-healing coatings against the background of normalization of the functioning of the microcirculatory system. It is advisable to use new collagen-based polymer sponge plates to increase the effectiveness of wound treatment of various origins, shorten recovery time, and optimize the course of typical physiological reactions during the wound process in order to accelerate tissue regeneration, as well as reduce mortality. Full article

Introduction: Biodegradable Temporizing Matrix (BTM) is a new synthetic dermal substitute suitable for wound closure and tissue regeneration. The data in paediatric population remain limited. The study purpose is to review the indications for BTM application in paediatric patients, evaluate the short-term and long-term results, including complications and functional outcomes, as well as to share some unique observations regarding the use of BTM in paediatric population. Patients and Methods: Patients undergoing reconstructive surgery and BTM application during the last three years were included. Data collected included patient demographics, primary diagnosis, previous surgical management, post-operative complications and final outcomes. BTM was used in 32 patients. The indications varied including epidermolysis bullosa (n = 6), burns (n = 4), trauma (n = 7), infection (n = 4), ischemia or necrosis (n = 11). Results: The results were satisfying with acceptable aesthetic and functional outcomes. Complications included haematoma underneath the BTM leading to BTM removal and re-application (n = 1), BTM infection (n = 1) and split-thickness skin graft failure on top of BTM requiring re-grafting (n = 2). Conclusions: BTM can be a good alternative to large skin grafts, locoregional flaps or even free flaps. The big advantages over other dermal substitutes or skin grafts are that BTM is less prone to infection and offers excellent scarring by preserving the normal skin architecture. Specifically in children, BTM might not require grafting, resulting in spontaneous healing with good scarring. In critically ill patients, BTM reduces the operation time and there is no donor site morbidity. BTM should be considered in the reconstructive ladder when discussing defect coverage options in children and young people. Full article

Scar development is a notable clinical and aesthetic issue in soft tissue healing, frequently compromising functionality and quality of life. Conventional treatments demonstrate limited efficacy in avoiding fibrosis and facilitating regenerative repair. Nevertheless, natural compounds have surfaced as viable alternatives owing to their biocompatibility, multitarget bioactivity, and historical application in traditional medicine. This review examines the therapeutic potential of plant-derived substances, marine agents, and microbial metabolites in influencing critical stages of wound healing, including inflammation, oxidative stress, fibroblast activation, and extracellular matrix remodeling. While these agents have demonstrated beneficial effects in preclinical models, their direct impact on functional or aesthetic clinical outcomes remains under investigation. We propose a hierarchical framework linking molecular mechanisms to clinical endpoints, suggesting that improvements at the cellular and molecular level may eventually support better healing quality. Natural bioactives, especially when integrated into advanced delivery systems such as hydrogels and nanocarriers, show promise for enhancing the regenerative microenvironment. By contextualizing these mechanisms within real-world therapeutic goals, this review highlights both the potential and limitations of natural products in the pursuit of improved soft tissue healing. Further translational research is needed to determine how modulation of these processes may reduce scarring and approach clinically meaningful outcomes. Full article

Tendon ruptures have recently reached incidences of 18–35 cases/100,000 and often lead to adhesion formation during healing. Furthermore, scar formation may result in inferior biomechanics and often leads to re-ruptures. To address these problems, we cultivated rabbit adipose-derived stem cells in a co-culture with rabbit Achilles tenocytes and harvested their secretome. Following a cell-free approach, we incorporated such secretome into an electrospun tube via emulsion electrospinning. These novel implants were characterized by SEM, the WCA, and FTIR. Then, they were implanted in the rabbit Achilles tendon full transection model with an additional injection of secretome, and the adhesion extent as well as the biomechanics of extracted tendons were assessed three weeks postoperatively. The fiber thickness was around 3–5 μm, the pore size 11–13 μm, and the tube wall thickness approximately 265 μm. The WCA indicated slightly hydrophilic surfaces in the secretome-containing layer, with values of 80–90°. In vivo experiments revealed a significant reduction in adhesion formation (−22%) when secretome-treated tendons were compared to DegraPol^® (DP) tube-treated tendons (no secretome). Furthermore, the cross-sectional area was significantly smaller in secretome-treated tendons compared to DP tube-treated ones (−32%). The peak load and stiffness of secretome-treated tendons were not significantly different from native tendons, while tendons treated with pure DP tubes exhibited significantly lower values. We concluded that secretome treatment supports tendon healing, with anti-adhesion effects and improved biomechanics at 3 weeks, making this approach interesting for clinical application. Full article

For centuries, the most prevalent antler abnormalities observed worldwide have been attributed to trauma. However, detailed pathological investigation of these cases has not yet been carried out. In free-living fallow deer (Dama dama), we identified a chronic osteomyelitis-like condition—Pedunculitis Chronica Deformans (PCD)—using pathological and radiological diagnostics. We propose that inflammation during post-casting wound healing and consequent scar formation can trigger the development of PCD. In this study, we characterize the pathomorphology of PCD and introduce a scoring system to describe its severity. Furthermore, we describe the histoanatomy of the junction between the pedicle and the surrounding skin—an area essential for the integrity of the integument—which, when compromised, may predispose cervids to PCD. Our findings suggest that the most common antler abnormality results from a pathological fracture associated with PCD, which can be further complicated by fatal meningoencephalitis and brain abscesses. PCD-related lesions, while less frequently observed, can also be identified in roe deer (Capreolus capreolus) and red deer (Cervus elaphus), with species-specific differences. These findings overlap with cases reported in other cervid species, suggesting a more general disorder of antler formation. Describing this condition provides a basis for assessing its epidemiology and understanding its relevance to wildlife health. Full article

Scarring is a prevalent and often undesirable outcome of the wound healing process, impacting millions worldwide. The complex and dynamic nature of wound healing, including hemostasis, inflammation, proliferation, and remodeling, necessitates precise, making it hard for stage-specific interventions to prevent pathological scarring. This study introduces a double-layer hydrogel system designed for sequential drug release, aligning with the stage-specific need for wound healing. The lower layer, containing curcumin-loaded chitosan nanoparticles, shows early anti-inflammatory and antioxidant effects, while the upper layer, with pirfenidone-encapsulated gelatin microspheres, presents late-stage anti-fibrotic activity. The hydrogel’s unique design, with varying degradation rates and mechanical properties in each layer, facilitates cascade drug release in synchrony with wound healing stages. Rapid release of curcumin from the lower layer promotes proliferation by mitigating inflammation and oxidative stress, while the sustained release of pirfenidone from the upper layer inhibits excessive fibrillation during late proliferation and remodeling. In a rat model of full-thickness skin defect, treatment with a double-layer hydrogel drug delivery system accelerated the wound closure, improved scar quality, and promoted the formation of hair follicles. Therefore, this innovative approach lays a promising foundation for future clinical applications in anti-scar therapies, offering a significant advancement in wound care and regenerative medicine. Full article