Impaired Healing Research Articles

Interleukin-24: A Versatile Regulator of Wound Healing.

The skin, as the body's largest organ, is crucial for maintaining homeostasis and providing protection, making it susceptible to wounds from various causes. Wound healing is a complex process involving numerous cellular activities. Any interruptions can lead to chronic, non-healing wounds, which present significant challenges in healthcare. Interleukin-24 (IL-24), a cytokine within the IL-10 family, has become recognized for its significant role in wound healing due to its diverse effects on cellular processes. IL-24 can inhibit keratinocyte migration, potentially leading to chronic wounds, and promote endothelial cell migration and angiogenesis, which are vital for tissue repair. This dual role highlights IL-24's intricate involvement in wound healing, as it can hinder and aid different aspects of the process. Research indicates that IL-24 expression increases in response to inflammatory mediators and is involved in various immune responses, emphasizing its regulatory function. Further research on IL-24's mechanisms and interactions is essential for developing new therapeutic strategies to enhance tissue regeneration and treat chronic wounds and skin disorders. A deeper understanding of IL-24's functions could transform wound care, providing new approaches for effectively managing and treating conditions involving impaired healing.

Smoking's Impact on 30-Day Complications in Mesh and Nonmesh Prolapse Surgery.

Tobacco smoking is linked to poor surgical outcomes, leading many physicians to avoid synthetic implants like mesh in smokers due to concerns about impaired healing. While long-term outcomes for smokers have been studied, the effect of smoking on 30-day postoperative complications, especially related to surgical mesh, is less understood. This study aimed to quantify the association between tobacco smoking and risk of postoperative infection, readmission, and reoperation within 30 days of minimally invasive apical prolapse repair. We also examined whether these associations differed based on whether mesh was used. We conducted a retrospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program database for patients who underwent minimally invasive apical pelvic organ prolapse repair from 2012 to 2022. Smoking in the last year was the exposure. Outcomes included postoperative infection, unplanned readmission, and reoperation within 30 days. We calculated adjusted risk ratios for complications and stratified results based on mesh use. Of 67,235 cases, 5,518 (8.2%) patients smoked in the past year. Smokers had a significantly higher likelihood of infection and unplanned readmission. Smoking did not increase the risk of unplanned reoperation. The association between smoking and 30-day complications did not differ based on mesh use (all P for interaction ≥0.24). Tobacco use was associated with an increase in postoperative complications within 30 days, though the absolute risk was low. There was no evidence of effect modification by mesh use; suggesting that mesh-augmented repairs could be considered in smokers who receive appropriate counseling.

Food Insecurity Is Common in the Orthopaedic Trauma Population.

Food insecurity is the condition of limited access to healthy and safe food. Malnutrition resulting from food insecurity is a concern particularly in the surgical population due to the association with impaired healing. This aim of this study was to report the incidence and risk factors for food insecurity in the orthopaedic trauma population. Orthopaedic trauma centers at three distinct regions of the United States enrolled patients who had undergone extremity or pelvis fracture fixation within the previous 6 months. Participants completed the United States Department of Agriculture Household Food Insecurity Survey, and food insecurity was defined as a score ≥3. In addition, participants recorded patient demographics and injury/treatment/household characteristics and completed information about diet quality. Diet quality was compared between households with and without food insecurity using chi-square or Fisher exact tests. Logistic regression was used to create a multivariable model of factors associated with greater odds of food insecurity. Food insecurity was documented in 11.5% (81/703) of households. Households with food insecurity were less likely to report daily consumption of fruit, vegetables, and protein-rich foods. We found a greater odds of food insecurity among households with a yearly income of <$50,000 (odds ratio = 4.30 [95% confidence interval = 2.07 to 8.92], P < 0.001), tobacco use (2.33 [1.26 to 4.28], P = 0.007), Medicaid or no insurance (2.34 [1.19 to 4.62], P = 0.014), and Hispanic or Latino ethnicity (4.55 [1.69 to 12.24], P = 0.003), for each 10-year decrease in age (1.19 [1.00 to 1.40], P = 0.045), multiple surgically treated fractures (2.41 [1.08 to 5.35], P = 0.031), and for each additional 15 minutes of travel time to the nearest grocery store (2.12 [1.37 to 3.26], P < 0.001). Food insecurity is common in the orthopaedic trauma population, and households with food insecurity are more likely to have low diet quality. Nutrition supplementation during the healing phase after trauma and referral to nutrition assistance programs has the potential to mitigate malnutrition and prevent negative outcomes resulting from food insecurity.

NLRP3: a key regulator of skin wound healing and macrophage-fibroblast interactions in mice

Wound healing is a highly coordinated process driven by intricate molecular signaling and dynamic interactions between diverse cell types. Nod-like receptor pyrin domain-containing protein 3 (NLRP3) has been implicated in the regulation of inflammation and tissue repair; however, its specific role in skin wound healing remains unclear. This study highlights the pivotal role of NLRP3 in effective skin wound healing, as demonstrated by delayed wound closure and altered cellular and molecular responses in NLRP3-deficient (NLRP3−/−) mice. Histological analysis revealed impaired healing processes, accompanied by reduced expression of key inflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2). Deficiencies in apoptosis were evident through altered expression of cysteine-aspartic acid protease 3 (Caspase-3), P53, and B-cell lymphoma-2 (Bcl-2). Furthermore, critical growth factors such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and matrix metalloproteinase-9 (MMP-9) were significantly decreased at the excisional skin wound sites. Furthermore, using co-culture systems, we found that NLRP3 mediated the interaction between macrophages and myofibroblasts. Wild-type fibroblast-conditioned media (MFbCM) enhanced nitric oxide (NO), IL-6, and tumor necrosis factor-α (TNF-α) production in M1 macrophages and arginase activity, chitinase 3-like protein 1 (Ym1), and IL-10 expression in M2 macrophages, effects significantly diminished with NLRP3−/− MFbCM. Similarly, conditioned media from wild-type M1 or M2 macrophages promoted the expression of FGF-2, VEGF, and MMP-2 expression in myofibroblasts, which was attenuated when using NLRP3−/− macrophage-conditioned media. PGE2 levels were reduced in both NLRP3−/− macrophages and myofibroblasts. Supplementing NLRP3−/− conditioned media with PGE2 partially restored the impaired functions, suggesting that PGE2 acts as a downstream mediator of NLRP3-regulated macrophage-myofibroblast interactions. These findings indicate that NLRP3 is a key regulator of skin wound healing, facilitating macrophage-myofibroblast communication.

Asiaticoside-nitric oxide synergistically accelerate diabetic wound healing by regulating key metabolites and SRC/STAT3 signaling

Abstract Background Diabetic wounds pose significant clinical challenges due to impaired healing processes, often resulting in chronic, non-healing ulcers. Asiaticoside (AC), a natural triterpene derivative from Centella asiatica, has demonstrated notable anti-inflammatory and wound-healing properties. However, the synergistic effects of nitric oxide (NO)—a recognized promoter of wound healing—combined with AC in treating diabetic wounds remain inadequately explored. Methods Ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) was utilized to identify differential metabolites and dysregulated metabolic pathways associated with diabetic wounds. Molecular docking analyses were conducted to confirm the binding affinity of AC to key therapeutic targets. The effects of Asiaticoside-nitric oxide hydrogel (ACNO) on gene and protein expression were evaluated using RT-qPCR and western blotting. In vitro experiments using SRC agonists and inhibitors were performed to investigate the impact of ACNO therapy on the expression of SRC, STAT3, and other proteins in HaCaT cells. Results Metabolomic profiling revealed that diabetic wounds in mice exhibited marked metabolic dysregulation, which was attenuated by ACNO treatment. Key metabolites modulated by ACNO included mandelic acid, lactic acid, and 3-hydroxyisovaleric acid. The primary metabolic pathways involved were methyl histidine metabolism and the malate–aspartate shuttle. Immunofluorescence staining confirmed that ACNO therapy enhanced angiogenesis, promoted cellular proliferation, and facilitated diabetic wound closure. RT–qPCR data demonstrated that ACNO regulated the transcription of critical genes (SRC, STAT3, EGFR, and VEGFA). Notably, ACNO attenuated SRC/STAT3 pathway activation while concurrently upregulating EGFR and VEGFA expression. Conclusions These findings emphasize the therapeutic potential of ACNO hydrogel in diabetic wound healing through the modulation of metabolic pathways and the SRC/STAT3 signaling axis. By correlating altered metabolites with molecular targets, this study elucidates the pharmacodynamic foundation for ACNO’s pre-clinical application and provides valuable insights into the development of targeted therapies for diabetic wound management.

Immunomodulation effects of collagen hydrogel encapsulating extracellular vesicles derived from calcium silicate stimulated-adipose mesenchymal stem cells for diabetic healing

Diabetic wounds are characterized by chronic inflammation, reduced angiogenesis, and insufficient collagen deposition, leading to impaired healing. Extracellular vesicles (EVs) derived from adipose-derived mesenchymal stem cells (ADSC) offer a promising cell-free therapeutic strategy, yet their efficacy and immunomodulation can be enhanced through bioactivation. In this study, we developed calcium silicate (CS)-stimulated ADSC-derived EVs (CSEV) incorporated into collagen hydrogels to create a sustained-release system for promoting diabetic wound healing. CSEV exhibited enhanced protein content, surface marker expression, and bioactive cargo enriched with pro-angiogenic and anti-inflammatory factors. In vitro, CSEV-loaded collagen significantly reduced reactive oxygen species production, promoted cell proliferation and migration compared to standard EV-loaded collagen. Cytokine profiling revealed the upregulation of anti-inflammatory cytokines and extracellular matrix components, highlighting their immunomodulatory and regenerative potential. In vivo, histological evaluation of diabetic rabbit models treated with CSEV-loaded collagen revealed superior reepithelialization and organized collagen deposition, indicating accelerated wound closure. These findings underscore the potential of CSEV-loaded collagen hydrogels as an innovative and effective therapeutic platform for enhancing diabetic wound healing by simultaneously addressing inflammation and tissue regeneration.Graphical abstract

Current and Emerging Therapeutic Strategies for the Management of Neurotrophic Keratitis.

Neurotrophic keratitis is a rare eye condition characterised by reduced or absent corneal sensation. This leads to impaired corneal healing through a loss of protective mechanisms such as blinking. The cornea becomes vulnerable to persistent epithelial defects, ulceration, infection and ultimately, vision loss or loss of the eye. Treatment strategies aim to protect the corneal surface and promote re-epithelialisation. Established treatments include specialised eye drops such as blood serum eye drops and topical nerve growth factor. In some cases, surgical interventions or procedures such as amniotic membrane transplantation or corneal neurotisation may be necessary. Emerging therapeutic drug options include insulin drops, BRM424, CSB-001 and varenicline. The aim of this Current Opinion is to introduce and review this field for the general reader, paying particular attention to emerging drug therapies for neurotrophic keratitis.

Impaired fracture healing is associated with callus chondro-osseous junction abnormalities in periostin-null and osteopontin-null mice

Periostin and osteopontin are matricellular proteins abundantly expressed in bone fracture callus. Null mutation of either the periostin (Postn) gene or the osteopontin (Spp1) gene can impair bone fracture healing. However, the cell and molecular pathways affected by loss of POSTN or SPP1 which lead to impaired fracture healing are not well understood. To identify potential pathways, a detailed radiological, histological, and immunohistochemical analysis of femur fracture healing in Postn-null (PostnKO), Spp1-null (Spp1KO), and normal (WT) mice was performed. Apparent changes in specific protein levels identified by immunohistochemistry were confirmed by mRNA quantitation. Comparisons between the PostnKO and Spp1KO fracture calluses were confounded by interactions between the two genes; loss of Postn reduced Spp1 expression and loss of Spp1 reduced Postn expression. Consequently, alterations in fracture healing between mice heterozygous for the Postn-null allele (PostnHET) as well as the PostnKO and Spp1KO mice were similar. Calluses from PostnHET, PostnKO, and Spp1KO mice all had dysmorphic chondro-osseous junctions and reduced numbers of osteoclasts. The dysmorphic chondro-osseous junctions in the PostnHET, PostnKO, and Spp1KO calluses were associated with reduced numbers of MMP-13 expressing hypertrophic chondrocytes, consistent with delayed cartilage resolution. Unlike collagen X expressing callus chondrocytes, chondrocytes only expressed MMP-13 when localized to the chondro-osseous junction or after traversing the chondro-osseous junction. Cyclooxygenase-2 (COX-2) expression also appeared to be reduced in osteoclasts from the PostnHET, PostnKO, and Spp1KO calluses, including in those osteoclasts localized at the chondro-osseous junction. The results indicate that POSTN and SPP1 are necessary for normal chondro-osseous junction formation and that signaling from the chondro-osseous junction, possibly from COX-2 expressing osteoclasts, regulates callus vasculogenesis and chondrocyte hypertrophy necessary for endochondral ossification during fracture healing.

P0075 Evaluation of the modulatory potential of polyphenolic compounds on intestinal inflammation at the transcriptomic level

Abstract Background Inflammatory bowel disease (IBD) is a chronic multifactorial gastrointestinal condition influenced by genetic, environmental, and immune system factors. Gut microbiota disruption plays a key role in disease onset and progression, leading to inflammation, impaired healing, and increased intestinal permeability1,2. Diet, particularly polyphenols from fruits, vegetables, and tea, can impact microbiota composition and offer anti-inflammatory benefits. This study explores the effects of these compounds on inflammation of the intestinal epithelium at the transcriptomic level. Methods A panel of polyphenolic compounds (n=8) was tested on Caco-2 cells, which were pre-treated with the metabolites before inflammation was induced for 24 h using TNF-α and IFN-γ. The effects were evaluated through targeted gene expression analysis using RT-qPCR. Prioritized compounds – Urolithin A (UroA) and Gallic Acid (GA) – were further tested on inflamed 3D colonic epithelial organoids derived from ulcerative colitis patient (UC) (n=1) and non-IBD individual (n=1), with mRNA sequencing performed on the NextSeq 550 (Illumina). Results Initial metabolite screening in Caco-2 cells was performed by analyzing the expression changes of pro-inflammatory cytokines-coding genes TNF-α, MCP-1, IL-8. Results demonstrated significant induction of cellular inflammation (p &amp;lt; 0.05) after exogenous stimullation with TNF-α and IFN-γ, which was most efficiently and consistenly reduced by GA and UroA. Therefore, GA and UroA were further selected for deeper evaluation on inflamed colonic epithelial organoids. RNA-seq revealed more pronounced cell reactivity to all treatments in UC-organoids compared to non-IBD-organoids and clear sample clustering based on treatment condition. DEA and GSEA of significantly dysregulated genes revealed interesting functional insights into potential mechanisms of action of UroA and GA. Importanly, in inflammed UC-organoids, pre-treatment with GA showed significant (FDR &amp;lt; 0.05) upregulation of pathways involved in cell junction assembly, and significant (FDR &amp;lt; 0.05) downregulation of pathways involved in metabolic processes. Together, these results suggest that GA may lead to colonic epithelial cell metabolic reprogramming in UC from energy-intensive and nucleotide-demanding processess and contribute to the resolution of inflammation and restoration of gut epithelial integrity. Conclusion In conclusion, during colonic inflammation, dietary polyphenol metabolites regulate inflammatory responses, epithelial barrier function, and energy production pathways at the transcriptomic level. Study was funded by the European Union and the State Secretariat for Education, Research and Innovation (SERI) (project: miGut-Health, grant no. 101095470). References 1 Jostins, L., et al. (2012). Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491(7422), 119-124. https://doi.org/10.1038/nature11582 2 Cleynen, I., et al. (2016). Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. The Lancet, 387(10014), 156-167. https://doi.org/10.1016/S0140-6736(15)00465-1

Masquelet Inspired in Vivo Engineered Extracellular Matrix as Functional Periosteum for Bone Defect Repair and Reconstruction.

The Masquelet technique that combines a foreign body reaction (FBR)-induced vascularized tissue membrane with staged bone grafting for reconstruction of segmental bone defect has gained wide attention in Orthopedic surgery. The success of Masquelet hinges on its ability to promote formation of a "periosteum-like" FBR-induced membrane at the bone defect site. Inspired by Masquelet's technique, here a novel approach is devised to create periosteum mimetics from decellularized extracellular matrix (dECM), engineered in vivo through FBR, for reconstruction of segmental bone defects. The approach involved 3D printing of polylactic acid (PLA) template with desired pattern/architecture, followed by subcutaneous implantation of the template to form tissue, and depolymerization and decellularization to generate dECM with interconnected channels. The dECM matrices produces from the same mice (autologous) or from different mice (allogenic) are used as a functional periosteum for repair of structural bone allograft in a murine segmental bone defect model. This study shows that autologous dECM performed better than allogenic dECM, further permitting local delivery of low dose BMP-2 to enhance allograft incorporation. The success of this current approach can establish a new line of versatile, patient-specific, and periosteum-like autologous dECM for bone regeneration, offering personalized therapeutics to patients with impaired healing.

Masterful macrophages: understanding and targeting activation dysfunction in diabetic wounds

Abstract Diabetes mellitus is a group of chronic metabolic diseases worldwide seriously threatens human health and increases social and economic burden; underlying drivers of impaired healing include uncontrolled inflammation, repeated ischemia–reperfusion injury, and neuropathy alongside infection risks. Macrophages orchestrate standard repair, exhibit sustained classical pro-inflammatory activation in diabetes, disrupting growth factor secretion, angiogenesis, and matrix regulation. Hyperglycemia- mediated advanced glycation end products and reactive oxygen species heighten pattern recognition receptor stimulation, causing reduced alternative macrophage differentiation. Promising immunomodulation approaches redirecting their phenotypes to resolve inflammation and stimulate regeneration provides optimism. We discuss macrophage origination, polarization dynamics, diabetic wound phenotypic imbalance, and critical microenvironmental disruptions perpetuating pathological function. Elucidating specific regulatory nodes upholding their activation states will inform intelligent targeting opportunities. Overall, infiltrating macrophages constitute indispensable yet amenable diabetic wound healing coordinators.

Novel insights into the role of gut microbiota and its metabolites in diabetic chronic wounds.

Wounds in patients with diabetes present significant physical and economic challenges due to impaired healing and prolonged inflammation, exacerbated by complex interactions between microbes. Especially, the development and healing of diabetic foot ulcers (DFUs) remain an urgent clinical problem. The human gut harbors a vast microbial ecosystem comprising intestinal flora and their metabolic products. Recent advancements in research have illuminated the concept of the "gut-skin axis," revealing intricate relationships between gut microbiota, microbiota-derived metabolites, and various skin diseases, including DFUs. This review aims to unravel the formation and healing process of DFUs in the context of the gut-skin axis. We reviewed the current research progress worldwide regarding to the gut-skin axis, compared and discussed significant changes in the microbiota colonizing the skin and gut in patients with DFUs. The roles of microbiota-derived metabolites such as lipopolysaccharides, short-chain fatty acids, and trimethylamine-N-oxide in the development of DFUs are highlighted. We also reviewed treatment strategies currently employed in clinical practice and identified potential therapeutic targets such as probiotics for treating DFUs. The need for more comprehensive experimental designs to elucidate the intricate relationship between gut microbiota and its metabolites in the context of DFUs are therefore highlighted.

Influencing fracture healing by specific osteoporosis medications

Osteoporosis is a widespread disease defined by areduction in bone mass and structure, thereby increasing the risk of fragility fractures. Treatment typically involves specific medications, which either inhibit bone resorption (antiresorptive) or stimulate bone formation (anabolic) and may potentially influence the healing of osteoporotic fractures. On the other hand, metabolic disorders, immune system dysfunctions or circulatory problems can impair fracture healing. Therefore, the targeted use of osteoporosis medications could be astrategy to promote the healing of impaired fractures. The aim of this study is to provide acurrent overview of the effects of osteoporosis medications approved in Germany on fracture healing. The focus is on the potential influence of these medications in the context of osteoporosis treatment. Additionally, the current state of research is examined to explore to what extent the targeted use of these medications could improve fracture healing. Aliterature search was conducted in the PubMed database using topic-specific keywords. Preclinical studies, clinical trials, review articles and meta-analyses were considered to present the current scientific knowledge with clinical relevance. Preclinical and clinical studies suggest that specific osteoporosis medications do not have aclinically relevant negative impact on the healing of fragility fractures. Osteoanabolic substances even tend to have apositive effect on fracture healing in both normal and impaired healing processes; however, the available studies are limited and none of the medications have been approved for this specific use. Osteoporosis medications with antiresorptive or osteoanabolic effects are primarily used to treat osteoporosis, especially after fragility fractures, to reduce the risk of further fractures. There is no clinically relevant impairment of fracture healing due to these medications. Further studies would be required to obtain approval for these medications specifically to improve fracture healing.

Methylglyoxal compromises callus mineralization and impairs fracture healing through suppression of osteoblast terminal differentiation.

Impaired fracture healing in diabetic patients leads to prolonged morbidity and increased healthcare costs. Methylglyoxal (MG), a reactive metabolite elevated in diabetes, is implicated in various complications, but its direct impact on bone healing remains unclear. Here, using a non-diabetic murine tibial fracture model, we demonstrate that MG directly impairs fracture healing. Micro-computed tomography revealed decreased volumetric bone mineral density in the callus, while callus volume remained unchanged, resulting in a brittle bone structure. This was accompanied by reduced expression of osteocalcin and bone sialoprotein, both critical for mineralization. Biomechanical analysis indicated that MG reduced the mechanical resilience of the fracture site without altering its elastic strength, suggesting that the impairment was not primarily due to the accumulation of advanced glycation end-products in the bone extracellular matrix. In vitro studies confirmed that non-cytotoxic concentrations of MG inhibited osteoblast maturation and mineralization. Transcriptomic analysis identified downregulation of Osterix, a key transcription factor for osteoblast maturation, without altering Runx2 levels, leading to decreased expression of key mineralization-related factors like osteocalcin. These findings align with clinical observations of reduced circulating osteocalcin levels in diabetic patients, suggesting that the detrimental effects of MG on osteoblasts may extend beyond bone metabolism. Our study highlights MG and MG-sensitive pathways as potential therapeutic targets for improving bone repair in individuals with diabetes and other conditions characterized by elevated MG levels.

Fabrication of Chitosan/PEO/Rosmarinic acid based nanofibrous mat for diabetic burn wound healing and its anti-bacterial efficacy in mice.

The pathophysiological relationship between wound healing impairment and diabetes is an intricate process. Burn injury among diabetes patients leads to neurological, vascular, and immunological abnormalities along with impaired activities of cell proliferation, collagen production, growth factors, and cytokine activities with huge bacterial infestation. In our study, we aimed to achieve a burn wound dressing material with the help of electrospun Chitosan/Polyethylene oxide/Rosmarinic acid (CS/PEO/RA) nanofibers. Chitosan is known for its biocompatibility and anti-bacterial properties; however, the electrospinning of CS requires a co-polymer such as PEO, a synthetic biodegradable polymer. With the addition of a low concentration of RA, known for its antibacterial, antioxidative nature, we enhanced the antibacterial efficacy of the electrospun nanofiber. Electrospinning CS/PEO/RA, we were able to develop a non-toxic scaffold with fibers having an average diameter of 127.035nm, mimicking the extracellular matrix and exhibiting sustained drug release. Excellent antimicrobial activity was observed against the identified bacterial species. It showed increased wound contraction and reduced scar formation in the diabetic mice model along with rapid repair of the damaged epithelial barrier. It enhanced the production of collagen, elastin, and α-smooth muscle actin (α-SMA). Thus, it justifies itself as a diabetic burn wound dressing at low drug concentration.

Hyaluronic Acid-Based Self-Healing Hydrogels for Diabetic Wound Healing.

Diabetic wounds, particularly diabetic foot ulcers (DFUs), are significant threats to human well-being due to their impaired healing from poor circulation and high blood sugar, increased risk of infection and potential for severe complications like amputation, all compounded by peripheral neuropathy and chronic inflammation. Most therapies and dressings for DFUs focus on one symptom at a time, however, multifunctional smart self-healing hydrogels can withstand multifactorial motional diabetic wounds. Motional wounds are easy-to-split wounds that experience tension, compression, and movement caused by stress now and then. Hyaluronic acid (HA) based self-healing hydrogels stand out among other biomaterials due to their ability to cover irregular wound surfaces, maintain a moist environment, repair themselves when ruptured, and exhibit excellent biocompatibility. These self-healing hydrogels can repair damages caused by movement and recover the functional properties during healing. These hydrogels can also act as therapeutic delivery vehicles and tissue regeneration systems. This review demonstrates the potential of HA-based self-healing hydrogels for diabetic wound healing. Due to its self-healing capabilities, these hydrogels offer a customized therapeutic approach for motional diabetic wounds. The review also critically examines the challenges and future directions for HA-based self-healing hydrogels in diabetic wound healing.

Large Bilobed Flap for Head and Neck Reconstruction: Technique and Outcomes.

Head and neck reconstruction after resection of cutaneous malignancies spans the entire reconstructive ladder. Local flaps, such as the bilobed flap, offer excellent versatility, negligible morbidity, and minimal hospitalization. However, there is sparse data regarding the bilobed flap for large defects of the head and neck. A retrospective case series identified patients undergoing head and neck reconstruction with a large bilobed flap for defect sizes ≥ 5 x 5 cm. Data collected included demographics, risk factors for impaired healing, operative variables, and complications. Nineteen patients were included; 15 (79%) were male, and median age was 80 years (47-88). Twelve patients had pertinent comorbidities and risk factors, including diabetes mellitus, current smoker, prior radiation to the operative area, and immunosuppressive state. Ten (53%) patients experienced complications, including infection, necrosis, or hematoma. Eleven (58%) patients received adjuvant radiation. Eleven (58%) patients were discharged within 1 day. The large bilobed flap is an effective reconstructive technique for large head and neck cutaneous defects in properly selected patients. This flap can be a useful alternative to free tissue transfer in elderly patients.

The Complex Role of Matrix Metalloproteinase-2 (MMP-2) in Health and Disease.

Matrix metalloproteinase-2 (MMP-2), a zinc-dependent enzyme, plays a critical role in the degradation and remodeling of the extracellular matrix (ECM). As a member of the gelatinase subgroup of matrix metalloproteinases, MMP-2 is involved in a variety of physiological processes, including tissue repair, wound healing, angiogenesis, and embryogenesis. It is primarily responsible for the degradation of type IV and V collagen, fibronectin, laminin, and elastin, which are essential components of the ECM. MMP-2 is secreted as an inactive pro-enzyme (proMMP-2) and activated through proteolytic cleavage, with its activity being precisely regulated by tissue inhibitors of metalloproteinases (TIMPs). Dysregulation of MMP-2 has been linked to a variety of pathological conditions, including cardiovascular diseases, diabetic complications, kidney diseases, and cancer. In cardiovascular diseases, it contributes to vascular remodeling, atherosclerosis, and aneurysms, while in fibrotic diseases, it mediates excessive ECM degradation leading to tissue scarring. In diabetes, elevated MMP-2 activity exacerbates complications such as nephropathy, retinopathy, and cardiovascular disease. In cancer, MMP-2 facilitates tumor invasion and metastasis by degrading ECM components and promoting angiogenesis. Despite its essential roles in both physiological and pathological processes, targeting MMP-2 for therapeutic purposes presents challenges due to its dual functions in tissue remodeling and repair, raising concerns about unplanned consequences such as impaired tissue healing or excessive tissue damage. These challenges underscore the need for future research to focus on developing selective modulators that can precisely balance their activity under specific disease environments. Clinical trials targeting MMP-2 modulation highlight the potential of gelatinase inhibitors, including those targeting MMP-2, to reduce tumor progression in fibrosarcoma, breast, and lung cancers. This paper reviews the structure, function, and regulation of MMP-2, its involvement in disease pathogenesis, and the potential challenges in the therapeutic implications of modulating its activity.

Rejuvenating aged osteoprogenitors for bone repair

Aging is marked by a decline in tissue regeneration, posing significant challenges to an increasingly older population. Here, we investigate age-related impairments in calvarial bone healing and introduce a novel two-part rejuvenation strategy to restore youthful repair. We demonstrate that aging negatively impacts the calvarial bone structure and its osteogenic tissues, diminishing osteoprogenitor number and function and severely impairing bone formation. Notably, increasing osteogenic cell numbers locally fails to rescue repair in aged mice, identifying the presence of intrinsic cellular deficits. Our strategy combines Wnt-mediated osteoprogenitor expansion with intermittent fasting, which leads to a striking restoration of youthful levels of bone healing. We find that intermittent fasting improves osteoprogenitor function, benefits that can be recapitulated by modulating NAD+-dependent pathways or the gut microbiota, underscoring the multifaceted nature of this intervention. Mechanistically, we identify mitochondrial dysfunction as a key component in age-related decline in osteoprogenitor function and show that both cyclical nutrient deprivation and Nicotinamide mononucleotide rejuvenate mitochondrial health, enhancing osteogenesis. These findings offer a promising therapeutic avenue for restoring youthful bone repair in aged individuals, with potential implications for rejuvenating other tissues.

Rejuvenating aged osteoprogenitors for bone repair.

Aging is marked by a decline in tissue regeneration, posing significant challenges to an increasingly older population. Here, we investigate age-related impairments in calvarial bone healing and introduce a novel two-part rejuvenation strategy to restore youthful repair. We demonstrate that aging negatively impacts the calvarial bone structure and its osteogenic tissues, diminishing osteoprogenitor number and function and severely impairing bone formation. Notably, increasing osteogenic cell numbers locally fails to rescue repair in aged mice, identifying the presence of intrinsic cellular deficits. Our strategy combines Wnt-mediated osteoprogenitor expansion with intermittent fasting, which leads to a striking restoration of youthful levels of bone healing. We find that intermittent fasting improves osteoprogenitor function, benefits that can be recapitulated by modulating NAD+-dependent pathways or the gut microbiota, underscoring the multifaceted nature of this intervention. Mechanistically, we identify mitochondrial dysfunction as a key component in age-related decline in osteoprogenitor function and show that both cyclical nutrient deprivation and Nicotinamide mononucleotide rejuvenate mitochondrial health, enhancing osteogenesis. These findings offer a promising therapeutic avenue for restoring youthful bone repair in aged individuals, with potential implications for rejuvenating other tissues.