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Nanocomposite films of (30% PVC/70% PVDF) blend containing silver nanoparticles were synthesized via pulsed laser ablation route (PLA). Changes in physical characterization of PVC/PVDF blend before and after the incorporation of AgNPs have been studied. FTIR results confirms the interaction between AgNPs and PVC/PVDF. XRD results obtain the existence of peak at 38.42̊ in sample PVC/PVDF/Ag4 which confirm the embedded AgNPs in the high concentration. SEM photos confirm the distribution of silver nanoparticles on the surface of the sample in spherical shape which approved the dispersion of silver nanoparticles in PVC/PVDF blend. The inhibitory zone diameters observed for PVC/PVDF/Ag4 against Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus, and Bacillus cereus were recorded as 11 ± 1, 10 ± 1, 15.7 ± 0.6, and 17.7 ± 0.6, respectively. PVC/PVDF/AgNPs nanocomposite film could be suggested for biomedical applications such as wound healing products., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Efficient wound and burn healing is crucial for minimising complications, preventing infections, and enhancing overall well-being, necessitating the development of innovative strategies. This study aimed to formulate a novel thin film combining chitosan, carboxymethyl cellulose, tannic acid, and beeswax for improved wound healing applications. Several formulations, incorporating chitosan, carboxymethyl cellulose, tannic acid, and beeswax in various percentages, were utilized to deposit thin films via the solvent evaporation technique, Mechanical properties, morphology, antioxidant activity, antibacterial efficacy, and wound healing potential were evaluated. The optimized thin film (M4), composed of 2% chitosan, 2% carboxymethyl cellulose, and 1% tannic acid, along with 0.2% glycerol and 0.2% tween80, exhibited a thickness of 39.0 ± 1.14 μm and a tensile strength of 0.275 ± 0.003 MPa. It demonstrated a swelling degree of 283.0 ± 2.0% and a drug release capacity of 89.4% within 24 h. The film also showed a low contact angle of 40.5° and a water vapour transmission rate of 1912.25 ± 13.10 g m -2 0.24 h -1 . FT-IR spectroscopy indicated that chitosan and carboxymethyl cellulose were cross-linked through amide linkages, with tannic acid occupying the interstitial spaces and hydrogen bonding stabilizing the structure. Microscopy of M4 revealed a uniform morphology. The film exhibited strong antioxidant activity of (95.17 ± 0.02%) and antibacterial efficiency (80.8%) against S. aureus. In a rabbit model, the film significantly enhanced burn and excision wound recovery, with 90.0 ± 3.3% healing for burns and 88.85 ± 1.7% for infected wounds by day 7. Complete skin regeneration was observed within 10-12 days. The M4 thin film demonstrated exceptional mechanical properties and bioactivity, offering protection against pathogens and promoting efficient wound healing. These findings suggest its potential for further investigation in treating various infections and its role in developing novel therapeutic interventions., (© 2024. The Author(s).)

Within the clinical realm, the complexities of wound healing have consistently presented formidable challenges. Recent advancements, notably in hydrogel technologies, have broadened the therapeutic spectrum. This study focuses on investigating a novel dual responsive composite hydrogel for wound healing. This hydrogel is ingeniously designed to maintain an optimal moist environment, expedite healing, and combat bacterial infection during wound recovery. This study combining carboxymethyl chitosan (CMC), oxidized hyaluronic acid (OHA), and sodium alginate (SA), in addition, tobramycin (TOB) was incorporated to create a CMC/OHA/SA/TOB hydrogel. Hydrogel cross-linking was verified by infrared spectroscopy, and the microstructure was examined with scanning electron microscopy. We explored its swelling and degradation behaviors in different pH environments. The drug release profile and biocompatibility was evaluated via cytotoxicity and hemolysis assays. The antibacterial efficacy of hydrogel was tested in both solid and liquid media. Additionally, the wound models in Sprague-Dawley (SD) rat was employed to investigate the hydrogel's wound healing capabilities in vivo. Results showed that CMCOHA/SA/TOB hydrogel was effectively cross-linked with a network structure. The hydrogel exhibited pronounced responsiveness in its swelling and degradation characteristics, which was significantly influenced by different levels of pH. In vitro results demonstrated that the CMC/OHA/SA/TOB hydrogel exhibits limited cytotoxicity and hemolysis, coupled with a drug release profile of dual responsive characteristics. Antibacterial activity of the hydrogel against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli was confirmed. Furthermore, in vivo experiments underscored the hydrogel's proficiency in promoting wound healing, highlighting its potential for clinical applications. The CMC/OHA/SA/TOB hydrogel not only fosters a moist environment essential for wound healing and enhances structural stability, but it also exhibits functional dual responsive capabilities in swelling and degradation. These distinctive abilities enable the precise release of TOB, thereby optimizing wound healing., (© 2024. The Author(s).)

Severe cutaneous injuries may not heal spontaneously and may necessitate the use of supplementary therapeutic methods. Electrospun nanofibers possess high porosity and specific surface area, which provide the necessary microenvironment for wound healing. Here in, the nanofibers of Soluplus-soy protein isolate (Sol-SPI) containing mupirocin (Mp) were fabricated via electrospinning for wound treatment. The fabricated nanofibers exhibited water absorption capacities of about 300.83 ± 29.72% and water vapor permeability values of about 821.8 ± 49.12 g/m 2 day. The Sol/SPI/Mp nanofibers showed an in vitro degradability of 33.73 ± 3.55% after 5 days. The ultimate tensile strength, elastic modulus, and elongation of the Sol/SPI/Mp nanofibers were measured as 3.61 ± 0.29 MPa, 39.15 ± 5.08 MPa, and 59.11 ± 1.94%, respectively. Additionally, 85.90 ± 6.02% of Mp loaded in the nanofibers was released in 5 days in vitro, and by applying the Mp-loaded nanofibers, 93.06 ± 5.40% and 90.40 ± 5.66% of S. aureus and E. coli bacteria were killed, respectively. Human keratinocyte cells (HaCat) demonstrated notable biocompatibility with the prepared nanofibers. Furthermore, compare to other groups, Sol-SPI-Mp nanofibers caused the fastest re-epithelialization and wound healing in a rat model. The findings of this study present a novel nanofiber-based wound dressing that accelerates the healing of severe skin wounds with the risk of infection., (© 2024. The Author(s).)

The transcription factor NRF2 plays an important role in many biological processes and is a promising therapeutic target for many disease states. NRF2 is highly expressed in the skin and is known to play a critical role in diabetic wound healing, a serious disease process for which treatment options are limited. However, many existing NRF2 activators display off-target effects due to their electrophilic mechanism, underscoring the need for alternative approaches. In this work, we investigated two recently described non-electrophilic NRF2 activators, ADJ-310 and PRL-295, and demonstrated their efficacy in vitro and in vivo in human keratinocytes and Lepr db/db diabetic mice. We also compared the downstream targets of PRL-295 to those of the widely used electrophilic NRF2 activator CDDO-Me by RNA sequencing. Both ADJ-310 and PRL-295 maintained human keratinocyte cell viability at increasing concentrations and maintained or improved cell proliferation over time. Both compounds also increased cell migration, improving in vitro wound closure. ADJ-310 and PRL-295 enhanced the oxidative stress response in vitro, and RNA-sequencing data showed that PRL-295 activated NRF2 with a narrower transcriptomic effect than CDDO-Me. In vivo, both ADJ-310 and PRL-295 improved wound healing in Lepr db/db diabetic mice and upregulated known downstream NRF2 target genes in treated tissue. These results highlight the non-electrophilic compounds ADJ-310 and PRL-295 as effective, innovative tools for investigating the function of NRF2. These compounds directly address the need for alternative NRF2 activators and offer a new approach to studying the role of NRF2 in human disease and its potential as a therapeutic across multiple disease states., (© 2024. The Author(s).)

This study investigates the fabrication and characterization of electrospun poly (ε-caprolactone)/poly (vinyl pyrrolidone) (PCL/PVP) fibers integrated with a nanocomposite of chitosan, silver nanocrystals, and graphene oxide (ChAgG), aimed at developing advanced wound dressing materials. The ChAgG nanocomposite, recognized for its antimicrobial and biocompatible properties, was incorporated into PCL/PVP fibers through electrospinning techniques. We assessed the resultant fibers' morphological, physicochemical, and mechanical properties, which exhibited significant enhancements in mechanical strength and demonstrated effective antimicrobial activity against common bacterial pathogens. The findings suggest that the PCL/PVP-ChAgG fibers maintain biocompatibility and facilitate controlled therapeutic delivery, positioning them as a promising solution for managing chronic and burn-related wounds. This study underscores the potential of these advanced materials to improve healing outcomes cost-effectively, particularly in settings plagued by high incidences of burn injuries. Further clinical investigations are recommended to explore these innovative fibers' full potential and real-world applicability., (© 2024. The Author(s).)

Gelatin methacryloyl (GelMA), typically derived from mammalian sources, has recently emerged as an ideal bio-ink for three-dimensional (3D) bioprinting. Herein, we developed a fish skin-based GelMA bio-ink for the fabrication of a 3D GelMA skin substitute with a 3D bioprinter. Several concentrations of methacrylic acid anhydride were used to fabricate GelMA, in which their physical-mechanical properties were assessed. This fish skin-based GelMA bio-ink was loaded with human adipose tissue-derived mesenchymal stromal cells (ASCs) and human platelet lysate (HPL) and then printed to obtain 3D ASCs + HPL-loaded GelMA scaffolds. Cell viability test and a preliminary investigation of its effectiveness in promoting wound closure were evaluated in a critical-sized full thickness skin defect in a rat model. The cell viability results showed that the number of ASCs increased significantly within the 3D GelMA hydrogel scaffold, indicating its biocompatibility property. In vivo results demonstrated that ASCs + HPL-loaded GelMA scaffolds could delay wound contraction, markedly enhanced collagen deposition, and promoted the formation of new blood vessels, especially at the wound edge, compared to the untreated group. Therefore, this newly fish skin-based GelMA bio-ink developed in this study has the potential to be utilized for the printing of 3D GelMA skin substitutes., (© 2024. The Author(s).)

Corneal ulcers, whether melting or indolent, are common in humans and companion animals. Treatment involves local administration of antibiotic eye drops and corneal healing drugs. Compared to traditional treatments for ulcerative keratitis, herbal medicines offer unique advantages, such as potent anti-inflammatory effects and inhibition of proinflammatory cytokines. Curcumin, extracted from the Curcuma Longa plant, possesses extensive pharmacological properties, such as anti-inflammatory, anti-cancer, and antioxidant properties, and is used in various medicines. In this study, we developed a novel ophthalmic drop hydrogel using a formulation of Curcumin NPs encapsulated with β-cyclodextrin and hyaluronic acid, to accelerate corneal healing and improve the quality of healed structures. The formation of Curcumin NPs into Hyaluronic acid-based hydrogels was characterized by zeta, FTIR, and scanning electron microscope (SEM) analyses. A total of 25 healthy male New Zealand Albino rabbits were experimentally induced with ulcerative keratitis and treated individually with topical medication. Rabbits were divided into five groups. Fluorescein dye staining, corneal clarity score, Schirmer tear test, proinflammatory cytokine measurement, and pathologic factors assessments were used to evaluate the optimised Curcumin NPs with β-cyclodextrin in Hyaluronic acid hydrogel. Our results demonstrated that the optimized Curcumin NPs with β-cyclodextrin in hyaluronic acid hydrogel significantly reduced the frequency of medication administration compared to conventional therapies, enhancing the quality of healed structures and effectively treating ulcerative keratitis. All findings in this study provide new insight into designing and fabricating novel ophthalmic medicine for ulcerative keratitis for topical usage., (© 2024. The Author(s).)

Infections originating from pathogenic microorganisms can significantly impede the natural wound-healing process. To address this obstacle, innovative bio-active nanomaterials have been developed to enhance antibacterial capabilities. This study focuses on the preparation of nanocomposites from thermally reduced graphene oxide and zinc oxide (TRGO/ZnO). The hydrothermal method was employed to synthesize these nanocomposites, and their physicochemical properties were comprehensively characterized using X-ray diffraction analysis (XRD), High-resolution transmission electron microscopy (HR-TEM), Fourier-transform infrared (FT-IR), Raman spectroscopy, UV-vis, and field-emission scanning electron microscopy (FE-SEM) techniques. Subsequently, the potential of TRGO/ZnO nanocomposites as bio-active materials against wound infection-causing bacteria, including Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, was evaluated. Furthermore, the investigated samples show disrupted bacterial biofilm formation. A reactive oxygen species (ROS) assay was conducted to investigate the mechanism of nanocomposite inhibition against bacteria and for further in-vivo determination of antimicrobial activity. The MTT assay was performed to ensure the safety and biocompatibility of nanocomposite. The results suggest that TRGO/ZnO nanocomposites have the potential to serve as effective bio-active nanomaterials for combating pathogenic microorganisms present in wounds., (© 2024. The Author(s).)

This study presents the development and characterization of a novel nanocomposite wound dressing material based on polylactic acid (PLA) nanofibers incorporating chitosan nanocapsules loaded with chamomile extract and cellulose nanoparticles. The nanofibers were fabricated using a three-step synthesis and electrospinning techniques, resulting in uniform, bead-free fibers with an average diameter of 186 ± 56 nm. Fourier-transform infrared spectroscopy confirmed the successful incorporation of all components, while tensile strength tests demonstrated improved mechanical properties by adding nanoparticles. Water contact angle measurements revealed enhanced surface wettability of the PLA-Cellulose-Chitosan complex compared to pure PLA nanofibers. In vitro biocompatibility assessments using MTT assays showed excellent cell viability and proliferation, with the optimized composite exhibiting the best performance. Scanning electron microscopy imaging confirmed robust cell adhesion and interaction with the nanofibers. The nanocomposite demonstrated significant antimicrobial activity against Escherichia coli, with a 20 mm inhibition zone observed for chamomile extract-loaded samples. Additionally, the material showed superior hemostatic ability compared to commercial gauze and high hemocompatibility. These comprehensive results indicate that the developed nanocomposite is a promising candidate for advanced wound management applications, offering a multifunctional approach to wound healing by combining antimicrobial activity, cell compatibility, and hemostatic properties., (© 2024. The Author(s).)

Diabetic ulcers (DUs) usually suffer from severe infections, persistent inflammation, and excessive oxidative stress during the healing process, which led to the microenvironmental alternation and severely impede DU healing, resulting in a delayed wound healing. Therefore, it is particularly important to develop a medical dressing that can address these problems simultaneously. To this end, self-healing composite hydrogels were prepared in this study utilizing Bletilla striata polysaccharide (BSP) and Berberine (BER) with borax via borate ester bond. The chemical and mechanical properties of the BSP/BER hydrogels were characterized, and their wound healing performance was investigated in vivo and in vitro. The results showed that the BSP/BER hydrogel significantly accelerated wound healing in DU mice with the healing rate of 94.90 ± 1.81% on the 14th day by using BSP/BER5, and this outstanding performance was achieved by the multi-targeted biological functions of antibacterial, anti-inflammatory and antioxidant, which provided favorable microenvironment for orderly recovery of the wound. Aside from exhibiting the antibacterial rate of over 90% against both Escherichia coli and Staphylococcus aureus, the BSP/BER5 hydrogel could significantly reduce NO levels 4.544 ± 0.32 µmol/L to exert its anti-inflammatory effects. Additionally, it demonstrated a hemolysis rate and promotes cell migration capabilities at (34.92 ± 1.66%). With the above features, the developed BSP/BER hydrogel in this study could be the potential dressing for clinical treatment of DU wound., (© 2024. The Author(s).)

Topical eye drop approaches to treat ocular inflammation in dry eyes often face limitations such as low efficiency and short duration of drug delivery. Nanofibers serve to overcome the limitation of the short duration of action of topical eye drops used against ocular inflammation in dry eyes. Several attempts to develop suitable nanofibers have been made; however, there is no ideal solution. Here, we developed polycaprolactone (PCL) nanofibers loaded with dexamethasone acetate (DEX), prepared by electrospinning, as a potential ocular drug delivery platform for corneal injury treatment. Thirty-nine Sprague Dawley rats (7 weeks old males) were divided into four treatment groups after alkaline burns of the cornea; negative control (no treatment group); dexamethasone eyedrops (DEX group); PCL fiber (PCL group); dexamethasone loaded PCL (PCL + DEX group). We evaluated therapeutic efficacy of PCL + DEX by examining the epithelial wound healing effect, the extent of corneal opacity and neovascularization. Additionally, various inflammatory factors, including IL-1β, were investigated through immunochemistry, western blot analysis, and quantitative real-time RT-PCR (qRT-PCR). PCL + DEX group showed histologically alleviated signs of corneal inflammation compared with DEX group, which showed a decrease in IL-1β and MMP9 in the corneal stroma. The quantitative expression on day 1 after alkaline burn of pro-inflammatory markers, including IL-1β and IL-6, in the PCL + DEX group was significantly lower than that in the DEX group. Notably, PCL + DEX treatment significantly suppressed neovascularization, and enhanced the anti-inflammatory function of DEX during the acute phase of ocular inflammation. Collectively, these findings suggest that PCL + DEX may be a promising approach to effective drug delivery in corneal burn injuries., (© 2024. The Author(s).)

This study aimed to assess the role of the combination of design techniques of the engineered substrates, and the effect of encapsulating Marjoram (Origanum Majorana L.) into the matrix network was studied. To this end, PVA-PEG matrices were designed through 3 techniques of freeze-thaw (FT), the combination of both methods of freeze-drying and freeze-thawing(FT-FD), and ternary technique(freeze-drying,freeze-thawing,cross-linking(FT-FD/CL)), by combining equal volume ratios of both polymers. The results indicated the ternary technique can provide better physicochemical properties(porosity: 96%, lower degradation rate, higher modulus) compared to FT and FT-FD methods. Afterward, encapsulation of Marjoram-extracted bio-actives in the matrix network designed with the ternary technique demonstrated that the increase in the extract concentration up to 3% can increase encapsulation efficiency. The encapsulation also caused a more cohesive network by better bonding between functional groups in herbal biomolecules and polymer chains of the matrix. Mass transport mechanisms and release kinetics of matrix-encapsulated bio-actives indicated a deviation from Fickian diffusion and the release by diffusion and swelling process. Biologically, matrix-loaded herbal carbohydrate(Epi-alpha-Cadinol) improved fibroblast adhesion and distribution on the substrate surface, and led to the better synthesis of collagen fibers, especially in 3% herbal extract, and antibacterial activities owing to the controlled release of sesquiterpenoids and N-Acetyl-L-proline., (© 2024. The Author(s).)

Chronic wounds represent a significant global health concern, statistically impacting 1-2% of the population in developed countries throughout their lifetimes. These wounds cause considerable discomfort for patients and necessitate substantial expenditures of time and resources for treatment. Among the emerging therapeutic approaches, medicated dressings incorporating bioactive molecules, including natural compounds, are particularly promising. Hence, the objective of this study was to develop novel antimicrobial dressings for wound treatment. Specifically, polycaprolactone membranes were manufactured using the electrospinning technique and subsequently coated with natural polyelectrolytes (chitosan as a polycation and a mixture of manuka honey with essential oils nanoemulsions as a polyanion) employing the Layer-by-Layer assembly technique. Physico-chemical and morphological characterization was conducted through QCM-D, FTIR-ATR, XPS, and SEM analyses. The results from SEM and QCM-D demonstrated successful layer deposition and coating formation. Furthermore, FTIR-ATR and XPS analyses distinguished among different coating compositions. The coated membranes were tested in the presence of fibroblast cells, demonstrating biocompatibility and expression of genes coding for VEGF, COL1, and TGF-β1, which are associated with the healing process (assessed through RT-qPCR analysis). Finally, the membranes exhibited excellent antibacterial activity against both Staphylococcus aureus and Pseudomonas aeruginosa, with higher bacterial strain inhibition observed when cinnamon essential oil nanoemulsion was incorporated. Taken together, these results demonstrate the potential application of nanocoated membranes for biomedical applications, such as wound healing., (© 2024. The Author(s).)

Failure rate after chronic rotator cuff repair is considerably high. Moreover, diabetes mellitus is known as a compromising factor of rotator cuff tear. The effect of Polydeoxyribonucleotide (PDRN) and polynucleotide (PN) on tendon healing and fatty infiltration is unclear as tissue regeneration activator in diabetic state. Therefore, a diabetic rat model with chronic rotator cuff tear was made for mechanical, histologic and blood tests. In the animal study using a diabetic rat cuff repair model, the administration of PDRN and PN increased the load to failure of repaired cuffs and improved tendon healing and decreased fatty infiltration. Also, the plasma levels of vascular endothelial growth factor and fibroblast growth factor were elevated in PDRN and PN administrated groups. We concluded that PDRN and PN appear to boost tendon recovery and reduce the presence of fatty infiltration following cuff repair in diabetic state. Also, PN showed a later onset and a longer duration than PDRN associated with the mean plasma growth factors., (© 2024. The Author(s).)

The impact of ustekinumab (UST) on mucosal- and fistula healing and extraintestinal manifestations (EIM) in Crohn's disease (CD) were not fully elucidated in the registration trials. In this prospective, multicenter study (EudraCT number: 2017-005151-83) we evaluated the German label real-world-effectiveness of UST to achieve the primary endpoint of combined clinical and endoscopic response at week 52 and several secondary endpoints. Of 79 screened we enrolled 52 patients (female n = 28, bionaïve n = 13, biologic n = 39). At week 52 (per protocol analysis), 52% (n = 13/25) of patients achieved the primary endpoint [50% (n = 3/6) in the bionaïve, 45.5% (n = 5/11) biologic, 62.5% (n = 5/8 ) multiple biologics cohorts, respectively with age as independent predictor [OR 95% CI 0.933 (0.873, 0.998) p = 0.043], 60% (n = 15/25) achieved endoscopic response [50% (n = 3/6) in the bionaïve, 54.5% (n = 6/11) biologic, 75% (n = 6/8) multiple biologics cohorts, respectively], 36% (n = 9/25) achieved endoscopic remission [50% (n = 3/6) in the bionaïve, 27.3% (n = 3/11) biologic, 37.5% (n = 3/8) multiple biologics cohorts, respectively], 48% (n = 12/25) achieved mucosal healing [50% (n = 3/6) in the bionaïve, 36.4% (n = 4/11) biologic, 62.5% (n = 5/8) multiple biologics cohorts, respectively]. All achieved a fistula response and 33.3% (n = 1/3) in the multiple biologics group fistula remission at week 52. EIM decreased (week 0 28.2% vs. week 52 8%). CRP, FCP, PRO-2, EQ-5D-5L improved throughout. 36 patients (69.2%) experienced ≥ 1 treatment emergent adverse event, in 8 (15.4%) cases rated as severe and in 5 (9.6%) leading to UST discontinuation, but no very severe events or deaths. The effectiveness of UST was better than in the registration trials., (© 2024. The Author(s).)

Impaired wound healing in diabetic individuals creates huge social and financial burdens for both diabetic patients and the health system. Unfortunately, the current treatment has not resulted in consistently lower amputation rates. Quinoxalines are heterocyclic compounds with multiple important pharmacological properties. Their effect on wound healing have not been closely studied. In the current work, the wound healing effect of 3-hydrazinylquinoxaline-2-thiol hydrogel is tested topically in a full-thickness excision wound in streptozotocin-induced type 1 diabetic rats. We examined the wound closure rate, expression of inflammatory factors, growth factors in addition to the histological analysis. The results revealed a significant acceleration in wound closure in the treated group compared with the control experimental animals. Histological data demonstrated enhanced re-epithelialization and collagen disposition. The healing effect was additionally evaluated by the inhibition of the inflammatory response of interleukin (IL)-1β interleukin (IL)-6, tumor necrosis factor (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) with a marked improvement of the transforming growth factor beta (TGFβ-1), antioxidant markers and collagen-1. In silico study indicated a favorable drug-like properties and toxicity profile. The present work showed that 3-hydrazinylquinoxaline-2-thiol holds great potential for the treatment of diabetic wounds., (© 2024. The Author(s).)

Wound healing is a complex process orchestrated by interactions between a variety of cell types, including keratinocytes, fibroblasts, endothelial cells, inflammatory cells, and bioactive factors such as extracellular matrix (ECM) components, growth factors, and cytokines. Chronic wounds exhibit delayed proliferative phase initiation, reduced angiogenesis, impaired ECM synthesis, and persistent inflammatory response. Chronic wounds are one of the main challenges to the healthcare system worldwide, with a high cost for medical services. Hence, investigation of new approaches to accelerate wound healing is essential. Phytomedicines are considered as potential agents for improving the wound healing by accelerating epithelization, collagen synthesis, and angiogenesis. These natural compounds have various advantages including availability, ease of application, and high effectiveness in wound managment. This study aimed to investigate the biological effects of saffron or Crocus sativus L. (C. sativus) petal extract on cell survival, migration, and angiogenesis using MTT, scratch and in vitro tube formation assays. Moreover, the expression of collagen type I alpha 1 (COL1A1) and vascular endothelial growth factor (VEGF) were evaluated in human dermal fibroblasts (HDF)s and human umbilical vein endothelial cells (HUVEC)s, respectively. The effect of the C. sativus extract on the skin of diabetic mice was also monitored. The results showed that C. sativus petal extract promoted the viability and migration of HDFs and HUVECs. Moreover, C. sativus petal extract enhanced the formation of tube-like structures by HUVECs cultured on the Matrigel basement membrane matrix, indicating its potential to stimulate angiogenesis. Gene expression studies have shown the the C. sativus extract increases wound healing by upregulation of COL1A1 and VEGF, which are crucial factors involved in collagen deposition, epithelialization, and angiogenesis. Histological analysis revealed that C. sativus petal extract enhanced vascularity and increased the number of fibroblasts and collagen synthesis, ultimately accelerating wound closure compared to wounds treated with eucerin and commercial ointment in diabetic mice. Therefore, C. sativus petal extract has potential as a herbal treatment to improve the healing of diabetic wounds., (© 2024. The Author(s).)

Nanofibers show promise for wound healing by facilitating active agent delivery, moisture retention, and tissue regeneration. However, selecting suitable dressings for diverse wound types and managing varying exudate levels remains challenging. This study synthesized carbon quantum dots (CQDs) from citrate salt and thiourea using a hydrothermal method. The CQDs displayed antibacterial activity against Staphylococcus aureus and Escherichia coli. A nanoscaffold comprising gelatin, chitosan, and polycaprolactone (GCP) was synthesized and enhanced with silver nanoparticle-coated CQDs (Ag-CQDs) to form GCP-Q, while citrate addition yielded GCP-QC. Multiple analytical techniques, including electron microscopy, FT-IR spectroscopy, dynamic light scattering, UV-Vis, photoluminescence, X-ray diffraction, porosity, degradability, contact angle, and histopathology assessments characterized the CQDs and nanofibers. Integration of CQDs and citrate into the GCP nanofibers increased porosity, hydrophilicity, and degradability-properties favorable for wound healing. Hematoxylin and eosin staining showed accelerated wound closure with GCP-Q and GCP-QC compared to GCP alone. Overall, GCP-Q and GCP-QC nanofibers exhibit significant potential for skin tissue engineering applications., (© 2024. The Author(s).)

Antibiotic resistance is a significant threat, leaving us vulnerable to bacterial infections. Novel strategies are needed to combat bacterial resistance beyond discovering new antibiotics. This research focuses on using maleimide conjugated PEGylated liposomes (Mal-PL-Ab) to individually encapsulate a variety of antibiotics (ceftriaxone, cephalexin, doxycycline, piperacillin, ampicillin, and ceftazidime) and enhance their delivery against multi-drug resistant (MDR) bacteria like Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae). Mal-PL-Ab, with an average size of 84.2 nm ± 4.32 nm, successfully encapsulated these antibiotics with an encapsulation efficiency of 37.73 ± 3.19%. Compared to non-PEGylated liposomes (L-Ab), Mal-PL-Ab exhibited reduced toxicity in human dermal cells, emphasizing the importance of PEGylation in minimizing adverse effects. Mal-PL-Ab significantly decreased the minimum inhibitory concentration (MIC) values against both E. coli and K. pneumoniae by 9.33-fold and eightfold reduction (compared to non-PEGylated liposomes with 2.33-fold and 2.33fold reduction), respectively, indicating enhanced efficacy against MDR strains. Furthermore, in vitro scratch assay and gene expression analysis of human dermal fibroblast revealed that Mal-PL-Ab promoted cell proliferation, migration, and wound healing through upregulation of cell cycle, DNA repair, and angiogenesis-related genes. Harnessing the power of encapsulation, Mal-PL-Ab presents a novel avenue for enhanced antibiotic delivery and wound healing, potentially transcending the limitations of traditional options., (© 2024. The Author(s).)

Pressure ulcers (PU) are caused by persistent long-term pressure, which compromises the integrity of the epidermis, dermis, and subcutaneous adipose tissue layer by layer, making it difficult to heal. Platelet products such as platelet lysate (PL) can promote tissue regeneration by secreting numerous growth factors based on clinical studies on skin wound healing. However, the components of PL are difficult to retain in wounds. Gelatin methacrylate (GelMA) is a photopolymerizable hydrogel that has lately emerged as a promising material for tissue engineering and regenerative medicine. The PL liquid was extracted, flow cytometrically detected for CD41a markers, and evenly dispersed in the GelMA hydrogel to produce a surplus growth factor hydrogel system (PL@GM). The microstructure of the hydrogel system was observed under a scanning electron microscope, and its sustained release efficiency and biological safety were tested in vitro. Cell viability and migration of human dermal fibroblasts, and tube formation assays of human umbilical vein endothelial cells were applied to evaluate the ability of PL to promote wound healing and regeneration in vitro. Real-time polymerase chain reaction (PCR) and western blot analyses were performed to elucidate the skin regeneration mechanism of PL. We verified PL's therapeutic effectiveness and histological analysis on the PU model. PL promoted cell viability, migration, wound healing and angiogenesis in vitro. Real-time PCR and western blot indicated PL suppressed inflammation and promoted collagen I synthesis by activating STAT3. PL@GM hydrogel system demonstrated optimal biocompatibility and favorable effects on essential cells for wound healing. PL@GM also significantly stimulated PU healing, skin regeneration, and the formation of subcutaneous collagen and blood vessels. PL@GM could accelerate PU healing by promoting fibroblasts to migrate and secrete collagen and endothelial cells to vascularize. PL@GM promises to be an effective and convenient treatment modality for PU, like chronic wound treatment., (© 2024. The Author(s).)

Structural failure is a well-established complication of rotator cuff repair procedures. To evaluate the effect of magnetic microbeads, designed for precise drug delivery via magnetic force, on sustained transforming growth factor-beta-1 (TGF-β1) release and rotator cuff healing in a rat rotator cuff repair model. TGF-β1 laden microbeads were prepared, and baseline in vitro experiments included the magnetization of the microbeads and TGF-β1 release tests. In an in vivo experiment using a rat rotator cuff repair model on both shoulders, 72 rats were randomly assigned to three groups (24 per group): group A, conventional repair; group B, repair with and simple TGF-β1 injection; and group C, repair with magnet insertion into the humeral head and TGF-β1 laden microbead injection. Delivery of TGF-β1 was evaluated at 1 and 7 days after the intervention using PCR, Western blot, and immunohistochemistry. At 6 weeks post-intervention, rotator cuff healing was assessed using biomechanical and histological analysis. The in vitro experiments confirmed the magnetization property of the microbeads and sustained delivery of TGF-β1 for up to 10 days. No difference in the TGF-β1 expression was found at day 1 in vivo. However, at day 7, group C exhibited a significantly elevated expression of TGF-β1 in both PCR and Western blot analyses compared to groups A and B (all P < 0.05). Immunohistochemical analysis revealed a higher expression of TGF-β1 at the repair site in group C on day 7. At 6 weeks, biomechanical analysis demonstrated a significantly higher ultimate failure load in group C than in groups A and B (P < 0.05) and greater stiffness than in group A (P = 0.045). In addition, histological analysis showed denser and more regular collagen fibers with complete continuity to the bone in group C than in groups A and B, a statistically significant difference according to the semi-quantitative scoring system (all P < 0.05). The use of the TGF-β1 laden magnetic microbeads demonstrated sustained delivery of TGF-β1 to the repair site, improving rotator cuff healing., (© 2024. The Author(s).)

With distinct advantages in clinical application, total knee arthroplasty (TKA) is an effective surgical option for treating end-stage osteoarthritis in the knee. After TKA, incisional problems are one of the major factors influencing the speed in which patients recover. Although it is widely acknowledged that preoperative hypoalbuminemia and the incidence of incisional complications are significantly associated, it is still unclear if postoperative hypoalbuminemia raises the risk of incisional complications following TKA. Furthermore, human serum albumin (HSA) is frequently utilized domestically and internationally to treat postoperative hypoalbuminemia; nevertheless, there is ongoing discussion on whether HSA supplementation can enhance postoperative clinical outcomes. To investigate the relationship between hypoalbuminemia and suboptimal incision healing following TKA, as well as to determine whether HSA supplementation can enhance incision healing after surgery, we collected clinical data for this study. The study sample consisted of 22 patients with poorly healed incisions and 120 cases with normal healing of incisions who underwent TKA treatment for knee osteoarthritis (KOA) in the operator's hospital's Department of Orthopaedics between July 1, 2020, and July 1, 2023. To determine the prevalence of postoperative poor incision healing, data on patients' basic characteristics, preoperative test results, surgical data, postoperative test results, and postoperative incision healing were gathered. The contributing factors to inadequate recovery after surgery were examined using SPSS software. After controlling for confounding variables, a multivariate regression analysis model was used to examine the relationship between postoperative hypoalbuminemia, HSA supplementation, and poor incision healing. 22 cases (15.49%) had poor wound healing following surgery. The findings of multivariate regression analysis after controlling for confounders indicated that there was no correlation between poor wound healing and postoperative albumin level (P > 0.05). Similarly, there was no association (P > 0.05) seen between HSA supplementation and poor incision healing. Following the TKA, postoperative hypoalbuminemia does not raise the risk of incisional problems, and postoperative HSA supplementation neither lowers nor enhances the risk of inadequate incisional healing., (© 2024. The Author(s).)

This study investigated the three-dimensional (3D) cellular interactions and tunneling nanotubes (TNTs) during fetal mouse skin regeneration on embryonic days 13 (E13) and 15 (E15). We aimed to understand spatial relationships among cell types involved in skin regeneration and assess the potential role of TNTs. Full-thickness skin incisions were performed in E13 and E15 embryos. Wound sites were collected, embedded in epoxy resin, processed for 3D reconstruction (1 μm thickness sections), and subjected to whole-mount immunostaining. We conducted in vitro co-culture experiments with fetal macrophages and fibroblasts to observe TNT formation. To assess the effect of TNTs on skin regeneration, an inhibiting agent (cytochalasin B) was administered to amniotic fluid. Results revealed that E13 epidermal keratinocytes interacted with dermal fibroblasts and macrophages, facilitating skin regrowth. TNT structures were observed at the E13-cell wound sites, among macrophages, and between macrophages and fibroblasts, confirmed through in vitro co-culture experiments. In vitro and utero cytochalasin B administration hindered those formation and inefficient skin texture regeneration at E13 wound sites. This emphasizes the necessity of 3D cellular interactions between epidermal and dermal cells during skin regeneration in mouse embryos at E13. The prevalence of TNT structures indicated their involvement in achieving complete skin texture restoration., (© 2024. The Author(s).)

Wounds that occur in adults form scars due to fibrosis, whereas those in embryos regenerate. If wound healing in embryos is mimicked in adults, scarring can be reduced. We found that mouse fetuses could regenerate tissues up to embryonic day (E) 13, but visible scars remained thereafter. This regeneration pattern requires actin cable formation at the epithelial wound margin via activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). Here, we investigated whether the AMPK-activating effect of salicylate, an anti-inflammatory drug, promotes regenerative wound healing. Salicylate administration resulted in actin cable formation and complete wound regeneration in E14 fetuses, in which scarring should have normally occurred, and promoted contraction of the panniculus carnosus muscle, resulting in complete wound regeneration. In vitro, salicylate further induced actin remodeling in mouse epidermal keratinocytes in a manner dependent on cell and substrate target-specific AMPK activation and subsequent regulation of Rac1 signaling. Furthermore, salicylate promoted epithelialization, enhanced panniculus carnosus muscle contraction, and inhibited scar formation in adult mice. Administration of salicylates to wounds immediately after injury may be a novel method for preventing scarring by promoting a wound healing pattern similar to that of embryonic wounds., (© 2024. The Author(s).)

Inflammation, corticosteroids, and loading all affect tendon healing, with an interaction between them. However, underlying mechanisms behind the effect of corticosteroids and the interaction with loading remain unclear. The aim of this study was to investigate the role of dexamethasone during tendon healing, including specific effects on tendon cells. Rats (n = 36) were randomized to heavy loading or mild loading, the Achilles tendon was transected, and animals were treated with dexamethasone or saline. Gene and protein analyses of the healing tendon were performed for extracellular matrix-, inflammation-, and tendon cell markers. We further tested specific effects of dexamethasone on tendon cells in vitro. Dexamethasone increased mRNA levels of S100A4 and decreased levels of ACTA2/α-SMA, irrespective of load level. Heavy loading + dexamethasone reduced mRNA levels of FN1 and TenC (p < 0.05), while resolution-related genes were unaltered (p > 0.05). In contrast, mild loading + dexamethasone increased mRNA levels of resolution-related genes ANXA1, MRC1, PDPN, and PTGES (p < 0.03). Altered protein levels were confirmed in tendons with mild loading. Dexamethasone treatment in vitro prevented tendon construct formation, increased mRNA levels of S100A4 and decreased levels of SCX and collagens. Dexamethasone during tendon healing appears to act through immunomodulation by promoting resolution, but also through an effect on tendon cells., (© 2024. The Author(s).)

Recent data indicate that extracellular ATP affects wound healing efficacy via P2Y2-dependent signaling pathway. In the current work, we propose double-modified ATP analogue-alpha-thio-beta,gamma-methylene-ATP as a potential therapeutic agent for a skin regeneration. For the better understanding of structure-activity relationship, beside tested ATP analogues, the appropriate single-modified derivatives of target compound, such as alpha-thio-ATP and beta,gamma-methylene-ATP, were also tested in the context of their involvement in the activation of ATP-dependent purinergic signaling pathway via the P2Y2 receptor. The diastereomerically pure alpha-thio-modified-ATP derivatives were obtained using the oxathiaphospholane method as separate S P and R P diastereomers. Both the single- and double- modified ATP analogues were then tested for their impact on the viability and migration of human keratinocytes. The involvement of P2Y2-dependent purinergic signaling was analyzed in silico by molecular docking of the tested compounds to the P2Y2 receptor and experimentally by studying intracellular calcium mobilization in the human keratinocytes HaCaT. The effects obtained for ATP analogues were compared with the results for ATP as a natural P2Y2 agonist. To confirm the contribution of the P2Y2 receptor to the observed effects, the tests were also performed in the presence of the selective P2Y2 antagonist-AR-C118925XX. The ability of the alpha-thio-beta,gamma-methylene-ATP to influence cell migration was analyzed in vitro on the model HaCaT and MDA-MB-231 cells by wound healing assay and transwell migration test as well as in vivo using zebrafish system. The impact on tissue regeneration was estimated based on the regrowth rate of cut zebrafish tails. The in vitro and in vivo studies have shown that the S P -alpha-thio-beta,gamma-methylene-ATP analogue promotes regeneration-related processes, making it a suitable agent for enhance wound healing. Performed studies indicated its impact on the cell migration, induction of epithelial-mesenchymal transition and intracellular calcium mobilization. The enhanced regeneration of cut zebrafish tails confirmed the pro-regenerative activity of this ATP analogue. Based on the performed studies, the S P -alpha-thio-beta,gamma-methylene-ATP is proposed as a potential therapeutic agent for wound healing and skin regeneration treatment., (© 2024. The Author(s).)

To evaluate the safety and efficacy of combining EW-7197 with irreversible electroporation (IRE) for improving wound healing, 16 male Sprague-Dawley rats were randomly divided into four groups of four rats each after dorsal excisional wound induction: sham control group; oral administration of EW-7197 for 7 days group; one-time application of IRE group; and one-time application of IRE followed by oral administration of EW-7197 for 7 days group. Measurement of wound closure rate, laser Doppler scanning, histological staining (hematoxylin and eosin and Masson's trichrome), and immunohistochemical analyses (Ki-67 and α-SMA) were performed to evaluate the efficacy. Fifteen of 16 rats survived throughout the study. Statistically significant differences in wound closure rates were observed between the combination therapy group and the other three groups (all P < 0.05). The degrees of inflammation, α-SMA, and Ki-67 were reduced in the EW-7197 and IRE monotherapy groups; however, not statistically significant. The fibrosis score exhibited significant reduction in all three treatment groups, with the most prominent being in the combination therapy group. This study concludes that oral administration of EW-7197 combined with IRE demonstrated effectiveness in improving skin wound in a rat excisional model and may serve as a potential alternative for promoting healing outcomes., (© 2024. The Author(s).)

The aim was clinical evaluation of the efficacy of topical insulin eye drops in patients with refractory persistent epithelial defects (PEDs). This prospective non-randomized investigation was conducted to examine the efficacy of insulin eye drops in treating patients with PEDs that did not respond to conventional therapy. A total of twenty-three patients were included in the study, and they were administered insulin eye drops formulated as 1 U/mL, four times a day. The rate of epithelial defect resolution and time to complete corneal re-epithelialization were considered primary outcome measures. The relative prognostic impact of initial wound size and other parameters, including age, sex, smoking, diabetes, and hypertension were also analyzed. The results showed that during follow-up (maximum 50 days), a total of 16 patients (69.6%) achieved improvement. Insulin eye drops significantly reduced the corneal wounding area in 75% of patients with small epithelial defects (5.5 mm 2 or less) during 20 days. Only 61% of patients with moderate epithelial defects (5.51-16 mm 2 ) showed a significant recovery in 20-30 days. Also, 71% of patients with a defect size greater than 16 mm 2 , demonstrated a significant improvement in the rate of corneal epithelial wound healing in about 50 days. In conclusion topical insulin reduces the PED area and accelerates the ocular surface epithelium wound healing., (© 2024. The Author(s).)

Alkaline burns to the cornea lead to loss of corneal transparency, which is essential for normal vision. We used a rat corneal alkaline burn model to investigate the effect of ophthalmic trimebutine solution on healing wounds caused by alkaline burns. Trimebutine, an inhibitor of the high-mobility group box 1-receptor for advanced glycation end products, when topically applied to the burned cornea, suppressed macrophage infiltration in the early phase and neutrophil infiltration in the late phase at the wound site. It also inhibited neovascularization and myofibroblast development in the late phase. Furthermore, trimebutine effectively inhibited interleukin-1β expression in the injured cornea. It reduced scar formation by decreasing the expression of type III collagen. These findings suggest that trimebutine may represent a novel therapeutic strategy for corneal wounds, not only through its anti-inflammatory effects but also by preventing neovascularization., (© 2024. The Author(s).)

Novel wound dressings with therapeutic effects are being continually designed to improve the wound healing process. In this study, the structural, chemical, physical, and biological properties of an electrospun poly glycerol sebacate/poly lactide acid/platelet-rich plasma (PGS/PLA-PRP) nanofibers were evaluated to determine its impacts on in vitro wound healing. Results revealed desirable cell viability in the Fibroblast (L929) and macrophage (RAW-264.7) cell lines as well as human umbilical vein endothelial cells (HUVEC). Cell migration was evident in the scratch assay (L929 cell line) so that it promoted scratch contraction to accelerate in vitro wound healing. Moreover, addition of PRP to the fiber structure led to enhanced collagen deposition (~ 2 times) in comparison with PGS/PLA scaffolds. While by addition PRP to PGS/PLA fibers not only decreased the expression levels of pro-inflammatory cytokines (IL-6 and TNF-α) in RAW-264.7 cells but also led to significantly increased levels of cytokine (IL-10) and the growth factor (TGF-β), which are related to the anti-inflammatory phase (M2 phenotype). Finally, PGS/PLA-PRP was found to induce a significant level of angiogenesis by forming branching points, loops, and tubes. Based on the results obtained, the PGS/PLA-PRP dressing developed might be a promising evolution in skin tissue engineering ensuring improved wound healing and tissue regeneration., (© 2024. The Author(s).)

Negative pressure wound therapy with instillation and dwell time (NPWTi-d) is increasingly used for a diverse range of wounds. Meanwhile, the topical wound irrigation solution consisting of polyhexamethylene biguanide and betaine (PHMB-B) has shown efficacy in managing wound infections. However, the effectiveness of this solution as a topical instillation solution for NPWTi-d in patients with diabetic foot infections (DFIs) has not been thoroughly studied. The objective of this retrospective study was to evaluate the impact of using PHMB-B as the instillation solution during NPWTi-d on reducing bioburden and improving clinical outcomes in patients with DFIs. Between January 2017 and December 2022, a series of patients with DFIs received treatment with NPWTi-d, using either PHMB-B or normal saline as the instillation solution. Data collected retrospectively included demographic information, baseline wound characteristics, and treatment outcomes. The study included 61 patients in the PHMB-B group and 73 patients in the normal saline group, all diagnosed with DFIs. In comparison to patients treated with normal saline, patients with PHMB-B exhibited no significant differences in terms of wound bed preparation time (P = 0.5034), length of hospital stay (P = 0.6783), NPWTi-d application times (P = 0.1458), duration of systematic antimicrobial administration (P = 0.3567), or overall cost of hospitalization (P = 0.6713). The findings of the study suggest that the use of either PHMB-B or normal saline as an instillation solution in NPWTi-d for DFIs shows promise and effectiveness, yet no clinical distinction was observed between the two solutions., (© 2024. The Author(s).)

To assess the efficacy and safety of topical insulin (TI) for treating neurotrophic keratopathy (NK) within one-month post-diabetic vitrectomy (DV) compared to conventional non-invasive measures, we conducted this retrospective case-control study including all eyes that developed acute NK (stages 2 and 3) following DV between October 2020 and June 2023. The control group included NK cases managed with preservative-free lubricant eye drops and prophylactic topical antibiotics. In contrast, the study group included NK cases treated with TI [1 unit per drop] four times daily, in addition to the previously mentioned treatment. The primary outcome measure was time to epithelial healing. Secondary outcome measures included any adverse effect of TI or the need for amniotic membrane transplantation (AMT). During the study period, 19 patients with a mean age of 49.3 ± 8.6 years received TI versus 18 controls with a mean age of 52.5 ± 10.7 years. Corneal epithelial healing was significantly faster in the TI-treated group compared to controls, with a mean difference of 12.16 days (95% CI 6.1-18.3, P = 0.001). Survival analysis indicated that the insulin-treated group had 0% and 20% of NK stages 2 and 3, respectively, that failed to achieve corneal epithelial healing, compared to 20% and 66.7% for the control group (P < 0.001). In the control group, two eyes required AMT due to progressive thinning. Additionally, three patients in the control group, progressing to stage 3 NK, were switched to TI, achieving healing after a mean of 14 days. No adverse effects were reported in the TI-treated group. Our study suggests that TI can effectively and safely promote the healing of NK after DV., (© 2024. The Author(s).)

Although self-medication in non-human animals is often difficult to document systematically due to the difficulty of predicting its occurrence, there is widespread evidence of such behaviors as whole leaf swallowing, bitter pith chewing, and fur rubbing in African great apes, orangutans, white handed gibbons, and several other species of monkeys in Africa, Central and South America and Madagascar. To the best of our knowledge, there is only one report of active wound treatment in non-human animals, namely in chimpanzees. We observed a male Sumatran orangutan (Pongo abelii) who sustained a facial wound. Three days after the injury he selectively ripped off leaves of a liana with the common name Akar Kuning (Fibraurea tinctoria), chewed on them, and then repeatedly applied the resulting juice onto the facial wound. As a last step, he fully covered the wound with the chewed leaves. Found in tropical forests of Southeast Asia, this and related liana species are known for their analgesic, antipyretic, and diuretic effects and are used in traditional medicine to treat various diseases, such as dysentery, diabetes, and malaria. Previous analyses of plant chemical compounds show the presence of furanoditerpenoids and protoberberine alkaloids, which are known to have antibacterial, anti-inflammatory, anti-fungal, antioxidant, and other biological activities of relevance to wound healing. This possibly innovative behavior presents the first systematically documented case of active wound treatment with a plant species know to contain biologically active substances by a wild animal and provides new insights into the origins of human wound care., (© 2024. The Author(s).)

The need for tumor postoperative treatments aimed at recurrence prevention and tissue regeneration have raised wide considerations in the context of the design and functionalization of implants. Herein, an injectable hydrogel system encapsulated with anti-tumor, anti-oxidant dual functional nanoparticles has been developed in order to prevent tumor relapse after surgery and promote wound repair. The utilization of biocompatible gelatin methacryloyl (GelMA) was geared towards localized therapeutic intervention. Zeolitic imidazolate framework-8@ceric oxide (ZIF-8@CeO2, ZC) nanoparticles (NPs) were purposefully devised for their proficiency as reactive oxygen species (ROS) scavengers. Furthermore, injectable GelMA hydrogels loaded with ZC NPs carrying doxorubicin (ZC-DOX@GEL) were tailored as multifunctional postoperative implants, ensuring the efficacious eradication of residual tumor cells and alleviation of oxidative stress. In vitro and in vivo experiments were conducted to substantiate the efficacy in cancer cell elimination and the prevention of tumor recurrence through the synergistic chemotherapy approach employed with ZC-DOX@GEL. The acceleration of tissue regeneration and in vitro ROS scavenging attributes of ZC@GEL were corroborated using rat models of wound healing. The results underscore the potential of the multifaceted hydrogels presented herein for their promising application in tumor postoperative treatments., (© 2024. The Author(s).)

In recent years, carbon quantum dots (CQDs) have garnered considerable attention as a promising material for biomedical applications because of their unique optical and biological properties. In this study, CQDs were derived from the leaves of Hibiscus rosa-sinensis Linn. via microwave-assisted technique and characterized using different techniques such as ultraviolet-visible, Fourier transform infrared, fluorescence spectrometry, X-ray diffraction, dynamic light scattering, transmission electron microscopy and energy-dispersive X-ray spectroscopy. Subsequently, their potential for biomedical applications was investigated through in vitro assays assessing scratch healing, anti-inflammatory, antibacterial, and cytotoxicity properties. It was found that the CQDs were fluorescent, polycrystalline, quasi-spherical, ~ 12 nm in size with presence of -OH and -COOH groups on their negatively charged surfaces, and demonstrated good anti-inflammatory by inhibiting protein denaturation, cyclooxygenase-2 and regulating inflammatory cytokines. The CQDs also exhibited antimicrobial activity against Klebsiella pneumoniae and Bacillus cereus, good biocompatibility, along with excellent promotion of cell proliferation in vitro, indicating their potential as a anti-inflammatory and wound healing material. The properties were more enhanced than their precursor, H. rosa-sinensis leaf extract. Hence, the CQDs synthesized from the leaves of H. rosa-sinensis can serve as a potential biomedical agent., (© 2024. The Author(s).)

Naringenin is a citrus flavonoid with various biological functions and a potential therapeutic agent for skin diseases, such as UV radiation and atopic dermatitis. The present study investigates the therapeutic effect and pharmacological mechanism of naringenin on chronic wounds. Using network pharmacology, we identified 163 potential targets and 12 key targets of naringenin. Oxidative stress was confirmed to be the main biological process modulated by naringenin. The transcription factor p65 (RELA), alpha serine/threonine-protein kinase (AKT1), mitogen-activated protein kinase 1 (MAPK1) and mitogen-activated protein kinase 3 (MAPK3) were identified as common targets of multiple pathways involved in treating chronic wounds. Molecular docking verified that these four targets stably bound naringenin. Naringenin promoted wound healing in mice in vivo by inhibiting wound inflammation. Furthermore, in vitro experiments showed that a low naringenin concentration did not significantly affect normal skin cell viability and cell apoptosis; a high naringenin concentration was cytotoxic and reduced cell survival by promoting apoptosis. Meanwhile, comprehensive network pharmacology, molecular docking and in vivo and in vitro experiments revealed that naringenin could treat chronic wounds by alleviating oxidative stress and reducing the inflammatory response. The underlying mechanism of naringenin in chronic wound therapy involved modulating the RELA, AKT1 and MAPK1/3 signalling pathways to inhibit ROS production and inflammatory cytokine expression., (© 2023. The Author(s).)

The anti-angiogenic effects of bisphosphonates have been hypothesized as one of the major etiologic factors in the development of medication-related osteonecrosis of the jaw (MRONJ), a severe debilitating condition with limited treatment options. This study evaluated the potential of a gelatine-hyaluronic acid hydrogel loaded with the angiogenic growth factor, vascular endothelial growth factor (VEGF), as a local delivery system to aid in maintaining vascularization in a bisphosphonate-treated (Zoledronic Acid) rodent maxillary extraction defect. Healing was assessed four weeks after implantation of the VEGF-hydrogel into extraction sockets. Gross examination and histological assessment showed that total osteonecrosis and inflammatory infiltrate was significantly reduced in the presence of VEGF. Also, total vascularity and specifically neovascularization, was significantly improved in animals that received VEGF hydrogel. Gene expression of vascular, inflammatory and bone specific markers within the defect area were also significantly altered in the presence of VEGF. Furthermore, plasma cytokine levels were assessed to determine the systemic effect of locally delivered VEGF and showed similar outcomes. In conclusion, the use of locally delivered VEGF within healing extraction sockets assists bone healing and prevents MRONJ via a pro-angiogenic and immunomodulatory mechanism., (© 2021. The Author(s).)

Mucosal integrity in the endometrium is essential for immune protection. Since breaches or injury to the epithelial barrier exposes underlying tissue and is hypothesized to increase infection risk, we determined whether endogenous progesterone or three exogenous progestins (medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG)) used by women as contraceptives interfere with wound closure of endometrial epithelial cells and fibroblasts in vitro. Progesterone and LNG had no inhibitory effect on wound closure by either epithelial cells or fibroblasts. MPA significantly impaired wound closure in both cell types and delayed the reestablishment of transepithelial resistance by epithelial cells. In contrast to MPA, NET selectively decreased wound closure by stromal fibroblasts but not epithelial cells. Following epithelial injury, MPA but not LNG or NET, blocked the injury-induced upregulation of HBD2, a broad-spectrum antimicrobial implicated in wound healing, but had no effect on the secretion of RANTES, CCL20 and SDF-1α. This study demonstrates that, unlike progesterone and LNG, MPA and NET may interfere with wound closure following injury in the endometrium, potentially conferring a higher risk of pathogen transmission. Our findings highlight the importance of evaluating progestins for their impact on wound repair at mucosal surfaces., (© 2021. The Author(s).)

Although endogenous cardiac repair by recruitment of stem cells may serve as a therapeutic approach to healing a damaged heart, how to effectively enhance the migration of stem cells to the damaged heart is unclear. Here, we examined whether the combined administration of prostacyclin agonist (ONO1301), a multiple-cytokine inducer, and stem cell niche laminin-221 (LM221), enhances regeneration through endogenous cardiac repair. We administered ONO1301- and LM221-immersed sheets, LM221-immersed sheets, ONO1301-immersed sheets, and PBS-immersed sheets (control) to an acute infarction rat model. Four weeks later, cardiac function, histology, and cytokine expression were analysed. The combined administration of LM221 and ONO1301 upregulated angiogenic and chemotactic factors in the myocardium after 4 weeks and enhanced the accumulation of ILB4 positive cells, SMA positive cells, and platelet-derived growth factor receptor alpha (PDGFRα) and CD90 double-positive cells, leading to the generation of mature microvascular networks. Interstitial fibrosis reduced and functional recovery was prominent in LM221- and ONO1301-administrated hearts as compared with those in ONO1301-administrated or control hearts. LM221 and ONO1301 combination enhanced recruitment of PDGFRα and CD90 double-positive cells, maturation of vessels, and functional recovery in rat acute myocardial infarction hearts, highlighting a new promising acellular approach for the failed heart., (© 2021. The Author(s).)

Biocompatible materials that act as scaffolds for regenerative medicine are of enormous interest. Hydrogel-nanoparticle composites have great potential in this regard, however evaluations of their wound healing and safety in vivo in animal studies are scarce. Here we demonstrate that a guar gum/curcumin-stabilized silver nanoparticle hydrogel composite is an injectable material with exceptional wound healing and antibacterial properties. We show that the curcumin-bound silver nanoparticles themselves exhibit low cytotoxicity and enhance proliferation, migration, and collagen production in in vitro studies of human dermal fibroblasts. We then show that the hydrogel-nanoparticle composite promotes wound healing in in vivo studies on rats, accelerating wound closure by > 40% and reducing bacterial counts by 60% compared to commercial antibacterial gels. Histopathology indicates that the hydrogel composite enhances transition from the inflammation to proliferation stage of healing, promoting the formation of fibroblasts and new blood vessels, while target gene expression studies confirm that the accelerated tissue remodeling occurs along the normal pathways. As such these hydrogel composites show great promise as wound dressing materials with high antibacterial capacity., (© 2021. The Author(s).)

Peri-implantitis may result in the loss of dental implants. Cold atmospheric pressure plasma (CAP) was suggested to promote re-osseointegration, decrease antimicrobial burden, and support wound healing. However, the long-term risk assessment of CAP treatment in the oral cavity has not been addressed. Treatment with two different CAP devices was compared against UV radiation, carcinogen administration, and untreated conditions over 12 months. Histological analysis of 406 animals revealed that repeated CAP exposure did not foster non-invasive lesions or squamous cell carcinoma (SCCs). Carcinogen administration promoted non-invasive lesions and SCCs. Molecular analysis by a qPCR screening of 144 transcripts revealed distinct inflammatory profiles associated with each treatment regimen. Interestingly, CAP treatment of carcinogen-challenged mucosa did not promote but instead left unchanged or reduced the proportion of non-invasive lesions and SCC formation. In conclusion, repeated CAP exposure of murine oral mucosa was well tolerated, and carcinogenic effects did not occur, motivating CAP applications in patients for dental and implant treatments in the future., (© 2021. The Author(s).)

Wound healing is a complicated multicellular process that involves several kinds of cells including macrophages, fibroblasts, endothelial cells, keratinocytes and platelets that are leading to their differentiation towards an anti-inflammatory response for producing several chemokines, cytokine and growth factors. In this study, electrospun nanofiber scaffold named (MNS) is composed of polyvinyl alcohol (PVA)/iota carrageenan (IC) and doped with partially reduced graphene oxide (prGO) that is successfully synthesized for wound healing and skin repair. The fabricated MNS was tested in case of infection and un-infection with E. coli and Staphylococcus and in both of the presence and in the absence of yeast as a natural nutritional supplement. Numerous biochemical parameters including total protein, albumin, urea and LDH, and hematological parameters were evaluated. Results revealed that the MNS was proved to be effective on most of the measured parameters and had exhibited efficient antibacterial inhibition activity. Whereas it can be used as an effective antimicrobial agent in wound healing, however, histopathological findings confirmed that the MNS caused re-epithelialization and the presence of yeast induced hair follicles growth and subsequently it may be used to hide formed head wound scar., (© 2021. The Author(s).)

This study investigated the role 5-lypoxigenase (5-LO) on alveolar socket healing in aged female mice treated with zoledronic acid (ZL). Forty 129/Sv female mice (64-68 weeks old), 20 wild type (WT) and 20 5-LO knockout (5LOKO) were equally distributed according to ZL treatment: WT Control, WT ZL, 5LOKO Control, and 5LOKO ZL. ZL groups were treated with an intraperitoneal injection of 250 µg/Kg of ZL, while controls were treated with saline. Treatments were administered once a week, starting four weeks before surgery for tooth extraction and until 7 and 21 days post-surgery. Mice were euthanized for a comprehensive microscopic analysis (microCT, histomorphometry and immunohistochemistry). WT ZL mice presented intense inflammatory infiltrate (7 days), delayed bone formation (21 days), reduced collagenous matrix quality, and a deficiency in Runx-2 + , TRAP + , and macrophages as compared to controls. 5LOKO ZL animals presented decreased number of Runx-2 + cells in comparison to 5LOKO Control at 7 days, but no major changes in bone healing as compared to WT or 5LOKO mice at 21 days. The knockout of 5LO favored intramembranous bone healing in aged female mice, with a direct impact on inflammatory response and bone metabolism on the development of ONJ-like lesions., (© 2021. The Author(s).)

The discovery of the expression of opioid receptors in the skin and their role in orchestrating the process of tissue repair gave rise to questions regarding the potential effects of clinical morphine treatment in wound healing. Although short term treatment was reported to improve tissue regeneration, in vivo chronic administration was associated to an impairment of the physiological healing process and systemic fibrosis. Human mesenchymal stem cells (hMSCs) play a fundamental role in tissue regeneration. In this regard, acute morphine exposition was recently reported to impact negatively on the functional characteristics of hMSCs, but little is currently known about its long-term effects. To determine how a prolonged treatment could impair their functional characteristics, we exposed hMSCs to increasing morphine concentrations respectively for nine and eighteen days, evaluating in particular the fibrogenic potential exerted by the long-term exposition. Our results showed a time dependent cell viability decline, and conditions compatible with a cellular senescent state. Ultrastructural and protein expression analysis were indicative of increased autophagy, suggesting a relation to a detoxification activity. In addition, the enhanced transcription observed for the genes involved in the synthesis and regulation of type I collagen suggested the possibility that a prolonged morphine treatment might exert its fibrotic potential risk, even involving the hMSCs., (© 2021. The Author(s).)

We aimed to prepare a bioactive and biodegradable bilayer mesh formed by fibroblast growth factor (FGF) loaded gelatin film layer, and poly ε-caprolactone (PCL) film layer, and to investigate its treatment efficacy on esophageal anastomosis. It is envisaged that the bioactive mesh in in vivo model would improve tissue healing in rats. The full thickness semicircular defects of 0.5 × 0.5 cm 2 were created in anterior walls of abdominal esophagus. The control group had abdominal esophagus isolated with distal esophageal blunt dissection, and sham group had primary anastomosis. In the test groups, the defects were covered with bilayer polymeric meshes containing FGF (5 μg/2 cm 2 ), or not. All rats were sacrificed for histopathology investigation after 7 or 28 days of operation. The groups are coded as FGF(-)-7th day, FGF(+)-7th day, and FGF(+)-28th day, based on their content and operation day. Highest burst pressures were obtained for FGF(+)-7th day, and FGF(+)-28th day groups (p < 0.005) and decreased inflammation grades were observed. Submucosal and muscular collagen deposition scores were markedly increased in these groups compared to sham and FGF(-)-7th day groups having no FGF (p = 0.002, p = 0.001, respectively). It was proved that FGF loaded bioactive bilayer mesh provided effective repair, reinforcement and tissue healing of esophageal defects., (© 2021. The Author(s).)

Collagens act as cellular scaffolds in extracellular matrixes, and their breakdown products may also have important biological functions. We hypothesize that collagen dipeptide Pro-Hyp induces favorable healing activities and examined the effects of Pro-Hyp administered via different routes on wound healing using our novel murine model, in which an advanced fibrosis-prone scar lesion was developed in the abdominal muscle wall under the skin. After excising a part of the abdominal wall, a free-drinking experiment was performed using solutions with casein (CS), high molecular weight collagen peptides (HP), and low molecular weight collagen peptides including Pro-Hyp and Hyp-Gly (LP), in addition to water (HO). On day 21 of the study, when compared to the HO and CS groups, muscle regeneration in the LP group was significantly advanced in the granulation tissue, which was associated with a decrease in fibrosis. To clarify the effects of Pro-Hyp, daily intraperitoneal administration of pure Pro-Hyp was performed. Pro-Hyp administration induced many myogenically differentiated cells, including myogenin-positive myoblasts and myoglobin-positive myocytes, to migrate in the granulation tissue, while scar tissue decreased. These results indicated that Pro-Hyp administration accelerates muscle regenerative healing accompanied by less scarring after wounding on the abdominal wall., (© 2021. The Author(s).)

Active wound dressings are attracting extensive attention in soft tissue repair and regeneration, including bacteria-infected skin wound healing. As the wide use of antibiotics leads to drug resistance we present here a new concept of wound dressings based on the polycaprolactone nanofiber scaffold (NANO) releasing second generation lipophosphonoxin (LPPO) as antibacterial agent. Firstly, we demonstrated in vitro that LPPO released from NANO exerted antibacterial activity while not impairing proliferation/differentiation of fibroblasts and keratinocytes. Secondly, using a mouse model we showed that NANO loaded with LPPO significantly reduced the Staphylococcus aureus counts in infected wounds as evaluated 7 days post-surgery. Furthermore, the rate of degradation and subsequent LPPO release in infected wounds was also facilitated by lytic enzymes secreted by inoculated bacteria. Finally, LPPO displayed negligible to no systemic absorption. In conclusion, the composite antibacterial NANO-LPPO-based dressing reduces the bacterial load and promotes skin repair, with the potential to treat wounds in clinical settings., (© 2021. The Author(s).)

This study was aimed to compare the vascular healing process of a SYNERGY stent with that of a PROMUS PREMIER stent in patients with acute coronary syndrome (ACS). In 71 patients with ACS, undergoing coronary stent implantation using the SYNERGY stent (n = 52) or PROMUS PREMIER stent (n = 19), we measured circulating CD34+/CD133+/CD45 null cells and CD34+/KDR+ cells and observed vascular healing at the stented sites using optical coherence tomography (OCT) and coronary angioscopy. On the day 7, circulating CD34+/CD133+/CD45 null cells increased in SYNERGY group (P < 0.0001), while it did not change in PROMUS group. The CD34+/KDR+ cells also increased in SYNERGY group (P < 0.0001) but less significantly in the PROMUS group (P < 0.05). The OCT-based neointimal thickness (P < 0.0005) and neointimal coverage rate (P < 0.05) at 12 months were greater in SYNERGY group, compared with PROMUS group. The coronary angioscopy-based neointimal coverage grade at 12 months was also greater in SYNERGY group (P < 0.001). In overall patients, the change in CD34+/KDR+ cells on the day 7 correlated with the OCT-based neointimal thickness at 12 months (R = 0.288, P < 0.05). SYNERGY stent seems to have potential advantages over PROMUS PREMIER stent for ACS patients in terms of vascular healing process at the stented sites., (© 2021. The Author(s).)

In this work we use Mimosa tenuiflora (MtE) extracts as reducing agents to synthesize silver nanoparticles (AgMt NPs) which were characterized by DPPH and Total Polyphenols Assays, UV-visible, X-ray diffractometer (XRD), high-resolution transmission electron microscopy (HRTEM), X-ray photoelectron spectroscopy (XPS) and Thermogravimetric analysis (TGA). AgMt NPs possess average sizes of 21 nm and fcc crystalline structure, it was also confirmed that the MtE is present in the AgMt NPs even after the cleaning protocol applied. Subsequently, carbopol hydrogels were made and the MtE and the synthesized AgMt NPs were dispersed in different gels (MtE-G and AgMt NPs-G, respectively) at 100 µg/g concentration. The gels were characterized by UV-Vis, IR, and rheology. Antimicrobial tests were performed using Staphylococcus aureus and Escherichia coli. Burn wound healing was evaluated in a second-degree burn injury on a Wistar rats model for 14 days and additional skin biopsies were examined with histopathological analysis. Gel with commercial silver nanoparticles (Ag NPs) was prepared and employed as a control on the biological assays. Hydrogel system containing silver nanoparticles synthesized with Mimosa tenuiflora (AgMt NPs-G) is a promising therapeutic strategy for burn wound healing, this due to bactericidal and anti-inflammatory effects, which promotes a more effective recovery (in percentage terms) by damaged area.