James H. -C. Wang

Aims: Surgical repair infrequently restores the native tendon–bone interface (TBI, also referred to as the enthesis), resulting in excessive scar formation, compromised biomechanics, and frequent re-tears. A simple, biodegradable surgical adjunct that supports tendon–bone healing could augment standard repair strategies. In this study, we evaluated a biomimetic, amino acid-based biodegradable polyurethane adhesive as an intraoperative adjunct to standard suture repair in a rat Achilles tendon–calcaneus model. Methods: A total of 90 female Sprague-Dawley rats (8 weeks old) were randomly assigned to two groups: suture-only and suture + adhesive (n = 45 per group). In the enthesis injury model, after transection and drilling, the polymer adhesive was freshly prepared and applied directly to the tendon–bone interface prior to suture tightening. The contralateral limb served as an intact control. Animals were sacrificed at four-, eight-, and 12-week timepoints, and tissues were evaluated using histological, imaging, micro-CT, and biomechanical analyses. Results: Compared with suture-only repair, the suture + adhesive treatment was associated with more organized fibrocartilage formation, improved collagen I/III organization, greater proteoglycan deposition, and a smaller, more compact repair interface. When normalized by cross-sectional area, the adhesive group exhibited higher ultimate stress (tissue-level mechanical strength), although ultimate stress remained below that of intact controls. Whole-construct mechanical properties were comparable between groups, suggesting that the adhesive served as a biological and structural adjunct that was associated with improved intrinsic tissue quality, rather than increased construct-level strength. Conclusion: These findings suggest that a biodegradable polyurethane adhesive is associated with improved structural organization and intrinsic tissue-level mechanical properties of the repaired tendon–bone interface. Its straightforward intraoperative use and favourable biocompatibility profile support further investigation of its potential as an adjunctive strategy for tendon–bone repair. Cite this article: Bone Joint Res 2026;15(9):1111–1122.

Femoral shaft fractures cause prolonged disability, and therapies that accelerate bone repair remain limited. Repurposing clinically approved drugs that target biological bottlenecks in healing is a promising strategy. This study investigated whether systemic metformin administration, an anti‐diabetic medication with known metabolic regulatory effects, enhances fracture repair in a rat open femoral shaft fracture model. Histological, immunofluorescent, micro‐CT, and biomechanical analyses were performed at 6 weeks post‐injury comparing metformin‐treated and vehicle‐treated animals. Metformin markedly accelerated callus maturation, evidenced by earlier hyaline cartilage ossification, increased collagen I deposition and fiber organization, and reduced collagen II and III expression compared with controls. Micro‐CT analysis demonstrated increased tissue mineral density, trabecular thickness, and bone volume fraction along with reduced connectivity density, indicating more advanced structural consolidation of the callus. Although biomechanical parameters were not significantly different at intermediate time point, ultimate load and stiffness trended higher in metformin‐treated animals, consistent with structural advancement. Mechanistically, metformin increased p‐AMPK expression, elevated mitochondrial markers (NDUFB8, TFAM), and reduced extracellular HMGB1 release, suggesting enhanced metabolic capacity and attenuated inflammatory stress during repair. Importantly, metformin's effects were most pronounced during the cartilage‐to‐bone transition phase, supporting a role for metabolic activation in promoting endochondral ossification. Together, these findings demonstrate that systemic metformin administration promotes earlier structural consolidation of the fracture callus through coordinated metabolic and inflammatory modulation, supporting the potential repurposing of this safe and inexpensive drug as an adjunct strategy to enhance bone repair.

We developed an injectable hyaluronic acid–metformin (HA–Met) conjugate gel for localized intra‐articular delivery to mitigate post‐traumatic osteoarthritis (PTOA). Conjugation was verified by Fourier‐transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and high‐performance liquid chromatography. In vitro studies showed an initial 24‐h burst attributable to unbound Met, followed by prolonged local retention from the conjugated fraction under physiological incubation without hyaluronidase treatment; by contrast, a simple HA + Met mixture released Met in phosphate‐buffered saline (PBS) completely in 3 days. In high dosage hyaluronidase‐containing PBS, Met retained in the HA–Met conjugate gel up to 4 days. In vivo, Met remained detectable in mouse knee tissues for up to 7 days after a single intra‐articular injection of HA–Met conjugate and accumulated with weekly dosing; in contrast, after Met solution or HA + Met mixture injection around 99% of Met was removed from the knee joint in 1 day, low dosage traces of Met remained in the joint up to 2–3 days. In a destabilization of medial meniscus‐induced murine PTOA model, weekly HA–Met conjugate injections attenuated cartilage degeneration and joint pathology versus HA or Met alone, which produced only modest effects; sham joints exhibited no pathological changes. The weekly interval was selected to ensure continuous exposure in mice with rapid metabolism and joint clearance and should be viewed as an accelerated proof‐of‐concept schedule rather than a clinical regimen. These findings support HA–Met conjugate gel as a translational platform that achieves prolonged intra‐articular Met retention and disease‐modifying benefit in a small‐animal PTOA model.

Metformin (Met), a highly hydrophilic drug, exhibits anti-inflammatory and regenerative effects beyond its antidiabetic role. However, its extreme polarity limits passive diffusion through the stratum corneum, necessitating optimized formulations for effective transdermal delivery. This study compared Met permeability through human and porcine ear skin using three lotion formulations containing different permeation enhancers: (1) 6% Met + glycerol (Gly); (2) 6% Met + Gly and propylene glycol (PG); and (3) 10% Met + PG and Transcutol^® (PG + T). In human skin, Gly and PG formulations showed minimal permeation, whereas PG + T markedly increased cumulative permeation and flux, confirming the critical role of Transcutol^®. Porcine skin displayed consistently higher permeability across all formulations (Gly < PG < PG + T), indicating that it may overestimate human permeability to hydrophilic drugs. Despite limited transdermal flux, Gly- and PG-based lotions produced measurable Met accumulation within the epidermis and dermis, suggesting potential for topical use. Overall, these results emphasize the importance of enhancer selection—particularly Transcutol^®—in improving dermal delivery of hydrophilic compounds and caution against relying solely on porcine skin as a human surrogate.

Porcine ear skin is widely used as a surrogate for human skin in in vitro permeation testing (IVPT) due to its structural and physiological similarities. However, commercial sourcing from the food industry often involves scalding, dehairing, and other processing steps that damage key layers of the skin barrier, potentially altering drug diffusion. Despite this, procurement and preparation methods are rarely standardized or reported in detail. In this study, we investigated how pork harvest processing affects the permeation of a topical 6% metformin lotion (ML) formulated with glycerol or glycerol plus propylene glycol. Permeation was evaluated using Franz diffusion cells over 48 hours, and skin structure was examined histologically. Processed porcine skin exhibited dramatically higher metformin flux — up to 20–60× greater within 2 hours — and cumulative diffusion (approximately 80% at 48 hours) compared to intact skin, which retained strong barrier function (< 30% total diffusion). Histology confirmed that pork harvest processing removed the stratum corneum and viable epidermis, facilitating rapid drug penetration. These findings demonstrate that commercially processed porcine skin is not an appropriate surrogate for human skin in permeation studies and highlight the critical need for standardized sourcing, documentation, and barrier integrity assessment in IVPT research.

Tendinopathy is a common overuse injury with limited preventive options. This study evaluated a novel topical metformin lotion (ML) for its ability to prevent Achilles tendinopathy induced by intensive treadmill running (ITR) in mice. ML at concentrations of 3% and 6% was topically applied daily to the skin overlying the Achilles tendons for four weeks prior to the initiation of ITR. After the four-week topical ML pretreatment period prior to ITR induction, blood samples were collected for ELISA-based analysis of inflammatory markers (HMGB1, IL-1β, and PGE₂), and tendons were examined using histological and immunofluorescent methods. ML inhibited the release of HMGB1 from cell nuclei into the tendon matrix, reduced serum levels of HMGB1, IL-1β, and PGE₂, and exerted anti-degenerative effects by decreasing chondroid metaplasia, lowering the number of rounded cells, and enhancing collagen fiber organization. These beneficial effects of ML appeared to be mediated through increased AMPK activity, reduced TGF-β1 expression, decreased myofibroblast presence, lower collagen III levels, and elevated collagen I production. In conclusion, ML effectively prevents tendinopathy development, primarily by inhibiting HMGB1 and activating AMPK. These findings suggest that ML may serve as a convenient, effective, and non-invasive strategy to prevent tendinopathy in at-risk populations—such as athletes and military personnel—while minimizing systemic side effects.

Aim: This study aimed to quantify the permeation of metformin (Met) lotion through pig ear skin using high-performance liquid chromatography, specifically hydrophilic interaction liquid chromatography (HILIC), to separate Met from biological contaminants and effectively measure its permeation through skin similar to human skin.Materials & methods: A Franz cell permeation assay was used to assess the permeation kinetics of 6% Met lotion through pig ear skin. Samples were collected at various time points and prepared for high-performance liquid chromatography analysis by removing large biological contaminants. The permeated Met was quantified by monitoring its retention time (RT) at 9 min using HILIC, with an acidic, polar mobile phase and a normal-phase column.Results: A distinct Met peak with a RT of approximately 9 min was observed in the 6% Met lotion, which was absent in the permeation samples from the 0% Met lotion. This peak (RT 9 min) was distinct from the 'biological-contaminants' peaks at RT 2-3 min and increased linearly over time, reaching 36.8% of the total applied Met at 24 h.Conclusion: These findings demonstrate that the HILIC method effectively separates Met from biological components in pig ear skin, allowing accurate quantification of Met despite the presence of skin lipids and proteins.

Scar tissue formation following skin wound healing is a challenging public health problem. Skin regeneration and preventing the formation of scar tissue by currently available commercial products are largely ineffective. This study aimed to test the efficacy of a novel topical metformin lotion (ML) in inhibiting scar tissue formation during skin wound healing in rats and to determine the mechanisms of action involved. A 6% ML was prepared in our laboratory. A skin wound healing model in rats was used. The wounded rats were divided into two groups and treated daily for 10 days as follows: Group 1 received a daily application of 50 mg of control lotion, or 0% ML (totaling 100 mg of lotion per rat), and Group 2 received a daily application of 50 mg of 6% ML (totaling 100 mg of 6% ML per rat). Blood samples from the heart of each rat were analyzed for inflammatory markers, HMGB1 and IL-1β, using ELISA, and immunological and histological analyses were performed on skin tissue sections. ML decreased levels of inflammatory markers HMGB1 and IL-1β in the serum of rats and inhibited the release of HMGB1 from cell nuclei into the skin tissue matrix. Additionally, ML demonstrated anti-fibrotic properties by enhancing AMPK activity, decreasing the expression of TGF-β1, reducing the number of myofibroblasts, decreasing the production of collagen III, and increasing the expression of collagen I. ML promotes the regeneration of high-quality skin during wound healing by reducing scar tissue formation. This effect is mediated through the activation of AMPK, inhibition of TGF-β1, and a decrease in the number of myofibroblasts.