Basic fibroblast growth factor(Kyoto University)

Tissue adhesives have become substitutes or adjuvants for surgical sutures owing to their minimal tissue damage and ease of application. However, limitations remain for existing tissue adhesives, such as weak adhesion strength, potential toxicity, and lack of bioactivities to promote wound healing. Here, we developed an injectable and biocompatible hydrogel tissue adhesive incorporating basic fibroblast growth factor (bFGF)-loaded liposomes for sutureless wound closure and promoting wound healing. The hydrogel, formed by 10 %(w/v) human serum albumin (HSA) and o-phthalaldehyde (OPA)-functionalized four-arm poly(ethylene glycol) (4aPEG-OPA) through irreversible OPA/amine condensation reaction, demonstrated strong tissue adhesion properties, biodegradability (complete degradation in PBS containing 1 U/mL elastase within 10 days), and biocompatibility. The hydrogel incorporating bFGF-loaded liposomes achieved sustained release of bFGF (cumulative release ratio of 65.4 % over 8 days), and promoted cell proliferation, migration, collagen production, and angiogenesis. In rat and porcine full-thickness skin incision models, the hydrogel effectively closed the wounds and facilitated wound healing within 14 days, outperforming commercially available fibrin glue and cyanoacrylate adhesives. RNA sequencing and western blotting analysis demonstrated that the hydrogel stimulated cell proliferation, collagen production, and angiogenesis. Overall, this hydrogel tissue adhesive shows great potential for encouraging wound closure without suture and promoting wound healing. STATEMENT OF SIGNIFICANCE: This study introduces a multifunctional tissue-adhesive hydrogel formed by covalent cross-linking of human serum albumin with o-phthalaldehyde (OPA)-terminated four-arm poly(ethylene glycol), and incorporated with bFGF-loaded liposomes. The catalyst-free OPA/amine reaction used in its synthesis ensures a mild and controllable gelation process, which is beneficial for maintaining the bioactivity of encapsulated growth factors. This composite system exhibited sustained growth factor release profile and remarkable bioactivity in regulating skin cell behaviors, which facilitates easier clinical translation compared to existing approaches. In rat and porcine models, it achieved sutureless wound healing and outperformed commercial adhesives in promoting re-epithelialization and angiogenesis, offering a promising alternative to traditional sutures and commercial adhesives.

Cushing's syndrome (CS) results from prolonged exposure to excessive glucocorticoids (GCs), leading to metabolic disturbances and adrenal insufficiency (AI). Fibroblast growth factor 21 (FGF21) has shown promise as a potential therapeutic target for metabolic disorders. This study explores the effects of FGF21 on adrenal gland function in a mouse model of AI following chronic hypercortisolism and investigates sex-dependent differences in the hypothalamic-pituitary-adrenal (HPA) axis response.

We employed a mouse model of AI after chronic corticosterone (CORT) treatment. The effects of recombinant human FGF21 (hFGF21) administration on adrenal function were evaluated in AI mice. Male and female wild-type (WT) and FGF21-overexpressing transgenic (Tg) mice were subjected to 5 weeks of CORT treatment, reaching CS phenotype, followed by immediate analysis or a 10-week recovery period. Metabolic parameters, HPA axis function, and adrenal gland morphology and gene expression were assessed.

Prolonged CORT exposure resulted in metabolic disturbances and HPA axis dysregulation. hFGF21 treatment increased CORT and ACTH secretion in AI mice. FGF21 overexpression influenced glucose homeostasis and insulin regulation during CORT treatment and recovery, with sex-specific effects. Tissue-specific regulation of Klb expression was observed across the HPA axis, with distinct patterns between males and females. Tg mice displayed altered adrenal progenitor cell activation and steroidogenic gene expression. Sex-specific differences were observed in adrenal capsule remodeling and gene expression patterns during recovery.

This study reveals the complex interplay between FGF21 signaling and GC-induced metabolic and endocrine changes, suggesting a potential sex-specific role of FGF21 in metabolic regulation and HPA axis recovery following after CS.