Burns Research and Reconstructive Surgery, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney, Australia.
Asbestos Disease Research Institute, Concord Hospital, Sydney, Australia.
FASEB J. 2022 May;36(5):e22310. doi: 10.1096/fj.202101803R.
Wound healing is a complex process involving multiple independent and overlapping sequential physiological mechanisms. In addition to cutaneous injury, a severe burn stimulates physiological derangements that induce a systemic hypermetabolic response resulting in impaired wound healing. Topical application of the anti-androgen drug, flutamide accelerates cutaneous wound healing, whereas paradoxically systemic dihydrotestosterone (DHT) improves burn wound healing. We developed and characterized a PCL scaffold that is capable of controlled release of androgen (DHT) and anti-androgen (F) individually or together. This study aims to investigate whether local modification of androgen actions has an impact on burn injury wound healing. In a full-thickness burn wound healing, mouse model, DHT/F-scaffold showed a significantly faster wound healing compared with F-scaffold or DHT-scaffold. Histology analysis confirmed that DHT/F-scaffold exhibited higher re-epithelization, cell proliferation, angiogenesis, and collagen deposition. Dual release of DHT and F from PCL scaffolds promoted cell proliferation of human keratinocytes and alters the keratinocyte cell cycle. Lastly, no adverse effects on androgen-dependent organs, spleen and liver were observed. In conclusion, we demonstrated DHT plus F load PCL scaffolds accelerated burn wound healing when loading alone did not. These findings point to a complex role of androgens in burn wound healing and open novel therapeutic avenues for treating severe burn patients.
伤口愈合是一个复杂的过程，涉及多个独立且重叠的连续生理机制。除了皮肤损伤外，严重的烧伤还会刺激生理失调，导致全身性高代谢反应，从而影响伤口愈合。抗雄激素药物氟他胺的局部应用可加速皮肤伤口愈合，而矛盾的是，全身性二氢睾酮（DHT）可改善烧伤伤口愈合。我们开发并表征了一种 PCL 支架，该支架能够单独或联合控制释放雄激素（DHT）和抗雄激素（F）。本研究旨在探讨局部改变雄激素作用是否对烧伤损伤伤口愈合有影响。在全层烧伤伤口愈合的小鼠模型中，DHT/F 支架的伤口愈合速度明显快于 F 支架或 DHT 支架。组织学分析证实，DHT/F 支架表现出更高的再上皮化、细胞增殖、血管生成和胶原沉积。PCL 支架中 DHT 和 F 的双重释放促进了人角质形成细胞的增殖，并改变了角质形成细胞的细胞周期。最后，没有观察到对依赖雄激素的器官（脾脏和肝脏）的不良影响。总之，我们证明了 DHT 和 F 联合加载 PCL 支架可加速烧伤伤口愈合，而单独加载时则没有这种效果。这些发现表明雄激素在烧伤伤口愈合中具有复杂的作用，并为治疗严重烧伤患者开辟了新的治疗途径。
