Doxycycline-loaded biodegradable microparticles as a novel safe anti-scarring strategy in the eye

青光眼和沙眼是世界范围内导致失明的主要原因，超过8000万人受到影响，近1000万人面临永久失明的直接风险。在这两种疾病中，术后瘢痕形成是手术治疗失败的主要原因。目前还没有预防沙眼瘢痕形成的治疗方法，尽管细胞毒性抗癌药物通常用于预防青光眼滤过手术后的瘢痕形成，但此类药物毒性很高，可能会产生严重的致盲副作用。我们发现，广泛使用的广谱抗生素多西环素能有效地预防结膜成纤维细胞的促炎/促纤维化反应，使其成为青光眼和沙眼手术后抗瘢痕形成辅助治疗的合适候选药物。我们设计了一种创新的药物-装置组合，由可生物降解的多西环素载药微粒组成，用于手术时的局部给药，以实现靶向和持续的抗瘢痕作用。这些微粒在仿生结膜中防止成纤维细胞介导的收缩，我们的初步数据表明，它们在动物模型中耐受性良好，并能减少炎症。该项目建议改进多西环素微粒的设计，以准备临床使用，使用我们验证的结膜仿生技术，利用药代动力学和微粒降解模型。这个项目的第二个补充方面将是利用多细胞结膜仿生学来阐明多西环素对促炎/促纤维化成纤维细胞反应的作用机制，这将使系统进一步完善，以确保我们达到最大潜能。技能发展：组织工程、3/4D成像、细胞生物学、化学、药代动力学、建模

Glaucoma and trachoma are leading causes of blindness worldwide, with over 80M people affected and close to 10M at immediate risk of permanent sight loss. In both diseases, postoperative scarring is the main cause of surgical treatment failure. There is currently no treatment to prevent scarring in trachoma and, while cytotoxic cancer drugs are routinely used to prevent postoperative scarring following filtration surgery for glaucoma, such drugs are highly toxic and can have serious blinding side effects. We have found that doxycycline, a widely used broad-spectrum antibiotic, effectively prevents pro-inflammatory/pro-fibrotic responses in conjunctival fibroblasts, making it a suitable candidate for an anti-scarring adjuvant treatment following surgery in glaucoma and trachoma. We have designed an innovative drug-device combination consisting of biodegradable doxycycline-loaded microparticles for local delivery at the time of surgery to achieve targeted and sustained anti-scarring action. These microparticles prevent fibroblast-mediated contraction in a conjunctiva biomimetic and our preliminary data indicates that they are well tolerated in animal models and reduce inflammation. This project proposes to refine the design of the doxycycline-loaded microparticles in readiness for clinical use, using pharmacokinetics and modelling of microparticle degradation using our validated conjunctiva biomimetics. The second, complementary aspect of this project will be to elucidate doxycycline's mechanism of action on the pro-inflammatory/pro-fibrotic fibroblasts' responses using multicellular conjunctiva biomimetics, which will enable further refinement of the system to ensure we achieve maximum potency.Skills development: tissue engineering, 3/4D imaging, cell biology, chemistry, pharmacokinetics, modelling