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

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