Ripple Therapeutics, MaRS Center, South Tower, 101 College Street, Suite 300, Toronto, ON, M5G 1L7, Canada; Faculty of Dentistry, University of Toronto, Toronto, ON, M5G 1G6, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada.
Laboratory of Tissue Repair and Regeneration, Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, 209 Victoria Street, Toronto, ON M5B 1T8, Canada; Faculty of Dentistry, University of Toronto, Toronto, ON, M5G 1G6, Canada.
Biomaterials. 2022 Jul;286:121586. doi: 10.1016/j.biomaterials.2022.121586. Epub 2022 May 18.
Inflammation-driven foreign body reactions, and the frequently associated encapsulation by fibrogenic fibroblasts, reduce the functionality and longevity of implanted medical devices and materials. Anti-inflammatory drugs, such as dexamethasone, can suppress the foreign body reaction for a few days post-surgery, but lasting drug delivery strategies for long-term implanted materials remain an unmet need. We here establish a thin-coating strategy with novel low molecular weight corticosteroid dimers to suppress foreign body reactions and fibrotic encapsulation of subcutaneous silicone implants. The dimer coatings are >75% dexamethasone by mass and directly processable into conformal coatings using conventional solvent-based techniques, such as casting or spray coating without added polymers or binding agents. In vitro, surface erosion of the coating, and subsequent hydrolysis, provide controlled release of free dexamethasone. In a rat subcutaneous implantation model, the resulting slow and sustained release profile of dexamethasone is effective at reducing the number and activation of pro-fibrotic macrophages both acutely and at chronic time points. Consequently, fibroblast activation, collagen deposition and fibrotic encapsulation are suppressed at least 45 days post-implantation. Thus, our approach to protect implants from host rejection is advantageous over polymeric drug delivery systems, which typically have low drug loading capacity (<30%), initial burst release profiles, and unpredictable release kinetics.
炎症驱动的异物反应，以及经常伴随的纤维母细胞形成的纤维化包裹，降低了植入式医疗设备和材料的功能和使用寿命。抗炎药物，如地塞米松，可以在手术后几天内抑制异物反应，但对于长期植入材料，持久的药物输送策略仍然是一个未满足的需求。我们在这里建立了一种使用新型低分子量皮质甾酮二聚体的薄涂层策略，以抑制异物反应和皮下硅酮植入物的纤维性包裹。二聚体涂层的质量超过 75%是地塞米松，可以使用常规的基于溶剂的技术（如浇铸或喷涂）直接加工成保形涂层，而无需添加聚合物或结合剂。在体外，涂层的表面侵蚀和随后的水解提供了游离地塞米松的控制释放。在大鼠皮下植入模型中，地塞米松的这种缓慢和持续释放的特性可以有效地减少促纤维化巨噬细胞的数量和激活，无论是在急性还是慢性时间点。因此，纤维母细胞的激活、胶原蛋白的沉积和纤维性包裹至少在植入后 45 天被抑制。因此，我们保护植入物免受宿主排斥的方法优于聚合物药物输送系统，后者通常具有低药物载量（<30%）、初始突释释放曲线和不可预测的释放动力学。
