Systemic drug administration has conventionally been prescribed to alleviate persistent local inflammation which is prevalent in chronic diseases. However, this approach is associated with drug-induced toxicity, particularly when the dosage exceeds that necessitated by pathological conditions of diseased tissues. Herein, we developed a modular hybrid hydrogel which could be triggered to release an anti-inflammatory drug upon exposure to elevated protease activity associated with inflammatory diseases. Modular design of the hybrid hydrogel enabled independent optimization of its protease-cleavable and drug-loaded subdomains to facilitate hydrogel formation, cleavability by matrix-metalloprotease-9 (MMP-9), and tuning drug release rate. In vitro study demonstrated the protease-triggered enhancement of drug release from the hybrid hydrogel system for effective inhibition of TNF-α production by pro-inflammatory macrophages and suggested its potential to mitigate drug-induced cytotoxicity. Using non-invasive imaging to monitor the activity of reactive oxygen species in biomaterial-induced host response, we confirmed that the hybrid hydrogel and its constituent materials did not induce adverse immune response after 5 days following their subcutaneous injection in immuno-competent mice. We subsequently incorporated this hybrid hydrogel onto a commercial wound dressing which could release the drug upon exposure to MMP-9. Together, our findings suggested that this hybrid hydrogel might be a versatile platform for on-demand drug delivery via either injectable or topical application to modulate inflammation in chronic diseases.

传统上已开出全身药物给药的处方，以减轻在慢性疾病中普遍存在的持续性局部炎症。然而，这种方法与药物诱导的毒性有关，特别是当剂量超过患病组织的病理条件所必需的剂量时。本文中，我们开发了一种模块化的混合水凝胶，当暴露于与炎症性疾病相关的升高的蛋白酶活性时，可以触发该混合物释放抗炎药。混合水凝胶的模块化设计能够对其蛋白酶可裂解和载药子域进行独立优化，以促进水凝胶的形成，基质金属蛋白酶9（MMP-9）的可裂解性以及调节药物的释放速率。体外这项研究证明了蛋白酶触发的从杂合水凝胶系统释放药物的增强作用，以有效抑制促炎性巨噬细胞产生TNF-α，并暗示了其减轻药物诱导的细胞毒性的潜力。使用非侵入性成像来监测活性物质在生物材料诱导的宿主反应中的活性，我们证实了杂化水凝胶及其组成材料在有免疫能力的小鼠中皮下注射5天后没有诱导不良的免疫反应。我们随后将这种杂化水凝胶掺入了商用伤口敷料中，该伤口敷料在暴露于MMP-9后会释放药物。一起，