Endogenously triggered delivery of therapeutics from injectable microgels for muscle regeneration

从可注射微凝胶内源触发治疗药物的递送以促进肌肉再生

• 批准号: 412891280
• 负责人: Professor Dr.-Ing. Taimoor Hasan Qazi
• 金额: --
• 依托单位: Department of Chemical and Biological Engineering
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/412891280?language=en
• 关键词: Endogenously; triggered; delivery; therapeutics; injectable

Unlike bone, muscle regeneration after severe injury remains an unmet clinical challenge. This is partly because existing interventional strategies are unable to target biological processes that occur in temporally distinct phases of healing. The principal aim of this project is to design, fabricate, test, and implement a biomaterial based approach that, with a single minimally invasive application, enables the delivery of multiple therapeutic factors at distinct stages of the muscle regeneration process. The key innovation will be the design and fabrication of micro-scale hydrogels (microgels) that retain therapeutics such as proteins or growth factors until their release is triggered in response to local enzymatic cues. Enzymes such as matrix metalloproteinases (MMPs) participate in matrix remodelling by cleaving various target substrates. Interestingly, our preliminary findings show that different MMPs are secreted in injured muscle in a two-wave fashion (MMP-9  early, MMP-2  late). This project will test the hypothesis that the naturally occurring MMP secretion pattern can be exploited to facilitate microgel based delivery of therapeutic factors that (1) attenuate the fibrotic activity of muscle resident fibroblasts, and (2) promote the maturation of muscle fibers, thereby leading to muscle regeneration. Therapeutic factors will be encapsulated in a hyaluronic acid based microgel system that is crosslinked using peptide sequences that are specific targets for MMP-9 or MMP-2, hence providing control over release kinetics. Injectability of the biomaterial will be achieved by assembling the microgel populations within a bulk matrix via affinity based guest-host reactions. The successful implementation of this project depends on advanced polymeric biomaterials design using supramolecular chemistry that has been pioneered in the host professor’s lab at University of Pennsylvania. The translational potential of this strategy will be demonstrated during a 6 month return phase at the Charité Universitätsmedizin Berlin where the applicant had previously helped establish a clinically relevant animal model of severe muscle injury. The project promises to result in the development of an innovative biomaterial based platform technology with high potential for customization and application to other musculoskeletal tissues. Importantly, international exposure to a world-renowned research group will further develop the scientific competitiveness and leadership potential of the applicant – preparing him for a successful academic career upon reintegration into the German research system.

与骨骼不同，严重损伤后的肌肉再生仍然是一个尚未解决的临床挑战。这部分是因为现有的干预策略无法针对在时间上不同的愈合阶段发生的生物过程。该项目的主要目的是设计，制造，测试和实施一种基于生物材料的方法，该方法具有单一的微创应用，能够在肌肉再生过程的不同阶段提供多种治疗因子。关键的创新将是设计和制造微尺度水凝胶（微凝胶），保留治疗剂，如蛋白质或生长因子，直到它们的释放被触发，以响应当地的酶线索。酶如基质金属蛋白酶（MMP）通过切割各种靶底物参与基质重塑。有趣的是，我们的初步研究结果表明，不同的MMP在损伤的肌肉中以两波方式分泌（MMP-9早期，MMP-2晚期）。该项目将测试这样的假设，即可以利用天然存在的MMP分泌模式来促进基于微凝胶的治疗因子的递送，所述治疗因子（1）减弱肌肉驻留成纤维细胞的纤维化活性，和（2）促进肌纤维的成熟，从而导致肌肉再生。治疗因子将被封装在基于透明质酸的微凝胶系统中，所述微凝胶系统使用作为MMP-9或MMP-2的特异性靶标的肽序列交联，因此提供对释放动力学的控制。生物材料的可注射性将通过基于亲和性的客体-主体反应在本体基质内组装微凝胶群体来实现。该项目的成功实施取决于先进的聚合物生物材料的设计，使用超分子化学，已率先在主持教授的实验室在宾夕法尼亚大学。该策略的转化潜力将在Charité Universitätsmedizin柏林的6个月返回阶段得到证明，申请人之前曾在该研究中帮助建立了临床相关的严重肌肉损伤动物模型。该项目有望开发出一种创新的基于生物材料的平台技术，该技术具有很高的定制和应用于其他肌肉骨骼组织的潜力。重要的是，国际接触到世界知名的研究小组将进一步发展申请人的科学竞争力和领导潜力-为他重新融入德国研究系统后成功的学术生涯做好准备。