Endogenously triggered delivery of therapeutics from injectable microgels for muscle regeneration

• Applicant: Professor Dr.-Ing. Taimoor Hasan Qazi
• Subject Area: Pharmacy ; Biomaterials ; Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 412891280

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Jason A. Burdick, Ph.D.