BME Seminar: “Engineering Injectable ‘ParenchyGel’ for Local Drug Delivery to the CNS”

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John R. Clegg, Ph.D.
Assistant Professor of Biomedical Engineering
University of Oklahoma

Abstract: Treatment of neurological diseases is limited by poor bioavailability of systemically administered drugs to the central nervous system (CNS) parenchyma. Local administration of therapeutics to the CNS parenchyma via biomaterial implants is a potentially promising approach for treating select neurological diseases that are already indicated for invasive neurosurgery. However, few biomaterials have been developed as intracerebral implants, and knowledge about the usefulness and performance of common biomaterials in CNS environments is poorly understood, relative to more typical dermal, musculoskeletal, dental, or ocular applications. To address this gap in knowledge and technology, my lab develops that brain-inspired hydrogels comprised of methacrylated hyaluronic acid, heparin, gelatin, and other for direct injection into the CNS parenchyma and highly localized drug delivery. These materials have been tested in rodents, and we are currently exploring translation with the long-term goal of treating human patients. Hydrogel blends were designed for brain biomimicry (i.e., composition, water content, and Young’s modulus), modularity, and their ability to encapsulated diverse payloads (i.e., ranging from small molecules to live cell therapeutics). We evaluated distinct designs in two rodent models. Local delivery of doxorubicin was evaluated for primary glioblastoma (G55 orthotopic xenograft in mice) Delivery of doxorubicin via a peri-tumorally injected hydrogel reduced the rate of G55 tumor growth and improved overall survival, relative to control mice. Local recombinant protein immunotherapy was tested for attenuation of secondary brain damage and recovery in intracerebral hemorrhage (ICH) in rats. Local delivery accelerated functional recovery post-ICH in the autologous blood rat model, relative to sham surgery and hydrogel carrier-only controls. Hydrogel injection was well tolerated in both models, as evidenced by behavioral, histological, and biochemical measures. Together, our results establish proof-of-concept that intracerebral injection of brain-inspired hydrogels, integrated with existing neurosurgical procedures, enables neurological disease treatment with agents (e.g., recombinant cytokines, doxorubicin) that do not reach the brain when dosed systemically. This student-invited seminar will also include associated anecdotes and candid discussions of challenges, pitfalls, and progress in my academic career, which I hope will be useful to trainees at earlier career stages.

Bio: Dr. John R. Clegg is an Assistant Professor of Biomedical Engineering at the University of Oklahoma (Norman, OK). He is concurrently an Adjunct Assistant Professor of Neurosurgery, a member of the Harrold Hamm Diabetes Center, and a member of the Stephenson Cancer Center at the University of Oklahoma Health Campus (Oklahoma City, OK). Dr. Clegg obtained his PhD from the University of Texas, Austin in the laboratory of Prof. Nicholas Peppas and completed postdoctoral training at Harvard University under Prof. Samir Mitragotri. His lab studies hydrogel delivery systems and combination products involving adoptively transferred immune cells for neurotrauma and brain tumors. His team also utilizes polymeric and hydrogel nanoparticles to influence innate immune cell phenotype, with application in both pre-conditioning of donor cells for adoptive transfer and immunomodulation following systemic delivery of nanoparticle suspensions. His team evaluates these therapeutics in cell culture, human organoid/spheroid, and rodent model systems. Dr. Clegg’s research has been recognized with several awards, including the NIH-NIGMS Maximizing Investigators’ Research Award, NSF GRFP, and the best paper award from the Controlled Release Society. He is an active member of the BMES, SFB, and CRS.