The Schmidt recently received three grants from the NIH, NSF and Conquer Paralysis Now (CPN) Foundation on natural-based scaffold development. Congratulations to Dr. Becky Wachs, who helped tremendously with writing these proposals! Michaela Mertz is working predominantly on the NIH grant, with some help from our new postdoc Dr. Young Hye Song. Young Hye is working predominantly on the new NSF award. Michaela is also working on the CPN award in collaboration with Dr. Mary Bunge’s lab at the University of Miami.
National Institutes of Health (NIH) – “Engineering In Vitro ECM Test Beds to Mimic Injury” (2/01/2016 – 1/31/2018)
The goal of this proposal is to develop an in vitro test bed capable of mimicking native and pathological extracellular matrix (ECM) to identify novel targets for treatment of traumatic neural injury. We will accomplish this goal through rational design of an ECM-based scaffold to mimic native temporal ECM damage observed after spinal cord injury (SCI). Chondroitin sulfate proteoglycans (CSPGs) are the largest component of the healthy and pathologic ECM in the central nervous system (CNS) and serve many functions. After SCI specifically, there is an increase in versican, neurocan, and brevican, and a decrease in aggrecan. There are also dynamic changes to specific proteases such at MMP-2 and -9 after SCI that will selectively cleave CSPGs. Furthermore, CSPG fragmentation has been implicated in progression of other diseases (e.g. osteoarthritis). We believe CSPG fragmentation plays a similar role in increasing unwanted glial scarring after SCI or traumatic neural injury. Currently, animal models are used to screen feasibility of biomaterials for tissue engineering. However, to examine injury and disease states an “induced” state must be created in the animal model that often does not represent native pathology of injury or disease. Creation of in vitro pathological ECM test beds has the potential to provide a lower cost, more relevant system for examining mechanistic responses and testing small molecule therapeutics and identifying relevant targets to treat patients with SCI.
National Science Foundation (NSF) – “Harnessing the Power of Apoptosis to Create Regenerative Acellular Biologic Scaffolds” (7/1/2016 – 6/31/2019)
This proposal seeks to shift the paradigm in decellularization techniques; rather than induce necrosis of cells to begin decellularization, we propose to induce apoptosis. During apoptosis cells detach from the matrix and form small apoptotic bodies containing cellular components which can be more easily removed from the matrix. In addition, during apoptosis cells secrete cytokines and signaling molecules that can be sequestered in the ECM, and are known to induce compensatory proliferation, stem cell recruitment, and immunomodulation thereby aiding in tissue regeneration. This approach has the potential to enhance matrix preservation and bioactivity, thus dramatically altering tissue engineering across a wide variety of tissue types.
Conquer Paralysis Now (CPN) Foundation – “A New Injectable Matrix to Maximize Schwann Cell Transplantation Efficacy Following Spinal Cord Injury” (9/1/2016 – 8/31/2017)
Improvements on current strategies is necessary to develop a clinically translatable therapy to promote functional recovery after SCI. The proposed regenerative therapy will contain 2 parts: 1) Schwann cells (SCs) and 2) an injectable decellularized peripheral nerve scaffold (iPN). The use of iPN for SCI repair allows for some of the challenges encountered with the methods mentioned above. Using decellularized peripheral nerve eliminates immunogenicity issues associated with grafts or foreign biomaterials because it removes cellular components and is composed of natural ECM components. It also should provide a more native environment for the Schwann cells and provide support to improve cell survival and maintenance. Since the scaffold is injectable, it will be less invasive, decrease risk of excess damage to the spinal cord, and decrease the severity of the boundary between the graft and the native spinal cord.