Stem Cell Impregnated Thread Reinforced Encapsulation Devices (THREDs) for Surgical Therapy of the Acute and Chronic Effects of Mesenteric Ischemia

About This Grant

PROJECT SUMMARY This investigator’s proposal describes a 5-year project of vertebral body derived mesenchymal stem cells within a Thread Reinforced Encapsulation Device (THRED) to treat the acute and long-term effects of mesenteric ischemia. The proposal evaluates intestinal organ recovery after treatment with cellular therapy and evaluates the metabolic and cellular host responses to massive surgical small bowel resection. The proposal provides basic and translational applications of emerging technologies relevant to the surgical treatment of intestinal ischemia. Investigators hypothesize that H2S is a critical component of VB-MSC mediated intestinal protection during mesenteric ischemia treatment, and that encapsulated MSCs can provide a stable source of H2S via an implantable, retrievable delivery system. They have developed a novel mouse with a mutation to test their hypothesis that VB-MSCs release hydrogen sulfide that then reacts at Cysteine440 on eNOS to bring about improved mesenteric blood flow. Through additional models, they investigate how VB-MSCs can be safely delivered within an implantable, retrievable, nanoporous device that allows cells to release their beneficial paracrine mediators while protecting them from host immune deletion. They propose three Specific Aims: 1) Develop a novel cellular delivery system to effectively deploy hydrogen sulfide from VB-MSCs in mesenteric ischemia, 2) Evaluate the interaction of THRED packaged VB-MSCs, H2S, and Nitric Oxide (NO) on chronic mesenteric vasodilation and long-term intestinal adaptation, and 3) Deploy THRED packaged VB-MSCs in a porcine model of mesenteric ischemia as final preclinical testing of scalability and effectiveness. The investigator is a pediatric surgeon scientist who completed his K08 funding through the NIDDK and was previously awarded an Early Stage Investigator R01 through the NIDDK. His career goals are to use this R01 to develop novel therapies and diagnostic tools for intestinal ischemia. He has collaborated with Dr. Minglin Ma at Cornell University who has extensive experience with implantable devices. Dr. Ma’s group has invented the THRED device, which is an electrospun nanoporous membrane that allows stem cells to interact with their local environment, while also containing them in a specific anatomical location and protecting them from immune destruction. Dr. Markel has also collaborated with Dr Tim Lescun, a large animal veterinarian at Purdue University which is approximately 45 minutes away from Dr. Markel’s institution. Additional collaborators include Dr. Erik Woods from Ossium Health, who will supply the VB-MSCs. In summary, this research aims to understand the mechanism that VB-MSCs use to provide acute and chronic protection in mesenteric ischemia. It also looks to identify appropriate delivery strategies so that cells can be delivered in an implantable, retrievable device for therapeutic use. The proposal is highly innovative and the investigator has the appropriate support, collaborations, and infrastructure in place to carry out the study.