Title: Outside-In Regenerative Therapy for Abdominal Aortic Aneurysm
Description: Few diseases represent the optimal potential target for regenerative cellular therapy more than the abdominal aortic aneurysm (AAA). A disease that affects a large number of elderly in the United States with a natural history that results in structural failure of the aortic wall and death, AAA continues to represent a critical need for biologic therapy. Regenerative therapy consisting of the delivery of stem cells to the damaged aorta presents a conceptually strong opportunity for the reconstitution of the aortic mural matrix and therefore aortic strength – any test of such a therapy must be done on an established aneurysm to most accurately represent what occurs in the clinic. In this proposal, we have combined the strengths of two laboratories with complementary scientific capability, and with a common interest in the development of effective biologic therapies for AAA disease. The early product of this collaborative pairing is published “proof of concept” evidence that mesenchymal stem cell (MSC) delivery to the wall of a murine AAA can slow progression. The purpose of this R21 Exploratory/Developmental Research Proposal is to develop a clinically- translatable MSC delivery system that would result in aortic matrix repair and regeneration. Our hypothesis is that local stem cell delivery to a murine AAA via an adventitially-applied hydrogel and magnetic assistance will result in intramural cell engraftment, matrix repair, and mechanical stabilization of the aortic wall. To address our hypothesis, we will execute the following specific aims: Specific Aim 1 is to develop and validate a technique to deliver MSCs into the aortic wall periadventitially using a hydrogel vehicle and magnetic guidance. The technique will be optimized by testing a cadre of iron nanoparticle types, fibrin hydrogel formulations, and stem cell concentrations both in vitro and in vitro. Specific Aim 2 is to demonstrate that local MSC delivery halts and reverses the functional and structural degeneration of an AAA in an established rodent model. MSC hydrogels developed in Specific Aim 1 will be applied to the adventitia of an elastase-induced model AAA after allowing for varying degrees of matrix degeneration. Metrics for success of the various therapies versus cell-free hydrogel controls on aortic tissue will involve: i) functional assessment (including aortic diameter and biomechanical parameters) and ii) detailed microstructural and cellular composition assessment. The expected outcome of this work is the development and proof-of-concept of a new technology for stem cell delivery to AAA.
PI: Michael L. Boninger, MD and Thomas A. Rando, MD
Title: Alliance for Regenerative Rehabilitation Research & Training (AR3T)
Description: The advancement of regenerative medicine principles and technologies holds great potential to drive progress in the prevention and treatment of individuals with a host of pathologies resulting from injury, disease or aging. The long-term goal of regenerative medicine is to promote the repair, replacement, or regeneration of tissues. Likewise, rehabilitation seeks to harness the body’s innate regenerative potential in order to maximize function. Both fields hold great potential to drive progress in the treatment of a host of acute and chronic pathologies. We propose that these two fields are inextricably intertwined; an intersection of disciplines known as Regenerative Rehabilitation. To fully realize the tremendous potential of Regenerative Rehabilitation, we must promote the interaction of basic scientists with rehabilitation specialists. We must also train rehabilitation clinicians who can help oversee the quality, safety, and validity of these innovative Regenerative Rehabilitation technologies. The overarching goal of the Alliance for Regenerative Rehabilitation Research & Training (AR3T) is to establish a national network that will expand scientific knowledge, expertise and methodologies across the domains of regenerative medicine and rehabilitation.
Description: Sepsis, a clinical systemic inflammatory response syndrome occurring in patients following infection or injury, remains the leading cause of death in intensive care units worldwide, including the United States. Emerging evidence indicates that immunometabolism may play an important role in the pathogenesis of sepsis through its ability to regulate the expression and release of cytokines. In particular, we recently provided the first direct evidence that PKM2-mediated aerobic glycolysis promotes the release of HMGB1, a late mediator of lethal systemic inflammation with a wider therapeutic time window for clinical intervention. These exciting findings raise several important questions regarding the previously unknown role of PKM2 in the pathogenesis of sepsis, as well as the novel mechanisms underlying the regulation of PKM2 expression and HMGB1 release. We hypothesize that PKM2-mediated immunometabolism is an emerging hallmark of sepsis that contributes to cytokine (e.g., HMGB1) release and the subsequent systemic inflammatory response. We propose the following specific aims:
Title: Extracellular Matrix as a Therapy for Inflammatory Bowel Disease
Description: Clinical Problem: Inflammatory Bowel Disease (IBD) affects nearly 1.5 million Americans with approximately 70,000 new cases diagnosed each year. There are a number of forms of IBD most notably ulcerative colitis (UC) and Crohn’s disease, but the medical device therapy described in this work could also address proctitis, proctosigmoiditis, and rectal mucositis. UC is the initial research target that may or may not include the other forms of inflammatory disease in the colon. UC significantly increases the risk of developing colorectal cancer and negatively impacts quality of life. The etiology of UC is unknown but altered intestinal barrier function and production of cytotoxic effector molecules within the mucosal lining of the colon are known to play central roles in the development of UC. The proposed work would investigate and evaluate the ability of a hydrogel form of extracellular matrix (ECM) to restore structure and function of the mucosal lining of the colon in a preclinical UC model. These findings would represent an important contribution to required regulatory filings prior to human studies.
PI Stephen Badylak
Title Development of Tissue Engineered Arterial Grafts
Description: The purpose of this study is to evaluate the effectiveness of TEAGs (cell coated) and uncoated (un-TEAGs) as peripheral blood conduits in a sheep animal model in relation to the following.
TEAGs revascularization in vivo
Source: CR Bard
Term 06/15/2015 – 12/31/2016
Title Evaluation of ECM Hydrogel as a Treatment for Stroke Injury
Description: Products composed of mammalian Extracellular Matrix (ECM) have been regulated as a “device” by the FDA, and these materials have been used as a bioscaffold for the repair and reconstruction of soft tissues for the past 15 years. Work in the Badylak laboratory has shown that such matrix materials, when properly prepared, can minimize fibrous tissue deposition and induce a constructive and functional tissue remodeling response. This constructive response is due, at least in part, to bioactive cryptic peptides created during the process of scaffold degradation. Bioactive properties of these oligopeptides include chemoattraction for endogenous stem and progenitor cells, angiogenesis, and modulation of the innate immune response toward a regulatory and constructive “M2”phenotype.
Title Injectable Engineered Tissue for Cancer Reconstruction
Description: Breast reconstruction relieves physical discomfort and psychological distress following mastectomy for over 90,000 women in the United States annually. The limitations of the two main methods, autologous flap procedures and implant procedures, have driven a search for new reconstructive techniques. Autologous tissue operations are highly invasive with a prolonged recovery and risk for major donor site morbidity. Implant reconstruction avoids a donor wound, but is fraught with problems of scar contracture (20%), displacement (5%), rupture (5% in 5 years), and an overall reoperation rate of 50%. Additionally, both these therapies are poorly suited for the significant number of women with deformities after lumpectomy.