Title ARM-IV Postdoctoral Program (Four Positions)
Description 1. “Rational Synthesis of Triggerably-Dissolvable Materials for Minimally Invasive Removal of WoundCAP Delivery Devices”
Mentors: Steven Little, Ph.D. and William Wagner, Ph.D.
Objective: The ultimate objective is to develop a robust, hollow fiber-based system (WoundCAP) to deliver regenerative growth factors to a wound site while including the means for minimally invasive removal/dissolution of the delivery system. We hypothesize that the resulting hollow fibers wound cap will have robust mechanical properties to maintain stable structures, but will dissolve rapidly upon application of a trigger, either a temperature change or enzyme solution injection.
Title A Multi-Center Group to Study Acute Liver Failure in Children
Co-Investigators Yoram Vodovotz
Description Our goal is to improve short- and long-term outcomes for pediatric acute liver failure (PALF) through a better understanding of patient phenotypes, reassessment of risk classifications, and associating early events to outcome at one year. We will integrate two research efforts (Vodovotz-3UO1DK-072146-05S1 and Roberts-1R21DK084201-01) currently collaborating with the PALF Study Group (NIH/NIDDK UO1 DK072146-05) which are (1) modeling PALF as a complex biological system using physiological and inflammatory biomarkers and (2) developing models to represent the liver transplant (LT) decisions in PALF. To examine our hypotheses that clinical, biochemical, genomic, proteomic, metabolomic, immunologic, and cytokine analyses in PALF can be used to accurately define phenotypes that respond favorably to directed therapy (e.g., immunomodulation) as well as predict disease progression, including potential for spontaneous recovery or risk of death, all of which will provide a platform on which computer/informatics-based (e.g., in silico) studies can inform the design and conduct of clinical trials, and evaluate the impact of therapeutic decisions, including LT; we propose these Aims: Aim 1: To comprehensively characterize PALF phenotypes utilizing traditional clinical, biochemical, diagnostic, and management profiles supplemented by immune, inflammatory and liver regeneration markers to identify factors that explain variations in outcomes for PALF phenotypes. Outcomes include survival, LT, neurocognitive function, health-related quality of life (HRQOL), depression and post-traumatic stress disorder (PTSD) 6 months and 1 year after enrollment. Aim 2: To model the dynamics of PALF within and between distinct phenotypes using serially collected clinical, physiological, and biomarker data. Statistical modeling techniques will be augmented with models used to represent complex biological systems to more accurately reflect the dynamic nature of PALF. The data and models will be utilized to create a computer-based or “in silico” analog of PALF to simulate interventional studies and to assess treatment, including LT decision processes and to estimate the impact of improved decision-making on organ allocation.
PI Thomas Gilbert
Title Cardiac Remodeling with Organ Specific Extracellular Matrix Scaffolds
Co-Investigators Kimimasa Tobita, Stephen Badylak
Description Improved materials for cardiac reconstruction of congenital defects and heart failure are needed. Current surgical approaches for cardiac reconstruction utilize synthetic materials that slow the progression of disease, but do not provide any contractile function and do not have the ability to grow with the patient. Recently, porcine urinary bladder matrix (UBM) has been used to repair myocardial tissue. The remodeled UBM contributed to regional function in both canine and porcine models, but did not fully restore myocardial tissue. Cardiac extracellular matrix (C-ECM) may promote faster reconstruction of functional tissue by providing a scaffold with a composition and architecture similar to the tissue that it is intended to replace. The proposed study will determine the morphologic and functional differences in cardiac remodeling after repair with C-ECM, UBM, and Dacron patches. Furthermore, the study will include analysis of the recruitment and fate of bone marrow derived progenitor cells at the site of remodeling.
An experienced interdisciplinary team consisting of biomechanical engineers, tissue engineers, physicians, and pathologists has been assembled to conduct these studies. A timeline for completion of these studies and quantitative criteria for success are provided.
PI Kacey Marra
Title 3D Culture of Adipose Tissue for Screening Obesity-related Drugs
Co-Investigators Joerg Gerlach, J. Peter Rubin, Donna Stolz
Description We have developed a novel, 3D bioreactor technology that permits the long-term culture of adipocytes, which is not possible using traditional 2D cell culture methods. In this study, we will utilize our technology to rapidly and effectively screen the effects of drugs on human adipose tissue function. We will examine the function of adipocytes in both obese and non-obese patients. One of the parameters we will study is cytokine/adipokine expression. With the bioreactor technology, we are able to rapidly and easily analyze daily expression of cytokines in the media. New drugs may target cytokine expression of adipocytes. It has been shown that involved cytokine behavior in obesity includes the increased expression of, but not limited to: MCP-1 (monocyte chemotactic protein-1, which can recruit macrophages to adipose tissue), TNF-α (tumor necrosis factor-α, a pro-inflammatory mediator secreted by macrophages), and IL-8 (interleukin-8, a pro-inflammatory cytokine secreted by macrophages). Also of interest is the expression of anti-inflammatory cytokines, such as IL-10 (interleukin-10). While these mediators have been examined using human and murine adipose tissue in 2D in vitro culture, improved experimental systems are necessary to allow the development of high throughput assays for drug discovery. Therefore, the specific aims of this proposal are to: 1) Isolate and characterize human adipose-derived stem cells from both male and female patients, age 40-60 years, (non-obese, vs. obese patients); 2) Develop a novel, multi-compartment, hollow fiber 3D perfusion bioreactor technology for ASC culture in 3D bioreactor; 3) Utilize the 3D perfusion bioreactor system as a tool to study the effects of drug therapies on adipose function. In summary, cell-cell contact in a 3D culture system mimicking natural adipose tissue represents an improvement over current petri-dish technologies aimed at developing high throughput assays for drug discovery.
Source The National Institutes of Diabetes and Digestive and Kidney Diseases
Description This collaborative research and development effort involves the characterization of various forms of extracellular matrix, especially porcine dermal derived extracellular matrix, for development and use as a biologic scaffold for pelvic floor reconstruction and general surgical use. The effort characterizes and identifies novel biomaterials for general surgical applications; particularly pelvic floor reconstruction and hernia repair. We will apply principles of regenerative medicine to principles of general surgery.
PI Alan J. Russell, Stephen F. Badylak, J. Peter Rubin, Bernard J. Costello, Prashant N. Kumta, Charles Sfeir, Paul Kemp
Title Limb Salvage and Regenerative Medicine Initiative
Co-Investigators Thomas Gilbert
Description This program will advance technologies that return wounded personnel to active duty, restore their limb, muscular, and skin form or function, and assist them in reclaiming independence, dignity, and self-confidence in the tasks of daily living. The program will fund rapid research, development and validation of innovative technologies to improve the clinical outcome of burn and blast injured personnel. Technology refers to integrated systems based on combinations of hardware, software, pharmaceuticals, biologics, and surgical methods. This initiative will advance medical technologies from their existing levels of maturation, through FDA trials and approval, to significantly improve upon current standard treatments for use by the Department of Defense, Veteran’s Administration, public health, and commercial health systems.
Description Regenerative medicine approaches for the reconstitution of missing or injured tissues and organs involves the use of scaffolds, cells, and bioactive molecules. The use of biologic scaffolds seeded with cells is a common approach and several applications have been successfully translated to clinical medicine including lower urinary tract, gastrointestinal tract, musculotendinous, and dermal skin regeneration. The principles that guide tissue remodeling and regeneration are only partially understood but the influence of biomechanical loading upon the remodeling process is accepted as an important variable. However, there is an almost complete absence of systematic, quantitative studies to determine the effect of this controllable factor upon tissue remodeling, especially tissues with a smooth muscle wall component.
Title Anaerobically stored red blood cells with extended shelf-life
Description As part of the overall project, the University of Pittsburgh, McGowan Institute of Regenerative Medicine under the leadership of Dr. William Federspiel, will develop the conceptual design for the Oxygen Depletion Device (ODD) for NHSi’s Hemanext Anaerobic Storage Platform (HASP) red blood storage system.