Grant of the Month 2012

Co-PI Jonathan Waters, MD

Title Blood Filtration System for the Treatment of Severe Malaria Patients

Description The overall goal of the proposed project is to develop a novel blood filtration system, mPharesis™, for the treatment of severe malaria patients. The World Health Organization estimates that each year approximately 300 million malaria episodes occur globally resulting in nearly one million deaths, 85% of which are children. The majority of deaths are caused by severe malaria. Severe malaria is a leading cause of pediatric morbidity, hospitalization, and mortality in Sub-Saharan Africa. It is responsible for more than 200,000 cases of fetal loss and more than 10,000 maternal deaths annually. Severe malaria also occurs in 5% of the nearly 30,000 imported malaria cases by travelers from endemic areas. Even when managed aggressively with intravenous antimalarial drugs (artesunate or quinine) mortality rates range between 10%-22%, and as high as 40% for the most complicated cases. Blood exchange transfusion (ET) and erythropheresis (EP) have been effectively used to significantly accelerate the clearance of malaria infected red blood cells from circulation. A large body of medical studies has shown that these treatments if available are beneficial. However, the current systems used to perform these therapies are not engineered to selectively separate the infected cells from the non infected. Thus, to remove these toxic infected cells the entire patient’s blood is disposed – wasting in most cases between to 70%-95% of the healthy blood. This inefficacy results in larger than needed consumption of donor blood. Consequently, ET and EP therapies remain a prerogative of industrialized nations. This is precisely the motivation for developing the proposed mPharesis™ system – a system that will allow the removal of toxic infected red blood cells from the patient’s blood circulation with minimal or no use of donor blood. The mPharesis™ filter operates by targeting these cells’ unique (and well-known) magnetic properties. This system represents the first medical device of its kind to employ magnetic separation technology to clear these toxic cells from circulation. In this SBIR Phase 1 effort, we will complete the design verification of a first-generation mPharesis™. This objective will be accomplished by entailing experimentation and numerical simulation, to achieve a prototype optimized for high-throughput, high separation efficiency, and low residual parasitic load. In specific, the successful completion of this Phase 1, will yield a working prototype, suitable for animal testing (in Phase 2), capable of reducing the parasitic load (40%) to less than 1.0% within a time period of 3-4 hours, and demonstrating satisfactory hemocompatibility. mPharesis™ is intended for those millions of children and adults who have already reached the severe malaria stage, and will provide a life-saving measure for cases that do not respond well to conventional treatments — as too often occurs in the advanced severe stages of this deadly disease. Read More

Co-PI Kacey Marra and Kris Matyjaszewski

Title Tissue Engineered Muscle Constructs as Bio-mimetic Peripheral Nerve Interfaces Read More

Co-PI Mary Goldberg

Title Experiential Learning for Veterans in Assistive Technology and Engineering

Description This engineering education research project will investigate the effectiveness of several different interventions designed to retain disabled veterans in engineering degree programs. A comparative study that looks at a range of characteristics related to retention in engineering will be done, and the results analyzed using the theoretical frameworks of social cognitive career theory and self-efficacy. Read More

Co-PI Michael John Becich and Stephen R Wisniewski

Title Sarcoidosis and A1AT Genomics & Informatics Center Read More

Title 3-D Osteochondral Micro-tissue to Model Pathogenesis of Osteoarthritis

Description Osteoarthritis (OA), the most prevalent form of arthritis, affects up to 15% of the adult population and is principally characterized by degeneration of the articular cartilage component of the joint, often with accompanying subchondral bone lesions. Understanding the mechanisms underlying the pathogenesis of OA is important for the rational development of disease modifying OA drugs (DMOADs). While most studies on OA have focused on the investigation of either the cartilage or the bone components of the articular joint, the osteochondral complex represents a more physiologically relevant target as the disease ultimately is a disorder of osteochondral integrity and function. In this application, we propose to construct an in vitro 3-dimensional microsystem that models the structure and biology of the osteochondral complex of the articular joint. Osteogenic and chondrogenic tissue components will be produced using adult human mesenchymal stem cells (MSCs) derived from bone marrow and adipose seeded within biomaterial scaffolds photostereolithographically fabricated with defined internal architecture. A 3D-printed, perfusion-ready container platform with dimensions to fit into a 96-well culture plate format is designed to house and maintain the osteochondral microsystem that has the following features: (1) an anatomic cartilage/bone biphasic structure with a functional interface; (2) all tissue components derived from a single adult mesenchymal stem cell source to eliminate possible age/tissue type incompatibility; (3) individual compartments to constitute separate microenvironment for the “synovial” and “osseous” components; (4) cell-seeded envelopes to represent “synovium” and “endothelium”; (5) accessible individual compartments that may be controlled and regulated via the introduction of bioactive agents or candidate effector cells, and tissue/medium sampling and compositional assays; (6) compatibility with the application of mechanical load and perturbation; and (7) imaging capability to allow for non-invasive functional monitoring. The robustness and physiological relevance of the osteochondral microsystem will be tested on the basis of: (1) structural integrity and potential connectivity of the separate “synovial” and “osseous” compartments; (2) maintenance of distinct cartilage and bone phenotypes and the development of a histologically distinct osteochondral junction or tidemark; (3) applicability and tissue responsiveness to mechanical loading; and (4) imaging and analytical capabilities. The consequences of mechanical injury, exposure to inflammatory cytokines, and compromised bone quality on degenerative changes in the cartilage component will be examined in the osteochondral microsystem as a first step towards its eventual application as an improved and high-throughput invitro model for prediction of efficacy, safety, bioavailability, and toxicology outcomes for candidate DMOADs. This grant is held in the Department of Orthopaedic Surgery, University of Pittsburgh.
Source National Institutes of Health – National Center for Advancing Translational Sciences Read More

Co-PI Spencer Brown, PhD; Rory Cooper, PhD; Albert Donnenberg, PhD; Vera Donnenberg, PhD; Gretchen Haas, PhD; Kacey Marra, PhD; Jonathon Pearlman, PhD; Sara Peterson, MBA, CPO; Aaron Wyse, MD
Title Autologous Fat Grafting for Treating Pain at Amputation Sites: A Prospective Randomized Trial Read More

Co-PI Tim Maul

Title A Regenerative Medicine Approach for TMJ Meniscus Restoration

Description This proposal seeks support to investigate the use of a biologic scaffold composed of extracellular matrix (ECM) as an inductive scaffold for the in vivo generation of a temporomandibular joint (TMJ) meniscus. Strong pilot studies indicate that this inductive template can stimulate the endogenous formation of a fibrocartilaginous disc that closely mimics the composition, structure, and mechanical properties of native disc material. Approximately 3% to 4% of the population seeks treatment for TMJ disorders; 90% of which are women. Approximately 70% of patients with TMJ disorders suffer from disc displacement; a fact that identifies the TMJ disc as a critical component in the cascade of events that lead to TMJ pathology. Spontaneous TMJ disc regeneration in vivo does not occur, and subsequent articulate surface degeneration can lead to the need for total joint replacement with marked negative consequences upon the quality of life. Development of a replacement disc would protect articulate joint surfaces, mitigate morbidity, and obviate the need for subsequent joint replacement. Read More

Co-PI Stephen F. Badylak DVM, PhD, MD

Title Mechanical loading as a critical determinant for functional skeletal muscle formation with a biological scaffold Read More

Co-PI Vijay Gorantla, Kacey Marra, Albert Donnenberg, Gretchen Haas

Title Targeted Immunomodulation and Tissue Repair with MSCs and ASCs Read More

Co-PI Nikolai M. Krivitski, Tim Maul

Title Bedside Monitor to Quantify Cardiac Shunt Flow in Newborns and Small Children Read More

Co-PI William R. Wagner

Title Optimization of Surgical Mesh Materials

Description This project involves a combination of in vitro and preclinical in vivo methods to develop and evaluate biologic surgical mesh materials. The work involves a combination of well described benchtop assays and animal models which can evaluate in vivo biocompatibility for novel surgical mesh materials. Read More

Title Generation of an Artificial Intestine for the Treatment of Short Bowel Syndrome in Children

Description The clinical condition in which the body is unable to absorb food after significant loss of the intestine is called short bowel syndrome (SBS). While its true incidence is unknown, in the United States the condition affects over 5000 children, with an estimated 15,000 older patients requiring long-term home parenteral nutrition. SBS can be caused by loss of large portions of functioning intestine – such as occurs typically as a consequence of necrotizing enterocolitis (NEC), Crohn’s disease, or as a result of a birth defect in which the intestines do not develop normally. Because food cannot be adequately absorbed by the shortened intestine, nutrients must be administered directly into the circulation through a vein. Although this approach can supply adequate calories, children who receive nutrition directly into the circulation commonly suffer from intravenous catheter infections and severe liver toxicity, with mortality around 30%. Only about one third of patients with SBS can expect to be weaned from parenteral nutrition. The majority of children with short bowel syndrome require intestinal transplantation and if toxicity from the administered nutrition is severe enough, liver transplantation, as well. While the outcome after intestinal transplantation is improving, this procedure is limited by a lack of suitable donors and complications from immunosuppressive therapy. To address the difficulty of managing short bowel syndrome in children, Hackam and March propose constructing an artificial intestine using cultured intestinal stem cells from the recipient’s intestine that can grow on a synthetic 3-dimensional bioscaffold. Read More