Yearly Archives: 2011

Co-PI Alan Russell and Mark Yazer

Title Continuous Red Blood Cell Production (Phase II)

Description A ready supply of safe and effective red blood cells is a critical component in the treatment of battlefield and civilian trauma. Conventional approaches to this challenge center around voluntary donation of whole blood, testing, processing, extended storage, shipping and therapeutic transfusion of blood or fractionated components. Many of the steps in this conventional approach are prone to error, are inefficient, and in some pathologies can be ineffective. We intend to transform this conventional approach by developing methods and systems to produce erythrocytes (and at a future time, other blood components) from readily available and expandable human non-embryonic progenitor cell populations in a safe, effective, robust and limited footprint in vitro manufacturing system.

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Co-PI William Wagner

Title Stem Cells for Corneal Engineering

Description The proposed research builds upon the pioneering work from the laboratory of Dr. Wagner in developing novel degradable biomaterials for a variety of soft tissue applications. Dr. Wagner’s group links polymer chemists, bioengineers and surgeons in this effort, and the proposed research takes advantage of this expertise. They have synthesized, characterized and processed a variety of biodegradable polymeric biomaterials and evaluated their performance for treating tissue insufficiency in vivo. The thermoplastic elastomeric materials proposed in this project have been synthesized and evaluated in the rat model in several different locations. Most of this in vivo work has involved the cardiovascular system for cardiac wall and blood vessel scaffolding. Other studies have evaluated application of the material in the abdominal wall and as subcutaneous implants for first level biocompatibility assessments. Dr. Wagner and Dr. Funderburgh have been collaborating over the past several years to begin translation of the Wagner lab’s materials expertise to the ophthalmic area.

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Title Innovative In Vivo-Like Model for Vascular Tissue Engineering

Description The shortage of donor organs for transplantation suggests a need to develop engineered tissue transplants. Proper in vitro vascularization, a key prerequisite for the development of functional engineered tissue constructs, would enable adequate mass exchange, gas supply, and functional mediator exchange in high-density tissue cultures. The impact of physical and mechanical factors supporting endothelial differentiation has been investigated, but not in three-dimensional (3D) co-culture models. We propose to address this gap in cellular models and technology model systems, by analyzing neo-vascularization in an organ-like environment in vitro designed to mimic human organogenesis and that can vary physical conditions, such as flow- and pressure changes in the rhythm of the heart rate.

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Co-PI Stephen Badylak, Marc Malandro

Title Coulter Translational Research Award in Biomedical Engineering

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Title Basic and Clinical Studies of Cystic Fibrosis: Ex Vivo Model of Cystic Fibrosis

Description Cystic fibrosis (CF) affects approximately 30,000 individualsin the United States, causing an accumulation of thick, sticky mucus that adversely impacts normal mucociliary clearance. The lack of proper clearance predisposes patients to chronic pulmonary infections, injury to the conducting airways in the form of bronchiectasis and bronchiolitis obliterans, and ultimately can lead to respiratory failure. CF is the leading diagnosis in children that require lung transplantation. Considerable resources have been applied to the study of CF with the hope of developing a treatment or cure, but progress has not been as rapid as anyone would desire. In the current research environment, the only way to determine if a treatment strategy has an effect on airway function is to move from in vitro studies to clinical studies in patients, which poses a very high bar to acceptance. The primary purpose of this proposal is to develop a humanized ex vivo model of the CF airway as a means to investigate the effect of new therapies on function, including ion transport and mucociliary clearance. A bioreactor has been developed that is capable of simulating the conditions in the trachea during respiration. With the expertise from the P30, decellularized tracheas will be seeded with airway epithelial cells from patients with and without cystic fibrosis and the culture conditions will be optimized. Then testing strategies will be developed to assess airway epithelial cell function without disrupting the trachea construct and the impact of various known medical treatments on the cultures will be tested. Finally, airway tissue will be obtain from patients with and without CF, the tissue will be decellularized and seeded with airway epithelial cells to begin to understand if the composition and structure of airways in CF contributes to the dysfunction. The end result of this work will be a robust testing platform that will enable functional testing of the airway which will allow a deeper understanding of the pathogenesis of CF and more robust testing of new drug therapies.

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Co-Investigators Rick Koepsel, Alan Russell, Tom Gilbert

Title Nanotechnology Based Infection Control for Ventricular Assist Devices

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Co-Investigators William Wagner

Title Non-invasive Monitoring of Tissue-Engineered Construct by US Elasticity Imaging

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Title The Role of mTOR (mammalian Target Of Rapamycin) Complex 1 and 2 in liver regeneration and ectopic liver organogenesis

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Co-Investigators Richard Koepsel

Title Miniature Biofuel Cell from Gold Microfiber Electrodes

Description Evolving research on implantable sensors, drug-delivery systems and other power consuming implantable devices like pacemakers and insulin pumps requires the matching development of power sources that can be used together with the implantable device. A great deal of research performed on miniature, lightweight, long-lived batteries resulted in the development of the small lithium ion battery [1]. The common battery is an energy source that contains reacting chemicals securely encased in an impermeable cell, and provides only the electrical leads to connect to devices. Current lithium iodide pace maker batteries have an open circuit voltage of 2.8 V, weigh about 13 g and have a relatively large volume of 5-8 ml. [2] Cardiac pacemaker battery design poses a number of special challenges including: the development of biocompatible materials; prevention of corrosion; preventing leakage of the contents; ensuring high reliability; and accurate determination of the end of the battery life. Many of these concerns and many of the inherent risks involved in battery replacement could be alleviated with a longer lasting biomimetic power source.

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Co-Investigators Marina Kameneva

Title Drag-reducing polymers to curb breast cancer metastasis

Description Adhesion of circulating tumor cells to microvascular endothelial cells is key for extravasation of tumor cells and therefore an important step for tumor metastasis. There is growing evidence that systemic inflammation facilitates adhesion of circulating tumor cells to endothelial cells hence promoting metastasis and progression of cancer. It has been hypothesized that leukocytes enhance attachment of tumor cells to endothelial cells by creating formation of a tripartite linkage between these three different cell types. Presence of leukocytes in the tumor microenvironment also leads to local release of cytokines that further promotes junctional disruption of endothelial cells and extravasation of tumor cells. Current strategies to inhibit extravasation which involve molecular targeting of either a single adhesion receptor on tumor cells or a specific signaling pathway are therapeutically inefficient because of involvement of multiple adhesion receptors and signaling pathways in the extravasation process. In complete contrast to these currently envisioned strategies, we proposed a conceptually novel paradigm that hemodynamic perturbation that inhibits attachment of inflammatory cells to endothelial cells is an efficient way to impair tumor cell attachment to endothelium thereby reducing extravasation and metastasis. Systemic administration of so called drag reducing polymers (DRP – long-chain viscoelastic polymers that are non-toxic and blood-soluble) at nanomolar concentrations was shown to reduce/eliminate the near-wall cell-free layer naturally existing in microvessels (Fåhraeus effect) and to increase blood flow in microcirculation. DRP-induced occupation of the near-wall space by red blood cells and increasing of near-wall shear rates may inhibit leukocyte rolling and attachment to blood vessel wall which can drastically reduce inflammatory responses (demonstrated in animals implanted with biodegradable scaffolds) and transendothelial migration of tumor cells. We therefore propose a working postulate that “systemic administration of DRP is a novel interventional approach to reduce extravasation and metastasis of tumor cells” and this hypothesis will be tested by

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Co-Investigators William Wagner, Marina Kameneva, Steve Webber, Peter Wearden

Title Pumps for Kids, Infants and Neonates (PumpKIN) Preclinical

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Title Biodegradable, Thermoresponsive Hydrogels to Treat Ischemic Cardiomyopathy

Description Cardiac failure incurs a major economic and social burden on the United States populace, while also providing a distinct technical challenge since options for treating this condition remain highly limited. In ischemic cardiomyopathy ventricular wall thinning is coupled with dilation of the ventricular cavity. This remodeling process is associated with elevated ventricular wall stress that positively drives the thinning and dilation process towards end-stage heart failure. In the proposed work we will create novel designs for injectable biomaterials to bulk the thinning, post-infarct cardiac wall, reducing elevated wall stress, and potentially improving cardiac remodeling outcomes. The design objectives include synthesizing materials with tensile properties suitable for reducing wall stresses, degradation properties that maintain the hydrogel in the infarcted wall for a period of months during the remodeling process, and drug delivery properties that allow the controlled release of multiple growth factors that may stimulate beneficial cardiac remodeling. We will evaluate 3 distinct hydrogel designs with increasing complexity, utilizing both rat and porcine models of ischemic cardiomyopathy and a minimally invasive robotic technology (the HeartLander device) designed to effectively deliver the targeted hydrogel injections. The project specific aims are to:

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