Grant of the Month | April 2013
|PI||David O. Okonkwo, MD, PhD|
|Co-PI||Walter Schneider, PhD|
|Title||High Definition Fiber Tracking Biological Diagnosis of TBI Providing Actionable Clinical Report of Quantified Damage|
Background: There is an urgent, yet unmet demand for a definitive biological diagnosis of traumatic brain injury (TBI) that applies non-invasive methods to pinpoint the location and extent of damage. This project develops and utilizes cutting-edge High Definition Fiber Tracking (HDFT), a technology to quantify TBI induced axonal injury in military and civilian brain injury patients. Current medical imaging (i.e., CT, MRI, DTI, fMRI) rarely visualizes or detects the white matter damage presumed to underlie much of the functional, cognitive, and/or psychological deficits seen following military blast TBI or civilian mild TBI. The goal of the current application is to deliver HDFT, a MRI-based diffusion technology that can provide a definitive biological diagnosis of TBI to aid prognosis and rehabilitation of individual patients.
High Definition Fiber Tracking is a DARPA-supported technology, invented by this group in the last two years, which has been used in the pilot clinical assessment of 53 cases of TBI at the University of Pittsburgh. HDFT overcomes the central challenges that limit the clinical applicability of currently available imaging methods for TBI diagnosis. Preliminary studies have validated the ability of this cutting-edge HDFT to detect white matter damage in the human brain following injury. HDFT quantifies TBI-induced axonal injury in individual patients, without the need for a reference pre-injury scan.
Objectives: This proposal has four objectives that will be completed through the recruitment of 240 acute TBI cases and 60 healthy volunteers. An intake examination and clinical assessment followed by 3T structural MRI and HDFT imaging will be performed on all subjects.
Objective #1: For subjects with HDFT quantitatively similar to healthy controls, determine whether HDFT of 19 major tracts within normal range will be associated with a normal neurologic examination, normal neuropsychological testing, and absence of post-concussion syndrome at 3 and 6 months post-injury.
Objective #2: For TBI subjects with abnormal HDFT, contrast differences in quantitative analysis of HDFT among blast-induced combat TBI, non-blast combat TBI, and civilian TBI. This aim will also determine whether HDFT has sufficient resolution and accuracy to detect white matter damage that DTI has not been able to document.
Objective #3: For subjects with neurologic deficits or post-concussion syndrome, determine whether quantitative analysis of HDFT in the acute phase of 19 major white matter tracts implicated in TBI can document and predict neurologic and neuropsychological deficits at 3 and 6 months post-injury. Statistical analysis of correlation between HDFT assessment and quality of life/neuropsychological outcomes will be performed. This will confirm that neuroimaging of white matter pathways in the acute phase has clinical relevance. The deliverable is an actionable clinical report of quantified damage that will empower treatment teams to employ this technology in the acute phase, aiding in the diagnosis and treatment of TBI patients.
Objective #4: For subjects with edema/hemorrhage on structural imaging in the acute phase, perform a repeat structural MRI and HDFT at 6 months to confirm that HDFT is resilient to the effects of edema/hemorrhage on the analysis. These will be compared against the susceptibility of standard DTI fractional anisotropy-based measurements to edema/hemorrhage.
Study Design: This project is a multi-site clinical trial to assert the clinical utility of a novel, advanced MR imaging technology (High Definition Fiber Tracking) for the clinical detection of white matter injury following TBI. Subjects with an acute history of military or civilian TBI will be recruited at Walter Reed (WRNMMC), Washington Hospital Center, and the University of Pittsburgh Medical Center to undergo HDFT and formal neuropsychological outcomes testing.
Relevance: This technology has been piloted in 53 TBI patients and has been well received in fifteen publications, by clinical treatment teams, and the scientific media. The project team includes leaders in fiber tracking imaging and military and civilian TBI clinical care and research. Military Benefit - with the availability of a definitive biological diagnosis in individual patients using HDFT, many of the thousands of warriors and 1.7 million U.S. civilians who sustain a TBI each year would gain assurance if HDFT confirms that their brain white matter tracts are normal. For those in whom damage is found, the family and the clinical professionals will “see the damage” and be provided with detailed prognoses based on damage to specific tracts, thus facilitating improved diagnosis, prognosis, and treatment of TBI-related damage.
|Source:||Department of the Army -- USMRAA|
|Term||09/30/12 – 09/29/16|
Grant of the Month | March 2013
|PI||Antonio D’Amore, PhD|
|Collaborator||William R. Wagner, PhD|
|Title||Structure-Function Controlled Scaffolds for Improved Soft Tissue Remodeling|
|Summary:||This research plan focuses on conduction on and mechanical stimulation in engineered soft tissues. Only a few soft tissue regeneration attempts have shown enough promise to enter both the clinic and the market, with the vast majority of efforts in this field presently limited to the realm of academic and industrial research laboratories. There is now a shared awareness for the need of a major paradigm shift from a “trial and error” approach to a more rational and effective design of tissue surrogates. In parallel, it has become increasingly evident that the state of the art in our understanding of and ability to control the interactions at the cell-extracellular matrix (ECM) interface is inadequate.
We propose here the use of a Structure-Function Controlled (SFC) electrospun PECUU scaffold to improve the in vivo performance of engineered scaffolds for soft tissue regeneration. More specifically we aim to achieve (1) better organ level functionality (e.g. more physiological echocardiographic/angiographic indicators, regional/static compliance better matching the native tissue), (2) improved micro-structure at tissue level (e.g. level of structural and mechanical anisotropy recapitulating the native tissues), (3) enhanced ECM formation (e.g. higher collagen mass, more mature collagen type). The overall objective of this proposal is to address unanswered questions of critical importance for the field: Can an engineered construct be designed on the basis of criteria involving its microstructure? How much control can we exert on the fabrication processes? Can an improved ECM micro-environment promote constructive remodeling? If so what is the impact on specific in vivo applications? This will be accomplished by leveraging our unique capacity to characterize, fabricate and predict structure function relationships in scaffolds.
|Term||02/01/2013 - 01/31/2014|
Grant of the Month | February 2013
|PI||William Federspiel, PhD, William R. Wagner, PhD , Christian A. Bermudez, MD, James Antaki, PhD|
|Co-PI||Greg Burgreen, PhD|
|Title||Paracorporeal Ambulatory Assist Lung (PAAL)|
|Summary:||Acute and chronic diseases of the lung remain major healthcare problems. Each year nearly 350,000 Americans die of some form of lung disease. Mechanical ventilation provides short-term support for these patients, but longer term support can lead to barotrauma, volutrauma, and other iatrogenic injuries, further exacerbating the respiratory insufficiency. Extracorporeal membrane oxygenation (ECMO) can provide longer term respiratory support but is complex and significantly limits a patient’s mobility. This project will develop a compact respiratory assist device, the Paracorporeal Ambulatory Assist Lung (PAAL), to replace ECMO as a bridge to transplant or recovery in patients with acute and chronic lung failure. The PAAL is a fully integrated blood pump and gas exchange module and is designed for peripheral cannulation (e.g. jugular to femoral) or central cannulation (e.g. right atrium to pulmonary artery and worn on a holster or vest. The PAAL will be designed for longer-term respiratory support (1-3 months before change-out) at 70-100% of normal metabolic requirements, while pumping blood from 2 to 3.5 Liters/min. The specific aims of project are 1) To optimize the design and operational parameters of the PAAL to meet requirements for blood pumping, gas exchange, priming volume, and form factor; 2) To build PAAL prototypes along the design development pathway for bench characterization studies; 3) To improve hemocompatibility of the PAAL by exploring novel molecular Zwitterionic coatings; and 4) To perform acute and chronic animal studies in healthy sheep to demonstrate the in-vivo performance and hemocompatibility of the PAAL device and its interaction with the cardiopulmonary system.|
|Source:||NIH: National Heart, Lung, and Blood Institute|
|Term||02/15/2013 – 01/31/2018|
|Amount||$508,437 (Direct Costs) $3,396,671 (total costs)|
Grant of the Month | January 2013
|PI||David A. Vorp|
|Co-PI||William Wagner and J. Peter Rubin|
|Title||Autologous Stem Cell-Based Tissue Engineered Vascular Grafts|
|Summary:||There are nearly one million aortocoronary bypass, peripheral arterial bypass and arterio-venous access graft procedures performed each year in the US. The limitations of current options, which include fully-synthetic grafts and autologous vein or artery, are well-documented3-5. Readily-available, biocompatible, tissue engineered vascular grafts (TEVGs) have great potential as suitable alternatives. However, to date, only a small number of TEVG approaches have been attempted clinically due to a number of barriers. Our laboratory has developed TEVGs constructed from a novel biodegradable elastomeric scaffold seeded with rat or human adult mesenchymal stem cells (MSCs). While we have demonstrated effectiveness with MSCs from bone marrow and muscle, this exploratory proposal will focus on use of human adult adipose derived stem cells (ADSCs), given their relative ease of isolation and the availability of fat in the patient
population in need.
Our approach in this proposal will consist of our novel methodology to create TEVGs by rapidly and efficiently bulk-seeding a biomimetic scaffold with adult human ADSCs. The TEVGs will be tested in a cost-effective, reliable and hardy rat model which is not immune compromised or immunosuppressed, but yet does not exhibit marked immunological response to xenotransplanted tissue or cells.
In summary, the significance of this work is the identification of what factors affect the successful performance of a human stem cell based TEVG, which would move this technology significantly closer to clinical translation. The primary innovation in this proposal lies in three areas: our unique method of creating a TEVG; the use of a rich and easily obtained source of autologous ADSCs; and the recognition that either toofew ADSCs may be available from a given patient, or that patient age and/or sex may be confounding factors, either of which will affect clinical translation of an ADSC-based TEVG. No other study, to our knowledge, has addressed these critical issues of clinical practicality in the development of a human, stem cell-based TEVG.
Department of Health and Human Services
Budget Period: 01/15/2013 – 12/31/2013
Grant of the Month | December 2012
|PI||Marina Kameneva, PhD|
|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.|
Grant of the Month | November 2012
|PI||C. Bettinger, PhD|
|Co-PI||Kacey Marra and Kris Matyjaszewski|
|Title||Tissue Engineered Muscle Constructs as Bio-mimetic Peripheral Nerve Interfaces|
|Description||The overall objective is to fabricate tissue engineered muscle constructs (TEMC) to be implanted subcutaneously where they will serve as synthetic targets for targeted muscle reinnervation.|
Grant of the Month | October 2012
|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.
The broader significance and importance of this project arise from the project's ability to inform other efforts aimed at engaging disabled veterans in career retraining, or all veterans in obtaining STEM degrees as well as the potential impact on the STEM workforce. This project overlaps with NSF's strategic goals of transforming the frontiers through preparation of an engineering workforce with new capabilities and expertise. Additionally NSF's goal of innovating for society is enabled by creating results and research that are useful for society by informing educational policy and practices.
|Source||National Science Foundation Engineering Education and Centers|
|Term||11/1/12 – 10/31/15|
Grant of the Month | September 2012
|Co-PI||Michael John Becich and Stephen R Wisniewski|
|Title||Sarcoidosis and A1AT Genomics & Informatics Center|
|Description||Alpha-1 antitrypsin deficiency (A1 AT), an autosomal recessive genetic disease that is associated with a variable risk of COPD, and Sarcoidosis, a systemic disease characterized by the formation of granulomatous lesions especially In the lungs, liver, skin, and lymph nodes that leads to a dramatically heterogeneous set of clinical manifestations, differ in etiology and clinicl presentation but share a variable and unpredictable course. To improve disease classification, facilitate biomarker discovery and accelerate advent of novel therapy an integrative approach that combines the results of clinical studies with molecular phenotyping results is required. The Sarcoidosis and A1 AT Genomics and Informatics Center (SAGIC) will facilitate this process by addressing the following objectives for the NHLBI Genomic Research In A1 AT and Sarcoidosis (GRADS) program: 1) Coordination of Clinical Centers activities that include patient recruitment and phenotyping and biospecimen collection. 2) Performance of transcriptome and microbiome analyses of the samples obtained by the Clinical Centers, 3) Data analysis and integration, 4) Dataset preparation for deposit in the NHLBI BloLINCC repository. The objectives will be addressed through two research projects. Project 1: A1 AT microbiome - will address the hypothesis that shifts in the lung microbiome determine the extent of lung involvement In A1 AT and that they are reflected in mRNA and microRNA changes in surrogate tissues, and Project 2: Novel molecular phenotypes in Sarcoidosis - will address the hypothesis that systemic Inflammation as reflected in gene expression changes in PBMC Is indicative of disease extent, microbiome shifts and granuloma molecular networks.|
|Term||05/01/12 – 04/30/15|
Grant of the Month | August 2012
|PI||Rocky S. Tuan|
|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|
|Term||7/24/12 – 6/30/14|
|Amount||$720,766 total costs for 2 years (includes $224,034 of indirect costs for 2 years)|
Grant of the Month | July 2012
|PI||J. Peter Rubin, MD|
|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|
|Description||The goal of this research study is to apply minimally invasive fat grafting to improve pain syndromes at amputation sites and result in improved ability to fit and use a prosthesis. The procedure will be performed on an outpatient basis. We will test two different methods of preparing the fat graft, including a regenerative medicine approach, and measure both physical function and quality of life during a 6 month post-surgical follow-up period. The total duration of participation is approximately 8 months for each subject.|
|Term||09/29/2012 – 03/29/2016|
Grant of the Month | June 2012
|PI||Alejandro Almarza and Stephen F. Badylak|
|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.
The central hypothesis of the proposed work is that constructive remodeling of an ECM scaffold toward a functional TMJ disc occurs as a result of recruitment of multipotential cells to the site of remodeling, modulation of the innate immune response, and that enhancement of the remodeling process can occur with associated mechanical preconditioning. In a focused 4-year study involving two Specific Aims, we will test this hypothesis. The first Specific Aim will determine whether controlled in vitro mechanical loading and seeding with a population of multipotential perivascular stem cells can enhance the ECM remodeling process. The second Specific Aim will compare the in vivo remodeling process of five different xenogeneic ECM constructs: 1) a non-crosslinked ECM scaffold, 2) a chemically cross-linked ECM scaffold, 3) a non-crosslinked cell seeded ECM scaffold, 4) a non-crosslinked, mechanically conditioned ECM scaffold, and 5) a non-crosslinked, cell seeded and mechanically conditioned scaffold. The temporo-spatial time course of remodeling will be determined and the relevance and importance of critical events at 4 separate time points post implantation: 2 weeks, 1, 3 and 6 months post implantation in a pig model of bilateral TMJ meniscectomy will be identified. This work is highly interdisciplinary and will utilize the ECM scaffold expertise of the Badylak laboratory, the mechanobiology expertise of the Almarza laboratory, and the surgical expertise of an accomplished oromaxillofacial surgeon to accomplish the Specific Aims. We have a biostatistician and a veterinary comparative anatomy consultant to complement our team. A clear timeline has been established and the studies are based upon solid preliminary data.
|Source||National Institute of Dental & Craniofacial Research|
|Term||07/01/2012 – 06/30/2013|
|Amount||Year 1 $628,939
Year 2 $628,939
Year 3 $634,550
Year 4 $634,550
Grant of the Month | May 2012
|PI||Fabrisia Ambrosio, PhD|
|Co-PI||Stephen F. Badylak DVM, PhD, MD|
|Title||Mechanical loading as a critical determinant for functional skeletal muscle formation with a biological scaffold|
|Description||Purpose: The purpose of this project is to investigate the effect of mechanical loading on remodeling of bioscaffolds composed of extracellular matrix, when used for skeletal muscle reconstruction.
Background: Technological advancements in body armor are keeping our servicemen and women alive, but limb injuries are exacting a high toll. In the case of volumetric muscle and tendon loss, there is a paucity of effective therapeutic interventions to restore lost function. The use of biologic scaffolds comprised of extracellular matrix (ECM) holds great promise for reducing disability following these injuries. Although there is mounting evidence that mechanical loading plays an important role in the functional incorporation of implanted ECM, there is little evidence to guide the rationale design of targeted and specific post-operative protocols.
Methods: Four to 6 month old female wild type mice will be divided into 3 groups (n=10 each): 1) Injury + normal cage activity (control group), 2. Injury + hindlimb unloading (HU) and 3. Injury + treadmill running (TM).
All animals will receive ECM scaffold implantation at the time of muscle injury. We have decided not to include non-implanted control groups for 2 primary reasons: 1) the study will be evaluating the effect of loading on remodeling of the scaffold, not remodeling of skeletal muscle per se; and 2) extensive studies have already clearly demonstrated a beneficial effect of ECM implantation for skeletal muscle remodeling, when compared to controls.
Injury: A 10mm segment of the gastrocnemius will be excised to create a volumetric muscle loss.
Hindlimb unloading (HU): HU will be performed as previously described (McCarthy et al, 1997).
Treadmill running (TM) : Animals in the TM group, will complete a running protocol 3x/week for up to 30 days.
Outcome variables: Thirty or 90 days after surgery, animals will complete in situ contractile testing to quantify strength, resistance to a fatiguing protocol, and recovery from fatigue. Histological variables will include: myofiber regeneration index, myofiber area, number of embryonic myosin heavy chain positive cells, vascularity and fibrosis.
Expected Results: We anticipate that the addition of a running protocol following ECM implantation will result in a significantly increased functional strength recovery and increased fatigue resistance, when compared to normal cage activity and HU counterparts. We further anticipate that improvement in functional capacity will be positively correlated with an increased histological evidence of regeneration.
Relevance to Rehabilitation: With the ever-increasing translation of regenerative medicine approaches to the clinic, there is a concurrent increased need to better understand how rehabilitation may play a role to maximize the therapeutic benefit of these therapies. Completion of this study will provide important information to guide the development of post-operative rehabilitation programs following ECM implantation into severely injured skeletal muscle.
|Source||National Skeletal Muscle Research Center at the University of California, San Diego|
Grant of the Month | April 2012
|PI||J. Peter Rubin|
|Co-PI||Vijay Gorantla, Kacey Marra, Albert Donnenberg, Gretchen Haas|
|Title||Targeted Immunomodulation and Tissue Repair with MSCs and ASCs|
|Description||The major goal of this project is to develop novel treatment protocols that will enhance immunotolerance after composite tissue allotransplantation using stem cells obtained from autologous adipose tissue.|
|Source||ARM V Project #2|
|Term||09/01/11 – 07/31/13|
|Amount||Direct: $567,160 Indirect: $232,840 Total: $800,000|
Grant of the Month | March 2012
|Co-PI||Nikolai M. Krivitski, Tim Maul|
|Title||Bedside Monitor to Quantify Cardiac Shunt Flow in Newborns and Small Children|
|Description||There is no current technology for routine measurement of shunt flow (Qp:Qs – ratio of pulmonary to systemic blood flow) in newborns and small children in the intensive care unit (ICU). Current methods either require placement of highly invasive catheter or depend on assumptions, leading to risky and less accurate measurement of shunt flow. Timely and accurate quantitative assessment of Qp/Qs permits successful pharmacologic, ventilator or fluid therapy or in time surgical intervention. Hence routine measurement of shunt flow is vital in the management of critically ill newborn and small children with cardiac defects.
This SBIR grant will allow us to develop mathematical models and algorithms accounting for various shunts, clinical and physiological conditions. These will then be implemented into a monitor that could be used clinically at the bedside in a non-invasive manner with patients having in situ arterial and central venous catheters. The approach is based on well-established indicator dilution principles using innocuous isotonic saline as an indicator. These factors make the proposed monitor eminently suitable for used with neonatal and pediatric ICU patients. Main objectives of this proposal include –
Successfully accomplishing Phase-I goals will test the feasibility of the proposed approach and guide further research to develop and clinically validate the first of its kind Bedside monitor for quantitative measurement of shunt flow in critically ill newborns and small children.
|Term||09/01/11 – 07/31/13|
|Amount||$60,000 total in Year 1: $50,000 total in Year 2|
Grant of the Month | February 2012
|PI||Stephen F. Badylak|
|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.|
|Term||01/01/12 – 12/31/12|
Grant of the Month | january 2012
|PI||David Hackam, MD, PhD and John March, PhD|
|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.
Based upon his discovery that expression and signaling activity of a molecular “switch” called toll-like receptor 4 (TLR4) was elevated in the intestine of human infants with NEC and that mice lacking TLR4 were protected from the development of NEC, Hackam proposed as a 2008 Hartwell Investigator to identify novel chemical compounds for the treatment of the disorder. He deployed a strategy to identify specific inhibitors of TLR4 signaling in the intestine utilizing high throughput computer-aided screening of chemical libraries, combined with whole animal screening. He successfully identified 67 novel TLR4 inhibitors, with one compound particularly effective in reducing the severity of experimentally induced NEC in mice. He is now focused on confirming the mechanism of action of the compound, while performing chemical modification to improve it as a powerful new treatment for the management of NEC in neonates.
|Source||The Hartwell Foundation|
|Amount||$543,571 in direct costs over three years|