ANN ARBOR, MI, United States
ANN ARBOR, MI, United States

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Patent
University of Michigan and Innovative Biotherapies, Inc. | Date: 2010-06-30

The present invention relates to systems and devices to treat and/or prevent inflammatory conditions within a subject and to related methods. More particularly, the invention relates to systems, devices, and related methods that sequester leukocytes and/or platelets and then inhibit their inflammatory action.


Patent
University of Michigan and Innovative Biotherapies, Inc. | Date: 2010-06-30

The present invention relates to systems and devices to treat and/or prevent inflammatory conditions within a subject and to related methods. More particularly, the invention relates to systems, devices, and related methods that sequester leukocytes and/or platelets and then inhibit their inflammatory action.


Patent
University of Michigan and Innovative Biotherapies, Inc. | Date: 2011-04-15

The present invention relates to systems and devices to treat and/or prevent inflammatory conditions within a subject and to related methods. More particularly, the invention relates to systems, devices, and related methods that sequester leukocytes and/or platelets and then inhibit their inflammatory action.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 588.70K | Year: 2015

DESCRIPTION provided by applicant The Problem Cardiovascular disease is the leading cause of death in the Western world In the US nearly coronary artery bypass surgeries are performed annually with an estimated of these using the technique of cardiopulmonary bypass CPB CPB patients experience complications many of which are considered to be due to the activation of leukocytes LE which can result in systemic inflammatory response syndrome SIRS The Product The Leukocyte Modulator L MOD is based on biomimetic membrane device BMD platform technology that has been shown to alter the state of systemic LE When the BMD is placed in a citrated extracorporeal blood circuit LE are transiently sequestered in the low ionized calcium environment within the BMD and released in an altered state back to the circulation The L MOD will be developed specifically to modulate the LE activation associated with CPB thereby mitigating the associated inflammatory response Innovation Previous approaches to block SIRS associated with cardiac surgery including use of pharmacologic agents operative techniques improved biocompatibility and LE depleting filters have failed to meet clinical endpoints The L MOD is the application of BMD technology to CPB associated SIRS and represents an innovative therapy option The goal of this proposal is to demonstrate efficacy of the L MOD in ameliorating the inflammatory response and the leukocyte mediated tissue damage that is associated with use of CPB during cardiac procedures Long Term Goal This proposal details the initial steps to assess the L MOD as an effective adjunct therapeutic device to be used in conjunction with current CPB clinical protocol Phase I Hypothesis L MOD therapy will effectively reduce LE activation minimizing SIRS and accompanying tissue damage resulting from CPB Specific Aim Confirm a study protocol that results in a robust CPB associated SIRS using a pig model of cardiac surgery with CPB Specific Aim Compare the SIRS and LE induced tissue damage resulting from cardiac surgery and CPB with and without including L MOD therapy using the developed model Phase II Objective Phase II will include survival studies in which the ability of LMOD to protect agains organ damage will be evaluated in recovered animals at h with an emphasis on evaluating the safety and efficacy of L MOD therapy for limiting activated innate immune system mediated tissue damage occurring in response to on pump CPB in patients undergoing cardiac surgery Commercial Opportunity The LMOD is inexpensive and easy to distribute Value will be realized in reduced health care cost from CPB complications PUBLIC HEALTH RELEVANCE The use of cardiopulmonary bypass CPB during corrective heart surgeries elicits a systemic inflammatory response syndrome SIRS that is associated with bleeding disorders and multiple organ dysfunctions in the post operative period Leukocyte activation a major component of this immune reaction contributes to the vascular dysfunction oxidative stress and organ injury resulting from leukocyte infiltration into tissues The leukocyte modulator L MOD is a biomimetic membrane device designed for use within the extracorporeal blood circuit during CPB and was developed to modulate leukocyte activation thereby mitigating this inflammatory response Clinical trials using this technology have demonstrated as much as a reduction in mortality and a faster return of lung and kidney function in patients with SIRS and multiple organ failure resulting from sepsis In this proposal pre clinical animal model of cardiac surgery with CPB will be used to assess the ability of L MOD therapy to ameliorate the inflammatory response and reduce leukocyte mediated organ injury arising from CPB surgery


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 655.21K | Year: 2015

DESCRIPTION provided by applicant Cardiovascular disease is the leading cause of mortality in the US accounting for of all deaths Chronic Heart Failure CHF is now understood to be a multi system disease process which involves not only the cardiovascular system but also the renal neuroendocrine and immune systems There is no effective therapy currently available to treat the most severe subset of CHF patients with acute decompensated HF An unconventional approach to reduce the cardiodepressant effects associated with the chronic inflammatory state of CHF may provide a breakthrough therapy for this disorder This proposal will evaluate the efficacy of an immunomodulatory device in a canine CHF model to identify opportunities for translation to clinical applications and eventual commercialization The Product The Biomimetic Membrane Device BMD is an immunoregulating extracorporeal fiber membrane device targeted to modulate the cardiodepressant effects that are associated with CHF BMD is a platform technology focused on immunomodulation of the acute and chronic inflammation associated with acute and chronic organ dysfunction BMD polysulfone fibers selectively sequester activated systemic leukocytes as they flow through the fiber casing via an extracorporeal circuit In preliminary studies the BMDCHF has shown promising therapeutic benefit in a canine model of CHF In novation In regard to current HF therapeutic strategies the BMDCHF is a totally different innovative approach to treat CHF Rather than utilizing small pharmacologic molecules to improve myocardial contractility the BMDCHF acts as an immunomodulatory device to dampen the cardio depressant effects of the chronic pro inflammatory state of CHF Long Term Goal This proposal will provide proof of concept for impact of the BMDCHF on CHF for up to weeks post therapy Phase I Hypothesis The planned experiments will demonstrate improvement of cardiovascular performance after multiple hour BMDCHF therapy sessions in a canine model of CHF Aim Assess impact of x hour BMDCHF sessions in a canine model of CHF at hours post therapy Aim Assess BMDCHF therapy in a canine model of CHF at and weeks post therapy Phase II Objective The Phase II plan will assess BMDCHF optimal dose with respect to number and length of sessions and long term impact months of therapeutic effect on cardiovascular and inflammatory parameters in a canine model of CHF Commercial Opportunity The data generated during the course of the Phase I and II study plans will be incorporated into the pre clinical section of an IDE submission to the FDA for testing of the BMDCHF in the treatment of CHF The market for these indications exceeds $ b annually in the US alone PUBLIC HEALTH RELEVANCE The goal of this proposal is to develop an effective therapy for treatment of Chronic Heart Failure CHF The therapeutic benefit afforded by the Biomimetic Membrane Device for treatment of CHF BMDCHF is based on its ability to sequester bind leukocytes that were activated due to the chronic inflammatory state associated with CHF immunomodulate and then release these leukocytes in a now andquot resetandquot state that is more close to normal The relevance of the work in this proposal to the general public is that the BMDCHF will improve the clinical outcome of patients who suffer from CHF and therefore increase the survival rates for this disease indication


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 323.82K | Year: 2015

DESCRIPTION provided by applicant The Selective Cytopheretic Device SCD is an extracorporeal medical device targeted to treat patients with inflammatory disease indications As patient blood passes through the SCD it comes in contact with the hemocompatible fibers inside the SCD These fibers are capable of immunomodulatory interactions with the patientandapos s over active white blood cells activated leukocytes The SCD has been used in three human clinical studies to date with positive clinical outcomes for critically ill adult patients with acte kidney injury AKI and multiorgan dysfunction MOD Long term objective to develop a process to manufacture fibers with an outer diameter OD m for use in a second generation SCD SCD with low blood fill volumes to enable the treatment of pediatric patients and critically ill adult patients with blood volume removal re strictions due to potential hemodynamic instability as well as treatment in out patient clinics via peripherally inserted central catheter PICC access which require low blood flow rates Fibers within the current SCD are made of polysulfone PSu and have an OD of m Current technology in hemodialysis fiber manufacturing is restricted to fabricating fibers with OD of between to m These fibers are far too large to be used in the SCD which would cause the blood priming volumes to be high and therefore not safe for pediatric patients and critically ill patiens In order to make the blood fill volumes andlt mL for these patients the fibers must be made m A lab at Virginia Tech will be used to manufacture fibers of the required specifications for the SCD device which will enable the rapid development of the fiber making process toward clinical translation for the SCD to save severely ill patientsandapos lives In this project the way in which the SCD works called the mechanism of action MoA will be explored by specifically looking at how white blood cells WBC interact with the fibers in the device Specific Aim by using fresh cow blood from a local slaughterhouse Production methodology for m OD fibers will be developed by finding just the right balance of polymers to change the surface of the fibers for the best interaction with WBC also tested with cow blood Specific Aim The fibers produced in Aim will be sterilized by different methods in Specific Aim and will be tested with cow blood These optimized sterilized fibers would be ready for use in a medical device to test in a preclinical large animal model to prove efficacy If they are safe and work well then the finalized devices could be used in a human clinical trial Health Related Impact The data generated from this proposal will advance the development of a critical manufacturing process for fabrica tion of PSu fibers needed to produce SCD It will also provide preclinical data for inclusion of regulatory sub missions to apply for IDE approval from the FDA to initiate clinical trials for the evaluation of SCD therapy in both acute and chronic disease indications including orphan diseases anti neutrophil cytoplasmic antibody ANCA vasculitis dermatomyositis Guillian Barre Syndrome GBS and pediatric AKI PUBLIC HEALTH RELEVANCE The Selective Cytopheretic Device SCD is a medical device applied during dialysis or hemofiltration that is designed for blood to flow through it with fiber inside the device that can interact with severely ill patientandapos s blood cells in order to reset and normalize their immune system The current SCD is designed for adults with kidney disease and organ failure but cannot be used on children or other severely ill patients that canandapos t withstand and arenandapos t safe if large amounts of blood is taken out of their bodies to be used in a blood circui This proposal seeks to develop a process to make special fibers for a new smaller SCD devices specifically for these sick children and critically sick patients called a second generatio SCD SCD


Patent
Innovative Biotherapies, Inc. | Date: 2011-02-15

Extracorporeal cell-based therapeutic devices and delivery systems are disclosed which provide a method for therapeutic delivery of biologically active molecules produced by living cells in response to a dynamic physiologic environment. One embodiment includes long hollow fibers in which a layer of cells are grown within the intraluminal volume or within a double hollow-filled chamber. Another embodiment includes a wafer or a series of wafers providing a substrate onto which cells are grown. The wafer(s) are inserted into a device. A device may deliver a pre-selected molecule, for example, a hormone, into a mammals systemic circulation and/or may deliver a member of different cell products. The device is adapted to secure viable cells which produce and secrete the pre-selected molecule into blood or fluid. The invention also provides a minimally invasive method for percutaneously introducing into a preselected blood vessel or body cavity the device of the invention.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 364.72K | Year: 2013

DESCRIPTION (provided by applicant): The Problem: The lack of devices specifically designed for pediatric applications has been recognized by directives in the Pediatric Medical Device Safety and Improvement Act of 2007, included in Public Law 110-85, andthe Institutes of Medicine, which has recommended pediatric studies to begin at the end of Phase II clinical trials involving adults. Acute kidney injury (AKI) and septic shock associated AKI (SSAKI) requiring renal replacement therapy (RTT) are significant complications in ICU patients with an associated mortality rate exceeding 50 percent. As with so many therapeutics, even the available sub-optimal treatment improvements for AKI and SSAKI have been predominantly targeted for use in adult AKI/SSAKI-RRT patients, with little consideration given to any adaption that would be required for pediatric application. The need for novel therapeutics that are specifically developed for pediatric AKI/SSAKI-RRT use is driven by the nearly 50% mortality rates of pediatric patients with MOD receiving RRT. The Product: The cSCD is a novel compact Selective Cytopheretic Device containing bundled biomimetic polysulfone fibers which selectively bind/sequester and deactivate leukocytes (LE) in a dialysis extracorporeal blood circuit, resulting in an immunomodulatory effect in the systemic inflammatory response associated with AKI and SSAKI. The cSCD is targeted to treat pediatric AKI/SSAKI-RRT patients Innovation: The SCD, combined with regional citrate anticoagulation, is a novel therapeutic application utilizing biocompatible membranes that allow LE attachment in a [iCa]low environment resulting in a diminution in the LE activated state. The SCD has demonstrated, in clinical trials of AKI, to be effective in reducing mortalityrate from the historcal matched control of 63% to 31%. i. Long Term Goal: To develop a cSCD with optimal flow characteristics, an effective surface area (SA) and a blood fill volume that is easily tolerated by pediatric AKI/SSAKI-RRT patients. Expected Outcome: SSAKI pigs treated with cSCD+RRT will demonstrate therapeutic efficacy when compared to SSAKI pigs treated with RTT alone. The following aims will guide this study plan: Specific Aim 1. Evaluate cSCD prototype designs in silico and via flow visualization system studies. Specific Aim 2. In Vitro Blood Circuit testing of cSCD to assess hemocompatibility and determine impact of SA on LE sequestration/modulation. Specific Aim 3. Assess cSCD efficacy using a 10kg porcine model of SSAKI. Phase II objective: Completion of the Phase I aims will demonstrate proof-of-concept for use of the cSCD in the treatment of pediatric AKI-RRT patients. The Phase II plan will treat additional SSAKI pigs with the cSCD to increase the preclinical data and to further defineoptimization of cSCD dose, for inclusion of regulatory submissions. With successful completion of the Phase II studies, IBT plans to apply for an IDE approval from the FDA to initiate a clinical trial for the evaluation of cSCD therapy in pediatric patients with AKI- RRT. IBT would seek either a corporate partner or private equity investors to undertake these clinical trials. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The goal of this proposal is to develop a compact Selective Cytopheretic Device (cSCD), an extracorporeal membrane device that can sequester activated leukocytes and inhibit their inflammatory activity in order to reduce tissue accumulation and resulting damage in patients. The cSCD would specifically be designed for use inpediatric patients that have acute kidney injury or septic shock associated acute kidney injury requiring renal replacement therapy. There is nearly a 50% mortality rate of pediatric patients with multiorgan dysfunction requiring renal replacement therapy.The lack of medical devices specifically designed for pediatric applications has been recognized by directives in the Pediatric Medical Device Safety and Improvement Act of 2007, included in Public Law 110-85, and the Institutes of Medicine, which has recommended pediatric studies to begin at the end of Phase II clinical trials involving adults Inflammatory. The relevance of this proposal to public health is tat the cSCD would greatly reduce the multiorgan effects in pediatric patients suffering from acute kidney injury or septic shock associated acute kidney injury, thus improving the clinical outcome of these pediatric patients affected by these disease processes.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.99M | Year: 2010

DESCRIPTION (provided by applicant): Renal cell therapy promises to improve the survival and overall health of patients suffering from acute renal failure (ARF), acute tubular necrosis (ATN), multiple organ failure (MOF), sepsis, cardiorenal syndrome (CRS) and end stage renal disease (ESRD). To this end, therapeutic biological devices addressing the neglected physiologic component of renal replacement therapy are rapidly being developed. Transfer of this innovative technology to the clinical setting will require the manufacture of devices using a large number of cells of human origin. Cells will be derived from human transplant discards using enhanced propagation (EP) techniques developed in the Phase 1 component of this proposal. Although the availability of human tissue remains limited, development of the EP protocol has greatly enhanced the amplification of renal cell progenitors, removing cell availability as the limiting factor to the clinical application of renal cell therapy. The overall goal of this proposal is to optimize the protocols necessary for the isolation, propagation, cryopreservation, differentiation, integration and maintenance of human EP cells in a bioartificial renal epithelial cell system (BRECS) with regard to manufacturing. Devices seeded with EP human renal epithelial cells (HRECs) will be used to demonstrate efficacy in a well established porcine model of sepsis. A broad panel of efficacy markers will be monitored in vitro using a whole blood bioassay and results correlated with therapy outcome in the septic pig model. Data will be used to develop release criteria for cells isolated and maintained under EP protocols relative to efficacy and to satisfy the potency requirement of the Biologic License Application. The targeted initial population for BRECS therapy will be acute renal failure patients with sepsis induced Systemic Inflammatory Response Syndrome (SIRS). The feasibility of maintaining the device and extracorporeal circuit will be demonstrated over the projected 7 day clinical time course of required renal support for this clinical target. Data derived from the successful completion of the Phase II proposal will be used for an Investigational New Drug (IND) submission to the Food and Drug Administration (FDA) for a Phase I/II clinical trial evaluating the safety and efficacy of biotherapeutic devices seeded with HREC derived from enhanced propagation protocols. PUBLIC HEALTH RELEVANCE: The long-term goal of this research is to develop and optimize the generation and qualification of enhanced propagation (EP) protocols for the isolation, expansion and maintenance of human renal epithelial cells (HREC) for use in biologic applications, thus eliminating the issue of limited tissue/cell sources for generation of HRECs. The specific application targeted in this research proposal is for the assessment of utilization of EP HRECs in a bioartificial renal epithelial cell system (BRECS) that effectively adds therapeutic value to a variety of disease processes, including the treatment of Systemic Inflammatory Response Syndrome (SIRS) and sepsis. Severe sepsis with SIRS occurs in 200,000 patients annually in the U.S. and has a mortality rate of 30-40%, even with use of intensive care units and broad spectrum antibiotics. Successful completion of the planned studies in this proposal will allow for an unlimited cell source for use in the BRECS application. This device would greatly reduce the multiorgan effects of sepsis and SIRS, thus improving the clinical outcome of patients affected by these disease processes.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.43M | Year: 2012

DESCRIPTION (provided by applicant): Leukocytes (LE) are major contributors to the pathogenesis and progression of many clinical inflammatory disorders, including the systemic inflammatory response syndrome, sepsis and acute respiratory distress syndrome.The need for new and innovative therapies to treat these inflammatory disease states presents a large commercial market opportunity. A large number of therapeutic approaches are under investigation to limit the activation and tissue accumulation of LE at sites of inflammation in order to minimize tissue destruction and disease progression. A therapeutic device within an extracorporeal blood circuit, called the selective cytopheretic device (SCD), sequesters activated LE in a low calcium environment and inhibits their release of inflammatory proteins and cytokines. This Phase II research proposal builds on the Phase I goals which successfully demonstrated the 1st generation SCD1G to have greater therapeutic efficacy with increasing surface area (SA) in a large animal model of septic shock, when compared to sham treated controls, in addition to establishing a simplified SCD extracorporeal circuit for ease of use under standard-of- care hospital settings. This Phase II proposal will determine the design and fabrication of a 2nd Generation SCD2G. Custom SCD2G designs will maintain the low shear force and low ionized calcium environment, shown to be efficacious for SCDG1, with variations to include flow path, flow rates, packing density, and SA, in addition to reduced blood fill volumes which were not achievable with the SCD1G commercially available hollow fiber cartridges. The lower blood fill volume and blood flow rate requirements, will allow SCD2G therapy to be administered via a peripherally inserted central catheter (PICC line) or to criticall ill patients with hemodynamic instability. SCD2G designs will be evaluated in silico via computational flow dynamics simulation to assess casing design and internal device geometry. Prototypes will be fabricated and flowvisualization studies performed to determine designs with advantageous flow profiles (Aim 1). In vitro blood circuits with fresh blood will be used to evaluate SCD2G designs selected from in silico studies with respect to hemocompatibility and LE bindingcharacteristics (Aim 2). Lastly, selected SCD2G designs will be evaluated in the porcine model of septic shock used in the Phase I studies. Various renal and cardiovascular parameters, pulmonary inflammation, cytokine levels, systemic neutrophil activationload and time to death will be compared between SCDG2 designs of varying SA and the SCDG1 (Aim 3). SCDG1 therapy has demonstrated an excellent safety profile and compelling efficacy impact in three exploratory clinical trials, reducing mortality rates from the control rate of 60% to 30%, in ICU patients with acute renal failure requiring continuous renal replacement therapy; 50-60% of these patients were also septic. This proposal will determine a finalized SCD2G design to treat a broad array of patientswith sepsis, severe sepsis and septic shock and will provide data for an application to the FDA for IDE approval for the SCD to be used in the treatment of sepsis. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to develop a Second Generation Selective Cytopheretic Device (SCD2G), an extracorporeal membrane device that can sequester activated leukocytes and inhibit their inflammatory activity in order to reduce tissue accumulation and resulting damage in patients. Inflammatory diseases such as sepsis and Systemic Inflammatory Response Syndrome (SIRS) are high impact medical indications, as severe sepsis with SIRS occurs in 200,000 patients annually in the U.S. and has a mortality rate of 30-40%, even with use of intensive care units and broadspectrum antibiotics. The relevance of this proposal to public health is that the SCD would greatly reduce the multiorgan effects of sepsis and SIRS, thus improving the clinical outcome of patients affected by these disease processes.

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