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Assessment of Bioreactor-Derived Human Platelet Quality, Storage Profile, Safety, and Function

生物反应器衍生的人血小板质量、储存概况、安全性和功能的评估

基本信息

批准号：
9229572
负责人：
SVEN M KARLSSON
金额：
$ 72.94万
依托单位：
PLATELET BIOGENESIS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9229572
关键词：
Address Adult Alkenes American Architecture Arterial Injury Behavior Biogenesis Biological Biological Markers Bioreactors Birth Blood Blood Circulation Blood Platelets Blood Vessels Bone Marrow Cell Culture Techniques Clinical Clinical Trials Clot retraction Coagulation Process Collection Computers Cytoplasmic Granules Cytoskeletal Modeling Data Devices Drug Kinetics Embryo Emergency Situation Engineering Equipment and supply inventories Exhibits FDA approved Freezing Funding Growth HIV Half-Life Hand Hemorrhage Hemostatic Agents Hemostatic function Hour Human Human Volunteers Immune Immunocompromised Host In Vitro Infusion procedures Label Life Liquid substance Malignant Neoplasms Medical Megakaryocytes Metabolic Microfluidics Modeling Morphology Mus Operative Surgical Procedures Patients Perfusion Phase Physiological Pilot Projects Platelet Count measurement Platelet Transfusion Polymers Positioning Attribute Pregnancy Production Research Residual state Rest Risk Safety Sepsis Site Small Business Innovation Research Grant Source Stem cells Sterility Structure Survival Rate Temperature Teratoma Therapeutic Thrombocytopenia Thrombus Time Transfusion Transplantation Viral Virus Virus Diseases White Blood Cell Count procedure cancer therapy cost design efficacy study humanized mouse improved in vivo induced pluripotent stem cell macrophage man mortality mouse model novel parallelization polydimethylsiloxane prevent progenitor public health relevance repaired screening septic shear stress standard of care volunteer

项目摘要

DESCRIPTION (provided by applicant): Platelet BioGenesis is developing a microfluidic bioreactor to produce human platelets at clinical scale. Platelets are the 'band-aids' of the bloodstream, responsible for clot formation and blood vessel repair. Low platelet count is a significant consequence of cancer treatment, transplant, and surgery, for which platelets are a critical first-line therapy to prevent mortality due to uncontrolled bleeding. Platelet units comprising 3x1011 platelets per 200-400 mL are at present derived exclusively from human volunteer donors, and must be stored at or above 22oC to avoid irreversible temperature-related activation/aggregation. Risk of bacterial growth during room temperature storage limits shelf life to 5 days, 2 of which are consumed by bacterial screening, and 1 by transport. As a result blood centers typically do not have more than a 1.5-day platelet inventory avail- able for transfusion, which is rapidly depleted in emergencies [1, 2]. To address this major unmet need we have developed a platelet bioreactor that reproduces key features of adult bone marrow (physiological microenvironment) to trigger new platelet production at increasing scale. To date we have shown that: (1) It is feasible to generate functional megakaryocytes and platelets from human induced pluripotent stem cells (iP-SCs, a replenishable source of progenitor cells which can be stored frozen for years)[3] and (2) our bioreactor will trigger platelet formation and improve the rate and extent of platelet production from human iPSC-derived MKs above established static culture approaches[4, 5]. This Direct-to-Phase II SBIR proposal outlines 3 specific aims to determine quality, safety, and function of bioreactor-derived platelets (bdPLTs) in humanized mouse models of thrombocytopenia, and to scale platelet production to yield a human transfusion unit: Aim 1. Assess bdPLT quality, storage profile, and safety in vitro. We will evaluate platelet structure, biomarker expression, metabolic activity, and function under FDA-approved storage conditions, and determine their safety by enumerating residual leukocyte counts, and assessing viral, septic, and teratoma risk. Aim 2. Assess the hemostatic and thrombogenic potential of bdPLT in humanized mice as well as platelet clearance and circulation time. We will evaluate the in vivo behavior of bdPLTs in a novel murine model that permits human but not mouse platelet accrual at sites of arterial injury (non-GLP pilot study). Hu- man donor platelets will serve as a physiological control. Aim 3. Scale production 3,000-fold to yield a human transfusion unit (3x1011 bdPLTs per 300 mL). We will optimize our bioreactor design for continuous media perfusion and parallelization, maximize megakaryocyte zonal distribution and trapping, and equalize shear stress exposure throughout the device.