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High Efficiency Microfluidic Purification of Stem Cells to Improve Transplants

高效微流体纯化干细胞以改善移植

基本信息

批准号：
8313288
负责人：
CURT I CIVIN
金额：
$ 24.13万
依托单位：
GPB SCIENTIFIC, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8313288
关键词：
Adult Adverse effects Arrhythmia Blood Blood Banks Body Weight Bone Marrow CD34 gene CSF3 gene Cell Separation Cell Size Cell Transplantation Cell Transplants Cell physiology Cells Cellular biology Child Clinical Clinical Research Collaborations Cryopreservation Density Gradient Centrifugation Development Devices Diagnostic Dimethyl Sulfoxide Disease Engraftment Ensure Erythrocytes Evaluation Event Excision Expert Systems Failure Flow Cytometry Future Goals Harvest Hematopoietic Hematopoietic stem cells Histocompatibility Hypertension In Vitro Lateral Lead Leukocyte Banking Leukocytes Liquid substance Malignant - descriptor Manuals Marketing Maryland Methods Microfluidics Minnesota Morbidity - disease rate Non-Malignant Outcome Output Patients Performance Peripheral Blood Stem Cell Phase Physicians Process Protocols documentation Reaction Recovery Research Residual state Risk Sales Sampling Scientist Sedimentation process Side Small Business Technology Transfer Research Source Speed Standardization Stem cell transplant Stem cells Sterility System Techniques Technology Testing Tissues Toxic effect Transfusion Transplant Recipients Transplantation Umbilical Cord Blood Umbilical Cord Blood Transplantation Universities White Blood Cell Count procedure austin base cell bank cell type clinically relevant cost design flexibility graft vs host disease high risk improved in vivo innovation instrument meetings mortality multidisciplinary novel patient population peripheral blood preclinical evaluation preclinical study prenatal prevent skills stem success

项目摘要

DESCRIPTION (provided by applicant): Hematopoietic stem-progenitor cell (HSPC) transplantation is an established therapy for many malignant and non-malignant diseases. HSPCs are harvested clinically from 3 sources: G-CSF mobilized adult peripheral blood (PBSC), bone marrow (BM), and umbilical cord blood (UCB). Because erythrocytes increase both the risk of harmful side effects in transplant patients and the cost of cryopreservation, they must be depleted from the harvested HSPC tissues. The major problem in UCB transplantation is the low total number of HSPCs in the small volume (100-300 ml) of UCB units. This leads to high risk for delayed engraftment or engraftment failure (with attendant high mortality, morbidity and costs), especially in larger children or adult patients. Current techniques, including density gradient centrifugation and differential sedimentation, result in incomplete erythrocyte depletion and may lose 25% leukocytes (on average) during processing. Since success and speed of engraftment depend on the numbers of leukocytes and HSPCs per recipient body weight, it is essential to develop new cell separation methods to ensure high yields of pure, viable leukocytes and HSPCs from harvested UCB. The commercial goal of this STTR project is to improve stem cell banking and transplantation by marketing an efficient and robust processing system that results in superior recoveries of viable leukocytes and HSPCs, focusing on UCB as an immediate objective but involving a microfluidic cell separation technology that can be modified in the future to further purify both HSPCs and other stem cell types. We will take advantage of microfluidic deterministic lateral displacement (DLD), in which the paths cells take through the microfluidic system is based on size and is deterministic, i.e. absolutely determined, not subject to random processes. The key innovation of this STTR project is the use of DLD to deplete erythrocytes from UCB for hematopoietic transplant; this is a new clinical use, making this application commercially novel as well as clinically beneficial. The research strategy leverages a collaboration among micromechanical systems experts at GPB Scientific LLC; hematopoietic cell biology and cell processing experts at University of Maryland (Civin lab); and microfluidics experts at Princeton University (Sturm-Austin lab). In Specific Aim 1, the team will optimize the efficacy of erythrocyte depletion and leukocyte recovery from UCB, solving cell clumping events which can block microfluidic flow and increasing microfluidic throughput to clinically relevant volumes. In Specific Aim 2, the system will be modified for aseptic clinical us such that in the subsequent Phase II project, this high- volume microfluidic blood separation system can be used to assess HSPCs in vitro and in vivo to determine if their functionalities are conserved after erythrocyte depletion. The technology will also be extended for use with PBSC and BM harvests. The value proposition is clear: the GPB technology should deliver greater numbers of higher quality transplant grafts (i.e. more grafts with more HSPCs) that will lead to greater transplant success. PUBLIC HEALTH RELEVANCE: There is a critical unmet need for rapid, efficient methods to deplete erythrocytes and recover leukocytes from G-CSF mobilized peripheral blood (PBSC), bone marrow (BM), and especially umbilical cord blood (UCB), prior to cryopreservation. Incomplete erythrocyte removal from transplant grafts increases the risk of harmful side effects in hematopoietic stem cell transplants, while poor recovery of viable leukocytes and CD34+ cells reduces engraftment success and limits the treatable patient population. Development of a novel, highly efficient system to remove erythrocytes and purify leukocytes would raise the quality of UCB and other transplant grafts, thereby significantly improving patient outcomes.

描述（由申请人提供）：造血干祖细胞（HSPC）移植是一种用于许多恶性和非恶性疾病的既定疗法。临床上从3个来源收获HSPC：G-CSF动员的成人外周血（PBSC）、骨髓（BM）和脐带血（UCB）。由于红细胞增加了移植患者有害副作用的风险和冷冻保存的成本，必须从收获的HSPC组织中耗尽。UCB移植的主要问题是在小体积（100-300 ml）的UCB单位中HSPC的总数低。这导致移植延迟或移植失败的高风险（伴随着高死亡率、发病率和成本），特别是在较大的儿童或成人患者中。目前的技术，包括密度梯度离心和差速沉降，导致不完全的红细胞消耗，并可能失去25%的白细胞（平均）在处理过程中。由于移植的成功和速度取决于每受体体重的白细胞和HSPC的数量，因此必须开发新的细胞分离方法，以确保从收获的UCB中获得高产量的纯活白细胞和HSPC。该STTR项目的商业目标是通过销售一种高效且稳健的处理系统来改善干细胞库和移植，该系统可实现活白细胞和HSPC的上级回收，重点关注UCB作为直接目标，但涉及微流体细胞分离技术，该技术可在未来进行修改以进一步纯化HSPC和其他干细胞类型。我们将利用微流体确定性横向位移（DLD），其中细胞通过微流体系统的路径是基于尺寸的并且是确定性的，即绝对确定的，不受随机过程的影响。该STTR项目的关键创新是使用DLD从UCB中消耗红细胞用于造血移植;这是一种新的临床用途，使该应用具有商业新颖性和临床益处。该研究策略利用了GPB Scientific LLC的微机械系统专家之间的合作;马里兰州大学（Civin实验室）的造血细胞生物学和细胞处理专家;以及普林斯顿大学（Sturm-Austin实验室）的微流体专家。在具体目标1中，该团队将优化红细胞去除和白细胞从UCB中回收的功效，解决可能阻止微流体流动的细胞聚集事件，并将微流体通量增加到临床相关体积。在具体目标2中，将针对无菌临床使用对系统进行修改，使得在随后的II期项目中，该高容量微流体血液分离系统可用于体外和体内评估HSPC，以确定其功能在红细胞消耗后是否保留。该技术还将扩展用于PBSC和BM收获。价值主张是明确的：GPB技术应该提供更多数量的更高质量的移植移植物（即更多的移植物和更多的HSPC），这将导致更大的移植成功。公共卫生相关性：对于在冷冻保存之前从G-CSF动员的外周血（PBSC）、骨髓（BM），特别是脐带血（UCB）中消耗红细胞和回收白细胞的快速、有效的方法存在关键的未满足的需求。从移植物中不完全去除红细胞会增加造血干细胞移植中有害副作用的风险，而存活白细胞和CD 34+细胞的恢复不良会降低植入成功率并限制可治疗的患者群体。开发一种新的，高效的系统来去除红细胞和纯化白细胞将提高UCB和其他移植物的质量，从而显着改善患者的结果。