Biomaterials Approach to Expand Hematopoietic Cells ex vivo

离体扩增造血细胞的生物材料方法

• 批准号: 7144520
• 负责人: KAM W LEONG
• 金额: $ 36.88万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7144520
• 关键词: CD34 molecule; NOD mouse; SCID mouse; bioengineering /biomedical engineering; biological signal transduction; biomaterial development /preparation; biomaterials; biomedical equipment development; biomimetics; bioreactors; biotechnology; bone marrow; cell adhesion molecules; cell differentiation; cell growth regulation; cell proliferation; cord blood; extracellular matrix; fibronectins; hematopoietic stem cells; heparin; human tissue; surface property; tissue /cell culture; tissue support frame

DESCRIPTION (provided by applicant): Hematopoietic cells can provide benefit in a variety of clinical settings. These include cells for support of patients undergoing high-dose chemotherapy, as a target for replacement gene therapy, and as a source of cells for immunotherapy. The limitation to many of these applications has been the insufficient number of donor cells. An efficient and practical ex vivo expansion of hematopoietic progenitors (HPC) and hematopoietic stem cells (HSC) is critical in realizing the tremendous potential of HPC/HSC transplantation. The overall objective of this project is to develop a clinically relevant approach, through biomaterials engineering, to efficiently expand human hematopoietic cells. Signals emanating from the HSC niche play a crucial role in regulating the fate decision of HSC on whether to self-renew or differentiate. Extracellular matrix (ECM) components are important elements of the HSC niche. They provide the adhesive interactions between HSCs and cell adhesion molecules in the regulation of hematopoiesis in bone marrow. In hypothesizing that a favorable hematopoietic, bone marrow-like topographical microenvironment can be created by immobilizing adhesion molecules on the surface of a three-dimensional scaffold, we propose to optimize the expansion of CD34-selected as well as unselected umbilical cord blood cells (CB) in these biofunctional scaffolds. We will first establish a robust synthetic scheme of conjugating fibronectin (FN), CS1 peptide, and heparin to the surface of poly(ethylene terephthalate) (PET) scaffolds with different topographical features. After evaluating the expansion of hematopoietic cells in these scaffolds with respect to their self-renewal, differentiation, and in vivo engraftment potential, we will test the most promising scaffolds in a scaled-up culture. We propose a novel bioreactor design that will take advantage of these optimized biofunctional scaffolds by maximizing the contact area of the hematopoietic cells with the scaffolds. There has not been a systematic effort to optimize the expansion of hematopoietic cells from cord blood through a combination of biomaterials and bioreactor design. With this systematic and focused approach we aspire to develop a clinically practical strategy of efficiently expanding hematopoietic cells.

描述（由申请人提供）：造血细胞可以在多种临床环境中提供益处。其中包括支持接受高剂量化疗的患者的细胞、作为替代基因治疗的靶标以及作为免疫治疗的细胞来源。许多这些应用的限制是供体细胞数量不足。高效实用的造血祖细胞 (HPC) 和造血干细胞 (HSC) 体外扩增对于实现 HPC/HSC 移植的巨大潜力至关重要。该项目的总体目标是通过生物材料工程开发一种临床相关的方法，以有效地扩增人类造血细胞。 HSC 生态位发出的信号在调节 HSC 自我更新或分化的命运决定中发挥着至关重要的作用。细胞外基质 (ECM) 成分是 HSC 生态位的重要组成部分。它们在骨髓造血的调节中提供造血干细胞和细胞粘附分子之间的粘附相互作用。假设通过将粘附分子固定在三维支架表面上可以创建有利的造血、骨髓样拓扑微环境，我们建议优化 CD34 选择和未选择的脐带血细胞 (CB) 的扩增）在这些生物功能支架中。我们将首先建立一个稳健的合成方案，将纤连蛋白（FN）、CS1肽和肝素结合到具有不同形貌特征的聚对苯二甲酸乙二醇酯（PET）支架的表面。在评估这些支架中造血细胞的自我更新、分化和体内植入潜力后，我们将在放大培养中测试最有前途的支架。我们提出了一种新颖的生物反应器设计，该设计将通过最大化造血细胞与支架的接触面积来利用这些优化的生物功能支架。目前还没有系统性的努力来通过生物材料和生物反应器设计的结合来优化脐带血造血细胞的扩增。通过这种系统性和集中的方法，我们渴望开发一种有效扩增造血细胞的临床实用策略。