Three-Dimensional Scaffolds for Bone Marrow Tissue Constructs

描述（由申请人提供）：药物的整个研发周期需要3亿至8亿美元的资金，时间长达10至12年。如此巨大的成本的原因之一是，绝大多数候选药物在动物和人体试验阶段就被筛选出来了。在离体研究阶段更有效的药物测试方法，比动物和人体测试周期便宜得多，将导致临床前试验成功率的提高，加速药物发现，降低药物开发成本，以及更好的药物。如果开发出更好的不同器官和组织的离体模型，则可以显著提高体外测试的功效。在这个涉及初创公司尼科技术公司（NTCorp）、密歇根大学、德克萨斯大学医学分支的一期STTR项目中，和弗雷德哈钦森癌症研究中心，我们提出了一种新型的三维支架的发展，可以（1）纠正现有的三维矩阵的问题和（2）为制药工业提供了开发用于器官复制品，特别是离体骨髓构建体中药物评估的方便和可靠的方案的可能性。该项目的第一阶段旨在证明基于倒置胶体晶体（ICC）支架的3D支架的概念，该支架的3D拓扑结构与骨髓的3D拓扑结构非常相似。它们将由水凝胶制成，并使传统上用于药物测试的表面标记物检测成为可能。具体目标（SA）。SA1：由水凝胶制造细胞粘附性ICC支架; SA 2：由ICC支架制备的骨髓基质中干细胞复制功能的评价。从长远来看，骨髓复制品可以是一个方便的模型系统，用于抗癌和抗病毒药物作为试剂盒和测定学术和工业研究人员。该模型目前没有类似物，可以显着改进传统的2D细胞培养发现工具，有可能减少动物和人体试验阶段的药物失败。公共卫生相关性：通过在组织类似物中进行测试，可以显着加速药物的评估，这需要一个合适的3D矩阵，提供不同组织的工程和细胞过程的光学监测。在这个项目中，我们建议制造透明的3D水凝胶支架与倒置胶体晶体（ICC）的几何形状。ICC支架的商业化生产将为药物制造商提供标准化、可靠、可重复、用户友好的3D矩阵，其可用于各种离体药物测试程序，具有降低药物开发成本和缩短药物开发时间的潜力。

DESCRIPTION (provided by applicant): The overall R&D cycle for drugs costs $300-800 million in capital and up to 10-12 years in time. One of the reasons for such great cost is that the vast majority of drug candidates are screened out at the stages of animal and human trials. More efficient methods of testing of drugs at the stage of ex-vivo studies, which are substantially less expensive than animal and human testing cycles, will lead to improvement of the success rate of preclinical trials, accelerate on of drug discovery, reduction of the cost of pharmaceutical development, and better drugs. Efficacy of in-vitro testing can be significantly increased provided that better ex-vivo models for different organs and tissues are developed. In this Phase I STTR project involving a start-up company Nico Technology Corporation (NTCorp), University of Michigan, University of Texas Medical Branch, and Fred Hutchinson Cancer Research Center we propose the development of a new type of 3D scaffold that can (1) rectify the problems of existing 3D matrixes and (2) provide the pharmaceutical industry the possibility to develop convenient and reliable protocols for drug assessment in organ replicas, and in particular ex-vivo bone marrow construct. Phase I of the project is aimed at the proof-of-concept demonstration that 3D scaffolds based on inverted colloidal crystal (ICC) scaffolds with remarkable resemblance of its 3D topology to that of bone marrow can be produced. They will be made from hydrogel and enable surface marker assays traditionally used in drug testing. Specific Aims (SA) for the project. SA1: Manufacturing of Cell-Adhesive ICC Scaffolds from Hydrogel; SA2: Evaluation of Stem cell Replication Functionality in a Bone Marrow Replica from ICC Scaffolds. In perspective, the bone marrow replica can be a convenient model system for the use in anticancer and antiviral drugs as kits and assays both for academic and industrial researchers. This model has no current analogs and can significantly improve the traditional 2D cell culture discovery tools with a potential to reduce the drug failures at animal and human trials stages. PUBLIC HEALTH RELEVANCE: Evaluation of drugs can be significantly accelerated by testing them in tissue analogs, which require a suitable 3D matrix that affords engineering of different tissues and optical monitoring of the cellular processes in it. In this project we propose manufacturing of transparent 3D hydrogel scaffolds with inverted colloidal crystal (ICC) geometry. Commercial production of ICC scaffolds will provide drug manufacturers with a standardized, reliable, reproducible, user- friendly 3D matrix that can be used in a variety of ex-vivo drug testing procedures that has a potential to reduce the cost and shorten the time of drug development.