I-Corps: Spheroidal engineered tissues for more efficient drug discovery

I-Corps项目更广泛的影响/商业潜力是开发一种药物测试模式，使制药公司能够在研究和开发过程的早期阶段消除无效的候选药物。在过去的10年里，制药公司在药物开发方面的研发回报一直在下降。减少的原因之一是，大多数进入临床试验的药物在最后和最昂贵的阶段失败了。目前，筛选从二维（2D）细胞培养开始，并发展到动物模型。这两种系统在复制人类疾病方面都存在固有缺陷。提出的技术使用更有效的3D组织模型进行药物筛选，提供更生理相关的药物反应，同时与当前可用的高通量筛选平台兼容。这项技术有可能提高研究人员和其他终端用户的工作效率，减少早期阶段候选药物的假阳性，从而增加制药公司的研发回报，并降低患者的医疗保健成本。此外，提出的技术可能使新疗法的发展更快。这个I-Corps项目是基于开发用于药物筛选的先进的3D细胞负载水凝胶微球。目前用于临床前药物试验的模型在复制人类疾病方面存在固有缺陷。三维球形细胞聚集体已被建立为更有效的癌症药物筛选模型；然而，现有的系统缺乏同质性、细胞微环境控制和总细胞数，这些都需要进行高保真端点筛选分析，并获得研究人员所需的质量和类型的信息。此外，许多类型的癌细胞不能一致地形成三维聚集体。因此，需要更先进的3D球体模型来支持高细胞密度、多细胞类型和细胞微环境的调制。使用定制开发的微流体封装平台，可以使用光交联水凝胶材料以极快的速度生产细胞负载的微球体。与自聚集和其他竞争技术相比，所提出的技术可能提供更大的灵活性来操纵细胞微环境，例如刚度，并且可能包括多种支持细胞类型，例如非常重要的基质细胞和免疫细胞。此外，与细胞聚集体相比，每口井中包含的细胞数量更多，因此可以在每口井的基础上进行高度敏感的端点分析。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this I-Corps project is the development of a drug testing model that enables pharmaceutical companies to eliminate ineffective drug candidates at much earlier stages in the research and development (R&D) process. For the past 10 years, pharmaceutical companies have been experiencing a decrease in R&D returns on drug development. One of the reasons for the decrease, is that most of the drugs entering clinical trials fail in this final and most costly stage. Currently, screening begins with 2-Dimensional (2D) cell cultures and progresses to animal models. Both systems have inherent deficiencies in replicating human disease. The proposed technology uses more effective 3D tissue models for drug screening by providing a more physiologically-relevant drug response while being compatible with currently available, high-throughput screening platforms. This technology has the potential to increase the work efficiency of researchers and other end-users, reduce false positive drug candidates at early stages to increase R&D returns for the pharmaceutical companies, and reduce healthcare costs for patients. In addition, the proposed technology may enable faster development of new therapies.This I-Corps project is based on the development of advanced 3D cell-laden hydrogel microspheroids for drug screening. Currently used models for pre-clinical drug testing have inherent deficiencies in replicating human disease. 3D spheroidal cell aggregates have been established as more effective models for cancer drug screening; However, existing systems lack the homogeneity, cellular microenvironmental control, and total cell numbers needed to perform high fidelity endpoint screening assays and obtain the quality and types of information that researchers require. In addition, many types of cancer cells do not consistently form 3D aggregates. Therefore, there is a need for more advanced 3D spheroidal models that can support high cell density, multiple cell types, and modulation of cellular microenvironment. Using a custom-developed microfluidic encapsualtion platform, cell-laden microspheroids may be produced at an extremely fast speed using photocrosslinkable hydrogel materials. Compared to self-aggregation and other competing technologies, the proposed technology may provide greater flexibility to manipulate the cellular microenvironment, such as stiffness, and may include multiple supporting cell types, such as highly important stromal and immune cells. Additionally, higher numbers of cells may be included per well compared to cell aggregates, making highly sensitive endpoint analyses feasible on a per well basis.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.