Collaborative Research: Composite vascularized niches for optogenetically actives beta-cells

合作研究：光遗传学活性β细胞的复合血管化生态位

• 批准号: 2326511
• 负责人: Gulden CamciUnal
• 金额: $ 24.18万
• 依托单位: University of Massachusetts Lowell
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2326511&HistoricalAwards=false
• 关键词: Collaborative; Research; Composite; vascularized; niches

The design and manufacturing of bioartificial tissues pose great challenges yet are essential for developing effective therapies for major diseases. Such tissues typically require a large number of functional cells, which cannot survive without vasculature that facilitates the transport of nutrients and oxygen and the removal of waste products. One way to reduce the requisite number of cells is to amplify their function using light as the stimulus. Based on previous work, pancreatic insulin-producing β-cells exhibit 2- to 3-fold higher glucose-stimulated insulin secretion when stimulated with blue light. Moreover, vascular network formation in synthetic tissues can be promoted with the use of appropriate biomaterials. This project seeks to develop design principles and address fundamental biological issues of implantable engineered tissues with light-activatable cells utilizing a novel pancreatic tissue equivalent developed for the management of diabetes. Diabetes afflicts almost 10% of the US population with the highest healthcare costs. All persons with type 1 diabetes and 30% of those with type 2 diabetes rely exclusively on the administration of exogenous insulin. However, blood glucose control is suboptimal and does not avert serious long-term complications. The project will address these issues through biomaterial discovery and innovation and cell and tissue engineering, thereby advancing relevant technologies that improve the quality of life of persons with diabetes. The research is intertwined with educational activities including interdisciplinary training for undergraduate and graduate students in STEM fields, outreach to K-12 students and the public, and promoting diversity in bioengineering sciences.This project is driven by a critical need to develop implantable engineered tissues for reconstituting vital bodily processes such as blood glucose (BG) homeostasis. Such tissues require significant numbers of cells and the formation of a supporting vascular network, which typically spans a few weeks. To address this need, this project proposes the use of optogenetically engineered human β-cells, which show 2- to 3-fold greater glucose-stimulated insulin secretion (GSIS) with illumination, to ameliorate diabetic hyperglycemia. First, a gelatin-based engineered tissue will be designed and constructed with oxygen-generating microparticles (OGMs) and optogenetically engineered human β-cells encapsulated in alginate. Essential design parameters such as the ratio of cells to supporting OGMs and the hydrogel formulation will be determined. Upon characterization of the composite hydrogels, human endothelial cells will be incorporated into the scaffolds to form a vascular network. Conditions will be established for intra-scaffold angiogenesis in the presence of optogenetically engineered, glucose-responsive β-cells. Finally, the functionality of the engineered tissue will be evaluated in a mouse model of diabetes. The research will address unique hurdles in the use of light-activatable cells, vascular network formation in synthetic tissues, and interfacing cells with suitable biomaterials for optimal in vivo function. These are universal considerations in the design of tunable tissue systems for the treatment of major maladies such as diabetes. Additionally, assemblies with photoactivatable human β-cells developed here will be a much-needed resource for basic research on β-cell physiologyThis 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.

生物人工组织的设计和制造带来了巨大的挑战，但对于开发重大疾病的有效疗法至关重要。这些组织通常需要大量的功能细胞，如果没有促进营养物质和氧气运输以及废物清除的脉管系统，这些细胞就无法生存。减少所需细胞数量的一种方法是使用光作为刺激来放大它们的功能。基于先前的工作，当用蓝光刺激时，胰腺产生胰岛素的β细胞表现出2至3倍的葡萄糖刺激的胰岛素分泌。此外，可以通过使用适当的生物材料来促进合成组织中的血管网络形成。该项目旨在开发设计原则，并利用开发用于糖尿病管理的新型胰腺组织等效物，解决具有光激活细胞的可植入工程组织的基本生物学问题。糖尿病困扰着近10%的美国人口，医疗费用最高。所有1型糖尿病患者和30%的2型糖尿病患者完全依赖外源性胰岛素的给药。然而，血糖控制是次优的，并不能避免严重的长期并发症。该项目将通过生物材料的发现和创新以及细胞和组织工程来解决这些问题，从而推进相关技术，提高糖尿病患者的生活质量。该研究与教育活动交织在一起，包括为本科生和研究生提供STEM领域的跨学科培训，为K-12学生和公众提供外展服务，以及促进生物工程科学的多样性。该项目是由开发可植入工程组织的迫切需求驱动的，用于重建重要的身体过程，如血糖（BG）稳态。这些组织需要大量的细胞和支持血管网络的形成，通常持续几周。 为了解决这一需求，该项目提出使用光遗传工程化的人β细胞来改善糖尿病高血糖症，所述人β细胞在照明下显示出2至3倍的葡萄糖刺激的胰岛素分泌（GSIS）。首先，将设计并构建基于明胶的工程化组织，其具有产氧微粒（OGM）和包封在藻酸盐中的光遗传工程化人β细胞。将确定基本设计参数，例如细胞与支持OGM的比率和水凝胶配方。在表征复合水凝胶后，人内皮细胞将并入支架中以形成血管网络。将在光遗传工程化的葡萄糖响应性β细胞存在下建立支架内血管生成的条件。最后，将在糖尿病小鼠模型中评估工程组织的功能。该研究将解决使用光激活细胞，合成组织中血管网络形成以及将细胞与合适的生物材料连接以实现最佳体内功能的独特障碍。这些是设计用于治疗诸如糖尿病等主要疾病的可调组织系统时的普遍考虑因素。此外，这里开发的具有光活化人类β细胞的组件将成为β细胞生理学基础研究的急需资源。该奖项反映了NSF的法定使命，并被认为值得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来支持。