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

Tufts University, Medford MA

Investigators

Abstract

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 physiology 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.