Understanding Multi-stage Neural Stem Cell Function via 4D Bioprinting Reprogrammable System

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Neural injuries represent one of the most common and devastating clinical challenges worldwide. Currently, stem cell-based technologies have shown great promise in treating nerve damage. However, one of the major challenges in successfully utilizing stem cells for clinical applications is the difficulty in providing proper environmental cues to regulate their behaviors. Most of the currently available techniques to guide stem cell behavior utilize simple 2D or 3D microenvironments, which are largely static in nature, and therefore fail to reflect the dynamic nature of the native neural tissue environment in which stem cells develop. Thus, the objective of this study is to develop a novel 4D (time being the 4th dimension) printed smart system, which can change its shape over time in order to improve neural stem cell (NSC) function and neural regeneration. This study will elucidate the fundamental mechanisms of NSC development and differentiation in a dynamic environment. Furthermore, the 4D bioprinting system will be promising for many potential applications ranging from tissue/organ regeneration to in vitro drug screening and disease modeling. Integrated research, educational, and outreach activities will place special emphasis on underrepresented minorities and female students at different levels, and will provide a diverse audience with a high-caliber science and engineering education. The goal of this project is to 4D print a novel reprogrammable smart system with a time-dependent dynamic transformation, which can provide an efficient means to cater to the different neurodevelopmental stages undergone by NSCs and will improve neural tissue regeneration. The 4D bioprinting system can provide a perfect self-morphing feature when exposed to a predetermined stimulus for controlling NSC fate. For this purpose, two specific study aims will be performed: Aim 1 will primarily focus on synthesizing reprogrammable 4D ink materials, which can execute a two-week shape change at physiological temperature. The 4D inks will be formulated by varying the ratios of different ink components in order to achieve desirable, printable rheological properties. Aim 2 will involve the bioprinting of smart neural constructs and will explore NSC functions and biomechanics during the 4D transformation process. The microstructure and mechanical properties of the bioprinted constructs will be characterized. Furthermore, NSC differentiation, axonal extension, and gene expression within the context of the 4D dynamic environment will be thoroughly evaluated in vitro. The successful completion of the project will provide a revolutionary smart system for enhancing the performance of NSCs for neural regeneration purposes.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.