Collaborative Research: Stem Cell Maturity Evaluation and Promotion with An Intelligent Lab-on-Chip Framework

Cardiovascular disease is the leading global cause of death. Future heart regeneration relies on mature cardiomyocytes (CMs) from stem cells that will improve heart function when transplanted in the heart. A major problem of the existing stem cell-derived heart tissues is that the cells remain immature, beat more rapidly, and when transplanted into adult failing hearts will eventually provoke lethal arrhythmias.

The primary goal of this research is to design and develop an intelligent device that will non-invasively monitor the maturity stage of stem cell-derived CMs in real-time, and adaptively stimulate the cells toward full maturation with electric pulsing and mechanical stretching. The research has the potential to revolutionize the generation of mature CMs.

This interdisciplinary collaboration among the New York Institute of Technology, City College of New York, and Rutgers University also plans to increase the participation and retention of underrepresented students in computer science, engineering, and biology and contribute to summer workshops with cutting-edge hands-on activities for local K-12 students.

It was already demonstrated that standard protocols of in-vitro differentiation of cultured human pluripotent stem cell (hPSC)-CMs without external stimulants yield immature cells. Existing biophysical methods are also incapable of adaptively selecting stimulation parameters based on the current cell state to support the continued cell growth until full maturation.

To understand the in-vitro maturation process of hPSC-CMs, this project will develop a data-driven technique and then leverage the gained insights to guide the promotion of cardiomyocyte maturity with unprecedented properties. In particular, a probabilistic graphical model will be designed to evaluate the maturation stage of the hPSC-CMs based on the beating activities recorded online by the electric cell substrate impedance spectroscopy (ECIS) technique.

A novel lab-on-chip device, integrating the ECIS sensing and stimulation functions, will monitor the cell maturation process in real-time and apply mechanical and/or electrical stimulation on the hPSC-CMs. The biological stimulation, following the Gsk3 inhibitor and Wnt inhibitor (GiWi) protocol, will remain fixed during the entire differentiation and maturation process.

Reinforcement learning techniques will be used to analyze the information obtained from ECIS measurements and select the electrical and mechanical biophysical stimulation strategies. The intelligent iterative adjustment of the stimuli protocol will auto-regulate the device and more efficiently produce mature, beating human cardiac myocytes derived from pluripotent stem cells.

The proposed innovative stem cell research will impact a wide range of fields, such as enhancing the applicability of hPSC-CM for disease modeling, drug toxicity screening, tissue engineering, and novel cell-based cardiac therapies. The novel device with stretchable electronics will function in the liquid environment of biological cells and generate new insights into the roles of biophysical stimulations in directing cardiomyocyte stem cell maturation.

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.