(2mg) Transforming cell therapy manufacturing and cancer management with large-volume microfluidics | AIChE

(2mg) Transforming cell therapy manufacturing and cancer management with large-volume microfluidics

Authors 

Mishra, A. - Presenter, Harvard Medical School
Background

My research interests are focused on developing translational tools at the intersection of bioengineering, fluid mechanics, and microsystems. I am an NIH K25 investigator and instructor at the Center for Engineering in Medicine and Surgery at Harvard Medical School (HMS) and Massachusetts General Hospital (MGH) in Boston. I completed my doctoral degree in Mechanical Engineering from Purdue University under Prof. Steve Wereley, followed by a postdoctoral stint at the lab of Profs. Mehmet Toner and Daniel Haber at Harvard Medical School. In 2020, I was promoted to an instructor position and recently awarded (August 2023) a five-year K25 Career Development Award from NIH. At MGH and HMS, I have been leading the development of hyper-throughput microfluidic technologies for sorting rare cells from large-volume apheresis products.

Research Interests

The ability to isolate viable rare sub-sets of cells from complex biofluids is paramount to the success of cell therapies and liquid biopsy. The conventional cell sorting methods, such as centrifugation and bulk magnetic sorting, are highly lossy in recovering rare cells, risk contamination, yield impure products, and prove averse to automation. While these bulk methods suffer from cell loss, microfluidic cell sorting approaches produce high-purity products and enable superior cell yield by utilizing controllability and precision of low-Reynolds number flow. However, current microfluidic platforms have limited cellular throughput (<50 million cells) and mostly process 10 µL to a few milliliters of biofluids. In fact, conventionally, microfluidics is defined as a multidisciplinary field that deals with manipulating tiny volumes of liquids. This is contrary to clinically relevant biofluids such as blood products, lavages, peritoneal and pleural fluids, and intermediate cell therapy products, which are often large in volume (~100 mL to 5,000 mL) and contain billions of cells. In my research program, I would challenge this conventional “tiny volume” paradigm and build hyper-throughput microfluidic bio-instruments that can process billions of cells and handle large-volume samples. I aspire to create a research program at the intersection of cell and gene therapies, bioengineering, oncology, and translational medicine. Specifically, I will focus on three broad research directions:

Stem cell purification from blood products for gene therapy using high-throughput microfluidics: Boosted by a 5-year K25 award from NIH, in this research aim, we will develop an efficient microfluidic technology for stem cell isolation from blood products of patients with hemoglobinopathies, such as Sickle Cell Disease and β-Thalassemia.

Tumor cell isolation from peritoneal and pleural fluids to enable highly sensitive cytology, therapy selection, and drug susceptibility screening: Peritoneal and pleural fluids act as a reservoir for cancer cells, which are shed from various abdominal and pelvic tumors, making them a valuable source for early detection and monitoring. These fluids are often large in volume (100 mL-5,000 mL) and contain rare tumor cells in a background of various immune cells, fibroblasts, and contaminating red blood cells. We will develop a set of microfluidic technologies for isolating tumor cells at high throughput (1,000 mL/h) from such large volume samples while providing gentle, uniform, and precise sorting conditions.

Wearable biosensors for continuous cytokine detection: Cytokines are signaling molecules involved in the immune response. Abnormal cytokine levels indicate the presence of various diseases, including infections, autoimmune disorders, and inflammatory conditions. Continuous monitoring will enable an early detection of these conditions, facilitating prompt intervention and improving patient outcomes. As part of this research aim, we will develop wearable biosensors for continuously measuring cytokine levels in the dermal interstitial fluid.

Teaching Interests

I eagerly anticipate the opportunity to offer both undergraduate and graduate-level courses in the areas of Fluid Mechanics, Heat and Mass Transfer, Transport Phenomena, and Thermodynamics. Additionally, I am keen on offering elective courses encompassing Microfluidics, Microfabrication, and BioMEMS. Furthermore, I am very interested in developing and teaching an advanced graduate-level course focused on Cellular Therapy Engineering, which is a very active area of development for countless pharmaceutical companies. At the core of my pedagogical approach, I am committed to fostering active discussions by incorporating intentional interactions during the class, thereby ensuring sustained student engagement.

Previous teaching and mentoring experience: During my doctoral studies at Purdue University, I served as a teaching assistant in the Undergraduate Fluid Mechanics class for 3 semesters. It was an incredibly rewarding experience. Following this TA experience, I was privileged to be selected as a Lead Teaching Assistant for this class for the next 5 semesters. In this capacity, I was responsible for the lab instruction of ~500 students each year. I led teams of more than ten graduate teaching assistants over various semesters, designed new labs, exams, homework problems, and reading assignments, delivered one recitation each week, and managed tutoring components. One of the most intellectually stimulating experiences occurred when I received the Lambert Teaching Fellowship to be an instructor for the fluid mechanics course. As part of it, I developed and delivered 42-course lectures to a class of 65 students. In the end, I received a teaching evaluation score of 4.8/5.0 from students. I was recognized with the Magoon Award for Excellence in Teaching and the Graduate Teaching Award from the Teaching Academy at Purdue University for my instructional effort. During my doctoral studies and instructorship at Harvard Medical School, I mentored 22 undergraduate students and research engineers, who went on to pursue highly competitive graduate engineering and medical programs.