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Microfluidic Devices for Digestion, Dissociation, and Filtration of Tissues into Single Cell Suspensions

  • Author(s): Qiu, Xiaolong;
  • Advisor(s): Haun, Jered B;
  • et al.

The ability to harvest primary cells from tissues is crucial in the fields of tissue engineering and regenerative medicine. Furthermore, achieving cellular suspensions from tissues in a timely and efficient manner is currently a bottleneck to the use of single cell-based technologies to analyze diseases such as cancer. Various enzymatic and mechanical approaches have attempted to solve this problem, but with limited success. Thus, there is a critical need to develop new techniques to improve the speed and efficiency of tissue dissociation at the point-of-care. One of the biggest advantages of microfluidics lies in its ability to precisely control flow profiles and thus the shear forces. This advantage provides an ideal platform for tissue dissociation at the single cell resolution. The overall goal of this dissertation is to develop a suite of microfluidic devices to achieve point-of-care tissue dissociation. First, to digest clinically resected tissue cores, we design a microfluidic device that utilizes precision fluid flows to rapidly digest tissues into cellular suspensions. Our microfluidic channels are designed to hydrodynamically mince tissues at discrete locations, while maximizing enzyme-tissue contact, thus accelerating digestion. We show our device is superior at recovering cells compared to conventional methods using animal organ tissues. Second, we employ a series of branching channel network in our dissociation device to gradually reduce device cross-section through a series of bifurcating stages. The constriction and expansion regions induce flow disturbances that help mix the sample and generate fluidic jets at different length scales to produce shear forces necessary to dissociate cell aggregates. Device performance has been characterized with tumor spheroids and human biopsies from cancer patients. Lastly, we demonstrate a microfluidic filter device with integrated microscale nylon mesh membranes to retain and recycle aggregates for further dissociation while selectively allowing single cells to elute from the device. Promising results have been achieved from device testing with cancer cell lines as well as animal organ tissues. At this point, each device has been developed with its specific goal in mind. In the future, all devices will be integrated to achieve a lab-on-a-chip tissue to single cell dissociation platform.

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