Development of a flexible micro spring array device for viable circulating tumor cell enrichment, analysis, primary culture and ex vivo therapeutic response test Metastatic cancer accounts for over 90% of cancer related deaths. Cancer metastasis is the process by which malignant circulating tumor cells (CTCs) detach from a primary tumor, spread through peripheral blood, then invade and proliferate in distant organs. The fundamental challenge of detecting CTCs in blood samples is the fact that they are so rare, requiring detection sensitivity of only a few tumors cells in billions of blood cells. Since the majority of solid tumor cells are of epithelial origin, and are almost always significantly larger and more rigid than normal blood cells, size based separation has been demonstrated as an effective method for CTC capture. The first goal of this project is to characterize and optimize a new flexible micro spring array (FMSA) device for the enrichment of CTCs from peripheral blood samples. The novel spring structures incorporated into the device design minimize concentrated stresses experienced by the CTCs and encourage their health, survival and proliferation. We have optimized the gap size of the device to reliably achieve over 85% recovery, 104 enrichment against leukocytes, 80% viability, and throughput of 5mL fresh blood in EDTA tube in 5 minutes. This technology is portable, cheap, fast, and more effective than CellSearchTM, which is the only current FDA approved system for CTC enumeration in a limited variety of cancers. In our preliminary study, we also found the driving differential pressure is critical for ell viability and proliferability. The safe operation pressure is orders of magnitude lower than the pressure normally used for conventional cell filtration. Thus our second goal is to develop a MEMS enabled automatic low pressure control system to facilitate the FMSA device. Together with the FMSA device, the whole system can solve the over 40 years'problem that widely used conventional filtration can't enrich viable mammalian cells because of cell damage and device clogging. More importantly, the FMSA system is capable of the capture of viable tumor cells that are available for primary culture and ex vivo therapeutic drug efficacy test, which is the third goal of the proposed study. The successful capture of viable CTCs will prompt the establishment of systems and protocols for their growth into a primary culture. This will provide the basis for testing the tumor cells'response to a variety of anticancer drugs ex vivo. If proven to be effective, a more specific and personalized treatment plan may be developed without having to unnecessarily expose a patient to the cost and toxic effects of chemotherapy. With further optimization for device flexibility and primary cell culture, and establishment of an automated low pressure control prototype, the FMSA enrichment system can be readily adapted for clinical usage. A pilot study of clinical samples obtained from our clinical collaborators will evaluate CTC detection, primary culture, and ex vivo drug efficacy tests with the FMSA system.

Public Health Relevance

The most deadly forms of cancer can release aggressive cells that travel through the bloodstream and spread throughout the body. This project will explore the use of a new microfabricated device to capture these invading cells and isolate them from a patient blood sample. The information obtained by growing and analyzing these cells can be used for improved detection, diagnosis, and development of personalized treatment plans.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Instrumentation and Systems Development Study Section (ISD)
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Ossandon, Miguel
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Pennsylvania State University
Biomedical Engineering
Schools of Engineering
University Park
United States
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Harouaka, Ramdane A; Zhou, Ming-Da; Yeh, Yin-Ting et al. (2014) Flexible micro spring array device for high-throughput enrichment of viable circulating tumor cells. Clin Chem 60:323-33
Harouaka, Ramdane; Kang, Zhigang; Zheng, Si-Yang et al. (2014) Circulating tumor cells: advances in isolation and analysis, and challenges for clinical applications. Pharmacol Ther 141:209-21
Harouaka, Ramdane A; Nisic, Merisa; Zheng, Si-Yang (2013) Circulating tumor cell enrichment based on physical properties. J Lab Autom 18:455-68