This SBIR Phase I project aims to demonstrate the technical feasibility of a microfluidic instrument as a clinical tool for measuring a new single-cell biophysical biomarker; mass accumulation rate (MAR). Successful completion of the proposed project will constitute the foundation of a medical instrument that will improve treatment strategies for cancer patients. Assigning the optimal therapy for individual patients is particularly important for the treatment of cancer, since every individual's cancer is unique. Although genetic profiling of tumor cells has been the gold standard for personalized medicine approaches in cancer, recent results demonstrate that only a small percentage of patients actually benefit from therapies specifically assigned for them. Aside from few cancer types, where drastic patient responses can be observed using genetic profiling, most cancer patients continue to suffer from ineffective or sub-optimal therapies, which in one of the main drivers of the cost of cancer treatment in the US. This stands in stark contrast to personalized medicine in infectious diseases, where almost all patients are prescribed optimal treatments determined by functional assays based on monitoring the proliferation of microbes ex vivo under the influence of a panel of drugs. Unfortunately, no proliferation-based test for cancer has proven to be sufficiently reliable to be widely adopted for clinical use, mostly because unlike bacteria most cancer cells quickly die when removed from the human body. This SBIR Phase I project will develop the techniques to measure MAR of cancer cells as a metric for drug response. MAR response reflects how individual cells change their growth in response to drugs in very short timescales without the long-term effects of ex vivo culturing. The research that will be conducted in this project will prove the technical feasibility of measuring MAR in a clinical setting for a panel of treatment options. Outcomes of this project will directly enable clinical studies to be conducted, before ultimately seeking FDA approval through clinical trials. The focus of this project is a new technology known as the serial Suspended Microchannel Resonator (sSMR), which can measure mass and mass accumulation rates (MAR) of single cells with extreme precision. This SBIR Phase I project will test the technical feasibility of the sSMR platform for measuring drug susceptibility of primary tumor samples with a clinically and commercially relevant speed, versatility and robustness. The company aims to develop sSMR as a platform and introduce MAR as biophysical biomarker guiding clinicians in identifying the best therapy options for a specific cancer patient. Therefore, the goals of this first phase are critical, as tumor cells in biopsy samples taken from patients show differences in heterogeneity, count, and in most cases, lose their viability within 24-48 ex vivo. In Phase I, key technologies will be developed that will enable a sSMR chip to process samples with various cell types and counts at a high throughput and rate. The research activities to address the technical challenges for analyzing primary samples will be three-fold. First, while maintaining the measurement precision, the flow rate of cells in the chip will be increased to prevent primary tumor cells from adhering to channel walls. This is challenging, because the precision of measurement is inversely proportional to the time duration each cell spends in the chip. Second, an opto-fluidic switching technique will be implemented on chips with a new microfluidic T-junction design enabling imaging and characterization of particle morphology, and the avoidance of dead cells, debris, and doublets to improve assay robustness and throughput. Third, by leveraging the microfluidic T-junction and developed imaging capabilities, a microfluidic cell enrichment technique will be developed. This feature will allow for a larger panel of drug conditions to be tested on tumor biopsies with limited cell counts. For validation of these innovations, response of tumor cells taken from 10 multiple myeloma patients to a panel of three drugs and their combinations will be measured and analyzed.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.
