SBIR Phase I: Developing serial suspended microchannel resonators as a platform for personalized medicine in cancer

该SBIR一期项目旨在证明微流体仪器作为测量新的单细胞生物物理生物标志物的临床工具的技术可行性；质量积累率（MAR）拟议项目的成功完成将构成一种医疗工具的基础，这种医疗工具将改善癌症患者的治疗策略。由于每个人的癌症都是独特的，因此为个体患者分配最佳治疗方法对癌症治疗尤为重要。尽管肿瘤细胞的基因图谱一直是癌症个体化治疗方法的黄金标准，但最近的结果表明，只有一小部分患者真正受益于专门为他们指定的治疗方法。除了少数癌症类型（通过基因图谱可以观察到患者的剧烈反应）之外，大多数癌症患者继续遭受无效或次优治疗的痛苦，这是美国癌症治疗成本的主要驱动因素之一。这与传染病的个体化治疗形成鲜明对比，在个体化治疗中，几乎所有患者都是通过功能分析来确定最佳治疗方案的，这种分析基于在一组药物的影响下监测体外微生物的增殖。不幸的是，没有一种基于增殖的癌症检测被证明是足够可靠的，不能广泛应用于临床，主要是因为与细菌不同，大多数癌细胞从人体中移除后会迅速死亡。这个SBIR一期项目将开发测量癌细胞MAR的技术，作为药物反应的指标。MAR反应反映了个体细胞如何在非常短的时间内改变其生长以响应药物，而没有体外培养的长期影响。在这个项目中进行的研究将证明在临床环境中测量MAR的技术可行性，以确定一组治疗方案。该项目的结果将直接用于临床研究，最终通过临床试验寻求FDA的批准。该项目的重点是一种被称为串行悬浮微通道谐振器（sSMR）的新技术，它可以以极高的精度测量单细胞的质量和质量积累率（MAR）。该SBIR一期项目将测试sSMR平台的技术可行性，该平台用于测量原发肿瘤样本的药物敏感性，具有临床和商业相关的速度、多功能性和稳健性。公司的目标是开发sSMR作为平台，并引入MAR作为生物物理生物标志物，指导临床医生为特定癌症患者确定最佳治疗方案。因此，第一阶段的目标是至关重要的，因为从患者身上采集的活检样本中的肿瘤细胞在异质性、计数方面存在差异，并且在大多数情况下，在24-48离体内失去活力。在第一阶段，将开发关键技术，使sSMR芯片能够以高通量和高速率处理各种细胞类型和计数的样品。解决分析主要样品的技术挑战的研究活动将分为三个方面。首先，在保持测量精度的同时，增加芯片内细胞的流速，防止原发肿瘤细胞粘附在通道壁上。这是具有挑战性的，因为测量的精度与每个细胞在芯片中花费的时间成反比。其次，将在芯片上实现光流开关技术，采用新的微流控t结设计，实现颗粒形态的成像和表征，避免死细胞、碎片和双峰，以提高分析的稳健性和吞吐量。第三，利用微流控t结和已开发的成像能力，开发微流控细胞富集技术。这一特点将允许在有限细胞计数的肿瘤活检中进行更大范围的药物条件测试。为了验证这些创新，将测量和分析从10名多发性骨髓瘤患者身上提取的肿瘤细胞对三种药物及其组合的反应。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.