SBIR-STTR Award

This Small Business Innovation Research (SBIR) Phase I project will address the challenge of integrating two powerful single-cell analysis tools with the aim of developing and validating new biomarkers for malignancy. The deformability of invasive cells has long been hypothesized to confer their ability to migrate through tight tissue barriers and form metastases. Recently, this idea has been supported by mechanical measurements of cells either isolated from or directly in biological fluid specimens. This convergence of ideas from both biological and physical sciences represents a mechanical biomarker, and tools to be employed clinically to assay these properties are rapidly being developed. Cytovale?s technology measures cell deformability at a throughput of several thousand cells per second, comparable to the ubiquitous flow cytometer, which allows immediate measurement of cells directly in biological fluids. This technology has a demonstrated utility: highly sensitive detection of malignancy in cellularly heterogeneous clinical pleural effusions. Its integration with fluorescence in this project will provide a transformational research and clinical tool, well-aligned with the critical aims of improving patient care and reducing costs through automation, early detection of disease, and use of quantitative, novel biomarkers.

The broader impact/commercial potential of this project is realized by appreciating the applicability of the technology across research and clinical settings. Even without integration with fluorescence (flow) cytometry the technology has demonstrated its utility as a sensitive detector of malignancy in clinical specimens, specifically, pleural effusions. However, cell mechanics is an attractive biomarker for invasiveness, and is likely conserved throughout cells found in many biological fluids, including urine and fine needle aspirates. The proposed activity will further enhance the technology?s diagnostic accuracy. The instruments developed by Cytovale will be placed in clinical cytology labs to complement gold standard cytological methods, performing high sensitivity screens of biological fluids and eliminating unnecessary, invasive, and costly follow-up procedures. The hybrid instrument will also be an especially powerful tool for exploring connections between cell mechanics and traditional markers, which greatly extends the number of research laboratories which would benefit from this enabling technology.

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is in detecting sepsis early in its course, before end organ damage when it is most treatable. Sepsis, an uncontrolled systemic response to local infection by bacteria or fungi, is responsible for more deaths than prostate cancer, breast cancer, and AIDS combined and is associated with ~$17B in annual U.S. healthcare expenditures. We anticipate that providing emergency department physicians with an earlier diagnostic will profoundly influence clinical outcomes (currently ~40% mortality), costs (>$22,000/case), and the quality of life for survivors and their families. Accumulating evidence connects systemic immune activation ? a key process in sepsis ? with single-cell architectural changes that are mechanically measured by high-speed mechanical phenotyping technology. This technology is well-suited for adult sepsis screening in the emergency department (market size of $1.5B) due to: (1) the functional analysis of cell state the mechanical measurement provides, (2) its high achievable throughput and therefore statistical accuracy, (3) exceedingly short turnaround time, (4) low cost of goods, and (5) the clinically-actionable information it provides. Beyond the adult sepsis screening market, several additional indications include neonatal sepsis, bladder cancer detection, academic research tools, and drug development.The proposed project brings an innovative new class of biomarkers to bear on a problem that has been intractable with current biomarkers. Briefly, the physical properties of cells have been known to be important for decades, but only with the advent of breakthrough microfluidic technology have we been able to measure these parameters in a high-throughput manner capable of diagnosing disease. This Small Business Innovation Research (SBIR) Phase II award will be used to develop and validate innovative sample preparation and image analysis modules for a sepsis screening technology as well as performance of proof-of-concept clinical studies that would be a flagship offering in using biomechanical biomarkers to diagnose disease. The technical objectives are designed to improve sensitivity to white blood cells, activated during sepsis, by microfluidic automation of sample preparation and optimization of the microscopic imaging optics. In addition to preparing the test for practical implementation in the emergency department, the test will be validated with a proof-of-concept clinical study, and a clinical scoring system will be devised.