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Sollier E.,University of California at Los Angeles | Sollier E.,Vortex Biosciences Inc. | Go D.E.,University of California at Los Angeles | Che J.,University of California at Los Angeles | And 18 more authors.
Lab on a Chip - Miniaturisation for Chemistry and Biology | Year: 2014

A blood-based, low cost alternative to radiation intensive CT and PET imaging is critically needed for cancer prognosis and management of its treatment. "Liquid biopsies" of circulating tumor cells (CTCs) from a relatively non-invasive blood draw are particularly ideal, as they can be repeated regularly to provide up to date molecular information about the cancer, which would also open up key opportunities for personalized therapies. Beyond solely diagnostic applications, CTCs are also a subject of interest for drug development and cancer research. In this paper, we adapt a technology previously introduced, combining the use of micro-scale vortices and inertial focusing, specifically for the high-purity extraction of CTCs from blood samples. First, we systematically varied parameters including channel dimensions and flow rates to arrive at an optimal device for maximum trapping efficiency and purity. Second, we validated the final device for capture of cancer cell lines in blood, considering several factors, including the effect of blood dilution, red blood cell lysis and cell deformability, while demonstrating cell viability and independence on EpCAM expression. Finally, as a proof-of-concept, CTCs were successfully extracted and enumerated from the blood of patients with breast (N = 4, 25-51 CTCs per 7.5 mL) and lung cancer (N = 8, 23-317 CTCs per 7.5 mL). Importantly, samples were highly pure with limited leukocyte contamination (purity 57-94%). This Vortex approach offers significant advantages over existing technologies, especially in terms of processing time (20 min for 7.5 mL of whole blood), sample concentration (collecting cells in a small volume down to 300 μL), applicability to various cancer types, cell integrity and purity. We anticipate that its simplicity will aid widespread adoption by clinicians and biologists who desire to not only enumerate CTCs, but also uncover new CTC biology, such as unique gene mutations, vesicle secretion and roles in metastatic processes. This journal is © 2014 The Royal Society of Chemistry.


Sollier E.,University of California at Los Angeles | Sollier E.,Vortex Biosciences Inc. | Amini H.,University of California at Los Angeles | Go D.E.,University of California at Los Angeles | And 4 more authors.
Microfluidics and Nanofluidics | Year: 2015

Control of particles/cells and the surrounding fluid is enabling toward the purification of complex cellular samples, which still remains a bottleneck for point-of-care diagnostic devices. We explore a newly developed approach to engineer fluid stream motion while simultaneously controlling particles using inertial lift force. We use inertial flow deformations induced by sequences of simple pillar microstructures to control the fluid stream. Instead of iterative experimental procedures to identify optimal sequences of structures, we use software that numerically predicts the total deformation function for any pillar sequence. Using this program, we engineer the cross-stream translation of a fluid stream to achieve solution exchange around particles, where both the particles and fluid stream remain focused and can be extracted at high purity. An extraction device, called a pillar separation device, is then designed and validated with suspensions of rigid particles to identify optimal operating parameters. At a flow rate of 250 µL/min, up to 96 % beads and 70.5 % of an initial buffer stream inputted into the system can be collected downstream in separate outlets, respectively, with 10.9 % buffer and 0.3 % bead contamination. This device was further applied to a functionalized bead bioassay, achieving high-yield and continuous separation of 98 % of biotin-coated beads from 72.2 % of extra FITC-biotin. In a last study, we performed the extraction of 80 % of leukocytes from lysed blood, which validates our platform can be applied on living cells and used for various functions of cellular sample preparation. © 2015, Springer-Verlag Berlin Heidelberg.


Dhar M.,University of California at Los Angeles | Wong J.,University of California at Los Angeles | Karimi A.,University of California at Los Angeles | Che J.,University of California at Los Angeles | And 11 more authors.
Biomicrofluidics | Year: 2015

Circulating tumor cells (CTCs) are important biomarkers for monitoring tumor dynamics and efficacy of cancer therapy. Several technologies have been demonstrated to isolate CTCs with high efficiency but achieve a low purity from a large background of blood cells. We have previously shown the ability to enrich CTCs with high purity from large volumes of blood through selective capture in microvortices using the Vortex Chip. The device consists of a narrow channel followed by a series of expansion regions called reservoirs. Fast flow in the narrow entry channel gives rise to inertial forces, which direct larger cells into trapping vortices in the reservoirs where they remain circulating in orbits. By studying the entry and stability of particles following entry into reservoirs, we discover that channel cross sectional area plays an important role in controlling the size of trapped particles, not just the orbital trajectories. Using these design modifications, we demonstrate a new device that is able to capture a wider size range of CTCs from clinical samples, uncovering further heterogeneity. This simple biophysical method opens doors for a range of downstream interventions, including genetic analysis, cell culture, and ultimately personalized cancer therapy. © 2015 AIP Publishing LLC.


Che J.,University of California at Los Angeles | Dhar M.,University of California at Los Angeles | Yu V.,University of California at Los Angeles | Go D.E.,University of California at Los Angeles | And 7 more authors.
18th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2014 | Year: 2014

Here we describe improvements for the rapid, size-based capture of circulating tumor cells (CTCs) from blood. We have previously presented the Vortex Chip [1], an inertial microfluidic device which isolates CTCs at high throughput (400 μL/min of whole blood), purity (>80%), and viability (∼80%), but was limited by ∼20% efficiency. Here, we demonstrate improved CTC capture efficiency (up to 40%) and speed of processing (up to 8 mL/min) with the High Throughput Vortex Chip (Vortex HT). We show in cancer cell lines and clinical samples that the Vortex HT purifies larger numbers of CTCs. © 14CBMS.


PubMed | Vortex Biosciences Inc., Stanford University and University of California at Los Angeles
Type: Journal Article | Journal: Biomicrofluidics | Year: 2015

Circulating tumor cells (CTCs) are important biomarkers for monitoring tumor dynamics and efficacy of cancer therapy. Several technologies have been demonstrated to isolate CTCs with high efficiency but achieve a low purity from a large background of blood cells. We have previously shown the ability to enrich CTCs with high purity from large volumes of blood through selective capture in microvortices using the Vortex Chip. The device consists of a narrow channel followed by a series of expansion regions called reservoirs. Fast flow in the narrow entry channel gives rise to inertial forces, which direct larger cells into trapping vortices in the reservoirs where they remain circulating in orbits. By studying the entry and stability of particles following entry into reservoirs, we discover that channel cross sectional area plays an important role in controlling the size of trapped particles, not just the orbital trajectories. Using these design modifications, we demonstrate a new device that is able to capture a wider size range of CTCs from clinical samples, uncovering further heterogeneity. This simple biophysical method opens doors for a range of downstream interventions, including genetic analysis, cell culture, and ultimately personalized cancer therapy.


PubMed | Vortex Biosciences Inc., Jonsson Comprehensive Cancer Center, Stanford University and University of California at Los Angeles
Type: | Journal: Scientific reports | Year: 2016

Circulating tumor cells (CTCs) have a great potential as indicators of metastatic disease that may help physicians improve cancer prognostication, treatment and patient outcomes. Heterogeneous marker expression as well as the complexity of current antibody-based isolation and analysis systems highlights the need for alternative methods. In this work, we use a microfluidic Vortex device that can selectively isolate potential tumor cells from blood independent of cell surface expression. This system was adapted to interface with three protein-marker-free analysis techniques: (i) an in-flow automated image processing system to enumerate cells released, (ii) cytological analysis using Papanicolaou (Pap) staining and (iii) fluorescence in situ hybridization (FISH) targeting the ALK rearrangement. In-flow counting enables a rapid assessment of the cancer-associated large circulating cells in a sample within minutes to determine whether standard downstream assays such as cytological and cytogenetic analyses that are more time consuming and costly are warranted. Using our platform integrated with these workflows, we analyzed 32 non-small cell lung cancer (NSCLC) and 22 breast cancer patient samples, yielding 60 to 100% of the cancer patients with a cell count over the healthy threshold, depending on the detection method used: respectively 77.8% for automated, 60-100% for cytology, and 80% for immunostaining based enumeration.


PubMed | Counsyl Inc., Stanford University, Comprehensive Cancer Center Charite, Charite University Hospital and 3 more.
Type: | Journal: Oncotarget | Year: 2016

Treatment of advanced colorectal cancer (CRC) requires multimodal therapeutic approaches and need for monitoring tumor plasticity. Liquid biopsy biomarkers, including CTCs and ctDNA, hold promise for evaluating treatment response in real-time and guiding therapeutic modifications. From 15 patients with advanced CRC undergoing liver metastasectomy with curative intent, we collected 41 blood samples at different time points before and after surgery for CTC isolation and quantification using label-free Vortex technology. For mutational profiling, KRAS, BRAF, and PIK3CA hotspot mutations were analyzed in CTCs and ctDNA from 23 samples, nine matched liver metastases and three primary tumor samples. Mutational patterns were compared. 80% of patient blood samples were positive for CTCs, using a healthy baseline value as threshold (0.4 CTCs/mL), and 81.4% of captured cells were EpCAM+ CTCs. At least one mutation was detected in 78% of our blood samples. Among 23 matched CTC and ctDNA samples, we found a concordance of 78.2% for KRAS, 73.9% for BRAF and 91.3% for PIK3CA mutations. In several cases, CTCs exhibited a mutation that was not detected in ctDNA, and vice versa. Complementary assessment of both CTCs and ctDNA appears advantageous to assess dynamic tumor profiles.


Sinkala E.,University of California at Berkeley | Sollier E.,Vortex Biosciences Inc. | Sollier E.,Stanford University | Jeffrey S.S.,Stanford University | Herr A.E.,University of California at Berkeley
18th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2014 | Year: 2014

We present a workflow that unifies rare-cell enrichment, selection and placement in microwells with single-cell western blotting (scWestern). The scWestern workflow delivers multiplexed, quantitation of single cells, unattainable in existing protein assays. We identify, pick and place single cells into 30-70 micron diameter microwells prior to electrophoretic analyses of proteins and subsequent antibody-based protein probing. Through scWestern analysis of breast cancer cells (MDA-MB-231), we observe positive signal for several downstream targets of the EGFR pathway, a pathway implicated in cancer metastasis. Successfully combining single-cell handling with scWestern, we are now applying the scWestern to protein analysis of rare cells. © 14CBMS.


Trademark
Vortex Biosciences Inc. | Date: 2016-04-05

Medical devices for use in the isolation and analysis of cells from bodily fluids for use in the field of oncology.

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