Deterministic Separation of Cancer Cells from Blood at 10 mL/min

Circulating tumor cells (CTCs) and circulating clusters of cancer and stromal cells have been identified in the blood of patients with malignant cancer and can be used as a diagnostic for disease severity, assess the efficacy of different treatment strategies and possibly determine the eventual location of metastatic invasions for possible treatment. There is thus a critical need to isolate, propagate and characterize viable CTCs and clusters. Here, we present a microfluidic device for mL/min flow rate, continuous-flow capture of viable CTCs from blood using deterministic lateral displacement arrays. We show here that a deterministic bump array can be designed such that it will isolate with efficiency greater than 85% CTCs over a large range in sizes from millimeter volume clinical blood samples in minutes, with no effect on cell vitality so that further culturing and analysis of the cells can be carried out

Anisotropic permeability in deterministic lateral displacement arrays

We uncover anisotropic permeability in microfluidic deterministic lateral displacement (DLD) arrays. A DLD array can achieve high-resolution bimodal size-based separation of microparticles, including bioparticles, such as cells. For an application with a given separation size, correct device operation requires that the flow remains at a fixed angle to the obstacle array. We demonstrate via experiments and lattice-Boltzmann simulations that subtle array design features cause anisotropic permeability. Anisotropic permeability indicates the microfluidic array's intrinsic tendency to induce an undesired lateral pressure gradient. This can cause an inclined flow and therefore local changes in the critical separation size. Thus, particle trajectories can become unpredictable and the device useless for the desired separation task. Anisotropy becomes severe for arrays with unequal axial and lateral gaps between obstacle posts and highly asymmetric post shapes. Furthermore, of the two equivalent array layouts employed with the DLD, the rotated-square layout does not display intrinsic anisotropy. We therefore recommend this layout over the easier-to-implement parallelogram layout. We provide additional guidelines for avoiding adverse effects of anisotropy on the DLD.Comment: 13 pages, 10 figures, 1 table, DLD, particle separation, microfluidics, anisotropic permeabilit

Microfluidic Blood Cell Sorting: Now and Beyond

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106971/1/smll201302907.pd

Breakdown of deterministic lateral displacement efficiency for non-dilute suspensions: a numerical study

We investigate the effect of particle volume fraction on the efficiency of deterministic lateral displacement (DLD) devices. DLD is a popular passive sorting technique for microfluidic applications. Yet, it has been designed for treating dilute suspensions, and its efficiency for denser samples is not well known. We perform 3D simulations based on the immersed-boundary, lattice-Boltzmann and finite-element methods to model the flow of red blood cells (RBCs) in different DLD devices. We quantify the DLD efficiency in terms of appropriate "failure" probabilities and RBC counts in designated device outlets. Our main result is that the displacement mode breaks down upon an increase of RBC volume fraction, while the zigzag mode remains relatively robust. This suggests that the separation of larger particles (such as white blood cells) from a dense RBC background is simpler than separating smaller particles (such as platelets) from the same background. The observed breakdown stems from non-deterministic particle collisions interfering with the designed deterministic nature of DLD devices. Therefore, we postulate that dense suspension effects generally hamper efficient particle separation in devices based on deterministic principles.Comment: 21 pages, 9 figure

One‐Way Particle Transport Using Oscillatory Flow in Asymmetric Traps

One challenge of integrating of passive, microparticles manipulation techniques into multifunctional microfluidic devices is coupling the continuous‐flow format of most systems with the often batch‐type operation of particle separation systems. Here, a passive fluidic technique—one‐way particle transport—that can conduct microparticle operations in a closed fluidic circuit is presented. Exploiting pass/capture interactions between microparticles and asymmetric traps, this technique accomplishes a net displacement of particles in an oscillatory flow field. One‐way particle transport is achieved through four kinds of trap–particle interactions: mechanical capture of the particle, asymmetric interactions between the trap and the particle, physical collision of the particle with an obstacle, and lateral shift of the particle into a particle–trapping stream. The critical dimensions for those four conditions are found by numerically solving analytical mass balance equations formulated using the characteristics of the flow field in periodic obstacle arrays. Visual observation of experimental trap–particle dynamics in low Reynolds number flow (<0.01) confirms the validity of the theoretical predictions. This technique can transport hundreds of microparticles across trap rows in only a few fluid oscillations (<500 ms per oscillation) and separate particles by their size differences.Passive fluidic particle transport using asymmetric traps in nonacoustic oscillatory flow is developed. The conditions to achieve this technique are based on the mass balance of fluid flows, the theory of deterministic lateral displacement of microparticles, and experimental validation. This technique can transport or separate microparticles in a closed chamber and facilitate the integration of the microparticle system into portable lab‐on‐a‐chip devices.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142443/1/smll201702724-sup-0001-S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142443/2/smll201702724.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142443/3/smll201702724_am.pd

Inertial focusing of cancer cell lines in curvilinear microchannels

Circulating tumor cells (CTCs) are rare cancer cells, which originate from the primary tumors and migrate to the bloodstream. Separation of CTCs from blood is critical because metastatic CTCs might hold different genomic and phenotypic properties compared to primary tumor cells. In this regard, accurate prognosis and effective treatment methods are necessary. For this purpose, focusing biological particles and cells using microfluidic systems have been implemented as an efficient CTCs enumeration and enrichment method. Passive, continuous, label-free and parallelizable size-dependent focusing based on hydrodynamic forces is preferred in this study to sort cancer cells while avoiding cell death and achieving high throughput. The focusing behavior of MDA-MB-231 (11–22 μm), Jurkat (8–17 μm), K562 (8–22 μm), and HeLa (16–29 μm) was examined with respect to different Reynolds numbers and Dean numbers. The effect of curvature on cell focusing was carefully assessed. The focusing positions of the cells clearly indicated that isolations of MDA cells from MDA-Jurkat cell mixtures as well as of HeLa cells from HeLa-Jurkat cell mixtures were possible by using the curvilinear channels with a curvature angle of 280° at the Reynolds number of 121. © 2019 The Author(s

Microfluidic Devices for High Throughput Cell Sorting and Chemical Treatment

Separation by size is a fundamental analytical and preparative technique in biology, medicine, and chemistry. Deterministic lateral displacement (DLD) arrays are microfluidic devices capable of high-precision particle sorting based on size. In this thesis, we will discuss improvements in the functionality of DLD arrays and several new applications. We'll rst discuss a methodology for performing sequential on-chip chemical treatment by using the DLD array to direct particles in the "bumping" trajectory across co-flowing reagent streams and demonstrates this technique with platelet labeling and washing and E. Coli lysis and chromosomal separation. We then discuss a deterministic microfluidic ratchet that could separate particles in an intermediate size range using a DLD array with triangular posts in an oscillating flow. We then extended this idea of using triangular posts in DLD arrays to continuous-flow operation and showed signicant performance enhancements over arrays with circular posts when the triangle vertex is used as the displacement edge. Taking this idea of increasing device throughput to the next step, we developed a highly parallelized DLD array architecture for processing macroscopic fluid volumes by operating many arrays in parallel and showed flow rates on the order of 10 mL/min with a single-layer device and applied these high throughput DLD arrays to isolating viable circulating tumor cells from blood and dewatering algae for biofuel production