Abstract:Circulating tumor cells (CTCs) are shed into the bloodstream from primary and metastatic tumor deposits. Their isolation and analysis hold great promise for the early detection of invasive cancer and the management of advanced disease, but technological hurdles have limited their broad clinical utility. We describe an inertial focusing–enhanced microfluidic CTC capture platform, termed “CTC-iChip,” that is capable of sorting rare CTCs from whole blood at 107 cells/s. Most importantly, the iChip is capable of i… Show more
“…These forces allow for the precise alignment of particles in a flow at throughputs orders of magnitudes higher than in previous microfluidic technologies. The high throughput nature of inertial focusing has enabled a range of microfluidic technologies for biomedical applications from separation technologies [8][9][10][11][12] , to automated sample preparations 13,14 , to novel cell analysis techniques such as cell deformability cytometry 15 and the isolation of circulating tumor cells from blood 16,17 .…”
mentioning
confidence: 99%
“…These forces allow for the precise alignment of particles in a flow at throughputs orders of magnitudes higher than in previous microfluidic technologies. The high throughput nature of inertial focusing has enabled a range of microfluidic technologies for biomedical applications from separation technologies [8][9][10][11][12] , to automated sample preparations 13,14 , to novel cell analysis techniques such as cell deformability cytometry 15 and the isolation of circulating tumor cells from blood 16,17 .It is generally accepted that inertial focusing in straight channels is dependent on two main parameters: Reynolds number, defined as Re C 5 rU Max D h /m, where r is the fluid density, m is the fluid viscosity, U Max > 3/2U Avg is the maximum velocity of the fluid and D h is the hydraulic diameter of the channel defined as D h 5 2hw/(h 1 w) where h and w are the height and width of the channel cross section respectively, and the particle confinement ratio, l 5 a/D h , where a, is the particle size. Prior research has determined a minimum threshold for inertial focusing to occur such that l .…”
The decoupled effects of Reynolds and Dean numbers are examined in inertial focusing flows. In doing so, a complex set of inertial focusing behavioral regimes is discovered within curved microfluidic channels over a range of channel Reynolds numbers, curvature ratios and particle confinement ratios. These regimes are characterized by particle migration either towards or away from the center of curvature as the channel Reynolds number is increased. The transition between these two regimes is shown to be a set of conditions where single-point equilibrium position focusing of particles of different sizes is achieved. A mechanism describing the observed motion of particles in such flows is hypothesized incorporating the redistribution of the main flow velocities caused by Dean flow and its effect on the balance forces on suspended particles.I nertial focusing is an area of significant interest in the realm of microfluidics because it combines high throughput capability with precision particle positioning and offers theoretical intrigue due to the seemingly endless surprises that accompany experimental results. Inertial focusing occurs under certain conditions as particles flowing through a microchannel migrate across streamlines to equilibrium positions within the flow. This migration is due to inertial effects of the fluid motion around the particle and the interaction of this flow field with the walls of the channel 1-5 . Equilibrium positions arise from a balance between two distinct effects; a shear gradient lift force directed towards the walls of the channel and an opposing wall effect 6,7 . These forces allow for the precise alignment of particles in a flow at throughputs orders of magnitudes higher than in previous microfluidic technologies. The high throughput nature of inertial focusing has enabled a range of microfluidic technologies for biomedical applications from separation technologies [8][9][10][11][12] , to automated sample preparations 13,14 , to novel cell analysis techniques such as cell deformability cytometry 15 and the isolation of circulating tumor cells from blood 16,17 .It is generally accepted that inertial focusing in straight channels is dependent on two main parameters: Reynolds number, defined as Re C 5 rU Max D h /m, where r is the fluid density, m is the fluid viscosity, U Max > 3/2U Avg is the maximum velocity of the fluid and D h is the hydraulic diameter of the channel defined as D h 5 2hw/(h 1 w) where h and w are the height and width of the channel cross section respectively, and the particle confinement ratio, l 5 a/D h , where a, is the particle size. Prior research has determined a minimum threshold for inertial focusing to occur such that l . 0.07 and Re C l 2 , also known as the particle Reynolds number, Re P , is $1 18 . The equilibrium positions can be further controlled using curved channels, where a secondary flow called Dean flow is established at finite Re C . The strength of this secondary flow is characterized by the inertia of the fluid and the curvature of the cha...
“…These forces allow for the precise alignment of particles in a flow at throughputs orders of magnitudes higher than in previous microfluidic technologies. The high throughput nature of inertial focusing has enabled a range of microfluidic technologies for biomedical applications from separation technologies [8][9][10][11][12] , to automated sample preparations 13,14 , to novel cell analysis techniques such as cell deformability cytometry 15 and the isolation of circulating tumor cells from blood 16,17 .…”
mentioning
confidence: 99%
“…These forces allow for the precise alignment of particles in a flow at throughputs orders of magnitudes higher than in previous microfluidic technologies. The high throughput nature of inertial focusing has enabled a range of microfluidic technologies for biomedical applications from separation technologies [8][9][10][11][12] , to automated sample preparations 13,14 , to novel cell analysis techniques such as cell deformability cytometry 15 and the isolation of circulating tumor cells from blood 16,17 .It is generally accepted that inertial focusing in straight channels is dependent on two main parameters: Reynolds number, defined as Re C 5 rU Max D h /m, where r is the fluid density, m is the fluid viscosity, U Max > 3/2U Avg is the maximum velocity of the fluid and D h is the hydraulic diameter of the channel defined as D h 5 2hw/(h 1 w) where h and w are the height and width of the channel cross section respectively, and the particle confinement ratio, l 5 a/D h , where a, is the particle size. Prior research has determined a minimum threshold for inertial focusing to occur such that l .…”
The decoupled effects of Reynolds and Dean numbers are examined in inertial focusing flows. In doing so, a complex set of inertial focusing behavioral regimes is discovered within curved microfluidic channels over a range of channel Reynolds numbers, curvature ratios and particle confinement ratios. These regimes are characterized by particle migration either towards or away from the center of curvature as the channel Reynolds number is increased. The transition between these two regimes is shown to be a set of conditions where single-point equilibrium position focusing of particles of different sizes is achieved. A mechanism describing the observed motion of particles in such flows is hypothesized incorporating the redistribution of the main flow velocities caused by Dean flow and its effect on the balance forces on suspended particles.I nertial focusing is an area of significant interest in the realm of microfluidics because it combines high throughput capability with precision particle positioning and offers theoretical intrigue due to the seemingly endless surprises that accompany experimental results. Inertial focusing occurs under certain conditions as particles flowing through a microchannel migrate across streamlines to equilibrium positions within the flow. This migration is due to inertial effects of the fluid motion around the particle and the interaction of this flow field with the walls of the channel 1-5 . Equilibrium positions arise from a balance between two distinct effects; a shear gradient lift force directed towards the walls of the channel and an opposing wall effect 6,7 . These forces allow for the precise alignment of particles in a flow at throughputs orders of magnitudes higher than in previous microfluidic technologies. The high throughput nature of inertial focusing has enabled a range of microfluidic technologies for biomedical applications from separation technologies [8][9][10][11][12] , to automated sample preparations 13,14 , to novel cell analysis techniques such as cell deformability cytometry 15 and the isolation of circulating tumor cells from blood 16,17 .It is generally accepted that inertial focusing in straight channels is dependent on two main parameters: Reynolds number, defined as Re C 5 rU Max D h /m, where r is the fluid density, m is the fluid viscosity, U Max > 3/2U Avg is the maximum velocity of the fluid and D h is the hydraulic diameter of the channel defined as D h 5 2hw/(h 1 w) where h and w are the height and width of the channel cross section respectively, and the particle confinement ratio, l 5 a/D h , where a, is the particle size. Prior research has determined a minimum threshold for inertial focusing to occur such that l . 0.07 and Re C l 2 , also known as the particle Reynolds number, Re P , is $1 18 . The equilibrium positions can be further controlled using curved channels, where a secondary flow called Dean flow is established at finite Re C . The strength of this secondary flow is characterized by the inertia of the fluid and the curvature of the cha...
“…Although much development has occurred in the last few years, there is still great need for effective, sensitive, and easy-to-use methods to capture and characterize these cells. Many microfluidic approaches are being developed, such as a high-throughput capture chip based on intertial focusing that enables sorting of magnetically labeled rare CTCs from the blood and of subsequent RNA-based single-cell characterization (85). Standard flow cytometry can also be used with fluorescence labels, but the relative scarcity of such cells makes detection difficult; approaches to overcome that includes an imaging flow cytometer that images streaks by adjusting exposure time and that allows very rare cells to be detected (86).…”
Section: Cancer Diagnosis and Monitoringmentioning
Immunotherapy has great potential to treat cancer and prevent future relapse by activating the immune system to recognize and kill cancer cells. A variety of strategies are continuing to evolve in the laboratory and in the clinic, including therapeutic noncellular (vector-based or subunit) cancer vaccines, dendritic cell vaccines, engineered T cells, and immune checkpoint blockade. Despite their promise, much more research is needed to understand how and why certain cancers fail to respond to immunotherapy and to predict which therapeutic strategies, or combinations thereof, are most appropriate for each patient. Underlying these challenges are technological needs, including methods to rapidly and thoroughly characterize the immune microenvironment of tumors, predictive tools to screen potential therapies in patient-specific ways, and sensitive, information-rich assays that allow patient monitoring of immune responses, tumor regression, and tumor dissemination during and after therapy. The newly emerging field of immunoengineering is addressing some of these challenges, and there is ample opportunity for engineers to contribute their approaches and tools to further facilitate the clinical translation of immunotherapy. Here we highlight recent technological advances in the diagnosis, therapy, and monitoring of cancer in the context of immunotherapy, as well as ongoing challenges.immunoengineering | cancer vaccine | adoptive T-cell therapy | diagnostic tools | checkpoint blockade
“…Applications of inertial focusing soared in the advent of microfluidics especially in curved channels where Dean forces could be used to enhance sorting accuracy 1,2,5 . Current understanding of sorting in curved channels rely on Ho and Leal description of a balance between shear-induced and wall-induced lift forces, suggesting that focusing is limited to low Reynolds (Re) numbers 6,7 .…”
Inertial focusing is the migration of particles in fluid toward equilibrium, where current theory predicts that shear-induced and wall-induced lift forces are balanced. First reported in 1961, this Segre-Silberberg effect is particularly useful for microfluidic isolation of cells and particles. Interestingly, recent work demonstrated particle focusing at high Reynolds numbers that cannot be explained by current theory. In this work, we show that non-monotonous velocity profiles, such as those developed in curved channels, create peripheral velocity maxima around which opposing shear-induced forces dominate over wall effects. Similarly, entry effects amplified in high Reynolds flow produce an equivalent trapping mechanism in short, straight channels. This new focusing mechanism in the developing flow regime enables a 10-fold miniaturization of inertial focusing devices, while our model corrects long-standing misconceptions about the nature of mechanical forces governing inertial focusing in curved channels.
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