Several biomedical analyses are performed on particular types of cells present in body samples or using functionalized microparticles. Success in such analyses depends on the ability to separate or isolate the target cells or microparticles from the rest of the sample. In conventional procedures, multiple pieces of equipment, such as centrifuges, magnets, and macroscale filters, are used for such purposes, which are time-consuming, associated with human error, and require several operational steps. In the past two decades, there has been a tendency to develop microfluidic techniques, so-called lab-on-a-chip, to miniaturize and automate these procedures. The processes used for the separation and isolation of the cells and microparticles are scaled down into a small microfluidic chip, requiring very small amounts of sample. Differences in the physical and biological properties of the target cells from the other components present in the sample are the key to the development of such microfluidic techniques. These techniques are categorized as filtration-, hydrodynamic-, dielectrophoretic-, acoustic- and magnetic-based methods. Here we review the microfluidic techniques developed for sorting, separation, and isolation of cells and microparticles for biomedical applications. The mechanisms behind such techniques are thoroughly explained and the applications in which these techniques have been adopted are reviewed.

A review of sorting, separation and isolation of cells and microbeads for biomedical applications: microfluidic approaches.

Particle manipulation is often required in many applications such as bioanalysis, disease diagnostics, drug delivery and self-cleaning surfaces. The fast progress in micro- and nano-engineering has contributed to the rapid development of a variety of technologies to manipulate particles including more established methods based on microfluidics, as well as recently proposed innovative methods that still are in the initial phases of development, based on self-driven microbots and artificial cilia. Here, we review these techniques with respect to their operation principles and main applications. We summarize the shortcomings and give perspectives on the future development of particle manipulation techniques. Rather than offering an in-depth, detailed, and complete account of all the methods, this review aims to provide a broad but concise overview that helps to understand the overall progress and current status of the diverse particle manipulation methods. The two novel developments, self-driven microbots and artificial cilia-based manipulation, are highlighted in more detail.

/pdf/a-concise-review-of-microfluidic-particle-manipulation-3zzef8uzki.pdf

A concise review of microfluidic particle manipulation methods

Significance Chimeric antigen receptor (CAR) T-cell therapy is approved by the US Food and Drug Administration (FDA) for the treatment of B-cell acute lymphoblastic leukemia. Efforts are now underway to evaluate the efficacy of CAR T-cell therapy in solid tumors. However, a key limitation in the advancement of T-cell therapy is the lack of information on the biodistribution of the T cells in patients. Therefore, there is a need for the identification of translatable methods for tracking the therapeutic T cells noninvasively. We describe the mechanical labeling of CAR T cells with an FDA-approved iron oxide nanoparticle to demonstrate the noninvasive and multimodal imaging of the CAR T cells. This method may be utilized for monitoring T cells in clinical trials. Metastatic osteosarcoma has a poor prognosis with a 2-y, event-free survival rate of ∼15 to 20%, highlighting the need for the advancement of efficacious therapeutics. Chimeric antigen receptor (CAR) T-cell therapy is a potent strategy for eliminating tumors by harnessing the immune system. However, clinical trials with CAR T cells in solid tumors have encountered significant challenges and have not yet demonstrated convincing evidence of efficacy for a large number of patients. A major bottleneck for the success of CAR T-cell therapy is our inability to monitor the accumulation of the CAR T cells in the tumor with clinical-imaging techniques. To address this, we developed a clinically translatable approach for labeling CAR T cells with iron oxide nanoparticles, which enabled the noninvasive detection of the iron-labeled T cells with magnetic resonance imaging (MRI), photoacoustic imaging (PAT), and magnetic particle imaging (MPI). Using a custom-made microfluidics device for T-cell labeling by mechanoporation, we achieved significant nanoparticle uptake in the CAR T cells, while preserving T-cell proliferation, viability, and function. Multimodal MRI, PAT, and MPI demonstrated homing of the T cells to osteosarcomas and off-target sites in animals administered with T cells labeled with the iron oxide nanoparticles, while T cells were not visualized in animals infused with unlabeled cells. This study details the successful labeling of CAR T cells with ferumoxytol, thereby paving the way for monitoring CAR T cells in solid tumors.

In vivo imaging of nanoparticle-labeled CAR T cells

Periostin promotes liver fibrogenesis by activating lysyl oxidase in hepatic stellate cells

Microfluidic generation of transient cell volume exchange for convectively driven intracellular delivery of large macromolecules

The enrichment of viable cells is an essential step to obtain effective products for cell therapy. While procedures exist to characterize the viability of cells, most methods to exclude nonviable cells require the use of density gradient centrifugation or antibody-based cell sorting with molecular labels of cell viability. We report a label-free microfluidic technique to separate live and dead cells that exploits differences in cellular stiffness. The device uses a channel with repeated ridges that are diagonal with respect to the direction of cell flow. Stiff nonviable cells directed through the channel are compressed and translated orthogonally to the channel length, while soft live cells follow hydrodynamic flow. As a proof of concept, Jurkat cells are enriched to high purity of viable cells by a factor of 185-fold. Cell stiffness was validated as a sorting parameter as nonviable cells were substantially stiffer than live cells. To highlight the utility for hematopoietic stem cell transplantation, frozen samples of cord blood were thawed and the purity of viable nucleated cells was increased from 65% to over 94% with a recovery of 73% of the viable cells. Thus, the microfluidic stiffness sorting can simply and efficiently obtain highly pure populations of viable cells.

Microfluidic Sorting of Cells by Viability Based on Differences in Cell Stiffness

Vaso-occlusive crisis (VOC) is a complex process that occurs in patients with sickle cell disease (SCD) and is often associated with pain and urgent hospitalization. A major instigator of VOC is microvascular obstruction by pathologically stiffened sickle red blood cells (RBCs), and thus therapy relies heavily on optimizing intravenous fluid (IVF) hydration to increase RBC deformability. However, no evidence-based guidelines regarding the choice of IVF currently exist. We therefore analyzed alterations in biomechanical properties of sickle RBCs isolated from patients with homozygous SCD (hemoglobin SS) after exposure to different osmolarities of clinical IVF formulations. Atomic force microscopy (AFM) was used to assess stiffness of RBCs after exposure to different IVFs. A microfluidic model of the human capillary system was used to assess transit time and propensity to occlusion after exposure to the different IVF formulations. Sickle RBCs exposed to normal saline (NS) had increased stiffness, transit times, and propensity to microchannel occlusion compared to other osmolarities. Normal saline, an IVF formulation often used to treat patients with SCD during VOC, may induce localized microvascular obstruction due to alterations of sickle RBC biomechanical properties.

This article is protected by copyright. All rights reserved.

/pdf/normal-saline-is-associated-with-increased-sickle-red-cell-na8nwz61o7.pdf

Normal saline is associated with increased sickle red cell stiffness and prolonged transit times in a microfluidic model of the capillary system

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Microfluidic Sorting of Cells by Viability Based on Differences in Cell Stiffness

Normal saline is associated with increased sickle red cell stiffness and prolonged transit times in a microfluidic model of the capillary system