The Fabrication and Application Mechanism of Microfluidic Systems for High Throughput Biomedical Screening: A Review

Microfluidic systems have been widely explored based on microfluidic technology, and it has been widely used for biomedical screening. The key parts are the fabrication of the base scaffold, the construction of the matrix environment in the 3D system, and the application mechanism. In recent years, a variety of new materials have emerged, meanwhile, some new technologies have been developed. In this review, we highlight the properties of high throughput and the biomedical application of the microfluidic chip and focus on the recent progress of the fabrication and application mechanism. The emergence of various biocompatible materials has provided more available raw materials for microfluidic chips. The material is not confined to polydimethylsiloxane (PDMS) and the extracellular microenvironment is not limited by a natural matrix. The mechanism is also developed in diverse ways, including its special physical structure and external field effects, such as dielectrophoresis, magnetophoresis, and acoustophoresis. Furthermore, the cell/organ-based microfluidic system provides a new platform for drug screening due to imitating the anatomic and physiologic properties in vivo. Although microfluidic technology is currently mostly in the laboratory stage, it has great potential for commercial applications in the future.

[1]  B. Mathew,et al.  Microfluidics Based Magnetophoresis: A Review. , 2018, Chemical record.

[2]  Noo Li Jeon,et al.  Microfluidics within a well: an injection-molded plastic array 3D culture platform. , 2018, Lab on a chip.

[3]  Mingrui Sun,et al.  Creating a capture zone in microfluidic flow greatly enhances the throughput and efficiency of cancer detection. , 2019, Biomaterials.

[4]  Mingqiang Li,et al.  Cell-laden microfluidic microgels for tissue regeneration. , 2016, Lab on a chip.

[5]  J. Keller,et al.  Brain-on-a chip technologies for investigating neuronal diseases: Toward precision medicine applications , 2018, 2018 IEEE International Symposium on Circuits and Systems (ISCAS).

[6]  Nupura S. Bhise,et al.  A liver-on-a-chip platform with bioprinted hepatic spheroids , 2016, Biofabrication.

[7]  D. Cho,et al.  Cell-printed 3D liver-on-a-chip possessing a liver microenvironment and biliary system , 2019, Biofabrication.

[8]  S. Hao,et al.  Nucleus of Circulating Tumor Cell Determines Its Translocation Through Biomimetic Microconstrictions and Its Physical Enrichment by Microfiltration. , 2018, Small.

[9]  Ruchuan Liu,et al.  Microfabrication-Based Three-Dimensional (3-D) Extracellular Matrix Microenvironments for Cancer and Other Diseases , 2018, International journal of molecular sciences.

[10]  Alex J. Thompson,et al.  Design Analysis and Optimization of a Single-Layer PDMS Microfluidic Artificial Lung , 2019, IEEE Transactions on Biomedical Engineering.

[11]  Xiaochen Wang,et al.  A novel 3-D bio-microfluidic system mimicking in vivo heterogeneous tumour microstructures reveals complex tumour-stroma interactions. , 2017, Lab on a chip.

[12]  E. Young,et al.  Microfluidic lung airway-on-a-chip with arrayable suspended gels for studying epithelial and smooth muscle cell interactions. , 2018, Lab on a chip.

[13]  Katja Schenke-Layland,et al.  ECM and ECM-like materials - Biomaterials for applications in regenerative medicine and cancer therapy. , 2016, Advanced drug delivery reviews.

[14]  Jia Yu,et al.  Therapy response testing of breast cancer in a 3D high-throughput perfused microfluidic platform , 2017, BMC Cancer.

[15]  Christopher Haslett,et al.  Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: A mechanism for small cell lung cancer growth and drug resistance in vivo , 1999, Nature Medicine.

[16]  V. Vandelinder,et al.  Separation of plasma from whole human blood in a continuous cross-flow in a molded microfluidic device. , 2006, Analytical chemistry.

[17]  Caixia Li,et al.  The Optimization of Electrophoresis on a Glass Microfluidic Chip and its Application in Forensic Science , 2017, Journal of forensic sciences.

[18]  Ziyi He,et al.  Recent advances in microfluidic 3D cellular scaffolds for drug assays , 2017 .

[19]  K. McCloskey,et al.  Mobility measurements of immunomagnetically labeled cells allow quantitation of secondary antibody binding amplification. , 2001, Biotechnology and bioengineering.

[20]  J. Brash,et al.  An ultra-thin, all PDMS-based microfluidic lung assist device with high oxygenation capacity. , 2019, Biomicrofluidics.

[21]  Dries Braeken,et al.  Brain-on-a-chip Devices for Drug Screening and Disease Modeling Applications. , 2019, Current pharmaceutical design.

[22]  F. Tan,et al.  Microfluidic techniques for tumor cell detection , 2018, Electrophoresis.

[23]  Jongyoon Han,et al.  Large-Volume Microfluidic Cell Sorting for Biomedical Applications. , 2015, Annual review of biomedical engineering.

[24]  Shay Soker,et al.  In situ patterned micro 3D liver constructs for parallel toxicology testing in a fluidic device , 2015, Biofabrication.

[25]  D. Ingber,et al.  Reconstituting Organ-Level Lung Functions on a Chip , 2010, Science.

[26]  Hywel Morgan,et al.  Skeletal stem cell isolation: A review on the state-of-the-art microfluidic label-free sorting techniques. , 2016, Biotechnology advances.

[27]  Soo Hyeon Kim,et al.  Sequential Cell-Processing System by Integrating Hydrodynamic Purification and Dielectrophoretic Trapping for Analyses of Suspended Cancer Cells , 2019, Micromachines.

[28]  Vivek Gupta,et al.  Microfluidics‐based 3D cell culture models: Utility in novel drug discovery and delivery research , 2016, Bioengineering & translational medicine.

[29]  M. Lutolf,et al.  Microfluidic synthesis of cell-type-specific artificial extracellular matrix hydrogels. , 2013, Biomacromolecules.

[30]  Feng Guo,et al.  A rapid pathway toward a superb gene delivery system: programming structural and functional diversity into a supramolecular nanoparticle library. , 2010, ACS nano.

[31]  M. Sefton,et al.  Hepatic organoids for microfluidic drug screening. , 2014, Lab on a chip.

[32]  S. Fan,et al.  Liver microsystems in vitro for drug response , 2019, Journal of Biomedical Science.

[33]  D. Poenar,et al.  An integrated on-chip platform for negative enrichment of tumour cells. , 2016, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[34]  G. Balogh,et al.  Liver-on-a-Chip‒Magnetic Nanoparticle Bound Synthetic Metalloporphyrin-Catalyzed Biomimetic Oxidation of a Drug in a Magnechip Reactor , 2019, Micromachines.

[35]  L. Mao,et al.  Biocompatible and label-free separation of cancer cells from cell culture lines from white blood cells in ferrofluids. , 2017, Lab on a chip.

[36]  Yeoheung Yun,et al.  Three-dimensional (3D) tetra-culture brain on chip platform for organophosphate toxicity screening , 2018, Scientific Reports.

[37]  Zhi Zhu,et al.  Hydrogel Droplet Microfluidics for High-Throughput Single Molecule/Cell Analysis. , 2017, Accounts of chemical research.

[38]  Hongtao Feng,et al.  High throughput capture of circulating tumor cells using an integrated microfluidic system. , 2013, Biosensors & bioelectronics.

[39]  J. Chalmers,et al.  Correlation of simulation/finite element analysis to the separation of intrinsically magnetic spores and red blood cells using a microfluidic magnetic deposition system , 2018, Biotechnology and bioengineering.

[40]  Dan Gao,et al.  A novel 3D breast-cancer-on-chip platform for therapeutic evaluation of drug delivery systems. , 2018, Analytica chimica acta.

[41]  Tao Xu,et al.  Single cell target gene mutation analysis by arc-edge-channel monolithic valve microfluidic cell isolation and locked nucleic acid-based PCR detection , 2019, Sensors and Actuators B: Chemical.

[42]  Jeong Ah Kim,et al.  Microfluidic three-dimensional cell culture of stem cells for high-throughput analysis , 2019, World journal of stem cells.

[43]  J. Friend,et al.  Microscale acoustofluidics: Microfluidics driven via acoustics and ultrasonics , 2011 .

[44]  Jin‐Ming Lin,et al.  Concentrating Single Cells in Picoliter Droplets for Phospholipid Profiling on a Microfluidic System. , 2019, Small.

[45]  M. Bélanger,et al.  Hemocompatibility, biocompatibility, inflammatory and in vivo studies of primary reference materials low-density polyethylene and polydimethylsiloxane: a review. , 2001, Journal of biomedical materials research.

[46]  R. Stevens,et al.  In situ X-ray analysis of protein crystals in low-birefringent and X-ray transmissive plastic microchannels. , 2008, Acta crystallographica. Section D, Biological crystallography.

[47]  H. M. Nielsen,et al.  The distribution of cell-penetrating peptides on polymeric nanoparticles prepared using microfluidics and elucidated with small angle X-ray scattering. , 2019, Journal of colloid and interface science.

[48]  O. Oderinde,et al.  Multifaceted polymeric materials in three‐dimensional processing (3DP) technologies: Current progress and prospects , 2018 .

[49]  M. Burghammer,et al.  Cyclic olefin copolymer as an X-ray compatible material for microfluidic devices. , 2017, Lab on a chip.

[50]  Kevin W Eliceiri,et al.  Control of 3-dimensional collagen matrix polymerization for reproducible human mammary fibroblast cell culture in microfluidic devices. , 2009, Biomaterials.

[51]  Changqing Yi,et al.  Controllable synthesis of functional nanoparticles by microfluidic platforms for biomedical applications - a review. , 2017, Lab on a chip.

[52]  T. Zhao,et al.  Microfluidic device embedding electrodes for dielectrophoretic manipulation of cells‐A review , 2018, Electrophoresis.

[53]  K. Cheung,et al.  A novel approach to producing uniform 3-D tumor spheroid constructs using ultrasound treatment , 2018, Biomedical microdevices.

[54]  Che-Yen Lee,et al.  Multilayer architecture microfluidic network array for combinatorial drug testing on 3D-cultured cells , 2019, Biofabrication.

[55]  H Tom Soh,et al.  Integrated acoustic and magnetic separation in microfluidic channels. , 2009, Applied physics letters.

[56]  F. Omenetto,et al.  Bio‐microfluidics: Biomaterials and Biomimetic Designs , 2010, Advanced materials.

[57]  A. Skjeltorp One- and two-dimensional crystallization of magnetic holes , 1983 .

[58]  Karl-Heinz Krause,et al.  A 3D printed microfluidic device for production of functionalized hydrogel microcapsules for culture and differentiation of human Neuronal Stem Cells (hNSC). , 2016, Lab on a chip.

[59]  R. Rubin The war on cancer. , 1996, U.S. news & world report.

[60]  Paolo A Netti,et al.  An Engineered Breast Cancer Model on a Chip to Replicate ECM‐Activation In Vitro during Tumor Progression , 2016, Advanced healthcare materials.

[61]  I. Mezić,et al.  Chaotic Mixer for Microchannels , 2002, Science.

[62]  A. M. Ortega-Prieto,et al.  "Liver-on-a-Chip" Cultures of Primary Hepatocytes and Kupffer Cells for Hepatitis B Virus Infection. , 2019, Journal of visualized experiments : JoVE.

[63]  Jaewon Lee,et al.  Lab on a chip for in situ diagnosis: From blood to point of care , 2013, Biomedical Engineering Letters.

[64]  Dongjin Lee,et al.  The Combined Effects of Co-Culture and Substrate Mechanics on 3D Tumor Spheroid Formation within Microgels Prepared via Flow-Focusing Microfluidic Fabrication , 2018, Pharmaceutics.

[66]  Po-Hsun Huang,et al.  High-throughput cell focusing and separation via acoustofluidic tweezers. , 2018, Lab on a chip.

[67]  Francis Barany,et al.  Fabrication of DNA microarrays onto polymer substrates using UV modification protocols with integration into microfluidic platforms for the sensing of low-abundant DNA point mutations. , 2005, Methods.

[68]  E. Leclerc,et al.  Liver and kidney cells cultures in a new perfluoropolyether biochip , 2016 .

[69]  Palaniappan Sethu,et al.  Microfluidic cardiac cell culture model (μCCCM). , 2010, Analytical chemistry.

[70]  Ali Akpek,et al.  Lung on a Chip for Drug Screening and Design. , 2019, Current pharmaceutical design.

[71]  Pierre-Alexandre Vidi,et al.  Breast on-a-chip: mimicry of the channeling system of the breast for development of theranostics. , 2011, Integrative biology : quantitative biosciences from nano to macro.

[72]  Maxim Shusteff,et al.  Spatial tuning of acoustofluidic pressure nodes by altering net sonic velocity enables high-throughput, efficient cell sorting. , 2015, Lab on a chip.

[73]  Yuanjin Zhao,et al.  Emerging Droplet Microfluidics. , 2017, Chemical reviews.

[74]  A. Fleischman,et al.  Continuous flow magnetic cell fractionation based on antigen expression level. , 2006, Journal of biochemical and biophysical methods.

[75]  Jae-Sung Kwon,et al.  Microfluidic Technology for Cell Manipulation , 2018, Applied Sciences.

[76]  Andre Sharon,et al.  Continuous-flow, microfluidic, qRT-PCR system for RNA virus detection , 2017, Analytical and Bioanalytical Chemistry.

[77]  Amir Sanati-Nezhad,et al.  Microfluidic integrated acoustic waving for manipulation of cells and molecules. , 2016, Biosensors & bioelectronics.

[78]  Hongbo Zhang,et al.  Current developments and applications of microfluidic technology toward clinical translation of nanomedicines☆ , 2017, Advanced drug delivery reviews.

[79]  Jin-Woo Choi,et al.  A novel in-plane passive microfluidic mixer with modified Tesla structures. , 2004, Lab on a chip.

[80]  Dai-Wen Pang,et al.  A chip assisted immunomagnetic separation system for the efficient capture and in situ identification of circulating tumor cells. , 2016, Lab on a chip.

[81]  K. Weis,et al.  Dynamics of synthetic membraneless organelles in microfluidic droplets. , 2019, Angewandte Chemie.

[82]  H. Gong,et al.  Fabrication of multi-layer polymeric micro-sieve having narrow slot pores with conventional ultraviolet-lithography and micro-fabrication techniques. , 2011, Biomicrofluidics.

[83]  O. Lindahl,et al.  Polymer-Based Microfluidic Devices for Pharmacy, Biology and Tissue Engineering , 2012 .

[84]  Pilnam Kim,et al.  Microdroplet-based cell culture models and their application , 2016, BioChip Journal.

[85]  Haluk Kulah,et al.  A High Throughput Lab-On-A-Chip System for Label Free Quantification of Breast Cancer Cells under Continuous Flow , 2017 .

[86]  Thomas Laurell,et al.  Rapid and effective enrichment of mononuclear cells from blood using acoustophoresis , 2017, Scientific Reports.

[87]  Whoi-Yul Kim,et al.  Continuous Separation of Circulating Tumor Cells from Whole Blood Using a Slanted Weir Microfluidic Device , 2019, Cancers.

[88]  Josue A. Goss,et al.  Microfluidic heart on a chip for higher throughput pharmacological studies. , 2013, Lab on a chip.

[89]  S. Farag,et al.  Negative selection of hematopoietic progenitor cells by continuous magnetophoresis. , 2007, Experimental hematology.

[90]  A. Middelberg,et al.  Microfluidic synthesis of multifunctional liposomes for tumour targeting. , 2016, Colloids and surfaces. B, Biointerfaces.

[91]  A. Wan,et al.  Engineering a functional three-dimensional human cardiac tissue model for drug toxicity screening , 2017, Biofabrication.

[92]  Ali Khademhosseini,et al.  A 3D-printed microfluidic-enabled hollow microneedle architecture for transdermal drug delivery , 2019, Biomicrofluidics.

[93]  M. Tokeshi,et al.  A method of cryoprotection for protein crystallography by using a microfluidic chip and its application for in situ X-ray diffraction measurements. , 2015, Analytical chemistry.

[94]  Yaowen Liu,et al.  Primary Hepatocytes Cultured on a Fiber-Embedded PDMS Chip to Study Drug Metabolism , 2017, Polymers.

[95]  H. Lilja,et al.  Microfluidic, label-free enrichment of prostate cancer cells in blood based on acoustophoresis. , 2012, Analytical chemistry.

[96]  An-Shik Yang,et al.  A high-performance micromixer using three-dimensional Tesla structures for bio-applications , 2015 .

[97]  Lingxiang Zhu,et al.  One-step bonding and hydrophobic surface modification method for rapid fabrication of polycarbonate-based droplet microfluidic chips , 2019, Sensors and Actuators B: Chemical.

[98]  Noo Li Jeon,et al.  High-Throughput Microfluidic 3D Cytotoxicity Assay for Cancer Immunotherapy (CACI-IMPACT Platform) , 2019, Front. Immunol..

[99]  Prashanta Dutta,et al.  Dielectrophoretic separation of bioparticles in microdevices: A review , 2014, Electrophoresis.

[100]  O. B. Usta,et al.  Dynamic interplay of flow and collagen stabilizes primary hepatocytes culture in a microfluidic platform. , 2014, Lab on a chip.

[101]  Kaitlyn Sadtler,et al.  Tissue matrix arrays for high throughput screening and systems analysis of cell function , 2015, Nature Methods.

[102]  Sudipto Guha,et al.  Fabrication of X-ray compatible microfluidic platforms for protein crystallization. , 2012, Sensors and actuators. B, Chemical.

[103]  Sudipto Guha,et al.  Towards time-resolved serial crystallography in a microfluidic device. , 2015, Acta crystallographica. Section F, Structural biology communications.

[104]  O. Yesil‐Celiktas,et al.  Cytotoxic responses of carnosic acid and doxorubicin on breast cancer cells in butterfly-shaped microchips in comparison to 2D and 3D culture , 2017, Cytotechnology.

[105]  Ehsan Samiei,et al.  A review of sorting, separation and isolation of cells and microbeads for biomedical applications: microfluidic approaches. , 2018, The Analyst.

[106]  Amir Shamloo,et al.  Investigation of a Novel Microfluidic Device for Label-Free Ferrohydrodynamic Cell Separation on a Rotating Disk , 2020, IEEE Transactions on Biomedical Engineering.

[107]  Kevin Ward,et al.  Mixing in microfluidic devices and enhancement methods , 2015, Journal of micromechanics and microengineering : structures, devices, and systems.

[108]  J. Chalmers,et al.  Cell tracking velocimetry as a tool for defining saturation binding of magnetically conjugated antibodies , 2005, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[109]  J. Miao,et al.  Highlighting the uniqueness in dielectrophoretic enrichment of circulating tumor cells , 2019, Electrophoresis.

[110]  Yuanjin Zhao,et al.  Porous scaffolds from droplet microfluidics for prevention of intrauterine adhesion. , 2019, Acta biomaterialia.

[111]  Daniel T Chiu,et al.  Fabrication improvements for thermoset polyester (TPE) microfluidic devices. , 2007, Lab on a chip.

[112]  Sajay Bhuvanendran Nair Gourikutty,et al.  Microfluidic immunomagnetic cell separation from whole blood. , 2016, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[113]  Samuel K Sia,et al.  Real-time microfluidic system for studying mammalian cells in 3D microenvironments. , 2008, Analytical chemistry.

[114]  Christoph A. Merten,et al.  Droplet-based microfluidics in drug discovery, transcriptomics and high-throughput molecular genetics. , 2016, Lab on a chip.

[115]  Sujin Park,et al.  Engineered Polymeric Hydrogels for 3D Tissue Models , 2016, Polymers.

[116]  Samar Damiati,et al.  Microfluidic Devices for Drug Delivery Systems and Drug Screening , 2018, Genes.

[117]  Andre Levchenko,et al.  Brain-on-a-chip model enables analysis of human neuronal differentiation and chemotaxis. , 2016, Lab on a chip.

[118]  D. Di Carlo,et al.  Rapid prototyping polymers for microfluidic devices and high pressure injections. , 2011, Lab on a chip.

[119]  R. Bashir,et al.  On-chip PMA labeling of foodborne pathogenic bacteria for viable qPCR and qLAMP detection , 2016 .

[120]  Robert Langer,et al.  Microfluidic platform for combinatorial synthesis and optimization of targeted nanoparticles for cancer therapy. , 2013, ACS nano.

[121]  Pedram Mohseni,et al.  A brain-spinal interface (BSI) system-on-chip (SoC) for closed-loop cortically-controlled intraspinal microstimulation , 2018, Analog integrated circuits and signal processing.

[122]  Min Yu,et al.  Droplet Array-Based 3D Coculture System for High-Throughput Tumor Angiogenesis Assay. , 2018, Analytical chemistry.

[123]  Sebastian J Maerkl,et al.  A 1024-sample serum analyzer chip for cancer diagnostics. , 2014, Lab on a chip.