On-chip hydrogel arrays individually encapsulating acoustic formed multicellular aggregates for high throughput drug testing

Hu, Xuejia; Zhao, Shukun; 羅, 志偉; Zuo, Yunfeng; Wang, Fang; Zhu, Jianhan; Chen, Longfei; Yang, Dongyong; Zheng, Y.; Yang, Zheng; Cheng, Yanxiang; Zhou, Fuling; Yang, Yi

doi:10.1039/d0lc00255k

Cited by 49 publications

(40 citation statements)

References 37 publications

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“…In brief, these cell microstructures can be used as a component for assembling a three-dimensional tissue-like cell structure in vitro. Hu et al [100] reported on-chip acoustic force assembly-assisted GelMA hydrogel arrays to rapidly obtain 3-D ECM mimics were supported multicellular. Each unit encapsulated in the 3-D ECM mimic hydrogel pillars was independent from the other units in the arrays.…”

Section: Components For Organs-on-a-chipmentioning

confidence: 99%

Applications of Gelatin Methacryloyl (GelMA) Hydrogels in Microfluidic Technique-Assisted Tissue Engineering

et al. 2020

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In recent years, the microfluidic technique has been widely used in the field of tissue engineering. Possessing the advantages of large-scale integration and flexible manipulation, microfluidic devices may serve as the production line of building blocks and the microenvironment simulator in tissue engineering. Additionally, in microfluidic technique-assisted tissue engineering, various biomaterials are desired to fabricate the tissue mimicking or repairing structures (i.e., particles, fibers, and scaffolds). Among the materials, gelatin methacrylate (GelMA)-based hydrogels have shown great potential due to their biocompatibility and mechanical tenability. In this work, applications of GelMA hydrogels in microfluidic technique-assisted tissue engineering are reviewed mainly from two viewpoints: Serving as raw materials for microfluidic fabrication of building blocks in tissue engineering and the simulation units in microfluidic chip-based microenvironment-mimicking devices. In addition, challenges and outlooks of the exploration of GelMA hydrogels in tissue engineering applications are proposed.

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Section: Components For Organs-on-a-chipmentioning

confidence: 99%

Applications of Gelatin Methacryloyl (GelMA) Hydrogels in Microfluidic Technique-Assisted Tissue Engineering

et al. 2020

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“…Hydrogels are network of cross-linked polymers with tuneable physical properties and high capacity of water retaining and interconnected pores enabling free diffusion of O2, nutrient and metabolic wastes, which make them favourable alternatives in micro-system applications. Various techniques using natural or synthetic hydrogels for MCTS formation, have been developed [28][29][30][31][32][33] . However, none of these set-ups meets all the criteria required for long-term time-lapse analysis (i.e.…”

Section: Graphical Abstract Introductionmentioning

confidence: 99%

Quantifying nanotherapeutics penetration using hydrogel based microsystem as a new 3Din vitroplatform

Goodarzi

Prunet

Rossetti

et al. 2021

Preprint

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Despite progress in therapeutic strategies and understanding of cancer cell biology, there is a large attrition of promising therapeutics into the clinic. One predominant reason is the huge gap between 2D in-vitro assays used for drug screening, and the in-vivo 3D-physiological environment. This is particularly important for a specific category of emerging therapeutics: nanoparticles. The lack of physiological context hampered reliable predictions for the route and accumulation of those nanoparticles in-vivo. For such nanotherapeutics, Multi-Cellular Tumour Spheroids (MCTS) is emerging as a good alternative in-vitro model. However, the classical approaches to produce MCTS suffer from low yield, poor reproducibility and slow process, while spheroid-on-chip set-ups developed so far require a microfluidic practical knowledge difficult to transfer to a cell biology laboratory.We present here a simple yet highly flexible 3D-model microsystem consisting of agarose-based micro-wells. Fully compatible with the multi-well plates format conventionally used in cell biology, our simple process enables the formation of hundreds of reproducible spheroids in a single pipetting. It is compatible with live high-resolution optical microscopy and provides a user-friendly platform for in-situ immunostaining.As a proof-of-principle of the relevance of such in-vitro platform for the evaluation of nanoparticles, the aim of this study was to analyse the kinetic and localization of nanoparticles within colorectal cancer cells (HCT-116) MCTS. The nanoparticles chosen are sub-5 nm ultrasmall nanoparticles made of polysiloxane and gadolinium chelates that can be visualized in MRI and confocal microscopy (AGuIX®, currently implicated in clinical trials as effective radiosensitizers for radiotherapy). We show that the amount of AGuIX® nanoparticles within cells is largely different in 2D and 3D. Using our flexible agarose-based microsystems, we are able to resolve spatially and temporally the penetration and distribution of AGuIX® nanoparticles within tumour spheroids. The nanoparticles are first found in both extracellular and intracellular space of spheroids, within lysosomes compartment. While the extracellular part is washed away after few days, we evidenced trafficking of AGuIX® nanoparticles that are also found within mitochondria. Our agarose-based microsystem appears hence as a promising 3D in-vitro platform for investigation of nanotherapeutics transport, ahead of in-vivo studies.

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“…For example, micropatterned 3D cultures have been used to replicate emergent tissue-level properties such as tissue hypoxia, 3,4 cell migratory and homing activity, 5,6 formation of signaling gradients, 7,8 and to form cell multi-arrays for high-throughput assays. [9][10][11] However, existing technologies are limited in their ability to create closely abutting, non-linear, cell-laden structures under fluidic control, and thus cannot fully replicate the complex spatial organization of native tissues or allow full freedom of high-throughput array design.…”

Section: Introductionmentioning

confidence: 99%

“…For example, micropatterned 3D cultures have been used to replicate emergent tissue-level properties such as tissue hypoxia, 3,4 cell migratory and homing activity, 5,6 formation of signaling gradients, 7,8 and to form cell arrays for high-throughput assays. 9–11 Integration of 3D cultures with platforms that enable fluidic control, such as microfluidic chips, is often advantageous, e.g. for control over media perfusion, but is challenging for spatially organized 3D cultures.…”

Section: Introductionmentioning

confidence: 99%

“…28,29 Recently, on-chip photolithography was used to create cell-laden micropillar arrays and organized tumor-on-chip cultures. 6,9,30 However, photopatterning of self-standing 3D cultures with more complex features such as non-linear boundaries or spatially organized co-cultures regions within a microfluidic chip remains a challenge, particularly with fragile primary cells.…”

Section: Introductionmentioning

confidence: 99%

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Generation of nonlinear and spatially-organized 3D cultures on a microfluidic chip using photoreactive thiol-ene and methacryloyl hydrogels

Ortiz-Cárdenas

Zatorski

Arneja

et al. 2020

Preprint

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Micropatterning techniques have enabled the use of 3D cell cultures to recreate tissue-level behavior such as hypoxia or signaling gradients, but their integration with microfluidics has been limited. To access complex, non-linear and concentric geometries seen in vivo and in high-throughput culture arrays, we developed an in-situ micropatterning strategy that integrated photolithography of crosslinkable, cell-laden hydrogels with a simple microfluidic housing. By shining 405 nm light through a photomask containing the desired design, we patterned 3D cultures directly in a 130-μm deep microfluidic chamber. As a model system, we used thiol-ene step growth polymerization with thiol-modified gelatin (GelSH) and PEG-norbornene linker; the technology was also applicable to other photo-crosslinkable chemistries, including gelatin methacryloyl (GelMA) and gelatin norbornene (GelNB) with PEG-thiol linker. The on-chip patterning strategy generated 3D cultures that were self-standing and that could be combined using serial photomasks. The method consistently generated features as small as 100 μm in diameter, and shared, non-linear boundaries between cultures were readily achieved. The modularity of the platform meant that designs were interchangeable in the same microfluidic housing, without requiring new master fabrication. As a proof-of-principle, a fragile cell type, primary human T cells, were patterned in varied geometries. Cells were patterned with high regional specificity and viability remained high. We expect that this technology will enable researchers to organize 3D cultures into geometries that were previously difficult to obtain, granting access to biomimetic tissue organizations and 3D-cultured microarray formats.

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On-chip hydrogel arrays individually encapsulating acoustic formed multicellular aggregates for high throughput drug testing

Abstract: Multicellular aggregates in three-dimensional (3D) environments provide novel solid tumor models that can provide insight into in vivo drug resistance.

Cited by 49 publications

References 37 publications

Applications of Gelatin Methacryloyl (GelMA) Hydrogels in Microfluidic Technique-Assisted Tissue Engineering

Applications of Gelatin Methacryloyl (GelMA) Hydrogels in Microfluidic Technique-Assisted Tissue Engineering

Quantifying nanotherapeutics penetration using hydrogel based microsystem as a new 3Din vitroplatform

Generation of nonlinear and spatially-organized 3D cultures on a microfluidic chip using photoreactive thiol-ene and methacryloyl hydrogels

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