Directed assembly of cell‐laden microgels for building porous three‐dimensional tissue constructs

Yanagawa, Fumiki; Kaji, Hirokazu; Jang, Yun-Ho; Bae, Hojae; Du, Yumin; Fukuda, Junji; Qi, Hao; Khademhosseini, Ali

doi:10.1002/jbm.a.33034

Cited by 59 publications

(45 citation statements)

References 32 publications

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“…In the last few years, modular approaches have been developed to circumvent these problems. 99 These systems offer greater control over cell-cell interactions 100,101 and building of the multicellular complexity by utilization of different building blocks. 102 These approaches would be helpful in the prevention of several bulk material-related problems such as nutrition or gas transfer.…”

Section: Modular Epithelial Layers and Their Application In Organ-on-mentioning

confidence: 99%

Engineering Functional Epithelium for Regenerative Medicine and In Vitro Organ Models: A Review

Vrana

Lavalle²,

Dokmeci³

et al. 2013

Tissue Engineering Part B: Reviews

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Recent advances in the fields of microfabrication, biomaterials, and tissue engineering have provided new opportunities for developing biomimetic and functional tissues with potential applications in disease modeling, drug discovery, and replacing damaged tissues. An intact epithelium plays an indispensable role in the functionality of several organs such as the trachea, esophagus, and cornea. Furthermore, the integrity of the epithelial barrier and its degree of differentiation would define the level of success in tissue engineering of other organs such as the bladder and the skin. In this review, we focus on the challenges and requirements associated with engineering of epithelial layers in different tissues. Functional epithelial layers can be achieved by methods such as cell sheets, cell homing, and in situ epithelialization. However, for organs composed of several tissues, other important factors such as (1) in vivo epithelial cell migration, (2) multicell-type differentiation within the epithelium, and (3) epithelial cell interactions with the underlying mesenchymal cells should also be considered. Recent successful clinical trials in tissue engineering of the trachea have highlighted the importance of a functional epithelium for long-term success and survival of tissue replacements. Hence, using the trachea as a model tissue in clinical use, we describe the optimal structure of an artificial epithelium as well as challenges of obtaining a fully functional epithelium in macroscale. One of the possible remedies to address such challenges is the use of bottom-up fabrication methods to obtain a functional epithelium. Modular approaches for the generation of functional epithelial layers are reviewed and other emerging applications of microscale epithelial tissue models for studying epithelial/mesenchymal interactions in healthy and diseased (e.g., cancer) tissues are described. These models can elucidate the epithelial/mesenchymal tissue interactions at the microscale and provide the necessary tools for the next generation of multicellular engineered tissues and organ-on-a-chip systems.

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Section: Modular Epithelial Layers and Their Application In Organ-on-mentioning

confidence: 99%

Engineering Functional Epithelium for Regenerative Medicine and In Vitro Organ Models: A Review

Vrana

Lavalle²,

Dokmeci³

et al. 2013

Tissue Engineering Part B: Reviews

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View full text Add to dashboard Cite

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“…6,7 Cell-laden microgels have been used in tissue engineering applications as building blocks for complex tissue mimics, 8 co-culture systems for developing three-dimensional organ models, 9 and controlled microenvironments for directing stem cell differentiation. 10 In all of these applications, control over the size and size distribution of the microgels is important as they can influence the phenotypes of the encapsulated cells.…”

Section: Introductionmentioning

confidence: 99%

Cell-laden microfluidic microgels for tissue regeneration

et al. 2016

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Regenerating the diseased tissue is one of the foremost concerns for the millions of patients who suffer from tissue damage each year. Local delivery of cell-laden hydrogels offers an attractive approach for tissue repair. However, due to the typical macroscopic size of these cell constructs, the encapsulated cells often suffer from poor nutrient exchange. These issues can be mitigated by incorporating cells into microscopic hydrogels, or microgels, whose large surface-to-volume ratio promotes efficient mass transport and enhanced cell-matrix interactions. Using microfluidic technology, monodisperse cell-laden microgels with tunable sizes can be generated in a high-throughput manner, making them useful building blocks that can be assembled into tissue constructs with spatially controlled physicochemical properties. In this review, we examine microfluidics-generated cell-laden microgels for tissue regeneration applications. We provide a brief overview of the common biomaterials, gelation mechanisms, and microfluidic device designs that are used to generate these microgels, and summarize the most recent works on how they are applied to tissue regeneration. Finally, we discuss future applications of microfluidic cell-laden microgels as well as existing challenges that should be resolved to stimulate their clinical application.

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“…30 While these earlier studies have focused on modeling the diseased state of tumor biology, here we seek to apply microtissues to primary mammalian cells and the area of hepatic tissue engineering. There has also been considerable interest in using microtissues as building blocks for bottom-up assembly of patterned tissues 28,31,32 and packed-reactor-like devices. [33][34][35] However, these studies have yet to be extended to primary hepatocytes, thus far incorporating only the more easily cultured but phenotypically distorted hepatic cell lines.…”

Section: Introductionmentioning

confidence: 99%

Micropatterned Cell–Cell Interactions Enable Functional Encapsulation of Primary Hepatocytes in Hydrogel Microtissues

Stevens

Schwartz

et al. 2014

Tissue Engineering Part A

123

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Drug-induced liver injury is a major cause of drug development failures and postmarket withdrawals. In vitro models that incorporate primary hepatocytes have been shown to be more predictive than model systems which rely on liver microsomes or hepatocellular carcinoma cell lines. Methods to phenotypically stabilize primary hepatocytes ex vivo often rely on mimicry of hepatic microenvironmental cues such as cell-cell interactions and cell-matrix interactions. In this work, we sought to incorporate phenotypically stable hepatocytes into threedimensional (3D) microtissues, which, in turn, could be deployed in drug-screening platforms such as multiwell plates and diverse organ-on-a-chip devices. We first utilize micropatterning on collagen I to specify cell-cell interactions in two-dimensions, followed by collagenase digestion to produce well-controlled aggregates for 3D encapsulation in polyethylene glycol (PEG) diacrylate. Using this approach, we examined the influence of homotypic hepatocyte interactions and composition of the encapsulating hydrogel, and achieved the maintenance of liver-specific function for over 50 days. Optimally preaggregated structures were subsequently encapsulated using a microfluidic droplet-generator to produce 3D microtissues. Interactions of engineered hepatic microtissues with drugs was characterized by flow cytometry, and yielded both induction of P450 enzymes in response to prototypic small molecules and drug-drug interactions that give rise to hepatotoxicity. Collectively, this study establishes a pipeline for the manufacturing of 3D hepatic microtissues that exhibit stabilized liver-specific functions and can be incorporated into a wide array of emerging drug development platforms.

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Directed assembly of cell‐laden microgels for building porous three‐dimensional tissue constructs

Cited by 59 publications

References 32 publications

Engineering Functional Epithelium for Regenerative Medicine and In Vitro Organ Models: A Review

Engineering Functional Epithelium for Regenerative Medicine and In Vitro Organ Models: A Review

Cell-laden microfluidic microgels for tissue regeneration

Micropatterned Cell–Cell Interactions Enable Functional Encapsulation of Primary Hepatocytes in Hydrogel Microtissues

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