Spatially arranged encapsulation of stem cell spheroids within hydrogels for the regulation of spheroid fusion and cell migration

Kim, Se-Jeong; Byun, Hayeon; Lee, Sang‐Min; Kim, Eunhyung; Lee, Gyeong Min; Huh, Seung Jae; Joo, Jinmyoung; Shin, Heungsoo

doi:10.1016/j.actbio.2022.01.047

Cited by 35 publications

(35 citation statements)

References 55 publications

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“…Such bridges could form between ASC and ASC+HUVEC spheroids, as was recently reported. [18] These results also further support our previous findings that highly-dense cell-laden droplets may behave partially like spheroids. While the same experimental setup containing ASCs without HUVECs also showed directional growth of ASCs, no such bridges and no relation to the pitch were observed (Figure S4).…”

Section: Ascs and Huvecs As Mixed Cell Suspensionsupporting

confidence: 90%

“…The first stands in contrast to findings in which also pure ASC spheroids formed such bridges. [18] After the ASCs started to form sprout-like structures, HUVECs also occasionally developed homogenous sprouts with no preferred sprouting direction, only 45 % of HUVECs in mixed cell-laden aggregates developed sprouts. This difference in behavior may be caused by inhibitory effects of the stem cells onto HUVECs .…”

Section: Ascs and Huvecs As Mixed Cell Suspensionmentioning

confidence: 98%

“…[15] For spheroids in hydrogels, active sprouting, migration and enhanced differentiation potential have been demonstrated. [16][17][18] Within spheroids, the cells interact with cells from neighboring spheroids through the secretion of growth factors or through physical contact, for example between sprouting/migrating cells. [19] Thus, the distance between spheroids is a crucial parameter for artificial tissues.…”

Section: Introductionmentioning

confidence: 99%

“…There is the Kenzan method, which uses microneedles called "kenzans" to align spheroids, placement of spheroids based on aspiration, and recently micropatterning of hydrogels based on a stamp technique and subsequent placement of spheroids into resulting gaps have been reported. [18,20,21] Previously, we have developed a printing process to precisely position HUVECs in a fibrin hydrogel and have shown that this approach can be used to compare highly-dense cell-laden droplets of HUVECs with HUVEC spheroids. [3] Also, in this study it was revealed, that a droplet-based approach yields longer cumulative sprout lengths (CSL) than spheroids, indicating a higher level of interaction between the cells.…”

Section: Introductionmentioning

confidence: 99%

“…There is the Kenzan method, which uses microneedles called “kenzans” to align spheroids, placement of spheroids based on aspiration, and recently micropatterning of hydrogels based on a stamp technique and subsequent placement of spheroids into resulting gaps have been reported. [18,20,21]…”

Section: Introductionmentioning

confidence: 99%

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A drop-on-demand bioprinting approach to spatially arrange multiple cell types and monitor their cell-cell interactions towards vascularization based on endothelial cells and mesenchymal stem cells

Weygant

Koch

Adam

et al. 2022

Preprint

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Spheroids, organoids, or highly-dense cell-laden droplets are often used as building blocks for bioprinting, but so far little is known about the spatio-temporal cellular interactions post printing. We present a drop-on-demand approach to study the biological interactions of such building blocks in micrometer dimensions. Droplets (containing approximately 700 cells in 10 nl) of multiple cell types are patterned in a 3D hydrogel matrix with a precision of less than 70 μm. It is applied to investigate interactions of cell types relevant for vascularization approaches. We show that a gap of 200 μm between droplets containing endothelial cells (HUVECs) and adipose-derived mesenchymal stem cells (ASCs) leads to decreased sprouting of HUVECs towards ASCs and increased growth from ASCs towards HUVECs. For mixed aggregates containing both cell types, cellular interconnections of ASCs with up to approximately 0.8 millimeter length and inhibition of HUVEC sprouting are observed. When ASCs are differentiated into smooth muscle cells (SMCs), HUVECs display decreased sprouting towards SMCs in separate aggregates, whereas no cellular interconnections or inhibition of HUVEC sprouting are detected for mixed aggregates. These findings demonstrate that this approach acts as a new tool to investigate cell-cell interactions of different cell types in 3D bioprinted constructs.

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Section: Ascs and Huvecs As Mixed Cell Suspensionsupporting

confidence: 90%

Section: Ascs and Huvecs As Mixed Cell Suspensionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A drop-on-demand bioprinting approach to spatially arrange multiple cell types and monitor their cell-cell interactions towards vascularization based on endothelial cells and mesenchymal stem cells

Weygant

Koch

Adam

et al. 2022

Preprint

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Bioprinting of Stem Cell Spheroids Followed by Post‐Printing Chondrogenic Differentiation for Cartilage Tissue Engineering

Decarli

Seijas‐Gamardo

Morgan

et al. 2023

Adv Healthcare Materials

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Cartilage tissue presents low self‐repair capability and lesions often undergo irreversible progression. Structures obtained by tissue engineering, such as those based in extrusion bioprinting of constructs loaded with stem cell spheroids may offer valuable alternatives for research and therapeutic purposes. Human mesenchymal stromal cell (hMSC) spheroids can be chondrogenically differentiated faster and more efficiently than single cells. This approach allows obtaining larger tissues in a rapid, controlled and reproducible way. However, it is challenging to control tissue architecture, construct stability, and cell viability during maturation. Herein, this work reports a reproducible bioprinting process followed by a successful post‐bioprinting chondrogenic differentiation procedure using large quantities of hMSC spheroids encapsulated in a xanthan gum‐alginate hydrogel. Multi‐layered constructs are bioprinted, ionically crosslinked, and post chondrogenically differentiated for 28 days. The expression of glycosaminoglycan, collagen II and IV are observed. After 56 days in culture, the bioprinted constructs are still stable and show satisfactory cell metabolic activity with profuse extracellular matrix production. These results show a promising procedure to obtain 3D models for cartilage research and ultimately, an in vitro proof‐of‐concept of their potential use as stable chondral tissue implants.

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Injectable MSC Spheroid and Microgel Granular Composites for Engineering Tissue

Caprio,

Davidson,

Daly

et al. 2024

Advanced Materials

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Many cell types require direct cell–cell interactions for differentiation and function; yet, this can be challenging to incorporate into 3‐dimensional (3D) structures for the engineering of tissues. Here, a new approach is introduced that combines aggregates of cells (spheroids) with similarly‐sized hydrogel particles (microgels) to form granular composites that are injectable, undergo interparticle crosslinking via light for initial stabilization, permit cell–cell contacts for cell signaling, and allow spheroid fusion and growth. One area where this is important is in cartilage tissue engineering, as cell–cell contacts are crucial to chondrogenesis and are missing in many tissue engineering approaches. To address this, granular composites are developed from adult porcine mesenchymal stromal cell (MSC) spheroids and hyaluronic acid microgels and simulations and experimental analyses are used to establish the importance of initial MSC spheroid to microgel volume ratios to balance mechanical support with tissue growth. Long‐term chondrogenic cultures of granular composites produce engineered cartilage tissue with extensive matrix deposition and mechanical properties within the range of cartilage, as well as integration with native tissue. Altogether, a new strategy of injectable granular composites is developed that leverages the benefits of cell–cell interactions through spheroids with the mechanical stabilization afforded with engineered hydrogels.

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Spatially arranged encapsulation of stem cell spheroids within hydrogels for the regulation of spheroid fusion and cell migration

Cited by 35 publications

References 55 publications

A drop-on-demand bioprinting approach to spatially arrange multiple cell types and monitor their cell-cell interactions towards vascularization based on endothelial cells and mesenchymal stem cells

A drop-on-demand bioprinting approach to spatially arrange multiple cell types and monitor their cell-cell interactions towards vascularization based on endothelial cells and mesenchymal stem cells

Bioprinting of Stem Cell Spheroids Followed by Post‐Printing Chondrogenic Differentiation for Cartilage Tissue Engineering

Injectable MSC Spheroid and Microgel Granular Composites for Engineering Tissue

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