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Dispersible hydrogel force sensors reveal patterns of solid mechanical stress in multicellular spheroid cultures.

ABSTRACT: Understanding how forces orchestrate tissue formation requires technologies to map internal tissue stress at cellular length scales. Here, we develop ultrasoft mechanosensors that visibly deform under less than 10 Pascals of cell-generated stress. By incorporating these mechanosensors into multicellular spheroids, we capture the patterns of internal stress that arise during spheroid formation. We experimentally demonstrate the spontaneous generation of a tensional 'skin', only a few cell layers thick, at the spheroid surface, which correlates with activation of mechanobiological signalling pathways, and balances a compressive stress profile within the tissue. These stresses develop through cell-driven mechanical compaction at the tissue periphery, and suggest that the tissue formation process plays a critically important role in specifying mechanobiological function. The broad applicability of this technique should ultimately provide a quantitative basis to design tissues that leverage the mechanical activity of constituent cells to evolve towards a desired form and function.

SUBMITTER: Lee W

PROVIDER: S-EPMC6329783 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Dispersible hydrogel force sensors reveal patterns of solid mechanical stress in multicellular spheroid cultures.

Lee Wontae W Kalashnikov Nikita N Mok Stephanie S Halaoui Ruba R Kuzmin Elena E Putnam Andrew J AJ Takayama Shuichi S Park Morag M McCaffrey Luke L Zhao Ruogang R Leask Richard L RL Moraes Christopher C

Nature communications 20190111 1

Understanding how forces orchestrate tissue formation requires technologies to map internal tissue stress at cellular length scales. Here, we develop ultrasoft mechanosensors that visibly deform under less than 10 Pascals of cell-generated stress. By incorporating these mechanosensors into multicellular spheroids, we capture the patterns of internal stress that arise during spheroid formation. We experimentally demonstrate the spontaneous generation of a tensional 'skin', only a few cell layers ...[more]

PMID: 30635553

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Project description:In conventional photodynamic therapy (PDT), effective delivery of photosensitizers (PS) to cancer cells can be challenging, prompting the exploration of active targeting as a promising strategy to enhance PS delivery. Typically, two-dimensional (2-D) monolayer cell culture models are used for investigating targeted photodynamic therapy. However, despite their ease of use, these cell culture models come with certain limitations due to their structural simplicity when compared to three-dimensional (3-D) cell culture models such as multicellular tumour spheroids (MCTSs). In this study, we prepared gold nanoparticles (AuNPs) that were functionalized with antibodies and loaded with tetra sulphonated zinc phthalocyanine (ZnPcS4). Characterization techniques including transmission electron microscopy (TEM) was used to determine the size and morphology of the prepared nanoconjugates. We also conducted a comparative investigation to assess the photodynamic effects of ZnPcS4 alone and/or conjugated onto the bioactively functionalized nanodelivery system in colorectal Caco-2 cells cultured in both in vitro 2-D monolayers and 3-D MCTSs. TEM micrographs revealed small, well distributed, and spherical shaped nanoparticles. Our results demonstrated that biofunctionalized nanoparticle mediated PDT significantly inhibited cell proliferation and induced apoptosis in Caco-2 cancer monolayers and, to a lesser extent, in Caco-2 MCTSs. Live/dead assays further elucidated the impact of actively targeted nanoparticle-photosensitizer nanoconstruct, revealing enhanced cytotoxicity in 2-D cultures, with a notable increase in dead cells post-PDT. In 3-D spheroids, however, while the presence of targeted nanoparticle-photosensitizer system facilitated improved therapeutic outcomes, the live/dead results showed a higher number of viable cells after PDT treatment compared to their 2-D monolayer counterparts suggesting that MCTSs showed more resistance to PS drug as compared to 2-D monolayers. These findings suggest a high therapeutic potential of the multifunctional nanoparticle as a targeted photosensitizer delivery system in PDT of colorectal cancer. Furthermore, the choice of cell culture model influenced the response of cancer cells to PDT treatment, highlighting the feasibility of using MCTSs for targeted PS delivery to colorectal cancer cells.

Dataset Information

Dispersible hydrogel force sensors reveal patterns of solid mechanical stress in multicellular spheroid cultures.

Publications

Dispersible hydrogel force sensors reveal patterns of solid mechanical stress in multicellular spheroid cultures.

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