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Microfluidic assembly of hydrogel-based immunogenic tumor spheroids for evaluation of anticancer therapies and biomarker release.

ABSTRACT: Diffuse large B cell lymphoma (DLBCL), the most common subtype of Non-Hodgkin lymphoma, exhibits pathologic heterogeneity and a dynamic immunogenic tumor microenvironment (TME). However, the lack of preclinical in vitro models of DLBCL TME hinders optimal therapeutic screening. This study describes the development of an integrated droplet microfluidics-based platform for high-throughput generation of immunogenic DLBCL spheroids. The spheroids consist of three cell types (cancer, fibroblast and lymphocytes) in a novel hydrogel combination of alginate and puramatrix, which promoted cell adhesion and aggregation. This system facilitates dynamic analysis of cellular interaction, proliferation and therapeutic efficacy via spatiotemporal monitoring and secretome profiling. The immunomodulatory drug lenalidomide had direct anti-proliferative effect on activated B-cell like DLBCL spheroids and reduced several cytokines and other markers (e.g., CCL2, CCL3, CCL4, CD137 and ANG-1 levels) compared with untreated spheroids. Collectively, this novel spheroid platform will enable high-throughput anti-cancer therapeutic screening in a semi-automated manner.

SUBMITTER: Sabhachandani P

PROVIDER: S-EPMC6396303 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Microfluidic assembly of hydrogel-based immunogenic tumor spheroids for evaluation of anticancer therapies and biomarker release.

Sabhachandani Pooja P Sarkar Saheli S Mckenney Seamus S Ravi Dashnamoorthy D Evens Andrew M AM Konry Tania T

Journal of controlled release : official journal of the Controlled Release Society 20181212

Diffuse large B cell lymphoma (DLBCL), the most common subtype of Non-Hodgkin lymphoma, exhibits pathologic heterogeneity and a dynamic immunogenic tumor microenvironment (TME). However, the lack of preclinical in vitro models of DLBCL TME hinders optimal therapeutic screening. This study describes the development of an integrated droplet microfluidics-based platform for high-throughput generation of immunogenic DLBCL spheroids. The spheroids consist of three cell types (cancer, fibroblast and l ...[more]

PMID: 30550941

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Project description:Current treatments for chronic xerostomia, or "dry mouth", do not offer long-term therapeutic benefits for head and neck cancer survivors previously treated with curative radiation. Towards the goal of creating tissue-engineered constructs for the restoration of salivary gland functions, we developed new hyaluronic acid (HA)-based hydrogels using thiolated HA (HA-SH) and acrylated HA (HA-AES) with a significant molecular weight mismatch. Four hydrogel formulations with varying HA concentration, (1-2.4 wt%) and thiol/acrylate ratios (2/1 to 36/1) and elastic moduli (G': 35 to 1897 Pa, 2 h post-mixing) were investigated. In our system, thiol/acrylate reaction was initiated rapidly upon mixing of HA-SH/HA-AES to establish thioether crosslinks with neighboring ester groups, and spontaneous sulfhydryl oxidation occurred slowly over several days to install a secondary network. The concurrent reactions cooperatively create a cell-permissive network to allow for cell expansion and aggregation. Multicellular spheroids formed readily from a robust ductal epithelial cell line (Madin-Darby Canine Kidney, MDCK cells) in all hydrogel formulations investigated. Primary salivary human stem/progenitor cells (hS/PCs), on the other hand, are sensitive to the synthetic extracellular environment, and organized acini-like structures with an average diameter of 50 µm were obtained only in gels with G' ≤ 216 Pa and a thiol/acrylate ratio ≥18. The spheroid size and size distribution were dependent on the HA content in the hydrogel. Cells in hS/PC spheroids formed tight junctions (occludin), remained viable and proliferative, secreted structural proteins (collagen IV and laminin) found in the basement membrane and maintained key stem/progenitor markers. We conclude that incorporation of time-dependent, dynamic features into a covalently crosslinked HA network produces an adaptable hydrogel framework that promotes hS/PC assembly and supports early aspects of salivary morphogenesis, key to reconstitution of a fully functional implantable salivary gland.

Dataset Information

Microfluidic assembly of hydrogel-based immunogenic tumor spheroids for evaluation of anticancer therapies and biomarker release.

Publications

Microfluidic assembly of hydrogel-based immunogenic tumor spheroids for evaluation of anticancer therapies and biomarker release.

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