Gelatine methacrylamide-based hydrogels: An alternative three-dimensional cancer cell culture system

被引:192
作者
Kaemmerer, Elke [1 ,3 ,5 ]
Melchels, Ferry P. W. [1 ,3 ,6 ]
Holzapfel, Boris M. [1 ,3 ,7 ]
Meckel, Tobias [5 ]
Hutmacher, Dietmar W. [1 ,3 ]
Loessner, Daniela [2 ,4 ]
机构
[1] Inst Hlth & Biomed Innovat, Regenerat Med Program, Brisbane, Qld 4059, Australia
[2] Inst Hlth & Biomed Innovat, Canc Program, Brisbane, Qld 4059, Australia
[3] Queensland Univ Technol, Fac Sci & Engn, Brisbane, Qld 4001, Australia
[4] Queensland Univ Technol, Fac Hlth, Brisbane, Qld 4001, Australia
[5] Tech Univ Darmstadt, Dept Biol, Darmstadt, Germany
[6] Univ Med Ctr Utrecht, Dept Orthopaed, Utrecht, Netherlands
[7] Univ Wurzburg, Dept Orthopaed Surg, Orthopaed Ctr Musculoskeletal Res, D-97070 Wurzburg, Germany
基金
澳大利亚研究理事会;
关键词
Animal model; Cell encapsulation; ECM; Hydrogel; Mechanical properties; OVARIAN-CANCER; EXTRACELLULAR-MATRIX; HYALURONIC-ACID; GROWTH-FACTORS; DIFFUSION; RESISTANCE; COLLAGEN; TUMORS; MODEL; MATRIX-METALLOPROTEINASE-9;
D O I
10.1016/j.actbio.2014.02.035
中图分类号
R318 [生物医学工程];
学科分类号
100103 [病原生物学];
摘要
Modern cancer research requires physiological, three-dimensional (3-D) cell culture platforms, wherein the physical and chemical characteristics of the extracellular matrix (ECM) can be modified. In this study, gelatine methacrylamide (GelMA)-based hydrogels were characterized and established as in vitro and in vivo spheroid-based models for ovarian cancer, reflecting the advanced disease stage of patients, with accumulation of multicellular spheroids in the tumour fluid (ascites). Polymer concentration (2.5-7% w/v) strongly influenced hydrogel stiffness (0.5 +/- 0.2 kPa to 9.0 +/- 1.8 kPa) but had little effect on solute diffusion. The diffusion coefficient of 70 kDa fluorescein isothiocyanate (FITC)-labelled dextran in 7% GelMA-based hydrogels was only 2.3 times slower compared to water. Hydrogels of medium concentration (5% w/v GelMA) and stiffness (3.4 kPa) allowed spheroid formation and high proliferation and metabolic rates. The inhibition of matrix metalloproteinases and consequently ECM degradability reduced spheroid formation and proliferation rates. The incorporation of the ECM components laminin-411 and hyaluronic acid further stimulated spheroid growth within GelMA-based hydrogels. The feasibility of pre-cultured GelMA-based hydrogels as spheroid carriers within an ovarian cancer animal model was proven and led to tumour development and metastasis. These tumours were sensitive to treatment with the anti-cancer drug paclitaxel, but not the integrin antagonist ATN-161. While paclitaxel and its combination with ATN-161 resulted in a treatment response of 33-37.8%, ATN-161 alone had no effect on tumour growth and peritoneal spread. The semi-synthetic biomaterial GelMA combines relevant natural cues with tunable properties, providing an alternative, bioengineered 3-D cancer cell culture in in vitro and in vivo model systems. (C) 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
引用
收藏
页码:2551 / 2562
页数:12
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