Stiffness of hyaluronic acid gels containing liver extracellular matrix supports human hepatocyte function and alters cell morphology

Deegan, Daniel B.; Zimmerman, Cynthia; Skardal, Aleksander; Atala, Anthony; Shupe, Thomas

doi:10.1016/j.jmbbm.2015.10.016

Cited by 61 publications

(44 citation statements)

References 79 publications

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“…Rheological data [Figure (E)] showed that for each cross‐linker geometry (linear, four‐arm, and eight‐arm), the corresponding HA‐HP and HA did not differ significantly in shear elastic modulus. Also, we have observed in other studies, as cross‐linking density increased, elastic modulus increased.…”

Section: Resultssupporting

confidence: 76%

A tunable hydrogel system for long‐term release of cell‐secreted cytokines and bioprinted in situ wound cell delivery

Skardal

Murphy

Crowell

et al. 2016

J. Biomed. Mater. Res.

Self Cite

101

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For many cellular therapies being evaluated in preclinical and clinical trials, the mechanisms behind their therapeutic effects appear to be the secretion of growth factors and cytokines, also known as paracrine activity. Often, delivered cells are transient, and half-lives of the growth factors that they secrete are short, limiting their long-term effectiveness. The goal of this study was to optimize a hydrogel system capable of in situ cell delivery that could sequester and release growth factors secreted from those cells after the cells were no longer present. Here, we demonstrate the use of a fast photocross-linkable heparin-conjugated hyaluronic acid (HA-HP) hydrogel as a cell delivery vehicle for sustained growth factor release, which extends paracrine activity. The hydrogel could be modulated through cross-linking geometries and heparinization to support sustained release proteins and heparin-binding growth factors. To test the hydrogel in vivo, we used it to deliver amniotic fluid-derived stem (AFS) cells, which are known to secrete cytokines and growth factors, in full thickness skin wounds in a nu/nu murine model. Despite transience of the AFS cells in vivo, the HA-HP hydrogel with AFS cells improved wound closure and reepithelialization and increased vascularization and production of extracellular matrix in vivo. These results suggest that HA-HP hydrogel has the potential to prolong the paracrine activity of cells, thereby increasing their therapeutic effectiveness in wound healing. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1986-2000, 2017.

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Section: Resultssupporting

confidence: 76%

A tunable hydrogel system for long‐term release of cell‐secreted cytokines and bioprinted in situ wound cell delivery

Skardal

Murphy

Crowell

et al. 2016

J. Biomed. Mater. Res.

Self Cite

101

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“…35 More advanced 3D cultures mimic the liver microenvironment in cross-linked hyaluronic acid gels supplemented with soluble ECM from de-cellularized organs to improve hepatocyte attachment and viability. 36 A scaffold-free approach to establish 3D conditions for PHH is based on the self-aggregation of the cells leading to the formation of spheroids. Such spheroid cultures can be obtained either by gravity-enforced cellular assembly in a hanging drop 37 or by seeding the cells in low-attachment culture vessels.…”

Section: D and 3d Culture Models For Phhmentioning

confidence: 99%

Cell sources forin vitrohuman liver cell culture models

Zeilinger

Freyer

Damm

et al. 2016

Exp Biol Med (Maywood)

178

160

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In vitro liver cell culture models are gaining increasing importance in pharmacological and toxicological research. The source of cells used is critical for the relevance and the predictive value of such models. Primary human hepatocytes (PHH) are currently considered to be the gold standard for hepatic in vitro culture models, since they directly reflect the specific metabolism and functionality of the human liver; however, the scarcity and difficult logistics of PHH have driven researchers to explore alternative cell sources, including liver cell lines and pluripotent stem cells. Liver cell lines generated from hepatomas or by genetic manipulation are widely used due to their good availability, but they are generally altered in certain metabolic functions. For the past few years, adult and pluripotent stem cells have been attracting increasing attention, due their ability to proliferate and to differentiate into hepatocyte-like cells in vitro. However, controlling the differentiation of these cells is still a challenge. This review gives an overview of the major human cell sources under investigation for in vitro liver cell culture models, including primary human liver cells, liver cell lines, and stem cells. The promises and challenges of different cell types are discussed with a focus on the complex 2D and 3D culture approaches under investigation for improving liver cell functionality in vitro. Finally, the specific application options of individual cell sources in pharmacological research or disease modeling are described.

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“…In this research, HA substrates were formulated to closely mimic the composition and stiffness of the normal liver cellular microenvironment. 48 Chondrocytes in self-crosslinking hyaluronic acid hydrogels were injected into the rat body. The delivery of chondrocytes was influenced by the storage modulus of hydrogels.…”

Section: Hydrogels-ecm Mechanical Property Mimicsmentioning

confidence: 99%

“…However, the hepatocyte marker hepatocyte nuclear factor 4 alpha and albumin significant decreased on the 4600 Pa stiffness at day 7 indicating that cells may not have maintained their phenotype long‐term at this stiffness. In this research, HA substrates were formulated to closely mimic the composition and stiffness of the normal liver cellular microenvironment . Chondrocytes in self‐crosslinking hyaluronic acid hydrogels were injected into the rat body.…”

Section: Introductionmentioning

confidence: 99%

A review of gradient stiffness hydrogels used in tissue engineering and regenerative medicine

Xia

Liu

Yang

2017

J Biomedical Materials Res

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Substrate stiffness is known to impact characteristics including cell differentiation, proliferation, migration and apoptosis. Hydrogels are polymeric materials distinguished by high water content and diverse physical properties. Gradient stiffness hydrogels are designed by the need to develop biologically friendly materials as extracellular matrix (ECM) alternatives to replace the separated and narrow-ranged hydrogel substrates. Important new discoveries in cell behaviors have been realized with model gradient stiffness hydrogel systems from the two-dimensional (2D) to three-dimensional (3D) scale. Basic and clinical applications for gradient stiffness hydrogels in tissue engineering and regenerative medicine continue to drive the development of stiffness and structure varied hydrogels. Given the importance of gradient stiffness hydrogels in basic research and biomedical applications, there is a clear need for systems for gradient stiffness hydrogel design strategies and their applications. This review will highlight past work in the field of gradient stiffness hydrogels fabrication methods, mechanical property test, applications as well as areas for future study. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1799-1812, 2017.

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Stiffness of hyaluronic acid gels containing liver extracellular matrix supports human hepatocyte function and alters cell morphology

Cited by 61 publications

References 79 publications

A tunable hydrogel system for long‐term release of cell‐secreted cytokines and bioprinted in situ wound cell delivery

A tunable hydrogel system for long‐term release of cell‐secreted cytokines and bioprinted in situ wound cell delivery

Cell sources forin vitrohuman liver cell culture models

A review of gradient stiffness hydrogels used in tissue engineering and regenerative medicine

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