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WIREs Syst Biol Med
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Hydrogels for in vivo‐like three‐dimensional cellular studies

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Abstract Extensive efforts have been made to understand the effects of extracellular microenvironments on phenotypic activities for a wide array of stem, progenitor, and precursor cells. Hydrogels have emerged as invaluable platforms for examining the effects of extracellular matrix (ECM) properties on cell activities because of their several advantageous features. Specifically, hydrogels are unique materials that enable cell studies in three‐dimensional (3D) environments, similar to in vivo environments. Recently, there have been increasing efforts to assemble cell‐encapsulating hydrogels; however, hydrogel design strategies for 3D cell cultures have not been systematically discussed to date. Therefore, this review article summarizes current hydrogel designs for 3D cell culture studies and further discusses current challenges and potential resolutions for enhancing the controllability of hydrogel properties and microstructures. The hydrogels discussed herein include those of natural polymers (e.g., collagen, fibrinogen, alginate, and hyaluronic acids), synthetic polymers [e.g., poly(ethylene glycol) (PEG) and its derivatives], and mixtures of natural and synthetic polymers. We envision that hydrogels that enable 3D studies will greatly assist in the understanding of emergent cell behaviors, and ultimately become important biomedical tools for enhancing the quality of in vitro drug screening and clinical treatments. WIREs Syst Biol Med 2012 doi: 10.1002/wsbm.1174 This article is categorized under: Biological Mechanisms > Cell Fates Models of Systems Properties and Processes > Cellular Models Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models Developmental Biology > Stem Cell Biology and Regeneration

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Schematic depiction of the factors that influence cell phenotype and overall cell activities. Cellular activities are modulated through the orchestration of soluble factors, cell–cell interactions, and cell–extracellular matrix (ECM) interactions. Cells probe for these signals through cell receptors, cadherins, and integrins.

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Photodegradable hydrogel synthesis and tunable degradation properties. A photodegradable acrylic monomer (a) was used to synthesize a photodegradable cross‐linker (b), and was copolymerized with poly(ethylene glycol) diacrylate (PEGDA) to form a hydrogel (c) consisting of acrylic chains (red) connected by PEG (black lines) with photolabile groups (solid blue boxes). Upon irradiation, the hydrogels degraded demonstrated by a continual decrease in the gel's storage moduli (d). The hydrogel degradation was controlled via the duration of irradiation (e).125

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Tuning the dependency between swelling ratio (Q) and elastic modulus (E) of poly(ethylene glycol) diacrylate (PEGDA) hydrogels. (a) PEGDA–poly(ethylene glycol) monomethacrylate (PEGMA) hydrogels (▪) exhibited a smaller inverse dependency between Q and E than pure PEGDA hydrogels prepared through the cross‐linking of PEGDA with varied molecular weights (•) (Reprinted with permission from Ref 110. Copyright 2011 Elsevier Limited). (b) The incorporation of methacrylic alginate (MA) in PEGDA hydrogels resulted in an increase of the elastic moduli (▴) and degree of swelling (•), while increasing the concentration of pure PEGDA hydrogels resulted in an increase of the elastic moduli (▵) and a decrease in the degree of swelling (○).109

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(a) The effects of alginate gels' RGD peptide numbers (NRGD) on the proliferation of preosteoblasts (MC3T3) and myoblasts (C2C12), characterized with 3H thymidine incorporation.77 (b) The dependency of NRGD on cellular proliferation was attributed to the change in the number of integrin‐RGD peptide bonds (Nbond), according to fluorescence resonance energy transfer (FRET) assay.77 (c) The effects of RGD peptides' nanoscale spacing (dRGD) on exogenous gene expression of preosteoblasts. In (a)–(c), cells were encapsulated in the hydrogels with varied NRGD or dRGD. (Reprinted with permission from Ref 78. Copyright 2007 American Chemical Society)

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(a) Alginate modification using carbodiimide chemistry to present an RGD sequenced oligeopeptide. (b) An ionically cross‐linking reaction of alginate's guluronic acid blocks to form a hydrogel network.

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Fibrin gel formation via thrombin‐mediated removal of terminal peptides. The subsequently modified fibrinogen yield fibrin monomers that form dimmers and laterally grow leading to the formation of protofibrils. Antiparallel cross‐linking of protofibrils form fibrin strands. (Reprinted with permission from Ref 48. Copyright 2001 Elsevier Limited)

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Control of collagen gel stiffness with poly(ethylene glycol) (PEG)‐diNHS. The soft pure collagen gel was formed from physical cross‐linking between self‐associated collagen fibers. Individual single collagen fibers consisted of multiple helical bundles of collagen fibrils. These fibrils were prepared by increasing the pH of the collagen solution to induce self‐assembly of collagen molecules. Stiffness of the collagen gel was increased by introducing covalent cross‐links between collagen fibrils and PEG‐diNHS. (Reprinted with permission from Ref 43. Copyright 2011 Elsevier Limited)

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Models of Systems Properties and Processes > Cellular Models
Biological Mechanisms > Cell Fates
Developmental Biology > Stem Cell Biology and Regeneration
Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models

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