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      Hydrogel scaffolds as in vitro models to study fibroblast activation in wound healing and disease

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          Abstract

          Hydrogels offer controllable and well-defined in vitro platforms to study the role of the fibroblast in wound healing and fibrosis.

          Abstract

          Wound healing results from complex signaling between cells and their environment in response to injury. Fibroblasts residing within the extracellular matrix (ECM) of various connective tissues are critical for matrix synthesis and repair. Upon injury or chronic insult, these cells activate into wound-healing cells, called myofibroblasts, and repair the damaged tissue through enzyme and protein secretion. However, misregulation and persistence of myofibroblasts can lead to uncontrolled accumulation of matrix proteins, tissue stiffening, and ultimately disease. Extracellular cues are important regulators of fibroblast activation and have been implicated in their persistence. Hydrogel-based culture models have emerged as useful tools to examine fibroblast response to ECM cues presented during these complex processes. In this Mini-Review, we will provide an overview of these model systems, which are built upon naturally-derived or synthetic materials, and mimic relevant biophysical and biochemical properties of the native ECM with different levels of control. Additionally, we will discuss the application of these hydrogel-based systems for the examination of fibroblast function and fate, including adhesion, migration, and activation, as well as approaches for mimicking both static and temporal aspects of extracellular environments. Specifically, we will highlight hydrogels that have been used to investigate the effects of matrix rigidity, protein binding, and cytokine signaling on fibroblast activation. Last, we will describe future directions for the design of hydrogels to develop improved synthetic models that mimic the complex extracellular environment.

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          Most cited references107

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          Hydrogels in regenerative medicine.

          Hydrogels, due to their unique biocompatibility, flexible methods of synthesis, range of constituents, and desirable physical characteristics, have been the material of choice for many applications in regenerative medicine. They can serve as scaffolds that provide structural integrity to tissue constructs, control drug and protein delivery to tissues and cultures, and serve as adhesives or barriers between tissue and material surfaces. In this work, the properties of hydrogels that are important for tissue engineering applications and the inherent material design constraints and challenges are discussed. Recent research involving several different hydrogels polymerized from a variety of synthetic and natural monomers using typical and novel synthetic methods are highlighted. Finally, special attention is given to the microfabrication techniques that are currently resulting in important advances in the field.
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            RGD and other recognition sequences for integrins.

            Proteins that contain the Arg-Gly-Asp (RGD) attachment site, together with the integrins that serve as receptors for them, constitute a major recognition system for cell adhesion. The RGD sequence is the cell attachment site of a large number of adhesive extracellular matrix, blood, and cell surface proteins, and nearly half of the over 20 known integrins recognize this sequence in their adhesion protein ligands. Some other integrins bind to related sequences in their ligands. The integrin-binding activity of adhesion proteins can be reproduced by short synthetic peptides containing the RGD sequence. Such peptides promote cell adhesion when insolubilized onto a surface, and inhibit it when presented to cells in solution. Reagents that bind selectively to only one or a few of the RGD-directed integrins can be designed by cyclizing peptides with selected sequences around the RGD and by synthesizing RGD mimics. As the integrin-mediated cell attachment influences and regulates cell migration, growth, differentiation, and apoptosis, the RGD peptides and mimics can be used to probe integrin functions in various biological systems. Drug design based on the RGD structure may provide new treatments for diseases such as thrombosis, osteoporosis, and cancer.
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              Acellular normal and fibrotic human lung matrices as a culture system for in vitro investigation.

              Extracellular matrix (ECM) is a dynamic tissue that contributes to organ integrity and function, and its regulation of cell phenotype is a major aspect of cell biology. However, standard in vitro culture approaches are of unclear physiologic relevance because they do not mimic the compositional, architectural, or distensible nature of a living organ. In the lung, fibroblasts exist in ECM-rich interstitial spaces and are key effectors of lung fibrogenesis. To better address how ECM influences fibroblast phenotype in a disease-specific manner, we developed a culture system using acellular human normal and fibrotic lungs. Decellularization was achieved using treatment with detergents, salts, and DNase. The resultant matrices can be sectioned as uniform slices within which cells were cultured. We report that the decellularization process effectively removes cellular and nuclear material while retaining native dimensionality and stiffness of lung tissue. We demonstrate that lung fibroblasts reseeded into acellular lung matrices can be subsequently assayed using conventional protocols; in this manner we show that fibrotic matrices clearly promote transforming growth factor-β-independent myofibroblast differentiation compared with normal matrices. Furthermore, comprehensive analysis of acellular matrix ECM details significant compositional differences between normal and fibrotic lungs, paving the way for further study of novel hypotheses. This methodology is expected to allow investigation of important ECM-based hypotheses in human tissues and permits future scientific exploration in an organ- and disease-specific manner.
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                Author and article information

                Journal
                Biomater Sci
                Biomater Sci
                Biomaterials Science
                Royal Society of Chemistry
                2047-4830
                2047-4849
                1 May 2014
                5 March 2014
                : 2
                : 5
                : 634-650
                Affiliations
                [a ] Chemical & Biomolecular Engineering , University of Delaware , Newark , DE 19716 , USA
                [b ] Materials Science & Engineering , University of Delaware , Newark , DE 19716 , USA . Email: akloxin@ 123456udel.edu
                Article
                c3bm60319a
                10.1039/c3bm60319a
                4217222
                25379176
                23fe4c0f-8de5-4312-bf5f-c346931d0712
                This journal is © The Royal Society of Chemistry 2014

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 December 2013
                : 19 February 2014
                Categories
                Chemistry

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