Engineering approaches to study fibrosis in 3-D in vitro systems.

Fibrotic diseases occur in virtually every tissue of the body and are a major cause of mortality, yet they remain largely untreatable and poorly understood on a mechanistic level. The development of anti-fibrotic agents has been hampered, in part, by the insufficient fibrosis biomimicry provided by traditional in vitro platforms. This review focuses on recent advancements toward creating 3-D platforms that mimic key features of fibrosis, as well as the application of novel imaging and sensor techniques to analyze dynamic extracellular matrix remodeling. Several opportunities are highlighted to apply new tools from the fields of biomaterials, imaging, and systems biology to yield pathophysiologically relevant in vitro platforms that improve our understanding of fibrosis and may enable identification of potential treatment targets.

[1]  Kristi S Anseth,et al.  Microarray analyses to quantify advantages of 2D and 3D hydrogel culture systems in maintaining the native valvular interstitial cell phenotype. , 2016, Biomaterials.

[2]  T. Wynn,et al.  Cellular and molecular mechanisms of fibrosis , 2008, The Journal of pathology.

[3]  Kristyn S Masters,et al.  Covalent growth factor immobilization strategies for tissue repair and regeneration. , 2011, Macromolecular bioscience.

[4]  M. Le Hir,et al.  Epithelial-mesenchymal transition (EMT) in kidney fibrosis: fact or fantasy? , 2011, The Journal of clinical investigation.

[5]  Kristi S Anseth,et al.  Clickable, Photodegradable Hydrogels to Dynamically Modulate Valvular Interstitial Cell Phenotype , 2014, Advanced healthcare materials.

[6]  L. Suggs,et al.  Dynamic phototuning of 3D hydrogel stiffness , 2015, Proceedings of the National Academy of Sciences.

[7]  S. Friedman,et al.  Therapy for Fibrotic Diseases: Nearing the Starting Line , 2013, Science Translational Medicine.

[8]  V. Moulin,et al.  The fibrotic phenotype of systemic sclerosis fibroblasts varies with disease duration and severity of skin involvement: reconstitution of skin fibrosis development using a tissue engineering approach , 2009, The Journal of pathology.

[9]  B. Hinz.  The extracellular matrix and transforming growth factor-β1: Tale of a strained relationship. , 2015, Matrix biology : journal of the International Society for Matrix Biology.

[10]  Igor Goryanin,et al.  Systems biology reveals new strategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab. , 2009, Cancer research.

[11]  K. Anseth,et al.  Photoresponsive elastic properties of azobenzene-containing poly(ethylene-glycol)-based hydrogels. , 2015, Biomacromolecules.

[12]  Jiří Kanta,et al.  Collagen matrix as a tool in studying fibroblastic cell behavior , 2015, Cell adhesion & migration.

[13]  Bin Duan,et al.  Stiffness and adhesivity control aortic valve interstitial cell behavior within hyaluronic acid based hydrogels. , 2013, Acta biomaterialia.

[14]  E. Gratton,et al.  Imaging Fibrosis and Separating Collagens using Second Harmonic Generation and Phasor Approach to Fluorescence Lifetime Imaging , 2015, Scientific Reports.

[15]  Helena N. Chia,et al.  Latent TGF‐β Hydrogels for Cartilage Tissue Engineering , 2012, Advanced healthcare materials.

[16]  Zimple Matharu,et al.  Liver injury-on-a-chip: microfluidic co-cultures with integrated biosensors for monitoring liver cell signaling during injury. , 2015, Lab on a chip.

[17]  Z. Darżynkiewicz,et al.  Col‐F, a fluorescent probe for ex vivo confocal imaging of collagen and elastin in animal tissues , 2013, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[18]  Guoying Yu,et al.  MicroRNA mimicry blocks pulmonary fibrosis , 2014, EMBO molecular medicine.

[19]  Giulio Gabbiani,et al.  The myofibroblast: one function, multiple origins. , 2007, The American journal of pathology.

[20]  Mark W. Tibbitt,et al.  Hydrogels preserve native phenotypes of valvular fibroblasts through an elasticity-regulated PI3K/AKT pathway , 2013, Proceedings of the National Academy of Sciences.

[21]  Marie-Claire Schanne-Klein,et al.  Three‐dimensional investigation and scoring of extracellular matrix remodeling during lung fibrosis using multiphoton microscopy , 2007, Microscopy research and technique.

[22]  M. Raghunath,et al.  Focus on collagen: in vitro systems to study fibrogenesis and antifibrosis _ state of the art , 2009, Fibrogenesis & tissue repair.

[23]  Matthew E. Berginski,et al.  Construction, imaging, and analysis of FRET-based tension sensors in living cells. , 2015, Methods in cell biology.

[24]  D. Kaplan,et al.  Tissue-engineered kidney disease models. , 2014, Advanced drug delivery reviews.

[25]  M. Ratner.  Landmark approvals in idiopathic pulmonary fibrosis , 2014, Nature Biotechnology.

[26]  Maarten Merkx,et al.  Colorful Protein-Based Fluorescent Probes for Collagen Imaging , 2014, PloS one.

[27]  Alexey Solovyev,et al.  A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression , 2014, Front. Bioeng. Biotechnol..

[28]  C. Rueden,et al.  Bmc Medicine Collagen Density Promotes Mammary Tumor Initiation and Progression , 2022 .

[29]  Junmin Zhu,et al.  Bioactive modification of poly(ethylene glycol) hydrogels for tissue engineering. , 2010, Biomaterials.

[30]  Craig A Simmons,et al.  Calcification by Valve Interstitial Cells Is Regulated by the Stiffness of the Extracellular Matrix , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[31]  Kristi S Anseth,et al.  Covalently tethered TGF-β1 with encapsulated chondrocytes in a PEG hydrogel system enhances extracellular matrix production. , 2014, Journal of biomedical materials research. Part A.

[32]  Michiya Matsusaki,et al.  Engineering fibrotic tissue in pancreatic cancer: a novel three-dimensional model to investigate nanoparticle delivery. , 2012, Biochemical and biophysical research communications.

[33]  Bagrat Grigoryan,et al.  A three-dimensional co-culture model of the aortic valve using magnetic levitation. , 2014, Acta biomaterialia.

[34]  B. Hinz,et al.  The myofibroblast matrix: implications for tissue repair and fibrosis , 2013, The Journal of pathology.

[35]  Yan Cai,et al.  Noninvasive monitoring of pulmonary fibrosis by targeting matrix metalloproteinases (MMPs). , 2013, Molecular pharmaceutics.

[36]  A. Schroer,et al.  Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease , 2015, Journal of Cell Science.

[37]  A. Pena,et al.  Second harmonic imaging and scoring of collagen in fibrotic tissues. , 2007, Optics express.

[38]  K. Anseth,et al.  The role of valvular endothelial cell paracrine signaling and matrix elasticity on valvular interstitial cell activation. , 2014, Biomaterials.

[39]  V. Grantcharova,et al.  Therapeutically Targeting ErbB3: A Key Node in Ligand-Induced Activation of the ErbB Receptor–PI3K Axis , 2009, Science Signaling.

[40]  H. Maynard,et al.  Synthesis of photodegradable macromers for conjugation and release of bioactive molecules. , 2013, Biomacromolecules.

[41]  Kristi S Anseth,et al.  Small peptide functionalized thiol-ene hydrogels as culture substrates for understanding valvular interstitial cell activation and de novo tissue deposition. , 2012, Acta biomaterialia.

[42]  Joshua D. Hutcheson,et al.  Directing Valvular Interstitial Cell Myofibroblast‐Like Differentiation in a Hybrid Hydrogel Platform , 2015, Advanced healthcare materials.

[43]  April M. Kloxin,et al.  Hydrogel scaffolds as in vitro models to study fibroblast activation in wound healing and disease , 2014, Biomaterials science.

[44]  S. Sen,et al.  Matrix Elasticity Directs Stem Cell Lineage Specification , 2006, Cell.

[45]  Helena N. Chia,et al.  Effect of substrate stiffness on pulmonary fibroblast activation by TGF-β. , 2012, Acta biomaterialia.

[46]  Kristi S. Anseth,et al.  Dynamic stiffening of poly(ethylene glycol)-based hydrogels to direct valvular interstitial cell phenotype in a three-dimensional environment. , 2015, Biomaterials.

[47]  W. Murphy,et al.  Design of growth factor sequestering biomaterials. , 2014, Chemical communications.

[48]  Kevin W. Eliceiri,et al.  Multiphoton microscopy and fluorescence lifetime imaging microscopy (FLIM) to monitor metastasis and the tumor microenvironment , 2008, Clinical & Experimental Metastasis.

[49]  K. Anseth,et al.  Thiol-ene and photo-cleavage chemistry for controlled presentation of biomolecules in hydrogels. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[50]  A. Rodríguez-Sinovas,et al.  Lysyl oxidase as a potential therapeutic target. , 2008, Drug news & perspectives.

[51]  Jennifer L. West,et al.  Tethered-TGF-β increases extracellular matrix production of vascular smooth muscle cells , 2001 .

[52]  Vikas Singh,et al.  Second harmonic generation microscopy analysis of extracellular matrix changes in human idiopathic pulmonary fibrosis. , 2014, Journal of biomedical optics.

[53]  Murat Guvendiren,et al.  Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics , 2012, Nature Communications.

[54]  Maarten Merkx,et al.  High resolution imaging of collagen organisation and synthesis using a versatile collagen specific probe. , 2007, Journal of structural biology.

[55]  Susan Gibbs,et al.  Human hypertrophic and keloid scar models: principles, limitations and future challenges from a tissue engineering perspective , 2014, Experimental dermatology.

[56]  Geoffrey C. Gurtner,et al.  Mechanotransduction and fibrosis. , 2014, Journal of biomechanics.

[57]  K. Anseth,et al.  Role of cell–matrix interactions on VIC phenotype and tissue deposition in 3D PEG hydrogels , 2016, Journal of tissue engineering and regenerative medicine.

[58]  D. Bluemke,et al.  Noninvasive imaging of myocardial extracellular matrix for assessment of fibrosis , 2013, Current opinion in cardiology.

[59]  J. Rosenbloom,et al.  Narrative Review: Fibrotic Diseases: Cellular and Molecular Mechanisms and Novel Therapies , 2010, Annals of Internal Medicine.

[60]  R. Kalluri,et al.  Epithelial to Mesenchymal Transition induces cell cycle arrest and parenchymal damage in renal fibrosis , 2015, Nature Medicine.