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WIREs Nanomed Nanobiotechnol
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Extracellular matrix biomimicry for the creation of investigational and therapeutic devices

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Abstract The extracellular matrix (ECM) is a web of fibrous proteins that serves as a scaffold for tissues and organs, and is important for maintaining homeostasis and facilitating cellular adhesion. Integrin transmembrane receptors are the primary adhesion molecules that anchor cells to the ECM, thus integrating cells with their microenvironments. Integrins play a critical role in facilitating cell–matrix interactions and promoting signal transduction, both from the cell to the ECM and vice versa, ultimately mediating cell behavior. For this reason, many advanced biomaterials employ biomimicry by replicating the form and function of fibrous ECM proteins. The ECM also acts as a reservoir for small molecules and growth factors, wherein fibrous proteins directly bind and present these bioactive moieties that facilitate cell activity. Therefore biomimicry can be enhanced by incorporating small molecules into ECM‐like substrates. Biomimetic ECM materials have served as invaluable research tools for studying interactions between cells and the surrounding ECM, revealing that cell–matrix signaling is driven by mechanical forces, integrin engagement, and small molecules. Mimicking pathological ECMs has also elucidated disease specific cell behaviors. For example, biomimetic tumor microenvironments have been used to induce metastatic cell behaviors, and have thereby shown promise for in vitro cancer drug testing and targeting. Further, ECM‐like substrates have been successfully employed for autologous cell recolonization for tissue engineering and wound healing. As we continue to learn more about the mechanical and biochemical characteristics of the ECM, these properties can be harnessed to develop new biomaterials, biomedical devices, and therapeutics. WIREs Nanomed Nanobiotechnol 2015, 8:5–22. doi: 10.1002/wnan.1349 This article is categorized under: Diagnostic Tools > Biosensing Diagnostic Tools > Diagnostic Nanodevices Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement
ECM‐integrin binding. Each ECM protein contains specific peptide sequences that act as ligands for integrin transmembrane receptors. Fibronectin is one example, with two important ligands for cell adhesion, RGD (pink) and LDV (yellow) (a). Most ECM proteins contain one or more integrin binding peptide sequence, which is able to bind to many different integrins to facilitate cell–matrix adhesion (b). *Strong affinity between ligand and integrin. Abbreviations: LDV, Leu‐Asp‐Val; RGD, Arg‐Gly‐Asp; DGEA, Asp‐Gly‐Glu‐Ala.
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SEM image of a human amniotic membrane (a) and a biomimetic, crystal templated poly (ethylene) glycol (PEG) hydrogel made using 10 kDa PEG and 40% urea for a crystal template (b); scale bars are 20 µm. An SEM cross section of the gel demonstrates the porous network that was created throughout the thickness of the gel (c); scale bar is 100 µm. Reprinted with permission from Ref . Copyright 2014 World Scientific Publishing Company.
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SEM images of a rat native trachea (a) and a biomimetic electrospun polyethylene terephthalate (PET) tracheal scaffold magnified 300× (b). Reprinted with permission from Ref . Copyright 2014 Elsevier.
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Examples of ‘inside‐out’ and ‘outside‐in’ signaling via integrin transmembrane receptors. When a cell first comes into contact with the ECM, integrins are inactive and in a low affinity state (a). In order to bind to the ECM, the cell must activate its integrin receptors, which results in a high affinity state that is able to bind an ECM ligand (b). This creates a trimeric complex between the integrin, the immobilized ECM ligand, and the cytoskeletal protein talin (b). After the trimeric complex is formed, the integrins are able to translocate along F‐actin fibers via talin, resulting in a cluster of ligand bound integrins (c). An increase in lateral membrane tension can lead to ion‐channel opening (d), which can cause an influx of ions (d). This is often seen with mechanically gated ion channels that act to regulate osmotic swelling.
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Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement
Diagnostic Tools > Diagnostic Nanodevices
Diagnostic Tools > Biosensing

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