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Cardiac Meets Skeletal: What’s New in Microfluidic Models for Muscle Tissue Engineering

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      Abstract

      In the last few years microfluidics and microfabrication technique principles have been extensively exploited for biomedical applications. In this framework, organs-on-a-chip represent promising tools to reproduce key features of functional tissue units within microscale culture chambers. These systems offer the possibility to investigate the effects of biochemical, mechanical, and electrical stimulations, which are usually applied to enhance the functionality of the engineered tissues. Since the functionality of muscle tissues relies on the 3D organization and on the perfect coupling between electrochemical stimulation and mechanical contraction, great efforts have been devoted to generate biomimetic skeletal and cardiac systems to allow high-throughput pathophysiological studies and drug screening. This review critically analyzes microfluidic platforms that were designed for skeletal and cardiac muscle tissue engineering. Our aim is to highlight which specific features of the engineered systems promoted a typical reorganization of the engineered construct and to discuss how promising design solutions exploited for skeletal muscle models could be applied to improve cardiac tissue models and vice versa.

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      Most cited references 97

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      Matrix elasticity directs stem cell lineage specification.

      Microenvironments appear important in stem cell lineage specification but can be difficult to adequately characterize or control with soft tissues. Naive mesenchymal stem cells (MSCs) are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity. Soft matrices that mimic brain are neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. During the initial week in culture, reprogramming of these lineages is possible with addition of soluble induction factors, but after several weeks in culture, the cells commit to the lineage specified by matrix elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types. Inhibition of nonmuscle myosin II blocks all elasticity-directed lineage specification-without strongly perturbing many other aspects of cell function and shape. The results have significant implications for understanding physical effects of the in vivo microenvironment and also for therapeutic uses of stem cells.
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        Rapid Prototyping of Microfluidic Systems in Poly(dimethylsiloxane).

        This paper describes a procedure that makes it possible to design and fabricate (including sealing) microfluidic systems in an elastomeric material [Formula: see text] poly(dimethylsiloxane) (PDMS) [Formula: see text] in less than 24 h. A network of microfluidic channels (with width >20 μm) is designed in a CAD program. This design is converted into a transparency by a high-resolution printer; this transparency is used as a mask in photolithography to create a master in positive relief photoresist. PDMS cast against the master yields a polymeric replica containing a network of channels. The surface of this replica, and that of a flat slab of PDMS, are oxidized in an oxygen plasma. These oxidized surfaces seal tightly and irreversibly when brought into conformal contact. Oxidized PDMS also seals irreversibly to other materials used in microfluidic systems, such as glass, silicon, silicon oxide, and oxidized polystyrene; a number of substrates for devices are, therefore, practical options. Oxidation of the PDMS has the additional advantage that it yields channels whose walls are negatively charged when in contact with neutral and basic aqueous solutions; these channels support electroosmotic pumping and can be filled easily with liquids with high surface energies (especially water). The performance of microfluidic systems prepared using this rapid prototyping technique has been evaluated by fabricating a miniaturized capillary electrophoresis system. Amino acids, charge ladders of positively and negatively charged proteins, and DNA fragments were separated in aqueous solutions with this system with resolution comparable to that obtained using fused silica capillaries.
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          Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment.

          Commitment of stem cells to different lineages is regulated by many cues in the local tissue microenvironment. Here we demonstrate that cell shape regulates commitment of human mesenchymal stem cells (hMSCs) to adipocyte or osteoblast fate. hMSCs allowed to adhere, flatten, and spread underwent osteogenesis, while unspread, round cells became adipocytes. Cell shape regulated the switch in lineage commitment by modulating endogenous RhoA activity. Expressing dominant-negative RhoA committed hMSCs to become adipocytes, while constitutively active RhoA caused osteogenesis. However, the RhoA-mediated adipogenesis or osteogenesis was conditional on a round or spread shape, respectively, while constitutive activation of the RhoA effector, ROCK, induced osteogenesis independent of cell shape. This RhoA-ROCK commitment signal required actin-myosin-generated tension. These studies demonstrate that mechanical cues experienced in developmental and adult contexts, embodied by cell shape, cytoskeletal tension, and RhoA signaling, are integral to the commitment of stem cell fate.
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            Author and article information

            Affiliations
            [1 ]Department of Electronics, Information and Bioengineering, Politecnico Di Milano, Milano 20133, Italy; roberta.visone@ 123456polimi.it (R.V.); marco.rasponi@ 123456polimi.it (M.R.)
            [2 ]Cell and Tissue Engineering Lab, IRCCS Istituto Ortopedico Galeazzi, Milano 20161, Italy; mara.gilardi@ 123456grupposandonato.it
            [3 ]Department of Biotechnology and Biosciences, PhD School in Life Sciences, University of Milano-Bicocca, Milano 20126, Italy
            [4 ]Departments of Surgery and Biomedicine, University Basel, University Hospital Basel, Basel 4065, Switzerland; anna.marsano@ 123456usb.ch
            [5 ]Regenerative Medicine Technologies Lab, Ente Ospedaliero Cantonale, Lugano 6900, Switzerland
            [6 ]Swiss Institute for Regenerative Medicine, Lugano 6900, Switzerland
            [7 ]Cardiocentro Ticino, Lugano 6900, Switzerland
            Author notes
            [* ]Correspondence: simone.bersini@ 123456grupposandonato.it (S.B.); matteo.moretti@ 123456grupposandonato.it (M.M.); Tel.: +39-02-6621-4061 (S.B.); Tel.: +39-02-6621-4049 (M.M.)
            [†]

            These authors contributed equally to this work.

            [‡]

            These authors contributed equally to this work.

            Contributors
            Role: Academic Editor
            Role: Academic Editor
            Journal
            Molecules
            Molecules
            molecules
            Molecules
            MDPI
            1420-3049
            26 August 2016
            September 2016
            : 21
            : 9
            27571058
            6274098
            10.3390/molecules21091128
            molecules-21-01128
            (Academic Editor), (Academic Editor)
            © 2016 by the authors.

            Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

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