title: Large strain stimulation promotes extracellular matrix production and stiffness in an elastomeric scaffold model.
abstract: Mechanical conditioning of engineered tissue constructs is widely recognized as one of the most relevant methods to enhance tissue accretion and microstructure, leading to improved mechanical behaviors. The understanding of the underlying mechanisms remains rather limited, restricting the development of in silico models of these phenomena, and the translation of engineered tissues into clinical application. In the present study, we examined the role of large strip-biaxial strains (up to 50%) on ECM synthesis by vascular smooth muscle cells (VSMCs) micro-integrated into electrospun polyester urethane urea (PEUU) constructs over the course of 3 weeks. Experimental results indicated that VSMC biosynthetic behavior was quite sensitive to tissue strain maximum level, and that collagen was the primary ECM component synthesized. Moreover, we found that while a 30% peak strain level achieved maximum ECM synthesis rate, further increases in strain level lead to a reduction in ECM biosynthesis. Subsequent mechanical analysis of the formed collagen fiber network was performed by removing the scaffold mechanical responses using a strain-energy based approach, showing that the denovo collagen also demonstrated mechanical behaviors substantially better than previously obtained with small strain training and comparable to mature collagenous tissues. We conclude that the application of large deformations can play a critical role not only in the quantity of ECM synthesis (i.e. the rate of mass production), but also on the modulation of the stiffness of the newly formed ECM constituents. The improved understanding of the process of growth and development of ECM in these mechano-sensitive cell-scaffold systems will lead to more rational design and manufacturing of engineered tissues operating under highly demanding mechanical environments.
authors.affiliation: Department of Bioengineering McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Fondazione RiMED, Italy; DICGIM, Università di Palermo, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Amore
authors.affiliation: Center for Cardiovascular Simulation, Institute for Computational Engineering and Sciences, Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Joao S
authors.initials: JS
authors.lastname: Soares
authors.affiliation: Department of Bioengineering McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Stella
authors.affiliation: Center for Cardiovascular Simulation, Institute for Computational Engineering and Sciences, Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Will
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Bioengineering McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Amoroso
authors.affiliation: Department of Cardiac Surgery Boston Children׳s Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Mayer
authors.affiliation: Department of Bioengineering McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Wagner
authors.affiliation: Center for Cardiovascular Simulation, Institute for Computational Engineering and Sciences, Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA. Electronic address: msacks@ices.utexas.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Sacks
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000648:ultrastructure; D004548:Elasticity; D020724:Elastomers; D005109:Extracellular Matrix / Q000737:chemistry*; D008962:Models, Theoretical; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D011917:Rats, Inbred Lew; D013314:Stress, Mechanical; D023822:Tissue Engineering; D054457:Tissue Scaffolds
chemical_list: D020724:Elastomers; D003094:Collagen
keywords: ECM (extracellular matrix); Elastomeric scaffold; Mechanical conditioning; Mechanical properties