title: Substrate modulus of 3D-printed scaffolds regulates the regenerative response in subcutaneous implants through the macrophage phenotype and Wnt signaling.
abstract: The growing need for therapies to treat large cutaneous defects has driven recent interest in the design of scaffolds that stimulate regenerative wound healing. While many studies have investigated local delivery of biologics as a restorative approach, an increasing body of evidence highlights the contribution of the mechanical properties of implanted scaffolds to wound healing. In the present study, we designed poly(ester urethane) scaffolds using a templated-Fused Deposition Modeling (t-FDM) process to test the hypothesis that scaffolds with substrate modulus comparable to that of collagen fibers enhance a regenerative versus a fibrotic response. We fabricated t-FDM scaffolds with substrate moduli varying from 5 to 266 MPa to investigate the effects of substrate modulus on healing in a rat subcutaneous implant model. Angiogenesis, cellular infiltration, collagen deposition, and directional variance of collagen fibers were maximized for wounds treated with scaffolds having a substrate modulus (Ks = 24 MPa) comparable to that of collagen fibers. The enhanced regenerative response in these scaffolds was correlated with down-regulation of Wnt/β-catenin signaling in fibroblasts, as well as increased polarization of macrophages toward the restorative M2 phenotype. These observations highlight the substrate modulus of the scaffold as a key parameter regulating the regenerative versus scarring phenotype in wound healing. Our findings further point to the potential use of scaffolds with substrate moduli tuned to that of the native matrix as a therapeutic approach to improve cutaneous healing.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: R
authors.initials: R
authors.lastname: Guo
authors.affiliation: Research Service, Department of Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Merkel
authors.affiliation: Research Service, Department of Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Sterling
authors.affiliation: Research Service, Department of Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Department of Pathology, Immunology, and Microbiology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Davidson
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA. Electronic address: scott.guelcher@vanderbilt.edu.
authors.forename: S A
authors.initials: SA
authors.lastname: Guelcher
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007700:Kinetics; D008264:Macrophages / Q000473:pathology*; D008297:Male; D009389:Neovascularization, Pathologic; D010641:Phenotype; D016062:Porosity; D011312:Pressure; D066330:Printing, Three-Dimensional; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000502:physiology*; D023822:Tissue Engineering; D054457:Tissue Scaffolds / Q000737:chemistry*; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D014945:Wound Healing; D051176:beta Catenin / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D003094:Collagen
keywords: Elastic modulus; Fibroblast; Macrophage polarization; Scaffold; Wnt signaling; Wound healing