Lewis A Reis1, Loraine L Y Chiu1, Jun Wu1, Nicole Feric1, Carol Laschinger1, Abdul Momen1, Ren-Ke Li1, Milica Radisic2. 1. From the Institute of Biomaterials and Biomedical Engineering (L.A.R., N.F., C.L., M.R.) and Department of Chemical Engineering and Applied Chemistry (L.L.Y.C., M.R.), University of Toronto, Canada; and Toronto General Research Institute, University Health Network, Canada (J.W., A.M., R.-K.L.). 2. From the Institute of Biomaterials and Biomedical Engineering (L.A.R., N.F., C.L., M.R.) and Department of Chemical Engineering and Applied Chemistry (L.L.Y.C., M.R.), University of Toronto, Canada; and Toronto General Research Institute, University Health Network, Canada (J.W., A.M., R.-K.L.). m.radisic@utoronto.ca.
Abstract
BACKGROUND: Hydrogels are being actively investigated for direct delivery of cells or bioactive molecules to the heart after myocardial infarction (MI) to prevent cardiac functional loss. We postulate that immobilization of the prosurvival angiopoietin-1-derived peptide, QHREDGS, to a chitosan-collagen hydrogel could produce a clinically translatable thermoresponsive hydrogel to attenuate post-MI cardiac remodeling. METHODS AND RESULTS: In a rat MI model, QHREDGS-conjugated hydrogel (QHG213H), control gel, or PBS was injected into the peri-infarct/MI zone. By in vivo tracking and chitosan staining, the hydrogel was demonstrated to remain in situ for 2 weeks and was cleared in ≈3 weeks. By echocardiography and pressure-volume analysis, the QHG213H hydrogel significantly improved cardiac function compared with the controls. Scar thickness and scar area fraction were also significantly improved with QHG213H gel injection compared with the controls. There were significantly more cardiomyocytes, determined by cardiac troponin-T staining, in the MI zone of the QHG213H hydrogel group; and hydrogel injection did not induce a significant inflammatory response as assessed by polymerase chain reaction and an inflammatory cytokine assay. The interaction of cardiomyocytes and cardiac fibroblasts with QHREDGS was found to be mediated by β1-integrins. CONCLUSIONS: We demonstrated for the first time that the QHG213H peptide-modified hydrogel can be injected in the beating heart where it remains localized for a clinically effective period. Moreover, the QHG213H hydrogel induced significant cardiac functional and morphological improvements after MI relative to the controls.
BACKGROUND: Hydrogels are being actively investigated for direct delivery of cells or bioactive molecules to the heart after myocardial infarction (MI) to prevent cardiac functional loss. We postulate that immobilization of the prosurvival angiopoietin-1-derived peptide, QHREDGS, to a chitosan-collagen hydrogel could produce a clinically translatable thermoresponsive hydrogel to attenuate post-MI cardiac remodeling. METHODS AND RESULTS: In a rat MI model, QHREDGS-conjugated hydrogel (QHG213H), control gel, or PBS was injected into the peri-infarct/MI zone. By in vivo tracking and chitosan staining, the hydrogel was demonstrated to remain in situ for 2 weeks and was cleared in ≈3 weeks. By echocardiography and pressure-volume analysis, the QHG213H hydrogel significantly improved cardiac function compared with the controls. Scar thickness and scar area fraction were also significantly improved with QHG213H gel injection compared with the controls. There were significantly more cardiomyocytes, determined by cardiac troponin-T staining, in the MI zone of the QHG213H hydrogel group; and hydrogel injection did not induce a significant inflammatory response as assessed by polymerase chain reaction and an inflammatory cytokine assay. The interaction of cardiomyocytes and cardiac fibroblasts with QHREDGS was found to be mediated by β1-integrins. CONCLUSIONS: We demonstrated for the first time that the QHG213H peptide-modified hydrogel can be injected in the beating heart where it remains localized for a clinically effective period. Moreover, the QHG213H hydrogel induced significant cardiac functional and morphological improvements after MI relative to the controls.
Authors: John W MacArthur; Amanda N Steele; Andrew B Goldstone; Jeffrey E Cohen; William Hiesinger; Y Joseph Woo Journal: Curr Treat Options Cardiovasc Med Date: 2017-04
Authors: Yun Xiao; Lewis A Reis; Nicole Feric; Erica J Knee; Junhao Gu; Shuwen Cao; Carol Laschinger; Camila Londono; Julia Antolovich; Alison P McGuigan; Milica Radisic Journal: Proc Natl Acad Sci U S A Date: 2016-09-19 Impact factor: 11.205
Authors: Rick Xing Ze Lu; Benjamin Fook Lun Lai; Naimeh Rafatian; Dakota Gustafson; Scott B Campbell; Arinjay Banerjee; Robert Kozak; Karen Mossman; Samira Mubareka; Kathryn L Howe; Jason E Fish; Milica Radisic Journal: Lab Chip Date: 2022-03-15 Impact factor: 7.517