title: pH-Sensitive and Thermosensitive Hydrogels as Stem-Cell Carriers for Cardiac Therapy.
abstract: Stem-cell therapy has the potential to regenerate damaged heart tissue after a heart attack. Injectable hydrogels may be used as stem-cell carriers to improve cell retention in the heart tissue. However, current hydrogels are not ideal to serve as cell carriers because most of them block blood vessels after solidification. In addition, these hydrogels have a relatively slow gelation rate (typically >60 s), which does not allow them to quickly solidify upon injection, so as to efficiently hold cells in the heart tissue. As a result, the hydrogels and cells are squeezed out of the tissue, leading to low cell retention. To address these issues, we have developed hydrogels that can quickly solidify at the pH of an infarcted heart (6-7) at 37 °C but cannot solidify at the pH of blood (7.4) at 37 °C. These hydrogels are also clinically attractive because they can be injected through catheters commonly used for minimally invasive surgeries. The hydrogels were synthesized by free-radical polymerization of N-isopropylacrylamide, propylacrylic acid, hydroxyethyl methacrylate-co-oligo(trimethylene carbonate), and methacrylate poly(ethylene oxide) methoxy ester. Hydrogel solutions were injectable through 0.2-mm-diameter catheters at pH 8.0 at 37 °C, and they can quickly form solid gels under pH 6.5 at 37 °C. All of the hydrogels showed pH-dependent degradation and mechanical properties with less mass loss and greater complex shear modulus at pH 6.5 than at pH 7.4. When cardiosphere-derived cells (CDCs) were encapsulated in the hydrogels, the cells were able to survive during a 7-day culture period. The surviving cells were differentiated into cardiac cells, as evidenced by the expression of cardiac markers at both the gene and protein levels, such as cardiac troponin T, myosin heavy chain α, calcium channel CACNA1c, cardiac troponin I, and connexin 43. The gel integrity was found to largely affect CDC cardiac differentiation. These results suggest that the developed dual-sensitive hydrogels may be promising carriers for cardiac cell therapy.
authors.affiliation: Department of Materials Science and Engineering and ⊥Department of Emergency Medicine, Davis Heart Lung Research Institute, The Ohio State University , Columbus, Ohio 43210, United States.|Department of Gerontology, Tongji Hospital, and ∥Tongji Hospital, Tongji University , Shanghai, China.
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Materials Science and Engineering and ⊥Department of Emergency Medicine, Davis Heart Lung Research Institute, The Ohio State University , Columbus, Ohio 43210, United States.|Department of Gerontology, Tongji Hospital, and ∥Tongji Hospital, Tongji University , Shanghai, China.
authors.forename: Zhaobo
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Department of Materials Science and Engineering and ⊥Department of Emergency Medicine, Davis Heart Lung Research Institute, The Ohio State University , Columbus, Ohio 43210, United States.|Department of Gerontology, Tongji Hospital, and ∥Tongji Hospital, Tongji University , Shanghai, China.
authors.forename: Yanyi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Materials Science and Engineering and ⊥Department of Emergency Medicine, Davis Heart Lung Research Institute, The Ohio State University , Columbus, Ohio 43210, United States.|Department of Gerontology, Tongji Hospital, and ∥Tongji Hospital, Tongji University , Shanghai, China.
authors.forename: Wilson
authors.initials: W
authors.lastname: Lo
authors.affiliation: Department of Materials Science and Engineering and ⊥Department of Emergency Medicine, Davis Heart Lung Research Institute, The Ohio State University , Columbus, Ohio 43210, United States.|Department of Gerontology, Tongji Hospital, and ∥Tongji Hospital, Tongji University , Shanghai, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Materials Science and Engineering and ⊥Department of Emergency Medicine, Davis Heart Lung Research Institute, The Ohio State University , Columbus, Ohio 43210, United States.|Department of Gerontology, Tongji Hospital, and ∥Tongji Hospital, Tongji University , Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Niu
authors.affiliation: Department of Materials Science and Engineering and ⊥Department of Emergency Medicine, Davis Heart Lung Research Institute, The Ohio State University , Columbus, Ohio 43210, United States.|Department of Gerontology, Tongji Hospital, and ∥Tongji Hospital, Tongji University , Shanghai, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Materials Science and Engineering and ⊥Department of Emergency Medicine, Davis Heart Lung Research Institute, The Ohio State University , Columbus, Ohio 43210, United States.|Department of Gerontology, Tongji Hospital, and ∥Tongji Hospital, Tongji University , Shanghai, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Materials Science and Engineering and ⊥Department of Emergency Medicine, Davis Heart Lung Research Institute, The Ohio State University , Columbus, Ohio 43210, United States.|Department of Gerontology, Tongji Hospital, and ∥Tongji Hospital, Tongji University , Shanghai, China.
authors.forename: Mahmood
authors.initials: M
authors.lastname: Khan
authors.affiliation: Department of Materials Science and Engineering and ⊥Department of Emergency Medicine, Davis Heart Lung Research Institute, The Ohio State University , Columbus, Ohio 43210, United States.|Department of Gerontology, Tongji Hospital, and ∥Tongji Hospital, Tongji University , Shanghai, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Guan
mesh_terms: D000178:Acrylamides; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D013234:Stem Cells
chemical_list: D000178:Acrylamides; D020100:Hydrogels; C067295:N-isopropylacrylamide
keywords: cardiac differentiation; cardiosphere-derived cells; catheter delivery; pH-sensitive hydrogel; thermosensitive hydrogel