Supporting Information

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1 Supporting Information Rebuilding post-infarcted cardiac functions by injecting NPs-crosslinked ROS sensitive hydrogels Wei Wang 1,#, Jingrui Chen 2,3,#, Min Li 2,3, Huizhen Jia 1, Xiaoxu Han 1, Jingxuan Zhang 1, Yang Zou 1, Baoyu Tan 1, Wei Liang 1, Yingying Shang 1, Qian Xu 4, Sigen A 4, Wenxin Wang 4, Jingyuan Mao 2, Xiumei Gao 3,*, Guanwei Fan 2,3,*, Wenguang Liu 1,* 1 School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin, , China 2 First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, , China 3 Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, , China 4 Charles Institute of Dermatology, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland. # The first two authors contributed equally to this paper *Corresponding author (Xiumei Gao, gaoxiumei@tjutcm.edu.cn); Guanwei Fan, fgw1005@163.com); Wenguang Liu, wgliu@tju.edu.cn) This supporting information file includes: Supplementary Figures 1 to 5 S-1

2 Figure S1 1 H-NMR spectrum of HB-PBAE S-2

3 0.75 Absorbance min 240 min 1440 min Wavelength (nm) Figure S2 UV-Vis absorbance of DPPH solution with the time extension. S-3

4 Figure S3 Schematic of degradation byproducts of HB-PBAE. In the previous study, 1 a series of HB-PBAEs were synthesized by poly(ethylene glycol) diacrylate (PEGDA, Mn = 258, 575, and 700 g/mol) with ethylenediamine (EDA) or hexamethylenediamine (HDA), which showed the similar PBAE chemical structure as the hyperbranched polymers in this research. The degradation profiles of PEGDA/EDA (HDA) polymers were assessed in PBS buffer solution at 37 o C via detection of molecular weight by GPC. PEGDA/EDA (HDA) polymers exhibit very fast degradation behavior with the molecular weight decreasing to less than 30% after 4 h in PBS. In addition, HP-PBAEs with longer PEG chain result in a much faster degradation speed. For the HP-PBAE with PEGDA 700 composition, the molecular weight decreases to 60% in 1 h. There were several reports to suggest that the restraint of swelling might reduce the degradation rate. In the previous study, 1 PEGDA/EDA (HDA) polymers were synthesized with diverse degradation properties to match up the different wound healing rate in various types of skin wounds (non-diabetic or diabetic wounds). Due to the hydrolysis mechanism, the hydrogels based on PEGDA/EDA (HDA) and HA-SH exhibited a much faster degradation rate in PBS than that in subcutaneous implantation due to restraint of swelling. As reported by Jason A. Burdick et al in their research, 2 a library of acrylate-terminated linear PBAEs were synthesized and then photopolymerized to form degradable networks, with a wide range of degradation times (< 1 day to minimal mass loss after three months). The degradation profiles follow a law that more hydrophilic macromers degraded faster than macromers with fewer ethylene glycol repeat units. The similar report on the degradation of PBAE network can be found in other literature. 3,4 Moreover, it has been found that the restraint of swelling may reduce the degradation rate in a rabbit osteochondral defect model. 5 The fibrin gel releases completely in DMEM at 37 o C within 3 days, which only can still be found 6 days later after loaded into the PLGA sponges. Degradation of the fibrin gel in vivo was qualitatively characterized by immunohistochemical staining. The fibrin gel was abundant and massive in the tissue sections within the first 2 week, while it was observed regionally after 4 weeks. After implantation for 12 weeks, only sporadic fibrin gel was observed. 24 weeks later, and no fibrin gel was remained. In contrast to this fast release in vitro, its degradation in vivo is much slower. In vivo degradation profile of fibrin gel is consistent with the results of van Susante et al. 6 They S-4

5 implanted the fibrin gel/chondrocytes into goat s cartilage defects, and observed the fibrin gel occasionally after 13 weeks. The difference of in vivo and in vitro degradation is attributed to the slower diffusion rate from the implanted construct, which is surrounded mostly by the host tissues and exposes only one side toward the articular cavity. S-5

6 Relatvie Cell Viability (%) TIIA NPs TIIA@PDA NPs Concentration of NPs ( g/ml) Figure S4 Cytotoxicity of the drug nanoparticles S-6

7 Relative cell viability (%) HB-PBAE (2.5wt%)/HA-SH HB-PBAE (5wt%)/HA-SH HB-PBAE (10wt%)/HA-SH HB-PBAE (5wt%)/HA-SH/TIIA@PDA (L) HB-PBAE (5wt%)/HA-SH/TIIA@PDA (H) Co-culture time (hour) Figure S5 Cytotoxicity of the hydrogels S-7

8 References (1) Xu Q.; Guo L. R.; Sigen A.; Gao Y. S.; Zhou D. Z.; Greiser U.; Creagh-Flynn J.; Zhang H.; Dong Y. X.; Cutlar L.; Wang F. G.; Liu W. G.; Wang W.; Wang W. X. Injectable Hyperbranched Poly(Beta-Amino Ester) Hydrogels with on-demand Degradation Profiles to Match Wound Healing Processes. Chem. Sci. 2018, 9, (2) Anderson D. G.; Tweedie C. A.; Hossain N.; Navarro S. M.; Brey D. M.; Van Vliet K. J.; Langer R.; Burdick J. A. A Combinatorial Library of Photocrosslinkable and Degradable Materials. Adv. Mater. 2006, 18, (3) Hawkins A. M.; Milbrandt T. A.; Puleo D. A.; Hilt J. Z. Synthesis and Analysis of Degradation, Mechanical and Toxicity Properties of Poly(β-amino ester) Degradable Hydrogels. Acta Biomater. 2011, 7, (4) Hawkins A. M.; Tolbert M. E.; Newton B.; Milbrandt T. A.; Puleo D. A.; Hilt J. Z. Tuning Biodegradable Hydrogel Properties via Synthesis Procedure. Polymer 2013, 54, (5) Wang W.; Li B.; Yang J.; Xin L.; Li Y.; Yin H.; Qi Y.; Jiang Y.; Ouyang H.; Gao C. The Restoration of Full-thickness Cartilage Defects with BMSCs and TGF-beta 1 Loaded PLGA/fibrin Gel Constructs. Biomaterials 2010, 31, (6) van Susante J. L.; Buma P.; Schuman L.; Homminga G. N.; van den Berg W. B.; Veth R. P.; Resurfacing Potential of Heterologous Chondrocytes Suspended in Fibrin Glue in Large Full-Thickness Defects of Femoral Articular Cartilage: An Experimental Study in the Goat. Biomaterials 1999, 20, S-8