A biomaterial-based therapy for lower limb ischemia using Sr/Si bioactive hydrogel that inhibits skeletal muscle necrosis and enhances angiogenesis

Ye Yuan; Zhaowenbin Zhang; Fandi Mo; Chen Yang; Yiren Jiao; Enci Wang; Yuchong Zhang; Peng Lin; Chengkai Hu; Weiguo Fu; Jiang Chang; Lixin Wang

doi:10.1016/j.bioactmat.2023.02.027

A biomaterial-based therapy for lower limb ischemia using Sr/Si bioactive hydrogel that inhibits skeletal muscle necrosis and enhances angiogenesis

Bioact Mater. 2023 Mar 10:26:264-278. doi: 10.1016/j.bioactmat.2023.02.027. eCollection 2023 Aug.

Authors

Ye Yuan¹, Zhaowenbin Zhang^{2

3

4}, Fandi Mo¹, Chen Yang^{2

3}, Yiren Jiao^{2

3}, Enci Wang¹, Yuchong Zhang¹, Peng Lin¹, Chengkai Hu¹, Weiguo Fu^{1

5}, Jiang Chang^{2

3

4}, Lixin Wang^{1

5}

Affiliations

¹ Department of Vascular Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
² Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
³ Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China.
⁴ Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Dingxi Road, Shanghai, 200050, China.
⁵ Department of Vascular Surgery, Zhongshan Xiamen Hospital, Fudan University, 668 JinhuRoad, Xiamen, 361015, China.

Abstract

Muscle necrosis and angiogenesis are two major challenges in the treatment of lower-limb ischemic diseases. In this study, a triple-functional Sr/Si-containing bioceramic/alginate composite hydrogel with simultaneous bioactivity in enhancing angiogenesis, regulating inflammation, and inhibiting muscle necrosis was designed to treat lower-limb ischemic diseases. In particular, sodium alginate, calcium silicate and strontium carbonate were used to prepare injectable hydrogels, which was gelled within 10 min. More importantly, this composite hydrogel sustainedly releases bioactive Sr²⁺ and SiO₃ ^2- ions within 28 days. The biological activity of the bioactive ions released from the hydrogels was verified on HUVECs, SMCs, C2C12 and Raw 264.7 cells in vitro, and the therapeutic effect of the hydrogel was confirmed using C57BL/6 mouse model of femoral artery ligation in vivo. The results showed that the composite hydrogel stimulated angiogenesis, developed new collateral capillaries, and re-established the blood supply. In addition, the bioactive hydrogel directly promoted the expression of muscle-regulating factors (MyoG and MyoD) to protect skeletal muscle from necrosis, inhibited M1 polarization, and promoted M2 polarization of macrophages to reduce inflammation, thereby protecting skeletal muscle cells and indirectly promoting vascularization. Our results indicate that these bioceramic/alginate composite bioactive hydrogels are effective biomaterials for treating hindlimb ischemia and suggest that biomaterial-based approaches may have remarkable potential in treating ischemic diseases.

Keywords: Angiogenesis; Bioactive hydrogel; Hindlimb ischemic diseases; Muscle necrosis; Strontium carbonate and calcium silicate bioceramic.