Glucose and MMP-9 dual-responsive hydrogel with temperature sensitive self-adaptive shape and controlled drug release accelerates diabetic wound healing

Wanyi Zhou; Zhiguang Duan; Jing Zhao; Rongzhan Fu; Chenhui Zhu; Daidi Fan

doi:10.1016/j.bioactmat.2022.01.004

Glucose and MMP-9 dual-responsive hydrogel with temperature sensitive self-adaptive shape and controlled drug release accelerates diabetic wound healing

Bioact Mater. 2022 Jan 19:17:1-17. doi: 10.1016/j.bioactmat.2022.01.004. eCollection 2022 Nov.

Authors

Wanyi Zhou^{1

2

3}, Zhiguang Duan^{1

2

3}, Jing Zhao^{1

2

3}, Rongzhan Fu^{1

2

3}, Chenhui Zhu^{1

2

3}, Daidi Fan^{1

2

3}

Affiliations

¹ Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an, 710069, Shaanxi, China.
² Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an, 710069, Shaanxi, China.
³ Biotech. & Biomed. Research Institute, Northwest University, Xi'an, 710069, Shaanxi, China.

Abstract

Chronic diabetic wounds are an important healthcare challenge. High concentration glucose, high level of matrix metalloproteinase-9 (MMP-9), and long-term inflammation constitute the special wound environment of diabetic wounds. Tissue necrosis aggravates the formation of irregular wounds. All the above factors hinder the healing of chronic diabetic wounds. To solve these issues, a glucose and MMP-9 dual-response temperature-sensitive shape self-adaptive hydrogel (CBP/GMs@Cel&INS) was designed and constructed with polyvinyl alcohol (PVA) and chitosan grafted with phenylboric acid (CS-BA) by encapsulating insulin (INS) and gelatin microspheres containing celecoxib (GMs@Cel). Temperature-sensitive self-adaptive CBP/GMs@Cel&INS provides a new way to balance the fluid-like mobility (self-adapt to deep wounds quickly, approximately 37 °C) and solid-like elasticity (protect wounds against external forces, approximately 25 °C) of self-adaptive hydrogels, while simultaneously releasing insulin and celecoxib on-demand in the environment of high-level glucose and MMP-9. Moreover, CBP/GMs@Cel&INS exhibits remodeling and self-healing properties, enhanced adhesion strength (39.65 ± 6.58 kPa), down-regulates MMP-9, and promotes cell proliferation, migration, and glucose consumption. In diabetic full-thickness skin defect models, CBP/GMs@Cel&INS significantly alleviates inflammation and regulates the local high-level glucose and MMP-9 in the wounds, and promotes wound healing effectively through the synergistic effect of temperature-sensitive shape-adaptive character and the dual-responsive system.

Keywords: AGEs, advanced glycation end-products; BA, Carboxyphenylboric acid; CBP, the CS-BA-PVA hydrogel; CS, chitosan; Cel, celecoxib; Diabetic wound healing; Dual-responsive; GMs, gelatin microspheres; IL-10, interleukin-10; INS, insulin; MMP-9, matrix metalloproteinase-9; MMPs, matrix metalloproteinases; PVA, polyvinyl alcohol; STZ, streptozotocin; Shape self-adaptive hydrogels; TNF-α, Tumornecrosisfactor-α; Temperature-sensitive; VEGF, vascularendothelialgrowthfactor.