Myocardial‐Infarction‐Responsive Smart Hydrogels Targeting Matrix Metalloproteinase for On‐Demand Growth Factor Delivery

Abstract

Although in situ restoration of blood supply to the infarction region and attenuating pre‐existing extracellular matrix degradation remain potential therapeutic approaches for myocardial infarction (MI), local delivery of therapeutics has been limited by low accumulation (inefficacy) and unnecessary diffusion (toxicity). Here, a dual functional MI‐responsive hydrogel is fabricated for on‐demand drug delivery to promote angiogenesis and inhibit cardiac remodeling by targeting upregulated matrix metalloproteinase‐2/9 (MMP‐2/9) after MI. A glutathione (GSH)‐modified collagen hydrogel (collagen‐GSH) is prepared by conjugating collagen amine groups with GSH sulfhydryl groups and the recombinant protein GST‐TIMP‐bFGF (bFGF: basic fibroblast growth factor) by fusing bFGF with glutathione‐S‐transferase (GST) and MMP‐2/9 cleavable peptide PLGLAG (TIMP). Specific binding between GST and GSH significantly improves the amount of GST‐TIMP‐bFGF loaded in collagen‐GSH hydrogel. The TIMP peptide enclosed between GST and bFGF responds to MMPs for on‐demand release during MI. Additionally, the TIMP peptide is a competitive substrate of MMPs that inhibits the excessive degradation of cardiac matrix by MMPs after MI. GST‐TIMP‐bFGF/collagen‐GSH hydrogels promote the recovery of MI rats by enhancing vascularization and ameliorating myocardium remodeling. The results suggest that on‐demand growth factor delivery by synchronously controlling binding and responsive release to promote angiogenesis and attenuate cardiac remodeling might be promising for the treatment of ischemic heart disease.

Stimuli‐Responsive Delivery of Growth Factors for Tissue Engineering

“…It was shown that an MMP‐responsive hydrogel alleviated MI‐induced vascular wall thinning and promoted the proliferation of vascular cells. [ 130 ] It is quite convenient to link hydrogels with protease cleavable linkers for responsive delivery. Similar MMP‐responsive features were adopted in SDF‐1α delivery.…”

“…MMP‐2/9 cleavable hydrogel that achieved on‐demand bFGF release for myocardial infarction. [ 130 ] A) Schematic illustration of the preparation and the process of the responsive release from the MMP responsive injectable hydrogel. B) bFGF release triggered by MMP‐2 at different time points.…”

Recent Advances on Magnetic Sensitive Hydrogels in Tissue Engineering

“…et al, 2019;Zhu et al, 2019). Meanwhile, hydrogel-based drug delivery systems for numerous therapeutic agents, with high water content, low interfacial tension with biological fluids, and soft consistency, have been shown to be more stable, economical, and efficient in comparison with conventional delivery systems (Li and Mooney, 2016;Moore and Hartgerink, 2017;Cheng et al, 2019;Fan et al, 2019;Zheng et al, 2019). Considering the above advantages, hydrogels have been conducted into the biomedical application to provide a tunable three-dimensional scaffold for cell adhesion, migration, and/or differentiation, and they could also be designed as the platform for the controlled release of cytokines and drugs in tissue engineering and drug delivery (Huang et al, 2017;Jiang et al, 2017;Hsu et al, 2019;Wei et al, 2019;Zheng et al, 2019).…”

Development and novel design of clustery Graphene Oxide formed Conductive Silk hydrogel cell vesicle to Repair Myocardial Infarction: Investigation of its biological activity for cell delivery applications

“…Particularly, favorable cell delivery via injectable hydrogel system can be a stimulating and effective alternative to attain the targeted site delivery of huge numbered live cells. Many biodegradable hydrogels designed containing a broad range of favorable mechanical and biocompatible properties have been investigated by clinical animal models to regeneration of myocardial infarction, cardiovascular diseases, etc., Numerous reported studies were suggested that high modulus injectable hydrogel matrix with conductive properties could be greatly in uence on recovery of heart functions after myocardial infarction [16][17][18][19].…”