Innovative hydrogel-based therapies for ischemia-reperfusion injury： bridging the gap between pathophysiology and treatment

Abstract

Ischemia-reperfusion injury (IRI) commonly occurs in clinical settings, particularly in medical practices such as organ transplantation, cardiopulmonary resuscitation, and recovery from acute trauma, posing substantial challenges in clinical therapies. Current systemic therapies for IRI are limited by poor drug targeting, short efficacy, and significant side effects. Owing to their exceptional biocompatibility, biodegradability, excellent mechanical properties, targeting capabilities, controlled release potential, and properties mimicking the extracellular matrix (ECM), hydrogels not only serve as superior platforms for therapeutic substance delivery and retention, but also facilitate bioenvironment cultivation and cell recruitment, demonstrating significant potential in IRI treatment. This review explores the pathological processes of IRI and discusses the roles and therapeutic outcomes of various hydrogel systems. By categorizing hydrogel systems into depots delivering therapeutic agents, scaffolds encapsulating mesenchymal stem cells (MSCs), and ECM-mimicking hydrogels, this article emphasizes the selection of polymers and therapeutic substances, and details special crosslinking mechanisms and physicochemical properties, as well as summarizes the application of hydrogel systems for IRI treatment. Furthermore, it evaluates the limitations of current hydrogel treatments and suggests directions for future clinical applications.

Keywords: Hydrogel; Ischemia-reperfusion injury; Mesenchymal stem cells; Reactive oxygen species; Therapeutic substance delivery.

Graphical abstract

Fig. 1

The illustration of the occurrence process of ischemia-reperfusion and the connection between key pathophysiological mechanisms.

Fig. 2

Schematic illustration of hydrogel depots for small molecule delivery. (A) Synthesis process and ROS scavenging function of pNVMT, the copolymer of the TEMPO hydrogel system, and its mimic pNVMC for controlled experiment [109]. (Adapted with permission; Copyright © 2018 Elsevier). (B) Preparation of the hydrogel for MT delivery [110]. (CC license; Copyright © 2018 by the authors). (C) Fabrication of the CS-B-NO hydrogel and its ability for ROS scavenging as well as NO delivering [112]. (CC license; Copyright © 2022 by the authors). (D) Synthesis of EGCG@Rh-gel hydrogel system. (Adapted with permission; Copyright © 2022 Elsevier) [115]. (E) Schematic illustration of PEG-based hydrogel systems delivery EDA and borneol through nasal administration [116]. (Adapted with permission; Copyright © 2024 Elsevier). NIPAAm, N-isopropylacrylamide; VP, vinylpyrrolidone; MAPLA, methacrylate-polylactide; MATEMPO, methacrylate-TEMPO; 4-amino-TEMPO, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl; MT, Mito-TEMPO; ROS, reactive oxygen species; EGCG, epigallocatechin gallate; EDA, edaravone; PEG, poly (ethylene glycol).

Fig. 3

Schematic illustration of hydrogel depots for biomacromolecule delivery. (A) Synthesis of pre-functionalized PEG hydrogel and release of GFs [119]. (CC license; Copyright © 2018 by the authors). (B) Preparation of PEG hydrogel delivering CD39 and CD73 to converted ATP and ADP into adenosine [120]. (Adapted with permission; Copyright © 2023 Elsevier). (C) Schematic illustration of KLD2R/Hep hydrogel system and its alibility for faster release of anti-TNF-α and sustained release of HGF [121]. (Adapted with permission; Copyright © 2020 Elsevier). PEG-MAL, poly(ethylene glycol) maleimide; GF, growth factor; VEGF, vascular endothelial growth factor; RGD, a peptide sequence used for hydrogel adhesion; VPM, a peptide sequence used for hydrogel cross-linking; ATP, adenosine triphosphate; ADP, adenosine diphosphate; AMP, adenosine monophosphate; HGF - hepatocyte growth factor; TNF-α - tumor necrosis factor alpha.

Fig. 4

Schematic illustration of hydrogel Depots for NPs Delivery [123]. (Adapted with permission; Copyright © 2019 American Chemical Society) (A) NPs-hydrogel systems delivering miNPs for restoring infarcted myocardium (B)The structure of the miNP (C) Images of H&E stained left ventricular tissue section with injection of NPs-hydrogel systems at 1 month. A stable engraftment of hydrogel was observed within the myocardium, and no immune response was observed. (D) Images of fibrosis evaluated by Picro Sirius Red staining. The NPs-hydrogel system effectively improved the myocardial fibrosis compared to the hydrogel/miNP-scramble. ELP, elastin-like polypeptide; PFBT, poly(9,9-dioctylfluorene-alt-benzothiadiazole); TAT, a peptide sequence; CPP, cell penetrating peptide; HA, hyaluronic acid. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 5

Schematic illustration of hydrogel Depots for EVs Delivery (A) Fabrication of MMP2-senstive KMP2 hydrogel to deliver MSC-EVs for enhancing tissue repair [124]. (Adapted with permission; Copyright © 2020 Elsevier). (B) Gel@Exo systems for myocardial IRI treatment [125]. (Adapted with permission; Copyright © 2019 American Chemical Society) (B1). Schematic illustration of the Gel@Exo restoring cardiac functions after myocardial I/R and synthesis through mixing precursor solution A and B. (B2) The synthesis of AT-EHBPE. MMP2，matrix metalloproteinase-2; KMP2，a peptide sequence; EVs，extracellular vesicles; MSCs，mesenchymal stem cells; AT, aniline tetramer; EHBPE, a hyperbranched epoxy macromer; HA-SH，thiolated hyaluronic acid; CP05，a peptide sequence; MI，myocardial infarction; Cx43，connexin 43; Ki67，a marker of cell proliferation; α-SMA，alpha-smooth muscle actin; VEGF，vascular endothelial growth factor; vWF，von Willebrand factor; Serca2a，sarcoplasmic reticulum Ca²⁺-ATPase 2a; TGF-β1，transforming growth factor beta 1.

Fig. 6

Schematic illustration of ECMH as Scaffolds for MSCs encapsulation [129]. (Adapted with permission; Copyright © 2020 Elsevier). (A) Schematic illustration of the ECMH encapsulating ad-MSCs for treating renal IRI. (B) The fabrication progress of the ECMH (C) The levels of BUN and SCr at 24 h, 72 h and 30 days after reperfusion with different treatment. (D) Representative images of TUNEL, PCNA, CD34 staining in kidneys at 72 h after reperfusion with different treatment. Ad-MSCs，adipose-derived mesenchymal stem cells; ECMH，extracellular matrix hydrogel; IRI，ischemia-reperfusion injury; BUN，blood urea nitrogen; SCr，serum creatinine; PCNA，proliferating cell nuclear antigen.