Hydrogel-exosome system in tissue engineering: A promising therapeutic strategy

Abstract

Characterized by their pivotal roles in cell-to-cell communication, cell proliferation, and immune regulation during tissue repair, exosomes have emerged as a promising avenue for "cell-free therapy" in clinical applications. Hydrogels, possessing commendable biocompatibility, degradability, adjustability, and physical properties akin to biological tissues, have also found extensive utility in tissue engineering and regenerative repair. The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process. This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin, bone, cartilage, nerves and tendons, with a focus on the methods for encapsulating and releasing exosomes within the hydrogels. It has also critically examined the gaps and limitations in current research, whilst proposed future directions and potential applications of this innovative approach.

Keywords: Exosome; Hydrogel; Regenerative medicine; Tissue engineering.

Graphical abstract

Fig. 1

Hydrogel-Exosome Systems. The Sankey diagram, leveraging bibliometric analysis, visually represents the distribution of published articles over the years (left) and categorizes them according to their application in various tissues or entire organs (right). The fields of bone and cartilage, skin, and neural tissue engineering emerge as the predominant areas of application for hydrogel-exosome systems. This diagram was developed using a comprehensive dataset of 175 published articles.

Fig. 2

Schematic illustration of the hydrogel-exosome system for tissue engineering and regenerative medicine.

Fig. 3

Developmental Timeline of hydrogel-exosome systems.

Fig. 4

(a) Schematic illustration of exosomes physically binding to the hydrogel and (b) release curves. Reproduced with permission from Ref. [175]. Copyright 2023, Elsevier.

Fig. 5

The chemical strategy for loading exosomes into hydrogels. (a) The method based on covalent crosslinking (with genipin as the crosslinker). Reproduced with permission from Ref. [178]. Copyright 2023, Elsevier. (b) Self-assembling peptide crosslinking. Reproduced with permission from Ref. [181]. Copyright 2022, Elsevier. (c) Surface functionalization. Reproduced with permission from Ref. [182]. Copyright 2021, Wiley.

Fig. 6

(a) Passive diffusion of exosomes based on hydrolytic degradation of hydrogel. Reproduced with permission from Ref. [183]. Copyright 2021, Elsevier. (b) Release curves of exosomes in hydrogels with varying molecular weights and cross-linking concentrations. Reproduced with permission from Ref. [184]. Copyright 2022, Wiley.

Fig. 7

Schematic diagram of exosome release in environmentally responsive hydrogels.

Fig. 8

Stacked confocal images of exosomes labeled with (a) CM-DiI, Reproduced with permission from Ref. [223]. Copyright 2020, American Chemical Society, and (b) PKH26 distributed in hydrogel. (c) SEM image of exosomes adhering to the internal surface of the hydrogel. Reproduced with permission from Ref. [143]. Copyright 2022, American Chemical Society. (d) FTIR of exosomes encapsulated within the hydrogel. Reproduced with permission from Ref. [227]. Copyright 2019, Elsevier.

Fig. 9

Design and application of hydrogel-exosome systems in skin tissue engineering. (a) Hydrogel microneedles loaded with exosomes and possessing antimicrobial properties. Reproduced with permission from Ref. [254]. Copyright 2022, Elsevier. (b) Extracellular matrix hydrogel loaded with ADSC-Exos promotes wound healing. Reproduced with permission from Ref. [185]. Copyright 20123, Wiley.

Fig. 10

Design and application of hydrogel-exosome systems in bone and cartilage tissue engineering. (a) Osteoarthritis. Reproduced with permission from Ref. [260]. Copyright 2024, Wiley. (b) Bone defect. Reproduced with permission from Ref. [269]. Copyright 2023, Wiley. (c) Intervertebral disc degeneration. Reproduced with permission from Ref. [275]. Copyright 2023, Wiley. (d) Fracture. Reproduced with permission from Ref. [279]. Copyright 2022, American Chemical Society.

Fig. 11

Design and application of hydrogel-exosome systems in nerve tissue engineering. (a) Spinal cord injury. Reproduced with permission from Ref. [232]. Copyright 2022, American Chemical Society. (b) Middle cerebral artery occlusion. Reproduced with permission from Ref. [285]. Copyright 2023, Elsevier. (c) Traumatic brain injury. Reproduced with permission from Ref. [293]. Copyright 2023, Elsevier.

Fig. 12

Design and application of hydrogel-exosome systems in tendon tissue engineering. (a) Application in a large animal pig model of urinary incontinence. Reproduced with permission from Ref. [236]. Copyright 2022, Springer Nature. (b) Simulating tendon environment with biomimetic biodegradable scaffolds. Reproduced with permission from Ref. [298]. Copyright 2023, Elsevier.

Fig. 13

Schematic illustration of perspectives of Hydrogel-Exosome System in regenerative medicine.