Synthesis and Properties of Injectable Hydrogel for Tissue Filling

Abstract

Hydrogels with injectability have emerged as the focal point in tissue filling, owing to their unique properties, such as minimal adverse effects, faster recovery, good results, and negligible disruption to daily activities. These hydrogels could attain their injectability through chemical covalent crosslinking, physical crosslinking, or biological crosslinking. These reactions allow for the formation of reversible bonds or delayed gelatinization, ensuring a minimally invasive approach for tissue filling. Injectable hydrogels facilitate tissue augmentation and tissue regeneration by offering slow degradation, mechanical support, and the modulation of biological functions in host cells. This review summarizes the recent advancements in synthetic strategies for injectable hydrogels and introduces their application in tissue filling. Ultimately, we discuss the prospects and prevailing challenges in developing optimal injectable hydrogels for tissue augmentation, aiming to chart a course for future investigations.

Keywords: hydrogel; injectability; tissue filling.

Figure 1

Schematic of chemical covalent crosslinked injectable hydrogel via (A) reversable bonding based on Michael addition method [30], (B) reversable bonding based on borate imine and borate bonds [45], (C) delayed gelatinization based on radical polymerization [48], (D) delayed gelatinization based on thiolated HA/CMC [52], (E) delayed gelatinization based on Schiff base reaction [54] and (F) delayed gelatinization based on Diels–Alder reaction [56]. Reproduced with permission.

Figure 2

Schematic of physical crosslinked injectable hydrogel via (A) reversable bonds based on hydrogen bonding [63], (B) reversable bonds based on hydrophobic interactions [70], (C) reversable bonds based on host−guest interaction [75] and (D) reversable bonds based on multiple physical interactions (including hydrogen bonding and ions coordination) [85]. Reproduced with permission.

Figure 3

Schematic of (A) biological crosslinked injectable hydrogel via delayed gelatinization based on the catalyzation by horseradish peroxidase [89] and (B) injectable microgel crosslinked by transglutaminase [91]. Reproduced with permission.

Figure 4

(A) The injection force of SF-HA and CaHA-CMC measured with a crosshead speed of 13 mm/min. (B) Hematoxylin and eosin staining (H&E) of tissue round the SF-HA and CaHA-CMC injected site (scale bar = 125 µm). Cellular infiltration, predominantly comprising macrophages and giant cells responsible for the enzymatic degradation of silk protein, is observed in proximity to silk particles (yellow arrows). Cross-sections of silk-HA exhibit vascularity (green arrows), within the tissue ingrowth. Areas of HA (blue arrows) demonstrate cell occlusion and undergo collapse during histological processing. Similarly, CaHA-CMC facilitates the infiltration of macrophages and giant cells in areas adjacent to CaHA particles (black arrows). Sections from both 9- and 12-month intervals were subjected to decalcification prior to staining, leading to the formation of "ghost" regions where CaHA particles were once located. Analogous to HA, CMC (orange arrows) exhibits cell occlusive properties. Reproduced with permission [128].

Figure 5

(A) H&E staining images and (B) immunostaining images of skin tissues injected with the PF127, levan/PF127, HA/CMC/PF127 and levan CMC/PF-127 (scale bar = 200 µm). (C) Schematic image for the construction of the hairless mice model with the skin wrinkling and the schedule for injection. (D) Skin surface images after injection with different hydrogel. Reproduced with permission [149].