Tailoring the Swelling-Shrinkable Behavior of Hydrogels for Biomedical Applications

Abstract

Hydrogels with tailor-made swelling-shrinkable properties have aroused considerable interest in numerous biomedical domains. For example, as swelling is a key issue for blood and wound extrudates absorption, the transference of nutrients and metabolites, as well as drug diffusion and release, hydrogels with high swelling capacity have been widely applicated in full-thickness skin wound healing and tissue regeneration, and drug delivery. Nevertheless, in the fields of tissue adhesives and internal soft-tissue wound healing, and bioelectronics, non-swelling hydrogels play very important functions owing to their stable macroscopic dimension and physical performance in physiological environment. Moreover, the negative swelling behavior (i.e., shrinkage) of hydrogels can be exploited to drive noninvasive wound closure, and achieve resolution enhancement of hydrogel scaffolds. In addition, it can help push out the entrapped drugs, thus promote drug release. However, there still has not been a general review of the constructions and biomedical applications of hydrogels from the viewpoint of swelling-shrinkable properties. Therefore, this review summarizes the tactics employed so far in tailoring the swelling-shrinkable properties of hydrogels and their biomedical applications. And a relatively comprehensive understanding of the current progress and future challenge of the hydrogels with different swelling-shrinkable features is provided for potential clinical translations.

Keywords: biomedical applications; high-swelling hydrogels; hydrogels; non-swelling hydrogels; shrinkable hydrogels.

Figure 1

Synthesis and characterization of HSHs based on natural polymer. a) Illustration of the CS‐PC/BG/RA hydrogel network. b) Scheme of the adding order of the ingredients. c) SEM images and EDX spectra of the THBA‐free and THBA‐containing hydrogels. Representative µCT analyses of 3D reconstructions, cross sections, and open porosity (OP) of the THBA‐containing hydrogels. Adapted with permission.^{[ 33 ]} Copyright 2022, The Authors. Published by Elsevier.

Figure 2

Synthesis and characterization of HSHs based on synthetic polymer. a,b) Representation of the synthetic polymer‐based cationic hydrogel with high water swelling ratio (WSR) and light transmittance after swollen, excellent mechanical property, surface patterning, and information camouflage and decryption. Scale bar: 1 cm. Adapted with permission.^{[ 12b ]} Copyright 2022, American Chemical Society.

Figure 3

Synthesis of HSHs based on natural and synthetic polymer. The double network hybrid hydrogel can be ingested orally. Adapted with permission.^{[ 12c ]} Copyright 2022, Elsevier Ltd.

Figure 4

Exploiting the high‐swelling properties for hemostasis and full‐thickness skin wound healing. a) Fabrication diagram of PEI/PAA/QCS powder and the formation of PEI/PAA/QCS hydrogel after adding anticoagulated blood. Adapted with permission.^{[ 88 ]} Copyright 2021, Wiley‐VCH GmbH. b) Synthesis scheme and macroscopic performance of HA‐DA/rGO hydrogel applicated in wound healing. Scale bar: 5 mm. Adapted with permission.^{[ 12d ]} Copyright 2019, Wiely‐VCH Verlag GmbH & Co. KGaA.

Figure 5

pH‐responsive HSHs for systemic and oral drug delivery. Synthesis pathways of CS nanohydrogel networks: a) CNHN I, b) CNHN III, c) CNHN II. d) Classification of hydrogels for oral and systemic drug delivery. Adapted with permission.^{[ 129 ]} Copyright 2022, Elsevier Ltd.

Figure 6

Redox‐responsive HSHs loaded with DOX for cancer therapy. Schematic representation for the construction and drug release mechanism of the redox‐responsive hydrogels. Adapted with permission.^{[ 12f ]} Copyright 2022, Elsevier B.V.

Figure 7

Synthesis of NSHs via dynamic covalent crosslinking. a) Schematic illustration of HA‐based NSHs formed via IEDDA reaction between HA‐norbornene and HA‐methylphenyltetrazine. Adapted with permission.^{[ 13b ]} Copyright 2020, Wiley‐VCH Verlag GmbH & Co. KGaA. b) Preparation of NSHs via thiol‐ene Michael addition between HB‐PEGDA and HA‐SH. Adapted with permission.^{[ 157 ]} Copyright 2018, American Chemical Society.

Figure 8

Synthesis of NSHs via H‐bonding crosslinking. a) Illustrations for the preparation and post‐processing of the 3D printed hydrogels composed by PVA and κ‐carrageenan; Adapted with permission.^{[ 169 ]} Copyright 2019, The Royal Society of Chemistry. b) Fabrication illustration of the tendon‐inspired PVA‐TA hydrogel. Adapted with permission.^{[ 13d ]} Copyright 2022, American Chemical Society.

Figure 9

Synthesis and characterization of NSHs based on solvent exchange‐intensified H‐bonding crosslinking. a) Fabrication of stiff and non‐swelling PVA exogel. b) Reversible sol‐gel transitions of PVA exogel achieved by altering solvent. c) Tensile stress‐strain curves, d) fracture energy, and e) comprehensive mechanical properties of PVA exogel and cryogel with varied PVA content. f) Optical images and g) SRs of PVA exogel and cryogel in water at determined time point. h) Tensile stress‐strain curves of PVA exogel before and after swelling for 7 days. Adapted with permission.^{[ 13c ]} Copyright 2020, Wiley‐VCH GmbH.

Figure 10

Synthesis of NSHs via hydrophobic association. Preparation scheme of the tough, anti‐swelling, and conductive P(AA‐co‐LMA)_CTAB hydrogel. Adapted with permission.^{[ 180 ]} Copyright 2022, American Chemical Society.

Figure 11

Synthesis and characterization of NSHs based on ionic crosslinking and metal nanoparticle coordination, respectively. a) Fabrication scheme of dual ionically cross‐linked DN SA/P(AM‐co‐AA)/Fe³⁺ hydrogels. Adapted with permission.^{[ 183 ]} Copyright 2018, American Chemical Society. b) Synthesis illustration of Al(OH)₃ crosslinked hydrogel (Al‐NC gel). c) Photographs and d) volume SRs of organic crosslinked hydrogel (OR gel), nanoclay crosslinked hydrogel (clay‐NC gel), and Al‐NC gel immersed in distilled water or seawater (scale bar: 10 mm). Adapted with permission.^{[ 13a ]} Copyright 2019, Elsevier B.V.

Figure 12

Synthesis and characterization of NSHs based on hybrid crosslinking. a) Schematic illustration of preparing self‐reinforced DC BC hydrogels. ECH, epichlorohydrin. Adapted with permission.^{[ 198 ]} Copyright 2019, The Royal Society of Chemistry. b) Reaction sequence of pHEMA‐alginate hydrogels. c) Demonstration of high stiffness and toughness and d) in vivo swelling ratios of pHEMA‐alginate hydrogels with hydrogel implanted in rats for 7 and 21 days. MBAA, N,N′‑methylenebisacrylamide. Adapted with permission.^{[ 203 ]} Copyright 2018, Elsevier B.V.

Figure 13

Synthesis and characterization of NSHs based on the solvent exchange approach. a) Schematic structure of the nucleobase pair‐assisted hydrogels. b) Underwater and underoil adhesion mechanism and shear strength of hydrogels on various substrates. Adapted with permission.^{[ 144 ]} Copyright 2020, Elsevier B.V. c) Illustration of the CMC/P(AA‐MEA)/Al³⁺ DN ionic conductive hydrogel. BIS, N,N‐methylenebisacrylamide; APS, ammonium persulfate; d) Photos of the hydrogel from transparency to opacity in water and returning to transparency in DMSO. e,f) Schematic illustrations and photos of information encrypting and decoding. Adapted with permission.^{[ 13f ]} Copyright 2021, Wiley‐VCH GmbH.

Figure 14

NSHs based on covering hydrophobic layers on hydrophilic hydrogel surfaces. a) Schematic formation of PAM nanocomposite hydrogel with gradient distribution of hydrophobic imide groups. Adapted with permission.^{[ 214 ]} Copyright 2020, The Royal Society of Chemistry. b) The preparation illustrations of anti‐swelling SGC with robust interface. Adapted under the terms of the Creative Commons CC BY license.^{[ 210b ]} Copyright 2022, The Authors.

Figure 15

NSHs utilized for wound sealing in spinal surgery. Schematic diagram on the anti‐swelling hydrogel with injectability and rapid‐adhesion property. Adapted with permission.^{[ 13h ]} Copyright 2022, Wiley‐VCH GmbH.

Figure 16

NSHs utilized as intraoral wound dressing. a) Preparation of the genipin‐crosslinked chitosan (G‐CS) meshwork and ECM‐mimicking hydrogel (EMH). SCFD, supercritical fluid drying; RT, room temperature; MBAA, N,N′‐methylene bisacrylamide; b) volume and weight change of the EMH and PAM hydrogel in PBS. c) Comparison of PAM and EMH hydrogel dressings in protecting oral extraction defects. d) Histological analysis of inflammatory cell infiltration (ICI) and provisional matrix (PM) at tooth extraction socket of the control and EMH‐treated groups. Adapted with permission.^{[ 219 ]} Copyright 2022, Wiley‐VCH GmbH.

Figure 17

Conductive NSHs utilized as implantable sensors for bioelectronics. Demonstration of the preparation scheme and bioelectric monitoring applications of poly(Cu‐NIPAm) hydrogels. CMAP, compound motor action potential. Adapted with permission.^{[ 244b ]} Copyright 2022, Wiley‐VCH GmbH.

Figure 18

SHs simultaneously accelerate wound closure and wound healing. Diagram of mechanoactive hydrogel dressings enlightened by the healing process of embryonic wounds, and the DTM hydrogel speeding up the contraction and healing of dynamic and static wound. Adapted with permission.^{[ 14b ]} Copyright 2022, American Chemical Society.

Figure 19

Two kinds of multifunctional PNIPAm hybrid hydrogel dressings enhanced wound healing through thermo‐responsive self‐contraction. a) QCS/rGO‐PDA/PNIPAm hydrogel. Adapted with permission.^{[ 261a ]} Copyright 2020, American Chemical Society. b) PNIPAm‐AA/QCS‐CD/PPY hydrogel. Scale bar: 1 cm. PPY NTs: polypyrrole nanotubes. Adapted with permission.^{[ 261b ]} Copyright 2022, Wiley‐VCH GmbH.

Figure 20

Exploiting the shrinkage behavior of SHs to acquire higher‐resolution hydrogel‐based scaffolds for tissue engineering. a–f) The shrinking behavior of the hydrogel. HAMA, hyaluronic acid methacrylate. g–i) Biocompatibility of the single and successive shrinkage in the existence of living cells. Adapted with permission.^{[ 14e ]} Copyright 2020, The Authors.

Figure 21

SHs simultaneously perform hyperthermia and deliver DOX for treating cancer. a) Macroscopic views and temperature distribution of the hydrogel samples before and after NIR irradiation. Scale bar: 1 cm. b) Volume contraction ratio of hydrogels with different PDA NPs contents. c) Cumulative DOX release curves of the hydrogels with/without NIR irradiation. d) Temperatures of mice tumors under different treatments within 10 min. f) Relative tumor volume and h) body weights of mice under different treatments within 15 days. e) Photographs and g) weights of mice tumors under different treatments at the 15th day. Adapted with permission.^{[ 270b ]} Copyright 2020, American Chemical Society.