Bioinspired Injectable Self-Healing Hydrogel Sealant with Fault-Tolerant and Repeated Thermo-Responsive Adhesion for Sutureless Post-Wound-Closure and Wound Healing

Abstract

Hydrogels with multifunctionalities, including sufficient bonding strength, injectability and self-healing capacity, responsive-adhesive ability, fault-tolerant and repeated tissue adhesion, are urgently demanded for invasive wound closure and wound healing. Motivated by the adhesive mechanism of mussel and brown algae, bioinspired dynamic bonds cross-linked multifunctional hydrogel adhesive is designed based on sodium alginate (SA), gelatin (GT) and protocatechualdehyde, with ferric ions added, for sutureless post-wound-closure. The dynamic hydrogel cross-linked through Schiff base bond, catechol-Fe coordinate bond and the strong interaction between GT with temperature-dependent phase transition and SA, endows the resulting hydrogel with sufficient mechanical and adhesive strength for efficient wound closure, injectability and self-healing capacity, and repeated closure of reopened wounds. Moreover, the temperature-dependent adhesive properties endowed mispositioning hydrogel to be removed/repositioned, which is conducive for the fault-tolerant adhesion of the hydrogel adhesives during surgery. Besides, the hydrogels present good biocompatibility, near-infrared-assisted photothermal antibacterial activity, antioxidation and repeated thermo-responsive reversible adhesion and good hemostatic effect. The in vivo incision closure evaluation demonstrated their capability to promote the post-wound-closure and wound healing of the incisions, indicating that the developed reversible adhesive hydrogel dressing could serve as versatile tissue sealant.

Keywords: Bioinspired injectable hydrogel; Reversible adhesion; Temperature-dependent adhesion; Tissue sealant; Wound healing.

Fig. 1

The schematic representations of the fault-tolerate detachment and temperature-responsive adhesive properties of the bioinspired adhesive hydrogel as tissue sealant. a Components of brown algae adhesives and marine mussel adhesives. b Schematic representations for the preparation of the bioinspired adhesive hydrogel. c The illustration for the fault-tolerate detachment of the hydrogel. The temperature-dependent adhesion is originated from the improved segment mobility of the GT due to the helix bundles in network transferred to random coils at body temperature, which increases the possibility of contact between the adhesives and the functional group. It might take several minutes for the temperature of the gel to warm up to body temperature, during which the mispositioning hydrogel could be removed and repositioned. d Schematic illustration for the temperature-dependent adhesive mechanism and repeated adhesion of the hydrogel as tissue sealant

Fig. 2

Characterization of the prepared hydrogels. a Original state (I), compressed state (II) and recovered state (III) of the hydrogel, and the original state (IV and VI) and distorted state (V and VII), scale bar: 1 cm. b FT-IR spectra of the samples. c The Raman spectrum of the GT-SA-TPF₂₀ hydrogel sample. d SEM images of the lyophilized original (I and II) and swollen GT-SA-TPF₂₀ hydrogel sample (III and IV). e The swelling ratio and f degradable behavior of the hydrogel samples. g Angular frequency sweep curve of GT-SA-TPF₂₀ hydrogel samples

Fig. 3

Self-healing properties and injectability of the adhesive hydrogel GT-SA-TPF₂₀. a Strain sweep of the hydrogel within the strain range of 0–500%. b Rheological self-healing properties of the hydrogel with strain switched from 1 to 400% for 5 cycles. c Shear rate-dependent viscosity of the hydrogel. Inset: image showing the injectability of the hydrogel. d Macroscopic self-healing display, a) The original (I), fractured (II), healed (III) for 1 h and the secondary fractured (IV) state of the hydrogel, b) The original (I), shattered (II), healed (III) for 3 h and stretched (IV) state of the hydrogel. e Stress–strain curves and f fracture stress of the original hydrogel and healed sample after cured for 1 h at 37 °C. Inset: images showing the tensile property of the hydrogel. g Illustration for the self-healing mechanism of the adhesive hydrogel. Scale bar: 1 cm

Fig. 4

Antibacterial activity, antioxidation and biocompatibility of the hydrogels. a Images of the survival E. coli treated by PBS (I) and hydrogel (II) under NIR irradiation for different time. Images of the survival MRSA treated by PBS (III) and hydrogel (IV) under NIR irradiation for different time. The quantitative results of the antibacterial effect against b E. coli and c MRSA. d DPPH scavenging capacity and e hemocompatibility of the hydrogel samples. f Relative viability of L929 cells after incubated with leaching solutions of different samples at varied concentration. g H&E staining images of the skin tissues after subcutaneously implanted with different hydrogel samples for one and three weeks. Arrow: the site of the samples

Fig. 5

Adhesive capacity and temperature responsive adhesion of the hydrogels on porcine skin tissues evaluated through lap-shear test. a Adhesive strength-displacement curves and b adhesive strength of different hydrogel samples on porcine skin tissue. c The temperature-dependent moduli of the hydrogel GT-SA-TPF₂₀. d Time sweep of the hydrogel GT-SA-TPF₂₀ with temperature alternated from 25 to 37 °C for 5 cycles. e Adhesive strength-displacement curves and f adhesive strength of the hydrogel GT-SA-TPF₂₀ on porcine skin tissues at different temperature. g The presentation of temperature-dependent adhesion on human skin tissues. h Illustration of the proposed temperature-dependent adhesion mechanism. ***p < 0.001

Fig. 6

Adhesive properties of the hydrogel. a Presentations of the hydrogels adhered to different surfaces of the tissues or materials. b Temperature-dependent viscosity of hydrogel GT-SA-TPF₂₀. c Illustration of the adhesive hydrogel in full contact with the surface of the tissues at body temperature. d Adhesive strength-displacement curves and e the ratio of adhesive strength of the repeated bonding cycles. f Illustration of the repeated temperature-responsive bonding of skin tissues

Fig. 7

Hemostasis evaluation of the hydrogels. a Illustration for the creating superficial bleeding model and stopping bleeding by using the adhesive hydrogel in mouse liver. b Blood loss of the bleeding liver treated with different strategies. c Burst pressure of the samples. d Illustration for the creating acute bleeding model and stopping bleeding by using the adhesive hydrogel in rabbit femoral vein. e Blood loss and f hemostasis time of the bleeding femoral veins treated with different samples. *p < 0.05, **p < 0.01, ***p < 0.001

Fig. 8

In vivo wound closure and healing evaluation. a Images of the incisions closed by suture, biomedical glue, adhesive hydrogel, and the wound without treatment was set as control. b The tensile strength of the healed skin tissues on day 21. c Images of H&E staining and Masson’s trichrome staining of the skin tissues after healed for 7 and 21 days. *p < 0.05