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Microenvironment‐Responsive Hydrogels with Detachable Skin Adhesion and Mild‐Temperature Photothermal Property for Chronic Wound Healing

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Advanced Functional Materials
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Huimin Geng at Shandong University
Huimin Geng
Xiaoyue Zheng
Xiaoyue Zheng
Xiaoyue Zheng
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Yulin Zhang at Shandong University
Yulin Zhang
Xiaomiao Cui
Xiaomiao Cui
Xiaomiao Cui
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Abstract and Figures

Chronic wounds have emerged as a global healthcare burden that have inability to heal within an expected time frame owing to the complex pathophysiological microenvironment, bacterial infection, multidrug resistance, and fragile skin tissue. Tailored to the features of chronic wounds, a multifunctional hydrogel (GA) composed of ethylenediamine‐modified gelatin (Gela‐amino) and oxidized sodium alginate (Alg─CHO) is reported. The thermosensitivity of gelatin and Schiff base bonds endow GA hydrogels with physiological temperature‐enhanced nonirritating tissue adhesion and low‐temperature‐triggered nondestructive separation, beneficial for the management of vulnerable and sensitive wounds. In addition, GA hydrogels exhibit pH‐responsive degradation that adapt to the acidic wound microenvironment. Under near‐infrared (NIR) irradiation, DNase I enzyme and indocyanine green‐loaded GA hydrogels (DI@GA) efficiently eradicate drug‐resistant bacteria biofilm and subsequently exert an antibacterial effect attributed to the bioactity of GA hydrogels and mild‐temperature photothermal therapy (≈45 °C). Remarkably, DI@GA/NIR hydrogels accelerate diabetic wound recovery and skin regeneration by dispersing biofilm, killing bacteria, inhibiting inflammation, promoting collagen deposition, and improving angiogenesis. The advanced hydrogels without the addition of antibiotics are promising to act as skin‐friendly wound dressings for rescuing infectious and stalled chronic wounds.
Preparation and characterization of GA and DI@GA hydrogels. Schematic representation of the synthesis of a) Gela‐amino and c) Alg─CHO. 4‐(4,6‐Dimethoxy‐1,3,5‐triazin‐2‐yl)‐4‐methylmpholin‐4‐ium chloride (DMTMM), sodium periodate (NaIO4). b) FTIR spectra of different materials. d) Photograph and illustration of GA hydrogels. e) Schematic diagram describing the formation of DI@GA hydrogels. f) Temperature sweep of G′ and G″ of gelatin, Gela‐amino, Alg, Alg─CHO, GA, and DI@GA hydrogels between 5 and 60 °C under a constant strain amplitude of 1% and frequency of 1 Hz. g) Viscoelastic analysis of GA hydrogels in a frequency sweep mode at 37 °C. h) Oscillatory time sweep of GA hydrogels at 4 and 37 °C. i) Dynamic oscillatory rheology under applied shear stress ranging from 1 to 5000 Pa and the time recovery dependence of the GA hydrogel. j) SEM image of GA hydrogel. Scale bar is 50 µm.
Preparation and characterization of GA and DI@GA hydrogels. Schematic representation of the synthesis of a) Gela‐amino and c) Alg─CHO. 4‐(4,6‐Dimethoxy‐1,3,5‐triazin‐2‐yl)‐4‐methylmpholin‐4‐ium chloride (DMTMM), sodium periodate (NaIO4). b) FTIR spectra of different materials. d) Photograph and illustration of GA hydrogels. e) Schematic diagram describing the formation of DI@GA hydrogels. f) Temperature sweep of G′ and G″ of gelatin, Gela‐amino, Alg, Alg─CHO, GA, and DI@GA hydrogels between 5 and 60 °C under a constant strain amplitude of 1% and frequency of 1 Hz. g) Viscoelastic analysis of GA hydrogels in a frequency sweep mode at 37 °C. h) Oscillatory time sweep of GA hydrogels at 4 and 37 °C. i) Dynamic oscillatory rheology under applied shear stress ranging from 1 to 5000 Pa and the time recovery dependence of the GA hydrogel. j) SEM image of GA hydrogel. Scale bar is 50 µm.
… 
Adhesion properties of the hydrogels. Photographs of body‐temperature‐induced gentle adhesion and ice‐compress‐triggered painless detachment of the GA hydrogels on a) a gloved finger and b) a nude mouse. c) Adhesion strengths of GA hydrogels on porcine skin upon heating to 37 °C and refrigerating to 4 °C. Data are showed as the mean ± SD. Unpaired Student's t‐test (two‐tailed) was used for comparison. ****p < 0.0001. d) Representative lap‐shear adhesion curves of the GA hydrogels to diverse substrates. e) Adhesive strength of GA hydrogels to various substrates compared with that of Gela‐amino. Schematic showing the proposed mechanism and photographs of f) body‐temperature‐triggered adhesion and g) ice‐compress‐induced detachment properties of GA hydrogels to the skin tissue.
Adhesion properties of the hydrogels. Photographs of body‐temperature‐induced gentle adhesion and ice‐compress‐triggered painless detachment of the GA hydrogels on a) a gloved finger and b) a nude mouse. c) Adhesion strengths of GA hydrogels on porcine skin upon heating to 37 °C and refrigerating to 4 °C. Data are showed as the mean ± SD. Unpaired Student's t‐test (two‐tailed) was used for comparison. ****p < 0.0001. d) Representative lap‐shear adhesion curves of the GA hydrogels to diverse substrates. e) Adhesive strength of GA hydrogels to various substrates compared with that of Gela‐amino. Schematic showing the proposed mechanism and photographs of f) body‐temperature‐triggered adhesion and g) ice‐compress‐induced detachment properties of GA hydrogels to the skin tissue.
… 
Photothermal performance of hydrogels. a) The schematic illustration and photograph of the I@GA hydrogel before and after NIR irradiation at a power density of 1.0 W cm⁻². b) Temperature variation curves and c) infrared thermal images of I@GA hydrogels with different ICG contents (0, 15, 30, 45, 60, and 90 µg mL⁻¹) under 808 nm laser with a power density of 1.0 W cm⁻² at different times. d) Heating curve of I@GA hydrogels with 30 µg mL⁻¹ ICG for four on/off cycles of consecutive laser irradiation at a power density of 1.0 W cm⁻². e) Photothermal‐modulated release profile of model drug from I@GA hydrogels at different treatments. f) Degradation of I@GA hydrogels with different treatments.
Photothermal performance of hydrogels. a) The schematic illustration and photograph of the I@GA hydrogel before and after NIR irradiation at a power density of 1.0 W cm⁻². b) Temperature variation curves and c) infrared thermal images of I@GA hydrogels with different ICG contents (0, 15, 30, 45, 60, and 90 µg mL⁻¹) under 808 nm laser with a power density of 1.0 W cm⁻² at different times. d) Heating curve of I@GA hydrogels with 30 µg mL⁻¹ ICG for four on/off cycles of consecutive laser irradiation at a power density of 1.0 W cm⁻². e) Photothermal‐modulated release profile of model drug from I@GA hydrogels at different treatments. f) Degradation of I@GA hydrogels with different treatments.
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In vitro biocompatibility and antibacterial assessment of hydrogels. a) Cell viability and b) live/dead staining images of GA‐based‐hydrogel‐treated NIH‐3T3 after incubation for 24 h. Live cells were stained in green, and dead cells were stained in red. Scale bars: 50 µm. c) Hemolytic ratios and d) photographs of hemolytic activity assay of GA‐based hydrogel, PBS as a negative control, and Triton X‐100 as a positive control. Images of agar plates with e) S. aureus and f) E. coli treated with different hydrogels. Statistical analysis of bacterial survival rates of g) S. aureus and h) E. coli treated with different hydrogels according to the plate colony counting. i) The schematic illustration of DI@GA/NIR against S. aureus. (a, c, g, h) All data represent the mean ± SD. One‐way ANOVA followed by Dunnett's test. *p < 0.05, and ****p < 0.0001 compared with the control groups. ##p < 0.01 and ####p < 0.0001 compared with the DI@GA/NIR group. n.s. = not significant.
In vitro biocompatibility and antibacterial assessment of hydrogels. a) Cell viability and b) live/dead staining images of GA‐based‐hydrogel‐treated NIH‐3T3 after incubation for 24 h. Live cells were stained in green, and dead cells were stained in red. Scale bars: 50 µm. c) Hemolytic ratios and d) photographs of hemolytic activity assay of GA‐based hydrogel, PBS as a negative control, and Triton X‐100 as a positive control. Images of agar plates with e) S. aureus and f) E. coli treated with different hydrogels. Statistical analysis of bacterial survival rates of g) S. aureus and h) E. coli treated with different hydrogels according to the plate colony counting. i) The schematic illustration of DI@GA/NIR against S. aureus. (a, c, g, h) All data represent the mean ± SD. One‐way ANOVA followed by Dunnett's test. *p < 0.05, and ****p < 0.0001 compared with the control groups. ##p < 0.01 and ####p < 0.0001 compared with the DI@GA/NIR group. n.s. = not significant.
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Hydrogel‐mediated eradication and inhibition of biofilms infected by S. aureus. a) Quantification of the different eliminations of biofilms by recording the absorbance of crystal violet at 590 nm. b) The representative photographs and respective microscopy images of crystal‐violet‐stained biofilms after different treatments. Scale bar is 50 µm. c) 3D confocal images and d) SEM images of biofilms with different treatments. Scale bar is 10 µm. e) Photographs of bacterial colonies spread on agar plates from the biofilms treated with different hydrogels for 4 h. f) The bacterial survival rate and g) biofilm inhibition rate of each treatment group. h) Illustration of biofilm dispersion and inhibition of DI@GA/NIR hydrogels. Data are shown as the mean ± SD. (a, g) One‐way ANOVA followed by Dunnett's test. (f) One‐way ANOVA followed by Tukey's test. **p < 0.01, ***p < 0.001, and ****p < 0.0001 compared with the control groups. #p < 0.05 and ##p < 0.01 compared with the DI@GA/NIR groups. n.s. = not significant.
+5
Hydrogel‐mediated eradication and inhibition of biofilms infected by S. aureus. a) Quantification of the different eliminations of biofilms by recording the absorbance of crystal violet at 590 nm. b) The representative photographs and respective microscopy images of crystal‐violet‐stained biofilms after different treatments. Scale bar is 50 µm. c) 3D confocal images and d) SEM images of biofilms with different treatments. Scale bar is 10 µm. e) Photographs of bacterial colonies spread on agar plates from the biofilms treated with different hydrogels for 4 h. f) The bacterial survival rate and g) biofilm inhibition rate of each treatment group. h) Illustration of biofilm dispersion and inhibition of DI@GA/NIR hydrogels. Data are shown as the mean ± SD. (a, g) One‐way ANOVA followed by Dunnett's test. (f) One‐way ANOVA followed by Tukey's test. **p < 0.01, ***p < 0.001, and ****p < 0.0001 compared with the control groups. #p < 0.05 and ##p < 0.01 compared with the DI@GA/NIR groups. n.s. = not significant.
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RESEARCH ARTICLE
www.afm-journal.de
Microenvironment-Responsive Hydrogels with Detachable
Skin Adhesion and Mild-Temperature Photothermal
Property for Chronic Wound Healing
Huimin Geng, Xiaoyue Zheng, Yulin Zhang, Xiaomiao Cui, Zhiwei Li, Xunhui Zhang,
Jiwei Cui, Fangang Meng,* Lei Sun,* and Shilei Ni*
Chronic wounds have emerged as a global healthcare burden that have
inability to heal within an expected time frame owing to the complex
pathophysiological microenvironment, bacterial infection, multidrug
resistance, and fragile skin tissue. Tailored to the features of chronic wounds,
a multifunctional hydrogel (GA) composed of ethylenediamine-modified
gelatin (Gela-amino) and oxidized sodium alginate (Alg─CHO) is reported.
The thermosensitivity of gelatin and Schiff base bonds endow GA hydrogels
with physiological temperature-enhanced nonirritating tissue adhesion and
low-temperature-triggered nondestructive separation, beneficial for the
management of vulnerable and sensitive wounds. In addition, GA hydrogels
exhibit pH-responsive degradation that adapt to the acidic wound
microenvironment. Under near-infrared (NIR) irradiation, DNase I enzyme
and indocyanine green-loaded GA hydrogels (DI@GA) efficiently eradicate
drug-resistant bacteria biofilm and subsequently exert an antibacterial effect
attributed to the bioactity of GA hydrogels and mild-temperature
photothermal therapy (≈45 °C). Remarkably, DI@GA/NIR hydrogels
accelerate diabetic wound recovery and skin regeneration by dispersing
biofilm, killing bacteria, inhibiting inflammation, promoting collagen
deposition, and improving angiogenesis. The advanced hydrogels without the
addition of antibiotics are promising to act as skin-friendly wound dressings
for rescuing infectious and stalled chronic wounds.
H. Geng, Y. Zhang, Z. Li, S. Ni
Department of Neurosurgery
Qilu Hospital of Shandong University and Institute of Brain and
Brain-Inspired Science
Cheeloo College of Medicine
Shandong University
Jinan, Shandong , China
E-mail: nishilei@sdu.edu.cn
H. Geng, X. Cui, X. Zhang, J. Cui
Key Laboratory of Colloid and Interface Chemistry of the Ministry of Educa-
tion
School of Chemistry and Chemical Engineering
Shandong University
Jinan, Shandong , China
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/./adfm.
DOI: 10.1002/adfm.202305154
1. Introduction
Chronic wounds including venous leg ul-
cers, diabetic foot ulcers, and pressure ul-
cers have become a major challenge to
worldwide healthcare systems and bring
an enormous socioeconomic burden.[1,2 ]
The complex molecular and cellular de-
ficiencies (e.g., excessive levels of proin-
flammatory cytokines, proteases, reactive
oxygen species, and a deficiency of stem
cells) in chronic wounds lead to their in-
ability to heal within an expected time
frame.[3,4 ] In addition, most of chronic
wounds are accompanied by bacterial con-
tamination and contain more than one
bacterial species (e.g., Staphylococcus,Pseu-
domonas,andEnterobacter).[5] Generally, the
microbial colonization in chronic wounds
can form robust biofilms with the aid
of self-produced extracellular polymeric
substances (i.e., polysaccharide, protein,
and external DNA) and organic acids.[6,7 ]
Biofilm can protect the bacteria from the
attack of conventional antibiotics and the
host’s immune clearance, eventually result-
ing in multidrug resistance.[2] Over 78%
X. Zheng, L. Sun
Department of Endocrinology
Qilu Hospital of Shandong University
Cheeloo College of Medicine
Shandong University
Jinan, Shandong , China
E-mail: Lei.Sun@email.sdu.edu.cn
F. Men g
Beijing Neurosurgical Institute
Beijing Tiantan Hospital
CapitalMedicalUniversity
Beijing , China
E-mail: fgmeng@ccmu.edu.cn
Adv. Funct. Mater. 2023,33,  ©  Wiley-VCH GmbH
2305154 (1 of 17)
... Compared with excisional infected wounds, burns are more likely to have heavier bacterial load and different healing outcomes requiring multi-modal therapies to meet the wound conditions. Several hydrogels have already been developed as drug delivery systems and can release antibacterial agents depending on environmental conditions using either light-triggered therapy [28] or environment stimuli-responsive systems [29]. However, the clinical translation of wound dressings relies heavily on effective release mechanisms to control highly resistant infections, ensure safety, modulate critical phases of burn healing, including, inflammation, and offer ease of application with high patient compliance. ...
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... Enhanced intensities of peaks at 1629, 1559, and 1423 cm −1 in the HGO spectrum, corresponding to amide I, amide II, and amide III bands respectively, confirm the formation of Schiff base bonds. [53] ...
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An asymmetrical wound dressing functions akin to human skin by serving as a protective barrier between a wound and its immediate environment. However, significant challenges persist concerning the robust adhesion and asymmetrical adhesion properties of hydrogels, particularly when applied in emergency hemostasis and wound healing contexts. Herein, the study has successfully synthesized hydrogel patches with Janus asymmetric‐adhesion, denoted as HGO‐C, exclusively comprised of natural polymers. This achievement is realized through the assembly of adhesive hydrogel (HGO) and non‐adhesive hydrogel (CGC), thereby amalgamating their distinct functionalities. The non‐adhesive hydrogel component served as a physical shield and safeguarding the wound against contamination, while the adhesive hydrogel, when in contacted with the wound surface, firmly adhered to it, swiftly arresting bleeding and facilitating wound healing. Cytocompatibility tests, hemolysis tests, antibacterial assays, and coagulation assays demonstrated excellent biocompatibility, antibacterial, and hemostatic properties of HGO‐C. Finally, the in vivo experiments, including a liver hemorrhage assay and a wound healing assay, unequivocally showed the rapid hemostatic and enhanced wound healing capabilities of HGO‐C. Consequently, these distinctive hydrogel patches, derived from natural polymers and characterized by their asymmetric adhesion properties, may have great potential for real‐life usage in clinical patients.
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Chronic wounds constitute an increasingly prevalent global healthcare issue, characterized by recurring bacterial infections, pronounced oxidative stress, compromised functionality of immune cells, unrelenting inflammatory reactions, and deficits in angiogenesis. In response to these multifaceted challenges, the study introduced a stimulus‐responsive glycopeptide hydrogel constructed by oxidized Bletilla striata polysaccharide (OBSP), gallic acid‐grafted ε‐Polylysine (PLY‐GA), and paeoniflorin‐loaded micelles (MIC@Pae), called OBPG&MP. The hydrogel emulates the structure of glycoprotein fibers of the extracellular matrix (ECM), exhibiting exceptional injectability, self‐healing, and biocompatibility. It adapts responsively to the inflammatory microenvironment of chronic wounds, sequentially releasing therapeutic agents to eradicate bacterial infection, neutralize reactive oxygen species (ROS), modulate macrophage polarization, suppress inflammation, and encourage vascular regeneration and ECM remodeling, playing a critical role across the inflammatory, proliferative, and remodeling phases of wound healing. Both in vitro and in vivo studies confirmed the efficacy of OBPG&MP hydrogel in regulating the wound microenvironment and enhancing the regeneration and remodeling of chronic wound skin tissue. This research supports the vast potential for herb‐derived multifunctional hydrogels in tissue engineering and regenerative medicine.
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