Biomembrane-Based Nanostructure- and Microstructure-Loaded Hydrogels for Promoting Chronic Wound Healing

Figures & data

Figure 1 The characteristics and healing mechanisms of biomembrane-based nanostructure- and microstructure-loaded hydrogels for chronic wounds. Nanostructures and microstructures can be loaded into hydrogels by various methods to produce carriers that have specific properties that can promote wound healing through different mechanisms.

Table 1 Representative Examples of Biomembrane-Based Nano- and Microstructure-Loaded Hydrogels in Diabetic Wounds

Biomembrane-Based Nano- and Microstructures	Hydrogels	Animal Models	Type of Wound	Sample Size	Results	Refs.
SDF-1α loaded liposomes	GelMA hydrogel	Female wild-type C57BL/6 and diabetic B6.BKS(D) Lepr^db/J mice	Round skin defect with a diameter of 4 mm on both sides of the back	n = 6/group	This hybrid system exhibits better retardation compared to water coagulation alone. The system is able to recruit macrophages and polarize it to the M2 phenotype. Hydrogel and liposome combination delivery of SDF-1α showed better efficacy with the most significant epidermal regeneration and angiogenesis	[236]
Th-loaded liposomes	GelMA hydrogel	10-week old rats	A full-length circular wound of 18 mm in diameter was created on the back	n = 10/group	The hydrogen bonds formed between the liposomes and networks of polymer chains results in contributing to the prolonged release of Th and enhancing the mechanical properties of hydrogels. Th-Lipo loaded GelMA hydrogels promote the contraction of wounds and synthesis of extracellular matrix.	[101]
BMSCs-Exos	Cryogenic 3D printed hydrogel scaffolds	Sprague–Dawley rats	Skin wound with a 15 mm diameter total excision	n = 3/group	This hydrogel scaffold has the right porosity, biocompatibility and hemostatic ability. Proliferation and migration of HUVECs were facilitated by this hydrogel scaffold. The hydrogel scaffold helps facilitate chronic wound healing by improving blood flow to the area and stimulating angiogenesis. This mode of administration increases the amount of blood perfusion to the wound, shortens the length of the wound and promotes collagen deposition.	[237]
MSCs-Exos	Carboxyethyl chitosan -dialdehyde carbo-xymethyl cellulose hydrogel	Sprague–Dawley rats aged 7–8 weeks	Skin wound with a 20 mm diameter total excision	n = 3/group	This hydrogel has some hemostatic and antibacterial properties. MSCs-Exos suppress inflammation by regulating the phenotype of macrophages. This system accelerates angiogenesis by affecting the VEGF-mediated pathway and by shifting the macrophage phenotypes from the detrimental M1to the beneficial M2.	[238]
BMSCs	N-isopropylacrylamide-based hydrogel	Forty-five 8- to 12-week-old female C57BKS Cg-m+/+ Leprdb type II diabetic mice	Circular wounds with a diameter of 8 mm	n = 3/group	The hydrogel inhibits the expression of pro-inflammatory M1 macrophages. The treatment increases granulation tissue, angiogenesis, and wound contraction, and promotes the rapid healing of diabetic skin wounds.	[239]
ADSCs	Pluronic F127 hydrogel	Adult male rats aged 8–12 weeks		n = 6/group	The system promotes angiogenesis and enhances cell proliferation at wound sites, resulting in faster wound closure, accompanied by rejuvenated granulation tissue. ADSCs transplanted via hydrogels are more effective at delivering cells and enhance the healing capacity of diabetic wounds.	[240]
Engineering L. lactis NZ9000	Heparin-poloxamer hydrogel	Mice	Two circular wounds of 6mm diameter on the back	n = 6/group	Release of lactate from hydrogel systems to induce conversion of macrophages to the M2 phenotype. Hydrogel system steadily releases bioactive proteins and immunomodulatory molecules to accelerate diabetic epithelial healing.	[177]
Active Synechococcus elongatus PCC7942	Sodium alginate gel particles	Balb/C mice (male, about 25g in weight)	Circular wounds with a diameter of 10 mm	n = 6/group	Transformation of nonhealing chronic wounds into acute wound healing phenotypes. This system promotes angiogenesis and flap regeneration.	[241]

Abbreviations: SDF-1α, stromal cell-derived factor-1 alpha; GelMA, methacrylated gelatin; Th, thrombin; Th-Lipo, Th-loaded liposomes; HUVECs, human umbilical vein endothelial cells; BMSC-Exos, bone marrow mesenchymal stem cell-derived exosomes; MSC-Exos, marrow mesenchymal stem cell-derived exosomes; VEGF, vascular endothelial growth factor; BMSCs, bone marrow mesenchymal stem cells; ADSCs, adipose-derived stem cells.

Figure 2 Anatomical and molecular mechanisms of Th and Th-Lipo-loaded GelMA hydrogel repairing and regenerating diabetic skin. Reprinted from Chemical Engineering Journal, 397, Wang C, Wu T, Liu G, et al. Promoting coagulation and activating SMAD3 phosphorylation in wound healing via a dual-release thrombin-hydrogel, 125414, Copyright © 2020, with permission from Elsevier B.V.¹⁰¹

Abbreviations: Th, thrombin; Th-Lipo, Th-loaded liposomes; GelMA, methacrylated gelatin.

Figure 3 Diagram illustrating how the RBCM scaffold was fabricated. Reprinted from Biomaterials, 197, Fan Z, Deng J, Li PY, et al. A new class of biological materials: Cell membrane-derived hydrogel scaffolds, 244-254, Copyright © 2019, with permission from Elsevier.¹²⁶

Abbreviations: RBCM, red blood cell membrane; EDC, 1-ethyl-3-(−3-dimethylamino-propyl) carbodiimide; NHS, N-hydroxysuccinimide.

Figure 4 (A) Schematic diagram of the self-healing process of hydrogels. (B) pH-dependent release of exosomes from hydrogels. (C) The healing process of wounds treated with hydrogel, exosomes, exosome-loaded hydrogel and control wounds. Adapted with permission from Wang C, Wang M, Xu T, et al. Engineering Bioactive self-healing antibacterial exosomes hydrogel for promoting chronic diabetic wound healing and complete skin regeneration. Theranostics. 2019;9:65–76, Open Access.¹³³ (D) Hydrogel consisting of Cothe HA@MnO2/FGF-2/Exos is formed by the Schiff base reaction of hydrazides and aldehydes. (E) HA@MnO2/FGF-2/Exos hydrogel can be quickly formed by simple mixing injections, in which grafted ortho-quaternary ammonium groups have long-term antibacterial efficacy. The MnO2/ε-PL nanosheet is a nanoenzyme that catalyzes the oxidation of H₂O₂ into O₂. The release of Exos^M2@miR−223 mimicked persistent angiogenesis, and the release of FGF-2 enhanced epithelial formation. Reprinted with permission from Xiong Y, Chen L, Liu P, et al. All-in-One: multifunctional Hydrogel Accelerates Oxidative Diabetic Wound Healing through Timed-Release of Exosome and Fibroblast Growth Factor. Small. 2022;18:e2104229.© 2021 The Authors. Small published by Wiley-VCH GmbH.¹⁴²

Abbreviations: F127, Pluronic F127; OHA, oxidative hyaluronic acid; EPL, Poly-ε-L-lysine; FHE, F127/OHA-EPL hydrogel; exo, exosomes; HAh, hydrazide-grafted HA; FGF-2, fibroblast growth factor 2.

Figure 5 Diagram of MSC-loaded hydrogels for chronic wounds. Adapted with permission from Chen S, Shi J, Zhang M, et al. Mesenchymal stem cell-laden anti-inflammatory hydrogel enhances diabetic wound healing. Sci Rep. 2015;5:18104, Open Access.¹⁶²

Abbreviation: BMSCs, bone marrow mesenchymal stem cells.

Figure 6 Schematic illustration of the preparation and acceleration of wound healing while using living probiotic hydrogels. (A) The process of encapsulating bacteria in microspheres. (B) Covalent cross-linking within light-irradiated microspheres containing active probiotics. (C) Procedure for treating wounds with live bacterial hydrogel. Reprinted from Ming Z, Han L, Bao M, et al. Living bacterial hydrogels for accelerated infected wound healing. Adv Sci. 2021;8:e2102545, © 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.¹⁷¹

Abbreviation: HAMA, hyaluronic acid methacryloyl.

Figure 7 (A) Schematic for fabricating PSB gel dressings to eliminate MRSA and accelerate wound healing. (B) Curves of photothermal temperature for PBS, PSB, and inactivated PSB irradiated with an 808 nm (1 W/cm²) laser. (C) Images of PSB, inactivated PSB, and phosphate-buffered saline exposed to an 808 nm laser (1 W/cm²) infrared thermography. (D) Antibacterial properties of PBS in vitro. (E) H&E staining of wound tissue. The data were presented as the mean ± standard deviation (SD) of measurements (*p < 0.05, **p < 0.01, and ***p< 0.001). Adapted from Acta Biomater, 140, Zhao E, Liu H, Jia Y, et al. Engineering a photosynthetic bacteria-incorporated hydrogel for infected wound healing. 302–313, Copyright 2022, with permission from Elsevier.¹⁷⁴

Abbreviation: PSB, photosynthetic bacteria.

Figure 8 (A) Diagram illustrating the preparation of AGP and the treatment of diabetic wounds by dissolved oxygen release in response to light. (B) Design scheme of the wound-healing process using algae gel. (C) Different groups of wounds showed regenerated skin by H&E and Masson staining at day 12. (D-G) Quantification of the epithelial gap (D), granulation tissue (E), collagen deposition (F) and average microvessel densities in different groups (G). Significantly different (one-way ANOVA): *P<0.05, **P<0.01, and ***P<0.001. Adapted from Chen H, Cheng Y, Tian J, et al. Dissolved oxygen from microalgae-gel patch promotes chronic wound healing in diabetes. Sci Adv. 2020;6:eaba4311, Open Access.⁶²

Abbreviations: AGP, microalga-hydrogel patch; PU; polyurethane; PTFE, polytetrafluoroethylene.

Yu JR, Varrey P, Liang BJ, et al. Liposomal SDF-1 Alpha Delivery in Nanocomposite Hydrogels Promotes Macrophage Phenotype Changes and Skin Tissue Regeneration. ACS Biomater Sci Eng. 2021;7:5230.

 PubMed Web of Science ®Google Scholar

Wang C, Wu T, Liu G, et al. Promoting coagulation and activating SMAD3 phosphorylation in wound healing via a dual-release thrombin-hydrogel. Chem Eng J. 2020;397:125414. doi:10.1016/j.cej.2020.125414

 Web of Science ®Google Scholar

Hu Y, Wu B, Xiong Y, et al. Cryogenic 3D printed hydrogel scaffolds loading exosomes accelerate diabetic wound healing. Chem Eng J. 2021;426:130634.

 Web of Science ®Google Scholar

Geng X, Qi Y, Liu X, et al. A multifunctional antibacterial and self-healing hydrogel laden with bone marrow mesenchymal stem cell-derived exosomes for accelerating diabetic wound healing. Mater Sci Eng. 2021;112613.

 Google Scholar

Chen S, Shi J, Zhang M, et al. Mesenchymal stem cell-laden anti-inflammatory hydrogel enhances diabetic wound healing. Sci Rep. 2015;5:1–12.

 Web of Science ®Google Scholar

Kaisang L, Siyu W, Lijun F, et al. Adipose-derived stem cells seeded in Pluronic F-127 hydrogel promotes diabetic wound healing. J Surg Res. 2017;217:63–74.

 PubMed Web of Science ®Google Scholar

Lu Y, Li H, Wang J, et al. Engineering bacteria-activated multifunctionalized hydrogel for promoting diabetic wound healing. Adv Funct Mater. 2021;31:2105749.

 Web of Science ®Google Scholar

Chen H, Cheng Y, Tian J, et al. Dissolved oxygen from microalgae-gel patch promotes chronic wound healing in diabetes. Sci Adv. 2020;6:eaba4311.

 PubMed Web of Science ®Google Scholar

Fan Z, Deng J, Li PY, et al. A new class of biological materials: cell membrane-derived hydrogel scaffolds. Biomaterials. 2019;197:244–254.

 PubMed Web of Science ®Google Scholar

Wang C, Wang M, Xu T, et al. Engineering Bioactive self-healing antibacterial exosomes hydrogel for promoting chronic diabetic wound healing and complete skin regeneration. Theranostics. 2019;9:65–76.

 PubMed Web of Science ®Google Scholar

Xiong Y, Chen L, Liu P, et al. All-in-One: multifunctional Hydrogel Accelerates Oxidative Diabetic Wound Healing through Timed-Release of Exosome and Fibroblast Growth Factor. Small. 2022;18:e2104229.

 PubMed Web of Science ®Google Scholar

Chen S, Shi J, Zhang M, et al. Mesenchymal stem cell-laden anti-inflammatory hydrogel enhances diabetic wound healing. Sci Rep. 2015;5:18104.

 PubMed Web of Science ®Google Scholar

Ming Z, Han L, Bao M, et al. Living bacterial hydrogels for accelerated infected wound healing. Adv Sci. 2021;8:e2102545.

 Web of Science ®Google Scholar

Zhao E, Liu H, Jia Y, et al. Engineering a photosynthetic bacteria-incorporated hydrogel for infected wound healing. Acta Biomater. 2022;140:302–313.

 PubMed Web of Science ®Google Scholar

Chen H, Cheng Y, Tian J, et al. Dissolved oxygen from microalgae-gel patch promotes chronic wound healing in diabetes. Sci Adv. 2020;6:eaba4311.

 PubMed Web of Science ®Google Scholar