Staying one step ahead of chronic wounds by designing symbiotic, responsive functionality into dynamic nanohydrogels

Abstract

The dynamic environment of chronic wounds makes them an on-going clinical challenge. Conventional treatments often fail to respond to the pharmacological complexities of the system effectively, which compounded by ineffective pharmacokinetics, means a new multifactorial paradigm is required. Simple hydrogels have long been proposed to be effective wound dressings, as they can provide a highly hydrated and regenerative microenvironment; however, their colloidal instability and inefficient loading parameters may cause burst release of therapeutics and require multiple reapplications, which is both pharmacologically and economically unfavourable. Nanomaterials, on the other hand, facilitate sustained therapeutic release and are generally regarded as stable; however, to avoid off target effects, they need to be spatially defined in a controlled fashion. Here, we discuss the progress made towards engineering the activity of these nanohydrogels through developments in multicomponent materials. The goal is to meet both the wound and clinically relevant demands via the inclusion of symbiotic features across multiple length scales. We introduce critical developments enabled by this approach and discuss their potential application as therapeutic delivery agents to treat various common chronic wounds. We propose future directions to further develop nanohydrogels as function-at-demand topical wound dressings to contain chronic wounds.

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1. Introduction

Chronic wounds present a significant clinical challenge, as they cannot fully heal spontaneously, demanding ongoing clinical interventions. Skin, the body's largest organ, acts as its first line of defence, preventing infection and protecting internal tissues from external injuries that may occur due to punctures, scratches, surgery, and dermatological conditions.¹ Any compromise to the skin's integrity can cause wounds, which rapidly initiates a regenerative cascade that quickly heals the damage. However, when the ordered procession through this cascade is interrupted, chronic wounds may then develop. These do not heal, or only partially heal, causing significant complications to the patient. A chronic wound can be caused by a variety of factors, including underlying medical conditions such as diabetes or vascular disease, as well as external factors such as infection, pressure ulcers or burns.²

According to market research datasets, the compound annual growth rate (CAGR) for the global chronic wound market is predicted to be between 5.2 and 7.5%.^3,4 Of these statistics, biomaterials-based approaches are forecasted to account for the largest share of 48%. This research also suggests that the wound care market for the Asia-Pacific region is predicted to grow at a 5.9% CAGR due to the changing lifestyles of its large population, which leads to an increase in the number of chronic wounds.^3,4 In Australia, over 420 000 people suffer from chronic wounds annually costing over $3 billion of the national care budget.⁵

Chronic wounds can be categorised as infectious, burns, diabetic, and venous and arterial/ischemic.² Though differently categorised, it is worth noting that these categories are not mutually exclusive as secondary infections become major challenges in the case of burns and diabetic wounds. These are not only difficult to manage but cause ongoing discomfort for the patient because they fail to regain anatomical and functional integrity in a timely and ordered manner.^2,6 This can be due to a variety of factors, including poor blood flow to the wound, pH, bacterial infection, and/or an imbalance in the levels of growth factors and other signalling molecules that are involved in the wound healing process.⁶ Senescent cell populations with decreased proliferative and secretory capacity, and excessive inflammation (including higher levels of proteases, reactive oxygen species, and inflammatory cytokines) are the hallmarks of such wounds.⁷ Overly active inflammation in the case of chronic wounds causes the extracellular matrix and freshly synthesised growth factors to degrade.⁷

Any effective therapeutic strategies for chronic wound management must cope with a cascade of challenges including inflammatory responses, elevated pH, degraded extracellular matrix along with significant infection. Functionalised hydrogels with nanomaterials are emerging as promising tools for chronic wound management. Hydrogels provide a moist environment that promotes wound healing by facilitating cellular migration, proliferation, and tissue regeneration. Additionally, they can release bioactive agents to accelerate healing and reduce inflammation. Nanomaterials, such as nanoparticles and nanofibres, offer tailored delivery of therapeutic agents and enhanced mechanical properties for wound dressings. Their high surface area-to-volume ratio enables efficient drug loading and controlled release kinetics, ensuring optimal therapeutic effects. The synergistic potential of (nano)materials and biomaterial development has facilitated several unique interventions for therapeutic delivery, tissue engineering and regenerative medicine. These complex and overlapping facets of chronic wounds need attention using different management approaches that include combinations of antibacterial therapy, moisture retention, anti-inflammatory therapy, matrix regeneration and cytokine delivery. Therefore, there is a requirement and wide scope to optimise chronic wound care using biomaterials such as functionalised hydrogels.^3–5

In this review article, we summarise and discuss nanomaterial functionalised hydrogels (NFHGs) that can be potentially explored for topical application in cases of infectious, burn, diabetic and venous and arterial/ischemic chronic wounds.

2. Chronic wound structure and pathology

An understanding of the pathological characteristics of chronic wounds is important to develop functional materials for optimal wound management. Normally, epidermal wounds initiate a spontaneous healing cascade within the localised region of the insult. These processes progress in overlapping phases of haemostasis, inflammation, cell proliferation, and tissue re-modelling.⁸ However, in the event of chronic infections, this well-synchronised procession is disrupted. In chronic wounds, excessive amounts of pro-inflammatory cytokines, proteases, reactive oxygen species (ROS), and senescent cells with impaired proliferative and secretory capacities are common features (Fig. 1). Moreover, during inflammation, the ROS and reactive nitrogen species secreted by cells damage extracellular matrix (ECM) proteins and affect cellular functions. As opposed to acute wounds where rapid keratinocyte migration takes place, in the case of chronic wounds, the process of cell proliferation that sustains migration and wound closure gets delayed due to hypoxia, pro-inflammatory cytokine secretions, proteolytic destruction of ECM, and bacterial infection.⁹ Once wounded, the soft tissue architecture becomes prone to further bacterial infections that lead to the formation of a biofilm. This is commonly associated with further prolonged inflammation and elevated protease levels, resulting in an imbalance of proteolytic enzymes and their inhibitors, as well as hypoxia.^8,9

Fig. 1 Schematic illustrating the molecular and cellular infiltration in chronic wounds as well as factors required to overcome the chronicity (shown in green). Chronic wounds exhibit persistent inflammation (characterised by overactivation and polarisation of neutrophils and macrophages), generate cytotoxic amounts of ROS and nitric oxides, demonstrate a prolonged and more pronounced presence of T cells with a reduced CD4⁺/CD8⁺ ratio, and generate excessive amounts of matrix metalloproteinase (MMPs) and pro-inflammatory cytokines.

3. Functionalised hydrogels with nanomaterials for wound healing

Clearly, any clinical intervention must present a solution to each of the localised and pathological mechanisms for the sustained chronic environment. Of the systems available to do this, hydrogels are of significant interest, as they are inert, provide hydration, and contain within their structure the room to incorporate compounds and structures that can be optimised to address each facet of the chronic wound. On a fundamental level, hydrogels are underpinned by a polymeric or colloidal network that entraps water to provide a physically isolated and moist environment. They are promising and well utilised materials that assist in wound healing owing to their high elasticity, water absorption and drug loading capacity.¹⁰ However, these properties of hydrogel are not sufficient to address the challenges of the dynamic chronic wound environment. Therefore, more active and dynamic components are required to address the wound-associated molecular and cellular dysfunctions (Fig. 1). Increasingly, nanomaterials have been proven to act either as standalone factors or as carriers for antibacterial, anti-inflammatory, angiogenic and antioxidant factors. Their small size and high surface area to volume ratio enables them to easily enter the biological system and present enhanced bioactivities.¹¹ Combining nanomaterials with hydrogels has been investigated to work against acute wounds and can be used as potential chronic wound healing materials to enhance the wound repair and tissue regeneration process.¹²

A nanomaterial functionalised hydrogel therefore becomes an overall efficient material at different scales and hence functions at different levels ranging from tiny nanoparticles and hydrogel pores influencing internal cellular interactions to a practically applicable wound dressing by influencing and supporting the different wound healing stages (Fig. 2). At nanoscale (1–100 nm), the nanoparticles assist in acting as carriers for slow and sustained release of drugs such as antibiotics relevant for infectious wound healing. At micrometre scale (1–1000 μm), the hydrogel pores become critical for biological function due their influence over cellular interaction and overall material presentation to cells. At macromolecular scale (>1000 μm), a functionalised hydrogel can be tailored for appropriate wound dressing to cater to practical convenience and applicability.

Fig. 2 Properties of nanomaterial functionalised hydrogels (NFHGs) to support different wound healing stages.

The collated data from the research articles published between January 2014 and April 2023 show an increasing trend in the published studies where nanomaterial functionalised hydrogels (NFHGs) have been reported for use in wound healing and suggest that overall, more than 170 peer reviewed studies report the use of NFHGs to address infectious, burn, diabetes and venous and arterial/ischemic wounds. Of these studies, about 75 to 78% focus on infectious wounds, 13–16% on diabetic wounds, 6–8% on burn wounds and 1–2% on venous and arterial/ischemic wounds. These results with increasing trend each year are indicative of a strong prior art in optimising the technology of nanohydrogels for accelerated wound repair and tissue engineering.

3.1. Hydrogels and nanoparticles: a symbiotic relationship

Hydrogels that contain nanoparticles can be considered as a composite system, where the individual properties of the two separate components combine to yield properties outside of the scope of the individual components. Classic materials engineering defines composite systems based on their chemical and physical properties, and in this context NFHGs can include symbiotic enhancement of the (i) mechanical, (ii) thermal, (iii) electrical, (iv) surface topography, and (v) optical properties. While these characteristics might not apply to all systems (e.g., electrical properties would only be considered for conductive materials), changes in mechanical properties by inclusion of nanoparticles to hydrogels is a prevalent effect.

In this context, an addition of nanoparticles at a sufficiently high concentration where they can interact with the bulk network of the hydrogel can modulate the mechanical stiffness; numerous studies have reported higher storage modulus.^13–15 This effect may be desirable to tune the often-weak mechanical characteristics of non-covalent hydrogel materials, a particularly important design metric for applications that demand mechanical resilience such as in percutaneous wound healing. For example, Lokhande et al. (2018) developed an injectable haemostatic dressing derived of kappa-carrageenan with nanosilicates, which were included to reinforce the mechanical properties of the hydrogels. This combination resulted in a modulation of the compressive stiffness from 20 to 200 kPa, when nanosilicates were added at 1 and 2 wt% to kappa-carrageenan (1 wt%) and accelerated the clotting time by two-fold. In addition to this effect, significant enhancement of the biological response was observed, with enhanced cell adhesion in hMSCs and spreading, and an increase in the binding of platelets.¹³

In line with the mechanical characteristics, the swelling behaviour of the formed composite can vary in respect to the hydrogel alone. For instance, if solid non-swellable nanoparticles (such as metallic or ceramic) are introduced, the overall swelling decreases. In contrast, in a polymeric nanoparticle–hydrogel system, the swelling might increase depending on the interaction between the polymer chains. In cases where hydrophilic nanomaterials are used, there is an increase in swelling which further aids in the controlled delivery of therapeutics.¹⁶ The ability to retain water (given by the relationship between the swollen and the dry weight) is recognised as beneficial for wound healing by promoting cell migration and enhancing enzymatic activity, increasing oxygen transport and promoting epithelialisation.^17,18

The third mechanical property to consider is the effect exerted by the nanoparticles introducing a change in porosity and permeability. As an example, introducing water-soluble nanoparticles can be utilised to create voids within a hydrogel scaffold, thus increasing the hydrogel porosities (an approach known as pore leaching, which can be achieved through freeze-drying, solvent-based dissolution or pH triggered dissolution). In the context of wound healing, another interesting property of composite hydrogel–nanoparticle systems is the manipulation of surface characteristics as this can influence the systems adhesion and wettability, and as a result, the cellular attachment.^19,20

From a nanoparticle perspective, the double encapsulation restricts mobility via physical entrapment. This has been utilised as a strategy to limit the rapid diffusion of soluble bioactive compounds and drugs encapsulated within nanoparticles that otherwise would experience a rapid release.^21,22 The physical encapsulation often prolongs the release of drugs by physically restricting the release where the drugs will find a longer diffusion pathlength.^23,24 Beyond physical encapsulation, nanoparticles can be functionalised to engage in electrostatic interactions with hydrogel networks or provide positive charges for antibacterial effects, tune particle size (<200 nm) to either remain trapped within the hydrogel mesh size or penetrate tissue, and graft ligands (e.g., biotin–avidin pairs) or complementary chemical handles (e.g., thiol-Michael additions) to achieve spatio-temporal, trigger-dependent release. This functionalisation however often suffer from trade-offs, for example a cationic charge modification can reduce the interaction with resident cells²⁵; the long debate of particle size to enhance tissue penetration has yet to achieve a delicate balance to avoid off-target effects and burst release, and surface functionalised nanoparticles must clear the immune system without off-target interactions. Among these modifications, an emerging trend is utilising nanoparticles that can self-adapt to the specific targets, such as in response to inflammatory environments, growth factor delivery targets and pH switches.^26–28 These adaptive functionalities can circumvent off target effects and could offer a trigger-specific function to initiate the wound healing cascade, however a consideration is that these modifications can amplify synthesis complexity, compromise batch-to-batch reproducibility and add layers of material variability that challenge scale-up and regulatory approval.

The distribution of these nanoparticles within the hydrogel matrix is often dictated by the fabrication or functionalisation process. Recent studies highlight the advances in nanoparticle chemistry and hydrogel crosslinking methods that drive substantial improvements in the therapeutic efficacy and in vivo stability of NFHGs. Smaller nanoparticles with controlled charge profiles have been reviewed to enhance cellular uptake, modulate immune interactions, and facilitate deeper tissue penetration.^29,30 Surface modifications, such as PEGylation or ligand functionalisation, can reduce immune recognition, prolong circulation time, and enable specific cell targeting, thus improving drug delivery precision and minimizing off-target effects.²⁹ Tuning the crosslinking kinetics during hydrogel formation can modulate nanoparticle entrapment, retention, and localisation within the hydrogel. Physical crosslinking (via hydrogen bonding, ionic interactions) offers reversible, stimuli-responsive properties but can compromise long-term mechanical stability. In contrast, chemical crosslinking (using covalent bonds like click chemistry or enzyme-catalyzed reactions) enhances structural integrity and retention at the wound site, crucial for sustained therapeutic release and in vivo resilience.³¹ Recently, Li et al. (2024), showed that the average hydrodynamic sizes of methylacrylyl hydroxypropyl chitosan nanocomposites gradually decreased with an increase in LAPONITE® particles content when preparing a fibril hydrogel, highlighting this parameter as critical in enhancing fibroblast migration and angiogenesis.³²

Similarly, post-crosslinking effects or reversible crosslinking kinetics can impact the hydrogel–nanoparticle interactions. Teng et al. (2024), showed that amino-rich silicon nanoparticles could reduce the gelation time of a xyloglucan/e-poly-lysine hydrogel, and that silicon acts as a mechanical reinforcement and facilitates the construction of a dynamic Schiff base network.³³ Given the reversable nature of the crosslinking mechanism the hydrogel had self-healing capacity, but the study does not clarify on the kinetics of release of the silicon particles upon hydrogel breaking. On the other hand, Zhang et al. (2025) developed a multiple-crosslinked injectable hydrogel via the radical polymerization of propenyl groups and the formation of copper–polyphenol coordination bonds and Schiff base bonds. Taking advantage of the Shiff base and the Cu–polyphenol coordination, the authors showed that the hydrogel could be disrupted in the acidic microenvironment of diabetic wounds, resulting in the release of copper and protocatechualdehyde (PA) to scavenge reactive oxygen species (ROS), promote angiogenesis and cell migration, and exert antibacterial and anti-inflammatory activities via the CuPA complexes.³⁴ This highlights the importance of choosing a tailored functionalisation strategy and adequate materials for the hydrogels and nanoparticles. Relevant examples of functionalisation can be found in Fig. 3. The natural and synthetic polymers used commonly for hydrogel preparation vary in strength, degradation and biocompatibility (Table 1). Synthetic polymers like PEG and PVA offer high strength but need modification for bioactivity, while natural polymers like collagen and fibrin are softer, elastic, and promote cell adhesion. Composites (e.g., alginate–PEG) combine strength with flexibility. Natural polymers degrade faster via enzyme actions, synthesize more slowly via hydrolysis, and degradation rates can be tuned through chemical or physical crosslinking.

Fig. 3 Five main approaches to fabricate nanocomposite hydrogels with a uniform distribution of nanoparticles: (1) formation of the hydrogels by adding a monomer and a crosslinker to the nanoparticle suspension; (2) incorporation of nanoparticles into pre-formed hydrogel; (3) formation of reactive nanoparticles within a pre-formed hydrogel; (4) cross-linking of hydrogels by nanoparticles and (5) hydrogel formation using nanoparticles, cross-linking agents, and polymers.³⁵

Table 1 Properties of hydrogel forming key polymers for efficient wound healing – polymer chemistry and hydrogel performance

Hydrogel polymer	Mechanical properties	Degradation properties	Biocompatibility	Key ref.
Natural polymers
Alginate	Low to moderate strength (∼10–100 kPa), weak elasticity	Fast degradation (days to weeks), ion-dependent (Ca^2+)	High biocompatibility and low immunogenicity	36–41
Chitosan	Moderate strength (∼50–200 kPa), improves with crosslinking	Enzymatic degradation (lysozyme), tuneable via degree of deacetylation	Antimicrobial and promotes cell adhesion	42–59
Collagen	Weak (∼1–50 kPa), highly elastic	Fast degradation (protease-mediated), can be slowed via crosslinking	Excellent biocompatibility and supports cell migration	52, 60 and 61
Hyaluronic acid (HA)	Soft (∼1–20 kPa), shear-thinning	Fast degradation (hyaluronidase), modified for stability	Low immunogenicity and promotes angiogenesis	62–64
Fibrin	Weak (∼1–10 kPa), highly elastic	Fast degradation (plasmin-mediated), can be stabilized	Excellent biocompatibility and supports cell infiltration	65
Synthetic polymers
Poly(ethylene glycol) (PEG)	Tuneable (∼1–1000 kPa), depends on MW & crosslinking	Slow degradation (hydrolysis), tunable via ester linkages	Low immunogenicity and inert	66
Poly(vinyl alcohol) (PVA)	High strength (∼100–1000 kPa), tough	Slow degradation (hydrolytic), resistant to enzymes	Biocompatible	67–71
Poly(acrylic acid) (PAA)	Moderate (∼10–500 kPa), pH-sensitive	Degrades slowly, can be modified	Biocompatible	72

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Hydrogels also have been designed to target specific chronic wounds by modifying the nature of the nanoparticles (Table 2); such as metallic nanoparticles, metal-oxide nanoparticles, carbon-based nanoparticles, ceramic nanoparticles, peptide/protein-based nanoparticles and polymeric nanoparticles. Each of these categories of functionalised hydrogels have been reported to show enhanced wound management and are discussed in the following sections.

Table 2 Hydrogels functionalised with metallic, metal-oxide, carbon-based, ceramic, peptide/protein-based and polymeric nanoparticles

S. no.	Nanomaterial functionalised hydrogel	Chronic wound	Ref.
A. Metallic nanoparticles
1	ZnS and CdS loaded arabic gum hydrogels	Infectious	73
2	Ag/Ag@AgCl/ZnO hybrid nanostructures	Infectious	74
3	Cysteine-directed silver–copper composite nanoclusters hydrogel	Infectious	75
4	Ag-doped Mo2C-derived polyoxometalate	Infectious	76
5	Silver and gold nanoparticles crosslinked with chitosan	Infectious	42
6	Alginate and gelatin hydrogel composited with nanozinc	Infectious	36
7	Polyvinyl (alcohol)/chitosan/nano zinc oxide nanocomposite hydrogels	Infectious	77
8	PVA/starch/chitosn and nano zinc oxide	Infectious	68
9	SilMA/HAMA/Cu-EGCG	Infectious	78
10	Photothermal hydrogel based on copper disulfide nanoparticles and thiolated gelatin	Infectious	79
11	Nano copper/chitosan–starch bio composite	Infectious	43
12	Alginate AND silver (GA@AgNPs-SA)	Infectious	37
13	Polyamide/Pistacia atlantica (P.a.) gum nanofibre, fabricated by electrospinning method, was coated on a layer of PEBAX/PVA hydrogel embedded with green synthesized Ag nanoparticles (AgNPs)	Infectious	69
14	SABA/Borax/PDA@AgNPs	Infectious	80
15	Amorphous hydrogel based on sodium alginate (NaAlg); type I collagen, isolated by the authors from silver carp tails (COL); glycerol (Gli); aloe vera gel powder (AV); and silver nanoparticles obtained by green synthesis with aqueous Cinnamomum verum extract (AgNPs@CIN) and vitamin C	Infectious	81
16	Keratin nanoparticles (Ker NPs) with facilitating epithelisation capability and nanosized-EGCG covered with Ag nano particles (AE NPs)	Infectious	82
17	Ag nanoparticles/phosphotungstic acid–polydopamine nano-flowers (AgNPs/POM–PDA)	Infectious	83
18	AgNP–impregnated PADM (AgNP–PADM) hydrogel	Infectious	84
19	AgNPs and chitosan and gelatin	Infectious	85
20	AgBr@SiO2 microspheres incorporated methacrylate gelatin	Infectious	86
21	Silver nanoparticles (AgNPs) into a calcium alginate–polydopamine–carboxymethyl chitosan (CA–PDA–CMCS)	Infectious	87
22	Silver nanoparticles (AgNPs) were introduced as antibacterial agents into a polyvinyl alcohol (PVA)/bacterial cellulose (BC) solution	Infectious	88
23	Nano silver alginate hydrogel	Infectious	89
24	Nanocomposite hydrogels based on carboxymethyl cellulose (CMC), aloe vera and green synthesized silver nanoparticles	Infectious	90
25	Polydopamine nanoparticles and silver nanoparticles and guar gum	Infectious	91
26	Dermlin and silver nanoparticles	Infectious	92
27	Nano silver loaded chitosan based biohydrogel	Infectious	44
28	Silver nanoparticles and Nigella sativa oil and PVA hydrogel film	Infectious	70
29	Collagen, aminated xanthan gum, bio-capped silver nanoparticles and melatonin	Infectious	60
30	Nanosilver doped carboxymethyl chitosan–polyamideamine alginate composite	Infectious	93
31	Silver–gelatin–cellulose composite	Infectious	94
32	Silver/polyvinyl hydrogel	Infectious	95
33	Silver doped silk fibroin/CMC nanocomposite hydrogels	Infectious	96
34	Carbohydrate polymer-based silver nanocomposite	Infectious	97
35	Silver nanoparticles and gelatin thermoresponsive nanocomposites	Infectious	98
36	Molybdenum hydrogel	Infectious	99
37	NanoFeS	Infectious	100
38	Iron-based metal–organic framework incorporated within the hydrogel	Infectious	101
39	Gold nanoclusters (GNCs) and carbomer (CBM)	Infectious	102
40	Gold nanoparticles and PEG hydrogel	Infectious	103
41	Au nanoclusters and cellulose nanofibrils	Infectious	104
42	MOF loaded in gelatin–chitosan hydrogels	Infectious	105
43	Two-dimensional (2D) transition metal carbides/nitrides (MXenes) multi-layer nano-flakes	Infectious	106
44	Liquid metal nanoparticles (gallium) with polymeric encapsulation	Infectious	107
45	Bi2S3 nano-heterojunctions	Infectious	108
46	Magnesium organic framework-based microneedle patch (denoted as MN–MOF–GO–Ag)	Diabetic	109
47	Mace-like Au–CuS heterostructural nanoparticles	Diabetic	110
48	Integrating Au–Pt alloy nanoparticles into a hydrogel – hyaluronic acid and carboxymethyl chitosan	Diabetic	111
49	Metformin-loaded mesoporous silica microspheres (MET@MSNs) and silver nanoparticles (Ag NPs)	Diabetic	112
50	Hydrogel/nano silver-based dressing	Diabetic	113
51	P. granatum peel crude extract (PGPC), ethyl acetate fraction (PGPEA) and their silver nanoforms (Ag-NPs)	Diabetic	45
52	Silver–chitosan	Diabetic	114
53	Nano-silver	Burn	115
54	PVA + nano silver	Burn	116
55	Thiolated hyaluronic acid (HA-SH) and bioactive silver–lignin nanoparticles	Venous and arterial/ischemic	117
B. Metal-oxide nanoparticles
1	Chitosan (Cs) encapsulated binary nano-composites (ZnO/CuO)	Infectious	46
2	MoS2-nanosheet hydrogels	Infectious	118
3	Chitin hydrogel/nano ZnO	Infectious	119
4	Multifunctional hydrogel (CMCS–brZnO) synthesized by incorporating fusiform-like zinc oxide nanorods (brZnO) into carboxymethyl chitosan (CMCS)	Infectious	120
5	Carrageenan + ZnONPs	Infectious	121
6	NanoZnO doped calcium phosphate–chitosan–alginate biocomposite	Infectious	122
7	NanoZnO/PVA/carboxymethyl cellulose	Infectious	123
8	PVA/ZnO nanocomposite	Infectious	124
9	Heparinised PVA/chitosan hydrogels + ZnO nanoparticles	Infectious	125
10	Carboxymethyl cellulose/ZnO impregnated MCM-41 nanocomposite	Infectious	126
11	Berberine-modified ZnO nano-colloids hydrogel (ZnO-Ber/H)	Diabetic	127
12	Nano-ZnO loaded to aminated gelatin and dextran	Diabetic	128
13	Keratin-chitosan/nano ZnO	Burn	47
14	Gelatin/HA/CS suffused with asiatic acid/ZnO and CuO	Burn	129
C. Carbon-based nanoparticles
1	Chitosan-based carbon nitride–polydopamine–silver composite	Infectious	48
2	Carboxylated chitosan modified carbon nanotubes	Infectious	49
3	Cellulose and curcumin-loaded graphene quantum dots	Infectious	130
4	Polymeric network of gelatin–polyvinyl alcohol–hyaluronic acid encapsulating a graphene oxide (GO) nanoconjugate on which silver nanoparticles (Ag NPs) have been grown	Infectious	131
5	PVA/PVP/nano-rGO	Infectious	132
6	Nano-clustery graphene-based macromolecular protein + ciprofloxacin	Burn	133
7	Hydrophilic poly(PEGMA-co-GMA-co-AAm) (PPGA) polymers with hyperbranched poly-L-lysine (HBPL)-modified manganese dioxide (MnO2) nanozymes	Diabetic	134
8	E-Polylysine (EPL)-coated MnO2 nanosheets (EM) and insulin-loaded self-assembled aldehyde Pluronic F127 (FCHO) micelles	Diabetic	135
D. Ceramic nanoparticles
1	PVA and nanohydroxyapatite hydrogels	Infectious	71
2	Iodine-doped titanium oxide nanoparticles–chitosan–PVA	Infectious	136
3	Glycol chitosan (GC) with silica nano-particles (SiNP)	Infectious	137
4	Mesoporous silica MCM-41 as a nano drug carrier into carboxymethylcellulose hydrogel. Tetracycline and methylene blue.	Infectious	138
5	Cerium oxide nanoparticles, polyacrylamide, and curcumin	Infectious	139
6	Nanoclay lithium magnesium silicate hydrate (LMSH) cross-linked semi-IPN sericin/poly(NIPAm/LMSH) (HSP) nanocomposite hydrogels	Infectious	140
7	LAPONITE® nanoclay and gelatin	Infectious	141
8	Dopamine-grafted-gelatin (GelDA) and LAPONITE® nanoclay	Infectious	142
9	Gellan gum methacrylate and LAPONITE® (clay) nanocomposite hydrogel	Burn	143
10	Nano-hydroxyapatite/chitosan/tilapia skin peptides hydrogels	Burn	50
E. Peptide/protein-based nanoparticles
1	Peptide nanogel RADA 16-I (RADARADARADARADA) and PDGF-BB	Infectious	144
2	Nano-lipopeptide	Infectious	145
3	Alginate–PVA–silk fibroin–magnesium hydroxide nanorods	Infectious	67
4	Silk fibroin nanofibres	Infectious	146
5	Octapeptide (IKFQFHFD) nano-networks	Diabetic	147
6	RADA16-I, KLT, and RGD nanopeptides were selected for self-assembly into hydrogels	Diabetic	148
F. Polymeric nanoparticles
1	Nanofibre – two-layer elctrospun	Infectious	149
2	PVA/(Gel/A-PRF) core–shell nanofibres	Infectious	65
3	Chitosan hydrogel AND PCL nanofibres	Infectious	51
4	DFO with silk nanofibres	Infectious	150
5	Core–shell hydrogel nanofibrous mats containing polylactic acid/sage extract in the core and polyvinylpyrrolidone/polyvinyl alcohol in the shell	Infectious	151
6	Bacterial cellulose/keratin nanofibrous mats conjugated with tragacanth gum	Infectious	152
7	Gelatin methacrylate (GelMA)/nano-cellulose (BNC)	Infectious	153
8	Polyethylenimine (PEI)–Ppy nanocomplex – gelatin	Infectious	154
9	Bioactive glasses nanoparticles and gelatin	Infectious	155
10	γ-PGA gelatin/chitosan/EGCG (epigallocatechin gallate)	Infectious	156
11	Calendula officinalis (CA) of various concentrations (5%, 10% and 15%)-loaded polyvinyl alcohol (PVA)/sodium alginate (SAIg) nanofibre mats	Infectious	157
12	In situ-forming collagen gels crosslinked through multifunctional polyethylene glycol (PEG)	Infectious	61
13	Succinyl chitosan-fish collagen composite hydrogel containing nano-encapsulated curcumin	Infectious	52
14	Eucalyptus extract encapsulated in aloe vera coated dextran sulfate/chitosan nanoparticles	Infectious	53
15	Chitosan nanofibre scaffolds	Infectious	54
16	Maleoyl-chitosan/poly(aspartic acid) (MAC5/PAS) nanogels into a polymer network based on thiolated hyaluronic acid	Infectious	62
17	Polyhydroxybutyrate/chitosan blend loaded with Kaempferol nanocrystals	Infectious	55
18	Curcumin-loaded chitosan nanoparticles modified with epidermal growth factor (EGF)	Infectious	56
19	Nano tigecycline/chitosan-PRP hydrogel	Infectious	57
20	Bacterial nano-cellulose – chitosan	Infectious	58
21	Aldehyde modified sodium hyaluronate (AHA), hydrazide-modified sodium hyaluronate (ADA), and aldehyde-modified cellulose nanocrystals (oxi-CNC)	Infectious	63
22	Polyvinyl alcohol with xanthan gum, hypromellose, or sodium carboxymethyl cellulose	Infectious	158
23	Minocycline-loaded cellulose nano whiskers/poly(sodium acrylate) composite hydrogel	Infectious	159
24	Ginseng-loaded sodium alginate nano hydrogel	Infectious	38
25	Alginate hydrogel containing pitavastatin nanovesicles	Infectious	39
26	CaF2 nanoparticles and alginate	Infectious	40
27	Alginate and nanotubes + rifampicin	Infectious	160
28	Nitric oxide releasing hydrogel	Infectious	161
29	Stanene nanosheet-based hydrogel	Infectious	162
30	Bi2S3 nano-heterojunctions	Infectious	108
31	Sericin/propolis/amoxicillin nanoparticles	Infectious	163
32	Kolliphor, acrylamide, and mint leaf hydrogels	Infectious	164
33	Nanosized graphdiyne-loaded sodium hyaluronate hydrogel	Infectious	165
34	Citric acid cross-linked carboxymethyl guar gum (CMGG) nanocomposite films	Infectious	166
35	Block copolymer DA95B5, dextran-block-poly((3-acrylamidopropyl) trimethylammonium chloride (AMPTMA)-co-butyl methacrylate (BMA))	Infectious	167
36	Lipid nanoparticles of tetrahydrocurcumin into hydrogel	Infectious	168
37	Hyaluronic acid-graft-dopamine (HA–DA) and polydopamine (PDA) coated Ti3C2 MXene nanosheets	Diabetic	169
38	PEI–PBA/insulin nano-particles	Diabetic	170
39	Self-assemble valsartan amphiphiles nanofilaments	Diabetic	171
40	Nano-hydrogel embedded with quercetin and oleic acid	Diabetic	172
41	Berberine nano-colloids hydrogels	Diabetic	173
42	Ferulic acid nanoparticles	Diabetic	174
43	Chitosan and carboxymethyl cellulose loaded with nanocurcumin	Diabetic	59
44	Insulin within chitosan nanoparticles	Diabetic	175
45	Chitosan-based hydrogel as a carrier for NaCMCh-rhEGF nanoparticles (a sodium carboxymethyl chitosan-recombinant human epidermal growth factor conjugate)	Diabetic	176
46	Glycol chitosan + PEG + colistin	Burn	177
47	Quaternized chitosan (QCS), oxidized dextran (OD), tobramycin (TOB), and polydopamine-coated polypyrrole nanowires (PPY@PDA NWs)	Burn	178
48	Nintedanib nanothermoreversible	Burn	179
49	Hyaluronic acid and indomethacin	Burn	64
50	Nano-sized suspended formulation of human fibroblast-derived matrix (sFDM), pluronic F127 and hyaluronic acid (HA)	Venous and arterial/ischemic	180

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3.2. Nanomaterial functionalised hydrogels to treat infected wounds

Most commonly infected chronic wounds are caused by bacterial or fungal diseases.¹⁸¹ Direct microbial infection, microbial infection after surgery, untreated infections related to burns, or underlying diseases like diabetes can all result in these wounds. When bacteria/fungus infect a wound, they may also create an ongoing inflammatory response at the site of the infection. This will prolong the inflammatory phase and the healing process overall. For cases of extreme inflammation, it may even cause sepsis. The systemic use of antibiotics can be used clinically to effectively manage infection; however, the issue of bacterial resistance is exponentially increasing.¹⁸² As a result, developing better, targeted antibacterial techniques has become a major challenge. Several researchers have used functionalised hydrogels to concomitantly combat microbial infections to promote wound healing. This section discusses different categories of hydrogels that have been functionalised to deliver antibacterial properties.

Hydrogels functionalised with metallic and metal oxide nanoparticles have been largely studied for treating infectious wound and have prominently involved the use of silver,^{37,44,60,69,70,80–98,131} zinc^36,68,77 and copper^43,78,79 based nanoparticles. Silver has long been recognised as a good antibacterial agent with broad-spectrum action against pathogenic bacteria. It has been incorporated into several types of composites such as alginate,^37,81,89 collagen,⁸¹ polyvinyl alcohol,^69,70,131 chitosan,^44,85 gelatin^85,131 and cellulose⁹⁰ to synthesise functionalised hydrogels. Most recently, in a study by Hu et al. (2023), silver nanoparticles functionalised with gallic acid (plant polyphenol) were loaded onto alginate hydrogels and the functionalised hydrogel was made injectable to work against MRSA infection in male Sprague Dawley rats³⁷ (Fig. 4). In another recent report by Rajati et al. (2023), green synthesised silver nanoparticles were embedded in PEBAX/PVA hydrogels further functionalised with electrospun polyamide/Pistacia atlantica (P.a.) gum nanofibres exhibiting excellent cytocompatibility and high antibacterial activity against E. coli.⁶⁹ Another study by Zhu et al. (2023), reports an injectable SABA/Borax/PDA@AgNPs self-healing hydrogel prepared for low-temperature photothermal antibacterial therapy and shows broad-spectrum antibacterial activity in an in vivo mice skin wound model.¹⁸³ After silver, zinc-based nanoparticles are most widely studied for their use in antibacterial wound dressings developed from functionalised hydrogels. In a clinical trial study by Meng et al. (2022), an alginate–gelatin hydrogel functionalised with nano zinc was shown to enhance caesarean section wound healing in 350 individuals as compared to the control cases where no functionalised hydrogel was administered.³⁶ Additionally, there have been several reports of using zinc oxide nanoparticles to functionalise polyvinyl alcohol/chitosan,^{68,77,124,125} chitin,¹¹⁹ carboxymethyl chitosan,¹²⁰ carrageenan,¹²¹ carboxymethyl cellulose^123,126 and alginate¹²² based hydrogels to work against bacterial infection especially those caused by E. coli, S. aureus and MRSA. Copper-based nanoparticles have also been used to functionalise the hydrogels to work against infections and promote wound healing. In a recent study by Liu et al. (2023), a multifunctional controlled-release hydrogel system was developed with Cu-epigallocatechin-3-gallate (Cu-EGCG) that showed inhibitory effects on E. coli and S. aureus and enhanced wound healing in an infected mice model.⁷⁸ Copper nanoparticle functionalised hydrogels have also been studied for photothermal therapy against infected tissue injury. In a report by Yin et al. (2022), thiolated gelatin was functionalised with copper disulfide nanoparticles and showed photothermal activity to inhibit S. aureus and promote wound closure in infected wounds.⁷⁹ Another study reports the bactericidal effects of nano copper/chitosan–starch bio-composite hydrogels on six different bacterial species, namely, Streptococcus pneumonia, Staphylococcus aureus, Salmonella typhimurium, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa. This functionalised hydrogel was also effective against four fungal species, Candida guilliermondii, Candida glabrata, Candida guilliermondii and Candida krusei. Alongside the antimicrobial effects, the functionalised hydrogel also was effective in promoting wound closure in Sprague Dawley rats.⁴³ Besides these most frequently studied metallic nanoparticles, hydrogels have been also functionalised with molybdenum,⁹⁹ iron,^100,101 gold,^102–104 gallium¹⁰⁷ and bismuth¹⁰⁸ nanoparticles to treat infectious wounds. Nanoparticle hybrid composites have also been explored for their potential antibacterial activities. In one of such studies, the metal composites of ZnS and CdS loaded Arabic gum hydrogels exhibited effective antioxidant and antimicrobial activities against E. coli and Candida albicans due to α-amylase, and α-glucosidase inhibition potential.⁷³ In another study, the photocatalytic and antioxidant ability of Ag/Ag@AgCl/ZnO hybrid nanostructure functionalised hydrogels was effective against E. coli and S. aureus in a wound healing model.⁷⁴ In another report, a silver–copper composite nanocluster hydrogel was developed using UV photoreduction and showed antibacterial activity against E. coli and S. aureus.⁷⁵ In another study by Govinasamy et al. (2022), zinc and copper oxide binary nanocomposites were used to functionalise chitosan-based hydrogels resulting in bactericidal effects against skin pathogens (S. aureus, K. pneumoniae, P. aeruginosa, E. coli, and MRSA) and enhanced wound closure.⁴⁶

Fig. 4 In vivo MRSA infection wound healing assessment of GA@AgNPs-SA hydrogels. (a) Representative picture of a wound treated with different samples. (b) Healing traces of wounds on days 0, 7 and 14. (c) Quantification of wound closure on days 0, 7 and 14. (d) Bacterial content in wound tissue after 7 days of different treatments. Reproduced from ref. 37 with permission from Elsevier, copyright 2023.

In one of the recent studies by Huang et al. (2023), multifunctional injectable hydrogels were designed based on Ag-doped Mo₂C-derived polyoxometalate (AgPOM) nanoparticles, urea, gelatin, and tea polyphenols (TPs).¹⁸⁴ Their study shows that once injected into the infected tissue, urea diffuses out under the concentration gradient, and TPs and gelatin chains recombine to trigger the in situ formation of hydrogel with excellent adhesiveness. The AgPOM by its ROS producing capability had bactericidal effects. In addition, the functionalised hydrogel converted the near-infrared region (NIR) to heat for sterilisation of wounds. This study forms a suitable reference to function-at-demand from nanomaterial functionalised hydrogels.

Carbon-based nanoparticles have also been used to functionalise hydrogels for antibacterial effects. In a recent report by Liu et al. (2023), carbon-nitride/polydopamine–silver based nano-composites were used to functionalise chitosan for bactericidal effects against E. coli and S. aureus and promote wound healing effects in an infected mice model.⁴⁸ Carbon nanotubes have also been used to modify chitosan to prepare temperature sensitive hydrogels to deliver ciprofloxacin for antibacterial effects against E. coli and S. aureus.⁴⁹ In another study, curcumin-loaded graphene quantum dots were used to modify cellulose to achieve enhanced bactericidal activity.¹³⁰ In another recent report by Esfahani et al. (2023), a hybrid network of polyvinyl alcohol/polyvinylpyrrolidone and nano-reduced graphene oxide was developed to have bactericidal activity against E. coli and S. aureus.¹³²

Another emerging popular choice to functionalise hydrogels is by using ceramic nanoparticles. Polyvinyl hydrogels are reported to be functionalised by hydroxyapatite⁷¹ and titanium oxide¹³⁶ nanoparticles. Silica nanoparticles have also been used to modify chitosan¹³⁷ and carboxymethyl cellulose¹³⁸ hydrogels. There are few reports also for hydrogels functionalised with nano-clays for activity against infectious wounds.^140–142 In one such study LAPONITE® nanoclay was used to functionalise gelatin to develop shape-recoverable microporous nanocomposite hydrogels for wound dressing that can be potentially used for function-at-demand to monitor wound healing.¹⁴¹ Cerium oxide nanoparticles have also been used to functionalise polyacrylamide hydrogels for loading and sustained release of curcumin to promote wound healing.¹³⁹

Several peptide and polymeric nanoparticles have also been used to functionalise hydrogels against infectious wounds. Peptide nanogels RADA 16-I and PDGF-BB have shown efficacy against S. aureus, E. coli and P. aeruginosa.¹⁴⁴ In another study by Afsharipour et al. (2021), nano-lipopetide exhibited enhanced wound healing in an infected rat model.¹⁴⁵ Another popular category of using polymeric nanofibres based out of silk fibroins has been reported frequently to work against infectious models. An alginate–PVA–silk fibroin magnesium hydroxide nanorod based hydrogel was shown to be effective against P. aeruginosa.⁶⁷ In another study in male C57BL/c mice, silk fibroin nanofibres showed enhanced wound closure.¹⁴⁶ Additionally, PVA,^65,151 chitosan,⁵¹ cellulose,¹⁵² and gelatin^153–155 were also reported to form nanostructures to treat infectious wound healing.

3.3. Nanomaterial functionalised hydrogels to treat diabetic wounds

Diabetes mellitus is a global health concern that has high incidence and co-morbidity rates.¹⁸⁵ Chronic diabetic wounds enhance the complication of diabetes and affect nearly one-fourth of diabetic patients.¹⁸⁶ Diabetic wounds pose significant challenges in their management due to chronic inflammation, angiogenic dysfunction, hyperglycaemia, microvascular complications such as hypoxia, neuropathy and infection.^187,188 Additionally, due to the pathophysiology of diabetes, advanced glycation end products impair the normal function and proliferation of keratinocytes and fibroblasts.¹⁸⁹ The current diabetic wound management relies majorly on glycaemic control and infection management by regular introduction of insulin and changing of wound dressings. In its chronic state, the current diabetic wound management practice is insufficient to provide early recovery for patients.^186,190 Functionalised nanoscale hydrogels on the other hand can be a suitable alternative to the conventional diabetic wound healing methods. Diabetic wound management comprises of therapeutic delivery and stimulus response for function-at-demand as discussed below.

Therapeutic delivery from functionalised hydrogels has been an amalgamation of delivery of anti-inflammatory drugs, bio-actives (such as exosomes, growth factors, probiotics, antioxidants), and antimicrobial components.¹¹¹

In a study by Xue et al., (2022), RADA16-I, KLT and RGD nanopeptides were self-assembled to form hydrogels that accelerated wound healing by decreasing the expressions of IL-6, IL-10, IL-1β, and TNF-α indicating anti-inflammatory properties and increasing expression of vascular endothelial growth factor (VEGF), indicating promoted angiogenesis.¹⁴⁸ In another study by Yin et al. (2022), an injectable, berberine modified zinc-oxide nano-colloid PVA hydrogel was used to enhance wound healing in a diabetic rat by up-regulating the antioxidant stress factors (Nrf2, HO-1, NQO1), vascular and growth factors (VEGF, CD31, EGFR and FGFR) and downregulating the inflammatory factors (TNF-α, IL-1β, and IL-6).¹⁹¹

A study by Shahverdi et al. (2016) showed that a hydrogel in conjunction with sodium carboxymethyl chitosan-recombinant human epidermal growth factor (NaCMCh-rhEGF) nanoparticles was more stable against proteases and resulted in improved wound closure in diabetic rats by the delivery of growth factors.¹⁷⁶ In another study, ferulic acid–poly(lactic-co-glycolic) acid nanoparticles were formulated with the Carbopol 980 to derive NFHG that on oral and topical administration have demonstrated antidiabetic and antioxidant properties resulting in promoted wound healing in diabetic rats.¹⁷⁴ In a diabetic mouse model, a magnesium organic framework-based microneedle patch was used for transdermal delivery of magnesium ions, graphene oxide–silver nanocomposite and gallic acid to realise cell migration, endothelial tubulogenesis, ROS scavenging and antibacterial effects for promoting wound healing.¹⁰⁹ In another study, silk fibroin-hyaluronic acid based injectable hydrogels incorporated with mace-like Au–CuS heterostructural nanoparticles (gAu–CuS HSs) were used to cure diabetic wounds by inducing an M2 macrophage phenotype, regulating cytokine expression (IL-6, TNF-β1, IF-γ, and IL-10), promoting angiogenesis, cell multiplication and fibroblast emigration to the wound area during the proliferation and remodelling phase.¹⁹²

Chitosan based hydrogel containing silver nanoparticles has shown efficacy against diabetic foot clinical bacterial isolates where S. aureus (37%) and P. aeruginosa (18.5%) were the predominant isolates in the ulcer samples.¹¹⁴ Another study with Punica granatum peel crude extract (PGPC), ethyl acetate fraction (PGPEA) and their silver nanoforms (Ag-NPs) has shown increased antibacterial effects on S. aureus and P. aeruginosa with active wound healing in diabetic rats with enhanced expressions of transforming growth factor beta (TGF-beta 1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) in the epidermal cells.⁴⁵ Few other studies also report the use of silver nanoparticles to fucntionalise hydrogels to reduce infection in diabetic wound microenvironments and aid in the wound healing.^45,112–114

In another report using ε-polylysine (EPL)-coated MnO₂ nanosheets (EM) and insulin-loaded self-assembled aldehyde Pluronic F127 (FCHO) micelles – a pH/redox dual responsive hydrogel, sustained release of insulin was achieved and the application of this multifunctional hydrogel showed accelerated wound-healing in a MRSA infected diabetic mouse model (Fig. 5).¹³⁵ Similar to this, another study reports the use of hydrophilic poly(PEGMA-co-GMA-co-AAm) (PPGA) polymers with hyperbranched poly-L-lysine (HBPL)-modified manganese dioxide (MnO₂) nanozymes, to promote healing of infected diabetic wounds by virtue of anti-inflammatory, anti-bacterial, nitric oxide generating and ROS-scavenging properties.¹³⁴ In another study, gold–platinum alloy nanoparticles were integrated into hydrogel containing hyaluronic acid and carboxymethyl chitosan to ameliorate the pathological microenvironment around the diabetic wound and accelerate wound healing.¹¹¹

Fig. 5 Schematic diagram illustrating multifunctional (FEMI) hydrogel for MDR bacteria-infected diabetic wound healing. (a) The FEMI hydrogel was fabricated by the reversible Schiff-based reaction between EM and insulin-loaded FCHO micelles. (b) The FEMI hydrogel could protect fibroblasts from oxidative stress by decomposing the extensive ROS (H₂O₂) into O₂. (c) An efficient antibacterial performance was achieved synergistically through the positive-charged EPL and the sharp nanoknife-like MnO₂ nanosheets. (d) The FEMI hydrogel accelerated hemostasis and eradicated MDR infection, consumed the extensive deleterious ROS and ameliorated the perpetual inflammatory microenvironment, thus contributing to the stimulated wound healing in vivo. Reproduced from ref. 135, with permission from American Chemical Society, copyright 2020.

There are several reports for the stimulus-response functionalised hydrogel system to treat diabetic wounds. In a study by Chen et al. (2019), a pH-switchable antimicrobial hydrogel based on the self-assembly of a designed octapeptide (IKFQFHFD) is reported to have antibacterial effects on MRSA infected diabetic mice.¹⁴⁷ In another study with zinc-oxide nanoparticles, gelatin and dextran based hydrogels were functionalised to achieve pH responsive wound healing in a diabetic model by promoting anti-bacterial and angiogenic activities.¹²⁸

3.4. Nanomaterial functionalised hydrogels to treat burn wounds

Burn wounds can be very difficult to cater for due to severe increases in infections and inflammation. There is also significant decreases in angiogenesis, ECM production and growth factors simulation in the case of burn wounds that make them life threatening.¹⁹³ Higher degree burn wounds are also characterised by the irreversible tissue damage and scarring as compared to superficial burns. Moreover, when subjected to extreme burning, the dermal cells incur membrane dysfunction and result in ionic disbalance. The current treatments of burn wounds are helpful to an extent but are still lacking in terms of providing patient comfort due to painful dressings, dryness and scratching of the wound area and secondary injuries and infections.¹⁹⁴ These become ever so prominent for secondary and tertiary burns that could lead to fatal situations. Due to several challenges in the case of burn wound healing, the treatment requires the wound dressing to bear the following properties: moisture retention, antibacterial, anti-inflammatory, delivery of bio-actives (cells, cytokines, and growth factors), stimulus responsiveness and burn wound monitoring (function-at-demand). The research progress of hydrogel dressings for burn wounds considering the above mentioned properties is discussed below. Due to their intrinsic swelling nature, all the hydrogels that are used to treat burn wounds act as a physical barrier and have moisture retention properties. Moreover, their easy removability does not cause painful dressing replacement for burn wounds.

Functionalised hydrogels with antimicrobials (including bactericidal nanomaterials such as those based on silver and copper) can address secondary infection that can arise in the peri-wound area of a burn wound.¹¹⁵ Such hydrogels can assist in preventing septicaemia and ultimately can act as a life saver from a compromised immune system. Several researchers have reported NFHGs that have antimicrobial and burn wound management properties. In a study by Zhu et al. (2021), a biocompatible ciprofloxacin (CF)-encapsulated graphene-silk fibroin macromolecular hydrogel was used as a dressing that had improved antibacterial activity against S. aureus and P. aeruginosa in a burn wound model of 5 week old Kunming mice.¹³³ In another study by Thanusha et al. (2018), gelatin and glycosaminoglycan were functionalised with hyaluronic acid, chondroitin sulphate, zinc-oxide, and copper-oxide nanoparticles to prepare hydrogels with antibacterial properties against E. coli and S. aureus. This functionalised hydrogel was also effective against second degree burns in Wistar rats.¹²⁹ Chitosan based hydrogels functionalised with several components have also been reported often against infection in burn wound models. An increase in wound closure was reported in Sprague–Dawley (SD) rats when treated with nano zinc-oxide functionalised keratin-chitosan hydrogels.⁴⁷ In a study by Zhu et al. (2016), colistin loaded aldehyde-modified poly(ethylene glycol)-glycol chitosan hydrogels exhibited antibacterial activity against both colistin sensitive and resistant strains of P. aeruginosa in neutropenic mice used to develop a burn wound model.¹⁷⁷ In a study by Huang et al. (2022), quaternised chitosan (QCS), oxidised dextran (OD), tobramycin (TOB), and polydopamine-coated polypyrrole nanowire (PPY@PDA NWs) based hydrogels were shown to have antibacterial activities against P. aeruginosa, E. coli and S. aureus. This functionalised hydrogel also resulted in enhanced wound healing in a P. aeruginosa infected burn wound Kunming mice model.¹⁷⁸ Another interesting cocktail of materials including nanohydroxyapatite–chitosan–tilapia skin peptides was used to prepare functionalised hydrogels to promote wound healing in rabbit burn models and have antibacterial effects against E. coli and S. aureus.⁵⁰

For the burn wound healing, an important characteristic of the wound dressing material is to promote angiogenesis, particularly in the case of higher degree burns. With angiogenesis, adequate nutrition and oxygen supply are ensured to expedite the wound healing. Although there are no direct reports of nanomaterial functionalised hydrogels on promoting angiogenesis in the case of a burn wound, there are few reports on functionalised hydrogels to promote angiogenesis as well as cater to inflammation. In a study by Sun et al. (2011), dextran-allyl isocyanate-ethylamine/polyethylene glycol diacrylate hydrogel was used to promote neovascularisation and skin generation in the case of third-degree burn wounds over 21 days in mice.¹⁹⁵ In another study by Yuan et al. (2021), a catechol-modified oxidised hyaluronic acid-amino-gelatin functionalised hydrogel with iron was used to promote vascularisation and reduce inflammation in the case of a burn wound mice model (Fig. 6).¹⁹⁶

Fig. 6 (a) Schematic illustrations of the burn wound healing process: (i) haemostasis/inflammation phase; (ii) proliferation phase; (iii) remodelling/maturation phase; (b) photographs of untreated wounds and wounds treated with commercial film dressing (SSD) and AG-OD/1.0-Fe(III) hydrogel on days 0, 5, 10 and 13; (c) wound contraction for each group; the data are presented as the mean ± SD (n = 5), *p < 0.05, ***p < 0.001; (d) traces of wound-bed closure on days 0, 5, 10 and 13 for each group. Reproduced from ref. 196, with permission from Elsevier, copyright 2021.

Stimulus-response NFHG system in the case of burn wound management can be developed using thermosensitive biocompatible polymers such as poly(N-isoprolylacrylamide), poly(ethylene glycol), poly(propylene glycol), poly(methacrylic acid), poly(vinyl alcohol) poly(vinyl pyrrolidone) and methylcellulose.^197,198 Although thermosensitive NFHG are yet to gain popularity for burn wound management, in one of the recent studies by de Castro et al. (2023), nano-sized micelles of hyaluronic acid and indomethacin were able to gel in situ and assisted in rapid healing of corneal chemical burns in New Zealand rabbits (Fig. 7).⁶⁴ In one of the earlier reports by Oliveira et al. (2014), biocompatible nano silver functionalised PVA hydrogels were shown to be effective against E. coli, S. aureus and C. albicans.¹¹⁶ Such candidate NFHGs that have both thermosensitive and antimicrobial components can be explored further for stimulus-response burn wound management.

Fig. 7 (A) Fluorescein-stained eyes under blue cobalt light demonstrating epithelial healing from injury until the 7th day. Reproduced from ref. 64, with permission from Elsevier, copyright 2023. (B) The graph indicates the injured area reduction, in percentage, for each group. Significant reduction (p ≤ 0.05) was only identified at the third day between hyaluronic acid and indomethacin formulation (F2) and commercial formulation (CF). NT denotes the untreated group. Data are expressed as mean ± SEM, n = 5. Reproduced from ref. 64, with permission from Elsevier, copyright 2023. (C) Burn wound monitoring – function-at-demand: CMC-DACNC based NFHG can be used to treat burn wounds and can be removed painlessly upon wound healing. Reproduced from ref. 199, with permission from American Chemical Society, copyright 2018.

Self-healing hydrogels can assist in burn wound monitoring where the on-demand removability/degradation is desired post healing without causing pain. One of the prominent examples of such on-demand self-healing NFHG was reported by Huang et al. (2018).¹⁹⁹ Their study reports a self-healing NFHG based on water-soluble carboxymethyl chitosan (CMC) and oxidised cellulose nanocrystal (DACNC) prepared via crosslinking with Schiff base bonds between the amino of the CMC and the aldehyde of DACNC. The gel could fill the large and irregular burn wound area and can be removed painlessly by dissolving in amino acid solution (Fig. 7).¹⁹⁹

3.5. Nanomaterial functionalised hydrogels to treat venous and arterial/ischemic wounds

The most prevalent chronic lesions in the lower extremity are venous and arterial/ischemic wounds, which frequently go through a cycle of slow healing and recurrence.²⁰⁰ Venous wounds develop due to impaired venous blood flow in the lower extremities. They are mostly found on the lower legs and ankles. A variety of factors, including decreased tissue perfusion, ambulatory venous hypertension, venous reflux, and oxygen diffusion, contribute to the slow healing of venous wounds.²⁰⁰ On the other hand, arterial or ischemic ulcers, are wounds that result from inadequate arterial blood supply to tissues. They most commonly occur on the lower extremities, particularly the feet, and are associated with peripheral arterial disease or arterial insufficiency. Arterial/ischemic wounds are caused by narrowed or blocked arteries, reducing blood flow and oxygen delivery to the tissues. These are typically found on the feet, toes, or areas exposed to pressure or trauma. Although there are no direct reports of NFHGs treating the venous wounds, however, in one of the reports, the antibacterial effects of NFHG based on thiolated hyaluronic acid (HA-SH) and bioactive silver–lignin nanoparticles were studied on the exudate extract rich in S. aureus and P. aeruginosa from venous leg ulcers from a patient.¹¹⁷ The results from this study are promising as the silver-lignin nanoparticle functionalised hydrogel was able to heal the wound without any inflammation after 15 days of treatment (Fig. 8A). Considering the underlying factors of arterial or ischemic wounds, NFHGs loaded with growth factors and having anti-inflammatory properties are desired for ischemic wound treatment. There is one prominent report on a hindlimb ischemia model where the healing effects have been shown by using a nano-formulation from a human fibroblast-derived matrix combined with pluronic F127 and hyaluronic acid.¹⁸⁰ In this study the histological analysis of ischemic hindlimb muscles at 21 days post-treatments suggest that the nano-formulation resulted in significant wound closure as compared to the non-functionalised treatment (Fig. 8B–E). It is worth mentioning that although more commonly associated with venous leg ulcers, chronic venous insufficiencies can also contribute to reduced blood flow and impair arterial/ischemic wound healing. Additionally, individuals with diabetes are at increased risk of developing arterial/ischemic wounds due to the associated vascular complications, such as peripheral neuropathy (nerve damage) and peripheral arterial disease.

Fig. 8 (A) Scheme on the in vivo mouse model and representative photos of full thickness skin wounds before and after application of the nano-enabled hydrogels. Reproduced from ref. 117, with permission from Elsevier, copyright 2021. Histological analysis of ischemic hindlimb muscles at 21 days post-treatments. (B) Necrosis and fibrosis in the gastrocnemius muscles was examined using hematoxylin and eosin (H&E) and Masson's trichrome (MT) staining, respectively (scale: 200 μm). (C) Quantitative analysis of the necrotic area and (D) the fibrosis area. (E) Fibrosis area in the tibialis muscles was examined using H&E and MT staining (scale: 200 μm). Statistically significant difference (*p < 0.05, **p < 0.01).¹⁸⁰

3.6. Immune response and gene expression in wound healing

Chronic wound healing also involves coordinated immune responses with underlying gene expression changes. The immune response towards chronic wounds can be staggered into different stages. The innate immune system is rapidly activated as wounding occurs, with neutrophils arriving first to phagocytose pathogens and release critical pro-inflammatory cytokines such as IL-6 and TNF-α. These cytokines orchestrate the transition to a robust inflammatory phase, fundamental for clearing infection and debris and laying the groundwork for subsequent tissue repair. Macrophages then infiltrate the region and undergo a pivotal shift from the pro-inflammatory M1 to the reparative M2 phenotype, secreting anti-inflammatory factors and growth mediators like VEGF, which stimulate angiogenesis and tissue remodelling. The adaptive immune system—particularly regulatory T cells—further fine-tunes this response, curbing excessive inflammation while influencing fibroblast-driven extracellular matrix (ECM) deposition and resolution of tissue injury.^29,201

Acute and chronic wounds display distinct gene expression profiles. While acute wounds typically show transient upregulation of genes related to inflammation, angiogenesis (such as VEGF), and ECM components (like COL1A1), chronic wounds are marked by the persistent overexpression of IL-6 and TNF-α, impaired angiogenic pathways, and active ECM breakdown, contributing to delayed healing and tissue degradation.^201,202 Recent transcriptomic analyses (2024–2025) have further identified upregulation of genes such as IER3, TSLP, and TNFAIP6 (TSG-6) in chronic wounds, underscoring the molecular complexity underlying chronicity.²⁰³

NFHGs have emerged as a promising intervention to steer these immune and gene expression landscapes toward regeneration. Next generation nanohybrid hydrogels actively modulate immune milieu at multiple stages of healing. For instance, injectable hydrogels with antibacterial nanostructures, such as silver–copper nanozymes, have been shown to not only inhibit pathogens but also reduce pro-inflammatory cytokines (IL-6, TNF-α) while upregulating anti-inflammatory IL-10 in infected wounds.²⁰⁴ This leads to accelerated inflammation resolution and promotes earlier granulation tissue formation and re-epithelialisation in murine models. Other designs, such as angiogenesis-responsive hydrogels with VEGF and Prussian Blue nanoparticles, dynamically respond to local oxidative stress, promote M2 macrophage polarization, stimulate new vessel formation, and enhance the expression of angiogenesis-related genes (VEGFA, ANGPT2), while suppressing chronic inflammatory mediators.²⁰⁴ Furthermore, stimuli-responsive nanohydrogels can deliver therapeutic agents in response to local wound cues, demonstrating significant healing advantages in diabetic and infection-prone models. NFHGs offer the ability to fine-tune immune responses, mitigate chronic inflammation, and foster robust tissue regeneration through targeted molecular and cellular action. Their tailored immunomodulatory capabilities are paving the way for advanced, precision wound therapies informed by the latest understanding of immune-gene crosstalk in chronic wounds.²⁰⁴

4. Opinion and conclusions

The aim of this review is to provide important insight into the development and potential of NFHGs that can be used as therapeutics to address wound management in cases of infectious, burn, diabetes and venous and arterial/ischemic wounds. Chronic wound management is a complex process that affects patient quality of life, is painful, and adds ongoing pressure to healthcare systems. Nanomaterials coupled with hydrogels have shown an increasing trend in research for wound dressing over the past decade, with ever increasing functionality and complexity. To address the multi-factorial demands of a clinical wound management scenario, several research groups have developed multi-functional combinations of hydrogels with nanomaterials. This review has summarised the application of NFHGs discussed in the existing reports to attend to various facets of chronic wounds. The combinatorial properties of carefully designed NFHGs have shown engineered activities/functions such as antibacterial, adhesion and haemostasis, anti-inflammatory and antioxidant, substance delivery, self-healing, and 4D stimuli responsiveness. It is clear, however, the most prevalent and inevitable challenge in the chronic wound healing is bacterial infection, not least due to increasing antibiotic resistance. Several key strategies to deal with this threat include the use of cationic polymers, and metallic nanoparticles such as those based on silver and copper with enhanced antibacterial activity were reported across studies to address bacterial infection in wounds. Once a response to the bacterial threat is engineered, NFHGs based on chitosan, gelatin, alginate, and polyvinyl alcohol have been reported with adhesive properties that could potentially aid in haemostasis and prevent the shedding of wound dressings. In other different strategies, self-healing hydrogels such as those based on polyacrylamide-glycolic acid, chitosan, and polyvinyl alcohol were also used to retain their structure and functionality even when subjected to external forces. When used in combination with antibacterial nanoparticles, these NFHG form flexible, responsive dressings to heal and resist bacterial invasion.

However, despite significant research efforts, clinical advances in chronic wound management using NFHGs is limited. The wound healing process involves several stages with a different therapeutic requirement that must be mediated in a timely and pharmacologically viable manner. The existing strategies for wound management are largely restricted to generalised antibacterial and anti-inflammatory responses. However, such general approaches fall short of meeting the evolving needs of diverse wound environments, especially for chronic wounds. In the following subsection, we critically highlight major challenges impeding the clinical translation of NFHGs and outline future directions for the development of advanced, symbiotic, and adaptive hydrogel platforms.

4.1. Material chemistry and scale-up challenges

Significant obstacles remain in the chemistry of NFHGs, particularly in achieving stable nanoparticle dispersion and consistent cross-linking density within hydrogels. Nanoparticle aggregation commonly results in heterogeneous particle distribution, diminishing both the material's performance and reproducibility. Moreover, it is challenging to preserve hydrogel stability under physiological stresses such as shifts in pH, temperature, or mechanical strain, which restricts the dependability of these materials in clinical applications. Transitioning from laboratory to industrial production introduces additional hurdles. Minor variations during synthesis can substantially alter nanoparticle features, including size and surface chemistry. Ensuring high purity is also costly but essential for safety and efficacy. Given the composite structure of NFHGs, rigorous quality control is required to monitor both nanoparticle integrity and hydrogel uniformity. Regulatory approval is intricately tied to material composition, especially due to the cytotoxic potential of metallic nanoparticles, and must comply with biocompatibility standards. The distinct properties of natural versus synthetic hydrogel polymers further influence safety profiles and regulatory pathways. Overcoming these issues around material design, scale-up, and approval is vital for the clinical and commercial success of NFHGs.

4.2. Toward modular, patient-specific platforms: age and sex considerations

The development of truly responsive and modular NFHGs is hindered by a lack of precise targeting strategies and insufficient real-time wound monitoring, particularly around age and sex-specific needs. Paediatric and geriatric wound environments display markedly different biological characteristics and healing capacities: children possess rapid repair capabilities but may be more sensitive to adhesive removal, necessitating non-toxic, hypoallergenic, and pain-free dressings; older adults often contend with comorbidities and fragile skin, requiring low-adherence, moisture-retentive dressings with robust antimicrobial defences. Sex differences in skin architecture, biomolecule secretion, and therapeutic responses further demand tailored hydrogel formulations. Bridging this gap will enable the creation of next generation, “4D” hydrogels capable of responding to varied chronic wound types and patient populations. Moreover, detailed monitoring of post-treatment microenvironments such as tracking angiogenesis, collagen synthesis, epithelialisation, and vascular regeneration will inform more dynamic and adaptable materials. The inherent tunability of NFHGs in terms of mechanical, release, and antimicrobial properties positions them as ideal candidates for truly patient-specific wound care solutions.

4.3. Embracing green synthesis and biodegradable nanomaterials

Rising environmental and biocompatibility concerns underscore the need for green synthesis and biodegradable nanomaterial solutions. Eco-friendly routes utilise renewable resources, benign solvents, and biological templates such as plant extracts or microbes, minimizing toxic byproducts and enhancing material biocompatibility. Biodegradable nanomaterials, such as PLA, PCL, or natural polymers like chitosan and alginate, degrade into harmless byproducts within the body, reducing long-term toxicity. These materials can be engineered for controlled breakdown, aligning degradation with therapeutic timelines. Yet, bringing green synthesis to an industrial scale poses challenges regarding batch consistency, raw material costs, and reliable quality assurance. Despite these issues, green and biodegradable NFHGs represent a promising avenue toward safer and more sustainable wound management products.

4.4. Integrating biosensors for closed-loop therapeutic delivery

A paradigm shift is underway with the integration of NFHGs and biosensor technology, enabling closed-loop, responsive drug delivery systems. These platforms can sense specific biomarkers such as glucose, pH, or enzymes, directly within the wound environment, triggering precise therapeutic release in real-time. For example, glucose-sensitive hydrogels may autonomously deliver insulin as needed, closely mimicking physiological control systems and reducing patient burden. Creating such intelligent systems requires overcoming challenges related to sensor sensitivity, stability within complex tissues, and the preservation of nanoparticle and hydrogel functionality. Scalable and reproducible manufacturing practices are essential for translating these innovations into routine clinical use. Altogether, biosensor-integrated NFHGs pave the way for highly personalised and adaptive wound treatments.

In conclusion, NFHGs have brought together the collaborative advantages of nanotechnology and hydrogels to provide a potentially improved clinical solution for wound healing. The need for chronic wound management is a growing area with tremendous research and translational potential. The modular and combinatorial nature arising from defined design choices enables NFHG advancements in each facet of their design and fabrication. NFHGs can be incorporated to several developing technologies; one of such rapidly developing technologies is 4D bioprinting where the functionalised hydrogels can be used as printable ink that responds after fabrication. This rapid manufacturing technology has the potential to advance wound care by precisely printing a spatial pattern with a concoction of cells, growth factors, drugs, and biomaterials. Therefore, advanced next generation wound dressing materials containing nanomaterial functionalised hydrogels can be developed in a patient and wound specific fashion using this technology. On the other hand, the simple, widely adopted and traditional approach of topical formulations can be applied to nanomaterial functionalised hydrogels. However, despite their development from cosmeceuticals with already approved base materials, a safe and effective translation of these emerging technologies from laboratory development is still only in the research and development phase and warrants further advancement to unlock the regenerative capacity of skin via rapid and selective wound management.

Author contributions

All authors made substantial contributions to this review.

Conflicts of interest

The authors declare no conflicts of interest.

Data availability

This review does not include primary research results, software, or code. No new data were generated or analysed during the review process.

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Footnote

† Equal contribution.

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