Current and promising applications of MOF composites in the healing of diabetes wounds

Abstract

Diabetes mellitus is an exponentially growing chronic metabolic disease identified by prolonged hyperglycemia that leads to a plethora of health problems. It is well established that the skin of diabetic patients is more prone to injury, and hence, wound healing is an utmost critical restorative process for injured skin and other tissues. Diabetes patients have problems with wound healing at all stages, which ultimately results in delays in the healing process. Therefore, it is vital to find new medications or techniques to hasten the healing of wounds. Metal–organic frameworks (MOFs), an assorted class of porous hybrid materials comprising metal ions coordinated to organic ligands, can display great potential in accelerating diabetic wound healing due to their good physicochemical properties. The release of metal ions during the degradation of MOFs can promote the differentiation of fibroblasts into myofibroblasts and subsequently angiogenesis. Secondly, similar to enzyme-like active substances, they can eliminate reactive oxygen species (ROS) overproduction (secondary to the bio-load of wound bacteria), which is conducive to accelerating diabetic wound healing. Subsequently, MOFs can support the slow release of drugs (molecular or gas therapeutics) in diabetic wounds and promote wound healing by regulating pathological signaling pathways in the wound microenvironment or inhibiting the expression of inflammatory factors. In addition, the combination of photodynamic and photothermal therapies using photo-stimulated porphyrin-based MOF nanosystems has brought up a new idea for treating complicated diabetic wound microenvironments. In this review, recent advances affecting diabetic wound healing, current means of rapid diabetic wound healing, and the limitations of traditional approaches are discussed. Further, the diabetic wound healing applications of MOFs have been discussed followed by the future challenges and directions of MOF materials in diabetic wound healing.

This perspective reviews recent advances in factors affecting diabetic wound healing in patients, the limitations of traditional approaches and the application of MOF materials in diabetic wound healing.

1. Introduction

Wounds in humans may result from trauma, vascular insufficiency, and underlying medical problems such as diabetes, hypertension, rheumatoid arthritis, and inflammatory disorders.¹ Chronic wounds, in general, have a prolonged healing process and incur higher treatment costs due to their abnormal healing patterns, characterised by persistent bleeding, ulceration, or even necrosis. Currently, the global population affected by diabetes exceeds 537 million individuals, and this number is growing at an exponential rate.² Diabetic foot ulcers (DFU) and chronic diabetic wounds (DW) are the most common complications in diabetic patients due to their unique blood properties. According to the American Diabetes Association, around 15–25% of individuals with diabetes worldwide have complications related to diabetic foot and wound healing, which may lead to a mortality risk of up to 50%.³ These repercussions have a detrimental impact on the patient's overall well-being, resulting in significant healthcare expenses and imposing economic hardships. Therefore, the medical community continues to have a strong interest in finding effective and expedited methods for treating diabetic wounds and preventing their recurrence.

Normally, wound healing/repair amongst humans usually operates in four main stages: hemostasis, inflammation, proliferation, and skin remodeling.⁴ Diabetic patients have disruptions in the wound-healing process due to many variables, such as elevated blood sugar levels, impaired circulation, and bacterial infection and these factors increase the risk of non-healing wounds and potential deterioration of the wound.⁵ Currently, diabetic wound treatment methods are categorised into two groups: standard treatments and advanced adjunctive treatments. Standard treatments consist of debridement, glycemic control, and decompression therapy, while advanced adjunctive treatments include negative pressure, hyperbaric oxygen, and electrical stimulation therapy techniques.^6–11 However, all these treatments suffer from poor efficacy, leading to high wound recurrence rates. Although some bioengineered skin implants, stem cell treatment, and growth factor therapy show potential, their broad implementation is hindered by their high cost and limited clinical studies.^12,13

Nano-medicine has shown extensive potential in recent years due to the ability of nanotechnology to produce reagents that can be administered by injection or applied as bandages to effectively cure patients' wounds with promising performance. Furthermore, MOF-based materials are gaining popularity because of their customizable combination of metal nodes and organic ligands suited for various applications.¹⁴ Specifically, MOF-based nanomaterials possess unique characteristics that make them promising contenders for biomedical and biosensing applications as they possess large specific surface area and porosity, allowing them to hold a high load, have a robust framework that when required could be degraded and possess good dispersing ability with appreciable biocompatibility, ensuring their safe medical applications.¹⁵ Some MOFs can target drug delivery in organisms, self-degrade, and release metals to play an antibacterial role and enzyme-like antioxidant role. Also, they are biocompatible and are a good choice for preparing nanomaterials. In addition, MOF-based composite materials can inhibit inflammation, enhance collagen deposition angiogenesis, and induce proliferation. Further, they can also re-epithelialise the skin wound. They can form the entire layer of skin to ensure defect-free healing in diabetic rats, showing critical potential for improving diabetic patients' wound healing.¹⁶

Fig. 1 illustrates the advancements in the use of MOF materials to enhance the healing of wounds in diabetic patients over the past five years. Additionally, it highlights the relative impact of MOF materials in various fields of application, drawing from a wealth of published articles from the past five years. In addition, Table 1 provides an overview of the MOF-based materials discussed in this review, including their therapeutic principles and the synthetic strategies used for their synthesis. Furthermore, this article delves into the intricate processes involved in wound healing in individuals with diabetes, while also exploring the latest advancements in therapeutic interventions.

Fig. 1. (a) A timeline for the developed MOFs for promoting diabetic patients' wound healing in the last five years. (b) Various applications measure the MOF proportion for diabetic patients' wound repair. (c) Overview of the related articles published in the last five years.

The MOF materials mentioned in this article and their respective therapeutic principles and synthetic strategies.

MOFs materials	Types of MOFs	Metal ions	Special characteristics	Applications	Ref.
Metal ion sustained release system	H-HKUST-1	Cu2+	Low toxic side effects, pro-angiogenesis	HKUST-1thermoresponsive polydiolcitrate hydrogel	17
	GOx@Fe-ZIF-TA	Zn2+/Fe2+	Antibacterial, re-epithelialization	Microneedle patch	18
	ZIF-67 NC	Co2+	Antibacterial, antioxidant, pro-angiogenesis		19
	MN-MOF-GO-Ag	Mg2+/Ag+	Antibacterial, antioxidant, pro-angiogenesis	Microneedle patch	20
Catalytic systems	Cu/Zn-MOF	Cu2+, Zn2+	Antibacterial, antioxidant, pro-angiogenesis	Microfluidic electrospray microcapsules	21
	Ce@LTA NPs	Ce3+/Ce4+	Antibacterial, antioxidant, hemostasis, pro-angiogenesis, HG-HUVECs proliferation	Thermo reversible hydrogel	22
Gas molecular NO transport systems	CuBTC	Cu2+	Promoted vascular proliferation and wound re-epithelialization		23
	Cu-BTTri/PVA	Cu2+	Antithrombotic, antibacterial	Poly(vinyl alcohol)membranes	24
	NO@HKUST-1	Cu2+	Promote angiogenesis and collagen deposition	Electrostatically spun nanofiber platforms	25
	NHG-MN	Cu2+	Accelerating vascularization, tissue regeneration, and collagen deposition	Microneedle patch	26
Drug molecular delivery systems	LA@ K-CD-MOFs	K+	Antibacterial, antioxidant	Composite biomaterial hydrogel	27
	FZ@ ZIF-67	Co2+	Inhibit inflammation		28
	DMOG@ ZIF-67	Co2+	Promoted vascular proliferation and wound re-epithelialization	Electrostatically spun nanofiber platforms	29
	GOx/CDs@MOF	Cu2+	Antibacterial, re-epithelialization	Electrostatically spun nanofiber platforms	30
Photoexcited porphyrin systems	Met@CuPDANPs/HG	Cu2+	Eliminating ROS, inhibiting the activation of NF-κB pathway, inhibiting inflammation, pro-angiogenesis	Composite hydrogel	31
	HA-DA/Fe3+/PCN@BP	Fe3+, Zr4+	Hemostasis, antibacterial, cell proliferation	Injectable hydrogels	32
	CPB–Ce6	Fe3+, K+	Pro-angiogenesis, relieve hypoxia, upregulating VEGF, effectively kill MRSA		33

2. Chronic wound healing and treatment strategies

Wound healing is an intricate and meticulously regulated biological process that is influenced by several elements. These factors must be carefully synchronised in order to effectively repair damaged tissue or regenerate skin and restore normal structures.³⁴ Wounds are classified as “acute” or “chronic” depending on their healing period and degree of infection.³⁵ Acute wounds are typically the consequence of trauma, such as lacerations or abrasions, or purposeful injury, such as surgery. Although acute wounds grow quickly, all stages of wound healing may be observed in a predictable period.

It should be noted, however, that any wound may suffer complications owing to infection.³⁶ The transition from a healthy healing wound to a non-healing chronic wound (CW) may be due to incomplete eradication of pathogens, persistent infection, ischemia, insufficient angiogenesis, and local hypoxia.³⁷ Chronic wounds, including diabetic foot ulcers, spinal cord injury, pressure sores, and venous ulcers, are frequently caused by underlying health conditions. The global need for treating these persistent wounds has seen a significant surge.³⁸ Hence, it is essential to enhance the biology and clinical comprehension of the wound-healing process. The preceding section has examined the many elements that impact the process of healing diabetic wounds and the treatment required for such wounds.

2.1. Factors influencing the process of wound healing in diabetes

Cutaneous wound healing helps to restore skin integrity after an injury. Four typical stages of wound healing are hemostasis, inflammation, proliferation, and tissue remodelling.³⁹ Although these phases serve unique tasks, overlapping numerous stages results in a complicated, systematic physiological process that results in architectural and physiological repair following damage (Fig. 2a).^39,40

Fig. 2. An overview of acute wound healing phenomenon: (a) cellular factors in acute wound healing; overlapping 4-phase acute wound healing model and timeframe; (b) reciprocal interaction of different types of cells with wound bed fibroblasts that affects multiple wound healing phenomena.

To promote quick closure of the skin barrier, acute wound healing involves a highly dynamic cascade of cellular signalling and behavioural processes (Fig. 2b). Extensive redundancy and compensatory mechanisms guarantee that minor modifications to this reaction seldom impede the healing process.⁴¹ Chronic wounds may occur if these wounds are unable to go through these phases. Diabetic wounds have an impact on every step of wound healing. The inflammation that persists for more than three months affects the normal healing processes in the body, causing a delay in healing that goes beyond the expected time frame.

When a skin tissue wound is present, it may result in bleeding, and initially vasoconstriction that occurs to stop the bleeding.^42,43 Subsequently, the coagulation process occurs in the wound, including platelet aggregation, leading to the formation of a scab via the formation of a fibrin mesh. Following the healing of the site, an extracellular matrix (ECM) is created, which releases pro-coagulants to generate thrombi.⁴⁴

The wound-healing inflammatory phase includes the migration of neutrophils, macrophages, and lymphocytes into the wound, inducing the inflammatory symptoms (redness, fever, pain, and edema) that last for around twenty three weeks.⁴⁵ In both type 1 and type 2 diabetes patients, there is an excessive inflammatory response, which leads to chronic perpetuation through continuous destruction of wound tissue. Massive infiltration of inflammatory cells, especially neutrophils, is usually observed in chronic wounds.⁴⁶ In addition to the elevated infiltration of definite immune cell subsets,⁴⁷ pathological immune cell function is perturbed that collectively results in poor healing. Hyperprimed neutrophils release cytotoxic protein-lined decondensed chromatin to form extracellular traps (NETs), which have the potential to induce tissue harm. Inflammatory mediators may cause the dilatation of peripheral blood vessels and increase their permeability. Once the bleeding has ceased, neutrophils, which are activated by the injury to adjacent blood vessels, go to the affected area and engulf harmful bacteria that have infiltrated there.⁴⁸ Macrophages play an active role in clearing apoptotic cells and repairing wounded tissue and host defence systems.⁴⁹ Neutrophil phagocytosis is also a significant factor in macrophage phenotypic switching from pro-inflammatory M1 to reparative M2.⁵⁰ Diabetes-related hyperglycemia impairs the function of white blood cells, causes non-enzymatic glycation, and leads to the production of advanced glycation end products (AGEs).^51,52 It also causes nitric oxide synthase (eNOS) uncoupling,⁵³ resulting in reduced production of nitric oxide (NO). These factors directly contribute to impaired tissue repair and make wound healing more difficult. Hyperglycemia and the generation of advanced glycation end products (AGEs) hinder the capacity of macrophages to engulf and remove dying neutrophils, leading to an increased presence of inflammatory macrophages in the wound and sustaining a state of inflammation.

The proliferative phase is sequenced by an inflammatory phase that involves new tissue formation, granulation, re-epithelialization, and the repair of vascular networks.⁵⁴ Furthermore, keratinocytes play a decisive role in epidermal barrier repair. At the same time, endothelial cells and fibroblasts ensure ECM formation and angiogenesis, accumulating macrophages at the wound site and producing various growth factors, like VEGF and TGF-β, as well as cytokines like TNF-α.^55–57 In the stage of diabetic patients' wound proliferation, AGEs inhibit the human dermal fibroblasts' proliferation and induce apoptosis, inhibit the migration and adhesion of fibroblasts, keratinocytes, and endothelial cells, enhance the fibroblast senescence and impede the fibrosis in normal healing by receptor activation for advanced glycation end products (RAGE) in the wounds' proliferative stage.⁵⁸

The final wound-healing step is the tissue remodelling phase, which involves reorganizing and contracting the newly formed matrix. It begins about the third week after the wound is formed and elongates for many years. Its primary purpose is to enhance tensile strength and restore healthy structural tissue, which includes remodelling and granulation of the tissues to form scars.⁴⁷ In diabetic patients, during wound contraction and remodelling, the level of antioxidant enzymes in the ECM's intercellular space is low, making it vulnerable to oxidative damage. High levels of ROS can significantly damage the number of proteins in the ECM and, at the same time, mediate the accumulation of AGEs through glycosylation and oxidation reactions, which further leads to the glycosylation of collagen, elastin, and fibronectin. At the same time, oxidative signals also regulate the expression of matrix metalloproteinase (MMP), thereby affecting the remodelling of the ECM.⁵⁹

It is important to note that the reasons for delayed wound healing, while simplified above, are usually multifactorial and complicated. The chronicity of wounds is influenced by local and systemic defects and many other factors, including reduced oxygenation, malnutrition, and insensitivity to heat and pain, contributing to pathological wound healing in diabetes. The patient's age, health condition, medications, and lifestyle (heavy alcohol use, physical inactivity, and smoking) are just a few of the negative characteristics that make wounds difficult to heal.³⁴ The influencing factors in chronic wound pathology are collected in Fig. 3a.

Fig. 3. (a) Factors that affect healing of chronic wounds. Reproduced with permission,⁶⁰ The Royal Society, 2020. (b) Schematic representation of MOF particles accelerating wound healing in diabetic patients by promoting angiogenesis, facilitating tissue regeneration, promoting the conversion of macrophage type M1 to type M2, and antibacterial and antioxidant pathways.

2.2. Limitations of treatment status

Although debridement is the most common treatment for diabetic wounds, its use with antibiotics and wound dressings must be refined further. However, this method faced criticism for causing an imbalance in the wound microbial environment.⁶¹ Wound debridement and blood sugar management therapy are only the primary basic care for diabetic wounds, and their healing cycle and effects are difficult to reach at a normal level. Therefore, other more advanced complementary therapies, commonly referred to as negative pressure, hyperbaric oxygen, and electrical stimulation therapy techniques, are also used for treating chronic wounds in diabetic patients. Negative pressure therapy can help the wound edge contract by applying vacuum, remove wound exudates, and promote wound angiogenesis and granulation. Hyperbaric oxygen therapy exposes patients to a high-pressure environment to absorb pure oxygen, thereby altering the hypoxia caused by vascular disease that is not conducive to wound healing, thereby reducing the inflammatory response and promoting angiogenesis (Fig. 4a).⁶² Both complementary therapies effectively promote wound healing in diabetic people but are still not commonly used due to their high cost and limited applicability.^63,64 In addition, electrical stimulation generates short pulses of electric current in the body, thus contributing towards the bio-current's homeostasis returning to the chronic wound's surface layer (Fig. 4c), which in turn facilitates many biological processes.⁶⁵ Advanced growth factor therapy and stem cell therapy (Fig. 4b) are promising in helping patients realize ideal wound healing. Nevertheless, these therapies continue to face the challenge of expensive treatment expenses and a scarcity of comprehensive clinical data.⁶⁶

Fig. 4. (a) Schematic illustration of the glucose-responsive antioxidant hydrogel platform for healing of diabetic wound. Reproduced with permission,⁶² Elsevier, 2022. (b) Representation of induced pluripotent stem cell-derived smooth muscle cells (hiPSCSMC) for accelerated diabetic wound healing. Reproduced with permission,⁷¹ Future Science Group, 2020. (c) (i–iv) Restored natural electrical current by externally applied DC pulses to facilitate wound healing. Reproduced with permission,⁶⁵ Springer, 2010.

The high cost and limited applicability of advanced complementary therapies have sparked a strong interest in alternative organic substances that can effectively expedite the healing process of diabetic wounds. Biological materials, such as hyaluronic acid, alginate, chitosan, and keratin, which possess high hydrophilicity and natural biological activity, demonstrate the ability to stimulate cell migration and angiogenesis while promoting wound healing.^67–70 Furthermore, synthetic polymers like polyvinyl-pyrrolidone are widely utilized in novel dressing drugs because they can gradually release NO at the wound site for accelerated healing.⁷¹ Although these biomaterials and polymers are diverse and inexpensive, none of them have presently produced the most effective wound-healing results in diabetes patients. Hence, the integration of bio-materials with other therapeutic engineering approaches is of utmost importance.

In recent years, as an emerging nanomaterial, metal–organic frameworks (MOFs) have gained significant attention for wound healing applications.⁷² This class of materials are coordination compounds consisting of metal centers and organic ligands as linkers with a homogeneous and relatively stable pore structure that can be loaded with drug molecules or therapeutic gas molecules to promote wound healing mainly by conversion of macrophage M1 to macrophage M2, pro-angiogenic factor production, epithelial tissue migration and antibacterial pathways (Fig. 3b).^73–76 Because of their ability to release metal ions for wound healing and having abundant organic or inorganic binding sites, this class of materials is often combined with various biomaterials or drugs to enhance therapeutic effects.⁷⁷ These materials can shorten the healing period and reduce the patient's pain compared to conventional treatment methods. Additionally, the cost of therapy is comparatively lower than that of sophisticated, intricate technological assistance and bio-engineering approaches, hence alleviating the financial strain on patients.

The peculiar features associated with metal–organic formulations include density, melting point, and tensile strength. Also, their efficacy depends on the route of administration, viz., oral, injection, transdermal absorption, or topical administration.⁷⁸ Meng and co-workers prepared an oral formulation by wrapping SiRNA-loaded MOF nanoparticles in sodium alginate to promote the integrity and bioavailability of the genetic drug at the site of inflammation in the colon. Using the dynamic light scattering (DLS) method, they detected the average size of these drug particles to be about 117.7 nm and 127.2 nm, respectively.⁷⁹ Meanwhile, the MOF-based local venous injection for tumors developed by Wang et al. was characterized by TEM and SEM that evinced a particle size of ∼60 nm. Also, it was noticed that there was a considerable gap between the particles of MOFs in the oral and vascular drug delivery routes, which also exhibited the flexible modulation of MOF particle size.⁸⁰ In addition, researchers in related fields give priority to adapting preparation methods according to different applications in order to produce materials with diverse particle sizes for MOFs.

MOF materials have the advantage of significantly reducing toxic side effects compared to conventional single materials and are more effective in treatment than single organic materials. Nevertheless, further research and development are required to overcome the obstacles posed by complex factors such as drug-carrying capacity, therapeutic efficacy, preparation cost, and potential toxicity of MOF particles in a complex body fluid environment. These factors currently hinder the application of synergistic therapeutic approaches or higher bioavailability to accelerate the healing of diabetic wounds.⁸¹

3. Biological applications of MOFs and functional MOF-based composites for promoting wound healing in diabetes

The MOFs' intriguing structural designability and versatile functioning may result in synergistic effects with the medications, assisting in their potential to heal various wounds.⁷⁹ Because of their greater drug loading, surface tuning property for targeted delivery, controlled release of the wound healing agents, lower toxicity, and inherent angiogenic and antibacterial qualities compared to other nanomaterials, MOFs, therefore, can be employed extensively for wound healing.

MOF-based materials are engendered by combining rationally selected metals that coordinate with targeted organic ligands and induce multi-faceted properties in the resulting materials. Moreover, surface engineering techniques can further enhance MOFs' capacity for wound healing. It is important to note that MOFs with free functional groups on their surfaces provide opportunities for surface functionalization or engineering. Surface-engineered MOFs offer a range of distinct features, such as the ability to control the release of their contents, targeted delivery, enhanced stability, and additional biochemical properties.

Also, through surface engineering, various functional biological molecules may be chemically or physically attached/adsorbed on the surfaces of MOFs, resulting in synergistic properties.⁸² Moreover, MOFs with surface engineering have better-sustained release properties, effectively sustaining the therapeutic concentration of their loaded pharmaceuticals for an extended time-period.⁸³ Additionally, when employed as structural building blocks in MOFs, certain metal centers, viz., zinc and copper, aid in wound healing of infectious wounds due to their natural antibacterial properties against S. aureus and E. coli, thereby leading to effective and rapid wound healing.

Similarly, MOF-based wound dressings accelerate wound healing because of their antibacterial properties and anti-inflammatory features, encouraging cell proliferation, angiogenesis, and collagen deposition. In the next section, some applications of the wound healing of MOF-based materials wherein they act by releasing metal ions with antibacterial properties, catalyzing bioenzyme-like reactions, delivering bioactive drugs, and mediating photodynamic therapy (PDT) and photothermal therapy (PTT), which exerts potent antibacterial and angiogenic functions, have been discussed.

3.1. MOF materials release antibacterial metal ions to promote wound repair

Metal nanoparticles are formed from metals and alloys with diameters between 5 and 10 nm and are characterized by higher energy, large surface area, and good grain boundary ratio. Medical research indicated that some metal nanoparticles, such as copper, gold, and magnesium nanoparticles, have many advantages in promoting wound healing.^84–87 First, they promote fibroblasts to differentiate between myofibroblasts and angiogenesis, and second, they have good antimicrobial properties. Although, in recent years, metal nanoparticles have achieved good results in the medical field, they have been associated with potentially toxic side effects and low water stability.⁸⁴

Investigators have prepared composite materials by combining biopolymers and metal nanoparticles, which have successfully improved the stability of metal nanoparticles in biological body fluids.⁸⁸ On this basis, metal–organic framework porous composites are now gaining significant attention. This is due to their better biocompatibility and targeted and controlled release of metal ions by MOF materials, effectively reducing wound healing time and promoting healing efficacy. In addition, studies indicated that the toxic effects of metal ions in wounds are related to the rate and concentration of their release. MOFs can be modified with surface coatings to enhance their stability and tune the release of metal ions. Xiao et al. used the copper-based MOF material HKUST-1 with the organic liquid PPCN (polyethyleneglycol citrate-co-N-isopropyl acrylamide) that engendered a hydrogel (H-HKUST-1) to enhance diabetic wound healing.¹⁷ By testing the toxicity of copper sulfate, H-CuSO₄, HKUST-1 NPs, and H-HKUST-1 NPs on human epithelial keratin-forming cells (HEKa) and human dermal fibroblasts (HDF), H-HKUST-1 was found to be the least toxic towards HEKa and HDF. This may be because the material induced a sustained release of copper ions through the interaction of PPCN and HKUST-1 and maintained thermal response and antioxidant properties (Fig. 5b). Xiao et al. also reported the use of folic acid (vitamin B9) as a HKUST-1 NP stabilizer in protein solutions to synthesize a copper-based MOF material (F-HKUST-1) containing a folic acid coating.⁸⁸ Similarly, comparative experiments showed that F-HKUST-1 was less toxic than HKUST-1, slowed the rate of release of copper ions, enhanced cell migration in vitro, and significantly accelerated diabetic mice wound healing (Fig. 5a).

Fig. 5. (a) The evaluation of body weight and dermal wound healing in diabetic mice administered F-HKUST-1. (i) Photographs of wounds treated with F-HKUST-1, folic acid, HKUST-1, or PBS. (ii) Quantification of the closed wound area (* refers to the wound treated with PBS). (ii) Body weight variations in mice throughout time (n = 6, * p < 0.05, ** p 0.01 vs. day 0). Reproduced with permission⁸⁹ ACS Nano, 2018. (b) Characterization of H-HKUST-1. (i) SEM photograph of H-HKUST-1. White arrows are pointed toward HKUST-1 NPs (scale bar: 500 nm). (ii) Cu-release from H-HKUST-1 and H-CuSO₄ in PBS or 10% FBS. (iii) Rheological studies on PPCN, H-HKUST-1, and H-CuSO₄. For the related hydrogel samples, the storage modulus G′ and loss modulus G′′ were plotted logarithmically versus temperature (20–40 °C at 10 Hz). (iv) At 22 °C, digital pictures of PPCN, H-CuSO₄, and H-HKUST-1. Reproduced with permission¹⁷ Wiley, 2017.

In addition to surface modification of the coating to control the release rate of metal ions, the morphological dimensions of MOF materials can be controlled by changing the synthesis conditions, which in turn affects the specific surface area, reactivity, and permeability, thereby leading to changes in the properties of MOF materials in accelerating wound healing. Cobalt nanoparticles and copper nanoparticles are also valuable in accelerating wound healing. This is because Co²⁺ significantly increases the gene expression of VEGF and the level of HIF-1α in osteoblasts, stimulating the proliferation of endothelial cells, tubule formation, and production of VEGF.⁹⁰ Chen et al. explored the role of Co²⁺ released from ZIF-67 NPs in accelerating diabetic wound healing by ZIF-67 NPs, wherein the Co-based MOF was synthesized from Co²⁺ and a dimethylimidazole ligand. These were prepared by varying the cetyltrimethylammonium bromide (CTAB) concentration that was added to synthesize nanospheres with different particle size distributions in ZIF-67 nano-composites (NC). Also, dodecahedral ZIF-67 NC was prepared by adding CATB-free methanol during synthesis.¹⁹ The results showed that the smallest particle size, ZIF-67 NC (with a particle size distribution of 96.18 ± 3.71 nm), offered the strongest antimicrobial activity, while dodecahedron ZIF-67 NC exhibited poor antimicrobial activity and biocompatibility. It was demonstrated that with the decrease in nanoparticle size, the specific surface area of nanoparticles increases, which led to increase in the number of reaction sites, eventually leading to an increase in bioactivity. In this study, the effect of Co²⁺ on accelerating diabetic wound healing was promoted by a relatively simple and effective preparation method in terms of altering the morphology of MOF particles. However, few drug-loading systems or other biomedical materials have been developed on this basis, and further design and investigation are required to improve the storage stability of these materials. Different types of metal nanoparticles possess different properties in wound healing. Mg²⁺ has been found to reduce the inflammatory response and promote angiogenesis in wounds, and it has lower toxic effects than Cu²⁺.⁹¹ At the same time, several studies have shown that Ag⁺ has strong antimicrobial activity compared to most other types of metal ions and is now widely used in wound or tumour inhibition applications in combination with other biocomposites.⁹² Combining metal ions with different effects could be expected to shorten the healing period and reduce the infection rate of diabetic wounds. Yin and co-workers combined the effects of Mg²⁺ and Ag⁺ by using Mg-based MOF and silver-based biomaterials employing a two-step template replication method that yielded a soluble microneedle patch (MN).²⁰ The MN was produced by first adding a γ-PGA hydrogel loaded with Mg-MOF and gallnut composites to the tip of a polydimethylsiloxane (PDMS) mould, then adding a γ-PGA hydrogel loaded with a silver-based graphene composite to the bottom of a PSMS feeler. In this microneedle patch, the tip was used to release magnesium ions.

The magnesium-based material formed a pointed cone, while the underlying silver-based material acted as a bacterial growth inhibitor and support. Immersion of MN in phosphate-buffered saline (PBS) and monitoring the absorbance of the supernatant at 260 nm revealed an excellent rate of Mg²⁺ release with the additional ability of sustained release. Antimicrobial and micro-angiogenesis studies have also shown that the bi-metals do not inhibit each other and can act as multifunctional synergistic therapeutics. Most importantly, the sub-cutaneous delivery of the material in the form of a microneedle patch reduces the potential for accumulation of toxicity in vivo and enhances the effectiveness of local administration. To replace relatively expensive silver-based materials, Yang's team chose the most classical zinc-based ZIF-8 and doped iron ions loaded with microneedle paste to synergize the treatment of diabetics.¹⁸ They first obtained Fe-doped ZIF-8 particles coated with GO_x, then surface-etched with tannic acid (TA) to produce GO_x@Fe-ZIF-TA NPs with layered pore structure, and prepared a novel microneedle paste by micro-molding technology. They demonstrated by electron tomography and fluorescence imaging that the microneedle patch exhibited homogeneous structure with a uniformly dispersed MOF at the tip of the needle, and as shown by animal experiments that the microneedle patch also had a distinct antibacterial and epithelial cell proliferation function (Fig. 6).

Fig. 6. Production of porous glucose-responsive antibacterial GOx@Fe-ZIF-TA and the entry of MOF-based MN into diabetic wounds infected with bacteria to release antibacterial particles for treating diabetic wounds. Reproduced with permission,¹⁸ Royal Society of Chemistry, 2022.

However, the disadvantage of these materials is that they are still in the animal testing stage, clinical trial data are less, and other unknown adverse reactions have yet to be discovered. For example, some patients with potential metal allergies may face difficulties with these materials, so additional adjuvants may be needed to reduce irritation.

3.2. MOF based nanozymes for exerting antioxidant and antibacterial effects to promote diabetic wound healing

In the past decade, nanozymes have rapidly developed and are still gaining attention due to their peculiar enzymatic features, low cost, high stability, and easy storage. Nanozymes are functional nanomaterials with catalytic activity similar to natural enzymes.^93,94 MOF-based catalysts are mainly based on their simulated activities of peroxidase (POD), oxidase (OXD), and superoxide dismutase (SOD) to eliminate the overproduction of ROS (secondary to the biological load of wound bacteria), which is beneficial to promote diabetic wound healing. Despite the essential need for ROS for the initial steps of wound healing, the imbalance in ROS production is detrimental in the later stages of wound healing. In addition to eliminating ROS to promote diabetic wound healing, monoatomic catalysts, which are based on MOF materials, can also be used to promote diabetic wound healing. In addition, nanozymes also exhibit certain antibacterial activity and significantly promote wound healing.⁹⁵

In the study by Chen et al. niacin-based MOF microcapsules were in situ generated via microfluidic electrospray with a sodium alginate shell and copper-/zinc-niacin framework cores for wound healing (Fig. 7a).²¹ The niacin MOFs had excellent angiogenesis, antioxidant, and antibacterial features. These MOF encased microcapsules may release Ca(ii), Cu(ii), and Zn(ii) ions in a controlled, intelligent, and programmable manner, depending on the severity of the infection. This release is triggered by the degradation of the alginate shells in response to bacteria. The discharged ions killed contagious microorganisms by rupturing their membranes thereby causing nutrient outflow. They also activated copper-/zinc-superoxide dismutase (Cu/Zn-SOD), which removed oxygen-free radicals and protected the cells from oxidative stress. When the fibroblasts came into contact with hydrogen peroxide, they were still able to maintain excellent cell viability. Thus, Cu/Zn-SOD acts as the primary oxygen free radicals' natural enemy due to eliminating oxygen free radicals, blocking oxygen free radicals that damage cells, and repairing damaged cells in time. Moreover, the simultaneous release of niacin enhanced hemangiectasis with simultaneous absorption of functional metal ions. Further, based on the in vivo studies, the niacin MOF microcapsule therapeutic agent critically improved the chronic wound healing process in infected full-thickness skin defect models.

Fig. 7. (a) The fabrication of the niacin MOF encapsulated microcapsules with a sodium alginate shell and copper/zinc nicotinic acid framework core by a microfluidic electrospray method and their use for chronic wound healing. Reproduced with permission,²¹ Science Partner Journals, 2019. (b) Ce@LTA-NP loaded Pluronic F127- CS hydrogel composite (Ce@LTA-NPs-F127/CS hydrogel) was designed as a multi-target combination therapy for healing of diabetic wound. *p < 0.05, **p < 0.01, ***p < 0.001. Reproduced with permission.²² Springer, 2021.

Qi et al. created a reversible hydrogel made of Pluronic F127 and chitosan (CS) to encapsulate Ce-doped linde type A (LTA) zeolite-based NPs (Ce@LTA-NPs). This hydrogel serves as a multi-targeted combination therapy for treating diabetic wound. The therapy takes into account the potential impact of bacterial infections, oxidative stress, and chronic inflammation on the regulation of diabetic wound healing.^96,97 Furthermore, it was shown that Ce@LTA-NPs exhibit robust biocompatibility and have the ability to effectively adsorb harmful substances, making them very promising for medical applications.⁹⁸Fig. 7b illustrates that Ce@LTA-NPs exhibited a unique adsorption capacity due to their regular and uniform pore structure and unique 3D architecture. They can absorb intense inflammatory factors (TNF-α, IL-6) induced by acute inflammation in diabetic wounds to neutralize harmful factors, speed up the transition from inflammation to proliferation, and remodel the wound microenvironment.²² However, Ce³⁺/Ce⁴⁺ doping of Ce@LTA-NPs replicates the catalytic functions of catalase (CAT) and superoxide dismutase (SOD), removing free radicals, including those brought on by hyperglycemia and controlling the oxidative state in the wound site's microenvironment. Further, Ce@LTA-NPs may also target mitochondria and treat hyperglycemia-related mitochondrial dysfunctions. The temperature-sensitive, biocompatible, antibacterial F127/CS hydrogels may be loaded with Ce@LTA-NP nano-biomaterials and then can be applied to the diabetic wound surface. The angiogenesis, migration, and proliferation of HG-HUVECs were all markedly enhanced by Ce@LTA-NPs.^94–96 The Ce@LTA-NPs-F127/CS hydrogels also accelerated the healing of diabetic wounds by promoting the production of granulation tissue, re-epithelialization, and collagen remodeling at the wound site, as demonstrated by in vivo investigations. The findings suggest that Ce@LTA-NPs-F127/CS hydrogels have the potential to be a valuable option for completely repairing diabetic wound damage in clinics.

3.3. MOF-mediated gas and drug delivery for diabetic wound repair

3.3.1. Gas molecular NO transport systems

Nitric oxide (NO) can regulate inflammatory responses, proliferation of cells, formation of collagen, antimicrobial action, and angiogenesis during various wound healing processes.^99,100 It can be produced in vivo in biochemical reactions catalysed by enzymes such as l-arginine.¹⁰¹ Increasing the endogenous synthesis of NO and providing exogenous NO donors are the two main routes of NO therapy (Fig. 8a). However, studies have shown that NO as a regulatory factor is strongly dependent on its release concentration; when the release concentration is less than 400 nM, NO inhibits apoptosis and promotes cell proliferation; when the release concentration is greater than 400 nM, NO blocks the cell growth cycle leading to apoptosis and increases the severity of the wound.¹⁰² Therefore, controlling the concentration of NO released by the organism is crucial. Furthermore, NO has been extensively researched, surpassing other gases in terms of study. It has superior healing qualities for diabetic wounds, which are absent in other gases such as hydrogen sulfide.

Fig. 8. (a) Pictures showing how nitric oxide (NO) is produced and used by the body naturally, how it solidifies to form different NO donors and NO prodrugs, how both organic and inorganic biomaterials carry NO donors, and how NO-loading biomaterials are used to treat wounds. Reproduced with permission,¹⁰¹ Royal Society of Chemistry, 2021. (b–d) Scheme showing the preparation of (b) NO@HKUST-1 and (c) NO@HKUST-1/PCL/gel (NO@HPG) scaffolds for healing of diabetic wounds. Reproduced with permission,²⁵ ACS Publication, 2020. (e) Diagrammatic representation of the porous MOF MN array's production and use. (f) Schematic representation of the NHG-MN patch preparation procedure; images of (i) the NHG-MN and (ii) its amplified needle-tips; (iii) SEM images of the porous MN patch; (iv) SEM images showing porous channels distributed over the porous MN patch. Reproduced with permission,²⁶ National Library of Medicine, 2022.

Due to their special and homogeneous pore structure, MOF materials exhibit good gas storage and release properties. Therefore, MOFs have immense application prospects as natural gas NO delivery carriers in promoting wound healing in diabetics. Amongst them, copper-based MOF materials (CMD) release copper ions that facilitate endogenous nitrous oxide synthesis by reducing nitrite to nitrous oxide in the presence of glucose, thereby enhancing the endogenous synthesis of NO.¹⁰³ Zhao and co-workers coated Cu-based MOF CuBTC (Cu(ii)benzene-1,3,5-tricarboxylate) on the surface of Ti-metal to form a SURMOF coating that steadily degraded to release copper ions.²³ Studies assessing the release behavior of copper ions and NO showed that the concentrations of both substances were within the normal range and effectively promoted vascular proliferation and wound re-epithelialization. However, the overall structure of the material was less stable, and there was a potential risk of significant NO release. To reduce this risk, Neufeld et al. combined a relatively hydrostable Cu-based MOF (Cu-BTTri, H₃BTTri = 1,3,5-tris[1H-1,2,3-triazol-5-yl]benzene) with a hydrophilic membrane made from polyvinyl alcohol to obtain the Cu-BTTri/PVA membrane.²⁴ The membrane application was assessed in an intravenous model that effectively induced NO production by GSNO (S-nitrosoglutathione) and inhibited thrombosis. Furthermore, the hydrostability of the material was comparatively greater when the stent was loaded onto the MOF material.

Due to differences in body composition, delivering exogenous NO donors is more effective than promoting endogenous NO synthesis. Electrostatically spun fiber scaffolds show similar promise for gas storage and release, which can release both NO donor molecules and metal ions that promote endogenous NO synthesis and provide a synergistic therapeutic boost. Zhang et al. used a copper-based metal–organic framework HKUST-1 as a NO loading carrier. They prepared a NO retardation system with a core–shell layer structure by the electrostatic spinning technique.²⁵ When the released NO was converted into nitrites and stabilized in solution, dinitrogen can render the solution purple with a Griess reagent. Therefore, this experiment used the Griess method to evaluate the NO release behavior of NO@HKUST-1 with and without electrostatically spun fibers. It was observed that the former exhibited a more stable NO release rate and sustained release of copper ions. In addition, HKUST-1 loaded with NO molecules could be converted into MOF microneedle patches, which then released NO molecules through a photothermal reaction (Fig. 8b–d). Yao and co-workers used graphene (GO) encapsulated on the surface layer of HKUST-1, followed by post-synthesis adsorption and array molding to produce NHGs microneedle patches (Fig. 8e and f).²⁶ The material increased the surface area of the wound in contact with the therapeutic gas NO and sped up the healing of chronic wounds. These two NO delivery-based synergistic therapies are very promising, but the clinical data of similar studies are still scanty.

3.3.2. Drug molecular delivery systems

Metal–organic frameworks not only absorb, store, and release nitric oxide gas to enhance wound healing in individuals with diabetes, but they also function as reliable transporters of negative ions for drug molecules. This improves the stability and compatibility of certain drugs that aid in the healing of wounds in diabetic patients. Because diabetic wounds have a lengthy healing process, the patient may experience further harm from repeated changes of dressings or injections containing medication. Further, most drugs that enhance diabetic wound healing have low stability and biocompatibility. Therefore, developing a nanoplatform for stable loading and slow release of drug molecules is expected to improve the shortcomings in drug therapy.

Novel nanomedicine loading platforms are designed not only to explore the improvement in drug performance but also to be closely integrated with the pathologic features or pathologic signaling pathways of diabetic wounds to improve their efficacy significantly. Because of this, α-lipoic acid (LA) as a lipophilic antioxidant was applied for loading drug, which was encapsulated in K-γ-cyclodextrin (CD)-MOFs (with hydrophobic cavities) and mixed into a hydrogel system scaffolded by chitosan and hyaluronic acid.²⁷ This confirmed the steady release of LA into the wound surface via K-γ-CD-MOF pores in a hydrogel system for scavenging ROS to decrease apoptosis. In addition, the autonomous degradation of the modified material over the wound surface produced non-toxic degradation products. For signaling pathways, the FZ (4-chloro-N-cyclohexyl-N-(phenylmethyl)-benzamide)@ZIF-67 NPs developed by Sun et al. not only released cobalt ions to promote angiogenesis but also inhibited the pathway of M2 macrophage polarisation by releasing the receptor FZ for advanced glycation end-product (RAGE) inhibitors. This inhibited the expression of inflammatory factors to promote wound re-epithelialization and neoangiogenesis (Fig. 9).²⁸ The material was synthesized using a simple one-pot method and offered significant efficacy. In addition, Demyanenko et al. showed that a platelet quinone derivative that binds to lipophilic cationic covalent substance (SkQ) mitochondria-targeted antioxidants, when taken orally, can treat wounds and inflammation in diabetic mice, which is promising for the treatment of diabetic wounds. However, whether the MOF can effectively encapsulate SkQ and facilitate its aggregation and cell penetration in wounds deserves further investigation.¹⁰⁴ Overall, it is also essential to consider synthetic strategies and costs when developing drug delivery systems for wound pathology and signaling pathways in patients with diabetes.

Fig. 9. (a) Synthetic scheme for ZIF-67 and FZ@ZIF-67 NPs and their respective SEM images, respectively; (b) scheme showing the delivery of Co²⁺ ions by FZ@ZIF-67 NPs for enhancing angiogenesis via activation of HIF-1α; (c) representation of diabetic cutaneous wounds after 0, 3, 7, 10, and 14 days of surgery. Scale bar: 1 cm; (d) presentation of wound closure rate in each group at different time intervals. *, p < 0.05 compared with the GelMA group, **, p < 0.01 compared with the GelMA group; #, p < 0.05 compared with the Gel-ZIF group, ##, p < 0.01 compared with the Gel-ZIF group. Reproduced with permission,²⁸ Springer, 2022.

Because of the excellent extracellular matrix and porous structure of electrostatically spun fibers (ESFs), novel electrostatic spun nano-fiber-coated MOFs presented great potential drug delivery features.¹⁰⁵ A synergized and promoted healing of diabetic patients' wounds was achieved by electrostatically spun fibers with MOF drug-carrying platforms because of the simultaneous release of metal nanoparticles and therapeutic drug molecules. The impregnation-prepared DMOG (dimethylacetylglycine)@ZIF-67 NPs (DMOG@ZIF-67 NPs) were added to the electrostatically spun nano-fibers composed of poly(l-lactic acid) (PLLA) and gelatine precursors, to synthesize porous fibrous materials with the assistance of an electrostatic spinning machine.²⁹ A drug loading capacity of up to 359.12 mg g⁻¹ was obtained for DMOG@ZIF-67 NPs in which the DMOG drug molecule and the Co²⁺ ions could be continuously released in the electrospun fiber scaffold for more than fifteen days. The electrospun fiber scaffold critically increased angiogenesis, collagen deposition, and inflammatory response in the trabeculae via the stable drug and metal ions release, thereby synergistically stabilizing HIF-1α and upregulating angiogenesis-related gene expression. Similarly, Zhang and co-workers reported the synthesis of CD@Cu-MOF NPs by the reaction of H₃BTC precursor Cu-ionic solution with prepared CDs (carbon points) at high temperature and pressure and then synthesizing GOx/CDs@MOF NPs by physical adsorption of encased glucosease (Fig. 10). For daily use, NFs were prepared by mixing GOx/CDs@MOF NPs with the spinning solution polyvinyl butyrate (PVB) and injected into the nozzle needle of a hand-held electrospinning machine. For the first time, this design improved the single function of conventional NFs and the reserve function of conventional MOF-NFs. The storage cost of MOF-NFs was significantly reduced by making MOF-based NPs into freeze-dried powder and using it on the go.³⁰

Fig. 10. Illustration of GOx/CDs@MOF NF dressing for visual monitoring and antibacterial treating of diabetic-infected wounds. Reproduced with permission,³⁰ ACS Publications, 2023.

In addition to the promising application of electrospun fiber scaffolding, scaffolding promotes the skin tissue cell's adhesion and growth. The steady release of the MOF material and the absorption of pus and other materials in the wound in time can be done due to the homogeneous pore structure to alleviate the patient's pain. Nevertheless, the cost of using an electrostatically spun fibre nano-MOF for drug administration is high, because of its more stringent preparation requirements compared to hydrogel systems. However, it is necessary to provide more economical and efficient alternatives for this system.¹⁰⁵

3.4. Photo stimulating MOF porphyrin nanoparticle mediated photodynamic therapy and photothermal therapy

Capillary damage in diabetic wounds reduces oxygen flow and immunity, exacerbates bacterial infections, and causes local inflammation. A high ROS of immune cells produced in wounds activates nuclear factor kappa B. It dramatically enhances the production of interleukin-6 (IL-6) inflammatory mediators and tumor necrosis factor-alpha, finally causing chronic inflammation. Otherwise, inadequate angiogenesis and bacterial infections of the skin or limbus may produce hypoxia and impede wound healing.^106–108 In addition, protracted wound healing, inadequate immunity, and a hyperglycemic condition render wounds more prone to infection.¹⁰⁹ As a result, it is critical to visualize real-time bacterial infections based on microenvironment changes once infection begins and destroy bacteria and reduce inflammation simultaneously.

Additionally, bacterial biofilm development and oxidative stress-induced tissue damage can be prevented by rapid sterilization. Photodynamic therapy (PDT) creates ROS using photosensitizers (PSs) and suitable excitation sources. ROS can kill bacteria and other disease-causing microbes through oxidative damage and degradation of surrounding biomolecules.¹¹⁰ To combat multidrug-resistant bacteria (MDRA), researchers looked at the combination of PS-MOFs and PDT since it has the lowest chance of drug resistance and the fewest possible safety issues.^111,112 When PSs are added to MOFs as ligands instead of individual porphyrin ligands, MOFs acquire additional characteristics, such as strong reactions to visible light and relatively significant ROS yields, in addition to limiting PSs' self-quenching phenomenon. The foundation of antibacterial photodynamic treatment (APDT) uses PSs to generate ROS when exposed to the correct amount of light. The resultant ROS interacts with several biological substrates, including proteins, lipids, DNA, and RNA, chemically altering their structures, which impairs bacterial function and ultimately leads to bacterial death.^113,114

Currently, most materials used for wound repair are passive and unable to react to the wound microenvironment, which leads to a limited use of bioactive chemicals and a poor therapeutic impact. Hence, Zhu and colleagues have designed an intelligent wound dressing that is sensitive to the wound microenvironment, intending to repair extremely complicated diabetic wounds that are linked to persistent inflammation and resistant bacterial infection.³¹ In their work, they used Cu-loaded polydopamine NPs (CuPDA NPs) and hyaluronic acid modified by phenyl boronated acid (HA-PBA) bonded dynamically to produce the metformin-laden CuPDA NP composite hydrogel (Met@CuPDANPs/HG), which demonstrated good injectability, self-healing, adhesive, and DPPH scavenging performance. Metformin was released slowly due to interactions with CuPDA NPs, boric groups (B–N coordination), and hydrogel network restriction. Metformin has a pH and glucose-sensitive release behavior that allows it to address various wound microenvironments intelligently. Furthermore, CuPDA NPs supplied the hydrogel with outstanding photothermal responsiveness, killing bacteria at a rate of >95% after 10 min and slowing the release of Cu²⁺ to protect the site from infection for an extended period. Met@CuPDA NPs/HG also stimulated vascularization by recruiting cells in a certain direction. More significantly, by ROS removing and preventing the NF-κB activating pathway, Met@CuPDA NPs/HG significantly decreased inflammation. Further, experiments on animals showed that by eliminating germs, reducing inflammation, enhancing angiogenesis, and quickening the deposition of collagen and extracellular matrix (ECM), Met@CuPDA NPs/HG dramatically accelerated wound healing in diabetic SD rats. Met@CuPDA NPs/HG thus has much practical potential for diabetic wound healing.

In PDT, bacterial cells can be oxidized and destroyed by ROS formed by photosensitizers under illumination.¹¹⁵ However, bacterial death usually necessitates a high concentration of ROS, which also permanently oxidizes tissue cells.¹¹⁶ More significantly, investigations have demonstrated that when combined with PDT, the therapeutic efficacy is significantly enhanced which successfully prevents wound infections and lessens harmful effects in milder cases than monotherapy, which has various side effects.¹¹⁷

A photo-initiated physical/chemical double cross-linked injectable hydrogel (HA-DA/Fe³⁺/PCN@BP) was described by Zhang et al.³² in which they firstly employed an amidation process to prepare hyaluronic acid-grafted dopamine (HA-DA). Subsequently, they loaded a commonly used nanoscale MOF photosensitizer, PCN-224, based on zirconium on the black phosphorous (BP) nanosheet surface to create PCN@BP, a nanomaterial with outstanding PDT and PTT effectiveness. A physically cross-linked hydrogel was created by combining HA-DA with PCN@BP and FeCl₃ because of the strong complexation and electrostatic contact between carboxylate, catechol, and Fe³⁺. The remarkable injectability of the hydrogel and its self-healing qualities stem from the reversible nature of dynamic non-covalent connections. Further, to encourage tissue penetration and UV light biocompatibility, the hydrogel was locally injected into the wound area and then exposed to a 660 nm laser. This caused PCN@BP to generate ROS, which resulted in the oxidative polymerization of DA and the introduction of chemical crosslinks into the hydrogel. They overcame the constraints of poor stability and insufficient mechanical strength. More crucially, by altering the lighting switch and duration, the degree of DA oxidative coupling could be accurately adjusted in time and place, making the in situ mechanical characteristics of the hydrogel tuneable. Furthermore, the residual ROS and low PTT (below 50 °C) prevented bacterial infection. When exposed to both 660 and 808 nm light, the bacterial membranes in the hydrogel + laser group underwent significant changes. They became distorted, wrinkled, and in some cases, even torn, leading to the leakage of their contents. The fact that the PTDT group suffered the greatest damage indicates how well PTT and PDT combined may kill bacteria and reactive oxygen species at comparatively low temperatures. Live/dead cell staining was used to further identify the NIH 3T3 cells' proliferation at 1, 3, and 5 days. The HA-DA/Fe³⁺/PCN@BP hydrogel facilitated cell growth, as evidenced by the increasing green fluorescence (living cells) and nearly imperceptible red fluorescence (dead cells) with increasing culture time. The in vitro series of experiments have shown that the hydrogel HA-Da/Fe³⁺/PCN@BP possesses biocompatibility, excellent tissue adhesion, antibacterial activity, and various mechanical characteristics that may be adjusted to encourage cell migration and proliferation.

Antibiotic treatments can also cause extremely severe bacterial resistance, making it harder to use the medications and treatment options already existing in the market. To efficiently remove drug-resistant microorganisms, new tactics must be developed. Chlorin e6 (Ce6) loaded Prussian blue nanoparticles (PB NPs) have been described by Tong et al. as a combinational technique for the eradication of drug-resistant bacteria (Fig. 11a).³³ These nanocomplexes displayed strong catalase activity and photodynamic properties, and in vitro, tests revealed that CPB–Ce6 NPs efficiently killed MRSA by producing ROS when exposed to laser light. In the meantime, the bacterial microenvironment's H₂O₂ can be broken down by the CPB NPs' nano-enzyme activity to increase the amount of O₂, which reduces hypoxia and strengthens PDT's antibacterial action. Through the upregulation of VEGF, in vivo results showed that CPB–Ce6 NPs with laser irradiation successfully eliminated MRSA and accelerated infected wound regeneration in both normal and diabetic mice (Fig. 11b). Additionally, CPB–Ce6 NPs demonstrated a superior biosafety profile under in vivo and in vitro conditions. Therefore, this PDT based on PB NPs with nano-enzyme activity could offer a successful therapy for infections linked to microorganisms resistant to drugs and tissue regeneration.

Fig. 11. (a) Schematic presentation of CPB–Ce6 NP preparation and their antibacterial pathway in vivo antibacterial therapy and healing of wound. (b) Pathology images for infected wound tissue. (i) Images of infected wound sections in H&E and Masson's stain. (ii) VEGF immunofluorescence images for wound tissue (blue, nucleus; red, VEGF). Reproduced with permission,³³ Royal Society of Chemistry, 2023.

4. Conclusions, challenges and prospects

The vast cellular diversity, complexity, and adaptability of diabetic wound healing pose a hurdle in understanding the healing mechanism completely. In short, both MOFs and functionally modified MOF matrix composites have certain advantages. MOF-based multifunctional biomaterials are paving the way for clinical treatment options for healing diabetic wounds. Investigations on managing the in vivo stability of MOFs and the biosafety of artificial materials, particularly long-term toxicity in vivo, have made significant strides in MOF design and synthesis. MOFs readily break down under complicated physiological settings; hence, adjusting MOF stability based on real needs is critical. A key issue in practical applications is achieving the targeted medication delivery and accurate release. Few reports have reported using MOFs as a medication carrier material for wound healing. This is because ideal drug carrier materials require a clear and stable structure and a high drug loading, which will be reasonably achieved by suitable particle size distribution. Furthermore, most MOF systems exhibit some degree of drug leakage during drug delivery, resulting in decreased effectiveness. Given the toxicity and instability of the MOFs used in the process, selecting more non-toxic and physiologically stable MOFs is crucial to provide a safe procedure.

The significance of MOF biomaterials has been extensively demonstrated due to the current emphasis on their production and customisation. Additionally, MOFs possess the ability to gradually degrade and release antibacterial metal ions, which can greatly enhance wound healing and regeneration. Additionally, the impressive catalytic capabilities of MOFs (acting as nano-cases) can enhance the control of oxidative stress and immune microenvironment in diabetic wounds. Furthermore, MOFs have the potential to facilitate the gradual release of medications (both molecular and gaseous therapeutics) in diabetic wounds. This can aid in the healing process by controlling the abnormal signalling pathways within the wound microenvironments or suppressing the production of inflammatory substances. However, there are certain unresolved matters that need to be addressed before they can be successfully applied in clinical practice. In the future, the use of MOFs and functionally modified MOF matrix composites will greatly enhance the potential treatment options for diabetic wound infections.

Author contributions

Y. Q., writing – original draft, Y. Zeng, writing – original draft, J. Zou: methodology, investigation, visualization, writing – original draft. J. Liu: investigation and resources. X. Liu, supervision: A. Kumar, supervision, A. Nezamzadeh-Ejhieh: editing, and, Y. Pan, E. Deng, X. Liu: supervision, writing – review and editing. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

The authors declare no conflicts of interest.