Application of metal–organic frameworks in stomatology

The development of biotechnology and related novel biomaterials is a major driver of research and clinical innovation in contemporary stomatology.^1–3 The use of nanomaterials in stomatology is growing in scope because of ongoing advancements in nanoscience.^4,5 A wide range of nanomaterials have been created thus far for use as therapeutic and diagnostic agents, and because of their high cargo capacity, unique surface characterization, and customizable size, stomatology has advanced greatly.^6,7 For instance, composite resins that can fix dental perforations have been created using a combination of silica and zirconia nanoparticles.⁸ Bacterial cell membranes, among other things, can be destroyed by adding antimicrobial quaternary ammonium salts to the resin polymers now used to manufacture teeth.⁹ It is important to remember that medications based on nanomaterials offer several advantages over other types of pharmaceuticals. such as regulated release, improved blood circulation, and increased accumulation, all of which improve therapeutic efficacy and reduce unfavorable effects. Currently, the majority of nanomaterials can be classified as organic (polymer nanoparticles, liposomes, micelles, and dendrimers) or inorganic (metal-based, metal–oxide-based, and carbon-based nanomaterials).^10,11 However, these nanostructures have certain intrinsic drawbacks, such as the inability of inorganic materials to degrade and the low rate at which organic materials load drugs. Hybrid nanomaterials have been developed to overcome these difficulties in biological applications of pure inorganic or organic material’s biological uses.^12,13

Metal–organic frameworks (MOFs) are a class of crystalline materials with structures that are formed by the coordination of metal ions with organic groups. The fact that they combine the benefits of organic and inorganic materials is significant because they increase their suitability for biomedicine.^14,15 First, because of the relatively weak metal–ligand coordination bonds, MOFs are easier to biodegrade; second, because of their large and high porosity, goods have a higher loading efficiency; and third, MOFs can be easily modified and can be used to encapsulate or modify a variety of goods. Therefore, MOFs have attracted considerable interest in medical applications.^16,17 In addition, a growing body of research has demonstrated the great promise of MOFs materials for a range of medical applications, including drug delivery, bioimaging, cancer diagnostics, and antibacterial coating. These results may also aid in the development of new approaches for oral disease diagnosis and treatment.^18,19

Stomatology extends beyond dental concerns to encompass the comprehensive study and treatment of the entire mouth structure including the lips, cheeks, and jaws. This field addresses more intricate diseases and conditions that may necessitate medical intervention surpassing conventional dental care. With a focus on four areas of oral medicine (as illustrated in Fig. 1), this study intends to investigate the introduction of MOFs materials and their possible uses in Stomatology. These include the treatment of oral cancer, implant surface modification, antibacterial dressings, and the treatment and regeneration of periodontitis. In this paper, we present a comprehensive review of the current research progress on the properties and applications of Metal–Organic Frameworks (MOFs). We evaluate their efficacy in oral disease treatment across various research domains and analyze the potential prospects and challenges associated with their application in stomatology. Our findings aim to establish a solid foundation for the future wider and safer implementation of MOFs in the field of stomatology.

Metal–organic frameworks (MOFs) are highly ordered crystalline porous coordination polymers.^20–22 They consist of inorganic metal (such as transition and lanthanide metals) ions/clusters as nodes, which self-assemble with organic units (such as carboxylates, phosphonates, imidazolates, and phenolates) through coordination bonds to form porous materials with periodic network structure.^23,24 Their unique structural properties, such as high specific surface area, large pore size, and high porosity, make them useful in a wide range of research, including gas storage and separation,^25,26 chemical separation,^27,28 catalysis,^29,30 sensing,^31,32 semiconductors,^33,34 and bioimaging.^35,36 In addition, in recent years, MOFs have shown a wide range of applications in the field of biomedicine.^37,38 MOFs possess intrinsic biological activity by delivering specific metal ions and ligands, or catalyzing the generation of messenger molecules owing to their clear structure, ultra-high surface area and porosity, adjustable pore size, and easy chemical functionalization. Compared to polymeric structures, their pore size and porosity are significantly smaller and can be precisely controlled, making MOFs suitable for drug delivery and for sustaining or triggering the release of nanoparticles.^39–41 

Metal–organic frameworks (MOFs) have proven to be highly effective drug delivery platforms, primarily owing to their remarkable drug-loading capabilities.^42,43 Metal–organic frameworks (MOFs) have distinctive characteristics, including a well-organized structure, considerable surface area, and significant pore volume. These features facilitate the adsorption of multifunctional molecules, either on the outer surface or in the free channels of the MOFs, allowing the entrapment of these molecules within the scaffold. In addition, functional molecules can be integrated into metal–organic frameworks (MOFs) by covalent bonding using either one-pot synthesis or post-synthetic modification techniques.^44,45

The use of endogenous stimuli, such as pH, to regulate the release of substances has been extensively investigated and applied in many drug delivery systems.^46–48 The pH fluctuation at the site of inflammation, in comparison to standard physiological settings, modulates the binding process and, therefore, facilitates medication release.^49,50 The coordinating bond by which a therapeutic agent is linked or loaded into metal–organic frameworks (MOFs) typically exhibits pH sensitivity, offering a more favorable delivery platform.^51,52 In addition to pH, various stimuli including heat, light, electric and magnetic fields, and pressure have the potential to trigger changes in the physical and chemical characteristics of metal–organic frameworks (MOFs).^53,54 Certain metal–organic frameworks (MOFs) have demonstrated photocatalytic capabilities, including the ability to switch photocurrents in response to light stimulation. These alterations encompass structural modifications resulting from bond breakage, as well as changes in the coordination number and mode of the metal ions and ligands. Consequently, these modifications facilitated drug release. The controlled release of therapeutic agents by light has gained interest because of its ability to achieve precise spatial and temporal control.^55,56 In addition, pressure-responsive delivery has been explored as a means of achieving the same goal. The delivery mechanism encompasses structural modifications, including variations in resilience, crystallization, and morphology, in response to varying pressure situations.^57,58

In summary, porous materials composed of metal ions and organic units are known as metal–organic frameworks (MOFs). However, not all MOFs are inherently active. In addition, MOFs have a large surface area, are well structured, and have porosity, which helps with multifunctional molecule adsorption and release. Covalent bonding or modification procedures can be utilized to insert functional molecules into MOFs, and endogenous stimuli, including pH, heat, light, electric and magnetic fields, and pressure can be employed to control the release of chemicals. Bond breaking and modifications to the coordination number and coordination pattern of metal ions and ligands can modify the characteristics of metal–organic frameworks (MOFs) and affect drug release. As a result, MOFs have been employed as a successful drug delivery technology that permits accurate control over the timing and location of drug release.

Titanium and its alloys have been widely recognized as optimal materials for dental implants because of their exceptional mechanical strength, commendable corrosion resistance, and biocompatibility.⁵⁹ However, it is important to note that the absence of bioactivity on the surface of natural titanium implants may potentially increase the risk of infection and often lead to insufficient osseointegration. The significance of modifying implant surfaces lies in their ability to augment antibacterial activity, impede biofilm formation, mitigate peri-implant infections, boost osseointegration, and elevate the success rates of implant surgeries.^60,61

We are aware of the potent bactericidal properties of metal ions, particularly those primarily composed of silver, copper, and zinc ions. Strong ion oxidation abilities allow these metal ions to quickly combine with the sulfhydryl group of the bacterial protease in the bacterial body, inactivating the protease and ultimately causing bacterial death. These metal ions can also destroy the bacterial cell membrane and metabolic process of the cell, thereby inhibiting bacterial reproduction. In addition, when the bacteria are eliminated, the metal ions may be left free to engage in further killing of additional bacteria until all the germs have been eliminated.^62–65 

Because the metal nodes in MOFs have the ability to release metal ions as they expand, MOFs have intrinsic biological activity.^66,67 The number of metal ions released has a direct correlation with the bactericidal efficiency of the released metal ions, which have significant antibacterial effects on oral bacterial strains, such as Clostridium nucleum, Porphyromonas gingivalis, Streptococcus mutans, and Streptococcus pyogenes. Applying ZIF-8 coatings, for instance, to titanium implants can release zinc ions and have a number of associated effects, including inhibiting the growth of S. mutans.⁶⁸ It can also raise MG63 cell ALP activity, encourage mineralization of the extracellular matrix, and upregulate the expression of osteoblast genes. Furthermore, MOFs can provide long-lasting and persistent antibacterial effects by gradually releasing ions when they degrade due to their role as metal ion reservoir.^69,70

Metal ions produced by MOFs can control angiogenesis by influencing vascular endothelial growth factor, hypoxia-inducing factor, angiogenesis-related genes, endothelial cells, and macrophage immune modulation.^71–74 In addition to their strong angiogenic effects, copper, magnesium, strontium, cobalt, and other metal ions stimulate osteogenesis via angiogenesis.^75,76 For instance, the ZIF-8/Cu precursor was carefully pyrolyzed to create a CuO@ZnO composite, which was subsequently grafted onto a titanium alloy that had been treated with PDA. It is possible to deliberately release zinc (Zn²⁺) and copper (Cu²⁺) ions to cause bacteria to produce too many intracellular reactive oxygen species (ROS), which will prevent bacteria from forming biofilms. By increasing vascular endothelial growth factor (VEGF) expression, liberated Cu²⁺ ions can induce angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, the CuO@ZnO-coated titanium markedly enhanced human bone marrow mesenchymal stem cells (hBMSC) adhesion, proliferation, and osteogenesis.⁷⁷ 

In addition, MOFs can achieve antibacterial and pro-new bone-formation effects by releasing metal ions, such as magnesium, zinc, silver, and copper. They can also increase the expression of anti-inflammatory genes and inhibit the expression of pro-inflammatory genes, thereby exerting anti-inflammatory effects.^78–80 

For instance, Shen et al. fabricated Mg/Zn-MOF74 hybridized organic skeleton coatings on alkali-heat-treated titanium (AT) surfaces. The composite coatings of Mg/Zn-MOF74 exhibited excellent stability, and the modified samples demonstrated sensitivity to bacterial acidic microenvironments, displaying strong antimicrobial activity against both Escherichia coli and Staphylococcus aureus. Moreover, the coatings displayed promising early anti-inflammatory properties compared to natural Ti substrates modified which MOF74 significantly increased the expression of anti-inflammatory genes, such as IL-10 and IL-1ra, while decreasing the expression of pro-inflammatory genes, such as IL-1β and TNFα.⁸¹ 

In vivo experiments were conducted by implanting different substrates [Ti, alkali treated titanium (AT), and AT-Mg/Zn3] in the presence of Sta. aureus for three days after implantation to investigate their antibacterial and anti-inflammatory capacities. Impressions and agar plates revealed minimal bacteria on the surface of the AT-Mg/Zn3 implants, as well as in the surrounding medullary cavity. Corresponding quantitative analysis further confirmed that AT-Mg/Zn3 implants exhibited the highest bacterial inhibition rate (>90%) among the three groups (p < 99.9%). In addition, hematoxylin-eosin (HE) staining and CD68 staining images showed a higher clustering of mononuclear cells (indicated by green arrows or red fluorescent markers) around Ti and AT implants compared to the AT-Mg/Zn3 group in both the epiphysis and medullary cavity regions.

These results further validated that, during the early stages of implantation, AT-Mg/Zn3 implants possessed remarkable antibacterial and anti-inflammatory properties and significantly enhanced new bone formation at infected and non-infected sites.⁸¹ 

Interferon-gamma (IFN-γ), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) are pro-inflammatory substances released by inflammatory cells, such as neutrophils, white blood cells, and macrophages, when they congregate in the affected area during the inflammatory response. These variables impair the metabolism of the mitochondrial electron transport chain (ETC) due to the release of reactive oxygen species (ROS).^82,83

MOFs can also efficiently control inflammation by assembling compounds with antioxidant effects to offset the excess ROS produced by the inflammatory response and altering the organic ligands that coordinate with metal ions or clusters. For instance, large numbers of manganese porphyrin molecules are regularly assembled into two-dimensional manganese oxide films (2D MOFs), which exhibit unique anti-inflammatory and biomineralizing capabilities, along with SOD and catalase-like activities.⁸⁴ 

MOFs can upregulate genes related to osteogenesis, leading to an increase in the formation of mineralized nodes and the promotion of osteogenesis by accelerating extracellular matrix mineralization and protein translation. The expressions of alkaline phosphatase (ALP), collagen I (COLI), osteopontin (OPN), and osteocalcin (OCN) genes were all up-regulated after doping the Mg-MOF74 coating with suitable Zn²⁺ (especially AT-Mg/Zn3).⁸¹ Calcium–strontium metal–organic frameworks (Ca–Sr MOFs) can increase alkaline phosphatase (ALP) production. Furthermore, the concomitant release of calcium and strontium from these MOFs can generate signals that stimulate bone formation, thereby facilitating bone mineralization.⁸⁵ 

Because of their exceptional qualities, such as large porosity and high specific surface area, metal–organic frameworks (MOFs) can be employed as efficient drug transporters. These characteristics improve the biological qualities of medications and other bioactive substances by facilitating their effective transit and collection. For instance, adding zeolite imidazolidine skeleton8 containing naringenin to the titanium substrate can increase the antibacterial capabilities of the coating and dramatically boost osteoblast proliferation and osteogenic differentiation.⁸⁶ 

In conclusion, because their metal nodes discharge metal ions, metal–organic frameworks (MOFs) are intrinsically bioactive substances with potent bactericidal properties. These metal ions can bind to the bacterial protease, inactivate it, and kill bacteria. They can also damage bacterial cell membranes and metabolism, preventing bacteria from reproducing. The long-lasting antibacterial activity of MOFs is attributed to their metal–ion reservoirs. Furthermore, MOFs can enhance angiogenesis and bone formation by releasing metal ions. They can also control the immune cells by minimizing oxidative stress and inflammatory reactions. Its large specific surface area and high porosity make it an effective drug-delivery vehicle. In addition to being antibacterial and anti-inflammatory, MOFs can promote angiogenesis and bone formation and have good biocompatibility when used as a covering. As a result, MOFs have several potential uses in implant surface modification.

Oral squamous cell carcinoma (OSCC) is a prevalent and fatal malignancy affecting the maxillofacial region. Its aggressive growth pattern and propensity for metastasis make it challenging to achieve complete eradication by surgical resection alone.^87,88 Chemotherapy is widely recognized as a highly efficacious therapeutic approach for eradicating cancer cells and mitigating the risk of tumor recurrence and metastasis. However, a significant drawback associated with traditional chemotherapy is the necessity to administer high drug dosages due to inadequate biodistribution, thereby leading to the frequent occurrence of side effects that are dose-dependent.^89,90 This necessitates the investigation of innovative and effective drug delivery systems (DDS). An effective approach to address the issue of drug buildup in healthy tissues is to enhance the targeted delivery of chemotherapeutic agents specifically toward cancer cells.^91,92 The implementation of a focused drug delivery system has the potential to mitigate the adverse effects associated with chemotherapeutic agents and enhance the efficacy of treatment for oral squamous cell carcinoma (OSCC). The intricate nature of the tumor microenvironment, characterized by diminished oxygen levels, acidic pH, and heightened levels of hydrogen peroxide (H₂O₂) and glutathione (GSH), frequently poses challenges to the effectiveness of cancer therapy.^93,94 To enhance the precision of anticancer therapy, it is possible to focus on targeting the microenvironmental stimuli. An illustration of this may be seen in the difference in pH levels between mildly acidic malignant settings and typical tissue environments, which provides a conceptual foundation for the development of drug delivery systems that respond to pH changes. In the context of local oral cancer treatment, a combination of doxorubicin (Dox) and celecoxib (Cel) was introduced into a system known as Dox/Cel/MOFs@Gel. The Dox/Cel/MOFs@Gel composite materials exhibited a notable ability to encapsulate Dox and Cel, excellent pH-responsive behavior, effectively induced apoptosis in cancer cells, and regulated tumor angiogenesis. The use of this localized therapeutic approach resulted in a substantial decrease in systemic toxicity and did not induce any noteworthy harm to adjacent organs.⁹⁵ 

The hydrogen sulfide (H₂S) pathway is activated within the tumor microenvironment. A high level of reduced hydrogen sulfide (H₂S) leads to the depletion of the generated hydroxyl radicals and impairs the effectiveness of chemodynamic therapy (CDT). To prevent the depletion of the hydroxyl radicals, the investigators incorporated Cu²⁺ ions into the MOF structure to produce CuS precipitates, which are insoluble when exposed to H₂S, thereby improving the efficacy of CDT.⁹⁶ 

The elevated concentration of H₂O₂ in tumor cells is another characteristic of the tumor microenvironment, according to which researchers have developed nanocomplexes based on metal–organic frameworks (MOFs) of titanium (Ti) that are capable of releasing CO based on the level of hydrogen peroxide present in the tumor. This nanocomplex enables both the controlled release of CO triggered by H₂O₂ within the tumor microenvironment and real-time monitoring of CO release through fluorescence imaging. This targeted release mechanism enables the nanocomplex to efficiently eradicate tumor cells while safeguarding normal cells.⁹⁷ Furthermore, it has been shown that metal–organic frameworks (MOFs) incorporating transition metal ions possess the capability to interact with hydrogen peroxide, thereby resulting in the production of detrimental hydroxyl radicals.⁹⁸ 

Metal–organic frameworks (MOFs) can act as carriers for drug molecules and can be modified on their surfaces to precisely target cancer cells, thus facilitating accurate medication delivery. Folic acid incorporation is one of the several surface modifications that have emerged as the most frequently employed strategy for targeted therapy in recent research and clinical practice. The overexpression of folate receptors has been observed on the cell membranes of cancer cells. Folate-modified MOFs have a distinctive inclination toward, which can enable the precise distribution of medicine, leading to its release within malignant tissue.^99,100

Furthermore, the modification of MOF at the cellular level can also be utilized to attain a targeted therapeutic outcome, as demonstrated by the utilization of CXCR2-containing dental pulp stem cells (DPSCs) membranes to modify/coat MOFs, leading to the production of MOF@DPSCM. This study revealed that CAL27 cells have the capacity to secrete CXCL8. This secretion leads to the upregulation of CXCR2 receptors on DPSC cellular membranes, ultimately resulting in the attraction of DPSCs to OSCC sites where CAL27 cells are present. In contrast to other metal–organic frameworks (MOFs), the MOF@DPSCM demonstrated a distinct capability to selectively adhere to and effectively penetrate CAL27 cells.¹⁰¹ 

In addition to the CDT treatment, metal–organic frameworks (MOFs) have the potential to be used in photodynamic therapy. MOFs consisting of porphyrin-based ligands have been developed as potential approaches for near-infrared (NIR) photodynamic therapy (PDT) treatment.¹⁰² These ligands act as photosensitizers, whereas the incorporation of high-Z metal ions into the MOF scaffolds of porphyrins serves as a radiosensitizer. This allows for the combination therapy of radiation therapy (RT) and PDT.¹⁰³ 

In summary, metal–organic frameworks (MOFs) include notable characteristics, such as a substantial specific surface area, considerable pore size, and significant porosity. These attributes enable MOFs to accommodate therapeutic substances efficiently, including antibiotics and natural compounds. The self-assembly of inorganic clusters within MOFs occurs through coordination bonds with organic units, facilitating the manipulation of their physical characteristics and chemical properties. In addition to incorporating desired functional groups into the organic ligand through pre-designed ligands or post-synthetic modification techniques, controlled release of the enclosed drug can be accomplished by subjecting the system to various external stimuli, including but not limited to pH, light, pressure, ions, magnetic fields, and temperature. Furthermore, the explicit organization of the content facilitates the examination of the dynamics between the host and client. Due to its distinctive characteristics, MOFs are widely regarded as highly promising contenders in the field of medication delivery and cancer therapy.

Periodontal disease is frequently correlated with the depletion of alveolar bone and the presence of microbial infections within periodontal tissues.^104,105

The abundance and complexity of oral micro-organisms are significant.^106,107 The combination of periodontal surgery with oral broad-spectrum antibiotics is commonly used to prevent or minimize postoperative infections. However, it is worth noting that the systemic drug concentration for target site treatment is quite low, leading to significant side effects and the potential for bacterial imbalance resulting from excessive medication administration. Hence, the implementation of a localized drug delivery system is crucial for effective management of periodontal diseases.^108–110 An optimal local drug delivery system should exhibit consistent and sustained drug release, exhibit prolonged therapeutic efficacy, and mitigate hazardous adverse reactions and dosing frequency.^111,112

Due to their substantial drug encapsulation capacity and minimal premature release, MOFs have been identified as promising candidates for local drug delivery systems in periodontics. ZIF-8 was chosen as the carrier for ceftazidime encapsulation. During the assay, the composite material demonstrated sustained release of ceftazidime for one week, producing a bactericidal effect against E. coli.¹¹³ 

In another study, composite microspheres composed of CD-MOF nanocrystals embedded in a biocompatible polymer (PAA) matrix were loaded with two drugs, ibuprofen (IBU) and lansoprazole (LPZ). The microspheres were spherical in shape and continued to release drugs over a long period. In addition, they exhibited reduced cytotoxicity.¹¹⁴ 

Photodynamic therapy (PDT) is currently utilized in clinical practice for the treatment of a range of diseases, with particular emphasis on its application in antibacterial treatments. Consequently, PDT is anticipated to serve as a promising alternative to the existing clinical therapies for periodontitis.¹¹⁵ 

Certain metal–organic frameworks (MOFs) have shown photocatalytic properties such as the capacity to change the optical flow in response to light stimulation, as previously described.^116,117 These modifications include shifts in the coordination numbers and coordination patterns of the metal ions and ligands, as well as structural modifications caused by bond breakage.^118,119 Two-dimensional porphyrin metal–organic frameworks (MOF) have the greatest potential for PDT. For example, two-dimensional MOF nanosheets composed of atoms and layers of ferric oxide can be combined with a polyethylene glycol matrix to create an ointment. Reactive oxygen species and released ions combine with light exposure to provide a broad spectrum of antibacterial action. This antibacterial activity has the capacity to reduce inflammation and encourage angiogenesis and is effective against a variety of oral infections, including P. gingivalis and Pseudomonas nucleomonas.¹²⁰ 

Furthermore, the ability of photocontrolled medicinal medications to achieve precise spatiotemporal control has drawn public interest. After loading the medication, MOFs can be used to create photosensitive composite materials by adding photosensitizers. This allows for the controlled release of drug molecules and the achievement of antibacterial properties. For example, AuNR@SiO₂@UIO-66 composite microspheres were created using UIO-66 as the framework. Drugs can be released from the composite using two distinct mechanisms: activation in response to near-infrared (NIR) light and slow passive release at low concentrations, followed by quick active release at high doses. Furthermore, gram-positive and gram-negative bacteria are significantly inhibited by a light-responsive material.¹²¹ 

In summary, because oral bacteria are numerous and intricate, broad-spectrum antibiotics are frequently administered to prevent infection during periodontal surgery. However, local delivery systems are essential because low systemic doses may cause adverse effects and bacterial imbalances. Because of their distinct benefits, metal–organic frameworks (MOFs) are regarded as excellent candidate materials for the treatment of periodontal disorders. In addition, the use of photodynamic therapy (PDT) in the management of periodontitis is promising. Certain MOFs, such as two-dimensional porphyrin MOFs, that have antimicrobial capabilities and stimulate angiogenesis possess photocatalytic properties. MOFs can be employed as photosensitive composite materials by adding photosensitizers to enable the precise release of medicinal molecules and their antibacterial characteristics. Research on photo-controlled pharmaceuticals has also attracted attention.

Periodontitis frequently coincides with alveolar bone depletion, prompting significant interest in the field of periodontal regeneration.^122,123 In the realm of biological strategies, the prevailing methodology for tissue engineering involves the integration of scaffolds, cells, and biologically active substances, such as drugs and growth factors to facilitate tissue regeneration. Numerous drugs and growth factors have been subjected to experimentation in the realm of periodontal regeneration. These conventional biological substances can be altered or amalgamated with inorganic materials and polymers to create composite materials. The objective is to establish a suitable microenvironment and scaffold system that can effectively induce periodontal regeneration.^124,125

Compared to conventional materials, metal–organic frameworks (MOFs) possess inherent bioactivity due to their ability to release specifically targeted metal ions. By integrating nanoscale metal–organic frameworks (NMOFs) into engineered scaffolds, it is possible to alter the functional groups, porosity, roughness, and hydrophilicity of the scaffolds, thereby enhancing the adhesion and interaction of mesenchymal stem cells (MSCs).^126,127

For instance, the incorporation of copper-loaded zeolitic imidazolate framework-8 (ZIF-8) onto poly l-lactic acid (PLLA) frameworks resulted in improved osteogenic differentiation in contrast to pure PLLA frameworks while also providing protection against bacterial infection.¹²⁸ 

Magnesium-based metal–organic framework (MOF)-doped cement has demonstrated favorable antimicrobial properties, potentially facilitating bone growth and reducing the risk of infection in wounds.¹²⁹ 

When used in combination with implant materials, MOFs can be loaded with drug molecules to provide additional antibacterial or anti-infective properties. The incorporation of levofloxacin-loaded ZIF-8 particles into implant materials can improve the osseointegration and antimicrobial capacity of the material,¹³⁰ and the incorporation of dexamethasone-loaded ZIF-8 into cellulose-hydroxyapatite nanocomposites can prolong and control the release of the dexamethasone material and improve resistance to infection.¹³¹ 

MOFs can potentially increase the osteogenic capability of scaffold materials by carrying proteins and drug molecules. By incorporating BMP-2-loaded ZIF-8 nanoparticles into porous scaffolds of polypropylene glycol and mesoporous bioactive glass (PLGA/MBG), enhanced osteogenic activity, promotion of new bone formation, and repair of bone defects can be achieved through slow and sustained release of bone morphogenetic protein 2 (BMP-2).¹³² 

Mesenchymal stem cells (MSCs) are able to adhere, develop, and specialize in an extracellular environment that is conducive to their growth when placed in nanoscale metal–organic frameworks (MOFs), according to prior research.¹³³ The combination of MOFs and bone scaffold materials can promote the growth of new bones and provide anti-infection properties. However, several researchers have questioned whether MOFs can be utilized as bone scaffold materials. To assess the potential of UIO-66 nanoparticles to stimulate bone growth in vivo, one study used a rabbit bone defect model. cd34-expressing cells were successfully transformed into osteoblasts by the nanomaterial, which also showed exceptional biocompatibility. This process leads to the stimulation of the BMP-2/SMAD pathway in vivo, osteoblast differentiation, and the eventual creation of bone tissue.¹³⁴ The regeneration of alveolar bone is currently a popular area of study in periodontal therapy, although the notion that MOFs can serve as bone scaffolds on their own is not well supported by available data. Nevertheless, this study offers a new concept for using MOFs for periodontal regeneration.

Furthermore, there is research indicating that metal–organic frameworks (MOFs) have potential research value in the field of endodontics, in addition to their application in periodontal treatment. Incorporation of olivetol (OLV) into γ-cyclodextrin metal–organic frameworks (γ-CD-MOFs) allows for effective management of dentin hypersensitivity. The therapeutic agent penetrates the pulp from the dentin layer without damaging the structural integrity of the tooth and demonstrates analgesic properties.¹³⁵ 

In conclusion, metal–organic frameworks (MOFs) are a new biomaterial with potential research value in periodontal regeneration and endodontics. MOFs can modify the functional groups, porosity, roughness, and hydrophilicity of scaffolds, thereby enhancing stem cell adhesion and interactions. In addition, MOFs can be loaded with drug molecules and proteins, providing additional antimicrobial, anti-infective, and osteogenic capabilities. This research has shown that MSCs can develop and specialize in an extracellular environment that promotes their growth when placed in nanoscale MOFs. However, further research is needed to support the use of MOFs as bone-scaffold materials. In addition, MOFs have potential in the field of endodontics for the treatment of dentin hypersensitivity by adding olive alcohol. Currently, the use of MOFs for the treatment of oral diseases is restricted to in vitro and in vivo studies. Further studies are needed to confirm the efficacy of these drugs.

The oral and maxillofacial regions are vulnerable areas of the human body, which are susceptible to injury in various contexts, such as daily activities, occupational hazards, traffic accidents, and warfare.^136,137 Given the unique anatomical structure of this region, any harm inflicted on it can facilitate the entry of microorganisms into the oral cavity, leading to potential infections. An ideal wound dressing is capable of maintaining a moist environment, avoiding wound dryness while preventing retting and absorption of wound drainage, providing protection against bacterial infection, stimulating angiogenesis and connective tissue growth, promoting gas exchange, increasing epidermal migration, maintaining adequate blood flow temperature, maintaining an electrical gradient, non-adhesion, rapid separation and debridement, non-allergenic, non-toxic, and sterile. These factors are beneficial for promoting wound healing.^138,139 Currently, compared to other nanomaterials, MOFs have great potential for antimicrobial dressing applications because of their increased drug load, targeted delivery of surface conditioning, and controlled release of wound healing agents, which are less toxic.^140–143 

A study was conducted on the development of a dressing using Ag–metal–organic framework-loaded chitosan nanoparticles and a poly(vinyl alcohol)/sodium alginate/chitosan (PACS) bilayered hydrogel. Ag@MOF served as a reservoir of Ag ions, which were released continuously, resulting in the long-lasting antibacterial properties of the dressing. This facilitated quick wound healing.¹⁴⁴ In another investigation, a polymeric CMC matrix was combined with tetracycline-loaded UIO-66, forming a dressing that sustained slow drug release in both artificial sweat and simulated wound exudate. This dressing showed effective antimicrobial activity against E. coli and Sta. aureus while also displaying good biocompatibility.¹⁴⁵ 

The findings from these studies indicate that MOFs have the potential to significantly enhance wound antimicrobial dressings through both their inherent properties and those acquired through further research.

Metal–organic frameworks (MOFs) have garnered significant attention in the biomedical field due to their favorable structural properties, including a well-defined structure, large specific surface area, remarkable porosity, and the ability to readily alter pore size and function. These unique properties make MOFs promising candidates for drug delivery and oral cancer therapy as well as potential treatments for periodontal and endodontic diseases, thanks to their antimicrobial, anti-infective, and osteogenic capabilities either by themselves or when loaded with cargoes. Despite notable progress in this area, there remain several challenges that require further investigation, such as complex functionalization techniques that can impact functional molecule activity during the synthesis of MOFs using organic ligands. In addition, researchers must consider drug loading/release kinetics along with in vivo toxicity/degradation mechanisms/pharmacokinetics of MOF nanoparticles. Further studies are necessary to rationalize MOFs while improving biostability/biocompatibility/therapeutic effects so that they may be applied more quickly toward diagnosing/treating oral diseases.

This study was supported by Hangzhou Normal University Affiliated Hospital. This work was carried out under the Research Program Peiyuan Plan of Hangzhou Normal University Affiliated Hospital.

The authors have no conflicts to disclose.

Minghe Zheng: Conceptualization (equal); Formal analysis (equal); Investigation (equal); Methodology (equal); Project administration (equal); Writing – original draft (equal). Ru Li: Investigation (equal); Project administration (equal); Resources (equal). Jiaye Wang: Validation (equal); Visualization (equal). Yanlin Huang: Project administration(equal), Resources (equal). Mingfang Han: Methodology (equal); Project administration (equal). Zehui Li: Formal analysis (equal); Writing – review & editing (lead).

The data that support the findings of this study are available within the article.