Metal‐organic framework‐based biomaterials for biomedical applications

Key‐Area Research and Development Programme of Guang Dong Province, Grant/Award Number: 2019B010941002; NSFC, Grant/Award Numbers: 82072071, 82072073; National Key Research and Development Programme of China, Grant/Award Number: 2016YFB0700800; Fundamental Research Funds for the Central Universities, Grant/Award Number: 2682020ZT79; Sichuan Science and Technology Programme, Grant/Award Number: 2020YJ0009 Abstract Metal‐organic frameworks (MOFs) refer to porous coordination materials that are formed from the assembly of metal ions and organic ligands. They have unique features, such as a large specific surface area, multiple active sites, easy functionalisation, and adjustable biocompatibility. MOFs have recently been widely used in the field of biomedical engineering owing to their unique structures and properties. This has enabled them to replace traditional materials and effectively address several problems. Through continuous development, MOF‐based biomaterials have been remarkably improved by clarifying the relationship between MOF structures and properties. As a result, they are being extensively studied in the fields of chemical and material science. MOF‐based biomaterials can meet the growing demands for efficient materials in biomedical applications. This review first discusses the basic structure of MOFs, followed by their preparation and functionalisation methods. The biomedical applications of MOF‐based biomaterials in the fields of antibacterial activity, tumour therapy, skin repair, and bone repair are then summarised. Finally, challenges and future perspectives in the biomedical applications of MOF‐based biomaterials are outlined.


| INTRODUCTION
Metal-organic frameworks (MOFs), which are crystalline porous materials consisting of intra-molecular pores formed by the self-assembly of organic ligands and metal ions or clusters through coordination bonds [1], have been developed recently. The variable metal centres and organic ligands of the MOFs lead to diversity in their structures and functions [2]. The coordination configuration of the metal ions and the spatial geometry of the organic ligands must be first considered while designing a MOF for a particular function. These factors determine the spatial topology of the MOF, which in turn affects its properties and functional efficacy.
The numerous combinations between the base material forming the metal node and the organic ligands of the MOFs have promoted the application of MOF substrates in various fields, such as molecule sensing [3], gas separation [4], molecule adsorption [5], drug delivery [6], and catalysis [7], especially in the biomedical field. In this review, we summarise the recent developments in the field of MOF-based biomaterials, with emphasis on their applications in microbial control, tumour therapy, wound healing, and bone regeneration ( Figure 1). First, an overview of the synthesis and functionalisation of MOFs is presented. This is followed by a discussion on the features of MOFs and the recent advances in their applications in different fields. Finally, the challenges and future prospects

| SYNTHESIS AND FUNCTIONALISATION OF MOFS
The continuous development of modern synthesis technology has provided numerous techniques for the synthesis of MOFs, such as water/solvothermal synthesis [8], microwave-assisted and ultrasonic-assisted syntheses [9], microemulsion-based synthesis [10], mechanochemical synthesis [11], continuous flow synthesis [12], and electrochemical synthesis [13]. These methods have both advantages and disadvantages in terms of synthesis efficiency, the scale of production, and the physical and chemical properties of the obtained MOFs. This study reviews and compares the most commonly used synthesis methods for MOFs.
The preparation of crystals through water/solvothermal synthesis is simple and easy to operate. It involves the dissolution of the metal ions and organic ligands in solvents, followed by their incubation in a reactor. The MOF crystals are obtained under high temperature and pressure after a fixed reaction time. Luo et al. [14] synthesised the MOF zeolitic imidazolate framework-8 (ZIF-8) by placing Zn 2+ metal ions and the organic ligand 2-methylimidazole in an aqueous solution, which was then incubated at 40°C for 48 h and vacuum dried. Subsequently, ZIF-8 was used as a carrier to produce the controllable assembly of Au 25 (SG) 18 nanoclusters in the inner and outer surfaces of the main frame of ZIF-8. This process was based on the coordination interaction between carboxyl groups and zinc ions in the thiol ligands on the surface of gold nanoclusters. Sun et al. [15] used FeCl 3 ·6H 2 O as a source of metal ions, 2-amino terephthalic acid as an organic ligand, and dimethyl formamide (DMF) as a solvent. The mixture was added into a suspension of polymeric graphite-like carbon nitride (g-C 3 N 4 ) and autoclaved at 110°C for 48 h to synthesise a g-C 3 N 4 -loaded MOF through heterojunction formation. This MOF was termed NH 2 -MIL-101(Fe)/g-C 3 N 4 . This product demonstrated excellent catalytic activity. For instance, the catalytic reduction of CO 2 to carbon monoxide by NH 2 -MIL-101(Fe)/g-C 3 N 4 -30 wt.% was 3.6 and 6.9 times faster than those by the original NH 2 -MIL-101(Fe) and g-C 3 N 4 , respectively. However, the water/solvothermal method is not suitable for large-scale production because it has a long reaction time and requires a substantial amount of organic solvent and the maintenance of a harsh environment (characterised by high temperature, high pressure, etc.).
The microwave synthesis method involves mixing the reaction reagent and solvent and placing the resulting solution in a microwave reactor. This method is advantageous because the reaction is relatively quick and the synthesis only takes tens of minutes, unlike the long reaction time of solvothermal synthesis. In addition, uniform heating permits the formation of nanoscale MOF particles. Laybourn et al. [16] used aluminium sulphate (Al 2 [SO 4 ] 3 ·18H 2 O) and terephthalic acid (H 2 BDC) to synthesise the MOF MIL-53 (Al) in 4.3 s through the microwave method, which is the fastest MOF synthesis method reported thus far. This study confirmed the viability of using microwave technology to mass produce MOFs significantly faster than the conventional heating methods. Haque et al. [17] used ferric chloride hexahydrate (FeCl 3 ·6H 2 O) and terephthalic acid (H 2 BDC) as raw materials to synthesise the MOF MIL-53 (Fe) through the traditional heating and microwave method. MIL-53 (Fe) was produced in approximately 1.5-2.5 h and 1.5-3 days through the microwave method and traditional heating reactions, respectively. These results confirm that microwave synthesis is faster than traditional heating methods.
The mechanochemical synthesis method involves the replacement of thermal energy with mechanical energy. The MOFs are produced by mixing ligands and metal salts and grinding them with a ball mill. This procedure is economical, rapid, and environment-friendly and significantly reduces the amount of solvent used while simultaneously improving production efficiency. Friščić et al. [18] mixed ZnO and 2-methylimidazole (HMeIm) and ground them to produce ZIF-8 through a mechanochemical reaction ( Figure 2). A small amount of acetic acid or water was also added to catalyse the reaction.
The ultrasonic method produces MOFs through the sonification of mixed raw materials. This method has a short reaction time. Qiu et al. [19] rapidly synthesised MOFs by using the ultrasonic method to combine copper acetate and homophthalic acid (H 3 BTC) in an ethanol solution. A yield of 75.3% was obtained after 5 min of ultrasonic irradiation. The diameters of the synthesised MOFs were 50-100 nm (5 and 10 min, as shown in Figure 3a and b) and increased over time. A reaction time of 30 min produced MOFs with diameters of 100-200 nm and lengths in excess of 100 mm (Figure 3c). Furthermore, a reaction time of 90 min produced MOFs with diameters of 700-900 nm (Figure 3d). Thus, MOFs with varying sizes can be efficiently synthesised through the ultrasonic method by providing different reaction times.
MOFs can be functionalised to obtain the desired properties. The functionalisation of MOFs can occur before or after their synthesis. The functionalisation of MOFs before synthesis involves the introduction of functional groups into the organic ligands, followed by the adoption of an appropriate synthesis method [20]. This method may require specific conditions, and the introduction of functional groups is likely to affect the formation of the frame structure. Therefore, this approach is not applicable to all MOFs. Deng et al. [21] modified the organic ligands during the preparation of MOF-5, wherein -NH 2 , -Br, -NO 2 and -(CH 3 ) 2 , -C4H4, -(OC3H5)2, -(OC7H7)2 were modified on terephthalic acid ligands. The functional MOF-5 was obtained by establishing a coordination bond with the metal ion Zn 2+ . The results demonstrated that different functional groups were attached within the pores of the material of the MOF, thereby providing it with diverse functions. Custelcean et al. [22] developed a pyridyl ligand with a free carboxylic acid group. A coordinate bond was formed between a copper ion and the ligand to obtain the desired MOF. The free carboxylic acid groups in this MOF, which were introduced by pre-modification, can selectively recognise Cl(H 2 O) 4 clusters. Thus, specific recognition of molecules can be performed with this MOF.
Functionalisation of MOFs after synthesis is more common than pre-synthesis functionalisation [23]. It involves postsynthesis modification of prepared MOFs [24]. The modification does not affect the integrity of the overall framework. Therefore, chemical reactions can be carried out to modify the MOFs and design multifunctional MOF materials. However, this method has several stringent requirements to ensure the stability of the MOFs. Sarker et al. [25] synthesised a stable, porous MOF named Zr-diaminostyrene dicarboxylic acid (Zr-DASDCA). The MOF was modified with oxaloyl chloride (OC) or p-benzoyl chloride (TC) after its synthesis to introduce different functional groups into Zr-DASDCA. The original MOF and functionalised post-MOF were both used as potential carriers for ibuprofen (IBU) storage and delivery. It was observed that the functionalised MOF reduced the release rate of IBU and stabilised its release for 10 days. Mortazavi et al. [26] used cysteamine molecules that contained amine and thiol groups to functionalise MIL-101 (Cr), thereby producing MIL-101 (Cr)-SH. It was oxidised with H 2 O 2 and then acidified with dilute sulphuric acid to produce the MIL-101 (Cr)-SO 3 H nano-catalyst. The activity of the prepared catalyst was then evaluated. It was observed that the conversion rate of MIL-101-SO 3 H into benzaldehyde was equal to 90% after 3 h. This was a significant improvement over the rates obtained from the blank test (25%) and the application of pure MIL-101 as catalyst (43%). These results demonstrated that the catalytic activity of MIL-101 (Cr) was significantly improved after functionalisation.

| METAL-ORGANIC FRAMEWORK-BASED BIOMATERIALS FOR ANTIBACTERIAL APPLICATIONS
Bacterial resistance has become an issue of grave concern. There is an urgent requirement for alternative antimicrobial biomedicines. Traditional antibacterial agents consist of antibiotics [27], chitosan, quaternary ammonium salts, and metal ions. Most of these antibacterial agents are highly toxic, have a poor antibacterial effect, and are subject to several limitations. Therefore, the preparation of effective antibacterial materials to ensure medical safety has become a challenge. In addition to being composed of metal ions and organic ligands, MOFs have a porous structure, a large specific surface area, and several semiconductor-like properties. The antimicrobial features and mechanisms of MOFs are discussed in this section, followed by a review of the several applications of MOFs in antibacterial biology.

| Metal-organic framework-based antibacterial nanomaterials
MOFs exhibited antibacterial activity because of their unique metal coordination structure which can release antibacterial metal ions, such as zinc (Zn 2+ ) and copper (Cu + /Cu 2+ ), during degradation. These metal ions encounter the microbial cell membrane and are attracted to the negatively charged cell membrane through Coulomb attraction, leading to the formation of a solid complex. The active centre of the cell synthase is composed of functional groups, such as the sulfhydryl, amino, and hydroxyl groups. The metal ions can penetrate the bacterial cell membrane and react with the functional groups attached to these proteins. As a result, the structure of the active centre of the protein is destroyed, resulting in the death of the microorganism or the loss of its proliferation ability.
Berchel et al. [28] studied Ag-MOFs that consisted of an organic portion of 3-phosphonylbenzoic acid with an Ag + metal ligand. Ag-MOFs demonstrated good antimicrobial activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. Yang et al. [29] developed MOF (ZIF-8) nanocrystals on cotton fibres and coated them with polydimethylsiloxane (PDMS). The prepared cotton fabric was F I G U R E 2 (a) Mechanical synthesis of zeolitic imidazolate framework-8 (ZIF-8) (b) Fragments of the ZIF-8 crystal structure [18] LUO ET AL. superhydrophobic and had antimicrobial properties ( Figure 4). The interaction between the Zn 2+ ions released by ZIF-8 and the cell membrane proteins destroyed the cell structure of the bacteria, resulting in membrane internalisation and cell death. As a result, this material had excellent antibacterial properties against E. coli and S. aureus. In addition, the fabric maintained its superhydrophobic and antibacterial nature even after being subjected to 3000 cycles of abrasion and 5 cycles of washing.

| Application of Metal-organic framework-based biomaterials as antibacterial drug carriers
Owing to their high porosity and large surface area, MOFs can be used as antimicrobial drug carriers, which can be released continuously for their therapeutic purpose. Wu et al. [30] developed MOF-53 (Fe), which was a porous iron-carboxylate MOF that was composed of iron ions and terephthalic acid to encapsulate the drug vancomycin (VAN; Figure 5). This MOF had good chemical stability and a high drug-loading capacity under acidic conditions (at pH values of 7.4, 6.5, and 5.5). The results of this study indicated that the drug-loading ratio of VAN and the antibacterial ratio of the MOF-53 (Fe)/VAN system against S. aureus were increased to 20 wt.% and 90%, respectively. In addition, the MOF-53 (Fe)/VAN system was highly biocompatible.
Shakya et al. [31] used biocompatible cyclodextrin (CD)-MOF as a template to develop a mesoporous CD-MOF skeleton by binding γ-cyclodextrin (γ-CD) to a potassium metal salt. Ag@CD-MOF, a CD-MOF that was loaded with ultrafine F I G U R E 3 Transmission electron microscopy images of the Metal-organic frameworks (MOFs) synthesised through the ultrasonic method at reaction times of (a) 5 min, (b) 10 min, (c) 30 min, and (d) 90 min [19] F I G U R E 4 Preparation of a Metal-organic framework (MOF)-based superhydrophobic and antibacterial cotton fabric [29] Ag nanoparticles (Ag NPs), was then synthesised by using tiny windows with a diameter of 1.7 nm to restrict the growth of Ag NPs in the CD-MOF structure. The chemical cross-linking of the CD unit on the surface of the particle through a carbonate bond was followed by attaching several ultrafine Ag NPs in the particle to obtain the desired reduction in the drug release rate and the persistent antibacterial effect. The results of antimicrobial assays demonstrated that the minimum inhibitory concentration (MIC) values of Ag@CD-MOF against E. coli and S. aureus were 16 μg/ml and 128 μg/ml, respectively.
Su et al. [32] successfully prepared voriconazole-inbuilt zinc 2-methylimidazolate frameworks (V-ZIF) that contained an antifungal drug named voriconazole. They combined Zn 2+ ions, which were obtained from zinc nitrate, with the ligand of voriconazole. The acidic environment of Candida albicans biofilms can trigger the separation of voriconazole from the metal-organic skeleton, resulting in the release of voriconazole. V-ZIF can penetrate C. albicans biofilms and prevent their expansion through the superior diffusion of voriconazole, thereby resulting in fungal cell membrane damage and the eventual death of C. albicans. V-ZIF demonstrated good antifungal properties when used on C. albicans infected wounds, in addition to promoting wound healing without obvious side effects.
Gallis et al. [33] used ZIF-8 to encapsulate an antimicrobial drug ceftazidime to treat intracellular infections. The results showed that the drug could be released from ZIF-8 for up to a week. Thus, ceftazidime-encapsulated ZIF-8 showed excellent antibacterial activity against E. coli, and its antibacterial activity was determined by the degradation kinetics of ZIF-8.

| Metal-organic framework-based biomaterials for photothermal antibacterial agents
The combination of different metal ions and ligands in MOFs allows them to be used as photothermal agent for heating and antibacterial activities.
Han et al. [34] inserted Cu 2+ into the porphyrin ring of a MOF. The photothermal effect of the Cu-MOF was enhanced due to the d-d transition. Cu 2+ doped particles can also trap electrons, thereby enhancing their photocatalytic performances. Thus, doping the MOF with 10% Cu 2+ made it an effective antibacterial agent. It reduced the count of S. aureus cells by 99.71% within 20 min of exposure to light radiation at 660 nm (0.4 W/cm 2 ). In addition, in vivo results demonstrated that the Cu-MOFs could efficiently kill bacteria. Luo et al. [35] prepared a core-shell bimetallic organic framework by using Prussian blue (PB@MOF) and porphyrin-doped UIO-66-TCPP MOF as the core and shell, respectively. PB@MOF reported a maximum photothermal conversion efficiency of 29.9% under near-infrared (NIR) light irradiation at 808 nm. This material displayed weak antibacterial characteristics under irradiation of 808 nm or 660 nm for 10 min. However, the material's antibacterial ratios against S. aureus and E. coli after 10 min of irradiation by a double-light lamp were 99.31% and 98.68%, respectively. Figure 6 shows the rapid sterilisation mechanism of PB@MOF.

| Metal-organic framework-based biomaterials for photodynamic antibacterial agents
Photodynamic antimicrobial agents utilise light to stimulate the transition of a photosensitiser from its low-energy ground state to a high-energy triplet state. The free electrons generated in this reaction can target biological molecules of microorganisms or trigger a similar photodynamic reaction in free radicals. Alternatively, the triplet photosensitiser molecules interact with the first triplet oxygen molecules to produce singlet oxygen, which is toxic for the target microorganisms and can inactivate them. Because the properties of MOFs are similar to those of semi-conductors, they can be used as photosensitisers exhibiting photodynamic antibacterial activity.
Pingli et al. [36] filtered various MOFs by analysing their photocatalytic activity. They identified ZIF-8, a MOF with ultra-high photocatalytic bactericidal activity, capable of killing E. coli in water. ZIF-8 had a bactericidal rate in excess of 99.9999% after being subjected to sunlight for 2 h. This led to the development of a novel and highly efficient integrated air filter through the hot-pressing method. This filter trapped more than 98% of the particulate matter and killed 99.99% of the bacteria in the air. This effect is attributed to the photogenerated electrons that are derived from ligand to metal charge transfer (LMCT) under the action of sunlight. These F I G U R E 5 Schematic of the Metal-organic framework (MOF)-53 (Fe) structure, and the loading and delivery of MOF-packaged drug molecules to kill bacteria [30] LUO ET AL. electrons activate O 2 to form O 2− and H 2 O 2 , which can oxidise the pathogenic bacteria in the air, thereby killing them.
Nie et al. [37] attached graphene quantum dots (GQDs) and MOF (PCN-224) on the surface of a cotton fibre through chemical coupling and in situ growth, respectively. GQDs with fluorescence resonance energy transfer (FRET) pairs that served as donors and PCN-224 as receptors were developed to study the photodynamic antibacterial activity of self-sterilised fabrics against gram-negative and gram-positive bacteria (Figure 7). The results showed that the incorporation of FRET pairs increased the production of 1 O 2 by 1.61 times. The fabric reported high bactericidal efficiency (>99% against four bacterial strains within 30 min) and low cytotoxicity.
Qu et al. [38] synthesised a porphyrin-based MOF nanoplatform (PMOF) that had high biofilm penetration abilities, high oxygen self-generation, and was highly efficient in photodynamic therapy. The PMOF particles were then encapsulated in human serum albumin (HSA)-coated manganese dioxide (MnO 2 ) through biomineralisation under alkaline conditions to produce a multi-component nano-platform (MMNP). The results of the antibacterial assays demonstrated that the addition of H 2 O 2 enhanced the bactericidal ability of the material (antibacterial ratios against E. coli and S. aureus were 99% and 90%, respectively). The nano-platform was used to treat subcutaneous abscesses infected with S. aureus in vivo without damaging healthy tissues and produced a very significant therapeutic effect.

| Metal-organic framework-based biomaterials for combinatory antibacterial therapy
In addition to individual antimicrobial treatment, synergistic therapeutic antimicrobial treatment can also be performed by utilising MOFs. Antimicrobials based on photothermal therapy (PTT) and photodynamic therapy (PDT) have disadvantages if they are used individually. The high temperatures required for PTT can burn healthy tissues, whereas the photodynamic molecules of PDT may not be very effective. Therefore, combinatory therapy must be given more importance while designing MOF-based antibacterial biomaterials.
Zhao et al. [39] developed a novel MOF/Ag-derived nanocomposite material that was used for synergistic antibacterial treatment. It was capable of releasing a large number of Ag ions and exhibited a strong photothermal conversion effect. This material was produced by first synthesising zincbased and graphite-based MOF derivatives, followed by the uniform introduction of Ag NPs through a Zn-Ag + substitution reaction. The prepared nanomaterial generated sufficient heat to destroy the bacterial membrane upon being irradiated with an NIR laser at 808 nm (3 W/cm 2 ) for 10 min. In addition, several Zn 2+ and Ag + ions were released simultaneously, thereby causing chemical damage to the intracellular components of bacterial substances. Antibacterial assays demonstrated that this dual antibacterial action ensured that the antibacterial ratio of the nanocomposite was approximately 100% at a very low dosage (0.16 mg/ml) against a high concentration of bacteria.
Wu et al. [40] developed a MOF named ZIF-8-ICG by encapsulating the photothermal agent, indocyanine green (ICG). The ICG component of ZIF-8-ICG effectively generated heat in response to NIR laser radiation, resulting in the precise, rapid, and effective photothermal killing of bacteria. Zn 2+ was simultaneously released from the ZIF-8 and inhibited bacterial growth by increasing the permeability of the bacterial cell membranes. This enhanced the efficacy of the photothermal therapy by reducing the heat resistance of the bacteria. Fan et al. [41] developed two-dimensional carbon nanosheets (2D-CNS) that were derived from a MOF and could trigger phase transformation and local bacterial eradication, thereby enhancing anti-infection therapy. MOF-derived ZnOdoped graphene (ZnO@G) was first synthesised and immobilised on a phase-change thermal response brush (TRB) through in situ polymerisation to produce TRB-ZnO@G. TRB-ZnO@G has a flexible two-dimensional nanostructure and exhibits high photothermal activity, continuous release of Zn 2+ , and switchable phase-size conversion. The bacteria gathered near the material were killed upon subjecting it to NIR irradiation due to the penetration of several Zn 2+ ions, physical cutting, and hyperthermia. These processes contributed synergistically to the destruction of the bacterial membrane and intracellular material. The bactericidal ratio of this synergistic system against E. coli and S. aureus was approximately 100% in a short period, without causing the accumulation of toxic compounds or damage to healthy tissues.
Although MOFs are widely used because of its antibacterial properties, MOFs-based antibacterial materials also have some disadvantages. The insufficient effect of single antibacterial and the potential toxicity of MOFs limited the clinical applications.

| METAL-ORGANIC FRAMEWORK-BASED BIOMATERIALS FOR TUMOR THERAPY
Cancer has become a major disease that is endangering the lives and health of several people worldwide. Clinical tumour treatment methods include surgery, chemotherapy, radiotherapy, etc. and in addition, MOF-based materials are being developed and studied for applications in basic research fields, such as tumour chemotherapy [42], photodynamic therapy [43], and combination therapy [44]. These treatments can delay the growth and metastasis of certain tumours to a certain extent. This section discusses the latest research on MOFbased biofunctional materials in tumour treatment.

| Application of Metal-organic framework-based biomaterials as antitumour drugs
Owing to their structural diversity, high stability, and biocompatibility, MOFs can be used as anti-cancer drugs. Several antineoplastic MOFs can be developed by directly selecting the active therapeutic substances, such as the ligands or metal ions, and assembling them onto metal-organic skeleton materials to execute their therapeutic functions. This method is relatively simple and can also improve the water solubility of drug molecules. Su et al. [45] used zinc ions and molecules of the drug curcumin to develop medi-MOF-1, which was a MOF with a maximum surface area of 3002 m 2 ·g −1 . Its pore channels were used to store and release ibuprofen. This method provides MOFs with antitumour functions.
Lei et al. [46] designed a light-sensitive and caspasesensitive multifunctional nanoprobe by assembling an organic porphyrin skeleton, a targeted motif, and the dye markers of the folic acid peptide in a metal cage. This method increased the rate of singlet oxygen release from the porphyrin by 6.2 times and enabled the effective activation of caspase-3 for cancer treatment and in situ monitoring. The integration of multiple therapeutic motifs in a single nanocarrier can provide accurate cancer diagnoses and treatments. The in vivo therapeutic effect of these nanocarriers can be further improved by controlling the sizes of the synthesised MOFs.

| Application of Metal-organic framework-based biomaterials as carriers for the delivery of antitumour drugs
The flexible topological structure, large specific surface area, and high porosity of MOFs allow them to be used as scaffolds for the immobilisation and delivery of antitumour drugs with high drug loading capacities and controllable release rates. Gao et al. [47] designed a hollow ZIF-8 drug delivery system with a high drug loading capacity that could perform the targeted delivery of advanced multifunctional molecules. They loaded it with 5-fluorouracil (5-FU) to verify its targeted antitumour drug transport abilities. The in vitro drug release experiments demonstrated that ZIF-8/5-FU@FA-CHI-5-FAM exhibited high drug loads (51%) and sustained its drug release behaviour. ZIF-8/5-FU@FA-CHI-5-FAM could effectuate targeted delivery, imaging tracking, and locally sustained release of drugs, thereby inhibiting tumour growth successfully.
Zheng et al. [48] used the one-pot method to synthesise ZIF-8 and simultaneously load it with an anticarcinogen named doxorubicin (DOX). Figure 8a and b show the schematics of the synthesis process of this MOF. Figure 8c demonstrates that the drug was encapsulated in the pores of the MOF and released in response to variations in the pH levels. The cytotoxicities of DOX@ZIF-8, ZIF-8 + DOX, ZIF-8, and free DOX were evaluated by using a 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay to measure cell viability. The results showed that the cytotoxicity of DOX@-ZIF-8 against breast cancer cells was 14-37 times higher than those of the other materials.
Gupta et al. [49] designed an MIL-101-Fe MOF and loaded it with ibuprofen. In addition, they added functionalised polyethylene glycol (PEG) layers on the drug-coupled MOF particles to prolong the drug release duration. The results indicated that the rate of drug release of the NH 2 -MIL-101-Fe MOF was reduced after coating it with PEG, thereby proving that PEG-coated particles are well-suited for drug delivery.

| Metal-organic framework-based biomaterials for photothermal tumour therapy
PTT involves the killing of tumour cells by irradiating photothermal materials with visible or NIR light to convert light LUO ET AL. energy into heat [50]. This method is advantageous due to its short execution time and convenient implementation. The MOF-based materials used for PTT consist of a MOF that is compounded with a photothermal agent, or a MOF loaded with a photothermal agent in its channels.
Huang et al. [51] used a MOF named MIL-53 as a microreactor for the in situ growth of polypyrrole (PPy) nanoparticles that have excellent photothermal conversion efficiency, high stability, and good biocompatibility. The PPy@MIL-53 nanocomposite was fabricated and loaded with DOX hydrochloride. The preparation process of this nanocomposite is shown in Figure 9. This material's photothermal abilities are activated upon being subjected to an appropriate pH and NIR laser irradiation, in addition to the release of drugs. This produces a significantly destructive effect on tumours. Because MIL-53 contains iron, it can also be used as a magnetic resonance imaging (MRI) reagent to monitor the distribution of the nanocomposites.
Deng et al. [52] successfully developed novel stimuliresponsive multifunctional yolk-shell nanoparticles (YSNs). Star-shaped gold nanoparticles formed the photothermal yolk, while the shell was made of the MOF ZIF-8. The chemotherapy drug DOX was encapsulated in the cavity. The gold nanostar@ZIF-8 (Au@MOF) exhibited excellent photothermal abilities upon being irradiated with a laser. These characteristics acted synergistically during cancer treatment by promoting drug release.
Zhang et al. [53] synthesised a self-mineralised photothermal bacterium (PTB) and a MOF named ZIF-90. The MOF was loaded with the photosensitiser methylene blue (MB) to form ZIF-90/MB, which was then conjugated on the surface of the PTB through an acid-sensitive imine bond to produce PTB@ZIF-90/MB. This material has excellent photothermal properties in the NIR region. It can also eliminate tumours in the body. This was demonstrated by using this material on the model of a mouse with a subcutaneous tumour. The mice were exposed to irradiation at wavelengths of 660 and 808 nm. The mice belonging to the PTB@ZIF-90/MB group survived for 40 days, whereas almost all the mice from the remaining groups died. These results confirmed that PTB@ZIF-90/MB was capable of completely eradicating the tumour. In addition, a biosafety assessment showed that PTB@ZIF-90/MB did not lead to significant tissue damage or severe inflammatory responses.

| Metal-organic framework-based biomaterials for photodynamic antitumour therapy
PDT utilises photosensitisers, light, and oxygen molecules to treat tumour diseases. Irradiating tumour sites with light at specific wavelengths can activate the photosensitive drugs accumulated in the tumour tissues, which transfers energy to the oxygen molecules and generates singlet oxygen. As a result, the nearby biological macromolecules are oxidised, leading to the eventual destruction of the tumour. The synthesis of MOFs for photodynamic antitumour treatment can be divided into two types. The first type involves the synthesis of the photosensitisers as organic ligands and metal ions to mediate the photodynamic antitumour activity. The second type involves loading the MOF with a photosensitiser or using a covalently bound photosensitiser to combat the tumour.
Wang et al. [54] synthesised a MOF that consisted of porphyrin-like monatomic Fe (III) centres (p-MOF). They evaluated the performance of this material for cancer therapy through the photodynamic method. The performance of PDT and PTT under NIR (808 nm) irradiation and tumour photoacoustic imaging (PAI) was also evaluated. The change in the spin states of the monatomic Fe (III) centres in p-MOF, which was induced by the NIR irradiation, easily transformed the coordinated triplet oxygen ( 3 O 2 ) into singlet oxygen ( 1 O 2 ), thereby confirming the viability of PDT. In addition, the narrow bandgap of p-MOF (1.31 eV) led to the absorption of NIR photons, resulting in a non-radiative transition that converted incident light into heat. This ensured the viability of PTT. Thus, this material efficiently regulated the hypoxic tumour microenvironment of HeLa cell tumours in mice and performed satisfactorily as a PAI agent.
Lan et al. [55] developed a nano-MOF named Fe-TBP to address the limited efficacy of PDT due to tumour hypoxia. Fe-TBP was composed of iron-oxo clusters and porphyrin ligands. The Fenton reaction, which was catalysed by the Fe-O cluster nodes of Fe-TBP, decomposed H 2 O 2 to generate oxygen upon irradiation under hypoxia. This oxygen was then converted into cytotoxic singlet oxygen ( 1 O 2 ) by the photoexcited porphyrin. Thus, Fe-TBP-mediated PDT significantly improved the therapeutic effect of the anti-programed death F I G U R E 8 The pH-induced one-pot synthesis method of metal-organic framework (MOF). (a) Metal ions and target organic molecules. (b) Self-assemble to form coordination polymers. (c) The metal ions in the target organic molecules are decomposed by adding an organic linker, and the target molecules are encapsulated in the coordination process between metal ions and organic ligands. [48] ligand 1 (α-PD-L1) and induced a tumour regression rate in excess of 90% in a colorectal cancer mouse model.
Fu et al. [56] developed a hyaluronic acid (HA)-modified ZIF-8 through one-pot encapsulation and self-assembly. It was then loaded with chlorin e6 (Ce6) and a photosensitiser for PDT to produce the therapeutic agent ZIF-8@Ce6-HA ( Figure 10). Laser irradiation at 660 nm led to the production of reactive oxygen species (ROS) through the photodynamic activity of ZIF-8@Ce6-HA. As this material had higher cytotoxicity than that of free Ce6, the death rate of the HepG2 cells was improved to approximately 88.4%.

| Metal-organic framework-based biomaterials for combinatory antitumour therapy
The antitumour systems discussed above are based on MOFs that have gained some progress in clinical therapy. However, a single therapeutic effect is insufficient to ensure efficient treatment. Therefore, the development of effective combination therapy systems wherein two treatments can be combined, such as chemotherapy and PTT or PTT and PDT, is being studied.
Zhang et al. [57] designed and synthesised a multifunctional nano-MOF that contains a porphyrin ligand and zirconium metal clusters to utilise the combined effects of PDT and cryogenic PTT. A C 48 H 32 ClFeN 4 O 16 Zr 3 MOF (MOF-545) was linked to the photosensitiser H 4 TBP-Fe and then coated with PEG. A short interfering RNA (siRNA) that inhibited the expression of the heat shock protein HSP70 was loaded outside the prototype nanostructure to produce the siRNA/Zr-FePMOF therapeutic platform. The SiRNA/ZR-FEPMOF platform can mediate the photothermal imaging (PTI), PAI, and computed tomography (CT) imaging of the tumours, thereby ensuring accurate tumour diagnoses. More importantly, this platform can convert H 2 O 2 and O 2 into a hydroxyl radical (•OH) and a singlet oxygen ( 1 O 2 ) for PDT. In addition, this platform displays an excellent therapeutic effect based on PTT. Thus, the synergistic effect of PDT and PTT ensured that the tumour growth was effectively inhibited.
Chen et al. [58] prepared core-shell nanoparticles wherein the MOF ZIF-8 formed the shell layer and polymeric graphitic carbon nitride (g-C 3 N 4 ) was the core. The nanoparticles were developed by growing ZIF-8 on g-C 3 N 4 nanosheets. DOX was then injected into the ZIF-8 shells of these core-shell nanoparticles to achieve the combined treatment effects of PDT and chemotherapy. The combination of the chemotherapeutic F I G U R E 9 Synthesis of PPy@MIL-53/DOX and its role in tumour photothermal chemotherapy and magnetic resonance imaging (MRI) [51] DOX, anticarcinogen named doxorubicin; PPy, polypyrrole F I G U R E 1 0 Schematic of the activity of a hyaluronic acid-mediated chlorin e6 therapeutic agent based on zeolitic imidazolate framework-8 (ZIF-8) for the photodynamic therapy of tumours [56] LUO ET AL. effect of DOX and the PDT effect of the nanometre-wide g-C 3 N 4 tablets significantly strengthened the curative effect of this complex.
Wu et al. [59] used the MOF UiO-66 to wrap polypyrrole nanoparticles (PPy NPs) that were capable of photothermal conversion, thereby producing PPy@UiO-66@WP6@PEI-Fa nanoparticles (PUWPFa NPs). The drug 5-fluorouracil (5-FU) was then loaded to utilise the combined effects of phototherapy and chemotherapy. The in vitro effect of this material was evaluated by the MTT assay. The 5-FU-loaded PUWPFa nano-platform had higher cytotoxicity against HeLa cells than those of PUWPFa NPs or 5-FU due to the synergistic effect of the NIR radiation at 808 nm and the chemicals. Further, the in vivo experiments showed that the growth of the tumours treated with PUWPFa NPs + 5-FU + NIR was significantly inhibited, whereas the sizes of the tumours subjected to other treatments continued to increase. This material demonstrated a significantly stronger anticancer effect than those of chemotherapy and PTT.
Jiang et al. [60] used ZIF-8 as a multifunctional nanoplatform. They loaded it with the anticancer agent quercetin (QT) and highly porous CuS nanoparticles as photothermal agents to utilise the synergistic combination of chemotherapy and PTT. A folic acid-bovine serum albumin (FA-BSA) conjugate was then used to stabilise CuS@ZIF-8-QT, promote the bioavailability of QT, and activate targeted drug delivery (Figure 11). The photothermal properties and antitumour activity of this material were evaluated by testing them in B16F10 tumour-bearing mice. The tumour inhibition ratio of the FA-BSA/CuS@ZIF-8-QT + NIR group was maximum and attained a value that varied between 91.8 ± 5.1%. This demonstrated the significantly improved antitumour effect of the loaded nano-platform. The results of the in vivo antitumour experiments proved that QT and PTT could function simultaneously and effectively under NIR irradiation.
Although MOF-based biomaterials are used as carriers of anti-tumour molecules, their biosafety, stability, and mechanism of biodegradation need to be further studied.

| METAL-ORGANIC FRAMEWORK-BASED BIOMATERIALS FOR TISSUE REGENERATION
MOF-based biomaterials are also widely used for tissue regeneration due to their structural variety and adjustable porosity. The MOFs are generally used as tissue repair materials, as carriers to load other biological macromolecules, and as platforms to combine with other materials. The applications of MOF-based biomaterials in skin and bone repair are discussed in this section.

| Metal-organic framework-based biomaterials for skin repair
MOFs combine different metal ions with different ligandssome of which interact with cells. Therefore, the application of MOFs in the field of biomedicine for the promotion of skin repair is very promising. Shakya et al. [31] used the CD-MOF, which was water-soluble and biocompatible, as a template to reduce AgNO 3 to Ag NPs. As the tiny windows, with a diameter of 1.7 nm, in the structure of the CD-MOF limited the growth of Ag NPs, the CD-MOF loaded with ultrafine Ag NPs (Ag@CD-MOF) was synthesised. The CD-MOF was modified with a GS5 oligopeptide (GS5-CL-Ag@CD-MOF), which promoted the haemostatic function of the platelets, the adhesion of particles to the wound site, and acted in synergy with the antibacterial effect of the Ag NPs to enhance wound healing. A wound healing experiment demonstrated the superiority of the GS5-CL-Ag@CD-MOF-treated group over the other groups. Zhao et al. [61] prepared microfibres using alginate gel as the shell and a copper-vitamin or zinc-vitamin MOF as the core. These zinc-vitamin and copper-vitamin MOF hydrogel microfibres were applied to an animal wound model to evaluate their practical ability to promote wound healing ( Figure 12). The results showed that after 9 days of treatment with MOF microfibres, the wound healed almost completely, whereas the control group took a relatively long time to heal the wounds. In addition, the combined use of zinc-vitamin and copper-vitamin MOF hydrogel microfibres produced faster healing than that of a single metal-loaded MOF.

| Metal-organic framework-based biomaterials for bone repair
MOFs are also widely used in the field of bone repair. Bone repair properties of MOFs are mostly based on the release of metal ions such as Zn 2+ and Mg 2+ , which can promote osteoblast proliferation and osteogenic differentiation [62].
Moreover, the porous structure of the MOFs can be used to load the growth factors [63]. In addition, MOFs can also be modified with other biomolecules to enhance the bone repair ability of the composites [64]. Shen et al. [62] developed a magnesium/zinc-MOF named Mg/Zn-MOF74 to coat the surface of alkali/heat-treated titanium (AT). The Mg/Zn-MOF74 hybrid coating was highly stable due to its Zn 2+ content. The MOF74-modified samples were sensitive to bacterial acidic microenvironments and displayed strong antibacterial activity against E. coli and S. aureus. This was attributed to the degradation of the MOF74 coating, which resulted in the formation of an alkaline microenvironment (pH ≈ 8.0) and the generation of degradation products (2,5dihydroxyterephthalic acid and Zn 2+ ). The coating also demonstrated good early anti-inflammatory properties against natural Ti substrates. In vivo studies further confirmed that the AT-Mg/Zn3 implants had strong antibacterial and antiinflammatory properties during the early stages of implantation. This significantly improved the formation of new bone around the implant at the uninfected and infected femoral sites. F I G U R E 1 2 (a) Schematic of the preparation of the microfibre preparation with the vitamin Metalorganic framework through microfluidic spinning. (b) Schematic of the applications of the microfibre in wound healing [61] F I G U R E 1 3 Schematic of the preparation of zeolitic imidazolate framework-8@ alkali and heat treatments (ZIF-8@AHT) and the mouse first molar (M1S) bone-implant experiment [64] LUO ET AL.
Zhang et al. [64] carried out alkali and heat treatments (AHTs) on the titanium coatings of several nanoscale ZIF-8 crystals to produce zeolitic imidazolate framework-8 (ZIF-8)modified titanium (ZIF-8@AHT). All kinds of titanium matrices were cultivated in vitro with MC3T3 E1 osteoblasts. The biological activity of the cells treated with ZIF-8@AHTs was higher than those treated with AHT and Ti as evidenced by the enhanced extracellular matrix (ECM) mineralisation, increased collagen secretion, and the increased expression of bone-building genes (Alp, Col1, Opg, and Runx2) and osteogenesis-related proteins (Alp and Opg). The prepared materials were then used to conduct a mouse first molar boneimplant experiment (Figure 13). The results showed that ZIF-8@AHT also promoted osteointegration at the bone-implant interface due to the combination of micro/nano morphology and ZIF-8@AHT components to promote bone regeneration, indicating that ZIF-8@AHT could promote osteoblast differentiation to some extent.
Wan et al. [65] incorporated ZIF-8 into a composite scaffold, which was constituted of dicalcium phosphate dihydrate (DCPD) and polycaprolactone (PCL). The scaffold was biocompatible with bone mesenchymal stem cells (BMSCs) and significantly upregulated the expression of osteogenesisrelated genes and proteins. ZIF-8 was released from the scaffold. It maintained the effective concentration of zinc ions and activated the protein kinase (AKT) and extracellular regulated kinases (ERK) pathways to enhance the differential regulation of genes. The composite scaffold improved the healing of the skull defects in comparison to the scaffold without nano ZIF-8. Therefore, this experiment proved that the incorporation of MOF into the 3D-printed composite scaffold promoted osteogenesis in the field of bone tissue engineering.
Although MOF-based biomaterials have been used for tissue regeneration, most of the MOF-based biomaterials were used as drug carriers. The intrinsic biological effects of MOFbased biomaterials should be considered. Especially, the biofunctional ligands can be induced into the structures of MOFs for improving tissue healing.

| CONCLUSIONS AND FUTURE PROSPECTS
The basic composition, common preparation and functionalisation methods of MOFs were first discussed in this review. The subsequent sections analysed the advancements made in the application of MOFs in antibacterial, antitumour, skin repair, and bone repair treatment. Although MOFs are characterised by their large specific surface area, high porosity, diverse structure, etc., their performances have been gradually developed and optimised. There are still challenges to overcome. First of all, most of the MOFs are expensive and cannot be prepared on a large scale. So more consideration should be given to the sources of synthetic materials in the future. Secondly, some synthesis conditions of MOFs are not suitable for biomedical applications. Thirdly, the stability of MOFs is poor. Finally, the research progress on the biological properties and effects of MOFs is still insufficient, which hinders the further development of clinical practice. The future development of MOFs should be oriented to expand material sources, and develop simpler synthesis methods, safer, more stable and more effective.