Mapping the landscape of metal-organic frameworks in orthopedics: a review

4.1.1 Zeolitic imidazolate frameworks series

Zeolitic imidazolate frameworks (ZIF), a subclass of MOF, are synthesized from metal ions and imidazolidone groups. Their structure, akin to zeolite, primarily comprises imidazolidone rather than oxygen, endowing ZIF with a highly ordered pore structure and surface area, exceptional thermal stability and solubility, and mild synthesis conditions. These features contribute to ZIF outstanding gas adsorption capabilities and multifunctionality, making them suitable for various applications such as gas adsorption, storage, drug delivery, and biological imaging. ZIF-8, a prominent MOF variant, exhibits excellent biocompatibility, pH-responsive drug release, high drug loading capacity, and stability under physiological neutral conditions, while gradually decomposing in acidic microenvironments. As one of the most extensively researched and promising types of MOF, ZIF-8 has extensive applications in the biomedical field and is a series with the most research literature.

4.1.2 Porphyrin series

The Porphyrin Series MOF consist of crystal-structured materials, derived from porphyrin organic ligands and metal ions or clusters. Porphyrins, a class of N-heterocyclic compounds prevalent in nature, possess notable photophysical and photochemical properties, as well as biosafety. These attributes make them ideal organic ligands in MOF. The structural flexibility of porphyrins allows for diverse coordination modes, thereby facilitating their utilization as multifunctional carriers. This versatility significantly enhances the loading and precise release of diverse functional materials, such as drugs, thereby increasing efficacy and minimizing side effects. The Porphyrin Series MOF have shown promising applications in biomedical, optoelectronic, energy storage, and environmental management fields. Notably, PCN-222, a standout in this series, demonstrates exceptional capabilities in gas adsorption, drug delivery, biological imaging, and photocatalysis, garnering significant attention and research interest.

4.1.3 Universitetet i Oslo series

The Universitetet i Oslo (UiO) series, a collection of MOF, consists of crystal-structured compounds featuring metal ions (predominantly transition metals) and organic ligands. These MOF are distinguished by their highly adjustable pore structures and surface characteristics, alongside exceptional gas adsorption capabilities, chemical stability, and biocompatibility. UiO-66, a zirconium-based MOF, is a notable example, renowned for its orderly pore structure, efficient gas adsorption, and versatile applications in gas separation, energy storage, catalysis, and drug delivery.

4.1.4 Isoreticular MOF series

Introduced in the 1990s by Professor Yaghi et al.,^[33] the isoreticular MOF (IRMOF) series comprises a family of structurally analogous MOF, designated as IRMOF-n, where “n” signifies varying structures. Despite their structural similarities, these MOF offer modifiable pore structures and surface properties through alterations in ligand length and bridging group types. Owing to their varied configurations, high porosity, and exceptional gas adsorption capacities, IRMOF have garnered significant interest in materials science. Their potential applications include across gas storage, catalysis, drug delivery, separation technologies, sensors, and energy storage. Notably, MOF-5 has been particularly recognized for its unique structure and outstanding properties, making it particularly useful in hydrogen storage and gas separation.

4.1.5 Materials of Institute Lavoisier series

Named in honor of the French chemist Lavoisier, the materials of Institute Lavoisier (MIL) series comprises a diverse range of MOF renowned for their tunable pore structures, extensive surface areas, biocompatibility, and chemical stability. Such characteristics render MIL series MOF highly valuable for research and applications, particularly in gas storage, separation, catalysis, drug delivery, and environmental protection. Notably, MIL-100 has attracted considerable attention due to its outstanding pore structure, high surface area, CO₂ adsorption capacity, and catalytic efficiency, showcasing its potential in fields such as gas adsorption, catalysis, and biomedicine.

4.1.6 Other series

This section includes specific, lesser-known series such as the Northwestern University (NU) series. Developed by a team at NU, USA, the NU series MOF exhibit highly controllable pore structures, remarkable gas adsorption capabilities, and catalytic efficiency, finding applications in gas adsorption, separation, and catalysis. Another notable series is the HKUST-1 series, named after the Hong Kong University of Science and Technology. HKUST-1, a copper-based MOF incorporating copper ions and benzoic acid, demonstrates efficacy in catalytic reactions. This type of MOF is distinguished by its excellent gas adsorption performance, highly porous structure, and large surface area. These characteristics suggest potential for applications in gas adsorption, catalysis, and biomedical applications.

4.2.1 Current key challenges and needs in orthopedics

Orthopedic medicine currently faces several critical challenges and demands. A primary area of concern involves the treatment of complex fractures and repair of extensive bone defects, such as those encountered in postsurgical reconstructions and severe trauma cases.^[34] Additionally, there is a pronounced need for the development of biomaterials characterized by biocompatibility and degradability to mitigate the risks of rejection and secondary surgeries.^[35,36] Moreover, there is a growing anticipation for functional materials that support bone cell proliferation, enhance bone tissue formation, accelerate healing, and prevent infection.^[37,38]

In the realm of drug delivery and bioactive substance integration, there is an escalating requirement for precise drug delivery systems that optimize therapeutic effectiveness while reducing side effects.^[39] Bioactive substances in orthopedics necessitate stable carriers and suitable release mechanisms to ensure long-term efficacy. Furthermore, there is a pressing need for advancements in clinical therapy. This encompasses personalized and customized treatment strategies, considering individual patient needs and conditions, and integrating advanced technologies like 3D printing and nanotechnology. Such innovations aim to develop more effective, sustainable therapies, thereby driving progress in orthopedics.

4.2.2 Advantages of MOF material properties

MOF offer a plethora of benefits due to their diverse series and structures, making them highly advantageous in various applications, particularly in addressing orthopedic challenges.^[40] These materials herald new prospects for tackling different facets of orthopedic issues, potentially revolutionizing the field. The highly adaptable and multifunctional nature of MOF introduces novel approaches to orthopedic treatments. Their flexible structure can be customized to meet specific requirements,^[41] fulfilling multiple roles such as promoting bone tissue regeneration,^[42] and preventing infections.^{[24,43–44–45]} This adaptability is essential for meeting the intricate demands of orthopedic treatments.

Moreover, MOF are characterized by their extensive surface area and intricate pore structure,^[13,46] enhancing their capacity to carry higher drug loads and support bone cell adhesion and proliferation.^{[47–48–49]} This feature addresses the requirement for materials with larger surface areas in therapeutic applications. Some MOF exhibit excellent biocompatibility and degradability,^[50,51] maintaining stability under physiological conditions and efficiently decomposing posttreatment, thereby minimizing the risks of foreign body rejection and secondary surgeries. These materials also provide controlled drug delivery and release capabilities, facilitating precise and sustained drug administration by modulating their pore structure and chemical properties.^[39] This avoids the “burst effect” – an immediate, concentrated drug release – making them ideal for delivering radiotherapy and chemotherapy agents in bone tumor treatments.

Since MOF are synthesized through the coordination of organic ligands with metal ions, they can incorporate a variety of metal ions with specific physiological functions into their structures. For instance, MOF incorporating Mg²⁺, Zn²⁺, Cu²⁺, Zr²⁺, and Co²⁺ ions have demonstrated significant osteogenic effects through the controlled release of these ions.^{[40,52–53–54]} Additionally, these MOF exhibit antibacterial and antiinflammatory properties. These characteristics position MOF as a promising approach for the treatment of orthopedic diseases. In addition, the nanoscale dimensions and customizability of MOF cater to the demand for small, precisely engineered materials in orthopedics, enabling targeted applications in tissue engineering and potentially enhancing therapeutic efficacy while reducing side effects.^[14]

4.2.3 The in vivo application of MOF in orthopedic diseases treatment

Recent studies have highlighted the significant potential of MOF in orthopedics, particularly within the realms of bone tissue engineering and repair. In vivo investigations are essential for confirming MOF efficacy and functionality, setting the stage for potential clinical applications.

4.2.3.1 Bone defect models

Significant research has demonstrated the effectiveness of MOF, such as ZIF-8, in enhancing osteogenesis and angiogenesis in rodent models with critical-sized bone deficits (Table 6). The research conducted by Li et al.^[58] demonstrates the role of MOF in promoting bone regeneration through a bone defect model (Figure 5A). Another study^[69] showcases the superior chondroprotective and antisynovial hyperplasia effects of MOF at the level of joint tissues (Figure 5B), Both contribute to bone tissue regeneration by promoting osteoblast differentiation. Building upon this, Shen et al.^[70] research further illustrated MOF role in combating osteoporosis by inhibiting osteoclast differentiation (Figure 5C). Moreover, MOF composites have been formulated to modulate drug release for angiogenesis induction, and magnesium-based MOF scaffolds have been demonstrated to optimize the bone healing environment.^{[60–61–62–63]} MOF hydrogel nanocomposites releasing cobalt ions have proven effective in vascular and bone tissue regeneration.^[67] These findings highlight MOF potential as multifaceted, bioactive scaffolds in bone tissue engineering, capable of orchestrating the release of biologically active molecules.

Table 6

Literature related to bone defect modeling.

Authors	Research findings and conclusions	References
Xue et al.	MOF triggered the recruitment of bone marrow mesenchymal stem cells by providing pH-responsive release of Zn2+ ions and provided the underlying microenvironment for osteoblasts, ultimately enabling simultaneous bone and vascular repair	[55]
Toprak et al.	Encapsulating BMP-6 within the ZIF-8 has shown significant efficacy in bone regeneration, attributable to the sustained and controlled release of BMP-6	[56]
Feng et al.	Encapsulation of MicroRNA using ZIF-8 notably enhances its stability against degradation, improves cellular absorption, and facilitates endosomal escape. This process significantly contributes to the promotion of osteogenesis and angiogenesis	[57]
Li et al.	Zeolitic imidazolate framework-8, infused with deferoxamine (DFO), effectively modulates the release of DFO and Zn2+, significantly enhancing angiogenesis and osteogenesis	[58]
Kang et al.	Exosome-functionalized magnesium organic frameworks synergize the advantages of magnesium ions, gallic acid, and exosomes from human adipose stem cells, enhancing osteogenesis and angiogenesis while exhibiting antiinflammatory effects, simultaneously improving the biocompatibility and functionality of the scaffold in bone regeneration	[19]
Lao et al.	Metformin-loaded ZIF-8 nanoparticles, a type of MOF, were integrated with methacrylated gelatin hydrogels to form a composite. The composite’s effectiveness lies in the combined action of metformin and zinc ions released from the MOF, which synergistically disrupts the ROS-inflammation cycle, thereby facilitating bone regeneration in diabetic conditions	[59]
Al-Baadani et al.	Alendronate-loaded ZIF-8 nanoparticles were successfully incorporated into electrospun nanofibers, forming a novel MOF composite. This innovative MOF-based material demonstrates significant potential in promoting bone regeneration and inhibiting osteoclast formation, offering a viable solution for treating osteoporotic bone defects	[60]
Xu et al.	The integration of exosomes with MOF-modified scaffolds facilitates a dual synergistic release of bioactive copper ions and exosomes, significantly enhancing bone regeneration and angiogenesis	[61]
Xu et al.	MOF composites, consisting of MIL-88 loaded with dimethyloxallyl glycine (DMOG) and combined with poly (lactic acid-co-glycolic acid) (PLGA), promote bone regeneration and vascularization in damaged areas. This effect is achieved through the synergistic release of DMOG and ferric ions	[62]
Zheng et al.	The magnesium-based metal-organic framework (Mg-MOF) scaffold significantly enhanced the bone repair microenvironment, markedly improving bone regeneration. This was achieved through the regulation of macrophage polarization, angiogenesis, and osteogenesis	[63]
Zhu et al.	These variants of Mg-MOF74 promote osteogenesis and angiogenesis, processes critical for bone formation and the development of new blood vessels, respectively. The nano-sized Mg-MOF74, in particular, is distinguished by its superior biological interactions and the continuous release of magnesium ions, making it especially suitable for biomedical applications	[64]
Gao et al.	Nano-structured ZIF-8 (nano ZIF-8) has shown considerable promise in facilitating the differentiation of rat bone mesenchymal stem cells (rBMSCs) into osteoblasts, thus promoting osteogenesis in both in vitro and in vivo settings. Furthermore, nano ZIF-8 endocytosis predominantly influences the canonical mitogen-activated protein kinase (MAPK) pathway, which plays a crucial role in the osteogenic differentiation of rBMSCs	[65]
Zhang et al.	Encapsulation of DMOG within nano-structured ZIF-8 nanoparticles significantly promotes osteogenesis and angiogenesis. The efficacy of this approach is linked to ZIF-8 nanoparticles’ proficient drug delivery and prolonged release properties	[66]
Sun et al.	An innovative hydrogel composed of a MOF designed for bone repair applications. The MOF-based composite material facilitates the controlled release of cobalt ions, effectively simulating hypoxia to enhance angiogenesis and osteogenesis	[67]
Liu et al.	The ZIF-8 modified hydrogel, meticulously engineered for bone regeneration. This hydrogel significantly enhances bone adhesion and mechanical stability while actively fostering angiogenesis and osteogenesis. Furthermore, its biocompatibility, combined with antibacterial attributes, effectively reduces the risk of infections after surgery.	[31]
Dong et al.	The MOF hydrogels, characterized by their pH-responsive nature, are engineered to selectively release biomolecules in reaction to pH fluctuations. This targeted release mechanism is crucial in effectively regulating inflammatory responses, as well as fostering angiogenesis and osteogenesis	[68]

4.2.3.3 Models of internal implant-associated infections

Recent progress in antibacterial coatings for titanium implants using MOF is noteworthy, particularly in preventing postsurgical infections and improving osteointegration. Bailong Tao and his team have pioneered the development of a multifunctional hybrid coating incorporating ZIF-67 nanoparticles on titanium substrates.^[74] This innovative coating has exhibited potent antibacterial properties against both Escherichia coli (Gram-negative bacteria) and Staphylococcus aureus (Gram-positive bacteria) in infected femoral animal models (Figure 6A). Furthermore, in addressing deeper levels of biofilm infections, Zhang et al.^[75] have developed ultrasound-activated, copper-doped porphyrin MOF-based nanodots that effectively mitigate implant biofilm infections (Figure 6B). Other innovations include Mg/Zn-MOF coatings,^[24] simvastatin-loaded MOF with polydopamine nanolayers,^[76] Co-MOF coatings with osteogenic growth peptides,^[47,74,77] and pH-responsive ZIF-8 frameworks containing antibiotics.^[78] These advancements play a pivotal role in the creation of orthopedic implants that exhibit superior biocompatibility and resistance to infection.

4.2.3.4 Tumor models

In the management of bone tumors, early studies leveraging 3D printing technology have shown that MOF scaffolds can effectively dissolve bone tumors in animal models. Due to their tunable structure, high loading capacity, biocompatibility, ease of modification, and functionalization, researchers increasingly utilize MOF as platforms for targeted drug delivery. Ma et al.^[79] developed a nanoplatform featuring an Au nanoparticle core with a dual shell comprising MOF and mesoporous silica, which demonstrated exceptional antitumor efficacy and significantly reduced bone resorption (Figure 7A). Further advancements by Tao Li and team explored novel approaches in combating the antiradiation and immunosuppressive microenvironments associated with metastatic osteosarcoma,^[80] culminating in the creation of a Ta-Zr codoped nano-MOF (TZM). This innovation marked a pioneering step in enhancing the efficacy of radiotherapy and radiodynamic therapy, eliciting strong antitumor immune responses and establishing TZM as a potential multifaceted radiosensitizer (Figure 7B). Moreover, the integration of MOF in sonodynamic therapy and as platforms for multimodal cancer treatment highlights their critical role in the development of personalized, minimally invasive, and precision-targeted therapeutic approaches.^[81,82]

In summary, MOF exhibit significant potential in the treatment of orthopedic diseases. However, the effectiveness of MOF varies across different conditions, with distinct advantages and limitations in each case. (1) In fracture repair, MOFs’ primary advantage lies in their ability to control the release of metal ions such as magnesium, calcium, and zinc, which promote osteoblast proliferation and differentiation, thereby accelerating bone tissue regeneration and effectively shortening the healing time. Additionally, MOF can be used for localized antiinflammatory and bone regeneration drug delivery, enhancing therapeutic efficacy due to their adjustable drug release properties. However, degradation of MOF may produce immunostimulatory byproducts that could trigger local inflammatory responses.^[83] (2) MOF have demonstrated promise in treating osteoporosis by promoting bone matrix mineralization, increasing bone mineral density, and addressing bone loss through the delivery of antiresorptive drugs. Some MOF also possess antiinflammatory and antioxidant properties, which may help mitigate bone degeneration. Nevertheless, their long-term stability and biodegradability in vivo require optimization to ensure safety and efficacy in managing osteoporosis over extended periods.^[40] (3) In bone tumor therapy, MOF offer distinct advantages by enabling targeted drug delivery, enhancing the concentration of antitumor agents at the tumor site while minimizing damage to healthy bone tissue. Furthermore, MOF can be combined with antimicrobial therapies to reduce the risk of postoperative infections. However, biologically active degradation byproducts may provoke local immune responses or adverse physiological effects, emphasizing the need for stringent safety standards in clinical applications.^[84] (4) Research on MOF in osteoarthritis treatment has largely focused on their antiinflammatory and slow-release drug capabilities. By releasing metal ions such as copper and zinc, MOF can directly inhibit inflammatory responses while also serving as carriers for antiinflammatory drugs or biologics to enhance therapeutic efficacy. However, certain metal ions may be toxic to joint tissues, particularly when used for prolonged periods or at high doses.^[85,86] Moreover, the therapeutic potential of MOF remains limited in cases of severely degenerated joint tissues. (5) The primary application of MOF in osteomyelitis treatment is their antimicrobial properties and targeted delivery capabilities. MOF can facilitate the loading and controlled release of antibiotics, increasing drug concentration at the infection site, enhancing antimicrobial effectiveness, and reducing the side effects associated with systemic antibiotic use. However, due to the need for prolonged implantation, the biocompatibility of MOF degradation products must be thoroughly evaluated to minimize potential immune reactions or toxic side effects.^[87,88]

Future research should focus on the following areas to optimize the application of MOF in orthopedic diseases: (a) Optimizing the synthesis process of MOF: Developing more efficient and controllable synthesis methods to improve biodegradability and ensure that degradation products do not exhibit toxic side effects on bone tissue or other organs. (b) Enhancing the long-term stability and controlled drug release of MOF: Improving the chemical stability of MOF in vivo through material modification or surface functionalization, enabling precise and controlled drug release to improve therapeutic outcomes. (c) Reducing the synthesis cost of MOF: Current synthesis methods are complex and costly, limiting their feasibility for large-scale clinical application. Future research should focus on developing simpler, more efficient, and cost-effective synthesis techniques to facilitate their application in orthopedic clinics. (d) Developing multifunctional MOF: Introducing additional functionalities, such as antitumor, antibacterial, and antioxidant properties, to enable MOF to address multiple aspects of orthopedic disease treatment, including bone tissue regeneration, inflammation control, and infection prevention.

4.2.4 Challenges in applying MOF materials in orthopedic clinics

Despite the vaired functional roles of MOF in orthopedics, identified through in vitro and in vivo animal studies, their application in orthopedic clinics faces significant challenges. Initially, while MOF have demonstrated biocompatibility and stability in simulated human physiological environments and animal studies, the complex, dynamic, and variable physiological environment of the human body, with its fluctuating pH levels, presents a stark contrast to animal models.^[89,90] This raises concerns about their stability and performance in humans, necessitating comprehensive studies on their response and stability across various biological environments, and their long-term safety and stability in vivo.

Moreover, most in vivo studies do not solely depend on MOF but combine them with other functional materials. Ensuring consistent quality and controllability of these MOF composites during fabrication is a formidable challenge. The effect of MOF composites also varies with size.^[91] Additionally, as drug carriers, nano-MOF must ensure stable and efficient drug release, prevent accumulation in biological media,^[92] and manage the complex interactions between drugs and MOF.^[51] The behavior, metabolism, and decomposition of MOF within the human body remain incompletely understood, making it challenging to develop techniques for accurate assessment and monitoring within organisms.

Finally, our literature review revealed no studies or reports on the use of MOF materials in orthopedic clinical settings. Thus, there is a need for more extensive research, support from preclinical trial data, and technological advancements to ensure the safe and effective use of MOF materials in clinical orthopedics.^[93]

4.3.1 Enhancement of MOF material applications through international and institutional collaboration

Our analysis of publication data reveals a dominant role of China in MOF materials research within orthopedics, both in terms of publication volume and international collaboration strength. Notably, partnerships have expanded with countries such as the United States, the United Kingdom, Germany, Australia, and Singapore, enhancing knowledge and expertise exchange. Institution-level analysis underscores the pivotal contributions of the Chinese Academy of Sciences, Sichuan University, and Shanghai Jiao Tong University, underlining their leadership in this field. Examination of author collaboration networks has identified key authors and clusters, highlighting the importance of these collaborations in advancing research. Looking forward, enhanced cross-institutional and international collaborations are anticipated to further propel the field, driving innovation and facilitating knowledge sharing.

4.3.2 Multidisciplinary field linkage to accelerate MOF in clinical application

Despite extensive research has been conducted on MOF materials in orthopedics, the translation of these findings into clinical applications remains a lengthy process. The development of MOF materials requires interdisciplinary expertise, encompassing materials science, chemistry, engineering, biomedical science, and clinical medicine, as evidenced by the diversity of author research areas in relevant literature.^{[20,26,69,72,94–95–96]} For successful clinical application, a collaborative effort is essential: first, to tailor MOF materials to specific clinical needs; second, to evaluate their safety and efficacy in living organisms; and third, to conduct preclinical studies in a clinical context to assess their practical viability. This necessitates subsequent material adjustments and optimizations for clinical utility.^[51] Consequently, a multidisciplinary collaborative approach will not only expedite the development and application of MOF materials in orthopedics but also facilitate their transition from laboratory to clinical settings. Such collaboration will broaden the scope of MOF applications in orthopedics, offering new therapeutic options and potentially enhancing patient quality of life. Moreover, this collaborative model may yield numerous applications across various disciplines.^[93,97,98]

Our study faces certain limitations, it is confined to a single database, WOSCC, potentially leading to an incomplete collection of relevant literature. Nevertheless, WOSCC is among the world’s most extensive and comprehensive databases, offering a substantial volume of literature that adequately represents the current state of research in this field and is widely utilized by scholars. Additionally, the impact of recent high-quality publications may be underestimated due to low citation rates. Furthermore, our analysis exclusively includes articles published in English.