Abstract
Bone tissue engineering is pivotal in facilitating bone reconstruction by promoting persistent angiogenesis and osteogenesis. Initially, the hot gel composite hydrogel scaffold technique was employed. However, to address various limitations, numerous gel structures have since been developed, including osteogenic gellan gels, semi-interpenetrating network hydrogels, photoinduced crosslinking methacrylate gels, and supramolecular hydrogels. This review examines the mechanisms, formation principles, and medical benefits of these gel structures. In addition, novel bioengineering techniques to regulate human bone growth are expected to emerge in the future. This work is expected to significantly expedite the advancement of hydrogel membranes in the field of bone repair.
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Introduction
A hydrogel is a three-dimensional (3D) network structure composed of hydrophilic polymer chains with a high content ranging from 90% to 99%, which facilitates efficient oxygen and substance exchange1. In recent decades, a variety of natural hydrogels (e.g., alginate (Alg)/gelatin) and synthetic hydrogels (e.g., gelatin-PEG and PAAm/Dex-U) have undergone unprecedented development in biomedical fields due to their high porosity, satisfactory nutritional permeability, high biocompatibility, low immunogenicity, and tunable physical and chemical properties2,3,4. Compared to other organic molecules or polymers, the multimolecular structure of hydrogels can provide a suitable matrix for cell transplantation and differentiation, endogenous regeneration, biorepair, wound healing and continuous drug delivery5,6,7,8. Moreover, the 3D network system of hydrogels can simulate the microstructure of the extracellular matrix (ECM) and provide a suitable environment for cell survival9,10,11,12.
In contemporary society, diseased or damaged bone tissue is a common clinical problem in orthopedic medicine, and bone has become the second most frequently transplanted tissue after blood13,14,15. Although both nonsurgical (e.g., casting, electrical stimulation, and ultrasound therapy) and surgical approaches (e.g., internal fixation, external fixation, bone grafting and bone regeneration) have been applied for bone repair, these existing treatments may not be suitable for all types of bone diseases16. For example, autologous or allogeneic bone transplantation is commonly used for treating bone defects; however, this therapy can cause damage at the donor site, and acquiring suitable donors can be challenging17,18. To address the aforementioned problems, bone tissue engineering utilizing hydrogels or hydrogel membranes as scaffolds has emerged as a promising solution. To the best of our knowledge, hydrogels composed of crosslinked polymer chains represent a unique class of scaffold materials characterized by a 3D hydrophilic network structure that can maintain its stability even after absorbing several times its own volume of water19,20,115. (b) Biomaterials: Biomaterials can be used to provide a scaffold for cell growth to promote bone regeneration. Synthetic biomaterials, such as polycaprolactone (PCL) and poly(lactic-co-glycolic acid) (PLGA), can be used to create 3D scaffolds that mimic the structure of natural bone tissue. These scaffolds can then be seeded with bone-forming cells and implanted at the site of bone injury to promote bone regeneration116,117,Bone substitutes Bone substitutes are biomaterials that can be used to replace or supplement bone tissue when the body is unable to heal itself or to aid in bone regeneration. They can be used in a variety of applications, including the repair of bone defects resulting from trauma, disease, or surgical intervention125,126. There are several types of inorganic and organic bone substitutes. (a) Ceramics: Ceramic bone substitutes, such as calcium phosphate and hydroxyapatite, are biocompatible and can stimulate bone growth. They are often used in dental implants, as well as in the repair of bone defects. (b) Polymers: Polymer bone substitutes, such as PCL, PLGA and some hydrogels, can serve as scaffolds for cell growth and bone regeneration. They can also be used to release growth factors or other signaling molecules to promote bone healing. (c) Metals: Metal bone substitutes, such as titanium and its alloys, are commonly used in orthopedic applications. These materials are solid and durable and can be designed to closely match the mechanical properties of natural bone tissue. (d) Composite materials: In composite bone substitutes, two or more materials, such as ceramics and polymers, are combined to achieve the desired properties for bone repair. For example, a composite material may be designed both to provide mechanical support and to promote bone growth. Bone substitutes can also be categorized as either synthetic or natural matrices. Synthetic bone substitutes are usually made from materials such as ceramics, polymers, or metals, while natural bone substitutes are derived from biological sources such as human or animal tissue. Morais et al. synthesized injectable hydrogel bone substitutes by combining Alg, chitosan, and hyaluronate (HA) with glass-reinforced hydroxyapatite (GR-HAP). At pH 7.4, the Alg/HA hydrogel exhibited 80% degradation, which lasted for three days. The results indicated that all the hydrogels exhibited non-Newtonian viscoelastic fluid characteristics with low maximum extrusion forces, making them suitable as carriers for bone substitutes. Although the use of bone substitutes is a promising approach for bone repair, these approaches are not without limitations127,128,129,130,131. For example, they may not be able to mimic the complex structure and mechanical properties of natural bone tissue. Additionally, there is a risk of immune response or rejection if the material is not biocompatible or is derived from an animal source. Ongoing research in this area has focused on improving the properties of bone substitutes and develo** more effective strategies for bone repair. Implant coatings are thin layers of material that are applied to the surface of an implant to enhance its biocompatibility and promote tissue integration140,141. Hydrogels have great potential as coatings in the field of bone repair due to their unique properties and versatility142. As shown in Fig. 4, antibacterial hydrogels have become increasingly popular for antimicrobial and orthopedic applications. To date, a wide range of anti-infective hydrogels have been developed and utilized for orthopedic implants, encompassing natural matrices such as hyaluronic acid (HA), synthetic matrices such as polyethylene glycol (PEG), and composites such as HA + polylactic acid (PLA). These materials possess distinct properties that can effectively combat implant-associated infections. However, additional research is needed to fully explore the effectiveness and safety of these agents in clinical applications. Reproduced with permission142. Copyright 2021, American Chemistry Society. Overall, hydrogels have attracted substantial attention for bone repair and bone regeneration. Due to their 3D network structure and their advantageous mechanical and biological properties, hydrogels can be utilized as bone substitutes and in tissue engineering applications. Additionally, hydrogels can serve as versatile platforms for cell and drug delivery systems, enabling controlled release in response to environmental stimuli during therapeutic processes. Therefore, the precise release of bone stem cells, drugs, and antimicrobial agents supports cell growth and proliferation, promoting osteogenesis and regeneration in various clinical scenarios. The use of hydrogels as implant coatings can effectively reduce bacterial adhesion and increase long-term durability. The aforementioned studies support the potential of hydrogels as promising vehicles for enhancing bone repair and regeneration. All of these functions of hydrogels in bone repair and the underlying mechanisms are summarized in Table 2.Implant coatings
Summary
Construction strategy of hydrogels for bone repair
Semi-interpenetrating network hydrogels (semi-IPNs)
In semi-IPNs, specific polymer-based networks are crosslinked to other polymer chains, resulting in improved physicochemical properties, such as biocompatibility, mechanical strength and suitable rheological properties. For instance, Park et al. reported a semi-IPN structure containing cellulose nanofibers (CNFs) with a high aspect ratio of 240 and a polyacrylamide (PAM) mesh. Due to the strong interaction between the PAM network and rigid natural nanofibers, the compression strength of this semi-IPN system up to 3-fold higher than that of pure PAM143. Intriguingly, the PAM/BCNF composite hydrogels can be utilized for mechanical stress-responsive drug release and delivery. Similarly, this kind of hydrogel has shown great potential in the field of bone repair. For instance, Cui et al. designed semi-IPNs (OSA/Gel/CNF) through a facile one-step reaction of oxidized alginate (OSA), cellulose nanofibers, and gelatin (Gel), which mainly relied on the cooperative effects of hydrogen bonds and imine bonds32. As shown in detail in Fig. 5, during the synthesis of OSA/Gel/CNF from its three components, OSA acted as a natural reagent to link Gel via Schiff base reactions between amino and aldehyde groups, whereas CNFs formed hydrogen-bond interactions. The advantages of these semi-IPNs are as follows: (1) Compared to SA, OSA is more readily degraded in vivo and is more suitable for cell encapsulation. (2) The semi-IPNs exhibited both excellent mechanical properties and a high compressive modulus (>361.3 KPa). (3) As a result, the semi-IPNs showed good injectability and self-healing ability, both of which are promising for bone repair applications.
Reproduced with permission32. Copyright 2023, Elsevier.
Interpenetrating network hydrogels (IPNs)
The design of IPNs, which consist of intertwining double hydrogel networks in a single system during gelation, is considered another effective strategy for bone repair. IPNs can synergistically present the advantages of both types of network, including biocompatibility and high mechanical strength. As shown in Fig. 6a, Macdougall et al. synthesized flexible poly(ethylene glycol)-only (PEG) interpenetrating meshes by the addition of unfunctionalized polysaccharides144. Here, the PEG-based hydrogels were first obtained in phosphate-buffered saline (PBS) through a reaction between the alkyne and thiol end groups (nucleophilic thiol-yne click reaction). Simultaneously, some unfunctionalized natural polymers (e.g., chitosan, gelatin, heparin, alginate, HA, etc.) were incorporated to form a secondary loose crosslinked network driven by electrostatic forces. This strategy endows the crosslinked IPNs with good stretchability and enhanced tensile performance (Fig. 6b), as well as self-healing capabilities (Fig. 6c). Therefore, IPN materials possess the advantages of both of their component systems and can effectively overcome the disadvantages associated with each network. Consequently, these materials have potential for further application in bone repair.
a Synthetic procedure for PEG-based hydrogels. b Measurements of tensile stress/strain and self-healing properties. Reproduced with permission144. Copyright 2018, Royal Society of Chemistry.
Hybrid hydrogels
Bioactive glass composite hydrogels
The periosteum is known to play key roles in mineralization, vascularization and protection during bone tissue regeneration145. However, many existing artificial periosteal grafts focus only on protection and lack the functions of osteogenesis and angiogenesis. **, have been employed to construct hydrogel materials (i.e., semi-IPNs, IPNs and hybrid hydrogels), which hold promise for fulfilling the material requirements for the clinical treatment of bone defects. In particular, different factors, including bioactive glass, cells or proteins, inorganic matrices (e.g., CaCO3), 2D nanosheets (e.g., black phosphorus) and nanoparticles (e.g., CdS NPs), have been incorporated into conventional hydrogel systems to investigate their effects in the treatment of bone defects. Accordingly, a synergistic treatment strategy has become crucial for the development of high-performance hydrogel systems whose osteogenic properties can increase therapeutic efficacy.
Conclusion and outlook
To effectively address bone defects, various therapeutic strategies, encompassing nonsurgical approaches such as casting, electrical stimulation, and ultrasound therapy as well as surgical interventions such as internal fixation, external fixation, bone grafting, and bone regeneration, are commonly employed in clinical practice. The limitations of these traditional treatment modalities, such as the risks associated with immune rejection, donor site injury, and transmission of infectious diseases, emphasize the urgency and challenge of the development of high-performance biomaterials.
The development of high-performance and multifunctional biomaterials for the treatment of bone defects is essential. At present, three types of materials are used in bone tissue engineering: naturally derived biomaterials, synthetic biomaterials, and metal materials. The earliest application of bone tissue engineering involved mainly thermal-composite hydrogels, but the ossification performance of this method was poor, so osteogenic hydrogels were developed by thermal annealing154,155. At that time, the main goal was to study the biomechanics of embryonic cartilage. Later, scientists used a solvent-free process to combine glial mesenchymal stem cells with human umbilical vein endothelial cell (HUVEC)-loaded hydrogels to prepare polyamine-modified calcium silicate/polycaprolactone scaffolds. The gelatin was modified with methacrylic anhydride to obtain photo crosslinked methacrylic gelatin. By photocrosslinking with methacrylate gelatin, the hydrogel films were prepared to release Ca and Si ions in a controlled manner at the early stage of bone regeneration for the long-term promotion of osteogenesis156,157,158. Since then, great breakthroughs have been made in bone tissue engineering, and a tough and flexible amphoteric copolymer-based hydrogel with bioactive groups has been created for bone regeneration. In 2019, Hasani’s group developed a unique bioinspired adhesive hydrogel with tunable mechanical properties and biodegradability that has been applied in dental clinical medicine. Subsequently, Wojda et al. developed a biomaterial system for the delivery of hydrogels to significant bone defects to promote bone regeneration159.
With the ongoing development of materials science, numerous multifunctional materials have emerged and been applied in various aspects of biomedicine. In recent years, hydrogels have been considered promising candidate materials for tissue engineering and bone repair research due to their structural and compositional similarity to the ECM, high water content, satisfactory biocompatibility, and tunable biophysical and biochemical properties160,161. In addition, some hydrogels also have the advantages of low cost, multifunctionality, renewability, degradability, and excellent biocompatibility159,162,163. Therefore, the present study offers a comprehensive overview of the recent advances and challenges in the utilization of hydrogels for bone repair and regeneration. The application of hydrogels in the field of orthopedics has focused mainly on tissue engineering, wound healing, and drug delivery. Excitingly, some research results have been applied in clinical practice. A variety of hydrogel structures, including osteogenic gellan gel, semi-interpenetrating network hydrogels (semi-IPNs), interpenetrating network hydrogels (IPNs), and photoinduced crosslinking methacrylate gelatin (MAGel), have been described. The functional, mechanistic, and medical advantages of these hydrogel structures are thoroughly examined in this review. With the development of hydrogels and bone repair techniques and further understanding of the cellular signaling mechanisms involved in tissue repair, hydrogels will be able to mimic the natural ECM more accurately and play a more effective role in bone and soft tissue engineering.
According to previous reports, conventional synthetic hydrogels still present several disadvantages and challenges, such as an isotropic network structure, insufficient mechanical properties, weak tissue adhesion and lack of bone conductivity. Most hydrogels serve as carriers rather than promoters of bone healing. The development of dual-functional or multifunctional hydrogels and their composites represents an intriguing research topic. Considering the diverse structures of hydrogels, it is essential to elucidate structure-property relationships to better understand the principles and mechanisms involved in bone repair. Furthermore, research on microfabrication techniques, including 3D printing, is necessary to achieve controllable nanostructures and large-scale production164,165,166,167,168. Therefore, collaborative research efforts are still needed to enhance the performance of these materials in the field of bone healing. The development of novel and highly efficient hydrogel systems could revolutionize bone defect treatment.
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Acknowledgements
This work was supported financially by the National Natural Science Foundation of China (Nos. 81772433 and 62304148), the Great Discipline Construction Project from Minhang District, Shanghai (No. 2017MWDXK04), Research in Cutting-Edge Technology of Suzhou (No. SYG202351), and the China Postdoctoral Science Foundation (No. 2023M730653).
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W. Ding and Y.X. Ge contributed equally to this work. All the authors contributed to the writing, review, and editing of the manuscript.
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Ding, W., Ge, Y., Zhang, T. et al. Advanced construction strategies to obtain nanocomposite hydrogels for bone repair and regeneration. NPG Asia Mater 16, 14 (2024). https://doi.org/10.1038/s41427-024-00533-z
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DOI: https://doi.org/10.1038/s41427-024-00533-z
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