Tissue and implant engineering have also benefited from the utilization of nanotechnology. The ability to modify the material’s surface texture and increase its surface area at the nanoscale is expected to result in improved osteogenic cell responses and efficient mechanical contact between the implant and tissue. There are three potential applications for metallic and metallic oxide nanoparticles in the field of bone science: delivery of bioactive molecules, labeling of cells, and improvement of orthopedic implants and scaffolds. The size (typically between 10 and 100 nm) and substantial surface area of nanoparticles render them optimal for the transportation of bioactive molecules, including genetic materials, pharmaceuticals, and growth factors (Kyllönen et al., 2015). Furthermore, orthopedic scaffolds and implants are capable of releasing metallic and metallic oxide nanoparticles that exhibit rapid responses to environmental stimuli, including but not limited to temperature, pH, magnetic field, and other relevant parameters (Walmsley et al., 2015). The integration of nanoparticles with orthopedic scaffolds or implants has the potential to enhance the rate of bone regeneration and facilitate targeted treatment. In conclusion, it is imperative that orthopedic scaffolds and implants possess adequate mechanical strength and biocompatibility. The exceptional mechanical and biological properties, as well as their potent antimicrobial capability, have contributed to the widespread application of nanoparticles in bone-related research (Grass et al., 2011). Specifically, because numerous commercial implants lack antimicrobial potential, which may result in infection or implant failure (Coelho et al., 2019a). To inhibit the development of bacteria, orthopedic scaffolds, and implants may be loaded with drugs like antibiotics. Therefore, it is possible to provide orthopedic implants or scaffolds with sustained antimicrobial activity by coating them with metallic and metallic oxide nanoparticles. In addition, metallic oxide and metallic nanoparticles can be utilized to strengthen scaffolds or enhance the growth rate of bone-related cells at specific dosages (Khoshroo et al., 2017; Zhu et al., 2019a). Consequently, these nanoparticles possess the capability to perform numerous functions concurrently. Orthopedic implants for internal fixation and weight-bearing are typically comprised of metals and alloys. To ensure load-bearing capabilities at the implantation location as well as minimal movement between the implant and host tissue, these implants are firmly attached to bones. Despite the extensive availability of these materials, only a small number of them possess the required biocompatibility and are therefore being successfully employed in long-term implant applications. For example, surgical-grade stainless steel is employed in temporary implants (like fracture plates and hip nails), titanium is used in joint and bone replacement, magnesium is used for load-bearing in biodegradable orthopedic implants, and cobalt-based alloys are used in orthopedic prostheses (for shoulder, hip, and knee) (Bandyopadhyay et al., 2019; Julmi et al., 2019; Zhang and Chen, 2019; Zlotnik et al., 2019). Specific mechanical characteristics are necessary for (i) stabilizing or promoting the fracture integrity, (ii) replacement of joints, and (iii) realignment of bone fragments in orthopedic usage of biomaterials. Patients with diverse medical conditions necessitate orthopedic scaffolds and implants to fulfill their specific mechanical and biological demands. During bone reconstruction, several clinical challenges are faced by surgeons due to patients’ varied anatomical sites, defect sizes, physical conditions, mechanical characteristics, and other factors. (Polo-Corrales et al., 2014). Research on bones has benefited from recent advancements in biomaterial sciences, bio-manufacturing, nanotechnology, and tissue engineering (Mohammadi et al., 2018). The characteristics of metallic and metallic oxide nanoparticles, including gold, silver, magnesium, and zirconia, among others, have been thoroughly documented by numerous researchers.

Many non-metallic materials show advanced features suitable for structural implantation. These include crystalline ceramics, polymeric materials, carbon composites, and amorphous glasses. Their poor mechanical properties as well as intrinsic bio-incompatibility, have restricted the widespread use of these materials. Significant efforts have been devoted to enhancing non-metallic materials for their use as structural implants over time (Terzopoulou et al., 2022). The advancement of nanotechnology has facilitated the development of a diverse array of nanophase (100 nm particle size) constituents, including composites, polymers, and ceramics, each possessing distinctive surface properties. Several of these materials exhibit enhanced capabilities in osseo-integration and the formation of new bone (Zhang and Webster, 2009). The more favorable environment provided by nanomaterials for osteoblast function and bone ingrowth results in the formation of a bioactive layer that is adherent, thereby mitigating issues such as implant loosening. To emulate the complex nanostructures found in natural bone, implants’ coatings are modified with nanoscale features, including carbon nanofibers and nanotubes. In joint replacement components, the friction and wear characteristics may be enhanced using nanostructured ceramics. Furthermore, due to their improved osseo-integration and bone regeneration capabilities as well as their ease of fabrication, biocompatibility, flexibility, and appropriate electro-mechanical characteristics, polymer-based materials are favored for (i) controlled drug delivery vehicles. And (ii) porous tissue engineering scaffolds (Al-Shalawi et al., 2023). Polymers, as opposed to metallic implants, possess the capacity to (i) progressively shift stress to a region that has been damaged, enabling appropriate tissue healing, and (ii) restore the function of tissue naturally without the need for catalysis or enzymes (Jain et al., 2022). The material that interfaces the human body and the implant device has to be carefully selected before the installation of implants in the body. These materials should have the capability to impede the transfer of waste material. Polyglycolide (PGA), poly (lactic acid) (PLA), polyhydroxyalkanoates (PHAs), ultra-high molecular weight polyethylene (UHMWPe), polyvinylidine fluoride (PVDF), and polyether ether ketone (PEEK) are the most frequently employed polymers for packaging of orthopedic implants (Gautam et al., 2022). A self-reinforced poly (lactic acid)-b-poly (lactide-co-caprolactone) block copolymer was reported by Wang et al. which manifested enhanced biocompatibility and controlled in vitro degradation via the generation of a highly oriented structure for orthopedic application (Wang et al., 2022). Yoon et al. reported a block copolymer consisting of polylactic acid and polyglycolic acid, characterized by excellent biocompatibility and a controlled biodegradation rate. This material was deemed suitable for application in resorbable spinal fixation materials (Yoon and Chung, 2022). Using varying laser powder bed fusion processing parameters, Schappo et al. examined the usage of various concentrations of spray-dried hydroxyapatite particles suspended within a polymeric matrix of ultra-high-molecular-weight polyethylene (UHMWPE) for bone tissue engineering (Schappo et al., 2022). However, the primary issues with polymers involve temperature increase and wear-dependent deformation under loading conditions, which are analogous to corrosive loss observed in metallic implants (Sabir et al., 2009). An appropriate crosslinking technique might be used to tackle UHMWPe’s most prevalent issue, referred to as oxidative deterioration, which is caused by shelf aging. Nevertheless, considering their low metal friction coefficient, they appear to be more suitable for implementation as a bearing surface in total joint devices (Sobieraj and Rimnac, 2009).

Due to their good biocompatibility, superior wear and corrosion resistance, high compressive strength in load-bearing conditions in the human body, and appropriate chemical stability in the physiological environment, ceramics and other non-metallic materials, have drawn significant interest for these applications (Shaaban et al., 2022). Hydroxyapatite (HA), silicon oxide, Calcium phosphates (CaP), and bioglass are the most popular ceramics used in orthopedic devices (Díaz-Cuenca et al., 2022; Montazerian et al., 2022; Van Rijt et al., 2022). CaP ceramics’ strong reactivity and biocompatibility make them particularly appealing as implant coatings. Strong implant fixation and rapid bone development are facilitated by the CaP porous implant coatings. These substances are neither fragile nor easily compressed. The main problem with ceramics is that they have a high noncompliant elastic modulus in contrast to the bone, which may lead to acetabular socket fractures or loosening. These materials’ success relies on their capacity to promote bone growth and regeneration at the tissue-implant interface (Reyes Rojas et al., 2023). Due to their weak ductility and brittleness, they have not yet been utilized for fracture fixation.

Currently, several efforts have been carried out to modify common biomaterials for bone regeneration and fusion with neighboring bone tissues (Thibault et al., 2013). Regarding their ability to precisely direct and impact the functions of cells and tissues in preparation for implantation at a particular location, however, more advancements are still required. Nanotechnology has drawn a lot of focus in the last 10 years due to the development of numerous nanomaterials via various physical, chemical, and biological processes. Natural tissues and organs can readily interact with nanostructured extracellular matrices due to their diverse dimensions (Kumar et al., 2017b; Dogra et al., 2018).

A biofilm is a highly organized, intricate, and spatially organized network where the majority of pathogenic microorganisms that are affiliated with the host can be found (Yazici et al., 2016). The extracellular matrix (ECM) that makes up biofilms comprises the bacteria’s secreted exopolysaccharides (EPSs), extracellular DNA, proteins, and specific quorum-sensing proteins needed for cell-to-cell transmission. Various bacterial populations are packed within the ECM. The surface characteristics of the implant, including hydrophobicity, physicochemical properties, roughness, and charge, play a crucial role in initiating biofilm formation by these microbes. Biofilm formed on implants or medical devices is more resistant to host defense mechanisms as well as antibiotics, in comparison to the free-floating planktonic variety (Saeed et al., 2018). Nanomaterials have become an effective way to eliminate drug-resistant biofilm-associated nosocomial implant infections, medical devices, and other biomaterials to fight the issue of antibiotic resistance in microbes that are involved in biofilm formation. Due to their small size, nanoparticles can easily penetrate the cell membranes of microbes and the EPS layer of biofilms. Moreover, nanoparticles have a high surface-to-volume ratio, which enhances their biological activities and chemical reactivity. This causes irreparable cell damage and, ultimately, cell death (Robino and Scavone, 2020; Sahoo et al., 2022). Nanocoating materials are employed to alter the surface characteristics of intrinsic implants, thereby mitigating the risk of biofilm infections. One strategy is to develop resistance on the surface against the formation of biofilm and to impede the process of protein adsorption to target the first stage of the formation of biofilm, which involves the adherence of planktonic bacteria to the surface of implants. To achieve this, the surface can be coated with antibacterial nanomaterials that inhibit the adhesion of bacteria and possess antifouling or antimicrobial characteristics that eliminate microorganisms coming into contact with the implant or device surface (Shahid et al., 2021).

Metal nanoparticles are the most widely used inorganic nanoparticles, and they present a promising therapeutic approach against antibiotic resistance. Various types of metal nanoparticles have been shown to enhance antibacterial properties. The most widely used antibacterial nanoagents include gold (Au), silver (Ag), magnesium (Mg), zinc (Zn), titanium (Ti), nickel (Ni), copper (Cu), and their oxide-based nanoparticles (Correa et al., 2020). Due to their high surface-to-volume ratio and smaller dimensions compared to bacteria, metal nanoparticles offer potent, targeted, and prolonged antimicrobial activity along with antibiofilm interactions (Gold et al., 2018; Correa et al., 2020). Recent research by Zhang et al. describes the application of an alkali-heat-treated nano-structured TiO₂/CuO/Cu₂O layer to a Ti-Cu alloy that has osteogenic and antibacterial properties. The nanostructured layer facilitated early adhesion, spread of MC3T3-E1 cells, osteogenic differentiation, and showed potent antibacterial activity against S. aureus. Zhang et al. suggested a new implant surface modification technique using an easy electron beam evaporation method to coat silver nanoparticles onto the porous Ti surface (Zhang et al., 2022). The growth of S. aureus (S. aureus) and E. coli (Escherichia coli) is successfully inhibited by the composite surfaces (Figure 5).

In recent years, the primary concern regarding metal oxide and metallic nanoparticles has been the emergence of microbial resistance to them. Therefore, achieving effectiveness often requires extremely high concentrations of nanoparticles, which, in turn, may pose toxicity risks to animal cells. 2D nanomaterials are used to address the issues with metal oxide as well as metallic nanoparticles. Many diverse 2D nanomaterials are used in antimicrobial coating agents, including black phosphorus, graphene oxide (GO), boron nitride, and MoS₂ molybdenum disulfide. A catheter with hydrated GO coating fabricated by Ruibin Li et al. and colleagues demonstrated outstanding antimicrobial potential on the density of carbon radicals (Li et al., 2016). In a recent study, it was found that a self-activating implant modified with hydroxyapatite (HA)/MoS₂ coating can effectively mitigate infections caused by E. coli and S. aureus. Moreover, this implant stimulates the regeneration of bone tissue by encouraging mesenchymal stem cells to differentiate into osteoblasts via alteration of the mitochondrial membrane and cell membrane potential (Fu et al., 2021). Shaw et al. reported that when applied to medically relevant surfaces, a layer of black phosphorus without solvents exhibited remarkable antimicrobial properties alongside good biocompatibility (Shaw et al., 2021). Ding et al. (2020) reported a titanium-based implant that incorporated silver nanoparticles loaded into mesoporous silica nanoparticles and coated in multilayer layers of polyallylamine hydrochloride and poly l-glutamic acid. This nanomaterial was specifically engineered to combat S. aureus-associated infections and to promote in vivo bone tissue growth (Ding et al., 2020). They concluded that the reported approach could effectively kill bacteria while promoting osseointegration in an environment infected with bacteria. Recent research by Li et al. has shown that a polyetheretherketone composite modified with black phosphorus and carbon fiber shows superior wear resistance, minimal cytotoxicity, and exceptional antimicrobial properties. These findings suggest that this composite could be an ideal material for implants (Li J. et al., 2022).

From nondegradable bone cement to bone graft substitutes crafted from biodegradable materials, bone grafting has emerged as a valuable strategy to address reconstruction needs with improved clinical use. Research on the interactions between cellular material and parameters such as topography, stiffness, porosity, and functional groups provided the basis for the ability to modify cell behavior. Smart/intelligent biomaterials and implants are produced by incorporating these characteristics into biomaterials and their 3D shapes (Intravaia et al., 2022). Smart or intelligent biomaterials are those that have the potential to stimulate tissue regrowth through physical, chemical, electrical, or magnetic stimuli. The goal is to stimulate the production of new bone tissue or osteogenesis, by the progenitor/stem cells either internally or externally using a biomaterial implant (Zhang et al., 2018). These stimuli have been incorporated using cutting-edge biomaterials and/or fabrication techniques. (Zhang et al., 2018).

The internal microenvironment contains a variety of biological and chemical features that, when incorporated into the composition of biomaterials, can enable stimuli-responsive bone regeneration (Kim et al., 2021; Wei et al., 2022). Surface chemical interactions, pH, and particular molecules like glucose are examples of chemical stimuli in the microenvironment, whereas enzymes, reactive oxygen species (ROS), and bioactive molecules are classified as biological signals. For example, Deng et al. developed porous PEEK scaffolds having a coating that gave the biomaterial a unique acidic pH-responsive property capable of being triggered by bacteria (Figure 6) (Deng et al., 2020). Recombinant human bone morphogenetic protein 2 (rhBMP-2) and glucose oxidase were grafted onto a new glucose-sensitive controlled-release fiber scaffold fabricated by Jiang et al. to support bone regeneration (Jiang et al., 2022). A titanium bone prosthesis with an immobilized surface that contains both an MMP-9 responsive peptide and the antimicrobial peptide GL13K was developed by Fischer et al. to respond to both MMPs and bacteria (Fischer et al., 2021). In addition to an acidic pH and dysfunctional enzymes, different disease environments exhibit abnormally high amounts of ROS. Higher levels of ROS have been linked to bone-related illnesses like rheumatoid arthritis, osteoporosis, and bone metastases (Ren et al., 2022). In a study conducted by Li et al., a Tb4-loaded titanium implant covered in a multifunctional hydrogel was investigated for its ability to target ROS within a femoral bone defect (Lu et al., 2004). The implant’s hydrogel coating had borate ester bonds in it that can quickly oxidize in the presence of H₂O₂, giving it ROS-responsive degradation properties.

While pathological conditions are primarily triggered by internal stimuli, some defect conditions necessitate the targeted administration of therapeutic agents and/or growth factors at a specific dose and time. By adjusting the activity and intensity of the applied stimulus, it is possible to regulate dosage and release periods when using an external source of stimuli. Magnetic fields and light are two frequently used external stimuli for smart biomaterials. Typically, magnetic nanoparticles (MNPs) and photothermal nano-agents can be used to incorporate these stimuli into the architecture of a biomaterial, respectively (Wei et al., 2022). Tanasa et al. incorporated this impact of magnetite nanoparticles into the silk fibroin scaffolds to stimulate and accelerate the osteogenic process in response (Tanasa et al., 2020). It was found that the implanted magnetic nanoparticles affected the distribution of cells around the scaffold and the orientation of actin filaments when a 120 mT magnetic field was applied. Additionally, stimulation by an exterior magnetic field boosted preosteoblasts’ capacity for osteogenesis and their capacity for cellular proliferation. An entirely different approach was adopted by Tang et al. (Julmi et al., 2019) who developed a magnetic responsive bioactive coating that may be added to titanium substrates employed for bone implants (Liu et al., 2011). In this method, CoFe₂O₄ nanoparticles were mixed into a P(VDF-TrFE) matrix to form a magnetically active coating. This study provided evidence indicating that nanoparticles of iron oxide do not possess critical properties for magnetically active biomaterials. This finding has paved the way for the exploration of further design concepts that incorporate an iron oxide coating. Being able to regulate the location, wavelength, duration, and intensity of the light source without causing any harm makes light-responsive biomaterials advantageous (Lee and Gaharwar, 2020). Recently, black phosphorus nanosheets (BP NSs), zinc oxide nanowires (NWs), and polydopamine (PDA) were combined with titanium (Ti) substrates to produce a phototherapeutic system. Fang et al. developed a phototherapeutic system showing exceptional antibacterial qualities against bacteria that cause biofilms (Fang et al., 2022). Recently, UV-grafting was used to fabricate multifunctional stimuli-responsive metal–organic framework (MOF) hydrogels on the surface of sulfonated long carbon fiber reinforced polyetheretherketone (LCFRPEEK) implants to facilitate osseointegration (Figure 7) (Dong et al., 2023). Hydrogels consist of methacryloyl chitosan and nano-hydroxyapatite-coated magnesium-gallic acid (HAP@Mg-GA) MOF nanoparticles. The stimuli-responsive MOF hydrogels demonstrate exceptional capabilities for the pH-sensitive release of biomolecules. Moreover, the superior in vivo immunomodulatory, angiogenesis, osteogenic differentiation, and osseointegration capabilities of the implant are further supported by the SD rat subcutaneous implantation and rabbit tibia defect models. Therefore, the research advances the effective applications of LCFRPEEK biomaterials in orthopedics by developing a novel multifunctional orthopedic implant capable of osseointegration. To take advantage of GO potential. For osteogenesis and its capabilities as a drug transport system, Wang et al. used NIR light to reduce GO loaded into a hydrogel film based on chitosan and incorporating teriparatide (Wang X. et al., 2021). It has been demonstrated that, in contrast to continuous release, the release of Teriparatide in a pulsatile fashion in vivo can stimulate angiogenesis and local bone regeneration in an osteoporotic bone defect (Figure 7). Nevertheless, additional investigation is needed to determine the most efficient pulsatile schedule. A pulsatile delivery schedule demonstrates the potential for automation in the design strategy, which potentially improves the regenerative impact.

In orthopaedics, drug delivery might represent the most significant future application of nanotechnology. Significant progress has been made in the area of nanotechnology-based drug delivery systems (DDS) designed for the specific, prolonged, and targeted delivery of pharmacological substances. These developments have shown improved therapeutic effectiveness and decreased incidence of adverse effects, therefore being especially beneficial in the domain of orthopedics. A wide variety of novel DDS has been developed to encapsulate, transport, and control the release of drugs by employing nanotechnology-derived nanomaterials with unique chemical, physical, and biological characteristics. Conventional pharmaceutical methods are constrained by their inability to overcome particular biological barriers, inadequate solubility, and a lack of specificity, which results in severe adverse effects (Lu et al., 2021). DDS based on nanotechnology have unique characteristics that enable them to avoid the aforementioned limitations. The above-mentioned benefits encompass improved targeting capabilities, which result in decreased toxicity and enhanced bioavailability. Moreover, their nanoscale dimensions strengthen them to overcome biological barriers, whereas their high surface area to volume ratio promotes efficient drug delivery. In addition, interactions with biological targeting molecules are facilitated by the abundance of surface chemistry in these systems (Yang et al., 2020). Innovative advancements have been made in the field of orthopedics through the utilization of nanotechnology-based DDS, including metallic NPs, polymeric NPs, and lipid NPs (Yang X. et al., 2019). Intelligent DDS have been extensively utilized for the identification and treatment of bone-related conditions, including osteoarthritis, orthopedic oncology, osteoporosis, and orthopedic infections, as well as the regeneration of cartilage and bone tissue. The objective of their application is to improve the precision and efficacy of existing therapeutic methods. Millions of individuals suffer from osteoporosis (OP), a prevalent progressive and deteriorating orthopaedic disease. However, adverse effects result from the systemic administration of current anti-osteoporotic medications, including calcitonin, bisphosphonates, and vitamin D. Hence, it is highly desirable and extremely challenging to develop novel DDS that exhibit improved treatment efficacy. Contemporary approaches to treating osteoporosis rely directly on the regulation of bone metabolism. Zheng et al. (2022), utilized alendronate, a clinical bisphosphonate approved by the Food and Drug Administration, to synthesize novel bone-targeting antioxidative nano-iron oxide (BTNPs) (Figure 8). By selectively targeting the surface of the bone, this technology has the potential to positively modulate the in vivo equilibrium between bone resorption and formation. Furthermore, employing nanotechnology for drug distribution presents a promising option for OA, a prevalent joint ailment for which therapeutic options are limited. Suboptimal targeting of cartilage after systemic administration and rapid clearance after intra-articular injection are the principal constraints associated with the treatment of osteoarthritis. To overcome these limitations, extensive nanotechnology-based research has been conducted on DDS. The study conducted by Wei et al. demonstrated that the combination of transforming growth factor (TGF) and novel polymeric micellar NPs revealed significant attributes including outstanding biocompatibility, stability, extended joint retention, and efficient cartilage infiltration. Following intra-articular injection, TGF-NPs exhibited a significant level of efficacy in ameliorating cartilage degeneration associated with arthritis, subchondral bone plate sclerosis, and post-surgical joint pain (Wei et al., 2021). Alternative methods of drug distribution have been implemented, including the use of recyclable polylactic acid (PLGA) to administer Kartogenin. PLGA is a small chemical compound that can differentiate mesenchymal stem cells derived from bone marrow into chondrocytes. It has been shown to promote the synthesis of hyaline cartilage and accelerate the correction of defects. (Shi et al., 2016). The potential of nanotechnology-based DDS to enhance the treatment of bone-related disorders has garnered considerable interest. Despite notable progress in the domain of nanotechnology-driven DDS for orthopedics, concerns persist concerning its metabolic pathways and long-term safety.