Recent advances in the application of nanotechnology in joint arthroplasty: a narrative review

Introduction

Originally introduced by the Nobel Prize laureate Richard Feynman in 1959, nanotechnology involves the use of particles at the nanoscale (1–100 nm) (1). The small size and large surface area of nanoparticles (NPs) introduces many unique properties, with the ability to be further specialized with surface modifications (2,3). Properties such as enhanced mechanical, thermal, and magnetic functions allow NPs to be advantageous in cellular uptake, directed drug-delivery, and imaging (4,5). These advances hold the potential to revolutionize medicine and the ability to diagnose and treat patients. Thus, over the past decade, nanotechnology has been rapidly gaining success and popularity in the medical world (6).

Orthopaedic surgery is one area of medicine with emerging interest in the applications of nanotechnology, with recent research focused on the potential uses of nanomedicine in implants, osteoarthritis (OA) treatment, bone regeneration, and infection management (7). Total joint replacements (TJRs) represent some of the most frequently performed surgeries in the world, with OA being a primary contributing factor (8,9). As the population continues to age, the incidence of joint replacement is expected to continue rising, with a growth of 71% for total hip arthroplasty (THA) and 85% for total knee arthroplasty (TKA) expected by the year 2030 (10). With the rapidly growing literature on the uses of nanotechnology in orthopaedics, there remains room to discuss the applications of this new technology within the realm of joint surgery. While numerous studies have explored nanotechnology in arthroplasty, there is no clear synthesis of how these interventions compare with conventional strategies in clinical contexts. This review focuses on the applications of nanomedicine in the treatment of joint disease, primarily recent advances in OA management and TJR. We present this article in accordance with the Narrative Review reporting checklist (available at https://aoj.amegroups.com/article/view/10.21037/aoj-24-50/rc).

Methods

This narrative review was performed following a computerized search of the electronic database on PubMed in September 2024. The search was limited to English-language studies published between 2000 and 2024 in PubMed. Search terms included the following keywords: “Nanotechnology”, “Nanoparticles”, “Orthopaedic Surgery”, “Joint Arthroplasty”, and “Joint Replacement”. Abstracts were originally screened to assess for applicability and inclusion into the review, with further publications pulled from the referenced materials within these initial inclusions. The selection process was completed by the first author. The specific search summary is reported in Table 1.

NP characterization

NP classification

NPs are defined by the International Organization for Standardization as objects on the nanoscale (1–100 nm) where the dimensions of the short and long axes do not significantly differ (11). These particles come in an array of shapes and sizes, varying from cylindrical to spherical to conical (12). Their structure can be uniform or layered, typically including three layers: a surface layer, the shell layer, and a core (13). NPs can be further categorized based on their composition, typically falling under one of three classes: organic, carbon-based, or inorganic (12) (Figure 1).

Figure 1 Nanoparticle classification.

Organic NPs are composed of proteins, lipids, polymers, or carbohydrates, often formed via non-covalent intermolecular interactions (14,15). This allows them to be bio-degradable and easily cleared from the body, with common examples including micelles and liposomes (12). These NPs are often used to encapsulate therapeutic drugs, allowing them to be released in a controlled manner and reducing cytotoxicity (16). These characteristics make organic NPs advantageous in targeted drug delivery and cancer therapy (12).

Carbon-based NPs are comprised solely of carbon atoms and include examples such as carbon black NPs, carbon quantum dots, and nanodiamonds (17-19). The sp²-hybridized carbon bonds allow for unique properties within this class of NPs, including electrical conductivity, thermal properties, magnetism, and high strength (20). These characteristics makes them incredibly useful in applications such as imaging, tissue engineering, and drug delivery (21,22). Furthermore, carbon dots have fluorescent emissions with lower cytotoxicity compared to normal fluorescence markers, making them useful as imaging probes (23).

Lastly, inorganic NPs include all particles not composed of organic or carbon-based materials, usually metals or ceramics (12). Metal NPs possess optical and electrical properties due to their localized surface plasmon resonance characteristics, as well as thermal and magnetic effects, giving them a broad range of applications (13). Some areas of utility include contrast agents during magnetic resonance imaging, cell labeling, drug delivery, and as antimicrobial agents against microorganisms (24). Ceramic NPs are useful in imaging and catalytic processes due to their high stability created during successive heating and cooling processes (13,25). Semiconductor NPs carry characteristics between those of metals and nonmetals, thus also contributing to a wide array of uses (13,26).

NP production

The production of NPs can be broadly classified into two main categories: top-down synthesis and bottom-up synthesis (13). During top-down synthesis, a larger molecule is degraded into smaller components, which are ultimately transformed into NPs (13). Contrastingly, bottom-up synthesis involves creating NPs from simpler building blocks (13).

When designing NPs, it is important to tailor the size, shape, and surface to the desired function of the particle (2). Fine-tuning the size of NPs aids in accumulation at the desired location, prolonging blood circulation half-life, and evasion of the immune system (2). These factors will ultimately determine the efficacy of cellular uptake of the NP (2). One modification often made to NPs is coating them with polyethylene glycol (PEG) to aid in immune system avoidance and therefore prolong circulation (27). While useful in avoidance of immune system clearance, this often poorly impacts the ability of cellular uptake and drug release (28). The addition of ligands to the NP’s surface helps ameliorate this effect and aid in active targeting (29).

Applications of nanotechnology in OA treatment

OA is a debilitating disease, impacting millions of people and costing the USA approximately $100 billion annually (30). Resulting from the progressive loss of articular cartilage, this disease results in changes to the structure and function of the entire joint (30). Age is the primary risk factor for OA, with 49.7% of individuals ≥65-years-old impacted (31). Additional risk factors include obesity, metabolic disease, and the female gender (30). As the population continues to age, so will the rate of individuals seeking treatment for degenerative joint disease (30,31).

Recent studies have suggested that OA includes biochemical, inflammatory, and metabolic components, complicating the underlying pathophysiology of this disease (30,32,33). As an individual ages, deterioration of the chondrocytes within the articular cartilage of a joint occurs (34). These altered chondrocytes increase production of matrix proteins and matrix-degrading enzymes, contributing to the degradation of the cartilage (34). This process is further aided by the infiltration of mononuclear cells and proinflammatory mediators (34,35). Ultimately, these processes result in joint pain, stiffness, and reduced mobility, impacting a patient’s quality of life (36).

Currently, OA can be managed conservatively or surgically, depending on the progression of the disease, patient comorbidities, and patient and surgeon preference (37). Conservative management is usually the preferred initial pathway, with the goal of alleviating symptoms and improving a patient’s quality of life (37). First line interventions typically include lifestyle modifications (including exercise therapy and weight management) and pharmacological interventions (including the use of topical and oral non-steroidal anti-inflammatory drugs, intra-articular corticosteroids, and hyaluronic acid injections) (37,38).

While potentially therapeutic, conservative management is unable to cure the underlying disease, thus progression to surgery is usually unavoidable. As recent studies suggest, addressing multifaceted health challenges like frailty requires innovative and accessible technologies that bridge clinical and societal needs (39). Finding novel ways to non-operatively treat OA is of great clinical interest and may help prolong the need for surgical intervention.

Nanotechnology treatment advancements

Conventional drugs, while easily administered via oral routes, require the need for frequent dosing to reach the desired effect (36). Intra-articular injections avoid some of these drawbacks by allowing for improved drug delivery to the desired site and reducing the systemic side-effects (36,40). Despite this, drugs administered intraarticularly are still subject to rapid clearance through enzymatic degradation (36,40). The use of nanocarriers for drug delivery seeks to remove these barriers, allowing for increased site-specific drug delivery and reduced systemic side-effects (7,36). The integration of manual therapy techniques with nanotechnological innovations could provide a synergistic approach to improving patient outcomes, as evidenced by Martínez-Pozas et al. (41). Various types of nanotechnology-based drug delivery systems have been developed, including lipid, polymeric, and metallic NPs (7).

Lipid NPs

Liposomes are typically comprised of a bilayer of phospholipids and cholesterol enclosing an aqueous center, making them ideal for carrying hydrophobic drugs (42). Their role as drug delivery vehicles serves multiple purposes, including protecting the therapeutic agent from rapid clearance, allowing for controlled drug release, and extending the half-life of the drug (43). Additionally, liposomes can target their delivery site, either actively or passively, thereby improving site-specific delivery and reducing systemic side-effects (44). Active targeting involves the use of interactions between ligands on the surface of the liposomes with receptors present at the target site (45). Passive targeting takes advantage of the microenvironment of the abnormal tissue (46). Inflammatory tissues and tumors typically have highly porous capillaries, preferentially aiding in the accumulation of liposomes at the desired location (46). Recent studies have focused on the application of liposomes in OA treatment.

For example, Williams et al. studied the anti-inflammatory effects of methotrexate-loaded vesicles in rats with antigen-induced arthritis, with a more pronounced reduction in swelling seen compared to free drugs (47). This study also demonstrated the importance of the size of liposomes, with greater anti-inflammatory effects witnessed with larger liposomes (1.2 µm) compared to smaller liposomes (100 nm), likely due to the increased clearance of smaller vesicles by the lymphatic system (47).

Another study of Corciulo et al. evaluated the targeting ability of liposomal encapsulated drugs in obesity-induced and post-traumatic OA animal models (48). Studies had previously demonstrated the importance of adenosine in maintaining cartilage by acting at its A2A receptor (48). In this study, Corciulo et al. prepared liposomes with adenosine and CGS21680, a selective A2A receptor agonist (48). They found a significant reduction in OA cartilage damage and joint swelling in their OA models, along with reduced expression of the genes associated with matrix degradation in the chondrocytes harvested (48). This study highlights the use of nanotechnology in providing targeted drug-delivery.

Polymeric NPs

Numerous polymers have been used to develop drug delivery systems, including chitosan, starch, and polylactic acid (49). These polymeric materials can be easily structurally modified, allowing for directed drug delivery similar to liposomes (49). Maudens et al. investigated the use of nanocrystal-polymer particles (NPPs) developed with kartogenin, a molecule capable of protecting and regenerating cartilage (50). In this study, in vitro experiments demonstrated the high-drug loading ability and extended drug release over a 3-month period of these NPs (50). In vivo experiments in a murine OA mouse model then compared the kartogenin NPPs to a kartogenin solution, with higher levels of bioactivity seen with the NPPs (50). This innovative idea holds the promise of improving OA treatment by reducing conventional drug clearance and promoting cartilage protection.

Kang et al. developed thermo-responsive polymeric nanospheres, capable of allowing dual drug delivery in a single system (51). These nanospheres were loaded with diclofenac within the inner core while kartogenin was covalently cross-linked on the outer surface, allowing for immediate release of the diclofenac and controlled release of the kartogenin independently based on temperature change (51). The dual function of these drugs demonstrated both anti-inflammatory and chondroprotective effects on OA in both in vitro and in vivo experiments (51).

Metallic NPs

Metals such as silver, copper, zinc, and iron have been widely used in various medical applications, including imaging and drug delivery (52). Their possession of anti-inflammatory and anti-bacterial properties make them extremely useful in areas such as wound healing and burn management (52). Metallic NPs can be synthesized via physical, chemical, or biological methods with their properties dependent on their size and composition (53). Alloy NPs composed of two or more metals have been shown to have enhanced properties and more stable structures when compared to monometallic NPs (53). This provides them with a more diverse portfolio of applications, including strong photocatalytic and magnetism effects (53). Recently, studies have focused on their applications in orthopaedics (52). A study conducted by Sang et al. evaluated the use of silver NPs in type II collagenase-induced knee OA in a mouse model (52). They found a significant reduction in synovial hyperplasia and neutrophil infiltration, suggesting a novel way of treating OA (52).

While most of the drug delivery and potential regenerative aspects of nanotechnology are largely theoretical at this stage, there are plausible mechanisms that hold promise for the future. One invention that is actively being used in orthopaedic clinics is extended-release triamcinolone acetonide (Zilretta^®) (54). This intra-articular injection is currently approved for management of knee OA in the USA, with excellent results demonstrated during clinical trials. This formulation involves the slow release of triamcinolone acetonide from poly lactic-co-glycolic acid (PLGA) microspheres into the synovium, prolonging the effects of the corticosteroid and reducing systemic side-effects (54). Clinical trials showed improved pain, stiffness, and physical function when compared to a placebo and triamcinolone acetonide crystalline suspension (CS), with similar tolerability to these alternatives (54).

Application of nanotechnology in joint replacement implants

Optimization of bone integration

Total joint arthroplasty aims to improve joint mobility and decrease pain associated with OA by replacing all or part of the joint with an artificial device (55). Achieving osseointegration of the implant is an important goal of surgery, otherwise there is a high risk of implant failure due to aseptic loosening (55). In addition to insufficient initial fixation being a leading cause of aseptic loosening, loss of mechanical fixation over time and biological loss of fixation due to osteolysis are other contributors to failure (56).

Implant-associated osteolysis is the result of inflammatory and enzymatic processes occurring at the implant-bone interface (56). This reaction results from a biological response to implant debris, starting with the development of fibrous tissue, then granulomatous tissue, before progressing to the production of inflammatory mediators which ultimately result in implant failure (56). Thus, finding the optimal implant material is of current interest amongst the orthopaedic community, with ceramic and highly cross-linked polyethylene showing promise in reducing the production of debris particles (56). Despite these advances, osteolysis remains a potential risk following joint replacement of near nanometer sized particles having a true clinical impact. Similarly metal debris from the bearing surface or corrosion at the trunnion can generate nanometer sized particles leading to pseudotumor and other physiologic effects.

The utilization of nanotextured materials in implants have shown promise in reducing the risk of implant failure by improving osseointegration (55). In nanometric terms, mature bone has a course surface while conventional implants often have a smooth surface at the nanometric level (55). This smoother surface often promotes the growth of fibrous tissue, contributing to the development of aseptic loosening (55). Meanwhile, studies have shown that a nanotextured surface may enhance osteoblast function while reducing fibroblast growth, therefore promoting bone growth and restricting the development of fibrous tissue (55). This nanotextured surface is often achieved via nanotextured hydroxyapatite (HA)-coated surfaces or nano-engineered titanium and cobalt-chromium-molybdenum (CoCrMo) (55). Webster et al. conducted an in vitro study evaluating the level of osteoblast adhesion to nanophase metals, specifically Ti, Ti6AL4V, and CoCrMo alloys (57). Their results demonstrated an increased rate of osteoblast adhesion to these metals compared to conventional metals, supporting the potential of improved osseointegration during TJR with the use of nano-based implants (57). Furthermore, there have been clinical studies done demonstrating the increased stability of hydroxyapatite (HA)-coated implants following TJRs in patients (58). A meta-analysis performed by Horváth et al., including 11 randomized control trials, compared the effects of HA-coated tibial stems on the stability and functionality of primary TKA. Their results demonstrated that the HA-coating had better stability compared to other uncemented implants, with a statistically significant difference in maximum total point motion of the tibial stem (P<0.01). Furthermore, the knee society score was significantly higher for the HA-coated group compared to cementless prosthesis (58).

Implant modifications

The application of bioactive coatings on total joint implants is another area of rapidly growing interest due to their wide array of properties (59,60). The use of diamond-like carbon (DLC) coatings on implants shows great promise given their significant mechanical hardness and antimicrobial effects (60). These coatings provide improved wear resistance to implants and help prevent biofilm formation, a major contributor to periprosthetic joint infection (PJI) (60). The addition of elements, such as silver and copper, to DLC coatings further improve in these mechanical and antimicrobial properties, helping to prolong the life of implants (60-62). Current studies are focused on identifying the ideal level of doping to achieve the desired effects without impacting the durability and mechanics of the DLC (60). Finally, a study by Song et al. looked at titanium implants coated with doxycycline-loaded coaxial nanofibers (63). The authors used electrospinning to directly despite the nanofibers onto the titanium implant surface, with a stand single-pass scratch test used to confirm the bonding strength of the coating. Their in vivo results in a rat model showed enhanced osseointegration and improved inhibition of S. aureus infections compared to the non-nanofiber group (63). Osseointegration was evaluated via scanning electron microscopy, histomorphometry, and micro computed tomography (63). The bone contact surface changes of the nanofiber group was 80% compared to the control group at <5% at measurements made at 2, 4, and 8 weeks post-implantation (P<0.05) (63). The doxy released from the nanofiber coating inhibited bacterial growth up to 8-week post-implantation (63).

Application of nanotechnology in joint infections

PJIs are a serious complication following TJR, resulting in significant patient morbidity and an estimated $1.62 billion cost to the United States’ healthcare system (64). The incidence of PJI has grown with the increasing prevalence of joint arthroplasty, with rates up to 4% in the United States (64,65). With the growing interest in nanomedicine comes novel ideas for the prevention and management of PJI.

Preventive nanotechnology

PJI is often a consequence of biofilm formation, which occurs over several sequential steps, involving attachment, maturation, and dispersal of bacteria (66). After introduction into the body, these bacteria are capable of producing proteins that quickly form strong interactions with the host extracellular matrix, making treatment with antibiotics extremely difficult (64). Thus, prevention of PJI from occurring in the first place is an important goal during surgery and perioperative care (64). Data has supported lower infection rates seen with the use of ceramic implants, likely attributed to the smoother surface inhibiting the formation of a biofilm (67,68). As previously discussed, the addition of NP-based coatings to implants has shown great promise in reducing infection by inhibiting biofilm formation (64). In particular, silver NPs have shown active anti-microbial effects against E. coli and S. aureus, as well as osteo-integrative capabilities and anti-corrosive properties, making them an ideal elemental choice (66,69,70). These silver NPs also exhibit slow solubilization, therefore preventing toxicity to osteoblasts that may otherwise occur with rapid increases local silver concentrations (71). While still under investigation, these modifications to implants hold the potential for reducing the incidence of PJI.

Prophylactic antibiotics are routinely used during joint replacement surgery to reduce the risk of infection (72). As aforementioned, however, conventional antibiotics face difficulty in disrupting biofilm formation (72). Not to mention the relatively low accumulation of antibiotics at the desired site contributing to their limitations (72). Recent developments have led to the development of antimicrobial NPs, capable of providing improved delivery of antibiotics (72). Feng et al. studied the incorporation of doxycycline, a routinely used broad-spectrum antibiotic, into PLGA nanospheres with the use of nanofibrous poly-L-lactic acid (PLLA) scaffolds (73). The in vitro studies performed by the authors illustrated controlled release of doxycycline over an extended period, with inhibition of bacterial growth seen for over 6 weeks (73). Their results showed 70% inhibition of S. aureus and 40% inhibition of E. coli at day 42 in the nanosphere group (73). This was compared to 18% S. aureus inhibition and 9% E. coli inhibition at the same time point for the adsorbed doxycycline control group (73). Similar studies have demonstrated equal success using PLLA and PLGA scaffolds for antibiotic delivery in animal models (74).

Therapeutic nanotechnology

Even in the setting of optimal operative management, PJI may occur (64). In these cases, reoperation is often necessitated, with a two-stage revision considered the “gold-standard” for treatment (64). While the preferred choice for chronic PJI management, two-stage revisions carry significant patient morbidity and an average mortality rate of 14.4% (75). Thus, NPs present an innovative way of treating PJI given their ability to deliver hydrophilic and hydrophobic drugs while limiting the systemic side-effects seen with large doses of conventional drugs (64,76).

The enhancement of bone cement with NPs for use in cement spacers during revisions has been studied in efforts to improve and prolong local drug delivery. Ayre et al. conducted in vitro experiments analyzing the incorporation of gentamicin sulfate loaded liposomes into polymethyl methacrylate (PMMA) bone cement (77). Their results showed higher delivery of antibiotics compared to conventional powdered antibiotic cement (77). Furthermore, the antibiotics were released over a 30-day period, allowing for controlled and extended release (77). The overall molecular structure of the cement remained unchanged with the addition of NPs (77). Similar studies have shown comparable results with the integration of silica-based NPs into PMMA cement (78).

Intraarticular injections of NP loaded drugs have shown improvements in penetrating biofilms and treating infections compared to free drugs (64). Fazly Bazzaz et al. loaded solid lipid nanoparticles (SLN) with rifampin and conducted in vitro experiments evaluating their efficiency against S. epidermis biofilm, with results showing a greater effect at eliminating the biofilm compared to free rifampin (79). Another study conducted by Li et al. used a mouse model to demonstrate the ability of liposomal encapsulated daptomycin at inhibiting S. aureus biofilm growth (80). While this study focused on the treatment of superficial skin infections, it nevertheless shows the ability of a NP drug delivery system being an effective treatment against biofilm in an in vivo model (80).

As the incidence of multidrug-resistant bacteria rises, so does the need for novel therapeutic approaches. Bacteriophages, or viruses that infect bacteria, have offered an alternative treatment route given their high bactericidal activity (81). Despite their promise for success, they are limited by bioavailability and stability (82). Combining the selectivity of bacteriophages with the targeted therapy of NPs has shown improvement of bacteriophage efficacy in vivo in areas of both bacteria detection and antimicrobial therapy (83). Nanotechnology has previously been used to develop biosensors and probes capable of detecting pathogens (84). Recent studies have focused on ways to combine NPs with phages to aid in pathogen detection (85). One study engineered a phage capable of targeting several bacterial species, including Escherichia coli, Pseudomonas aeruginosa, Vibrio cholerae, and Xanthomonas campestris and modified them to react with NPs (85). Gold NPs were then able to form a thiol bond to the phage causing a change in color to the solution indicating the presence of the target bacteria (85).

In addition to the potential diagnostic uses, combining phage and NP therapy has also proved promising in therapeutic ventures (83). Encapsulation of phages within polymeric nano and microparticles aids the phage in overcoming environmental obstacles, including degradation by the immune system and low bioavailability (86). This also allows for controlled release of the phage, with numerous in vitro and in vivo studies offering promising results (83). Lastly, NPs have been used to kill bacteria through photothermal and photodynamic therapies, by causing localized hyperthermia and oxidative stress respectively (87). The use of NPs comprised of Cu₉S₈ and covered in PEG has demonstrated the ability to destroy S. aureus biofilms present on titanium surfaces using these therapies (87). Furthermore, photothermal therapy holds the capacity to destroy phages after bacterial identification, reducing the risk of potential transduction or evolution (88). One study evaluated the linkage of phages with gold nanorods via a sulfur bond, forming a “phanorod” (88). The phages were able to target specific bacterial species and photothermal therapy was used for ablation (88). The results demonstrated efficacy against the bacteria with minimal damage to the surrounding tissues (88). While still under investigation, these early studies hold the potential for treatment against localization bacterial infections.

Conclusions

The use of nanotechnology in medicine is a rapidly growing area of clinical interest, with the US government having contributed nearly $1.4 billion to its research since 2008 (55). Nano-sized molecules contain unique properties, allowing for their utilization in directed drug-delivery and implant design (6,89-92). This holds the promise for increased delivery of drugs to the desired site while simultaneously decreasing the typical systemic side-effects (6,89-92). OA is a devastating disease impacting millions of people worldwide with a cure yet to be discovered (30). This review discussed the recent advances made with nanotechnology in improving conservative management of OA, refining orthopaedic implants, and in the prevention and treatment of joint infections. Current clinical applications in the conservative management of OA include Zilretta^®, an intra-articular injection useful in prolonging the effects of corticosteroids. This advancement may provide superior benefits compared to traditional intra-articular injections, helping to improve management of OA and prolong surgical intervention. Further advancements include the integration of nanotechnology coatings in joint implants, which could become the standard of care within the next decade, especially for patients at high risk of infectious complications. These highlights show the potential nanotechnology holds in revolutionizing the treatment of OA and joint arthroplasty.

Safety profile of NPs

While nanotechnology holds the possibility of improving patient care, the question of clinical safety must first be addressed (55). Various organ systems, including the liver and kidneys, are involved in the metabolism of NPs (55). This has raised concerns for potential inflammation, oxidative stress, and cytotoxicity (93). Further concerns surround the development of implant debris leading to increased levels of systemic particles, soft tissue damage, and pseudotumor formation (93). Despite these potential safety concerns, only 3% of the aforementioned $1.4 billion in nanotechnology research funding has been directed to safety concerns (55). Thus, the potential health impacts of NPs are relatively uncertain, with the need for further investigation.

Limitations and future implications

Further limitations of nanotechnology use include the paucity of in vivo studies and the high cost of NP production (7). Development of a novel drug is an expensive and timely matter, thus explaining the limited clinical uses of nanotechnology in joint replacement at this time. It currently takes up to two decades for a drug, conventional or nanopharmaceutical, to enter the market after its discovery (94). Even after years of development and testing, only 11.8% of drugs eventually succeed in achieving final approval following clinical trials (95). During this time, it costs approximately $2,870 million to reach the profitable stage of a drug (96). Prior research has shown variability in NP effects in vitro versus in vivo, thus necessitating extensive testing using animal models before progression to clinical models (94). This, along with the safety and ethical questions surrounding nanotechnology, limits the studies currently available for review (94). Although preclinical studies suggest significant improvements in implant resistance and biocompatibility, randomized controlled trials are needed to evaluate their impact on long-term outcomes, such as joint functionality and patient quality of life (7). Despite these current limitations, nanotechnology has the prospect of impacting joint arthroplasty. Emerging methodologies, such as big data analytics and machine learning, are reshaping the diagnostic landscape, enabling predictive and patient-specific interventions (97,98). Likewise, as research continues to progress, the translation of these early studies will hopefully translate into clinical applications for nanotechnology.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aoj.amegroups.com/article/view/10.21037/aoj-24-50/rc

Peer Review File: Available at https://aoj.amegroups.com/article/view/10.21037/aoj-24-50/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aoj.amegroups.com/article/view/10.21037/aoj-24-50/coif). N.M.B. serves as an unpaid editorial board member of Annals of Joint from July 2024 to December 2026. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bayda S, Adeel M, Tuccinardi T, et al. The History of Nanoscience and Nanotechnology: From Chemical-Physical Applications to Nanomedicine. Molecules 2019;25:112. [Crossref] [PubMed]
2. Hoshyar N, Gray S, Han H, et al. The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. Nanomedicine (Lond) 2016;11:673-92. [Crossref] [PubMed]
3. Roduner E. Size matters: why nanomaterials are different. Chem Soc Rev 2006;35:583-92. [Crossref] [PubMed]
4. Buzea C, Pacheco II, Robbie K. Nanomaterials and nanoparticles: sources and toxicity. Biointerphases 2007;2:MR17-71. [Crossref] [PubMed]
5. Lines MG. Nanomaterials for practical functional uses. J Alloys Compd 2008;449:242-5. [Crossref]
6. Wong IY, Bhatia SN, Toner M. Nanotechnology: emerging tools for biology and medicine. Genes Dev 2013;27:2397-408. [Crossref] [PubMed]
7. Güven E. Nanotechnology-based drug delivery systems in orthopedics. Jt Dis Relat Surg 2021;32:267-73. [PubMed]
8. Pappas MA, Spindler KP, Hu B, et al. Volume and Outcomes of Joint Arthroplasty. J Arthroplasty 2022;37:2128-33. [Crossref] [PubMed]
9. Cram P, Lu X, Kates SL, et al. Total knee arthroplasty volume, utilization, and outcomes among Medicare beneficiaries, 1991-2010. JAMA 2012;308:1227-36. [Crossref] [PubMed]
10. Sloan M, Premkumar A, Sheth NP. Projected Volume of Primary Total Joint Arthroplasty in the U.S., 2014 to 2030. J Bone Joint Surg Am 2018;100:1455-60. [Crossref] [PubMed]
11. Mulvaney P. Nanoscience vs nanotechnology--defining the field. ACS Nano 2015;9:2215-7. [Crossref] [PubMed]
12. Joudeh N, Linke D. Nanoparticle classification, physicochemical properties, characterization, and applications: a comprehensive review for biologists. J Nanobiotechnology 2022;20:262. [Crossref] [PubMed]
13. Khan I, Saeed K, Khan I. Nanoparticles: Properties, applications and toxicities. Arabian Journal of Chemistry 2019;12:908-31. [Crossref]
14. Pan K, Zhong Q. Organic Nanoparticles in Foods: Fabrication, Characterization, and Utilization. Annu Rev Food Sci Technol 2016;7:245-66. [Crossref] [PubMed]
15. Ng KK, Zheng G. Molecular Interactions in Organic Nanoparticles for Phototheranostic Applications. Chem Rev 2015;115:11012-42. [Crossref] [PubMed]
16. Xu X, Ho W, Zhang X, et al. Cancer nanomedicine: from targeted delivery to combination therapy. Trends Mol Med 2015;21:223-32. [Crossref] [PubMed]
17. Lu KQ, Quan Q, Zhang N, et al. Multifarious roles of carbon quantum dots in heterogeneous photocatalysis. Journal of Energy Chemistry 2016;25:927-35. [Crossref]
18. Yuan X, Zhang X, Sun L, et al. Cellular Toxicity and Immunological Effects of Carbon-based Nanomaterials. Part Fibre Toxicol 2019;16:18. [Crossref] [PubMed]
19. Mochalin VN, Shenderova O, Ho D, et al. The properties and applications of nanodiamonds. Nat Nanotechnol 2011;7:11-23. [Crossref] [PubMed]
20. Mauter MS, Elimelech M. Environmental applications of carbon-based nanomaterials. Environ Sci Technol 2008;42:5843-59. [Crossref] [PubMed]
21. Oh WK, Yoon H, Jang J. Size control of magnetic carbon nanoparticles for drug delivery. Biomaterials 2010;31:1342-8. [Crossref] [PubMed]
22. Chandra S, Das P, Bag S, et al. Synthesis, functionalization and bioimaging applications of highly fluorescent carbon nanoparticles. Nanoscale 2011;3:1533-40. [Crossref] [PubMed]
23. Du J, Xu N, Fan J, et al. Carbon Dots for In Vivo Bioimaging and Theranostics. Small 2019;15:e1805087. [Crossref] [PubMed]
24. Agha A, Waheed W, Stiharu I, et al. A review on microfluidic-assisted nanoparticle synthesis, and their applications using multiscale simulation methods. Discov Nano 2023;18:18. [Crossref] [PubMed]
25. Moreno-Vega AI, Gómez-Quintero T, Nuñez-Anita RE, et al. Polymeric and Ceramic Nanoparticles in Biomedical Applications. Journal of Nanotechnology 2012;2012:936041. [Crossref]
26. Gupta SM, Tripathi M. An overview of commonly used semiconductor nanoparticles in photocatalysis. High Energy Chem 2012;46:1-9. [Crossref]
27. Ruiz A, Salas G, Calero M, et al. Short-chain PEG molecules strongly bound to magnetic nanoparticle for MRI long circulating agents. Acta Biomater 2013;9:6421-30. [Crossref] [PubMed]
28. Salvati A, Pitek AS, Monopoli MP, et al. Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nat Nanotechnol 2013;8:137-43. [Crossref] [PubMed]
29. McNeeley KM, Karathanasis E, Annapragada AV, et al. Masking and triggered unmasking of targeting ligands on nanocarriers to improve drug delivery to brain tumors. Biomaterials 2009;30:3986-95. [Crossref] [PubMed]
30. Mobasheri A, Batt M. An update on the pathophysiology of osteoarthritis. Ann Phys Rehabil Med 2016;59:333-9. [Crossref] [PubMed]
31. Centers for Disease Control and Prevention (CDC). Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation--United States, 2010-2012. MMWR Morb Mortal Wkly Rep 2013;62:869-73. [PubMed]
32. Felson DT. Osteoarthritis as a disease of mechanics. Osteoarthritis Cartilage 2013;21:10-5. [Crossref] [PubMed]
33. Wang X, Hunter D, Xu J, et al. Metabolic triggered inflammation in osteoarthritis. Osteoarthritis Cartilage 2015;23:22-30. [Crossref] [PubMed]
34. Goldring MB. Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis. Ther Adv Musculoskelet Dis 2012;4:269-85. [Crossref] [PubMed]
35. Fernandes JC, Martel-Pelletier J, Pelletier JP. The role of cytokines in osteoarthritis pathophysiology. Biorheology 2002;39:237-46. [Crossref] [PubMed]
36. Bruno MC, Cristiano MC, Celia C, et al. Injectable Drug Delivery Systems for Osteoarthritis and Rheumatoid Arthritis. ACS Nano 2022;16:19665-90. [Crossref] [PubMed]
37. Sinatti P, Sánchez Romero EA, Martínez-Pozas O, et al. Effects of Patient Education on Pain and Function and Its Impact on Conservative Treatment in Elderly Patients with Pain Related to Hip and Knee Osteoarthritis: A Systematic Review. Int J Environ Res Public Health 2022;19:6194. [Crossref] [PubMed]
38. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage 2019;27:1578-89. [Crossref] [PubMed]
39. Fernández-Carnero S, Martínez-Pozas O, Cuenca-Zaldívar JN, et al. Addressing frailty in older adults: an integrated challenge for health, science, and society. Aging (Albany NY) 2024;16:13176-80. [Crossref] [PubMed]
40. Evans CH, Kraus VB, Setton LA. Progress in intra-articular therapy. Nat Rev Rheumatol 2014;10:11-22. [Crossref] [PubMed]
41. Martínez-Pozas O, Sánchez-Romero EA, Beltran-Alacreu H, et al. Effects of Orthopedic Manual Therapy on Pain Sensitization in Patients With Chronic Musculoskeletal Pain: An Umbrella Review With Meta-Meta-analysis. Am J Phys Med Rehabil 2023;102:879-85. [Crossref] [PubMed]
42. Bozzuto G, Molinari A. Liposomes as nanomedical devices. Int J Nanomedicine 2015;10:975-99. [Crossref] [PubMed]
43. Wang N, Wang T, Li T, et al. Modulation of the physicochemical state of interior agents to prepare controlled release liposomes. Colloids Surf B Biointerfaces 2009;69:232-8. [Crossref] [PubMed]
44. Liu P, Chen G, Zhang J. A Review of Liposomes as a Drug Delivery System: Current Status of Approved Products, Regulatory Environments, and Future Perspectives. Molecules 2022;27:1372. [Crossref] [PubMed]
45. Zhang M, Gao S, Yang D, et al. Influencing factors and strategies of enhancing nanoparticles into tumors in vivo. Acta Pharm Sin B 2021;11:2265-85. [Crossref] [PubMed]
46. Kalyane D, Raval N, Maheshwari R, et al. Employment of enhanced permeability and retention effect (EPR): Nanoparticle-based precision tools for targeting of therapeutic and diagnostic agent in cancer. Mater Sci Eng C Mater Biol Appl 2019;98:1252-76. [Crossref] [PubMed]
47. Williams AS, Camilleri JP, Goodfellow RM, et al. A single intra-articular injection of liposomally conjugated methotrexate suppresses joint inflammation in rat antigen-induced arthritis. Br J Rheumatol 1996;35:719-24. [Crossref] [PubMed]
48. Corciulo C, Castro CM, Coughlin T, et al. Intraarticular injection of liposomal adenosine reduces cartilage damage in established murine and rat models of osteoarthritis. Sci Rep 2020;10:13477. [Crossref] [PubMed]
49. Lu Y, Cheng D, Niu B, et al. Properties of Poly (Lactic-co-Glycolic Acid) and Progress of Poly (Lactic-co-Glycolic Acid)-Based Biodegradable Materials in Biomedical Research. Pharmaceuticals (Basel) 2023;16:454. [Crossref] [PubMed]
50. Maudens P, Seemayer CA, Thauvin C, et al. Nanocrystal-Polymer Particles: Extended Delivery Carriers for Osteoarthritis Treatment. Small 2018;14: [Crossref] [PubMed]
51. Kang ML, Kim JE, Im GI. Thermoresponsive nanospheres with independent dual drug release profiles for the treatment of osteoarthritis. Acta Biomater 2016;39:65-78. [Crossref] [PubMed]
52. Sang Y, Zhang J, Liu C, et al. Ameliorating Osteoarthritis in Mice Using Silver Nanoparticles. J Vis Exp 2023; [Crossref] [PubMed]
53. Huynh KH, Pham XH, Kim J, et al. Synthesis, Properties, and Biological Applications of Metallic Alloy Nanoparticles. Int J Mol Sci 2020;21:5174. [Crossref] [PubMed]
54. Paik J, Duggan ST, Keam SJ. Triamcinolone Acetonide Extended-Release: A Review in Osteoarthritis Pain of the Knee. Drugs 2019;79:455-62. [Crossref] [PubMed]
55. Sullivan MP, McHale KJ, Parvizi J, et al. Nanotechnology: current concepts in orthopaedic surgery and future directions. Bone Joint J 2014;96-B:569-73. [Crossref] [PubMed]
56. Abu-Amer Y, Darwech I, Clohisy JC. Aseptic loosening of total joint replacements: mechanisms underlying osteolysis and potential therapies. Arthritis Res Ther 2007;9:S6. [Crossref] [PubMed]
57. Webster TJ, Ejiofor JU. Increased osteoblast adhesion on nanophase metals: Ti, Ti6Al4V, and CoCrMo. Biomaterials 2004;25:4731-9. [Crossref] [PubMed]
58. Horváth T, Hanák L, Hegyi P, et al. Hydroxyapatite-coated implants provide better fixation in total knee arthroplasty. A meta-analysis of randomized controlled trials. PLoS One 2020;15:e0232378. [Crossref] [PubMed]
59. Love CA, Cook RB, Harvey TJ, et al. Diamond like carbon coatings for potential application in biological implants—a review. Tribology International 2013;63:141-50. [Crossref]
60. Birkett M, Zia AW, Devarajan DK, et al. Multi-functional bioactive silver- and copper-doped diamond-like carbon coatings for medical implants. Acta Biomater 2023;167:54-68. [Crossref] [PubMed]
61. Mazare A, Anghel A, Surdu-Bob C, et al. Silver doped diamond-like carbon antibacterial and corrosion resistance coatings on titanium. Thin Solid Films 2018;657:16-23. [Crossref]
62. Chan YH, Huang CF, Ou KL, et al. Mechanical properties and antibacterial activity of copper doped diamond-like carbon films. Surf Coat Technol 2011;206:1037-40. [Crossref]
63. Song W, Seta J, Chen L, et al. Doxycycline-loaded coaxial nanofiber coating of titanium implants enhances osseointegration and inhibits Staphylococcus aureus infection. Biomed Mater 2017;12:045008. [Crossref] [PubMed]
64. Indelli PF, Ghirardelli S, Iannotti F, et al. Nanotechnology as an Anti-Infection Strategy in Periprosthetic Joint Infections (PJI). Trop Med Infect Dis 2021;6:91. [Crossref] [PubMed]
65. Li H, Ogle H, Jiang B, et al. Cefazolin embedded biodegradable polypeptide nanofilms promising for infection prevention: a preliminary study on cell responses. J Orthop Res 2010;28:992-9. [Crossref] [PubMed]
66. Mooney JA, Pridgen EM, Manasherob R, et al. Periprosthetic bacterial biofilm and quorum sensing. J Orthop Res 2018;36:2331-9. [Crossref] [PubMed]
67. Madanat R, Laaksonen I, Graves SE, et al. Ceramic bearings for total hip arthroplasty are associated with a reduced risk of revision for infection. Hip Int 2018;28:222-6. [Crossref] [PubMed]
68. Blom AW, Beswick AD, Burston A, et al. Infection after total joint replacement of the hip and knee: research programme including the INFORM RCT. Southampton: National Institute for Health and Care Research; 2022.
69. Ciobanu G, Ilisei S, Luca C. Hydroxyapatite-silver nanoparticles coatings on porous polyurethane scaffold. Mater Sci Eng C Mater Biol Appl 2014;35:36-42. [Crossref] [PubMed]
70. Zhang X, Wu H, Geng Z, et al. Microstructure and cytotoxicity evaluation of duplex-treated silver-containing antibacterial TiO₂ coatings. Mater Sci Eng C Mater Biol Appl 2014;45:402-10. [Crossref] [PubMed]
71. Yanovska AA, Stanislavov AS, Sukhodub LB, et al. Silver-doped hydroxyapatite coatings formed on Ti-6Al-4V substrates and their characterization. Mater Sci Eng C Mater Biol Appl 2014;36:215-20. [Crossref] [PubMed]
72. Tautzenberger A, Kovtun A, Ignatius A. Nanoparticles and their potential for application in bone. Int J Nanomedicine 2012;7:4545-57. [Crossref] [PubMed]
73. Feng K, Sun H, Bradley MA, et al. Novel antibacterial nanofibrous PLLA scaffolds. J Control Release 2010;146:363-9. [Crossref] [PubMed]
74. Johnson CT, García AJ. Scaffold-based anti-infection strategies in bone repair. Ann Biomed Eng 2015;43:515-28. [Crossref] [PubMed]
75. Lum ZC, Natsuhara KM, Shelton TJ, et al. Mortality During Total Knee Periprosthetic Joint Infection. J Arthroplasty 2018;33:3783-8. [Crossref] [PubMed]
76. Taha M, Abdelbary H, Ross FP, et al. New Innovations in the Treatment of PJI and Biofilms-Clinical and Preclinical Topics. Curr Rev Musculoskelet Med 2018;11:380-8. [Crossref] [PubMed]
77. Ayre WN, Birchall JC, Evans SL, et al. A novel liposomal drug delivery system for PMMA bone cements. J Biomed Mater Res B Appl Biomater 2016;104:1510-24. [Crossref] [PubMed]
78. Shen SC, Ng WK, Dong YC, et al. Nanostructured material formulated acrylic bone cements with enhanced drug release. Mater Sci Eng C Mater Biol Appl 2016;58:233-41. [Crossref] [PubMed]
79. Fazly Bazzaz BS, Khameneh B, Zarei H, et al. Antibacterial efficacy of rifampin loaded solid lipid nanoparticles against Staphylococcus epidermidis biofilm. Microb Pathog 2016;93:137-44. [Crossref] [PubMed]
80. Li C, Zhang X, Huang X, et al. Preparation and characterization of flexible nanoliposomes loaded with daptomycin, a novel antibiotic, for topical skin therapy. Int J Nanomedicine 2013;8:1285-92. [Crossref] [PubMed]
81. Chan BK, Abedon ST, Loc-Carrillo C. Phage cocktails and the future of phage therapy. Future Microbiol 2013;8:769-83. [Crossref] [PubMed]
82. Nilsson AS. Pharmacological limitations of phage therapy. Ups J Med Sci 2019;124:218-27. [Crossref] [PubMed]
83. Pardo-Freire M, Domingo-Calap P. Phages and Nanotechnology: New Insights against Multidrug-Resistant Bacteria. Biodes Res 2023;5:0004.
84. Chen J, Andler SM, Goddard JM, et al. Integrating recognition elements with nanomaterials for bacteria sensing. Chem Soc Rev 2017;46:1272-83. [Crossref] [PubMed]
85. Peng H, Chen IA. Rapid Colorimetric Detection of Bacterial Species through the Capture of Gold Nanoparticles by Chimeric Phages. ACS Nano 2019;13:1244-52. [Crossref] [PubMed]
86. Malik DJ, Sokolov IJ, Vinner GK, et al. Formulation, stabilisation and encapsulation of bacteriophage for phage therapy. Adv Colloid Interface Sci 2017;249:100-33. [Crossref] [PubMed]
87. Wang W, Cheng X, Liao J, et al. Synergistic Photothermal and Photodynamic Therapy for Effective Implant-Related Bacterial Infection Elimination and Biofilm Disruption Using Cu(9)S(8) Nanoparticles. ACS Biomater Sci Eng 2019;5:6243-53. [Crossref] [PubMed]
88. Peng H, Borg RE, Dow LP, et al. Controlled phage therapy by photothermal ablation of specific bacterial species using gold nanorods targeted by chimeric phages. Proc Natl Acad Sci U S A 2020;117:1951-61. [Crossref] [PubMed]
89. Malik S, Muhammad K, Waheed Y. Emerging Applications of Nanotechnology in Healthcare and Medicine. Molecules 2023;28:6624. [Crossref] [PubMed]
90. Singh A, Amiji MM. Application of nanotechnology in medical diagnosis and imaging. Curr Opin Biotechnol 2022;74:241-6. [Crossref] [PubMed]
91. Misra R, Acharya S, Sahoo SK. Cancer nanotechnology: application of nanotechnology in cancer therapy. Drug Discov Today 2010;15:842-50. [Crossref] [PubMed]
92. Sahu T, Ratre YK, Chauhan S, et al. Nanotechnology based drug delivery system: Current strategies and emerging therapeutic potential for medical science. J Drug Deliv Sci Technol 2021;63:102487. [Crossref]
93. Polyzois I, Nikolopoulos D, Michos I, et al. Local and systemic toxicity of nanoscale debris particles in total hip arthroplasty. J Appl Toxicol 2012;32:255-69. [Crossref] [PubMed]
94. Farjadian F, Ghasemi A, Gohari O, et al. Nanopharmaceuticals and nanomedicines currently on the market: challenges and opportunities. Nanomedicine (Lond) 2019;14:93-126. [Crossref] [PubMed]
95. DiMasi JA, Grabowski HG, Hansen RW. The cost of drug development. N Engl J Med 2015;372:1972. [Crossref] [PubMed]
96. DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: New estimates of R&D costs. J Health Econ 2016;47:20-33. [Crossref] [PubMed]
97. Sánchez-Romero EA, Battaglino APT, Campanella W, et al. Impact on Blood Tests of Lower Limb Joint Replacement for the Treatment of Osteoarthritis: Hip and Knee. Topics in Geriatric Rehabilitation 2021;37:227-9. [Crossref]
98. Fernández-CarneroSMartínez-PozasOPecos-MartínDUpdate on the Detection of Frailty in the Older Adult: A Multicenter Cohort Big Data-Based Study Protocol.Research Square 2024. doi: .10.21203/rs.3.rs-4190311/v1