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Research Article| Volume 21, 101536, October 2021

Silver Nanoparticle (AgNP) Technology applications in trauma and orthopaedics

      Abstract

      Recently Nanotechnology advances continue to accelerate with development of incredible new materials and products in the field of science. The Nanotechnology has evolved in the domains of prevention, diagnosis and treatment in the field of trauma and orthopaedics. It provides a spectrum of new tools such as drug delivery (chemotherapy in orthopaedic oncology), diagnosis (bone diseases, osteoporosis, metastatic osteosarcoma), improving osteointegration of implant materials (implants & total joint replacements), combating infection (trauma implants and prosthesis), tissue engineering (hydroxyapatite scaffolds, cartilage defects, stem cell regeneration) and prevention of osteoporosis. The current article highlights the role of Silver Nanoparticle (AgNP) Technology applications in Trauma and Orthopaedics.

      Keywords

      Introduction

      Nanotechnology is the branch of technology which deals with use and application of nanoscale materials (materials whose structure is on the scale of nanometres, i.e. billionths of a meter). Nanomedicine represents medical application of nanotechnologies in healthcare. Advances in genetics, molecular biology, tribology and bioengineering has enabled researchers in harnessing different physiological processes on a nanoscale level in the delivery of patient care.
      • Ventola C.L.
      The nanomedicine revolution: part 1: emerging concepts.
      Nanomedicine is an important field of research which has the potential to both produce novel devices and improve existing products that cannot be achieved on a larger physical scale. Currently, the most popular spheres of research in nanomedicine involve diagnostics, implants, drug delivery systems and therapeutics. A wide variety of Nanoparticles (NPs) and delivery systems (e.g. liposomes, polymers, nanotubes, nano shells, nanorods) are used in nanomedicine, depending on the application. Nanotechnology has evolved in the domains of prevention, diagnosis and treatment in the field of trauma and orthopaedics.
      • Garimella R.
      • Eltorai A.E.
      Nanotechnology in orthopedics.
      It provides a spectrum of new tools such as drug delivery (chemotherapy in orthopaedic oncology), diagnosis (bone diseases, osteoporosis, metastatic osteosarcoma), improving osteointegration of implant materials (implants & total joint replacements), combating infection (trauma implants and prosthesis), tissue engineering (hydroxyapatite scaffolds, cartilage defects, stem cell regeneration) and prevention of osteoporosis.
      • Sullivan M.P.
      • McHale K.J.
      • Parvizi J.
      • Mehta S.
      Nanotechnology: current concepts in orthopaedic surgery and future directions.
      ,
      • Mazaheri M.
      • Eslahi N.
      • Ordikhani F.
      • Tamjid E.
      • Simchi A.
      Nanomedicine applications in orthopedic medicine: state of the art.
      (Table 1). We discuss the role and applications of Silver nanoparticles especially its role in osteointegration and combating orthopaedic infection.
      Table 1Applications of nanotechnology in trauma and orthopaedics.
      Indication/RoleNanoparticle/technologyMechanism of actionTrauma and Orthopaedic condition
      1Combating Infection

      - Implant Surgery

      - Total Joint Replacement
      - Titanium dioxide nanotubes with Silver Nanoparticles (AgNP)Nanophase drug delivery -antibiotic elution and release of silver particles which affects bacterial cell wall, DNA and RNA function

      - To decrease risk of infection

      - Reduce Bacterial ingrowth e,g, E.coli

      - Biofilm inhibition

      - Stimulation of new bone formation
      1. Osteomyelitis and infected nonunion

      2. External fixator pins- Sliver coated

      3. Intra-medullary nails

      4. Bone grafting material/Scaffolds
      2Drug delivery-Gold nanoparticles (AuNPs)-Coupling drug delivery to Nano sensors (Biosensors)

      -Nanophase delivery systems e.g. Reduce inflammatory cytokines
      Achilles Tendinopathy
      - AgNP poly-L-lactic-acid (PLLA)-Bone morphogenetic protein (BMP) delivery (Composite

      (BMP-2) coupled with Nano silver polylactic-co-glycolic acid (PLGA)
      Reducing time to seal large bone defects
      3Total Joint Replacement (TJR)-Biodegradable polypeptides

      -Nanophase selenium
      Nanophase drug delivery e.g. Cefazolin/antibiotics and to target release after implantation1. To decrease risk of infection

      2. Improve Osteo-integration

      3. Tumour prostheses (Titanium with silver-coated) (Nanophase selenium)
      4Tumour/Orthopaedic Oncology-magnetite-enriched collagen hydroxyapatite bio -composite

      -Nano magnetite-chitosan rod

      -Gelatin nanoparticles

      - Iron Oxide NP
      Targeted delivery of chemotherapy

      Identification of Pulmonary metastasis
      1. Osteosarcoma

      2. Metastatic Bone Disease (MBD)

      3. Tumour prostheses

      4. Mutated p15 gene marker for Osteosarcoma
      5Diagnosis
      Bone DiseasesCarbon nanotubes (CNTs)Biosensor- Implants

      Improve Conductivity
      1. Paget's disease,

      2. Renal osteodystrophy,

      3. Osteoporosis.
      OsteoporosisGold nanoparticles (AuNPs)-Detects a protein that is indicative of osteoporosis, Non-invasive method1. Early detection of Osteoporosis

      2. Evaluate bone conditioning
      Abbreviations: NP= Nanoparticles.

      Silver nanoparticles (AgNP)

      Silver and its ions have traditionally noted to have antimicrobial and bactericidal properties. Consequently, introduction of anti-microbial agents containing silver have assumed an influential role in the treatment of infections. The clinical application of AgNP has evolved considerably in the field of trauma and orthopaedics, where peri-operative infection of implanted devices or prosthesis in joint replacement surgery is a persistent threat.

      Mechanism of action

      As a non-specific biocidal agent silver has a wide spectrum of activity against Gram positive, Gram negative bacteria and antibiotic resistant strains. Silver acts at several levels of the bacterial cell cycle. Release of silver ions from AgNP cause degradation of peptidoglycan component of the cell wall, inhibit bacterial protein synthesis binding to Ribonucleic acid (RNA) and interact with Deoxyribonucleic acid (DNA) to impede replication signals.
      • Brennan S.A.
      • Ní Fhoghlú C.
      • Devitt B.M.
      • O'Mahony F.J.
      • Brabazon D.
      • Walsh A.
      Silver nanoparticles and their orthopaedic applications.
      In its elemental form, silver has also been shown to be antibacterial through its ability to attach to bacterial cell walls and promote oxidative stress, resulting in cytoplasmic leakage and death of bacteria. Silver has also been shown to inhibit the formation of a ‘biofilm’ and promote osteogenesis through increased cell proliferation. However, like silver's ability to kill bacteria, the same mechanism has been shown to be cytotoxic to human cells in concentrations above 10 μg/mL.

      Significant applications of silver nanoparticles (AgNP)

      A. AgNP in combating orthopaedic infection

      Over the past decade, various innovative methods of utilizing AgNP in nanomedicine have been explored. One of the most common design has been its addition to the outer layers of implants to reduce failure rates by infection. In a study by Zhao et al., AgNP were formed and deposited in titanium nanotubes via electrochemical anodization.
      • Zhao Y.
      • Xing Q.
      • Janjanam J.
      • et al.
      Facile electrochemical synthesis of antimicrobial TiO₂ nanotube arrays.
      The nanorods not only increased the surface area for interaction, but also resulted in the production of two sizes of silver nanoparticles found, 5–10 nm within and 80 nm outside. The difference in sizes is thought to have led to an initial burst of silver ions from the smaller particles followed by a slow dispersal from the larger particles, resulting in a logarithmic release of silver over 30 days. The results demonstrated effective resistance to E. coli on exposure to the modified titanium film but also showed significant osteoblast cytotoxicity. Contrary to the cytotoxicity to osteoblasts mentioned above, a study from Chen et al demonstrated desirable pro-osteogenic effects of AgNP through regulation of M1/M2 macrophages.
      • Chen Y.
      • Guan M.
      • Ren R.
      • et al.
      Improved immunoregulation of ultra-low-dose silver nanoparticle-loaded TiO2 nanotubes via M2 macrophage polarization by regulating GLUT1 and autophagy.
      In their in-vivo study, the release of a concentration of 0.2 ppm AgNP over 24 h demonstrated an increase in the pro-osteogenic M2 expression of macrophages via the inhibition of glucose transporter (GLUT1) expression and promotion of autophagy. Low concentrations of silver nanoparticles resulted in greater osteogenesis and increased presence of trabeculae. Tissue engineered composite bone graft development, consisting of bone morphogenetic protein 2 (BMP-2) coupled with nano silver polylactic-co-glycolic acid (PLGA) will have significant role in osteomyelitis and infected nonunion management with the ability of controlling infection whilst promoting osteogenesis.
      • Zheng Z.
      • Yin W.
      • Zara J.N.
      • et al.
      The use of BMP-2 coupled - nanosilver-PLGA composite grafts to induce bone repair in grossly infected segmental defects.
      AgNP coated external fixators pins with ability to reduce pin tract associated infection is another explored role.
      • Brennan S.A.
      • Ní Fhoghlú C.
      • Devitt B.M.
      • O'Mahony F.J.
      • Brabazon D.
      • Walsh A.
      Silver nanoparticles and their orthopaedic applications.

      B. AgNP in osteointegration

      Osteointegration of prosthesis used in total joint replacements and prevention of peri-prosthetic infection are key mechanisms in achieving long term, functional outcomes following arthroplasty surgery. The impact of the host response on the implant is dependent on several parameters such as surface topography and surgical technique. Titanium has been the most used material due to its tribological properties such as inertness and corrosion resistance. To reduce infection, mixture of AgNP in a nanocomposite film of tantalum oxynitride (TaON) improved the resistance to a range of bacteria, reinforcing the coating's function as a broad-spectrum antibiotic agent. The combination of the two compounds and the presence of oxygen, improved the biocompatibility of the coating resulting in an significant effect on osteogenic function.
      • Hu C.C.
      • Chang C.H.
      • Chang Y.
      • Hsieh J.H.
      • Ueng S.W.
      Beneficial effect of TaON-Ag nanocomposite titanium on antibacterial capacity in orthopedic application.
      Other AgNP polymers have been experimented in promoting host reactions to implants. Through a complex multi-layered method of encapsulating AgNP within polyvinyl alcohol containers, which were evenly dispersed across a chitosan coating, Mishra et al demonstrated that not only did the coating provide good antibacterial and anti-biofilm effects, but it also promoted cellular adhesion, proliferation and improved on the mechanical qualities of the implant.
      • Mishra S.K.
      • Teotia A.K.
      • Kumar A.
      • Kannan S.
      Mechanically tuned nanocomposite coating on titanium metal with integrated properties of biofilm inhibition, cell proliferation, and sustained drug delivery.

      Conclusion

      Research with the incorporation of silver nanoparticles has expanded from a novel standalone component with strong antibacterial ability to innovative, complex composites with additional desirable traits. With the success of in-vivo testing of these new designs, silver nanoparticles can potentially change the structure of the modern implant to combat infection and improve osteointegration.

      Author's contributions

      CT and VKJ involved in Conceptualization, literature search, manuscript writing and editing. KPI in Literature search, methodology, Data curation, manuscript review and editing. KPI supervised overall submission and approved final draft. All authors read and agreed the final draft submitted.

      Funding statement

      The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

      Statement of ethics

      The current submitted article is not a clinical study and does not involve any patients.

      Declaration of competing interest

      None declared.

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