The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 90, Issue Supplement 1

Symposium Articles | February 01, 2008

Nanofibers and Nanoparticles for Orthopaedic Surgery Applications

Lakshmi S. Nair, MPhil, PhD; Cato T. Laurencin, MD, PhD

Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

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J Bone Joint Surg Am, 2008 Feb 01;90(Supplement 1):128-131. doi: 10.2106/JBJS.G.01520

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Abstract

The ability of nanostructures to elicit altered cell behaviors, including cell adhesion, proliferation, orientation, motility, integrin expression, cytoskeletal organization, and modulation of intracellular signaling, has raised heightened interest in these materials for various biomedical applications, including orthopaedic repair and regeneration. Studies have demonstrated that nanofibrous structures can favorably modulate osteoblast, osteoclast, and fibroblast activities toward implant and/or scaffold materials. Nanomaterials based on silver nanoparticles have received significant attention. Apart from their unique wound-healing ability, silver nanoparticles also exhibit high antibacterial properties, making them potential candidates for use in the development of infection-resistant biomaterials.

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Nanostructures for Orthopaedic Applications

Nanostructures for Orthopaedic Applications | Polymeric Nanofibers for Orthopaedic Applications | Silver Nanoparticles for Wound-Healing Applications | Conclusions | References

Recent developments in nanotechnology have enabled the fabrication of materials and structures with nanosize features for biological applications. Nanostructured materials with surface features in the range of 1 to 100 nm exhibit altered and/or increased biological responses compared with micrometer-size surfaces¹. Nanostructured surfaces have been shown to influence protein adsorption and cell adhesion morphology and differentiation as well as the production and secretion of extracellular matrix molecules². The rationale for developing nanostructured materials for orthopaedic applications stems from the structure of bone itself, a composite nanostructured tissue composed of hydroxyapatite crystals (20 to 80 nm long and 2 to 5-nm thick) and collagen fibrils with diameters of less than 500 nm¹. The fact that bone cells are naturally adapted to nanophase materials has led to a series of studies investigating the response of bone cells toward synthetic nanostructures.

Dalby et al. investigated the feasibility of modulating the adhesion and behavior of human bone-marrow cells toward biomaterial surfaces with use of surfaces containing nanometric-scale shallow pits and grooves³. The topographies were manufactured with use of photolithography followed by the production of nickel shims and embossing into poly(methyl methacrylate). The ability of a biomaterial surface to induce differentiation of osteoprogenitor cells to mature mineral-producing osteoblasts is highly crucial for osseointegration; otherwise, bone-marrow cells differentiate to form soft tissue, leading to fibrous encapsulation. The cells on nanopatterned surfaces showed filopodial interactions, specifically in sensing nanotopographical features, cytoskeletal arrangements important in cell adhesion, function, and differentiation, and produced the osteoblast marker proteins osteocalcin and osteopontin without the addition of media supplements such as dexamethasone or ascorbate. Even at an earlier time-point (four days), the cells on nanostructured surfaces showed endogenous matrix production. The study demonstrated that nanotopographies can be used to control the adhesion, cytoskeleton, growth, and production of osteoblastic markers such as osteocalcin and osteopontin of human osteoprogenitor cells³.

Similarly, nanophase materials composed of alumina, titania, and hydroxyapatite with grain sizes of <100 nm have demonstrated favorable and enhanced osteoblast and osteoclast activity compared with conventional (micrometer-size) particles of the same materials^4,5. Elias et al.⁶ investigated the performance of human osteoblast cells cultured on carbon nanofibers with diameters of less than or greater than 100 nm. Increased proliferation of osteoblast cells was noted on fibers with diameters of <100 nm compared with fibers that had higher diameters. In addition, the cells cultured on fibers with diameters of <100 nm produced higher alkaline phosphatase and deposited more extracellular calcium. The study attributed the enhanced performance of osteoblasts on fibers with diameters of <100 nm to their dimensional similarity to hydroxyapatite crystals found in bone⁶. The enhanced activity of osteoblasts coupled with greater functions of osteoclasts is highly desirable for healthy remodeling of juxtaposed bone formed at implant surfaces. Subsequent in vivo studies have supported this hypothesis, demonstrating increased new bone formation on metals coated with nanophase apatite compared with conventional apatite when implanted in rats⁷.

Similarly, nanofibrous structures exhibit better osteoblast performance, presumably due to their extracellular mimetic structure. Woo et al. studied the osteoblast response to three-dimensional, porous, polymeric nanofibrous structures with interconnected spheroid pores (fiber diameter ranging from 50 to 500 nm) and compared it with the osteoblast response to structures with solid pore walls⁸. Enhanced osteoblast adhesion was observed on the nanofibrous structures. This has been attributed to the increased protein adsorption (four times more serum protein adsorption observed on nanofibrous structures) as well as to the selective adsorption of fibronectin and vitronectin on nanostructured structures; the presence of these proteins is known to enhance osteoblast adhesion⁸. With use of atomic force microscopy, Liu and Webster⁷ demonstrated the increased interaction of fibronectin with nanostructured surfaces that had a feature size of <100 nm. Also, increased unfolding of vitronectin on nanophase ceramics has been reported. This promoted the availability of specific cell-adhesive epitopes on the surface, which subsequently enhanced osteoblast adhesion⁷.

Apart from osteoblast and osteoclast responses, the fibroblast activity around an implant plays an important role in determining its fate. The formation of a fibrous soft-tissue capsule around an implant prevents proper biomechanical fixation and osseointegration that ultimately could lead to implant failure. A recent study demonstrated the possibility of using nanostructured implants as means to reduce fibrous encapsulation⁹. An appreciable decrease in fibroblast number was observed on nanostructured surfaces when compared with smooth surfaces that had the same surface chemistry and wettability⁹. Similarly, Dalby et al. demonstrated that fibroblasts changed their cytoskeleton organization on surfaces that had islands in the nanometer range, which subsequently suppressed the spreading and formation of confluent cell layers¹⁰.

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Fig. 1: Scanning electron micrograph showing the interaction between BALB/c C7 mouse fibroblasts cells and electrospun nanofibrous structures after three days in culture (magnification, ×3000). (Reproduced, with permission, from: Li WJ, Laurencin CT, Caterson EJ, Tuan RS, Ko FK. Electrospun nanofibrous structure: a novel scaffold for tissue engineering. J Biomed Mater Res. 2002;60:613-21.)

Polymeric Nanofibers for Orthopaedic Applications

Nanostructures for Orthopaedic Applications | Polymeric Nanofibers for Orthopaedic Applications | Silver Nanoparticles for Wound-Healing Applications | Conclusions | References

One of the most extensively investigated nanostructures for orthopaedic tissue-engineering application is polymeric nanofibers. The interconnecting porous structure of the nanofibrous scaffold provides a large surface area for cell attachment and sufficient space for nutrient transportation. Li et al. demonstrated the efficacy of polymeric nanofiber scaffolds in enhancing osteoblast adhesion and proliferation (Fig. 1)¹¹. The enhanced performance has been attributed to the ability of the matrix to closely mimic the structure of the natural extracellular matrix^12,13. Several techniques, such as electrospinning, phase-separation, and self-assembly, have been developed to fabricate polymeric nanofibers for orthopaedic applications^11,14,15. Among these, electrospinning has emerged as one of the most versatile techniques to develop nanofibrous structures from a wide range of polymers and composites. Nair et al. demonstrated the feasibility of developing nanofibrous structures from a variety of biodegradable polymers, including poly(DL-lactic-co-glycolic acid) and polyphosphazenes^16-18. Due to their chemical versatility, biodegradable polyphosphazene nanofibers have raised heightened biomedical interest for developing bioactive fibrous structures¹⁹. Fibers with diameters ranging from 3 nm to several micrometers can be obtained by the process of electrospinning. Unlike the other two processes, electrospinning enables the development of oriented nanofibers. Along with providing a high surface area for cell adhesion and proliferation, oriented nanofibers exhibit the ability to guide the orientation of cytoskeletal proteins of cells.

The extracellular matrix-like properties of electrospun nanofibers have also been shown to promote in vivo-like organization and morphogenesis of cells in culture²⁰. NIH 3T3 fibroblasts, rat kidney cells, and breast epithelial cells seeded onto polymeric nanofibers rearranged their actin cytoskeleton to a more in vivo-like morphology and exhibited vinculin distribution indicative of cellular differentiation and morphogenesis.

The spatial and temporal presentation of various biological factors that direct stem cell behavior has been shown to alter or accelerate natural healing events. The ability to encapsulate appropriate concentrations of the bioactive molecules in the native form within the carrier as well as the localized and controlled release of the same is vital to the success of regeneration. One of the growth factors that has raised appreciable clinical interest for repairing bone defects is bone morphogenetic protein-2. Nanostructured biomaterials combined with growth factors have emerged as an alternative treatment for bone repair and regeneration. The mild nanofabrication processes enable the incorporation of labile biomolecules within these structures. Hosseinkhani et al. demonstrated the feasibility of inducing homogeneous ectopic bone formation with use of injectable nanofibrous structures compared with use of a direct bone morphogenetic protein-2 injection²¹. Another study demonstrated the enhanced healing effect of bone morphogenetic protein released from a composite nanofiber matrix composed of collagen/poly(lactic acid) and nanosize hydroxyapatite²². The enhanced healing potential of the bone morphogenetic protein-2-releasing composite nanofiber matrix has been attributed to the ability of nanofiber materials to better retain growth factors due to their high surface area and nanotextures.

These studies collectively demonstrate the possibility of improving osseointegration and osseoinduction with use of implants and/or scaffolds with nanostructural features, thereby also improving their potential for orthopaedic applications.

Silver Nanoparticles for Wound-Healing Applications

Nanostructures for Orthopaedic Applications | Polymeric Nanofibers for Orthopaedic Applications | Silver Nanoparticles for Wound-Healing Applications | Conclusions | References

Infections of open fractures are known to complicate bone healing. Local infection has been recognized as one of the potential factors inhibiting fracture union, thereby leading to delayed unions or nonunions^23,24. The efficacy of nanostructured surfaces in reducing bacterial adhesion has also been investigated. This research is highly important considering the high occurrences of implant-associated infections, the lessthan-optimal in vivo performance of antibiotic-eluting orthopaedic implants, and the concern that long-term elution of low concentrations of antibiotics could lead to antibiotic resistance²⁵. With use of nanophase ceramics such as zinc oxide and titanium dioxide, Colon et al. demonstrated the decreased adhesion of Staphylococcus epidermidis and increased adhesion as well as functions of osteoblast cells on nanostructured surfaces²⁶.

Silver nanoparticles are another nanostructured material that is attracting increasing attention lately as an effective antimicrobial agent. The efficacy of silver as an antimicrobial agent has been recognized for centuries, and silver sulfadiazine is one of the most potent and widely used antibacterial agents. Bottom-up nanofabrication approaches have enabled the formation of silver nanoparticles of varying sizes and shapes with high biological activity. Silver nanoparticles maintain broad antibacterial, antiviral, and antifungal properties and are also considered to have a very low potential for inducing antibacterial resistance²⁷. Wound dressings containing nanocrystalline silver particles have already been used clinically with excellent results against gram-positive and gram-negative bacteria²⁸. In addition to their antibacterial property, silver nanoparticles have also been shown to facilitate wound-healing due to their ability to exhibit a wide range of biochemical effects²⁹. Silver-based compounds have shown the ability to downregulate matrix metalloproteinase to levels that facilitate wound-healing³⁰. Silver has the ability to promote epithelialization, as studies have indicated the ability of silver compounds to upregulate the metabolism of zinc and copper, two essential micronutrients for epithelial cell proliferation³¹. Apart from these, the inhibitory effect of silver on certain proinflammatory cytokines has also been demonstrated³².

The effect of silver nanoparticles on wound-healing and the formation of scar tissue have been investigated in mice with use of thermal injury, diabetic wound, and chronic wound models³¹. A comparison of the antibacterial property of silver nanoparticles to sulfadiazine was also performed. Wound cultures showed no microorganism growth for up to seven days after injury in the silver nanoparticle group, whereas bacterial growth was found in the silver sulfadiazine group three days after injury. The overall healing rate was higher in the silver nanoparticle-treated group compared with the silver sulfadiazine group. The study also demonstrated the efficacy of silver nanoparticles to control local and systemic inflammatory response by cytokine modulation upon burn injury. The results indicate the possibility of achieving scarless wound-healing with use of silver nanoparticles. These studies indicate that incorporation of silver nanoparticles in biomaterials carries potential in the development of next-generation infection-resistant implants and scaffolds.

Conclusions

Nanostructures for Orthopaedic Applications | Polymeric Nanofibers for Orthopaedic Applications | Silver Nanoparticles for Wound-Healing Applications | Conclusions | References

The development of nanostructured implants and scaffolds can be considered to be one of the promising strategies to increase osseointegration and reduce implant-associated infection, two significant problems associated with current orthopaedic biomaterials. The nanofibrous structures have been shown to favorably affect cell adhesion, proliferation, and phenotypic expression. The potential of nanofibrous structures to act as bone morphogenetic protein-releasing substrates has generated interest in the area of bone-defect healing. However, the effects of nanostructures on cellular functions as well as the possible in vivo toxicity of nanostructured materials have not yet been elucidated completely. Additional studies will be required to establish the potential use of this novel technology in biomedical applications. ?

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Nanostructures for Orthopaedic Applications | Polymeric Nanofibers for Orthopaedic Applications | Silver Nanoparticles for Wound-Healing Applications | Conclusions | References

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Topics

biomaterials ; osteoblasts ; polymers ; wound healing ; infection ; silver ; nanoparticles ; nanofibers ; nanostructures

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Lakshmi S. Nair, Cato T. Laurencin; Nanofibers and Nanoparticles for Orthopaedic Surgery Applications. The Journal of Bone & Joint Surgery. 2008 Feb;90(Supplement_1):128-131.

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