Nanotechnology applications in osteodistraction

Introduction

The most common form of bone regeneration is fracture healing, during which the pathway of normal fetal skeletogenesis is reactivated. However, with substantial loss of bone tissue the regenerative process is compromised, as is seen in cases of avascular necrosis and osteoporosis. These challenging situations often necessitate the augmentation of natural bone repair.

Distraction osteogenesis (DO) is a method of producing large quantities of bone using local host tissues stimulated by mechanical distraction forces. After an osteotomy the continuously enlarging gap is filled with living bone via intramembranous ossification of the newly built bone. The main advantage of DO is that it can achieve regeneration of living bone with the same strength and width as that of the native bone. Peripheral nerves, vessels, muscles, tendons, ligaments, and skin are also gradually lengthened in proportion to the lengthening bone. DO has been widely used for the treatment of leg-length discrepancy, nonunion, traumatic bone defect, deformity, musculoskeletal tumor and osteomyelitis.

Recent discoveries have highlighted that nanotechnology may universally augment all materials used for regrowing bone. Nanotechnology, a new focus in the area of biomedical research, involves the visualization, manipulation, and fabrication of materials on the smallest scales, in dimensions of 1 µm down to 10 Ε. The unique feature of this nanotechnological approach is that it enables consideration of the spatial and temporal levels of material organization in order to develop appropriate hierarchical structures. These nanomaterials have shown superior properties over their conventional counterparts owing to their distinctive nanoscale features and novel physical properties. Currently, applications of nanomaterials in osteodistraction include the use of nanofilms and nanoparticles to protect against infection in surgical implants, and the use of engineered surfaces to improve bone healing and formation and to assist in osteogenesis via the distribution of osteogenic factors. This review seeks to demonstrate the potential of nanobiomaterials to augment biological applications pertinent to osteodistraction.

Nanofeatures Influence Cell Behavior

The topography of nanomaterials (e.g. pores, ridges, grooves, fibers, nodes, and combinations of these features) is known to significantly influence cell behavior.

Furthermore, implant surface chemistry plays a critical role in deciding the performance and success of these devices. The interaction of four proteins - fibronectin, vitronectin, laminin, and collagen - is known to enhance osteoblast function on nanomaterials compared to conventional materials. Proteins and other biomolecules that dynamically adsorb to biomaterial surfaces upon implantation can trigger nonspecific inflammatory responses, which can limit integration of the device and influence in vivo performance.

The wettability of a nanomaterial can significantly alter cell behavior. The surface composition, surface treatment, surface roughness, immobilization of various chemical agents to the surface of the implant or biomaterial, and the presence of nanofeatures on the surface, alter surface wettability and affect cell behavior. Increased surface wettability, or hydrophilicity, has been associated with enhanced protein adsorption, and consequently, cell adhesion on biomaterials. The ability to synthesize and process nanomaterials with tailored structures and topographies to direct subsequent functions of specific cell lines provides potential for the design of novel proactive biomaterials that could improve the efficacy of bone implants.

Osteodistraction and Nanotechnology

Although DO with an external fixator has become a popular method of treating cases with substantial bone loss, it is not without complications [Figure 1]. One of the major drawbacks of this method is that it is time-consuming and the ring fixator must be maintained in situ until full consolidation of the bone. This is inconvenient and even uncomfortable for the patient. Further, Paley reported pin tract infections in 36% of patients, and Karger et al. noted joint contractures in 65% of patients when the limb was lengthened by 24% (7 cm) of its initial length.

Advances in nanotechnology have stimulated investigations into cell-substrate interactions from the microscale to the nanoscale. Using this technique, it is now possible to fabricate advanced materials with more favorable properties for orthopedic applications. There have been quite a few reports in the literature investigating the usefulness of various nanomaterials for reducing the risk of implant-associated infections and accelerating the bone healing process.

  Nanocomposites for Bone Tissue Regeneration

The introduction of polymer nanocomposites into bone tissue engineering allows the complex architecture of native bone tissue to be mimicked, providing a novel and practical approach to the massive production of materials for bone tissue engineering. ^[8] Synthetic or natural polymer matrices offer a wide range of mechanical properties and exhibit different biodegradation features, whereas various inorganic nanoparticles provide bioactivity. Furthermore, their integration makes it possible to fabricate materials that mimic the structural and morphological organization of native bone. Although there is great potential to improve current biomaterials and develop advanced nanocomposite scaffolds for bone regeneration, each of these materials has specific drawbacks.
Bioceramic/synthetic polymer nanocomposites for bone regeneration
Nanocomposites based on bioceramics and biodegradable polymers (e.g. calcium phosphate, calcium sulfate, beta-tricalcium phosphate [β-TCP], hydroxyapatite [HA], poly-lactic acid [PLA], poly-glycolic acid, and poly-lactide-co-glycolide) have attracted much attention for bone tissue regeneration because of the excellent combination of bioactivity and osteoconductivity of bioceramics with the flexibility and shape controllability of polymers. Such nanocomposites are also able to closely mimic the microstructure of bone. These composites have shown a better cell response than conventional composites, depending on different factors, such as material composition, fabrication method, microstructure and mechanical properties of the composites, among others. Nonbiodegradable polymers have been used in bone tissue engineering for their better mechanical properties and chemical stability than biodegradable polymers. However, some of these polymers, such as polyethylene, polypropylene and poly (etherether ketone), demonstrate severe immune responses.
Bioceramic/natural polymer nanocomposites for bone regeneration
Natural biopolymers (e.g. chitosan, collagen, HA, silk fibroin, and calcium phosphate) are currently of interest in tissue engineering because their biological recognition may positively support cell adhesion and function. However, these polymers have poor mechanical properties. HA-reinforced natural polymers exhibit much better mechanical and biological properties, and thus may resolve many of these difficulties.
Carbon nanotube/polymer nanocomposites for bone regeneration
Carbon nanotubes (CNTs) have excellent mechanical properties, a highly specific surface area and a low density, which makes them ideal for the fabrication of tissue engineering scaffolds with polymers. The addition of CNTs to a polymer helps cell growth and promotes cell attachment, proliferation and differentiation. The cytotoxicity of CNTs is still obscure, but their toxicity can be reduced when incorporated into a polymeric matrix, thus making it possible to fabricate CNT - polymer nanocomposites for bone tissue engineering. However, the long-term toxicity of CNTs in human tissue and their influence on bone remodeling need further investigation.

 Implant-Associated Infection and Nanotechnology

Implant-associated infection is one of the most serious complications in orthopedic surgery. Bone infections associated with foreign body materials are especially difficult to treat. Removal of the infected implants, long-term systemic antibiotic therapy, and multiple revisions with radical debridement are frequently required. The consequences of infection can be devastating and may lead to prolonged hospitalization, poor functional outcome, sepsis, and even amputation.

Implant-associated infections are the result of bacterial adhesion to an implant surface and subsequent biofilm formation at the implantation site. The formation of biofilm takes place in several stages, starting with rapid surface attachment, followed by multilayered cellular proliferation and intercellular adhesion in an extracellular polysaccharide matrix. Biofilms are resistant to both the immune response and systemic antibiotic therapies.

Different surface modification strategies for orthopedic implants have been investigated, including (a) the addition of materials with desired functions to the surface; (b) the conversion of the existing surface into more desirable chemistries and/or topographies; and (c) the removal of material from the existing surface to create new relevant topographies. The latter, which was tested during in vitro studies, provides the surface with a specific roughness to promote osteoblast proliferation and cell adhesion.

Coating metal implants with a bactericidal film would inhibit bacteria from colonizing implant surfaces and provide a high antibiotic concentration in a local region commonly known as a nidus for bacterial infection. Different surface modifications and coating techniques can be used, such as direct impregnation with antibiotics and immobilization of an antimicrobial agent in a matrix capable of binding to different surfaces, as well as coating with antimicrobial, active metals such as copper and silver, nitric oxide-releasing materials and titanium dioxide films.

Ainslie et al. have shown in vitro that nanostructured surfaces display reduced inflammation in comparison with a respective flat control. Controlled drug release from the surfaces of implanted medical devices coated with nanostructured films is expected to yield additional advantages over conventional coatings. However, so far this approach has gained limited clinical use for orthopedic coatings.

Li et al. developed biodegradable polypeptide multilayer nanofilms to potentially serve as antibiotic carriers at the implant-tissue interface. They demonstrated that polypeptide multilayer nanofilms, with or without cefazolin, have antibacterial activity against organisms frequently associated with osteomyelitis, and may improve bone healing through improving osteoblast cell adhesion, viability, and proliferation.

Etienne et al. developed a strategy based on the insertion of an antimicrobial peptide (defensin) into polyelectrolyte multilayer films built by the alternate deposition of polyanions and polycations. Examination of Escherichia More Details coli D22 growth at the surface of defensin-functionalized films revealed 98% inhibition when positively charged poly (l-lysine) was the outermost layer of the film, owing to the interaction of the bacteria with the positively charged ends of the film.

Diamond nanoparticles or nanodiamonds (ND) have recently gained significant attention for local drug release in the form of coatings. Recent studies of cell viability, such as the production of luminescent adenosine 5' triphosphate, have shown that ND are not toxic to a variety of cell types. Huang et al. have examined the cytotoxicity and anti-inflammatory response of dexamethasone-loaded ND nanofilms in vivo and found that the nanofilms are non-apoptotic and non-cytotoxic, with efficient drug-eluting characteristics, thus being of great interest as novel implant coatings.

Rauschmann et al. have developed a bioresorbable composite of calcium sulfate and nanoparticulate HA for the local delivery of antibiotics to tackle bone infection. No in vitro cytotoxicity was noticed, and the composite material exhibited better biocompatibility than pure calcium phosphate. Owing to its high porosity, it revealed initial high antibiotic release followed by a subsequent decline, ensuring concentrations well above the respective minimal inhibition concentrations of gentamicin- and vancomyin-susceptible bacteria within the first 3-4 days.

Adams et al. have examined the release of vancomycin from thin sol-gel films deposited on titanium alloy surfaces implanted in an animal model. The coatings exhibited a significant inhibiting effect against the adhesion and biofilm formation of Staphylococcus aureus.

Active coatings for the delivery of therapeutic molecules using the advantages of nanotechnology have a bright future. Implant-related microbial infection is a serious threat after orthopedic surgery. The literature review has revealed that an increasing volume of research is focusing on developing antimicrobial agents with high efficiency and controlled-release ability. This method is very efficient because it reduces systemic toxicity and the side-effects of parenteral antibiotics, while also yielding higher drug concentrations in the relevant tissues.

Future Challenges

Bone growth and remodeling involves a plethora of growth factors, recruitment of mesenchymal stem cells, and the action of three different mature cell types (osteoblasts, osteocytes and osteoclasts) as well other factors that are yet to be revealed. To move to the next developmental phase of nanobiomaterials science, it is critical to understand the cellular and molecular basis governing the interaction between nanostructure and cells.

It has become more apparent that nanomaterials hold much promise for bone regeneration applications, and this warrants further exploration. The endpoint is limited only by the extent of our imaginations.

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