Advances in dual functional antimicrobial and osteoinductive biomaterials for orthopaedic applications.

A vast growing problem in orthopaedic medicine is the increase of clinical cases with antibiotic resistant pathogenic microbes, which is predicted to cause higher mortality than all cancers combined by 2050. Bone infectious diseases limit the healing ability of tissues and increase the risk of future injuries due to pathologic tissue remodelling. The traditional treatment for bone infections has several drawbacks and limitations, such as lengthy antibiotic treatment, extensive surgical interventions, and removal of orthopaedic implants and/or prosthesis, all of these resulting in long-term rehabilitation. This is a huge burden to the public health system resulting in increased healthcare costs. Current technologies e.g. co-delivery systems, where antibacterial and osteoinductive agents are delivered encounter challenges such as site-specific delivery, sustained and prolonged release, and biocompatibility. In this review, these aspects are highlighted to promote the invention of the next generation biomaterials to prevent and/or treat bone infections and promote tissue regeneration.

Effect of Silicon Dioxide and Magnesium Oxide on the Printability, Degradability, Mechanical Strength and Bioactivity of 3D Printed Poly (Lactic Acid)-Tricalcium Phosphate Composite Scaffolds.

BACKGROUND: Poly (lactic acid) (PLA) is a biodegradable polyester that has been exploited for a variety of biomedical applications, including tissue engineering. The incorporation of ß-tricalcium phosphate (TCP) into PLA has imparted bioactivity to the polymeric matrix. METHODS: We have modified a 90%PLA-10%TCP composite with SiO2 and MgO (1, 5 and 10 wt%), separately, to further enhance the material bioactivity. Filaments were prepared by extrusion, and scaffolds were fabricated using 3D printing technology associated with fused filament fabrication. RESULTS: The PLA-TCP-SiO2 composites presented similar structural, thermal, and rheological properties to control PLA and PLA-TCP. In contrast, the PLA-TCP-MgO composites displayed absence of crystallinity, lower polymeric molecular weight, accelerated degradation ratio, and decreased viscosity within the 3D printing shear rate range. SiO2 and MgO particles were homogeneously dispersed within the PLA and their incorporation increased the roughness and protein adsorption of the scaffold, compared to a PLA-TCP scaffold. This favorable surface modification promoted cell proliferation, suggesting that SiO2 and MgO may have potential for enhancing the bio-integration of scaffolds in tissue engineering applications. However, high loads of MgO accelerated the polymeric degradation, leading to an acid environment that imparted the composite biocompatibility. The presence of SiO2 stimulated mesenchymal stem cells differentiation towards osteoblast; enhancing extracellular matrix mineralization, alkaline phosphatase (ALP) activity, and bone-related genes expression. CONCLUSION: The PLA-10%TCP-10%SiO2 composite presented the most promising results, especially for bone tissue regeneration, due to its intense osteogenic behavior. PLA-10%TCP-10%SiO2 could be used as an alternative implant for bone tissue engineering application.

Additive manufacturing of bioactive and biodegradable poly (lactic acid)-tricalcium phosphate scaffolds modified with zinc oxide for guided bone tissue repair.

Bioactive and biodegradable scaffolds that mimic the natural extracellular matrix of bone serve as temporary structures to guide new bone tissue growth. In this study, 3D-printed scaffolds composed of poly (lactic acid) (PLA)-tricalcium phosphate (TCP) (90-10 wt.%) were modified with 1%, 5%, and 10 wt.% of ZnO to enhance bone tissue regeneration. A commercial chain extender named Joncryl was incorporated alongside ZnO to ensure the printability of the composites. Filaments were manufactured using a twin-screw extruder and subsequently used to print 3D scaffolds via fused filament fabrication (FFF). The scaffolds exhibited a homogeneous distribution of ZnO and TCP particles, a reproducible structure with 300 µm pores, and mechanical properties suitable for bone tissue engineering, with an elastic modulus around 100 MPa. The addition of ZnO resulted in enhanced surface roughness on the scaffolds, particularly for ZnO microparticles, achieving values up to 241 nm. This rougher topography was responsible for enhancing protein adsorption on the scaffolds, with an increase of up to 85% compared to the PLA-TCP matrix. Biological analyses demonstrated that the presence of ZnO promotes mesenchymal stem cell (MSC) proliferation and differentiation into osteoblasts. Alkaline phosphatase (ALP) activity, an important indicator of early osteogenic differentiation, increased up to 29%. The PLA-TCP composite containing 5% ZnO microparticles exhibited an optimized degradation rate and enhanced bioactivity, indicating its promising potential for bone repair applications.

3D printed bioabsorbable composite scaffolds of poly (lactic acid)-tricalcium phosphate-ceria with osteogenic property for bone regeneration.

The fabrication of customized implants by additive manufacturing has allowed continued development of the personalized medicine field. Herein, a 3D-printed bioabsorbable poly (lactic acid) (PLA)- ß-tricalcium phosphate (TCP) (10 wt %) composite has been modified with CeO2 nanoparticles (CeNPs) (1, 5 and 10 wt %) for bone repair. The filaments were prepared by melt extrusion and used to print porous scaffolds. The nanocomposite scaffolds possessed precise structure with fine print resolution, a homogenous distribution of TCP and CeNP components, and mechanical properties appropriate for bone tissue engineering applications. Cell proliferation assays using osteoblast cultures confirmed the cytocompatibility of the composites. In addition, the presence of CeNPs enhanced the proliferation and differentiation of mesenchymal stem cells; thereby, increasing alkaline phosphatase (ALP) activity, calcium deposition and bone-related gene expression. Results from this study have shown that the 3D printed PLA-TCP-10%CeO2 composite scaffold could be used as an alternative polymeric implant for bone tissue engineering applications: avoiding additional/revision surgeries and accelerating the regenerative process.

Polycaprolactone usage in additive manufacturing strategies for tissue engineering applications: A review.

Polycaprolactone (PCL) has been extensively applied on tissue engineering because of its low-melting temperature, good processability, biodegradability, biocompatibility, mechanical resistance, and relatively low cost. The advance of additive manufacturing (AM) technologies in the past decade have boosted the fabrication of customized PCL products, with shorter processing time and absence of material waste. In this context, this review focuses on the use of AM techniques to produce PCL scaffolds for various tissue engineering applications, including bone, muscle, cartilage, skin, and cardiovascular tissue regeneration. The search for optimized geometry, porosity, interconnectivity, controlled degradation rate, and tailored mechanical properties are explored as a tool for enhancing PCL biocompatibility and bioactivity. In addition, rheological and thermal behavior is discussed in terms of filament and scaffold production. Finally, a roadmap for future research is outlined, including the combination of PCL struts with cell-laden hydrogels and 4D printing.

Engineering multifunctional bactericidal nanofibers for abdominal hernia repair.

The engineering of multifunctional surgical bactericidal nanofibers with inherent suitable mechanical and biological properties, through facile and cheap fabrication technology, is a great challenge. Moreover, hernia, which is when organ is pushed through an opening in the muscle or adjacent tissue due to damage of tissue structure or function, is a dire clinical challenge that currently needs surgery for recovery. Nevertheless, post-surgical hernia complications, like infection, fibrosis, tissue adhesions, scaffold rejection, inflammation, and recurrence still remain important clinical problems. Herein, through an integrated electrospinning, plasma treatment and direct surface modification strategy, multifunctional bactericidal nanofibers were engineered showing optimal properties for hernia repair. The nanofibers displayed good bactericidal activity, low inflammatory response, good biodegradation, as well as optimal collagen-, stress fiber- and blood vessel formation and associated tissue ingrowth in vivo. The disclosed engineering strategy serves as a prominent platform for the design of other multifunctional materials for various biomedical challenges.

Hydroxyapatite and ß-TCP modified PMMA-TiO2 and PMMA-ZrO2 coatings for bioactive corrosion protection of Ti6Al4V implants.

Organic-inorganic hybrid coatings deposited on different types of metallic alloys have shown outstanding anticorrosive performance. The incorporation of osteoconductive additives such as hydroxyapatite (HA) and ß-tricalcium phosphate (ß-TCP) into organic-inorganic hybrid coatings is promising to improve the osseointegration and corrosion resistance of Ti6Al4V alloys, which are the most widely used metallic orthopedic and dental implant materials today. Therefore, this study evaluated the capability of poly(methyl methacrylate) (PMMA)-TiO2 and PMMA-ZrO2 hybrid coatings modified with HA and ß-TCP to act as bioactive and corrosion protection coatings for Ti6Al4V alloys. In terms of cell growth and mineralization, osteoblast viability, Ca+2 deposition and alkaline phosphatase assays revealed a significant improvement for the HA and ß-TCP modified coatings, compared to the bare alloy. This can be explained by an increase in nanoscale roughness and associated higher surface free energy, which lead to enhanced protein adsorption to promote osteoblast attachment and functions on the coatings. The effect of HA and ß-TCP additives on the anticorrosive efficiency was studied by electrochemical impedance spectroscopy (EIS) in a simulated body fluid (SBF) solution. The coatings presented a low-frequency impedance modulus of up to 430 GΩ cm2, 5 decades higher than the bare Ti6Al4V alloy. These findings provide clear evidence of the beneficial role of HA and ß-TCP modified hybrid coatings, improving both the biocompatibility and corrosion resistance of the Ti6Al4V alloy.

PMMA-silica nanocomposite coating: Effective corrosion protection and biocompatibility for a Ti6Al4V alloy.

Ti6Al4V is the mostly applied metallic alloy for orthopedic and dental implants, however, its lack of osseointegration and poor long-term corrosion resistance often leads to a secondary surgical intervention, recovery delay and toxicity to the surrounding tissue. As a potential solution of these issues poly(methyl methacrylate)-silicon dioxide (PMMA-silica) coatings have been applied on a Ti6Al4V alloy to act simultaneously as an anticorrosive barrier and bioactive film. The nanocomposite, composed of PMMA covalently bonded to the silica phase through 3-(trimethoxysilyl)propyl methacrylate (MPTS), has been synthesized combining the sol-gel process with radical polymerization of methyl methacrylate. The 5 µm thick coatings deposited on Ti6Al4V have a smooth surface, are homogeneous, transparent, free of pores and cracks, and show a strong adhesion to the metallic substrate (11.6 MPa). Electrochemical impedance spectroscopy results proved an excellent anticorrosive performance of the coating, with an impedance modulus of 26 GΩ cm2 and long-term durability in simulated body fluid (SBF) solution. Moreover, after 21 days of immersion in SBF, the PMMA-silica coating presented apatite crystal deposits, which suggests in vivo bone bioactivity. This was confirmed by biological characterization showing enhanced osteoblast proliferation, explained by the increased surface free energy and protein adsorption. The obtained results suggest that PMMA-silica hybrids can act in a dual role as efficient anticorrosive and bioactive coating for Ti6Al4V alloys.

Dual Role of Lithium on the Structure and Self-Healing Ability of PMMA-Silica Coatings on AA7075 Alloy.

In this work, structural and active corrosion inhibition effects induced by lithium ion addition in organic-inorganic coatings based on poly(methyl methacrylate) (PMMA)-silica sol-gel coatings have been investigated. The addition of increasing amounts of lithium carbonate (0, 500, 1000, and 2000 ppm), yielded homogeneous hybrid coatings with increased connectivity of nanometric silica cross-link nodes, covalently linked to the PMMA matrix, and improved adhesion to the aluminum substrate (AA7075). Electrochemical impedance spectroscopy (EIS), performed in 3.5% NaCl aqueous solution, showed that the improved structural properties of coatings with higher lithium loadings result in an increased corrosion resistance, with an impedance modulus up to 50 GΩ cm2, and revealed that the lithium induced self-healing ability significantly improves their durability. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS) suggest that the regeneration process occurs by means of lithium ions leaching from the adjacent coating toward the corrosion spot, which is restored by a protective layer of precipitated Li rich aluminum hydroxide species. An analogue mechanism has been proposed for artificially scratched coatings presenting an increase of the impedance modulus after salt spray test compared to the lithium free coating. These results evidence the active role of lithium ions in improving the passive barrier of the PMMA-silica coating and in providing through the self-restoring ability a significantly extended service life of AA7075 alloy exposed to saline environment.

Structure and properties of epoxy-siloxane-silica nanocomposite coatings for corrosion protection.

HYPOTHESIS: The fraction of the silica/siloxane phase is a crucial parameter, which determines the structure and thus the properties of epoxy-siloxane-silica hybrid coatings. A careful adjustment of the colloidal precursor formulation allows tuning the nanostructure towards a highly condensed and cross-linked hybrid nanocomposite, suitable as an efficient anticorrosive coating. EXPERIMENTS: Novel epoxy-siloxane-silica hybrids have been prepared through the curing reaction of poly(bisphenol A-co-epichlorohydrin) (DGEBA) with diethyltriamine (DETA) and (3-glycidoxypropyl)methyltriethoxysilane (GPTMS), followed by hydrolytic condensation of tetraethoxysilane (TEOS) and GPTMS. At a constant proportion of the organic phase, the effects of the varying molar proportions of siloxane (GPTMS) and silica (TEOS) on the film properties have been investigated. FINDINGS: A detailed structural analysis suggests for intermediate TEOS to GPTMS ratios a structure of highly condensed silica-siloxane domains covalently bonded to the embedding epoxy phase. The homogeneous distribution of the quasi-spherical sub-nonmetric silica-siloxane nodes is in agreement with low surface roughness (<5 nm), observed by atomic force microscopy. This dense nanostructure results in high thermal stability (>300 °C), strong adhesion to steel substrate and excellent barrier property in saline solution, with corrosion resistance in the GΩ cm2 range.

Understanding the impact of crosslinked PCL/PEG/GelMA electrospun nanofibers on bactericidal activity.

Herein, we report the design of electrospun ultrathin fibers based on the combination of three different polymers polycaprolactone (PCL), polyethylene glycol (PEG), and gelatin methacryloyl (GelMA), and their potential bactericidal activity against three different bacteria Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Methicillin-resistant Staphylococcus aureus (MRSA). We evaluated the morphology, chemical structure and wettability before and after UV photocrosslinking of the produced scaffolds. Results showed that the developed scaffolds presented hydrophilic properties after PEG and GelMA incorporation. Moreover, they were able to significantly reduce gram-positive, negative, and MRSA bacteria mainly after UV photocrosslinking (PCL:PEG:GelMa-UV). Furthermore, we performed a series of study for gaining a better mechanistic understanding of the scaffolds bactericidal activity through protein adsorption study and analysis of the reactive oxygen species (ROS) levels. Furthermore, the in vivo subcutaneous implantation performed in rats confirmed the biocompatibility of our designed scaffolds.

A Comparative Study on Graphene Oxide and Carbon Nanotube Reinforcement of PMMA-Siloxane-Silica Anticorrosive Coatings.

Carbon nanotubes (CNTs) and graphene oxide (GO) have been used to reinforce PMMA-siloxane-silica nanocomposites considered to be promising candidates for environmentally compliant anticorrosive coatings. The organic-inorganic hybrids were prepared by benzoyl peroxide (BPO)-induced polymerization of methyl methacrylate (MMA) covalently bonded through 3-(trimethoxysilyl)propyl methacrylate (MPTS) to silica domains formed by hydrolytic condensation of tetraethoxysilane (TEOS). Single-walled carbon nanotubes and graphene oxide nanosheets were dispersed by surfactant addition and in a water/ethanol solution, respectively. These were added to PMMA-siloxane-silica hybrids at a carbon (CNT or GO) to silicon (TEOS and MPTS) molar ratio of 0.05% in two different matrices, both prepared at BPO/MMA molar ratios of 0.01 and 0.05. Atomic force microscopy and scanning electron microscopy showed very smooth, homogeneous, and defect-free surfaces of approximately 3-7 µm thick coatings deposited onto A1020 carbon steel by dip coating. Mechanical testing and thermogravimetric analysis confirmed that both additives CNT and GO improved the scratch resistance, adhesion, wear resistance, and thermal stability of PMMA-siloxane-silica coatings. Results of electrochemical impedance spectroscopy in 3.5% NaCl solution, discussed in terms of equivalent circuits, showed that the reinforced hybrid coatings act as a very efficient anticorrosive barrier with an impedance modulus up to 1 GΩ cm(2), approximately 5 orders of magnitude higher than that of bare carbon steel. In the case of GO addition, the high corrosion resistance was maintained for more than 6 months in saline medium. These results suggest that both carbon nanostructures can be used as structural reinforcement agents, improving the thermal and mechanical resistance of high performance anticorrosive PMMA-siloxane-silica coatings and thus extending their application range to abrasive environments.