Selective laser melting-produced porous titanium scaffolds regenerate bone in critical size cortical bone defects

Porous titanium scaffolds have good mechanical properties that make them an interesting bone substitute material for large bone defects. These scaffolds can be produced with selective laser melting, which has the advantage of tailoring the structure's architecture. Reducing the strut size reduces the stiffness of the structure and may have a positive effect on bone formation. Two scaffolds with struts of 120-μm (titanium-120) or 230-μm (titanium-230) were studied in a load-bearing critical femoral bone defect in rats. The defect was stabilized with an internal plate and treated with titanium-120, titanium-230, or left empty. In vivo micro-CT scans at 4, 8, and 12 weeks showed more bone in the defects treated with scaffolds. Finally, 18.4 ± 7.1 mm3(titanium-120, p = 0.015) and 18.7 ± 8.0 mm3(titanium-230, p = 0.012) of bone was formed in those defects, significantly more than in the empty defects (5.8 ± 5.1 mm3). Bending tests on the excised femurs after 12 weeks showed that the fusion strength reached 62% (titanium-120) and 45% (titanium-230) of the intact contralateral femurs, but there was no significant difference between the two scaffolds. This study showed that in addition to adequate mechanical support, porous titanium scaffolds facilitate bone formation, which results in high mechanical integrity of the treated large bone defects. Copyrigh

Corrosion behaviour of porous Ti intended for biomedical applications

Porous Ti implants are being developed inorder to reduce the biomechanical mismatch between theimplant and the bone, as well as increasing the osseointegrationby improving the bone in-growth. Most of the focusin the literature has been on the structural, biological andmechanical characterization of porous Ti whereas there islimited information on the electrochemical characterization.Therefore, the present work aims to study the corrosionbehaviour of porous Ti having 30 and 50 % ofnominal porosity, produced by powder metallurgy routeusing the space holder technique. The percentage, size anddistribution of the pores were determined by image analysis.Electrochemical tests consisting of potentiodynamicpolarization and electrochemical impedance spectroscopywere performed in 9 g/L NaCl solution at body temperature.Electrochemical studies revealed that samples presenteda less stable oxide film at increased porosity, morespecifically, the complex geometry and the interconnectivityof the pores resulted in formation of less protectiveoxide film in the pores.This study was supported by FCT with the reference project UID/EEA/04436/2013, by FEDER funds through the COMPETE 2020 – Programa Operacional Competitividade e Internacionalizac¸a˜o (POCI) with the reference project POCI-01-0145- FEDER-006941, Programa de Acc¸o˜es Universita´rias Integradas LusoFrancesas’ (PAUILF TC-12_14), and The Calouste Gulbenkian Foundation through ‘‘Programa de Mobilidade Acade´mica para Professores’’. The authors would also like to acknowledge Prof. Ana Senos (University of Aveiro) and Prof. Jose´ Carlos Teixeira (University of Minho) for the provision of the characterization facilities.info:eu-repo/semantics/publishedVersio

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting

Porous titanium for bone substitution: Mechanobiology meets surface science

People in both developing and developed worlds are increasingly facing musculoskeletal problems that require long-term clinical performance of orthopaedic implants including bone substitutes. Porous biomaterials could play an important role in improving the longevity and overall performance of orthopaedic implants and that is why they have been extensively studied recently. Highly porous biomaterials hold promise for such applications partly because their porous structures provide enough space for bone in-growth and vascularization. Controllability of mechanical properties is another favorable feature of such biomaterials that has led to their increased popularity for bone substitution. Nevertheless, the full potential of porous metallic biomaterials in general and porous titanium alloy structures in particular has not yet been fully exploited. In this thesis, some important aspects relevant for application of porous titanium alloy biomaterials as bone substitutes have been studied. In particular, we focus on the mechanical properties of porous titanium biomaterials, the modification of the surface properties of such biomaterials using chemical and electrochemical surface treatments, and on the effects of applied surface treatment on the mechanical properties of porous titanium biomaterials. To study the mechanical properties of porous titanium biomaterials, it is important to study the mechanical properties of bone that is replaced by the biomaterial. Given the fact that bone is a complex and heterogeneous material, a recently developed method called digital image correlation (DIC) was employed to study the full-field strain map and fracture behavior of the rat femur (chapter 2). It was found that bone fracture is strain-controlled and that the onset of fracture could be predicted using the equivalent strain criterion. On the other hand, segmental bone defect animal models are often used in pre-clinical studies of the bone regeneration performance of bone substitutes. In such animal models, it is very important to study how mechanical load is transferred after stabilization of the defect. In chapter 3, a specific animal model and fixation technique were considered. The load transferred through the femur and the distribution of the transferred load between the implant and fixation plate were studied for the considered animal model and fixation technique. It was found that there is a large variability in terms of the transmitted loads and that one needs to optimize the fixation technique in order to obtain a more consistent mechanical loading after surgery. Dynamic and static mechanical properties of selective laser melted porous titanium were studied in chapter 4 where the S-N curves of the porous structures were obtained for four different porosities. The S-N curves of the porous structures with different porosities were drastically different with more porous structures demonstrating a weaker fatigue behavior. When normalized with respect to the plateau stress, the S-N curves were mostly overlapping and very well conforming to a power law (R2=0.94). This power law might be useful for estimating the fatigue life of similar porous structures in the cases where actual fatigue tests could not be performed. In addition, it was found that the normalized endurance limit of porous structures is somewhat lower than that of the matrix material. Bio-functionalizing surface treatment are important for improving the surface properties of biomaterials. However, they might adversely affect the mechanical properties of the biomaterial. The effects of two different types of chemical surface treatments, namely alkali-acid-heat treatment and acid-alkali treatment, on the mechanical properties of porous titanium biomaterials were studied. It was found that while one of the surface treatments, namely alkali-acid-heat treatment, did not have any major adverse effect on the mechanical properties of the tested biomaterials, the other surface treatment resulted in significant mass loss and, thus, significant loss of mechanical properties. The nanotopographical features and crystal structure of an additional surface treatment technique, namely anodizing, were studied as well. The parameters of the surface treatment procedure were optimized to achieve a hierarchical structure on the surface of porous titanium biomaterials. In addition, it was found that the temperature and heat treatment duration need to be optimized, so as to ensure the nanotopographical features created using the surface treatment are not disrupted after heat treatment. All the three above-mentioned surface treatment techniques were subsequently evaluated in a longitudinal in-vivo and in-vitro study to assess the bone regeneration performance, apatite-forming ability, and cell response of the surface-treated porous titanium biomaterials. It was found that the applied surface treatments notably influenced both in-vitro and in-vivo performances of porous titanium alloy biomaterials. Acid-alkali treatment resulted in the best apatite forming ability and significantly larger volumes of regenerated bone as compared to anodizing. However, porous titanium biomaterials treated with anodizing exhibited significantly higher torsional strength. It was concluded that larger volumes of regenerated bone does not necessarily translate to better mechanical stability. Although this thesis tried to cover several aspects relevant for application of porous titanium biomaterials as bone substitutes, further research is needed to explore several other unexplored aspects of porous titanium biomaterials.BioMechanical EngineeringMechanical, Maritime and Materials Engineerin

Fatigue crack propagation in additively manufactured porous biomaterials

Additively manufactured porous titanium implants, in addition to preserving the excellent biocompatible properties of titanium, have very small stiffness values comparable to those of natural bones. Although usually loaded in compression, biomedical implants can also be under tensional, shear, and bending loads which leads to crack initiation and propagation in their critical points. In this study, the static and fatigue crack propagation in additively manufactured porous biomaterials with porosities between 66% and 84% is investigated using compact-tension (CT) samples. The samples were made using selective laser melting from Ti-6Al-4V and were loaded in tension (in static study) and tension-tension (in fatigue study) loadings. The results showed that displacement accumulation diagram obtained for different CT samples under cyclic loading had several similarities with the corresponding diagrams obtained for cylindrical samples under compression-compression cyclic loadings (in particular, it showed a two-stage behavior). For a load level equaling 50% of the yield load, both the CT specimens studied here and the cylindrical samples we had tested under compression-compression cyclic loading elsewhere exhibited similar fatigue lives of around 104 cycles. The test results also showed that for the same load level of 0.5 Fy, the lower density porous structures demonstrate relatively longer lives than the higher-density ones. This is because the high bending stresses in high-density porous structures gives rise to local Mode-I crack opening in the rough external surface of the struts which leads to quicker formation and propagation of the cracks. Under both the static and cyclic loading, all the samples showed crack pathways which were not parallel to but made 45° angles with respect to the notch direction. This is due to the fact that in the rhombic dodecahedron unit cell, the weakest struts are located in 45° direction with respect to the notch direction.Accepted Author ManuscriptBiomaterials & Tissue Biomechanic

Bone regeneration in critical-sized bone defects treated with additively manufactured porous metallic biomaterials: The effects of inelastic mechanical properties

Additively manufactured (AM) porous metallic biomaterials, in general, and AM porous titanium, in particular, have recently emerged as promising candidates for bone substitution. The porous design of such materials allows for mimicking the elastic mechanical properties of native bone tissue and showed to be effective in improving bone regeneration. It is, however, not clear what role the other mechanical properties of the bulk material such as ductility play in the performance of such biomaterials. In this study, we compared the bone tissue regeneration performance of AM porous biomaterials made from the commonly used titanium alloy Ti6Al4V-ELI with that of commercially pure titanium (CP-Ti). CP-Ti was selected because of its high ductility as compared to Ti6Al4V-ELI. Critical-sized (6 mm diameter) femoral defects in rats were treated with implants made from both Ti6Al4V-ELI and CP-Ti. Bone regeneration was assessed up to 11 weeks using micro-CT scanning. The regenerated bone volume was assessed ex vivo followed by histology and biomechanical testing to assess osseointegration of the implants. The bony defects treated withAMCP-Ti implants generally showed higher volumes of regenerated bone as compared to those treated with AM Ti6Al4V-ELI. The torsional strength of the two titanium groups were similar however, and both considerably lower than those measured for intact bony tissue. These findings show the importance of material type and ductility of the bulk material in the ability for bone tissue regeneration of AM porous biomaterials.</p

Relationship between unit cell type and porosity and the fatigue behavior of selective laser melted meta-biomaterials

Meta-materials are structures when their small-scale properties are considered, but behave as materials when their homogenized macroscopic properties are studied. There is an intimate relationship between the design of the small-scale structure and the homogenized properties of such materials. In this article, we studied that relationship for meta-biomaterials that are aimed for biomedical applications, otherwise known as meta-biomaterials. Selective laser melted porous titanium (Ti6Al4V ELI) structures were manufactured based on three different types of repeating unit cells, namely cube, diamond, and truncated cuboctahedron, and with different porosities. The morphological features, static mechanical properties, and fatigue behavior of the porous biomaterials were studied with a focus on their fatigue behavior. It was observed that, in addition to static mechanical properties, the fatigue properties of the porous biomaterials are highly dependent on the type of unit cell as well as on porosity. None of the porous structures based on the cube unit cell failed after 106 loading cycles even when the applied stress reached 80% of their yield strengths. For both other unit cells, higher porosities resulted in shorter fatigue lives for the same level of applied stress. When normalized with respect to their yield stresses, the S-N data points of structures with different porosities very well (R2>0.8) conformed to one single power law specific to the type of the unit cell. For the same level of normalized applied stress, the truncated cuboctahedron unit cell resulted in a longer fatigue life as compared to the diamond unit cell. In a similar comparison, the fatigue lives of the porous structures based on both truncated cuboctahedron and diamond unit cells were longer than that of the porous structures based on the rhombic dodecahedron unit cell (determined in a previous study). The data presented in this study could serve as a basis for design of porous biomaterials as well as for corroboration of relevant analytical and computational models

Additively Manufactured and Surface Biofunctionalized Porous Nitinol

Enhanced bone tissue regeneration and improved osseointegration are among the most important goals in design of multifunctional orthopedic biomaterials. In this study, we used additive manufacturing (selective laser melting) to develop multifunctional porous nitinol that combines superelasticity with a rationally designed microarchitecture and biofunctionalized surface. The rational design based on triply periodic minimal surfaces aimed to properly adjust the pore size, increase the surface area (thereby amplifying the effects of surface biofunctionalization), and resemble the curvature characteristics of trabecular bone. The surface of additively manufactured (AM) porous nitinol was biofunctionalized using polydopamine-immobilized rhBMP2 for better control of the release kinetics. The actual morphological properties of porous nitinol measured by microcomputed tomography (e.g., open/close porosity, and surface area) closely matched the design values. The superelasticity originated from the austenite phase formed in the nitinol porous structure at room temperature. Polydopamine and rhBMP2 signature peaks were confirmed by X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy tests. The release of rhBMP2 continued until 28 days. The early time and long-term release profiles were found to be adjustable independent of each other. In vitro cell culture showed improved cell attachment, cell proliferation, cell morphology (spreading, spindle-like shape), and cell coverage as well as elevated levels of ALP activity and increased calcium content for biofunctionalized surfaces as compared to as-manufactured specimens. The demonstrated functionalities of porous nitinol could be used as a basis for deployable orthopedic implants with rationally designed microarchitectures that maximize bone tissue regeneration performance by release of biomolecules with adjustable and well-controlled release profiles