Improving Biocompatibility for Next Generation of Metallic Implants.

The increasing need for joint replacement surgeries, musculoskeletal repairs, and orthodontics worldwide prompts emerging technologies to evolve with healthcare's changing landscape. Metallic orthopaedic materials have a shared application history with the aerospace industry, making them only partly efficient in the biomedical domain. However, suitability of metallic materials in bone tissue replacements and regenerative therapies remains unchallenged due to their superior mechanical properties, eventhough they are not perfectly biocompatible. Therefore, exploring ways to improve biocompatibility is the most critical step toward designing the next generation of metallic biomaterials. This review discusses methods of improving biocompatibility of metals used in biomedical devices using surface modification, bulk modification, and incorporation of biologics. Our investigation spans multiple length scales, from bulk metals to the effect of microporosities, surface nanoarchitecture, and biomolecules such as DNA incorporation for enhanced biological response in metallic materials. We examine recent technologies such as 3D printing in alloy design and storing surface charge on nanoarchitecture surfaces, metal-on-metal, and ceramic-on-metal coatings to present a coherent and comprehensive understanding of the subject. Finally, we consider the advantages and challenges of metallic biomaterials and identify future directions.

Translation of 3D printed materials for medical applications.

During the past 30 years, 3D printing (3DP) technologies significantly influenced the manufacturing world, including innovation in biomedical devices. This special issue reviews recent advances in translating 3DP biomaterials and medical devices for metallic, ceramic, and polymeric devices, as well as bioprinting for organ and tissue engineering, along with regulatory issues in 3DP biomaterials. In our introductory article, besides introducing selected 3DP processes for biomaterials, current challenges and growth opportunities are also discussed. Finally, it highlights a few success stories for the 3D printed biomaterials for medical devices. We hope these articles will educate engineers, scientists, and clinicians about recent developments in translational 3DP technologies.

Plasma sprayed fluoride and zinc doped hydroxyapatite coated titanium for load-bearing implants.

Titanium (Ti) alloys show excellent fatigue and corrosion resistance, high strength to weight ratio, and no toxicity; however, poor osseointegration ability of Ti may lead to implant loosening in vivo. Plasma spraying of hydroxyapatite [HA, Ca10 (PO4)6 (OH)2] coating on Ti surfaces is commercially used to enhance osseointegration and the long-term stability of these implants. The biological properties of HA can be improved with the addition of both cationic and anionic dopants, such as zinc ions (Zn2+) and fluoride (F-). However, the hygroscopic nature of fluoride restricts its utilization in the radiofrequency (RF) plasma spray process. In addition, the amount of doping needs to be optimized to ensure cytocompatibility. We have fabricated zinc and fluoride doped HA-coated Ti6Al4V (Ti64) to mitigate these challenges using compositional and parametric optimizations. The RF induction plasma spraying method is utilized to prepare the coatings. Multiple parametric optimizations with amplitude and frequency during the processing result in coating thicknesses between 80 and 145 µm. No adverse effects on the adhesion properties of the coating are noticed because of doping. The antibacterial efficacy of each composition is tested against S. aureus for 24, 48, and 72 h, and showed that the addition of zinc oxide and calcium fluoride to HA leads to nearly 70 % higher antibacterial efficacy than pure HA-coated samples. The addition of osteogenic Zn2+and F- leads to 1.5 times higher osteoblast viability for the doped samples than pure HA-coated samples after 7-days of cell culture. Zn2+ and F- doped HA-coated Ti64 with simultaneous improvements in anti-bacterial efficacy and in vitro biocompatibility can find application in load-bearing implants, particularly in revision surgeries and immune-compromised patients.

Additive manufacturing of Ti-Ni bimetallic structures.

Bimetallic structures of nickel (Ni) and commercially pure titanium (CP Ti) were manufactured in three different configurations via directed energy deposition (DED)-based metal additive manufacturing (AM). To understand whether the bulk properties of these three composites are dominated by phase formation at the interface, their directional dependence on mechanical properties was tested. X-ray diffraction (XRD) pattern confirmed the intermetallic NiTi phase formation at the interface. Microstructural gradient observed at the heat-affected zone (HAZ) areas. The longitudinal samples showed about 12% elongation, while the same was 36% for the transverse samples. During compressive deformation, strain hardening from dislocation accumulation was observed in the CP Ti and transverse samples, but longitudinal samples demonstrated failures similar to a brittle fracture at the interface. Transverse samples also showed shear band formation indicative of ductile failures. Our results demonstrate that AM can design innovative bimetallic structures with unique directional mechanical properties.

Nature-inspired materials and structures using 3D Printing.

Emulating the unique combination of structural, compositional, and functional gradation in natural materials is exceptionally challenging. Many natural structures have proved too complex or expensive to imitate using traditional processing techniques despite recent advances. Recent innovations within the field of additive manufacturing (AM) or 3D Printing (3DP) have shown the ability to create structures that have variations in material composition, structure, and performance, providing a new design-for-manufacturing platform for the imitation of natural materials. AM or 3DP techniques are capable of manufacturing structures that have significantly improved properties and functionality over what could be traditionally-produced, giving manufacturers an edge in their ability to realize components for highly-specialized applications in different industries. To this end, the present work reviews fundamental advances in the use of naturally-inspired design enabled through 3DP / AM, how these techniques can be further exploited to reach new application areas, and the challenges that lie ahead for widespread implementation. An example of how these techniques can be applied towards a total hip arthroplasty application is provided to spur further innovation in this area.

3D Printing in alloy design to improve biocompatibility in metallic implants.

3D Printing (3DP) or additive manufacturing (AM) enables parts with complex shapes, design flexibility, and customization opportunities for defect specific patient-matched implants. 3DP or AM also offers a design platform that can be used to innovate novel alloys for application-specific compositional modifications. In medical applications, the biological response from a host tissue depends on a biomaterial's structural and compositional properties in the physiological environment. Application of 3DP can pave the way towards manufacturing innovative metallic implants, combining structural variations at different length scales and tailored compositions designed for specific biological responses. This study shows how 3DP can be used to design metallic alloys for orthopedic and dental applications with improved biocompatibility using in vitro and in vivo studies. Titanium (Ti) and its alloys are used extensively in biomedical devices due to excellent fatigue and corrosion resistance and good strength to weight ratio. However, Ti alloys' in vivo biological response is poor due to its bioinert surface. Different coatings and surface modification techniques are currently being used to improve the biocompatibility of Ti implants. We focused our efforts on improving Ti's biocompatibility via a combination of tantalum (Ta) chemistry in Ti, the addition of designed micro-porosity, and nanoscale surface modification to enhance both in vitro cytocompatibility and early stage in vivo osseointegration, which was studied in rat and rabbit distal femur models.

Biotribocorrosion of 3D-Printed silica-coated Ti6Al4V for load-bearing implants.

Laser-based 3D Printing was utilized to deposit a silica (SiO2) coating on the surface of Ti6Al4V (Ti64) alloy for implementation onto articulating surfaces of load-bearing implants. The surface laser melting (SLM) technique was implemented in 1, and 2 laser passes (1LP and 2LP) after SiO2 deposition to understand the influence of remelting on the coating's hardness and tribological performance. It was observed that compositional and microstructural features increased the cross-sectional hardness. Wear rate was observed to decrease from 2.9×10-4 in the Ti64 to 5.2 ×10-6, 3.8×10-6, and 2.1×10-7 mm3/Nm for the as-processed or zero laser-pass (0LP), 1LP, and 2LP, respectively. Coated samples displayed a positive shift in open-circuit potential (OCP) during linear wear by displaying a 368, 85, and 613 mV increase compared to Ti64 for 0LP, 1LP, and 2LP, respectively. Our results showed promising tribological performance of SiO2 coated Ti6Al4V for articulating surfaces of load-bearing implants.

Mechanical properties of additively manufactured variable lattice structures of Ti6Al4V.

Engineered micro- and macro-structures via additive manufacturing (AM) or 3D-Printing can create structurally varying properties in part, which is difficult via traditional manufacturing methods. Herein we have utilized powder bed fusion-based selective laser melting (SLM) to fabricate variable lattice structures of Ti6Al4V with uniquely designed unit cell configurations to alter the mechanical performance. Five different configurations were designed based on two natural crystal structures - hexagonal closed packed (HCP) and body-centered cubic (BCC). Under compressive loading, as much as 74% difference was observed in compressive strength and 71% variation in elastic modulus, with all samples having porosities in a similar range of 53 to 65%, indicating the influence of macro-lattice designs alone on mechanical properties. Failure analysis of the fracture surfaces helped with the overall understanding of how configurational effects and unit cell design influence these samples' mechanical properties. Our work highlights the ability to leverage advanced manufacturing techniques to tailor the structural performance of multifunctional components.

Zirconia-Toughened Alumina Coated Ti6Al4V via Additive Manufacturing.

CoCr alloy-based femoral heads have failed prematurely due to galvanic-induced corrosion when coupled with a titanium hip stem. Coupling a titanium based-femoral head with the titanium hip stem is ideal in addressing this failure mode. Ti6Al4V (Ti64) alloy was reinforced with zirconia-toughened alumina (ZTA) by directed-energy deposition (DED)-based additive manufacturing (AM) to address that concern. Preliminary materials processing work resulted in failed samples due to cracking, porosity, and delamination. After careful parameter optimization, a Ti64+5wt.%ZTA (5ZTA) composition produced a metallurgically sound and coherent interface, minimal porosity, and bulk structures. Hardness was observed to increase by 27%, normalized wear rate reduced by 25%, and contact resistance increased during in vitro tribological testing along with faster surface re-passivation.

Processing and Thermal Diffusivity Measurements of Compositionally Graded Al-12Si to Al2O3 Structures.

The directed energy deposition (DED)-based additive manufacturing (AM) was used to create compositionally graded pure Al-12Si to pure Al2O3 structures varying the powder feed rates during deposition. Thermal diffusivity of Al-12Si+Al2O3 structures was reduced by >60% compared to pure Al-12Si. With a pure Al2O3 ceramic layer on Al-12Si+Al2O3, our results confirm the feasibility of designing and manufacturing metal-ceramic composites via AM with tailored thermal properties.

Designing high-temperature oxidation-resistant titanium matrix composites via directed energy deposition-based additive manufacturing.

Composite material development via laser-based additive manufacturing offers many exciting advantages to manufacturers; however, a significant challenge exists in our understanding of process-property relationships for these novel materials. Herein we investigate the effect of input processing parameters towards designing an oxidation-resistant titanium matrix composite. By adjusting the linear input energy density, a composite feedstock of titanium-boron carbide-boron nitride (5 wt% overall reinforcement) resulted in a highly reinforced microstructure composed of borides and carbides and nitrides, with variable properties depending on the overall input energy. Crack-free titanium-matrix composites with hardness as high as 700 ± 17 HV0.2/15 and 99.1% relative density were achieved, with as high as a 33% decrease in oxidation mass gain in the air relative to commercially pure titanium at 700 °C for 50 h. Single-tracks and bulk samples were fabricated to understand the processing characteristics and in situ reactions during processing. Our results indicate that input processing parameters can play a significant role in the oxidation resistance of titanium matrix composites and can be exploited by manufacturers for improving component performance and high temperature designs.

3D Printing for Bone Regeneration.

PURPOSE OF REVIEW: The purpose of this review is to illustrate the current state of 3D printing (3DP) technology used in biomedical industry towards bone regeneration. We have focused our efforts towards correlating materials and structural design aspects of 3DP with biological response from host tissue upon implantation. The primary question that we have tried to address is-can 3DP be a viable technology platform for bone regeneration devices? RECENT FINDINGS: Recent findings show that 3DP is a versatile technology platform for numerous materials for mass customizable bone regeneration devices that are also getting approval from different regulatory bodies worldwide. After a brief introduction of different 3DP technologies, this review elaborates 3DP of different materials and devices for bone regeneration. From cell-based bioprinting to acellular patient-matched metallic or ceramic devices, 3DP has tremendous potential to improve the quality of human life through bone regeneration among patients of all ages.

Clinical significance of three-dimensional printed biomaterials and biomedical devices.

Three-dimensional printing (3DP) is becoming a standard manufacturing practice for a variety of biomaterials and biomedical devices. This layer-by-layer methodology provides the ability to fabricate parts from computer-aided design files without the need for part-specific tooling. Three-dimensional printed medical components have transformed the field of medicine through on-demand patient care with specialized treatment such as local, strategically timed drug delivery, and replacement of once-functioning body parts. Not only can 3DP technology provide individualized components, it also allows for advanced medical care, including surgical planning models to aid in training and provide temporary guides during surgical procedures for reinforced clinical success. Despite the advancement in 3DP technology, many challenges remain for forward progress, including sterilization concerns, reliability, and reproducibility. This article offers an overview of biomaterials and biomedical devices derived from metals, ceramics, polymers, and composites that can be three-dimensionally printed, as well as other techniques related to 3DP in medicine, including surgical planning, bioprinting, and drug delivery.

High-intensity exercise-induced oxidative stress in sedentary pre-pubertal & post-pubertal boys: A comparative study.

Background & objectives: High-intensity exercise results in oxidative stress in adult population. Impact of pubertal attainment on high-intensity exercise-induced oxidative stress in sedentary paediatric population has not been investigated in detail. The present study was conducted to investigate the extent of high-intensity exercise-induced oxidative stress in sedentary pre- and post-pubertal boys through estimation of serum thiobarbituric acid reactive substances (TBARS), total thiol content and activities of superoxide dismutase (SOD) and catalase (CAT). Methods: Sixty four sedentary pre-pubertal (n=32, age = 10.21±0.67 yr) and post-pubertal (n=32, age = 15.58±0.47 yr) boys performed incremental treadmill running exercise at 80 per cent of the age predicted maximum heart rate till volitional exhaustion. Blood sample (5 ml) was drawn from each individual before and after the exercise for estimation of oxidative stress markers. Results: Pre-exercise SOD activity and total thiol level showed significant positive relationship with age and were significantly higher in post-pubertal boys. Serum TBARS level, SOD and CAT activities increased while total thiol content decreased in both the groups following exercise. Post-exercise percentage change in TBARS, SOD activity and total thiol level was significantly higher in post-pubertal boys, and these variables had significant positive relationship with age. No significant intergroup variations were noted in CAT activity before or after exercise. Interpretation & conclusions: Extent of post-exercise oxidative stress increased significantly with attainment of puberty. However, baseline and post-exercise antioxidation status also increased significantly as a function of age with pubertal maturation allowing the post-pubertal boys to counter relatively higher oxidative stress more efficiently than their pre-pubertal counterparts. Post-exercise upregulation in CAT activity might not be influenced by age or pubertal maturation in this age group.

Influence of boron nitride reinforcement to improve high temperature oxidation resistance of titanium.

Influence of boron nitride (BN) addition in commercially pure titanium (Cp-Ti) was characterized for their microstructural variation, hardness and oxidation kinetics. Feedstock powders Cp-Ti with 3 wt.% BN (3BN) and 6 wt.% BN (6BN) were prepared by roller mill followed by additive manufacturing using laser engineered net shaping (LENS™). Rate of oxidation was measured from thermogravimetric analysis (TGA) at 1000°C for 50 h. Average instantaneous parabolic constants (k p ) for Cp-Ti, 3BN and 6BN were 41.2±12.0, 28.6±2.8 and 18.2±9.2 mg2·cm-4·h-1, respectively. Cp-Ti displayed acicular α-Ti microstructure. After TGA, large equiaxed grains along with TiO2 formation at the grain boundaries was observed, which increased the hardness. With BN addition, plate-like TiN and needle-like TiB secondary phases were also observed. Hardness for Cp-Ti, 3BN and 6BN were 256.9, 424.0 and 548.3 HV0.2, respectively. Overall, a small addition of BN was effective in improving the oxidation resistance of Cp-Ti.

Influence of deposition orientation on fatigue response of LENS™ processed Ti6Al4V.

Understanding processing-property relationships for directed-energy-deposition (DED) parts remains a major roadblock to widespread process implementation. Herein we investigate the effect of scanning-strategy and testing-orientation on the fatigue response of as-printed Ti6Al4V components. At ~106 cycles, samples tested in the build-direction exhibited ~ 45% decrease in fatigue strength relative to the horizontally-tested samples, owing to higher overall porosity and the testing orientation relative to residual pores. Samples failing <106 cycles demonstrated tortuous surfaces, whereas samples enduring >106 cycles exhibited smoother-surfaces. Our results indicate that DED-produced parts can exhibit directionally-dependent fatigue performance, and print-strategy must be taken into consideration for dynamic-loading applications.

Additive manufacturing of biomaterials.

Biomaterials are used to engineer functional restoration of different tissues to improve human health and the quality of life. Biomaterials can be natural or synthetic. Additive manufacturing (AM) is a novel materials processing approach to create parts or prototypes layer-by-layer directly from a computer aided design (CAD) file. The combination of additive manufacturing and biomaterials is very promising, especially towards patient specific clinical applications. Challenges of AM technology along with related materials issues need to be realized to make this approach feasible for broader clinical needs. This approach is already making a significant gain towards numerous commercial biomedical devices. In this review, key additive manufacturing methods are first introduced followed by AM of different materials, and finally applications of AM in various treatment options. Realization of critical challenges and technical issues for different AM methods and biomaterial selections based on clinical needs are vital. Multidisciplinary research will be necessary to face those challenges and fully realize the potential of AM in the coming days.

3D printed ß-TCP bone tissue engineering scaffolds: Effects of chemistry on in vivo biological properties in a rabbit tibia model.

In this study the effects of 3D printed SiO2 and ZnO doped tricalcium phosphate (TCP) scaffolds with interconnected pores were evaluated on the in vivo bone formation and healing properties of a rabbit tibial defect model. Pure and doped TCP scaffolds were fabricated by a ceramic powder-based 3D printing technique and implanted into critical sized rabbit tibial defects for up to 4 months. In vivo bone regeneration was evaluated using chronological radiological examination, histological evaluations, SEM micrographs and fluorochrome labeling studies. Radiograph results showed that Si/Zn doped samples had slower degradation kinetics than the pure TCP samples. 3D printing of TCP scaffolds improved bone formation. The addition of dopants in the TCP scaffolds improved osteogenic capabilities when compared to the pure scaffolds. In summary, our findings indicate that addition of dopants to the TCP scaffolds enhanced bone formation and in turn leading to accelerated healing.

High-Intensity Exercise Induced Oxidative Stress and Skeletal Muscle Damage in Postpubertal Boys and Girls: A Comparative Study.

Pal, S, Chaki, B, Chattopadhyay, S, and Bandyopadhyay, A. High-intensity exercise induced oxidative stress and skeletal muscle damage in post-pubertal boys and girls: a comparative study. J Strength Cond Res 32(4): 1045-1052, 2018-The purpose of this study was to examine the sex variation in high-intensity exercise induced oxidative stress and muscle damage among 44 sedentary postpubertal boys and girls through estimation of postexercise release pattern of muscle damage markers like creatine kinase, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and oxidative stress markers like extent of lipid peroxidation (thiobarbituric acid-reactive substances) and catalase activity. Muscle damage markers like creatine kinase, LDH, ALT, and AST were measured before, immediately after, and 24 and 48 hours after high-intensity incremental treadmill running. Oxidative stress markers like thiobarbituric acid-reactive substances and catalase activity were estimated before and immediately after the exercise. Lipid peroxidation and serum catalase activity increased significantly in both groups after exercise (p < 0.001) with postexercise values and percentage increase significantly higher in postpubertal boys as compared to girls (p < 0.001). Creatine kinase and LDH activity also increased significantly above pre-exercise level at 24 and 48 hours after exercise in both the sexes, (p < 0.001) with values significantly higher for boys than the girls (p < 0.001). Although ALT and AST increased significantly in both the groups after exercise, the pattern of postexercise release of these markers were found to be similar in both the groups. Accordingly, it has been concluded from the present investigation that high-intensity exercise induces significant oxidative stress and increases indices of skeletal muscle damage in both postpubertal girls and boys. However, postpubertal girls are relatively better protected from oxidative stress and muscle damage as compared to the boys of similar age and physical activity level. It is further evident that sex difference may not be apparent for all the biomarkers of muscle damage in this age group.

Calcium phosphate coated 3D printed porous titanium with nanoscale surface modification for orthopedic and dental applications.

This study aims to improve the interfacial bonding between the osseous host tissue and the implant surface through the application of doped calcium phosphate (CaP) coating on 3D printed porous titanium. Porous titanium (Ti) cylinders with 25% volume porosity were fabricated using Laser Engineered Net Shaping (LENS™), a commercial 3D Printing technique. The surface of these 3D printed cylinders was modified by growing TiO2 nanotubes first, followed by a coating of with Sr2+ and Si4+ doped bioactive CaP ceramic in simulated body fluid (SBF). Doped CaP coated implants were hypothesized to show enhanced early stage bone tissue integration. Biological properties of these implants were investigated in vivo using a rat distal femur model after 4 and 10 weeks. CaP coated porous Ti implants have enhanced tissue ingrowth as was evident from the CT scan analysis, push out test results, and the histological analysis compared to porous implants with or without surface modification via titania nanotubes. Increased osteoid-like new bone formation and accelerated mineralization was revealed inside the CaP coated porous implants. It is envisioned that such an approach of adding a bioactive doped CaP layer on porous Ti surface can reduce healing time by enhancing early stage osseointegration in vivo.