Curcumin and Vitamin C dual release from Hydroxyapatite coated Ti6Al4V discs enhances in vitro biological properties.

Titanium alloys are widely used as implant materials due to their biocompatibility and superior mechanical properties for high-load-bearing applications. However, one of the major challenges is their inferior bioactivity and osseoconductivity. Hydroxyapatite is widely used as an alternative material for bone implants due to its compositional similarity to natural bone. In this study, hydroxyapatite is coated on Ti6Al4V discs to enhance its bioactivity. The coated discs are drop-casted with curcumin in the lower layer and vitamin C in the upper layer. This study aims to evaluate the effects of this dual drug delivery system on osteoblast cell proliferation, inhibition of osteoclastogenesis, chemo-preventive and infection control properties. The coating strength obtained is 22 ± 2 MPa. The release from the dual delivery system shows a 1.5-fold increase in osteoblast cell viability, a 1.5-fold reduction in osteoclast cell differentiation, a 2-fold decrease in osteosarcoma growth. The release of curcumin demonstrates a 94% antibacterial efficacy, while the release of vitamin C exhibits an efficacy of 98.6% aganist Staphylococcus aureus. This multifunctional system can be used as a potential implant for load-bearing applications.

Ginger extract loaded Fe2O3/MgO-doped hydroxyapatite: Evaluation of biological properties for bone-tissue engineering.

Since antiquity, the medicinal properties of naturally sourced biomolecules such as ginger (Zingiber officinale) extract are documented in the traditional Indian and Chinese medical systems. However, limited work is performed to assess the potential of ginger extracts for bone-tissue engineering. Our work demonstrates the direct incorporation of ginger extract on iron oxide-magnesium oxide (Fe2O3 and MgO) co-doped hydroxyapatite (HA) for enhancement in the biological properties. The addition of Fe2O3 and MgO co-doping system and ginger extract with HA increases the osteoblast viability up to ~ 1.4 times at day 11. The presence of ginger extract leads to up to ~ 9 times MG-63 cell viability reduction. The co-doping does not adversely affect the release of ginger extract from the graft surface in the biological medium at pH 7.4 for up to 28 days. Assessment of antibacterial efficacy according to the modified ISO 22196: 2011 standard method indicates that the combined effects of Fe2O3, MgO, and ginger extract lead to ~ 82 % more bacterial cell reduction, compared to the control HA against S. aureus. These ginger extract-loaded artificial bone grafts with enhanced biological properties may be utilized as a localized site-specific delivery vehicle for various bone tissue engineering applications.

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.

Curcumin and resveratrol delivery from multi-functionalized calcium phosphate scaffold enhances biological properties.

Natural medicinal compounds (NMCs) can assist effectively in treating bone disorders. NMC release kinetics from a ceramic bone tissue engineering scaffold can be tailored. However, inferior physicochemical properties halt their therapeutic applications and need a carrier system for delivery. We developed a multi-functionalized scaffold to understand the effect of curcumin (Cur) and resveratrol (Rsv) on in vitro biological properties. Polycaprolactone (PCL) nanoparticles encapsulated resveratrol in the polymeric matrix. Nanoparticles showed a hydrodynamic diameter of about 180 nm, - 16 mV zeta potential, and up to ~65 % encapsulation efficiency. Scaffolds made of zinc-doped tricalcium phosphate (Zn-TCP) were coated with curcumin followed by either resveratrol (Cur-Rsv) or resveratrol nanoparticles (Cur-Rsv-NP). NMC-loaded scaffolds exhibited a biphasic release pattern over 60 days. Solubility and hydrophobic-hydrophilic interactions affected the NMC release profile. Resveratrol showed rapid release as compared to curcumin. The treated scaffold increased the cell viability of human fetal osteoblast (hFOB) by 1.8-fold as compared to the control. It exhibited a 6-fold increase in cytotoxicity toward osteosarcoma (MG-63) cells as compared to the untreated scaffold. NMCs loaded scaffold effectively inhibited Staphylococcus aureus from colonizing over the scaffold. Zinc doping enhanced osteoblast growth and prevented bacterial colony formation. Such design principle provided a direction for developing multi-functionalized calcium phosphate (CaP) scaffolds against bone diseases for orthopedic applications.

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.

Zinc curcumin complex on fluoride doped hydroxyapatite with enhanced biological properties for dental and orthopedic applications.

Since antiquity, curcumin, from turmeric is utilized in traditional Indian medicine (Ayurveda) to treat bone disorders. However, the hydrophobic nature and poor absorption of curcumin limit its clinical applications. There is a need to develop a novel strategy that can significantly enhance curcumin's biological properties. The current work reports the utilization of Zn2+-curcumin complex from a fluoride doped hydroxyapatite matrix for osteosarcoma inhibition, osteoblast growth, and anti-bacterial properties. The interaction between Zn2+ and curcumin increases curcumin release by ~ 2.5 folds. The fabricated drug delivery system shows up to ~ 1.6 times enhancement in osteoblast cell viability. The presence of curcumin results in ~ 4 times more osteosarcoma inhibition compared to control. The antibacterial efficacy of this system is confirmed against Staphylococcus aureus, due to the presence of antibacterial fluoride, zinc, and curcumin. This multifunctional drug delivery system can be utilized for various bone-tissue engineering and dental applications.

3D printed hydroxyapatite-nacre-starch based bone grafts: Evaluation of biological and mechanical properties.

The possibilities of utilizing nacre as a reinforcing material to manufacture 3D printed bone grafts are yet to be explored. This work reports the feasibility of fabricating 3D printed nacre-hydroxyapatitestarch composite bone graft substitutes, emphasizing the effects of nacre addition on biological and mechanical properties. Pressure-less extrusion-based 3D printing of ceramic-polymer viscous slurry is challenging due to the composition and process-parameter variations. To overcome these challenges, a dual extrusion solid freeform fabricator (SFF) has been designed. An increase in nacre loading improves the compressive strength from 9.5 ± 0.1 MPa to 11.7 ± 0.2 MPa, without any post-processing or sintering. Nacre's in vitro osteogenic properties lead to a slight increase in hFOB cellular attachment on the graft surface by day 11. The fabricated structures show good mechanical integrity during the dissolution study in simulated body fluid (SBF). These bone graft substitutes may be utilized to repair low load bearing skeletal defects.

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.

Allicin-Loaded Hydroxyapatite: Enhanced Release, Cytocompatibility, and Antibacterial Properties for Bone Tissue Engineering Applications.

Allicin, the active compound of garlic extract, is a naturally sourced biomolecule, which promotes a vast range of health benefits. However, the limited stability of allicin restricts its applications in tissue engineering. Additionally, the detailed effects of allicin in bone health are yet to be explored. Our work reports on the fabrication of a novel allicin-loaded hydroxyapatite drug delivery system with enhanced biological properties. The fabricated system shows excellent antibacterial efficiency against S. aureus after 36 h of bacterial interaction with a sample. The allicin release kinetics are enhanced with polycaprolactone (PCL). The obtained results after 20 days of drug release study indicate that PCL coating leads to an increase in cumulative allicin release from ~ 35% to 70% at a physiological pH of 7.4. These scaffolds maintain stability during the whole period of drug release. Cytocompatibility of tested compositions with osteoblasts indicates enhanced cell viability and good filopodial attachment on the sample surface at day 7. These allicin-loaded antibacterial and cytocompatible scaffolds can find applications as localized delivery vehicles for bone tissue engineering.

3D printed hydroxyapatite - Zn2+ functionalized starch composite bone grafts for orthopedic and dental applications.

Hydroxyapatite (HA) - polymer composite based 3D printed bone grafts require extensive mechanical and biological property optimization for specific clinical needs. This fuels the need to develop innovative methods of optimization. Using an in-house extrusion-based 3D printer, we show the feasibility of fabricating hydroxyapatite- Zn2+ functionalized starch composites as artificial bone graft substitutes. The experimental procedure for this purpose is fortified with a univariate multi-objective optimization strategy to predict the best composition. The compressive strength of the grafts improves up to ~ 4 folds by parametric optimization and Zn2+ functionalization, without any post-processing. These grafts maintain mechanical integrity and strength during 6 weeks of dissolution study in simulated body fluid (SBF), while the non -functionalized starch-HA grafts fully degrade within a week. The Zn2+ functionalization results in up to ~ 79% antibacterial efficacy against S. aureus. Osteoblast cell viability increases ~ 1.6 folds on these graft surfaces on day 11. Our innovative methods of optimization are expected to reduce the experiment time, cost, and chance of human error in 3D printing. This study redefines the importance of understanding composition and process dependence for making a functionalized 3D printed bone graft for repairing low load-bearing defects such as craniomaxillofacial bone.

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.

Beta-phase Stabilization and Increased Osteogenic Differentiation of Stem Cells by Solid-State Synthesized Magnesium Tricalcium Phosphate.

In this study, magnesium and strontium-doped ß-tricalcium phosphates were synthesized to understand dopant impact on substrate chemistry and morphology, and proliferation and osteogenic differentiation of mesenchymal stem cells. Under solid-state synthesis, magnesium doping stabilized the ß-phase in tricalcium phosphate, with 22% less α-phase content than control. Strontium doping increased α-phase formation by 17%, and also resulted in greater surface porosity, leading to greater crystal precipitation in vitro. Magnesium also significantly enhanced the proliferation of stem cells (P < 0.05) and differentiation into osteoblasts with increased alkaline phosphatase production (P < 0.05) at all time points. These results indicated that magnesium stabilizes ß-tricalcium phosphate in vitro and enhanced early and late-time-point osteoconduction and osteoinduction of mesenchymal stem cells.

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.

Effects of vitamin C on osteoblast proliferation and osteosarcoma inhibition using plasma coated hydroxyapatite on titanium implants.

Plasma-sprayed hydroxyapatite (HAp) coated titanium (Ti) implants are being extensively used in orthopedic surgeries and post-tumor resection to repair load-bearing segmental bone defects. In this study, vitamin C, an abundantly available natural biomolecule, is loaded onto plasma-sprayed HAp-coated commercially pure titanium (cpTi) surface to evaluate its chemopreventive and osteogenic properties, suggesting its clinical significance as an alternative or adjunct therapy in the treatment for osteosarcoma bone resection. Controlled release of vitamin C from HAp coated cpTi implant is assessed by in vitro drug release study, where Korsmeyer-Peppas model was applied to understand the release kinetics. After 21 days, the implants loaded with 400 and 800 µg of vitamin C showed a cumulative release of 62.7 and 74.1% in acidic microenvironment, whereas, 50.9% and 53.1% of total vitamin C release were observed by the implants loaded with 400 and 800 µg of vitamin C in physiological pH, respectively. To observe the effects of in vitro vitamin C release on osteosarcoma and osteoblast cellular activity, MG-63 (human osteosarcoma) and hFOB (human fetal osteoblast) cells were cultured on the surface of the implant and MTT cell viability assay and FESEM were carried out at 3 and 7 days of culture. Presence of high dosages 25 mM vitamin C shows a statistically significant (p≤0.05) decrease in osteosarcoma cell viability after 3 days, while both 5 mM and 25mM vitamin C reduced cellular viability by 2.5 folds (p≤0.05) compared to the control after 7 days. Interestingly, the presence of vitamin C showed no obvious signs of cytotoxicity towards osteoblast cell-line at day 3 and day 7, as confirmed by the MTT assay. Additionally, the FESEM images depict layers of hFOB cellular morphology on the surface of the implants, suggesting excellent cytocompatibility towards the osteoblast cells. These results suggest that vitamin C loaded HAp coated cpTi implant with improved osteogenic and chemopreventive properties can be considered as a promising reconstructive option to repair the post-tumor resection defects in osteosarcoma.

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.

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.

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.