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A schematic of sample preparation using 3D printing, assessment of in vivo rat distal femur model with the 3D printed curcumin loaded scaffolds, and demonstration of in vitro properties including osteosarcoma inhibition and antibacterial properties.

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, Ca(10) (PO(4))(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 (Zn(2+)) 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 Zn(2+)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. Zn(2+) 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, 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

Vitamin A is a fat-soluble compound widely known for vision health. Highly variable reports on its effects on bone health have necessitated further research to truly understand its role on bone cell proliferation. Retinol, one bioactive form of vitamin A, is incorporated into synthetic bone graft scaffolds for low load-bearing clinical bone treatment. The objective of this work is to understand the effects of retinol on osteoblast and osteoclast cells when embedded within calcium phosphate matrices, including interconnected porous 3D printed tricalcium phosphate scaffolds. Results show that hydrophobic retinol can be released from bone scaffolds when a combination of biodegradable polymers, polycaprolactone and polyethylene glycol, are employed as drug carriers. The release of retinol in vitro can support a 20 ± 1% increase in osteoblast (bone-forming) cell proliferation with proper cell adhesion and filopodial extensions. Osteoclast cell morphology is necrosed and torn with a reduction in proliferation at approximately 6 ± 1% when retinol is present. In addition, inhibition of osteoclastic resorption pit bays is noted using scanning electron microscopy. With the scaffolds’ round pore interconnectivity facilitating retinol release, this system can provide an alternative to traditional bone grafts while additionally supporting bone healing through enhanced osteoblast cell proliferation and inhibition of osteoclast resorption activity.

Preparation process of the EGCG-loaded 3D printed scaffold and its in vitro biological evaluation for low-load bearing patient-specific bone implants.

Directed energy deposition (DED) is a branch of additive manufacturing (AM) processes in which a feedstock material in the form of powder or wire is delivered to a substrate on which an energy source such as laser beam, electron beam, or plasma/electric arc is simultaneously focused, thus forming a small melt pool and continuously depositing material, layer by layer. DED has several unique advantages compared to other AM processes, such as site-specific deposition and repair, alloy design, and three-dimensional printing of complex shapes. Herein, recent advances as well as the main aspects governing laser-material interactions during the DED process, melt pool thermal behavior, advanced in situ monitoring, and interaction mechanisms are critically reviewed. The most critical processing variables and their influence on the deposited material properties, along with defect formation mechanisms and characterization techniques, are also identified and discussed. An overview of high-end applications, current challenges associated with DED processing, and a critical outlook of the technology are presented.

The addition of dopants in biomaterials has emerged as a critical regulator of bone formation and regeneration due to their imminent role in the biological process. The present work evaluated the role of strontium (Sr) and magnesium (Mg) dopants in brushite cement (BrC) on in vivo bone healing performance in a rabbit model. Pure, 1 wt% SrO (Sr-BrC), 1 wt% MgO (Mg-BrC), and a binary composition of 1.0 wt% SrO + 1.0 wt% MgO (Sr + Mg-BrC) BrCs were implanted into critical-sized tibial defects in rabbits for up to 4 months. The in vivo bone healing of three doped and pure BrC samples was examined and compared using sequential radiological examination, histological evaluations, and fluorochrome labeling studies. The results indicated excellent osseous tissue formation for Sr-BrC and Sr + Mg-BrC and moderate bone regeneration for Mg-BrC compared to pure BrC. Our findings indicated that adding small amounts of SrO, MgO, and binary dopants to the BrC can significantly influence new bone formation for bone tissue engineering.

Additive manufacturing (AM) technologies print three-dimensional (3D) parts through layer-by-layer deposition based on the digital input provided by a computer-aided design file. This article focuses on the binder jet printing process, common biomaterials used in this AM technique, and the clinical applications relevant to these systems. It reviews the challenges and future directions of binder-jetting-based 3D printing.

This article discusses some of the additive manufacturing (AM) based fabrication of alloys and their respective mechanical, electrochemical, and in vivo performance. Firstly, it briefly discusses the three AM techniques that are most commonly used in the fabrication of metallic biomedical-based devices: binder jetting, powder-bed fusion, and directed-energy deposition. The article then characterizes the electrochemical properties of additive-manufactured/processed cobalt-chromium alloys. This is followed by sections providing an evaluation of the biological response to CoCr alloys in terms of the material and 3D printing fabrication. Discussion on the biological response as a function of direct cellular activity on the surface of CoCr alloys in static conditions (in vitro), in dynamic physiological conditions (in vivo), and in computer-simulated conditions (in silico) are further discussed in detail. Finally, the article provides information on the qualification and certification of AM-processed medical devices.

Load-bearing bone substitutes must be designed to stimulate bone formation and allow crosstalk between the two primary skeletal cells, bone-forming osteoblasts, and bone-resorbing osteoclasts. Compared to the dense implants, surface-modified, additively manufactured porous implants have shown osteogenic potential. Surface modification of metal implants by plasma-sprayed hydroxyapatite (HA) coating, show better clinical applicability due to their significant osteogenic potential, through better osteoblast proliferation and osseointegration. This study investigates additively manufactured porous metallic surface and plasma-sprayed HA-coated Ti on the proliferation and differentiation of monocytic cells into osteoclasts and their resorptive activity. Our results reveal that porous Ti6Al4V and porous Ta enhanced TRAP activity, compared to the control (p

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.

In this study, magnesium and strontium-doped β-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 β-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 β-tricalcium phosphate in vitro and enhanced early and late-time-point osteoconduction and osteoinduction of mesenchymal stem cells.

With an increasing life expectancy and aging population, orthopedic defects and bone graft surgeries are increasing in global prevalence. Research to date has advanced the understanding of bone biology and defect repair mechanism, leading to a marked success in the development of synthetic bone substitutes. Yet, the quest for functionalized bone grafts prompted the researchers to find a viable alternative that regulates cellular activity and supports bone regeneration and healing process without causing serious side-effects. Recently, researchers have introduced natural medicinal compounds (NMCs) in bone scaffold that enables them to release at a desirable rate, maintains a sustained release allowing sufficient time for tissue in-growth, and guides bone regeneration process with minimized risk of tissue toxicity. According to World Health Organization (WHO), NMCs are gaining popularity in western countries for the last two decades and are being used by 80% of the population worldwide. Compared to synthetic drugs, NMCs have a broader range of safety window and thus suitable for prolonged localized delivery for bone regeneration. There is limited literature focusing on the integration of bone grafts and natural medicines that provides detailed scientific evidences on NMCs, their toxic limits and particular application in bone tissue engineering, which could guide the researchers to develop functionalized implants for various bone disorders. This review will discuss the emerging trend of NMC delivery from bone grafts, including 3D-printed structures and surface-modified implants, highlighting the significance and potential of NMCs for bone health, guiding future paths toward the development of an ideal bone tissue engineering scaffold. STATEMENT OF SIGNIFICANCE: To date, additive manufacturing technology provids us with many advanced patient specific or defect specific bone constructs exhibiting three-dimensional, well-defined microstructure with interconnected porous networks for defect-repair applications. However, an ideal scaffold should also be able to supply biological signals that actively guide tissue regeneration while simultaneously preventing post-implantation complications. Natural biomolecules are gaining popularity in tissue engineering since they possess a safer, effective approach compared to synthetic drugs. The integration of bone scaffolds and natural biomolecules exploits the advantages of customized, multi-functional bone implants to provide localized delivery of biochemical signals in a controlled manner. This review presents an overview of bone scaffolds as delivery systems for natural biomolecules, which may provide prominent advancement in bone development and improve defect-healing caused by various musculoskeletal disorders.

Titanium has been used in various biomedical applications; however, titanium exhibits poor wear resistance, and its bioinert surface slows osseointegration in vivo. In this study, directed energy deposition (DED)-based additive manufacturing (AM) was used to process hydroxyapatite (HA) reinforced Ti6Al4V (Ti64) composites to improve biocompatibility and wear resistance simultaneously. Electron micrographs of the composites revealed dense microstructures where HA is observed at the β-phase grain boundaries. Hardness was observed to increase by 57% and 71% for 2 and 3 wt.% HA in Ti64 composites, respectively. XRD analysis revealed no change in the present phases. Tribological studies revealed an increase in contact resistance due to in situ HA-based tribofilm formation, reduction in wear rate when testing in DMEM with a ZrO(2) counter wear ball

Natural medicines have long been used to treat physiological ailments where both ginger (gingerol) and garlic (allicin) are key players in immune system promotion, reduction in blood pressure, and lowering inflammation response. With their efficacy in bone healing, these compounds have great value as medicinal additives in bone scaffolds for localized treatment to support tissue formation, along with providing their natural therapeutic benefits. Utilization of 3D-printed (3DP) bone tissue engineering scaffolds as drug delivery vehicles for ginger and garlic extracts enables patient specificity in bone defect applications with enhanced osseointegration. Our objective is to understand their combined efficacy on osteogenesis when released from 3DP calcium phosphate bone scaffolds designed with a bimodal pore distribution. With a porous core and dense exterior, the resulting scaffolds have good mechanical integrity with 10 ± 1 MPa compressive strengths. Results show that ginger + garlic extracts released from bone scaffolds enhance their osteogenic potential through on site drug delivery. Both compounds exhibit exponential drug release profiles which fit Weibull distribution equations. The release of ginger extract also increases osteoblast proliferation by 59%. Both compounds show decreased osteoclast resorption activity, with a greater than 20% reduction in pit area on sample surfaces. Ginger + garlic extract induces a twofold increase in early osteoid tissue formation in vivo at week 4, in addition to a 30% increase in total bone area and a 90% increase in osteocytes with respect to control 3DP tricalcium phosphate scaffolds. Late-stage bone healing at week 10 reveals healthy angiogenic tissue, a twofold higher bone mineralization, and significant enhancement of type I collagen formation in the presence of ginger and garlic extracts. Naturally sourced ginger and garlic extracts provide osteogenic promotion and improved bone tissue in-growth in a patient-specific 3DP scaffold biomedical device for low load-bearing bone tissue engineering and dental applications.

Traditional infection prevention and treatment methods include synthetic antibiotics, which can cause severe adverse side effects. Carvacrol and thymol are biologically active monoterpenoid extractants from oregano leaves with antibiotic capabilities; however, little is known regarding their effects on bone tissue engineering. The objective of this work is to understand their effects on osteogenesis, specifically with osteoblast and osteoclast cells, from surface-modified Ti6Al4V with plasma sprayed hydroxyapatite (HA) coatings. This system is an alternative to cemented implants to aid in bone healing. Results reveal that full carvacrol release from the HA matrix is successful in aqueous environments and modulation of release kinetics can also be made using polycaprolactone (PCL) and polyethylene glycol (PEG) polymers. From HA-pressed disc samples in physiological pH, full carvacrol release is achieved in 10 days using PCL/PEG, about 95% release in 50 days using no polymer, and 60% in 50 days when using a PCL coating. Without polymer, full carvacrol release is achieved after 3 days from HA coatings in both physiological pH and acidic pH, mimicking the post-surgery environment. The release is assessed as a diffusion-based mechanism in phosphate-buffered saline but degradation-based mechanism in acetate buffer solution. Carvacrol and thymol show bacterial inhibition of Staphylococcus epidermidis and no cytotoxic effects on osteoblast proliferation in vitro. Carvacrol and thymol also induce a significant 7% reduction in osteoclast tartrate-resistant acid phosphatase (TRAP) activity, caused by poorly attached cellular morphologies, leading to an approximately 65% reduction in osteoclast resorption pit formation. Our goal is to demonstrate a natural medicinal system that can support bone healing while providing infection prevention and reducing costly revision surgeries for orthopedic and dental applications.

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. SUMMARY: 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.

The stability of plasma-sprayed hydroxyapatite (HA) coatings on metallic implants in vivo remains a significant challenge for load-bearing orthopedic implants despite their excellent mechanical and osteoconductive properties. This study focuses on oxide layer formation on the surface of Ti6Al4V samples through furnace heating at 600, 700, and 800 °C for 10 min for optimization of the most effective oxide layer to increase plasma coating crystallinity and improve plasma coating bond strength with the metal surface. The 800 °C heat treatment shows an effective oxide layer which increases coating crystallinity from 64 to 75% and coating adhesive bond strength from 25.9 ± 2.3 to 30.7 ± 1.1 MPa, while simultaneously reducing the dissolution rate of HA coatings. The addition of biologically relevant dopants, MgO and SiO(2), show negligible effects on crystallinity and adhesive bond strength on plasma-sprayed HA coatings and additionally show an enhancement effect on osteoblast proliferation and differentiation. Moreover, the inclusion of these additivess shows an increase in osteogenesis in a rat distal femur model after 6 and 10 weeks of implantation. Overall, this study provides a direct solution to improve the crystallinity, adhesive bond strength, and osteogenic properties of plasma-sprayed HA coatings on orthopedic implants that is more manufacturable and translational from research to an industrial scale.

Additive manufacturing (AM) or 3D printing has revolutionized the modern metal manufacturing industry. AM technology allows for fabrication of highly customized 3D objects where both shape and composition can be tailored. Compared to traditional methods, metal AM technology has advantages in saving time and cost. Recent developments in metal AM systems include upgrades in energy source and part resolution, which leads to better part quality and improved reliability. This brief review article summarizes recent developments in metal AM technologies as well as the current challenges and future trends.

Successful repair of critical-sized tumor-resection defects, especially in load-bearing bones, still remains a major challenge in clinical orthopedics. Titanium (Ti) implants have been increasingly used in the past few decades because of titanium’s suitable mechanical properties and biocompatibility; however, it shows insufficient integration with the surrounding bone. In this study, the plasma spray technique is utilized to form homogeneous hydroxyapatite (HA) coating on the surface of the Ti implant to enhance osseointegration at the tissue-implant interface. These coated implants are loaded with curcumin and vitamin K2 to introduce chemopreventive and osteogenesis ability via controlled release of these biomolecules. The synergistic effect of these two biomolecules showed enhanced in vitro osteoblast (hFOB) cell attachment and proliferation for 11 days. Moreover, these biomolecules showed lower in vitro osteosarcoma (MG-63) cell proliferation after 3, 7, and 11 days. An in vivo study was carried out to evaluate the bone bonded zone in a rat distal femur model at an early wound healing stage of 5 days. Modified Masson Goldner staining of the tissue-implant section showed improved contact between tissue and implant in dual drug-loaded HA-coated Ti implants compared to control implants. This work presents a successful fabrication of a mechanically competent functional Ti implant with the advantages of enhanced in vitro osteoblast proliferation, osteosarcoma inhibition, and in vivo osseointegration, indicating the potential for load-bearing bone-defect repair after tumor resection.

Through the development of additive manufacturing (AM), significant progress has been made in the field of biomedical devices and bone tissue engineering. AM allows for the fabrication of site-specific implants with tailorable porosity and controlled chemistry through the utilization of innovative materials. With the development of composite scaffolds, valiant efforts have been made in relation to the biosignificance of synthetic bone grafting materials. This paradigm shift is only made possible by the discovery of new and novel compounds for scaffold preparation. There is a growing clinical interest regarding natural polymers in order to generate novel properties and functionalities in biomaterial applications. Through 3D printing (3DP) and AM techniques, natural polymer incorporation into bioceramic-based scaffolds and hydrogels has allowed for the advanced treatment of bone ailments and defects through the creation of novel, functionalized composite surfaces. Naturally sourced polymers including chitosan, alginate, collagen, gelatin, cellulose, hyaluronate, silk, fibrinogen, and starch show great potential in the biomedical field due to their inherent biocompatibility, bioactivity, and bioresorbability. This review paper will introduce these natural biopolymers alongside their traditional biomedical applications followed by traditional processing techniques of these biopolymers in conjunction with calcium phosphate in the manufacturing of scaffolds that can be used in the bone tissue engineering field. The final section of the review focuses on the advancement of AM of natural polymers with an emphasis on their applications as scaffolds and hydrogels also for utilization in the bone tissue engineering field.

Hydroxyapatite-coated titanium alloys have been a popular choice as bone implants for load-bearing applications for the compositional similarity of hydroxyapatite to natural bone. The limited osteoinductive properties exhibited by the hydroxyapatite (HA) coatings have led to the incorporation of growth factor or dopants for improved osseointegration. This study aims to investigate the effects of a naturally occurring aloe vera gel extract, acemannan, in doped hydroxyapatite coatings on the