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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.

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

Additive manufacturing (AM) of metals attracts attention because it can produce complex structures in a single step without part-specific tooling. Wire arc additive manufacturing (WAAM), a welding-based method that deposits metal layer by layer, is gaining popularity due to its low cost of operation, feasibility for large-scale part fabrication, and ease of operation. This article presents the fabrication of cylindricalshaped mild steel (ER70S-6) samples with a gas metal arc (MIG)—based hybrid WAAM system. A mechanism for actively cooling the substrate is implemented. Deposition parameters are held constant to evaluate the impact of active cooling on deposition quality, inter-pass cooling time, and internal defects. Surface and volume defects can be seen on the cylindrical sample fabricated without an active cooling setup. Defect quantification and phase analysis are performed. The primary phase formed was α-iron in all samples. Actively cooled deposition cross section showed a 99% decrease of incomplete fusion or porosity, with temperature measured 60 s after deposition averaging 235°C less than non-cooled. Microstructural analysis revealed uniformity along the build direction for actively cooled deposition but non-uniform microstructures without cooling. Hardness decreased by approximately 22HV from the first layer to the final layer in all cases. Property variation can be attributed to the respective processing strategies. The current study has demonstrated that active cooling can reduce production time and porosity while maintaining uniform microstructure along the build direction. Such an approach is expected to enhance the reliability of WAAM-processed parts in the coming days.

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.

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.

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.

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.

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.

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.

Calcium phosphate (CaP)-based ceramics are a popular choice for bone-graft applications due to their compositional similarities with bone. Similarly, Bioactive glass (BG) is also common for bone tissue engineering applications due to its excellent biocompatibility and bone binding ability. We report tricalcium phosphate (TCP)-BG (45S5 BG) composite scaffolds using conventional processing and binder jetting-based 3D printing (3DP) technique. We hypothesize that BG's addition in TCP will enhance densification via liquid phase sintering and improve mechanical properties. Further, BG addition to TCP should modulate the dissolution kinetics in vitro. This work's scientific objective is to understand the influence of random vs. designed porosity in TCP-BG ceramics towards variations in compressive strength and in vitro biocompatibility. Our findings indicate that a 5 wt% BG in TCP composite shows a compressive strength of 26.7 ± 2.7 MPa for random porosity structures having a total porosity of ~47.9%. The same composition in a designed porosity structure shows a compressive strength of 21.3 ± 2.9 MPa, having a total porosity of ~54.1%. Scaffolds are also tested for their dissolution kinetics and in vitro bone cell materials interaction, where TCP-BG compositions show favorable bone cell materials interactions. The addition of BG enhances a flaky hydroxycarbonate apatite (HCA) layer in 8 weeks in vitro. Our research shows that the porous TCP- BG scaffolds, fabricated via binder jetting method with enhanced mechanical properties and dissolution properties can be utilized in bone graft applications.

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.

The objective of this study was to understand the effects of ceramic polymer composite and pH of the surrounding vicinity on the release kinetics of doxorubicin. Different concentrations of polymers with polycaprolactone (PCL), poly glycolic lactic acid (PLGA), and a blend of PCL–PLGA with hydroxyapatite (HA) were investigated for doxorubicin release at physiological pH of 7.4 and an acidic pH of 5.0 caused by immediate surgery. Burst release of 20% was observed from bare HA at pH 7.4 over a week, whereas all the polymer incorporated discs showed sustained release. The hydrophilic–hydrophobic and hydrophobic–hydrophobic interactions between the polymer and the drug altered by the surrounding pHs were found to be pivotal in controlling the release kinetics of drug. No cytotoxicity of the drug at a concentration of 50 µg per disc was observed at early time points when cultured with osteoblast cells; however, the same drug dosage inhibited osteosarcoma cell viability. This study mainly bases on the comprehension of the effects of chemistry, environment, and polymer–drug interactions, leading to a beneficial understanding towards the design of drug delivery devices.

Curcumin, the active constituent for turmeric, is known for its antioxidant, anti-inflammatory, anticancer, and osteogenic activities. However, it shows extremely poor bioavailability, rapid metabolism, and rapid systemic elimination. In this study, we have increased the bioavailability of curcumin by encapsulating it in a liposome, followed by the incorporation onto 3D printed (3DP) calcium phosphate (CaP) scaffolds with designed porosity. 3DP scaffolds with a designed shape and interconnected porosity allow for the fabrication of patient-specific implants, providing new tissue ingrowth by mechanical interlocking between the surrounding host tissue and the scaffold. Upon successful encapsulation of curcumin into the liposomes, we have investigated the effect of liposomal curcumin released from the 3DP scaffolds on both human fetal osteoblast cells (hFOB) and human osteosarcoma (MG-63) cells. Interestingly, liposomal curcumin released from the 3DP scaffold showed significant cytotoxicity toward in vitro osteosarcoma (bone cancer) cells, whereas it promoted osteoblast (healthy bone cell) cell viability and proliferation. These results reveal a novel approach toward the fabrication of tissue engineering scaffolds, which couples the advanced additive manufacturing technology with the wisdom of alternative medicine. These bifunctional scaffolds eradicate the osteosarcoma cells and also promote osteoblast proliferation, offering new opportunities to treat bone defects after tumor resection.

Significant efforts have been made to treat bone disorders through the development of composite scaffolds utilizing calcium phosphate (CaP) through additive manufacturing techniques. However, the incorporation of natural polymers with CaP during 3D printing is difficult and remains a formidable challenge in bone and tissue engineering applications. The objective of this study is to understand the use of a natural polymer binder system in ceramic composite scaffolds using a ceramic slurry-based solid freeform fabricator (SFF). This was achieved through the utilization of naturally sourced gelatinized starch with hydroxyapatite (HA) ceramic in order to obtain high mechanical strength and enhanced biological properties of the green part without the need for cross-linking or post processing. The parametric effects of solids loading, polycaprolactone (PCL) polymer addition, and designed porosity on starch-HA composite scaffolds were assessed through mechanical strength, microstructure, and in vitro biocompatibility utilizing human osteoblast cells. It was hypothesized that starch incorporation would improve the mechanical strength of the scaffolds and increase proliferation of osteoblast cells in vitro. Starch loading was shown to improve mechanical strength from 4.07 ± 0.66 MPa to 10.35 ± 1.10 MPa, more closely resembling the mechanical strength of cancellous bone. Based on these results, a reinforcing mechanism of gelatinized starch based on interparticle and apatite crystal interlocking is proposed. Morphological characterization utilizing FESEM and MTT cell viability assay showed enhanced osteoblast cell proliferation in the presence of starch and PCL. Overall, the utilization of starch as a natural binder system in SFF scaffolds was found to improve both green strength and in vitro biocompatibility.

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.

Additive manufacturing (AM), or 3D printing, of bioceramic scaffolds promises personalized treatment options for patients with site-specific designability for repair and reconstruction of bone defects. Although the theory for creating these complex geometries has already been made possible through AM's advancement, such shapes' manufacturability is difficult due to printing with ceramics' inherent complexities. Ceramics have the added challenge of being highly brittle, poor handleability of green (pre-sintered) parts, making complex shape high strength parts challenging to manufacture. This has led to a significant literature gap regarding the feasibility of creating bioceramic scaffolds with unique architectures that can be used in site-specific, individualized patient treatment. This work aims to successfully create complex topographical surfaces of cylindrical bone-like scaffolds to understand the correlation of increasing the scaffold surface area on mechanical properties and in vitro osteoblast cell proliferation. An increase in osteoblast cell proliferation and facilitation in cellular attachment can ultimately lead to improved bone healing. This work explores the printing parameters within an Innovent+® ExOne binder jet 3D printer to produce scaffold designs from synthesized tricalcium phosphate powder. Mechanical testing reveals the designed structures enhance scaffold compressive strength by 30% compared to control dense cylindrical scaffolds. Osteoblast cell proliferation is also increased due to changes in surface topography with a nearly 2-fold increase. Our work incorporates macro-level topographical changes to increase surface area, which is another avenue that could be combined with other scaffold features such as porosity. Results show bulk surface topography modifications via 3D printing can increase surface area to support enhanced biological response without compromising mechanical properties. This discovery may enable a future generation of porous scaffolds with external structures for further progress towards proper defect-specific synthetic bone grafts.

Directed-energy deposition (DED)-based additive manufacturing (AM) was explored for composite development using silicon (Si) and hydroxyapatite (HA) in Ti-6Al-4 V (Ti64) matrix for articulating surfaces of load-bearing implants. Specifically, laser engineered net shaping (LENSTM) – a commercially available DED-based AM technique – was used to fabricate composites from premixed-feedstock powders. The AM’d composites proved to not only improve upon Ti64’s mechanical properties but also produced an in-situ Si-based tribofilm during tribological testing that minimized wear induced damage. Additionally, it was found that with the introduction of Si, titanium silicides and vanadium silicides were formed; allowing for 114% increased hardness, decreased coefficient of friction (COF) and a reduction of wear rate of 38.1% and 70.8%, respectively, for a 10 wt.% Si presence. The produced composites also displayed a positive shift in open-circuit potential (OCP) during linear wear, along with a reduction in the change of OCP from idle to linear wear conditions. Additionally, contact resistance (CR) values increased with a maximum value of 1500 ohms due to the formation of Si-based tribofilm on the wear surface. Such composite development approach using DED-based AM can open up the possibilities of innovating next-generation implants that are designed and manufactured via multi-material AM.

Delayed healing and nonhealing of bone defects or resected bone sites remains an important clinical concern in the biomedical field. Osteosarcoma is one of the most common types of primary bone cancers. Among calcium phosphates, hydroxyapatite (HA) and tricalcium phosphate (TCP) are the most widely used in various biomedical applications for bone reconstruction and replacement. In this study, crocin, saffron's natural bioactive and anti-inflammatory molecule, and bicarbonate, a neutralizing agent, were directly loaded onto HA disks to evaluate their in vitro release and effect on human osteoblast and osteosarcoma cell lines. This was assessed through release, initial toxicity, drug optimization, final toxicity studies and in vivo anti-inflammatory assessment through H&E indexing. It is hypothesized that the release of crocin, bicarbonate, and the dual release of both agents will decrease osteosarcoma cellular viability with no effect on osteoblast cells. A plateaued release of crocin and bicarbonate was achieved over seven weeks in physiological and acidic environments, where bicarbonate was shown to modulate the release of crocin. Through morphological characterization and MTT assay analysis, bicarbonate showed no toxicity to human fetal osteoblast (hFOB) cells and crocin significantly enhanced osteoblast proliferation. Through drug concentration optimization, all drug loaded samples decreased human osteosarcoma (MG-63) viability by 50% compared to control samples by Day 11, with clear changes in cell spreading and morphology. Moreover, 3D printed TCP scaffolds loaded with crocin and bicarbonate were tested in vivo in order to assess their preliminary effects on inflammation in a rat distal femur model at 4 days. Lower inflammatory cellular recruitment was achieved in the presence of crocin and bicarbonate, compared to the control. These results suggest a pro-apoptotic mechanism against osteosarcoma as well as anti-inflammatory properties of crocin and bicarbonate, elucidating a potential application for osteosarcoma regulation and wound healing for bone tissue regeneration applications.

Porous tricalcium phosphate (TCP) scaffolds are becoming more and more important for treating musculoskeletal diseases. With the maturation of 3D printing (3DP) technology in the past two decades, porous TCP scaffolds can also be easily prepared with complex design and high dimensional accuracy. However, the mechanical and biological properties of porous TCP scaffolds prepared by 3D printing still need improvements. In this study, novel 3D printed TCP and MgO/ZnO-TCP scaffolds were prepared by an binder-jet 3D printer. Scaffolds had a dense core and porous surface feature with a designed pore size of 500 μm and a designed porosity of 18%. After printing, scaffolds were sintered in a muffle furnace at 1250 °C. The presence of MgO and ZnO increased the surface area of TCP from 1.18 ± 0.01 m2/g to 2.65 ± 0.02 m2/g, the bulk density from 37.89 ± 0.83% to 50.82 ± 1.10%, and the compressive strength from 17.94 ± 1.65 MPa to 27.46 ± 2.63 MPa. Enhanced osteoblast proliferation was shown in doped 3D printed TCP scaffolds compared to the pure 3DP TCP. In addition, the use of 3D printing as well as dense core and porous surface design enhanced the surface roughness and osteoblast proliferation of TCP scaffolds. This novel 3D printed MgO/ZnO-TCP scaffold shows enhanced mechanical and biological properties, which is promising for orthopedic and dental applications.

Seeking to improve the wear resistance of the Ti6Al4V (Ti64) alloy for biomedical applications, carbon nanotubes (CNTs) and calcium phosphate (CaP) ceramics were added to Ti64 powder and successfully 3D-printed using a commercial laser engineered net shaping (LENS™) system. It was hypothesized that CNTs would allow for in situ carbide formation during laser processing, resulting in increased surface hardness. It was also hypothesized that CaPs would allow for protective tribofilm formation during wear, reducing material loss from wear-induced damage. Scanning electron microscopy images reveal defect-free microstructures with fine carbides evenly distributed, while X-ray diffraction confirms the presence of carbides without additional unwanted intermetallic phases. Vickers microhardness shows an increase in surface hardness in coatings containing both CNTs and CaPs. In vitro tribological studies found reduced coefficient of friction, reduced wear rates, and reduced metal ion-release concentrations in coatings containing both CNTs and CaPs. This study demonstrates the efficacy of CNTs and CaPs to improve wear resistance of Ti64 for potential applications in articulating surfaces of load-bearing implants.

Additive manufacturing (AM) is fundamentally different from traditional formative or subtractive manufacturing in that it is the closest to the ‘bottom up’ manufacturing where a structure can be built into its designed shape using a ‘layer-by-layer’ approach rather than casting or forming by technologies such as forging or machining. AM is versatile, flexible, highly customizable and, as such, can suite most sectors of industrial production. Materials to make these parts/objects can be of a widely varying type. These include metallic, ceramic and polymeric materials along with combinations in the form of composites, hybrid, or functionally graded materials (FGMs). The challenge remains, however, to transfer this ‘making’ shapes and structures into obtaining objects that are functional. A great deal of work is needed in AM in addressing the challenges related to its two key enabling technologies namely ‘materials’ and ‘metrology’ to achieve this functionality in a predictive and reproductive ways. The good news is that there is a significant interest in industry for taking up AM as one of the main production engineering route. Additive Manufacturing, in our opinion, is definitely at the cross-road from where this new, much-hyped but somewhat unproven manufacturing process must move towards a technology that can demonstrate the ability to produce real, innovative, complex and robust products.

Correction for ‘Additive manufacturing of natural biopolymers and composites for bone tissue engineering’ by Susmita Bose et al., Mater. Horiz., 2020, DOI: 10.1039/d0mh00277a.

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.

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 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 were 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. Keywords: 3D printing, Porous cylinders, Surface modification, Titania nanotubes, in vivo osseointegration, Accelerated healing

Cobalt-chromium-molybdenum (CoCrMo) alloys are widely used in load-bearing implants; specifically, in hip, knee, and spinal applications due to their excellent wear resistance. However, due to in vivo corrosion and mechanically assisted corrosion, metal ion release occurs and accounts for poor biocompatibility. Therefore, a significant interest to find an alternative to CoCrMo alloy exists. In the present work we hypothesize that calcium phosphate (CaP) will behave as a solid lubricant in CoCrMo alloy under tribological testing, thereby minimizing wear and metal ion release concerns associated with CoCrMo alloy. CoCrMo-CaP composite coatings were processed using laser engineered net shaping (LENS™) system. After LENS™ processing, CoCrMo alloy was subjected to laser surface melting (LSM) using the same LENS™ set-up. Samples were investigated for microstructural features, phase identification, and biocompatibility. It was found that LSM treated CoCrMo improved wear resistance by 5 times. CoCrMo-CaP composites displayed the formation of a phosphorus-based tribofilm. In vitro cell-material interactions study showed no cytotoxic effect. Sprague-Dawley rat and rabbit in vivo study displayed increased osteoid formation for CoCrMo-CaP composites, up to 2 wt.% CaP. Our results show that careful surface modification treatments can simultaneously improve wear resistance and in vivo biocompatibility of CoCrMo alloy, which can correlate to a reduction of metal ion release in vivo.

Material properties of implants such as volume porosity and nanoscale surface modification have been shown to enhance cell-material interactions in vitro and osseointegration in vivo. Porous tantalum (Ta) and titanium (Ti) coatings are widely used for non-cemented implants, which are fabricated using different processing routes. In recent years, some of those implants are being manufactured using additive manufacturing. However, limited knowledge is available on direct comparison of additively manufactured porous Ta and Ti structures towards early stage osseointegration. In this study, we have fabricated porous Ta and Ti6Al4V (Ti64) implants using laser engineered net shaping (LENS™) with similar volume fraction porosity to compare the influence of surface characteristics and material chemistry on in vivo response using a rat distal femur model for 5 and 12 weeks. We have also assessed whether surface modification on Ti64 can elicit similar in vivo response as porous Ta in a rat distal femur model for 5 and 12 weeks. The harvested implants were histologically analyzed for osteoid surface per bone surface. Field emission scanning electron microscopy (FESEM) was done to assess the bone-implant interface. The results presented here indicate comparable performance of porous Ta and surface modified porous Ti64 implants towards early stage osseointegration at 5 weeks post implantation through seamless bone-material interlocking. However, a continued and extended efficacy of porous Ta is found in terms of higher osteoid formation at 12 weeks post-surgery.

For decades, research has been attributed to the monoculture of either mesenchymal stem cells (MSCs) or monocytes to differentiate into osteoblasts (OBs) and osteoclasts (OCs) respectively, however, this is far from being realistic. For improved research in the field of biomaterials, the balance between OBs and OCs needs to be investigated simultaneously on in vitro models for a better understanding and prediction of the bone remodeling process in vivo. The study aims to investigate the effects of Mg+2 and Sr+2 dopant in hydroxyapatite coating on the simultaneous differentiation of human MSCs and Tamm Horsfall Protein 1 (THP-1) monocytes into OBs and OCs respectively. We hypothesize that a cultivation regime can be established to show simultaneous proliferation and differentiation of the MSCs and monocytes into OBs and OCs. Also, the presence of Sr+2 and Mg+2 will induce faster bone remodeling and demonstrate enhanced osteogenic properties. Doped hydroxyapatite coatings were fabricated on CpTi substrates using plasma spray coating technique and the influence of dopants on the in vitro OB−OC co-culture was studied by specific marker genes, namely OPG, RANKL, RUNX2, and ACP5. Comparison amongst the expressions of genes reveals the differentiation of the primary cells as early as 5-day time-point. Downregulation of RUNX2 and ACP5 in the doped HA coated samples at 15-day time-point are a proof of the effective role of the dopants in the enhancement of bone remodeling. This study shows the possibility of simultaneous culturing of human OB and OC precursors and demonstrates the efficacy of dopants in the pace change of bone remodeling for bone tissue engineering applications.

Recent efforts in the bone and tissue engineering field have been made to create resorbable bone scaffolds that mimic the structure and function of natural bone. While enhancing mechanical strength through increased ceramics loading has been shown for sintered parts, few studies have reported that the crosslinked polymer provides strength for the composite parts without post processing. The objective of this study is to assess the effect of amylose content on the mechanical and physical properties of starch-hydroxyapatite (HA) composite scaffolds for bone and tissue engineering applications. Starch-HA composite scaffolds utilizing corn, potato, and cassava sources of gelatinized starch were fabricated through the utilization of a self-designed and built solid freeform fabricator (SFF). It was hypothesized that the mechanical strength of the starch-HA scaffolds would increase with increasing amylose content based on the botanical source and weight percentage added. Overall, compressive strengths of scaffolds were achieved up to 12.49 ± 0.22 MPa, through the implementation of 5.46 wt% corn starch with a total amylose content of 1.37%. The authors propose a reinforcement mechanism through a matrix of gelled starch particles and interlocking of hydroxyl-rich amylose with hydroxyapatite through hydrogen bonding. XRD, FTIR, and FESEM were utilized to further characterize these scaffold structures, ultimately elucidating amylose as a biologically relevant reinforcement phase of resorbable bone scaffolds.

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 the addition of dopants to the TCP scaffolds enhanced bone formation and in turn leading to accelerated healing.

Three-dimensional (3D) printing represents the direct fabrication of parts layer-by-layer, guided by digital information from a computer-aided design file without any part-specific tooling. Over the past three decades, a variety of 3D printing technologies have evolved that have transformed the idea of direct printing of parts for numerous applications. Three-dimensional printing technology offers significant advantages for biomedical devices and tissue engineering due to its ability to manufacture low-volume or one-of-a-kind parts on-demand based on patient-specific needs, at no additional cost for different designs that can vary from patient to patient, while also offering flexibility in the starting materials. However, many concerns remain for widespread applications of 3D-printed biomaterials, including regulatory issues, a sterile environment for part fabrication, and the achievement of target material properties with the desired architecture. This article offers a broad overview of the field of 3D-printed biomaterials along with a few specific applications to assist the reader in obtaining an understanding of the current state of the art and to encourage future scientific and technical contributions toward expanding the frontiers of 3D-printed biomaterials.

The aim of this work was to evaluate the effect of in vitro alendronate (AD) release behavior through polycaprolactone (PCL) coating on in vivo bone formation using PCL-coated 3D printed interconnected porous tricalcium phosphate (TCP) scaffolds. Higher AD and Ca(2+) ion release was observed at lower pH (5.0) than that at higher pH (7.4). AD and Ca(2+) release, surface morphology, and phase analysis after release indicated a matrix degradation dominated AD release caused by TCP dissolution. PCL coating showed its effectiveness for controlled and sustained AD release. Six different scaffold compositions, namely, (i) TCP (bare TCP), (ii) TCP + AD (AD-coated TCP), (iii) TCP + PCL (PCL-coated TCP), (iv) TCP + PCL + AD, (v) TCP + AD + PCL, and (vi) TCP + AD + PCL + AD were tested in the distal femoral defect of Sprague-Dawley rats for 6 and 10 weeks. An excellent bone formation inside the micro and macro pores of the scaffolds was observed from histomorphology. Histomorphometric analysis revealed maximum new bone formation in TCP + AD + PCL scaffolds after 6 weeks. No adverse effect of PCL on bioactivity of TCP and in vivo bone formation was observed. All scaffolds with AD showed higher bone formation and reduced TRAP (tartrate resistant acid phosphatase) positive cells activity compared to bare TCP and TCP coated with only PCL. Bare TCP scaffolds showed the highest TRAP positive cells activity followed by TCP + PCL scaffolds, whereas TCP + AD scaffolds showed the lowest TRAP activity. A higher TRAP positive cells activity was observed in TCP + AD + PCL compared to TCP + AD scaffolds after 6 weeks. Our results show that in vivo local AD delivery from PCL-coated 3DP TCP scaffolds could further induce increased early bone formation.

With the advent of additive manufacturing technologies in the mid 1980s, many applications benefited from the faster processing of products without the need for specific tooling or dies. However, the application of such techniques in the area of biomedical devices has been slow due to the stringent performance criteria and concerns related to reproducibility and part quality, when new technologies are in their infancy. However, the use of additive manufacturing technologies in bone tissue engineering has been growing in recent years. Among the different technology options, three dimensional printing (3DP) is becoming popular due to the ability to directly print porous scaffolds with designed shape, controlled chemistry and interconnected porosity. Some of these inorganic scaffolds are biodegradable and have proven ideal for bone tissue engineering, sometimes even with site specific growth factor/drug delivery abilities. This review article focuses on recent advances in 3D printed bone tissue engineering scaffolds along with current challenges and future directions.