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Special Section: 3D Printing and Bioprinting for the Future of Healthcare

Guest Editors: Associate Professor Wai Yee Yeong, Dr. Shweta Agarwala & Dr. Lifeng Kang

Original research article

by Li Tian, Jianmin Zheng, Yiyu Cai, Muhammad Faaiz Khan Bin Abdul Halil, Nadia Magnenat Thalmann, Daniel Thalmann, Hanhui Li

Current research of designing prosthetic robotic hands mainly focuses on improving their functionality by devising new mechanical structures and actuation systems. Most of existing work relies on a single structure/system (e.g., bone-only or tissue-only) and ignores the fact that the human hand is composed of multiple functional structures (e.g., skin, bones, muscles, and tendons). This may increase the difficulty of the design process and lower the flexibility of the fabricated hand. To tackle this problem, this paper proposes a three-dimensional (3D) printable multi-layer design that models the hand with the layers of skin, tissues, and bones. The proposed design first obtains the 3D surface model of a target hand via 3D scanning, and then generates the 3D bone models from the surface model based on a fast template matching method. To overcome the disadvantage of the rigid bone layer in deformation, the tissue layer is introduced and represented by a concentric tube based structure, of which the deformability can be explicitly controlled by a parameter. The experimental results show that the proposed design outperforms previous designs remarkably. With the proposed design, prosthetic robotic hands can be produced quickly with low cost and be customizable and deformable.

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Original research article

by Wei Long Ng, Xi Huang, Viktor Shkolnikov, Guo Liang Goh, Ratima Suntornnond, Wai Yee Yeong

Three-dimensional (3D) bioprinting systems serve as advanced manufacturing platform for the precise deposition of cells and biomaterials at pre-defined positions. Among the various bioprinting techniques, the drop-on-demand jetting approach facilitates deposition of pico/nanoliter droplets of cells and materials for study of cell-cell and cell-matrix interactions. Despite advances in the bioprinting systems, there is a poor understanding of how the viability of primary human cells within sub-nanoliter droplets is affected during the printing process. In this work, a thermal inkjet system is utilized to dispense sub-nanoliter cell-laden droplets, and two key factors – droplet impact velocity and droplet volume – are identified to have significant effect on the viability and proliferation of printed cells. An increase in the cell concentration results in slower impact velocity, which leads to higher viability of the printed cells and improves the printing outcome by mitigating droplet splashing. Furthermore, a minimum droplet volume of 20 nL per spot helps to mitigate evaporation-induced cell damage and maintain high viability of the printed cells within a printing duration of 2 min. Hence, controlling the droplet impact velocity and droplet volume in sub-nanoliter bioprinting is critical for viability and proliferation of printed human primary cells.

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Original research article

by Mick Iversen, Monisha Monisha, Shweta Agarwala

Wound healing is a complex and dynamic regeneration process, wherein the physical and chemical parameters are continuously changing. Its management and monitoring can provide immense benefits, especially for bed-ridden patients. This work reports a low-cost, flexible, and fully printed on-skin patch sensor to measure the change in pH and fluid content in a wound. Such a bendable sensor can also be easily incorporated in a wound dressing. The sensor consists of different electrodes printed on polydimethylsiloxane (PDMS) substrate for pH and moisture sensing. The fabricated sensor patch has a sensitivity of 7.1 ohm/pH for wound pH levels. The hydration sensor results showed that moisture levels on a semi-porous surface can be quantified through resistance change.

Original research article

by Miriam Seiti, Paola Serena Ginestra, Rosalba Monica Ferraro, Silvia Giliani, Rosaria Maria Vetrano, Elisabetta Ceretti, Eleonora Ferraris

In neural tissue engineering (NTE), topographical, electrical, mechanical and/or biochemical stimulations are established methods to regulate neural cell activities in in vitro cultures. Aerosol Jet® Printing is here proposed as enabling technology to develop NTE integrated devices for electrically combined stimulations. The printability of a poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT: PSS) commercial ink onto a reference substrate was firstly investigated and the effect of the process parameters on the quality of printed lines was analyzed. The study was then extended for printing thick electrodes and interconnects; the print strategy was finally transferred to a silicon-based wafer with patterned microchannels of proven cellular adhesion and topographical guidance. The results showed values of electrical resistance equal to ~16 Ω for printed electrodes which are ~33 μm thick and ~2 mm wide. The electrical impedance of the final circuit in saline solution was detected in the range of 1 – 2 kΩ at 1 kHz, which is in line with the expectations for bioelectronic neural interfaces. However, cells viability assays on the commercial PEDOT: PSS ink demonstrated a dose dependent cytotoxic behavior. The potential cause is associated with the presence of a cytotoxic co-solvent in the ink’s formulation, which is released in the medium culture, even after a post-sintering process on the printed electrodes. This work is a first step to develop innovative in vitro NTE devices via a printed electronic approach. It also sheds new insights the transfer of AJ® print strategies across different substrates, and biocompatibility of commercial PEDOT: PSS inks.

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Original research article

by Yuchun Liu, Swee Leong Sing, Rebecca Xin En Lim, Wai Yee Yeong, Bee Tin Goh

Additive manufacturing has proven to be a viable alternative to conventional manufacturing methodologies for metallic implants due to its capability to customize and fabricate novel and complex geometries. Specific to its use in dental applications, various groups have reported successful outcomes for customized root-analog dental implants in preclinical and clinical studies. However, geometrical accuracy of the fabricated samples has never been analyzed. In this article, we studied the geometric accuracy of a 3D printed titanium dental implant design against the tooth root of the monkey maxilla incisor. Monkey maxillas were scanned using cone-beam computed tomography, then segmentation of the incisor tooth roots was performed before the fabrication of titanium dental implants using a laser powder bed fusion (PBF) process. Our results showed 68.70% ± 5.63 accuracy of the 3D printed dental implant compared to the actual tooth (n = 8), where main regions of inaccuracies were found at the tooth apex. The laser PBF fabrication process of the dental implants showed a relatively high level of accuracy of 90.59% ± 4.75 accuracy (n = 8). Our eventual goal is to develop an accurate workflow methodology to support the fabrication of patient-specific 3D-printed titanium dental implants that mimic patients’ tooth anatomy and fit precisely within the socket upon tooth extraction. This is essential for promoting primary stability and osseointegration of dental implants in the longer term.

Perspective article

by Swee Leong Sing

“Stress shielding” caused by the mismatch of modulus between the implant and natural bones, is one of the major problems faced by current commercially used biomedical materials. Beta-titanium (β-Ti) alloys are a class of materials that have received increased interest in the biomedical field due to their relatively low elastic modulus and excellent biocompatibility. Due to their lower modulus, β-Ti alloys have the potential to reduce “stress shielding.” Powder bed fusion (PBF), a category of additive manufacturing, or more commonly known as 3D printing techniques, has been used to process β-Ti alloys. In this perspective article, the emerging research of PBF of β-Ti alloys is covered. The potential and limitations of using PBF for these materials in biomedical applications are also elucidated with focus on the perspectives from processes, materials, and designs. Finally, future trends and potential research topics are highlighted.

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Regular Section

Original research article

by Guibin Lou, Ya Chen, Junwei Xu, Yingjuan Qian, Haixia Cheng, Zhen Wei, Youwen Yang, Lida Shen, Cijun Shuai

Graphene oxide (GO) is recognized as a promising antibacterial material that is expected to be used to prepare a new generation of high-efficiency antibacterial coatings. The propensity of GO to agglomeration makes it difficult to apply it effectively. A new method of preparing GO-loaded nickel (GNC) with excellent antibacterial property is proposed in this paper. In this work, GNC was prepared on a titanium sheet by magnetic field-assisted scanning jet electrodeposition. The massive introduction of GO on the coating was proven by energy disperse spectroscopy and Raman spectroscopy. The antibacterial performance of GNC was proven by agar plate assessment and cell living/dead staining. The detection of intracellular reactive oxygen species (ROS) and the concentration of nickel ions, indicate that the antibacterial property of GNC are not entirely derived from the nickel ions released by the coating and the intracellular ROS induced by nickel ions, but rather are due to the synergistic effect of nickel ions and GO.

Original research article

by Jingzhou Yang, Hairui Gao, Dachen Zhang, Xia Jin, Faqiang Zhang, Shupei Zhang, Haishen Chen, Xiaopeng Li
Additively manufactured trabecular tantalum (Ta) scaffolds are promising bone repair materials for load-bearing applications due to their good pore interconnectivity. However, a thorough mechanical behavior evaluation is required before conducting animal studies and clinical research using these scaffolds. In this study, we revealed the compressive mechanical behavior and material failure mechanism of trabecular tantalum scaffolds by compression testing, finite element analysis (FEA), and scanning electron microscopy (SEM). Trabecular tantalum scaffolds with porosities of 65%, 75%, and 85% were fabricated by laser powder bed fusion-based additive manufacturing. Porosity has a significant effect on their compressive mechanical properties. As the porosity decreased from 85% to 65%, the compressive yield strength and elastic modulus increased from 11.9 MPa to 35.7 MPa and 1.1 GPa to 3.0 GPa, respectively. Compression testing results indicate that trabecular tantalum scaffolds demonstrate ductile deformation and excellent mechanical reliability. No macroscopic cracks were found when they were subjected to strain up to 50%. SEM observations showed that material failure results from tantalum strut deformation and fracture. Most microcracks occurred at conjunctions, whereas few of them appear on the struts. FEA-generated compressive stress distribution and material deformation were consistent with experimental results. Stress concentrates at strut conjunctions and vertical struts, where fractures occur during compression testing, indicating that the load-bearing capability of trabecular tantalum scaffolds can be enhanced by strengthening strut conjunctions and vertical struts. Therefore, additively manufactured trabecular tantalum scaffolds can be used in bone tissue reconstruction applications.
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Original research article

by Leonie Waldburger, Romain Schaller, Christina Furthmüller, Lorena Schrepfer, Dirk J. Schaefer, Alexandre Kaempfen

In this randomized controlled pilot trial, we compared three-dimensional (3D)-printed made-to-measure splints to conventional custom-made thermoplastic splints. In a clinical setting, we evaluated their general applicability and possible benefits for immobilization in hand surgical patients. We included 20 patients with an indication for immobilization of at least 4 weeks, regardless of the splint design. Patient comfort and satisfaction were assessed with questionnaires at splint fitting, as well as 2 and 4–6 weeks later. The 3D splints were designed and printed in-house with polylactic acid from a 3D surface scan. Our data suggest that 3D-printed splinting is feasible, and patient satisfaction ratings were similar for 3D-printed and thermoplastic splints. The 3D splint production process needs to be optimized and other materials need to be tested before routine implementation is possible or more patients can be enrolled in further studies. Validated quality assessment tools for current splinting are lacking, and further investigation is necessary.

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Original research article

by Chun-Li Lin, Yu-Tzu Wang, Chun-Ming Chang, Cheng-Hsien Wu, Wei-Heng Tsai

This study developed design criterion for patient-specific reconstructed implants with appearance consideration and structural optimization of various mandibular continuity defects. The different mandible continuity defects include C (from left to right canines), B (from 1st premolar to 3rd molar), and A (from 3rd molar to ramus) segments defined based on the mandible image. The finite element (FE) analysis and weighted topology optimization methods were combined to design internal support beam structures within different reconstructed implants with corresponding occlusal conditions. Five continuity mandibular defects (single B/C/A+B and combination of B+C and B+C+B segments) were restored using additive manufacturing (AM) reconstructed implant and bone plate to confirm reasonable design criterion through biomechanical fatigue testing. The worst mandible strength was filtered based on the material mechanics and results from segmental bone length, thickness, and height statistics from the established database containing mandible images of 105 patients. The weighted optimization analysis results indicated that the sizes and positions of internal supporting beams within the reconstructed C, B, and A+B implants can be defined parametrically through corresponding segmental bone length, width, and height. The FE analysis found that the weight variation percentage between the parametric designed implants and original core solid implants in the C, B, and A+B was reduced by 54.3%, 63.7%, and 69.7%, respectively. The maximum stress values of the reconstructed implant and the remaining bone were not obviously reduced but the stress values were far lower than the material ultimate strength. The biomechanical fatigue testing indicated that all cases using the AM reconstructed implant could pass the 250,000 dynamic load. However, condyle head, bone plate fracture, and bone screw loosening could be found in cases using bone plates. This study developed a design criterion for patient-specific reconstructed implants for various mandibular continuity defects applicable for AM to further clinical use.

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Original research article

by Patiguli Aihemaiti, Houfeng Jiang, Aiyiti Wurikaixi, Ayiguli Kasimu

The building parameters of three-dimensional (3D) printed polylactic acid/hydroxyapatite (HA) composite bone plates were optimized by an orthogonal experiment, and the effects of the layer thickness, printing speed, filament feeding speed, and HA content on the bending strengths of the specimens were analyzed. The deformation characteristics of the specimens were studied by 3D full-field strain analysis, and the internal defects of the specimens were analyzed. The effects of different combinations of the process parameters on the cross-sectional shape of the single deposited line, printing temperature, and pressure of the molten material were further analyzed. The results showed that the factors affecting the bending properties were the layer thickness, printing speed, filament feeding speed, and HA content, successively. The optimized process parameters were an HA content of 10%, a layer thickness of 0.1 mm, a printing speed of 30 mm/s, and a filament feeding speed of 0.8 mm/s, and the optimized specimen bending strength was 103.1 ± 5.24 MPa. The deposited line with a flat section shape and width greater than the print spacing helped to reduce the porosity of the specimens. The process parameters that resulted in large high-temperature areas and a high extrusion pressure could better promote material fusion.

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Original research article

by Kai Yao, Jie Sun, Kaizhu Huang, Linzhi Jing, Hang Liu, Dejian Huang, Curran Jude

Fibrous scaffolds have been extensively used in three-dimensional (3D) cell culture systems to establish in vitro models in cell biology, tissue engineering, and drug screening. It is a common practice to characterize cell behaviors on such scaffolds using confocal laser scanning microscopy (CLSM). As a noninvasive technology, CLSM images can be utilized to describe cell-scaffold interaction under varied morphological features, biomaterial composition, and internal structure. Unfortunately, such information has not been fully translated and delivered to researchers due to the lack of effective cell segmentation methods. We developed herein an end-to-end model called Aligned Disentangled Generative Adversarial Network (AD-GAN) for 3D unsupervised nuclei segmentation of CLSM images. AD-GAN utilizes representation disentanglement to separate content representation (the underlying nuclei spatial structure) from style representation (the rendering of the structure) and align the disentangled content in the latent space. The CLSM images collected from fibrous scaffold-based culturing A549, 3T3, and HeLa cells were utilized for nuclei segmentation study. Compared with existing commercial methods such as Squassh and CellProfiler, our AD-GAN can effectively and efficiently distinguish nuclei with the preserved shape and location information. Building on such information, we can rapidly screen cell-scaffold interaction in terms of adhesion, migration and proliferation, so as to improve scaffold design.

Original research article

by S Lopez de Armentia, S Fernández-Villamarín, Y. Ballesteros, J.C. del Real, N. Dunne, E. Paz

Additive manufacturing is gaining importance thanks to its multiple advantages. Stereolithography (SLA) shows the highest accuracy and the lowest anisotropy, which has facilitated the emergence of new applications as dentistry or tissue engineering. However, the availability of commercial photopolymers is still limited, and there is an increasing interest in developing resins with properties adapted for these new applications. The addition of graphene-based nanomaterials (GBN) may provide interesting advantages, such as improved mechanical properties and bioactivity. However, there is a lack of knowledge regarding the effect of GBNs on the polymerization reaction. A photopolymerizable acrylic resin has been used, and the effect of the addition of 0.1wt% of graphene (G); graphene oxide (GO) and graphite nanoplatelets (GoxNP) on printability and polymerization have been investigated. It was observed that the effect depended on GBN type, functionalization and structure (e.g., number of layers, size, and morphology) due to differences in the extent of dispersion and light absorbance. The obtained results showed that GO and GoxNP did not significantly affect the printability and quality of the final structure, whilst the application of G exhibited a negative effect in terms of printability due to a reduction in the polymerization degree. GO and GoxNP-loaded resins showed a great potential to be used for manufacturing structures by SLA.

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Original research article

by Haowen Liang, Yue Wang, Shangsi Chen, Yang Liu, Zhengbai Liu, Jiaming Bai

The morphologies and structures of the scaffold have a significant influence on their mechanical and biological properties. In this work, different types of porous structures: Triply periodic minimal surface-Schwarz primitive (P), body centered cubic, and cubic pore-shaped (CPS) hydroxyapatite scaffolds with ~70% porosity were fabricated through digital light processing (DLP) 3D printing technology. The compressive properties and in vitro cell evaluations such as cell proliferation and attachment morphology of these scaffolds were systematically compared. The results showed that the CPS scaffolds exhibited the highest compressive strength (~22.5 MPa) and modulus (~400 MPa). In addition, the CPS scaffolds also performed the most active cell metabolisms as compared to other two structures, which may account for the larger pore size and smaller curvature of the substrate. This study provides a general guidance for the fabrication and selection of porous bone scaffolds processed by DLP 3D printing.

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Review article

by Yan Zhou, Jingwen Wang, Youwen Yang, Mingli Yang, Haizhong Zheng, Deqiao Xie, Dongsheng Wang, Lida Shen

Biodegradable zinc (Zn) is expected to be used in clinical application like bone tissue engineering scaffolds, since it possesses favorable biocompatibility and suitable degradation rate. Laser powder bed fusion (LPBF), which is a typical additive manufacturing technique, offers tremendous advantages in fabricating medical devices with personalized geometric shape and complex porous structure. Therefore, the combination of LPBF and biodegradable Zn has gained intensive attention and also achieved rapid development in recent years. However, it severely challenges the formation quality and resultant performance of LPBF-processed Zn-based materials, due to the evaporation and element loss during laser processing. In this study, the current research status and future research trends for LPBF of Zn-based implants are reviewed from comprehensive viewpoints including formation quality, microstructure feature, and performance. The influences of powder characteristics and process parameters on formation quality are described systematically. The microstructure evolution, mechanical properties, as well as the degradation behavior are also discussed. Finally, the research perspectives for LPBF of Zn are summarized, aiming to provide guideline for future study.

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