Table of Contents

Special Section: Bioprinting of 3D Functional Tissue Constructs















Regular Section

Review Articles

by Pei Zhuang, Yi-Hua Chiang, Maria Serafim Fernanda, Mei He
329 Views, 34 PDF Downloads

Cancer still ranks as a leading cause of mortality worldwide. Although considerable efforts have been dedicated to anticancer therapeutics, progress is still slow, partially due to the absence of robust prediction models. Multicellular tumor spheroids, as a major three-dimensional (3D) culture model exhibiting features of avascular tumors, gained great popularity in pathophysiological studies and high throughput drug screening. However, limited control over cellular and structural organization is still the key challenge in achieving in vivo like tissue microenvironment. 3D bioprinting has made great strides toward tissue/organ mimicry, due to its outstanding spatial control through combining both cells and materials, scalability, and reproducibility. Prospectively, harnessing the power from both 3D bioprinting and multicellular spheroids would likely generate more faithful tumor models and advance our understanding on the mechanism of tumor progression. In this review, the emerging concept on using spheroids as a building block in 3D bioprinting for tumor modeling is illustrated. We begin by describing the context of the tumor microenvironment, followed by an introduction of various methodologies for tumor spheroid formation, with their specific merits and drawbacks. Thereafter, we present an overview of existing 3D printed tumor models using spheroids as a focus. We provide a compilation of the contemporary literature sources and summarize the overall advancements in technology and possibilities of using spheroids as building blocks in 3D printed tissue modeling, with a particular emphasis on tumor models. Future outlooks about the wonderous advancements of integrated 3D spheroidal printing conclude this review.

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Review Articles

by Ying Lu, Jianbo Song, Xiaohong Yao, Meiwen An, Qinying Shi, Xiaobo Huang
195 Views, 29 PDF Downloads

Bolus is a kind of auxiliary device used in radiotherapy for the treatment of superficial lesions such as skin cancer. It is commonly used to increase skin dose and overcome the skin-sparing effect. Despite the availability of various commercial boluses, there is currently no bolus that can form full contact with irregular surface of patients’ skin, and incomplete contact would result in air gaps. The resulting air gaps can reduce the surface radiation dose, leading to a discrepancy between the delivered dose and planned dose. To avoid this limitation, the customized bolus processed by three-dimensional (3D) printing holds tremendous potential for making radiotherapy more efficient than ever before. This review mainly summarized the recent development of polymers used for processing bolus, 3D printing technologies suitable for polymers, and customization of 3D printing bolus. An ideal material for customizing bolus should not only have the feature of 3D printability for customization, but also possess radiotherapy adjuvant performance as well as other multiple compound properties, including tissue equivalence, biocompatibility, antibacterial activity, and antiphlogosis.

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Review Articles

by Chengxiong Lin, Yaocheng Wang, Zhengyu Huang, Tingting Wu, Weikang Xu, Wenming Wu, Zhibiao Xu
194 Views, 62 PDF Downloads

Conventional bone repair scaffolds can no longer meet the high standards and requirements of clinical applications in terms of preparation process and service performance. Studies have shown that the diversity of filament structures of implantable scaffolds is closely related to their overall properties (mechanical properties, degradation properties, and biological properties). To better elucidate the characteristics and advantages of different filament structures, this paper retrieves and summarizes the state of the art in the filament structure of the three-dimensional (3D) bioprinted biodegradable bone repair scaffolds, mainly including single-layer structure, double-layer structure, hollow structure, core-shell structure and bionic structures. The eximious performance of the novel scaffolds was discussed from different aspects (material composition, ink configuration, printing parameters, etc.). Besides, the additional functions of the current bone repair scaffold, such as chondrogenesis, angiogenesis, anti-bacteria, and anti-tumor, were also concluded. Finally, the paper prospects the future material selection, structural design, functional development, and performance optimization of bone repair scaffolds.

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Original Articles

by Alan Avila-Ramírez, Alexander U. Valle-Perez, Hepi Hari Susapto, Rosario Perez-Pedroza, Giuseppina R. Briola, Abdulelah Alrashoudi, Zainab Khan, Panagiotis Bilalis, Charlotte Hauser
563 Views, 107 PDF Downloads, 10 Supp.File Downloads

 The development of three-dimensional (3D)-printable inks is essential for several applications, from industrial manufacturing to novel applications for biomedical engineering. Remarkably, biomaterials for tissue engineering applications can be expanded to other new horizons; for instance, restoration of rigid living systems as coral reefs is an emergent need derived from recent issues from climate change. The coral reefs have been endangered, which can be observed in the increasing bleaching around the world. Very few studies report eco-friendly inks for matter since most conventional approaches require synthetic polymer, which at some point could be a pollutant depending on the material. Therefore, there is an unmet need for cost-effective formulations from eco-friendly materials for 3D manufacturing to develop carbonate-based inks for coral reef restoration. Our value proposition derives from technologies developed for regenerative medicine, commonly applied for human tissues like bone and cartilage. In our case, we created a novel biomaterial formulation from biopolymers such as gelatin methacrylate, poly (ethylene glycol diacrylate), alginate, and gelatin as scaffold and binder for the calcium carbonate and hydroxyapatite bioceramics needed to mimic the structure of rigid structures. This project presents evidence from 2D/3D manufacturing, chemical, mechanical, and biological characterization, which supports the hypothesis of its utility to aid in the fight to counteract the coral bleaching that affects all the marine ecosystem, primarily when this is supported by solid research in biomaterials science used for living systems, it can extend tissue engineering into new approaches in different domains such as environmental or marine sciences.

Original Articles

by Abdulelah A. Alrashoudi, Hamed I. Albalawi, Ali H. Aldoukhi, Manola Moretti, Panayiotis Bilalis, Malak Abedalthagafi, Charlotte Hauser
286 Views, 66 PDF Downloads, 11 Supp.File Downloads, 55 Supp. File (Video 1) Downloads

 The development of lateral flow immunoassay (LFIA) using three-dimensional (3D) printing and bioprinting technologies can enhance and accelerate the optimization process of the fabrication. Therefore, the main goal of this study is to investigate methods to speed up the developing process of a LFIA as a tool for community screening. To achieve this goal, an in-house developed robotic arm and microfluidic pumps were used to print the proteins during the development of the test. 3D printing technologies were used to design and print the housing unit for the testing strip. The proposed design was made by taking into consideration the environmental impact of this disposable medical device.

Original Articles

by Xiao Zhang, Yang Liu, Qiang Zuo, Qingyun Wang, Zuxi Li, Kai Yan, Tao Yuan, Yi Zhang, Kai Shen, Rui Xie, Weimin Fan
233 Views, 45 PDF Downloads, 10 Supp.File Downloads

Recently, three-dimensional (3D) bioprinting technology is becoming an appealing approach for osteochondral repair. However, it is challenging to develop a bilayered scaffold with anisotropic structural properties to mimic a native osteochondral tissue. Herein, we developed a bioink consisting of decellularized extracellular matrix and silk fibroin to print the bilayered scaffold. The bilayered scaffold mimics the natural osteochondral tissue by controlling the composition, mechanical properties, and growth factor release in each layer of the scaffold. The in vitro results show that each layer of scaffolds had a suitable mechanical strength and degradation rate. Furthermore, the scaffolds encapsulating transforming growth factor-beta (TGF-β) and bone morphogenetic protein-2 (BMP-2) can act as a controlled release system and promote directed differentiation of bone marrow-derived mesenchymal stem cells. Furthermore, the in vivo experiments suggested that the scaffolds loaded with growth factors promoted osteochondral regeneration in the rabbit knee joint model. Consequently, the biomimetic bilayered scaffold loaded with TGF-β and BMP-2 would be a promising strategy for osteochondral repair.

Original Articles

by Ye Li, Kegong Xie, Chong Wang, Chengliang Yang, Ke Huang, Feng Li, Chuanchuan Zheng, Jian Chen, Shujun Dong, Guangfeng Deng, Gege Huang, Qiaoyan Lu, Jia Liu, Kai Li, Yujin Tang, Liqiang Wang
276 Views, 30 PDF Downloads

The rapid development of scaffold-based bone tissue engineering strongly relies on the fabrication of advanced scaffolds and the use of newly discovered functional drugs. As the creation of new drugs and their clinical approval often cost a long time and billions of U.S. dollars, producing scaffolds loaded with repositioned conventional drugs whose biosafety has been verified clinically to treat critical-sized bone defect has gained increasing attention. Carfilzomib (CFZ), an approved clinical proteasome inhibitor with a much fewer side effects, is used to replace bortezomib to treat multiple myeloma. It is also reported that CFZ could enhance the activity of alkaline phosphatase and increase the expression of osteogenic transcription factors. With the above consideration, in this study, a porous CFZ/β-tricalcium phosphate/poly lactic-co-glycolic acid scaffold (designated as “cytidine triphosphate [CTP]”) was produced through cryogenic three-dimensional (3D) printing. The hierarchically porous CTP scaffolds were mechanically similar to human cancellous bone and can provide a sustained CFZ release. The implantation of CTP scaffolds into critical-sized rabbit radius bone defects improved the growth of new blood vessels and significantly promoted new bone formation. To the best of our knowledge, this is the first work that shows that CFZ-loaded scaffolds could treat nonunion of bone defect by promoting osteogenesis and angiogenesis while inhibiting osteoclastogenesis, through the activation of the Wnt/β-catenin signaling. Our results suggest that the loading of repositioned drugs with effective osteogenesis capability in advanced bone tissue engineering scaffold is a promising way to treat critical sized defects of a long bone.

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Original Articles

by Yuecheng Cui, Ronghua Jin, Yifan Zhang, Meirong Yu, Yang Zhou, Li-Qun Wang
231 Views, 43 PDF Downloads, 5 Supp.File Downloads

 The hydrogel formed by polyethylene glycol-aliphatic polyester block copolymers is an ideal bioink and biomaterial ink for three-dimensional (3D) bioprinting because of its unique temperature sensitivity, mild gelation process, good biocompatibility, and biodegradability. However, the gel forming mechanism based only on hydrophilic-hydrophobic interaction renders the stability and mechanical strength of the formed hydrogels insufficient, and cannot meet the requirements of extrusion 3D printing. In this study, cellulose nanocrystals (CNC), which is a kind of rigid, hydrophilic, and biocompatible nanomaterial, were introduced to enhance the hydrogels so as to meet the requirements of extrusion 3D printing. First, a series of poly(ε-caprolactone/lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone/ lactide) (PCLA-PEG-PCLA) triblock copolymers with different molecular weights were prepared. The thermodynamic and rheological properties of CNC-enhanced hydrogels were investigated. The results showed that the addition of CNC significantly improved the thermal stability and mechanical properties of the hydrogels, and within a certain range, the enhancement effect was directly proportional to the concentration of CNC. More importantly, the PCLA-PEG-PCLA hydrogels enhanced by CNC could be extruded and printed through temperature regulation. The printed objects had high resolution and fidelity with effectively maintained structure. Moreover, the hydrogels have good biocompatibility with a high cell viability. Therefore, this is a simple and effective strategy. The addition of the hydrophilic rigid nanoparticles such as CNC improves the mechanical properties of the soft hydrogels which made it able to meet the requirements of 3D bioprinting.

Original Articles

by Shiya Li, Yongxuan Tan, Samuel Willis, Mohanad Bahshwan, Joseph Folkes, Livia Kalossaka, Usman Waheed, Connor Myant
310 Views, 34 PDF Downloads

Respiratory protective equipment (RPE) is traditionally designed through anthropometric sizing to enable mass production. However, this can lead to long-standing problems of low-compliance, severe skin trauma, and higher fit test failure rates among certain demographic groups, particularly females and non-white ethnic groups. Additive manufacturing could be a viable solution to produce custom-fitted RPE, but the manual design process is time-consuming, cost-prohibitive and unscalable for mass customization. This paper proposes an automated design pipeline which generates the computer-aided design models of custom-fit RPE from unprocessed three-dimensional (3D) facial scans. The pipeline successfully processed 197 of 205 facial scans with <2 min/scan. The average and maximum geometric error of the mask were 0.62 mm and 2.03 mm, respectively. No statistically significant differences in mask fit were found between male and female, Asian and White, White and Others, Healthy and Overweight, Overweight and Obese, Middle age, and Senior groups.

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Original Articles

by Yucheng Mei, Chengzu He, Chunxia Gao, Peizhi Zhu, Guanming Lu, Hongmian Li
270 Views, 34 PDF Downloads

In this study, porous polylactic acid/methotrexate (PLA/MTX) scaffolds were successfully fabricated by three-dimensional (3D) printing technology as controllable drug delivery devices to suppress tumor growth. Scanning electron microscopy and energy-dispersive spectrometer confirmed that MTX drug was successfully incorporated into the PLA filament. 3D-printed PLA/MTX scaffolds allow sustained release of drug molecules in vitro for more than 30 days, reducing systemic toxic side effects caused by injection or oral administration. In vitro cytotoxicity assay revealed that PLA/MTX scaffolds have a relatively high inhibitory effect on the tumor cells (MG-63, A549, MCF-7, and 4T1) and relatively low toxic effect on the normal MC3T3-E1 cells. Furthermore, results of in vivo experiments confirmed that PLA/MTX scaffolds highly suppressed tumor growth and no obvious side effects on the organs. All these results suggested that 3D-printed PLA/MTX scaffolds could be used as controllable drug delivery systems for tumor suppression.

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Original Articles

by Laszlo Jaksa, Dieter Pahr, Gernot Kronreif, Andrea Lorenz
237 Views, 37 PDF Downloads

Anatomic models are important in medical education and pre-operative planning as they help students or doctors prepare for real scenarios in a risk-free way. Several experimental anatomic models were made with additive manufacturing techniques to improve geometric, radiological, or mechanical realism. However, reproducing the mechanical behavior of soft tissues remains a challenge. To solve this problem, multi-material structuring of soft and hard materials was proposed in this study, and a three-dimensional (3D) printer was built to make such structuring possible. The printer relies on extrusion to deposit certain thermoplastic and silicone rubber materials. Various objects were successfully printed for testing the feasibility of geometric features such as thin walls, infill structuring, overhangs, and multi-material interfaces. Finally, a small medical image-based ribcage model was printed as a proof of concept for anatomic model printing. The features enabled by this printer offer a promising outlook on mimicking the mechanical properties of various soft tissues.

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Original Articles

by Amelia Yilin Lee, Aakanksha Pant, Kanitthamniyom Pojchanun, Cheng Pau Lee, Jia An, Michinao Hashimoto, U-Xuan Tan, Chen Huei Leo, Gladys Wong, Chee Kai Chua, Yi Zhang
395 Views, 100 PDF Downloads, 17 Supp.File Downloads

Three-dimensional food printing offers the possibility of modifying the structural design, nutrition, and texture of food, which may be used for consumers with special dietary requirements such as dysphagic patients. One of the food matrices that can be used for liquid delivery to dysphagic patients is food foams. Foams are widely used in different food products to adjust food density, rheological properties, and texture. Foams allow the food to stay in the mouth for sufficient time to provide hydration while minimizing the danger of choking. Our work studies the foam properties and printability of both egg white foams and eggless foams with a strong focus on their foaming properties, rheological properties, printability, and suitability for dysphagic patients. Food hydrocolloid, xanthan gum (XG), is added to improve foam stability and rheological properties so that the inks are printable. Rheological and syneresis properties of the pre-printed foam inks are examined. The texture profile and microstructure properties are studied post-printing. International dysphagia diet standardization initiative tests are carried out to assess the inks’ potential for dysphagic diets. Inks with XG performed better with minimal water seepage, better foam stability, and excellent printability. This suggests that hydrocolloids lead to more stable food foams that are suitable for 3DFP and safe for hydration delivery to dysphagic patients.

Original Articles

by Ali Zolfagharian, Mohammad Lakhi, Sadegh Ranjbar, Mahdi Bodaghi
462 Views, 186 PDF Downloads

This study introduces a design procedure for improving an individual’s footwear comfort with body weight index and activity requirements by customized three-dimensional (3D)-printed shoe midsole lattice structure. This method guides the selection of customized 3D-printed fabrications incorporating both physical and geometrical properties that meet user demands. The analysis of the lattice effects on minimizing the stress on plantar pressure was performed by initially creating various shoe midsole lattice structures designed. An appropriate common 3D printable material was selected along with validating its viscoelastic properties using finite element analysis. The lattice structure designs were analyzed under various loading conditions to investigate the suitability of the method in fabricating a customized 3D-printed shoe midsole based on the individual’s specifications using a single material with minimum cost, time, and material use.

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Original Articles

by Zhouquan Fu, Vincent Angeline, Wei Sun
590 Views, 34 PDF Downloads, 8 Supp.File Downloads

Bioprinting is an emerging technology for the construction of complex three-dimensional (3D) constructs used in various biomedical applications. One of the challenges in this field is the delicate manipulation of material properties and various disparate printing parameters to create structures with high fidelity. Understanding the effects of certain parameters and identifying optimal parameters for creating highly accurate structures are therefore a worthwhile subject to investigate. The objective of this study is to investigate high-impact print parameters on the printing printability and develop a preliminary machine learning model to optimize printing parameters. The results of this study will lead to an exploration of machine learning applications in bioprinting and to an improved understanding between 3D printing parameters and structural printability. Reported results include the effects of rheological property, nozzle gauge, nozzle temperature, path height, and ink composition on the printability of Pluronic F127. The developed Support Vector Machine model generated a process map to assist the selection of optimal printing parameters to yield high quality prints with high probability (>75%). Future work with more generalized machine learning models in bioprinting is also discussed in this article. The finding of this study provides a simple tool to improve printability of extrusion-based bioprinting with minimum experimentations.