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Among different treatments of critical-sized bone defects, bone tissue engineering (BTE) is a fast-developing strategy centering around the fabrication of scaffolds that can stimulate tissue regeneration and provide mechanical support at the same time. This area has seen an extensive application of bioceramics, such as calcium phosphate, for their bioactivity and resemblance to the composition of natural bones. Moreover, recent advances in additive manufacturing (AM) have unleashed enormous potential in the fabrication of BTE scaffolds with tailored porous structures as well as desired biological and mechanical properties. Robocasting is an AM technique that has been widely applied to fabricate calcium phosphate scaffolds, but most of these scaffolds do not meet the mechanical requirements for load-bearing BTE scaffolds. In light of this challenge, various approaches have been utilized to mechanically strengthen the scaffolds. In this review, the current state of knowledge and existing research on robocasting of calcium phosphate scaffolds are presented. Applying the Gibson-Ashby model, this review provides a meta-analysis from the published literature of the compressive strength of robocast calcium phosphate scaffolds. Furthermore, this review evaluates different approaches to the mechanical strengthening of robocast calcium phosphate scaffolds. The aim of this review is to provide insightful data and analysis for future research on mechanical strengthening of robocast calcium phosphate scaffolds and ultimately for their clinical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Any opinions, findings and conclusions or recommendations expressed in this material are those of the author(s) and do not reflect the views of the A*STAR., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The design and fabrication of tissue engineering scaffolds is a highly complex process. In order to provide a proper architecture for cells to grow, proliferate, and differentiate to form tissues, scaffolds have to be made with suitable properties. However, the limited structural designs and conventional fabrication techniques severely cripple the improvement of scaffold properties. To overcome these limitations, many researchers have recently adopted computational methods combined with 3D printing techniques as a new approach for scaffold design and fabrication. This approach allows scaffolds to be designed and fabricated with highly complex microstructures and good control and accuracy. Previous works have also shown this approach to be a very useful tool to predict the scaffold properties and to optimize the scaffold designs with a great reduction of experimental iterations. As this approach combining computational methods and 3D printing techniques for scaffold design and fabrication has many advantages over the conventional trial-and-error based approach, it is imperative to provide a state-of-the-art review on the topic. To this end, this article reviews the various applications of computational methods in scaffold design and simulation; it also briefly reviews the application of 3D printing techniques to fabricate the computationally designed scaffolds. Finally, the limitations and future trends of this approach are discussed. Overall, this review will enable readers to understand the benefits of using computational methods coupled with 3D printing to design and fabricate scaffolds, and thus help researchers to improve and optimize the scaffold properties for future tissue engineering research. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1329-1351, 2019., (© 2018 wiley periodicals, inc.)

Several attempts have been made to fabricate esophageal tissue engineering scaffolds. However, most of these scaffolds possess randomly oriented fibres and uncontrollable pore sizes. In order to mimic the native esophageal tissue structure, electro-hydrodynamic jetting (e-jetting) was used in this study to fabricate scaffolds with aligned fibres and controlled pore size. A hydrophilic additive, Pluronic F127 (F127), was blended with polycaprolactone (PCL) to improve the wettability of the scaffolds and hence the cell adhesion. PCL/F127 composite scaffolds with different weight ratios (0-12%) were fabricated. The wettability, phase composition, and the mechanical properties of the fabricated scaffolds were investigated. The results show that the e-jetted scaffolds have controllable fibres orientated in two perpendicular directions, which are similar to the human esophagus structure and suitable pore size for cell infiltration. In addition, the scaffolds with 8% F127 exhibited better wettability (contact angle of 14°) and an ultimate tensile strength (1.2 MPa) that mimics the native esophageal tissue. Furthermore, primary human esophageal fibroblasts were seeded on the e-jetted scaffolds. PCL/F127 scaffolds showed enhanced cell proliferation and expression of the vascular endothelial growth factor (VEGF) compared to pristine PCL scaffolds (1.5- and 25.8- fold increase, respectively; P < 0.001). An in vitro wound model made using the PCL/F127 scaffolds showed better cell migration than the PCL scaffolds. In summary, the PCL/F127 e-jetted scaffolds offer a promising strategy for the esophagus tissue repair.

3D bioprinting is a pioneering technology that enables fabrication of biomimetic, multiscale, multi-cellular tissues with highly complex tissue microenvironment, intricate cytoarchitecture, structure-function hierarchy, and tissue-specific compositional and mechanical heterogeneity. Given the huge demand for organ transplantation, coupled with limited organ donors, bioprinting is a potential technology that could solve this crisis of organ shortage by fabrication of fully-functional whole organs. Though organ bioprinting is a far-fetched goal, there has been a considerable and commendable progress in the field of bioprinting that could be used as transplantable tissues in regenerative medicine. This paper presents a first-time review of 3D bioprinting in regenerative medicine, where the current status and contemporary issues of 3D bioprinting pertaining to the eleven organ systems of the human body including skeletal, muscular, nervous, lymphatic, endocrine, reproductive, integumentary, respiratory, digestive, urinary, and circulatory systems were critically reviewed. The implications of 3D bioprinting in drug discovery, development, and delivery systems are also briefly discussed, in terms of in vitro drug testing models, and personalized medicine. While there is a substantial progress in the field of bioprinting in the recent past, there is still a long way to go to fully realize the translational potential of this technology. Computational studies for study of tissue growth or tissue fusion post-printing, improving the scalability of this technology to fabricate human-scale tissues, development of hybrid systems with integration of different bioprinting modalities, formulation of new bioinks with tuneable mechanical and rheological properties, mechanobiological studies on cell-bioink interaction, 4D bioprinting with smart (stimuli-responsive) hydrogels, and addressing the ethical, social, and regulatory issues concerning bioprinting are potential futuristic focus areas that would aid in successful clinical translation of this technology., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Three-dimensional (3D) bioprinting is an advanced technology to fabricate artificial 3D tissue constructs containing cells and hydrogels for tissue engineering and regenerative medicine. Nanocomposite reinforcement endows hydrogels with superior properties and tailored functionalities. A broad range of nanomaterials, including silicon-based, ceramic-based, cellulose-based, metal-based, and carbon-based nanomaterials, have been incorporated into hydrogel networks with encapsulated cells for improved performances. This review emphasizes the recent developments of cell-laden nanocomposite bioinks for 3D bioprinting, focusing on their reinforcement effects and mechanisms, including viscosity, shear-thinning property, printability, mechanical properties, structural integrity, and biocompatibility. The cell-material interactions are discussed to elaborate on the underlying mechanisms between the cells and the nanomaterials. The biomedical applications of cell-laden nanocomposite bioinks are summarized with a focus on bone and cartilage tissue engineering. Finally, the limitations and challenges of current cell-laden nanocomposite bioinks are identified. The prospects are concluded in designing multi-component bioinks with multi-functionality for various biomedical applications. 3D bioprinting, an emerging technology of additive manufacturing, has been one of the most innovative tools for tissue engineering and regenerative medicine. Recent developments of cell-laden nanocomposite bioinks for 3D bioprinting, and cell-materials interactions are the subject of this review paper. The reinforcement effects and mechanisms of nanocomposites on viscosity, printability and biocompatibility of bioinks and 3D printed scaffolds are addressed mainly for bone and cartilage tissue engineering. It provides detailed information for further designing and optimizing multi-component bioinks with multi-functionality for specialized biomedical applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Bioprinting three‐dimensional (3D) tissue equivalents have progressed tremendously over the last decade. 3D bioprinting is currently being employed to develop larger and more physiologic tissues, and it is of particular interest to generate vasculature in biofabricated tissues to aid better perfusion and transport of nutrition. Having an advantage over manual culture systems by bringing together biological scaffold materials and cells in precise 3D spatial orientation, bioprinting could assist in placing endothelial cells in specific spatial locations within a 3D matrix to promote vessel formation at these predefined areas. Hence, in the present study, we investigated the use of bioprinting to generate tissue‐level capillary‐like networks in biofabricated tissue constructs. First, we developed a bioink using collagen type‐1 supplemented with xanthan gum (XG) as a thickening agent. Using a commercial extrusion‐based multi‐head bioprinter and collagen‐XG bioink, the component cells were spatially assembled, wherein the endothelial cells were bioprinted in a lattice pattern and sandwiched between bioprinted fibroblasts layers. 3D bioprinted constructs thus generated were stable, and maintained structural shape and form. Post‐print culture of the bioprinted tissues resulted in endothelial sprouting and formation of interconnected capillary‐like networks within the lattice pattern and between the fibroblast layers. Bioprinter‐assisted spatial placement of endothelial cells resulted in fabrication of patterned prevascularized constructs that enable potential regenerative applications in the future. [ABSTRACT FROM AUTHOR]

The incidence of peripheral nerve injuries is on the rise and the current gold standard for treatment of such injuries is nerve autografting. Given the severe limitations of nerve autografts which include donor site morbidity and limited supply, neural guide conduits (NGCs) are considered as an effective alternative treatment. Conductivity is a desired property of an ideal NGC. Reduced graphene oxide (rGO) possesses several advantages in addition to its conductive nature such as high surface area to volume ratio due to its nanostructure and has been explored for its use in tissue engineering. However, most of the works reported are on traditional 2D culture with a layer of rGO coating, while the native tissue microenvironment is three‐dimensional. In this study, PCL/rGO scaffolds are fabricated using electrohydrodynamic jet (EHD‐jet) 3D printing method as a proof of concept study. Mechanical and material characterization of the printed PCL/rGO scaffolds and PCL scaffolds was done. The addition of rGO results in softer scaffolds which is favorable for neural differentiation. In vitro neural differentiation studies using PC12 cells were also performed. Cell proliferation was higher in the PCL/rGO scaffolds than the PCL scaffolds. Reverse transcription polymerase chain reaction and immunocytochemistry results reveal that PCL/rGO scaffolds support neural differentiation of PC12 cells. [ABSTRACT FROM AUTHOR]

The prevalence of peripheral nerve injuries resulting in loss of motor function, sensory function, or both, is on the rise. Artificial Nerve Guide Conduits (NGCs) are considered an effective alternative treatment for autologous nerve grafts, which is the current gold-standard for treating peripheral nerve injuries. In this study, Polycaprolactone-based three-dimensional porous NGCs are fabricated using Electrohydrodynamic jet 3D printing (EHD-jetting) for the first time. The main advantage of this technique is that all the scaffold properties, namely fibre diameter, pore size, porosity, and fibre alignment, can be controlled by tuning the process parameters. In addition, EHD-jetting has the advantages of customizability, repeatability, and scalability. Scaffolds with five different pore sizes (125 to 550 μm) and porosities (65 to 88%) are fabricated and the effect of pore size on the mechanical properties is evaluated. In vitro degradation studies are carried out to investigate the degradation profile of the scaffolds and determine the influence of pore size on the degradation rate and mechanical properties at various degradation time points. Scaffolds with a pore size of 125 ± 15 μm meet the requirements of an optimal NGC structure with a porosity greater than 60%, mechanical properties closer to those of the native peripheral nerves, and an optimal degradation rate matching the nerve regeneration rate post-injury. The in vitro neural differentiation studies also corroborate the same results. Cell proliferation was highest in the scaffolds with a pore size of 125 ± 15 μm assessed by the PrestoBlue assay. The Reverse Transcription-Polymerase Chain Reaction (RT-PCR) results involving the three most important genes concerning neural differentiation, namely β3-tubulin, NF-H, and GAP-43, confirm that the scaffolds with a pore size of 125 ± 15 μm have the highest gene expression of all the other pore sizes and also outperform the electrospun Polycaprolactone (PCL) scaffold. The immunocytochemistry results, expressing the two important nerve proteins β3-tubulin and NF200, showed directional alignment of the neurite growth along the fibre direction in EHD-jet 3D printed scaffolds. [ABSTRACT FROM AUTHOR]