3D printing alias additive manufacturing can transform 3D virtual models created by computer-aided design (CAD) into physical 3D objects in a layer-by-layer manner dispensing with conventional molding or machining. Since the incipiency, significant advancements have been achieved in understanding the process of 3D printing and the relationship of component, structure, property and application of the created objects. Because hydrogels are one of the most feasible classes of ink materials for 3D printing and this field has been rapidly advancing, this Review focuses on hydrogel designs and development of advanced hydrogel-based biomaterial inks and bioinks for 3D printing. It covers 3D printing techniques including laser printing (stereolithography, two-photon polymerization), extrusion printing (3D plotting, direct ink writing), inkjet printing, 3D bioprinting, 4D printing and 4D bioprinting. It provides a comprehensive overview and discussion of the tailorability of material, mechanical, physical, chemical and biological properties of hydrogels to enable advanced hydrogel designs for 3D printing. The range of hydrogel-forming polymers covered encompasses biopolymers, synthetic polymers, polymer blends, nanocomposites, functional polymers, and cell-laden systems. The representative biomedical applications selected demonstrate how hydrogel-based 3D printing is being exploited in tissue engineering, regenerative medicine, cancer research, in vitro disease modeling, high-throughput drug screening, surgical preparation, soft robotics and flexible wearable electronics. Incomparable by thermoplastics, thermosets, ceramics and metals, hydrogel-based 3D printing is playing a pivotal role in the design and creation of advanced functional (bio)systems in a customizable way. An outlook on future directions of hydrogel-based 3D printing is presented.

3D printing of hydrogels: Rational design strategies and emerging biomedical applications

Melt electrospun fibers of poly(ϵ-caprolactone) are accurately deposited using an automated stage as the collector. Matching the translation speed of the collector to the speed of the melt electrospinning jet establishes control over the location of fiber deposition. In this sense, melt electrospinning writing can be seen to bridge the gap between solution electrospinning and direct writing additive manufacturing processes.

Direct writing by way of melt electrospinning

Three-dimensional bioprinting uses additive manufacturing techniques for the automated fabrication of hierarchically organized living constructs. The building blocks are often hydrogel-based bioinks, which need to be printed into structures with high shape fidelity to the intended computer-aided design. For optimal cell performance, relatively soft and printable inks are preferred, although these undergo significant deformation during the printing process, which may impair shape fidelity. While the concept of good or poor printability seems rather intuitive, its quantitative definition lacks consensus and depends on multiple rheological and chemical parameters of the ink. This review discusses qualitative and quantitative methodologies to evaluate printability of bioinks for extrusion- and lithography-based bioprinting. The physicochemical parameters influencing shape fidelity are discussed, together with their importance in establishing new models, predictive tools and printing methods that are deemed instrumental for the design of next-generation bioinks, and for reproducible comparison of their structural performance.

Printability and Shape Fidelity of Bioinks in 3D Bioprinting.

Stereolithography is a solid freeform technique (SFF) that was introduced in the late 1980s Although many other techniques have been developed since then, stereolithography remains one of the most powerful and versatile of all SFF techniques It has the highest fabrication accuracy and an increasing number of materials that can be processed is becoming available In this paper we discuss the characteristic features of the stereolithography technique and compare it to other SFF techniques The biomedical applications of stereolithography are reviewed, as well as the biodegradable resin materials that have been developed for use with stereolithography Finally, an overview of the application of stereolithography in preparing porous structures for tissue engineering is given

A review on stereolithography and its applications in biomedical engineering

A Review of 3D Printing Technologies for Soft Polymer Materials

Photo-crosslinkable gelatin methacrylate (GelMA) has become an attractive ink in 3D printing due to its excellent biological performance. However, limited by low viscosity and long cross-linking time, it is still a challenge to directly print GelMA by extrusion-based 3D printing. Here, to balance the printability and biocompatibility, biomaterial ink composed of GelMA and nanoclay was specially designed. Using this ink, complex scaffolds with high shape fidelity can be easily printed based on the thixotropic property of nanoclay. In this study, we tried to answer some basic printing-required questions of this ink, including the printability window, general properties (porosity, mechanical strength, et al), and biocompatibility. We found that the GelMA/Nanoclay ink enabled printing complex 3D scaffolds, such as a bionic ear and a branched vessel. Furthermore, the addition of nanoclay improved the porosity, increased the mechanical strength, reduced the degradation ratio, and maintained a good biocompatibility of the printed scaffolds. Therefore, this method offers an easy way to print complex scaffolds with good shape fidelity and biological performance, and it might open up new potential applications for the customized therapy of tissue defects.

https://iopscience.iop.org/article/10.1088/1758-5090/ab0cf6/pdf

3D printing of complex GelMA-based scaffolds with nanoclay.

Despite the substantial progress in the construction of vascular structures in the past few years, building a whole blood circulatory system model containing both large vessels and capillaries inside cell-laden hydrogels remains a big challenge. Here, we present a flexible and novel process to construct a hydrogel-based microfluidic chip with such a multi-scale network by combining high-resolution three-dimensional (3D) printing and a twice-crosslinking strategy. The whole process includes: (1) vascular system design (from arteries and capillaries to veins), (2) template printing (ultrafine fiber network), (3) hydrogel material casting (formation of partially-crosslinked hydrogel sheets), (4) template peeling off (creation of microgrooves on the surfaces of the hydrogel sheets), (5) hydrogel sheet bonding (formation of a closed channel network) and (6) cell loading (specific cells seeded onto specific positions mimicking in vivo conditions). We demonstrated that it is easy to fabricate the ubiquitous structures of biological vascular systems, highly-branched networks, spiral vessels, stenosis, etc. The endothelial cell (EC) channels exhibit representative vascular functions. As a proof of concept, a bulk breast tumor tissue with a functional vascular network was built. Additionally, a vascular–tumour co-culture concept has been proposed and constructed through the process to investigate the interaction between tumours and blood vessels. The proposed strategy can also be applied to help engineer diverse meaningful in vitro models for extensive biomedical applications, from physiology and disease study to therapy evaluation.

Construction of multi-scale vascular chips and modelling of the interaction between tumours and blood vessels

Lightweight 3D bioprinting with point by point photocuring.

Food safety has been an issue of common concern in today’s society. Excessive benzoic acid (BA) additives in wheat flour would pose a huge threat to human health. In this paper, terahertz (THz) time-domain spectroscopy was used to detect BA quantitatively, which is a preservative additive in flour. Samples were prepared by grinding, drying, weighing, mixing and performing successively according to the designed concentration gradient (concentration 0.04%, 0.08%, 0.1%, 0.2%, 0.4%, 0.5%, 1%, 1.5%, …, 10%), with the BA concentration ranging from 0.040% to 19.99%. Then the THz Spectra of wheat flour samples with different concentrations of BA were collected. After preprocessing the original terahertz spectra with multiple scattering correction and other methods, Competitive Adaptive Reweighted Sampling (CARS), Genetic Algorithm (GA), Principal Component Analysis (PCA) and Uninformative Variable Elimination (UVE) were used to select effective spectral bands, and then Partial Least Squares (PLS) and Least Square Support Vector Machine (LS-SVM) models were established respectively. It turned out that the absorption peak of BA was at 1.94 THz of terahertz absorption coefficient, which increased with the rise of BA concentration. The results also indicated that better modeling results could be obtained by using CARS method for variable selection. And the established CARS-PCA-LS-SVM model had the best prediction result by combining PCA with CARS, with the correlation coefficient of the prediction (Rp) of 0.9956 and Root Mean Square Error of Prediction (RMSEP) of 0.64%. Hence, it can be concluded that terahertz technology combined with LS-SVM model can well achieve the quantitative detection of BA concentration in flour. Although the model is not universal since samples size is not large enough, the research method provides a basis for the detection of BA additives in flour.

Optimization of quantitative detection model for benzoic acid in wheat flour based on CARS variable selection and THz spectroscopy

The safety of milk powder is closely related to everyone’s life. In the production of milk powder, it is often easy to mix in foreign bodies, such as light and thin plastic, insects, metals, and other foreign bodies. In this paper, THz spectroscopy is used to detect common foreign bodies in milk powder, such as polymer materials (i.e., PP, PVC, and PE), insects, and metal gaskets. The detection of foreign bodies in milk powder can be realized by using THz spectroscopy combined with random forest discrimination method, and the recognition accuracy rate reaches 100%. The accuracy rate also reaches 100% when the types of foreign bodies are distinguished, thus, successfully realizing the identification and qualitative discrimination of foreign bodies in milk powder. At the same time, THz imaging technology is used to detect milk powder with foreign bodies. The outline and the boundaries of foreign bodies in milk powder are clear in the imaging from 0.5 to 1.0 THz. Thus, the size and shape of foreign bodies in milk powder can be well distinguished. This experiment verifies the feasibility of qualitative detection of foreign bodies in milk powder by the combination of terahertz imaging and spectrum, and established a better random forest detection model, which proposes a solution to ensure the safety of milk powder.

Yande Liu

Papers

3D printing of complex GelMA-based scaffolds with nanoclay.

Construction of multi-scale vascular chips and modelling of the interaction between tumours and blood vessels

Lightweight 3D bioprinting with point by point photocuring.

Optimization of quantitative detection model for benzoic acid in wheat flour based on CARS variable selection and THz spectroscopy

Detection of Foreign-Body in Milk Powder Processing Based on Terahertz Imaging and Spectrum