Three-dimensional bioprinting of gelatin methacryloyl (GelMA)

Bio-Design and Manufacturing (2018) 1:215–224 https://doi.org/10.1007/s42242-018-0028-8 REVIEW Three-dimensional bioprinting of gelatin methacryloyl (GelMA) Guoliang Ying1,2 · Nan Jiang3 · Cunjiang Yu4 · Yu Shrike Zhang1 Received: 20 October 2018 / Accepted: 3 November 2018 / Published online: 16 November 2018 © Zhejiang University Press 2018 Abstract The three-dimensional (3D) bioprinting technology has progressed tremendously over the past decade. By controlling the size, shape, and architecture of the bioprinted constructs, 3D bioprinting allows for the fabrication of tissue/organ-like constructs with strong structural–functional similarity with their in vivo counterparts at high fidelity. The bioink, a blend of biomaterials and living cells possessing both high biocompatibility and printability, is a critical component of bioprinting. In particular, gelatin methacryloyl (GelMA) has shown its potential as a viable bioink material due to its suitable biocompatibility and readily tunable physicochemical properties. Current GelMA-based bioinks and relevant bioprinting strategies for GelMA bioprinting are briefly reviewed. Keywords Bioprinting · Bioink · Gelatin methacryloyl (GelMA) · Biofabrication · Tissue engineering · Tissue model Introduction The demand for organ replacement or tissue regeneration is quickly expanding, while the number of donor organs is far from sufficient [1, 2]. Tissue engineering, initially proposed approximately three decades ago, has thus emerged as an alternative strategy aiming to generate tissues and organs that are functionally relevant to their in vivo counterparts, to replace those that are damaged or diseased in the body [3]. Besides this conventional aspect, tissue engineering has found additional applications over the past years in servGuoliang Ying and Nan Jiang have contributed equally to this work. B Cunjiang Yu B Yu Shrike Zhang 1 Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA 2 School of Materials Science and Engineering, Wuhan Institute of Technology, Wuhan 430205, People’s Republic of China 3 School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02139, USA 4 Departments of Mechanical Engineering, Electrical and Computer Engineering, Biomedical Engineering, Materials Science and Engineering Program, The Texas Center for Superconductivity, University of Houston, Houston, TX 77204, USA ing as a tool to produce biomimetic miniaturized human tissue models for the purpose of improving the accuracy of drug screening and of promoting personalized medicine [4, 5]. Nevertheless, it is still a great challenge to fabricate complex living tissues except for a few simple organs such as skin [6] and cartilage [7]. Recently, the advancements in three-dimensional (3D) bioprinting seem to have brought us a step closer to realizing the ambitious aim of tissue engineering, by providing an unprecedented means to control, in precision, the deposition/patterning of cells and biomaterials in the volumetric space at high reproducibility [8]. While there are several bioprinting modalities commonly used for tissue fabrication, the bioink consisting of a mixture of biomaterial(s) and cell(s) is the unanimously vital component serving as the building block of bioprinted 3D tissue structures [9, 10]. Taking extrusion bioprinting as an example, the bioinks play key roles in dispersing the cells prior to bioprinting, in maintaining the integrity of the structures during bioprinting, and in supporting the adhesion, spreading, and functionality of encapsulated cells post-bioprinting [11, 12]. The bioprinted cell-laden constructs featuring arbitrary shapes and architectures finally form 3D tissue-like structures following a period of culture [13]. In principle, an ideal bioink should possess physicochemical properties suitable for the bioprinting process, and the bioprinted constructs should have proper biological and mechanical properties close to those of the native 123 216 tissues. Hydrogel-based bioinks encapsulating living cells and bioactive components are of particular interest for bioprinting [14]. To this end, numerous hydrogel-based bioink formulations such as gelatin methacryloyl (GelMA) [15–17], acrylate-functionalized poly(ethylene glycol) [18, 19], alginate [20, 21], agarose [22], and collagen [23] have been adopted, either used alone or in combinations, as bioinks. Among the different types of hydrogel bioinks, those based on GelMA hold good promise attributed to the superior biocompatibility, on-demand photocrosslinkability, and broadly tunable physicochemical properties of this biomacromolecule denatured from collagen [22]. This review outlines recent advances in the development of GelMA-based bioink formulations and strategies suitable for GelMA bioprinting. GelMA-based bioink formulations Pure GelMA bioink To produce hydrogel constructs through extrusion bioprinting, it is necessary to control the viscosity of the bioink as an important rheological parameter [24]. High viscosity of the bioink is essential to maintain the structural fidelity of the extruded filaments deposited layer by layer in 3D. Direct bioprinting of pure GelMA hydrogel as the bioink has been a challenge because of its generally low viscosity at room or higher temperatures. Yet, GelMA could still be directly bioprinted through adjusting several parameters to reach appropriate viscosity: the concentration of the polymer, the temperature, and the degree of crosslinking [25]. First, higher viscosity can be obtained by increasing the concentration of the GelMA solution potentially allowing for high-fidelity bioprinting. The challenge associated with this approach is that the elevated concentration of GelMA solution (such as > 30 w/v%) will inevitably lead to low cell bioactivity due to the presence of the dense polymer network [26]. Second, owing to its temperature sensitiveness, reduced temperature at close to 0 °C would induce the formation of the GelMA physical gels (GPGs) that are shear-thinning and self-healing, enabling direct extrusion bioprinting of pure GelMA constructs at relatively low concentrations of the bioinks (down to 3 w/v%, Fig. 1A) [15, 17]. The formation of the GPGs could be achieved by cooling down the GelMA bioinks prior to bioprinting [15] or by using a cooling printhead during bioprinting [27–29]. In the third option, by taking advantage of the in situ crosslinking strategy, GelMA bioinks could be partially photocrosslinked during extrusion to enhance the viscosity and thus the fidelity of their direct extrusion bioprinting (Fig. 1B) [30]. 123 Bio-Design and Manufacturing (2018) 1:215–224 Pore-forming GelMA bioink Direct bioprinting of pure GelMA bioinks provides programmable and customizable platforms to engineer cell-laden constructs mimicking human tissues for a wide range of biomedical applications. However (...truncated)