ReviewSynthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels
Introduction
Hydrogels are crosslinked network of hydrophilic polymers that can swell in water to capture many times their original mass. Physical and biochemical properties of hydrogels largely depend on their compositions, methods used for their polymerization, and their crosslinking density. Hydrogels provide a versatile platform to include desired combinations of properties for designed applications [1]. Numerous hydrogels have been developed based on natural and/or synthetic polymers using various kinds of crosslinking chemistry towards different biomedical applications, such as regenerative medicine, drug delivery, and tissue adhesives [2]. In particular, hydrogels for biomedical applications are designed to resemble the characteristics of native extracellular matrix (ECM) and to provide three-dimensional (3D) supports for cellular growth and tissue formation [3]. Hydrogels have been also widely used in 3D culturing to study cell-matrix and cell–cell interactions, and cellular proliferation, migration [4], and differentiation [5]. To this aim, hydrogels based on naturally occurring biopolymers have potential advantages over synthetic polymers, such as excellent biocompatibility, low immunoresponse, and possible bioactive motifs encoded in their chemical structures.
In this contribution, we review recent research on the synthesis, characterizations, and biomedical applications of gelatin methacryloyl (GelMA), which is also frequently referred as gelatin methacrylate [6], [7], [8], [9], methacrylated gelatin [10], [11], [12], [13], methacrylamide modified gelatin [14], or gelatin methacrylamide [15], [16], [17], [18] in literature by different authors. Based on the fact that GelMA is a gelatin derivative containing a majority of methacrylamide groups and a minority of methacrylate groups, we suggest that “gelatin methacryloyl” is a more suitable name, which also matches the widely accepted abbreviation GelMA.
GelMA undergoes photoinitiated radical polymerization (i.e. under UV light exposure with the presence of a photoinitiator) to form covalently crosslinked hydrogels. As the hydrolysis product of collagen, the major component of ECM in most tissues, gelatin contains many arginine-glycine-aspartic acid (RGD) sequences that promote cell attachment [19], as well as the target sequences of matrix metalloproteinase (MMP) that are suitable for cell remodeling [20]. When compared to collagen, the advantages of gelatin include better solubility and less antigenicity [21], [22]. The hydrolysis process also denatures the tertiary structure of collagen, reducing its structural variations due to different sources. A gelatin solution has, on its own, the unique property of gelation at low temperatures to form physically crosslinked hydrogels [14], [23]. In addition, several chemical reactions have been applied to covalently crosslink gelatin [24], [25], [26], [27]. Conveniently, introduction of methacryloyl substituent groups confers to gelatin the property of photocrosslinking with the assistance of a photoinitiator and exposure to light, due to the photopolymerization of the methacryloyl substituents [14]. This polymerization can take place at mild conditions (room temperature, neutral pH, in aqueous environments, etc.), and allows for temporal and spatial control of the reaction [6]. This enables microfabrication of the hydrogels to create unique patterns, morphologies, and 3D structures, providing ideal platforms to control cellular behaviors, to study cell–biomaterial interactions, and to engineer tissues [6], [28].
It is worth mentioning that the chemical modification of gelatin by methacrylic anhydride (MA) generally only involves less than 5% of the amino acid residues in molar ratio [14], which implies that most of the functional amino acid motifs (such as the RGD motifs and MMP-degradable motifs) will not be significantly influenced. Specifically, the RGD motifs do not contain groups that will react with MA, which ensures the retention of good cell adhesive properties of GelMA [6], [19], [29]. Furthermore, the in vitro enzymatic degradation of GelMA hydrogels by type I and type II collagenases (also known as MMP-1 and MMP-8, respectively) proceeds at accelerated rates, indicating the existence of MMP-sensitive motifs in GelMA [30], [31].
Since its first synthesis report [14], GelMA hydrogels have been thoroughly studied in terms of physical and biochemical properties for many different applications ranging from tissue engineering, to drug and gene delivery. In this review, we will focus on studies related to GelMA hydrogel synthesis and characterization as well as its composites. We will also summarize the reported methods for microfabrication of GelMA hydrogels, and the applications of resulting GelMA-based biomaterials.
Section snippets
Synthesis and characterization of GelMA hydrogels
Different protocols have been reported for the preparation of GelMA, but they are all essentially minor variations of a general method first reported by Van Den Bulcke et al. [14]. Briefly, GelMA is synthesized by the direct reaction of gelatin with MA in phosphate buffer (pH = 7.4) at 50 °C. This reaction introduces methacryloyl substitution groups on the reactive amine and hydroxyl groups of the amino acid residues [14] (Fig. 1A). Different degrees of methacryloyl substitution can be achieved
Microfabrication of GelMA hydrogels
The excellent biocompatibility of GelMA hydrogels makes them suitable as cell culture matrices that mimic native ECM. However, to fabricate tissue constructs similar to living tissues, one of the essential requirements is to generate organized assemblies of various types of cells to resemble the complex architectures of the targeting tissues in vitro. Recently, several state-of-the-art microfabrication techniques have been applied to control the 3D microstructure of GelMA hydrogels, and in
Hybrid hydrogels based on GelMA
Hybrid hydrogels are constructed from blends of different components, which are selected to possess specific properties. Although GelMA is a cell-responsive material with wide-spectrum of tunable properties, tailored design of hybrid materials has been a useful strategy to improve some characteristics of GelMA for certain applications. Table 1 summarizes some examples of hybrid hydrogels based on GelMA and their targeting properties. In this section, we review hybrid hydrogels based on GelMA
Tissue engineering
In general, GelMA possesses many relevant characteristics to serve as tissue engineering scaffolds. GelMA-based hydrogels are biocompatible, biodegradable, non-cytotoxic, and non-immunogenic. GelMA is also a versatile biomaterial with tunable physicochemical properties, promising remarkable compatibility for a wide spectrum of applications. In addition, the photocrosslinkable feature of GelMA enables flexibility for microengineering by different microfabrication methods as explained previously
Conclusions and outlook
We have reviewed several important aspects of GelMA-based hydrogel systems for biomedical applications. GelMA is developed from a natural polymer gelatin via one-step chemical modification. The introduction of photocrosslinkable methacryloyl substitution groups enables convenient and fast gelation upon exposure to light irradiation at the presence of photoinitiators. Many physical parameters of GelMA hydrogels, such as mechanical properties, pore sizes, degradation rates, and swell ratio can be
Acknowledgments
NA acknowledges the support from the National Health and Medical Research Council. The authors acknowledge funding from the National Science Foundation (EFRI-1240443), IMMODGEL (602694), and the National Institutes of Health (EB012597, AR057837, DE021468, HL099073, AI105024, AR063745). MMA gratefully acknowledge the institutional funding received from Tecnológico de Monterrey (seed funding to Strategic Research Groups, 2015) and funding provided from the Consejo Nacional de Ciencia y
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Kan Yue and Grissel Trujillo-de Santiago contributed equally to this work.