Gelatin Methacrylate Review

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Gelatin methacrylate, commonly referred to as gelMA, is a photocrosslinkable natural bioink derived from a hydrolytic degradation of collagen (1). GelMA is commonly used in drug delivery systems and wound dressing applications (1). With its cell encapsulation properties and thixotropic nature, gelMA is also a common reagent used for bioprinting (8). It has been used with a variety of cell types, including fibroblasts, chondrocytes (3), endothelial cells (4) and human umbilical vein endothelial cells (5).

As a naturally derived reagent, gelMA has many properties useful in biological interactions, including its hydrophilicity, integrin binding motifs, and matrix metalloprotein (MMP) degradation sites (5). Its highly hydrophilic nature allows it to dissolve in water or media, creating a hydrogel. With high water content, permeability to small molecules and high biocompatibility, hydrogels display good cell encapsulation qualities. Due to the integrin binding sites, gelMA also displays high cellular adhesion. GelMA also has a pathway to degrade gradually within the body, as the MMP sites are degraded by enzymes, mainly certain metalloproteinases.

GelMA has a reversible thermal gelation and can be permanently crosslinked through photopolymerization. Before bioprinting, gelMA can be mixed with photoinitiators, such as Irgacure 2959 (1,3) or LAP (2). When exposed to a certain wavelength of light, the photoinitiators release free radicals which interact with the methacrylate groups on GelMA to create a solid gel through covalent bonds. Because of exposure to free radicals and sometimes harmful wavelengths, crosslinking time should be minimized to avoid effects on viability. This gelation process does not affect viscosity during extrusion and allows for tunable mechanical properties through post-process crosslinking, with an increasing elastic modulus with increasing crosslinking time.

In addition to crosslinking time, the mechanical properties of GelMA can be adjusted in a variety of ways. Varying the degrees of methacrylation during synthesis lead to varying compressive moduli, with increasing concentrations correlating to increasing compressive moduli (3). Additionally, increased gelMA concentration leads to increased elastic modulus and decreased mass swelling ratio (3). Ali Khademhosseini and his team of researchers tested gelMA concentrations ranging from 7-15%, establishing a link between printability and hydrogel properties (7).

Researchers at Harvard University led by J. A. Lewis have also demonstrated the printability of gelMA through the fabrication of vascularized 3D tissue constructs. Lewis’s team, which printed gelMA with sacrificial pluronic F127,  was successful in using their technique to create vasculature and maintain high viability up to 7 days after printing (5).

Figure-5-Schematic-views-of-the-top-down-and-side-views-of-a-heterogeneous-engineered

Figure 1: (adapted from 5) b) Schematic of the heterogeneous engineered tissue construct, in which blue, red, and green filaments correspond to printed 10T1/2 fibroblast-laden GelMA, fugitive, and GFP HNDF-laden GelMA, inks, respectively. c,d) Bright field microscopy image of the 3D printed tissue construct. f) Composite image (top view) of the 3D printed tissue construct acquired using three fluorescent channels: 10T1/2 fibroblasts (blue), HNDFs (green), HUVECs (red). (5)

In addition to sacrificial reagents, GelMA has also been printed with hard thermoplastics such as polycaprolactone. Simultaneous printing with a thermoplastic, such as PCL or poly(propylene fumarate), increases the mechanical strength of a print, which is particularly beneficial for applications such as cartilage tissue engineering (3). This is known as a hybrid construct. For example, Dr. Z. Wang and his team of researchers used poly(propylene fumarate) to print and analyze the degradation of 3D scaffolds in bone tissue engineering applications (9).

GelMA has also been used in hybrid bioinks for enhanced properties. The addition of hyaluronic acid causes an increase in GelMA’s viscosity, allowing for improved properties for hydrogel printing (6). To increase mechanical strength, carbon nanotubes can be incorporated, as shown by Ali Khademhosseini and his team (10).

As a hydrogel, gelMA can be used as a very effective matrix bioink. It inherently has the beneficial properties of high cell adhesion and biocompatibility and tunable mechanical properties. This material offers further versatility when combined with a variety of components for specific purposes.

References

[1]
Van Den Bulcke Al et al, “Structural and Rheological Properties of Methacrylamide Modified Gelatin Hydrogels,” Biomacromolecules, vol. 1, no 1, pp. 31-38, 2000.
[2]
Khademhosseini A et al, “Synthesis, properties, and biomedical application of gelatin methacryloyl (GelMA) hydrogels,” Biomaterials, vol. 73, pp. 254-271, 2015.
[3]
Malda J et al, “Gelatin-Methacrylamide Hydrogels as Potential Biomaterials for Fabrication of Tissue-Engineered Cartilage Constructs,” Macromolecular Bioscience, vol. 13, no. 5, pp. 551-561, 2013.
[4]
Khademhosseini A et al, “Hydrogel bioprinted microchannel networks for vascularization of tissue engineering constructs,” Lab Chip, vol. 14, no. 13, pp. 2202-2011, 2014.
[5]
Lewis JA et al, “3D Bioprinting of Vascularized, Heterogeneous Cell-Laden Tissue Constructs,” Advanced Materials, vol. 26, no. 19, pp. 3124-3130, 2014.
[6]
Malda J et al, “25th Anniversary Article: Engineering Hydrogels for Biofabrication,” Advanced Materials, vol. 25, no. 36, pp. 5011-5028, 2013.
[7]
Khademhosseini A et al, “Direct-write bioprinting of cell-laden methacrylated gelatin hydrogels,” Biofabrication, vol. 6, no. 2, 2014.
[8]
L. Djakovic, V. Sovilj and S. Milosevic, “Rheological Behaviour of Thixotropic Starch and Gelatin Gels,” Starch, vol. 42, no. 10, pp. 380-385, 1990.
[9]
Wang Z et al, “3D bioprinting for engineering complex tissues,” Biotechnology Advanced, vol. 34, no. 4, pp. 422-434, 2016.
[10]
Khademhosseini A et al, “Carbon Nanotube Reinforced Hybrid Microgels as Scaffold Materials for Cell Encapsulation,” ACS Nano, vol. 6, no. 1, pp. 362-372, 2012.