Abstract
The strength of the extracellular matrix (ECM) is that it is hierarchical in terms of matrix built-up, matrix density and fiber structure, which allows for hormones, cytokines, and other small biomolecules to be stored within its network. The ECM-like hydrogels that are currently used do not possess this ability, and long-term storage, along with the need for free diffusion of small molecules, are generally incompatible requirements. Nanogels are able to fulfill the additional requirements upon successful integration. Herein, a stable hierarchical nanogel–gelatin methacryloyl (GelMA) composite hydrogel system is provided by covalently embedding nanogels inside the micropore network of GelMA hydrogel to allow a controlled local functionality that is not found in a homogenous GelMA hydrogel. Nanogels have emerged as a powerful tool in nanomedicine and are highly versatile, due to their simplicity of chemical control and biological compatibility. In this study, an N-isopropylacrylamide-based nanogel with primary amine groups on the surface was modified with methacryloyl groups to obtain a photo-cross-linking ability similar to GelMA. The nanogel-GelMA composite hydrogel was formed by mixing the GelMA and the photo-initiator within the nanogel solution through UV irradiation. The morphology of the composite hydrogel was observed by scanning electron microscopy, which clearly showed the nanogel wrapped within the GelMA network and covering the surface of the pore wall. A release experiment was conducted to prove covalent bonding and the stability of the nanogel inside the GelMA hydrogel. In addition, 3D printability studies showed that the nanogel-GelMA composite ink is printable. Therefore, the suggested stable hierarchical nanogel-GelMA composite hydrogel system has great potential to achieve the in situ delivery and controllable release of bioactive molecules in 3D cell culture systems.
Highlights
Three-dimensional (3D) cell culture has shown great potential in the fields of tissue engineering, wound healing, and drug screening because its structure is more compatible with human physiology, and because of its ability to be designed to mimic the characteristics of the native extracellular matrix (ECM) [1,2]
The decrease of the integrated signal was used to calculate the degree of functionalization (DoF) as the primary amine of lysine is the target site for the reaction, minor reactions occurred with other reactive groups than amine groups in gelatin
To achieve the covalent bonding of the nanogel within the gelatin methacryloyl (GelMA) network, the nanogel was modified with methacryloyl groups on the surface to obtain the necessary photo-cross-linking ability by coupling methacrylic anhydride (MA) with the primary amine groups on the shell of the nanogel
Summary
Three-dimensional (3D) cell culture has shown great potential in the fields of tissue engineering, wound healing, and drug screening because its structure is more compatible with human physiology, and because of its ability to be designed to mimic the characteristics of the native extracellular matrix (ECM) [1,2]. The implanted human cells subsequently generated an extensive vasculature and were uniformly distributed throughout the construct [17] It is the encapsulation of stem cells in a 3D culture system that is essential for therapeutic applications like bone tissue engineering; the in situ delivery of localized, sustained bioactive molecules, such as nutrients, drugs, and growth factors, plays an important role [18,19]. The highly hydrated, porous structure of GelMA hydrogels with micrometer range aqueous pore size results in the rapid diffusive loss of entrapped biomolecules under physiological conditions, which limits their uses in long-term biomedical applications [20,21]
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