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International Journal of Bioprinting Dual tuning of 3D-printed SilMA hydrogel

1. Introduction phases without surfactants. The higher volume fraction
is used as the continuous phase, and the smaller volume
Articular cartilage injuries caused by aging, obesity, fraction is used as the dispersed phase (water-in-water
occupational injury, and trauma often develop into emulsion). Combining ultraviolet (UV)-curable gelatin
16
osteoarthritis, a leading cause of disability worldwide. precursors with poly(ethylene oxide) (PEO) solutions has
While approximately 300 million people were affected in yielded porous hydrogels compatible with 3D printing.
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2019, this number surged to 3.53 billion by 2021. Articular However, gelatin’s inherent mechanical weakness might
1
cartilage is a highly hydrated connective tissue devoid of be exacerbated by internal porosity, limiting its utility in
nerves, blood vessels, and lymphatic vessels, consisting osteochondral engineering. Thus, enhancing hydrogel
primarily of chondrocytes and dense extracellular matrix mechanical stability while retaining porosity is crucial. 18
(ECM). These histological structural characteristics limit
2
its self-repair capacity, placing a substantial burden on Silk fibroin (SF), a natural polymer known for its robust
the global healthcare system and economy. In response, mechanical properties, biocompatibility, degradability,
advancements in tissue engineering and regenerative aqueous processability, and functionalizable chemical
medicine have led to the development of various scaffolds groups, presents a promising matrix for biomedical
5,19
designed to support cartilage repair. scaffolds. Silk methacryloyl (SilMA) and methacrylated
3–5
SF serve as an advanced bio-ink for 3D printing,
Hydrogels are three-dimensional (3D) hydrophilic outperforming methacrylated gelatin in simulating tissues
polymer networks capable of water absorption. They like the heart, blood vessels, trachea, and cartilage. Kim
mimic the biphasic structure of cartilage, offering et al. detailed the synthesis of SilMA and its
20
a suitable environment for cell growth and matrix characterization in 3D-printed hydrogel applications for
formation. Compared to conventional two-dimensional tissue engineering. It was found that a 30% SilMA hydrogel
6
cultures (2D), 3D cell cultivation within hydrogels more was suitable for cartilage tissue engineering, fulfilling
accurately replicates in vivo conditions, enhancing matrix mechanical and biological requirements. Although the
production. Nevertheless, uneven cell distribution within high concentration of SilMA enhanced mechanical
these gels can hinder uniform matrix formation. 3D properties and clinical operability, it also significantly
7
bioprinting emerges as a refined technique, precisely reduced the pore size of the hydrogel (well below 100
controlling biomaterial deposition and cellular placement, μm), which diverges from the ideal pore size for cartilage
and fabricating intricate and biomimetic scaffolds. It scaffolds (150–250 μm). This reduction in porosity
8
21
can also produce large channels (typically hundreds of hinders efficient gas–liquid exchange, adversely affecting
micrometers) within the scaffolds. However, the intrinsic the cells loaded in the hydrogel scaffold material through
pore structure of most hydrogel scaffold materials is 3D bioprinting. A recent study has explored the fabrication
often limited to the submicron or nanometer scale, which of porous gelatin methacryloyl hydrogels by incorporating
impedes the acquisition of nutrients and the exchange of PEO. However, this approach also compromised the
metabolic waste in hydrogels, potentially compromising mechanical properties of the hydrogel.
22
long-term cell viability and tissue functionality. 9
Recent advances in nanotechnology have integrated
Porous hydrogels exhibit advantages over their non- nanomaterials into hydrogels to enhance their mechanical
porous counterparts in supporting 3D cell culture. properties, broadening their tissue engineering
However, traditional methods of porosity introduction, 10,11 applications. Electrospun NFs are widely used as tissue
such as particle leaching, gas foaming, and freeze-drying, regeneration scaffolds due to their structure and size
involve cytotoxic agents, rendering them unsuitable for resembling collagen fibers in the ECM, as well as their
live cell encapsulation or integration with 3D printing. high specific surface area. 23,24 However, the inherent 2D
12
The Pluronic micellar template method offers a gentle, all- architecture of electrospun membranes substantially
aqueous approach to hydrogel pore formation, but struggles limits cellular infiltration into the scaffold interior,
to create macropores due to micelle size constraints. compromising their effectiveness in 3D tissue regeneration.
13
Consequently, developing a biocompatible, porous bio- This structural limitation has driven recent investigations
ink that supports cell encapsulation remains a formidable into developing 3D nanofibrous scaffolds with enhanced
challenge. Alternative strategies, like phase separation cellular interactivity. In our previous study, we developed
in emulsions, are hindered by surfactant-induced an innovative 3D SF aerogel by incorporating short
cytotoxicity, restricting their use in 3D bioprinting. 14,15 electrospun SF NFs into an SF hydrogel matrix, followed
The water-in-water system circumvents this issue by by freeze-drying. The resulting nanofibrous aerogel
segregating two hydrophilic polymer solutions beyond a exhibited significantly improved mechanical properties
critical concentration, forming two immiscible aqueous compared to conventional hydrogels. More importantly,

Volume 11 Issue 4 (2025) 279 doi: 10.36922/IJB025140118