For the past decade, advances in bioinks for regenerative medicine were made by developing dynamic chemistries or light/ion crosslinkable hydrogels. Recently, however, Scandinavian scientists achieved greater success by combining certain dynamic and nondynamic linkages into bioink used for stem cell therapies.

The research, detailed in a recent paper, has “…expanded the horizons of bioink development by highlighting the crucial role played by the synergy between diverse crosslinking mechanisms in optimizing the performance and functionality of bioinks,” Oommen Varghese, PhD, associate professor, Uppsala University, tells GEN. These bioinks can be used to help scientists understand cellular interactions in 3D, as well as for in vivo implantation, he says.

The team developed three gels. Each used disulfide (D-gel), thiazolidine (T-gel), or both disulfide and thiazolidine (DT-gel) linkages.

DT-gel “most promising”

They found that disulfide and thiazolidine linkages modulated interactions between the cells and the biomaterials. “Specifically,” Varghese says, “the presence of disulfide crosslinking contributed to self-healing and facilitated cell migration, while thiazolidine crosslinking played a vital role in reducing gelation time, enhancing long-term stability, and promoting cell proliferation. This DT-gel demonstrates exceptional versatility and efficacy, making it particularly suitable for cartilage regeneration,” Varghese says. His team considers it the most promising candidate for bioink applications.

Attributes for the D-gel, he continues, include “a significant influence on cell migration. Its injectability and self-healing properties make it a valuable tool for understanding the underlying mechanisms of physiological activities, such as wound healing and cancer cell metastasis. The presence of thiol groups suggests it may have anti-inflammatory properties.” The group is improving its kinetic rate now.

The T-gel’s strength is in supporting cell proliferation and maintaining long-term stability. “As a result,” he says, “it holds considerable potential for facilitating cancer research and monitoring cancerous cells in 3D.”

Each of these hydrogels was stable for more than a month in a buffer environment. “When cells were present [in the bioink], however, stability depended upon the interplay between disulfide and thiazolidine linkages,” Varghese says. As evidence, hydrogels with the most disulfide linkages tended to degrade when encapsulated cells were present, which may be attributable to cell-produced factors that cleave disulfide bonds.

In other findings, exposure to the bioink also increased the expressions of stemness markers for human mesenchymal stem cells by more than two-fold and appears to preserve cellular integrity during the printing process. The resulting high viability rate post-printing thus makes this a positive option for cell culture media.

Going forward, Varghese and colleagues plan to explore the chondrogenic properties of the hydrogels, with the goal of promoting cartilage regeneration and easing osteoarthritis symptoms. Eventually, he says they also may leverage this hydrogel to “construct complex tissue models that simulate interactions between diverse cell types—particularly cancer and immune cells.”

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