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In situ rheological monitoring of diffusion-controlled hydrogel crosslinking for embedded 3D bioprinting
Audrey Shih1, Fotis Christakopoulos2, Stella J. Chung1, Lucia G. Brunel1, Noah Eckman2, Yueming Liu2, Junyi Tao3, Sarah C. Heilshorn2, Gerald G. Fuller1
1Department of Chemical Engineering, Stanford University, CA, USA
2Department of Materials Science and Engineering, Stanford University, CA, USA
3Department of Mechanical Engineering, University of Tokyo, Japan
In embedded 3D bioprinting, hydrogel biomaterial inks are extruded into sacrificial support baths, where the diffusion of small molecules into or out of the support bath can facilitate ink crosslinking before the removal of the support bath. Despite the importance of tuning the mechanical properties of these inks, there are currently no methods to accurately predict ink stiffness over time throughout the crosslinking process. Here, we use a custom-developed magnetic stress rheometer, adapted for dual-layered ink-support bath systems to monitor diffusion-driven crosslinking in situ. Our approach reveals how gelation kinetics depend on the thickness of the ink layer andenables predictive estimation of mechanical evolution in these reaction- and diffusion-dependent systems. These insights help inform the design of inks and timing of bioprinting protocols for tissue engineering applications. Two different systems were evaluated: a diffusion-in ink using azide-modified collagen and a diffusion-out ink using functionalized polyethylene glycol (PEG) crosslinked through dynamic covalent chemistry.
The mechanical properties were evaluated in terms of viscosity and inverse compliance, showing a temporal evolution that depends on the thickness of the ink layer. The results are analyzed in terms of the characteristic diffusion time (tD), defined as the time needed to reach 90% of the stiffness of the fully crosslinked material, and correlated to the ink layer thickness (L). The linear relationship between tD and L2 show a diffusion-driven crosslinking mechancism with an effective diffusivity value of 89.7 μm2/sfor the diffusion-in collagen ink system. In a similar manner, the effective diffusivity of the diffusion-out PEG ink system was found to be 620 μm2/s.These findings provide a framework to quantitatively characterize inks for embedded 3D bioprinting.
Biosketch:
Prof. Gerald Fuller is a distinguished chemical engineer and an internationally recognized expert in the rheology of complex fluids and fluid interfaces. He received his B.S. in chemical engineering from the University of Calgary in 1975 and his Ph.D. from Caltech in 1980.
His research focuses on the processing of complex liquids—including polymers, suspensions, emulsions, and biological fluids—and how their microstructure changes through orientation and deformation. A pioneer in optical rheometry, Prof. Fuller has developed advanced measurement techniques such as high-speed polarimetry and various microscopy methods that have become instrumental in understanding fluid behavior at molecular and interfacial levels. His work has broad applications ranging from tissue engineering and biomedicine to industrial processes involving emulsions, foams, and nanomaterials.
In 2005, Prof. Fuller was elected to the National Academy of Engineering for his contributions toward understanding the rheology of complex fluids, fluid interfaces, and rheo-optical technique development. He was also elected as a Fellow of the American Academy of Arts and Sciences in 2016. Among his many honors, he has received the Bingham Medal from The Society of Rheology, served as President of the International Committee on Rheology, and was named one of the "One Hundred Engineers of the Modern Era" by AIChE in 2008.
Prof. Fuller continues to lead an active research group at Stanford, advancing our understanding of complex fluids with applications in healthcare, biotechnology, and advanced materials.
