Abstract
Gradient biomaterials are considered as preferable matrices for tissue engineering due to better simulation of native tissues. The introduction of gradient cues usually needs special equipment and complex process but is only effective to limited biomaterials. Incorporation of multiple gradients in the hydrogels remains challenges. Here, beta-sheet rich silk nanofibers (BSNF) were used as building blocks to introduce multiple gradients into different hydrogel systems through the joint action of crosslinking and electric field. The blocks migrated to the anode along the electric field and gradually stagnated due to the solution-hydrogel transition of the systems, finally achieving gradient distribution of the blocks in the formed hydrogels. The gradient distribution of the blocks could be tuned easily through changing different factors such as solution viscosity, which resulted in highly tunable gradient of mechanical cues. The blocks were also aligned under the electric field, endowing orientation gradient simultaneously. Different cargos could be loaded on the blocks and form gradient cues through the same crosslinking-electric field strategy. The building blocks could be introduced to various hydrogels such as Gelatin and NIPAM, indicating the universality. Complex niches with multiple gradient cues could be achieved through the strategy. Silk-based hydrogels with suitable mechanical gradients were fabricated to control the osteogenesis and chondrogenesis. Chondrogenic-osteogenic gradient transition was obtained, which stimulated the ectopic osteochondral tissue regeneration in vivo. The versatility and highly controllability of the strategy as well as multifunction of the building blocks reveal the applicability in complex tissue engineering and various interfacial tissues.
Highlights
Native tissues such as skin, bone, nerve and muscle have multiple gradients to regulate cell behaviors and guide tissue functions (Lu and Thomopoulos, 2013; Vedadghavami et al, 2017; Di Donato et al, 2018; Li et al, 2018; Radhakrishnan et al, 2018; Wu et al, 2018)
As a proof of concept, beta-sheet rich silk nanofiber solutions (BSNF) were blended with amorphous silk nanofiber solutions (ASNF) where betasheet rich silk nanofibers (BSNF) was used as reinforcement fibers to provide mechanical and oriented gradients while ASNF was crosslinked to form hydrogel matrices
After the electric field treatment, the moduli gradually increased from 12.4 kPa to 54.9 kPa, from 18.8 kPa to 81.2 kPa, from 20.7 kPa to 139.3 kPa and from 21.5 kPa to 137.1 kPa when the mechanical properties of the hydrogels were measured from the anode to the cathode under the direction perpendicular to the electric field (Fig. 1F). All these results suggested that both mechanical and oriented gradients could be regulated through tuning multiple factors superior to gradient hydrogel systems reported previously (Wang et al, 2018b; Yang et al, 2018; Gao et al, 2019)
Summary
Native tissues such as skin, bone, nerve and muscle have multiple gradients to regulate cell behaviors and guide tissue functions (Lu and Thomopoulos, 2013; Vedadghavami et al, 2017; Di Donato et al, 2018; Li et al, 2018; Radhakrishnan et al, 2018; Wu et al, 2018). Microfluidic devices, 3D printing and magnetic field are used to fabricate gradients in biomaterials (Bracaglia et al, 2017; Moller et al, 2017; Zhang et al, 2017; Kokkinis et al, 2018; Li et al, 2018) These approaches usually need special apparatus and rigorous parameters and are only feasible for specific materials. A gap remains for the biomaterials with gradients and native microenvironments of tissues in vivo
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