Aligned hydrogels with continuous gradients for the design of complex bioactive niches

Abstract

Continuous gradient signals play a vital role in maintaining tissue homeostasis and repairing damaged tissues. A challenge remains for biomaterials to design complex continuous gradients similar to the niches in vivo. Here, a simple but effective strategy is developed to introduce continuous gradient cues to aligned hydrogels by regulating the slow diffusion of nanosized aggregates. Beta-sheet enriched silk nanofibers were tuned to shorter nanoaggregates with ultrasonic treatment to change its diffusion activity. The nanoaggregates were arranged into the pre-designed discontinuous gradient patterns and incubated for several days to convert to continuous gradients through slow diffusion. The low-voltage electrical field was used to stabilize the gradients, following aligned structure formation. The resulting continuous gradients exhibited flexibility, high controllability, and versatility, enabling the formation of multiple complex gradients. Significantly better bioactivity was achieved for the hydrogels with continuous gradients, superior to that with discontinuous gradients. The rat full-thickness wound model indicated that the hydrogels with continuous SDF-1α gradients accelerated scarless wound healing and functional recovery, confirming the critical roles of the gradients in tissue regeneration. Our present study provides a universal platform to design complex niches with multiple continuous gradients, opening a new path for regenerative medicine and bionic organoids.

Statement of Significance

Both continuous gradient cues and alignment structures play crucial roles in tissue regeneration. Controlled diffusion behaviors were introduced to silk nanofiber systems with pre-designed discontinuous gradients to construct continuous gradients in the aligned hydrogels after electrical field treatment. The biomimetic hydrogels with alignment structure and flexible continuous gradients achieved improved simulation of complex microenvironment in vitro, which effectively regulated cell behaviors and accelerated tissue regeneration. The present work provides a platform to design bioactive materials and study cell-microenvironment interaction.