Simulation of Cortical and Cancellous Bone to Accelerate Tissue Regeneration

Abstract

Different tissues have complex anisotropic structures to support biological functions. Mimicking these complex structures in vitro remains a challenge in biomaterials designs. Here, inspired by different types of silk nanofibers, a composite materials strategy is pursued toward this challenge. A combination of fabrication methods is utilized to achieve separate control of amorphous and beta‐sheet rich silk nanofibers in the same solution. Aqueous solutions containing two types of silk nanofibers are simultaneously treated with an electric field and with ethylene glycol diglycidyl ether (EGDE). Under these conditions, the beta‐sheet rich silk nanofibers in the mixture responded to the electric field while the amorphous nanofibers are active in the crosslinking process with the EGDE. As a result, cryogels with anisotropic structures are prepared, including mimics for cortical‐ and cancellous‐like bone biomaterials as a complex osteoinductive niche. In vitro studies revealed that mechanical cues of the cryogels induced osteodifferentiation of stem cells while the anisotropy inside the cryogels influenced immune reactions of macrophages. These bioactive cryogels also stimulated improved bone regeneration in vivo through modulation of inflammation, angiogenesis and osteogenesis responses, suggesting an effective strategy to develop bioactive matrices with complex anisotropic structures beneficial to tissue regeneration.

Silk Nanofiber Scaffolds with Multiple Angiogenic Cues to Accelerate Wound Regeneration

“…With 120 μM of DFO loaded on the BSNFs, the best angiogenic outcomes were identified while avoiding significant toxicity due to chemicals. , The stiffness also has a significant influence on cell behavior. , SF scaffolds with a modulus of 4–7 kPa supported endothelial differentiation, while the best angiogenic properties were achieved when the modulus was 5–6 kPa. , Lyophilized ASNF scaffolds with tunable stiffness were developed by changing the freezing temperature, forming soft (modulus, below 4 kPa) scaffolds due to the amorphous state of the silk . Similar to our recent study, when the ASNFs and BSNFs were blended in aqueous solution, the ASNFs maintained their temperature sensitivity while the BSNF still migrated under an electrical field. Considering the independent roles of ASNFs and BSNFs in the fabrication processes, the optimized parameters described above were used to fuse the multiple angiogenic cues in the same scaffolds.…”

“…50,51 Lyophilized ASNF scaffolds with tunable stiffness were developed by changing the freezing temperature, forming soft (modulus, below 4 kPa) scaffolds due to the amorphous state of the silk. 45 Similar to our recent study, 47 when the ASNFs and BSNFs were blended in aqueous solution, the ASNFs maintained their temperature sensitivity while the BSNF still migrated under an electrical field. Considering the independent roles of ASNFs and BSNFs in the fabrication processes, the optimized parameters described above were used to fuse the multiple angiogenic cues in the same scaffolds.…”

“…The reverse function of different cues in scar inhibition was reported by different groups, − ,− suggesting that the fine regulation of different cues is critical for scarless tissue regeneration. For example, some studies indicated that high angiogenesis usually results in serious scarring, while other groups found that the matrices with better angiogenic capacity resulted in scarless wound healing. − Anisotropic patterns not only induce the differentiation of fibroblast to myofibroblasts (indicative of scar tissue) but also stimulate M2 polarization of macrophages to inhibit scar formation. ,− Compared to the RSS scaffolds, the introduction of DFO and anisotropic features (RSS–DFO and ASS) improved angiogenesis but resulted in more scarring. When both DFO and anisotropic structures were present in the scaffolds (ASS–DFO), scarring was inhibited.…”

“…46 Based on the different responsive capacities of ASNFs and BSNFs, a novel composite strategy was developed to introduce multiple cues inside the same hydrogel where the cues could be tuned independently. 47 Cryogels with both cortical-and cancellous-like structures were prepared to simultaneously modulate inflammation, angiogenesis, and osteogenesis responses, stimulating improved bone regeneration. This composite strategy should also be feasible toward the development of bioactive wound matrices.…”

“…Unlike traditional silk solutions, ASNFs and BSNFs exhibit responsive behaviors in aqueous solution when exposed to different fabrication processes . Based on the different responsive capacities of ASNFs and BSNFs, a novel composite strategy was developed to introduce multiple cues inside the same hydrogel where the cues could be tuned independently . Cryogels with both cortical- and cancellous-like structures were prepared to simultaneously modulate inflammation, angiogenesis, and osteogenesis responses, stimulating improved bone regeneration.…”