Silk Biomaterials-Mediated miRNA Functionalized Orthopedic Devices

Abstract

Silk-based bioresorbable medical devices, such as screws, plates, and rods, have been under investigation due to their promising properties for orthopedic repairs. Options to functionalize these new devices for enhanced control of bone regeneration would also exploit the compatible processing methods used to generate the devices. MicroRNAs are important regulators of bone maintenance and formation, and miRNA-based therapeutics have the potential to aid bone repair, utilizing a transient therapeutic approach with local bioactivity. We hypothesized that silk-based orthopedic devices could be used for the local delivery of miRNAs, using anti-sense miR-214 (AS-miR-214), to inhibit endogenous expression of osteoinductive antagonist and thereby supporting the upregulation of osteoinductive target molecules activating transcription factor 4 (ATF4) and Osterix (Osx). AS-miR-214 silk devices, prepared using surface coating, demonstrated continuous release of miRNA inhibitors up to 7 days in vitro. Additionally, human mesenchymal stem cells seeded on AS-miR-214 silk films expressed higher levels of osteogenic genes ATF4, Osx, Runx2, and Osteocalcin. Interestingly, these cells exhibited lower cell viability and DNA content over 21 days. Conversely, the cells demonstrated significantly higher levels of alkaline phosphatase expression and calcium deposition compared with cells seeded on silk films with nontargeting miRNA controls. The study demonstrated that the silk-based orthopedic devices, in conjunction with bioactive miRNA-based therapeutics, may serve as a novel system for localized bone tissue engineering, enhancing osteogenesis at the implant interface while avoiding detrimental systematic side effects.

Mechanism of Endoplasmic Reticulum Stress Pathway in the Osteogenic Phenotypic Transformation of Aortic Valve Interstitial Cells

“…In this study, the gene and protein expression levels of BMP2, PERK, ATF4, and CHOP in ox-LDL-stimulated valvular interstitial cells showed differences between the experimental group and the control group, and the transcription factor ATF4 downstream of PERK was confirmed to be involved in osteogenesis ( 29 ). It can be speculated that ATF4 in the PERK pathway has a significant correlation with BMP2 expression, but the specific mechanism in valve interstitial cells remains to be further studied.…”

Advancements in nucleic acids‐based techniques for bone regeneration

“…Thus, utilizing antagonistic miRNAs against versatile regulatory miRNAs could be highly efficient in accomplishing vascularized tissue formation. [47] Lipidoids are cationic lipid-like agents that can form into spherical particles at a nanometer scale. Due to its cationic properties, it is an efficient carrier of nucleic acids, especially miRNAs.…”

The Delivery of RNA-Interference Therapies Based on Engineered Hydrogels for Bone Tissue Regeneration

“…A range of biomaterials have been investigated as molecular RNAi carriers for bone tissue engineering, including nanoparticles (Schade et al, 2014;Levingstone et al, 2019), bioactive glass (Kim et al, 2016a,b), multilayer films (James et al, 2019), TABLE 1 | Advantages and disadvantages of using scaffolds as RNAi delivery method for bone tissue engineering.…”