Injectable, self-healable zwitterionic cryogels with sustained microRNA - cerium oxide nanoparticle release promote accelerated wound healing

Abstract

Diabetics are prone to chronic wounds that have slower healing, and methods of accelerating the wound closure and to ensure protection from infections are critically needed. MicroRNA-146a gets dysregulated in diabetic wounds and injection of this microRNA combined with reactive oxygen species-scavenging cerium oxide nanoparticles (CNPs) can reduce inflammation and improve wound healing; however, a better delivery method than intradermal injections is needed. Here we demonstrate a biomaterial system of zwitterionic cryogels (gels formed below freezing temperatures) laden with CNP-miR146a that are topically applicable, injectable, self-healable, and provide sustained release of the therapeutic molecules. These cryogels are comprised of CBMA or SBMA and HEMA, and do not contain chemical crosslinkers. Properties of the gels can be manipulated by changing monomer type and ratio. These materials have demonstrated efficacy and viability in vivo with a diabetic mouse wound healing model. Overall, these materials have a high potential for application in wound treatments due to their ease of production, antifouling characteristics, durability, topical application, and sustained release mechanics. STATEMENT OF SIGNIFICANCE: This work presents the development of zwitterionic cryogels with unique physical properties including injectability and self-healing, that also offer highly sustained release of nanoparticles over time to improve wound healing in a diabetic mouse model. The nanoparticles are made of cerium oxide, which is known to scavenge reactive oxygen species and reduce oxidative stress, and these particles have been further tagged with a microRNA146a that has been shown to reduce inflammation. Zwitterionic materials are known for their superior antifouling properties and good biocompatibility and ability to incorporate bioactive factors. Given these properties, the use of these materials as wound healing dressings would be exciting, yet to date it has been difficult to prolong the release of bioactive factors from them due to their hydrophilicity. Previously we developed zwitterionic cyrogels with very sustained protein release over time, but those materials were quite brittle and difficult to handle. Here, we demonstrate for the first time that by removing the crosslinker molecule from our reaction and polymerizing gels under cryo-conditions, we are able to form zwitterionic cryogels that are injectable, self-healing, and with sustained release profiles. The sustained release of miRNA146a-tagged cerium oxide nanoparticles from these gels is demonstrated to speed up diabetic wound healing time and significantly reduce inflammation.

Keywords: Cerium oxide; Cryogels; MicroRNA; Sustained release; Wound healing; Zwitterionic polymers.