Biocompatibility of injectable resilin‐based hydrogels

Abstract

Vocal folds are connective tissues housed in the larynx, which can be subjected to various injuries and traumatic stimuli that lead to aberrant tissue structural alterations and fibrotic-induced biomechanical stiffening observed in patients with voice disorders. Much effort has been devoted to generate soft biomaterials that are injectable directly to sites of injury. To date, materials applied toward these applications have been largely focused on natural extracellular matrix-derived materials such as collagen, fibrin or hyaluronic acid; these approaches have suffered from the fact that materials are not sufficiently robust mechanically nor offer sufficient flexibility to modulate material properties for targeted injection. We have recently developed multiple resilin-inspired elastomeric hydrogels that possess similar mechanical properties as those reported for vocal fold tissues, and that also show promising in vitro cytocompatibility and in vivo biocompatibility. Here we report studies that test the delivery of resilin-based hydrogels through injection to the subcutaneous tissue in a wild-type mice model; histological and genetic expression outcomes were monitored. The rapid kinetics of crosslinking enabled facile injection and ensured the rapid transition of the viscous resilin precursor solution to a solid-like hydrogel in the subcutaneous space in vivo; the materials exhibited storage shear moduli in the range of 1000-2000 Pa when characterized through oscillatory rheology. Histological staining and gene expression profiles suggested minimal inflammatory profiles three weeks after injection, thereby demonstrating the potential suitability for site-specific in vivo injection of these elastomeric materials. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2229-2242, 2018.

Redox‐Responsive Resilin‐Like Hydrogels for Tissue Engineering and Drug Delivery Applications

“…Furthermore, human mesenchymal stem cells showed high viability when cultured on RZ10‐RGD crosslinked with transglutaminase or when encapsulated in RLP hydrogels crosslinked with THP or PEG . Recent studies demonstrated the promise of resilin‐like proteins in tissue engineering and drug delivery applications by showing the biocompatibility in an animal model . DTSSP has also been shown to trigger minimal inflammation in the rat subcutaneous space …”

Recent developments in sustainably sourced protein-based biomaterials

“…Animal-derived tropoelastin, recombinant production [16]. Recombinant elastin-like recombinamers (ELRs) [11,36,39]; Recombinant resilin-like peptides (RLPs)/ protein [50][51][52] or protein [53].…”

“…Elastin has also been shown to improve the mechanical properties of other protein-based materials, such as gelatin and cellulose acetate scaffolds for skin tissue engineering where the ability of the graft to flex with surrounding healthy tissue is paramount [123]. Resilin, much like elastin, is a protein with high elasticity and resilience to repetitive mechanical loading [50]. Although natively found in insects, resilin and modified resilin-like proteins are commonly produced by expression in bacterial culture [50][51][52].…”

Production and Characterization of Recombinant Collagen-Binding Resilin Nanocomposite for Regenerative Medicine Applications

“…A few studies have directly explored resilin for applications in regenerative medicine [18,19]. Rivkin et al [20] and Verker et al [21] engineered resilin to include a cellulosebinding domain (CBD) and explored it potential to bind to cellulose nanocrystals (CNCs). Kiick and coworkers [20] have developed injectable resilin hydrogels for the repair and regeneration of vocal folds.…”

“…Thus, optimal cellular growth, migration, and differentiation could be achieved by tuning the combination different biological domains within an RLP. Recently, the same group demonstrated the cytocompatibility of the injectable hydrogel in a mouse subcutaneous model for potential applications in regenerative medicine [21]. Although some early acute inflammation attributed to the cross-linker tris (hydroxymethyl phosphine) was observed, resilin showed good overall cytocompatibility.…”