Localized application of SAG21k-loaded fibrin hydrogels for targeted modulation of the hedgehog pathway in facial nerve injury.

Given the broad biological effects of the Hedgehog (Hh) pathway, there is potential clinical value in local application of Hh pathway modulators to restrict pathway activation of target tissues and avoid systemic pathway activation. One option to limit Hh pathway activation is using fibrin hydrogels to deliver pathway modulators directly to tissues of interest, bypassing systemic distribution of the drug. In this study, we loaded the potent Hh pathway agonist, SAG21k, into fibrin hydrogels. We describe the binding between fibrin and SAG21k and achieve sustained release of the drug in vitro. SAG21k-loaded fibrin hydrogels exhibit strong biological activity in vitro, using a pathway-specific reporter cell line. To test in vivo activity, we used a mouse model of facial nerve injury. Application of fibrin hydrogels is a common adjunct to surgical nerve repair, and the Hh pathway is known to play an important role in facial nerve injury and regeneration. Local application of the Hh pathway agonist SAG21k using a fibrin hydrogel applied to the site of facial nerve injury successfully activates the Hh pathway in treated nerve tissue. Importantly, this method appears to avoid systemic pathway activation when Hh-responsive organs are analyzed for transcriptional pathway activation. This method of local tissue Hh pathway agonist administration allows for effective pathway targeting surgically accessible tissues and may have translational value in situations where supranormal pathway activation is therapeutic.

A novel mouse model of chronic suppurative otitis media and its use in preclinical antibiotic evaluation.

Chronic suppurative otitis media (CSOM) is a neglected pediatric disease affecting 330 million worldwide for which no new drugs have been introduced for over a decade. We developed a mouse model with utility in preclinical drug evaluation and antimicrobial discovery. Our model used immune-competent mice, tympanic membrane perforation and inoculation with luminescent Pseudomonas aeruginosa that enabled bacterial abundance tracking in real-time for 100 days. The resulting chronic infection exhibited hallmark features of clinical CSOM, including inhibition of tympanic membrane healing and purulent ear discharge. We evaluated the standard care fluoroquinolone ofloxacin and demonstrated that this therapy resulted in a temporary reduction of bacterial burden. These data are consistent with the clinical problem of persistent infection in CSOM and the need for therapeutic outcome measures that assess eradication post-therapeutic endpoint. We conclude that this novel mouse model of CSOM has value in investigating new potential therapies.