Biomaterial Strategies and Therapeutic Delivery Systems to Model, Prevent, and Treat Laryngotracheal Stenosis

Laryngotracheal stenosis is a fibrotic disorder known to be a late-stage complication following prolonged intubation or tracheostomy. Prevention of scar tissue formation during intubation and controlling restenosis are currently open challenges in the field of otolaryngology. The present research focuses on addressing the multiple clinical needs arising from laryngotracheal stenosis and fibroplasia. In Aim I, we focus on controlling focal tissue damage and achieve local delivery of anti-inflammatory agents by using modified endotracheal tubes (ETTs). ETTs modified with Polycaprolactone-4–arm-Poly(EthyleneGlycol)Acrylate (PCL-4APEGA) composite were developed to decrease the possible damage using a self-lubricating system which is also capable of simultaneously releasing dexamethasone in a sustained manner and small interfering RNA (siRNA) targeting smad3 in a burst release fashion to suppress possible inflammation and fibroplasia during prolonged intubation. In Aim II, a minimally invasive therapeutic epithelial wound-coverage alternative was developed to facilitate local drug delivery to the defect site. A gecko-inspired tracheal mucosa-adhesive patch was designed based on PCL-4APEGA capable of controlled multimodal dexamethasone delivery to ameliorate local inflammation and promote tissue healing. In Aim III, we investigate the underlying physiology and model the microenvironment of the epithelial-mucosal lining of the trachea by establishing an in vitro three-dimensional microphysiological model. In this model, electrospun PCL fibers were used as a substrate for epithelial-fibroblast coculture in order to mimic the mucosal layer and the basement membrane of the trachea and establish the biophysical milieu of the native tissue. This research demonstrated the novel approaches to control possible damage to the trachea during prolonged intubation. Alternative approaches have been developed to deliver medications locally. And finally, an in vitro model has been established to mimic the mucosal lining of the upper airway.