80. Vaginal healing research: from bench to bedside and beyond

Abstract

<h3>Background</h3> Adolescents undergoing vaginal surgery are often left with scaring and lifelong sequelae that can interfere with their daily lives, including retained menstruation and painful vaginal exams and dyspareunia. While vaginal stents are known to aid in healing, there are no current stents available for young patients and furthermore, we do not fully understand why some girls scar while others do not. It is our goal to understand vaginal healing at the mechanistic level in order to prevent scaring while at the same time provide solutions in the clinic. <h3>Methods</h3> To elucidate fundamental mechanisms of vaginal healing, both in vitro and in vivo methods were developed. Using primary murine fibroblasts, the expression of hyaluronan (HA) related genes and cell migration in response to estrogen and mechanical stretch were evaluated. To model the interplay between vaginal layers, a vagina-on-a-chip is being designed. Murine models, including full thickness wounds and bleomycin instillation plus vaginal trauma, were developed to study regenerative vaginal healing and fibrosis, respectively. In combination with oophorectomy, histologic and gene expression changes were evaluated at various time points after insults. Clinically, vaginal stents were designed and validated in a porcine model and review panels. Virtual reality (VR) technology and 3D imaging is being used for pre-operative training. <h3>Results</h3> We have successfully isolated and rapidly expanded murine primary vaginal fibroblasts, and our ongoing in vitro work suggests that estrogen influences HA via upregulation of HA synthesis genes. Full thickness murine vaginal wounds result in complete epithelial layer closure and resolution of inflammatory changes by 72 hours, which is altered in oopherectomized mice. Bleomycin instillation alone did not lead to fibrosis, but in combination with wire brush trauma led to disrupted collagen organization. The design criteria for a vagina-on-a-chip has been established including sustaining 3D cell culture and matching biomechanical properties. Physical vaginal stent designs to improve retention and patient comfort were validated and two designs were chosen for further benchtop testing in a novel pressurized 3D-printed model and a funded Phase I clinical trial. Resorbable stents were designed with polycaprolactone-based shape memory foams to provide sufficient radial force to maintain vaginal caliber over a target healing time of 4 weeks. Lastly, we are improving clinical training with 3D imaging and VR modeling. <h3>Conclusions</h3> We are advancing vaginal healing research by translating clinical problems into basic science questions and closing the loop ultimately back to bedside improvements.