Electrospun poly-4-hydroxybuterate scaffolds enable local zero-order estradiol delivery and promote collagen maturation in a hypoestrogenic rat model for pelvic organ prolapse repair

Abstract

Pelvic organ prolapse (POP) affects millions of women globally, with postmenopausal hypoestrogenism playing a critical role in its development. Pelvic floor repair faces two major challenges: high recurrence rates and clinical complications that have been associated with permanent impants. Clinical complications may be reduced by using degradable implants. In fact, our previous research showed that absorbable poly-4-hydroxybutyrate (P4HB) implants result in fewer complications. We hypothesized that the high failure rates stem from impaired tissue regeneration and healing capacity, particularly in postmenopausal women requiring prolapse surgery who experience hypoestrogenism. Since estrogen is essential for tissue regeneration and pelvic floor integrity, we developed electrospun (ES) P4HB scaffolds with controlled estradiol (E2) release to enhance healing at the surgical site. In this study, we aimed to improve tissue regeneration through controlled release of estradiol (E2) at the surgical site. We investigated electrospun (ES) P4HB scaffolds loaded with E2 as a biodegradable alternative for POP repair. P4HB ES scaffolds with varying E2 concentrations (0%, 1%, 2%, and 5%) were fabricated and characterized for their physicochemical, mechanical, degradation, and drug eluting properties. Scaffolds had a suitable pore structure for tissue ingrowth and were strong and elastic enough to comply with native vaginal tissue, even after in vitro degradation for 20 weeks. In vitro drug release followed zero-order kinetics, with sustained E2 elution over 19 to 110 days. To evaluate in vivo host response, scaffolds were implanted subcutaneously in an ovariectomized rat model simulating postmenopausal estrogen deficiency. Both ES P4HB and ES P4HB-E2 scaffolds exhibited excellent biocompatibility, with no infections observed. Notably, ES P4HB-E2 scaffolds demonstrated significantly higher collagen type I/III ratio (11.5±6.3 vs 7.3±3.3, p=0.047), indicating enhanced collagen maturation and tissue remodeling. Total collagen deposition was high with no fibrotic response. LC-MS analyses confirmed local E2 delivery without systemic effects. The controlled local E2 release offers a promising therapeutic approach for POP treatment in hypoestrogenic patients.