Title : Promoting mitocytosis via gene-engineered aligned fibers for pelvic floor reconstruction
Abstract:
Severe Pelvic Organ Prolapse (POP) relies primarily on pelvic floor reconstructive surgery for repair. Polypropylene mesh, currently the mainstay in clinical practice, is associated with poor biocompatibility and serious surgical complications, leading to safety warnings and sales restrictions by the U.S. Food and Drug Administration (FDA). Therefore, developing novel biocompatible meshes tailored to the pathological features of pelvic floor disorders is urgently needed. Our team previously identified that abnormal accumulation of damaged mitochondria represents a key pathological barrier to pelvic fascial tissue repair, yet conventional therapeutic approaches, including pharmacological interventions, fail to effectively clear these damaged organelles. In this study, we integrated microfluidic chip technology with micro-solution coaxial aligned electrospinning to develop a gene-engineered aligned electrospun fiber scaffold. We demonstrate for the first time that upregulating tetraspanin 9 (TSPAN9) to promote mitocytosis enables effective repair of damaged fascial tissue.
Specifically, we first encapsulated the key gene TSPAN9, which regulates mitocytosis, into liposome nanocarriers using microfluidic technology. We then fabricated core-shell structured aligned fibers via micro-solution coaxial electrospinning, with TSPAN9-loaded liposomes protected within a hyaluronic acid (HA) core and aligned polylactic acid (PLA) fibers forming the outer shell. In vitro studies showed that these aligned fibers closely mimicked the anisotropic architecture of native fascia and significantly promoted directional cell migration through provision of aligned topographical cues. Sustained release of gene-loaded liposomes to target cells effectively restored mitochondrial quality control homeostasis, re-established mitochondrial respiratory function, reduced reactive oxygen species (ROS) levels, and stabilized mitochondrial membrane potential.
In vivo studies confirmed that this gene-engineered fiber scaffold promoted clearance of damaged mitochondria through TSPAN9-mediated mitocytosis, significantly suppressed local inflammatory responses, and facilitated functional regeneration of fascial tissue. In summary, this study presents a novel and translationally promising therapeutic strategy for fascial tissue repair through mitocytosis-enhancing gene-engineered fibers.
