ENGINEERING NOVEL SUSTAINED-RELEASE HYDROGEL IMPLANTS VIA ADVANCED ADDITIVE MANUFACTURING FOR CANCER THERAPY

Ovarian cancer (OC) remains the most lethal gynecologic malignancy, largely due to its frequent diagnosis at a late stage with widespread intraperitoneal (IP) metastasis. While cell-based therapies hold immense promise for treating this disease, their clinical translation has been severely hampered by the rapid clearance and poor persistence of therapeutic cells when delivered directly into the peritoneal cavity. This dissertation addresses this critical delivery challenge through the development of a novel, implantable hydrogel scaffold platform fabricated using Continuous Liquid Interface Production (CLIP), a high-resolution 3D printing technology. This work follows a logical progression of engineering design, beginning with the establishment of a foundational platform and culminating in a therapeutically effective, optimized device. First, we developed and characterized ultra-soft, porous hydrogel scaffolds for external seeding of therapeutic cells. While this approach protected cells from the harsh fabrication process, it suffered from low and inconsistent cell loading efficiency, a key limitation for clinical translation. To overcome this, we developed a direct bioprinting approach, creating a novel GelMA-PEGDA bioink that, for the first time, incorporated the FDA-approved UV-filter Ecamsule to enable high-resolution printing with high cell viability. This bioprinted platform demonstrated a transformative, ~10-fold improvement in IP cell persistence compared to direct cell injection, with cells retained for nearly two months in vivo. Finally, we applied this optimized bioprinting platform to a metastatic murine model of ovarian cancer, using TRAIL-secreting human induced neural stem cells as the therapeutic payload. We investigated the role of scaffold porosity, a critical architectural parameter, and found that both non-porous and porous therapeutic scaffolds nearly doubled the median survival of tumor-bearing mice compared to controls. Histological analysis of retrieved scaffolds confirmed long-term cell retention and limited tumor colonization on the device surface. Collectively, this dissertation establishes CLIP-based 3D bioprinting as a powerful and clinically relevant manufacturing paradigm for creating the next generation of IP cell delivery devices. By engineering a protective and retentive niche, this platform overcomes the primary obstacle to effective IP cell therapy and provides a promising new strategy for the treatment of metastatic ovarian cancer and other peritoneal diseases.