OPTIMIZATION OF POLYMER-BASED ETHANOL ABLATION FOR HIGH- AND LOW-GRADE CERVICAL DYSPLASIA USING 3D BIOMIMETIC CONSTRUCTS

Abstract

Cervical dysplasia remains a major global health challenge, especially in low and middle income countries (LMICs), where limited access to surgical infrastructure and high loss to follow up rates hinder effective treatment. Ethanol ablation offers a highly portable, low cost alternative, but its clinical translation is limited by poor injectate retention, uncontrolled diffusion, and the absence of human relevant preclinical models capable of resolving treatment precision in the anatomically complex cervix. This dissertation presents an integrated engineering framework to optimize polymer based ethanol ablation using ethyl cellulose (EC) and methyl cellulose (MC), combining application-mechanics characterization with human scaled 3D biomimetic models of cervical dysplasia. Systematic studies in tissue mimicking phantoms and ex vivo swine cervices defined the biophysical determinants of EC–ethanol distribution, identifying needle depth, gauge, and infusion volume as critical parameters and establishing quantitative design rules for safe, predictable depot formation. Building on these insights, a clinically scaled 3D model of high‑grade cervical dysplasia was engineered to replicate epithelial stratification, stromal mechanics, and lesion geometry, thereby providing a physiologically relevant platform for evaluating EC–ethanol ablation. Within this construct, EC–ethanol generated sharply localized ablation, confining cytotoxicity to approximately 1.5 mm from the depot boundary and overcoming the non selective necrosis associated with pure ethanol.While EC–ethanol injections effectively address the deeper lesions characteristic of high‑grade dysplasia, a different strategy is required for the more superficial architecture of low‑grade disease. To address the distinct needs of low grade dysplasia, a surface restricted MC–ethanol topical gel and a custom applicator device were developed to achieve controlled, superficial ablation. The optimized formulation (10% MC, 70% ethanol) exhibited high viscosity, stability, and tunable cytotoxic penetration, achieving approximately 1.5 mm depth after three hours application while maintaining sharply defined treatment boundaries. The applicator substantially improved lesion coverage and reduced off target exposure compared to manual application. Collectively, this work establishes a grade specific strategy for polymer assisted ethanol ablation and introduces the first human relevant, scalable platform capable of resolving spatial ablation patterns in cervical tissue. These contributions provide essential design principles, mechanistic insight, and translational tools to advance low cost, locally deliverable therapies toward clinical implementation, particularly in resource limited settings.