Nanoparticle-Mediated Plaque Dissolution and Stem-Cell-Driven Vascular Regeneration: A Reproducible Simulation Framework

Atherosclerosis is a leading global cause of cardiovascular morbidity and mortality, driven by the progressive accumulation of lipid plaque, fibrous tissue, and calcification within the arterial wall. This manuscript presents a purely conceptual, hypothesis-generating protocol, the Vascular Purification Cascade (VPC), coupling two experimentally motivated mechanisms into a single simulated framework: (i) high-density-lipoprotein (HDL)-mimetic nanoparticle delivery of matrix metalloproteinases for targeted plaque dissolution, and (ii) mesenchymal stem cell (MSC) infusion intended to support endothelial regeneration. No clinical efficacy or safety claims are made for humans; every quantitative result is the output of an idealized, seeded, fully reproducible dynamical model, not of patient data. A third mechanism, adjunctive EDTA chelation, is deliberately excluded from the core model: it is not numerically coupled to the simulated dynamics, and the most rigorous available trial evidence (TACT2, 2024) does not support a cardiovascular event benefit. It is documented separately as a clearly labeled, unmodeled possible future extension (Appendix A).The core model couples a diffusion reaction PDE for spatial plaque density with a nonlinear ODE system for MSC population dynamics and paracrine growth factor signalling. All results are reported with the exact numbers the accompanying code produced. The deterministic well-mixed baseline shows a 76.20% reduction in normalized plaque burden over 30 days. A Saltelli Jansen sensitivity analysis over all six free model parameters (kn, rm, beta, lambda_g, delta_m, alpha I; 2,048 model evaluations) attributes 58.0% of first-order output variance to the nanoparticle clearance-rate parameter kn, 15.3% to the regeneration-coupling parameter lambda_g, and 13.2% to beta, with MSC proliferation rate, death rate, and infusion rate each contributing under 1%. A three-chain Metropolis Hastings simulation-based calibration (R-hat of 1.05 or less for all parameters) recovers a synthetic true parameter vector within its 95% credible interval, with an appropriately wide interval for the practically unidentifiable rm. A 200-run Latin-hypercube ensemble gives a mean reduction of 81.6% (95% CI 35.4% to 96.0%) and identifies a boundary failure mode, net plaque growth when nanoparticle activity is too low relative to regenerative signalling, in 0.5% of sampled parameter combinations. Three further analyses extend the core results: (1) a spatially resolved 1D finite-difference solution of the governing PDE, showing the failure mode not only persists but is amplified away from the nanoparticle-targeted lesion center (edge plaque burden reaches 4.25 times baseline versus 1.19 times at the center, under matched boundary-case parameters); (2) a literature-informed plausibility bound on kn from published HDL-mimetic nanoparticle circulating half-lives (12 to 24 hours), used as an upper constraint rather than a direct point estimate, since no published study reports the model's clearance-rate parameter directly; and (3) a direct nanoparticle-only versus nanoparticle plus MSC ensemble comparison (200 runs each) quantifying the regenerative term's net contribution as plus 7.2 percentage points of mean plaque reduction (Mann Whitney p less than 0.0001), while also being the sole source of the failure-mode risk. Dedicated sections address scientific and technical risk (including the model's exclusion of coagulation, immune-response, and hemodynamic terms), falsifiability criteria, and a staged preclinical-to-clinical roadmap with explicit quantitative success thresholds. All code, parameters, and seeds needed to reproduce every number in this manuscript are given in full in Section 5 and the appendix.