When Genes Meet Gels: Computational Immunogenetics of Dermal Fillers and Stratified Risk of Immune and Fibrotic Reactions across Compositions and Genotypes.

[BACKGROUND] Delayed inflammatory and fibrotic reactions to dermal fillers remain unpredictable, reflecting complex interactions between product composition and host genetics.

[OBJECTIVE] To develop and validate a computational framework integrating filler physicochemical attributes with simulated genetic variation to estimate relative immunologic and fibrotic risk across commercially available products.

[METHODS] Twenty-six fillers were analysed using a hierarchical Bayesian model combining rheologic, structural, and compositional parameters with genotype-specific modifiers in AesthetiSIM™, a reproducible Docker-based environment. Posterior distributions were derived for biostimulatory, immunogenic, and fibrotic indices, and composite scores were normalized to the [0-1] interval. Sensitivity analyses included exposure-adjusted validation, leave-one-product-out cross-validation, and variance decomposition to assess robustness.

[RESULTS] Risk scores formed a continuous spectrum. Profhilo, Juvéderm Volite, Voluma XC, and Evolysse™ SMOOTH occupied the lowest strata (mean < 0.15), whereas Sculptra, Radiesse, and HArmonyCa showed the highest (mean > 0.75). The scores quantify relative risk gradients rather than absolute event probabilities. Cluster and heatmap analyses revealed distinct mechanistic classes consistent with known material properties.

[CONCLUSION] Dermal filler safety exists on a graded continuum determined jointly by composition and genetic susceptibility. This integrative, reproducible model provides an evidence-organized framework for personalized product selection and informed patient counselling in precision aesthetic practice.

[LEVEL OF EVIDENCE IV] This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .