A Dual-Index Framework for Cold Atmospheric Plasma Dosing: A Meta-Analysis of Parametric Control from Volumetric Redox Flux to Redox Homeostatic Status

Cold atmospheric plasma (CAP) has emerged as a versatile therapeutic platform with demonstrated efficacy across diverse disease models. Despite significant preclinical progress, clinical translation remains hindered by the absence of standardized dosing protocols and consensus on dosimetric quantification. This systematic review and meta-analysis synthesizes evidence from 2020 to 2025 to establish a parametric framework for CAP dosing grounded in quantitative analysis of dose-dependent biological responses. We first characterize the biphasic, hormetic nature of CAP biological effects, demonstrating that moderate-to-high doses induce pro-oxidant cytotoxicity via oxidative stress-mediated cell death, whereas low-to-moderate doses activate antioxidant defense pathways favoring cytoprotection. Through systematic analysis of 400+ studies meeting inclusion criteria, we quantitatively map five critical control parameters, frequency, flow rate, voltage, processing time, and gas composition, elucidating their individual and synergistic influences on reactive species profiles and therapeutic outcomes. Our meta-analysis reveals distinct parametric distributions across discharge configurations, treatment modalities, and disease applications. Based on this quantitative synthesis, we propose a dual-index integrative framework for CAP dosage: volumetric reactive oxygen and nitrogen species flux as the physical dosimetric index governing parametric control, and redox homeostatic status as the biological dosimetric index reflecting cellular heterogeneity and therapeutic sensitivity. Current limitations arising from device heterogeneity and treatment form diversity are discussed alongside emerging solutions including machine learning-assisted dose prediction and closed-loop control systems. Cold atmospheric plasma (CAP) elicits a hormetic, biphasic dose-response curve fundamentally governed by the concentration and composition of delivered reactive oxygen and nitrogen species (RONS). While, low-to-moderate RONS fluxes activate adaptive antioxidant pathways, conferring cytoprotection and enhanced stress resistance, moderate-to-high RONS fluxes overwhelm cellular antioxidant capacity, triggering oxidative damage and programmed cell death. To address this dose-dependent duality, we propose a dual-index integrative framework for CAP dosage comprising ‘volumetric RONS flux’ (ΦRONS) as the physical dosimetric index and ‘redox homeostatic status’ as the biological dosimetric index. ΦRONS integrates three determinant factors, interfacial RONS concentration, transport velocity, and treatment area, into a quantifiable, device-agnostic metric; redox homeostatic status captures biological response through endogenous markers that reflect both the pre-treatment redox setpoint and CAP-induced shifts. Together, these twin indices establish a closed-loop adaptive control architecture bridging plasma device operation and clinical efficacy, offering a roadmap toward reproducible, personalized plasma medicine.