Plasma-Modified Collagen Nanofibers for Accelerated Wound Healing: A Genetic and Epigenetic Framework for Precision Tissue Regeneration

Abstract

Chronic and non-healing wounds represent a growing clinical and economic burden worldwide, and conventional scaffolds still largely fail to actively instruct the cellular programs required for organized dermal regeneration. This integrative narrative review synthesizes evidence from plasma physics, collagen bioscience, cell biology, and epigenomics into a mechanism-oriented framework for next-generation wound-care matrices, with explicit and sustained attention to the strength of the underlying evidence. To make the basis of the synthesis transparent, the literature was identified through structured searches of PubMed/MEDLINE, Scopus, and the Web of Science Core Collection (January 2000–December 2025), and each principal mechanistic claim is graded according to whether it is directly demonstrated in plasma-treated collagen systems (Tier A), well established in an adjacent context and extrapolated by analogy (Tier B), or advanced as a testable hypothesis awaiting validation (Tier C).
We examine how cold atmospheric plasma (CAP) treatment of electrospun type I collagen nanofibers remodels surface chemistry, mechanical integrity, and biological signaling. Drawing on surface science, proteomics, transcriptomics, and epigenomics, we describe how reactive oxygen and nitrogen species (RONS) covalently modify collagen side chains, introduce polar functional groups, increase nanoscale roughness, and reorganize fibril packing—effects that are, for the most part, directly measurable and therefore well supported. These physicochemical changes are associated with enhanced adhesion, proliferation, and directional migration of keratinocytes, dermal fibroblasts, and endothelial progenitor cells, and with upregulation of extracellular-matrix (ECM) biosynthetic genes—including COL1A1, COL3A1, FN1, and VEGFA—through integrin–FAK/ILK, Rho/ROCK, YAP/TAZ, and TGF-β/SMAD signaling.
We argue that epigenetic reprogramming—context-specific DNA-methylation changes, histone-modification remodeling, and non-coding RNA networks—represents a plausible but as-yet incompletely validated intermediary that may convert transient biophysical cues into durable transcriptional states. We deliberately distinguish this proposal, which remains largely at the level of extrapolation and hypothesis, from the better-established physicochemical and short-term cellular effects, and we set out the loss-of-function, durability, and dose–response experiments required to test it. Preclinical studies in murine, diabetic-rat, and porcine models report accelerated re-epithelialization, enhanced vascularization, and improved collagen remodeling relative to unmodified controls, although heterogeneity in plasma dosimetry and outcome reporting currently precludes quantitative pooling. We further address plasma-dose standardization, scaffold-design hierarchy, long-term biocompatibility, batch reproducibility, safety evaluation, and regulatory classification as prerequisites for clinical translation. The framework presented here is intended not as a settled account but as a rational, evidence-graded roadmap for the epigenetically informed design of plasma-functionalized collagen scaffolds.