A Systematic Review of the Mechanisms and Therapeutic Applications of GHK-Cu (Glycyl-L-Histidyl-L-Lysine-Copper Complex) in Topical Microneedle Delivery: A Case for Expanded Clinical Trials.

GHK-Cu, the copper-bound form of the human tripeptide glycyl-L-histidyl-L-lysine has accumulated more than four decades of pre-clinical evidence for tissue regeneration, anti-inflammatory action, antioxidant capacity, and broad gene-expression remodeling. Yet despite this volume, the clinical literature in humans remains thin and fragmented: most randomized trials are small, conducted on facial cosmetic creams, and rarely paired with delivery technologies capable of reliably crossing the stratum corneum. The microneedle-mediated delivery route which has been shown in vitro and in porcine ex vivo models to dramatically enhance GHK-Cu skin uptake has yet to be evaluated in a single registered, adequately powered human randomized controlled trial published in the peer-reviewed literature. This systematic review synthesizes the body of GHK-Cu literature published between 2005 and 2026, mapped against the PRISMA framework. Searches across PubMed, Elsevier ScienceDirect, and the Cochrane CENTRAL Registry yielded 1,247 records; after deduplication and screening, 64 records were retained for qualitative synthesis. Studies were stratified by study model (in vitro, ex vivo, in vivo rodent, in vivo non-rodent, and human) so that comparator therapies could be matched on equivalent footing. A critical discussion is provided on the physiology and underlying mechanistic foundation of GHK-Cu activity, including its role as an endogenous matricryptin released from collagen Iα2 and SPARC, copper's essential cofactor function for the lysyl oxidase family of cross-linking enzymes, decorin and glycosaminoglycan organization of newly deposited matrix, TGF-β3-mediated reduction of fibrosis, and ferritin-iron-modulated antioxidant defense. A dedicated surgical wound healing section addresses the evidence base for GHK-Cu in CO2 laser resurfacing, irradiated tissue and post-radiation reconstruction, Mohs micrographic surgery wounds, skin grafts, and hair transplant sites. The synthesis confirms a deep, mechanistically coherent body of preclinical evidence and reveals a defined evidence gap: well-designed human trials of GHK-Cu delivered via microneedle or microneedle-adjacent platforms (dissolvable patches, hollow microneedle arrays, dermaroller-assisted serums) are needed to translate the strong cellular and animal data into validated clinical practice. Specific recommendations for trial design stratified by indication (photoaging, androgenetic alopecia, atrophic acne scarring, chronic wound healing, post-Mohs cosmetic outcomes, post-radiation surgical reconstruction) are provided.