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
Abstract
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,…
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