INTRODUCTION
DELAYED WOUND HEALING, PROLIFERATION, INFLAMMATION, ADVERSE EFFECTS, DELAYED WOUND HEALING
Delayed wound healing represents an area of significant unmet medical need. Chronic wounds affect 1%–2% of the population in developed world countries, costing more than US$25 billion annually in healthcare (Järbrink et al., Chronic wounds arise when wound healing processes become disrupted. Normal, healthy wound healing consists of four sequential, overlapping phases: haemostasis; inflammation; cell proliferation; and re‐modelling culminating in wound closure. Chronic wounds, however, typically enter a persistent inflammatory state and fail to transition through the cell proliferation and remodelling phases of healing (Falanga et al., Platelets are the first responders to injury within the body and have been shown to possess a remarkable ability to induce tissue growth and repair (Eisinger et al., Upon activation, platelets release intracellular stores of growth factors, cytokines, and extracellular matrix modulators (Torreggiani et al., Several studies have demonstrated the capability of platelet EVs (pEVs) to improve cellular processes essential to wound healing, including proliferation, angiogenesis, and immunomodulation (Guo et al., In this study, we provide the first evidence for the safety and therapeutic utility of clinical‐grade pEVs to humans. We demonstrated that pEVs isolated by a novel chromatography‐based process, Ligand‐based Exosome Affinity Purification (LEAP), retain regenerative properties of their parent cell type. LEAP‐isolated pEVs induced healing‐associated proliferation, migration, and angiogenic behaviours in fibroblast and dermal endothelial cells. Proteomic analysis of the isolated pEVs revealed the presence of multiple growth factors, and we confirmed that cellular response to pEVs was mediated at least in part by their activation of the ERK and Akt signalling pathways. As a step toward developing pEVs as a potential therapeutic for chronic wounds, LEAP‐isolated pEVs were formulated as a clinical‐grade, allogeneic, candidate therapeutic product, and assessed in a randomised placebo‐controlled phase I clinical trial for wound healing in healthy volunteers. No significant adverse effects were observed. These results show that pEVs manufactured through the LEAP isolation process warrant clinical investigation as a therapeutic for delayed wound healing, such as chronic wounds.