Topical cutaneous application of carbon dioxide via a hydrogel for improved fracture repair: results of phase I clinical safety trial

BACKGROUND: Clinicians have very limited options to improve fracture repair. Therefore, it is critical to develop a new clinically available therapeutic option to assist fracture repair biologically. We previously reported that the topical cutaneous application of carbon dioxide (CO(2)) via a CO(2) absorption-enhancing hydrogel accelerates fracture repair in rats by increasing blood flow and angiogenesis and promoting endochondral ossification. The aim of this study was to assess the safety and efficacy of CO(2) therapy in patients with fractures. METHODS: Patients with fractures of the femur and tibia were prospectively enrolled into this study with ethical approval and informed consent. The CO(2) absorption-enhancing hydrogel was applied to the fractured lower limbs of patients, and then 100% CO(2) was administered daily into a sealed space for 20 min over 4 weeks postoperatively. Safety was assessed based on vital signs, blood parameters, adverse events, and arterial and expired gas analyses. As the efficacy outcome, blood flow at the level of the fracture site and at a site 5 cm from the fracture in the affected limb was measured using a laser Doppler blood flow meter. RESULTS: Nineteen patients were subjected to complete analysis. No adverse events were observed. Arterial and expired gas analyses revealed no adverse systemic effects including hypercapnia. The mean ratio of blood flow 20 min after CO(2) therapy compared with the pre-treatment level increased by approximately 2-fold in a time-dependent manner. CONCLUSIONS: The findings of the present study revealed that CO(2) therapy is safe to apply to human patients and that it can enhance blood flow in the fractured limbs. TRIAL REGISTRATION: This study has been registered in the UMIN Clinical Trials Registry (Registration number: UMIN000013641, Date of registration: July 1, 2014).