Plexaa for Preconditioning: The development of a preconditioning device to improve surgical outcomes

Background Skin- and nipple-sparing mastectomy is a commonly performed operation for breast cancer management, with the resulting skin envelope facilitating implant-based and/or autologous reconstruction. However, the fragile blood supply of the resulting mastectomy flap, leaves a high risk of skin necrosis, with incidence ranging from 1-30%, potentially requiring further surgical intervention, longer inpatient stays, delays to adjuvant chemo- and radiotherapy, and psychological impacts. Animal trials have demonstrated that providing local supraphysiological preconditoining with heat at 43°C to the skin prior to surgical insult can prevent skin necrosis. The mechanism is mediated by the intracellular release of chaperone proteins, namely, Heat Shock Proteins. One protein, HSP-32, catalyses the break-down of haem to several components including Carbon Monoxide (CO), which is released into the surrounding tissue. CO is a potent vasodilator causing the upregulation of blood flow to the skin, thus improving oxygenation and priming the skin for surgery. Clinical benefits have been demonstrated in two previous translational clinical studies, including an NIHR RfPB RCT, where breast cancer patients undergoing mastectomy and reconstruction were thermally preconditioned using a hot water bottle preoperatively. Preconditioned patients had lower rates of skin necrosis, length of stay, return to theatre and outpatient follow-up than controls. However, a hot water bottle is an unreliable method of heat delivery and there is a putative dose-response effect if the preconditioning is accurately controlled. To overcome these challenges Plexaa has developed a prototype device which delivers preconditioning therapy in an accurate, safe and consistent manner. Aims and objectives To assess the safety and feasibility of the Plexaa preconditioning device; To undertake user validation and seek feedback on the existing device, developed through the Innovate UK Biomedical Catalyst funding; To generate baseline data for future clinical efficacy trials and health economic analyses; To create formal documentation to submit for UKCA/CE and regulatory approval, prior to commercialisation of the product. Methods and timelines for delivery We plan to meet the above objectives within a 2-year timeframe, with the proposed devised a workplan: User validation of the existing device with input all stakeholders including our dedicated PPI group; Heathy volunteer trial: twenty healthy volunteers will be recruited to assess device safety Clinical trial: delivered in collaboration with Portsmouth University, Chelsea and Westminster and the Royal Marsden Hospitals. This will be a feasibility trial to assess the usability, acceptability and safety of the device in breast cancer patients. We aim to complete these within the first 14 months of the project, allowing sufficient time for further analysis of the information, including health economic analyses. Anticipated impact and dissemination The data generated from the healthy volunteer and feasibility studies, will allow Plexaa to seek UKCA/CE and regulatory approval, prior to commercialisation and adoption by the NHS and international institutions. Dissemination will be through peer-reviewed publications and charities such as Future Dreams, Black Women Rising and South Asian Super Nova's ensuring awareness across all patient groups including minority and underserved patients. The ultimate goal is to ensure all breast cancer patients benefit from supraphysiological preconditioning.