To develop an implantable device capable of delivering intracranial cytostatic hypothermia in swine.

Patients with glioblastoma (GBM) require novel approaches to treatment. We have previously demonstrated that intra-tumoral, non-freezing, ‘cytostatic’ hypothermia, can safely stunt GBM growth and effectively prolong survival in rodents with GBM. This was demonstrated through a device consisting of a thermoelectric cooler, probe, heat sink, and fan. Unlike targeted therapeutics that are successful in preclinical models but fail in clinical trials, cytostatic hypothermia leveraged fundamental physics that influenced biology broadly. This makes biological translation more feasible but engineering challenges to larger animals and eventually patients remain unsolved.

Here we used finite element modeling to simulate heat transfer in a fully implantable system that incorporates corporal fluid-based heat distribution. We then designed devices consisting of a multiprobe array and artificial internal circulation system. Devices were successfully fabricated via CAD software, a desktop CNC machine, and a 3D printer. They were tested under lab conditions in vitro and then in vivo in anesthetized swine.

Modeling demonstrated that a multi-probe array strategy could homogenously cool a region of brain tissue to 25°C. The heat transferred out of the tissue did not raise skin temperature by >3°C from baseline (the temperature at which continuous exposure could induce thermal damage). In vitro testing validated these findings. Subsequent testing in anesthetized pigs successfully reached the target temperature that would otherwise be cytostatic: 25°C, without heating the skin by >3°C from baseline. The power source and data collection were also made fully portable, paving the way for survival surgeries.

Cytostatic hypothermia is effective in prolonging the survival of rodents with GBM. Here we have demonstrated that this approach can be scaled to larger animals and made implantable. Both these characteristics bring this novel approach closer to becoming a real option for patients with GBM.