Acute Pain Management in Children: A Systematic Review and GRADE-Based Recommendations.

Electronic devices implanted in the body provide powerful tools for diagnosis, therapeutics and research. For example, bioelectronic implants for brain stimulation have provided biological insights and have proved effective for treating many brain diseases. However, placing a medical implant inside the brain typically requires invasive intracranial surgery, with associated pain and tissue damage along with risks of infection, ischemia, psychological distress, morbidity and mortality. Even endovascular electrodes, although not requiring intracranial access, still need endovascular surgery with its associated risks and complications. Moreover, they cannot achieve submillimeter spatial targeting precision and are unable to access most brain regions. While attempts have been made to explore intravenous (i.v.) injection routes, these have led to nonspecific stimulation of large brain regions without focality. On the other hand, existing noninvasive brain stimulation technologies, such as transcranial magnetic stimulation and transcranial direct current stimulation, lack the necessary spatio-temporal resolution. Here we have developed bioelectronic devices that, after i.v. injection, are trafficked through the circulatory system and implant autonomously in brain regions of inflammation. We also demonstrate that they enable wirelessly controlled focal stimulation of deep brain regions such as ventrolateral thalamic nucleus in the rodent brain providing a nonsurgical brain implant for focal neuromodulation that takes advantage of immune cells’ natural trafficking to sites of inflammation. We name electronics that circulate through the vasculature ‘Circulatronics’ (Fig. ). Realization of the Circulatronics brain stimulator requires overcoming several hurdles: (1) development of efficient wireless free-floating electronic devices that are miniaturized to fit inside the vasculature, (2) circulation of these devices without being eliminated from the bloodstream and (3) recognition of and self-implantation in desired brain regions. To overcome these challenges, we built wireless optical energy harvesting electronic devices that are subcellular sized and self-standing with high efficiency (to achieve point (1)) and created hybrids with living immune cells (to achieve points (2) and (3)). We demonstrate this technology for brain regions of inflammation, an important therapeutic target for many neurologic diseases, including Alzheimer’s disease, multiple sclerosis, ischemic stroke, brain tumor, neuropathic pain, spinal cord and peripheral nerve injury, whose treatment may benefit from electrical modulation targeted at the inflamed region. We describe the electronic device design and fabrication, the creation of cell–electronics hybrids, the nonsurgical focal brain stimulation and biocompatibility studies. Schematic diagram illustrating the concept of Circulatronics. Credit: Pablo Penso; human anatomy image from Shutterstock.