The curved surfaces and complex geometries of the human body create challenges in achieving soft conformal contact at the cellular scale with many existing classes of wearable health monitors, surgical tools and minimally-invasive medical devices. This size mismatch is pervasive in cardiology, where existing implantable and cardiac ablation catheters contain several orders fewer microelectrodes than there are addressable cardiomyocytes, fibroblasts, and smooth muscle cells in the heart. A similar tradeoff exists in systems designed for a brain–computer interface (BCI). To date, bio-integrated devices that interface with the curvilinear surface of the brain have largely relied on arrays of rigid microelectrodes in planar or needle-like configurations. Although successful for simple clinical practice, most conventional bio-integrated devices in use today contain widely spaced electrodes (∼0.5–1 cm), are stiff (gigapascal modulus levels for devices compared to megapascal and kilopascal ranges for soft tissue), and thus are limited to achieving poor interfacial contact at low spatial resolution. For catheter mapping systems, in particular, the large millimeter-scale size of electrodes leads to significant under-sampling of electrophysiological signals, thereby limiting the ability to identify regions of disease.
A more powerful approach involves the fabrication of silicon-based integrated circuits, associated electronics and distributed sensors in ultrathin formats onboard surgical and medical devices, allowing for flexibility or even stretching [1], [2] and [3]. Flexible/stretchable electronics, as this new class of systems has been referred to in the research literature, exploit monocrystalline silicon (Si). These Si-based electronics maintain the same high performance processing power of conventional silicon wafers to achieve multiplexing at high sampling rates and high temporal resolution. However, they also are processed to be strikingly soft and elastic compared to conventional rigid/brittle Si wafers. Their high performance, relative to organic semiconductors, coupled with their extremely low bending stiffness, therefore allows for a new class of biointegrated devices to seamlessly laminate onto deformable biological tissues for mapping electrical, mechanical, chemical and thermal properties at the cellular level [1].
Several important innovations in materials science underlie these advances in emerging biointegrated devices. The first relies on a dramatic reduction in the thickness profile of semiconductor materials (e.g. Si nanoribbons) and interconnecting metals down to the nanoscale (∼250 nm) via anisotropic wet and dry etching techniques of silicon-on-insulator (SOI) wafers [1], [2], [3] and [4]. The second depends on strategies to spatially configure discrete chiplets of silicon and passive elements in distributed arrays based on analytical and numerical modeling simulations [2]. Finally, these distributed arrays of nanomaterials are embedded on unusual substrates – deflectable catheters, elastic sheets, or bio-resorbable protein layers through wet and dry surface treatment techniques using transfer printing tools that facilitate strong adhesion between two dissimilar surfaces. The end result is a new class of bio-integrated devices containing ultrathin complementary metal oxide semiconductor (CMOS) transistors, filters, amplifiers and multiplexor circuits, matching the performance of conventional wafer-based systems, but with extreme rubber band-like mechanical characteristics. These features are useful for cardiovascular and neural applications, and may also fundamentally change the way devices are designed and integrated on human skin for health monitoring and point of care diagnostic applications [4].
In cardiac rhythm management, integration of high-density electrodes containing platinum and gold interfacing metals, with local amplifiers (for improved signal quality) and nearby multiplexing (to reduce the number of routed wires) provide routes to map and treat (via cardiac ablation) complex arrhythmias, including persistent atrial fibrillation. The new devices born out of this technology allow for much higher definition mapping of activation patterns, with substantially less interpolation processing between neighboring electrodes compared to conventional basket catheters with millimeter electrode spacing. Electrograms collected at high sampling rates (∼2 kHz per electrode) and combined spatiotemporally across ∼60–300 electrodes yield voltage and isochronal activation maps, demonstrating the natural electrophysiology of the heart, with very little to no interpolation [1], [2] and [3] and with little to no mechanical loading side effects. These advances over conventional systems offer new ways to seamlessly integrate with the heart and to clearly visualize complex arrhythmia patterns.
Much like the biointegrated systems constructed for the heart, BCI devices that localize aberrant activity on the surface of the brain have recently revealed important new insight into the mechanisms underlying micro-seizures and epilepsy triggers [2]. This technology is similar in form and implementation to cardiac devices in the sheet-based design, but for BCI, the devices have been specifically tuned to match the mechanical properties and shape of the brain. The promise of new BCI devices is to permit precise spatial localization of neurological disease triggers in order to minimize excessive resection of brain matter during therapy.
For skin-based and point-of-care health diagnostics, there are many applications ranging from tracking heart rate and measuring brain activity to hydration measurements from light-based assessment of bioanalytes in sweat secreted through skin pores. Skin based systems also have brought to the forefront ultrathin, flexible antenna designs and stretchable batteries to power such systems during continuous and/or intermittent use [4] and [5].
Advances in biointegrated devices described in this comment highlight important innovations in semiconductor and polymer fabrication processes that were once limited to the microchip and computer industries. New mechanics optimization and integration strategies for distributed nanosensors, actuators and flexible/stretchable electronics onboard existing medical device platforms have led to new breakthroughs in translational medicine. Despite the necessary clinical trials being pursued to assure biocompatibility and overall safety, it is apparent from the number of clinical applications underway in cardiac, neural, and health monitoring applications that systems containing active electronics mounted on sheets and catheters will bring forth new generations of devices in many areas of healthcare over the next decade.
Further reading
[1] D.H. Kim et al. Proc. Natl. Acad. Sci. U. S. A., 109 (49) (2012), pp. 19910–19915
[2] D.H. Kim et al. Annu. Rev. Biomed. Eng., 14 (2012), pp. 113–128
[3] J. Viventi et al. Sci. Transl. Med., 2 (2010), p. 24ra22
[4] D.H. Kim et al. Science, 333 (2011), pp. 838–843
[5] S. Xu et al. Nature Commun. (2013) http://dx.doi.org/10.1038/ncomms2553