The brain's complex network of neurons is vulnerable to abnormalities that cause neurological disorders. Implantable neural probes monitor neuronal activity, but conventional probes, made of rigid materials, cause inflammation and device migration. Soft electronics with brain-like mechanical properties offer improved long-term stability and reduced immune response. However, existing systems still rely on bulky, rigid external electronics, limiting subject mobility and long-term usability. This research aimed to create a fully integrated, soft neural interface system by directly printing electronics onto the cranium, improving biocompatibility and allowing for free movement of the subject. This approach uses high-resolution printing of liquid metals to create soft neural probes with cellular-scale diameters and adaptable lengths. The printed circuitry on the cranium enables conformal integration of electronics, wirelessly transmitting neural signals to a smartphone. This novel approach addresses the limitations of current neural interfaces by combining soft, biocompatible probes with directly printed cranial electronics, minimizing tissue damage and maximizing subject freedom during long-term studies.

Numerous studies have focused on developing soft neural probes to improve the long-term stability of devices and signal quality. However, the subsidiary electronics for signal processing and wireless transfer remain rigid and bulky, hindering the system's integration with biological systems and restricting free movement of the subject. Stretchable electronics offer improved conformability to curved body surfaces, but fixed geometries of pre-fabricated devices limit spatial variability in neural recordings. Direct printing techniques offer flexibility in design and rapid prototyping, but current printable conductive materials often require thermal annealing or solvent drying, unsuitable for biological applications. This study addresses these challenges by utilizing a high-resolution printing method with liquid metals to create a fully integrated soft neural interface system.

The researchers developed a system for high-resolution printing of liquid metal, specifically eutectic gallium-indium alloy (EGaln). This system comprised a nozzle connected to an ink reservoir, a pneumatic pressure controller, and a 6-axis stage for precise movement control. EGaln was directly printed using capillaries with inner diameters of 5–60 μm. The printing process facilitated the creation of soft neural probes with a 5 μm diameter, comparable to the size of neuronal axons. Parylene was deposited for passivation, except at the probe tip. Platinum nanoclusters (PtB) were electrodeposited onto the tip to lower impedance. The mechanical properties of the probes were characterized through tensile tests, revealing an elastic modulus several orders of magnitude lower than that of conventional electrode materials, ensuring minimal tissue damage. The self-healing properties of liquid metal were demonstrated through resistance measurements during repeated disconnection and reconnection cycles, both in air and saline solution. For cranial electronics, a conformal 3D printing method directly onto the mouse cranium was developed. A medical-grade polymer was first printed for passivation, followed by the printing of EGaln circuits and interconnections. Near-field communication (NFC) chips and antennas were integrated into the circuit. The printed circuit was encapsulated in a medical-grade silicone layer to ensure electrical stability during skin closure. For wireless neural recording, a cranial circuit integrating soft neural probes, an analog front-end chip, an NFC microcontroller unit, and a chip antenna was printed onto the cranium. The system wirelessly transmitted LFP signals to a smartphone. The stability of the cranial circuit was assessed using micro-CT and accelerated aging tests. Signal quality was compared using both monolithic (EGaln probe - EGaln interconnect) and heterogeneous (EGaln probe - Au interconnect) in vitro setups. The adaptability of the printing method was demonstrated by creating various cranial circuit configurations for multi-region neural recordings. A wi-fi based wireless neural recording system was also implemented, integrating a commercial wi-fi module with the printed cranial circuit. To assess biocompatibility and long-term stability, histological analysis and immunostaining were performed, revealing no significant immune response or neuron depletion around the probes. Finally, behavioral studies using a T-maze were conducted to demonstrate behavior-induced neuronal activation in freely moving mice.

The study successfully demonstrated a novel method for creating soft, implantable neural probes with a cellular-scale diameter (5 μm) using high-resolution liquid metal printing. The probes exhibited excellent self-healing capabilities, maintaining electrical conductivity even after significant deformation. The conformal printing of liquid metal circuits directly onto the cranial surface enabled the seamless integration of electronics, creating a miniaturized and biocompatible neural interface system. The system achieved long-term (33 weeks) stable recordings of neural signals (LFPs and single-unit spikes) in multiple brain regions (motor cortex, hippocampus, visual cortex) of freely moving mice. The monolithic integration of the probes and cranial electronics resulted in superior signal quality compared to heterogeneous connections (EGaln probe-Au interconnect), as evidenced by a 1.5 times higher potential and less distortion in the waveform. The wi-fi based wireless neural recording showed high signal quality, with a signal-to-noise ratio (SNR) 1.5 times higher than a conventional system. Behavioral studies in a T-maze confirmed the ability to record behavior-induced neuronal activation in the hippocampus and visual cortex. The histological analysis demonstrated excellent biocompatibility, with no significant inflammation or neuron depletion near the implanted probes. The study demonstrated high yield of single-unit recording (100% at 11 weeks post-implantation) that was maintained for the duration of the 33 week study. The system showed negligible heat generation during use, indicated by infrared camera observations, and the mice displayed normal behavior.

This study successfully addressed the limitations of current neural interface systems by developing a monolithic, biocompatible system combining soft, self-healing neural probes with directly printed cranial electronics. The high-resolution printing method enabled flexible customization of circuit configurations, addressing individual variations in brain and cranium anatomy. The findings demonstrate the potential for long-term, high-fidelity neural recordings in freely moving animals, providing valuable insights into brain function and behavior. This approach offers significant advantages for both fundamental neuroscience research and clinical applications, including the study of neurological disorders and the development of advanced brain-computer interfaces. The system's biocompatibility and minimal invasiveness open up new possibilities for chronic neural recording in various settings.

The researchers successfully developed and validated a novel monolithic neural interface system using high-resolution liquid metal printing. This system demonstrates long-term stability, high signal quality, and excellent biocompatibility. The ability to customize circuit configurations for various brain regions opens exciting opportunities for neuroscience research and clinical applications. Future work could focus on improving printing speed and yield for human translation and integrating miniaturized power sources directly onto the cranium.

While the study demonstrated excellent results in mice, translation to larger animals or humans may require modifications to the printing process to improve speed and yield for larger cranial surface areas. Further investigations are needed to fully assess the long-term systemic toxicity of the liquid metals and to evaluate the system's performance in different species and neurological conditions.