Progress in Mechanical Modeling of Implantable Flexible Neural Probes

Implanted neural probes can detect weak discharges of neurons in the brain by piercing soft brain tissue,thus as important tools for brain science research,as well as diagnosis and treatment of brain diseases.However,the rigid neural probes,such as Utah arrays,Michigan probes,and metal microfilament electrodes,are mechanically unmatched with brain tissue and are prone to rejection and glial scarring after implantation,which leads to a significant degradation in the signal quality with the implantation time.In recent years,flexible neural electrodes are rapidly developed with less damage to biological tissues,excellent biocompatibility,and mechanical compliance to alleviate scarring.Among them,the mechanical modeling is important for the optimization of the structure and the implantation process.In this review,the theoretical calculation of the flexible neural probes is firstly summarized with the processes of buckling,insertion,and relative interaction with soft brain tissue for flexible probes from outside to inside.Then,the corresponding mechanical simulation methods are organized considering multiple impact factors to realize minimally invasive implantation.Finally,the technical difficulties and future trends of mechanical modeling are discussed for the next-generation flexible neural probes,which is critical to realize low-invasiveness and long-term coexistence in vivo.

Coexistent Charcot-Marie-Tooth type 1A and type 2 diabetes mellitus neuropathies in a Chinese family

Charcot-Marie-Tooth disease type 1A（CMT1A） is caused by duplication of the peripheral myelin protein 22（PMP22） gene on chromosome 17. It is the most common inherited demyelinating neuropathy. Type 2 diabetes mellitus is a common metabolic disorder that frequently causes predominantly sensory neuropathy. In this study, we report the occurrence of CMT1 A in a Chinese family affected by type 2 diabetes mellitus. In this family, seven individuals had duplication of the PMP22 gene, although only four had clinical features of polyneuropathy. All CMT1 A patients with a clinical phenotype also presented with type 2 diabetes mellitus. The other three individuals had no signs of CMT1 A or type 2 diabetes mellitus. We believe that there may be a genetic link between these two diseases.

Dantrolene enhances the protective effect of hypothermia on cerebral cortex neurons

Therapeutic hypothermia is the most promising non-pharmacological neuroprotective strategy against ischemic injury. However, shivering is the most common adverse reaction. Many studies have shown that dantrolene is neuroprotective in in vitro and in vivo ischemic injury models. In addition to its neuroprotective effect, dantrolene neutralizes the adverse reaction of hypothermia. Dantrolene may be an effective adjunctive therapy to enhance the neuroprotection of hypothermia in treating ischemic stroke. Cortical neurons isolated from rat fetuses were exposed to 90 minutes of oxygen-glucose deprivation followed by reoxygenation. Neurons were treated with 40 μM dantrolene, hypothermia（at 33°C）, or the combination of both for 12 hours. Results revealed that the combination of dantrolene and hypothermia increased neuronal survival and the mitochondrial membrane potential, and reduced intracellular active oxygen cytoplasmic histone-associated DNA fragmentation, and apoptosis. Furthermore, improvements in cell morphology were observed. The combined treatment enhanced these responses compared with either treatment alone. These findings indicate that dantrolene may be used as an effective adjunctive therapy to enhance the neuroprotective effects of hypothermia in ischemic stroke.

Fabrication and characterization of implantable silicon neural probe with microfluidic channels

In this paper, a silicon-based neural probe with microfluidic channels was developed and evaluated. The probe can deliver chemicals or drugs to the target neurons while simultaneously recording the electrical action of these neurons extracellularly. The probe was fabricated by double-sided deep reactive ion etching （DRIE） from a silicon-on-insulator （SO1） wafer. The flu- idic channels were formed with V-shape groove etching on the silicon probe and sealed with silicon nitride and parylene-C. The shank of the probe is 4 mm long and 120 ~tm wide. The thickness of the probe is 100 ~tm. The probe has two fluidic chan- nels and two recording sites. The microfluidic channels can withstand a pressure drop as much as 30 kPa and the flow resisti ity of the microfluidic channel is 0.13 μL min-1 kPa-1, The typical impedance of the neural electrode is 32.3 kΩ at 1 kHz at room temperature.

Effects of Micro-Milling and Laser Engraving on Processing Quality and Implantation Mechanics of PEG-Dexamethasone Coated Neural Probe

Compared with stiff silicon-based probes,flexible neural probes can alleviate biological inflammation and tissue rejection.A polyethylene glycol(PEG)coating can facilitate the insertion of flexible probes,and the fabrication methods have a significant impact on the dimensional accuracy and structural strength of the coating.In this study,a novel melting injection moulding method is used to process a PEG-dexamethasone(PEG-DEX)coating with high structural strength for a type of mesh-shaped photosensitive polyimide(PSPI)based neural probe.Combined with the digital image correlation(DIC)method,an in vitro test system with high accuracy is developed to evaluate the effects of the elastic modulus of the PEG component and two fabrication methods,i.e.,computer-numerical-control(CNC)micro-milling and laser engraving,on the processing quality and implantation mechanics of a PEG-DEX coated probe.The results show that compared with laser engraving,CNC micro-milling can ensure high dimensional accuracy and sharpness for the composite coating,thus leading to small damage from implantation,whereas the elastic modulus of the composite coating has a limited effect on the implantation mechanics of the PEG-DEX coated probe.

A tassel-type multilayer flexible probe for invasive neural recording

Invasive neural probes are one of the most critical components in the intracortical neural signal recording system.However,they can cause brain damage and tissue response during and after implantation.Thus,neural probes with high flexibility,biocompatibility,and simple implantation methods are required in brain research.Here we present a novel approach to fabricating a multilayer flexible tassel-type neural probe using low-cost maskless laser direct-write lithog-raphy,combined with straightforward release and assembly methods to prepare a whole implantation system.The probe has 32 recording electrodes with an area of 8×8μm^(2),arranged into two rows of different depths and 16 separated shanks,aiming at the neural signal recording in an extensive range.Polyimide and gold are used as the insulating and conductive layers,respectively.With the help of a polyethylene glycol(PEG)coating,the tassel structure was mechanically enhanced for successful implantation,and our morphology characterization showed that the diameter of the coated probe was less than 50μm.Mechanical property tests also proved that it had the necessary stiffness for brain implantation.Afterwards,electrochemical tests were carried out,which showed that the probe had a rather low impedance after a simple gold electroplating.Finally,in vivo experiments demonstrated our probe can be successfully used in neural recording.

Nanoscience and the nano-bioelectronics frontier

This review describes work presented in the 2014 inaugural Tsinghua University Press-Springer Nano Research Award lecture, as well as current and future opportunities for nanoscience research at the interface with brain science. First, we briefly summarize some of the considerations and the research journey that has led to our focus on bottom-up nanoscale science and technology. Second, we recapitulate the motivation for and our seminal contributions to nanowire- based nanoscience and technology, including the rational design and synthesis of increasingly complex nanowire structures, and the corresponding broad range of ＂applications＂ enabled by the capability to control structure, com- position and size from the atomic level upwards. Third, we describe in more detail nanowire-based electronic devices as revolutionary tools for brain science, including （i） motivation for nanoelectronics in brain science, （ii） demonstration of nanowire nanoelectronic arrays for high-spatial/high-temporal resolution extracellular recording, （iii） the development of fundamentally-new intracellular nanoelectronic devices that approach the sizes of single ion channels, （iv） the introduction and demonstration of a new paradigm for innervating cell networks with addressable nanoelectronic arrays in three-dimensions. Last, we conclude with a brief discussion of the exciting and potentially transformative advances expected to come from work at the nanoelectronics-brain interface.