Advanced materials for implantable neuroelectronics.

Materials innovation has arguably played one of the most important roles in the development of implantable neuroelectronics. Such technologies explore biocompatible working systems for reading, triggering, and manipulating neural signals for neuroscience research and provide the additional potential to develop devices for medical diagnostics and/or treatment. The past decade has witnessed a golden era in neuroelectronic materials research. For example, R&D on soft material-based devices have exploded and taken center stage for many applications, including both central and peripheral nerve interfaces. Recent developments have also witnessed the emergence of biodegradable and multifunctional devices. In this article, we aim to overview recent advances in implantable neuroelectronics with an emphasis on chronic biocompatibility, biodegradability, and multifunctionality. In addition to highlighting fundamental materials innovations, we also discuss important challenges and future opportunities.

Inferring the Regulatory Network of miRNAs on Terpene Trilactone Biosynthesis Affected by Environmental Conditions.

As a medicinal tree species, ginkgo (Ginkgo biloba L.) and terpene trilactones (TTLs) extracted from its leaves are the main pharmacologic activity constituents and important economic indicators of its value. The accumulation of TTLs is known to be affected by environmental stress, while the regulatory mechanism of environmental response mediated by microRNAs (miRNAs) at the post-transcriptional levels remains unclear. Here, we focused on grafted ginkgo grown in northwestern, southwestern, and eastern-central China and integrally analyzed RNA-seq and small RNA-seq high-throughput sequencing data as well as metabolomics data from leaf samples of ginkgo clones grown in natural environments. The content of bilobalide was highest among detected TTLs, and there was more than a twofold variation in the accumulation of bilobalide between growth conditions. Meanwhile, transcriptome analysis found significant differences in the expression of 19 TTL-related genes among ginkgo leaves from different environments. Small RNA sequencing and analysis showed that 62 of the 521 miRNAs identified were differentially expressed among different samples, especially the expression of miRN50, miR169h/i, and miR169e was susceptible to environmental changes. Further, we found that transcription factors (ERF, MYB, C3H, HD-ZIP, HSF, and NAC) and miRNAs (miR319e/f, miRN2, miRN54, miR157, miR185, and miRN188) could activate or inhibit the expression of TTL-related genes to participate in the regulation of terpene trilactones biosynthesis in ginkgo leaves by weighted gene co-regulatory network analysis. Our findings provide new insights into the understanding of the regulatory mechanism of TTL biosynthesis but also lay the foundation for ginkgo leaves' medicinal value improvement under global change.

Cracking modes and force dynamics in the insertion of neural probes into hydrogel brain phantom.

Objective. The insertion of penetrating neural probes into the brain is crucial for advancing neuroscience, yet it involves various inherent risks. Prototype probes are typically inserted into hydrogel-based brain phantoms and the mechanical responses are analyzed in order to inform the insertion mechanics duringin vivoimplantation. However, the underlying mechanism of the insertion dynamics of neural probes in hydrogel brain phantoms, particularly the phenomenon of cracking, remains insufficiently understood. This knowledge gap leads to misinterpretations and discrepancies when comparing results obtained from phantom studies to those observed under thein vivoconditions. This study aims to elucidate the impact of probe sharpness and dimensions on the cracking mechanisms and insertion dynamics characterized during the insertion of probes in hydrogel phantoms.Approach. The insertion of dummy probes with different shank shapes defined by the tip angle, width, and thickness is systematically studied. The insertion-induced cracks in the transparent hydrogel were accentuated by an immiscible dye, tracked byin situimaging, and the corresponding insertion force was recorded. Three-dimensional finite element analysis models were developed to obtain the contact stress between the probe tip and the phantom.Main results. The findings reveal a dual pattern: for sharp, slender probes, the insertion forces remain consistently low during the insertion process, owing to continuously propagating straight cracks that align with the insertion direction. In contrast, blunt, thick probes induce large forces that increase rapidly with escalating insertion depth, mainly due to the formation of branched crack with a conical cracking surface, and the subsequent internal compression. This interpretation challenges the traditional understanding that neglects the difference in the cracking modes and regards increased frictional force as the sole factor contributing to higher insertion forces. The critical probe sharpness factors separating straight and branched cracking is identified experimentally, and a preliminary explanation of the transition between the two cracking modes is derived from three-dimensional finite element analysis.Significance. This study presents, for the first time, the mechanism underlying two distinct cracking modes during the insertion of neural probes into hydrogel brain phantoms. The correlations between the cracking modes and the insertion force dynamics, as well as the effects of the probe sharpness were established, offering insights into the design of neural probes via phantom studies and informing future investigations into cracking phenomena in brain tissue during probe implantations.

Array-wide uniform PEDOT:PSS electroplating from potentiostatic deposition.

Electroplating of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) is important in many neuroelectronic applications but is challenging to achieve uniformity on large-scale microelectrode arrays (MEA) using conventional galvanostatic methods. In this study, we address this challenge through a potentiostatic method and demonstrate highly uniform electroplating of PEDOT:PSS on MEA with more than one hundred electrodes, all at cellular sizes. The validation of this approach involves comparisons with galvanostatic deposition methods, showcasing unparalleled deposition yield and uniformity. Systematic electrochemical characterizations reveal similarities in structure and stability from potentiostatic deposited coatings. The advances developed here establish the potentiostatic method and detailed process to achieve a uniform coating of PEDOT:PSS on large-scale MEA, with broad utility in neuroelectronics.

Long-Term Efficacy of Biodegradable Metal-Polymer Composite Stents After the First and the Second Implantations into Porcine Coronary Arteries.

A biodegradable coronary stent is expected to eliminate the adverse events of an otherwise eternally implanting material after vessel remodeling. Both biocorrodible metals and biodegradable polymers have been tried as the matrix of the new-generation stent. Herein, we utilized a metal-polymer composite material to combine the advantages of the high mechanical strength of metals and the adjustable degradation rate of polymers to prepare the biodegradable stent. After coating polylactide (PLA) on the surface of iron, the degradation of iron was accelerated significantly owing to the decrease of local pH resulting from the hydrolysis of PLA, etc. We implanted the metal-polymer composite stent (MPS) into the porcine artery and examined its degradation in vivo, with the corresponding metal-based stent (MBS) as a control. Microcomputed tomography (micro-CT), coronary angiography (CA), and optical coherence tomography (OCT) were performed to observe the stents and vessels during the animal experiments. The MPS exhibited faster degradation than MBS, and the inflammatory response of MPS was acceptable 12 months after implantation. Additionally, we implanted another MPS after 1-year implantation of the first MPS to investigate the result of the MPS in the second implantation. The feasibility of the biodegradable MPS in second implantation in mammals was also confirmed.

Mechanism of Acceleration of Iron Corrosion by a Polylactide Coating.

Strong and biodegradable materials are key to the development of next-generation medical devices for interventional treatment. Biodegradable polymers such as polylactide (PLA) have controllable degradation profiles, but their mechanical strength is much weaker than some metallic materials such as iron; on the other hand, tuning the corrosion rate of iron to a proper time range for biomedical applications has always been a challenge. Very recently, we have achieved a complete corrosion of iron stent in vivo within the clinically required time frame by combining a PLA coating, which provides a new biomaterial type for the next-generation biodegradable coronary stents termed as a metal-polymer composite stent. The underlying mechanism of accelerating iron corrosion by a PLA coating remains an open fundamental topic. Herein, we investigated the corrosion mechanism of an iron sheet under a PLA coating in the biomimetic in vitro condition. The Pourbaix diagram (potential vs pH) was calculated to present the thermodynamic driving force of iron corrosion in the biomimetic aqueous medium. Electrochemical methods were applied to track the dynamic corrosion process and inspect various potential cues influencing iron corrosion. The present work reveals that acceleration of iron corrosion by the PLA coating arises mainly from decreasing the local pH owing to PLA hydrolysis and from alleviating the deposition of the passivation layer by the polymer coating.

Apoptosis of mesenchymal stem cells is regulated by Rspo1 via the Wnt/ß-catenin signaling pathway.

OBJECTIVE: The aim of this study was to investigate the effect and possible mechanism of action of roof plate-specific spondin1 (Rspo1) in the apoptosis of rat bone marrow mesenchymal stem cells (BMSCs). METHODS: Osteogenic and adipogenic differentiation of BMSCs was identified by Alizarin Red and Oil Red O staining, respectively. BMSC surface markers (cluster of differentiation 29 [CD29], CD90, and CD45) were detected using flow cytometry. BMSCs were transfected with an adenoviral vector encoding Rspo1 (BMSCs-Rspo1 group). The expression levels of Rspo1 gene and Rspo1 protein in the BMSCs-Rspo1 group and the two control groups (untransfected BMSCs group and BMSCs-green fluorescent protein [GFP] group) were analyzed and compared by quantitative polymerase chain reaction and Western blot. The occurrence of apoptosis in the three groups was detected by flow cytometry and acridine orange-ethidium bromide (AO-EB) double dyeing. The activity of the Wnt/ß-catenin signaling pathway was evaluated by measuring the expression levels of the key proteins of the pathway (ß-catenin, c-Jun N-terminal kinase [JNK], and phospho-JNK). RESULTS: Osteogenic and adipogenic differentiation was confirmed in cultured BMSCs by the positive expression of CD29 and CD90 and the negative expression of CD45. Significantly increased expression levels of Rspo1 protein in the BMSCs-Rspo1 group compared to those in the BMSCs (0.60 ± 0.05 vs. 0.13 ± 0.02; t=95.007, P=0.001) and BMSCs-GFP groups (0.60 ± 0.05 vs. 0.10 ± 0.02; t=104.842, P=0.001) were observed. The apoptotic rate was significantly lower in the BMSCs-Rspo1 group compared with those in the BMSCs group ([24.06 ± 2.37]% vs. [40.87 ± 2.82]%; t = 49.872, P = 0.002) and the BMSCs-GFP group ([24.06 ± 2.37]% vs. [42.34 ± 0.26]%; t = 62.358, P = 0.001). In addition, compared to the BMSCs group, the protein expression levels of ß-catenin (2.67 ± 0.19 vs. 1.14 ± 0.14; t = -9.217, P = 0.000) and JNK (1.87 ± 0.17 vs. 0.61 ± 0.07; t = -22.289, P = 0.000) were increased in the BMSCs-Rspo1 group. Compared to the BMSCs-GFP group, the protein expression levels of ß-catenin (2.67 ± 0.19 vs. 1.44 ± 0.14; t = -5.692, P = 0.000) and JNK (1.87 ± 0.17 vs. 0.53 ± 0.06; t = -10.589, P = 0.000) were also upregulated in the BMSCs-Rspo1 group. Moreover, the protein expression levels of phospho-JNK were increased in the BMSCs-Rspo1 group compared to those in the BMSCs group (1.89 ± 0.10 vs. 0.63 ± 0.09; t = -8.975, P = 0.001) and the BMSCs-GFP group (1.89 ± 0.10 vs. 0.69 ± 0.08; t = -9.483, P = 0.001). CONCLUSION: The Wnt/ß-catenin pathway could play a vital role in the Rspo1-mediated inhibition of apoptosis in BMSCs.

Strategy of Metal-Polymer Composite Stent To Accelerate Biodegradation of Iron-Based Biomaterials.

The new principle and technique to tune biodegradation rates of biomaterials is one of the keys to the development of regenerative medicine and next-generation biomaterials. Biodegradable stents are new-generation medical devices applied in percutaneous coronary intervention, etc. Recently, both corrodible metals and degradable polymers have drawn much attention in biodegradable stents or scaffolds. It is, however, a dilemma to achieve good mechanical properties and appropriate degradation profiles. Herein, we put forward a metal-polymer composite strategy to achieve both. Iron stents exhibit excellent mechanical properties but low corrosion rate in vivo. We hypothesized that coating of biodegradable aliphatic polyester could accelerate iron corrosion due to the acidic degradation products, etc. To demonstrate the feasibility of this composite material technique, we first conducted in vitro experiments to affirm that iron sheet corroded faster when covered by polylactide (PLA) coating. Then, we fabricated three-dimensional metal-polymer stents (MPS) and implanted the novel stents in the abdominal aorta of New Zealand white rabbits, setting metal-based stents (MBS) as a control. A series of in vivo experiments were performed, including measurements of residual mass and radial strength of the stents, histological analysis, micro-computed tomography, and optical coherence tomography imaging at the implantation site. The results showed that MPS could totally corrode in some cases, whereas iron struts of MBS in all cases remained several months after implantation. Corrosion rates of MPS could be easily regulated by adjusting the composition of PLA coatings.