3D high-density microelectrode array with optical stimulation and drug delivery for investigating neural circuit dynamics

AbstractInvestigation of neural circuit dynamics is crucial for deciphering the functional connections among regions of the brain and understanding the mechanism of brain dysfunction. Despite the advancements of neural circuit models in vitro, technologies for both precisely monitoring and modulating neural activities within three-dimensional (3D) neural circuit models have yet to be developed. Specifically, no existing 3D microelectrode arrays (MEAs) have integrated capabilities to stimulate surrounding neurons and to monitor the temporal evolution of the formation of a neural network in real time. Herein, we present a 3D high-density multifunctional MEA with optical stimulation and drug delivery for investigating neural circuit dynamics within engineered 3D neural tissues. We demonstrate precise measurements of synaptic latencies in 3D neural networks. We expect our 3D multifunctional MEA to open up opportunities for studies of neural circuits through precise, in vitro investigations of neural circuit dynamics with 3D brain models.

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Recent advances in three-dimensional microelectrode array technologies for in vitro and in vivo cardiac and neuronal interfaces

Biosensors and Bioelectronics ◽

10.1016/j.bios.2020.112687 ◽

2021 ◽

Vol 171 ◽

pp. 112687

Author(s):

Jong Seob Choi ◽

Heon Joon Lee ◽

Swaminathan Rajaraman ◽

Deok-Ho Kim

Keyword(s):

Microelectrode Array ◽

Three Dimensional ◽

Recent Advances

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Challenges in Modeling Human Neural Circuit Formation via Brain Organoid Technology

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2020.607399 ◽

2020 ◽

Vol 14 ◽

Author(s):

Takeshi K. Matsui ◽

Yuichiro Tsuru ◽

Ken-ichiro Kuwako

Keyword(s):

Human Brain ◽

Brain Development ◽

Neural Circuit ◽

Disease Modeling ◽

Three Dimensional ◽

Neural Lineage ◽

Human Brain Development ◽

Brain Organoid ◽

Circuit Formation

Human brain organoids are three-dimensional self-organizing tissues induced from pluripotent cells that recapitulate some aspects of early development and some of the early structure of the human brain in vitro. Brain organoids consist of neural lineage cells, such as neural stem/precursor cells, neurons, astrocytes and oligodendrocytes. Additionally, brain organoids contain fluid-filled ventricle-like structures surrounded by a ventricular/subventricular (VZ/SVZ) zone-like layer of neural stem cells (NSCs). These NSCs give rise to neurons, which form multiple outer layers. Since these structures resemble some aspects of structural arrangements in the developing human brain, organoid technology has attracted great interest in the research fields of human brain development and disease modeling. Developmental brain disorders have been intensely studied through the use of human brain organoids. Relatively early steps in human brain development, such as differentiation and migration, have also been studied. However, research on neural circuit formation with brain organoids has just recently began. In this review, we summarize the current challenges in studying neural circuit formation with organoids and discuss future perspectives.

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Development of a Biodegradable Subcutaneous Implant for Prolonged Drug Delivery Using 3D Printing

Pharmaceutics ◽

10.3390/pharmaceutics12020105 ◽

2020 ◽

Vol 12 (2) ◽

pp. 105 ◽

Cited By ~ 15

Author(s):

Sarah Stewart ◽

Juan Domínguez-Robles ◽

Victoria McIlorum ◽

Elena Mancuso ◽

Dimitrios Lamprou ◽

...

Keyword(s):

Drug Delivery ◽

3D Printing ◽

Three Dimensional ◽

In Vitro Models ◽

Implant Design ◽

The Past ◽

Drug Delivery Devices ◽

Potential Use ◽

Subcutaneous Implant

Implantable drug delivery devices offer many advantages over other routes of drug delivery. Most significantly, the delivery of lower doses of drug, thus, potentially reducing side-effects and improving patient compliance. Three dimensional (3D) printing is a flexible technique, which has been subject to increasing interest in the past few years, especially in the area of medical devices. The present work focussed on the use of 3D printing as a tool to manufacture implantable drug delivery devices to deliver a range of model compounds (methylene blue, ibuprofen sodium and ibuprofen acid) in two in vitro models. Five implant designs were produced, and the release rate varied, depending on the implant design and the drug properties. Additionally, a rate controlling membrane was produced, which further prolonged the release from the produced implants, signalling the potential use of these devices for chronic conditions.

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Microcapsules functionalized with neuraminidase can enter vascular endothelial cells in vitro

Journal of The Royal Society Interface ◽

10.1098/rsif.2014.1027 ◽

2014 ◽

Vol 11 (101) ◽

pp. 20141027 ◽

Cited By ~ 11

Author(s):

Weizhi Liu ◽

Xiaocong Wang ◽

Ke Bai ◽

Miao Lin ◽

Gleb Sukhorukov ◽

...

Keyword(s):

Drug Delivery ◽

Endothelial Cells ◽

Mechanical Stability ◽

Vascular Endothelial Cells ◽

Umbilical Vein ◽

Three Dimensional ◽

Endothelial Barrier ◽

Live Cells ◽

Umbilical Vein Endothelial Cells

Microcapsules made of polyelectrolyte multilayers exhibit no or low toxicity, appropriate mechanical stability, variable controllable degradation and can incorporate remote release mechanisms triggered by various stimuli, making them well suited for targeted drug delivery to live cells. This study investigates interactions between microcapsules made of synthetic (i.e. polystyrenesulfonate sodium salt/polyallylamine hydrochloride) or natural (i.e. dextran sulfate/poly- l -arginine) polyelectrolyte and human umbilical vein endothelial cells with particular focus on the effect of the glycocalyx layer on the intake of microcapsules by endothelial cells. Neuraminidase cleaves N -acetyl neuraminic acid residues of glycoproteins and targets the sialic acid component of the glycocalyx on the cell membrane. Three-dimensional confocal images reveal that microcapsules, functionalized with neuraminidase, can be internalized by endothelial cells. Capsules without neuraminidase are blocked by the glycocalyx layer. Uptake of the microcapsules is most significant in the first 2 h. Following their internalization by endothelial cells, biodegradable DS/PArg capsules rupture by day 5; however, there is no obvious change in the shape and integrity of PSS/PAH capsules within the period of observation. Results from the study support our hypothesis that the glycocalyx functions as an endothelial barrier to cross-membrane movement of microcapsules. Neuraminidase-loaded microcapsules can enter endothelial cells by localized cleavage of glycocalyx components with minimum disruption of the glycocalyx layer and therefore have high potential to act as drug delivery vehicles to reach tissues beyond the endothelial barrier of blood vessels.

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Optical Stimulation Effects on TiO2Sensor Dielectric Used in Capacitively-Coupled High-Density CMOS Microelectrode Array

IEEE Electron Device Letters ◽

10.1109/led.2017.2701901 ◽

2017 ◽

Vol 38 (7) ◽

pp. 967-970 ◽

Cited By ~ 5

Author(s):

Gabriel Bertotti ◽

Florian Jetter ◽

Stefan Keil ◽

Normal Dodel ◽

Matthias Schreiter ◽

...

Keyword(s):

Microelectrode Array ◽

High Density ◽

Optical Stimulation ◽

Capacitively Coupled

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Three-Dimensional Printing of Curcumin-Loaded Biodegradable and Flexible Scaffold for Intracranial Therapy of Glioblastoma Multiforme

Pharmaceutics ◽

10.3390/pharmaceutics13040471 ◽

2021 ◽

Vol 13 (4) ◽

pp. 471

Author(s):

Ruixiu Li ◽

Yunmei Song ◽

Paris Fouladian ◽

Mohammad Arafat ◽

Rosa Chung ◽

...

Keyword(s):

Drug Delivery ◽

Glioblastoma Multiforme ◽

Drug Delivery System ◽

Delivery System ◽

Treatment Options ◽

Three Dimensional ◽

Great Promise ◽

Porous Scaffolds ◽

3D Printed

A novel drug delivery system preventing Glioblastoma multiforme (GBM) recurrence after resection surgery is imperatively required to overcome the mechanical limitation of the current local drug delivery system and to offer personalised treatment options for GBM patients. In this study, 3D printed biodegradable flexible porous scaffolds were developed via Fused Deposition Modelling (FDM) three-dimensional (3D) printing technology for the local delivery of curcumin. The flexible porous scaffolds were 3D printed with various geometries containing 1, 3, 5, and 7% (w/w) of curcumin, respectively, using curcumin-loaded polycaprolactone (PCL) filaments. The scaffolds were characterised by a series of characterisation studies and in vitro studies were also performed including drug release study, scaffold degradation study, and cytotoxicity study. The curcumin-loaded PCL scaffolds displayed versatile spatiotemporal characteristics. The polymeric scaffolds obtained great mechanical flexibility with a low tensile modulus of less than 2 MPa, and 4 to 7-fold ultimate tensile strain, which can avoid the mechanical mismatch problem of commercially available GLIADEL wafer with a further improvement in surgical margin coverage. In vitro release profiles have demonstrated the sustained release patterns of curcumin with adjustable release amounts and durations up to 77 h. MTT study has demonstrated the great cytotoxic effect of curcumin-loaded scaffolds against the U87 human GBM cell line. Therefore, 3D printed curcumin-loaded scaffold has great promise to provide better GBM treatment options with its mechanical flexibility and customisability to match individual needs, preventing post-surgery GBM recurrence and eventually prolonging the life expectancy of GBM patients.

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Electrically Controlled Neurochemical Delivery from Microelectrodes for Focal and Transient Modulation of Cellular Behavior

Biosensors ◽

10.3390/bios11090348 ◽

2021 ◽

Vol 11 (9) ◽

pp. 348

Author(s):

Chao Tan ◽

Neetu Kushwah ◽

Xinyan Tracy Cui

Keyword(s):

Drug Delivery ◽

Endothelial Cells ◽

Conducting Polymer ◽

Neural Circuit ◽

Loading Capacity ◽

Gamma Aminobutyric Acid ◽

Cellular Behavior ◽

Dual Functional ◽

Neural Activities ◽

Endothelial Cell Cultures

Electrically controlled drug delivery of neurochemicals and biomolecules from conducting polymer microelectrode coatings hold great potentials in dissecting neural circuit or treating neurological disorders with high spatial and temporal resolution. The direct doping of a drug into a conducting polymer often results in low loading capacity, and the type of molecule that can be released is limited. Poly(3,4-ethylenedioxythiophene) (PEDOT) doped with sulfonated silica nanoparticles (SNP) has been developed as a more versatile platform for drug delivery. In this work, we demonstrate that neurochemicals with different surface charge, e.g., glutamate (GLU), gamma-Aminobutyric acid (GABA), dopamine (DA), 6,7-Dinitroquinoxaline- 2,3-dione (DNQX) and bicuculline, can be, respectively, incorporated into the SNP and electrically triggered to release repeatedly. The drug loaded SNPs were incorporated in PEDOT via electrochemical deposition on platinum microelectrodes. After PEDOT/SNP(drug) coating, the charge storage capacity (CSC) increased 10-fold to 55 ± 3 mC/cm2, and the impedance at 1 kHz was also reduced approximately 6-fold. With the aid of a porous SNP, the loading capacity and number of releases of GLU was increased >4-fold and 66-fold, respectively, in comparison to the direct doping of PEDOT with GLU (PEDOT/GLU). The focal release of GLU and GABA from a PEDOT/SNP (drug) coated microelectrode were tested in cultured neurons using Ca imaging. The change in fluo-4 fluorescence intensity after electrically triggered GLU (+6.7 ± 2.9%) or GABA (−6.8 ± 1.6%) release indicated the successful modulation of neural activities by neurotransmitter release. In addition to activating neural activities, glutamate can also act on endothelial cells to stimulate nitric oxide (NO) release. A dual functional device with two adjacent sensing and releasing electrodes was constructed and we tested this mechanism in endothelial cell cultures. In endothelial cells, approximately 7.6 ± 0.6 nM NO was detected in the vicinity of the NO sensor within 6.2 ± 0.5 s of GLU release. The rise time of NO signal, T0–100, was 14.5 ± 2.2 s. In summary, our work has demonstrated (1) a platform that is capable of loading and releasing drugs with different charges; (2) proof of concept demonstrations of how focal release of drugs can be used as a pharmacological manipulation to study neural circuitry or NO’s effect on endothelial cells.

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A quantitative in silico platform for simulating cytotoxic and nanoparticle drug delivery to solid tumours

Interface Focus ◽

10.1098/rsfs.2018.0063 ◽

2019 ◽

Vol 9 (3) ◽

pp. 20180063 ◽

Cited By ~ 6

Author(s):

Peter A. Wijeratne ◽

Vasileios Vavourakis

Keyword(s):

Drug Delivery ◽

In Silico ◽

Fluid Velocity ◽

Three Dimensional ◽

Tumour Regression ◽

High Porosity ◽

Heterogeneous Distribution ◽

Nanoparticle Drug Delivery

The role of tumour–host mechano-biology and the mechanisms involved in the delivery of anti-cancer drugs have been extensively studied using in vitro and in vivo models. A complementary approach is offered by in silico models, which can also potentially identify the main factors affecting the transport of tumour-targeting molecules. Here, we present a generalized three-dimensional in silico modelling framework of dynamic solid tumour growth, angiogenesis and drug delivery. Crucially, the model allows for drug properties—such as size and binding affinity—to be explicitly defined, hence facilitating investigation into the interaction between the changing tumour–host microenvironment and cytotoxic and nanoparticle drugs. We use the model to qualitatively recapitulate experimental evidence of delivery efficacy of cytotoxic and nanoparticle drugs on matrix density (and hence porosity). Furthermore, we predict a highly heterogeneous distribution of nanoparticles after delivery; that nanoparticles require a high porosity extracellular matrix to cause tumour regression; and that post-injection transvascular fluid velocity depends on matrix porosity, and implicitly on the size of the drug used to treat the tumour. These results highlight the utility of predictive in silico modelling in better understanding the factors governing efficient cytotoxic and nanoparticle drug delivery.

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Biomedical Applications of Graphene-Based Structures

Nanomaterials ◽

10.3390/nano8110944 ◽

2018 ◽

Vol 8 (11) ◽

pp. 944 ◽

Cited By ~ 49

Author(s):

Krzysztof Tadyszak ◽

Jacek Wychowaniec ◽

Jagoda Litowczenko

Keyword(s):

Drug Delivery ◽

Graphene Oxide ◽

Biomedical Applications ◽

Three Dimensional ◽

Real Life ◽

Biological Applications ◽

Proliferation And Differentiation ◽

Reduced Forms

Graphene and graphene oxide (GO) structures and their reduced forms, e.g., GO paper and partially or fully reduced three-dimensional (3D) aerogels, are at the forefront of materials design for extensive biomedical applications that allow for the proliferation and differentiation/maturation of cells, drug delivery, and anticancer therapies. Various viability tests that have been conducted in vitro on human cells and in vivo on mice reveal very promising results, which make graphene-based materials suitable for real-life applications. In this review, we will give an overview of the latest studies that utilize graphene-based structures and their composites in biological applications and show how the biomimetic behavior of these materials can be a step forward in bridging the gap between nature and synthetically designed graphene-based nanomaterials.

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