Biomedical Technologies for In Vitro Screening and Controlled Delivery of Neuroactive Compounds

Abstract

Cell culture models can provide information pertaining to the effective dose, toxiciology, and kinetics, for a variety of neuroactive compounds. However, many in vitro models fail to adequately predict how such compounds will perform in a living organism. At the systems level, interactions between organs can dramatically affect the properties of a compound by alteration of its biological activity or by elimination of it from the body. At the tissue level, interaction between cell types can alter the transport properties of a particular compound, or can buffer its effects on target cells by uptake, processing, or changes in chemical signaling between cells. In any given tissue, cells exist in a three-dimensional environment bounded on all sides by other cells and components of the extracellular matrix, providing kinetics that are dramatically different from the kinetics in traditional two-dimensional cell culture systems. Cell culture analogs are currently being developed to better model the complex transport and processing that occur prior to drug uptake in the CNS, and to predict blood-brain barrier permeability. These approaches utilize microfluidics, hydrogel matrices, and a variety of cell types (including lung epithelial cells, hepatocytes, adipocytes, glial cells, and neurons) to more accurately model drug transport and biological activity. Similar strategies are also being used to control both the spatial and temporal release of therapeutic compounds for targeted treatment of CNS disease.

Microfluidic cell culture systems for drug research

“…Throughout the drug discovery and development processes, a microfluidic-based cell culture or cellular assay systems can play critical roles in, for example, target validation, 62,139 lead compound identification, 49,68,149,150 pre-clinical studies including toxicity testing, 51,52,54,66,151 efficacy study 20,22,44,48,[57][58][59][60] and the study of drug delivery mechanisms. 31,61,63,152 Herein, some microfluidic-based, cell-culture systems designed for in vitro toxicity testing and those with a high-throughput capability are highlighted.…”

Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB)

“…6,14 Recently, dynamic in vitro BBB (DIV-BBB) [15][16][17] models have been developed which utilize hollow fibers to mimic the BBB architecture and flow conditions, providing adequate shear stress. However, wall thickness (150mm) is significantly higher than transwell thickness (10mm), discouraging cell-cell interaction, and DIV-BBBs take significantly longer to reach steady-state TEER values 15,32 than static transwell models. To our knowledge, no existing BBB systems have addressed each of these shortcomings yet.…”

Tissue engineering the monosynaptic circuit of the stretch reflex arc with co-culture of embryonic motoneurons and proprioceptive sensory neurons

“…In vitro models have been reported for a plethora of systems including liver [1,2], kidney [3], skin [4,5], cardiac [6,7], lung [8], neuromuscular junction [9,10], muscle [11,12], nervous system [13,14] and combinations of systems [15,16]. The reflex circuit represents the basic structure by which the central nervous system senses and responds to peripheral stimuli.…”