Abstract
Establishing robust pharmacokinetics-pharmacodynamics (PK-PD) correlations remains a major challenge owing to high selectivity and low permeability of the blood-brain barrier (BBB), which limits the predictive power of conventional plasma pharmacokinetics on specific brain tissue. Here, we present a highly biomimetic microfluidic BBB-brain organ-on-a-chip combined with liquid chromatography-mass spectrometry (LC-MS) and electrochemical sensing technology for micro PK-PD monitoring with target cells. The platform incorporates human cerebral microvascular endothelial cells and neuron-like cells cultured on opposite sides of a collagen/fibronectin-modified porous membrane under physiological shear stress. This configuration reinforces the physical, metabolic and physiological barrier functions of BBB, as evidenced by the high expression of tight junction proteins, low apparent permeability, expression of efflux transporters, and reversible response to hypertonic stimuli. A neurodegenerative disease model is induced using 1-methyl-4-phenylpyridinium iodide (MPP(+)) to recapitulate key pathological features of early-stage Parkinson's disease. The pharmacokinetic profile of pramipexole (PPX) is monitored using both LC-MS and an integrated, regenerable electrochemical sensor. The sensor enables in situ, real-time and online detection of PPX with high sensitivity and specificity, showing strong concordance with LC-MS. Furthermore, neurotransmitter (norepinephrine) exocytosis level is quantified as a pharmacodynamic indicator, enabling micro PK-PD correlation within the disease-on-a-chip model. Collectively, the proposed new method for micro PK-PD study is expected to provide great prospects for the preclinical screening and action mechanism research of novel anti-Parkinson's disease drugs.