Abstract
Electrical stimulation of cells and tissues for therapeutic benefit is a well-established method. Although animal studies can emulate the complexity of an organism’s physiology, lab-on-a-chip platforms provide a suitable primary model for follow-up animal studies. Thus, inexpensive and easy-to-use platforms for in vitro human cell studies are required. In the present study, we designed a micro-electrical impulse (micro-EI)-on-a-chip (micro-EI-chip), which can precisely control electron density and adjust the frequency based on a micro-EI. The micro-EI-chip can stimulate cells at various micro-EI densities (0–500 mV/mm) and frequencies (0–300 Hz), which enables multiple co-culture of different cell types with or without electrical stimulation. As a proof-of-concept study, a model involving degenerative inflamed human annulus fibrosus (hAF) cells was established in vitro and the effects of micro-EI on inflamed hAF cells were evaluated using the micro-EI-chip. Stimulation of the cells (150 mV/mm at 200 Hz) inhibited the secretion of inflammatory cytokines and downregulated the activities of extracellular matrix-modifying enzymes and matrix metalloproteinase-1. These results show that micro-EI stimulation could affect degenerative diseases based on inflammation, implicating the micro-EI-chip as being useful for basic research of electroceuticals.
Highlights
Symptomatic disc degeneration is a major cause of lower back pain[1]
After observing that inflammatory mediators www.nature.com/scientificreports and extracellular matrix (ECM)-modifying enzymes in disc tissue are upregulated during intervertebral disc degeneration, we examined whether activated macrophages induce the production of these factors in human annulus fibrosus (hAF) by paracrine signaling
After observing that activated macrophages secreted a variety of mediators and enzymes affecting hAFs, we investigated the intrinsic mechanism by which the soluble factors derived from activated macrophages regulate the production of inflammatory mediators and ECM enzymes
Summary
Symptomatic disc degeneration is a major cause of lower back pain[1]. In general, disc degeneration in the lumbar spine appears to result from inflammatory reactions involving various macrophages in the outer annulus fibrosus (AF)[2]. Continuous biomechanical loading on AF tissue leads to damage and induces inflammatory reactions[5,6,7]. The latter subsequently induce ingrowth of nerves positioned near the outer AF tissue toward the inner AF tissue[8]. A previous study reported the inhibitory effect of ES toward inflammatory reactions induced by treatment with dilute recombinant IL-1β reagent[18] This approach has limitations in mimicking the actual inflammatory mechanism of the human body because typical processes can produce inflammation based on complex interactions between damaged tissue and immune cells[2]. We used a micro-EI-chip system to investigate the effects of electrical impulses using a degenerative human AF model to reduce disc pain-related factors
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