Wireless Electronic Controlled Extracellular Vesicle Release And Disease Treatment

Extracellular vesicles（EVs）are vesicular structures with a diameter of 30 to 150 nm and typical lipid bilayer characteristics.Extracellular vesicles devived from different cells carry different proteins and genetic information,can regulate various physiological functions such as cell communication,angiogenesis,cell migration,and can be used in many disease treatment fields such as immunotherapy,cardiovascular disease treatment,tissue repair,drug loading treatment,and so on.Compared with cells,extracellular vesicles show a smaller volume,better biological safety,and significant advantages in disease treatment,such as inhibiting inflammation,restoring cell vitality,promoting vascular regeneration,and crossing the blood-brain barrier.Therefore,a large number of cell-based treatment technologies are gradually shifting towards the field of extracellular vesicles,resulting in unique extracellular vesicle treatment strategies.The treatment technology based on extracellular vesicles has put forward a demand for the dosage of extracellular vesicles,posing a challenge to their large-scale production technology.The gold standard for mass production of extracellular vesicles-three-dimensional space culture can only produce a large number of extracellular vesicles in vitro.The separation and purification process has problems such as long time consumption,low yield,damage to the extracellular vesicle membrane,and surface protein denaturation.Exogenous extracellular vesicles are often treated through in vitro injection,making it difficult to have a large number of therapeutic extracellular vesicles in the target area for a long time.The technology of large-scale,industrialized,and in situ production of extracellular vesicles is becoming a new direction in the study of extracellular vesicles.Research on extracellular biogenesis has shown that the release of extracellular vesicles is regulated by calcium ions.Calcium ions,as the second messenger of intercellular communication,can activate protein kinases,induce a series of protein phosphorylation,and ultimately cause cellular effects.Electric stimulation of cells can change the resting membrane potential of cells,open the voltage-gated calcium channel of cells,lead to calcium influx,and promote the release of extracellular vesicles.Based on the above research status,we have developed two implantable micro electrical stimulation devices for in situ release of extracellular vesicles in vivo,which are applied in immune regulation and cardiovascular disease treatment.The main content of this paper is as follows:1.Develop a passive miniature LED chip consisting of a 3D spiral coil that extracts energy from the incident RF field,an integrated RF rectifier,and a miniature printed circuit board with a light-emitting diode.Spiral coils and micro printed circuit boards are packaged in optically transparent medical grade silica gel,thus making a wireless bioelectronic device with a weight of 30 mg and a volume of 15 mm³.In the outer layer of the device,the sodium alginate hydrogel loaded with DC cells and WS₂ quantum dots is used for packaging,and the LED excites the semiconductor WS₂quantum dots to generate about 0.12μA/cm² of photocurrent.Stimulating DC cells can produce 15times the difference in the number of extracellular vesicles.The effect of DC extracellular vesicles on T cell proliferation and killing MB49 bladder cancer was verified in vitro.The anti-tumor effect of implantable wireless bioelectricity stimulation chip was demonstrated in bladder cancer model mice.2.A thin film electrode modified with polyarginine based on PEDOT:PSS was designed.After the electronic film is modified by polyarginine,the surface of the electronic film is suitable for the growth of cells.After the electronic film is encapsulated by dopamine hydrogel,an adhesive extracellular vesicle film with electrical stimulation is prepared.Stimulating macrophages can produce a 25-fold difference in the number of extracellular vesicles.The polarization ability of extracellular vesicles of macrophages,their proliferation effect on myocardial cells,and their angiogenesis ability were verified in vitro.In the rat myocardial infarction model,the bioelectronic device can effectively reduce the myocardial infarction area,improve the ejection fraction,and alleviate the symptoms of myocardial infarction.