Design And Evaluation Of Micro-cannon Drug Delivery Systems For Overcoming The Physiological Barrier

The physiological barrier constitutes a close defense system for the human body,which can prevent external enemies from"invasion"and play an important physiological function in the human body.However,it is also a key obstacle to breakthroughs in drug administration.According to the latest data from the World Health Organization（WTO）,5%of the world’s population,almost 360 million people,suffers from hearing loss.As we all know,the tympanic membrane and round window membrane are important physiological barriers that need to be overcome in the treatment of hearing loss.Nanoparticles,as a way to overcome physiological barriers,are widely used in the medical field due to their advantages such as non-toxicity,low molecular weight,and increased solubility of the carriers.In many fields of medicine,not only can the drug’s permeability to the skin be enhanced,but it also enhances the ability of the drug to penetrate the tympanic membrane and the round window membrane.Whereas the nanoparticles are limited because of their physical and chemical properties when passing through the membrane and entering the targeted site.In order to change the transmembrane behavior from passively infiltrate into an active"breakthrough,"this paper constructed an ejection-controllable drug delivery device,which use nanoparticles as the"bullet",dry chemical propellant as the"fuel",microtubes as the“cannon wall”,and the water as the natural,non-toxic"igniter".Furthermore,the external magnetic field can control the cannon’s direction to toward the target.The microtubes were prepared by layer-by-layer self-assembly method.The polyelectrolyte membrane was mainly formed by the positive and negative charge attraction of A and B solution.The diameter of the prepared microtube was 5μm and the length was 15μm.The SEM present that the wall thickness of the microtubes can be controlled by loading different layers.The loading of Fe₃O₄-NPs into the wall of the microtubes enables the control of the microtube direction.Ion cross-linking method was used to prepare nanoparticles with or without loading Fe₃O₄-NPs.The average particle size and the polydispersity index（PDI）of nanoparticles was about 160 nm and 0.102,respectively.The solid dispersion（SD）entrapped dry chemical propellant（citric acid,sodium bicarbonate）was prepared using solvent fusion method.The loading amount of D and E was measured using the bubble release rate as an indicator.After successfully preparing nanoparticles,solid dispersions and microtubes,the controllable loading of nanoparticles and solid dispersions in the microtubes was achieved using the thermal expansion principle.According to the result of confocal laser scanning,the nanoparticles occupy two thirds of the volume of the microtubes when the loading time is 10s;the nanoparticles occupy one third of the volume of the microtubes when the solid dispersion is loaded for 15s.In order to verify the ability of micro-cannons to launch nanoparticles,the theoretical calculations results demonstrated that the nanoparticles’velocity was 23.53 times faster than microtubes,which means that nanoparticles can achieve emission beyond the microtube itself.A gel was used as a model to test the ability of the device to emit nanoparticles.Finally,it was applied to the tympanic membrane and the round window membrane,and the ability of the nanoparticles to penetrate the membrane was examined by laser confocal microscopy and SEM.The pharmacokinetic properties of the nanoparticles after passing through the membrane were examined by HPLC,and the layer-by-layer distribution of nanoparticles in the membrane was investigated by confocal laser scanning confocal scanning.Different from the round window membrane,the tympanic membrane structure is special,which the squamous epithelial cell layer of the outermost structure and the mucosal layer of the innermost structure are tightly connected tissues.Thus,it is required to drive the microcannon and the magnetic field force to overcome this barrier.The round window membrane has been experimentally proven that the NPs enable quickly penetrate only using microcannon.Compared with the nanoparticle group,the microcannons have a greater advantage that nanoparticles can be used as a“reservoir”in the epithelial layer to achieve sustained delivery of nanoparticles.Membrane healing time was studied by optical microscopy and SEM.In addition,we compared the healing time of the tympanic membrane after treating with miarocannon and clinical tympanic injection.The results showed that the tympanic membrane trauma caused by the microcannon could be completely recovered at 24 hour,while the trauma caused by the clinical tympanic injection group at 24 hours did not change significantly.The round window membrane wound caused by the microcannon can basically recover at 12 hours.Taking together,the micro-cannon drug delivery device prepared in this article successfully broke through the epithelial layer of the membrane.The nanoparticles launched can act as a“reservoir”in the epithelial layer to achieve continuous delivery,which greatly improves the delivery efficiency of the nanoparticles.The design of the device provides a new delivery platform for the treatment of diseases of the middle ear and inner ear,opening a door to overcome the physiological barrier in the medical field.