Design,Fabrication And Applications Of Responsive Hydrogel Microneedles

Drug-delivery microneedle technology has outstanding advantages over oral drug delivery systems.Microneedles can penetrate the stratum corneum to deliver drugs safely and efficiently into the human body.Currently,most of the reported studies insert microneedles into the skin and allow drugs to automatically diffuse into the human body,which can easily lead to issues such as drug overdose and poor therapeutic effects.In this thesis,the photothermal-and pH-responsive hydrogel microneedle patches were designed and prepared.The material properties such as compressive strength,swelling property and self-healing property of responsive microneedle were characterized,and the application potential of responsive microneedles in the field of drug delivery was explored.The effects of microneedle tip diameter and microneedle spacing on the skin penetration of microneedle arrays were analyzed through simulation.A feasibility study was conducted on the preparation method of microneedles based on 3D printing.A new photothermal responsive hydrogel microneedle(Fe3O4@MN)material system containing Fe3O4 nanoparticles was proposed.The photothermal responsive hydrogel microneedle material(Fe3O4-GP)is composed of polyethylene(glycol)diacrylate(PEGDA),gelatin and Fe3O4 nanoparticles,and is prepared by ultraviolet photopolymerization.A systematic study has been conducted on this photothermal responsive microneedle,including its compressive strength,swelling property,and photothermal conversion performance.The results show that the stress of Fe3O4-GP in compression fracture was 4.25 times that of gelatin hydrogel.When the mass fraction of Fe3O4 nanoparticles is 0.92%,after 5 minutes of NIR irradiation,the temperature of the Fe3O4@MN patch increased by a maximum of about 50℃,exhibiting good photothermal conversion capabilities.Using Rhodamine B and doxycycline hydrochloride as model drugs,the potential of this photothermal responsive microneedle in drug delivery applications was explored.The results show that after 20 minutes of NIR irradiation,the in vitro drug release rate of the Fe3O4@MN patch was higher than that of the microneedle patch without Fe3O4 nanoparticles(GP@MN)and has almost doubled.By adjusting the content of Fe3O4 nanoparticles or NIR irradiation time,Fe3O4@MN Patch is expected to achieve controllable drug delivery.The drug release mechanism of Fe3O4@MN is that under NIR irradiation,Fe3O4 nanoparticles rapidly heat up,resulting in gelatin dissolution,accelerating drug release in the microneedle,and improving drug release efficiency.The photothermal responsive hydrogel microneedles prepared in this thesis have good controllable drug release ability,and its use needs external stimulation.As an internal stimulus responsive microneedle,the pH responsive microneedle does not need to consider the issue of external stimulus devices.A new pH responsive hydrogel microneedle system was proposed.After mixing PEGDA,chitosan and dialdehyde-functionalized polyethylene glycol,pH responsive hydrogel(CDP)was prepared by two-step method.The process of preparing pH responsive microneedles by CDP,the effect of PEGDA content on the swelling property,injectability,self-healing property of CDP were explored.The results show that at a compressive strain of 60%,the compressive stress of CDP with a PEGDA mass fraction of 2.5%was 2.13 times that of CDP with a PEGDA mass fraction of 0.5%.After 72 hours,in phosphate buffer salt solutions with pH of 3,4,5 and 7,the model drug release rates of CDP with a PEGDA mass fraction of 2.5%were 100%,96%,99%and 87%,respectively;In a phosphate buffer salt solution with a pH of 5,the model drug release rates for CDP with a PEGDA mass fraction of 0,0.5%,2.5%,and 5%were 98%,99%,98%and 76%,respectively.The results show that the drug release efficiency of CDP can be controlled by both pH and the content of PEGDA.The drug release mechanism of CDP is that acidic environment can accelerate the destruction of CDP structure,making the drug release faster;PEGDA can enhance the stability of the internal structure of CDP,thereby locking drugs in the CDP structure and limiting the diffusion of drug molecules.After exploring and proving the feasibility of photothermal and pH responsive hydrogel microneedle patches,the optimization of the structure of the microneedle array and the large-area manufacturing of the microneedle array with good structural integrity have become the urgent problems to be solved in this thesis.The effects of tip diameter and microneedle spacing on the puncture of skin with microneedle arrays were evaluated through simulation.and the feasibility of fabricating microneedle arrays based on 3D printing was analyzed.The study shows that when the tip diameters were 35 μm and 40 μm,the maximum stress on the microneedle tip were 447.97 MPa and 298.61 MPa,respectively.Too small diameter of the microneedle tip will make the microneedle more vulnerable to damage during skin piercing;The distance between microneedles should be reasonably increased,otherwise the microneedle array will be more difficult to penetrate the skin.Microneedle arrays in a large area can be produced based on 3D printing,but their accuracy often does not meet the predesigned requirements,requiring post processing of the printed microneedle arrays.