| According to IDF reports,there were 537 million diabetes patients worldwide in 2021,and it is expected to increase to 783 million by 2045.One method of treating typeⅠ and severe type Ⅱ diabetes is subcutaneous injection of insulin,but this method can cause pain,skin damage,and risks of hypoglycemia due to insulin not being supplied according to real-time needs of the body.To address these issues,researchers have proposed glucose-responsive microneedle(MN)for insulin delivery.Microneedle delivery is a painless transdermal delivery method,when combined with glucoseresponsive materials,can control insulin release based on blood glucose levels to achieve real-time blood glucose regulation.In this study,hyaluronic acid(HA)was used as the matrix of MNs,PBA based polymers were used for glucose-response to prepare the glucose-responsive MNs.A series of glucose-responsive MN patches for insulin delivery were prepared and their glucose-responsive insulin release performance and biocompatibility were studied,as well as their possible mechanisms.1.Four kinds of HAPBA with different grafting ratios were synthesized by grafting 3-aminophenylboronic acid(3APBA)on HA,whose structure were characterized.6 kinds of HAPBA-PVA hydrogels were obtained by mixing polyvinyl alcohol(PVA)and HAPBA,and their properties were characterized.By casting the hydrogel into a mold and centrifugation,5 types of microneedle patches were prepared,and their mechanical properties and morphology were studyed.The results showed that HAPBA was successfully synthesized and formed a glucose-responsive hydrogel HAPBA-PVA.The average length of the microneedles made from HAPBA-PVA hydrogel was about 500 μm,and their strength was sufficient to penetrate the epidermis.In vitro experiments showed that the microneedle patches released 28.6 μg(0 g/L glucose),37.2μg(1g/L glucose),and 47.4 μg(4 g/L glucose)of insulin in 10 hours,demonstrating their ability to deliver insulin in a glucose-responsive manner.Hemolysis and cytotoxicity tests showed that the microneedle patches had good biocompatibility.2.Polyethylene glycol(PEG)and 2-(dodecylsulfanylthiocarbonylsulfanyl)-2methylpropionic acid(DDMAT)were used to synthesize the macro-RAFT agent PEGDDMAT.Block copolymers PEG-b-PAAPBA with 7 different chain segment lengths were synthesized by reacting PEG-DDMAT with 3-acetamidophenylboronic acid(AAPBA).Glucose-responsive particles loaded with insulin were self-assemblied via hydrophilic and hydrophobic interactions.Glucose-responsive microneedle patches loaded with these particles were then prepared using HA as the martix,with vacuum and centrifugation methods,respectively.The results showed that under conditions of high glucose concentrations,particles’ hydrophilic and hydrophobic structure were changed for triggering response due to glucose bounding to PBA.Particle size analysis showed that as glucose concentration increased,the particles contracted and released the encapsulated insulin.In vitro release experiments demonstrated significant glucose responsiveness in 0,1 and 4 g/L glucose solutions.Blood glucose control experiments in rats of microneedle patches showed that one MN-va-7.5%-2 microneedle patch effectively maintained normal blood glucose levels for more than 7 hours.Hemolysis experiment and MTT analysis showed that the glucose-responsive microneedle patches had high biocompatibility.3.N-acryloylaminglucose(AGA)was synthesized from D-glucosamine(GA)and acryloyl chloride(AC).PEG-b-PAGA was then synthesized by reacting PEG-DDMAT with AGA.Glucose-responsive particle NP-P1G1 was assembled by block copolymers PEG-b-PAAPBA and PEG-b-PAGA.The glucose-responsive insulin release performance was evaluated through particle size analysis and in witro insulin release experiments.Drug-loaded particles were then encapsulated in HA microneedle patches to produce insulin-loaded microneedle patches.The results showed that PEG-b-PAGA and PEG-b-PAAPBA were successfully synthesized,and glucose-responsive particle NP-P1G1 was successfully prepared by dialysis method.NP-P1G1 was less affected by pH.Its particle size increased with increasing glucose concentration,indicating its glucose responsiveness.In vitro release experiments showed significant differences in insulin release of NP-P1G1-ins particle at glucose concentrations of 0 g/L,1 g/L,and 4 g/L.In 8 hours,the MN-P1G1-ins-1 released a low level of insulin at the glucose concentration of 0 g/L or 1 g/L while about 0.12 mg of insulin was released at 4 g/L,demonstrating glucose-responsive insulin release of the MN patch.Hemolysis tests of the microneedle patches showed good biocompatibility. |
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