Fabrication Of Bioinspired Micro/nano-structured Microneedles For Biomedical Applications

Transdermal administration,injection and oral administration are three main strategies for drug delivery.Compared with injection,transdermal administration is nearly non-invasive,hardly causes pain or bleeding,and is easy to perform without professional involvement.Besides,in contrast to oral administration,transdermal administration has a wider range of applicable dosage forms,and can better target local lesions to enable precise drug delivery and faster action.However,due to the existence of skin barriers,transdermal administration faces challenges of low drug availability.To solve this problem and improve drug absorption,microneedle techniques come into being.Generally speaking,microneedles refer to cones or pyramids with sharp tips and microscale sizes,or their composed arrays.The fundamental components of microneedles are a supporting substrate and several sharp tips.On the one hand,the sharp tips enable microneedles to penetrate the skin,overcome skin barriers and contact deep tissues,which greatly promote drug transdermal absorption.On the other hand,the microscale sizes of microneedles make them effectively avoid subcutaneous capillaries and nerve endings,thus getting rid of bleeding,pain and other side effects and becoming a minimally invasive and safe drug delivery device.Additionally,there are a variety of materials suitable for microneedles,including inorganic ones such as silicon,stainless steel,gold,silver and other heavy metals,synthetic organic ones such as polyethylene glycol derivatives and gelatin derivatives,as well as natural organic ones such as silk fibroin,chitosan and hyaluronate.These colorful material ingredients not only impart microneedles with the capacity to carry many kinds of drugs like hydrophilic small molecules,lipophilic small molecules,proteins,nucleic acids,exosomes,probiotics,etc.,but also largely broaden the applications of microneedles,making them available in transdermal delivery,oral delivery,interstitial fluid detection,bioelectrical signal sensing and other biomedical fields.To further improve the microneedle technology,scientists begin to introduce bionics into microneedle technologies.By learning from fantastic creatures in nature,microneedles are endowed with many novel structures,features and functions.Besides,it has been another main research direction in microneedle fields to improve the fabrication methods for better flexibility and generalizability.Based on the above ideas,in this thesis,we get inspiration from nature,design and fabricate microneedles with biomimetic micro/nano-structures,improve or develop original or new fabrication strategies,and apply these microneedles to delivering drugs to the skin,wound beds and the mucosa.The main research contents are as follows:(1)By mimicking the suction cup structure of octopi,the barbed structure of bee needles as well as the molecular component of mussel adhesive proteins,bioinspired microneedle arrays with enhanced tissue adhesion ability were developed.Using the multi-step template replication method,microneedles with different material components were fabricated and material optimization was made.With optimized material and structure of the supporting substrate,the microneedles were investigated to show ideal adhesion ability on joints and other frequently moving parts.The microneedles could also well adhere to mucosae and other irregularly shaped parts with improved microneedle tip structure.By co-cultivating the microneedle materials with cells,their biocompatibility and safety were demonstrated.Their drug delivery ability of small molecules and proteins,as well as their practical performances in disease treatment were further investigated by establishing animal models of arthritis,uterine injury,etc.(2)By mimicking the behavior of a bee’s needle disengaging from its tail after a bee sting,bioinspired separable microneedle arrays were developed.Using the multi-step template replication method,microneedle arrays whose tip material and supporting substrate material were different could be fabricated.The material compositions of the supporting substrate and microneedle tips were optimized to explore their skin penetration ability and tip-substrate separation performance.With photothermal two-dimensional materials and protein carriers loaded in their microneedle tips,the microneedles were demonstrated to have good hotothermal response and release performances of active molecules.Their application in promoting wound repair was further investigated by establishing diabetic wound models in rats.(3)By mimicking the magnetic response ability of magnetotactic microorganisms and the mucosal puncture ability of intestinal parasites,a bioinspired magnetically responsive independent microneedle motor was developed.Using a microfluidic printing and drawing method,the desired triple-layered microneedle motor could be fabricated.The control and adjustment of the morphology of the microneedle motor were realized by optimizing parameters such as flow rate and solution compositions.With magnetic microparticles added to the supporting substrate,the microneedle motor was found to show good responsiveness to the external magnetic field.With a rapidly dissolvable layer added between the supporting substrate and the microneedle tip,the tissue penetration ability and the tip-substrate separation behavior were explored.To further investigate the practical application of the microneedle motor,insulin was added to the microneedle tip and a diabetic rabbit model was established to see the oral insulin delivery and blood glucose control performances of such a microneedle motor.