Study on the Preparation and Application of Nanocellulose-based Composite Hydrogels in Controlled Drug Delivery System

Author:Liu Ying Ying

Supervisor:li you ming

Database:Doctor

Degree Year:2019

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Pages:171

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It has attracted great attention that using renewable bio-based materials to replace traditional petroleum-based materials,due to the over-exploitation of fossil resources and people’s increasing attention to environmental problems.Cellulose is the most abundant organic polymer in nature,with many advantages including low-cost,degradability and environment-friendly.It has received a wide range of attentions in the field of paper,food and biomedicine.Moreover,researchers have found that the nanocellulose prepared from cellulose has many appealing intrinsic properties,such as low density,high surface area and mechanical strength.Over the last decade,nanocellulose based hydrogels have emerged as promising materials in the field of biomedical applications,including drug delivery,wound dressings,tissue engineering scaffolds,due to their low toxicity biocompatibility,biodegradability,as well as excellent mechanical stability.In this work,different nanocellulose based composite hydrogels were prepared for on-demand drug delivery under the irradiation of near-infrared light and in low pH buffer liquid in which nanocellulose provided 3D network and polydopamine(PDA)or mesoporous polydopamine(MPDA)served as drug carriers.The main contents are as follows:Firstly,a novel multi-responsive PDA/TOCNFs composite hydrogel film was prepared by filtration after mixing PDA and TOCNFs.PDA was used as drug loading particles to load tetracycline hydrochloride(TH)as well as reinforcement agent to improve the physical strength of the PDA/TOCNFs composite hydrogel films.The structure,the physical strength,drug sustained-release behavior,and the drug sustained-release behavior of the composite hydrogel films were explored.In addition,the antibacterial properties of the composite hydrogel films were also evaluated.Results showed that the drug loading ratio of PDA/TOCNFs composite film could be improved by adding PDA and increasing the carboxyl group content of TOCNFs.Drug release behavior of PDA/TOCNFs composite hydrogel film could be controlled in low pH buffer liquid or under the irradiation of near-infrared light.Most significantly,the PDA/TOCNFs hydrogel films had long-acting release ability of drugs(30 h)without NIR laser irradiation under PBS solution(pH=5.0).Moreover,the mechanism of drug release of the pure TOCNFs hydrogel film and the composite hydrogel film was mainly driven by Case-II transport.Secondly,we reported a pH/near-infrared(NIR)-responsive hydrogel for on-demand drug delivery and wound healing.PDA was introduced into TOCNFs network to fabricate a PDA/TOCNFs hydrogel through ion-crosslinking with calcium ion as a crosslinker.The PDA acted as highly effective photothermal and reinforcing agents as well as drug carriers of TH,while TOCNFs provided a 3D framework structure.The maximum drug loading ratio and drug encapsulation of PDA was 14.4% and 21%,respectively.PDA/TOCNFs composite hydrogels had excellent pH and NIR sensitive drug release characteristics.The hydrogels could continuously release the drugs over 24 h without NIR laser irradiation under PBS solution(pH=5.0).The maximum drug release ratio reached to 77%,indicating the excellent long period drug delivery properties.The drug release mechanism of the pure TOCNFs hydrogel and composite hydrogel might be mainly driven by anomalous transport.Furthermore,the composite hydrogel was successfully applied to rat skin wound dressing test,illustrating that the PDA/TOCNFs composite hydrogels could be potentially used for skin tissue repair.In addition,the resultant composite drug hydrogel displayed good antibacterial properties against Staphylococcus aureus and Escherichia coli.Importantly,in vitro cytotoxicity tested illustrated that the composite hydrogels showed a good biocompatibility.Thirdly,in order to further improving the drug load rate and extending the drug release time,MPDA nanoparticles were successfully developed.The positively charged PCNC was obtained by adsorbing the positively charged polyethylenimine(PEI)onto the negatively charged cellulose nanocrystalline(CNC).PCNC was used to package negative MPDA,and then the MPDA@PCNC complex was obtained.Finally,MPDA@PCNC/TOCNFs composite hydrogel was obtained by calcium ion crosslinking.The maximum drug encapsulation efficiency and drug loading ratio of MPDA for TH were 58% and 35%,respectively.According to drug release profiles,in the acidic buffer liquid,the drug release time was 30 h,and the drug release ratio was 70%.According to mathematical model fitting,the drug release mechanism of the composite hydrogels was primarily come from Fickian transport.Importantly,in vitro cytotoxicity tested illustrated that the composite hydrogels showed a good biocompatibility.Then,a composite hydrogel based on MPDA nanoparticles wrapped with graphene oxide(GO)and physically crosslinked with nanocellulose(MPDA@GO/TOCNFs)were manufactured as a novel drug delivery vehicle.The construction of this drug released material is universal and can be applied to the construction of other inorganic/organic intelligent composite hydrogels.GO was used to package MPDA and strengthen the nanocellulose hydrogels.MPDA@GO/TOCNFs composite hydrogels had good mechanical strength,and they also had excellent pH and NIR sensitive drug release characteristics.According to drug release profiles,when the ratio of MPDA to GO was 1:2 and in the acidic buffer liquid,the drug release time was 72 h,and the drug release ratio was 77%.Korsmeyer-peppas model was the best model to fit the drug release kinetics of hydrogels,and the drug release mechanism of the composite hydrogels was primarily come from anomalous transport.Importantly,in vitro cytotoxicity tested illustrated that the composite hydrogels showed a good biocompatibility.Finally,PDA@ZIF-8 complex was obtained by regulating in-situ growth of ZIF-8 on PDA surface.PDA@ZIF-8 was used to load TH,and it was introduced into TOCNFs network to fabricate a PDA@ZIF-8/TOCNFs hydrogel through ion-crosslinking with calcium ion as a crosslinker.The maximum drug encapsulation efficiency and drug loading ratio of PDA@ZIF-8 for tetracycline hydrochloride were 89% and 58%,respectively.The drug loading ratio of PDA@ZIF-8/TOCNFs composite hydrogel was 1.7 times,4 times and 19 times higher than that of MPDA@GO/TOCNFs composite hydrogel,PDA/TOCNFs composite hydrogel,and PDA/TOCNFs composite hydrogel film,respectively.PDA@ZIF-8/TOCNFs composite hydrogels had excellent pH and NIR sensitive drug release characteristics.In the acidic buffer liquid,the drug release time was 85 h,and the drug release ratio was 72%.The drug release time of PDA@ZIF-8/TOCNFs composite hydrogel was 1.18 times,2.83 times,3.54 times and 3 times longer than that of the MPDA@GO/TOCNFs composite hydrogel,MPDA@PCNC/TOCNFs composite hydrogel,PDA/TOCNFs composite hydrogel,and PDA/TOCNFs composite hydrogel film,respectively.Korsmeyer-peppas model was the best model to fit the drug release kinetics from PDA@ZIF-8/TOCNFs composite hydrogels,and the drug release mechanism of the composite hydrogels was primarily come from anomalous transport.Importantly,in vitro cytotoxicity tested illustrated that the composite hydrogels showed a good biocompatibility.Therefore,the nanocellulose-based composite hydrogels prepared in this paper have many appealing intrinsic properties,such as higher drug loading rate and better drug slow-release performance.This can expand the applications of nanocellulose,and it also provide theoretical basis for the application of nanocellulose based composite hydrogel materials in the biomedical field.