Preparation and Performance Evaluation of Lacrimal Plug Based Hydrogel Composed of Konjac Glucomannan/Polyvinyl Alcohol/Alginate

Author:Xu Ning Xia

Supervisor:xue wei ming


Degree Year:2019





With the characteristics of high operability,small trauma and easy removal,the lacrimal plug is an effective method in treatment of dry eye disease.Based on the polymer hydrogel as materials,lacrimal plug has advantages of small limited application and easy controlling of embolization,as well as the ability of responding to the changes of environment and achieving an intelligent delivery of object drugs.Furthermore,polymer hydrogel can maintain the activity and efficacy of certain drugs in the process of loading and transportation without negative effecive.Therefore,how to prepare lacrimal plug with good performance,safety and effectiveness is one of the hotspots in the field of medical engineering.In this paper,konjac glucomannan(KGM),polyvinyl alcohol(PVA)and sodium alginate(SA)were used as materials to prepare the composite hydrogel.Ca(OH)2 solution was used as deacetylated agent to KGM as well as the crosslinking agent of SA.KGM/PVA/Alg-Ca composite hydrogel was fabricated by freeze-thawing process first,and then crosslingked with Ca(OH)2.Scanning electron microscopy(SEM),fourier infrared spectroscopy(FT-IR),small angle X ray scattering(SAXS),nitrogen adsorption and differential scanning calorimetry(DSC)were used to characterize the structural properties of the composite hydrogel.The mechanical properties of the composite hydrogel were evaluated by universal electronic tensile test.The swelling ratio and keniticas were also tested to evaluate the swelling properties of composite hydrogel.The mechanism of the hydrogel and interaction between the molecular chains was investigated and correlated with the properties of gel elasticity and toughness.Cyclosporine A(CsA)was used as a model drug to perform the release kinetics in composite hydrogel.Furthermore,the composite hydrogels were imputed in the canaliculus of rabbits to evaluate the effect of lacrimal embolization and the potential effectiveness on the tissues of body.The main conclusions are as follows:(1)Based on the differet concentration of Ca2+in CaCl2,Ca(OH)2 and CaCO3 solution,the composite hydrogel formed different interpenetrating structure coded as KPS-1(CaCl2 as crosslinking agent),KPS-2(Ca(OH)2 as crosslinking agent)and KPS-3(CaCO3 as crosslinking agent),and using KPS-4(no Ca2+)as control sample,respectively.The results showed that the network of KPS-2 composite hydrogel has highly porosity and compact structure,and the elongation at break was 706.3%,which was 1.11,4.01and 3.88 times of KPS-1,KPS-3 and KPS-4 respectively.The time for swelling equilibrium was 50 min,0.25,0.29 and 0.42 times of KPS-1,KPS-3 and KPS-4,respectively.Compression modulus test results showed that KPS-2 had good flexibility.In addition,the thermal stability of the composite hydrogel was higher than that of the single component material.Based on this,the hydrogel prepared by Ca(OH)2 as crosslinking agent had excellent mechanical strength,flexibility and swelling property.(2)After deacetylation in Ca(OH)2,the properties of KGM molecules might changed because of removing acetyl groups form KGM molecules.Therefore,this chapter evaluates the structure and properties of Da-KGM/PVA/Alg-Ca hydrogel with different deacetylation degrees.The results showed that when the concentration of KGM was 10 g·L(K1),the elongation at break was 683.3%.Compared with 0 g﹒L-1(K0),5 g﹒L-1(K0.5)and 15 g﹒L-1(K1.5),which was 1.23,1.03 and 1.58 times respectively.Furthermore,the elastic properties were better than those of other samples.The swelling equilibrium time was 60 min,0.02,0.03and 0.67 times of K0,K0.5 and K1.5,respectively,which means that K1 had more sensitive ability to environmental response and might obstruction of lacrimal canaliculus effectively.Furthermore,the degree deacetylation of KGM had nonlinear influence on the properties of composite hydrogel.When the concentration of KGM was 10 g﹒L-1,the prepared composite hydrogel was homopolymer system and had good compatibility.The results showed that the mechanical strength and swelling stability of K1 were appropriate for potential using as lacrimal plug in clinical.(3)Cyclosporine A(CsA)as a model drug,the drug-loaded Da-KGM/PVA/Alg-Ca composite hydrogel was also prepared.The experimental results showed that the loading drug had negative effect on the mechanical strength and swelling property of the composite hydrogel.CsA was detected by HPLC method.The results showed that the drug release rate was significantly correlated with ambient temperature in vitro drug release experiments.The release rate at 40℃was 2.8 times that of 37℃,which means that when the ambient temperature increased,the drug might release rapidly from the composite hydrogel.Based on these experiments results,the drug loaded Da-KGM/PVA/Alg-Ca composite hydrogel had suitable properties of mechanical strength and swelling property,and can also loaded object drugs to improve the bioavailability of intraocular drugs.(4)Using L929 fibroblast as the model cell to study the biocompatibility of Da-KGM/PVA/Alg-Ca composite hydrogel,the cell survival rate of Da-KGM/PVA/Alg-Ca composite hydrogel sample groups were more than 80%,indicating that the composite hydrogel had good biocompatibility.The composite hydrogel embolizated the lacrimal passage in New Zealand rabbits as animal model to study the embolization effect on lacrimal canaliculus.The results showed that the height of the lower lacrimal river of composite hydrogel and drug-loaded hydrogel were 8.52 times higher than that of the dry eye group,the area of the lower lacrimal river area was 59.57 times respectively,indicating that the compound hydrogel effectively blocked the lacrimal canaliculus,delayed the tear discharge,and significantly improved the tear film stability of dry eye.The content of mucin in the solution was normal,and the stimulation to rabbit eye tissue was showed no obvious effect,which means the composite hydrogel was more safety to organism body.(5)The relationship between hydrogel properties and mechanism was analyzed by FT-IR,DSC,rheology and SAXS analysis.The results showed that KGM molecular chain in Da-KGM/PVA/Alg-Ca might formed an elastic chain and entangled on the PVA/SA skeleton.Furthermore,the hydrogen bonds formed inter or the intro chains enhanced the strength and toughness of the hydrogel,resulting the improvement and stability of the composite hydrogel,which might be based on the higher crosslinking degree between molecular chains.The degree of deacetylation of KGM might be the reason of the formation of micro heterogeneity,and the surface had rough physical entanglement.The study showed that the degree of KGM deacetylation in the composite gel was a major factor in the nonlinear change of macroscopical properties.When KGM concentration was 10 g﹒L-1,Ca(OH)2 as cross-linking agent and deacetylation agent,the composite hydrogel prepared by blending KGM,PVA and SA had good biocompatibility and safety,high mechanical strength,flexibility and swelling response.Meanwhile,cyclosporine A was sustained release from the composite hydrogel,which could improve the utilization rate of drugs inside the eye tissue.Also the composite hydrogel can effectively blocked the lacrimal canaliculus and reduced tear discharge in rabbit eyes.The discharge of liquid can obviously alleviate the dry eye condition and has the feasibility of being used as a product of lacrimal plug in clinical application.