Synergistic Control To Achieve Sustained Release Of Mesoporous Silica/Cellulose Composite Dressings With High Drug Loading

A sustained release of anti-infection drugs is beneficial for the reduction of required dressing change times and the protection of the granulation tissue against further infection.Cellulose is a promising wound dressing material because of its high biocompatibility,mechanical properties,non-immunogenicity,flexibility and biodegradability,but it does not possess active antimicrobial activity for combating wound and skin infections.However,due to the poor binding capability of cellulose and drugs,the cellulose dressing has low drug loading and releases the drug quickly.It is a way to solve these problems by modifying chemically the cellulose structure through introduction of functional groups for the drug absorbing,but chemical pollution would be produced in chemical modification process.To combine cellulose with biocompatible particles which have high drug loading capacity might be a direct way to enhance antibacterial activity of cellulose based composite membrane.Mesoporous silica is one of the most common drug carriers.Studies on the preparation of antimicrobial dressings by directly combining the advantages of cellulose and mesoporous silica have not been reported yet.The method of direct blending cellulose with mesoporous silica in this solvent is one of the most straightforward methods for introducing mesoporous silica into cellulose.However,mesoporous silica could be easily corroded by strong alkali.The structure of mesoporous silica would be destroyed by strong alkali and it would lose its ability to act as a drug carrier.In order to overcome the corrosion of mesoporous silica by strong alkali solvent during the blending process,three methods were used to prepare cellulose/mesoporous silica composite membranes in this dissertation:(1)ZnO was added in cellulose solution as porogen to prepare modified regenerated membrane(MRC)with suitable pore structure.Then,by changing the synthesis conditions of nanometer mesoporous silica(MSN),MSN with small particle size was prepared.MSN were pressed into a loose porous MRC by a differential pressure method to prepare a composite membrane MRC-MSN.(2)Directly,the SBA-15 particles coated with newly generated calcium carbonate(CaCO3)layer were added to alkaline cellulose solution to obtain casting solution.Then casting solution was immersed in hydrochloric acid aqueous solution(HCl)to remove CaCO3 and regenerate cellulose.Finally,a porous cellulose/SBA-15 composite membrane(CM-Ca-SBA)was prepared by this method.(3)SBA-15 was dispersed into phosphate buffer saline(PBS).Then the mixture was directly blended with cellulose under strong alkali conditions to obtain casting solution.At last,casting solution was immersed in coagulation bath(sulfuric acid aqueous solution)to regenerate porous cellulose/SBA-15 composite membrane(P-CM-S).On this basis,chitosan/mesoporous silica/cellulose composite membrane(CS-CM-SBA)was prepared by coating the chitosan on P-CM-SBAwith immersion methodThen,the specific surface area,pore size and pore volume of the particles in each composite membrane were determined by BET and BJH.The morphology of pristine mesoporous particles,particles in each composite membrane and membranes were examined by FTIR,XRD,SEM and TEM.In addition,tensile strength,water vapor transmission rate(WVTR),swelling property,etc.,of the composite membrane were also determined.Spectrophotometry was used to determine the drug adsorption and release characteristics of the composite membranes.The antimicrobial properties of the composite membrane against E.coli and S.aureus were evaluated.On this basis,the protective mechanism of CaCO3 or PBS to mesoporous silica was discussed.The drug release data of the composite membrane were fitted to investigate the dual controlled release mechanism of the composite membrane.Finally,combined with the comparative literature,technical and economic assessment was carried out.The results were shown as follow(1)Among the composite membranes prepared by the three methods,the loading amount of mesoporous silica particles in the composite membranes prepared by calcium carbonate protection method and PBS protection method are large and adjustable,and the loading amount can reach 30wt%.The loading amount of mesoporous silica in the composite membrane prepared by differential pressure method is small the highest loading amount can only reach 3.9 wt%and can not be adjusted easily.(2)BET,BJH,SEM and TEM results of the samples prepared by calcium carbonate protection method and PBS protection method show that particles in CM-Ca-SBA,P-CM-SBA,and pristine SBA-15 particles possess close values of the specific surface area,pore size and pore volume.In fact,there are not statistical significance difference on specific surface area,pore size and pore volume between three particles(n=5,P>0.05),manifesting the excellent protection effect by CaCO3 and PBS in alkali environment during blending process.(3)The composite membranes prepared by the calcium carbonate protection method and the PBS protection method all have a high drug loading amount,and the drug loading amount of the composite membrane containing 30 wt%mesoporous silica can be as high as 3.7 wt%and 3.6 wt%,respectively,which is 9 times higher than that of the cellulose membrane.The drug loading amount of the composite membranes prepared by differential pressure method is only 0.93 wt%,which is only 2.3 times higher than that of cellulose membrane.The high drug loading and dual controlled release of the composite membrane endow sustained and stable drug release characteristics of the composite dressing.In terms of initial abrupt release,the drug release rate of CM-Ca-SBA and P-CM-SBA composite membranes are much slower than that of pure cellulose membranes.In the first 24 hours,the drug release rate decreases from 70%to 30%,while that of MRC-MSN membranes decreases to 50%.CM-Ca-SBA and P-CM-SBA can release drugs at a substantially stable and appropriate rate in the period from 24 hours to 160 hours.MRC-MSN releases the drug at a slow and steady rate in the period from 24 hours to 80 hours.However,the drug-loaded cellulose membrane nearly no longer release drugs after 24 hours.The relative antibacterial response(ratio of the diameter of inhibition zone to the diameter of sample)of CM-Ca-SBA and P-CM-SBA are both above 4.0(S.aureus),MRC-MSN is 1.4 while the drug-loaded cellulose membrane was only 1.1.Strong antibacterial activity of CM-Ca-SBA and P-CM-SBA against S.aureus and E.coli.can last 144 hours.The above results further demonstrate the effectiveness of the CaCO3 protection method and the PBS protection method.Chitosan coated on the composite membrane prepared by PBS protection method almost does not affect the drug loading amount and further improves the long-term antibacterial activity of dressing.(4)CM-Ca-SBA and P-CM-SBA have roughly the same mesoporous silica content,approximate drug loading capacity,sustained release profile and long-term antibacterial activity,both of which are better than that of MRC-MSN and drug-loaded cellulose membrane.The results of technical and economic assessment show that compared with the literature CMC/MCM-41 composite dressing,the cost of CM-Ca-SBA and P-CM-SBA reduces from 1551 yuan RMB per kilogram to 1110 yuan RMB and 1095 yuan RMB,respectively.The cost of CM-Ca-SBA and P-CM-SBA is roughly equivalent,but the calcium carbonate protection method requires a long process flow,a large variety of reagents,a large equipment investment.In addition,there is a problem that the composite membrane needs to be immersed in hydrochloric acid for a long time to remove calcium carbonate,resulting in the decrease of mechanical strength of composite membrane Therefore,PBS protection method is the optimal preparation process for cellulose/mesoporous silica composite dressings.(5)The direct blending of mesoporous silica and cellulose in strong alkali/urea system has been successfully achieved.The antimicrobial dressing with high drug loading amount,sustained drug release profile,strong antibacterial activity,good mechanical properties,biocompatibility,swelling ratio and moisture permeability are successfully developed.The preparation process of the dressing is simple and it has good potential medical application.