Functional Materials Constructed By The Polysaccharide Of Hyaluronan And Their Applications In Biomedical Field

Hyaluronan?HA?is a linear polysaccharide with disaccharide repeats of D-glucuronic acid and N-acetyl-Dglucosamine.It is evolutionarily conserved and abundantly expressed in the extracellular matrix?ECM?,on the cell surface and even inside cells.Recently,a variety of biological functions of HA have been explored and a number of customized applications have been investigated taking advantages of the interaction between HA and biological tissues.As a naturally-occurring polysaccharide,HA has been used for joint lubrication and prevention of peritoneal adhesion in its intact form due to the excellent biocompatibility,viscoelasticity,biodegradability,and hygroscopic properties.HA can be easily functionalized via the chemical modification of its carboxyl and hydroxyl groups.In addition,the interaction of HA with the CD44 receptor,whose expression is elevated on the surface of many types of tumor cells,makes this polymer a promising candidate for intracellular delivery of imaging and anticancer agents exploiting a receptor-mediated active targeting strategy.In recent years,HA has become key candidate for the preparation of HA-based PEMs using the LbL assembly technique mostly due to its tunability through assembly conditions,hydrophilicity,biocompatibility,bioactivity,and biodegradability.Thus,taking advantage of the inherent biocompatibility and biodegradability of HA,as well as its susceptibility to chemical modification,we have developed various HA-based biomaterials with promising and broad potential in biomedical field.HA is a major component of synovial fluid in normal knee joints and provides viscoelastic properties to synovial fluid.In osteoarthritic joints,synovial fluid loses its unique viscoelastic and lubrication properties.Intra-articular injection of HA in osteoarthritic knee joints is believed to restore viscoelasticity and lubrication abilities to synovial fluid.However,the main drawback of HA is its rapid degradation in synovial fluid.In order to overcome the problem of rapid clearance of HA,an HA-based hydrogel?vinyl sulfone-modified HA crosslinked by dithiol-terminated poly?ethylene glycol?,HA-VS/SH-2-PEG?was synthesized in this study.Injectable fluid hydrogels?viscosupplements?possessing tunable viscoelasticity and controllable degradation rates were then prepared by adding HA-VS/SH-2-PEG microgels to HA solutions.The resultant viscosupplements exhibited enhanced viscoelastic properties,lubrication effects,efficient triamcinolone acetonide payload capacity,and high resistance to enzymatic degradation?45%of initial storage modulus?along with good biocompatibility and the capability to inhibit the progression of osteoarthritis in vivo.The average scores for macroscopic assessment of rabbits treated with viscosupplements?HV-1,HV-2,HV-3?were 1.85,1.75,and 1.75,respectively.Overall,the results provided support for the use of injectable fluid hydrogels as a strategy for the treatment of osteoarthritis and potential for the clinical translation.Peritoneal adhesion is very common after abdominal and pelvic surgery,which leads to a variety of severe complications.Although numerous pharmacological treatments and barrier-based devices have been investigated to minimize or prevent postoperative adhesion,the clinical efficacy is not very encouraging.In this work,a biodegradable and biocompatible HA cryogel was developed and the efficacy of HA cryogel in preventing postoperative peritoneal adhesion was investigated.In vitro cell tests showed that HA cryogel was non-toxic.Moreover,the rat model of sidewall defect-cecum abrasion was employed to evaluate the anti-adhesion efficacy of the HA cryogel.The results demonstrated that HA cryogel could effectively prevent postoperative peritoneal adhesion without side effects.The combination of biocompatibility,appropriate biodegradation period,and excellent postoperative anti-adhesion efficacy make HA cryogel a promising candidate for the prevention of postsurgical peritoneal adhesion.The organoiridium complex?Ir?III??[??⁵-Cpxbiph?Ir?phpy??py?]PF₆containing?-bonded biphenyltetramethylcyclopentadienyl(Cp^xbiph),C^?N-chelated phenylpyridine?phpy?,and pyridine?py?ligands has more potent antitumor activity as a new generation of drug than cisplatin toward various cancer cells.However,poor site-specific delivery,low solubility,and poor tumor penetration are common limitations of chemotherapy drugs.To develop CD44-targetable,pH-,and reduction-responsive drug delivery systems for Ir?III?drugs,the amphiphilic hyaluronan?HA?-based conjugates of HA-cystamin-pyrenyl?HA-ss-Py?containing disulfide bonds and HA-pyrenyl?HA-Py?were designed?mean diameter 250-260 nm?.The Ir?III?drug was readily loaded into these two amphiphilic conjugates and nanoparticles were formed with 33.5³6.4%drug loading content.Dynamic light scattering?DLS?studies showed that the micelles formed from HA-ss-Py were sufficiently stable under physiological conditions,but were prone to rapid dissociation in reducing environments?20 mM glutathione?GSH??.In subsequent confocal microscopy analyses,A549 cancer cells efficiently internalized HA-based micelles.Moreover,in vitro cytotoxicity assays in A549 cells demonstrat that Ir-loaded HA-based nanoparticles have higher cytotoxicity?tumor inhibition rate of 92%?than the free Ir?III?anticancer drug.Finally,systemic administration of Ir?III?-loaded HA-ss-Py nanoparticles enhanced tumor inhibition in vivo,and the corresponding biodistribution experiments showed that HA-ss-Py micelles accumulate in tumors.Overall,our results suggest that HA-ss-Py micelles have a great potential to be used as an effective Ir?III?drug carrier for targeted cancer therapy.In this study,a novel drug delivery system?HMSNs-NH₂-CBA-DTPA-HA?based on hollow mesoporous silica nanoparticles?HMSNs?was developed for delivering anticancer drugs?e.g.,doxorubicin?DOX?,drug loading content of12.5%?to targeted tumour cells by using disulfide bonds and boronic acid-catechol ester bonds as redox and pH-sensitive linkers and hyaluronic acid?HA?molecules as both capping and targeting agents.Detailed physiochemical characterization further demonstrated that HMSNs-NH₂-CBA-DTPA-HA has been successfully constructed.The in vitro drug release experiments displayed the pH and redox dual-responsive and sustained drug release properties of DOX loaded HMSNs-NH₂-CBA-DTPA-HA?drug release of 80.7%?.Additionally,a series of biological evaluations indicated that these DOX loaded HMSNs-NH₂-CBA-DTPA-HA could accurately target A549 cells to induce cell apoptosis in vitro.These results demonstrated that DOX loaded HMSNs-NH₂-CBA-DTPA-HA was suitable as a potential and efficient drug delivery nanosystem for cancer therapy.A promising strategy for lipase immobilization based on the natural polymers of polysaccharides?hyaluronan?HA?and chitosan?CHI??functionalized magnetic microspheres?Fe₃O₄@SiO₂@{CHI/HA}₃,630 nm?was developed.First,Fe₃O₄ magnetic microspheres and Fe₃O₄@SiO₂core/shell microspheres were synthesized by hydrothermal reaction and sol-gel method,respectively.Owing to the abundant carboxyl groups in HA chains,the lipase was covalently bonded on the surface of the polysaccharide functionalized magnetic supports by ultilizing 1-ethyl-3-?3-?dimethylamino?-propyl?carbodiimide?EDC?and N-hydroxysuccinimide?NHS?chemistry to produce robust biocatalysts of Fe₃O₄@SiO₂@{CHI/HA}₃@lipase.The morphology,core–shell structure,and magnetic property of the supports and immobilized lipase were investigated through various analytical techniques,including FT-IR analysis,TEM,SEM equipped with energy dispersive spectrometer?SEM-EDS?,elemental analysis,vibrating sample magnetometer?VSM?,thermogravimetric analysis?TGA?,and X-ray diffraction?XRD?.Consequently,the magnetic Fe₃O₄@SiO₂@{CHI/HA}₃microspheres exhibited a superior performance in terms of immobilizing lipase?48.6 mg/g?.The magnetic immobilized lipase showed good thermal?retained 53.9%of its initial activity at 60 ^oC after 48 h?and long-term stability?retained 78%of its initial activity after 30 days at 4 ^oC?,and reusability?nine consecutive cycles?for the synthesis of the structured lipid of 1,3-dioleoyl-2-palmitoylglycerol?OPO?,which has recently received much interest as a healthy component of food,oil,and pharmaceutical intermediates.The magnetic immobilized lipase could be considered a green and sustainable biocatalyst for the highly efficient synthesis of OPO.