| Polylactic acid(PLA),as a biodegradable material from biomass,has excellent mechanical properties,processability and biocompatibility,and represents a wide range of applications in the field of biomedical materials.Among series PLA materials,PLA fiber materials with micro or nano scale,and their fiber aggregates show a great application potential in the tissue function repairing scene of the biomedical field,which attract great attention of researchers in scientific and industrial circles.Throughout the development history of PLA materials,the molecular structure and physicochemical properties can be clarified;through the researches of PLA fiber based biomedical materials for the function repairing of muscle and bone tissue as well as cardiovascular tissue,it can be concluded that,promotion effects of functional bionic reconstruction,physiological repair promotion and pathological behavior inhibition can be achieved,with the approaches of designing the structure of materials and effectively loading bioactive components.However,focusing on onedimensional micro or nano scale PLA fiber biomedical materials,further researches are still needed in many aspects,such as the design and preparation of fiber materials,the hybridization of bioactive substances and the integration of fiber aggregate.The main shortcomings of the tissue function repairing application are as follows:(1)The PLA micro fiber materials present a weak effect of inducing tissue repairing with the low degree of biological functionalization;(2)Most of the loaded bioactive components have single biological function,which is difficult to regulate the physiological and pathological behavior of tissues at the same time.In view of the shortcomings above,we proposed the design strategy of PLA drug loaded nanofiber system for vascular tissue repairing,as well as PLA hybrid micron fiber materials and their specific braided aggregates for musculoskeletal tissue repairing.Starting from the application scenario of vascular tissue repairing and ligament function reconstruction,we prepared a series of drug loaded nanofiber stent coatings with long-term effect and local release of drugs,and artificial ligament material for promoting musculoskeletal tissue repairing.The main content of this dissertation is divided into four parts as follow:1.PLA-TEMPOL drug loaded nanofibers for inhibiting various ROS related pathological behaviors of vascular cells: Aimming at the common problem that pathological behaviors of various vascular cells caused by excessive reactive oxygen species(ROS)after percutaneous coronary intervention(PCI),ROS scavenger-4-hydroxy 2,2,6,6-tetramethylpiperidine-n-oxy(TEMPOL)was effectively introduced into PLA nanofibers by coaxial electrospinning.By studying the release kinetics of PLA-TEMPOL nanofiber drug loaded system,the drug release mechanism(Fickian diffusion)was clarified.Then,taking defective vascular tissue after PCI as the application scenario,the influence of their TEMPOL loading amount on the endothelial cell compatibility and anti-inflammatory performances were studied.The results of cell experiments showed the mechanism that the nanofiber membranes(P-T-1)introduced with an appropriate amount of TEMPOL(3 ng/mg loaded)could effectively scavenge excessive ROS,and resulted in the reducing of inflammatory factors expression in vascular cells and inhibition a variety of cell pathological behavior.At the same time,the results of relevant cell experiments also confirmed that PLA nanofibers with ROS scavenging drug loaded exhibited multiple functions,such as physiological repair of vascular cells(endothelial cell proliferation),inhibition of pathological changes(overexpression of inflammatory factors in macrophages,migration of smooth muscle cells),which put forward a new idea for the design of drug loaded coating of stents.2.PLA-TEMPOL/RAPA nanofiber dual drug coating integrated with stent for the inhibition of vascular restenosis: The second drug of rapamycin(RAPA)was introduced into PLA-TEMPOL nanofibers;in order to inhibit smooth muscle hyperplasia and ensure endothelial regeneration at the same time,we optimize the drug proportion.Then taking the sample with the optimal proportion as the research target,the mechanism of synergistic inhibition on smooth muscle proliferation by TEMPOL and RAPA in PLA-TEMPOL/RAPA nanofibers was analyzed by cytocompatibility test and anti-inflammation experiments.Therefore,such nanofibers was integrated with stent as a coating for animal experiments to explore its vascular tissue repair performance in three aspects: vascular function reconstruction,physiological repair guarantee and pathological proliferation inhibition.The experimental results in vitro and in vivo showed that TEMPOL can ensure the repairing of endothelial cells by scavenging ROS,and RAPA effectively inhibit the proliferation and migration of smooth muscle cells by inhibiting related factors expression of phenotypic transformation and proliferation,as well as inducing apoptosis.In addition,PLA-TEMPOL/RAPA integrated stents could effectively maintain the size of vascular lumen and inhibited intimal hyperplasia in 3 months,a complete regeneration of endothelial layer could be achieved in 1 month,which indicated such integration stent presented better treatment than commercial drug loaded stent(EXCEL(？)),for the overcame the shortcoming of ensuring endothelial physiological repairing.3.Regulating fiber structure to optimize PLA based high-strength artificial ligament and its soft tissue repairing performance: Devoted to the key problems of less study on absorbable artificial ligament and low degree of biological functionalization.Based on PLA melt spinning,the internal relationship between key factors in the forming process(such as cooling conditions,drawing ratio,drawing temperature)and the aggregation structure of PLA micro scale fibers was systematically studied.By optimizing the drawing process,the PLA micro scale fiber with high mechanical strength was obtained,which was used as the basic unit for braiding and constructing the artificial ligament with uniform and stable structure.On this basis,through special-shaped spinning technology and post-processing teccan be continuously produced was obtained.At the same time,the related cytocompatibility study was carried out.The results showed that with the regulation and optimization of spinning process and drawing process,the six leaves shaped PLA fiber with “six pointed star like” cross-section and mechanical strength up to 3.28 c N/dtex was successfully obtained;taking it as the basic unit for braiding artificial ligament,the breaking strength of obtained artificial ligament was still much higher than that of the human anterior cruciate ligament,and had a more dense groove topology.The results of cell experiments showed that the PLA artificial ligament with profiled cross section,thanks to its larger specific surface area,significantly promoted the adhesion and proliferation of fibroblasts,and effectively accelerated the ligament soft tissue repairing behavior of skeletal muscle derived fibroblasts.Based on the structural regulation of PLA fiber,a high-strength and high cellular activity artificial ligament that can be used for anterior cruciate ligament reconstruction is constructed,which provides a solid process foundation for subsequent the biological functionalization of high-strength artificial ligament.4.Nano HAp hybrid PLA fiber artificial ligament for enhancing osteocyte activity.The bioactivity hybridization of PLA micron fiber was focused,with the application scenario of promoting bone repairing of absorbable artificial ligament.Based on the melt spinning technology for high-strength PLA fiber preparation,the bone bioactive nanoparticles of hydroxyapatite(HAp)were effectively hybridized into the PLA fiber.With the help of hybrid fiber preparing process,the aggregate structure(orientation and crystallinity)of PLA molecules in PLA-HAp hybrid fiber,and the scale,dispersion of HAp carrier were regulated.Combining with the braiding process,PLAHAp hybrid fiber-based artificial ligaments with better tensile strength than natural ligament were obtained,and the related cytocompatibility studies were carried out.The results showed that PLAHAp hybrid fibers with excellent mechanical properties(strength not less than 3.16 c N/dtex)were obtained by optimizing HAp hybrid introduction process and hybrid fiber spinning process;braiding with such hybrid fibers,the high-strength artificial ligament materials with a breaking stress over twice of human anterior cruciate ligament could be obtained.The results of cell experiments showed that the addition of HAp in hybrid fibers significantly introduced calcium and phosphorus,which could effectively promote the proliferation of Mouse embryonic osteoblast precursor cells(MC3T3)on the surface of artificial ligament materials. |
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