Synthesis And Study Of Oviduct Contraceptive Materials With Shape Memory Properties Based On Poly(D,L-Lactide)

Biodegradable shape memory polymers are the novel intelligent materials which have the excellent biodegradable and shape memory properties. They have the important application value in the surgical micro-invasive operation, medical device implants and are the focal point of research in multifunctional biomaterials. In this paper, several kinds of biodegradable poly(urethane urea) shape memory polymers (PDLLA-PUU SMPs) based on PDLLA Diols are synthesized. Multi-angle laser light scattering (MALLS), fourier transform infrared spectrometry (FTIR), nuclear magnetic resonance spectrometer (NMR), differential scanning calorimeter (DSC), mechanical tensile tests and classical chemical analysis were used to explore the structures, mechanical and shape memory properties of PDLLA-PUU SMPs. Thereafter, biodegradation, cell biocompatibility, biological safety and medical application in contraception of the PDLLA-PUU SMPs were investigated. The main works and conclusions are included as follows:1. Hydroxyl-terminated poly(D,L-lactide) (PDLLA Diols) were synthesized by melt ring-opening polymerization of D,L-lactide using Sn(Oct)2 as initiator and butanediol as coinitiator. Then, an extensive investigation effort was expended in understanding the effects of reacting time, dosage of coinitiator on the molecular weight, then the structure and thermal properties were characterized.①FTIR, 1HNMR, 13CNMR showed that PDLLA Diols was successfully prepared by using above-mentioned system. Hydroxyl value, GPC-MALLS analysis indicated that PDLLA Diols with different molecular could synthesized by varying the dosage of coinitiator.②The results indicated that polymerization reaction time affected the molecular weight and the yield of PDLLA Diols. The best result was obtained in a high yield of 90% and narrower polydispersity when reaction time was 24h. The results of DSC showed that the glass transition temperature (Tg) of PDLLA Diols have molecular weight dependence and the Tg increased from 14.27 to 45.2℃with the increasing of molecular weight.2. Shape memory poly(urethane urea) were synthesized by polymerization of PDLLA Diols, hexamethylene diisocyanate (HDI) with butanediamine (BDA) as a chain extender. The effects of content of catalyst and the reactive temperature on the reactive activity of PDLLA Diols and HDI were discussed and the structure and thermal properties of PDLLA-PUU SMPs were characterized.①FTIR, 13CNMR exhibited that, PDLLA Diols have successfully reacted with HDI and then the high molecular weight could obtained by chain extending reaction using BDA as a chain extender. By varying the molecular weight of soft segment and the ratio of soft segment/hard segment, the PDLLA-PUU SMPs with different physicochemical properties could be synthesized.②The reactive activity of PDLLA Diols and HDI was affected by content of catalyst and reactive temperature, the optimum reactive condition was that: the mol ratio of catalyst and PDLLA Diols was 0.75%, the reactive temperature was 75℃.③The results of TGA analysis indicated that, the thermal degradation process of PDLLA-PUU SMPs was one step and showed very effective charring ability. Moreover, the thermal stability of PDLLA-PUU SMPs was better than that of PDLLA. The results of DSC showed that the Tg of SMPs were about 35~60℃. The shape memory polymers, whose shape memory transition temperature was near the body temperature, could be synthesized by changing the components of reactants and satisfied the biomedical application.3. The mechanical and shape memory properties of PDLLA-PUU SMPs were characterized by mechanical tensile tests and dynamic mechanical analysis (DMA). This paper primarily investigated the influences of molecular weight of soft segment, the ratio of soft segment/hard segment, shape deformation and temperature on the shape memory fixation and recovery ratio.①The results indicated that PDLLA-PUU SMPs have nice mechanical properties. The modulus and maximum stress increased with the increasing of the hard segment content, while the elongation at break had the opposite trend. DMA showed that SMPs had the process from the glassy state to high elastic state and when the temperature was above the Tg, the polymers still had higher modulus, which facilitated the shape memory properties of SMPs.②PDLLA-PUU SMPs had good shape memory properties which their shape recovery and fixation ratio were more than 95%. Meanwhile, the shape memory properties were affected by the components and the hard segment content. The fixation ratio of SMPs showed slightly downward trend with the increasing of the molecular weight of soft segment, and the shape recovery ratio decreased with the increasing of the hard segment content, however, the shape fixation ratio had the opposite trend. ③The deformation strain, deformation and recovery temperature had effects on the shape memory properties. With the deformation strain increasing, the shape recovery ratio decreased. When the deformation range was from 50 to 200%, there were slightly influence on shape memory properties, but when the deformation increased to 300%, the shape recovery ratio decreased to 85%; SMPs showed good shape memory behavior when the deformation temperature was Tg+15℃, while the shape recovery ratio had apparent decrease when the deformation temperature was above Tg+25℃; recovery time shortened with the increasing of the recovery temperature.4. The surface wettability and biodegradation of PDLLA-PUU SMPs were investigated. The evaluating indicators of surface wettability were static water contact angle and water absorption ratio, while the evaluating indicators of degradation behavior were the weight loss ratio and pH value changes. Moreover, the sample surfaces were observed by SEM during degradation.①The static water contact angle of SMPs was smaller than PDLLA controls. This is mainly due to the fact that the hydrophilic BDA segment could form more hydrogen bond with water molecules and improved the hydrophilicity of SMPs. Meanwhile, the static water contact angle had a downtrend with the increasing of hard segment content.②In vitro degradation of PDLLA controls revealed that the weight of samples and pH value of the medium decreased significantly, exhibiting obvious acid catalyzed auto-accelerating degradation. However, the weight and pH value changes of SMPs decreased slowly because the alkaline substance during the degradation of SMPs could eliminate or weaken the acid induced auto-catalysis.③During the degradation, water absorption increased with the degradation time and the variation rate of PDLLA controls were larger than that of SMPs, indicating the degradation rate was faster than SMPs. The SEM showed that the surface of PDLLA controls became rough and appeared large crack compared to SMPs after 8 weeks. These results suggested that the introduction of BDA segment could adjust the biodegradation rate and pH value changes of SMPs.5. The cytocompatibility of PDLLA-PUU SMPs with human umbilical vein endothelial cells (HUVEC) was estimated by means of cell morphology (HE staining method), proliferation (MTT assay). Moreover, biological safety evaluation of SMPs was carried out according to national relevant standards, including endotoxin assay, sensitization test, acute toxicity tests, Ames test, CHL cell chromosomal aberration test and micronucleus tests. The results revealed: ①Compared with PDLLA controls, all results showed that PDLLA-PUU SMPs had the better cytocompatibility, which was mainly due to the considerable -CONH- and -NHCONH- groups in SMPs backbone. All these functional groups could improve the protein adsorption ability of materials through the increase of surface wettability and charge, and then promote HUVEC attachment and cell growth.②The results of biological safety evaluation showed that the endotoxin content conformed to the standard and the sensitivity response was negative; Ames test, CHL chromosomal aberration test and micronucleus test of mice bone marrow polychromatic erythrocytes suggested that the SMPs had no significant genotoxicity. The above results confirmed that the PDLLA-PUU SMPs had great biological safety.6. The medical application of the oviduct contraceptive devices made from PDLLA-PUU SMPs was investigated. The model animals were female New Zealand rabbits. The contraceptive devices were implanted into oviduct by means of minimally invasive surgery and the histopathologic changes of oviductal mucosa were observed to evaluate the histocompatibility.①The oviduct contraceptive devices was smooth and had recovered original shape, and oviduct mucosa had slight hyperemia and edema after being implanted for two weeks, while the oviduct mucosa was no hyperemia and edema after four and twelve weeks.②When the contraceptive devices were implanted for two weeks, the results of TEM and HE staining suggested that there were histopathological changes such as few lymphocytes and neutrophils infiltration in mucosal fold interstitium, cell vacuole degeneration, organelles swelling and no toxic granulation. After 4 weeks, there existed few lymphocytes infiltration proliferation of fibroblast, slightly mitochondrial swelling and the oviduct mucosal fold was flatted. While after 12 weeks, the fibroblasts hyperplasia of oviduct lamina propria mucosae, secretory granule, collagenoblast were observed and there were no organelles vacuolar degeneration, swelling and no toxic granulation. These results suggested that induced inflammatory stimulation was temporary and the inflammatory reaction decreased with implantation time.③In vivo tests demonstrated that SMPs have good histocompatibility and could be designed to the oviduct contraceptive devices.