醫(yī)用功能性可降解聚氨酯復(fù)合體系構(gòu)建的研究
發(fā)布時(shí)間：2018-07-25 11:23
【摘要】：軟骨組織無血管、無神經(jīng)、無淋巴，在關(guān)節(jié)腔內(nèi)僅靠滑液來獲取營養(yǎng)，其代謝主要以無氧酵解為主，決定了其有限的自身修復(fù)能力。然而，現(xiàn)有的修復(fù)治療技術(shù)無法實(shí)現(xiàn)從生物學(xué)環(huán)境及力學(xué)環(huán)境來進(jìn)行構(gòu)建，以適于軟骨的再生修復(fù)，從而使得臨床上關(guān)節(jié)軟骨的修復(fù)至今難以取得突破性的進(jìn)展。根據(jù)生物學(xué)環(huán)境及力學(xué)環(huán)境來重構(gòu)是未來軟骨再生修復(fù)的重要研究方向，而如何實(shí)現(xiàn)以可降解材料為基礎(chǔ)構(gòu)建軟骨再生的生物學(xué)環(huán)境及力學(xué)環(huán)境是未來軟骨修復(fù)材料研究的重點(diǎn)與熱點(diǎn)。 本研究從上述角度出發(fā)，合成了一種新型的功能性醫(yī)用可降解聚氨酯（PU），在此基礎(chǔ)上，通過改變合成PU的軟硬段比例構(gòu)建了不同模量的PU材料，然后采用相轉(zhuǎn)變-粒子瀝濾法制備了不同孔結(jié)構(gòu)特性的PU多孔支架，以滿足骨和軟骨再生對(duì)力學(xué)環(huán)境要求的不同。同時(shí)，通過表面改性的方法構(gòu)建了適于軟骨及骨再生的PU表面微環(huán)境以及通過復(fù)合的方法構(gòu)建了適于軟骨及骨再生的功能性微球/PU復(fù)合支架,以此來滿足骨和軟骨再生對(duì)生物學(xué)環(huán)境要求的不同，期望應(yīng)用于一體化關(guān)節(jié)軟骨組織工程。 在構(gòu)建不同彈性模量的PU材料上，以賴氨酸二異氰酸乙酯為硬段，平均分子量為2000的聚己內(nèi)酯二醇為軟段，具有藥理活性的異山梨醇為擴(kuò)鏈劑，采用不同的軟硬段比例合成了不同模量的PU。利用FTIR、1H-NMR、GPC、XRD、DSC對(duì)合成的聚合物進(jìn)行了表征。FTIR、1H-NMR結(jié)果表明合成的聚合物的結(jié)構(gòu)是典型PU的結(jié)構(gòu)；GPC測(cè)試結(jié)果顯示聚合物的數(shù)均分子量超過5萬，分布指數(shù)在1.6~2.0，分子量分布較窄；DSC分析結(jié)果顯示軟段比例較大合成得到的聚合物在42℃存在著結(jié)晶熔融峰，而硬段比例較大合成得到的聚合物，沒有結(jié)晶熔融峰；而XRD結(jié)果證明合成的聚合物存在部分結(jié)晶，但是結(jié)晶不是很完整。通過材料的拉伸力學(xué)試驗(yàn)，結(jié)果證明合成得到的PU材料具有很好的彈性，其斷裂伸長率超過700%；同時(shí)其酶解性能也表明，相比較傳統(tǒng)的PLGA材料的降解性能，合成得到的PU具有更慢的降解速度，且降解后溶液呈弱堿性，表現(xiàn)出更加理想的降解特性。該P(yáng)U材料，可以滿足軟骨組織工程需要承受一定的負(fù)荷的要求，且解決工程支架植入到體內(nèi)與自體組織相連不緊密，而在界面上產(chǎn)生剪切力造成植入體與自體相分離的問題，同時(shí)不至于因?yàn)椴牧辖到舛a(chǎn)生酸性積累，導(dǎo)致無菌性炎癥的發(fā)生。潛在應(yīng)用于骨及軟骨組織工程。 在構(gòu)建適于軟骨及骨再生的表面微環(huán)境上，對(duì)PU進(jìn)行了一系列的表面改性。首先利用1,3-丙二胺與PU鏈上的酯基基團(tuán)發(fā)生胺解反應(yīng)，在PU的表面形成游離的胺基，然后利用產(chǎn)生的胺基，一是通過與Ⅰ型膠原在EDC/NHS的作用下進(jìn)行化學(xué)反應(yīng)，使材料的表面接枝上膠原，構(gòu)建骨再生的微環(huán)境，有利于骨細(xì)胞的增殖和分化；二是將游離的胺基酸化，使材料表面帶正電荷，再通過靜電作用力，在材料表面進(jìn)行層層自組裝硫酸軟骨素和Ⅰ型膠原，構(gòu)建軟骨再生的微環(huán)境。RBITC-Col、QCM、XPS和AFM測(cè)試結(jié)果證明膠原和硫酸軟骨素成功地吸附在PU的表面，使材料的表面變得更平整，形成比較均一的納米級(jí)形貌結(jié)構(gòu)，這樣的一個(gè)表面納米結(jié)構(gòu)應(yīng)該有利于細(xì)胞的粘附，促進(jìn)細(xì)胞的增殖和分化。 在不同孔結(jié)構(gòu)特性的PU支架制備上，采用相轉(zhuǎn)變-粒子瀝濾法，通過改變良溶劑和不良溶劑的比例以及造孔劑的比例等來控制PU支架的孔徑、分布、孔之間的連通性以及支架的力學(xué)性能等。結(jié)果表明添加了不良溶劑和造孔劑制備得到的PU三維支架是由大小不同的孔構(gòu)成，孔與孔之間連通性較好，大孔孔徑可達(dá)幾百微米，孔隙率超過75%，可以滿足細(xì)胞在支架上生長、增殖的需要；同時(shí)，支架的抗壓性能較好，具有較好的形變回復(fù)能力，通過加入不良溶劑得到的三維支架在壓縮過程中不會(huì)發(fā)生崩塌的現(xiàn)象。當(dāng)PU溶液的濃度為14.5%，良溶劑和不良溶劑的比例為2:1，造孔劑與PU的質(zhì)量比為5:1時(shí)，且在37℃進(jìn)行干燥除去溶劑制備得到的PU三維多孔支架的性能較好。此時(shí)得到的支架的孔隙率為84.2%，孔徑大于100μm所占的比例為87.5%，且孔之間的連通性較好；壓縮應(yīng)變?yōu)?0%時(shí)的抗壓強(qiáng)度為0.31MPa，滿足軟骨組織工程的力學(xué)性能要求。 在構(gòu)建適于軟骨及骨再生的功能性微球/PU復(fù)合支架上，分別采用乳化法制備了明膠/肝素微球和雙乳化溶劑揮發(fā)法制備了內(nèi)部具有多孔結(jié)構(gòu)的PLGA/氧氟沙星載藥微球。明膠濃度，乳化劑濃度，水油比對(duì)明膠/肝素微球的粒徑和分布有較大的影響。通過明膠微球包裹肝素，為明膠微球吸附bFGF提供活性位點(diǎn)，盡量保持bFGF的活性，構(gòu)建軟骨再生的緩釋結(jié)構(gòu)體系。而在PLGA/氧氟沙星載藥微球制備中，在內(nèi)水相中加入介孔二氧化硅、透明質(zhì)酸、多聚賴氨酸對(duì)微球的粒徑、分布及載藥效率和釋放都有影響。內(nèi)水相中添加劑的物理吸附作用和靜電吸引作用可以改善高親水性藥物在內(nèi)水相中的留存量，并提高藥物的包封率，但靜電作用也可能會(huì)影響表面活性劑的乳化效果，破壞乳液的穩(wěn)定性，造成較低的包封率。內(nèi)水相中添加劑的親水性的增加改善了高分子材料整體的親水性，提高了親水性藥物在微球表面的吸附率，造成初期爆釋較高。通過PLGA微球包裹氧氟沙星，構(gòu)建骨再生的緩釋結(jié)構(gòu)體系。通過制得的功能性微球與PU三維多孔支架相復(fù)合，考察微球在PU支架中的分布，結(jié)果表明微球較均勻地分布在支架的孔壁和孔的里面，說明了這一功能性PU復(fù)合體系構(gòu)建的可行性。 通過PU材料的生物相容性及PU材料對(duì)滑膜干細(xì)胞分化為軟骨細(xì)胞實(shí)驗(yàn)，，對(duì)PU材料的生物學(xué)性能進(jìn)行了評(píng)價(jià)。結(jié)果表明不管是PU材料還是PU自組裝膠原/硫酸軟骨素材料，兩者都沒有毒性或者毒性很小，且支持細(xì)胞的生長和增殖。相比較單純的PU材料，在PU材料表面組裝上膠原和硫酸軟骨素更有利于滑膜干細(xì)胞的生長及向軟骨細(xì)胞分化。 未來，單一的生物材料在復(fù)雜組織的再生中將難以起主導(dǎo)作用。把各種信號(hào)因子復(fù)合在材料主體結(jié)構(gòu)上，以實(shí)現(xiàn)材料體系的多功能、多效用，將成為組織工程材料構(gòu)建的發(fā)展趨勢(shì)。本研究從力學(xué)環(huán)境和生物學(xué)環(huán)境角度構(gòu)建了功能性PU復(fù)合支架材料體系，為一體化軟骨組織工程的開發(fā)應(yīng)用奠定了基礎(chǔ)，為未來多功能復(fù)合支架材料的研究提供了一定的參考依據(jù)。
[Abstract]:The cartilage tissue has no blood vessel, no nerve, no lymph, and is only dependent on the synovial fluid to obtain nutrition in the articular cavity. Its metabolism is mainly based on anaerobic fermentation, which determines its limited self repair ability. However, the existing repair and treatment technology can not be constructed from the biological environment and the mechanical environment to fit for the regeneration of cartilage. It is difficult to make a breakthrough in the repair of articular cartilage in clinical. Reconstruction is an important research direction in the future of cartilage regeneration based on the biological environment and mechanical environment. How to build the biological environment and mechanical environment on the basis of biodegradable materials to build cartilage regeneration is the key point in the study of cartilage repair materials in the future. And hot spots.
In this study, a new functional medical degradable polyurethane (PU) was synthesized. On this basis, different moduli of PU materials were constructed by changing the proportion of soft and hard segments of synthetic PU. Then phase transition particle leaching method was used to prepare PU porous scaffolds with different pore structure properties to meet the regenerative force of bone and cartilage. At the same time, the PU surface microenvironment suitable for cartilage and bone regeneration is constructed by surface modification, and a functional microsphere /PU composite scaffold suitable for cartilage and bone regeneration is constructed by compound method, in order to meet the different biological environment requirements for bone and cartilage regeneration, and be expected to be applied to integration. Articular cartilage tissue engineering.
On the PU materials with different modulus of elasticity, the lysine two isocyanate was used as the hard segment and the average molecular weight was 2000. The pharmacologically active isosorbide was used as the chain extender. The PU. of different moduli was synthesized by different soft and hard segments, and the synthesized polymers were made by FTIR, 1H-NMR, GPC, XRD, DSC. The results of.FTIR, 1H-NMR show that the structure of the synthesized polymer is the structure of the typical PU; the results of GPC test show that the average molecular weight of the polymer is more than 50 thousand, the distribution index is 1.6~2.0, the distribution of the molecular weight is narrow, and the result of DSC analysis shows that the polymer obtained by the larger proportion of the soft segments has the crystallization melting peak at 42, and the ratio of the hard segment. The polymer obtained by the larger synthesis did not crystallize the melting peak, and the XRD results showed that the synthesized polymer was partially crystallized, but the crystallization was not very complete. Through the tensile mechanical test of the material, the results showed that the synthesized PU material had good elasticity, its elongation at break was over 700%, and its enzymatic properties also showed that compared with the results of its enzymatic hydrolysis, Compared with the degradation performance of the traditional PLGA material, the synthesized PU has a slower degradation rate, and the solution is weak alkaline after degradation, showing a more ideal degradation characteristic. The PU material can meet the requirement of the cartilage tissue engineering to bear a certain load, and the solution of the scaffold is not closely connected with the autograft in the body. The shear force on the interface causes the separation of the implant from the autologous phase, and it does not produce acid accumulation because of the degradation of the material, which leads to the occurrence of aseptic inflammation. It is potentially used in bone and cartilage tissue engineering.
In the construction of a surface microenvironment suitable for cartilage and bone regeneration, a series of surface modification has been carried out on PU. First, the amine solution of 1,3- propyl two amine and ester group on PU chain is used to form a free amino group on the surface of PU, and then the produced amine group is used, one is by chemical reaction with type I collagen under the action of EDC/NHS. The surface of the material is grafted with collagen, and the microenvironment of bone regeneration is constructed, which is beneficial to the proliferation and differentiation of the bone cells. Two the free amino group is acidified, the surface of the material is positively charged, and the electrostatic force is used to build the self assembled chondroitin sulfate and type I gluin on the surface of the material, and the microenvironment.RBITC-Col, QCM, XPS of the cartilage regeneration is constructed. The results of the AFM test showed that collagen and chondroitin sulfate were successfully adsorbed on the surface of PU, making the surface of the material more smooth and forming a relatively uniform nanoscale structure. Such a surface nanostructure should be beneficial to cell adhesion, promote cell proliferation and differentiation.
In the preparation of PU stents with different pore structure characteristics, the phase transition particle leaching method was used to control the pore size, distribution, connectivity between the holes and the mechanical properties of the scaffolds by changing the proportion of good solvent and bad solvent and the proportion of pore forming agent to control the mechanical properties of the scaffolds. The results showed that the PU obtained by the bad solvent and pore making agent was added to the PU. Three dimensional scaffolds are composed of different sizes of holes, with good connectivity between holes and holes, a large pore diameter of up to a few hundred microns and a porosity of more than 75%, which can meet the needs of cell growth and proliferation on the scaffold. At the same time, the compression performance of the scaffold is good, and the three-dimensional scaffold obtained by adding bad solvent is pressed. When the concentration of the PU solution is 14.5%, the proportion of the good solvent and the bad solvent is 2:1, the mass ratio of the pore forming agent to PU is 5:1, and the performance of the PU three-dimensional porous scaffold obtained by removing the solvent at 37 C is better. The porosity of the support frame is 84.2%, the pore size is more than 100 mu m. The compressive strength is 0.31MPa when the compressive strain is 20%, which meets the requirements of mechanical properties of cartilage tissue engineering.
In the construction of a functional microsphere /PU composite scaffold suitable for cartilage and bone regeneration, gelatin / heparin microspheres and double emulsified solvent evaporation method were prepared by emulsification. The concentration of gelatin, the concentration of emulsifier, and the ratio of water to oil to gelatin / heparin microspheres were larger than those of the gelatin / heparin microspheres. By wrapping the heparin with gelatin microspheres, the active site was provided for the gelatin microsphere to adsorb bFGF, and the activity of bFGF was maintained as far as possible to construct the sustained release structure of cartilage regeneration. In the preparation of PLGA/ ofloxacin microspheres, mesoporous silica, hyaluronic acid and polylysine were added to the internal aqueous phase, and the particle size, distribution and drug loading of polylysine were added to the microspheres. The physical adsorption and electrostatic attraction of additives in the internal water phase can improve the retention of high hydrophilic drugs in the internal water phase and increase the encapsulation efficiency of the drugs, but the electrostatic effect may also affect the emulsifying effect of the surfactant, destroy the stability of the emulsion, and cause the lower encapsulation efficiency. The hydrophilicity of the additive improves the hydrophilicity of the polymer as a whole, improves the adsorption rate of the hydrophilic drug on the surface of the microspheres, and causes a high initial detonation. Through the encapsulation of ofloxacin by PLGA microspheres, the sustained release structure of bone regeneration is constructed. The functional microspheres are combined with the PU three-dimensional porous scaffold. The distribution of microspheres in the PU scaffold shows that the microspheres are distributed evenly in the pores and holes of the scaffolds, indicating the feasibility of this functional PU complex system.
The biological properties of PU materials were evaluated by the biocompatibility of PU materials and the differentiation of synovial stem cells into chondrocytes by PU materials. The results showed that both PU and PU self assembled collagen / chondroitin sulfate have no toxicity or small toxicity, and support cell growth and proliferation. Collagen and chondroitin sulfate assembled on the surface of PU are more conducive to the growth and differentiation of synovial stem cells into chondrocytes.
In the future, a single biological material will be difficult to play a leading role in the regeneration of complex tissues. Combining various signal factors on the material body structure to realize the multi-function and utility of the material system will become the development trend of the construction of tissue engineering materials. This study has constructed the functional PU complex from the angle of mechanical and biological environment. The scaffold material system has laid a foundation for the development and application of the integrated cartilage tissue engineering, and provides some reference for the future research of multi-functional composite scaffold materials.
【學(xué)位授予單位】：華南理工大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類號(hào)】：R318.08;TQ323.8
本文編號(hào)：2143673
[Abstract]:The cartilage tissue has no blood vessel, no nerve, no lymph, and is only dependent on the synovial fluid to obtain nutrition in the articular cavity. Its metabolism is mainly based on anaerobic fermentation, which determines its limited self repair ability. However, the existing repair and treatment technology can not be constructed from the biological environment and the mechanical environment to fit for the regeneration of cartilage. It is difficult to make a breakthrough in the repair of articular cartilage in clinical. Reconstruction is an important research direction in the future of cartilage regeneration based on the biological environment and mechanical environment. How to build the biological environment and mechanical environment on the basis of biodegradable materials to build cartilage regeneration is the key point in the study of cartilage repair materials in the future. And hot spots.
In this study, a new functional medical degradable polyurethane (PU) was synthesized. On this basis, different moduli of PU materials were constructed by changing the proportion of soft and hard segments of synthetic PU. Then phase transition particle leaching method was used to prepare PU porous scaffolds with different pore structure properties to meet the regenerative force of bone and cartilage. At the same time, the PU surface microenvironment suitable for cartilage and bone regeneration is constructed by surface modification, and a functional microsphere /PU composite scaffold suitable for cartilage and bone regeneration is constructed by compound method, in order to meet the different biological environment requirements for bone and cartilage regeneration, and be expected to be applied to integration. Articular cartilage tissue engineering.
On the PU materials with different modulus of elasticity, the lysine two isocyanate was used as the hard segment and the average molecular weight was 2000. The pharmacologically active isosorbide was used as the chain extender. The PU. of different moduli was synthesized by different soft and hard segments, and the synthesized polymers were made by FTIR, 1H-NMR, GPC, XRD, DSC. The results of.FTIR, 1H-NMR show that the structure of the synthesized polymer is the structure of the typical PU; the results of GPC test show that the average molecular weight of the polymer is more than 50 thousand, the distribution index is 1.6~2.0, the distribution of the molecular weight is narrow, and the result of DSC analysis shows that the polymer obtained by the larger proportion of the soft segments has the crystallization melting peak at 42, and the ratio of the hard segment. The polymer obtained by the larger synthesis did not crystallize the melting peak, and the XRD results showed that the synthesized polymer was partially crystallized, but the crystallization was not very complete. Through the tensile mechanical test of the material, the results showed that the synthesized PU material had good elasticity, its elongation at break was over 700%, and its enzymatic properties also showed that compared with the results of its enzymatic hydrolysis, Compared with the degradation performance of the traditional PLGA material, the synthesized PU has a slower degradation rate, and the solution is weak alkaline after degradation, showing a more ideal degradation characteristic. The PU material can meet the requirement of the cartilage tissue engineering to bear a certain load, and the solution of the scaffold is not closely connected with the autograft in the body. The shear force on the interface causes the separation of the implant from the autologous phase, and it does not produce acid accumulation because of the degradation of the material, which leads to the occurrence of aseptic inflammation. It is potentially used in bone and cartilage tissue engineering.
In the construction of a surface microenvironment suitable for cartilage and bone regeneration, a series of surface modification has been carried out on PU. First, the amine solution of 1,3- propyl two amine and ester group on PU chain is used to form a free amino group on the surface of PU, and then the produced amine group is used, one is by chemical reaction with type I collagen under the action of EDC/NHS. The surface of the material is grafted with collagen, and the microenvironment of bone regeneration is constructed, which is beneficial to the proliferation and differentiation of the bone cells. Two the free amino group is acidified, the surface of the material is positively charged, and the electrostatic force is used to build the self assembled chondroitin sulfate and type I gluin on the surface of the material, and the microenvironment.RBITC-Col, QCM, XPS of the cartilage regeneration is constructed. The results of the AFM test showed that collagen and chondroitin sulfate were successfully adsorbed on the surface of PU, making the surface of the material more smooth and forming a relatively uniform nanoscale structure. Such a surface nanostructure should be beneficial to cell adhesion, promote cell proliferation and differentiation.
In the preparation of PU stents with different pore structure characteristics, the phase transition particle leaching method was used to control the pore size, distribution, connectivity between the holes and the mechanical properties of the scaffolds by changing the proportion of good solvent and bad solvent and the proportion of pore forming agent to control the mechanical properties of the scaffolds. The results showed that the PU obtained by the bad solvent and pore making agent was added to the PU. Three dimensional scaffolds are composed of different sizes of holes, with good connectivity between holes and holes, a large pore diameter of up to a few hundred microns and a porosity of more than 75%, which can meet the needs of cell growth and proliferation on the scaffold. At the same time, the compression performance of the scaffold is good, and the three-dimensional scaffold obtained by adding bad solvent is pressed. When the concentration of the PU solution is 14.5%, the proportion of the good solvent and the bad solvent is 2:1, the mass ratio of the pore forming agent to PU is 5:1, and the performance of the PU three-dimensional porous scaffold obtained by removing the solvent at 37 C is better. The porosity of the support frame is 84.2%, the pore size is more than 100 mu m. The compressive strength is 0.31MPa when the compressive strain is 20%, which meets the requirements of mechanical properties of cartilage tissue engineering.
In the construction of a functional microsphere /PU composite scaffold suitable for cartilage and bone regeneration, gelatin / heparin microspheres and double emulsified solvent evaporation method were prepared by emulsification. The concentration of gelatin, the concentration of emulsifier, and the ratio of water to oil to gelatin / heparin microspheres were larger than those of the gelatin / heparin microspheres. By wrapping the heparin with gelatin microspheres, the active site was provided for the gelatin microsphere to adsorb bFGF, and the activity of bFGF was maintained as far as possible to construct the sustained release structure of cartilage regeneration. In the preparation of PLGA/ ofloxacin microspheres, mesoporous silica, hyaluronic acid and polylysine were added to the internal aqueous phase, and the particle size, distribution and drug loading of polylysine were added to the microspheres. The physical adsorption and electrostatic attraction of additives in the internal water phase can improve the retention of high hydrophilic drugs in the internal water phase and increase the encapsulation efficiency of the drugs, but the electrostatic effect may also affect the emulsifying effect of the surfactant, destroy the stability of the emulsion, and cause the lower encapsulation efficiency. The hydrophilicity of the additive improves the hydrophilicity of the polymer as a whole, improves the adsorption rate of the hydrophilic drug on the surface of the microspheres, and causes a high initial detonation. Through the encapsulation of ofloxacin by PLGA microspheres, the sustained release structure of bone regeneration is constructed. The functional microspheres are combined with the PU three-dimensional porous scaffold. The distribution of microspheres in the PU scaffold shows that the microspheres are distributed evenly in the pores and holes of the scaffolds, indicating the feasibility of this functional PU complex system.
The biological properties of PU materials were evaluated by the biocompatibility of PU materials and the differentiation of synovial stem cells into chondrocytes by PU materials. The results showed that both PU and PU self assembled collagen / chondroitin sulfate have no toxicity or small toxicity, and support cell growth and proliferation. Collagen and chondroitin sulfate assembled on the surface of PU are more conducive to the growth and differentiation of synovial stem cells into chondrocytes.
In the future, a single biological material will be difficult to play a leading role in the regeneration of complex tissues. Combining various signal factors on the material body structure to realize the multi-function and utility of the material system will become the development trend of the construction of tissue engineering materials. This study has constructed the functional PU complex from the angle of mechanical and biological environment. The scaffold material system has laid a foundation for the development and application of the integrated cartilage tissue engineering, and provides some reference for the future research of multi-functional composite scaffold materials.
【學(xué)位授予單位】：華南理工大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類號(hào)】：R318.08;TQ323.8
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