本文選題：支架 + 有限元法�。� 參考：《吉林大學(xué)》2016年博士論文

【摘要】：骨缺損是由創(chuàng)傷、腫瘤、先天性畸形、骨感染等原因引起的臨床常見疾病,是造成肢體殘障的重要原因之一。近年來,骨組織工程技術(shù)已成為骨缺損疾病治療的重要手段。骨缺損部位的骨組織-支架復(fù)合植入物需通過體外培養(yǎng)獲得。體外培養(yǎng)條件、支架材料、以及支架的形態(tài)特征是決定能否成功獲取骨-支架復(fù)合物的關(guān)鍵因素。在體外培養(yǎng)過程中,支架表面黏附的種子細(xì)胞存在于復(fù)雜的力學(xué)環(huán)境下。骨組織工程支架將力學(xué)激勵(lì)傳遞給種子細(xì)胞以促使其增殖與分化,同時(shí)也為骨的生長(zhǎng)提供了臨時(shí)的力學(xué)支撐。然而,目前的實(shí)驗(yàn)手段無法準(zhǔn)確測(cè)得支架內(nèi)的力學(xué)環(huán)境參數(shù),通過有限元分析方法可以很好地解決這一問題。本研究采用Micro-CT影像與有限元技術(shù)相結(jié)合的方法,建立了具有不同形態(tài)、材料的骨組織工程支架有限元模型,定量分析了支架內(nèi)的力學(xué)激勵(lì),并模擬預(yù)測(cè)骨髓間充質(zhì)干細(xì)胞(BMSCs)在不同支架結(jié)構(gòu)上的分化結(jié)果。本研究主要可以分為以下三個(gè)部分:第一部分對(duì)基于松質(zhì)骨理想化胞元形態(tài)的骨支架模型進(jìn)行細(xì)胞分化仿真分析。測(cè)量支架的三維孔形態(tài)參數(shù),并且對(duì)體外培養(yǎng)條件對(duì)細(xì)胞分化結(jié)果的影響進(jìn)行了預(yù)測(cè)。首先利用Rhino三維建模軟件建立了5種孔隙率為65%的三維骨組織工程支架模型。支架采用線彈性PDLLA材料,在0.5-5%的壓應(yīng)變作用下,分析模型表面的應(yīng)變分布情況,同時(shí)在孔內(nèi)模擬穩(wěn)態(tài)流,入口流速為0.01-1 mm/s,計(jì)算支架表面的流體剪應(yīng)力(FSS)。最后,基于細(xì)胞分化定量理論對(duì)不同支架表面的BMSCs分化結(jié)果進(jìn)行了預(yù)測(cè)分析。結(jié)果表明,應(yīng)變和流體剪應(yīng)力的分布取決于支架內(nèi)孔隙的分布。進(jìn)口流體速度和壓應(yīng)變以及支架的形態(tài)均會(huì)影響支架表面BMSCs的分化結(jié)果。當(dāng)軸向壓應(yīng)變?cè)?.5-5%,流體初速度在0.01-1 mm/s范圍內(nèi)時(shí),所有支架的骨和軟骨分化面積可達(dá)到90%以上。本研究設(shè)計(jì)的不同孔結(jié)構(gòu)支架在壓力和流體流動(dòng)作用下可以產(chǎn)生不同程度激勵(lì)以利于BMSCs的分化,并滿足不同骨缺損部位對(duì)力學(xué)性能的需要。第二部分依據(jù)動(dòng)物松質(zhì)骨形態(tài),對(duì)顯微結(jié)構(gòu)參數(shù)與力學(xué)參數(shù)、細(xì)胞分化參數(shù)的關(guān)系進(jìn)行了分析。首先對(duì)雄鼠和牛的松質(zhì)骨進(jìn)行Micro-CT掃描,選取孔隙率為65%左右的松質(zhì)骨結(jié)構(gòu)建立1 mm3的三維立方體支架,施加進(jìn)口流體速度和壓應(yīng)變,進(jìn)行體外灌流培養(yǎng)條件下的有限元數(shù)值模擬。支架固體采用線彈性的聚乳酸(PDLLA)材料,對(duì)其施加0.5-5%的壓縮載荷,同時(shí)模擬入口流速為0.01-1mm/s的牛頓流。根據(jù)細(xì)胞分化定量理論確定不同初始條件下,力學(xué)激勵(lì)對(duì)每種結(jié)構(gòu)表面BMSCs分化結(jié)果的影響。結(jié)果表明,應(yīng)變和流體剪應(yīng)力的分布取決于松質(zhì)骨結(jié)構(gòu)支架的形態(tài)。不規(guī)則的形態(tài)結(jié)構(gòu)使激勵(lì)分布極不均勻,并且細(xì)小孔道處出現(xiàn)應(yīng)力集中現(xiàn)象。細(xì)胞分化過程中對(duì)于進(jìn)口流體流速比支架所受軸向應(yīng)變更加敏感。當(dāng)入口流體速度在0.01-1 mm/s,整體壓應(yīng)變?cè)?.5-5%范圍內(nèi)時(shí),所有支架壁表面的骨分化面積可達(dá)到90%以上。與牛松質(zhì)骨結(jié)構(gòu)支架相比,鼠松質(zhì)骨結(jié)構(gòu)支架骨分化區(qū)在60-90%之間的分化激勵(lì)值范圍較大。相對(duì)于鼠松質(zhì)骨結(jié)構(gòu)支架,具有更多板狀結(jié)構(gòu)的牛松質(zhì)骨結(jié)構(gòu)支架的軟骨分化情況更好,軟骨分化區(qū)在60-90%之間的分化激勵(lì)值范圍遠(yuǎn)遠(yuǎn)大于鼠松質(zhì)骨結(jié)構(gòu)支架。本研究依據(jù)松質(zhì)骨形態(tài)建立支架結(jié)構(gòu),提取出了能夠全面反映支架形態(tài)的3個(gè)主元素,對(duì)顯微結(jié)構(gòu)參數(shù)與力學(xué)參數(shù)、細(xì)胞分化參數(shù)進(jìn)行了相關(guān)性分析,并建立了主元素與力學(xué)參數(shù)、細(xì)胞分化參數(shù)之間的回歸方程。在進(jìn)行細(xì)胞體外培養(yǎng)時(shí),可以為BMSCs提供更貼近于體內(nèi)的力學(xué)環(huán)境,為支架形態(tài)的設(shè)計(jì)和臨床治療骨缺損提供了理論基礎(chǔ)。第三部分針對(duì)不同工藝制備的生物材料支架,比較了支架在不同流體加載參數(shù)條件下的力學(xué)環(huán)境�；贛icro-CT影像重建三維Ti O2生物材料支架,測(cè)量支架的孔形態(tài)參數(shù),并通過掃描電鏡觀察支架表觀形貌。另外,將本研究得到的滲透率結(jié)果與其它研究進(jìn)行了比較,驗(yàn)證了仿真分析的有效性。最后,對(duì)支架內(nèi)的力學(xué)激勵(lì)(流體剪應(yīng)力和固體應(yīng)變)進(jìn)行定量分析,同時(shí)與其他三種商業(yè)骨支架材料(Bio-Oss,Cerabone,Maxresorb)進(jìn)行了比較。結(jié)果表明Ti O2的力學(xué)性能相對(duì)較差,但壁面流體剪應(yīng)力明顯高于其他商業(yè)骨支架替換材料。另外,不規(guī)則的支架形態(tài)會(huì)形成不均勻的激勵(lì)分布,且在四種支架內(nèi)產(chǎn)生的流體剪應(yīng)力均在BMSCs產(chǎn)生生物學(xué)反應(yīng)的激勵(lì)范圍內(nèi)。本研究從力學(xué)性能、生物材料、組織學(xué)等多角度評(píng)價(jià)了骨組織工程支架的性能,研究結(jié)果可以為生物反應(yīng)器內(nèi)體外培養(yǎng)條件的設(shè)計(jì),以及臨床特定部位骨缺損的修復(fù)提供重要的理論依據(jù)。所建立的三種不同形式的支架模型(理想化支架模型,動(dòng)物松質(zhì)骨支架模型,以及合成生物材料支架模型)可以作為研究體外灌流培養(yǎng)實(shí)驗(yàn)的基礎(chǔ),并為體外培養(yǎng)條件下支架的制備與臨床應(yīng)用提供更為直觀的依據(jù)。
[Abstract]:Bone defect is a common clinical disease caused by trauma, tumor, congenital malformation and bone infection. It is one of the important causes of the disability of the limb. In recent years, bone tissue engineering has become an important means for the treatment of bone defects. Bone tissue scaffold composite implant in bone defect needs to be obtained through culture in vitro. The condition, scaffold material, and the morphological characteristics of the scaffold are the key factors determining whether the bone scaffold complex can be successfully obtained. In the process of culture, the adherent seed cells of the scaffold exist in the complex mechanical environment. The bone tissue engineering scaffold transfers mechanical stimulation to the seed cells to promote its proliferation and differentiation. It provides a temporary mechanical support for bone growth. However, the mechanical environment parameters in the scaffold can not be accurately measured by the present experimental methods. The finite element method can be used to solve this problem well. In this study, a combination of Micro-CT images and finite element method was used to establish a bone tissue worker with different shapes and materials. The finite element model of range stents is used to quantitatively analyze the mechanical excitation in the scaffold and to simulate and predict the differentiation of bone marrow mesenchymal stem cells (BMSCs) on different scaffolds. This study can be divided into three parts: the first part is the simulation analysis of the cell differentiation based on the idealized bone scaffold model of the cancellous bone. The three-dimensional pore shape parameters of the scaffold were measured and the effects of the culture conditions on the cell differentiation were predicted. First, 5 three-dimensional bone tissue engineering scaffolds with 65% porosity were established by using Rhino 3D modeling software. The scaffolds were linear elastic PDLLA material, and the model surface should be analyzed under the 0.5-5% pressure strain. At the same time, the steady flow is simulated in the hole, and the flow velocity of the inlet is 0.01-1 mm/s. The fluid shear stress (FSS) on the surface of the stent is calculated. Finally, the results of the BMSCs differentiation on the different scaffolds are predicted based on the cell differentiation theory. The results show that the distribution of the strain and the shear stress of the flow body depends on the distribution of the pores in the scaffold. The velocity and strain of the oral fluid and the shape of the scaffold affect the differentiation of BMSCs on the surface of the scaffold. The bone and cartilage differentiation area of all scaffolds can reach more than 90% when the axial compression strain is 0.5-5% and the initial velocity of the fluid is within the range of 0.01-1 mm/s. Different extent of stimulation was produced to help BMSCs differentiation and to meet the needs of mechanical properties of different bone defects. The second part, based on the shape of the cancellous bone, analyzed the relationship between the microstructure parameters and the mechanical parameters and the cell differentiation parameters. First, the Micro-CT scan was performed on the cancellous bone of male and cattle, and the porosity was 65%. The left and right cancellous bone structures set up a 1 mm3 three-dimensional cube scaffold, applying the inlet fluid velocity and pressure strain to simulate the finite element numerical simulation under the condition of in vitro perfusion culture. The scaffold solid adopts the linear elastic polylactic acid (PDLLA) material to apply the 0.5-5% compression load to it, and simulates the Newton flow of the inlet velocity of 0.01-1mm/s. The quantitative theory of cell differentiation determines the effect of mechanical excitation on the results of BMSCs differentiation on the surface of each structure under different initial conditions. The results show that the distribution of the strain and the shear stress of the fluid depends on the shape of the structure of the cancellous bone structure. The irregular shape and structure make the excitation distribution very uneven, and the stress concentration in the small pores. In the process of cell differentiation, the flow velocity of the inlet fluid is more sensitive than the axial stress of the stent. When the inlet fluid velocity is at 0.01-1 mm/s and the overall compressive strain is within the 0.5-5% range, the bone differentiation area of all the wall surfaces can reach more than 90%. Compared with the bovine cancellous bone structure scaffold, the bone differentiation area of the rat cancellous bone structure is between 60-90% and the bone structure. The differentiation incentive value is larger. Compared with the structure of the bone structure of the rat, the cartilage differentiation of the bovine cancellous bone structure with more plate structure is better, the differentiation incentive value of the differentiation area between 60-90% is far greater than that of the rat cancellous bone structure. The 3 main elements of the scaffold form are fully reflected. The correlation analysis of the microstructure parameters and the mechanical parameters and the cell differentiation parameters is carried out. The regression equation between the main elements and the mechanical parameters and the cell differentiation parameters is established. In the culture of the cells in vitro, the BMSCs can provide a more close to the internal mechanical environment for the scaffolding. The design of state and the clinical treatment of bone defect provide a theoretical basis. The third part compares the mechanical environment of the scaffold under the conditions of different fluid loading parameters for the scaffolds prepared by different processes. The reconstruction of the three-dimensional Ti O2 biomaterial scaffold based on the Micro-CT image is used to measure the pore shape parameters of the scaffold, and the scanning electron microscope is observed by scanning electron microscope. In addition, the results obtained from this study were compared with other studies to verify the effectiveness of the simulation analysis. Finally, the mechanical excitation (fluid shear stress and solid strain) in the support was quantitatively analyzed, and compared with the other three kinds of commercial bone scaffolds (Bio-Oss, Cerabone, Maxresorb). The results show that the mechanical properties of Ti O2 are relatively poor, but the shear stress of the wall fluid is significantly higher than that of other commercial bone scaffold replacement materials. In addition, the irregular shape of the scaffold forms an uneven excitation distribution, and the fluid shear stress produced in the four kinds of scaffolds is within the excitation range of the biologic reaction in BMSCs. The performance of bone tissue engineering scaffolds is evaluated by many angles, such as biomaterials and histology. The results can provide important theoretical basis for the design of the culture conditions in the bioreactor and the repair of bone defects in specific sites. Three different forms of scaffold models (idealized scaffold model, animal cancellous bone) have been established. The scaffolding model, as well as the synthetic biomaterial scaffold model, can be used as the basis for the study of in vitro perfusion culture, and provide a more intuitive basis for the preparation and clinical application of scaffolds in vitro culture conditions.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R318.04;R683

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