基于碱金属的肿瘤微创消融方法研究
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摘要
基于射频、微波、超声及激光加热等原理制成的传统医疗设备在确保有效杀灭肿瘤的同时又不伤及正常组织的问题上面临共同难题,并且大多存在结构复杂、手术费用高昂等特点。为克服上述问题,本文首次提出了碱金属热化学消融方法,并从理论和实验两方面,深入探索了新型热消融模式下的一系列关键基础问题。
为全面认识碱金属消融方法对生物组织的破坏机制,本文对碱金属作用后的热效应、化学效应及空穴效应给予了全面评估,获取了描述细胞损伤速率的动力学参数,同时结合细胞损伤过渡态理论,通过活化自由能与温度之间的关系指出了不同处理下细胞损伤反应方向及速率的变化。
通过剖析碱金属与组织间质水之间化学反应的特点,指出化学反应的放热率主要取决于组织中水分子的扩散通量,由此建立了碱金属放热率方程。同时对OH-在组织中反应扩散形成的溶解层及渗透层位移变化进行了定量刻画。基于对放热特性及生成物扩散特性的了解,建立了描述流体输运的传热传质模型,并分析了组织含水量、血液灌注率等参数对温度场及浓度场的影响。
考虑到传统热损伤理论在描述碱金属消融损伤问题上的局限性,建立了热传导、扩散及化学反应相耦合的评价热化学损伤的熵产理论。构建了基于变色明胶体模的消融区形态和空间分布的三维重建方法,提供了精确的剂量定量化工具。
本文还通过荷瘤小鼠统计学实验比较了该方法与单一热疗或化学消融的肿瘤抑制率,同时引入红外测温手段发展了体表热学监测与术后评估体系,并提出了基于红外数据的体内温度场重构方法。尝试建立了注射式液态碱金属治疗平台,并考察了损伤后的病理变化及消融范围与注射量之间的关系。
针对大多热疗方法中血管冷却效应制约热疗效果的问题,本文对存在大血管的碱金属消融后温度分布也进行了研究,由此明确了血管参数及血流速度对消融剂量的影响程度。
以上研究可望引申出一种全新的低成本肿瘤微创治疗手段,就其中生物传热传质等基础问题的研究,对建立适宜于临床应用的高效热化学消融方法及其有效应用具有重要意义。
Traditional hyperthermia techniques based on radiofrequency, microwave, ultrasound and laser often encounter a common bottleneck. That is, they will inevitably cause thermal damage to the healthy tissues along the path heat energy is transmitted to the tumor. In addition, the complex operation and high cost also limit their application. To resolve these problems, this thesis is dedicated to establish a new therapy, the alkali metal ablation for localized killing of tumors via exothermic chemical reaction. Theoretical and experimental investigations were performed on several typical issues raised from the new modality.
Aiming for a comprehensive understanding the mechanisms of the alkali metal ablation, the thermal effect, chemical effect and cavity effect during ablation process were evaluated based on multiple experiments, respectively. Dynamic parameters related with the cell damage rate were obtained. Further more, the temperature response of the activiation free energy at different situations were given to reveal damage reaction direction and the rate based on transtsion state theory.
Following the analysis of chemical reaction between alkali metal and water, it was proposed that exothermic rate mainly depends on the water diffusion flux. A heat release equation of alkali metal was established. In addition, the reaction production OH- diffusion characteristics were simultaneously performed both in experiments and theoretical analysis. Through a combination between heat transfer and reaction diffusion equation, a heat and mass transfer model is established and studied.
Considering the limitation on heat damage function to describe the alkali metal damage, a multi-factor coupling model was proposed to estimate the injury of tissue subject to alkali metal ablation based on entropy production theory. And the relationship between entropy production and damage degree was originally established. In order to quantify the damage scope, a three-dimensional imaging reconstruction method to presisly refect shape and size of ablation area was built, which provides a useful tool to quantify the ablation dose.
Statistic animal experiments were performed to comprare anti-tumor effect among chemical ablation, hyperthermia and alkali metal on mice implanted with EMT6 breast tumor, and the infrared thermography was introduced as an effective imaging tool for administration and evaluation of alkali metal ablation therapy. Endosomatic temperature field reconstruction method utilizing surface infrared imaging data was developed by conjugate gradient method. A liquid alkali metal ablation system was also set up, and tissue pathological changes after ablation and the relationship between injection quantity and ablation area were investigated.
Considering that the effect of large blood vessel may lead to thermal under-dosage in most conventional thermal ablation, the cool effect of large vessel during alkali metal ablation was also studied, and effects of the parameters such as blood diameter and velocity on temperature distribution were clarified.
This thesis is expected to establish a low cost mean of minimally invasive treatment of tumors. Further efforts on conresponding bioheat and mass transfer are of great significance to promote effective clinical application of the new ablaion method.
为全面认识碱金属消融方法对生物组织的破坏机制,本文对碱金属作用后的热效应、化学效应及空穴效应给予了全面评估,获取了描述细胞损伤速率的动力学参数,同时结合细胞损伤过渡态理论,通过活化自由能与温度之间的关系指出了不同处理下细胞损伤反应方向及速率的变化。
通过剖析碱金属与组织间质水之间化学反应的特点,指出化学反应的放热率主要取决于组织中水分子的扩散通量,由此建立了碱金属放热率方程。同时对OH-在组织中反应扩散形成的溶解层及渗透层位移变化进行了定量刻画。基于对放热特性及生成物扩散特性的了解,建立了描述流体输运的传热传质模型,并分析了组织含水量、血液灌注率等参数对温度场及浓度场的影响。
考虑到传统热损伤理论在描述碱金属消融损伤问题上的局限性,建立了热传导、扩散及化学反应相耦合的评价热化学损伤的熵产理论。构建了基于变色明胶体模的消融区形态和空间分布的三维重建方法,提供了精确的剂量定量化工具。
本文还通过荷瘤小鼠统计学实验比较了该方法与单一热疗或化学消融的肿瘤抑制率,同时引入红外测温手段发展了体表热学监测与术后评估体系,并提出了基于红外数据的体内温度场重构方法。尝试建立了注射式液态碱金属治疗平台,并考察了损伤后的病理变化及消融范围与注射量之间的关系。
针对大多热疗方法中血管冷却效应制约热疗效果的问题,本文对存在大血管的碱金属消融后温度分布也进行了研究,由此明确了血管参数及血流速度对消融剂量的影响程度。
以上研究可望引申出一种全新的低成本肿瘤微创治疗手段,就其中生物传热传质等基础问题的研究,对建立适宜于临床应用的高效热化学消融方法及其有效应用具有重要意义。
Traditional hyperthermia techniques based on radiofrequency, microwave, ultrasound and laser often encounter a common bottleneck. That is, they will inevitably cause thermal damage to the healthy tissues along the path heat energy is transmitted to the tumor. In addition, the complex operation and high cost also limit their application. To resolve these problems, this thesis is dedicated to establish a new therapy, the alkali metal ablation for localized killing of tumors via exothermic chemical reaction. Theoretical and experimental investigations were performed on several typical issues raised from the new modality.
Aiming for a comprehensive understanding the mechanisms of the alkali metal ablation, the thermal effect, chemical effect and cavity effect during ablation process were evaluated based on multiple experiments, respectively. Dynamic parameters related with the cell damage rate were obtained. Further more, the temperature response of the activiation free energy at different situations were given to reveal damage reaction direction and the rate based on transtsion state theory.
Following the analysis of chemical reaction between alkali metal and water, it was proposed that exothermic rate mainly depends on the water diffusion flux. A heat release equation of alkali metal was established. In addition, the reaction production OH- diffusion characteristics were simultaneously performed both in experiments and theoretical analysis. Through a combination between heat transfer and reaction diffusion equation, a heat and mass transfer model is established and studied.
Considering the limitation on heat damage function to describe the alkali metal damage, a multi-factor coupling model was proposed to estimate the injury of tissue subject to alkali metal ablation based on entropy production theory. And the relationship between entropy production and damage degree was originally established. In order to quantify the damage scope, a three-dimensional imaging reconstruction method to presisly refect shape and size of ablation area was built, which provides a useful tool to quantify the ablation dose.
Statistic animal experiments were performed to comprare anti-tumor effect among chemical ablation, hyperthermia and alkali metal on mice implanted with EMT6 breast tumor, and the infrared thermography was introduced as an effective imaging tool for administration and evaluation of alkali metal ablation therapy. Endosomatic temperature field reconstruction method utilizing surface infrared imaging data was developed by conjugate gradient method. A liquid alkali metal ablation system was also set up, and tissue pathological changes after ablation and the relationship between injection quantity and ablation area were investigated.
Considering that the effect of large blood vessel may lead to thermal under-dosage in most conventional thermal ablation, the cool effect of large vessel during alkali metal ablation was also studied, and effects of the parameters such as blood diameter and velocity on temperature distribution were clarified.
This thesis is expected to establish a low cost mean of minimally invasive treatment of tumors. Further efforts on conresponding bioheat and mass transfer are of great significance to promote effective clinical application of the new ablaion method.
引文
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