冷热交替条件下的肿瘤微循环损伤及机理研究
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摘要
恶性肿瘤是危害人类健康的最严重疾病之一。传统治疗肿瘤的手术切除对病人创伤较大，而放疗和化疗具有较大的毒副作用，制约了治疗效率。肿瘤热物理治疗通过改变人体局部目标组织的温度(冷冻或热疗)来实现治疗目的，具有微创、副作用小、成本低等优点，被誉为肿瘤的微创“绿色疗法”。然而，单一的冷冻手术或热疗仍然存在各自的局限性，如热疗过程中出现的肿瘤边缘血流量增加和温度控制问题，以及低温手术后的肿瘤复发率较高等问题。冷热交替治疗这一新型治疗方法有望突破单一疗法的局限性,大大提高肿瘤治疗效果。目前该方向主要研究初步证实了其对不同肿瘤治疗的效果，但其治疗机理尚不清晰，有待进一步探讨。肿瘤新生血管为肿瘤细胞提供生长所必需的营养，对其生长以及转移有着重要影响。冷热交替作用不仅对肿瘤细胞有直接杀伤作用，而且会对肿瘤微循环造成极大的破坏。因此研究冷热交替条件下肿瘤微循环损伤及机理，对进一步优化治疗方案、揭示冷热交替治疗机制至关重要。
本文首先利用激光共聚焦荧光显微镜，采用裸鼠脊背皮翼肿瘤视窗模型，通过尾静脉注射纳米脂质体示踪剂，成功地观察了不同热物理条件对在体肿瘤微循环损伤的动态过程与规律，并获得了肿瘤中央微血管壁对纳米脂质体渗透的三维荧光定量信息。肿瘤微循环对示踪粒子的通透性以及其在肿瘤间质中的分布浓度是定量评价血管壁结构改变及损伤的重要手段。本文根据纳米脂质体在组织间质中分布的荧光图像，建立了三维定量模型，获得了未破损血管在不同热物理作用后对纳米脂质体的渗透率，结果表明肿瘤中央血管由于其结构较完整而比边缘血管具有更好的热承受力，单冷、单热均不能造成严重的损伤。然而，在-10°C和42°C的冷热交替作用过程中，无论是在中央还是边缘，肿瘤间质内均出现大量的脂质体渗透，随后的血管结构观察表明内皮细胞间的连接完全被破坏。为了更深入了解冷热交替对肿瘤微循环的损伤程度，本研究应用组织病理切片方法对治疗后7天内的肿瘤微血管进行了跟踪观察和分析，发现-10°C/42°C冷热交替治疗后第7天仍未见肿瘤微血管修复，且肿瘤组织完全坏死。实验结果证实冷热交替治疗对肿瘤微循环造成了不可逆的结构性破坏，而这应该与肿瘤微血管在冷热交替过程中承受的应力作用相关。
为了进一步揭示肿瘤微血管损伤机制，本研究接着对治疗过程中血管的受力情况进行了理论分析。首先，在降温过程中，生物组织发生相变而凝结，组织内温度梯度的存在，以及血管与组织间力学性能差异，使得冻结组织中的热应力产生。本研究基于肿瘤血管的实际形态，并将其与周围组织及血液区别对待，创建了描述肿瘤冷热交替治疗过程中的热应力模型。数值计算结果发现在降温过程中血管内壁承受压应力，其幅值与文献报道的一些生物材料的应力强度阈值相当，可能造成肿瘤血管壁上微小裂纹的产生。而且，结构扭曲的肿瘤血管壁上存在应力集中点，是造成血管壁损伤的重要原因。在冷热交替的加热过程中，热应力随着相变得到快速释放。同时，血流的快速恢复，对血管壁产生应力作用，造成了血管的最终破裂。
本研究基于实验获取荧光图像重构三维肿瘤血管，建立了三维有限元模型进行血液动力学分析。计算结果表明肿瘤血管壁的分叉或者弯曲段存在应力集中现象。此外，在冷热交替的快速变化过程中，血管壁所受应力上升速率比单冷后的自然复温过程要快得多。而前者幅值略大于后者，推断应力上升的速率应是造成血管壁破裂的关键因素。同时，周边新生血管由于结构不完整而更易被破坏，造成下游流阻的升高而使上游血管壁承受更大的压力，应该是肿瘤中央区域血管相继破裂的重要原因，这解释了实验中观察到的现象。
本研究的创新性主要包括：
一、将激光共聚焦荧光显微技术和裸鼠脊背皮翼视窗技术相结合，成功观察了在体肿瘤三维微循环损伤的动态过程，首次发现-10°C/42°C的冷热交替过程可对整个肿瘤区域的微循环造成严重的、不可修复的结构性损伤；
二、建立了不同热物理条件下计算肿瘤微循环对纳米脂质体通透性的三维定量方法，获得了冷热交替条件下纳米脂质体在肿瘤间质内的相对浓度值，发现纳米脂质体渗透在冷热交替的过程中快速增强。该结果为发展新型肿瘤热物理靶向治疗设计提供了思路；
三、创建了肿瘤微循环在冷冻及复温过程中的热应力模型，从力学角度分析肿瘤微循环损伤机制。在模型中，综合考虑了冻结造成的体积膨胀、肿瘤区域的异质性、肿瘤微血管形态结构的异常性以及血管与组织物性的差异等因素，得到了血管壁的热应力空间上和时间上的分布；
四、基于实测荧光图像建立了肿瘤血管三维构型，综合考虑多种不同的肿瘤微血管壁形态以及下游分支血管阻力增大等因素，应用流体力学理论对肿瘤微血管血流恢复过程进行了动力学研究，获得了血管壁的应力分布信息，初步揭示了肿瘤血管结构性破坏的机理。
本研究通过实验研究发现了冷热交替治疗对肿瘤微循环造成了不可修复的结构性损伤，并且从力学角度理论分析了其损伤的机制，揭示了冷热交替疗法的肿瘤微循环损伤机理，为研发新型微创冷热交替治疗系统提供了重要依据。同时，本研究表明冷热交替造成纳米脂质体在肿瘤中央和边缘的大幅度增强，因此具有与纳米药物结合治疗的潜力，有望提高肿瘤治疗效果。而冷热交替治疗温度和循环条件的优化，以及肿瘤对冷热交替条件的耐受性等则需要进一步的研究。
Cancer has been one of the most dangerous threats to human beings. Throughchanging the temperature of local target tissue, thermal modalities, cryosurgery orhyperthermia, have advantages of minimal invasion, low side effects, low cost withless pain for patients and no dose limit over traditional surgery, chemotherapy andradiotherapy. Thus, they are known as “Green Therapy” of tumor. However, there aresome limitations for single thermal treatment, such as tumor periphery bloodperfusion rate increase resulting in the difficulty of temperature control duringhyperthermia, and the high rate of tumor cell recurrence after cryosurgery. Alternatecooling and heating, a new treatment through combining cryo-therapy withhyperthermia, has been proven to have better therapeutic outcomes over singlethermal treatment. Nevertheless, the underlying mechanisms are yet to be furtherstudied. Specifically, the damage to tumor vasculature injury may be one of the majormechanisms as blood supply is crucial to tumor growth and metastasis. Thus,investigation of the tumor microvasculature injury is extremely important to optimizethe therapeutic protocols.
In this study, tumor microvasculature alterations during different thermaltreatments are observed successfully in vivo through intravital microscopy using thenude mice dorsal skin fold4T1tumor chamber model and nano-liposome tracersinjected through tail vein for the first time. Three-dimensional fluorescence intensitiesof nano-liposomes extravasated from vessels are quantified in the tumor center. Thetumor microvasculature permeability is a quantitative measure for vascular injury orstructural change. According to the acquired fluorescence images, three-dimensionalmethod has been established to measure tumor microvasculature permeability ofunbroken vessels in the present study. Results show that vessels in the tumor centerare more resistive to single cooling or heating treatment than the peripheral ones dueto their relative mature wall structure. However, cooling at-10oC for1/2hr beforeheating at42oC significantly enhances liposome extravasation in both the center andperiphery regions of a tumor. The subsequent microscope observation indicates thatthe tumor vessel endothelium structures are completely disrupted. Histo-pathologicalanalyses further confirm the damaging effect by showing rare tumor vessel recurrenceand large necrotic tumor tissue areas on the7thday after the alternate treatment. Theirreversible structural damage should be closely related to the mechanical stresses the vessels suffered thru the alternate thermal histories.
To reveal the tumor vessel damage mechanisms of the alternate treatment,analysis of stresses on the tumor vessel wall are performed. First, during the freezingprocess, thermal stresses are often induced due to the temperature gradientsthroughout biological tissues with ice formation in phase transition and propertydifferences between vessel wall and tissue. A thermal stress model is establishedusing the tumor vessel model in real morphology, distinguished from the surroundingtissue and blood. The numerical simulations of thermal stress distributions showcompressive stresses on the inner vessel wall. The maximum value is comparable tothe compression failure strength of biomaterial reported. They are likely to inducemicro-cracks on tumor vessels. Besides, high stress concentrations existing in tumorvessel wall with irregular shape are expected to induce vessel wall rupture. During theheating process, thermal stresses are released quickly. Subsequently, mechanicalstresses on the tumor microvessel wall induced by quick blood reperfusion in theheating process would cause the final rupture of vessels in the tumor center.
The blood reperfusion induced stresses on the vessel wall during the heatingfollowed are further investigated. Three-dimensional tumor microvessel models areestablished based on the fluorescence images. Non-uniform stress foci occur at thenarrow or flexural regions in the tumor vessel wall, and higher stress level normallyappears at the vessel bifurcations. During the heating process, the stress rising rate ismuch faster than that of the natural thawing process. It can be interpreted that thestress increasing rate should be crucial to cause collapse of the tumor vessel structure.In addition, the tumor periphery circulation can be easily injured due to the looseendothelium lining, which increases the downstream resistance of blood flow and inturn affects the vessel in the upstream via an increased flow pressure. This wellexplains the successive tumor vessel rupture as observed in the experimental study.
In the present study, the innovative components are given in the follows:
First, the dynamic process of tumor microvasculature damage is successfullyobserved in vivo using the laser confocal microscopy and the nude mice dorsal skinfold tumor window chamber model. It is found for the first time that the alternatecooling and heating has induced severe and irreversible damage to the microvesselstructure throughout the entire tumor;
Secondly, three-dimensional method is established to quantify tumormicrovasculature permeability to particles under different thermal conditions. Therelative fluorescence intensities of the nano-liposomes extravasation to theinterstitium are quantified. The alternate treatment induced quick increase ofliposomes extravasation. It may provide a novel approach to improve the thermallytargeted therapy of cancer;
Thirdly, thermal stress model of tumor microvessel in the alternate treatment hasbeen established to analyze the damage mechanisms. Variable issues are considered in the model, including volume expansion effect, tumor spatial heterogeneity, abnormalstructure of tumor vessels, and mechanical property differences between vessel andtissues. Thermal stresses are simulated both temporally and spatially;
Fourthly, three-dimensional tumor microvessel wall models are establishedbased on the optical slices of fluorescence images for the first time to studymechanical stresses in the tumor microvessel wall induced by blood flow reperfusion.The irregular structure and the downstream resistance increase effects are analyzedand discussed. The preliminary results of the stress analysis have partly revealed themechanisms underlying the serious tumor microvasculature damage caused by thealternate cooling and heating treatment.
The present study finds that the alternate cooling and heating treatment inducesirreversible structural damage to microvessels throughout the entire tumor throughexperimental investigations. The underlying mechanisms are revealed by thetheoretical studies of mechanical stresses on the tumor microvascular wall. The resultsobtained are expected to better understand the vascular injury induced by thealternated cooling and heating treatment, and to help develop a more effective thermaltreatment for tumor therapy. In addition, the strong enhancement of nano-liposomesextravasation provides great potentials for combining the alternate treatment withnano-medicine applications. The optimization of the end temperatures,freezing-heating cycles and tissue thermal tolerance effect to the alternate treatmentshould be further investigated in future.
本文首先利用激光共聚焦荧光显微镜，采用裸鼠脊背皮翼肿瘤视窗模型，通过尾静脉注射纳米脂质体示踪剂，成功地观察了不同热物理条件对在体肿瘤微循环损伤的动态过程与规律，并获得了肿瘤中央微血管壁对纳米脂质体渗透的三维荧光定量信息。肿瘤微循环对示踪粒子的通透性以及其在肿瘤间质中的分布浓度是定量评价血管壁结构改变及损伤的重要手段。本文根据纳米脂质体在组织间质中分布的荧光图像，建立了三维定量模型，获得了未破损血管在不同热物理作用后对纳米脂质体的渗透率，结果表明肿瘤中央血管由于其结构较完整而比边缘血管具有更好的热承受力，单冷、单热均不能造成严重的损伤。然而，在-10°C和42°C的冷热交替作用过程中，无论是在中央还是边缘，肿瘤间质内均出现大量的脂质体渗透，随后的血管结构观察表明内皮细胞间的连接完全被破坏。为了更深入了解冷热交替对肿瘤微循环的损伤程度，本研究应用组织病理切片方法对治疗后7天内的肿瘤微血管进行了跟踪观察和分析，发现-10°C/42°C冷热交替治疗后第7天仍未见肿瘤微血管修复，且肿瘤组织完全坏死。实验结果证实冷热交替治疗对肿瘤微循环造成了不可逆的结构性破坏，而这应该与肿瘤微血管在冷热交替过程中承受的应力作用相关。
为了进一步揭示肿瘤微血管损伤机制，本研究接着对治疗过程中血管的受力情况进行了理论分析。首先，在降温过程中，生物组织发生相变而凝结，组织内温度梯度的存在，以及血管与组织间力学性能差异，使得冻结组织中的热应力产生。本研究基于肿瘤血管的实际形态，并将其与周围组织及血液区别对待，创建了描述肿瘤冷热交替治疗过程中的热应力模型。数值计算结果发现在降温过程中血管内壁承受压应力，其幅值与文献报道的一些生物材料的应力强度阈值相当，可能造成肿瘤血管壁上微小裂纹的产生。而且，结构扭曲的肿瘤血管壁上存在应力集中点，是造成血管壁损伤的重要原因。在冷热交替的加热过程中，热应力随着相变得到快速释放。同时，血流的快速恢复，对血管壁产生应力作用，造成了血管的最终破裂。
本研究基于实验获取荧光图像重构三维肿瘤血管，建立了三维有限元模型进行血液动力学分析。计算结果表明肿瘤血管壁的分叉或者弯曲段存在应力集中现象。此外，在冷热交替的快速变化过程中，血管壁所受应力上升速率比单冷后的自然复温过程要快得多。而前者幅值略大于后者，推断应力上升的速率应是造成血管壁破裂的关键因素。同时，周边新生血管由于结构不完整而更易被破坏，造成下游流阻的升高而使上游血管壁承受更大的压力，应该是肿瘤中央区域血管相继破裂的重要原因，这解释了实验中观察到的现象。
本研究的创新性主要包括：
一、将激光共聚焦荧光显微技术和裸鼠脊背皮翼视窗技术相结合，成功观察了在体肿瘤三维微循环损伤的动态过程，首次发现-10°C/42°C的冷热交替过程可对整个肿瘤区域的微循环造成严重的、不可修复的结构性损伤；
二、建立了不同热物理条件下计算肿瘤微循环对纳米脂质体通透性的三维定量方法，获得了冷热交替条件下纳米脂质体在肿瘤间质内的相对浓度值，发现纳米脂质体渗透在冷热交替的过程中快速增强。该结果为发展新型肿瘤热物理靶向治疗设计提供了思路；
三、创建了肿瘤微循环在冷冻及复温过程中的热应力模型，从力学角度分析肿瘤微循环损伤机制。在模型中，综合考虑了冻结造成的体积膨胀、肿瘤区域的异质性、肿瘤微血管形态结构的异常性以及血管与组织物性的差异等因素，得到了血管壁的热应力空间上和时间上的分布；
四、基于实测荧光图像建立了肿瘤血管三维构型，综合考虑多种不同的肿瘤微血管壁形态以及下游分支血管阻力增大等因素，应用流体力学理论对肿瘤微血管血流恢复过程进行了动力学研究，获得了血管壁的应力分布信息，初步揭示了肿瘤血管结构性破坏的机理。
本研究通过实验研究发现了冷热交替治疗对肿瘤微循环造成了不可修复的结构性损伤，并且从力学角度理论分析了其损伤的机制，揭示了冷热交替疗法的肿瘤微循环损伤机理，为研发新型微创冷热交替治疗系统提供了重要依据。同时，本研究表明冷热交替造成纳米脂质体在肿瘤中央和边缘的大幅度增强，因此具有与纳米药物结合治疗的潜力，有望提高肿瘤治疗效果。而冷热交替治疗温度和循环条件的优化，以及肿瘤对冷热交替条件的耐受性等则需要进一步的研究。
Cancer has been one of the most dangerous threats to human beings. Throughchanging the temperature of local target tissue, thermal modalities, cryosurgery orhyperthermia, have advantages of minimal invasion, low side effects, low cost withless pain for patients and no dose limit over traditional surgery, chemotherapy andradiotherapy. Thus, they are known as “Green Therapy” of tumor. However, there aresome limitations for single thermal treatment, such as tumor periphery bloodperfusion rate increase resulting in the difficulty of temperature control duringhyperthermia, and the high rate of tumor cell recurrence after cryosurgery. Alternatecooling and heating, a new treatment through combining cryo-therapy withhyperthermia, has been proven to have better therapeutic outcomes over singlethermal treatment. Nevertheless, the underlying mechanisms are yet to be furtherstudied. Specifically, the damage to tumor vasculature injury may be one of the majormechanisms as blood supply is crucial to tumor growth and metastasis. Thus,investigation of the tumor microvasculature injury is extremely important to optimizethe therapeutic protocols.
In this study, tumor microvasculature alterations during different thermaltreatments are observed successfully in vivo through intravital microscopy using thenude mice dorsal skin fold4T1tumor chamber model and nano-liposome tracersinjected through tail vein for the first time. Three-dimensional fluorescence intensitiesof nano-liposomes extravasated from vessels are quantified in the tumor center. Thetumor microvasculature permeability is a quantitative measure for vascular injury orstructural change. According to the acquired fluorescence images, three-dimensionalmethod has been established to measure tumor microvasculature permeability ofunbroken vessels in the present study. Results show that vessels in the tumor centerare more resistive to single cooling or heating treatment than the peripheral ones dueto their relative mature wall structure. However, cooling at-10oC for1/2hr beforeheating at42oC significantly enhances liposome extravasation in both the center andperiphery regions of a tumor. The subsequent microscope observation indicates thatthe tumor vessel endothelium structures are completely disrupted. Histo-pathologicalanalyses further confirm the damaging effect by showing rare tumor vessel recurrenceand large necrotic tumor tissue areas on the7thday after the alternate treatment. Theirreversible structural damage should be closely related to the mechanical stresses the vessels suffered thru the alternate thermal histories.
To reveal the tumor vessel damage mechanisms of the alternate treatment,analysis of stresses on the tumor vessel wall are performed. First, during the freezingprocess, thermal stresses are often induced due to the temperature gradientsthroughout biological tissues with ice formation in phase transition and propertydifferences between vessel wall and tissue. A thermal stress model is establishedusing the tumor vessel model in real morphology, distinguished from the surroundingtissue and blood. The numerical simulations of thermal stress distributions showcompressive stresses on the inner vessel wall. The maximum value is comparable tothe compression failure strength of biomaterial reported. They are likely to inducemicro-cracks on tumor vessels. Besides, high stress concentrations existing in tumorvessel wall with irregular shape are expected to induce vessel wall rupture. During theheating process, thermal stresses are released quickly. Subsequently, mechanicalstresses on the tumor microvessel wall induced by quick blood reperfusion in theheating process would cause the final rupture of vessels in the tumor center.
The blood reperfusion induced stresses on the vessel wall during the heatingfollowed are further investigated. Three-dimensional tumor microvessel models areestablished based on the fluorescence images. Non-uniform stress foci occur at thenarrow or flexural regions in the tumor vessel wall, and higher stress level normallyappears at the vessel bifurcations. During the heating process, the stress rising rate ismuch faster than that of the natural thawing process. It can be interpreted that thestress increasing rate should be crucial to cause collapse of the tumor vessel structure.In addition, the tumor periphery circulation can be easily injured due to the looseendothelium lining, which increases the downstream resistance of blood flow and inturn affects the vessel in the upstream via an increased flow pressure. This wellexplains the successive tumor vessel rupture as observed in the experimental study.
In the present study, the innovative components are given in the follows:
First, the dynamic process of tumor microvasculature damage is successfullyobserved in vivo using the laser confocal microscopy and the nude mice dorsal skinfold tumor window chamber model. It is found for the first time that the alternatecooling and heating has induced severe and irreversible damage to the microvesselstructure throughout the entire tumor;
Secondly, three-dimensional method is established to quantify tumormicrovasculature permeability to particles under different thermal conditions. Therelative fluorescence intensities of the nano-liposomes extravasation to theinterstitium are quantified. The alternate treatment induced quick increase ofliposomes extravasation. It may provide a novel approach to improve the thermallytargeted therapy of cancer;
Thirdly, thermal stress model of tumor microvessel in the alternate treatment hasbeen established to analyze the damage mechanisms. Variable issues are considered in the model, including volume expansion effect, tumor spatial heterogeneity, abnormalstructure of tumor vessels, and mechanical property differences between vessel andtissues. Thermal stresses are simulated both temporally and spatially;
Fourthly, three-dimensional tumor microvessel wall models are establishedbased on the optical slices of fluorescence images for the first time to studymechanical stresses in the tumor microvessel wall induced by blood flow reperfusion.The irregular structure and the downstream resistance increase effects are analyzedand discussed. The preliminary results of the stress analysis have partly revealed themechanisms underlying the serious tumor microvasculature damage caused by thealternate cooling and heating treatment.
The present study finds that the alternate cooling and heating treatment inducesirreversible structural damage to microvessels throughout the entire tumor throughexperimental investigations. The underlying mechanisms are revealed by thetheoretical studies of mechanical stresses on the tumor microvascular wall. The resultsobtained are expected to better understand the vascular injury induced by thealternated cooling and heating treatment, and to help develop a more effective thermaltreatment for tumor therapy. In addition, the strong enhancement of nano-liposomesextravasation provides great potentials for combining the alternate treatment withnano-medicine applications. The optimization of the end temperatures,freezing-heating cycles and tissue thermal tolerance effect to the alternate treatmentshould be further investigated in future.
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