Theoretical Study On Accurate Control Of Damage Region In Thermal Treatment Of Tumor

Malignant tumor is considered as one of the major causes to the human death. Thermal treatment, which is usually applied through energy intervention in malignant tissues using either freezing or heating, has recently been accepted as an alternative modality to conventional clinical treatments of cancer. It is minimally invasive and has limited side effects. Furthermore, it has no dose limit and could be used repeatedly.However, thermal treatment of tumor has not been widely used in clinics due to the difficulties associated with non-invasive monitoring and controlling of tissue temperature in real-time, which significantly affects the treatment outcome, especially at the tumor boundary. When extreme low or high temperature is applied, the safety issue and possible recurrence are major clinical concerns. On the other hand, recent research showed that local hyperthermia treatment at mildly elevated temperature could break tumor cells in situ, which might release tumor antigens and activate the immunological response. Thus, through accurate control optimization of thermal dose during the treatment, it could not only ensure a complete abalation of tumor locally but might also trigger the body immunological response which could further inhibit the tumor recurrence and metastasis,resulting in an effective treatment outcome. Upon further understanding of the relationship between the thermal dose, and tumor metabolism and growth, this might be further developed to become an innovative thermally based molecular treatment of tumor in near futhre.In this study, to better control the thermal treatment, system modeling and optimization was performed for the treatment system built in our lab using RF heating and LN2 based cryo-probe. The unstable two-phase flow of LN2 with boiling makes the freezing ability hard to be predicted. Moreover, the probe shape causes the nozzle effect at the interface of inner and outer tube, and thus makes actual two-phase flow even more complex. In this study, a simple and effective two-phase flow model was developed to simulate the freezing process under different probe shapes and flow conditions to optimize the design of cryo-probe. Experiments were carried out to validate the model and test the dynamic performance of the whole thermal system. Results showed that applying LN2 cooling with RF heating and probe shape optimization, the system could provide different thermal therapy modalities to meet the needs for different tumor treatments.Another key step to improve the tumor treatment effects and solve the safety problems is the protocol optimization based on the tissue damage model. Most damage models of thermal treatment focus on direct cell injury by neglecting indirect injury. Especially the tumor growth inhibition and apoptosis induced by thermal damage in DNA replication is an important factor influencing protocol optimization and treatment outcome assessment. Based on the molecular mechanism of heat-induced tumor growth inhibition, an integrated model was established for tumor growth and thermal damage with consideration of both direct and indirect damages. The direct damage was calculated using the thermal dose model while the indirect damage incorporated exponential-decayed relationship of replication fork displacement and temperature, which could be used to describe tumor growth variation due to tumor cell death through DNA damage. The current model incorporating both direct and indirect damage was evaluated using the experimental results of tumor growth in long-term hyperthermia and proved to be effective. Finally, the current damage model was used to evaluate the treatment effects for different freezing and heating modalities. While under moderate heating the indirect damage might play an important role, it could also enhance the killing effect at the treatment boundary when direct damage was dominant in the treatment center.Heat could not only reduce the DNA fork displacement rate, but also alter the association between the nuclear matrix and the reactants, and therefore affect the DNA replication process. The nuclear matrix ensures the DNA replication process in vivo by absorbing the proteins, enzymes and templates within its surroundings. Given that the DNA replication mechanism could not be directly studied in vivo currently, this study finally explored the regulation mechanism in DNA replication process in vitro (PCR) assisted with Gold nanoparticles by analyze the published experimental results. Current research found that the addition of certain amount of gold nanoparticles into PCR reactants could greatly enhance the reaction efficiency. In this part of the study, by introducing the competing mechanism of specific and non-specific bindings, the error-prone PCR model based on experiments was established to simulate the thermally-induced non-specific amplification of products. The simulation successfully explained the positive effects of gold nanoparticles on PCR efficiency and specificity as a selector and a bioreactor and revealed the function of nuclear matrix in DNA replication in vivo.In conclusion, considering the two important aspects of accurate damage region control in thermal treatment (accurate control and protocol design), simulations were performed in this study on the unsteady two-phase flow in cryo-probes, based on which design optimization standards were proposed for cryo-probes to ensure accurate control of damage region in thermal treatment of tumor. Different treatment protocols coupled with the cell damage model under hyperthermia were also studied, which laid the theoretical basis for further applications of thermal treatment and quantitative evaluation of the treatment effect. Besides, this study also investigate the effects of gold nanoparticles on PCR process theoretically which might be used to explore the temperature effects on DNA replication in vivo in future.