Minimally invasive thermal techniques represent promising therapeutic procedures, in which biological tissues are exposed to elevated temperatures (hyperthermia) or even very low temperatures (hypothermia) with the final aim of treating a disease. The local application of extreme temperatures for tumor removal is provided in order to induce irreversible damage to the target cancer cells and consequently tumor apoptosis and coagulative necrosis. The optimal implementation of these minimally invasive treatments could show many advantages when compared to conventional therapies. In particular, the reduction of the operative trauma would lead to the decrease of pain and the minimization of nonfunctional scarring tissue formation, as well as the decrease of adhesions and wound dehiscence. Among the different therapeutic thermal techniques, laser ablation, which refers to the exposure of biological tissues to near infrared laser light, represents an interesting hyperthermia therapy for the potential management of cancer tissue, since it has shown encouraging results in solid tumors treatment. The new frontiers of laser ablation focus on the optimization of several technical aspects, such as: measurement systems to monitor in real time the thermal effect of the procedure, in order to control the tissue damage; approaches for enhancing the selective absorption of the laser light by the target tissue; simulation-based tools, which would be useful for deciding the laser setting parameters and also for the design of experimental tests. In these concerns, the present thesis work, developed within the Laser Optimal project (Laser ablation selectivity and monitoring for optimal tumor removal), has foreseen the investigation of laser ablation in presence of gold nanorods (NRs), used as enhancers of the treatment selectivity, both from a theoretical and experimental perspective. A computational model has been implemented in order to simulate the heat transfer in tissue undergoing laser ablation treatment, both in presence of biocompatible NRs and without nanostructures. The finite element model has been developed through the modeling of the geometry of a subcutaneous tumor, the choice of a suitable mesh and the simulation of the heat source and the heat distribution across biological material. Regarding the experimental section, temperature data were obtained through in vivo laser ablation experiments performed on animal models, at the Beckman Research Institute of City of Hope (COH), in Duarte, California, USA. The experiments concerned the establishment of xenograft tumors on nude mice and then the injection of either gold NRs, Neural Stem Cells (NSCs) embedding gold NRs or Phosphate-Buffered Saline (PBS). NSCs were used to better control the NRs distribution inside tumor and PBS served as control. Four different laser emitters were used, at wavelengths of 810 nm, 945 nm, 975 nm and 1064 nm and different NR sizes were used according to the wavelength of the laser radiation provided, in order to exploit the surface plasmon resonance phenomenon. A thermographic camera was used to accurately assess the superficial temperatures reached during the tumor irradiations. Fiber Bragg Gratings (FBG) sensors were inserted into subcutaneous tumors and used to measure temperature values. Temperature data analysis was carried out to investigate the best laser radiation-NR type combination in terms of temperature outcome to find out the most suitable laser radiation that combined with a proper nanometric structure could lead to an enhanced treatment selectivity. Furthermore, a first attempt to evaluate the more homogenous temperature distribution of gold NRs when NSCs are used as cell delivery system of gold NRs was done. Moreover, temperature results measured during experiments were compared to the ones predicted by the developed computational model for its validation. Despite it was not possible to assess a more uniform temperature distribution in presence of NSCs, the overall analysis results were satisfying. The 810 nm and 1064 nm lasers and the corresponding NRs types represented the most suitable laser radiation-NRs combinations for the obtainment of an enhanced treatment selectivity, since they exhibited the highest difference in temperature with and without NRs. The computational model demonstrated to well predict the steady-state superficial temperatures reached during treatments (1 °C error between experimental data and simulated ones, in the best case).
Le tecniche termiche minimamente invasive costituiscono promettenti procedure terapeutiche, in cui i tessuti biologici sono esposti ad elevate temperature (ipertermia) o temperature molto basse (ipotermia) con il fine ultimo di trattare una malattia. L’applicazione locale di temperature estreme per la rimozione di tumori è effettuata allo scopo di indurre un danno irreversibile nelle cellule bersaglio e conseguentemente l’apoptosi tumorale e la necrosi coagulativa. L’implementazione ottimale di tali trattamenti minimamente invasivi può presentare numerosi vantaggi rispetto alle terapie convenzionali. In particolare, la riduzione del trauma operatorio può favorire la riduzione del dolore e limitare la formazione di tessuto cicatriziale non funzionale e di adesioni e deiscenze dovute alla ferita. Tra le differenti tecniche termiche terapeutiche, l’ablazione laser, la quale consiste nell’esposizione del tessuto biologico a luce laser nel vicino infrarosso, rappresenta un’interessante terapia ipertermica per il trattamento del tessuto cancerogeno, che ha mostrato risultati promettenti nel trattamento di tumori solidi. Le nuove frontiere dell’ablazione laser si focalizzano sull’ottimizzazione di diversi aspetti tecnici, come: sistemi di misura per monitorare in tempo reale l’effetto termico della procedura, al fine di controllare il danno tissutale; approcci per aumentare l’assorbimento selettivo della luce laser nel tessuto bersaglio; strumenti di simulazione, utili al fine di decidere i parametri di impostazione del laser e anche per la progettazione di test sperimentali. In questo scenario, il presente lavoro di tesi, sviluppato all’interno del progetto Laser Optimal (Laser ablation selectivity and monitoring for optimal tumor removal), ha previsto lo studio dell’ablazione laser in presenza di nanorod (NR) d’oro, utilizzati per aumentare la selettività del trattamento, sia da un punto di vista teorico che sperimentale. Un modello computazionale è stato implementato con l’obiettivo di simulare il trasferimento di calore nel tessuto sottoposto al trattamento di ablazione laser, sia in presenza di NR biocompatibili sia in assenza di nanostrutture. Il modello agli elementi finiti è stato sviluppato mediante la modellizzazione della geometria di un tumore subcutaneo, la scelta di una mesh opportuna e la simulazione della sorgente termica e della distribuzione di calore, nel tessuto biologico. Per quanto concerne la parte sperimentale, i dati di temperatura sono stati ottenuti attraverso esperimenti di ablazione laser in vivo effettuati su modelli animali, presso il Beckman Research Institute di City of Hope (COH), a Duarte, California, Stati Uniti d’America. Gli esperimenti hanno riguardato l’innesto di tumori xenotrapiantati su topi e la successiva iniezione di NR d’oro, cellule staminali neurali (CSN), contenenti NR d’oro, o tampone fosfato salino (PBS). Le CSN sono state utilizzate al fine di ottenere un migliore controllo della distribuzione dei NR all’interno del tumore e i tumori trattati con PBS hanno rappresentato i campioni di controllo. Si sono utilizzati quattro differenti emettitori laser, alle lunghezze d’onda di 810 nm, 945 nm, 975 nm e 1064 nm e differenti dimensioni di NR a seconda della lunghezza d’onda della radiazione laser fornita, al fine di sfruttare il fenomeno di risonanza plasmonica superficiale. Una camera termografica è stata utilizzata al fine di misurare le temperature superficiali raggiunte durante l’irradiazione dei tumori. Sensori Fiber Bragg Grating (FBG) sono stati inseriti all’interno dei tumori subcutanei e utilizzati per misurare i valori di temperatura all’interno dei tumori. L’analisi dei dati di temperatura è stata effettuata allo scopo di indagare la migliore combinazione di radiazione laser e tipo di NR, in termini di risultati di temperatura, per individuare quale tipo di radiazione laser, combinata con un’opportuna struttura nanometrica, potesse garantire un aumento della selettività del trattamento. Inoltre, un primo tentativo di valutare la capacità delle CSN di distribuire in maniera più omogenea i NR d’oro è stato effettuato. I risultati di temperatura misurati durante gli esperimenti sono stati confrontati con i valori predetti dal modello computazionale sviluppato. Nonostante non sia stato possibile verificare l’ottenimento di una distribuzione più uniforme della temperatura in presenza di CSN, i risultati complessivi dell’analisi sono stati soddisfacenti. I laser con lunghezze d’onda di 810 nm e 1064 nm e i corrispondenti tipi di NR hanno costituito le migliori combinazioni per l’ottenimento di un’aumentata selettività del trattamento, esibendo le maggiori differenze di temperatura con e senza NR. Il modello ha inoltre dimostrato di predire in modo corretto le temperature superficiali allo stato stazionario raggiunte durante i trattamenti (1 °C di errore tra dati sperimentali e quelli ottenuti tramite simulazione, nel caso migliore).
Gold nanorods-enhanced laser ablation for tumor treatment : theoretical and experimental analysis
BIANCHI, LEONARDO
2018/2019
Abstract
Minimally invasive thermal techniques represent promising therapeutic procedures, in which biological tissues are exposed to elevated temperatures (hyperthermia) or even very low temperatures (hypothermia) with the final aim of treating a disease. The local application of extreme temperatures for tumor removal is provided in order to induce irreversible damage to the target cancer cells and consequently tumor apoptosis and coagulative necrosis. The optimal implementation of these minimally invasive treatments could show many advantages when compared to conventional therapies. In particular, the reduction of the operative trauma would lead to the decrease of pain and the minimization of nonfunctional scarring tissue formation, as well as the decrease of adhesions and wound dehiscence. Among the different therapeutic thermal techniques, laser ablation, which refers to the exposure of biological tissues to near infrared laser light, represents an interesting hyperthermia therapy for the potential management of cancer tissue, since it has shown encouraging results in solid tumors treatment. The new frontiers of laser ablation focus on the optimization of several technical aspects, such as: measurement systems to monitor in real time the thermal effect of the procedure, in order to control the tissue damage; approaches for enhancing the selective absorption of the laser light by the target tissue; simulation-based tools, which would be useful for deciding the laser setting parameters and also for the design of experimental tests. In these concerns, the present thesis work, developed within the Laser Optimal project (Laser ablation selectivity and monitoring for optimal tumor removal), has foreseen the investigation of laser ablation in presence of gold nanorods (NRs), used as enhancers of the treatment selectivity, both from a theoretical and experimental perspective. A computational model has been implemented in order to simulate the heat transfer in tissue undergoing laser ablation treatment, both in presence of biocompatible NRs and without nanostructures. The finite element model has been developed through the modeling of the geometry of a subcutaneous tumor, the choice of a suitable mesh and the simulation of the heat source and the heat distribution across biological material. Regarding the experimental section, temperature data were obtained through in vivo laser ablation experiments performed on animal models, at the Beckman Research Institute of City of Hope (COH), in Duarte, California, USA. The experiments concerned the establishment of xenograft tumors on nude mice and then the injection of either gold NRs, Neural Stem Cells (NSCs) embedding gold NRs or Phosphate-Buffered Saline (PBS). NSCs were used to better control the NRs distribution inside tumor and PBS served as control. Four different laser emitters were used, at wavelengths of 810 nm, 945 nm, 975 nm and 1064 nm and different NR sizes were used according to the wavelength of the laser radiation provided, in order to exploit the surface plasmon resonance phenomenon. A thermographic camera was used to accurately assess the superficial temperatures reached during the tumor irradiations. Fiber Bragg Gratings (FBG) sensors were inserted into subcutaneous tumors and used to measure temperature values. Temperature data analysis was carried out to investigate the best laser radiation-NR type combination in terms of temperature outcome to find out the most suitable laser radiation that combined with a proper nanometric structure could lead to an enhanced treatment selectivity. Furthermore, a first attempt to evaluate the more homogenous temperature distribution of gold NRs when NSCs are used as cell delivery system of gold NRs was done. Moreover, temperature results measured during experiments were compared to the ones predicted by the developed computational model for its validation. Despite it was not possible to assess a more uniform temperature distribution in presence of NSCs, the overall analysis results were satisfying. The 810 nm and 1064 nm lasers and the corresponding NRs types represented the most suitable laser radiation-NRs combinations for the obtainment of an enhanced treatment selectivity, since they exhibited the highest difference in temperature with and without NRs. The computational model demonstrated to well predict the steady-state superficial temperatures reached during treatments (1 °C error between experimental data and simulated ones, in the best case).File | Dimensione | Formato | |
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https://hdl.handle.net/10589/151138