Tesi etd-04032025-101314
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Tipo di tesi
Dottorato
Autore
ZINNO, CIRO
URN
etd-04032025-101314
Titolo
Bioelectronic medicine approaches for closed-loop cardiac regulation and cancer therapy
Settore scientifico disciplinare
ING-INF/06
Corso di studi
Istituto di Biorobotica - PHD IN BIOROBOTICA
Relatori
relatore Prof. MICERA, SILVESTRO
Parole chiave
- bioelectronic medicine
- neural interfaces
- neuroprostheses
- cardiovascular diseases
- cancer
Data inizio appello
15/10/2025;
Disponibilità
parziale
Riassunto analitico
Neural interfaces have recently become widespread in both research laboratories and industry, largely due to the emergence of bioelectronic systems designed to restore or enhance human capabilities, ranging from motor/sensory disabilities to internal organs functioning. Specifically, the autonomic nervous system is often selected as target as it controls homeostatic functions and regulates the activity of the majority of the internal organs. While bioelectronic medicine is promising for many different applications, many challenges remain to be tackled, including stimulation selectivity, adaptation and long-term biocompatibility. By addressing these challenges, it will be possible to enlarge bioelectronic medicine applications to enable its full therapeutic potential.
In this framework, the work of this thesis is divided into three main applications of neurotechnology and bioelectronic medicine: cardiovascular regulation, technological advancements of innovative neural interface, and cutting-edge bioelectronic approaches for cancer treatment.
The first chapter is related to a preclinical study on a swine model of intraneural vagus nerve stimulation for the closed-loop control of cardiac activity. We designed an intraneural electrode tailored to the histology of the right vagus nerve, and then validated it benchtop and in vivo by characterizing the cardiovascular response to selective intraneural stimulation and identifying an ideal set of stimulation parameters to elicit cardiac modulation. Then, we worked towards the closed-loop modulation of heart activity, by running a pilot experiment where we controlled vagus nerve stimulation through blood pressure in real time. To improve the reliability of the controlling variable, we then implemented an implantable heart rate sensor based on MEMS technology, that was chronically validated for 1 month. In parallel, we also designed and validated a custom neurostimulator (external and implantable version), that was eventually implanted in chronic settings for 1 month. The results of our study allowed us to precisely modulate the heart activity without eliciting visible adverse effect and minimizing the stimulation current delivered to the nerve. However, chronic studies highlighted the need for more biocompatible devices to reduce foreign body reaction, especially in chronic scenarios.
To address this challenge, the second chapter of the thesis consists of innovative, alternative fabrication approaches for neural interfaces, with a focus on the design and fabrication of fully polymeric neural interfaces. We devised and patented two different fabrication approaches, based on 3D printing and a combination of casting and screen-printing. These approaches allowed us to increase our flexibility In terms of materials choice, thus enabling the fabrication of fully polymeric cuff electrodes, with enhanced biocompatibility and mechanical/electrochemical features. The materials and the electrodes were benchtop tested and preliminary validated in a swine model of vagus nerve stimulation and recording.
Finally, the last chapter of this thesis presents innovative applications of bioelectronic medicine, specifically for the treatment of lung cancer. Starting from recent studies in the field of cancer neuroscience, we established a preclinical murine model of non-small cells lung cancer for autonomic innervation studies. Then, we used light-sheet microscopy to investigate the 3D innervation pathway of lung tumors.
The results of this thesis set the basis for further bioelectronic medicine studies concerning the use of innovative, fully polymeric devices combined with closed-loop control strategies. Furthermore, the last chapter paves the way for a completely new application of bioelectronic medicine as an adjuvant therapy in cancer treatment pipelines.
In this framework, the work of this thesis is divided into three main applications of neurotechnology and bioelectronic medicine: cardiovascular regulation, technological advancements of innovative neural interface, and cutting-edge bioelectronic approaches for cancer treatment.
The first chapter is related to a preclinical study on a swine model of intraneural vagus nerve stimulation for the closed-loop control of cardiac activity. We designed an intraneural electrode tailored to the histology of the right vagus nerve, and then validated it benchtop and in vivo by characterizing the cardiovascular response to selective intraneural stimulation and identifying an ideal set of stimulation parameters to elicit cardiac modulation. Then, we worked towards the closed-loop modulation of heart activity, by running a pilot experiment where we controlled vagus nerve stimulation through blood pressure in real time. To improve the reliability of the controlling variable, we then implemented an implantable heart rate sensor based on MEMS technology, that was chronically validated for 1 month. In parallel, we also designed and validated a custom neurostimulator (external and implantable version), that was eventually implanted in chronic settings for 1 month. The results of our study allowed us to precisely modulate the heart activity without eliciting visible adverse effect and minimizing the stimulation current delivered to the nerve. However, chronic studies highlighted the need for more biocompatible devices to reduce foreign body reaction, especially in chronic scenarios.
To address this challenge, the second chapter of the thesis consists of innovative, alternative fabrication approaches for neural interfaces, with a focus on the design and fabrication of fully polymeric neural interfaces. We devised and patented two different fabrication approaches, based on 3D printing and a combination of casting and screen-printing. These approaches allowed us to increase our flexibility In terms of materials choice, thus enabling the fabrication of fully polymeric cuff electrodes, with enhanced biocompatibility and mechanical/electrochemical features. The materials and the electrodes were benchtop tested and preliminary validated in a swine model of vagus nerve stimulation and recording.
Finally, the last chapter of this thesis presents innovative applications of bioelectronic medicine, specifically for the treatment of lung cancer. Starting from recent studies in the field of cancer neuroscience, we established a preclinical murine model of non-small cells lung cancer for autonomic innervation studies. Then, we used light-sheet microscopy to investigate the 3D innervation pathway of lung tumors.
The results of this thesis set the basis for further bioelectronic medicine studies concerning the use of innovative, fully polymeric devices combined with closed-loop control strategies. Furthermore, the last chapter paves the way for a completely new application of bioelectronic medicine as an adjuvant therapy in cancer treatment pipelines.
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