Identifying Visible Tissue in Intraoperative Ultrasound Images during Brain Surgery: A Method and Application

Intraoperative ultrasound scanning is a demanding visuotactile task. It requires operators to simultaneously localise the ultrasound perspective and manually perform slight adjustments to the pose of the probe, making sure not to apply excessive force or breaking contact with the tissue, whilst also characterising the visible tissue. In this paper, we propose a method for the identification of the visible tissue, which enables the analysis of ultrasound probe and tissue contact via the detection of acoustic shadow and construction of confidence maps of the perceptual salience. Detailed validation with both in vivo and phantom data is performed. First, we show that our technique is capable of achieving state of the art acoustic shadow scan line classification - with an average binary classification accuracy on unseen data of 0.87. Second, we show that our framework for constructing confidence maps is able to produce an ideal response to a probe's pose that is being oriented in and out of optimality - achieving an average RMSE across five scans of 0.174. The performance evaluation justifies the potential clinical value of the method which can be used both to assist clinical training and optimise robot-assisted ultrasound tissue scanning

Using Raman Spectroscopy for Intraoperative Margin Analysis in Breast Conserving Surgery

Breast Conserving Surgery (BCS) in the treatment of breast cancer aims to provide optimal oncological results, with minimal tissue excision to optimise cosmetic outcome. Positive margins due to an inadequate resection occurs in 17% of UK patients undergoing BCS and prompts recommendation for further tissue re-excision to reduce recurrence risk. A second operation causes patient anxiety and significant healthcare costs. This issue could be resolved with accurate intra-operative margin analysis (IMA) to enable excision of all cancerous tissue at the index procedure. High wavenumber Raman Spectroscopy (HWN RS) is a vibrational spectroscopy highly sensitive to changes in protein/lipid environment and water content –biochemical differences found between tumour and normal breast tissue. We proposed that HWN RS could be used to differentiate between tumour and non-tumour breast tissue with a view to future IMA. This thesis presents the development of a Raman system to measure the HWN region capable of accurately detecting changes in protein, lipid and water content, in the presence of highly fluorescent surgical pigments such as blue dye that are present in surgically excised specimens. We investigate the relationship between changes in the HWN spectra with changes in water content in constructed breast phantoms to mimic protein and lipid rich environments and biological tissue. Human breast tissue of paired tumour and non-tumour samples were then measured and analysed. We found that breast tumour tissue is a protein rich, high water, low fat environment and that non-tumour is a low protein, fat rich environment with a low water content, and this can be used to identify breast cancer using HWN RS with excellent accuracy of over 90%. This thesis demonstrates a HWN RS Raman system capable of differentiating between tumour and non-tumour tissue in human breast tissue, and this has the potential to provide IMA in BCS

Direct current electrical resistance measurement techniques for assessment of colorectal cancer during laparoscopic surgery

The next generation of surgical tools will employ intraoperative sensing technologies to provide real-time information to the surgeon. Sensing in this way may facilitate personalised tissue resections during cancer surgery, thereby reducing radicality and improving outcomes for the patient. This thesis details the development and testing of electrochemical based sensing techniques aimed at integration into the next generation of laparoscopic surgical tools. Literature reviewed as part of the work highlights the broad nature of surgically appropriate sensing technologies. Based on the features of simplicity and scalability, the biogalvanic tissue characterisation technique was explored as the most practically suitable candidate. Development and systematic testing of a biogalvanic measurement system with porcine tissues showed variation that is not explained using the current system model. Correlation with electrochemical measurements verified this unaccounted system complexity. Electrode polarisation and diffusion controlled reduction at the cathode limit the tissue specificity of the output metrics. An improved analytic model fitting technique was developed to reduce the influence of the electrodes. Through collaborative development of a numerical model of the system, the practical limitations of the biogalvanic techniques as a surgical sensor were realised. To mitigate these limitations, a novel galvanostatic technique for improved resistance characterisation was developed. Testing was conducted on ex vivo tissues, showing stability for relevant parametric variation. Surgical applicability was found from a practical perspective, with results showing low sensitivity to switching rate, current range and tissue contact conditions. Testing was also conducted on a number of freshly excised cancerous human colon samples. Measurements were centralised on each tumour and compared to a corresponding healthy region. Every case showed a highly significant difference between tissue types with cancerous tissues having a consistently lower resistance. These findings suggest that the proposed technique of multi-reference galvanostatic resistance characterisation may be a suitable candidate for integration into surgical tools for colorectal cancer surgery

Diffusion imaging and tractography in the paediatric neurosurgical population

Diffusion MRI uses magnetic field gradients to sensitise a MR sequence to in vivo water diffusion. Application of these gradients in specific directions (20 in this work) enables a 3D representation of diffusion on a voxel basis. Quantitative diffusion measures are derived; using the voxel maximal diffusion direction and linking neighbouring voxels iteratively based on this creates a visual construct of the white matter: tractography. It is not possible, currently, to non-invasively determine the histological nature of an intracranial tumour. We recruited paediatric patients with radiological evidence of such lesions from April 2006 to January 2008 and retrospectively to August 2003. We used diffusion MR metrics to discriminate paediatric central nervous system tumours based on existing histological diagnoses. Using apparent diffusion coefficient histograms, common posterior fossa childhood tumours were differentiated with 93% success; Primitive neuroectodermal tumours (PNET) and supratentorial atypical teratoid rhabdoid tumours (ATRT) were separated in 100% of cases. Development of these methods with a larger population may facilitate the obviation of surgical biopsy and its attendant risks. Diffusion data was used to reconstruct the cerebellar white matter anatomy using tractography. Initially a population of normal subjects were investigated using single region of interest (ROI) analysis. DTI metrics were implemented, demonstrating the existence of white matter asymmetry where lateralisation corresponded to handedness in 17 right-handed subjects. To asses functional significance of changes in DTI metrics; clinical cerebellar dysfunction was correlated with changes in cerebellar white matter DTI metrics in a patient population with posterior fossa tumours and with the normal population. Fractional anisotropy of the tracts was reduced in patients with tumours d clinical cerebellar signs as compared to healthy individuals. This work demonstrates that diffusion MRI and tractography metrics may enable discrimination of paediatric CNS tumour type and are related to the functional integrity of cerebellar white matter tracts

OPTIMIZATION OF TIME-RESPONSE AND AMPLIFICATION FEATURES OF EGOTs FOR NEUROPHYSIOLOGICAL APPLICATIONS

In device engineering, basic neuron-to-neuron communication has recently inspired the development of increasingly structured and efficient brain-mimicking setups in which the information flow can be processed with strategies resembling physiological ones. This is possible thanks to the use of organic neuromorphic devices, which can share the same electrolytic medium and adjust reciprocal connection weights according to temporal features of the input signals. In a parallel - although conceptually deeply interconnected - fashion, device engineers are directing their efforts towards novel tools to interface the brain and to decipher its signalling strategies. This led to several technological advances which allow scientists to transduce brain activity and, piece by piece, to create a detailed map of its functions. This effort extends over a wide spectrum of length-scales, zooming out from neuron-to-neuron communication up to global activity of neural populations. Both these scientific endeavours, namely mimicking neural communication and transducing brain activity, can benefit from the technology of Electrolyte-Gated Organic Transistors (EGOTs). Electrolyte-Gated Organic Transistors (EGOTs) are low-power electronic devices that functionally integrate the electrolytic environment through the exploitation of organic mixed ionic-electronic conductors. This enables the conversion of ionic signals into electronic ones, making such architectures ideal building blocks for neuroelectronics. This has driven extensive scientific and technological investigation on EGOTs. Such devices have been successfully demonstrated both as transducers and amplifiers of electrophysiological activity and as neuromorphic units. These promising results arise from the fact that EGOTs are active devices, which widely extend their applicability window over the capabilities of passive electronics (i.e. electrodes) but pose major integration hurdles. Being transistors, EGOTs need two driving voltages to be operated. If, on the one hand, the presence of two voltages becomes an advantage for the modulation of the device response (e.g. for devising EGOT-based neuromorphic circuitry), on the other hand it can become detrimental in brain interfaces, since it may result in a non-null bias directly applied on the brain. If such voltage exceeds the electrochemical stability window of water, undesired faradic reactions may lead to critical tissue and/or device damage. This work addresses EGOTs applications in neuroelectronics from the above-described dual perspective, spanning from neuromorphic device engineering to in vivo brain-device interfaces implementation. The advantages of using three-terminal architectures for neuromorphic devices, achieving reversible fine-tuning of their response plasticity, are highlighted. Jointly, the possibility of obtaining a multilevel memory unit by acting on the gate potential is discussed. Additionally, a novel mode of operation for EGOTs is introduced, enabling full retention of amplification capability while, at the same time, avoiding the application of a bias in the brain. Starting on these premises, a novel set of ultra-conformable active micro-epicortical arrays is presented, which fully integrate in situ fabricated EGOT recording sites onto medical-grade polyimide substrates. Finally, a whole organic circuitry for signal processing is presented, exploiting ad-hoc designed organic passive components coupled with EGOT devices. This unprecedented approach provides the possibility to sort complex signals into their constitutive frequency components in real time, thereby delineating innovative strategies to devise organic-based functional building-blocks for brain-machine interfaces.Nell’ingegneria elettronica, la comunicazione di base tra neuroni ha recentemente ispirato lo sviluppo di configurazioni sempre più articolate ed efficienti che imitano il cervello, in cui il flusso di informazioni può essere elaborato con strategie simili a quelle fisiologiche. Ciò è reso possibile grazie all'uso di dispositivi neuromorfici organici, che possono condividere lo stesso mezzo elettrolitico e regolare i pesi delle connessioni reciproche in base alle caratteristiche temporali dei segnali in ingresso. In modo parallelo, gli ingegneri elettronici stanno dirigendo i loro sforzi verso nuovi strumenti per interfacciare il cervello e decifrare le sue strategie di comunicazione. Si è giunti così a diversi progressi tecnologici che consentono agli scienziati di trasdurre l'attività cerebrale e, pezzo per pezzo, di creare una mappa dettagliata delle sue funzioni. Entrambi questi ambiti scientifici, ovvero imitare la comunicazione neurale e trasdurre l'attività cerebrale, possono trarre vantaggio dalla tecnologia dei transistor organici a base elettrolitica (EGOT). I transistor organici a base elettrolitica (EGOT) sono dispositivi elettronici a bassa potenza che integrano funzionalmente l'ambiente elettrolitico attraverso lo sfruttamento di conduttori organici misti ionici-elettronici, i quali consentono di convertire i segnali ionici in segnali elettronici, rendendo tali dispositivi ideali per la neuroelettronica. Gli EGOT sono stati dimostrati con successo sia come trasduttori e amplificatori dell'attività elettrofisiologica e sia come unità neuromorfiche. Tali risultati derivano dal fatto che gli EGOT sono dispositivi attivi, al contrario dell'elettronica passiva (ad esempio gli elettrodi), ma pongono comunque qualche ostacolo alla loro integrazione in ambiente biologico. In quanto transistor, gli EGOT necessitano l'applicazione di due tensioni tra i suoi terminali. Se, da un lato, la presenza di due tensioni diventa un vantaggio per la modulazione della risposta del dispositivo (ad esempio, per l'ideazione di circuiti neuromorfici basati su EGOT), dall'altro può diventare dannosa quando gli EGOT vengono adoperati come sito di registrazione nelle interfacce cerebrali, poiché una tensione non nulla può essere applicata direttamente al cervello. Se tale tensione supera la finestra di stabilità elettrochimica dell'acqua, reazioni faradiche indesiderate possono manifestarsi, le quali potrebbero danneggiare i tessuti e/o il dispositivo. Questo lavoro affronta le applicazioni degli EGOT nella neuroelettronica dalla duplice prospettiva sopra descritta: ingegnerizzazione neuromorfica ed implementazione come interfacce neurali in applicazioni in vivo. Vengono evidenziati i vantaggi dell'utilizzo di architetture a tre terminali per i dispositivi neuromorfici, ottenendo una regolazione reversibile della loro plasticità di risposta. Si discute inoltre la possibilità di ottenere un'unità di memoria multilivello agendo sul potenziale di gate. Viene introdotta una nuova modalità di funzionamento per gli EGOT, che consente di mantenere la capacità di amplificazione e, allo stesso tempo, di evitare l'applicazione di una tensione all’interfaccia cervello-dispositivo. Partendo da queste premesse, viene presentata una nuova serie di array micro-epicorticali ultra-conformabili, che integrano completamente i siti di registrazione EGOT fabbricati in situ su substrati di poliimmide. Infine, viene proposto un circuito organico per l'elaborazione del segnale, sfruttando componenti passivi organici progettati ad hoc e accoppiati a dispositivi EGOT. Questo approccio senza precedenti offre la possibilità di filtrare e scomporre segnali complessi nelle loro componenti di frequenza costitutive in tempo reale, delineando così strategie innovative per concepire blocchi funzionali a base organica per le interfacce cervello-macchina

A combined microwave and optical sensor system with application in cancer detection

Cancer remains a significant health problem, despite great scientific advances in recent years. Biomedical imaging procedures are commonly used to facilitate the diagnosis and treatment of different types of cancer. However, there are still many limitations to these diagnostic techniques. To overcome some of these issues, new approaches are urgently needed. This study aims to establish potential new techniques to improve disease staging diagnosis through more accurate detection and allow real-time monitoring of sample characteristics to help the surgeons reduce the number of biopsies for making a diagnosis. An optical probe has been fabricated in our laboratory with specific characteristics resulting from modelling and experimental exploration. This probe produced encouraging results from a tissue phantom with an ability to distinguish between different particle sizes 2, 0.8 and 0.413 μm with various polystyrene spheres in suspension (PS) concentrations. A Microwave cavity resonator showed the ability to distinguish between different saline dilutions for two types of preparation and different PS concentrations with some limitations. Many correction techniques were developed to enhance the quality of the data obtained. A novel T- Structure and capacitive coupling technique enabled a more robust S21 measurement to be made utilising a resonant coaxial probe at microwave frequencies between around 0.1 GHz and 6 GHz. This structure was modelled and used in experimental scenarios leading to the ability to distinguish between various saline dilutions and different concentrations of PS. Additional correction techniques showed a significant improvement in PS detection limits. Some difficulties have been overcome, relating to settling the PS particles in suspension, corrosion of the microwave probe, and signal processing. All of this has led to a novel system design by combined the optical and microwave sensor system to facilitate effective and efficient tumour detection. This novelty demonstrated that this new system could distinguish between different particles sizes by optical detection and dielectric properties by microwave characterisation. The concluding section of this thesis presents the simultaneous detection of PS samples of different concentrations optically and with the microwave probe. This represents the first time such simultaneous measurements have been carried out using a combined probe such as that described here

Measurement of tissue optical properties in a wide spectral range: a review

A distinctive feature of this review is a critical analysis of methods and results of measurements of the optical properties of tissues in a wide spectral range from deep UV to terahertz waves. Much attention is paid to measurements of the refractive index of biological tissues and liquids, the knowledge of which is necessary for the effective application of many methods of optical imaging and diagnostics. The optical parameters of healthy and pathological tissues are presented, and the reasons for their differences are discussed, which is important for the discrimination of pathologies and the demarcation of their boundaries. When considering the interaction of terahertz radiation with tissues, the concept of an effective medium is discussed, and relaxation models of the effective optical properties of tissues are presented. Attention is drawn to the manifestation of the scattering properties of tissues in the THz range and the problems of measuring the optical properties of tissues in this range are discussed. In conclusion, a method for the dynamic analysis of the optical properties of tissues under optical clearing using an application of immersion agents is presented. The main mechanisms and technologies of optical clearing, as well as examples of the successful application for differentiation of healthy and pathological tissues, are analyzed