DR riconosce il sostegno della Fondazione tedesca per la ricerca (DFG) Research Grant (RA 1848/1) e il Consiglio europeo della ricerca Starting Grant. VN riconosce il sostegno finanziario della Investigator Award avanzato Consiglio europeo della ricerca e dell&#39;innovazione della BMBF in Medicina Award.

1. Optoacoustic Caratterizzazione del rivelatore π-FBG <ol><li> Preparazione di una sfera microscopica sospesa in agar: <ol><li> Mescolare la polvere di agar (1,3% in peso) con acqua distillata in un bicchiere di vetro. Utilizzare un dispositivo magnetico-agitatore piastra calda per riscaldare la soluzione vicino a temperatura di ebollizione e sciogliere la polvere di agar fino a quando la soluzione diventa limpida e priva di bolle d&#39;aria. In alternativa, la soluzione di agar può essere riscaldato con un forno convenzionale con agitazione eseguita manualmente mediante una bacchetta di vetro. Versare la soluzione calda in uno stampo di plastica, ad esempio, la siringa con la punta tagliata fuori. </li><li> Cospargere una piccola quantità di sfere microscopiche sulla soluzione agar e attendere che la soluzione solidifica completamente. Prendere il solido fantasma agar dallo stampo spingendo lo stantuffo. </li><li> Visualizza il fantasma sotto un microscopio stereoscopico tagliare un pezzetto di agar che contiene una singola sfera microscopica. </li><li> Ripetere passo 1.1.1 e aggiungere to la soluzione di agar agar pezzo solido contenente sfera microscopica singolo. </li><li> Dopo solidificazione, intercettato fantasma agar al microscopio tale che la sfera microscopica si trova vicino alla superficie del fantoccio. </li></ol></li><li> Misurazione Optoacoustic <ol><li> Utilizzare due supporti in fibra v-scanalatura per tenere la fibra saldamente su entrambi i lati del π-FBG, e collegato al detentore di un dimensionale (XYZ) Traduzione terza fase del computer a comando. Assicurarsi che la fibra è sommerso per consentire la propagazione degli ultrasuoni. </li><li> Trovare la posizione approssimativa del rilevamento dell&#39;elemento π-FBG illuminando diverse parti della fibra con il fascio laser nanosecondo impulsi ad alta potenza. L&#39;assorbimento ottico del rivestimento, per quanto debole, creerà un segnale quando l&#39;illuminazione viene eseguita sul π-FBG. </li><li> Posizionare la sfera microscopica agar-embedded direttamente sotto il π-FBG. La sfera microscopica dovrebbe essere visibile ad occhio nudo. </li><li> Utilizzando la fase di traduzione, eseguire una scansione 2D del π-FBG nel piano parallelo al terreno per trovare la posizione in cui il segnale dalla sfera microscopico è più forte e la sua temporizzazione corrispondente è minore. </li><li> Eseguire ultimi aggiustamenti per l&#39;illuminazione per fornire la massima potenza alla sfera microscopica. </li><li> Utilizzando la fase di traduzione eseguire una scansione 3D del π-FBG e registrare il segnale per ogni posizione. </li><li> Per avere la risposta in frequenza spazialmente dipendente del rivelatore di ultrasuoni, eseguire la trasformata di Fourier del segnale a ultrasuoni nel dominio del tempo registrata. </li></ol></li></ol> 2. Stima della robustezza e la sensibilità delle prestazioni del rivelatore π-FBG <ol><li> Utilizzare due supporti in fibra v-scanalatura per tenere la fibra saldamente su entrambi i lati del π-FBG e immergere il π-FBG. </li><li> Posizionare una piastra scura o una bacchetta di grafite robusta per affrontare il π-FBG e illuminarlo spiritoh l&#39;alta potenza nanosecondi-fascio laser per creare un campo acustico forte. </li><li> Mettere una pompa d&#39;acqua all&#39;interno del serbatoio dell&#39;acqua e accenderlo per creare rapide variazioni delle condizioni ambientali. </li><li> Per stimare la robustezza del sistema, misurare l&#39;uscita con il circuito di blocco attivato sia dentro che fuori. Quando viene eseguita alcuna chiusura, non è possibile rilevare con precisione il segnale ultrasonico. </li><li> Spegnere la pompa dell&#39;acqua off. </li><li> Per stimare il beneficio della sensibilità a causa della elevata coerenza della sorgente, sostituire il laser ad impulsi a banda larga con una sorgente coerenza basso e ripetere la misurazione acustica. Una diminuzione di oltre un ordine di grandezza della sensibilità è previsto quando viene utilizzata la sorgente a bassa coerenza. </li></ol>

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W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ultrasound+transducers+for+pulse-echo+medical+imaging.">Ultrasound transducers for pulse-echo medical imaging.</a> IEEE Transactions on Biomedical Engineering. 30, 453-481 (1983).</li><li>Razansky, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Multispectral+opto-acoustic+tomography+of+deep-seated+fluorescent+proteins+in+vivo.">Multispectral opto-acoustic tomography of deep-seated fluorescent proteins in vivo.</a> Nature Photon. 3, 412-417 (2009).</li><li>Ntziachristos, V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Going+deeper+than+microscopy:+the+optical+imaging+frontier+in+biology.">Going deeper than microscopy: the optical imaging frontier in biology.</a> Nature Methods. 7, 603-614 (2010).</li><li>Wang, L. H., Hu, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Photoacoustic+tomography:+In+vivo+imaging+from+organelles+to+organs.">Photoacoustic tomography: In vivo imaging from organelles to organs.</a> Science. 23, 1458-1462 (2012).</li><li>Sethuraman, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Photoacoustic+imaging+using+an+IVUS+imaging+catheter.">Photoacoustic imaging using an IVUS imaging catheter.</a> IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control. 54, 978-986 (2007).</li><li>Rosenthal, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Optoacoustic+methods+for+frequency+calibration+of+ultrasonic+sensors.">Optoacoustic methods for frequency calibration of ultrasonic sensors.</a> IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control. 58, 316-326 (2011).</li><li>Rosenthal, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=High-sensitivity+compact+ultrasonic+detector+based+on+a+pi-phase-shifted+fiber+Bragg+grating.">High-sensitivity compact ultrasonic detector based on a pi-phase-shifted fiber Bragg grating.</a> Optics Letters. 36, 1833-1835 (2011).</li><li>Beard, P. C., Mills, T. N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Extrinsic+optical+fibre+ultrasound+sensor+using+a+thin+polymer+film+as+a+low+finesse+Fabry-Perot+interferometer.">Extrinsic optical fibre ultrasound sensor using a thin polymer film as a low finesse Fabry-Perot interferometer.</a> Applied Optics. 35, 663-675 (1996).</li><li>Xiong Pernice, W. H. 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Express. 19, 25057-25065 (2011).</li><li>Rosenthal, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Wideband+optical+sensing+using+pulse+interferometry.">Wideband optical sensing using pulse interferometry.</a> Optics Express. 20, 19016-19029 (2012).</li><li>Rosenthal, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Wideband+fiber-interferometer+stabilization+with+variable+phase.">Wideband fiber-interferometer stabilization with variable phase.</a> IEEE Photonics Technology Letters. 24, 1499-1501 (2012).</li><li>Rosenthal, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Spatial+characterization+of+the+response+of+a+silica+optical+fiber+to+wideband+ultrasound.">Spatial characterization of the response of a silica optical fiber to wideband ultrasound.</a> Optics Letters. 37, 15-3174 (2012).</li><li>Rosenthal, A., Razansky, D., Ntziachristos, V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Model-based+optoacoustic+inversion+with+arbitrary-shape+detectors.">Model-based optoacoustic inversion with arbitrary-shape detectors.</a> Medical Physics. 38, 4285-4295 (2011).</li></ol>

Gli autori dichiarano di non avere interessi finanziari in competizione.

In conclusione, si introduce un nuovo metodo ottico per il rilevamento ad ultrasuoni, che si basa sulla combinazione di un π-FBG e impulsi interferometria. La tecnica è particolarmente adatta per applicazioni di imaging optoacoustic causa della trasparenza dell&#39;elemento sensibile, che ha la quasi arbitrari schemi di illuminazione oggetto. Al contrario, rilevatori ultrasuoni piezoelettrici base standard sono opachi e quindi bloccare alcuni dei percorsi ottici all&#39;oggetto ripreso, portando a configurazioni di im...

Rilevatori ultrasuoni svolgono un ruolo fondamentale in molte applicazioni di imaging. Convenzionalmente, ultrasuoni viene rilevata da trasduttori piezoelettrici che trasformano onde di pressione in segnali di tensione 1. Nell&#39;imaging optoacoustic, ultrasuoni viene generato tramite un processo di espansione termica illuminando l&#39;oggetto con alta potenza a luce modulata 2-6. Sebbene trasduttori piezoelettrici sono il metodo di scelta nelle applicazioni optoacoustic, il loro uso spesso ostacola miniaturizzazione soprattutto perché trasduttori piezoelettrici miniaturizzati sono spesso caratterizzate da una bassa sensibilità. Inoltre, poiché trasduttori piezoelettrici sono otticamente opachi, possono interferire pesantemente con la consegna di luce all&#39;oggetto ripreso, possibilità di configurazioni di imaging utilizzabili limitante. Luce che viene retrodiffusa dall&#39;oggetto al trasduttore può anche limitare la corretta rilevazione di ultrasuoni e complicare la progettazione del sistema di imaging a causa parasit otticamente indottaic segnala nel trasduttore 7. Rivelatori ottici di ultrasuoni sono stati riconosciuti come una possibile alternativa di trasduttori piezoelettrici, che offre molti vantaggi in scenari di imaging optoacoustic 8-12: Spesso sono trasparenti e possono essere di solito miniaturizzati, senza perdita di sensibilità. Il principio di funzionamento dei rilevatori ottici è rilevazione interferometrica della deformazione minuto creato nel mezzo ottico a causa della presenza di ultrasuoni. Spesso, risonatori ottici sono utilizzati per migliorare la sensibilità di rilevamento intrappolando luce nel mezzo perturbato per durate estese, aumentando così l&#39;effetto della deformazione sulla fase del segnale ottico. In tali casi, schemi di rilevazione ottici si basano sulle variazioni di monitoraggio nella lunghezza d&#39;onda di risonanza, che sono direttamente connessi a strutturare deformazioni nel risonatore. Più comunemente, vengono utilizzate tecniche stretta linewidth onda continua (CW) in cui un laser CW è sintonizzato al secoloe risonanza lunghezza d&#39;onda. Piccoli spostamenti nella lunghezza d&#39;onda di risonanza cambiare la posizione relativa della lunghezza d&#39;onda del laser all&#39;interno della risonanza, causando variazioni nell&#39;intensità del / luce laser riflessa trasmessa, che può essere facilmente controllata. Tuttavia, se i turni di risonanza sono troppo forti, ad esempio a causa dei forti variazioni di pressione, temperatura e vibrazioni, la risonanza può spostarsi completamente dalla lunghezza d&#39;onda del laser, saturando efficacemente il rivelatore 13. Pulse interferometria 14 offre una soluzione per la limitazione di saturazione del segnale e permette un rilevamento ultrasuoni in condizioni ambientali volatili. A differenza di restringere-linewidth regimi CW, impulso interferometria utilizza una sorgente di impulsi a banda larga per illuminare il risonatore. In questo caso, il risonatore agisce come un filtro passa-banda, trasmettendo solo le lunghezze d&#39;onda corrispondenti alla propria frequenza di risonanza, mentre la risonanza sposta unri rilevata misurando le variazioni di lunghezza d&#39;onda del segnale ottico in uscita del risonatore, ad esempio utilizzando un interferometro Mach-Zehnder bloccato quadratura 14,15. Un circuito di reset automatico viene utilizzato per ripristinare immediatamente il punto di lavoro del interferometro in caso di smarrimento a causa dell&#39;estrema variabilità delle condizioni ambientali. A causa della relativamente ampia larghezza di banda della sorgente, la lunghezza d&#39;onda di risonanza rimane all&#39;interno della banda illuminato anche sotto forti perturbazioni, consentendo un funzionamento stabile rivelatore anche in condizioni ambientali difficili. L&#39;utilizzo di una sorgente coerente per l&#39;interrogazione, cioè impulsi ottici, facilita la rilevazione a basso rumore. Il corrispondente sistema interferometria impulso utilizzato nei nostri esperimenti è mostrato in Figura 1. L&#39;impulso laser utilizzato per l&#39;interrogazione prodotto 90 impulsi FSEC cadenza di ripetizione di 100 MHz, con potenza di uscita di 60 mW e larghezza spettrale di oltre 100nm. Il filtro ottico aveva una larghezza spettrale FWHM di circa 0,4 nm ed era sintonizzato alla frequenza di risonanza. Seguendo il filtro, un amplificatore ottico è stato utilizzato per compensare la perdita significativa nel filtraggio. Filtraggio supplementare è stato applicato dopo la fase di amplificazione per ridurre l&#39;emissione spontanea amplificata dall&#39;amplificatore. Il risonatore utilizzato nei nostri esperimenti è un pi-sfasato fibra a reticolo di Bragg (π-FBG) 8, prodotto da Teraxion Inc. In particolare per l&#39;applicazione medica di rilevamento ultrasuoni, π-FBGs hanno il vantaggio di essere tutti i componenti in fibra, e quindi robusta e piccola. Figura 2 mostra un confronto tra le dimensioni della fibra ottica utilizzata in questo lavoro e 15 MHz ultrasuoni intravascolare miniaturizzato (IVUS) trasduttore piezoelettrico. Alcuni approcci alternativi di rilevamento basato risonanza, come risonatori micro-ring fabbricati in guide d&#39;onda planari, richiedono fibre accoppiamento al componente diingresso e uscita, sia portando a dispositivi più fragili o ostacolare miniaturizzazione. Al contrario, π-FBGs sono in fibra di componenti, e non richiedono l&#39;accoppiamento fibra supplementare. La risonanza in π-FBGs viene creato dal sfasamento pi nel loro centro; luce è intrappolato intorno sfasamento pi sopra porzione della fibra che è notevolmente più corta della lunghezza del reticolo stesso. Nei nostri esperimenti, il π-FBG aveva una lunghezza di 4 mm e coefficiente di accoppiamento di κ = 2 millimetri -1 e la sua sensibilità è stato distribuito in modo non uniforme lungo la sua lunghezza, con la sensibilità esponenziale decrescente dal centro della griglia con un tasso di κ . La larghezza piena-metà del massimo (FWHM) della distribuzione sensibilità (SD) era di circa 350 micron. La larghezza di risonanza del reticolo è determinata sia la sua lunghezza e il suo coefficiente di accoppiamento secondo la seguente equazione: <img alt="Equazione 1" fo:content-width="1.5in" src= &quot;Files/ftp_upload/50847/50847eq1.jpg /&quot; width = &quot;150&quot; /&gt; (1) dove λ è la lunghezza d&#39;onda di risonanza e n eff è l&#39;indice di rifrazione efficace del modo guidato nella fibra 8. Per valutare se il rilevatore π-FBG è appropriato per applicazioni di imaging, la sua risposta spazialmente dipendente deve essere misurata su un&#39;ampia banda di frequenze. Tuttavia, questo compito è estremamente difficile quando si utilizzano tecniche acustiche convenzionali. Abbiamo quindi impiegare un metodo per optoacoustic rilevatore ultrasuoni caratterizzazione 16 in cui una sfera microscopica scuro incorporato in agar trasparente funge da sorgente puntiforme optoacoustic. Nel nostro esperimento, la sfera microscopica ha un diametro di circa 100 micron ed è illuminata con alto potere nanosecondi impulsi ottici con una frequenza di ripetizione di 10 Hz, durata dell&#39;impulso di circa 8 nsec, e potenza media di 200 mW. L&#39;energia ottica depositato nel SPH microscopicaeres genera segnali a banda larga ultrasuoni causa l&#39;effetto optoacoustic. Il rivelatore π-FBG è tradotto relativamente alla sfera microscopica avere la sua risposta acustica spazialmente dipendente. Figura 3 mostra un esempio dell&#39;esperimento optoacoustic. Generalmente, questa tecnica può essere utilizzata per individuare i diversi tipi di rivelatori ad ultrasuoni.

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			<td height="43" style="height:43px;width:216px;">&#960;-FBG</td>
			<td style="width:71px;">Teraxion Inc.</td>
			<td style="width:119px;"></td>
			<td style="width:167px;">&#160;Custom made device</td>
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			<td height="43" style="height:43px;width:216px;">microscopic sphere</td>
			<td style="width:71px;">Cospheric LLC</td>
			<td style="width:119px;">BKPMS 90-106um- 10g</td>
			<td style="width:167px;">100 &#181;m polyethylene microsphere</td>
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			<td height="64" style="height:64px;width:216px;">Femto-second pulse laser used for interrogation&#160;</td>
			<td style="width:71px;">Menlo Systems GmbH</td>
			<td style="width:119px;">T-Light Femtosecond Laser</td>
			<td style="width:167px;"></td>
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			<td height="64" style="height:64px;width:216px;">Optical filter</td>
			<td style="width:71px;">Optoplex Corporation</td>
			<td style="width:119px;">2-Port Optical Tunable Filter (50 GHz)</td>
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			<td height="64" style="height:64px;width:216px;">Optical amplifier</td>
			<td style="width:71px;">Amonics</td>
			<td style="width:119px;">AEDFA-PM-PA-35-B-FC</td>
			<td style="width:167px;">Benchtop 35dB Gain Pre Amp Polarization Maintaining EDFA&#160;</td>
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			<td height="232" style="height:232px;width:216px;">50/50 coupler</td>
			<td style="width:71px;">OZ-Optics</td>
			<td style="width:119px;">FUSED-22-1550-8/125-50/50-3S3S3S3S-3-0.5-PM</td>
			<td style="width:167px;">Fused 2x2 fiber splitter with 0.5 meter long, 3mm OD PVC jacketed 1550nm 8/125&#956; PM fiber 
			pigtails, 50/50 split ratio in the slow axes of PM fibers and with super FC/PC connectors on all 
			ports.</td>
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			<td height="43" style="height:43px;width:216px;">Fiber holder</td>
			<td style="width:71px;">Thorlabs</td>
			<td style="width:119px;">T711/M-250</td>
			<td style="width:167px;">Metric, Post-Mountable Fiber Clamp, 250 &#181;m&#160;</td>
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			<td height="43" style="height:43px;width:216px;">Agar for microbiology</td>
			<td style="width:71px;">Sigma Aldrich</td>
			<td style="width:119px;">05039-500G</td>
			<td style="width:167px;"></td>
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			<td height="64" style="height:64px;width:216px;">Nano-second pulse laser used for generating the optoacoustic signals</td>
			<td style="width:71px;">Opotek</td>
			<td style="width:119px;">VIBRANT Arrow 532 type I</td>
			<td style="width:167px;"></td>
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			<td height="43" style="height:43px;width:216px;">Graphite rod</td>
			<td style="width:71px;">&#160;Faber-Castell</td>
			<td style="width:119px;">120700</td>
			<td style="width:167px;">Faber-Castell Pencil Leads - 0.7 mm</td>
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wideband optical detector of ultrasound for medical imaging applications

Sensori ottici di ultrasuoni sono una promettente alternativa alle tecniche piezoelettrici, come è stato recentemente dimostrato nel campo dell&#39;imaging optoacoustic. In applicazioni mediche, una delle principali limitazioni della tecnologia di rilevamento ottico è la sua sensibilità alle condizioni ambientali, ad esempio variazioni di pressione e temperatura che si possono saturare il rilevamento. Inoltre, l&#39;ambiente clinico spesso impone limiti rigorosi sulle dimensioni e la robustezza del sensore. In questo lavoro, la combinazione di interferometria impulso e rilevamento ottico a base di fibre è dimostrato per il rilevamento a ultrasuoni. Pulse interferometria permette solido andamento del sistema di lettura in presenza di rapide variazioni delle condizioni ambientali, mentre l&#39;uso di tecnologia interamente fibra porta ad un elemento sensibile meccanicamente flessibile compatibile con altamente esigenti applicazioni mediche come l&#39;imaging intravascolare. Al fine di conseguire una breve lunghezza del sensore, unfibra pi-sfasato reticolo di Bragg è usato, che agisce come un risonatore intrappolare luce su una lunghezza utile di 350 micron. Per attivare elevata larghezza di banda, il sensore viene utilizzato per il rilevamento sideway di ultrasuoni, che è estremamente utile in geometrie di imaging circonferenza come l&#39;imaging intravascolare. Una configurazione di imaging optoacoustic viene utilizzato per determinare la risposta del sensore per sorgenti puntiformi acustiche in posizioni diverse.

Figure 4a e 4b mostrano rispettivamente i segnali ei loro spettri corrispondente dalla sfera microscopica ad una distanza di 1 mm dalla fibra per tre offset dal centro del π-FBG. Gli offset sono riportati nella direzione z, come illustrato nella Figura 3. Chiaramente, la sensibilità del rilevatore ottico a ultrasuoni ad alta frequenza (f&gt; 6 MHz) è anisotropo ed è più alta quando il centro del π-FBG è direttamente sopra la sfera microscopica . Nonostante l&#39;...

Watch this Scientific Journal Video about Wideband Optical Detector of Ultrasound for Medical Imaging Applications at JoVE.com

Wideband Optical Detector of Ultrasound for Medical Imaging Applications

Rilevazione ottica degli ultrasuoni è impraticabile in molti scenari di imaging, perché spesso richiede condizioni ambientali stabili. Dimostriamo una tecnica ottica per il rilevamento a ultrasuoni in ambienti volatili con miniaturizzazione e sensibilità livelli appropriati per l&#39;imaging optoacoustic in scenari restrittive, come ad esempio le applicazioni intravascolari.

Wideband rivelatore ottico di ultrasuono per applicazioni Medical Imaging

Optical sensors of ultrasound are a promising alternative to piezoelectric techniques, as has been recently demonstrated in the field of optoacoustic ...

wideband-optical-detector-ultrasound-for-medical-imaging

Research

JoVE Journal

Bioengineering

10.7K Views.  Technical University of Munich and Helmholtz Center Munich.  Rilevazione ottica degli ultrasuoni è impraticabile in molti scenari di imaging, perché spesso richiede condizioni ambientali stabili. Dimostriamo una tecnica ottica per il rilevamento a ultrasuoni in ambienti volatili con miniaturizzazione e sensibilità livelli appropriati per l'imaging optoacoustic in scenari restrittive, come ad esempio le applicazioni intravascolari. 

Video: Wideband Optical Detector of Ultrasound for Medical Imaging Applications

Three-dimensional Optical-resolution Photoacoustic Microscopy

Optical microscopy, providing valuable insights at the cellular and organelle levels, has been widely recognized as an enabling biomedical technology. As the mainstays of in vivo three-dimensional (3-D) optical microscopy, single-/multi-photon fluorescence microscopy and optical coherence tomography (OCT) have demonstrated their extraordinary sensitivities to fluorescence and optical scattering contrasts, respectively. However, the optical absorption contrast of biological tissues, which encodes essential physiological/pathological information, has not yet been assessable. 
The emergence of biomedical photoacoustics has led to a new branch of optical microscopy optical-resolution photoacoustic microscopy (OR-PAM)1, where the optical irradiation is focused to the diffraction limit to achieve cellular1 or even subcellular2 level lateral resolution. As a valuable complement to existing optical microscopy technologies, OR-PAM brings in at least two novelties. First and most importantly, OR-PAM detects optical absorption contrasts with extraordinary sensitivity (i.e., 100%). Combining OR-PAM with fluorescence microscopy3 or with optical-scattering-based OCT4 (or with both) provides comprehensive optical properties of biological tissues. Second, OR-PAM encodes optical absorption into acoustic waves, in contrast to the pure optical processes in fluorescence microscopy and OCT, and provides background-free detection. The acoustic detection in OR-PAM mitigates the impacts of optical scattering on signal degradation and naturally eliminates possible interferences (i.e., crosstalks) between excitation and detection, which is a common problem in fluorescence microscopy due to the overlap between the excitation and fluorescence spectra. 
Unique for optical absorption imaging, OR-PAM has demonstrated broad biomedical applications since its invention, including, but not limited to, neurology5, 6, ophthalmology7, 8, vascular biology9, and dermatology10. In this video, we teach the system configuration and alignment of OR-PAM as well as the experimental procedures for in vivo functional microvascular imaging.

Optical-resolution photoacoustic microscopy (OR-PAM) is an emerging technology capable of imaging optical absorption contrasts in vivo with cellular resolution and sensitivity. Here, we provide a visualized instruction on the experimental protocols of OR-PAM, including system configuration, system alignment, typical in vivo experimental procedures, and functional imaging schemes.

Tridimensionale con risoluzione ottica Microscopia fotoacustico

Optical microscopy, providing valuable insights at the cellular and organelle levels, has been widely recognized as an enabling biomedical technology. As ...

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Bioingegneria

Optical Frequency Domain Imaging of Ex vivo Pulmonary Resection Specimens: Obtaining One to One Image to Histopathology Correlation

Lung cancer is the leading cause of cancer-related deaths1. Squamous cell and small cell cancers typically arise in association with the conducting airways, whereas adenocarcinomas are typically more peripheral in location. Lung malignancy detection early in the disease process may be difficult due to several limitations: radiological resolution, bronchoscopic limitations in evaluating tissue underlying the airway mucosa and identifying early pathologic changes, and small sample size and/or incomplete sampling in histology biopsies. High resolution imaging modalities, such as optical frequency domain imaging (OFDI), provide non-destructive, large area 3-dimensional views of tissue microstructure to depths approaching 2 mm in real time (Figure 1)2-6. OFDI has been utilized in a variety of applications, including evaluation of coronary artery atherosclerosis6,7 and esophageal intestinal metaplasia and dysplasia6,8-10.
Bronchoscopic OCT/OFDI has been demonstrated as a safe in vivo imaging tool for evaluating the pulmonary airways11-23 (Animation). OCT has been assessed in pulmonary airways16,23 and parenchyma17,22 of animal models and in vivo human airway14,15. OCT imaging of normal airway has demonstrated visualization of airway layering and alveolar attachments, and evaluation of dysplastic lesions has been found useful in distinguishing grades of dysplasia in the bronchial mucosa11,12,20,21. OFDI imaging of bronchial mucosa has been demonstrated in a short bronchial segment (0.8 cm)18. Additionally, volumetric OFDI spanning multiple airway generations in swine and human pulmonary airways in vivo has been described19. Endobronchial OCT/OFDI is typically performed using thin, flexible catheters, which are compatible with standard bronchoscopic access ports. Additionally, OCT and OFDI needle-based probes have recently been developed, which may be used to image regions of the lung beyond the airway wall or pleural surface17.
While OCT/OFDI has been utilized and demonstrated as feasible for in vivo pulmonary imaging, no studies with precisely matched one-to-one OFDI:histology have been performed. Therefore, specific imaging criteria for various pulmonary pathologies have yet to be developed. Histopathological counterparts obtained in vivo consist of only small biopsy fragments, which are difficult to correlate with large OFDI datasets. Additionally, they do not provide the comprehensive histology needed for registration with large volume OFDI. As a result, specific imaging features of pulmonary pathology cannot be developed in the in vivo setting. Precisely matched, one-to-one OFDI and histology correlation is vital to accurately evaluate features seen in OFDI against histology as a gold standard in order to derive specific image interpretation criteria for pulmonary neoplasms and other pulmonary pathologies. Once specific imaging criteria have been developed and validated ex vivo with matched one-to-one histology, the criteria may then be applied to in vivo imaging studies. Here, we present a method for precise, one to one correlation between high resolution optical imaging and histology in ex vivo lung resection specimens. Throughout this manuscript, we describe the techniques used to match OFDI images to histology. However, this method is not specific to OFDI and can be used to obtain histology-registered images for any optical imaging technique. We performed airway centered OFDI with a specialized custom built bronchoscopic 2.4 French (0.8 mm diameter) catheter. Tissue samples were marked with tissue dye, visible in both OFDI and histology. Careful orientation procedures were used to precisely correlate imaging and histological sampling locations. The techniques outlined in this manuscript were used to conduct the first demonstration of volumetric OFDI with precise correlation to tissue-based diagnosis for evaluating pulmonary pathology24. This straightforward, effective technique may be extended to other tissue types to provide precise imaging to histology correlation needed to determine fine imaging features of both normal and diseased tissues.

Optical Frequency Domain Imaging of Ex vivo Pulmonary Resection Specimens: Obtaining One to One Image to Histopathology Correlation

A method to image ex vivo pulmonary resection specimens with optical frequency domain imaging (OFDI) and obtain precise correlation to histology is described, which is essential to developing specific OFDI interpretation criteria for pulmonary pathology. This method is applicable to other tissue types and imaging techniques to obtain precise imaging to histology correlation for accurate image interpretation and assessment. Imaging criteria established with this technique would then be applicable to image assessment in future in vivo studies.

Optical Frequency Domain Imaging di<em&gt; Ex vivo</em&gt; I campioni polmonari Resezione: Ottenere One to One immagine per Istopatologia Correlazione

Lung cancer is the leading cause of cancer-related deaths1. Squamous cell and small cell cancers typically arise in association with the conducting ...

Preparation of Mica Supported Lipid Bilayers for High Resolution Optical Microscopy Imaging

Supported lipid bilayers (SLBs) are widely used as a model for studying membrane properties (phase separation, clustering, dynamics) and its interaction with other compounds, such as drugs or peptides. However SLB characteristics differ depending on the support used. 
Commonly used techniques for SLB imaging and measurements are single molecule fluorescence microscopy, FCS and atomic force microscopy (AFM). Because most optical imaging studies are carried out on a glass support, while AFM requires an extremely flat surface (generally mica), results from these techniques cannot be compared directly, since the charge and smoothness properties of these materials strongly influence diffusion. Unfortunately, the high level of manual dexterity required for the cutting and gluing thin slices of mica to the glass slide presents a hurdle to routine use of mica for SLB preparation. Although this would be the method of choice, such prepared mica surfaces often end up being uneven (wavy) and difficult to image, especially with small working distance, high numerical aperture lenses. Here we present a simple and reproducible method for preparing thin, flat mica surfaces for lipid vesicle deposition and SLB preparation. Additionally, our custom made chamber requires only very small volumes of vesicles for SLB formation. The overall procedure results in the efficient, simple and inexpensive production of high quality lipid bilayer surfaces that are directly comparable to those used in AFM studies.

We present a method of preparing mica supported lipid bilayers for high resolution microscopy. Mica is transparent and flat on an atomic scale, but rarely used in imaging because of handling difficulties; our preparation results in even deposition of the mica sheet, and reduces the material used in bilayer preparation.

Preparazione di Mica supportati doppi strati lipidici per alta risoluzione microscopia ottica Imaging

Supported lipid bilayers (SLBs) are widely used as a model for studying membrane properties (phase separation, clustering, dynamics) and its interaction ...

Biofunctionalized Prussian Blue Nanoparticles for Multimodal Molecular Imaging Applications

Multimodal, molecular imaging allows the visualization of biological processes at cellular, subcellular, and molecular-level resolutions using multiple, complementary imaging techniques. These imaging agents facilitate the real-time assessment of pathways and mechanisms in vivo, which enhance both diagnostic and therapeutic efficacy. This article presents the protocol for the synthesis of biofunctionalized Prussian blue nanoparticles (PB NPs) - a novel class of agents for use in multimodal, molecular imaging applications. The imaging modalities incorporated in the nanoparticles, fluorescence imaging and magnetic resonance imaging (MRI), have complementary features. The PB NPs possess a core-shell design where gadolinium and manganese ions incorporated within the interstitial spaces of the PB lattice generate MRI contrast, both in T1 and T2-weighted sequences. The PB NPs are coated with fluorescent avidin using electrostatic self-assembly, which enables fluorescence imaging. The avidin-coated nanoparticles are modified with biotinylated ligands that confer molecular targeting capabilities to the nanoparticles. The stability and toxicity of the nanoparticles are measured, as well as their MRI relaxivities. The multimodal, molecular imaging capabilities of these biofunctionalized PB NPs are then demonstrated by using them for fluorescence imaging and molecular MRI in vitro.

This protocol describes the synthesis of biofunctionalized Prussian blue nanoparticles and their use as multimodal, molecular imaging agents. The nanoparticles have a core-shell design where gadolinium or manganese ions within the nanoparticle core generate MRI contrast. The biofunctional shell contains fluorophores for fluorescence imaging and targeting ligands for molecular targeting.

Biofunctionalized Prussian Blue Nanoparticelle per applicazioni di imaging multimodale molecolari

Multimodal, molecular imaging allows the visualization of biological processes at cellular, subcellular, and molecular-level resolutions using multiple, ...

Real-time Monitoring of High Intensity Focused Ultrasound (HIFU) Ablation of In Vitro Canine Livers Using Harmonic Motion Imaging for Focused Ultrasound (HMIFU)

Harmonic Motion Imaging for Focused Ultrasound (HMIFU) is a technique that can perform and monitor high-intensity focused ultrasound (HIFU) ablation. An oscillatory motion is generated at the focus of a 93-element and 4.5 MHz center frequency HIFU transducer by applying a 25 Hz amplitude-modulated signal using a function generator. A 64-element and 2.5 MHz imaging transducer with 68kPa peak pressure is confocally placed at the center of the HIFU transducer to acquire the radio-frequency (RF) channel data. In this protocol, real-time monitoring of thermal ablation using HIFU with an acoustic power of 7 W on canine livers in vitro is described. HIFU treatment is applied on the tissue during 2 min and the ablated region is imaged in real-time using diverging or plane wave imaging up to 1,000 frames/second. The matrix of RF channel data is multiplied by a sparse matrix for image reconstruction. The reconstructed field of view is of 90&#176; for diverging wave and 20 mm for plane wave imaging and the data are sampled at 80 MHz. The reconstruction is performed on a Graphical Processing Unit (GPU) in order to image in real-time at a 4.5 display frame rate. 1-D normalized cross-correlation of the reconstructed RF data is used to estimate axial displacements in the focal region. The magnitude of the peak-to-peak displacement at the focal depth decreases during the thermal ablation which denotes stiffening of the tissue due to the formation of a lesion. The displacement signal-to-noise ratio (SNRd) at the focal area for plane wave was 1.4 times higher than for diverging wave showing that plane wave imaging appears to produce better displacement maps quality for HMIFU than diverging wave imaging.

Real-time Monitoring of High Intensity Focused Ultrasound HIFU Ablation of In Vitro Canine Livers Using Harmonic Motion Imaging for Focused Ultrasound HMIFU

This article describes real-time monitoring of HIFU ablation in canine liver with high frame rate ultrasound imaging using diverging and plane wave imaging. Harmonic Motion Imaging for Focused Ultrasound is used to image the decrease of acoustic radiation force induced displacement in the ablated region.

Monitoraggio in tempo reale di alta intensità ultrasuoni focalizzati (HIFU) Ablazione<em&gt; In Vitro</em&gt; Canine Livers Uso Harmonic Imaging Movimento per Focused Ultrasound (HMIFU)

Harmonic Motion Imaging for Focused Ultrasound (HMIFU) is a technique that can perform and monitor high-intensity focused ultrasound (HIFU) ablation. An ...

Computed Tomography and Optical Imaging of Osteogenesis-angiogenesis Coupling to Assess Integration of Cranial Bone Autografts and Allografts

A major parameter determining the success of a bone-grafting procedure is vascularization of the area surrounding the graft. We hypothesized that implantation of a bone autograft would induce greater bone regeneration by abundant blood vessel formation. To investigate the effect of the graft on neovascularization at the defect site, we developed a micro&#8211;computed tomography (&#181;CT) approach to characterize newly forming blood vessels, which involves systemic perfusion of the animal with a polymerizing contrast agent. This method enables detailed vascular analysis of an organ in its entirety. Additionally, blood perfusion was assessed using fluorescence imaging (FLI) of a blood-borne fluorescent agent. Bone formation was quantified by FLI using a hydroxyapatite-targeted probe and &#181;CT analysis. Stem cell recruitment was monitored by bioluminescence imaging (BLI) of transgenic mice that express luciferase under the control of the osteocalcin promoter. Here we describe and demonstrate preparation of the allograft, calvarial defect surgery, &#181;CT scanning protocols for the neovascularization study and bone formation analysis (including the in vivo perfusion of contrast agent), and the protocol for data analysis.
The 3D high-resolution analysis of vasculature demonstrated significantly greater angiogenesis in animals with implanted autografts, especially with respect to arteriole formation. Accordingly, blood perfusion was significantly higher in the autograft group by the 7th day after surgery. We observed superior bone mineralization and measured greater bone formation in animals that received autografts. Autograft implantation induced resident stem cell recruitment to the graft-host bone suture, where the cells differentiated into bone-forming cells between the 7th and 10th postoperative day. This finding means that enhanced bone formation may be attributed to the augmented vascular feeding that characterizes autograft implantation. The methods depicted may serve as an optimal tool to study bone regeneration in terms of tightly bounded bone formation and neovascularization.

Implantation of autologous and allogeneic bone grafts constitute accepted approaches to treat major craniofacial bone loss. Yet the effect of graft composition on the interplay among neovascularization, cell differentiation and bone formation is unclear. We present a multimodal imaging protocol aimed to elucidate the angiogenesis-osteogenesis interdependence at the graft proximity.

Tomografia Computerizzata e Optical Imaging di osteogenesi-angiogenesi Accoppiamento per valutare l&#39;integrazione di craniche Bone Autoinnesti e Alloinnesti

A major parameter determining the success of a bone-grafting procedure is vascularization of the area surrounding the graft. We hypothesized that ...

High-throughput Identification of Bacteria Repellent Polymers for Medical Devices

Medical devices are often associated with hospital-acquired infections, which place enormous strain on patients and the healthcare system as well as contributing to antimicrobial resistance. One possible avenue for the reduction of device-associated infections is the identification of bacteria-repellent polymer coatings for these devices, which would prevent bacterial binding at the initial attachment step. A method for the identification of such repellent polymers, based on the parallel screening of hundreds of polymers using a microarray, is described here. This high-throughput method resulted in the identification of a range of promising polymers that resisted binding of various clinically relevant bacterial species individually and also as multi-species communities. One polymer, PA13 (poly(methylmethacrylate-co-dimethylacrylamide)), demonstrated significant reduction in attachment of a number of hospital isolates when coated onto two commercially available central venous catheters. The method described could be applied to identify polymers for a wide range of applications in which modification of bacterial attachment is important.

A high-throughput microarray method for the identification of polymers which reduce bacterial surface binding on medical devices is described.

High-throughput identificazione di batteri Polimeri repellente per dispositivi medici

Medical devices are often associated with hospital-acquired infections, which place enormous strain on patients and the healthcare system as well as ...

Medical-grade Sterilizable Target for Fluid-immersed Fetoscope Optical Distortion Calibration

We have developed a calibration target for use with fluid-immersed endoscopes within the context of the GIFT-Surg (Guided Instrumentation for Fetal Therapy and Surgery) project. One of the aims of this project is to engineer novel, real-time image processing methods for intra-operative use in the treatment of congenital birth defects, such as spina bifida and the twin-to-twin transfusion syndrome. The developed target allows for the sterility-preserving optical distortion calibration of endoscopes within a few minutes. Good optical distortion calibration and compensation are important for mitigating undesirable effects like radial distortions, which not only hamper accurate imaging using existing endoscopic technology during fetal surgery, but also make acquired images less suitable for potentially very useful image computing applications, like real-time mosaicing. In this paper proposes a novel fabrication method to create an affordable, sterilizable calibration target suitable for use in a clinical setup. This method involves etching a calibration pattern by laser cutting a sandblasted stainless steel sheet. This target was validated using the camera calibration module provided by OpenCV, a state-of-the-art software library popular in the computer vision community.

This article describes the design and development of a sterilizable custom camera optical distortion calibration target for the peri-operative, fluid-immersed calibration of endoscopes during endoscopic interventions.

Medico-grade di destinazione sterilizzabile per fetoscope ottico Distortion calibrazione Fluid-immersi

We have developed a calibration target for use with fluid-immersed endoscopes within the context of the GIFT-Surg (Guided Instrumentation for Fetal ...

Long-term Live Imaging Device for Improved Experimental Manipulation of Zebrafish Larvae

The zebrafish larva is an important model organism for both developmental biology and wound healing. Further, the zebrafish larva is a valuable system for live high-resolution microscopic imaging of dynamic biological phenomena in space and time with cellular resolution. However, the traditional method of agarose encapsulation for live imaging can impede larval development and tissue regrowth. Therefore, this manuscript describes the zWEDGI (zebrafish Wounding and Entrapment Device for Growth and Imaging), which was designed and fabricated as a functionally compartmentalized device to orient larvae for high-resolution microscopy while permitting caudal fin transection within the device and subsequent unrestrained tail development and re-growth. This device allows for wounding and long-term imaging while maintaining viability. Given that the zWEDGI mold is 3D printed, the customizability of its geometries make it easily modified for diverse zebrafish imaging applications. Furthermore, the zWEDGI offers numerous benefits, such as access to the larva during experimentation for wounding or for the application of reagents, paralleled orientation of multiple larvae for streamlined imaging, and reusability of the device.

This manuscript describes the zWEDGI (zebrafish Wounding and Entrapment Device for Growth and Imaging), which is a compartmentalized device designed to orient and restrain zebrafish larvae. The design permits tail transection and long-term collection of high-resolution fluorescent microscopy images of wound healing and regeneration.

Dispositivo di Imaging dal vivo a lungo termine per una migliore manipolazione sperimentale delle larve di Zebrafish

The zebrafish larva is an important model organism for both developmental biology and wound healing. Further, the zebrafish larva is a valuable system for ...

Optical Imaging of Isolated Murine Ventricular Myocytes

The ability to isolate adult cardiac myocytes has permitted researchers to study a variety of cardiac pathologies at the single cell level. While advances in calcium sensitive dyes have permitted the robust optical recording of single cell calcium dynamics, recording of robust transmembrane optical voltage signals has remained difficult. Arguably, this is because of the low single to noise ratio, phototoxicity, and photobleaching of traditional potentiometric dyes. Therefore, single cell voltage measurements have long been confined to the patch clamp technique which while the gold standard, is technically demanding and low throughput. However, with the development of novel potentiometric dyes, large, fast optical responses to changes in voltage can be obtained with little to no phototoxicity and photobleaching. This protocol describes in detail how to isolate adult murine myocytes which can be used for cellular shortening, calcium, and optical voltage measurements. Specifically, the protocol describes how to use a ratiometric calcium dye, a single-excitation calcium dye, and a single excitation voltage dye. This approach can be used to assess the cardiotoxicity and arrhythmogenicity of various chemical agents. While phototoxicity is still an issue at the single cell level, methodology is discussed on how to reduce it.

We present the methodology for the isolation of murine myocytes and how to obtain voltage or calcium traces simultaneously with sarcomere shortening traces using fluorescence photometry with simultaneous digital cell geometry measurements.

Imaging ottico di miociti Murine Ventricolari isolati

The ability to isolate adult cardiac myocytes has permitted researchers to study a variety of cardiac pathologies at the single cell level. While advances ...