Name: evaluating regional pulmonary deposition using patient-specific 3d printed lung models
Uploaded: 2020-11-11T13:00:00
Description: Watch this Scientific Journal Video about Evaluating Regional Pulmonary Deposition using Patient-Specific 3D Printed Lung Models at JoVE.com

Gli autori ringraziano il professor Yu Feng, la dott.ssa Jenna Briddell, Ian Woodward e Lucas Attia per le loro utili discussioni.

1. Preparazione di componenti sperimentali stampati in 3D
NOTA: Tutti i software utilizzati nel protocollo sono indicati nella Tabella dei Materiali. Inoltre, il software di affezione utilizzato è specifico della stampante 3D elencata nella tabella dei materiali; tuttavia, questo protocollo può essere esteso a una vasta gamma di stampanti 3D stereolitografiche (SLA).
<ol><li>Convertire le scansioni CT del paziente in oggetti 3D (file stl). NOTA: Per una...

<ol>
	<li>Goel, A., Baboota, S., Sahni, J. K., Ali, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Exploring+targeted+pulmonary+delivery+for+treatment+of+lung+cancer.">Exploring targeted pulmonary delivery for treatment of lung cancer.</a> International Journal of Pharmaceutical Investigation. 3 (1), 8-14 (2013).</li><li>Kleinstreuer, C., Zhang, Z., Li, Z., Roberts, W. L., Rojas, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+new+methodology+for+targeting+drug-aerosols+in+the+human+respiratory+system.">A new methodology for targeting drug-aerosols in the human respiratory system.</a> International Journal of Heat and Mass Transfer. 51 (23), 5578-5589 (2008).</li><li>Feng, Y., Chen, X., Yang, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=An+In+Silico+Investigation+of+a+Lobe-Specific+Targeted+Pulmonary+Drug+Delivery+Method.">An In Silico Investigation of a Lobe-Specific Targeted Pulmonary Drug Delivery Method.</a> Design of Medical Devices Conference. , (2018).</li><li>Marple, V. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Next+generation+pharmaceutical+impactor+(a+new+impactor+for+pharmaceutical+inhaler+testing).+Part+I:+Design.">Next generation pharmaceutical impactor (a new impactor for pharmaceutical inhaler testing). Part I: Design.</a> Journal of Aerosol Medicine. 16 (3), 283-299 (2003).</li><li>Feng, Y., Zhao, J., Chen, X., Lin, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=An+In+Silico+Subject-Variability+Study+of+Upper+Airway+Morphological+Influence+on+the+Airflow+Regime+in+a+Tracheobronchial+Tree.">An In Silico Subject-Variability Study of Upper Airway Morphological Influence on the Airflow Regime in a Tracheobronchial Tree.</a> Bioengineering. 4 (4), 90 (2017).</li><li>Huynh, B. K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Development+and+Validation+of+an+In+Vitro+Airway+Model+to+Assess+Realistic+Airway+Deposition+and+Drug+Permeation+Behavior+of+Orally+Inhaled+Products+Across+Synthetic+Membranes.">The Development and Validation of an In Vitro Airway Model to Assess Realistic Airway Deposition and Drug Permeation Behavior of Orally Inhaled Products Across Synthetic Membranes.</a> Journal of Aerosol Medicine and Pulmonary Drug Delivery. 31 (2), 103-108 (2018).</li><li>Lizal, F., Elcner, J., Hopke, P. K., Jedelsky, J., Jicha, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+of+a+realistic+human+airway+model.">Development of a realistic human airway model.</a> Proceedings of the Institution of Mechanical Engineers, Part H: Journal of Engineering in Medicine. 226 (3), 197-207 (2011).</li><li>Wei, X., Hindle, M., Delvadia, R. R., Byron, P. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+Vitro+Tests+for+Aerosol+Deposition.+V:+Using+Realistic+Testing+to+Estimate+Variations+in+Aerosol+Properties+at+the+Trachea.">In Vitro Tests for Aerosol Deposition. V: Using Realistic Testing to Estimate Variations in Aerosol Properties at the Trachea.</a> Journal of Aerosol Medicine and Pulmonary Drug Delivery. 30 (5), 339-348 (2017).</li><li>Kolewe, E. L., Feng, Y., Fromen, C. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Realizing+Lobe-Specific+Aerosol+Targeting+in+a+3D-Printed+In+Vitro+Lung+Model.">Realizing Lobe-Specific Aerosol Targeting in a 3D-Printed In Vitro Lung Model.</a> Journal of Aerosol Medicine and Pulmonary Drug Delivery. , (2020).</li><li>Sul, B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessing+Airflow+Sensitivity+to+Healthy+and+Diseased+Lung+Conditions+in+a+Computational+Fluid+Dynamics+Model+Validated+In+Vitro.">Assessing Airflow Sensitivity to Healthy and Diseased Lung Conditions in a Computational Fluid Dynamics Model Validated In Vitro.</a> Journal of Biomechanical Engineering. 140 (5), (2018).</li><li>Martonen, T. B., Katz, I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Deposition+Patterns+of+Polydisperse+Aerosols+Within+Human+Lungs.">Deposition Patterns of Polydisperse Aerosols Within Human Lungs.</a> Journal of Aerosol Medicine. 6 (4), 251-274 (1993).</li><li>Nahar, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+vitro,+in+vivo+and+ex+vivo+models+for+studying+particle+deposition+and+drug+absorption+of+inhaled+pharmaceuticals.">In vitro, in vivo and ex vivo models for studying particle deposition and drug absorption of inhaled pharmaceuticals.</a> European Journal of Pharmaceutical Sciences. 49 (5), 805-818 (2013).</li><li>Nichols, S. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+Multi-laboratory+in+Vitro+Study+to+Compare+Data+from+Abbreviated+and+Pharmacopeial+Impactor+Measurements+for+Orally+Inhaled+Products:+a+Report+of+the+European+Aerosol+Group+(EPAG).">A Multi-laboratory in Vitro Study to Compare Data from Abbreviated and Pharmacopeial Impactor Measurements for Orally Inhaled Products: a Report of the European Aerosol Group (EPAG).</a> AAPS PharmSciTech. 17 (6), 1383-1392 (2016).</li><li>Yoshida, H., Kuwana, A., Shibata, H., Izutsu, K. I., Goda, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparison+of+Aerodynamic+Particle+Size+Distribution+Between+a+Next+Generation+Impactor+and+a+Cascade+Impactor+at+a+Range+of+Flow+Rates.">Comparison of Aerodynamic Particle Size Distribution Between a Next Generation Impactor and a Cascade Impactor at a Range of Flow Rates.</a> AAPS PharmSciTech. 18 (3), 646-653 (2017).</li><li>Feng, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=An+in+silico+inter-subject+variability+study+of+extra-thoracic+morphology+effects+on+inhaled+particle+transport+and+deposition.">An in silico inter-subject variability study of extra-thoracic morphology effects on inhaled particle transport and deposition.</a> Journal of Aerosol Science. 123, 185-207 (2018).</li><li>Kleinstreuer, C., Seelecke, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inhaler+system+for+targeted+maximum+drug-aerosol+delivery.">Inhaler system for targeted maximum drug-aerosol delivery.</a> United States patent. , (2005).</li><li>. How Medical 3D Printing is Gaining Ground in Top Hospitals Available from: <a target="_blank" href="https://www.materialise.com/en/blog/3d-printing-hospitals">https://www.materialise.com/en/blog/3d-printing-hospitals</a> (2019)</li><li>Weber, P. W., Price, O. T., McClellan, G. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Demographic+Variability+of+Inhalation+Mechanics:+A+Review.">Demographic Variability of Inhalation Mechanics: A Review.</a> Defense Threat Reduction Agency. , (2016).</li><li>Jiang, Y. Y., Xu, X., Su, H. L., Liu, D. X. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gender-related+difference+in+the+upper+airway+dimensions+and+hyoid+bone+position+in+Chinese+Han+children+and+adolescents+aged+6-18+years+using+cone+beam+computed+tomography.">Gender-related difference in the upper airway dimensions and hyoid bone position in Chinese Han children and adolescents aged 6-18 years using cone beam computed tomography.</a> Acta Odontologica Scandinavica. 73 (5), 391-400 (2015).</li><li>Martin, S. E., Mathur, R., Marshall, I., Douglas, N. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+effect+of+age,+sex,+obesity+and+posture+on+upper+airway+size.">The effect of age, sex, obesity and posture on upper airway size.</a> European Respiratory Journal. 10 (9), 2087 (1997).</li><li>Xi, J., Longest, P. W., Martonen, T. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+the+laryngeal+jet+on+nano-+and+microparticle+transport+and+deposition+in+an+approximate+model+of+the+upper+tracheobronchial+airways.">Effects of the laryngeal jet on nano- and microparticle transport and deposition in an approximate model of the upper tracheobronchial airways.</a> Journal of Applied Physiology. 104 (6), 1761-1777 (2008).</li><li>Zhao, J., Feng, Y., Fromen, C. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Glottis+motion+effects+on+the+particle+transport+and+deposition+in+a+subject-specific+mouth-to-trachea+model:+A+CFPD+study.">Glottis motion effects on the particle transport and deposition in a subject-specific mouth-to-trachea model: A CFPD study.</a> Computers in Biology and Medicine. 116, 103532 (2020).</li><li>Kim, S. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chronic+obstructive+pulmonary+disease:+lobe-based+visual+assessment+of+volumetric+CT+by+Using+standard+images--comparison+with+quantitative+CT+and+pulmonary+function+test+in+the+COPDGene+study.">Chronic obstructive pulmonary disease: lobe-based visual assessment of volumetric CT by Using standard images--comparison with quantitative CT and pulmonary function test in the COPDGene study.</a> Radiology. 266 (2), 626-635 (2013).</li><li>. The Cancer Imaging Archive Available from: <a target="_blank" href="https://www.cancerimagingarchive.net/">https://www.cancerimagingarchive.net/</a> (2020)</li><li>Li, A., Ahmadi, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Computer+Simulation+of+Deposition+of+Aerosols+in+a+Turbulent+Channel+Flow+with+Rough+Walls.">Computer Simulation of Deposition of Aerosols in a Turbulent Channel Flow with Rough Walls.</a> Aerosol Science and Technology. 18 (1), 11-24 (1993).</li><li>Khalili, S. F., Ghanbarzadeh, S., Nokhodchi, A., Hamishehkar, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+effect+of+different+coating+materials+on+the+prevention+of+powder+bounce+in+the+next+generation+impactor.">The effect of different coating materials on the prevention of powder bounce in the next generation impactor.</a> Research in Pharmaceutical Sciences. 13 (3), 283-287 (2018).</li><li>Galliger, Z., Vogt, C. D., Panoskaltsis-Mortari, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=3D+bioprinting+for+lungs+and+hollow+organs.">3D bioprinting for lungs and hollow organs.</a> Translational Research. 211, 19-34 (2019).</li><li>Schwarz, K., Biller, H., Windt, H., Koch, W., Hohlfeld, J. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Characterization+of+exhaled+particles+from+the+healthy+human+lung--a+systematic+analysis+in+relation+to+pulmonary+function+variables.">Characterization of exhaled particles from the healthy human lung--a systematic analysis in relation to pulmonary function variables.</a> Journal of Aerosol Medicine and Pulmonary Drug Delivery. 23 (6), 371-379 (2010).</li><li>Patton, J. S., Byron, P. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inhaling+medicines:+delivering+drugs+to+the+body+through+the+lungs.">Inhaling medicines: delivering drugs to the body through the lungs.</a> Nature Reviews Drug Discovery. 6 (1), 67-74 (2007).</li><li>Zhang, Z., Kleinstreuer, C., Kim, C. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cyclic+micron-size+particle+inhalation+and+deposition+in+a+triple+bifurcation+lung+airway+model.">Cyclic micron-size particle inhalation and deposition in a triple bifurcation lung airway model.</a> Journal of Aerosol Science. 33 (2), 257-281 (2002).</li><li>Ju, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Engineering+of+Nebulized+Metal-Phenolic+Capsules+for+Controlled+Pulmonary+Deposition.">Engineering of Nebulized Metal-Phenolic Capsules for Controlled Pulmonary Deposition.</a> Advanced Science. 7 (6), 1902650 (2020).</li></ol>

L'attuale dispositivo all'avanguardia per il test farmaceutico polmonare di una dose completa di inalazione è il Next Generator Impactor (NGI), che misura il diametro aerodinamico di un aerosol4. Questi dati di dimensionamento vengono quindi utilizzati per prevedere la generazione polmonare in cui l'aerosol si depositerà sulla base di una correlazione sviluppata per un maschio adultosano 11. Sfortunatamente, questo metodo è limitato nella sua capacità di valutare le dif...

Molte malattie polmonari come il cancro ai polmoni e la broncopneumopatia cronica ostruttiva (BPCO) presentano differenze regionali nelle caratteristiche della malattia; tuttavia, mancano tecniche terapeutiche disponibili per indirizzare la somministrazione di farmaci solo alle regioni masmato del polmone1. Molteplici modelli di fluidodinamica computazionale (CFD) hanno dimostrato che è possibile modulare i profili di deposizione dei farmaci identificando specifiche snellenel polmone 2,3. Nello stesso laboratorio sono in corso lo sviluppo di inalatori e adattatori per tubi endotracheali (ET) con capacità di targeting regionali per controllare la distribuzione di aerosol nelle regioni polmonari mante. L'estensione di questi principi all'uso clinico è limitata dall'attuale capacità di test preclinici. La posizione precisa in cui un farmaco si deposita all'interno del polmone è nota per essere il miglior predittore di efficacia; tuttavia, le attuali valutazioni farmaceutiche delle terapie inalabili sono più spesso previste utilizzando correlazioni in vitro-in vivo della dimensione delle particelle per approssimare semplicemente la deposizione4. Questa tecnica non consente alcuna analisi spaziale per determinare gli effetti delle diverse geometrie delle vie aeree sulla distribuzione regionale attraverso i vari lobi del polmone. Inoltre, questo test manca di geometrie polmonari anatomicamente accurate, che i ricercatori hanno dimostrato possono avere un impatto significativo sui profili di deposizione5. Sono stati compiuti alcuni sforzi per incorporare geometrie polmonari specifiche del paziente nei protocolli di prova attraverso l'aggiunta delle vie aeree superiori; tuttavia, la maggior parte di questi approcci campiona l'erogazione di aerosol a varie generazioni del polmone piuttosto che a ciascun lobopolmonare 6,7,8. Il seguente protocollo presenta un metodo ad alta produttività per generare modelli polmonari specifici del paziente con la capacità di quantificare la deposizione relativa di particelle in ciascuno dei cinque lobi delpolmone 9.
I polmoni modello anatomicamente accurati sono generati dalla stampa 3D di scansioni di tomografia computerizzata (CT) del paziente. Se utilizzate in combinazione con un sistema di flusso facilmente assemblabile, le portate relative attraverso ciascuno dei lobi del polmone modello possono essere controllate in modo indipendente e su misura per imitare quelle di diversi stati demografici e / o di malattia del paziente. Con questo metodo, i ricercatori possono testare l'efficacia di potenziali metodi terapeutici in una geometria polmonare rilevante e correlare le prestazioni di ogni metodo con la progressione della morfologia masabile. Qui, due progetti di dispositivi sviluppati nel nostro laboratorio vengono testati per la loro capacità di aumentare la deposizione in un lobo polmonare desiderato controllando la posizione del rilascio di aerosol in bocca o trachea. Questo protocollo ha anche il potenziale per influire in modo significativo sullo sviluppo di procedure personalizzate per i pazienti facilitando la rapida previsione dell'efficacia del trattamento in un polmone modello specifico per i dati di TAC di quel paziente.

<table>
	<tbody>
		<tr>
			<td>1/4&#34; Plastic Barbed Tube Fitting</td>
			<td>McMaster Carr</td>
			<td>5372K111</td>
			<td></td>
		</tr>
		<tr>
			<td>10 um Filter Paper</td>
			<td>Fisher</td>
			<td>1093-110</td>
			<td></td>
		</tr>
		<tr>
			<td>1um Fluorescent Polystyrene Particles</td>
			<td>Polysciences</td>
			<td>15702-10</td>
			<td></td>
		</tr>
		<tr>
			<td>1um Non-Fluorescent Polystyrene Particles</td>
			<td>Polysciences</td>
			<td>8226</td>
			<td></td>
		</tr>
		<tr>
			<td>2-Propanol</td>
			<td>Fisher</td>
			<td>A516-4</td>
			<td>Referred to in protocol as &#34;IPA&#34;</td>
		</tr>
		<tr>
			<td>3/8&#34; Plastic Barbed Tube Fitting</td>
			<td>McMaster Carr</td>
			<td>5372K117</td>
			<td></td>
		</tr>
		<tr>
			<td>Air Flow Meter (1 - 280 mL/min)</td>
			<td>McMaster Carr</td>
			<td>41695K32</td>
			<td>Referred to in protocol as &#34;flow meter&#34;</td>
		</tr>
		<tr>
			<td>Carbon M1 3D Printer</td>
			<td>Carbon 3D</td>
			<td></td>
			<td>https://www.carbon3d.com/, Associated software referred to in protocol as &#34;slicing software&#34;</td>
		</tr>
		<tr>
			<td>Collison Jet Nebulizer</td>
			<td>CH Technologies</td>
			<td>ARGCNB0008 (CN-25)</td>
			<td>6 Jet MRE style horizontal collision with glass jar, Referred to in protocol as &#34;nebulizer&#34;, http://chtechusa.com/Manuals/MRE_Collison_Manual.pdf</td>
		</tr>
		<tr>
			<td>Convection Oven</td>
			<td>Yamato</td>
			<td>DKN602</td>
			<td></td>
		</tr>
		<tr>
			<td>Copley Critical Flow Controller TPK2000 Reve 120V</td>
			<td>MSP Corp</td>
			<td>0001-01-9810</td>
			<td>Referred to in protocol as &#34;flow controller&#34;</td>
		</tr>
		<tr>
			<td>Copley High Capacity Pump Model HCP5</td>
			<td>MSP Corp</td>
			<td>0001-01-9982</td>
			<td>Referred to in protocol as &#34;vacuum pump&#34;</td>
		</tr>
		<tr>
			<td>Cytation</td>
			<td>BioTek</td>
			<td>CYT5MPV</td>
			<td>Multifunctional Spectrophotometer/Fluorescent imager equiped with 4x/20x/40x objectives and DAPI/GFP/TexasRed laser/filter cubes</td>
		</tr>
		<tr>
			<td>EPU40 Resin</td>
			<td>Carbon 3D</td>
			<td></td>
			<td>https://www.carbon3d.com/materials/epu-elastomeric-polyurethane/, Referred to in protocol as &#34;soft resin&#34;</td>
		</tr>
		<tr>
			<td>Filter for vacuum pump</td>
			<td>Whatman</td>
			<td>6722-5000</td>
			<td></td>
		</tr>
		<tr>
			<td>Flow Meter Model DFM 2000</td>
			<td>MSP Corp</td>
			<td>0001-01-8764</td>
			<td>Referred to in protocol as &#34;electronic flow meter&#34;</td>
		</tr>
		<tr>
			<td>ImageJ Software</td>
			<td>ImageJ</td>
			<td></td>
			<td>https://imagej.nih.gov/ij/download.html</td>
		</tr>
		<tr>
			<td>Inline Air Flow Control Valve (Push-to-Connect)</td>
			<td>McMaster Carr</td>
			<td>62005K333</td>
			<td>Referred to in protocol as &#34;valve&#34;</td>
		</tr>
		<tr>
			<td>Inline Filter Devices</td>
			<td>Whatman</td>
			<td>WHA67225000</td>
			<td></td>
		</tr>
		<tr>
			<td>Marine-Grade Plywood Sheet</td>
			<td>McMaster Carr</td>
			<td>62005K333</td>
			<td>Referred to in protocol as &#34;wooden board&#34;</td>
		</tr>
		<tr>
			<td>Materialise Mimics Software</td>
			<td>Materialise</td>
			<td></td>
			<td>https://www.materialise.com/en/medical/mimics-innovation-suite, Referred to in protocol as &#34;CT scan software&#34;</td>
		</tr>
		<tr>
			<td>Meshmixer Software</td>
			<td>Autodesk</td>
			<td></td>
			<td>http://www.meshmixer.com/, Referred to in protocol as &#34;mesh editing software&#34;</td>
		</tr>
		<tr>
			<td>Methanol</td>
			<td>Fisher</td>
			<td>A454-4</td>
			<td></td>
		</tr>
		<tr>
			<td>Opticure LED Cube</td>
			<td>APM Technica</td>
			<td>102843</td>
			<td>Referred to in protocol as &#34;UV oven&#34;</td>
		</tr>
		<tr>
			<td>PR25 Resin</td>
			<td>Carbon 3D</td>
			<td></td>
			<td>https://www.carbon3d.com/materials/uma-urethanemethacrylate, /Referred to in protocol as &#34;hard resin&#34;</td>
		</tr>
		<tr>
			<td>PVC Tube for Chemicals</td>
			<td>McMaster Carr</td>
			<td>5231K161</td>
			<td>1/4&#34; ID</td>
		</tr>
		<tr>
			<td>Screws</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>SolidWorks Software</td>
			<td>Dassault Syst&#232;mes&#160;SolidWorks Corporation</td>
			<td></td>
			<td>https://www.solidworks.com/, Referred to in protocol as &#34;3D modeling software&#34;</td>
		</tr>
		<tr>
			<td>Straight Flow Rectangular Manifold</td>
			<td>McMaster Carr</td>
			<td>1125T31</td>
			<td></td>
		</tr>
		<tr>
			<td>Tubing to Flow Controller</td>
			<td>McMaster Carr</td>
			<td>5233K65</td>
			<td>3/8&#34; ID</td>
		</tr>
		<tr>
			<td>Wire</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

evaluating regional pulmonary deposition using patient-specific 3d printed lung models

Lo sviluppo di terapie mirate per le malattie polmonari è limitato dalla disponibilità di metodi di test preclinici con la capacità di prevedere l'erogazione regionale di aerosol. Sfruttando la stampa 3D per generare modelli polmonari specifici del paziente, descriviamo la progettazione di una configurazione sperimentale in vitro ad alta produttività per quantificare la deposizione polmonare lobulare. Questo sistema è realizzato con una combinazione di componenti stampati in commercio e stampati in 3D e consente di controllare in modo indipendente la portata attraverso ogni lobo del polmone. La consegna di aerosol fluorescenti a ciascun lobo viene misurata utilizzando la microscopia a fluorescenza. Questo protocollo ha il potenziale per promuovere la crescita della medicina personalizzata per le malattie respiratorie attraverso la sua capacità di modellare una vasta gamma di dati demografici dei pazienti e stati di malattia. Sia la geometria del modello polmonare stampato in 3D che l'impostazione del profilo del flusso d'aria possono essere facilmente modulate per riflettere i dati clinici per pazienti con età, razza e sesso variabili. I dispositivi di somministrazione dei farmaci clinicamente rilevanti, come il tubo endotracheale mostrato qui, possono essere incorporati nella configurazione del test per prevedere in modo più accurato la capacità di un dispositivo di indirizzare l'erogazione terapeutica in una regione masabile del polmone. La versatilità di questa configurazione sperimentale permette di personalizzarla per riflettere una moltitudine di condizioni di inalazione, esaltando il rigore dei test terapeutici preclinici.

Particelle in questo intervallo di dimensioni (1-5 μm) e condizioni di flusso (1-10 L/min) seguono le linee del flusso fluido in base sia al loro numero teorico di Stokes che ai dati in vivo; pertanto, in assenza di un dispositivo di consegna mirato, le particelle rilasciate nel modello polmonare dovrebbero depositarsi in base alla percentuale del flusso d'aria totale dirottato su ciascun lobo. Le quantità relative di consegna di particelle a ciascun lobo possono quindi essere confrontate con i dati clinici sulla porta...

Watch this Scientific Journal Video about Evaluating Regional Pulmonary Deposition using Patient-Specific 3D Printed Lung Models at JoVE.com

Evaluating Regional Pulmonary Deposition using Patient-Specific 3D Printed Lung Models

Presentiamo un metodo in vitro ad alta produttività per quantificare la deposizione polmonare regionale a livello di lobo utilizzando modelli polmonari stampati in 3D derivati dalla TAC con profili di flusso d'aria tonnibili.

Valutazione della deposizione polmonare regionale utilizzando modelli polmonari stampati in 3D specifici del paziente

Development of targeted therapies for pulmonary diseases is limited by the availability of preclinical testing methods with the ability to predict ...

This protocol has the potential to drive the development of new targeted pulmonary therapeutics by enabling the pre-clinical predictions of regional deposition. This technique incorporates anatomically accurate lung models, 3D printed from patient's CT scans for the rapid generation of personalized predictive results regarding the efficacy of potential treatments. This technique can be used to develop targeted therapies that minimize off target effects for diseases that are characterized by regional area obstructions such as lung cancer or COPD.After printing the experimental components and completing post-processing as per the manufacturer's instructions, carefully wash the parts printed in soft resin with at least 99%purity isopropyl alcohol to remove any excess uncured resin before thermal curing the parts in a convection oven for eight hours according to the manufacturer's specifications. Then, wash the parts printed in hard resin with the alcohol to remove any excess uncured resin and cure the parts in a UV oven for one minute per side. For lobe outlet cap assembly, insert one end of the oval barbed tubing connection base into the cap before carefully stretching the flexible cap over the other end of the oval base, taking special care not to crack the thin base and with the nozzle protruding through the opening in the cap base.Next, cut 10 microliter filter paper to a size slightly larger than the outlet area and fold the filter paper over the lobe outlet, holding the paper in place with one hand. Then use tweezers in the other hand, to stretch the cap with the barbed tubing connection over the outlet and press the cap down until the notch matches the corresponding notch on the lobe outlet. Before each experimental run, connect each lung model lobe outlet to the tubing of the corresponding flow meter and valve taking care not to apply too much lateral pressure to the barbed tubing connection.Attach the electronic flow meter to the lung model mouth inlet to measure the total airflow rate to the lung model and turn on the flow controller and vacuum pump. In the flow controller, select the test setup setting and slowly increase the flow rate until the electronic flow meter displays the desired total flow rate. Use the valves to adjust the flow rate through the right upper, right middle, right lower, left upper and left lower lung lobes.Once the load flow rates shown on the flow meters are steady at the desired value, check the overall flow rate again on the electronic flow meter to verify that there are no leaks in the system. Then, exit the test setup in the flow controller leaving the vacuum pump on. For aerosol delivery to the lung model, fill a nebulizer with a solution of the desired fluorescent particles and connect the nebulizer to the lung model inlet.To measure the efficacy of the targeting device, insert the device into the lung model and connect the nebulizer to the device. Connect the compressed airline to the nebulizer. Set the flow controller to run for one ten second trial and open the compressed air valve slightly to begin generating an aerosol within the nebulizer.Press start on the flow controller and immediately open the compressed air valve fully. When the flow controller reaches about nine seconds, begin closing the compressed air valve and close the fume hood sash as much as possible. Once the valve is fully closed, disconnect the nebulizer from the compressed airline.Fully close the fume hood sash, shut off the vacuum pump and let any aerosols clear from the fume hood. After about 10 minutes, disconnect the lung model from the tubing system, taking care not to crack the barbed tubing connections and run a pair of tweezers under the edge of each lobe outlet cap to remove the caps from the outlets. Then transfer the filter paper from each cap into individual wells of a 24-well plate particle depositions side down.When all of the filter paper has been collected, place the plate onto the stage of a digital fluorescence microscope and set the microscope to a 4X magnification and the appropriate fluorescence channel. Then take at least three images of the filter paper from each lobe at random locations and save the images as TIF files. Under one liter per minute collection conditions in a healthy lung, ended along effected by COPD, the experimentally determined deposition profile is not statistically different from the clinical data demonstrating that the setup accurately mimics the distribution of air flow to each of the lung lobes.Compared to the non-targeted particle deposition profile, the use of a modified endotracheal tube generates a nearly four fold increase in left lower lobe delivery. In addition to diverting over 96%of the delivered particles to the left lung. Altering the release location setting to target the right lower lobe, this device generates more than double the particle delivery to the right lobe and diverts 94%of the delivered particles to the right lung.Compared to the non-targeted particle deposition profile, the concentric cylinder device causes a nearly three fold increase in left upper lobe delivery in addition to diverting over 87%of the delivered particles to the left lung. Targeting efficiency can also be observed qualitatively by comparing the images of the target lobe filter to the other outlet filters. As illustrated, the most effective targeting method will yield a high particle deposition at the intended lobe of interest and a low deposition at the remaining lobe outlets.It is essential to make sure that components are properly connected to prevent leaks within the system as leaks will impact deposition results. This protocol permits researchers to test potential drug delivery devices for targeting specific regions of the lung prior to clinical trials reducing the cost associated with drug development and efficacy enhancement in human patients.

Research

JoVE Journal

Bioengineering

Patient-specific Modeling of the Heart: Estimation of Ventricular Fiber Orientations

Paziente-specifica modellazione del Cuore: Stima di orientamento delle fibre ventricolari

Patient-specific  simulations of heart (dys)function aimed at personalizing cardiac therapy are hampered  by the absence of in vivo imaging technology for ...

Ricerca

Bioingegneria

Rapid and Low-cost Prototyping of Medical Devices Using 3D Printed Molds for Liquid Injection Molding

Rapida e basso costo Prototipazione di dispositivi medici che usano 3D Stampo Stampato per stampaggio ad iniezione Liquid

Biologically inert elastomers such as silicone are favorable materials for medical device fabrication, but forming and curing these elastomers using ...

Improving 2D and 3D Skin In Vitro Models Using Macromolecular Crowding

Improving 2D and 3D Skin In Vitro Models Using Macromolecular Crowding

Migliorare 2D e 3D della pelle<em&gt; In Vitro</em&gt; modelli con Macromolecole affollamento

The glycoprotein family of collagens represents the main structural proteins in the human body, and are key components of biomaterials used in modern ...

Scaling of Engineered Vascular Grafts Using 3D Printed Guides and the Ring Stacking Method

Scaling di Engineered vascolari innesti Usando 3D Stampato Guide e il metodo di impilamento Anello

Coronary artery disease remains a leading cause of death, affecting millions of Americans. With the lack of autologous vascular grafts available, ...

Fabrication of Custom Agarose Wells for Cell Seeding and Tissue Ring Self-assembly Using 3D-Printed Molds

Fabbricazione di pozzi di agarosio personalizzato per la semina delle cellule e tessuto anello auto-assemblaggio utilizzando stampi 3D-stampato

Engineered tissues are being used clinically for tissue repair and replacement, and are being developed as tools for drug screening and human disease ...

Targeting Neuronal Fiber Tracts for Deep Brain Stimulation Therapy Using Interactive, Patient-Specific Models

Tratti della fibra di un neurone di targeting per la terapia di stimolazione cerebrale profonda utilizzando modelli interattivi, specifico per ogni paziente

Deep brain stimulation (DBS), which involves insertion of an electrode to deliver stimulation to a localized brain region, is an established therapy for ...

High-resolution Patterned Biofilm Deposition Using pDawn-Ag43

Alta risoluzione svevapacifico modellato mediante deposizione di Biofilm-Ag43

Spatial structure and patterning play an important role in bacterial biofilms. Here we demonstrate an accessible method for culturing E. coli biofilms ...

3D Printed Porous Cellulose Nanocomposite Hydrogel Scaffolds

3D stampato cellulosa porosa dell'idrogelo Nanocomposite ponteggi

This work demonstrates the use of three-dimensional (3D) printing to produce porous cubic scaffolds using cellulose nanocomposite hydrogel ink, with ...

3D Cell-Printed Hypoxic Cancer-on-a-Chip for Recapitulating Pathologic Progression of Solid Cancer

Cancro ipossia stampato in cellule 3D su chip per ricapitolare la progressione patologica del cancro solido

Cancer microenvironment has a significant impact on the progression of the disease. In particular, hypoxia is the key driver of cancer survival, invasion, ...

Creation of Patient-Specific Silicone Cardiac Models with Applications in Pre-surgical Plans and Hands-on Training

Creazione di modelli cardiaci in silicone specifici per il paziente con applicazioni in piani pre-chirurgici e formazione pratica

Three dimensional&#160;models can be a valuable tool for surgeons as they develop surgical plans and medical fellows as they learn about complex cases. In ...