Evaluering af regional lungeaflejring ved hjælp af patientspecifikke 3D-printede lungemodeller
Summary
Vi præsenterer en high-throughput, in vitro metode til kvantificering regionale lungeaflejring på lobe niveau ved hjælp af CT-scanning-afledte, 3D trykte lunge modeller med tunable luftstrøm profiler.
Abstract
Udviklingen af målrettede behandlingsformer for lungesygdomme er begrænset af tilgængeligheden af prækliniske testmetoder med evnen til at forudsige regional aerosollevering. Ved at udnytte 3D-udskrivning til at generere patientspecifikke lungemodeller skitserer vi designet af en høj gennemløbshastighed, in vitro eksperimentel opsætning til kvantificering af lobulær lungeaflejring. Dette system er lavet med en kombination af kommercielt tilgængelige og 3D-trykte komponenter og gør det muligt at styre strømningshastigheden gennem hver lap af lungen uafhængigt. Levering af fluorescerende aerosoler til hver lap måles ved hjælp af fluorescensmikroskopi. Denne protokol har potentiale til at fremme væksten af personlig medicin til luftvejssygdomme gennem sin evne til at modellere en bred vifte af patientdemografi og sygdomstilstande. Både geometrien i den 3D-printede lungemodel og indstillingen for luftstrømsprofilen kan let moduleres for at afspejle kliniske data for patienter med forskellig alder, race og køn. Klinisk relevante lægemiddelleveringsenheder, såsom det endotrachealrør, der vises her, kan indarbejdes i testopsætningen for mere præcist at forudsige en enheds evne til at målrette terapeutisk levering til en syg region i lungerne. Alsidigheden i denne eksperimentelle opsætning gør det muligt at tilpasse den til at afspejle et væld af indåndingsforhold, hvilket forbedrer strengheden af præklinisk terapeutisk testning.
Introduction
Mange lungesygdomme som lungekræft og kronisk obstruktiv lungesygdom (KOL) udviser regionale forskelle i sygdomskarakteristika; der er dog mangel på terapeutiske teknikker til rådighed til at målrette lægemiddellevering til kun syge regioner i lungerne1. Flere CFD-modeller (Computational Fluid Dynamic) har vist , at det er muligt at modulere narkotikadepositionsprofiler ved at identificere specifikke strømlinjer i lungerne2,3. Udvikling af både inhalatorer og endotracheal (ET) røradaptere med regionale målretningskapaciteter er i gang i vores laboratorium for at kontrollere aerosolfordeling til syge lungeregioner. Udvidelsen af disse principper til klinisk brug er begrænset af den nuværende prækliniske testkapacitet. Den nøjagtige placering et lægemiddel indskud i lungerne er kendt for at være den bedste prædiktor for effekt; de nuværende lægemiddelvurderinger af inhalerbar behandling forudsiges dog oftest ved hjælp af in vitro-in vivo-korrelationer af partikelstørrelse til blot omtrentlig deposition4. Denne teknik giver ikke mulighed for nogen rumlig analyse for at bestemme virkningerne af forskellige luftvejsgeometrier på den regionale fordeling gennem de forskellige lapper i lungerne. Derudover mangler denne test anatomisk nøjagtige lungegeometrier, som forskere har vist kan have en betydelig indvirkning på depositionsprofiler5. Der er gjort en vis indsats for at indarbejde patientspecifikke lungegeometrier i testprotokollerne gennem tilsætning af de øvre luftveje; men de fleste af disse metoder prøve aerosol levering til forskellige generationer af lungerne i stedet for hver lunge lap6,7,8. Følgende protokol præsenterer en høj gennemløbsmetode til generering af patientspecifikke lungemodeller med kapacitet til at kvantificere relativ partikelaflejring i hver af de fem lapper i lungerne9.
Anatomisk nøjagtige model lunger er genereret af 3D-udskrivning patient computertomografi (CT) scanninger. Når det bruges sammen med en let samlet flow system, den relative strømningshastigheder gennem hver af modellen lunges lapper kan uafhængigt kontrolleres og skræddersyet til at efterligne dem af forskellige patient demografi og / eller sygdomstilstande. Med denne metode kan forskere teste effekten af potentielle terapeutiske metoder i en relevant lungegeometri og korrelere hver metodes ydeevne med udviklingen af syge morfologi. Her testes to enhedsdesign udviklet i vores laboratorium for deres evne til at øge depositionen i en ønsket lungelap ved at kontrollere placeringen af aerosoludslip i munden eller luftrøret. Denne protokol har også potentiale til at påvirke udviklingen af personlige procedurer for patienter betydeligt ved at lette den hurtige forudsigelse af behandlingseffektiviteten i en model lunge, der er specifik for den pågældende patients CT-scanningsdata.
Protocol
Representative Results
Discussion
Den nuværende state-of-the-art enhed til lungelægetest af en komplet indåndingsdosis er Next Generator Impactor (NGI), som måler den aerodynamiske diameter af en aerosol4. Denne dimensionering data bruges derefter til at forudsige lunge generation, hvor aerosolen vil deponere baseret på en korrelation udviklet til en sund voksen mand11. Desværre er denne metode begrænset i sin evne til at vurdere forskelle i regionale lungeaflejring, bestemme virkningerne af sygdomst…
Disclosures
The authors have nothing to disclose.
Acknowledgements
Forfatterne takker professor Yu Feng, Dr. Jenna Briddell, Ian Woodward, og Lucas Attia for deres nyttige diskussioner.
Materials
| 1/4" Plastic Barbed Tube Fitting | McMaster Carr | 5372K111 | |
| 10 um Filter Paper | Fisher | 1093-110 | |
| 1um Fluorescent Polystyrene Particles | Polysciences | 15702-10 | |
| 1um Non-Fluorescent Polystyrene Particles | Polysciences | 8226 | |
| 2-Propanol | Fisher | A516-4 | Referred to in protocol as "IPA" |
| 3/8" Plastic Barbed Tube Fitting | McMaster Carr | 5372K117 | |
| Air Flow Meter (1 – 280 mL/min) | McMaster Carr | 41695K32 | Referred to in protocol as "flow meter" |
| Carbon M1 3D Printer | Carbon 3D | https://www.carbon3d.com/, Associated software referred to in protocol as "slicing software" | |
| Collison Jet Nebulizer | CH Technologies | ARGCNB0008 (CN-25) | 6 Jet MRE style horizontal collision with glass jar, Referred to in protocol as "nebulizer", http://chtechusa.com/Manuals/MRE_Collison_Manual.pdf |
| Convection Oven | Yamato | DKN602 | |
| Copley Critical Flow Controller TPK2000 Reve 120V | MSP Corp | 0001-01-9810 | Referred to in protocol as "flow controller" |
| Copley High Capacity Pump Model HCP5 | MSP Corp | 0001-01-9982 | Referred to in protocol as "vacuum pump" |
| Cytation | BioTek | CYT5MPV | Multifunctional Spectrophotometer/Fluorescent imager equiped with 4x/20x/40x objectives and DAPI/GFP/TexasRed laser/filter cubes |
| EPU40 Resin | Carbon 3D | https://www.carbon3d.com/materials/epu-elastomeric-polyurethane/, Referred to in protocol as "soft resin" | |
| Filter for vacuum pump | Whatman | 6722-5000 | |
| Flow Meter Model DFM 2000 | MSP Corp | 0001-01-8764 | Referred to in protocol as "electronic flow meter" |
| ImageJ Software | ImageJ | https://imagej.nih.gov/ij/download.html | |
| Inline Air Flow Control Valve (Push-to-Connect) | McMaster Carr | 62005K333 | Referred to in protocol as "valve" |
| Inline Filter Devices | Whatman | WHA67225000 | |
| Marine-Grade Plywood Sheet | McMaster Carr | 62005K333 | Referred to in protocol as "wooden board" |
| Materialise Mimics Software | Materialise | https://www.materialise.com/en/medical/mimics-innovation-suite, Referred to in protocol as "CT scan software" | |
| Meshmixer Software | Autodesk | http://www.meshmixer.com/, Referred to in protocol as "mesh editing software" | |
| Methanol | Fisher | A454-4 | |
| Opticure LED Cube | APM Technica | 102843 | Referred to in protocol as "UV oven" |
| PR25 Resin | Carbon 3D | https://www.carbon3d.com/materials/uma-urethanemethacrylate, /Referred to in protocol as "hard resin" | |
| PVC Tube for Chemicals | McMaster Carr | 5231K161 | 1/4" ID |
| Screws | |||
| SolidWorks Software | Dassault Systèmes SolidWorks Corporation | https://www.solidworks.com/, Referred to in protocol as "3D modeling software" | |
| Straight Flow Rectangular Manifold | McMaster Carr | 1125T31 | |
| Tubing to Flow Controller | McMaster Carr | 5233K65 | 3/8" ID |
| Wire |
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