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Micro Swirl-Nozzle Enables Portable Delivery ofLarge-Molecule Biopharmaceuticals to the Lung
KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Micro and Nanosystems.ORCID iD: 0000-0001-9947-5011
Karolinska Institute.ORCID iD: 0000-0003-0163-2678
KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Micro and Nanosystems.
KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Micro and Nanosystems.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Large-molecule pharmaceuticals offer new treatment options for severe lung disease. However, delivering these drugs to the lung is challenging due to the elevated shear rates during the aerosolization process. So far, this has prevented an application in portable inhalers, holding back the portable use of biopharmaceuticals for drug delivery. We demonstrate that a micro swirl nozzle can aerosolize fragile biopharmaceuticals in an aqueous solution. Shear rate simulations of the nozzle unit indicate orders of magnitude in shear rate reduction compared with conventional aqueous aerosolization units. Catalase protein can survive the aerosolization process at up to 50 bar without significant degradation. The protein further remains enzymatically active after the spray event.

Using an in-vitro model, we present the delivery of more complex and fragile mRNA structures (Nanoluc mRNA) at high concentrations when encapsulated in solid lipid nanoparticles (LNPs) or Extracellular vesicles (EVs). These vesicles maintain their capability to pass the cell wall in in-vitro cell cultures, leading to an expression of the encapsulated protein structure within the celll. Micro swirl nozzles can enable the portable delivery of large molecule pharmaceuticals and bring new treatment options to patients who have so far had to rely on stationary devices.

Keywords [en]
Swirl nozzle, Aerosolization, LNPs, transport vesicles, large-molecule pharmaceutics
National Category
Medical Engineering
Research subject
Applied Medical Technology
Identifiers
URN: urn:nbn:se:kth:diva-320163OAI: oai:DiVA.org:kth-320163DiVA, id: diva2:1703855
Note

QC 20221018

Available from: 2022-10-14 Created: 2022-10-14 Last updated: 2022-10-18Bibliographically approved
In thesis
1. Advancing portable, aqueous drug delivery to the human lung
Open this publication in new window or tab >>Advancing portable, aqueous drug delivery to the human lung
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lung disease profoundly impacts human health: many lung diseases are currently without cure and require continued treatment. Due to their ease of use and integration into the daily routine, portable inhalers are the preferred treatment option for patients. Efforts to replace greenhouse-gas active portable inhalers have led to portable aqueous systems, so-called Soft mist inhalers (SMIs). However, compared to propellant-driven systems on the market, SMI aerosolization units still face drawbacks in their pathogenic safety, have a big silicon footprint, and must be manufactured in cleanroom environments. Three different types of spray nozzle were developed in this thesis, that improve upon the state of the art in pathogenic safety, fabrication cost, and aerosolization performance. For the first time, a novel 3D-printed, monolithic Swirl nozzle allows the fabrication of such an aerosolization unit outside a cleanroom environment. This device further enables the soft aerosolization of fragile and shear-sensitive large molecule pharmaceutics. A new approach to handling and packaging silicon MEMS allowed the demonstration of the world’s smallest aqueous spray nozzle for portable inhalers with a silicon footprint of just 1/6 of a square millimeter. Improving upon the lacking pathogenic safety of SMI devices, a valved spray nozzle was developed that effectively seals the inhalation unit at nozzle level against pathogenic ingrowth of motile enteric bacteria.

These developments may enable environmentally friendly SMIs to improve the treatment of a broad range of lung diseases.

Abstract [sv]

Lungsjukdom har en enorm påverkan på människors hälsa: många lungsjukdomar saknar för närvarande botemedel och kräver kontinuerlig behandling. På grund av att de är enkla att använda och integrera i den dagliga rutinen är bärbara inhalatorer det föredragna behandlingsalternativet för patienter. Försök att ersätta bärbara inhalatorer som släpper ut växthusgaser har lett till bärbara vattenbaserade system, så kallade soft mist-inhalatorer (SMI). Jämfört med drivmedelsdrivna system på marknaden har enhe- ter för SMI-aerosolisering dock fortfarande nackdelar i sin patogena säkerhet, har ett stort kiselfotavtryck och måste tillverkas i renrumsmiljöer. Tre olika typer av sprutmunstycken utvecklades i denna avhandling, som förbättrar den senaste tekniken vad gäller patogen säkerhet, tillverkningskostnad och aerosoliseringsprestanda. För första gången möjliggör ett nytt 3D-printat, monolitiskt virvelmunstycke tillverkning av en sådan aerosoliseringsenhet utanför en renrumsmiljö. Denna anordning möjliggör mjuk aerosolisering av ömtåliga och skjuvkänsliga läkemedel med stora molekyler. Ett nytt tillvägagångssätt för hantering och för- packning av kisel MEMS möjliggjorde demonstrationen av världens minsta vattenbaserade spraymunstycke för bärbara inhalatorer med ett kiselfotavtryck på bara 1/6 av en kvadratmillimeter. För att förbättra den bristande patogena säkerheten hos SMI-enheter, utvecklades ett ventilförsett spraymunstycke som effektivt tätar inhalationsenheten på munstycksnivå mot patogen inväxt av rörliga enteriska bakterier.

Denna utveckling kan göra det möjligt för miljövänliga SMI:er att förbättra behandlingen av ett brett spektrum av lungsjukdomar.

Place, publisher, year, edition, pages
Stockholm: Kungliga Tekniska högskolan, 2022. p. 76
Series
TRITA-EECS-AVL ; 2022:49
Keywords
Portable Inhaler, Biopharmaceuticals, Soft-mist inhaler, Transport vesicles, Microfluidic packaging, High-pressure microfluidics, aerosolization, cleanroom-free fabrication, drug delivery, micro-electromechanical systems (MEMS)
National Category
Medical Engineering
Research subject
Applied Medical Technology
Identifiers
urn:nbn:se:kth:diva-320164 (URN)978-91-8040-314-6 (ISBN)
Public defence
2022-11-04, F3, Lindstedtsvägen 26 & 28, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20221019

Available from: 2022-10-19 Created: 2022-10-14 Last updated: 2022-10-19Bibliographically approved

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Last, TorbenIordanidis, Theocharis N.Spyrou, ArgyrisStemme, GöranRoxhed, Niclas

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