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Self-sealing MEMS spray-nozzles to prevent bacterial contamination of portable inhalers for aqueous drug delivery
KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Micro and Nanosystems.ORCID iD: 0000-0001-9947-5011
KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Micro and Nanosystems. Tech Univ Carolo Wilhelmina Braunschweig, Braunschweig, Germany..ORCID iD: 0000-0002-2331-4833
KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Micro and Nanosystems.ORCID iD: 0000-0001-9552-4234
KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Micro and Nanosystems. Karolinska Univ Hosp, Bioclinicum, Solna, Sweden..ORCID iD: 0000-0002-7147-6730
2022 (English)In: Biomedical microdevices (Print), ISSN 1387-2176, E-ISSN 1572-8781, Vol. 24, no 3, article id 25Article in journal (Refereed) Published
Abstract [en]

Pulmonary drug delivery by portable inhalers is the gold standard in lung disease therapy. An increasing focus on environmentally friendly inhalation currently spurs the development of propellant-free devices. However, the absence of propellants in the drug creates a need for suitable sealing systems that can ensure the pathogenic safety of devices. Traditionally, liquid drug inhalers incorporate a spray nozzle and a separate check valve. Here we show a fully integrated MEMS -based spray system for aqueous drug solutions and demonstrate its bacterial safety. The device comprises a thin silicon membrane with spray orifices, which self-seal against a compliant parylene valve seat underneath. This sealing system prevents bacterial ingrowth in its default closed state, while actuation lifts the membrane from the valve seat upon pressurization and sprays an inhalable aerosol from the nozzles. To seal against bacterial contamination effectively, we found that a contact force between the valve seat and the membrane (featuring the spray nozzles) is needed. In our testing, both self-sealing and an otherwise identical unvalved version of the spray chip can be bacterially safe in continued use when thoroughly cleaned of excess fluids and subjected to low bacterial loads for brief periods. However, when directly exposed to 10(7) CFU/ml of our test organism Citrobacter rodentium for 24 h, unvalved systems become contaminated in nearly 90% of cases. In contrast, self-sealing spray chips reduced contamination probability by 70%. This development may enable preservative-free drug formulations in portable inhalers that use propellant-free aqueous drug solutions.

Place, publisher, year, edition, pages
Springer Nature , 2022. Vol. 24, no 3, article id 25
Keywords [en]
MEMS, Portable inhaler, Drug delivery, Aerosol, Bacterial safety
National Category
Fluid Mechanics Respiratory Medicine and Allergy Nursing
Identifiers
URN: urn:nbn:se:kth:diva-316707DOI: 10.1007/s10544-022-00628-wISI: 000836597100001PubMedID: 35931869Scopus ID: 2-s2.0-85135453974OAI: oai:DiVA.org:kth-316707DiVA, id: diva2:1692962
Note

QC 20220905

Available from: 2022-09-05 Created: 2022-09-05 Last updated: 2025-02-09Bibliographically 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, TorbenWinkler, ThomasStemme, GöranRoxhed, Niclas

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