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Schmid Lab

Pulmonary Aerosol Delivery

Our objective is to translate new concepts of aerosol research, biotechnology and physics into technological advances facilitating the development of novel inhaled drugs for the treatment of lung diseases.

Our objective is to translate new concepts of aerosol research, biotechnology and physics into technological advances facilitating the development of novel inhaled drugs for the treatment of lung diseases.

Our Key Questions

  • How can we improve aerosolized drug delivery to the lung in both preclinical (cells, animal models) and clinical (human) settings?
  • How can we determine both dose and bioactivity of the pulmonary drug dose in real-time?
  • Can physiologically more realistic cell-based drug screening methods improve the predictive power of these tests for the efficacy of novel drugs in clinical settings?
  • How can inhaled drugs be targeted specifically to the site of interest (e.g. bronchial or alveolar region or specific cell types depending on disease type)? 

Our Main Projects

We aim to design and validate systems for aerosolized drug delivery to pulmonary cells (in vitro) and to mouse models of disease (in vivo). Furthermore, methods for (real-time) in vivo monitoring of both delivered and bioactive pulmonary drug dose are developed. Our mini-lung-fibrosis-model for example may change the way we can imitate the processes in the lung during inhalation therapy.

Also, the ALICE-CLOUD technology was introduced which combines ease-of-handling with rapid, efficient and accurate delivery of aerosolized drugs to cells cultured at air-liquid interface conditions. This technology may pave the way for screening of inhalable drugs under physiologically more relevant and thus clinically more predictive conditions than the currently used submerged cell culture systems.

Picture right: Aeorosole distribution in the lung under microscope.

Scientists at Schmid Lab

Blayac_Marion_Portrait

Dr. Marion Blayac

Postdoc
Portrait Ashesh Chakraborty LHI

Dr. Ashesh Chakraborty

Postdoc
Portrait Penghang Chen LHI

Penghang Chen

PhD Student
Fuchs_Anna_Portrait_LHI

Anna Fuchs

Biologisch Technische Assistentin
Gabriel_Christina_Portrait

Christina Gabriel

PhD
Hidalgo_Alberto_Portrait

Dr. Alberto Hidalgo

Postdoc
Portrait Elisabeth Schindler LHI

Elisabeth Schindler

Lab Manager
Portrait Andreas Schröppel LHI

Andreas Schröppel

IT, Engineer
Stremlau_Marleen_Portrait

Marleen Stremlau

PhD Student
Porträt Magdalena Weiß

Magdalena Weiß

PhD Student
Porträt Lin Yang

Dr. Lin Yang

Postdoctoral Fellow

Publications

2024, Scientific Article in Journal of Aerosol Science

Aerosol dosimetry in the whole conducting zone of a murine left-lung using CF-PD and LSFM images.

Aerosol dosimetry in respiratory airways is relevant for pulmonary drug delivery and inhalation toxicology. Consequently, computational fluid-particle dynamics (CF-PD) modelling of pulmonary aerosol delivery is an active research field. Additionally, mice are the most commonly used animals in medical research. Technological advances have provided information on whole mice lung morphologies with unprecedented high resolution. Therefore, in this study, we used high-resolution light sheet fluorescent microscopy (LSFM) images of a healthy C57BL/6 mouse lung with a constant air flow rate of 72 ml/min, to extract an anatomical 3-dimensional (3D) geometry of the entire airway tree of the left lung from the primary bronchi to the most distal bronchioles excluding the trachea. The airways were segmented based on an order- and generation-based method. Also, to compare the morphological data and regional deposition, a generation-based investigation including 25 generations was employed in the present model. One-way coupling of CF-PD modeling was applied to model an intubated and mechanically-ventilated mouse. Maximum values of the velocity and vorticity magnitude of 3.2 m/s and 200,000 1/s were reached in the second order, respectively, and maximum pressure and wall shear stress levels were 30 Pa and 3.5 Pa, respectively. Finally, order- and generation-based particle deposition efficiency and dose per lung area were obtained for the particle size range of 1 μm ≤ dp ≤ 10 μm yielding pronounced hotspot deposition patterns mainly near the proximal bifurcations. The results showed a positive correlation between deposition efficiency and particle size due to a size-dependent increase in inertial and gravitational effects. Maximum regional deposition and normalized dose was seen for 10 μm particles in the 1st order of the murine left lung. Smaller peak sizes of deposition efficiency were seen in the third and fourth orders of the mouse left lung due to almost complete loss of the largest particles in lower order airways. It also justifies the close to zero deposition efficiency in the highest orders (fifth to sixth). Both lung morphology as well as total and regional aerosol deposition showed reasonably good agreement with empirical data from the literature. The present CF-PD model with accurate realistic lung morphology, improves our knowledge of airway aerosol deposition hotspots. The obtained modeling method and the qualitative results can be implemented on human airways.

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2024, Scientific Article in Nature Communications

LungVis 1.0: An automatic AI-powered 3D imaging ecosystem unveils spatial profiling of nanoparticle delivery and acinar migration of lung macrophages.

Targeted (nano-)drug delivery is essential for treating respiratory diseases, which are often confined to distinct lung regions. However, spatio-temporal profiling of drugs or nanoparticles (NPs) and their interactions with lung macrophages remains unresolved. Here, we present LungVis 1.0, an AI-powered imaging ecosystem that integrates light sheet fluorescence microscopy with deep learning-based image analysis pipelines to map NP deposition and dosage holistically and quantitatively across bronchial and alveolar (acinar) regions in murine lungs for widely-used bulk-liquid and aerosol-based delivery methods. We demonstrate that bulk-liquid delivery results in patchy NP distribution with elevated bronchial doses, whereas aerosols achieve uniform deposition reaching distal alveoli. Furthermore, we reveal that lung tissue-resident macrophages (TRMs) are dynamic, actively patrolling and redistributing NPs within alveoli, contesting the conventional paradigm of TRMs as static entities. LungVis 1.0 provides an advanced framework for exploring pulmonary delivery dynamics and deepening insights into TRM-mediated lung immunity.

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2024, Scientific Article in NanoImpact

Next generation risk assessment approaches for advanced nanomaterials: current status and future perspectives.

This manuscript discusses the challenges of applying New Approach Methodologies (NAMs) for safe by design and regulatory risk assessment of advanced nanomaterials (AdNMs). The authors propose a framework for Next Generation Risk Assessment of AdNMs involving NAMs that is aligned to the conventional risk assessment paradigm. This framework is exposure-driven, endpoint-specific, makes best use of pre-existing information, and can be implemented in tiers of increasing specificity and complexity of the adopted NAMs. The tiered structure of the approach, which effectively combines the use of existing data with targeted testing will allow safety to be assessed cost-effectively and as far as possible with an even more limited use of vertebrates. The regulatory readiness of state-of-the-art emerging NAMs is assessed in terms of Transparency, Reliability, Accessibility, Applicability, Relevance and Completeness, and their relevance for AdNMs are discussed in relation to each step of the risk assessment paradigm along with providing perspectives for future developments in the respective scientific and regulatory areas.

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2024, Scientific Article in Environmental Science: Nano

Advanced materials earliest assessment (AMEA).

Advanced materials are rapidly being developed in different material categories. They share little commonalities apart from their novelty, which raises concerns that these materials may fall into a regulatory gap with potentially inappropriate risk management. But how to assess materials that are still under development? Here we present the Advanced Materials Earliest Assessment (AMEA) approach to fill this gap by proposing simple assessment steps and guidance for design rules meant to be applied by innovators in early material development phases (ideation, business case and lab phases). AMEA provides a structured approach to exploit the available knowledge at each phase, starting from the intended product, application and global region, starting also from the conventional material in the same application, of which the sustainability benefits and sustainability challenges often constitute the motivation for advanced material development. During the lab phase, AMEA recommends focusing on acquisition of data with discriminating power, and triggers more requirements and/or specific testing methods depending on the positioning of the material with respect to the three dimensions “nano-enabled?”, “advanced?”, and “containing particles?” The methodological part can be amended for other material classes without relevance of nanostructures. Similarity and ranking approaches compare material versions synthesized in lab phases against each other and the conventional material in terms of performance, lifecycle emissions/exposures and hazards. AMEA prioritizes the discriminating power of specific data to refine the design targets instead of using generic assumptions with high uncertainties. It is the entry point of the HARMLESS decision support system covering the ensuing pilot and launch phases of innovation management to fulfill safe-and-sustainable-by-design material development.

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2024, Scientific Article in Thorax

COPD basal cells are primed towards secretory to multiciliated cell imbalance driving increased resilience to environmental stressors.

INTRODUCTION: Environmental pollutants injure the mucociliary elevator, thereby provoking disease progression in chronic obstructive pulmonary disease (COPD). Epithelial resilience mechanisms to environmental nanoparticles in health and disease are poorly characterised. METHODS: We delineated the impact of prevalent pollutants such as carbon and zinc oxide nanoparticles, on cellular function and progeny in primary human bronchial epithelial cells (pHBECs) from end-stage COPD (COPD-IV, n=4), early disease (COPD-II, n=3) and pulmonary healthy individuals (n=4). After nanoparticle exposure of pHBECs at air-liquid interface, cell cultures were characterised by functional assays, transcriptome and protein analysis, complemented by single-cell analysis in serial samples of pHBEC cultures focusing on basal cell differentiation. RESULTS: COPD-IV was characterised by a prosecretory phenotype (twofold increase in MUC5AC+) at the expense of the multiciliated epithelium (threefold reduction in Ac-Tub+), resulting in an increased resilience towards particle-induced cell damage (fivefold reduction in transepithelial electrical resistance), as exemplified by environmentally abundant doses of zinc oxide nanoparticles. Exposure of COPD-II cultures to cigarette smoke extract provoked the COPD-IV characteristic, prosecretory phenotype. Time-resolved single-cell transcriptomics revealed an underlying COPD-IV unique basal cell state characterised by a twofold increase in KRT5+ (P=0.018) and LAMB3+ (P=0.050) expression, as well as a significant activation of Wnt-specific (P=0.014) and Notch-specific (P=0.021) genes, especially in precursors of suprabasal and secretory cells. CONCLUSION: We identified COPD stage-specific gene alterations in basal cells that affect the cellular composition of the bronchial elevator and may control disease-specific epithelial resilience mechanisms in response to environmental nanoparticles. The identified phenomena likely inform treatment and prevention strategies.

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2024, Scientific Article in Environmental Science: Nano

Similarity of multicomponent nanomaterials in a safer-by-design context: The case of core-shell quantum dots.

Concepts of similarity, such as grouping, categorization, and read-across, enable a fast comparative screening of hazard, reducing animal testing. These concepts are established primarily for molecular substances. We demonstrate the development of multi-dimensional similarity assessment methods that can be applied to multicomponent nanomaterials (MCNMs) for the case of core-shell quantum dots (QDs). The term ‘multicomponent’ refers to their structural composition, which consists of up to four different heavy metals (cadmium, zinc, copper, indium) in different mass percentages, with different morphologies and surface chemistries. The development of concepts of similarity is also motivated by the increased need for comparison of innovative against conventional materials in the safe and sustainable by design (SSbD) context. This case study thus considers the industrial need for an informed balance of functionality and safety: we propose two different approaches to compare and rank the case study materials amongst themselves and against well-known benchmark materials, here ZnO NM110, BaSO4 NM220, TiO2 NM105, and CuO. Relative differences in the sample set are calibrated against the biologically relevant range. The choice of properties that are subjected to similarity assessment is guided by the integrated approaches to testing and assessment (IATA) for the inhalation hazard of simple nanomaterials, which recommends characterizing QDs by (i) dynamic dissolution in lung simulant fluids and (ii) the surface reactivity in the abiotic ferric reducing ability of serum (FRAS) assay. In addition, the similarity of fluorescence spectra was assessed as a measure of the QD performance for the intended functionality as a color converter. We applied two approaches to evaluate the data matrix: in the first approach, specific descriptors for each assay (i.e., leachable mass (%) and mass based biological oxidative damage (mBOD)) were selected based on expert knowledge and used as input data for generation of similarity matrices. The second approach introduces the possibility of evaluating multidimensional raw data by a meaningful similarity analysis, without the need for predefined descriptors. We discuss the strengths and weaknesses of each of the two approaches. We anticipate that the similarity assessment approach is transferable to the assessment of further advanced materials (AdMa) that are composed of multiple components.

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2024, Review in Advanced science

Bridging smart nanosystems with clinically relevant models and advanced imaging for precision drug delivery.

Intracellular delivery of nano-drug-carriers (NDC) to specific cells, diseased regions, or solid tumors has entered the era of precision medicine that requires systematic knowledge of nano-biological interactions from multidisciplinary perspectives. To this end, this review first provides an overview of membrane-disruption methods such as electroporation, sonoporation, photoporation, microfluidic delivery, and microinjection with the merits of high-throughput and enhanced efficiency for in vitro NDC delivery. The impact of NDC characteristics including particle size, shape, charge, hydrophobicity, and elasticity on cellular uptake are elaborated and several types of NDC systems aiming for hierarchical targeting and delivery in vivo are reviewed. Emerging in vitro or ex vivo human/animal-derived pathophysiological models are further explored and highly recommended for use in NDC studies since they might mimic in vivo delivery features and fill the translational gaps from animals to humans. The exploration of modern microscopy techniques for precise nanoparticle (NP) tracking at the cellular, organ, and organismal levels informs the tailored development of NDCs for in vivo application and clinical translation. Overall, the review integrates the latest insights into smart nanosystem engineering, physiological models, imaging-based validation tools, all directed towards enhancing the precise and efficient intracellular delivery of NDCs.

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2023, Scientific Article in Journal of Drug Delivery Science and Technology

Breathing-induced stretch enhances the efficacy of an inhaled and orally delivered anti-fibrosis drug in vitro.

Mechanical forces, which are crucial for most downstream signaling pathways in lung (patho-)physiology, may also regulate the efficacy of drugs. We investigated the role of mechanical forces on the effectiveness of inhaled and systemic (oral) administration of an anti-fibrosis drug. We established an induced triple coculture fibrosis model of a tight alveolar endothelial-epithelial barrier combined with pro-fibrotically stimulated primary fibroblasts derived from healthy donors and compared it to an analogous triple coculture model with fibroblasts from idiopathic pulmonary fibrosis (IPF) patients (innate IPF model). The 3D in vitro fibrosis models were established on a biomimetic, stretchable basement (BETA) membrane and cultured at an air-liquid interface (ALI). These fibrosis models were treated with an FDA-approved anti-fibrosis drug (oral and aerosolized application of Nintedanib) under static and dynamic culture conditions – including cyclic mechanical stretch and medium-flow induced shear stress – leveraging our advanced millifluidic CIVIC mini-lung technology. Fibrosis markers were characterized by protein and immunofluorescence analysis supplemented with real-time measurement of pulmonary compliance as a functional assay. Nintedanib shows more potent anti-inflammatory (IL1β, IL-6, and IL8) and anti-fibrotic (αSMA, soluble and deposited (type I) collagen, and compliance) effects on our IPF models under dynamic culture conditions for both delivery methods. Mechanotransduction enhanced the restoration of alveolar phenotypes after drug delivery, as indicated by surfactant protein C and Yes-associated protein levels. Our findings suggest that cyclic mechanical stretch plays a crucial role in the drug efficacy of Nintedanib. Albeit Nintedanib's anti-fibrotic and anti-inflammatory potency in both delivery routes is similar, the inhaled administration has a lower off-target dose fraction than oral application. Thus, inhaled Nintedanib showed a superior therapeutic index to systemic (oral) application.

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Contact

Porträt Otmar Schmid

Dr. Otmar Schmid

Team Leader