First Steps to Develop and Validate a CFPD Model in Order to Support the Design of Nose-to-Brain Delivered Biopharmaceuticals

Engelhardt, Lucas; Röhm, Martina; Mavoungou, Chrystelle; Schindowski, Katharina; Schafmeister, Annette; Simon, Ulrich

doi:10.1007/s11095-016-1875-7

Cited by 19 publications

(6 citation statements)

References 57 publications

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“…While a transparent and flexible silicone cast successfully mimics the cartilage-like texture of the murine skull, the hydrophobic surface characteristics of silicone are far from that of a mucosal surface. Nevertheless, the use of 3D printing is a promising approach to refine and advance drug delivery technologies under the 3R criteria ( Engelhardt et al, 2016 ). Despite the above-mentioned limitations, the murine 3D casts have provided a good basis for the development and training of the catheter-based refined technique.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it is believed that the olfactory mucosa mediates predominantly drug delivery to the CNS while the respiratory mucosa mediates drug absorption into the blood stream. Hence, nose-to-brain (N2B) delivery via the olfactory mucosa may be a suitable delivery route for bypassing the blood brain barrier ( Illum, 2004 ; Lochhead and Thorne, 2014 ; Engelhardt et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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Establishment of an Olfactory Region-specific Intranasal Delivery Technique in Mice to Target the Central Nervous System

et al. 2022

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We have recently developed a region-specific catheter-based intranasal application method in mice by using CT scan-based 3D cast models of the murine nose (DOI: 10.2376/0005-9366-17,102). This technique is able to specifically deliver drugs to the olfactory region or to the respiratory region only. Thereby, intranasally administered drugs could be delivered either via neuronal connections to the central nervous system or via the well-perfused rostral parts of the nasal mucosa to the systemic circulation. In the present study, we transferred successfully this novel delivery technique to C57Bl/6 mice and determined parameters such as insertions depth of the catheter and maximum delivery volume in dependence to the weight of the mouse. Breathing was simulated to verify that the volume remains at the targeted area. A step-by-step procedure including a video is presented to adopt this technique for standardized and reproducible intranasal central nervous system (CNS) delivery studies (DOI: 10.3390/pharmaceutics13111904).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Establishment of an Olfactory Region-specific Intranasal Delivery Technique in Mice to Target the Central Nervous System

et al. 2022

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“…We based the parameter setting for CFD on Engelhardt et al [33] which models airflow and particle deposition in the nasal cavity and presents calculated Reynolds (Re) numbers for various flow rates. For the breathing rate of 30 L/min a Re > 3000 was calculated, indicating turbulent flow.…”

Section: Cfd Evaluation Setupmentioning

confidence: 99%

An automated segmentation framework for nasal computational fluid dynamics analysis in computed tomography

Huang

Nedanoski

Fletcher

et al. 2019

Computers in Biology and Medicine

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The use of computational fluid dynamics (CFD) to model and predict surgical outcomes in the nasal cavity is becoming increasingly popular. Despite a number of well-known nasal segmentation methods being available, there is currently a lack of an automated, CFD targeted segmentation framework to reliably compute accurate patient-specific nasal models. This paper demonstrates the potential of a robust nasal cavity segmentation framework to automatically segment and produce nasal models for CFD. The framework was evaluated on a clinical dataset of 30 head Computer Tomography (CT) scans, and the outputs of the segmented nasal models were further compared with ground truth models in CFD simulations on pressure drop and particle deposition efficiency. The developed framework achieved a segmentation accuracy of 90.9 DSC, and an average distance error of 0.3 mm. Preliminary CFD simulations revealed similar outcomes between using ground truth and segmented models. Additional analysis still needs to be 37 conducted to verify the accuracy of using segmented models for CFD purposes.

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“…In addition, the generation of micron-sized aerosol droplets can have tremendous effects on proteins. The shear stress occurring during aerosol formation can induce the formation of unfolded proteins or protein aggregation [ 56 , 57 , 58 , 59 , 60 ], with a subsequent decrease in biological efficiency and immune side effects [ 61 ]. Therefore, it is of great importance to further study the behaviour of biologics after their intranasal delivery in various preclinical models.…”

Section: Introductionmentioning

confidence: 99%

FcRn as a Transporter for Nasal Delivery of Biologics: A Systematic Review

Fieux

Quellec

Bartier

et al. 2021

IJMS

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FcRn plays a major role in regulating immune homeostasis, but it is also able to transport biologics across cellular barriers. The question of whether FcRn could be an efficient transporter of biologics across the nasal epithelial barrier is of particular interest, as it would allow a less invasive strategy for the administration of biologics in comparison to subcutaneous, intramuscular or intravenous administrations, which are often used in clinical practice. A focused systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. It was registered on the international prospective register of systematic reviews PROSPERO, which helped in identifying articles that met the inclusion criteria. Clinical and preclinical studies involving FcRn and the nasal delivery of biologics were screened, and the risk of bias was assessed across studies using the Oral Health Assessment Tool (OHAT). Among the 12 studies finally included in this systematic review (out of the 758 studies screened), 11 demonstrated efficient transcytosis of biologics through the nasal epithelium. Only three studies evaluated the potential toxicity of biologics’ intranasal delivery, and they all showed that it was safe. This systematic review confirmed that FcRn is expressed in the nasal airway and the olfactory epithelium, and that FcRn may play a role in IgG and/or IgG-derived molecule-transcytosis across the airway epithelium. However, additional research is needed to better characterize the pharmacokinetic and pharmacodynamic properties of biologics after their intranasal delivery.

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First Steps to Develop and Validate a CFPD Model in Order to Support the Design of Nose-to-Brain Delivered Biopharmaceuticals

Abstract: The developed CFPD model could be directly translated to the in vitro results. Hence, it can be applied for parameter screening and will contribute to the improvement of aerosol particle deposition at the olfactory cleft for CNS drug delivery in particular for biopharmaceuticals.

Cited by 19 publications

References 57 publications

Establishment of an Olfactory Region-specific Intranasal Delivery Technique in Mice to Target the Central Nervous System

Establishment of an Olfactory Region-specific Intranasal Delivery Technique in Mice to Target the Central Nervous System

An automated segmentation framework for nasal computational fluid dynamics analysis in computed tomography

FcRn as a Transporter for Nasal Delivery of Biologics: A Systematic Review

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