evaluating-regional-pulmonary-deposition-using-patient-specific-3d

Evaluating Regional Pulmonary Deposition using Patient-Specific 3D Printed Lung Models

Development of targeted therapies for pulmonary diseases is limited by the availability of preclinical testing methods with the ability to predict ...

University of Delaware

Computational Fluid-Particle Dynamics (CFPD) models have been employed to predict lung aerosol dynamics for decades, estimating the delivery efficiency of inhaled drugs into the tracheobronchial tree. However, existing CFPD models assume the glottis is static during the breathing cycle. Failing to capture the dynamic motion of the glottis may introduce significant errors in drug deposition estimations.

Glottis motion effects on the particle transport and deposition in a subject-specific mouth-to-trachea model: A CFPD study.

Frenulectomy for ankyloglossia is an intervention that often improves breastfeeding quality for both the mother and infant. Current classification systems assess and identify patients with ankyloglossia, but they do not predict the degree of improvement after lingual frenulectomy. We propose an idealized geometric model to quantify the potential effect of frenulectomy for ankyloglossia.

Geometric model to predict improvement after lingual frenulectomy for ankyloglossia.

 Delivery of aerosols to isolated lobes of the lungs would be beneficial for diseases that have lobe-specific effects, such as cancer, pneumonia, and chronic obstructive pulmonary disorder. Recent computational fluid-particle dynamic (CFPD) modeling has demonstrated that in low flow rates, the inlet location of a particle at the mouth dictates the lobe into which it will deposit. However, realization of this lobe-specific deposition has yet to be attempted experimentally or in the clinic. To address this, we sought to develop a proof-of-concept  model and targeting device for achieving lobe-specific delivery.  Using 3D printing, a lung replica was created from a computed tomography scan of a healthy 47-year-old male volunteer and connected to a flow setup to control inlet flow rate and outlet airflow distribution to each lobe. A device was designed and fabricated that directs particles to an inlet location that is 5% of the total inlet area and described by radial coordinates (,). Filter paper at sampling ports for each lobe was used to capture fluorescent polystyrene particles to quantify particle collection. We evaluated lobe-specific targeting at varied inlet coordinates, particle diameters, inlet flow rates, and disease lobe flow rate distribution profiles.  Guided by CFPD modeling, inlet locations were identified that increased particle collection to a target lobe between 63% and 90%. For example, release of fluorescent particles at the inlet location  = 4.67 mm,  = 252° with respect to the center of the inlet using 1 μm particles, 1 L/min inlet flow rate, and healthy subject lobe flow distribution profile yielded 90% of the aerosol dose to the right upper lobe, corresponding to an increase of 4.6 × above the non-targeted percent particle collection. Particle size, inlet flow rate, and disease airflow distributions were all shown to generally decrease the efficiency of lobe-specific targeting.  Our results indicate that aerosol targeting of a specific lobe is possible  under optimized conditions and that controlling inlet locations could be a potentially useful method for treatment of lobe-specific diseases. This is the first demonstration of lobe-specific particle collection in a physical lung model and illuminates numerous challenges that will be faced as this method is translated to clinical applications.

Realizing Lobe-Specific Aerosol Targeting in a 3D-Printed  Lung Model.

Developing novel drug carriers for pulmonary delivery is necessary to achieve higher efficacy and consistency for treating pulmonary diseases while limiting off-target side effects that occur from alternative routes of administration. Metal-organic frameworks (MOFs) have recently emerged as a class of materials with characteristics well-suited for pulmonary drug delivery, with chemical tunability, high surface area, and pore size, which will allow for efficient loading of therapeutic cargo and deep lung penetration. UiO-66, a zirconium and terephthalic acid-based MOF, has displayed notable chemical and physical stability and potential biocompatibility; however, its feasibility for use as a pulmonary drug delivery vehicle has yet to be examined. Here, we evaluate the use of UiO-66 nanoparticles (NPs) as novel pulmonary drug delivery vehicles and assess the role of missing linker defects in their utility for this application. We determined that missing linker defects result in differences in NP aerodynamics but have minimal effects on the loading of model and therapeutic cargo, cargo release, biocompatibility, or biodistribution. This is a critical result, as it indicates the robust consistency of UiO-66, a critical feature for pulmonary drug delivery, which is plagued by inconsistent dosage because of variable properties. Not only that, but UiO-66 NPs also demonstrate pH-dependent stability, with resistance to degradation in extracellular conditions and breakdown in intracellular environments. Furthermore, the carriers exhibit high biocompatibility and low cytotoxicity in vitro and are well-tolerated in  murine evaluations of orotracheally administered NPs. Following pulmonary delivery, UiO-66 NPs remain localized to the lungs before clearance over the course of seven days. Our results demonstrate the feasibility of using UiO-66 NPs as a novel platform for pulmonary drug delivery through their tunable NP properties, which allow for controlled aerodynamics and internalization-dependent cargo release while displaying remarkable pulmonary biocompatibility.

Evaluating UiO-66 Metal-Organic Framework Nanoparticles as Acid-Sensitive Carriers for Pulmonary Drug Delivery Applications.

COVID-19 is a disease that manifests itself in a multitude of ways across a wide range of tissues. Many factors are involved, and though impressive strides have been made in studying this novel disease in a very short time, there is still a great deal that is unknown about how the virus functions. Clinical data has been crucial for providing information on COVID-19 progression and determining risk factors. However, the mechanisms leading to the multi-tissue pathology are yet to be fully established. Although insights from SARS-CoV-1 and MERS-CoV have been valuable, it is clear that SARS-CoV-2 is different and merits its own extensive studies. In this review, we highlight unresolved questions surrounding this virus including the temporal immune dynamics, infection of non-pulmonary tissue, early life exposure, and the role of circadian rhythms. Risk factors such as sex and exposure to pollutants are also explored followed by a discussion of ways in which bioengineering approaches can be employed to help understand COVID-19. The use of sophisticated  models can be employed to interrogate intercellular interactions and also to tease apart effects of the virus itself from the resulting immune response. Additionally, spatiotemporal information can be gleaned from these models to learn more about the dynamics of the virus and COVID-19 progression. Application of advanced tissue and organ system models into COVID-19 research can result in more nuanced insight into the mechanisms underlying this condition and elucidate strategies to combat its effects.

Article	Year
Glottis motion effects on the particle transport and deposition in a subject-specific mouth-to-trachea model: A CFPD study. Computers in biology and medicine\| PubMed ID: 31751812	2020
Geometric model to predict improvement after lingual frenulectomy for ankyloglossia. International journal of pediatric otorhinolaryngology\| PubMed ID: 32387707	2020
Realizing Lobe-Specific Aerosol Targeting in a 3D-Printed Lung Model. Journal of aerosol medicine and pulmonary drug delivery\| PubMed ID: 32678723	2020
Evaluating UiO-66 Metal-Organic Framework Nanoparticles as Acid-Sensitive Carriers for Pulmonary Drug Delivery Applications. ACS applied materials & interfaces\| PubMed ID: 32805901	2020
Significant Unresolved Questions and Opportunities for Bioengineering in Understanding and Treating COVID-19 Disease Progression. Cellular and molecular bioengineering\| PubMed ID: 32837585	2020

Catherine A. Fromen

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