The majority of research into respiratory transport phenomena has commonly centred on adults, yet these findings are not always transferable, as children have distinct lung structures. Mapping and quantifying the nature of respiration in children could help clinicians treat respiratory conditions more effectively, as Associate Professor Josué Sznitman of the RespMicroFlows project explains
A deeper picture of respiratory transport The lungs are
a highly complex structure that closely resemble an upsidedown tree, with branches bifurcating from the main trunk into very small airspaces which are populated with alveoli, tiny sacs in which carbon dioxide and oxygen are exchanged. This is an area of great interest to Dr Josué Sznitman, the Principal Investigator of the RespMicroFlows project. “The essence of our research is that we work on mapping and quantifying the nature of respiration.
physics of flows and particle transport. “RespMicroFlows is taking these kinds of concepts and developing strategies on medication delivery through the lungs, with a focus on children,” says Dr Sznitman. The majority of research on respiratory transport phenomena has historically focused on adults, but now Dr Sznitman and his colleagues are looking to redress the balance. “In RespMicroFlows, we’re looking to see if we can make children-tailored models, to resolve the
The essence of our research is that we work on mapping and quantifying the nature of respiration. We’re very interested in delivering aerosols, in the context of inhalation therapy, to target specific regions of the respiratory tract and even more so for the young populations We’re very interested in delivering aerosols, in the context of inhalation therapy, to treat various types of diseases through inhaled medication,” he outlines. One important issue in treating certain respiratory conditions, including emphysema, is delivering drugs deeper into the lungs, past the main branches and into these very small airspaces where alveoli are located. “One of the approaches that has been advocated is to use inhalation therapy to deliver drugs directly to the deep lungs either for topical or systemic treatment,” explains Dr Sznitman.
RespMicroFlows project The primary focus in the RespMicroFlows project is investigating how aerosols can be delivered much deeper into the lung, which could greatly improve the effectiveness of treatment. This involves looking at a number of physical questions, including around fluid dynamics, the
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specificity of delivering aerosols in children,” he continues. “We’re developing numerical simulations and physical models of how air travels through the lung, how it travels through the trachea and makes its way down to the distal ends, or deep lungs.” This is a world that is characterised by very small scales, in the range of around 100 microns or so, with cavities barely the thickness of a hair. Delivering medication deep into this dense and populous environment is a complex challenge; researchers are using computational fluid dynamics (CFD) and physical models to build a clearer picture of how it can be achieved. “This includes using microfluidics very intensively in order to make airway models that capture the right scales of the alveolar environment, under a few hundred microns,” outlines Dr Sznitman. The project is also using sophisticated techniques to model airflows
in the lungs of an infant. “If you think about a new-born baby, or even a 2 year old, you can imagine their lungs are substantially smaller than an adult’s,” points out Dr Sznitman. “The largest airway is just a few millimetres, so you can imagine that everything downstream of that is going to be extremely small. There, we are using 3D printing techniques to reconcile the microfluidic world with these small yet millimetre-sized dimensions in upper airways.” The lung of an infant of course differs in size from that of an adult, but there is also still debate over exactly how the lung develops as we grow. It is thought that the main conductive structure of the lung is in place in a new-born, but the number of
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Fabricating airway models begins with Computer-Aided Design (CAD) to 3D printing and casting a negative (Y. Ostrovski, PhD candidate). 1) Aerosol Inhalation
Systemic Delivery
2) Transport in air-phase
Air Blood
Air 3) Deposition Macrophage
Schematic of pulmonary acini and alveolar capillary networks.
Dendretic cell
6) Systemic circulation
4) Translocation
ALI
Alveolar epithelium
5) Transport in blood phase
From airborne aerosols to systemic delivery (adapted from Dr. J. Tenenbaum-Katan). alveoli grows dramatically in the early years of life, helping to remove CO2 and supply oxygen more efficiently. “Very complex mechanisms allow tissue to expand and create more and more surface area. A large surface area is required for efficient gas ventilation,” says Dr Sznitman. Infants also have different ventilatory patterns, in terms of the quantity of air they take in and breathing rates for example, another issue which Dr Sznitman and his colleagues need to consider. “There are structural differences, anatomical differences and physiological differences, in terms of breathing patterns,” he continues. “However, while you can ask an adult to modify and control their breathing patterns, you can’t ask the same from a two-year-old.”
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This further underlines the importance of developing reliable simulations of airflow in the infant lung, with researchers investigating the underlying transport problems affecting the delivery of aerosols, right down to the particle level. Aerosols are often comprised of a wide variety of different particles, but Sznitman says the project’s research is blind to the nature of what’s being carried. “I’m trying to understand underlying transport problems in delivery, to build a deeper physical understanding. This helps us understand the fate of particles,” he explains. This includes the pollutants that we all inhale on a daily basis, many of which are extremely small – from nanometers to a
few microns in size – and atmospheric particles more generally. “A man-made particle could be designed for therapeutic purposes, or it could originate from natural or anthropogenic activities in the environment. If they have the same shape and size, they will experience the same dynamics and ultimately the same deposition properties inside the lungs,” continues Dr Sznitman. The fate of pollutants is of course an area of interest, yet it is targeted drug delivery that is the more central part of the project’s agenda, with researchers developing both advanced in silico numerical simulations and microfluidic in vitro platforms. There are a number of factors to consider in simulating the
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Microfluidic Acinus Chip (Dr. R. Fishler).
At a glance Full Project Title Unravelling respiratory microflows in silico and in vitro: novel paths for targeted pulmonary delivery in infants and young children (RespMicroFlows) Project Objectives In RespMicroFlows, researchers aim to unravel the complex microflows characterizing alveolar airflows in the developing pulmonary acini. New discoveries will foster ground-breaking transport strategies to tackle two urgent clinical needs that burden infants and young children. The first challenge relates to radically enhancing the delivery and deposition of therapeutics using inhalation aerosols; the second involves targeting liquid bolus installations in deep airways for surfactant replacement therapy. Project Funding Funded under: H2020-EU.1.1. EXCELLENT SCIENCE - European Research Council (ERC) Contact Details Josué Sznitman, Dr. Sc. Associate Professor Julius Silver Bldg., Office 246 Department of Biomedical Engineering Technion - Israel Institute of Technology Haifa 32000, Israel T: +972 77 887 5678 E: sznitman@bm.technion.ac.il W: http://biofluids.technion.ac.il
Associate Professor Josué Sznitman
Josué Sznitman holds degrees from MIT (BSc) and ETH Zurich (Dipl.-Ing. and Dr. Sc.). Prior to joining the Technion, he was a a postdoctoral researcher at the University of Pennsylvania and a Fellow of the Princeton Council for Science & Technology. Sznitman currently serves as an Academic Editor for the journal PLoS One and sits on the Editorial Board of Biomicrofluidics (AIP). He serves on the Management Committee of COST Action MP1404 “SimInhale” and CA16125 on Children and Adult Interstitial Lung Disease. Sznitman has published over 50 peer-reviewed articles and was awarded the 2015 Young Investigator Award from the International Society for Aerosols in Medicine (ISAM) for a researcher under the age of 40. He is a member of the MIT Educational Council and a co-founder of GradTrain, an online education and media business.
Trachea
Main Bronchus Terminal Bronchioles
Respiratory Bronchioles
Acinus
Bronchioles Alveolar Sacs
transport and deposition of particles in the lung, including their size and weight. “Particles that are a micron or larger start experiencing their own weight to an increasing degree as a result of gravity,” continues Dr Sznitman. “On the other hand, if a particle is under a few hundred nanometers or so, then it will experience so-called Brownian motion as it diffuses” explains Dr Sznitman. If a particle is neither small enough to diffuse, nor big enough to fall under its own weight due to sedimentation, then its fate is strongly determined by the nature of the respiratory airflows carrying the aerosol.” These are important considerations in terms of the wider goal of delivering aerosols deeper into the lung. While aerosols bigger than around 10 microns are simply too large to be delivered deep into the lung, Dr Sznitman says it is feasible with smaller aerosols. “They don’t feel any diffusion – they feel a mixture of the flow, and then when that slows down, they feel their own weight,” he outlines. Deeper knowledge of these respiratory transport phenomena could enable clinicians to tailor inhalation therapy more precisely to suit the needs of individual patients, including paediatric populations, taking into account their age, physiology and other factors. “From this
research, hopefully new strategies will be developed to deliver aerosols to targeted cells. For example, a clinician may want to deliver drugs into a specific area of the lung,” says Dr Sznitman. “Within the project, we’re supporting the development of strategies to deliver aerosols, we’re looking at how to deliver drugs more effectively.” This can vary according to the individual. While some underlying physical properties of the lung stay the same across the wider population, deeper analysis reveals significant variations, so available therapies aren’t always tailored to individual needs. “With a first order approximation, the lungs of two people of around the same age may look exactly the same, but when we go down to the specifics they certainly don’t,” says Dr Sznitman.
Computational fluid dynamics (CFD) of aerosol transport in model acini (Dr. P. Hofemeier).
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