MODIFLOW
A FLOW MODIFICATION DEVICE
CONTENTS
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Asthma and other respiratory illnesses
Inhalable medications
Forms of delivery to the lungs
Spacer devices
Fractal geometry
Fractality in living systems
Turbulence
How do the biological systems deal with it?
ModiFlow
The Patent
CIP
FDA regulation
Testing
Financing
Future developments
ASTHMA STATS
• The number of people with asthma continues to grow.
One in 12 people (about 25 million, or 8% of the U.S.
population) had asthma in 2009, compared with 1 in 14
(about 20 million, or 7%) in 2001.2
• More than half (53%) of people with asthma had an
asthma attack in 2008. More children (57%) than adults
(51%) had an attack. 185 children and 3,262 adults died
from asthma in 2007.2
• About 1 in 10 children (10%) had asthma and 1 in 12
adults (8%) had asthma in 2009. Women were more likely
than men and boys more likely than girls to have asthma.2
• In 2010, 3 out of 5 children who have asthma had one
or more asthma attacks in the previous 12 months.6
COST
• Asthma cost the US about $3,300 per person with
asthma each year from 2002 to 2007 in medical
expenses, missed school and work days, and early
deaths.2
• Asthma costs in the US grew from about $53 billion in
2002 to about $56 billion in 2007, about a 6% increase.2
• More than half (59%) of children and one-third (33%) of
adults who had an asthma attack missed school or work
because of asthma in 2008. On average, in 2008 children
missed 4 days of school and adults missed 5 days of work
because of asthma.2
MORBIDITY
• More than half (53%) of people with asthma
had an asthma attack in 2008. More children
(57%) than adults (51%) had an attack. 185
children and 3,262 adults died from asthma in
2007.2
• Asthma was linked to 3,447 deaths (about 9
per day) in 2007.
INTERNATIONAL
• The prevalence of asthma in different countries varies widely, but the
disparity is narrowing due to rising prevalence in low and middle
income countries and plateauing in high income countries.3
• An estimated 300 million people worldwide suffer from asthma, with
250,000 annual deaths attributed to the disease.1
• It is estimated that the number of people with asthma will grow by
more than 100 million by 2025.1
• Workplace conditions, such as exposure to fumes, gases or dust, are
responsible for 11% of asthma cases worldwide.1
• About 70% of asthmatics also have allergies.1
• Approximately 250,000 people die prematurely each year from
asthma. Almost all of these deaths are avoidable.1
• Occupational asthma contributes significantly to the global burden of
asthma, since the condition accounts for approximately 15% of asthma
amongst adults.
OTHER RESPIRATORY ILLNESSES
•
•
•
•
•
•
•
•
Chronic lung disease
Bronchiolitis
Bronchitis
COPD
Cystic fibrosis
Croup
Pneumoconioses
Others
INHALABLE MEDICATIONS
•
•
•
•
•
•
•
•
•
•
•
•
Bronchodilators
Steroids
Anti-allergics
Antimicrobials
Insulin
Vitamins (LeWhif)
Chemotherapy
Anti-migrain (Levadex)
Anti-tuberculosis
Pain medications
Gene therapy
Anti-Parkinson’s (levodopa)
FORMS OF DELIVERY
•
•
•
•
Nebulizer machines
Pressurized metered dose inhalers (pMDI)
Dry powder discs (DPI)
MDI’s with Spacers
SPACER DEVICES
•
•
•
•
•
•
•
•
•
•
•
•
ACE® (Aerosol Cloud Enhancer)
Aerochamber®
Azmacort®
Easivent®
Ellipse®
Babyhaler
Volumatic
NebuChamber
Inspirease
Fisonair
500ml modified plastic bottle
Coffee cup
DPI
•
•
•
•
Turbohaler
Diskhaler
Accuhaler
Rotahaler
Activated by inspiration
Lung deposition of aerosol—a comparison of different
spacers
•
•
•
Arch Dis Child 2000;82:495-498 doi:10.1136/adc.82.6.495
Methodology
H J Zar, E G Weinberg, H J Binns, F Gallie, M D Mann
•
•
Abstract
AIMS To investigate (1) aerosol lung deposition obtained from two small volume conventional spacers (Babyhaler
and Aerochamber) and a home made spacer (modified 500 ml plastic cold drink bottle); (2) the effect of using a
face mask or mouthpiece; and (3) the relation between age and pulmonary deposition.
METHODS Lung deposition of aerosolised technetium-99m DTPA inhaled via spacer was measured in 40 children
aged 3–7 years with stable asthma. Each patient performed sequential randomly assigned inhalations using two
spacers. Three studies were performed: Babyhaler compared to Aerochamber (with facemasks); Babyhaler with
facemask compared to Babyhaler with mouthpiece; and Babyhaler with mouthpiece compared to a 500 ml bottle.
RESULTS Median lung aerosol deposition from a Babyhaler and Aerochamber with masks were similar (25% v 21%,
p = 0.9). Aerosol lung deposition from a Babyhaler with mask compared to a Babyhaler with mouthpiece was
equivalent (26% v 26%, p = 0.5). Lung deposition was higher from a 500 ml bottle compared to a Babyhaler in both
young (25% v 12.5%, p = 0.005) and older children (42% v22.5%, p = 0.003). A notable reduction in pulmonary
deposition occurred at 50 months of age.
CONCLUSION A Babyhaler or Aerochamber produce equivalent lung deposition of aerosol. There is no difference
in lung deposition when a mask or mouthpiece is used. A modified 500 ml plastic bottle produces greater
pulmonary aerosol deposition than a conventional small volume spacer.
•
•
•
• Volume varies from tube spacers <50ml to
holding chambers 750ml
• The higher the volume, the better efficiency
• Minimize coordination difficulties
• Reduce oropharyngeal deposition
• Increase lung deposition
Metered-dose inhalers with spacers produced
outcomes that were at least equivalent to
nebulizer delivery
Adrenal suppression in asthmatic children receiving lowdose inhaled budesonide: comparison between dry powder
inhaler and pressurized metered-dose inhaler attached to a
spacer
Treatment of asthmatic children with
budesonide 400 mcg daily given via a DPI for 1
month was associated with hypothalamicpituitary-adrenal axis suppression. This effect
was not observed with the same dose of
budesonide administered via pMDI + spacer.
This indicates that systemic absorption might be
reduced with pMDI + spacer therapy
Randomized trial of spacers in asthma
Dahiya B, Mathew JL, Singh M.Postgraduate Institute of Medical Education and
Research (PGIMER), Chandigarh, India. meenusingh4@rediffmail.com.
Abstract
OBJECTIVE:
To compare the efficacy of all types of spacers commonly available to children in India.
METHODS:
150 children 5-14 yr of age with persistent asthma presenting with peak expiratory flow
(PEF) < 70% of personal best were randomized to receive 200 mg salbutamol through
one of five spacers: A) 750 ml spacer with valve, B) 165 ml spacer with valve, C) 250 ml
spacer without valve, D) 1000 ml indigenously made spacer without valve and E) 500 ml
indigenously made spacer without valve. PEF measurement was repeated 15 minutes
later. Children> 8 yr old performed spirometry in addition to PEF. Absolute change and
percentage improvement of PEF and FEV1 were compared among the groups.
RESULTS:
Subjects in all groups had comparable baseline demographic characteristics and PEF. All
showed significant improvement in PEF and FEV1 over baseline values. The change in
PEF and percentage improvement were comparable among all five groups (p=0.780 and
p=0.955 respectively). Likewise change in FEV1 and percentage improvement were also
comparable. The five groups showed no difference in efficacy, irrespective of severity of
baseline airway obstruction.
CONCLUSION:
The five spacers were equally efficacious for the delivery of bronchodilator in children
with moderate persistent asthma presenting with airway obstruction.
Electrostatics and inhaled medications: influence on delivery
via pressurized metered-dose inhalers and add-on devices
•
•
•
Mitchell JP, Coppolo DP, Nagel MW.Trudell Medical International, 725 Third Street,
London, Ontario N5V5G4 Canada. jmitchell@trudellmed.com
Abstract
The movement of inhaler-generated aerosols is significantly influenced by
electrostatic charge on the particles and on adjacent surfaces. Particle charging
arises in the aerosol formation process. Since almost all inhalers contain
nonconducting components, these surfaces can also acquire charge during
manufacture and use. Spacers and valved holding chambers used with pressurized
metered-dose inhalers to treat obstructive lung diseases are particularly prone to
this behavior, which increases variability in the amount of medication available for
inhalation, and this is exacerbated by low ambient humidity. This may result in
inconsistent medication delivery. Conditioning the device by washing it with a
conductive surfactant (detergent) or using devices made of chargedissipative/conducting materials can mitigate electrostatic charge. This review
discusses sources of electrostatic charge, the processes that influence aerosol
behavior, methods to mitigate electrostatic charge, and potential clinical
implications.
The importance of nonelectrostatic materials in holding
chambers for delivery of hydrofluoroalkane albuterol
HCs made from electrically conductive materials
emit significantly greater fine-particle mass,
with either a 2-s or 5-s delay, than do HCs made
from nonconducting materials, even with
wash/rinse pretreatment.
Comparison of the bronchodilating effects of albuterol
delivered by valved vs. non-valved spacers in pediatric
asthma
In stable asthmatic children, albuterol
administered through MDI using a non-valved
spacer produces a bronchodilator response
similar to that of a spacer with a valve that
requires an inhalatory opening pressure (with
flows between 2 and 32 l/min) that even
toddlers with bronchial obstruction can easily
generate.
FRACTAL GEOMETRY
•
•
•
•
•
•
Fractal dimension
Iteration
Self-similarity
Appear the same on different scales
Can fit a large surface area in a small volume
Widespread in the nature, especially in living
organisms
MANDELBROT SET
FRACTALS IN LIVING SYSTEMS
•
•
•
•
•
•
•
•
Lungs
Vascular system
Nervous system
Bones
Cell membranes
Parenchimal organs
Plants
Viruses
[A three dimensional fractal simulation of the lung
bronchial tree]
The lungs are naturally irregular and asymmetrical organ in anatomy. The
conducting bronchial trees in the lungs display complex self-similar structure.
We have established the host mesh coordinates of the right lung on the basis
of the anatomical data from the literature. A three-dimensional fractal model
of the conducting airways was set up by calculating the coordinates of the
mass centers of the divided blocks, searching the branch direction and
determining branch lengths with the use of the drawing tool OpenGL. Specific
data of the lengths at various grades, branching angles, and capillary
diameters were obtained. As a result, the computed data were identical with
those of the existing statistical data. The fractal covering dimensionality
obtained in the computation of this model was 2.19, which is very close to
the ideal dimensionality, 2.17, from the literature. The present model has laid
the foundation for further research of the gas diffusion and transfer
performance in the lungs using the fractal concept, and furthermore, it helps
to save the computer memories and fastening the graphic transfer.
Emergence of matched airway and vascular trees from
fractal rules
The bronchial, arterial, and venous trees of the lung are complex interwoven
structures. Their geometries are created during fetal development through
common processes of branching morphogenesis. Insights from fractal
geometry suggest that these extensively arborizing trees may be created
through simple recursive rules. Mathematical models of Turing have
demonstrated how only a few proteins could interact to direct this branching
morphogenesis. Development of the airway and vascular trees could,
therefore, be considered an example of emergent behavior as complex
structures are created from the interaction of only a few processes. However,
unlike inanimate emergent structures, the geometries of the airway and
vascular trees are highly stereotyped. This review will integrate the concepts
of emergence, fractals, and evolution to demonstrate how the complex
branching geometries of the airway and vascular trees are ideally suited for
gas exchange in the lung. The review will also speculate on how the
heterogeneity of blood flow and ventilation created by the vascular and
airway trees is overcome through their coordinated construction during fetal
development.
On the asymmetry of bifurcations in the bronchial
tree.
The branching pattern of the conducting airways is significantly asymmetrical
in the human, and even more so in other species. Although this asymmetry is
believed to have an important effect on air flow and other transport
processes in the bronchial tree, both experimental and theoretical studies
have predominantly employed symmetrical model bifurcations. In this paper,
published morphometric data for four species (human, dog, rat and hamster)
is used to calculate the frequencies with which different degrees of
asymmetry occur, and to examine the relationships between four of its
manifestations, asymmetry of the cross-sectional areas, the lengths, the
branching angles and the flow rates of the daughter branches. The observed
characteristics are compared with some of the theoretical 'branching laws'
which have been proposed. Quantification of the correlations between the
different manifestations of asymmetry allows the geometrical characteristics
to be specified for a range of realistic asymmetrical bifurcations, for use in
either theoretical or experimental studies of transport in the bronchial tree.
Fractal nature of regional ventilation distribution
High-resolution measurements of pulmonary perfusion reveal substantial
spatial heterogeneity that is fractally distributed. This observation led to the
hypothesis that the vascular tree is the principal determinant of regional
blood flow. Recent studies using aerosol deposition show similar ventilation
heterogeneity that is closely correlated with perfusion. We hypothesize that
ventilation has fractal characteristics similar to blood flow. We measured
regional ventilation and perfusion with aerosolized and injected fluorescent
microspheres in six anesthetized, mechanically ventilated pigs in both prone
and supine postures. Adjacent regions were clustered into progressively
larger groups. Coefficients of variation were calculated for each cluster size to
determine fractal dimensions. At the smallest size lung piece, local ventilation
and perfusion are highly correlated, with no significant difference between
ventilation and perfusion heterogeneity. On average, the fractal dimension of
ventilation is 1.16 in the prone posture and 1. 09 in the supine posture.
Ventilation has fractal properties similar to perfusion. Efficient gas exchange is
preserved, despite ventilation and perfusion heterogeneity, through close
correlation. One potential explanation is the similar geometry of bronchial
and vascular structures.
Fractal geometry of airway remodeling in human
asthma.
• RESULTS:
• Nonasthma control casts had smooth walls and dichotomous branching
patterns with nontapering segments. Asthmatic casts showed many
abnormalities, including airway truncation from mucous plugs,
longitudinal ridges, and horizontal corrugations corresponding to elastic
bundles and smooth muscle hypertrophy, respectively, and surface
projections associated with ectatic mucous gland ducts. Fractal
dimensions were calculated from digitized images using an information
method. The average fractal dimensions of the airways of both the fatal
asthma (1.72) and nonfatal asthma (1.76) groups were significantly
(p<0.01 and p=0.032, respectively) lower than that of the nonasthma
control group (1.83). The lower fractal dimension of asthmatic airways
correlated with a decreased overall structural complexity and pathologic
severity of disease.
• CONCLUSION:
• Fractal analysis is a simple and useful technique for quantifying the
chronic structural changes of airway remodeling in asthma.
TURBULENCE
"the most important unsolved problem of
classical physics“
Richard Feynman
TURBULENT FLOW
• Unsteady vortices appear on many scales and
interact with each other
• Increased resistance to flow
• Unpredictable, chaotically disorganized
• Deterministic chaos
• Extreme sensitivity to initial conditions:
“a butterfly in Korea can cause a tsunami in
the US”
LAMINAR FLOW
•
•
•
•
Dies out due to molecular viscosity
Orderly, organized
Follows rules and equations
Very small lateral force unable to break the
flow, reflects from one edge to the other,
iterates multiple times, and grows until it is
strong enough to break the flow – turbulence
sets in
HOW DO THE BIOLOGICAL SYSTEMS DEAL WITH IT?
BRONCHIAL TREE
the total alveolar volume is the size of a tennis
ball..
but
the total alveolar surface area is the size of a
tennis court
VASCULAR TREE
the entire vascular system comprises only 3% of
the total volume of the body..
yet
it bleeds if you puncture anywhere in the body !
LYMPHATIC TREE
if you put together the lengths of all the blood
vessels in the body including the tiniest
capillaries, they would line up from Earth to the
Moon..
yet the heart is able to pump the blood through
them for 100 years !
Subdivision of the main flow into two sub-flows
iterated multiple times (a tree) seems to disrupt
the cycle of growth of the lateral force,
preventing the emergence of a high Reynolds
number turbulence.
At the same time it allows for a large “exchange”
surface area to be fitted into a relatively small
volume, making the exchange of substances,
energy, information extremely efficient.
A distribution to a large number of elements
without major losses is best achieved via a
fractal tree-like hierarchic structure.
For the flow in the tree to remain continuous
and relatively laminar, and for the turbulence
not to emerge at every subdivision, it is
important for certain “preservation” rules to be
employed.
The total cross-sectional area of the sub-flows
should be equal to the cross-sectional area of
the preceding flow.
That area should in fact remain constant
throughout the entire tree structure and at
every cross-sectional level
ModiFlow
A NEW GENERATION SPACER DEVICE
THE PATENT
EXISTING SPACERS
•
•
•
•
•
•
•
Usually cylindrical
Unstructured inner flow
Always turbulent
Little room for improvement
The back end always closed
Often a valve on the front end
Fixed volume
MODIFLOW
•
•
•
•
•
•
•
Sufficiently cylindrical
Inner septi subdividing the flow
Sequential lamination
Tree-like flow structure
Multilayer outflow
Open on both ends (unlimited volume)
Multiple designs possible
It is a spacer..
But it’s also a Flow Modification Device
CIP APPLICATION
• RELATED APPLICATION
•
This is a continuation-in-part of application
Serial No. 11/975,592, filed October 19, 2007,
entitled “Flow Modification Device”, now
Patent No. 8,371,291, which application
claimed the benefit of provisional Application
Serial No. 60/853,347, filed October 19, 2006,
and entitled “Flow Modification Device”, both
hereby incorporated by reference.
THE PLANT MODEL
• Multiple microtubular vascular elements
aligned in parallel and running continuously
from rootlet to leaf
FDA
•
•
•
•
•
Class 2 medical device
Premarket Notification – 510K
90 days to respond after 510K submission
Testing in FDA-designated labs
Proof of sufficient similarity to existing ones
PROOF OF CONCEPT TESTING
•
•
•
•
Colored air testing
Non-FDA lab testing
Computational Fluid Dynamics
Clinical testing with FDA’s permission
Development of new spacer device geometry: a CFD
study (part I).
• Asthma is a widespread disease, affecting more than 300 million
individuals. The treatment in children is based upon an
administration of a pressurised metered-dose inhaler added with a
spacer. The efficiency of drug delivery to the patient is strongly
affected by the transient airflow pattern inside the spacer device.
This paper presents a computational fluid dynamics (CFD) analysis
of airflow inside a commercially available spacer device with wide
application. This study, carried out in Fluent™, was the basis of an
optimisation procedure developed to improve the geometry of the
spacer and develop a more efficient product. The results show that
an appropriate control of the boundary layer development, by
changing the spacer shape, reduces the length of the recirculation
zones and improves the flow. It can be concluded that CFD is a
powerful technique that can be successfully applied to optimise the
geometry of such medical devices.
DESIGNING, PROTOTYPING
• Several different designs can be made to be
tested for maximum efficiency
• Different designs may be better suitable for
delivery of different aerosolized medications
• Therefore, tailored designs may be made for
different medication classes
FINANCING
•
•
•
•
•
•
•
•
•
•
•
Proof of concept testing - $5-25K ?
Designing, prototyping - $5-25K ?
FDA lab testing - $30-130K ?
510K submission - $1-10K ?
Manufacturing (molding and initial production) - $20-50K ?
Trademarking - $1-10K ?
Patenting (CIP) - $5-25K ?
Marketing - $50-100K ?
Distribution - $1-50K ?
Management - $2-125K ?
Total initial investment - $120-550K ?
ROI
•
•
•
•
Insurances reimburse for spacers $4-30+
Target market size ?
Cost of the business cycle per unit ?
Time to start of cash flow ?
FUTURE DEVELOPMENTS
• The cylindrical structure is the common
feature of almost all spacers
• The inner structure of ModiFlow is unique
• It is possible to augment all existing spacers
with the inner structure of ModiFlow to
improve their performance
• This could potentially tap into the entire
spacer market
• The principles of flow modification described here have
universality that is applicable in any device concerned with
transfer of fluid, gas, or information
• Potential targets include:
• Endotracheal tubes
• Oxygen masks
• Attachments to nebulizer machines
• Enteral systems
• Infant bottles
• IV systems
• Medical error prevention systems
• others
THANK YOU