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 low-dose 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 hypothalamic-pituitary-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.AbstractOBJECTIVE: 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 charge-dissipative/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