Sustainability of Medical Therapeutics

Sustainability of Medical
Therapeutics
Michael N. Helmus, Ph.D., Consultant
Medical Devices, Biomaterials
Drug Delivery, and Nanotechnology
(508) 767 0585
mnhelmus@msn.com

Sustainability of Medical Therapeutics/US healthcare delivery
- Sustainablility of Medical Therapuetics
- Identification of Drivers for New Technology
- The bridge to commercialization
- Leverage Potential Emergent/Disruptive Technology
-- Personalized Medicine
-- Wireless Medicine
-- Nanotechnology: example of emergent technology
-- Electroceuticals
Agenda

mnhelmus@msn.com
STRUCTURAL MATERIALS
SURFACE MATERIALS:
BIOLOGIC INTERACTIONS AND LUBRICITY
CONTROLLED DRUG
DELIVERY MATERIALS
METALS ENGINEERING
PLASTICS
PLASTICS
ELASTOMERS
CERAMICS
BIOACTIVE
CERAMICS
BIOACTIVE
COATINGS
BIOLOGICS
BIODERIVED
MACROMOLECULES
HYDROPHILIC
COATINGS
HIGH STRENGTH
MODERATE
STRENGTH
HIGH
PERMEABILITY
SURFACE
COATINGS
SPECTRUM OF MATERIALS AND PROPERTIES
Bioactivity
COMPOSITES
AEROSPACE
DEFENSE
ORTHOPEDIC
DENTAL
RESEARCH PHARMACEUTICAL AND BIOTECH
Plastics
& Textiles
IndustryMEMS
Nano technology
Self Assembled Molecules
Biomimetics
Tissue Engineering

mnhelmus@msn.com
Sustainablility of Medical Therapuetics
Sustainability of US healthcare delivery
- return patient to active member of society
How to develop highly efficacious and safe technologies
- reduction of acute health costs
- reduction of chronic health costs
-- infection
-- heart disease
-- cancer
-- dementia

Challenges of Developing Medical
Technology
Clinical Centers
Investors/ROI
Physician
Collaborators
IP Strategy
Competition
Resource Limits
M&A and
Downsizing
Regulatory
Strategy
Commercial Lifetime
Technical Challenge
- Design Intent
Bundled Insurance
Reimbursement

mnhelmus@msn.com
http://money.cnn.com/2013/04/16/news/companies/ho
spitals-complications/index.html?source=cnn_bin
Example of the challenges:
Hospitals profit more from surgical complications - report
“No patient wants to experience complications after surgery. But
such complications can actually lead to higher profits for hospitals
if the patients are covered by Medicare or private insurance,
according to a report released Tuesday by the Boston Consulting
Group.”

Will bundled payments hurt healthcare innovation?
Written by Helen Adamopoulos | October 25, 2014
Bundled payment models —which involve a set price
intended to cover each element of clinical care or support
for a specific procedure or condition — could prove an
effective way for the care providers to contain costs while
improving quality. However, some healthcare industry
stakeholders have raised concerns about a possible
downside to bundling payments: stifling innovation.

mnhelmus@msn.com
Trends:
Younger patients
requiring
longer term
performance
requirements!
The Wall Street Journal
Fri. Aug 22, 2003

• Sustainability of Medical Therapeutics/US healthcare delivery
- Sustainablility of Medical Therapuetics
- Identification of Drivers for New Technology
- The bridge to commercialization
- Leverage Potential Emergent/Disruptive Technology
-- Personalized Medicine
-- Wireless Medicine
-- Nanotechnology: example of emergent technology
-- Electroceuticals
Agenda

Identification of Drivers for New
Technology
• Cost Containment/Bundled Reimbursement
• New Diagnostics and Point of Care
• Infectious Disease
• Epidemic/Pandemic Surveillance
• Biomarkers for Disease
• Enablement for interventions: e.g.
vulnerable plaque
Personalized
Medicine

• New Therapeutics
– Cancer
– Infectious Disease
– Immune Disease
– Minimally/Less Invasive Procedures
– Implants
– Tissue Engineering/Cell Therapy
Drivers for New Technology cont.

mnhelmus@msn.com
Leverage Potential Disruptive Technologies
Drug Delivery
Therapeutic Polymers
Biodegradables
3D Printing
Tissue Engineering
Stem Cells
Smart Materials
Imaging, e.g. Molecular Imaging
Genomics
Proteomics
Glycomics
Computation
NanoStructures
MEMS, eg CardioMems
Telemetered/sensored implants

mnhelmus@msn.com
Leverage ongoing Advances
LVAS and TAH implants
Drug-eluting stents to prevent reblockage of coronary arteries.
Less Invasive Spinal Repair: Fusion Cages, Kyphoplasty and Vertebroplasty
Robotically assisted cardiac surgery successfully corrects heart defects.
Less invasisve cardiac surgery, eg Transcatheter valve implantation
Tissue Engineering & Stem Cell transplants: potential for stroke recovery;
tendon grafts; CHF; Blood Vessel replacement; bone grafts; nerve regrowth
Molecular imaging biomarker for early disease detection
Telehealth monitoring for individuals with heart failure
Exhaled nitric oxide (NO) breath analysis for diagnosing asthma
Capsule endoscopy for diagnosis of pediatric GI disorders
Modified from AHA top ten innovations and CCF top ten
innovations

Personalized Medicine to Drive New Technology
Less Invasive Therapies
Custom Implants
Biosensors
Implantable biosensors, eg CHF
Telemetered devices and implants
Molecular Diagnostics
Genomic basis of Disease
Local and Targeted Drug Delivery
Pharmacogenomics
Tissue Engineering
Cell Therapy
New Imaging, eg. Histologic Grade
OCT
Personalized Medicine:
Local and Targeted
Diagnostics and Therapeutics
to allow “individualized
treatment for each patient”

mnhelmus@msn.com
Interventional Placements
of Implantable Devices and Treatments
e.g. CABG, Heart Valves, Joints
Tissue Engineered Constructs, Chordae Tendon
Repair, Biodegradable
Injectables for Heart Failure
Implantable Sensors
Functionality
Time
Surgical
Interventional/
MIS -
Stents , HVs
Implantable
Sensors
Disruptive Technology: Surgical Procedures
Genomics
Identifying Effective
Therapies

Nano-
Disruptive Therapeutics
Time
Biomaterials will drive new
disruptive Medical Therapeutics as
part of the Sustainability of Health
Care Delivery

mnhelmus@msn.com
Example Cell Therapy for Diabetes
ViaCyte

mnhelmus@msn.com
Medtech Strategist Nov. 2014

mnhelmus@msn.com

•The bridge to commercialization
• Proof of principle in a clinically relevant setting
• Drivers for Development
• Cost Containment, New Therapies, New
Diagnostics and Point of Care Medicine
•Intellectual Property
Commercializing

http://www.omeris.org/programs/RegForum/Schultz.pdf
Medical Device Design

mnhelmus@msn.com
Commercializing New Technology: Development Cycle
Start
Preclinical /Clinical
Animal testing
IDE/IND
Human Clinical
Concept
Prototype
Quality Systems
Packaging
CMC
Chemistry
Manufact.
Controls
Sterility
Inventory
Marketing
Epidemiology, Adverse
Reporting, Post-Market
Surveillance
Toxicology, Hazard Analysis, Study Design, Statistics
Toxicokinetics
Pharmacology,
Pharmacokinetics,
ADME, Biocompatibility
FMEA
Design Freeze
National
Materials
Components
Technology
Pharma
Biologics
Modified from
Helmus, Nature
Nanotechnology
1, 157 - 158
(2006)
510K, PMA,
NDA

MEDICAL DEVICE VALUE CHAIN
• Powders
• Dispersions
• Coatings
• Composites
• Biomaterials
• Proteomics
• Genomics
Formulation Fabrication Integration
Synthesis Modification
Separation,
Purification
Technology Medicine
Develop IP Strategy: Composition of Matter Applications
File IP

mnhelmus@msn.com
Commercializing Technology
Pulling Technology across the Valley of Death
Product Commercialization
Discovery &
Research
Development &
Engineering
Manufacturing &
Marketing
“Valley of Death”
Value

Technology Investment & Risk
Research
• Studies & Analysis
• Lab-Scale Demos
Cost
Risk
Manufacturing &
Commercialization
• Technology Transfer
• Production Line Layouts
• Production Prove-out
• System Integration
• Distribution & Deployment Logistics
Engineering &
Development
• Technology Assessment &
Evaluation
• Manufacturing Assessment
• Product Prototyping
• Pilot-Scale Demos
• Process Models
• Production Simulations
• Quality Control
• Life Cycle Assessments
Technology Maturity

PRODUCT LIFECYCLE FOR MEDICAL
DEVICES

Medical Device Market
• Device Company Aggregate Top line 11%
annually
• from 1995-2005
• R&D Funding at 10.3 % of sales
• Compound Annual Growth Rate – CAGR
15.3% compared to Pharma at 6.7% and
S&P at 6.0 %
• 510K’s in 2006 – 3,210
• PMA’s in 2006 - 39
P. LAWYER, J. P. ANDREW, M. GJAJA, AND C. SCHWEIZER, PAYBACK II: MEDICAL DEVICES RIDE
THE CASH CURVE IN VIVO: THE BUSINESS & MEDICINE REPORT | March 2007

Medical Device Market – Examples of Cash Curves
510K A 510k B PMA
R&D Costs
$ 0.25M $ 2 M $80M
Regulatory Approval and Time to
Market
15 mos 27 mos 15 mos
20% Operating Profit 30%
2yr life 6 yr life 8 yr life
$1.6 M pk sales $5.4M $215M

• PMA’s have high cost of failure
• Creating markets for niche products
• Leverage the physician and medical center
• Cost Containment
• Reduced downstream health costs
• Improved safety and efficacy
Medical Device Market – Challenges

mnhelmus@msn.com
Traditional Definition:
Personalized Medicine
'The molecular methods that make personalized medicine
possible include testing for variations in genes, gene
expression, proteins and metabolites, as well as new
treatments that target molecular mechanisms. Test results
are correlated with clinical factors - such as disease state,
prediction of future disease states, drug response, and
treatment prognosis - to help physicians individualize
treatment for each patient'
Personalized Medicine Coalition
www.personalizedmedicinecoalition.org/sci
encepolicy/personalmed-101_overview.php

Broader Definition of Personalized Medicine
Local and Targeted Diagnostics and
Therapeutics to allow “individualized

mnhelmus@msn.com
Recent Examples
Personalized Medicine
* Microfluidics chip can spot rare cancer cells in blood
Mass General Hospital - microfluidics chip to detect groups of rare
tumor cells in a patient's blood sample. The technique could help
improve research into cancer metastasis and spare patients from
undergoing invasive procedures used for collecting tumor samples. MIT
Technology Review (10/5)
*J&J Invests in New Noninvasive Cancer Test
Johnson & Johnson (J&J) has announced that it is investing $30 million
in a new test that could detect—and help doctors treat—a variety of
cancers from a simple blood draw, according to reporting by Yahoo
Canada News. While experts concede that such a test is still years away,
some are predicting that it could revolutionize cancer detection and
treatment.
AdvaMed Smart Briefs

mnhelmus@msn.com
Setting Expectations
How to innovate while addressing concerns.
Suggests need to establish well delineated practice
guidelines as the technology translates into the
clinic
(CNN) – Cancer breakthrough -- or nightmare?
January 11, 2011
“A simple blood test. It's able to detect minute quantities of cancer cells
that might be circulating in your bloodstream.
It's reported to be able to detect a single cell. It's intended to allow
cancer patients to start treatment much earlier.
It's supposed to save lives. It's a cancer breakthrough.
But it's not that simple. The test could just as easily start a cancer
epidemic.”

Personalized medicine. Personalized medicine includes the detection of disease
predisposition, screening and early disease diagnosis, prognosis assessment,
pharmacogenomic measurements of drug efficacy and risk of toxic effects, and the
monitoring of the illness until the final disease outcome is known.
JS Ross, GS Ginsburg, The Integration of Molecular Diagnostics With Therapeutics
Jeffrey S. Ross, MD, Geoffrey S. Ginsburg, MD, PhD American Journal of Clinical Pathology. 2003;119(1)
http://www.medscape.com/viewarticle/447846

When its
personal, its
not quick
enough!!!

When it becomes personal!!
Hi Fever, fainting, coughing
ER visit, immediate admission to ICU
Chest X-Ray consistent with bacterial infection
Hi dose Antibiotics
Rapid progression to BiPap and intubation and ventilator
within 4 days with continuing deterioration

Discussion with family
About 4 weeks prior: Exposure to Polyurethane sealant during
renovation, poor ventilation, walls exposed
2 weeks prior: reexposure to Polyurethane sealant
Immediately administered prednisone and antifungal (as precaution)
Lavage indicated no fungal or bacterial involvment
Stopped Antifungal
9 days on ventilator
Diagnosis hypersensitivity pneumonia

Disease Management
Admission
Circulating WBC Biomarkers
Circulating Antibodies
Biosensors
Radiology
Complete blood count
Complete metabolic profile
Blood gases or pulse
oximetry
Bronschoscopy, Bronchoalveolar lavage,
transbronchial biopsy
Thoracoscopic or open-lung biopsy
Radiographically guided transthoracic aspirate
Legionella, Chlamydia, Mycoplasma serology
Fungal serology
Evaluation for congestive heart failure,
pulmonary embolus, neoplasm, connective
tissue disease
Deteriorating patient without definitive
diagnosis of cause
Earlier impetus for lavage and biopsy
Earlier treatment with steroids
Eliminate diagnosis of fungal infection
Eliminate or reduce need for ventilation
More rapid recovery, mitigating DVT
Personalized Medicine Early Disease Diagnosis: Molecular Pathology
Screening
Subclinical Disease processes
Predisposition

Bilateral below knee DVT
Increased heparin, Vena cava filter
Indication of allergic reaction to due to skin hives/rash
Suspicion heparin allergy, change to LMW heparin
Significant bodywide rash
Warfarin therapy
Post release, discovery of hi FVIII disease

Disease Management cont.
Hospital based complications
DVT Increase heparin, Vena Cava Filter
Heparin Allergy LMW Heparin
More severe Heparin Allergy Warfarin
Personalized Medicine Mitigating Complications: Molecular Pathology
Screening Pharmacogenomics
Subclinical Disease processes
Biosensors High FVIII disease
Identification of Heparin allergy
Earlier Warfarin administration
Pharmacogenetics Titrate Warfarin dose
When can Warfarin dose be
eliminated

This is Siri. We
have news for you.
You appear to be
dead!!!
Patients will be monitoring their own health with
Smart phone sensors and apps. They will be
taking control of their own health before they
even see the Dr.

Wireless Monitoring
Ultralow power analogue transmission platform for remote patient
management, reprogrammable to operate in different frequency bands
and under standard wireless platforms for First Response and Triage
• Bandage-like patch with sensor to
monitor skin – moisture, pH,
temperature, EKG, etc
• Ultra-low power, wireless enabled
sensor platform using mixed signal,
analogue processing
• Vital sensing for military and triage
applications

Eric Topol
http://books.google.com/books?id=5Q-
O9vnNqPkC&pg=PR3&lpg=PP1&dq=creati
ve+destruction+of+medicine

LifeWatch launches world's first medical smartphone
The smartphone has built-in sensors for monitoring heart rate, pulmonary function, blood sugar
levels, body temperature and more.

mnhelmus@msn.com
Next Gen Sensors will drive the thrust for
the evolution of personalized medicine and
on demand therapy to mitigate adverse
events as they happen:
- implantable sensors for diagnostics and
closed loop feedback for drug delivery and
Electroceuticals.
Next Gen Sensors

Micromechanical Sensing & Detection
Nanotechnology Approaches to Sensing and Detection
Dr. James S. Murday Dr. Richard J. Colton, Naval Research Laboratory
http://www.frtr.gov/pdf/meetings/dec04/murday_12-04.pdf
C nanotube networks: Detection via field-
induced polarization of adsorbates on
SWNT surface
BioFETs: thin for efficient sensing (~2 nm).
source drain; specific attachment of DNA or protein
Biosensor Examples

Nano-materials for biosensor applications
Material Biosensor Application
Carbon nanotubes Single molecule detection
Titania nanotubes Hydrogen sensors; Enzyme immobilization
Nickel nanowhiskers Biomolecules impart "fingerprint" by changing the electrical signal of the
nanocontact
Metallic nanowires and
nanospheres
Nanoantennas, Molecular detection
Tin-Oxide platinum
electrodes sandwhich
Highly sensitive and stable nerve-gas sensor with potential ability to detect a
single molecule
Gold Nanocluster Chemical
Sensor
Molecular detection in solution
Antibody conjugated
Quantum dot
Molecular detection: Competition assays in solution; identification of tissue
biomarkers.
DNA-gold nanoparticles Highly sensitive and selective colormetric biosensor
Protein-encapsulated single-
walled carbon nanotubes
Near-infrared nanoscale sensor that detects target molecules
Polymers with optical
properties of hard crystalline
sensors
A silicon wafer is treated with an electrochemical etch to produce nano-
porous silicon chip - optical properties of a photonic crystal. Used as mold
for polymers - “replica” of the porous silicon chip.

mnhelmus@msn.com
INSTRUMENTATION/PACKAGING
• Spectrometry
• Light Scattering
• Microfluidics
• Nanosensors
• Biochips
• Thin film transistor arrays
• Scattering techniques
• Tissue culture techniques
MODELING
• Computational modeling:
- biomolecules
- crystallographic structures
- biokinetics and dosimetry
• Tissue-light interactions modeling
APPLICATIONS
• Disease Biomarkers
• DNA/Gene expression
• Chemical and Biotoxin Exposure
• Pathogen sensing
• Molecule detection
• Single molecule detection
Biosensor Development
Modified from:
http://www.ornl.gov/sci/biosensors/a
bstg_orgchart.pdf#search=%22Adva
nced%20Biomedical%20Science%20
and%20Technology%20Group%22

Disease Applications
Deliver nano-enabled solutions for biosensors
•Detection of disease and infection
• Wireless Monitors for triage, and first response therapy
• Management of Chronic Diseases

mnhelmus@msn.com
Example Implantable Glucose Sensor
Senseonics

mnhelmus@msn.com
Key Requirement for Chronic Sensors and
Electrodes
Stability of Sensor
Biocompatibilty
Mitigate Fibrous Capsule Formation
Next Gen Bioactive Biocompatible Coatings

mnhelmus@msn.com
Nanopores for drug
delivery
Nanoenabled Diagnostics and
Therapies
Nanoparticles to cross
The blood brain barrier:
Diagnostics, drug delivery
Gold shell nanoparticles for
Tumor ablation
Nanofiber Scaffolds for
Vascular prostheses &
Tissue engineering
Nanodiagnostics for point of care
Diagnosis: infectious disease,
biomarkers
Quantum Dots for
Molecular
Imaging
Nanoporous filters: Drug delivery,
Hemodialysis, Plasmapheresis,
Oxygenation – Celgard has been
available for 30 + years

The final report of the Triennial Review of
the National Nanotechnology Initiative has
been released today.
https://download.nap.edu/catalog.php?reco
rd_id=18271#toc
It was with great satisfaction working with
the co-chair, committee members and the
National Academies' staff on this important
document. Please read through the
findings and recommendations on a
program that has significant impact on
"basic and applied research and for
development of applications in
nanotechnology that will provide economic,
societal, and national security benefits to
the United States."

mnhelmus@msn.com
Example of Emergent Technology

mnhelmus@msn.com
carbon nanotube
http://smalley.rice.edu
domains in triblock copolymer
Helmus, ACS, 1982

The development of efficacious
therapeutic and diagnostic
procedures based on
nanotechnology will require the
early collaboration of clinicians
and an understanding of the
clinical environment
Nanomedicine

The Promise and the Challenge of Nano-enabled
technologies for Medical Applications
•Enhanced functionality and
biocompatibility
•Potential new paradigms required for
biocompatibility evaluations of nano-
structures and particles

Short
Long
Medical Applications
enabled by nanotechnologies
• Improved catheters, balloons, implants: Polymer Nano-Composites to
improve strength, stiffness and toughness
• Joint prostheses, stents: Metallic alloys - nano-grained, composites, and
coatings for strength, toughness, lubricity and wear resistance
• Biocompatible Surfaces and Drug Delivery Coatings: Nano-structured
surfaces
• Diagnostics and Imaging: Nanoparticles and carbon nanotubes
• Implantable biosensors and active muscle, nerve, neural electrodes:
MEMs and NEMs, tissue interfacing electrodes; small, low-power
processors with wireless communications
• Targeted drug delivery& cancer therapy: nanoparticles
Timetocommercialize

mnhelmus@msn.com
On this T2*-weighted gradient-echo image obtained after the
administration of Feridex (ferumoxides), the lesion (arrow) has become
very hyperintense to the liver.
http://www.kjronline.org/abstract/files/v04n019.pdf
Jeong Min Lee, et al Korean J Radiol 4(1), March 2003
Superparamagnetic Nanoparticulate Iron Oxide for Liver Imaging

http://www.nature.com/news/Functional Electrical Stimulation-spark-interest-1.15494

First Neurally Controlled, Powered Prosthetic Limb Is 2,109 Steps Closer To
Realization
http://www.prnewswire.com/news-releases/first-neurally-controlled-powered-prosthetic-
limb-is-2109-steps-closer-to-realization-177780951.html
IRVINE, Calif., Nov. 7, 2012 /PRNewswire/ -- Freedom Innovations, LLC, a leading
developer of high technology prosthetic medical devices, announced today that research
participant Zac Vawter utilized the world's first neurally controlled, powered prosthetic
limb to climb 103 floors (2,109 steps) of Chicago's Willis Tower at the SkyRise Chicago
fundraiser. In this most grueling test of the technology to date, Vawter demonstrated that
this advanced research is quickly on its way to becoming available to lower-limb
amputees worldwide.
The computerized prosthetic limb Vawter used in the climb incorporates two significant
advancements in prosthetic technology. First, as the only system to feature fully-
powered knee and ankle prosthetic joints, the prosthetic limb is no longer passive.
Motors in the system replace muscle function lost from an amputation. This facilitates
power-driven ambulation that also allows an amputee to actively climb stairs and slopes.
Second, Vawter benefited from neural control of this powered system where his thoughts
helped to direct the software and action of the prosthetic limb via targeted muscle
reinnervation (TMR). Brain signals from nerves severed during amputation are rerouted
to intact muscles, allowing patients to control their robotic prosthetic devices by merely
thinking about the action that they want to perform

http://www.experts.sci
val.com/cwru/pubDetai
l.asp?t=pm&id=111442
29477&o_id=1&n=Ken
neth+J+Gustafson&u_
id=223

Personalized Medicine to Drive New Technology
Local and Targeted
Diagnostics and Therapeutics
to allow “individualized
Drug Delivery,
Tissue Engineering
& Cell Therapy
Biomarker &
Disease
Detection
Less Invasive
Procedures
Medical Devices, Biomaterials
Drug Delivery, and Nanotechnology
(508) 767 0585

Sustainability of Medical Therapeutics

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