Sustainability Medical Therapeutics 2015

Sustainability of Medical Therapeutics

Michael N. Helmus, Ph.D., Consultant Medical Devices, Biomaterials

Drug Delivery, and Nanotechnology

(508) 767 0585 [email protected]

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

21st

Century

?

Michael N. Helmus, Ph.D., Consultant [email protected]

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

Industry

MEMS

Nano technology

Self Assembled Molecules

Biomimetics

Tissue Engineering


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


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.

https://www.facebook.com/sharer/sharer.php?u=http://www.beckershospitalreview.com/finance/will-bundled-payments-hurt-healthcare-innovation.html





Trends:

Younger patients

requiring

longer term

performance

requirements!

The Wall Street Journal

Fri. Aug 22, 2003

• Sustainability of Medical Therapeutics/US healthcare delivery








-- 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.


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


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”


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

Funct

ional

ity

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


Example Cell Therapy for Diabetes

ViaCyte


Medtech Strategist Nov. 2014










-- Electroceuticals

Agenda

•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


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


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









-- Electroceuticals

Agenda


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



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

http://ca.news.yahoo.com/j-j-helps-develop-blood-test-spot-1-20110102-211742-558.html


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.”

http://www.cnn.com/2011/HEALTH/01/03/cancer.test/index.html?iref=allsearch

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

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









-- Electroceuticals

Agenda

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.

http://www.globes.co.il/serveen/globes/nodeview.asp?fid=1725


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.


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


Example Implantable Glucose Sensor

Senseonics




Key Requirement for Chronic Sensors and

Electrodes

Stability of Sensor

Biocompatibilty

Mitigate Fibrous Capsule Formation

Next Gen Bioactive Biocompatible Coatings











-- Electroceuticals

Agenda


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."

https://download.nap.edu/catalog.php?record_id=18271

https://download.nap.edu/catalog.php?record_id=18271


Example of Emergent Technology


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

Tim

e t

o c

om

merc

iali

ze


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.kjronline.org/abstract/files/v04n019.pdf









-- Electroceuticals

Agenda

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

Michael N. Helmus, Ph.D., Consultant Medical Devices, Biomaterials

Drug Delivery, and Nanotechnology

(508) 767 0585

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Sustainability Medical Therapeutics 2015

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