CSIRO Biomedical Manufacturing

DR PAUL SAVAGE

64% of our people hold

university degrees over

2000 hold doctorates

over 500 hold masters

CSIRO

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Budget $1B+

We develop 832postgraduate research students with our university partners

DIGITAL PRODUCTIVITY AND SERVICES

BIOSECURITY ENERGY

Our Flagships

OCEANS AND ATMOSPHERE

FOOD AND NUTRITION

AGRICULTURE

MINERAL RESOURCES

MANUFACTURINGLAND AND WATER

BioMedical Manufacturing

Cell Biology (David Haylock)Structure, physiological properties, environmental interactions, replication, proliferation, and death of cells in the biomedical context, with a particular focus on stem cell biology.

Biomedical Synthetic Chemistry (Jack Ryan)A capability concerned with molecular synthesis, including small molecules, polymers, bio-conjugates, and peptides with the intention of eliciting a biological response. Examples include medicinal chemistry, peptide chemistry, drug delivery systems, polymer-drug conjugates, biocompatible and bioactive polymers.

Protein Science (Tom Peat)Research on the structure, function, and biochemical significance of proteins, their role in molecular and cell biology, and their regulation and mechanisms of action. In particular, using bioscience skills to engineer the appropriate vectors in order to produce proteins of interest, either on a laboratory or large scale. Includes protein and antibody engineering, protein purification, fermentation.

Biophysics (Natasha Wright)Core competencies include the use of both experimental and theoretical tools to interrogate physical samples. These instruments and techniques are used to observe, determine, and model structures of, e.g., individual molecules, surfaces, cells, or nanostructures. Examples include: SEM, X-Ray crystallography, NMR, mass spect, SPR, XPS, SAXS, AFM.

To leverage our expertise in biological and materials science to develop materials and processes that

provide growth opportunities and

commercial competitiveness for

Australia’s high value medical technology

sector.

125 FTEProgram Director: Paul Savage

Track Record

Commercial translation: Top 10 CSIRO

4. EXTENDED WEAR CONTACTS

2. POLYMER BANKNOTES

3. RELENZA FLU DRUG

1. WLANWireless Local Area Network

5. AEROGARD 6. TOTAL WELLBEING DIET

7. RAFT POLYMERISATION

8. BARLEYMAX 9. SELF TWISTING YARN

10. SOFTLY WASHING LIQUID

• CSIRO partnership with the Vision CRC and CIBA Vision Corporation

• Focus Night and Day™ and O2OPTIX™ contact lenses

• A soft silicone hydrogel lens that can be worn continuously for 30 days

Extended Wear Contact Lens

Relenza – Flu Drug

• Structural biology approach to drug design

• CSIRO with the CRC for Cardiac Technology developed a suite of silicone-polyurethane co-polymers

• Materials have excellent physical and mechanical properties and biological stability

• ElastEonTM commercialised by AorTech Biomaterials Plc

• More than one million patients have been implanted with pacemakers insulated with ElastEonTM

ElastEon™

Reversible Addition Fragmentation Chain Transfer Polymerisation (RAFT Polymerisation)

Biomaterial Capabilities

Capabilities

CSIRO Capabilities

Polymer Chemistry and Fabrication

Biological Materials and Protein Chemistry

Surface Modification Cell and Stem Cell Biology

Materials EvaluationMedicinal Chemistry Design and Synthesis

Antibody EngineeringProtein Expression

Instrumentation/Software Development

Biomedical Materials and Regenerative Medicine

Design and synthesis of materials for biomedical use as devices and scaffolds to improve function of damaged and diseased tissues and organs by regeneration, repair, augmentation or replacement.

Cell BiologyCSIRO has expertise in cell biology:

• Isolation/expansion of primary cells

• Cell-matrix interactions

• Stem cell isolation, expansion, differentiation

• Antibody technology

• Cytotoxicity testing

Biocompatibility

• Biological Evaluation

• Cell-material interactions• Histology/cytology• Immuno-histology/cytology• Microscopy – standard, confocal, TEM, SEM• Histopathology • Image analysis

Animal Testing

• State of the Animal Facility

• PC2 and PC3 (quarantine) capability

• Small animal model research, expertise with mice, rats, rabbits

• Modern animal surgery

• Collaborations for large animal evaluations

High Throughput Synthesis and Analysis Facility

Microarray robots• Combinatorial resin formulation array

• Piezo and solid pin spotters

High cell attachment

on high concentration

Low cell attachment on

low concentration

HeLa cell attachment on collagen IV printed on GMA/PEGMA array

Flow Technologies at CSIROFlow Chemical Laboratory

2 x Thales Nano H-Cubes

1 x AMT Coflore ACR1 x Uniqsis FlowSyn

5 x Vapourtec R2/R4

For both• Small molecules synthesis• Polymer synthesis and modification

Proximity to and Member of Key Centres for Characterisation

• Australian Synchrotron• SAXS/WAXS beamline

• XPS beamline/NEXAFS

• Imaging and medical beamline

• Melbourne Centre for Nanofabrication• Ellipsometry

• Other AFMs

• FIB-SEM, FIG-SEM

• Screening/interrogation facilities

• Access to other surface characterisation instruments • ToFSIMS through LaTrobe University surface characterisation facility

• X-ray and neutron reflectometers through ANSTO

Molecular Characterisation Capability

• Coordinated access to complementary techniques• Nuclear Magnetic Resonance Spectroscopy

• Mass Spectrometry

• X-ray Photoemission Spectroscopy

• Chromatography

• Atomic Force Microscopy

• Infrared Spectroscopy

• Polymer Characterisation

• Specialist skills in each technique• Expertise in interpretation of

complementary data

Material Scale-Up Synthesis

Polymer processing (grams to tons) Monomer/polymer synthesis scale-up (<1L to 250L)

Scale-up synthesis of

precursors & polymers

Wiped-film evaporator

for monomer purification

Current Interests

Antibody-Drug Conjugates

Currently cytotoxic drugs are directly conjugated to humanised antibodies

ADCs – An Emerging New Technology

• Direct conjugation of drugs onto antibodies• Relies on availability of suitable amino acid side chains (-COOH, -NH2, -OH,

-SH) or genetically engineered sequences

• Can interfere with activity, e.g. through interference with binding sequence or impact on tertiary structure

• Antibody-drug stoichiometry• Difficult to control and reproduce

• Usually get a mixture of drug/ADC ratios

• Separation issues e.g. ADCs from free antibody

• Solid tumour penetration is low

• High manufacturing costs

Antibody-Polymer-Drug Conjugates

RAFT derived polymer(tailored MW, charge,

hydrophobicity, pharmacokinetics)

Linker for covalent site specific coupling

(chemical, biological)

Targeting Studies Efficacy StudiesADMET Studies

Drug copies(multiple drugs)

Targeting ligand(antibody, antibody fragment, receptor ligand, other biologic)

Antibacterial Polymers

• Use controlled free radical polymerisation (RAFT)• Polymers which mimic the structure and action of host defense peptides

• Optimise properties to maximise efficacy and minimise toxicity

• Effective against:• Bacteria and fungi (S. epidermidis, S. aurius (MRSA and VISA), C. albicans)

• Do not appear to develop resistance• Sub MIC application to C. albicans for 21 days

• Opportunities to optimise polymer composition against additional bacteria, in particular gram negative

Antimicrobial Host Defence Peptides• Broad spectrum antimicrobial effects

• Low human cell toxicity

• Low susceptibility to resistance

• Amphiphilic structure governs mechanism of action:

• Cationic side chains bind to bacterial membrane

side chains inserts into membrane cell lysis

Arginine

Lysine

Mimicking Peptides with Polymers•Amphiphilic polymethacrylates:

• Mimic antimicrobial peptides amphiphilic structure

• Potent antibacterial effects

• Low human cell toxicity

• Less expensive to produce & manipulate chemically

Collagen in medicine

• Collagen extensively proven as a medical material

• As tissue-based devices; as reconstituted devices

• Animal derived

Recombinant Collagen Scaffolds

• Novel, collagen proteins produced from bacteria (non-animal)

• Can be scaled up for medical and tissue engineering

applications

Materials for Cell therapies

• Cellular therapies is a growth industry• 100s of clinical trials worldwide

• First cell therapies were actually bone marrow transplants

• A cellular therapy can be a “cure” rather than simply treating symptoms or managing pain

• Recent FDA approved example is Provenge® (Dendreon) - treatment for prostate cancer using dendritic cells (Autologous)

• The costs of producing cells for therapy are very high (US$90 k)

• Treatments are either:• Autologous (from the patient) or

• Allogeneic (from a donor)

• Each requires a different manufacturing strategy

Background: scale up of cell culture• 2D flasks to cell factories

• 3D cells in suspension or attached onto plastic particles called microcarriers (typically 200 um in diameter and made from materials like polystyrene)

T75= 75 cm2 of cell culture area6300 cm2 = 36 x T175 flasks

T175 = 175 cm2 of cell culture area40 layer cell factories

pneumatically controlled unitwhich automates the filling/emptying of

medium or cell suspension

Spinner Flask125 mL

Stirred large scale bioreactor150 Litres

Cells on microcarriers

Material development: platform approach• Multiple chemistries and properties

• In a stem cell context:

1. Non-adherent surfaces – low protein adsorption

2. Adherent surfaces which encourage the right sort of protein adsorption

3. Chemically defined surfaces with molecules which interact very specifically with cell attachment proteins on cell surfaces

• Ideally one step

• Simple, scalable manufacture

• Low cost (disposable items)

Cell attachment in response to adsorbed proteins

(serum-containing media)

Cell attachment in response to specific signals

(serum-free conditions)

No adsorbed proteins – no cell attachment in response to

(serum-containing or serum free media)

• Metal Organic Frameworks mimic biomineralisation

• Enzymes can be protected from high temperatures

• Rapid, low-cost biomineralisation using MOF synthesis

MOF protection of Biomacromolecules

Nature Communications, 2015, 6, 7240. doi:10.1038/ncomms8240

Technology Emphasis

Point of Care Diagnostics Chemiresistor

Sensing technologies Wearables, imaging

RAFT (biomedical) Materials and conjugates

Stem cell manufacture MSB; HSC; iPS

Rec. Protein Production Contract research

Improved bioactive delivery siRNA, lipids, injectables

Coatings technologies Tissue integration, anti microbial

Flow Chemistry Improved synthesis of small molecules

3D Printing Ti powder - orthopaedics

Customised medical polymers Siloxane and PU

Medicinal Chemistry Contract research

RAMP – high throughput Materials synthesis/testing

Main current Activities

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Technology Market Status

Fibre Optic Catheter IPC; Lower GI Clin. trials

Drug Depots Injectable, dermal Preclinical

Exolon Coatings Medical device Tie layers Pre-clinical

Recombinant Collagen medical Pre-clinical/Scale-up

3D mammography Breast cancer Pre-clinical

ElastEon and PDMS Cardiovascular Commercial

Photoactive drug delivery ophthalmic Preclinical

Lipid nanoparticles Pro-Drug delivery Pre-clinical

RT Endoscopy Assistance Endoscopy Pre-clinical

Blood tests for Cancer SSA, Prostate, recurrence 1st test launched CRC

RAFT polymers Anti-viral/bacterial; ADC Pre-clinical

Chemiresistor & CyberNose Point of Care Diagnostics Clinical

Opportunities – Devices Technologies

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Working with us

• There are many different models of engaging with CSIRO for successful outcomes for your business:• Joint venture

• Spinout company

• Contract services

• Licensing of technologies

• Collaborative researcher

• Co-investment

• Contract research

Thank you

Paul Savage BSc PhD MBA FRACI FAICD

Program Director | Biomedical ManufacturingCSIRO Manufacturing Flagship

T: +61 (0) 3 9545 2523 | M: +61 (0) 407 357 776 | Skype: g.paul.savagepaul.savage@csiro.au | www.csiro.au | au.linkedin.com/in/gpsavage/

Personal Assistant: Amy Garland | T +61 (0) 3 9545 2097 | amy.garland@csiro.auAddress: Ian Wark Laboratory, Bayview Ave, Clayton VIC 3168, Australia.Postal: Bag 10, Clayton South, VIC 3169, Australia.