csiro biomedical manufacturing
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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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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
| Page 35
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
| Page 36
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.
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