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					                                                                  National Centre for Biosecurity




Nanotechnology in medicine and biosecurity: dilemmas for
  bioethics, public health law and international human rights

                    Thomas Alured Faunce BA LLB (Hons) B Med PhD.
    Senior Lecturer Faculty of Medicine and College of Law, Australian National University,
   Director Globalisation and Health Project, Board Member National Centre for Biosecurity.
                                Thomas.Faunce@anu.edu.au

                     Johns Hopkins Bloomberg School of Public Health
                                       Hapton House Room 688
                            Johns Hopkins Bloomberg School of Public Health
                                           624 N Broadway
                                         Baltimore, MD 21205

                                        Tuesday, April 17, 2007

                                            2:30 - 4:00 p.m.
                                    National Centre for Biosecurity




                        OVERVIEW

• Research background

• Introduction to nanotechnology in biosecurity

• Introduction to nanotechnology in medicine (with
  particular focus on Australian nano/bio-tech.
  companies and cost-effectiveness regulation)

• Related dilemmas for bioethics, public health law and
  international human rights
     Relevant Research and Professional Background

 Project Director of three year ARC trade and medicines
  grant (2005-2007)
 Project Director of three year ARC Discovery grant in
  regulation of nanotechnology in medicine (2007-2009)
 Founding Board Member Australian National Centre for
  Biosecurity (NCB)
 Former senior registrar in intensive care at Alfred
  Hospital (Melb)
 Consultant with UNESCO on its global data base of
  bioethics, health law and international human rights
                                             National Centre for Biosecurity



Australian National Centre for Bioecurity (NCB) aims:

Facilitate academic and policy engagement with:

1)Fast-moving infectious disease outbreaks of natural origin

2) Biological weapons threats

3) Risks associated with research on pathogenic organisms

4) Implications of emerging technologies for biosecurity

5) Disease impact on health governance, state functioning and
   economy
Nanotech. In Biosecurity
                      Biosecurity and the dilemma of medical chaos
                                 after terrorist bombings

 On 12 October 2002 a bomb containing approximately
  500mg-1g TNT, and 80-120cm above the ground, exploded
  near the northern wall of a bar in Kuta, Bali.
 Survivors underwent debridement, removal of shrapnel and
  suturing of multiple lacerations under general anaesthetic at
  the Sanglah Central General Hospital in Denpasar, Bali,
  being further assessed by a team of Australian medical
  specialists on the tarmac.
 Transported by RAAF Hercules aircraft to Darwin and at
  Darwin Hospital resuscitated in the general ward, before
  being transferred to Australian ICUs via RAAF Hercules
  aircraft then helicopter transfer.
   •   TA Faunce, The Bali Disaster: Principles of Management for Australian Intensive Care
       Australian and New Zealand Anaesthesia and Intensive Care Scientific Meeting, Hobart May
       2003
             Primary, secondary and tertiary injuries from
                         terrorist bombings


• ―Primary‖ terrorist bomb injuries: deriving from the blast
  wave itself: cerebral gas embolism and extensive pulmonary
  contusions as well as bilateral ruptured tympanic membranes.
• ―Secondary‖ injuries from shrapnel, structural debris or heat
  propelled by the blast wave: severe and extensive burns as well
  as wounds which became ongoing sources of infection and
  sepsis
• ―Tertiary‖ injuries from immediate displacement against solid
  objects or from building collapse or fire: simple fractures,
  contusions, abrasions and lacerations consistent with either
  being blown against a structure, or having it fall or burn upon
  them. Building collapse is a deliberate terrorist aim to
  maximise casualties from a bomb blast.
               Dilemmas with delayed deliberate terrorist post-
                               blast injuries

 Delayed deliberate post-blast injuries to create secondary hazards
  for victims, rescuers or medical staff: second bomb attached to a
  mock or pseudo-victim, or radiation or biologic vectors.
 The secondary targeting of hospitals by terrorists in this manner
  may be part of a tactic to disable disaster response plans.
 Our ICU patients developed complex gram negative infections due
  to atypical organisms. The dominant organism was acinetobacter,
  but of a type not previously seen in our unit. What if it had been a
  form of the 1918 influenza virus, a deliberately mutated mousepox
  or smallpox?
 A protocol requiring use of nanotechnology rapid surveillance for
  such bio-hazards could be critical to minimizing injury in this
  phase. But what should be the form and content of laws and
  guidelines to control the response to a positive result?
                          Nanotech in Biosecurity

The United States Department of Justice (DOJ) National Institute
    of Justice (NIJ) has two separate biosecurity-related projects
    that incorporate nanotechnology -
1) DNA Research: to develop a nanotechnology device that will
    be integrated into the current crime laboratory processes
    and protocols to rapidly and accurately analyze forensic
    DNA samples.
2) Chemical detection: developing a wearable, low-cost device
    to provide better warning of exposure to unanticipated
    chemical and biological hazards than current approach
    relying on vapor exposure of an immobilized enzyme
      surface.
 M.C.Roco.National Nanotechnology Investment in the FY 2003 Budget Request by the President. National
      Science and Technology Council's subcommittee on Nanoscale Science, Engineering and Technology
                                 Nanotech in Biosecurity


 The Forensic Science Center at Lawrence Livermore National
  Laboratory in the US aims to develop nanostructured materials
  for the collection, concentration and detection of chemical
  weapons or other related compounds :
 Silica-based nanomaterials,
 Molecular imprinted polymers and
 Silicon platforms
    Reynolds J.G.;Hart B.R Nanomaterials and Their Application to Defense and Homeland
      Security , 2004; 56 (1): 36-39
 US Defense-funded basic research programs include 16
  multimillion-dollar annual grants to university researchers as part
  of the defense university-research initiatives in nanotechnology
  and some 25 grants under the multidisciplinary university-
  research initiative.
                Dilemmas from US-China interests in military
                             nanotechnology
The Institute for Soldier Nanotechnologies (ISN), is a research
collaboration between the United States Army and the
Massachusetts Institute of Technology (MIT).
The ISN combines basic and applied research into military
applications of nanoscience and nanotechnology in: protection,
performance improvement, injury intervention and cure.

Strategists within China's People's Liberation Army (PLA)
reportedly understand the strategic significance of such military
nanotechnology research in the United States.
The Center for Nanotechnologies at the Chinese Academy of
Sciences (CAS) in Beijing opened in 2000. Uniting over a dozen
CAS institutes and several university laboratories, the aim of the
center was to upgrade scientific cooperation while accelerating
nanotech industrial development in Beijing. Military research?
Implications of ―nano-war‖ rivalry for peace and fundamental
freedoms?
                                                 National Centre for Biosecurity


 U.S. National Academies Globalization, Biosecurity, and the
                  Future of the Life Sciences
 Focusing on known bio-weapon pathogens may miss the bigger picture
  of non-traditional attacks.
 Laws such as PATRIOT and the Bioterrorism Response Acts may
  discourage research that could be helpful to the U.S and humanity.
 Ethical guidelines and codes for scientists in nano/biosecurity research
  could be useful if combined with education programs
 Restrictive regulations and the imposition of constraints on the flow of
  life sciences information are unlikely to reduce risks of its malevolent
  use.
 Such restrictions will limit the potential for continuing advances in the
  life sciences and its related technologies to improve health, provide
  secure sources of food and energy, contribute to economic development
  in both resource-rich and resource-poor parts of the world.
                                                                    National Centre for Biosecurity


                          BWC and CWC and International Law

• “The 1972 Biological and Toxin Weapons Convention (BWC) and the
  1993 Chemical Weapons Convention (CWC) serve as cornerstones of
  the global biological-chemical regime, which has expanded to include
  rules and procedures rooted in measures ancillary to the two treaties.”
•   U.S. National Academies Globalization, Biosecurity, and the Future of the Life Sciences


•   The Biological Weapons Convention (BWC) prohibits the development and
    acquisition of biological weapons and is the foundation of international efforts
    to prevent their use. Member states meet every five years in Geneva,
    Switzerland to review and improve the operation of the Convention. The Sixth
    Review Conference of the BWC took place from November 20 through
    December 8, 2006, seventh Review Conference takes place in 2011.

•   Article X (2) This Convention shall be implemented in a manner designed to
    avoid hampering the economic or technological development of States Parties
    to the Convention
   Universality, national implementation, confronting non-compliance.
                                                 National Centre for Biosecurity


    UNESCO Universal Declaration on Bioethics and
                   Human Rights
Assume: Nano-computer power for face recognition, speech
   recognition, and object tracking on ubiquitous public cameras:
 Article 8 – Respect for human vulnerability and personal integrity
   In applying and advancing scientific knowledge, medical practice and
   associated technologies, human vulnerability should be taken into
   account. Individuals and groups of special vulnerability should be
   protected and the personal integrity of such individuals respected.
 Article 15 – Sharing of benefits
   1. Benefits resulting from any scientific research and its applications
   should be shared with society as a whole and within the international
   community, in particular with developing countries. In giving effect to
   this principle, benefits may take any of the following forms:
 Article 16 – Protecting future generations
   The impact of life sciences on future generations, including on their
   genetic constitution, should be given due regard.
Nanotech. in Medicine
                    Nanomedicine Research is Developing Rapidly




 The research budget of every major pharmaceutical
  company now has a considerable component devoted to
  nanotechnology.
 Nanomedicine is a major area of interest for Australian bio-
  tech. companies

   Nanotherapeutics: new challenges for safety and cost-effectiveness regulation in
    Australia
    Thomas Alured Faunce — Med J Aust 2007; 186 (4): 189-191 (free on-line).
                                                                       Nanomedicine

Nanoparticles may provide an efficient delivery system for DNA vaccines
and gene therapy. They may assist speedier and more efficient delivery of
drugs to diseased cells with less pain. They have been investigated in
neurosurgery, cardiac surgery and blood disorders.
Peptide nanotubes have been investigated as the next generation of
antibiotics and as immune modulators. Nanogenerators are being
engineered that utilise an antibody to direct a caged radioactive atoms to
destroy cancer cells.

 Mumper RJ and Cui Z Genetic Immunization by Jet Injection of Targeted pDNA-coated Nanoparticles (2003) 31 Methods 255-262
 Roy I, Ohulchanskyy TY, Bharali DJ et al Optical Tracking of Organically Modified Silica Nanoparticles as DNA Carriers: A Nonviral, Nanomedicine
Approach for Gene Delivery (2005) 102(2) Proc. Nat. Acad. Sci 279-284.
 Kreuter J, Nanoparticulate Systems for Brain Delivery of Drugs(2001) 47 Adv Drug Deliv 65-81.
 Shaffer C. Nanomedicine transforms drug delivery. (2005) 10(23-24) Drug Discov Today 1581-2.
 Leary SP, Liu CY, Yu C et al Toward the Emergence of Nanoneurosurgery: Part I-Progress in Nanoscience, Nanotechnology and the Comprehension of
Events in the Mesoscale Realm (2005) 57 (4) Neurosurgery 606-633
 Kong DF, Goldschmidt-Clermont PJ. Tiny Solutions for Giant Cardiac Problems (2005) 15(6) Trends Cardiovasc Med 207-11.
 Hulstein JJ et al A Novel Nanobody that Detects the Gain-of-function Phenotype of von Willebrand Factor in ADAMTS13 Deficiency and von Willebrand
Disease Type 2B (2005)106(9) Blood 3035-42.
Vinogradov S. The second annual symposium on nanomedicine and drug delivery: exploring recent developments and assessing major
advances 2004 1(1) Expert Opin Drug Deliv 181-4
Ghadiri MR Antibacterial Agents Based on the Cyclic D, L Peptide Architecture (2001) 412 Nature 451-455
Bottini, MBruckner S, Nika K et al, Multi-Walled Carbon Nanotubules Induce T Lymphocyte Apoptosis (2006) 160 Toxicology Letters 121-
126.
Scheinberg DA et al Tumor Therapy with Targeted Atomic Nanogenerators (2001) 294 Science 1537-1542
                               Nano Vic


 Nanotechnology Victoria. Not-for-profit collaboration
  between RMIT, CSIRO, Monash Uni. and Swinburne IT.
  $28 million govt. funding to drive commercial outcomes
  from Victoria‟s strong nanocapability base.
 Pulmonary drug delivery: insulin, erythropoietin
 In vivo diagnostics: nanoparticle contrast agents for
  coronary atheroscelosis
 In vitro diagnostics: gold nanoparticles coated with
  diagnostic antibodies-contact with antigen causes them to
  aggregate and change colour (to blue)
                                      Miconisers
   Manufactures bulk nanoproducts for sunscreens, diagnostics and targeted drug
    delivery
   MicrosunTM Nano sized Zinc Oxide powder, (30nm) and blends of Nano
    sized Zinc Oxide with Nano particles of Titanium Oxide, Iron, Aluminium,
    Zirconium, Silver and Manganese
   Concentrated dispersions of Nano sized Zinc & Titanium with a range of
    solids from 40-80% in water, esters (IPP, IPM, Capric/caprylic), mineral oil
    (paraffin, white oil) and Silicones (Dimethicones, cyclomethicones, etc)
   Micronised high quality cosmetic grades of talc coated with Boron Nitride,
    Ceramide, Chitin, Siloxane, Stearic Acid, Vitamin C, Vitamin E and
    Betacarotene.
   Zinc Oxide has been used for many years in a wide range of cosmetic
    products; eg, moisturisers lip products, foundations, make-up bases, face
    powders, hand creams, etc.
   The availability of Micronisers transparent Nano-sized Zinc Oxide
    (NanosunTM) has enhanced the effectiveness of Zinc Oxide and overcome the
    “whitening” aspect of normal Zinc Oxide powder.
                                             pSivida
   pSivida has developed the only two FDA approved sustained release treatments
    for chronic eye disease – Vitrasert ® and Retisert™. Both manufactured and
    sold by global ophthalmology company, Bausch & Lomb (B&L).
   Medidur™ in Phase III clinical trials, is licensed to Alimera Sciences for the
    treatment of Diabetic Macular Edema.

   Modified form (porosified or nano-structured) of silicon BioSilicon™, for drug
    delivery, wound healing, orthopedics, and tissue engineering (exclusive licenses
    to subsidiaries, AION Diagnostics Limited and pSiNutria Limited, to develop
    and commercialize)
   BrachySil™, a brachytherapy product in Phase IIb clinical trials, for the
    treatment of inoperable primary liver cancer.
   Licensing agreement with Beijing Med-Pharm Corporation for the clinical
    development, marketing and distribution of BrachySil™ in China.

   Four evaluation agreements for its drug delivery technologies with three of the
    world‟s largest pharmaceutical companies.
   Listed on NASDAQ (PSDV), Australian (PSD), and Frankfurt (PSI) stock
    exchanges and is a member of the NASDAQ Health Care Index (Nasdaq:
    IXHC) and the Merrill Lynch Nanotechnology Index. In 2005 pSivida acquired
    Controlled Delivery Systems from Boston.
                                       Starpharma

   Specialist in dendritic nanotechnology

   Dow Chemical‟s 8.6% ownership in Starpharma Holdings and recent acquisition
    of Dendritic Nanotechnologies from US (focus on life sciences and industrial
    applications (research reagents, industrial chemicals and fine chemicals).

   Starpharma focus on dendritic nanotechnologies: pharmaceutical (viva gel,
    protein PK modifications and cancer therapies) and life sciences (medical
    diagnostics, drug optimisation, drug delivery).

   Viva Gel is bottom up technology. Well-defined synthetic polymer, made in vat
    by adding monomers. “Can decorate the surface with functionality.” Has same
    electrical charge as receptors on T cells, so “gums” up HIV before it can get to T
    cells, in dose-response manner.

   Starpharma has collaborations with Qiagen, Dadebehring and EMD
    Bioseciences (Merck (Germany))). Also has sought and obtained funding from
    US NIH.
                          Advanced Nanotechnologies (WA)

   Mechanochemical Processing (MCP) technology is a novel, patented solid-
    state process for the manufacture of a wide range of nanopowders. Dry milling
    is used to induce chemical reactions through ball-powder collisions (low
    temperature chemical reactor) that result in nanoparticles formed within a salt
    matrix. Particle size is defined by the chemistry of the reactant mix, milling
    and low heat treatment conditions.
   Particle size distribution curve for MCP ~30nm zinc oxide nanopowder shows
    a mean particle size of 30nm with a standard deviation of less than 4nm.
 Alusion™ - the latest in soft focus effect pigments for
  hiding the effects of ageing.
 ZinClear™ - for the first time enabling transparent SPF
  30+ sunscreens containing only zinc oxide as the UV
  absorber.
 Zinc Oxide “is ideal for all cosmetic and industrial
  transparent UV absorbing applications, and antibacterial
  functions”.
 Commercialisation arrangements with Samsung Corning
                                     Ceramisphere

    Commercialising sol-gel (Si02) encapsulation technology developed at the
    federally funded Australian Nuclear Science and Technology Organisation
    (ANSTO). Ceramisphere is fully owned subsidiary of ANSTO
   CeramiSphere™ can produce a range of ceramic particles from materials such
    as silica, titania, alumina and zirconia. Particle sizes from 10 nanometers to
    100 microns depending on the application. The particle surface is hydrophilic
    and may be functionalised, microporous or mesoporous.
   Applicable to hydrophilic and hydrophobic molecules, drugs, proteins,
    enzymes, fragrance and DNA can be encapsulated
   No need for reformulation for different target molecules
   True controlled release by diffusion, release rate (hours to months)
    independent of particle size (10 nm – 100 microns)
   High mechanical resistance, chemical inertness and biocompatibility
   SiO2 is already an FDA approved material for oral and topical use
   Wide range of potential applications including drug delivery, encapsulation of
    biocides, pesticides and insecticides, food and fragrance encapsulation and
    veterinary applications
                                  Alchemia


 Alchemia has developed and applied to patent a new and efficient
  process for the preparation of Synthetic Heparin.
 The Company intends to commercialise Alchemia's Synthetic Heparin
  with its partner, The Dow Chemical Company (Dow). In the US
  market, approval will be sought through the ANDA route (Abbreviated
  New Drug Application). The cGMP pilot scale production of Synthetic
  Heparin has been successfully completed at Dow's US facilities.
 VAST technology: nanoscale drug discovery technique for
  systematically scanning molecular diversity space.
                                Eiffel Technologies

   Eiffel's focus is on modification and re-engineering of pharmaceutical
    compounds and supercritical fluid research.

   Supercritical Fluid technologies can be used to produce uniform, very small
    drug particles. Drugs produced in this way have the potential to be delivered in
    more convenient and effective dose forms. For example, a drug previously
    administered via injection could be re-engineered to be delivered via an
    inhaler. Supercritical Fluid technology is therefore well placed to enable the
    development of line extension products with superior performance to protect
    market share once patent life of branded pharmaceuticals expires.

   Eiffel sponsors continuing research in pharmaceutical processing at its
    Pharmaceutical Re-engineering Facility, located at the University of NSW.
    Pharmaceutical development and scale-up activities are conducted at the
    Company‟s headquarters in North Ryde, Sydney, Australia.
                    Other Australian nanomedicine
                             capabilities
•Nanotechnology and biomaterials centre Uni Qld (Nanomic Biosystems):
rapid DNA sequencing using colloidal practicles
•ANU Dept. Applied Mathematics: „Fibrin Lite‟ radio-labelled nanoparticle
for diagnosis of fibrin deposition diseases and DVT
•Centre for Nanoscience and Nanotechnology Uni Melb: polymer
encapsulation for cotrolled release of Doxorubicin
•Monash University, Dept. Biochemistry and molecular biology and school of
physics and materials engineering and synchrotron research program
•Flinders University, School of Chemistry, Physics and Earth Sciences:
nanotech. Polymers, sol-gels, silicon materials, biosensors, carbon nanotubes,
surface characterisation and bio-sensors
•University of Technology Sydney (UTS): researching artificial membranes to
improve the bio-compatibility of implanted tissue and cells
                Dilemmas for Bioethics and Health Law



 Safety assessment of therapeutic goods (medicines
  and medical devices) is a relatively data rich field
  with considerable capacity in regulators to require
  additional targeted studies where novel concerns
  are identified
 Safety assessment of nanotechnology industrial
  chemical production is a relatively data poor
  environment
                        Dilemmas for Bioethics and Health Law


Are there likely to be “class” nanotech.
effects in medicine and biosecurity?
Or will these be confined to uniquely
engineered nanomaterials with novel surface
binding properties?

Nanotherapeutics: new challenges for safety and cost-effectiveness regulation in Australia
Thomas A Faunce — Med J Aust 2007; 186 (4): 189-191.
                            Dilemmas for regulation of nanomedicine
    Terminological definitions and standards used in differing nanotherapeutic
    assessments need to be clarified.

   Long-term safety of engineered nanoparticles (ENPs) in humans needs to be
    established. ENPs in isolated cell experiments have caused DNA damage. Short-
    term ENP exposure in animals has produced dose-dependent inflammatory
    responses and pulmonary fibrosis. Chronic in-vivo exposure studies (in
    particular, of reproductive toxicity) are yet to be published. Some ENPs
    preferentially accumulate in mitochondria and inhibit function. Others may
    become unstable in biological settings and release elemental metals.

   Gaps in nanotherapeutic safety data need to be systematically determined, and
    government support needs to be directed to the relevant fields of
    nanotoxicological research.

   Workable and consistent standards and guidelines for therapeutic ENP use and handling,
    monitoring and labelling need to be developed.

   Individual nanotherapeutic applications may overlap different classifications of
    medicines, medical devices, and diagnostic and therapeutic risk assessment
    classifications and pathways. Potential or actual weaknesses in the existing
    regulatory framework need to be located and addressed.
                    Dilemmas for Nanomedicine Regulation


   Any revised regulatory system needs to factor in the likely high cost for
    “innovative” nanotherapeutics, as well as difficulties in classifying nanotech
    versions of existing off-patent pharmaceuticals as “generic”.

   Reimbursement for new and often “innovative” pharmaceuticals and medical
    devices (such as those likely to use ENPs) is a significant and increasing
    component of government health care expenditure. In this context, cost-
    effectiveness assessment of allegedly innovative medical products, linked to a
    central government price negotiation, is internationally becoming an accepted
    part of the health techno-logy regulatory approval process.

   Pharmaceutical “innovation” may be achieved either through the operation of
    “competitive markets” (requiring a greater role for competition regulators) or
    through expert evaluations of “objectively demonstrated therapeutic
    significance”
                  Dilemmas for Regulation of Nanomedicine
   One of the first nanomedical devices approved by the United States Food and
    Drug Administration (FDA) bypassed the requirement for a lengthy and costly
    clinical study because regulators deemed that its constituent nanoscale calcium
    phosphate fitted a category of existing approved macroscale products.

   Similarly, a nanoparticulate reformulation of an existing drug has been
    deemed by the FDA not to require an Abbreviated New Drug Application
    because bioequivalence was established.

   Gathering, analysing, categorising and characterising safety data for individual
    nanotherapeutic products may be unusually difficult.

    Recently Australian TGA regulators reviewing the scientific literature on
    nanoparticulate titanium dioxide and zinc oxide in sunscreens found evidence,
    from isolated cell experiments, of DNA-damaging free radical formation on
    light exposure, but apparent lack of penetration below surface layers of the
    skin

   Should FDA be the global benchmark for safety regulation?
                Dilemmas For Bioethics, Health Law and International Human
                                          Rights


UNESCO Universal Declaration of Bioethics and Human Rights
Article 2. This Declaration is addressed to States. As appropriate and relevant, it
      also provides guidance to decisions or practices of individuals, groups,
      communities, institutions and corporations, public and private.
Article 14 – Social responsibility and health
2. Taking into account that the enjoyment of the highest attainable standard of
      health is one of the fundamental rights of every human being without
      distinction of race, religion, political belief, economic or social condition,
      progress in science and technology should advance:
(a) access to quality health care and essential medicines, especially for the
      health of women and children, because health is essential to life itself and
      must be considered to be a social and human good;

Bioethics and International Human Rights as calibration systems for health law:
Faunce TA, Who Owns Our Health? Medical Professionalism, Law and
     Leaderhip Beyond the Age of the Market State. UNSW Press 2007
                                     National Centre for Biosecurity




                       CONCLUSION


• Introduction to nanotechnology in biosecurity

• Introduction to nanotechnology in medicine (with
  particular focus on Australian nano/bio-tech.
  companies)

• Related dilemmas for bioethics, public health law and
  international human rights

				
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