Tamar Chachibaia, PhD candidate Tamar Chachibaia, PhD candidate Presented by

• Conception of medical nanorobotics first was Conception of medical nanorobotics first was described by pioneer of nanomedicine, practitioner described by pioneer of nanomedicine, practitioner futurist, Robert A. Freitas Jr. futurist, Robert A. Freitas Jr.

• ””RespirocytesRespirocytes” is the short title of the original ” is the short title of the original technical paper - “technical paper - “A Mechanical Artificial Red Cell: A Mechanical Artificial Red Cell: Exploratory Design in Medical Nanotechnology”,Exploratory Design in Medical Nanotechnology”, which was issued in 1996.which was issued in 1996.

Tiny diamondoid spheres, known as Tiny diamondoid spheres, known as respirocitesrespirocites, representing , representing hypothetical new class of medical device, filled with high pressure hypothetical new class of medical device, filled with high pressure oxygen could release gases at a constant rate. Mechanical rotor oxygen could release gases at a constant rate. Mechanical rotor

maintains diffusion and exchange of oxygen, carbon dioxide, and water maintains diffusion and exchange of oxygen, carbon dioxide, and water around the respirocyte – providing locomotion through the body.around the respirocyte – providing locomotion through the body.

CREDIT: URL: Nanomedicine Art Gallery http://www.foresight.org/Nanomedicine/Gallery/index.html

Blood substitutes are oxygen-carrying fluids

• In his monograph R. Freitas highlights existing artificial respiratory gas carriers such as hemoglobin formulations and perfluorocarbon emulsions. These two concepts differ significantly from each other in several aspects.

• 1st class of oxygen-carrying fluids are naturally occurring respiratory pigment, haemoglobin (Hb), second is synthetic, chemically inert, based on fluorinated liquids called perfluorochemicals (PFCs). Commercial products in both categories have been developed and some approved for clinical use, primarily to facilitate oxygen supply to tissues during surgery or therapy.

HOW THE RESULTS OF THE PROJECT HOW THE RESULTS OF THE PROJECT WILL CONTRIBUTE TO IMPROVED WILL CONTRIBUTE TO IMPROVED

SECURITY?SECURITY? Not only atomic bomb explosions and nuclear Not only atomic bomb explosions and nuclear

powerplant accidents may raise awareness of lay powerplant accidents may raise awareness of lay people. Stunning criminal case committed against people. Stunning criminal case committed against former Russian resident in London unleashed former Russian resident in London unleashed dreadful disadvantage of radiation danger for dreadful disadvantage of radiation danger for citizens as obvious threat to their security. citizens as obvious threat to their security.

In the time of asymmetric warfare, those countries In the time of asymmetric warfare, those countries and groups with less conventional power will look and groups with less conventional power will look for unconventional methods. These include nuclear, for unconventional methods. These include nuclear, biological, and chemical weapons. Only through biological, and chemical weapons. Only through research will we know the extent to which research will we know the extent to which nanotechnologies may be used in these nanotechnologies may be used in these unconventional methods. Studies of unconventional methods. Studies of nanotechnologies would be directed at defence nanotechnologies would be directed at defence rather than offensive tools to rather than offensive tools to counteract measures counteract measures of effect on people of radiological nuclear agents of effect on people of radiological nuclear agents and weapons. and weapons.

Research is fostered by: 1. permanent shortages of donor blood supply, as well 2. risk awareness of HIV and Hepatitis viruses infections, 3. blood-type mix-up during transfusion. Precautionary alert is raised about dissemination of 4. specific protein, termed as prion, which is responsible for spongiform encephalopathy, capable to provoke disastrous outbreak of human variant Creutzfield-Jacobs disease. Along with physiological and economic aspects, public perception should be recognized about benefits and risks, associated with transfusion of blood, blood products or potential blood substitutes. Recent survey performed among young adults in UK finds that medical and law students differ over transfusion medical ethics.

• In the special sections of medical manuals one can find In the special sections of medical manuals one can find numerous case studies with the descriptions of treatment numerous case studies with the descriptions of treatment guidelines, proposed to save critically ill patients in guidelines, proposed to save critically ill patients in intensive care units without whole blood supply. intensive care units without whole blood supply. Synthesized blood substitutes sought to match patient’s Synthesized blood substitutes sought to match patient’s needs equally, while blood loss may cause inevitable needs equally, while blood loss may cause inevitable threat of life. threat of life. Suggestion by doctors to their patients Suggestion by doctors to their patients alternative choice of nonblood treatment may facilitate to alternative choice of nonblood treatment may facilitate to better cooperation between them, lower the emotional better cooperation between them, lower the emotional tension and avoid risk of religious stigma. tension and avoid risk of religious stigma. Perhaps Perhaps bloodless surgery is only an alternative therapy for bloodless surgery is only an alternative therapy for Jehovah's Witnesses, thus bovine hemoglobin derived Jehovah's Witnesses, thus bovine hemoglobin derived oxygen carriers is acceptable by Jehovah's Witnesses as oxygen carriers is acceptable by Jehovah's Witnesses as yet. yet.

Particular clerical and cultural Particular clerical and cultural objectionobjection

• The risk of disease transmission, bacterial contamination or The risk of disease transmission, bacterial contamination or blood-type mix-up is entirely excluded by using a non-blood-type mix-up is entirely excluded by using a non-biological or ‘abiotic’ oxygen carrier, that biological or ‘abiotic’ oxygen carrier, that has been on-going has been on-going for many yearsfor many years. First experiments with . First experiments with perfluorocarbon perfluorocarbon (PFC)(PFC) compounds conducted in the 1960's paved the way compounds conducted in the 1960's paved the way for developing totally synthetic chemicals, that can dissolve for developing totally synthetic chemicals, that can dissolve and transport oxygen and other gases. While and transport oxygen and other gases. While perfluorocarbon emulsions (PFCE)perfluorocarbon emulsions (PFCE) may never surpass the may never surpass the practice of blood transfusion, they have potential to reduce practice of blood transfusion, they have potential to reduce the need for transfused blood and to explore additional the need for transfused blood and to explore additional applications, such as applications, such as conservation of organs for conservation of organs for transplantation, in cardio-pulmonary transplantation, in cardio-pulmonary bypass bypass and other and other blood preserving manipulations. blood preserving manipulations.

Nanotechnology perfluorocarbon Nanotechnology perfluorocarbon emulsions (PFCE)emulsions (PFCE)

• Currently only some recognized Currently only some recognized perfluororganic carbon perfluororganic carbon emulsion (PFCE)emulsion (PFCE) with gas transporting function are with gas transporting function are presented on the world market. In 1989 FDA first approved presented on the world market. In 1989 FDA first approved Fluosol-DA (Green Cross Corp., Japan)Fluosol-DA (Green Cross Corp., Japan) for use during for use during angioplasty. It was withdrawn just five years later. angioplasty. It was withdrawn just five years later. CompanyCompany began developing a second generation PFC began developing a second generation PFC called called PHER-O2PHER-O2 in an effort to overcome the shortcomings in an effort to overcome the shortcomings of of FluosolFluosol..

• Another prominent preparation Another prominent preparation OXYGENT OXYGENT developed by developed by Alliance Pharmaceutical Group Alliance Pharmaceutical Group -- Johnson & Johnson i Johnson & Johnson in n 2007 is applied for FDA approval.2007 is applied for FDA approval.

Nanotechnology perfluorocarbon emulsions (PFCE)Nanotechnology perfluorocarbon emulsions (PFCE)

Fluosol-DA (Green Cross Corp., Japan)Fluosol-DA (Green Cross Corp., Japan)&&

OXYGENT OXYGENT ((Alliance Pharmaceutical GroupAlliance Pharmaceutical Group))

• Another PFC-based oxygen carrier, Another PFC-based oxygen carrier, PerftoranPerftoran, , waswas approvedapproved in 1996 in 1996 for clinical usefor clinical use in Russia, which was in Russia, which was originally developed at the originally developed at the Institute of Theoretical and Institute of Theoretical and Experimental Biophysics (Puschino, Russia),Experimental Biophysics (Puschino, Russia), but but relatively little information is available in the English relatively little information is available in the English literature for this productliterature for this product, hence it is not , hence it is not yet FDA yet FDA approved. approved.

• More than thousands of patients participated in clinical More than thousands of patients participated in clinical studies of studies of PerftoranPerftoran. . The indication statement for The indication statement for PerftoranPerftoran claims that it is to be used claims that it is to be used in case of in case of hemorrhagic and traumatic shock, hemorrhagic and traumatic shock, blood losses, multiple blood losses, multiple trauma, burning of large surface of skin, conditions of trauma, burning of large surface of skin, conditions of apparent death, apparent death, ischemic brain edema and acute ischemic brain edema and acute ischemia, ischemia, in regional perfusion to treat limb ischemia.in regional perfusion to treat limb ischemia.

anotechnology perfluorocarbon anotechnology perfluorocarbon emulsions (PFCE)emulsions (PFCE) PerftoranPerftoran Credit: G. R. Ivanitsky, 2008, July 09.Credit: G. R. Ivanitsky, 2008, July 09.

Perftoran is considered to be the safest of the rest PFCEs. Average Perftoran is considered to be the safest of the rest PFCEs. Average particle size in the Perftoran emulsion is in range of 65-70 nm. This particle size in the Perftoran emulsion is in range of 65-70 nm. This is most optimal dimention of molecules in nanothechnology is most optimal dimention of molecules in nanothechnology practice, as is determined by US National Nanotechnology practice, as is determined by US National Nanotechnology Initiative guidelines. Particle size and surface characteristics are Initiative guidelines. Particle size and surface characteristics are determining factors for decrease of reactivity of preparation. While determining factors for decrease of reactivity of preparation. While altered erythrocytes fail to squeeze through contracted capillaries, altered erythrocytes fail to squeeze through contracted capillaries, or lumen, sludged by aggregated blood calls, or lumen, sludged by aggregated blood calls, 70 nm size 70 nm size molecules of Perftoran easily deliver gases to the oxygen deprived molecules of Perftoran easily deliver gases to the oxygen deprived tissues, simultaneously carry carbon dioxide from tissues and tissues, simultaneously carry carbon dioxide from tissues and transport it to the lungs for removal.transport it to the lungs for removal. Perftoran particles are removed from the bloodstream within 18-24 Perftoran particles are removed from the bloodstream within 18-24 hours after administration. hours after administration.

Why Perftoran?Why Perftoran?

Understanding Size• 1 nanometersource: CERN http://microcosm.web.cern.ch/microcosm

Capillary cross-section with red blood cells or erythrocytes inside. Capillaries are the small blood vessels that connect arteries and veins.Red blood cells carry oxygen throughout the body. SEM X5140

Credit: Photo by Kessel and Kardon, Visuals Unlimited

Definitions of Nanotechnology adopted by FDA

• FDA has not established its own formal definition .. FDA currently relies on the NNI definition.

• National Nanotechnology Initiative (NNI): – Nanotechnology is the understanding and control of matter at dimensions of

roughly 1 to 100 nanometers, where unique phenomena enable novel applications. …. At the nanoscale, the physical, chemical, and biological properties of materials differ in fundamental and valuable ways from the properties of individual atoms and molecules or bulk matter.

• NCI Cancer Nanotechnology Plan (July 2004): – Nanotechnology refers to the interactions of cellular and molecular

components and engineered materials - typically clusters of atoms, molecules, and molecular fragments - at the most elemental level of biology. Such nanoscale objects - typically, though not exclusively, with dimensions smaller than 100 nanometers - can be useful by themselves or as part of larger devices containing multiple nanoscale objects.

The image to the right is a picture taken of a mouse completely The image to the right is a picture taken of a mouse completely submerged in liquid perfluorocarbon and still breathing!submerged in liquid perfluorocarbon and still breathing!

• In In 19661966: firstfirst report of mice immersed in a report of mice immersed in a perfluorocarbon liquid saturated with oxygen; perfluorocarbon liquid saturated with oxygen; mice survived up to 10 minutesmice survived up to 10 minutes

• На каждый эритроцит приходится свыше 105 частичек эмульсии Перфторана. Таким образом, эффективная поверхность 105 молекул Перфторана больше по сравнению с суммарной поверхностью одного эритроцита. Несмотря на то, что кислородная ёмкость ПФ приблизительно в 5 раз ниже цельной крови, благодаря оптимальному размеру частичек эмульсии Перфторана т.е. 70 нм, они способны проникать в стенозированный или закупоренный просвет капилляров, в местах недоступных для эритроцитов из-за их размера и деформации мембраны.

Effects of Perftoran• Перфторан в большей степени оказывает не анти-

анемическое действие, а точнее анти-ишемическое на тканевом и органном уровнях вследствии комплексного антигипоксического защитного механизма. То что до определенного момента является защитной функцией крови, впоследствии может служить повреждающим тригером (пусковым механизмом). В биологической крови присутствуют медиаторы воспаления, цитокины, активированные тромбогенетические факторы, фибрин и др.

• Преимущество Перфторана заключается в том, что препарат лишен данных свойств биологической крови и является интактным для эндотелия.

PFCE Perfluorocarbon emulsion

• Перфторан может стать средством спасения для той группы больных, которые находятся на лечении в палатах интенсивной терапии и шанс на улучшение общего тяжелого состояния не так велик.

• У пациентов, попавшим в палату интенсивной терапии с тяжелыми состояниями различного генеза в большинстве случаев, т.е. от 40 до 100% по данным разных клиник, развивается т.н. «Синдром эутиреоидного недуга». Отмечается критическое падение гормонов щитовидной железы, которое может наступить в течении 2-3 часов.

• Смертность высокая и достигает 85%. Негативным прогностичским критерием является показатель Т4 ниже 2 ug/dl. При показателях Т4

ниже 4 ug/dl погибает половина больных .

Alternative treatment options using Perftoran additionally to complex

intensive insulin therapy in “Euthiroid Sick Syndrome”

and possible role on improvement of morph-functional status of the

kidney .

PFCE Perfluorocarbon emulsion

• Действие тиреоидных гормонов в организме на поглощение кислорода, обмен газов, окислительные процессы хорошо изучены, как на целом организме, так на органном и тканевом уровнях.

• Вопрос о применении заместительная терапии по сей день

остается открытым. Использование тироксина однозначно не даёт никаких результатов.

• Поиску новых средств, способных внести перелом в хрупком равновесии в борьбе за жизнь пациента уделяется немало усилий, времени и ресурсов. Препарат Перфторан может служить тем звеном, который внесет перелом в равновесии в борьбе за жизнь пациента, тем более что успешно применяется в интенсивной терапии в течении последних лет.

Georgian National NanoInnovation Initiative

is the Alliance Union inclusive of   Initiative Group &

NanoInnovation Center

http://gnni.com.gehttp://gnni.com.ge

Founder Georgian National NanoInnovation Initiative

& CEO of NanoInnovation Center: Ms. Tamar Chachibaia  Tel/Fax: +(99532) 454556 E-mail: nanogeorgia@hotmail.com

Thank you for your time