Rotational%20Field%20Quantum%20Magnetic%20Resonance%20in%20Tissue%20Engineering%20A%20Preliminary%20Experience

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Rotational Field Quantum Magnetic Resonance in
Tissue EngineeringA Preliminary Experience

• Dr. R. V. Kumar
• Center for Advanced Research and Development
• Institute of Aerospace Medicine,
• Indian Air Force, Bangalore

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Rotational Field Quantum Magnetic Resonance

• Establishing Communication with
• Living Cells

Centre for Advanced Research and Development
(CARD)
Institute of Aerospace Medicine (IAM) Bangalore
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Where did it all start..

• In 1996, the Centre for Advanced Research and
  Development (CARD), initiated a project to study
  the effect of modulated Radio Frequency (RF) in
  the so far unexplored frequency band of 1 kHz to
  10 MHz.
• Our engineers by simulation established that,
  when a biological Cell is exposed to such RF
  under a instantaneous magnetic field of several
  Tesla should alter many cell parameters,
  including its resting Transmembrane Potentials
  (TMP)

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Where did it all start..

• Many Cellular activity is closely linked with the
  TMP. TMP plays an Important role in the synthesis
  of many proteins (Cone CD. et. al., Variation of
  transmembrane potential level as a basic
  mechanism of mitosis control Oncology
  197024438-470)
• Powerful Mathematical Models and real time
  simulation in combination with MRI data of the
  tissue is used to precisely alter transmembrane
  potentials of target tissue.

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The Hypothesis..

• Selectively altering TMP, can initiate synthesis
  of HSP group of proteins or P53 group of proteins
  that generally control mitotic activities in
  biological systems.
• Alternatively, Rotational Field Quantum Nuclear
  Magnetic Resonance (RFQMR) is probably triggering
  the msx1, BMP4, and the NOTCH group of Genes that
  is dormant in mammals, but is well expressed in
  primitive biological systems, where
  dedifferentiation of terminally differentiated
  cells and redifferentiation in to specific organs
  cells is well established eg. In Salamander or
  Zebra fish. (Shannon J Odelberg., et.,al,.
  Dedifferentiation of Mammalian Myotubes Induced
  by msx1 Cell 103 1099-1109 Dec. 22, 2000).

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In Cancer....

• We need to understand Cytonics, the electronics
  of the biological cell, its control and
  communication. We have, to a large extent
  understood the Phenome and the Genome but very
  little on cellular cytonics.
• CARD has in the past few years, accrued
  considerable data to work on Cytonics of
  neoplastic cells. A lot remains to be proved, but
  it is a good and humble beginning.

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The Technology..

• The RFQMR or the Cytotron Technology was patented
  by us under PCT.
• The Cytotron Device will deliver precise dose of
  RF radiation in the unexplored 1Khz to 10 MHz
  Range in the presence of high instantaneous
  magnetic field, which is perfectly focused. There
  has been anecdotal reference of MRI, providing
  significant changes in patients with depression
  not responding to other treatments.
• Cytotron has been in use for the last two years
  for the treatment of Osteoarthrites and Cancer as
  part of a clinical trial.

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A small bit of the theory...

• Problem of RF wave incidence on a lossy medium
  (tissue)
• Incident RF energy is reflected and refracted at
  the interface of air and tissue
• Fundamental constants defining how much is
  reflected and refracted are parameters of the
  medium

Biological Tissue
Air
Er
Et
Sr
Hr
Interface
St
Ht
Ei
Si
Hi
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RFQMR incidence

• Relative amplitudes of the reflected and
  transmitted components of the incident electric
  field wave are defined below
• Reflection coefficient, gamma, and,
  appropriately, transmission coefficient, tau, are
  determined purely by the parameters of the two
  media of conduction

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Parameters of media

• Permittivity, ?, defines the polarizability of a
  material
• Applied E-field gives rise to dipole moment
  distribution in atoms or molecules
• Secondary fields are set up, thus net E-field is
  different
• If dipole moment distribution is denoted by
  vector P, the relationship between applied
  electric field and P is
• Conductivity, ?, summarizes the microscopic
  behavior of conductors
• Applied E-field gives rise to electron drift
• This drift results in a current density in the
  direction of the E-field
• Conductivity is the factor which relates the
  E-field to the drift current

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Parameters of media

• Permeability, ?, is analogous to the permittivity
  in that it describes the relationship between the
  magnetic dipole vector and the magnetic field
• Most of the cells and tissues that will be of
  interest are non-magnetic
• For these types of materials, ? is considered to
  be equivalent to ?0, the permeability of free
  space
• It is, therefore, much less critical to our
  analysis of RF interaction with biological tissue
  than permittivity and conductivity
• These three parameters fundamentally characterize
  any medium macroscopically
• Parameters can be used to determine depth of
  penetration and absorbed power of an incident RF
  wave on the medium

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Permittivity of tissues
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Conductivity of tissues
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Depth of penetration

• Any wave that enters a lossy medium will be
  attenuated after some distance
• Depth of penetration (D.O.P.) characterizes the
  distance after which the field intensity is 1 / e
  of its incident value
• For a low-loss dielectric medium, the D.O.P. is
  described by the following equation, in which
  tan(?c) is the loss tangent of the material

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DOP of tissues
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Non-ionizing radiation

• Microscopic effects of non-ionizing RF energy
  have been studied extensively over the past few
  decades because we are exposed to these waves
  more often than ever before
• However, many mechanisms of interaction are still
  not well known nor are relevant results
  consistent
• In contrast, effects and health/safety standards
  are widely accepted in the science community
• Level of understanding of mechanisms of
  interaction decreases as we move from
  extracellular (membrane) to intracellular
  (enzyme, DNA) components
• We will consider these effects of non-ionizing
  radiation in two separate frequency bands,
  distinguished by the relative size of wavelength
  versus medium (human body)
• Low Radio frequency radiation ? gtgt D
• MHz Radio frequency radiation ? D, ? ltlt D

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Lower frequencies
Radio beacons (Navigation)
Submarine Comm.
LF
VLF
30kHz
300kHz
Power Lines
Audio (sound)
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Low frequency RF effects

• Prevailing theory is that interactions occur
  primarily in the plasma membrane, then a cascade
  of changes propagates from the membrane to the
  nucleus of the cell as shown below2
• An alternate theory suggests the possibility that
  low frequency RF interacts directly with the
  nucleus and the DNA based on the following
  analysis
• Membrane blocks low-level electric fields but not
  magnetic fields
• Although cellular dimensions limit the induced
  electric field resulting from the penetrating
  magnetic field to very small values, the magnetic
  field itself may interact with cellular
  components
• Recent studies by Blank and Goodman show that the
  magnetic field may interact with enzymes and DNA
  within the cell through classical physics based
  mechanisms

Plasma Membrane
Enzymes, Genes, Proteins
Biochemical Messenger
Cellular Membrane
Nucleus
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Theory of signal transduction

• First, consider the signal transduction theory in
  which an enzymatic cascade is responsible for
  changes in biosynthesis
• The following is a step by step account (from
  Behari 1999) of how the signal reaches the DNA in
  order for changes in biosynthesis to occur
• Faraday induction creates currents in the ionic
  aqueous solution of the plasma membrane
• These currents are blocked by the strong
  dielectric barrier of the cell membrane however,
  they cause changes in the cell surface involving
  counter ion layer, ion channel permeability,
  glycoproteins, and ligand receptors
• Consequently, there is enzyme activation, gene
  induction, protein synthesis, and mitogenesis /
  cell proliferation / retardation
• Secondary biochemical messengers then pass this
  signal to the nucleus and the DNA of the cell

Enzymes, Genes, Proteins
Biochemical Messenger
Plasma Membrane
Cellular Membrane
Nucleus, DNA
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Direct interaction theory

• Many current studies present possible direct RF
  interaction mechanisms with DNA to explain
  changes in biosynthesis of the cell exposed to
  Controlled RF under the influence of high
  magnetic fields
• Blank suggests Mobile Charge Interaction (MCI)
  model from a variety of experiments.
• Magnetic fields interact with moving charges via
  the classical electromagnetic relation
• In the case of intracellular flowing charges,
  such as enzymes, this force will result in a
  change in velocity and a resulting alteration in
  intended biological function (demonstrated in Na,
  K-ATPase and cytochrome oxidase reactions)
• In addition, moving electrons in DNA helices will
  begin to experience forces which may repel them
  from each other and bend, or even break, the
  chain, resulting in increased DNA multiplication

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DNA chain bending
B
After time
F
I
I
I
F
I

• A direct result of equation (7) is the
  relationship between flowing charge (current),
  magnetic field, and induced force shown in
  equation below
• When two wires have currents flowing in opposite
  directions, an applied magnetic field will cause
  repulsion
• Expanding this idea by thinking about the DNA
  helix simply as two wires which may carry
  charge through electron transport in opposing
  directions, we expect chain bending in some
  instances

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MHz Radio frequencies
Satellite Comm.
AM Broadcasting
Microwave Oven
RF
300kHz
300GHz
Cellular Phone
TV Broadcasting, FM Radio
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Where does RFQMR fit on the EM Spectrum
Sub-Radio and Near-Radio, A part of the spectrum
used for the first time in Medical Field.
Currently used in Oceanography and Submarines
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MHz Radio frequency effects

• Mechanisms of interaction for RF radiation on the
  body are very different at low-levels of
  radiation versus higher levels
• Low-level RF radiation causes predominantly
  non-thermal effects because the intensity is not
  high enough to significantly change tissue
  temperature
• Non-thermal effects are direct interactions of RF
  with biological cells
• Very important because most common exposure is at
  low-levels
• Not as well understood specifically, mechanisms
  are not fully explored nor consistently
  documented
• High-level RF radiation causes thermal effects
• Thermal effects are indirect interactions EMF -gt
  heat -gt biological effect
• RF energy and, specifically, Specific Absorption
  Rate (SAR), are high enough to significantly heat
  the tissue
• Hazards are well established, safety levels are
  well documented

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Non-thermal effects of MHz RF

• RF fields induce torque on molecular dipoles
  which can result in ion displacement, vibrations
  in bound charges, and precession
• This effect is characterized by the Bloch
  Equation which is fundamental to MR Imaging
• With an applied magnetic field, the nuclear spins
  will precess in a left-hand direction around the
  field with angular frequency proportional to its
  amplitude
• No observable biological hazards have been noted
  as a result of these mechanisms because they are
  outweighed by random thermal agitation in
  low-level fields

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THE CYTOTRON
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THE CYTOTRON
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Typical RFQMR Gun Assembly
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RFQMR can be successful in .

• the non-invasive treatment of.
• Many Degenerative Diseases like,
  Osteoarthrites, Osteoporosis, Tendenitis,
  aseptic necrosis, Migraine, acute burns, drug
  resistant epilepsy, diabetic neuropathy,
  peripheral and coronary Angiogenesis grow new
  blood vessels in the heart muscle in place of a
  bypass surgery etc.,
• where ever Tissue Regeneration is essential...

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With RFQMR...

• We will be able to communicate with the cancer
  cells in cancer patients and take over the cells
  command and control and effect successful
  degeneration by,
• 1. Directly halting active cell division.
• 2. Opening up Protein path ways to allow
  Chemotherapy molecules without effecting
  other healthy cells.
• 3. Or guide glucose coated ferrite
  nanoparticles into the tumor cells and Rip
  them apart.

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Regenerative and Degenerative Experiences with
RFQMR
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OSTEOARTHRITIS
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OSTEOARTHRITIS
Inclusion Volunteers posted for Knee
Replacement Surgery.
Presentation

• Pain
• Restriction of movements
• Option - surgery

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RESULTS
Evaluation Criteria

• International Knee society rating system
• -Range of knee movement
• -Pain score
• -Dynamometry
• -Total knee score
• -Functional knee score
• Radiological Evidence
• Quality of Life (FACT)

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PRE
POST
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PRE
POST
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CANCER
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CMP in Living Cell ...

• Altering the Cell Membrane Potential (CMP) is a
  complex process. However.
• -70 to -90 mV is the CMP in Healthy Cells.
• -40 to -60 mV when Infected.
• -20 to -30 mV in Cancer
• and 0 when the Cell dies.
• RFQMR is capable of altering this potential, to
  achieve cellular control.

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RFQMR Treatment Process

• RFQMR treatment procedure starts with a
  conventional Diagnostic MRI.
• The Radiologist Prepares the Planning film
  positioning the RFQMR guns around the region of
  interest (ROI)
• He also does the surface marking of the ROI
• A template is made from the surface markings
• The Planning film is fed into the Cytotron
  Machine, that calculates the required dose.
• Thereafter the exposure continues for the
  determined period.

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Planning film
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Typical Dose Planning Process

• The Gun emission depends on the tissue that come
  in the gun path.
• Air is the best friend and Fat is the worst enemy
  of RFQMR.
• PD or Proton Density is simply the H2 atom
  concentration in a given tissue.

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CANCER PROJECT

• Phase-1
• Terminal cancer
• Not amenable to Surgery/ RT/ CT
• Single lesion
• Pain alleviation

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Criteria

• Clinical assessment
• Radiological assessment
• Tumor markers
• Histopathology
• QOL

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Case- 1

• Mr R,68 yrs
• Nov-2003-Ca Lung RLL T2N0 (Adeno ca)
• Chemo (Carbo Eto) 3 till March 2004
• April 2004 Prog of disease (vide CT)
• Presented Cough Hemoptysis
• - Breathlessness
• - Pallor
• - Debility

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Case 1

• RFQMR-126/11/2004 09/12/2004
• 2 24/12/2004 07/1/2005
• CT Jan 2005 Aug 2005 - Static
• Now - No Complaints
• - Energetic
• - Walks 30 m daily
• - Appetite Good

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Pre-exposure
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Post-exposure
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Post-exposure
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Post-exposure
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Brain tumours

• Brain tumours initial results are encouraging

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CASE 2

• Mr R, 56yrs
• Nov 2004 MRI Brain Left frontal SOL (4 x 4 x
  3 cm)
• - SX Craniotomy x decompression of insular
  glioma
• HPR Glioblastoma Grade IV
• RT 60 Gy/30 till Jan 2005
• CT Temedol x 2 till Feb 2005

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• Presented Feb 05
• - Loss of memory
• - Apathetic
• - Hemiparesis (power3/5)
• Today after 1 course of RFQMR
• - No focal/Gen Neuro
  deficit
• - Normal higher functions and
  back to work.

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Pre-exposure
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Pre-exposure
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Post-exposure
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Post-exposure
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CASE 3

• Mr RG, 5yrs
• May 2004 Right Hemiparesis with ICSOL
• - MRI Left Thalamic glioma with systi
  changes obst. Hydrocephalus
• - Op n Right VP shunt
• - Neuro improvement
• Jun 2004 Neuro deterioration
• - Op n Revision of VP shunt
• .

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• At Presentation Nov 04
• - Hemiparesis
• -Headache
• -Diplopia
• RFQMR Nov 2004
• Today - No increase ICT
• - Mild
  residual Hemiparesis

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Pre-exposure
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Pre-exposure
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Post-exposure
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Post-exposure
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Pre-exposure
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CASE 4

• Mr D, 44yrs
• Sept 2003-SOJ (Se Bil4.5, AlkPO4450
• BX of pre-op lesion PD Adeno Ca
• Nov 2003-Op n-Inoperable mass head
  
• pancreas (1)
• -Infiltrating SMR/PV
• gtPalliative-C cys J
  GJ
• Chemo gemcit 5
• Presentation Cachexic
• - Wt loss 20 Kg

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• RFQMR-1 01Jan 31 Jan 2005
• -2 15Feb 28 Feb 2005
• CT scans
• Sept 2003 Jan 2005
  Progress of Lesion
• Jan 2005 Sept 2005 static
• Went back to Duty- April 05

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Pre-exposure
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Pre-exposure
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Post-exposure
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CA 19-9

• 18.5
• gt 13.8
• gt 13.7
• gt 13.8
• gt13.7

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CASE 5

• Mrs NK 41 Yrs
• Ca Ovary III C
• Sx Jul 03- Sub optional debulking
• - Jan 04- Sub optional debulking
• Chemo- Post operative x02 complete course
• HPE - Mucin Secreting Adeno Ca
• Oct 04 Slowly increasing cyst behind bladder

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• RFQMR- Nov 04
• Expl Lap - 13.04.05
• - Solid intra abdominal
  masses
• - 10 Cm cyst from bladder
• - Partial cystectomy
• HPE - Mesothelial Cyst

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Our experiences with cancer treatment

• An Overview

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Spectrum of Patients
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Overall Outcome
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Survival Period
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CNS Tumours Outcome
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Survival Period CNS Tumours
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Evaluation CriteriaCNS Tumours Overall
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Evaluation CriteriaCNS Tumours Localised (N13)
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Evaluation CriteriaCNS Tumours Disseminated (N9)
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Cancer Treatment Results
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Potential Appliations

• Diabetes
• Angiogenesis
• Tinnitus
• Macular Degeneration
• Nanoporation
• Delivery of Genetherapy
• Nanoblasting