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Rotational Field Quantum Magnetic Rotational Field Quantum Magnetic Resonance in Tissue EngineeringResonance in Tissue Engineering
A Preliminary ExperienceA Preliminary Experience
Dr. R. V. Kumar
Center for Advanced Research and Development
&
Institute of Aerospace Medicine,
Indian Air Force, Bangalore
Rotational Field Quantum Rotational Field Quantum Magnetic ResonanceMagnetic Resonance
Establishing Communication with
Living Cells
Centre for Advanced Research and Development (CARD)
Institute of Aerospace Medicine (IAM) Bangalore
Where did it all start..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)
Where did it all start..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: 1970;24:438-470)
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.
The Hypothesis..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).
In Cancer....In Cancer....We need to understand Cytonics, the electronics of
the biological cell, it’s 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.
The Technology…..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...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 TissueAir
Ei
SiHi
Et
StHt
Er
Sr Hr
Inte
rfac
e
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RFQMR incidenceRFQMR 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:
E r E i (1a)
E t E i (1b)
1 2
1 2
(2a)
2 1
1 2
(2b)
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Parameters of mediaParameters 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
P ( 0)
E (3)
J
E (4)
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Parameters of mediaParameters 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
B
H (5)
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Permittivity of tissuesPermittivity of tissues
101 102 103 104 105 106 107 108 109 1010 10110
1
2
3
4
5
6
7
8
Frequency (Hz)
log
Relat
ive P
erm
ittivi
ty
Relative Permittivity versus Frequency for Six TissuesDry SkinWet SkinMuscleBloodBrain, White MatterFatPronounced Drop in Permittivity
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Conductivity of tissuesConductivity of tissues
101 102 103 104 105 106 107 108 109 1010 1011-4
-3
-2
-1
0
1
2
Frequency (Hz)
log
Cond
uctiv
ity (S
/ m
) Conductivity versus Frequency for Six Tissues
Dry SkinWet SkinMuscleBloodBrain, White MatterFat
Significant Increases in Conductivity
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Depth of penetrationDepth 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
D.O.P.c 2
rr '[ 1 tan2c 1]1/ 2(6)
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DOP of tissuesDOP of tissues
101 102 103 104 105 106 107 108 109 1010 1011-4
-3
-2
-1
0
1
2
3
4
5
Frequency (Hz)
log
Dep
th o
f Pen
etratio
n (m
eters)
DOP versus Frequency for Six TissuesDry SkinWet SkinMuscleBloodBrain, White MatterFat
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Non-ionizing radiationNon-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: >> D– MHz Radio frequency radiation: ~ D, << D
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VL
F
LF
30kH
z
300k
Hz
Lower frequenciesLower frequencies
Power Lines
Submarine Comm.
Audio (sound)
Radio beacons (Navigation)
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Low frequency RF effectsLow 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
PlasmaMembrane
CellularMembrane
Enzymes,Genes,
Proteins
BiochemicalMessenger Nucleus
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Theory of signal transductionTheory 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
PlasmaMembrane
CellularMembrane
Enzymes,Genes,
Proteins
BiochemicalMessenger
Nucleus,DNA
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Direct interaction theoryDirect 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
BvqF
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DNA chain bendingDNA chain bending
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:
F I dl
B (8)
II
B
F
FAftertime I I
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MHz Radio frequenciesMHz Radio frequencies
RF
300k
Hz
300G
Hz
AM Broadcasting
TV Broadcasting, FM Radio
Cellular Phone
Microwave Oven
Satellite Comm.
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Where does RFQMR fit on the EM Where does RFQMR fit on the EM SpectrumSpectrum
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 effectsMHz 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 -> heat -> 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 RFNon-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
d
M
dt
M
B (9)
RFQMR can be successful in …….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…...
With RFQMR…...With RFQMR…... We will be able to communicate with the cancer cells
in cancer patients and take over the cell’s 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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OSTEOARTHRITISOSTEOARTHRITIS
PainRestriction of movementsOption - surgery
Inclusion: Volunteers posted for Knee Replacement Surgery.
Presentation:
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RESULTSRESULTS
International Knee society rating system
-Range of knee movement-Pain score-Dynamometry-Total knee score-Functional knee score
Radiological Evidence Quality of Life (FACT)
Evaluation Criteria
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CMP in Living Cell …...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 ProcessRFQMR 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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Typical Dose Planning ProcessTypical 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 PROJECTCANCER PROJECT
Phase-1 Terminal cancer Not amenable to Surgery/ RT/ CT Single lesion Pain alleviation
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CriteriaCriteria
Clinical assessment Radiological assessment Tumor markers Histopathology QOL
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Case- 1Case- 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 1Case 1
RFQMR-1#26/11/2004 – 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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Brain tumoursBrain tumours
Brain tumours: initial results are encouraging
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CASE 2CASE 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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CASE 3CASE 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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CASE 4CASE 4
Mr D, 44yrs Sept 2003-SOJ (Se Bil=4.5, AlkPO4=450 BX of pre-op lesion = PD Adeno Ca Nov 2003-Op n-Inoperable mass head
pancreas (1”) -Infiltrating SMR/PV =>Palliative-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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CASE 5CASE 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 Our experiences with cancer treatmenttreatment
An Overview
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Spectrum of PatientsSpectrum of Patients
30%
18%15%
9%
8%
8%
12%
Brain
Gynae
Hepatobiliary
Upper GI
Lung
Colorectal
Misc
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Survival PeriodSurvival Period
0
10
20
30
40
50
60
70
80
Surviving
> 3 months
< 3 months
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CNS Tumours: Outcome CNS Tumours: Outcome
59%
41%
Survived
Died
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Survival Period: CNS Survival Period: CNS TumoursTumours
0
10
20
30
40
50
60
70
80
90
Surviving
< 3 months
> 3 months
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Evaluation CriteriaEvaluation CriteriaCNS Tumours : OverallCNS Tumours : Overall
02468
10121416
18
LOC Speech MusclePower
Gait Memory
Yes
No
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Evaluation CriteriaEvaluation CriteriaCNS Tumours Localised CNS Tumours Localised
(N=13)(N=13)
0
2
4
6
8
10
12
LOC Speech MusclePower
Gait Memory
Yes
No
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Evaluation CriteriaEvaluation CriteriaCNS Tumours Disseminated CNS Tumours Disseminated
(N=9)(N=9)
0
1
2
3
4
5
6
7
8
LOC Speech MusclePower
Gait Memory
Yes
No
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Cancer Treatment ResultsCancer Treatment Results
0
20
40
60
80
100
Surviving SymptomaticRelief
Back to Work
Treatment Result Criterion