CA1331162C - Techniques for enhancing the permeability of ions through membranes - Google Patents
Techniques for enhancing the permeability of ions through membranesInfo
- Publication number
- CA1331162C CA1331162C CA000561802A CA561802A CA1331162C CA 1331162 C CA1331162 C CA 1331162C CA 000561802 A CA000561802 A CA 000561802A CA 561802 A CA561802 A CA 561802A CA 1331162 C CA1331162 C CA 1331162C
- Authority
- CA
- Canada
- Prior art keywords
- flux density
- magnetic field
- predetermined
- predetermined rate
- magnitude
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N13/00—Treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N2/00—Magnetotherapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N2/00—Magnetotherapy
- A61N2/02—Magnetotherapy using magnetic fields produced by coils, including single turn loops or electromagnets
Abstract
ABSTRACT OF THE DISCLOSURE
A method and apparatus are provided for enhancing the transport of a selected ion having a predetermined charge-to-mass ratio through a biomolecular membrane located in a space subjected to a local magnetic field. The space defines at least one reference path passing through the membrane in opposite first and second directions. The invention includes the steps of creating a magnetic field which, when combined with the local magnetic field, produces a magnetic field having a flux density with at least one component representable by a component vector having a direction extending in the first direction along the path. This component of the magnetic field has a magnitude that fluctuates at a predetermined rate to produce a nonzero average value. A predetermined relationship between the ratio of the selected rate to the nonzero average value and the charge-to-mass ratio of the predetermined ion is thereby created. The predetermined relationship, is a function of the cyclotron resonance frequency of the ion.
A method and apparatus are provided for enhancing the transport of a selected ion having a predetermined charge-to-mass ratio through a biomolecular membrane located in a space subjected to a local magnetic field. The space defines at least one reference path passing through the membrane in opposite first and second directions. The invention includes the steps of creating a magnetic field which, when combined with the local magnetic field, produces a magnetic field having a flux density with at least one component representable by a component vector having a direction extending in the first direction along the path. This component of the magnetic field has a magnitude that fluctuates at a predetermined rate to produce a nonzero average value. A predetermined relationship between the ratio of the selected rate to the nonzero average value and the charge-to-mass ratio of the predetermined ion is thereby created. The predetermined relationship, is a function of the cyclotron resonance frequency of the ion.
Description
~ -2- 1331162 BACKGROUND AND SUM~ARY OP THE INVENTION
Pield of the l.~vention This invention relates to the transfer o~ ions through membr~nes9 and more specifically relates to the electromagnetic alteration of biochemical activity in living cells.
Description of Relsted Art and Summary of the Invention The biochemical and medical fields have long sought an inexpensive and accurate method of enhancing the movement of selected ions involved in lire processes across living cell membranes. Until the discovery described in this 10 specificstion, no investigstor had found a satisfactory technique for achieving such results. The control of such ions has been achieved up to now solely by theadministration of pharmaceutical agents which often entail invssive hazard and which ~t best are less than efficaciols in their results. The applicants hflve succeeded where others failsd because they have discovered the cause and effect 15 relstionship between certain types of extremely low frequency (ELP) magnetic fields and the movement of selected iorls across the membranes of living cells.
The closest known related work is described by Blackman et aL in "A Role For The MQgnetic Field In The Rsdiation-lnduced Efflux Of Calcium Ions From Brain Tissue In Vitro," 6 Bioelectroma~netics 327-337 (1985). Blackman et al.
20 noted changes in the efflux of calcium ion from brain tissue in response to various magnetic fields. Since Blackman et al. used tissue specirnens rather than single cells, it is impossible to te~l whether the efflux of calcium ions noted by them was due to 8 cell membrane response as opposed to movement Or ions in bulk interstitial nuids or in damaged cells.
Blackman et aL used both ~ constant unipolar magnetic field and a iluctuating bipolar magnetic rield arranged perpendicular to each other. The fluctuating biopolar field was generated by a transmission line. Aceording to conventional field theory, the transmission line produced magnetic nu~ lines arranged in concentric rings around the axis of the line. Blackman et al. noted 30 modest cQlcium efnlL~c (e.g., 20 to 30% increase when compared to controls) when the constant and nuctuating rield~ were perpendicular, but ~iled to note any e~nu~ for any other orientation o- the nuctuating neld snd constant ~ield (p.
33~). Purthermore, according to the BEMS Se~enth Annual Meeting Abstract~
~ .
~ .
~ , : , ". ..... .
~ ~3~ 1331162 (1985), Blackman et al. ruled out a simple cyclotron resonance model as the underlying causative mechani m for their observations.
Contrary to the observations of Blaclcrnan et al., the appli~snts have discovered that they can substantially increase the perme~bility of a selected ion 5 through a membrane subjected to either the earth's geomagnetic field or to an arbitr~rily chosen static magnetic ~ield by superimposing a fluctuating magneticfield with a flux denslty having a nonzero net average value that is properly proportioned with respect to the frequency of the fluctu~tions. The applicants have succeeded by creating a magnetic field whieh, when combined with either 10 the earth's geomagnetic field or an arbitrarily chosen static magnetic field,results in a magnetic field havir~ at least one rectangular component extending along an axis projecting through the cell and having a magnitude thst nuctuates at a prescribed predetermined rate to create a nonzero average value. The field is generated so that the ratio of this predetermined rate to the nonzero average15 value is limited by means of a predetermined relationship with respect to the charge to mass ratio of the predetermined ion.
According to a preferred prQctice of the invention, the predetermined rate (in Hz) times 2 ~r is substantislly equal to the charge-to-mass ratio (in Coulombs per kilogram) of the predetermined ion times the nonzero average value of 20 magnetic flux density (in Tesla). This is a relationship of the type rejected by Blackman et al. and hereafter called the "C~clotron Resonan~e Rel~tionshipn:
Pield of the l.~vention This invention relates to the transfer o~ ions through membr~nes9 and more specifically relates to the electromagnetic alteration of biochemical activity in living cells.
Description of Relsted Art and Summary of the Invention The biochemical and medical fields have long sought an inexpensive and accurate method of enhancing the movement of selected ions involved in lire processes across living cell membranes. Until the discovery described in this 10 specificstion, no investigstor had found a satisfactory technique for achieving such results. The control of such ions has been achieved up to now solely by theadministration of pharmaceutical agents which often entail invssive hazard and which ~t best are less than efficaciols in their results. The applicants hflve succeeded where others failsd because they have discovered the cause and effect 15 relstionship between certain types of extremely low frequency (ELP) magnetic fields and the movement of selected iorls across the membranes of living cells.
The closest known related work is described by Blackman et aL in "A Role For The MQgnetic Field In The Rsdiation-lnduced Efflux Of Calcium Ions From Brain Tissue In Vitro," 6 Bioelectroma~netics 327-337 (1985). Blackman et al.
20 noted changes in the efflux of calcium ion from brain tissue in response to various magnetic fields. Since Blackman et al. used tissue specirnens rather than single cells, it is impossible to te~l whether the efflux of calcium ions noted by them was due to 8 cell membrane response as opposed to movement Or ions in bulk interstitial nuids or in damaged cells.
Blackman et aL used both ~ constant unipolar magnetic field and a iluctuating bipolar magnetic rield arranged perpendicular to each other. The fluctuating biopolar field was generated by a transmission line. Aceording to conventional field theory, the transmission line produced magnetic nu~ lines arranged in concentric rings around the axis of the line. Blackman et al. noted 30 modest cQlcium efnlL~c (e.g., 20 to 30% increase when compared to controls) when the constant and nuctuating rield~ were perpendicular, but ~iled to note any e~nu~ for any other orientation o- the nuctuating neld snd constant ~ield (p.
33~). Purthermore, according to the BEMS Se~enth Annual Meeting Abstract~
~ .
~ .
~ , : , ". ..... .
~ ~3~ 1331162 (1985), Blackman et al. ruled out a simple cyclotron resonance model as the underlying causative mechani m for their observations.
Contrary to the observations of Blaclcrnan et al., the appli~snts have discovered that they can substantially increase the perme~bility of a selected ion 5 through a membrane subjected to either the earth's geomagnetic field or to an arbitr~rily chosen static magnetic ~ield by superimposing a fluctuating magneticfield with a flux denslty having a nonzero net average value that is properly proportioned with respect to the frequency of the fluctu~tions. The applicants have succeeded by creating a magnetic field whieh, when combined with either 10 the earth's geomagnetic field or an arbitrarily chosen static magnetic field,results in a magnetic field havir~ at least one rectangular component extending along an axis projecting through the cell and having a magnitude thst nuctuates at a prescribed predetermined rate to create a nonzero average value. The field is generated so that the ratio of this predetermined rate to the nonzero average15 value is limited by means of a predetermined relationship with respect to the charge to mass ratio of the predetermined ion.
According to a preferred prQctice of the invention, the predetermined rate (in Hz) times 2 ~r is substantislly equal to the charge-to-mass ratio (in Coulombs per kilogram) of the predetermined ion times the nonzero average value of 20 magnetic flux density (in Tesla). This is a relationship of the type rejected by Blackman et al. and hereafter called the "C~clotron Resonan~e Rel~tionshipn:
2 fc (~ B
By properly orienting 6nd control}ing the resultant magnetic field, the 25 applicants have discovered that the cyclotron resonance can be used to enhance the transfer of a selected ion across the membrane of a living cell. This technique enables the applicants to alter the transfer of some ions by a substQntial fsctor up to ten or more times greater than would occur normally, orby any other technique. By using this technique, the influx or efflu~ ot selected 30 ions from living cells CQn be regulated economically with a degree of precision and speed previously ~known.
~' ,.
. .. ;',.
. ~:
~ ~ ~4~ ~331162 DESCRIPTION OP TH~ DRAWINGS
'`, :'' These and other advantages and features of the invention will herea~ter ~ appear for purposes of illustration, but not of limitation, in connection with the ; ~ accompanying drswings, wherein like number3 refer to like parts throughout, and 5 wherein:
FIG. 1 is a schematic, perspective view of an~ exemplary livis~g cell located in a bounded active volume in a space defining a rectangular coordinate axis system and subjeeted, within this active volume, to a magnetic flux density created by an electrical coil, or an equivalent permanent magnetic array or any 10 other e9uivalent source of magnetic nux density, such as the earth's geomag-netic field;
~ IG. 2 is a schematic electrical diagram of Q preferred form of generatingapparatus used to drive the coil shown in ~IG. 1 and the signal shapes employed;PIGS. 2A-2D are diagrams of signal waveshapes generated by the apparatus 15 shown in FIG. 2;
FIGS 3A and 3B are schematic diagrams of an active volume containing an exemplary living cell located in OE space defining a rectangular coordinate axissystem, showing the combination of magnetic flux densities created by a pair of electrical coils and by the locsl magnetic field;
FIG. 4 is a schematic, perspective view of another exemplary lir,ing cell located in a space defining a rectangular coordinate axis system and subjected, within a bounded active volume, to a magnetic nwc density created by a pair of electrical coils, or by an equivalent combination of sources of magnetic fields,such as a permanent magnetic and/or the earth's geomagnetic field;
FIG. 5 is an electrical, schematic diagram of 8 preferred form of signal generating apparatus used to drive the coils shown in FIG. 4;
FIG. 6 is a schematic, perspective view of the active volume surrounding an exemplary living cell located in a space defining a rectangular coordinate a~is system and subjected, within this active active volume, to a magnetic flux density created by three pairs o~ electrical coils, or an equivalent combination of sources of magnetic fields, such as permanent magnets and/or the earth's magnetic field;
~5- 1331162 ~ ~ ... .
. ~ ` ~ . .. . .
FIG. 6A is a schematic, perspective view of a preferred form o~ eoil pairs . used to subject the active volume shown in FIG. 6 to magnetic waves;
I~IGS. 6B and 6C are vector diagrams illustrating R preferred form of magnetic flux density located within the active volume shown in FIG. 6;
PIG. 7 is a schematic electrical diagram o~ a tgpical signal generating apparatus used to drive the coils in PIG. 6; and FIGS. 7A-7C are diagrams of signal waveshapes generated by the apparatus shown in FIG. 7.
j,#~,, r~
DESCRIPTION OF THE PRE~ERRED EMBODIMENTS
~; When used in the present application and claims:
tq3" represents Magnetic ~lu~ Density measured in Tesla (1 Tesla = 1 x 104 gauss). B is also often referred to as Magnetic Induction or Magnetic ~ield (seeP.A. Tipler, Physics, 2nd ed., p. 723, Worth PublisheRs, Inc., 1982, New York).
"m" represents ionic mass, measured in ldlograms.
"q" represents ionic charge, measured in Coulombs.
"f" represents frequency, measured in Hertz.
"fc" represents cyclotron resonance frequency, measured in Hertz.
"Helmholtz coils" refers to a coaxial configuration of a pair of equal electrical coils, each having the same number of total tllrns of wire, with the mi~planes of the two coils separated by a distance equal to the radius of eithercoil, with the two coils wound and electrically connected such that the msgneticflux density from each coil at the point on the axis halfway between the coils points in the same direction. ~ i "Local magnetic nux density" refers to the ambient magnetic field that is substanti~lly constant in time and omnipresent in all environments. This will include the earth's geomagnetic field as it occurs naturally or altered levels of the earth's field that result from the presence of local magnetic materials or the energization of electrical coils for the purpose of augmenting or decreasing theearth's geomagnetic field.
"Active volume" is the working volume within the refion defined by a set of Helmholtz coils, or a solenoid, or any other arrangement of electrical coils or permanent magnets, used in con~unction with the local magnetic field, to ereate a net magnetic flux density. The magnetic flus density everywhere within the actiYe volume is predictable, measurable and uniform, (i.e., substantially equaleverywhere within this volume). The actiYe volume, in the present case, encompasses the totel volume of cell or tissue that are exposed to the magnetic -flus density required in the preferred practice of this invention. The magnetic flus density over the total ~olume of expo6ed oells or tissue will thereby be ~ub~t~ntially the 3ame.
Referring to the drawings, the transfer of a predetermined ion through a membrane can be dramatlcally enhanced by ~ vAriety of magnetic nux densities.
' : ' ' '; . ~ '.' .' !
~7~ 1331162 Three preferred arrangements for achieving such nw~ densities are shown schematically in PIGS. 1, 4 and 6.
- Referring to PIG. 1, coils 10A and 10B of a conventional Helmholtz coil pair h~ving N turns of wire making ~ loop with diameter 2R, have a longitudinal S a2~is identified by the letter Z (PlG. 1). The mid-planes Or each coil, located at X1Yl and at X2Y2 are separated by a distance R. (The scale in the direction of the Z-axis has been expanded to more c2early show volume 14.) One such coil pair has 500 turns of No. a4 wire on each loop, with a 23 centimeter diameter for each loop; the two loops are separated by 11.5 centimeters. Helmholtz coils are 10 described in Scott, The Physics of Electricity and Magnetism (John Wiley ~c Sons, Inc. 1962) at p. 315. The number of turns N, the diameter of the coils 2R, the separation of the coils R, ~nd the wire gauge are only critical insofar as conventional practice requires constraints on these and other design parameters to allow optimal performance characteristics in achieving predetermined flux 15 densities as reguired in the preferred practice of the present invention. These predetermined nux densities may also be achieved by conventional devices other than Helmholtz coils, such es solenoids, electromagnets, and permanent magnets.
Whatever the means of generating this flux density, the essential aspect relevant to this invention is that a predictHble, measurable and uniform magnetic 20 flux density having the value Bo be established everywhere within active volume 14, and that this active volume will encompass the total volume of cells and/or tissue that are exposed to this nux density Bo. A unipolar vector representing '.tjj~
magnetic flux density Bo i8 pictured in FIG. 1 with arrows A1 and A2 separated by a "." that represents the average nonzero value of the vector. The opposed 25 arrows represent the fact that t3~e magnitude of Bo changes at a predetermined rste. Por purposes Or illustration, a single exemplary living cell 12 is pictured in FIG. 1 within sctive volume 14.
Referring to PIG. 2, coils 10A and 10B receive electrical signals from a conventionsl AC sine wave generator 20 connected by means ol a switch 26 30 either to a DC offset networ~c 24 or to a full wave rectifier 22. The instantaneous current I supplied to coils 10A and 10B as a function of time t isshown for both switch po~itions a6a and 26b in PIGS. 2A and 2B, respectively.
Similarly, the instgntaneoug magneti~ nux deni~ity Bo produced within sctive volume 14 is depicted as a funcUon Or time for both switch positions 26A and . ",, ~ , - . . . .
?r ~
~:
26B in FIGS. 2C and 2D, respectively. The frequency and amplitude of the signals generated by circuits 20, 22 and 24 are -~
explained later in detail.
Cell 12 contains a specific complement of intrinsic ~
ionic species and is surrounded by a liquid or tissue medium ;~ ;
containing ionic species required for cell and tissue function.
TABLE 1 lists a typical, but incomplete, group of such ionic ;~
species suitable for use with the invention and shows the charge~
to-mass ration (q/m) of each species, in units of Coulombs per ~ ~;
:- ::~. ..
kilogram, as well as a preferred repetition rate or frequency (fc), in Hz, for each species, for the specific case in which the magnetic flux density is 5 X 10 Tesla. For any other ionic species not indicated in TABLE 1, or for any magnetic flux density other than 5 X 10 Tesla, the preferred frequency is found using the Cyclotron Resonance Relationship.
i The preferred ratio of the predetermined rate of the ¦ average non-zero magnitude of flux density is substantially between 152.5 X 105 and 2.50 X 105, where the predetermined rate is measured in Hertz and the flux density is measure in Tesla.
`' TABLE 1 ~, Ionic Species(m) ~ Coulombs per Kilogram (fc), Hz Hydrogen, H 95.6 x 106 761 Lithium, Li 13.9 x 106 111 Magnesium, Mg +7.93 x 106 63.1 Calcium, Ca++4.81 x 106 38.3 Sodium, Na 4 19 1o6 33.3 Chlorine, Cl2.72 x 106 21.6 ~LI
TABLE 1 CON'T.
Potassium, K 2.46 x 106 19.6 Bicarbonate, HC03 1.57 x 10 12.5 * Resonance frequencies at 5 x 10 Tesla.
When coils lOA and lOB are energized by the apparatus shown in FIG. 2, the coils generate a magnetic flux density within active volume 14 that varies with time as shown in FIGS.
2C and 2D. A nonzero average magnetic flux density Bo, uniform throughout the active volume, results either from an offset sinusoidal signal or from a full-wave rectified signal applied to .
coils lOA and lOB.
.s~"~
Referring th FIG. 3A, the local constant magnetic flux density BL will in general be superposed on the applied magnetic flux density Bo generated by coils lOA and 10 B in active volume .
14. The local flux density BL will have three ~
.',., ' ' '.' ~ ' ' rectangular components, one of which is a component along the direction o~ the Z-a2cis. The effect or the Z-component o~ the local flux density will be to change the nonzero sverage magnetic flux density Bo created by coils 10A and 108 within active volume 14 to a different net aver~é value B1.
S ~or purposes of illustration, in order to transfer calcium ions across the membrane of cell la, sine wave generator 20 and ~ither offset circuit 24 or fullwave rectifier 22 are regulated such that the charge-to-mass ratio for the Ca ion equals the ratio of the supplied frequency fc to the resultant average magnetic flux density Bl times 2 lr . Referring to ~IG. 2, the frequency supplied 10 to coils 10A ~nd lOB will change depending on switch 26. Assuming sine wave generator 20 has an amplitude that creates an averqge flux density in sctive volume 14 which, when combined with the Z-components of the local magnetic nux density, produces a net average value of B1 equal to 5 ~c 10 5 Tesla, the frequency of the sine wave generator should be set, for switch position 26a, to 38.3 Hz.- If one chooses switch position 26b, the frequency of the sine wave generfltor should be set to (38.3/2) Hz, because rectifier 22 doubles the frequency output of the sine wave generator.
The resultant nonzero average magnetic flux density B1 can be sdjusted for maximum ion transfer in two ways; first, without adjusting the local magnetic 20 rield Bz, and second, by separately reducing Bz to zero. The first case hss already been described, wherein sine wave generator 20 is regulated to create, via coils 10A and IOB, magnetic nux density Bo~ which when added to Bz, results in Bl. In the second case, 8z can be separately reduced to zero with a simple set ot coils or a permanent magnet array, and sine wave generator 20 regulated to 25 create, via coils lOA and lOB, a magnetic tlux density Bo already equal to the desired flux density B1.
Referring to FIG. 4, one example Or the manner in which the local magnetic field Bz can be reduced to zero i~ illustrated. This is achieved by means of additional Helmholtz ~oils 8A and 8B having N2 turns Or wire in each 30 loop, with the loop diameter 2R2 and the separation o~ the midplanes of each loop equal to R2. Coils 8A and 8B have their Qxi~ colinear with that Or coil~ lOA
and lOB, and eoincident with the Z-axis.
-lo- 1331162 Referring to PIG. 5, coils 8A and 8B are energized by a DC power supply 28. When coils 8A and 8B are energized in the manner described, they create in ~i active volume 14 a unipolar constant magnetic flux dersity directed along the Z-a~s such that the local magnetic field in the Z-direction (Bz) can be enhanced or 5 decreased, and in particular, can be reduced to zero.
The apparatus shown in FIG. 4 also can b~ used to generate a nonzero unipol~r resultant flux density B1 if coils 8A and 8B are energized with a constant DC current that does not cancel the local magnetic field Bz, and coils 10A and lOB are energized by an AC current, such as the current generated by 10 AC sine wave generator 20, having the frequency described in connection with FIG. 2. The DC current creates a unipolar magnetic field represented by arrows Bz in FIG. 3B having a constant magnitude, and the AC current creates a biopolar magnetic field having periodically opposed directions that reverse at the same rate as the AC current and having a magnitude that varies at the same rate 15 as the AC signaL
PIG. 6 illustrates active volume 14 corresponding to a coil array in which a substantially constant field magnitude having a uniformly changing direction canbe used to enhance the transfer of a selected ionic species across cell membranes. As shown in FIG. 6A, coils 8A, 8B, lOA snd 10B are oriented in the 20 same manner as shown in FIGS. 1 and 4. The local magnetic flux density in thedirection of Z (Bz) is either reduced to zero by creating an opposite but equal field via coils 8A and 8B as shown in ~IG. 4, or is added to, via coils lOA and 10B, to produce an overall net nonzero nux density Blin the Z-direction. Coils 4A, 4B, 6~ and 6B are arranged such that their axes are perpendicul~r to each 25 other and to Z. Coils 4A and 4B have their axis slong the Y coordinate axis and coils 6A and 6B have their axis along the X coordinate direction. Coil~ 4A, 4B, 6A, 6B, 8A, 8B, lOA and lOB are all deployed symmetrically about the XGYO
lnteNection on the Z-axis snd each coil pair h~ the same physical properties described previously, that is, a sufficient number of turns, a sufficient separation 30 between loop midplanes, a loop diameter equal to twice this separation, and 8su~ficient gauge of wire, all properties chosen to ~1) match the impedsnce and ¢urrent ~apacity Or the power supply, (2) provide an adequate~level of magnetic n~ density, consistent with the requirements o- this invention, and ~3) pro-~ide 1 3 3 1 1 6 2 : ~
the desired active volume to expose a predetermined quantity of eells and tissueto the combined msgnetic nux densities created by these coils.
Referring to FIG. 6, one example Gf operation is to sUgn the Z-sxis of the coil system with the direction of the 2Ocal magnetic field and use power supply 28 and coils 8A and 8B to reduce the local magnetic nLx density to zero. A
rotating magnetic field Bxy is created by the join~ ~ction of coils 4A and 4B and 6A and 6B and another field B1 is created by coils 10A and lOB. As Bxy rotates in the XOYO plane, the net magnetic flux density resulting from the superposition of magnetic fields by coils 4A, 4B, 6A, 6B, lOA and lOB within sctive volume 14 is the resultant BR, the direction of which sweeps out a cone, as indicated in ~IG. 6B.
Referring to FIG. 7, coils 4A, 4B, 6A, 6B, 10A and lOB are driven by a function generator 30 that generates three synchronous outputs, a special voltage function g(t) 32 at frequency f1 (FIG. 7A) that is generated on a conductor 31A ~FIG. 7), a sinusoidal signal 34 at frequence fc~ modulated by a ramp function (sawtooth voltage) at frequence f1 (FIG. 7B) that is generated on a conductor 31B (PIG. 7), and a cosine signal 36 st frequency fc~ 90 out of phssewith signsl 34, and modulated by a ramp function at frequency fl (FIG. 7C) that is generated on a conductor 31C ~FIG. 7). These three synchronous outputs from generator 30, in turn, drive three programmQble power supplies 38, 40 and 42.
The frequenc~ f1 is determined by the relation fc = cfl, where c is a large integer (i.e., sn integer greater than or equal to 20). The frequence fc is the Cyclotron Resonsnce Relationship frequency fc for the msgnetic flux density having the msgnitude BR, when one wishes to transfer ions having ~harge-to-mass ratio qlm scross membranes loc~ted in 8ctive volume 14. Thus, to trsnsfer c~lcium ions when BR= S ~c 10 5Tesla, tc will be set in generator 30 to the trequency 38.3 Hz snd a typical vslue for fl will be 0.383 Hz (i.e., c = 100).
Referring to PIG. 7, the period (or cycle time or modulstion time) ~or each or the three outputs driving power supplies, 38, 40 and 42 will be ~l/rl) seconds.
In the example given in which rl = 0.383 Hz, the modulation period for the 81gnal~ supplied to coils 4A, 4B, 6A, 6B, lOA and lOB is 2.61 seconds.
Power supply 40 is ~ed by ~ signsl which (over one period) varies in time ss the tunction fl sin (2~ rct), where t is the time, given as zero 8econd~ at the beginning Or each period. Power supply 42 is ~ed by ~ signsl which over one ,; . . , - .
r.t,`~
~ .
period varies as the ~unction ~1tcos (2 ~ fct). Referring to FIG. 7, i~ A1 is the amplification Or power supplies 40 and 4a, the signal strength driving the Y-axis coils 4A and 4B over one period is Al~ltsin ~2 ~r fct) and ehe corresponding signal strength driving the x-axis coils 6A and 6B is Alfl tcos (2~r fct~ When energized 5 in the manner indicated, coils 4A, 4B, 6A and 6B ~enerate a magnetic field that rotates in time at the frequency fc within the plane defined by axes XO and YO~
as iUustr~ted in PIG. 6B. Since the local magnetic nux density has been canceUed ViQ coils 8A and 8B, the resultant msgneti~ field BR equals the sguare root of the sum of the squares of the magnetic field creeted by coils 10 along the 10 Z-axis and the magnitude of the magnetic vector that rotates in time in the XOYo plane. The rotating vector is designated by Bxy~
To cover all possible ion channels located in the active volume 14, the value of Bxy increases linearly in time, foUowing the modulating function A1flt,until the maximum signal occurs at t = 1/fl seconds, whereupon the entire 15 process repeats. At any instant of time, the resultant magnetic field is 8 = ~B2 + B2 ~,~a 20 Inasmuch as it is desirsble to maintain the Cyclotron Resonance Relationship as given in TABLE 1 for the purposes of this invention, ie is also desirable to maintain BR constant in magnitude over the course o- this process. An ideal condition in this regard is shown in ~IG. 6C, in which BR describes a cone in space, the half-angle Or which wiU increase over one period from 0 to any angle25 equal to or less than 180, during which time BR remains constant in magnitude.
Because the value Bxy inereases in time, it i8 necessary to decrease B1 synchronously in order to hold BR constant. 171e output of generator 30 to powersupply 38 is designed to vary in time in such a manner as to reduce the field Blcteated by coils 10A and 10B by the proper factor required to maintain BR
30 constant over the entire period. Referring to PIG. 7, the input 32 to power 8upply 38 is g(t) and the amplification of power supply 38 is AR, resulting in adrlving signal to coils 10A nnd 10B equal to ARg(t). Over one period, ~tarting at tim~ t egual~ zero seconds, the runct~on g(t) is given by g(t) = (1 = ~t2) 2 ~,,.. ,.,... ,.. " ,.,.. , .~ ~.; . . . .. .. ..
; -13- 13311S2 In the practice of this invention, the values of amplificstion of power supplies38, 40 and 42, corresponding respectively to Al, Al Qnd AR, are selected primarily with Qn eye towards convenienee in producing a required BR.
If coils 8A and 8B do not cancel the local field Bz, such that the magnetic flux density along the Z-a~is is not merely that prloduced by coils lOA Qnd lOB,but includes an extra local component Bz, the process pertinent to FIGS. 6 and 7remains unchanged, e~cept that the magnetic field 81 is in part produced by coils lOA and lOB. Over the course of one modulation period, the angle between the Z-axis and the resultant magnetic field BR increases so that the tip of the vector sweeps out an ever-increasing circle, but the magnitude of the resultant vector remains constant since Bl is being decreased at the same time. Thus, over one modulation period, the tip of the resultant magnetic field vector BR
traces out some portion of a hemisphere, depending on how large the angle between the Z-axis and BR is allowed to become. The locus or points traced out lS by BR can cover a complete sphere by reducing Bl below zero. By adjusting the value of large integer c, vector BR can be tuned to complete the generation of ahemisphere or 8 sphere or any frsction thereof at a specified rate. In this way,Pll directions for variously oriented membrane surfaces will be covered by BR in6 repetitive and efficacious manner, thereby allowing the Cyclotron Resonance Relationship for enhanced permeability of ions to be met for elements of each membrane and ion channels that have various orientations. In this mode the frequency fc corresponds to the Cyclotron Resonance Relationship frequency fc~
Coincidentally, a second, alternate mode Or spplication is possible, in that the arrangement in YIGS. 6 and 7 can slso be used to simultaneously enhsnce the as transfer Or two distinctly different ionic species. In this mode, fc will correspond to the Cyclotron Resonance Relaffonship frequency for one species and fl to the Cyclotron Resonance Relationship frequency for another. Thus, consider TABLE 1 in ~hich the resonance frequency for hydrogen ions is 761 Hz and the resonance ~requency for pot~ium ions is 19.6 Hz ror a magnetic nux density equal to 5 s lO S Te~la. If ~oils 6A, 6B, 8A, 8B, lOA and 108 are energized to ereate a field BR equal to S ~10 5 Tesla in the aaffve volume 14, and it fl is ad~usted to 19.6 Hs, then choosing factor c to be 39 results in ~
frequency ~c substantially the same as required to enhance hydrogen ion tran~er. The result o~ this proced~e will be to simultaneou~ly enhflnce the transfer of both hydrogen and potassium ions across membrane surfaces within active volume 14.
Those sldlled in the art will recognize the embodiments described herein may be modified or altered without departing from the true spirit and scope of S the invention as defined in the appended claims. Por e~cample, the linear axesshown in the drawing may have more complicated paths, or the axes may be oriented along planes other than the conventional XYZ planes, or the size, ~hapeand physical properties of the coils may be altered, or the coils may take formsother than Hemholtz coils, such as solenoids, wires and sheets, or the coils may10 be replaced by equivalent devices for producing the required flux densities. The ions may be put into cyclotron resonance in a wide variety of ways as long as the relationship between the charge-to-mass ratio and the frequency and magnetic flux density is maintained. Por some applications, appropriate mechanical signals may be substituted for the described electrical signals.
.i.. , ...... -
By properly orienting 6nd control}ing the resultant magnetic field, the 25 applicants have discovered that the cyclotron resonance can be used to enhance the transfer of a selected ion across the membrane of a living cell. This technique enables the applicants to alter the transfer of some ions by a substQntial fsctor up to ten or more times greater than would occur normally, orby any other technique. By using this technique, the influx or efflu~ ot selected 30 ions from living cells CQn be regulated economically with a degree of precision and speed previously ~known.
~' ,.
. .. ;',.
. ~:
~ ~ ~4~ ~331162 DESCRIPTION OP TH~ DRAWINGS
'`, :'' These and other advantages and features of the invention will herea~ter ~ appear for purposes of illustration, but not of limitation, in connection with the ; ~ accompanying drswings, wherein like number3 refer to like parts throughout, and 5 wherein:
FIG. 1 is a schematic, perspective view of an~ exemplary livis~g cell located in a bounded active volume in a space defining a rectangular coordinate axis system and subjeeted, within this active volume, to a magnetic flux density created by an electrical coil, or an equivalent permanent magnetic array or any 10 other e9uivalent source of magnetic nux density, such as the earth's geomag-netic field;
~ IG. 2 is a schematic electrical diagram of Q preferred form of generatingapparatus used to drive the coil shown in ~IG. 1 and the signal shapes employed;PIGS. 2A-2D are diagrams of signal waveshapes generated by the apparatus 15 shown in FIG. 2;
FIGS 3A and 3B are schematic diagrams of an active volume containing an exemplary living cell located in OE space defining a rectangular coordinate axissystem, showing the combination of magnetic flux densities created by a pair of electrical coils and by the locsl magnetic field;
FIG. 4 is a schematic, perspective view of another exemplary lir,ing cell located in a space defining a rectangular coordinate axis system and subjected, within a bounded active volume, to a magnetic nwc density created by a pair of electrical coils, or by an equivalent combination of sources of magnetic fields,such as a permanent magnetic and/or the earth's geomagnetic field;
FIG. 5 is an electrical, schematic diagram of 8 preferred form of signal generating apparatus used to drive the coils shown in FIG. 4;
FIG. 6 is a schematic, perspective view of the active volume surrounding an exemplary living cell located in a space defining a rectangular coordinate a~is system and subjected, within this active active volume, to a magnetic flux density created by three pairs o~ electrical coils, or an equivalent combination of sources of magnetic fields, such as permanent magnets and/or the earth's magnetic field;
~5- 1331162 ~ ~ ... .
. ~ ` ~ . .. . .
FIG. 6A is a schematic, perspective view of a preferred form o~ eoil pairs . used to subject the active volume shown in FIG. 6 to magnetic waves;
I~IGS. 6B and 6C are vector diagrams illustrating R preferred form of magnetic flux density located within the active volume shown in FIG. 6;
PIG. 7 is a schematic electrical diagram o~ a tgpical signal generating apparatus used to drive the coils in PIG. 6; and FIGS. 7A-7C are diagrams of signal waveshapes generated by the apparatus shown in FIG. 7.
j,#~,, r~
DESCRIPTION OF THE PRE~ERRED EMBODIMENTS
~; When used in the present application and claims:
tq3" represents Magnetic ~lu~ Density measured in Tesla (1 Tesla = 1 x 104 gauss). B is also often referred to as Magnetic Induction or Magnetic ~ield (seeP.A. Tipler, Physics, 2nd ed., p. 723, Worth PublisheRs, Inc., 1982, New York).
"m" represents ionic mass, measured in ldlograms.
"q" represents ionic charge, measured in Coulombs.
"f" represents frequency, measured in Hertz.
"fc" represents cyclotron resonance frequency, measured in Hertz.
"Helmholtz coils" refers to a coaxial configuration of a pair of equal electrical coils, each having the same number of total tllrns of wire, with the mi~planes of the two coils separated by a distance equal to the radius of eithercoil, with the two coils wound and electrically connected such that the msgneticflux density from each coil at the point on the axis halfway between the coils points in the same direction. ~ i "Local magnetic nux density" refers to the ambient magnetic field that is substanti~lly constant in time and omnipresent in all environments. This will include the earth's geomagnetic field as it occurs naturally or altered levels of the earth's field that result from the presence of local magnetic materials or the energization of electrical coils for the purpose of augmenting or decreasing theearth's geomagnetic field.
"Active volume" is the working volume within the refion defined by a set of Helmholtz coils, or a solenoid, or any other arrangement of electrical coils or permanent magnets, used in con~unction with the local magnetic field, to ereate a net magnetic flux density. The magnetic flus density everywhere within the actiYe volume is predictable, measurable and uniform, (i.e., substantially equaleverywhere within this volume). The actiYe volume, in the present case, encompasses the totel volume of cell or tissue that are exposed to the magnetic -flus density required in the preferred practice of this invention. The magnetic flus density over the total ~olume of expo6ed oells or tissue will thereby be ~ub~t~ntially the 3ame.
Referring to the drawings, the transfer of a predetermined ion through a membrane can be dramatlcally enhanced by ~ vAriety of magnetic nux densities.
' : ' ' '; . ~ '.' .' !
~7~ 1331162 Three preferred arrangements for achieving such nw~ densities are shown schematically in PIGS. 1, 4 and 6.
- Referring to PIG. 1, coils 10A and 10B of a conventional Helmholtz coil pair h~ving N turns of wire making ~ loop with diameter 2R, have a longitudinal S a2~is identified by the letter Z (PlG. 1). The mid-planes Or each coil, located at X1Yl and at X2Y2 are separated by a distance R. (The scale in the direction of the Z-axis has been expanded to more c2early show volume 14.) One such coil pair has 500 turns of No. a4 wire on each loop, with a 23 centimeter diameter for each loop; the two loops are separated by 11.5 centimeters. Helmholtz coils are 10 described in Scott, The Physics of Electricity and Magnetism (John Wiley ~c Sons, Inc. 1962) at p. 315. The number of turns N, the diameter of the coils 2R, the separation of the coils R, ~nd the wire gauge are only critical insofar as conventional practice requires constraints on these and other design parameters to allow optimal performance characteristics in achieving predetermined flux 15 densities as reguired in the preferred practice of the present invention. These predetermined nux densities may also be achieved by conventional devices other than Helmholtz coils, such es solenoids, electromagnets, and permanent magnets.
Whatever the means of generating this flux density, the essential aspect relevant to this invention is that a predictHble, measurable and uniform magnetic 20 flux density having the value Bo be established everywhere within active volume 14, and that this active volume will encompass the total volume of cells and/or tissue that are exposed to this nux density Bo. A unipolar vector representing '.tjj~
magnetic flux density Bo i8 pictured in FIG. 1 with arrows A1 and A2 separated by a "." that represents the average nonzero value of the vector. The opposed 25 arrows represent the fact that t3~e magnitude of Bo changes at a predetermined rste. Por purposes Or illustration, a single exemplary living cell 12 is pictured in FIG. 1 within sctive volume 14.
Referring to PIG. 2, coils 10A and 10B receive electrical signals from a conventionsl AC sine wave generator 20 connected by means ol a switch 26 30 either to a DC offset networ~c 24 or to a full wave rectifier 22. The instantaneous current I supplied to coils 10A and 10B as a function of time t isshown for both switch po~itions a6a and 26b in PIGS. 2A and 2B, respectively.
Similarly, the instgntaneoug magneti~ nux deni~ity Bo produced within sctive volume 14 is depicted as a funcUon Or time for both switch positions 26A and . ",, ~ , - . . . .
?r ~
~:
26B in FIGS. 2C and 2D, respectively. The frequency and amplitude of the signals generated by circuits 20, 22 and 24 are -~
explained later in detail.
Cell 12 contains a specific complement of intrinsic ~
ionic species and is surrounded by a liquid or tissue medium ;~ ;
containing ionic species required for cell and tissue function.
TABLE 1 lists a typical, but incomplete, group of such ionic ;~
species suitable for use with the invention and shows the charge~
to-mass ration (q/m) of each species, in units of Coulombs per ~ ~;
:- ::~. ..
kilogram, as well as a preferred repetition rate or frequency (fc), in Hz, for each species, for the specific case in which the magnetic flux density is 5 X 10 Tesla. For any other ionic species not indicated in TABLE 1, or for any magnetic flux density other than 5 X 10 Tesla, the preferred frequency is found using the Cyclotron Resonance Relationship.
i The preferred ratio of the predetermined rate of the ¦ average non-zero magnitude of flux density is substantially between 152.5 X 105 and 2.50 X 105, where the predetermined rate is measured in Hertz and the flux density is measure in Tesla.
`' TABLE 1 ~, Ionic Species(m) ~ Coulombs per Kilogram (fc), Hz Hydrogen, H 95.6 x 106 761 Lithium, Li 13.9 x 106 111 Magnesium, Mg +7.93 x 106 63.1 Calcium, Ca++4.81 x 106 38.3 Sodium, Na 4 19 1o6 33.3 Chlorine, Cl2.72 x 106 21.6 ~LI
TABLE 1 CON'T.
Potassium, K 2.46 x 106 19.6 Bicarbonate, HC03 1.57 x 10 12.5 * Resonance frequencies at 5 x 10 Tesla.
When coils lOA and lOB are energized by the apparatus shown in FIG. 2, the coils generate a magnetic flux density within active volume 14 that varies with time as shown in FIGS.
2C and 2D. A nonzero average magnetic flux density Bo, uniform throughout the active volume, results either from an offset sinusoidal signal or from a full-wave rectified signal applied to .
coils lOA and lOB.
.s~"~
Referring th FIG. 3A, the local constant magnetic flux density BL will in general be superposed on the applied magnetic flux density Bo generated by coils lOA and 10 B in active volume .
14. The local flux density BL will have three ~
.',., ' ' '.' ~ ' ' rectangular components, one of which is a component along the direction o~ the Z-a2cis. The effect or the Z-component o~ the local flux density will be to change the nonzero sverage magnetic flux density Bo created by coils 10A and 108 within active volume 14 to a different net aver~é value B1.
S ~or purposes of illustration, in order to transfer calcium ions across the membrane of cell la, sine wave generator 20 and ~ither offset circuit 24 or fullwave rectifier 22 are regulated such that the charge-to-mass ratio for the Ca ion equals the ratio of the supplied frequency fc to the resultant average magnetic flux density Bl times 2 lr . Referring to ~IG. 2, the frequency supplied 10 to coils 10A ~nd lOB will change depending on switch 26. Assuming sine wave generator 20 has an amplitude that creates an averqge flux density in sctive volume 14 which, when combined with the Z-components of the local magnetic nux density, produces a net average value of B1 equal to 5 ~c 10 5 Tesla, the frequency of the sine wave generator should be set, for switch position 26a, to 38.3 Hz.- If one chooses switch position 26b, the frequency of the sine wave generfltor should be set to (38.3/2) Hz, because rectifier 22 doubles the frequency output of the sine wave generator.
The resultant nonzero average magnetic flux density B1 can be sdjusted for maximum ion transfer in two ways; first, without adjusting the local magnetic 20 rield Bz, and second, by separately reducing Bz to zero. The first case hss already been described, wherein sine wave generator 20 is regulated to create, via coils 10A and IOB, magnetic nux density Bo~ which when added to Bz, results in Bl. In the second case, 8z can be separately reduced to zero with a simple set ot coils or a permanent magnet array, and sine wave generator 20 regulated to 25 create, via coils lOA and lOB, a magnetic tlux density Bo already equal to the desired flux density B1.
Referring to FIG. 4, one example Or the manner in which the local magnetic field Bz can be reduced to zero i~ illustrated. This is achieved by means of additional Helmholtz ~oils 8A and 8B having N2 turns Or wire in each 30 loop, with the loop diameter 2R2 and the separation o~ the midplanes of each loop equal to R2. Coils 8A and 8B have their Qxi~ colinear with that Or coil~ lOA
and lOB, and eoincident with the Z-axis.
-lo- 1331162 Referring to PIG. 5, coils 8A and 8B are energized by a DC power supply 28. When coils 8A and 8B are energized in the manner described, they create in ~i active volume 14 a unipolar constant magnetic flux dersity directed along the Z-a~s such that the local magnetic field in the Z-direction (Bz) can be enhanced or 5 decreased, and in particular, can be reduced to zero.
The apparatus shown in FIG. 4 also can b~ used to generate a nonzero unipol~r resultant flux density B1 if coils 8A and 8B are energized with a constant DC current that does not cancel the local magnetic field Bz, and coils 10A and lOB are energized by an AC current, such as the current generated by 10 AC sine wave generator 20, having the frequency described in connection with FIG. 2. The DC current creates a unipolar magnetic field represented by arrows Bz in FIG. 3B having a constant magnitude, and the AC current creates a biopolar magnetic field having periodically opposed directions that reverse at the same rate as the AC current and having a magnitude that varies at the same rate 15 as the AC signaL
PIG. 6 illustrates active volume 14 corresponding to a coil array in which a substantially constant field magnitude having a uniformly changing direction canbe used to enhance the transfer of a selected ionic species across cell membranes. As shown in FIG. 6A, coils 8A, 8B, lOA snd 10B are oriented in the 20 same manner as shown in FIGS. 1 and 4. The local magnetic flux density in thedirection of Z (Bz) is either reduced to zero by creating an opposite but equal field via coils 8A and 8B as shown in ~IG. 4, or is added to, via coils lOA and 10B, to produce an overall net nonzero nux density Blin the Z-direction. Coils 4A, 4B, 6~ and 6B are arranged such that their axes are perpendicul~r to each 25 other and to Z. Coils 4A and 4B have their axis slong the Y coordinate axis and coils 6A and 6B have their axis along the X coordinate direction. Coil~ 4A, 4B, 6A, 6B, 8A, 8B, lOA and lOB are all deployed symmetrically about the XGYO
lnteNection on the Z-axis snd each coil pair h~ the same physical properties described previously, that is, a sufficient number of turns, a sufficient separation 30 between loop midplanes, a loop diameter equal to twice this separation, and 8su~ficient gauge of wire, all properties chosen to ~1) match the impedsnce and ¢urrent ~apacity Or the power supply, (2) provide an adequate~level of magnetic n~ density, consistent with the requirements o- this invention, and ~3) pro-~ide 1 3 3 1 1 6 2 : ~
the desired active volume to expose a predetermined quantity of eells and tissueto the combined msgnetic nux densities created by these coils.
Referring to FIG. 6, one example Gf operation is to sUgn the Z-sxis of the coil system with the direction of the 2Ocal magnetic field and use power supply 28 and coils 8A and 8B to reduce the local magnetic nLx density to zero. A
rotating magnetic field Bxy is created by the join~ ~ction of coils 4A and 4B and 6A and 6B and another field B1 is created by coils 10A and lOB. As Bxy rotates in the XOYO plane, the net magnetic flux density resulting from the superposition of magnetic fields by coils 4A, 4B, 6A, 6B, lOA and lOB within sctive volume 14 is the resultant BR, the direction of which sweeps out a cone, as indicated in ~IG. 6B.
Referring to FIG. 7, coils 4A, 4B, 6A, 6B, 10A and lOB are driven by a function generator 30 that generates three synchronous outputs, a special voltage function g(t) 32 at frequency f1 (FIG. 7A) that is generated on a conductor 31A ~FIG. 7), a sinusoidal signal 34 at frequence fc~ modulated by a ramp function (sawtooth voltage) at frequence f1 (FIG. 7B) that is generated on a conductor 31B (PIG. 7), and a cosine signal 36 st frequency fc~ 90 out of phssewith signsl 34, and modulated by a ramp function at frequency fl (FIG. 7C) that is generated on a conductor 31C ~FIG. 7). These three synchronous outputs from generator 30, in turn, drive three programmQble power supplies 38, 40 and 42.
The frequenc~ f1 is determined by the relation fc = cfl, where c is a large integer (i.e., sn integer greater than or equal to 20). The frequence fc is the Cyclotron Resonsnce Relationship frequency fc for the msgnetic flux density having the msgnitude BR, when one wishes to transfer ions having ~harge-to-mass ratio qlm scross membranes loc~ted in 8ctive volume 14. Thus, to trsnsfer c~lcium ions when BR= S ~c 10 5Tesla, tc will be set in generator 30 to the trequency 38.3 Hz snd a typical vslue for fl will be 0.383 Hz (i.e., c = 100).
Referring to PIG. 7, the period (or cycle time or modulstion time) ~or each or the three outputs driving power supplies, 38, 40 and 42 will be ~l/rl) seconds.
In the example given in which rl = 0.383 Hz, the modulation period for the 81gnal~ supplied to coils 4A, 4B, 6A, 6B, lOA and lOB is 2.61 seconds.
Power supply 40 is ~ed by ~ signsl which (over one period) varies in time ss the tunction fl sin (2~ rct), where t is the time, given as zero 8econd~ at the beginning Or each period. Power supply 42 is ~ed by ~ signsl which over one ,; . . , - .
r.t,`~
~ .
period varies as the ~unction ~1tcos (2 ~ fct). Referring to FIG. 7, i~ A1 is the amplification Or power supplies 40 and 4a, the signal strength driving the Y-axis coils 4A and 4B over one period is Al~ltsin ~2 ~r fct) and ehe corresponding signal strength driving the x-axis coils 6A and 6B is Alfl tcos (2~r fct~ When energized 5 in the manner indicated, coils 4A, 4B, 6A and 6B ~enerate a magnetic field that rotates in time at the frequency fc within the plane defined by axes XO and YO~
as iUustr~ted in PIG. 6B. Since the local magnetic nux density has been canceUed ViQ coils 8A and 8B, the resultant msgneti~ field BR equals the sguare root of the sum of the squares of the magnetic field creeted by coils 10 along the 10 Z-axis and the magnitude of the magnetic vector that rotates in time in the XOYo plane. The rotating vector is designated by Bxy~
To cover all possible ion channels located in the active volume 14, the value of Bxy increases linearly in time, foUowing the modulating function A1flt,until the maximum signal occurs at t = 1/fl seconds, whereupon the entire 15 process repeats. At any instant of time, the resultant magnetic field is 8 = ~B2 + B2 ~,~a 20 Inasmuch as it is desirsble to maintain the Cyclotron Resonance Relationship as given in TABLE 1 for the purposes of this invention, ie is also desirable to maintain BR constant in magnitude over the course o- this process. An ideal condition in this regard is shown in ~IG. 6C, in which BR describes a cone in space, the half-angle Or which wiU increase over one period from 0 to any angle25 equal to or less than 180, during which time BR remains constant in magnitude.
Because the value Bxy inereases in time, it i8 necessary to decrease B1 synchronously in order to hold BR constant. 171e output of generator 30 to powersupply 38 is designed to vary in time in such a manner as to reduce the field Blcteated by coils 10A and 10B by the proper factor required to maintain BR
30 constant over the entire period. Referring to PIG. 7, the input 32 to power 8upply 38 is g(t) and the amplification of power supply 38 is AR, resulting in adrlving signal to coils 10A nnd 10B equal to ARg(t). Over one period, ~tarting at tim~ t egual~ zero seconds, the runct~on g(t) is given by g(t) = (1 = ~t2) 2 ~,,.. ,.,... ,.. " ,.,.. , .~ ~.; . . . .. .. ..
; -13- 13311S2 In the practice of this invention, the values of amplificstion of power supplies38, 40 and 42, corresponding respectively to Al, Al Qnd AR, are selected primarily with Qn eye towards convenienee in producing a required BR.
If coils 8A and 8B do not cancel the local field Bz, such that the magnetic flux density along the Z-a~is is not merely that prloduced by coils lOA Qnd lOB,but includes an extra local component Bz, the process pertinent to FIGS. 6 and 7remains unchanged, e~cept that the magnetic field 81 is in part produced by coils lOA and lOB. Over the course of one modulation period, the angle between the Z-axis and the resultant magnetic field BR increases so that the tip of the vector sweeps out an ever-increasing circle, but the magnitude of the resultant vector remains constant since Bl is being decreased at the same time. Thus, over one modulation period, the tip of the resultant magnetic field vector BR
traces out some portion of a hemisphere, depending on how large the angle between the Z-axis and BR is allowed to become. The locus or points traced out lS by BR can cover a complete sphere by reducing Bl below zero. By adjusting the value of large integer c, vector BR can be tuned to complete the generation of ahemisphere or 8 sphere or any frsction thereof at a specified rate. In this way,Pll directions for variously oriented membrane surfaces will be covered by BR in6 repetitive and efficacious manner, thereby allowing the Cyclotron Resonance Relationship for enhanced permeability of ions to be met for elements of each membrane and ion channels that have various orientations. In this mode the frequency fc corresponds to the Cyclotron Resonance Relationship frequency fc~
Coincidentally, a second, alternate mode Or spplication is possible, in that the arrangement in YIGS. 6 and 7 can slso be used to simultaneously enhsnce the as transfer Or two distinctly different ionic species. In this mode, fc will correspond to the Cyclotron Resonance Relaffonship frequency for one species and fl to the Cyclotron Resonance Relationship frequency for another. Thus, consider TABLE 1 in ~hich the resonance frequency for hydrogen ions is 761 Hz and the resonance ~requency for pot~ium ions is 19.6 Hz ror a magnetic nux density equal to 5 s lO S Te~la. If ~oils 6A, 6B, 8A, 8B, lOA and 108 are energized to ereate a field BR equal to S ~10 5 Tesla in the aaffve volume 14, and it fl is ad~usted to 19.6 Hs, then choosing factor c to be 39 results in ~
frequency ~c substantially the same as required to enhance hydrogen ion tran~er. The result o~ this proced~e will be to simultaneou~ly enhflnce the transfer of both hydrogen and potassium ions across membrane surfaces within active volume 14.
Those sldlled in the art will recognize the embodiments described herein may be modified or altered without departing from the true spirit and scope of S the invention as defined in the appended claims. Por e~cample, the linear axesshown in the drawing may have more complicated paths, or the axes may be oriented along planes other than the conventional XYZ planes, or the size, ~hapeand physical properties of the coils may be altered, or the coils may take formsother than Hemholtz coils, such as solenoids, wires and sheets, or the coils may10 be replaced by equivalent devices for producing the required flux densities. The ions may be put into cyclotron resonance in a wide variety of ways as long as the relationship between the charge-to-mass ratio and the frequency and magnetic flux density is maintained. Por some applications, appropriate mechanical signals may be substituted for the described electrical signals.
.i.. , ...... -
Claims (15)
1. A method of regulating the permeability of a predetermined ion having a predetermined charge-to-mass ratio through a biochemical membrane located in a space subjected to a local magnetic field, the space defining at least one reference path passing through the membrane, the reference path extending in a first direction and also extending in a second direction opposite the first direction, said method comprising the steps of:
creating a magnetic field which, when combined with the local magnetic field, results in a resultant magnetic field having a flux density with at least one component representable by a component vector having a direction extending in the first direction along the path and having a magnitude that fluctuates at a predetermined rate to create a non-zero average value; and creating a predetermined relationship between the ratio of the predetermined rate to the non-zero average value, wherein said ratio is a function of the charge-to-mass ratio of the predetermined ion.
creating a magnetic field which, when combined with the local magnetic field, results in a resultant magnetic field having a flux density with at least one component representable by a component vector having a direction extending in the first direction along the path and having a magnitude that fluctuates at a predetermined rate to create a non-zero average value; and creating a predetermined relationship between the ratio of the predetermined rate to the non-zero average value, wherein said ratio is a function of the charge-to-mass ratio of the predetermined ion.
2. A method, as claimed in claim 1, wherein the resultant magnetic field comprises:
a unipolar magnetic field having a flux density with at least one unipolar component representable by a unipolar vector having a direction extending in the first direction along the path and having a substantial constant magnitude; and a bipolar magnetic field having a flux density with at least one bipolar component representable by a bipolar vector having periodically opposed directions that reverse at the predetermined rate and that extend along the path, said bipolar component having a magnitude that varies at the predetermined rate.
a unipolar magnetic field having a flux density with at least one unipolar component representable by a unipolar vector having a direction extending in the first direction along the path and having a substantial constant magnitude; and a bipolar magnetic field having a flux density with at least one bipolar component representable by a bipolar vector having periodically opposed directions that reverse at the predetermined rate and that extend along the path, said bipolar component having a magnitude that varies at the predetermined rate.
3. A method, as claimed in claim 1, wherein the resultant magnetic field comprises a unipolar magnetic field having a flux density with at least one unipolar component representable by a unipolar vector having:
a direction extending only in the first direction along the path; and a magnitude fluctuating at the predetermined rate.
a direction extending only in the first direction along the path; and a magnitude fluctuating at the predetermined rate.
4. A method, as claimed in claim 1, wherein the resultant magnetic field comprises a magnetic field having a flux density with at least one component representable by a unipolarvector having a direction that sweeps across the path at the predetermined rate and having a substantially constant magnitude.
5. A method, as claimed in claim 4, wherein:
said space defines first and second intersecting coordinate axes lying in a first plane and a third coordinate axis perpendicular to the first plane and passing through the point of intersection of the first and second axes; and the resultant magnetic field comprises a magnetic field having a flux density with at least one component representable by a vector having a direction that passes through said point of intersection and precesses around said third coordinate axis to define a cone, the rate at which the angle between the unipolar vector and the first plane changes being proportional to the predetermined rate.
said space defines first and second intersecting coordinate axes lying in a first plane and a third coordinate axis perpendicular to the first plane and passing through the point of intersection of the first and second axes; and the resultant magnetic field comprises a magnetic field having a flux density with at least one component representable by a vector having a direction that passes through said point of intersection and precesses around said third coordinate axis to define a cone, the rate at which the angle between the unipolar vector and the first plane changes being proportional to the predetermined rate.
6. A method, as claimed in claim 1, wherein the charge-to-mass ratio of the predetermined ion is substantially equal to 2 .pi. times the ratio of the predetermined rate to the non-zero average value.
7. A method, as claimed in claim 1, wherein the ratio of the predetermined rate to the average non-zero magnitude of flux density is substantially between 152.5 x 105 and 2.50 x 105, where the predetermined rate is measured in Hertz and the flux density is measured in Tesla.
8. A method, as claimed in claim 2, wherein the charge-to-mass ratio of the predetermined ion is substantially equal to 2 .pi. times the ratio of the predetermined rate to the flux density magnitude of the unipolar vector.
9. A method, as claimed in claim 2, wherein the ratio of the predetermined rate to the flux density magnitude of the unipolar vector is substantially between 152.5 x 105 and 2.50 x 105, where the predetermined rate is measured in Hertz and the flux density is measured in Tesla.
10. A method, as claimed in claim 3, wherein the charge-to-mass ratio of the predetermined ion is substantially equal to 2 .pi. times the ratio of the predetermined rate to the average value of the flux density magnitude of the unipolar vector.
11. A method, as claimed in claim 3, wherein the ratio of the predetermined rate to the non-zeroaverage value of the flux density magnitude of the unipolar vector is substantially between 152.5 x 105 and 2.50 x 105, where the predetermined rate is measured in Hertz and the flux density is measured in Tesla.
12. A method, as claimed in claim 4, wherein the charge-to-mass ratio of the predetermined ion is substantially equal to 2 .pi. times the ratio of the predetermined rate to the average flux density magnitude of the unipolar vector in the first direction.
13. A method, as claimed in claim 4, wherein the ratio of the predetermined rate to the average flux density magnitude of the unipolar vector in the first direction is substantially between 152.5 x 105 and 2.50 x 105, where the predetermined rate is measured in Hertz and the flux density is measured in Tesla.
14. A method, as claimed in claim 1, wherein the predetermined ion is selected from a group consisting of H+, Li+, Mg2+, Ca2+, Na+, K+, Cl- and HCO?.
15. A method for controlling the transfer of a predetermined ion across the membrane of a living cell comprising the steps of:
placing at least one living cell having a membrane and said predetermined ion within an active volume having an axis extending therethrough;
determining the charge-to-mass ratio of said predetermined ion;
applying a fluctuating magnetic field to said active volume containing said living cell and said predetermined ion such that the total magnetic flux density in the direction of said axis has a non-zero net average value;
controlling said fluctuating magnetic field such that the frequency (Fc) of said fluctuating magnetic field is substantially equal to a value determined using the equation, 2.pi.Fc=(q/m)B, where Fc is in Hertz, q/m is the charge-to-mass ratio in Couloumbs per kilogram of the predetermined ion and B is the non-zero net average value of said total flux density in Tesla along said axis;
thereby controlling the transfer of said predetermined ion across said membrane of said living cell.
placing at least one living cell having a membrane and said predetermined ion within an active volume having an axis extending therethrough;
determining the charge-to-mass ratio of said predetermined ion;
applying a fluctuating magnetic field to said active volume containing said living cell and said predetermined ion such that the total magnetic flux density in the direction of said axis has a non-zero net average value;
controlling said fluctuating magnetic field such that the frequency (Fc) of said fluctuating magnetic field is substantially equal to a value determined using the equation, 2.pi.Fc=(q/m)B, where Fc is in Hertz, q/m is the charge-to-mass ratio in Couloumbs per kilogram of the predetermined ion and B is the non-zero net average value of said total flux density in Tesla along said axis;
thereby controlling the transfer of said predetermined ion across said membrane of said living cell.
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/923,760 US4818697A (en) | 1986-10-27 | 1986-10-27 | Techniques for enhancing the permeability of ions through membranes |
| CA000561802A CA1331162C (en) | 1986-10-27 | 1988-03-17 | Techniques for enhancing the permeability of ions through membranes |
| US07/278,688 US5059298A (en) | 1986-10-27 | 1988-12-01 | Method and apparatus for regulating transmembrane ion movement |
| US07/280,848 US5312534A (en) | 1986-10-27 | 1988-12-07 | Techniques for enhancing the permeability of ions through membranes |
| CA000615555A CA1308690C (en) | 1988-03-17 | 1989-11-09 | Techniques for enhancing the permeability of ions through membranes |
| AU45501/89A AU636314B2 (en) | 1986-10-27 | 1989-11-23 | Improved apparatus for regulating transmembrane ion movement |
| US07/561,844 US5143588A (en) | 1986-10-27 | 1990-08-02 | Techniques for enhancing the permeability of ions through membranes |
| US07/778,730 US5215642A (en) | 1986-10-27 | 1991-10-16 | Improved method and apparatus for regulating transmembrane ion movement |
| US07/764,666 US5160591A (en) | 1986-10-27 | 1991-10-25 | Methods and apparatus for regulating transmembrane ion movement utilizing selective harmonic frequencies and simultaneous multiple ion regulation |
| US07/813,240 US5215633A (en) | 1986-10-27 | 1991-12-23 | Techniques for enhancing the permeability of ions through membranes |
| US07/932,615 US5290409A (en) | 1986-10-27 | 1992-08-20 | Methods and apparatus for regulating transmembrane ion movement utilizing selective harmonic frequencies and simultaneous multiple ion regulation |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/923,760 US4818697A (en) | 1986-10-27 | 1986-10-27 | Techniques for enhancing the permeability of ions through membranes |
| CA000561802A CA1331162C (en) | 1986-10-27 | 1988-03-17 | Techniques for enhancing the permeability of ions through membranes |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000615555A Division CA1308690C (en) | 1986-10-27 | 1989-11-09 | Techniques for enhancing the permeability of ions through membranes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1331162C true CA1331162C (en) | 1994-08-02 |
Family
ID=25671783
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000561802A Expired - Fee Related CA1331162C (en) | 1986-10-27 | 1988-03-17 | Techniques for enhancing the permeability of ions through membranes |
Country Status (3)
| Country | Link |
|---|---|
| US (3) | US4818697A (en) |
| AU (1) | AU636314B2 (en) |
| CA (1) | CA1331162C (en) |
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-
1986
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-
1988
- 1988-03-17 CA CA000561802A patent/CA1331162C/en not_active Expired - Fee Related
- 1988-12-01 US US07/278,688 patent/US5059298A/en not_active Expired - Lifetime
- 1988-12-07 US US07/280,848 patent/US5312534A/en not_active Expired - Lifetime
-
1989
- 1989-11-23 AU AU45501/89A patent/AU636314B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| US4818697A (en) | 1989-04-04 |
| US5059298A (en) | 1991-10-22 |
| AU4550189A (en) | 1990-06-07 |
| AU636314B2 (en) | 1993-04-29 |
| US5312534A (en) | 1994-05-17 |
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