CN101421005A - The system and method for the cell-specific laser therapy of atheromatous plaque is provided by the light absorber in the targeting macrophage - Google Patents
The system and method for the cell-specific laser therapy of atheromatous plaque is provided by the light absorber in the targeting macrophage Download PDFInfo
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Abstract
The invention provides a kind of equipment and method, the cell-specific laser therapy that it for example is used for atheromatous plaque particularly is provided for targeting and is in the interior endogenous light absorber of plaque macrophages and the system and method for exogenous nano-particle targeting.In a kind of example embodiment, electromagnetic radiation can be sent to anatomical structure.This electromagnetic radiation can have following at least one character, is used for: at least one feature of (a) revising at least one first cell; And any modification that (b) makes at least one feature of at least one second cell minimizes and/or revises at least one feature of this at least one second cell.This first and second cell can differ from one another, the feature of first and second cells can differ from one another, and first cell and/or second cell can have at least one macrophage characteristic, and the feature of at least one first cell and/or at least one second cell can be a temperature.According to going back an example embodiment, can determine the position that is associated with first cell and second cell.For example, can near transmission electromagnetic radiation this position.
Description
The cross reference of related application
The U.S. Patent Application Serial Number the 60/778th that the application submitted to based on March 1st, 2006, the U.S. Patent Application Serial Number the 60/783rd that on March 17th, 336 and 2006 submitted to, 599 and advocate the rights and interests of their priority, its full content is herein incorporated by reference.
Technical field
The present invention relates to be used to provide the system and method for the cell-specific laser therapy of atheromatous plaque, and be particularly related to and be used for targeting and be in the endogenous light absorber in the plaque macrophages and the system and method for exogenous nano-particle targeting.In addition, the invention further relates to the biodistribution that is used for noble metal nano particles and to the system and method for the evaluation of the optical markings (signature) that is associated in the distribution of the tissue that is rich in macrophage with this nano-particle.
Background technology
The selecting cell targeting that is used for the treatment of
For multiple disease, the targeting specific cells with the necrosis of induced selective local cells, keep the health of surrounding tissue and this ability of integrity simultaneously and have great treatment benefit.Earlier detection and selectivity targeting to cancerous cell might limit tumor propagation and breeding, cause better clinical effectiveness.(referring to A.F.Chambers et al, " Critical steps in hematogenous metastasis:anoverview ", Surg Oncol Clin N Am.2001; 10, pp.243-55, vii).Making many effort aspect the identification factor relevant, and might control neoplasm metastasis the identification and the selective killing of the cancerous cell that oozes out with neoplasm metastasis.(referring to A.F.Chambers et al, " The metastasisprocess:basic research and clinical implications ", Oncol Res.1999; 11, pp.161-8).The selecting cell targeting also has potential treatment and uses in ischemic cardiovascular, ischemic cerebrovascular and peripheral arterial disease.Atherosclerosis generate and plaque rupture in have involve to the selective killing of macrophage (referring to I.Tabas, " Consequences andtherapeutic implications of macrophage apoptosis in atherosclerosis:theimportance of lesion stage and phagocytic efficiency ", ArterisosclerThromb Vasc Biol.2005; 25, pp.2055-64) to plaques stabilize and the risk that therefore reduces the ischemic incident may have far-reaching treatment benefit.Influence in the diseases associated with inflammation of skeleton, blood vessel, skin, heart and lung in rheumatic arthritis etc., the topical therapeutic that is undertaken by macrophage that selective killing soaked into and inflammatory cells can be alleviated the process of this debilitating chronic disease.
It is many that to cause the feature of the ocular disease of retinal degeneration be the feeling of loss photo-cell---rod cell and cone cell, and be attended by the focus hypertrophy of retinal pigment epithelium (RPE).By optionally destroying pigment RPE cell, keeping the existence of peripheral cell simultaneously, can obtain great treatment benefit (referring to R.Brinkmann et al. " Origin of retinal pigment epithelim cell damage bypulsed laser irradiance in the nanosecond to microsecond time regimen ", Lasers Surg Med.2000; 27, pp.451-64).The selectivity targeting of pair cell has following several application in dermatological: be used for the treatment of blood capillary in the hepatic haemangioma, remove hair follicle, optionally damage fatty body of gland with treatment acne and selectivity heating adipose cell to remove subcutaneous fat.(referring to D.Manstein et al. " Selective photothermolysis of lipid rich tissue " .Annualmeeting of Lasers in Surgery and medicine, 2001; Supplement 13:Abs No.17; And R.R.Anderson et al. " Selective photothermolysis of cutaneouspigmentation by Q-switched Nd:YAG laser pulses at 1064,532, and 355nm ", J Invest Dermatol.1989; 93, pp.28-32).
The example technique that is used for the selecting cell targeting
Recently, several research groups have been engaged in important research work, are used for having the specific cells that involves to implement the method for topical therapeutic to disease process with research and development.Realize the destructive exemplary method of selecting cell comprise use light-activated drug, nano material and based on the technology of laser to carry out the cell-specific treatment.Optical dynamic therapy (PDT) can use immunity to put together photosensitizer, and its pair cell that only just becomes in the zone that is exposed to light is toxic.(referring to M.Del Governatore et al., " Experimentalphotoimmunotherapy of hepatic metastases of colorectal cancer with a 17.1Achlorin (e6) immunoconjugate " Cancer Res.2000; 60, pp.4200-5).Especially, the photosensitizer Mo Teshafen lutecium of being drawn by the atherosclerosis speckle can cause macrophage and smooth muscle cell (SMC) apoptosis when photoactivation in animal.(M.Hayase?et?al.，《Photoangioplastywith?local?motexafin?lutetium?delivery?reduces?macrophages?in?a?rabbitpost-balloon?injury?model》，Cardiovasc?Res.2001；49，pp.449-55)。
Along with the appearance of nanotechnology, can use material and quantum dots such as noble metal and magnetic fluorescent nano-particle, make in vivo identification of cell and can be used for the treatment of purposes.(referring to G.M.Whitesides. " The " right " size in nanobiotechnology ", Nat Biotechnol.2003; 21, pp.1161-5).Researching and developing the nano material with accurate biological function is used for medical diagnosis on disease and sends medicament to carry out the local cells treatment.(referring to R.Weissleder et al., " Cell-specifictargeting of nanoparticles by multivalent attachment of small molecules ", Nat Biotechnol.2005; 23:1418-23; And N.Tsapis, " Trojan particles:largeporous carriers of nanoparticles for drug delivery ", Proc Natl Acad Sci USA.2002; 99, pp.12001-5).
Laser is used for the purposes of selecting cell treatment, studies in the multiple application that utilizes exogenous and endogenous light absorber.Be used to realize strict local cells destruction by cytophagic micron particle of target and nano-particle by applying nanosecond laser pulses.(referring to C.M.Pitsillides et al., " Selective cell targeting with light-absorbing microparticle sandnanoparticles ", Biophys is J.2003; 84, pp.4023-32).In the ophthalmology, studied the endogenous chromophore in the cell has been used as the near infrared light absorbent optionally to destroy the pigment cell of RPE, and in dermatological, come optionally the targeting melanocyte to be proved to can be used for treating the skin pigment sexually transmitted disease (STD) to become with short laser pulse.(referring to R.R.Anderson et al. " Selectivephotothermolysis of cutaneous pigmentation by Q-switched Nd:YAG laserpulses at 1064,532, and 355nm ", J Invest Dermatol.1989; 93, pp.28-32).
Selecting cell targeting in the atheromatous plaque of rapid wear
Atherosclerosis is a kind of systemic disease, and breaking of atheromatous plaque is the main mechanism omen of acute coronary syndrome, Ischemic Stroke and peripheral arterial disease.It is initial to each stage that clinical manifestation is arranged from damaging that macrophage has related to atherosclerosis.(referring to R.Ross, " Atherosclerosis-an inflammatory disease ", N Engl J Med.1999; 340, pp.115-26; And P.Libby, " Inflammation in atherosclerosis ", Nature, 2002; 420, pp.868-74).In the damage, macrophage is taken in lipid and is caused the accumulation that fat drips in the Cytoplasm in early days, and the result causes the formation of tremulous pulse foam cell.As shown in Figure 1, the apoptosis of macrophage can produce the downright bad nuclear of thrombinogen in the unstable damage of severe.
The most common plaque type related with acute myocardial infarction and acute coronary event is thin medicated cap shape fiber medicated porridge sample tumor.This speckle can comprise the fibrous cap 100 that is stacked on the necrosis nuclear 105 that is rich in lipid.Macrophage 110 and 115 can be the cell that the speckle unstability in these damages is responsible for, and this is because they are secreted digestion collagen, weaken the matrix metalloproteinase of fibrous cap 100, thereby has increased the disruptive tendency of downright bad nuclear fiber medicated porridge sample tumor.(referring to P.Libby, " Inflammation inatherosclerosis ", Nature, 2002; 420, pp.868-74).And then the macrophage exhibit tissue factor (a kind of known coagulant) also has been found in harmful pathological changes of acute myocardial infarction and acute coronary artery syndrome patient and is more prone to be positioned near the luminal surface place.(referring to B.D.MacNeill etal., " Focal and multi-focal plaque macrophage distributions in patients withacute and stable presentations of coronary artery disease ", J Am Coll Cardiol.2004; 44, pp.972-9).
Because macrophage generally can play a significant role in plaque rupture and thrombosis, so the minimizing of the quantity of these cells might make plaques stabilize.The acute coronary event of using the systemic treatment of the Statins of blood fat reducing significantly to reduce to cause and the appearance of apoplexy by plaque rupture, and do not cause stricture of artery aspect significant change.This treatment benefit can realize by the plaques stabilize that quantity reduces and the follow-up accumulation of collagen fiber in the lipid storehouse causes by macrophage.(referring to P.Libby et al., " Stabilization of atherosclerotic plaques:new mechanisms and clinicaltargets ", Nat Med.2002; 8, pp.1257-62).In that to keep epithelial integrity combined to induce macrophages die can reduce that patient's medium-sized artery atherosclerotic plaque is broken and the threat of follow-up acute coronary event with general Statins treatment and localised patches treatment simultaneously.
Carry out the selecting cell targeting by using metal nanoparticle
Noble metal nano particles generally comprises a class optical contrast agents, and it can strengthen the macrophage visibility in position.Gold and silver nano-grain strengthen the ability of linear and nonlinear optics processing when the harmonic(-)mean laser power and the biocompatibility of their height shows that these granules can be used as optical contrast agents in the patient who lives.Nano-particle can be used as contrast agent to strengthen various imaging techniques.Their less diameters (5～20 nanometer) make and can connect and the blood capillary diffusion by intercellular.Particularly ultra-fine (15～20 nanometer) the paramagnetic iron oxide granule of MRI contrast agent (USPIO) has demonstrated and penetrated endothelium and also being engulfed by the macrophage selectivity in atheromatous plaque.(referring to S.G.Ruehm et al., " Magneticresonance imaging of atherosclerotic plaque with ultrasmallsuperparamagnetic particles of iron oxide in hyperlipidemic rabbits ", Circulation, 2001; 103, pp.415～22).Based on this sample data, the macrophage of atheromatous plaque is selectivity picked-up noble metal nano particles also.
In the time of in residing at tissue, noble metal nano particles can provide the signal of the high strength optics in Laser Scanning Confocal Microscope and the optical coherence tomography because of its elastomeric scattering efficiency.In addition, related with the noble metal nano particles of resonance excitation nonlinear optical phenomena can be used to diagnosis.When the plasma (plasmon) of laser field frequency and noble metal nano particles when frequency of oscillation is consistent, can realize that near the particle surface place bigger field strengthens.This effect can be used to greatly to increase raman scattering cross section, the automatic fluorescent radiation of two-photon and absorb molecule secondary and triple-frequency harmonics generate.These local enhanced processing can provide exclusive optical markings, and it provides about nano-particle and distributes and both information of regional chemical composition.
Thereby, need overcome the defective of above explanation.
Summary of the invention
In order to solve and/or to overcome the problems referred to above and/or defective and other defective, can provide the system and method for the cell-specific laser therapy that helps atheromatous plaque.For example, targeting be can be provided for and the interior endogenous light absorber of plaque macrophages and the system and method for exogenous nano-particle targeting are in.In addition, can be provided for the biodistribution of noble metal nano particles and to the system and method for the evaluation of the optical markings that is associated with the distribution of this nano-particle in being rich in the tissue of macrophage.
This defective can use example embodiment of the present invention to solve.In an exemplary embodiment of the present invention, in an example embodiment, electromagnetic radiation can be sent (forward) to anatomical structure.This electromagnetic radiation with at least one character can be used for: at least one feature of (a) revising at least one first cell; And any modification that (b) makes at least one feature of at least one second cell minimizes and/or revises at least one feature of at least one second cell.This first and second cell can differ from one another, the feature of first and second cells can differ from one another, and first cell and/or second cell can have at least one macrophage characteristic, and the feature of at least one first cell and/or at least one second cell can be a temperature.
This character can comprise wavelength, mean power, instantaneous power, pulsewidth and/or always expose to the open air period.Wavelength can be roughly the same with the absorbing wavelength feature of the first intracellular chemical compound.Pulsewidth can cause this feature roughly to be limited in first cell.Power can cause this feature irreversibly to destroy at least one part of first cell.The temperature that this feature of first cell can damage greater than at least one part to first cell.Destruction to this part of first cell can be irreversible.First cell can be positioned at blood vessel wall.Blood vessel wall can be a part coronarius.
According to another example embodiment of the present invention, this configuration can be located in the conduit.The macrophage characteristic can be the lysosome that comprises at least one lipid.This lipid can comprise at least one low density lipoprotein, LDL (LDL), oxidized ldl, cholesterol or cholesteryl ester.The macrophage characteristic can be the lysosome that comprises downright bad fragment, a large amount of lysosomes and/or at least one nano-particle.Equipment according to claim 1 can provide to be positioned at cell and/or lysosome nano-particle.The size of single nanoparticle can be between 1～20 nanometer.This nano-particle can be made of metal, noble metal, ultra-fine paramagnetic iron oxide, gold and/or silver.But this nano-particle intravenous is administered to object.When electromagnetic radiation puts on the nano-particle, can generate surface plasma.According to another example embodiment of the present invention, can outwards send electromagnetic radiation from subject's body.And then the macrophage feature that is provided can be in fibrous cap.
According to going back an example embodiment, can determine the position that is associated with first cell and second cell.For example, can near transmission electromagnetic radiation this position.This position can be determined based on the image of at least one part of anatomical structure.Can use such configuration to determine the position: this configuration can comprise relevant range finding configuration, hot spot analysis configuration, thermal imaging configuration and/or spectroscope configuration.
By reading below in conjunction with the detailed description of claims to the embodiment of the invention, it is clear and definite that these and other purposes, features and advantages of the present invention will become.
Description of drawings
From the following detailed description that combines with the accompanying drawing that shows example embodiment of the present invention, more purposes of the present invention, feature and advantage will become clearly, in the accompanying drawings:
Fig. 1 is the example micro-image of lipid-filled macrophage in the human atheromatous plaque;
Fig. 2 carries out the sectional view of non-specific heating to it during the laser ablation (ablation) of tissue;
Fig. 3 is the sectional view of the cell of cell-specific heating;
Fig. 4 shows the figure of the selective light absorption of the subcutaneous fat that uses spectrophotometry and record, and different absorption spectras is wherein arranged between fat and the water;
Fig. 5 A is the sketch map that cell-specific therapy system according to one example embodiment is shown;
Fig. 5 B is the sketch map that illustrates according to the cell-specific therapy system of another example embodiment of the present invention;
Fig. 6 is the sketch map according to the cell-specific laser therapy conduit of a ultimate fibre embodiment of the present invention;
Fig. 7 is the sketch map according to the cell-specific laser therapy conduit of another ultimate fibre embodiment of the present invention, and this conduit is near near the arterial blood tube wall;
Fig. 8 is that this conduit is enclosed in the example disposition of gasbag according to the sketch map of the cell-specific laser therapy conduit of another ultimate fibre embodiment of the present invention;
Fig. 9 is the sketch map according to the cell-specific laser therapy conduit of diffusion fiber embodiment of the present invention;
Figure 10 is the sketch map according to the cell-specific laser therapy conduit of image guide catheter embodiment of the present invention;
Figure 11 is the flow chart according to the example embodiment of the technology that is used for tremulous pulse cell-specific treatment of the present invention;
Figure 12 is the flow chart according to the example embodiment of exogenous Therapeutic Method of the present invention;
Figure 13 is the flow chart according to the example embodiment of general cell-specific Therapeutic Method of the present invention, and when target position and/or definite treatment that this method can be utilized image to guide and be identified for treating are finished.
In institute's drawings attached, unless otherwise stated, otherwise identical characteristics, key element, assembly or the part of illustrated embodiment represented everywhere in same reference numerals and literal.And, although followingly will describe the present invention in detail, carry out this explanation in conjunction with illustrated embodiment with reference to accompanying drawing.Intention is not break away from the true scope of the present invention that defines in the appended claims and can illustrated embodiment be made changes and modifications with spirit.
The specific embodiment
Chromophore is light absorbing molecule.When not having Photochemical effects, absorbing light can cause heating.The endogenous chromophore is that cell is intrinsic or be present in intracellular biological light absorption molecule.These molecules can absorb the photon 200 that can make the cell heating.Chromophoric some example of endogenous can be hydrone, lipid, cytochrome etc." Physics of thermal processes inlaser-tissue interaction " (Phys Med Biol.1990 as A.L.McKenzie; 35, to be put down in writing in pp.1175-209), cell death and irreversible protein denaturation can occur in 60 ℃～temperature more than 70 ℃.As at A.Vogel et al. " Mechanisms of pulsed laser ablation of biological tissues " (Chem Rev.2003; 103, put down in writing in pp.577-644), when not having photochemical process or vaporescence, the energy that is absorbed in laser emission by tissue response is convertible into heat.When absorbing energy, by heat radiation with heat from target be sent to its colder around.
Depend on laser parameter, can occur different by thermoinducible effect.When the temperature that reaches 60 ℃, proteinic cohesion and irreversible degeneration can appear, and this can cause cell death.Surpassing under 100 ℃ the high temperature, occurring vaporization probably.When absorbing energy, can carry out the space by heat radiation and distribute again.Conducting the required time of this energy can be depending on the chromophoric thermal relaxation time of target.As shown in Figure 2, depend on laser parameter and can occur heat damage band 205,210 and 307 and 310 (respectively as shown in Figures 2 and 3) around in the laser ablation zone, and the energy that is absorbed can be carried out the space and distributes by conduction of heat.Based on these principles, opened the tremulous pulse that narrows with regard to the technology of having introduced laser intravascular formation art by name in the past.(referring to W.H.Ahmed et al., " Excimer laser coronary angioplasty ", Cardiol Clin.1994; 12, pp.585-93).In this traditional method, vaporize by the speckle in laser ablation and the follow-up coronary artery and to carry out the disintegration of speckle.Be likely endotheliocyte destructions, initial smooth muscle cell (SMC) breeding, the neointimal hyperplasia that causes because of the heating of the unspecific tissue during the laser ablation and narrow again, and make laser intravascular formation art in the patient, cause higher tremulous pulse to narrow rate again.
The selective thermal of macrophage is destroyed
Example embodiment of the present invention relates to the system and method for cell-specific treatment, it passes through targeting endogenous (for example lipid) and exogenous (as nano-particle and micron particle) light absorber, thereby causes the heat damage of induced with laser in the atheromatous plaque macrophage.The specimen way that example embodiment according to the present invention is used is not to implement the excision of speckle as being done with laser intravascular formation art in the past, but induce the cell-specific heat damage that preferably only limits in the macrophage, for example to be confined to destroy with 307 and 310 (see figure 3)s, keep endotheliocyte and surrounding tissue 215,220 (see figure 2)s thus and organize the health of 320,305 (see figure 3)s.The cell-specific laser therapy of example can be used as independent program to be carried out, or forms art, fluorescent radiation, fluorescence spectroscopy, time-resolved fluorescence radiation, intravascular ultrasound (IVUS) system/program or any other imaging system as known in the art/program associating with OCT, OFDI, SD-OCT, Raman and IR spectroscopy, laser facula imaging (LSI), laser intravascular and carry out.Example embodiment of the present invention can be related with this observation: promptly the optimized choice of laser parameter can be used to cause the cell-specific heat damage.
The front has illustrated by the limited heat in selective light pyrolysis implementation space in tissue this notion that localizes.Use this exemplary method, meeting induced selective heat damage when the wavelength of laser 300 (as shown in Figure 3) has tendency ground to be absorbed by target chromophore 307, influence required or that wish high enough strikings group, and be shorter than chromophoric thermal relaxation time during the pulsewidth that exposes to the open air of laser.(referring to R.R.Anderson etal. " Selective photothermolysis:precise microsurgery by selective absorptionof pulsed radiation ", Science.1983; 220, pp.524-7).(t during the pulsewidth that laser exposes to the open air
d) can influence the specificity or the limitation scope of heat damage, and can be by the chromophoric thermal relaxation time (t of target
r) determine during this pulsewidth.When ratio is (t
d/ t
rTransformation from specificity to non-specific heat damage o'clock can appear in) 〉=1.(referring to R.R.Anderson et al. " Selective photothermolysis:precisemicrosurgery by selective absorption of pulsed radiation ", Science.1983; 220, pp.524-7).For the scope d and the coefficient of heat transfer κ of diameter, can be by t
r=(d
2/ 27 κ) provide thermal relaxation time.
In order to induce in specific cells by the heat damage of targeting simultaneously at the integrity of keeping surrounding tissue, preferably the target chromophore has in the light absorption of given laser wave strong point greater than its surrounding tissue.According to example embodiment of the present invention, can drip the various endogenous absorbent that are present in the macrophage with cholesteryl ester etc. by targeting fat in the intragroup hot limitation of specific cells and realize as light absorber.(referring to C.M.Pitsillides et al., " Selective cell targeting with light-absorbingmicroparticles and nanoparticles ", Biophys is J.2003; 84, pp.4023-32).
As shown in Figure 1, plaque macrophages 105 can comprise abundant lipid, and it can provide the property ground heating and damage these cells, keep the existence of supportive cell and substrate on every side simultaneously for you to choose of endogenous chromophore.By endogenous absorbent such as targeting lipid, cholesterol or cholesteryl esters, can induced selective heat damage in plaque macrophages.According to some example embodiment of the present invention, targeting endogenous chromophore can not need or be not inclined to administration of exogenous medicament or chromophore to induce macrophages die.Limited energy deposition can use such laser energy to realize in being full of the macrophage of lipid: the wavelength of this laser energy can make it by the lipid strong absorption but not by water quality tissue absorption on every side, and can be less than t during the laser pulse width of this laser energy
r, to reduce heat passage from the light absorbing macrophage that is rich in lipid.Shown in the exemplary plot of Fig. 4, by using the frequency spectrum spectroscopic measurements, 915 nanometers (400) in near-infrared and middle infrared spectrum, 1205 nanometers (410), 1715 nanometers (420) and 2305 nanometers (430) are located, and the tissue that is rich in lipid can have than water quality organizes higher absorbability.(referring to D.Manstein et al. " Selective photothermolysis of lipid rich tissue " .Annual meeting of Lasersin Surgery and medicine, 2001; Supplement 13:Abs No.17).Can utilize 1206 nanometer lasers to come induced selective heat damage in subcutaneous fat, keep the health that is covered in the epidermis above it simultaneously.In example embodiment of the present invention, near the optical maser wavelength the chromophoric absorption bandses of endogenous such as low density lipoprotein, LDL (LDL), free cholesterol, cholesteryl ester can be used to induce the selective thermal of plaque macrophages to destroy.
The confirmation of the cell-specific treatment of macrophage
In an example embodiment that is used for realizing the target of cell-specific laser therapy according to the present invention, shown in Fig. 5 A, can comprise the treatment delivery system of example, to realize selective thermal constraint (confinement).For example, lasing light emitter 510 has near the wavelength the absorption bands of the target chromophore (for example lipid, cholesterol, cholesteryl ester etc.) in macrophage, and this lasing light emitter 510 can be used for the cell-specific treatment.The output 505 of laser 510 can be controlled to realize macrophages die.In order to carry out the thermal confinement of induced with laser, lasing light emitter can be arranged to irradiation tissue 520.Lasing light emitter 510 can be arranged to allow pulse operation to be undertaken to help to apply short laser pulse by merging with diaphragm, acoustooptical modulator 507.Can adjust laser pulse width (t
d) so that ratio (t
d/ t
r)≤1, wherein t
rIt is thermal relaxation time.
According to one example embodiment, can use 100 microns zones that comprise lipid-filled macrophage, and t
rCan approximate 2 milliseconds.Permission can provide targeting to single macrophage (t for example than the pulse laser system of short pulse duration (～10 microsecond)
r=20 microseconds).But the thermal camera of this instantiation procedure usage example or other measuring device 510 and monitor, or monitor by another kind of diagnosing image technology/programs such as laser facula imaging or optimal frequency domain imagings by direct heat is visual.For example, shown in Fig. 5 B, can be used to and calibrate the center of curing laser beam from the visual alignment in helium-neon (632 nanometer) source 540 and coincide, as shown in Figure 5.For example can using, lens 515 and photographing unit 510 come the recording laser hot spot.The modulation of time of hot spot collection of illustrative plates can with the temperature correlation of the tissue 520 of the selective laser ablation that is subjected to example.
The example identification that is used for the suitable wavelength of selective laser ablation and exposure time for example can use cell culture experiments to determine.Can carry out cell culture is rich in the macrophage of lipid with evaluation the heat damage of induced with laser.Macrophage can be cultivated in 75 ml flasks that have DMEM, 0.1M HEPES, 1% penicillin-streptomycin and 10% hyclone and at 10%CO
2The middle cultivation.Can cultured cell arrive and converge, then scrape it is scraped from flask with cell up to their.Cell can dilute by 1:10 in fresh culture to be cultivated to prevent macrophage activation.Can use hematimeter to come counting cells, and be transferred to 10 6 well culture plates.For example, in 5 culture plates, can add to cultivate then and for example reach 4 days with the low density lipoprotein, LDL (for example, being positioned at the Molecular Probes company in Eugene city, Oregon) of FITC labelling.
Macrophage can use fluorescence microscope to assess to the picked-up of fluorescently-labeled LDL.For example might utilizing, two control cells colonies examine closely: (a) macrophage of not hatching with LDL, and (b) cultured human coronary artery smooth muscle system (HCASMC-c) can be grown in the culture and not and hatches with LDL.Macrophage and control cells culture plate can use the pulse laser excision system of above explanation to expose to the open air in laser emission.Laser therapy can or use the laser beam irradiation of calibration to carry out than large tracts of land by scanning focused laser beam.Can change laser pulse width and number of pulses to estimate the influence that these parameters apply the necrocytosis of induced with laser.After the exemplary laser treatment, can use the cell death after cell survival mensuration (for example propidium iodide) is estimated heat damage.Can use microscope to evaluate cell, and come quantitative cell death percentage ratio by the cell counting that uses flow cytometer.Can relatively take in the cell death percentage ratio of macrophage colony and the control cells colony of LDL.Can use regression analysis to estimate the dependency that cell death percentage ratio and laser expose parameter to the open air.
The sample of human carotid artery, coronary artery, iliac artery and the aortal fresh results that obtain in postmortem can be used to estimate the cell-specific of thermal confinement.Can longitudinally open specimen and it is pegged to expose the tube chamber side.Then can use the pulse laser excision system of above explanation to shine this tissue specimen.Can change laser pulse width and number of pulses instrument and estimate of the influence of these parameters the thermal confinement in the zone of being rich in macrophage in the atheromatous plaque.After exposing to the open air under treatment laser, next specimen can be cut into large slices and prepare for the histology handles.The CD68 that can use hematoxylin Yihong and supply macrophage to use comes this specimen is dyeed.Can use oxidation nitro blue tetrazolium (NBTC) dyeing to evaluate the degree of heat damage.NBTC dyeing is that a kind of heat labile enzyme is positive for lactic acid dehydrogenase (LDH).Very fast LDH loss of activity behind the thermoinducible cytoclasis, and forfeiture LDH is active relevant with cell lethality.(referring to M.H.Khan et al., " Intradermally focused infrared laserpulses:thermal effects at defined tissue depths ", Lasers Surg Med.2005; 36, pp.270-280).
Be unstained and painted tissue between juncture area can measure by morphometry, to estimate the area of heat damage.By the painted stripping and slicing of CD68 can with by the painted stripping and slicing co-registered of NBTC to estimate the cell-specific of laser therapy.Can be by measuring CD68 dyeing and the tolerance of recently estimating downright bad cell-specific of losing the painted area of LDH.Can determine the dependency of cell-specific tolerance and laser pulse width and number of pulses.Can determine so best laser parameter: it has been realized near unified cell-specific tolerance.So, can determine that it can be identified the zone of being rich in macrophage and optionally damage them with laser energy for next developing the optimal treatment laser parameter and the therapy equipment of screening in real time in the coronary artery.This exemplary exploitation can fill up that unstable spot detects and the topical therapeutic of these pathological changes between blank.This example embodiment can further provide the basis of cell-specific laser therapy in various other diseases, but wherein targeting endogenous absorbent is kept Normocellular existence on every side simultaneously to influence paracytic selective destruction.
Cell-specific treatment by the administration of exogenous nano-particle
Another example embodiment of system and a method according to the invention can comprise through subcutaneous, per os or intravenous route comes administration of exogenous metal or noble metal nano particles.The penetrable blood vessel endothelium of the nano-particle of suitable size (for example being preferably less than about 5 nanometers), and the macrophage that is positioned in the destination organization absorbs.These nano-particle can be then by rayed.Direct absorption related with these nano-particle or surface plasma body resonant vibration can cause local and the specificity heating, and it makes the cell that comprises nano-particle be subjected to heat damage.According to an also example embodiment of the present invention, these nano-particle can be by those technology that include but not limited to mention in this document, come imaging to determine this mode of suitable location of using selective laser treatment light.
An also example embodiment of system and a method according to the invention also can be provided, be used for the cell-specific laser therapy of image guiding.In these example system and method, can use high-resolution volume (volumetric) screening that optimal frequency domain imaging imaging techniques such as (OFDI) organizes, thereby detect tissue macrophages, and make and to guide therapeutic laser emission simultaneously to induce macrophages die by detecting by the exogenous chromophore of macrophage phagocytic.The comprehensive volume screening that example OFDI technology, the system and program can be used for organizing, but it makes original position discern tissue macrophages.(referring to B.D.MacNeill et al., " Focal and multi-focal plaque macrophage distributions in patients withacute and stable presentations of coronary artery disease ", J Am Coll Cardiol.2004; 44, pp.972-9).Can provide according to example system of the present invention, conduit and method, be used for detecting simultaneously macrophage and apply the treatment laser energy.The exogenous chromophore of being used can comprise noble metal nano particles, biodegradable nano-particle or ferrum oxide micron particle so that the thermal confinement of induced with laser in macrophage, keep the health of surrounding tissue simultaneously.
The example embodiment of laser therapeutic system and method can be provided, and it can utilize the lasing light emitter that disposes acousto-optic modulator to realize thermal confinement to allow pulse operation.Can be depending on the chromophore of being investigated and the wavelength of light source is provided.Can use culture medium in 75 ml flasks, to cultivate macrophage (J774 cell line).In order to imitate plaque macrophages, available fluorescently-labeled low density lipoprotein, LDL (LDL) (for example, being positioned at the Molecular Probes company in Eugene city, Oregon) is cultivated institute's cultured cells individually and is for example reached 4 days.Can use fluorescence microscope to estimate the picked-up of LDL.
For endogenous selecting cell treatment, can use cell culture studies to determine to realize the proper exposure and the power preferred value of cytoclasis.The macrophage colony that has taken in LDL will be hatched separately, wherein with noble metal nano particles, biodegradable nano-particle or ferrum oxide micron particle be tuned to therapeutic optical maser wavelength.For example, can use two control cells colonies: (i) macrophage of not hatching with LDL or exogenous chromophore, and (ii) cultured human coronary artery smooth muscle system (HCASMC-c) can be grown in the culture plate and not and hatches with LDL or nano-particle.Most or whole culture plates can be exposed to laser emission and can use the propidium iodide chemical examination to come quantitative cell death percentage ratio.Can change laser pulse width, incident power and number of pulses to estimate of the influence of these parameters to the cell death of induced with laser in whole cell colonys.
Also can utilize zooscopy to determine the bio distribution of nano-particle and suitable the exposing of using for the cell-specific laser therapy to the open air and power parameter.According to one example embodiment, preferably determine gold, silver and the distribution of USPIO nano-particle in the animal atheromatous plaque of hyperlipidemia.For example, can use similar research design to test each of gold, silver and these 3 kinds of nano-particle of USPIO independently.For various nano-particle, this point can be by accomplishing to get off: use this medicament (referring to P.M.McCabe et al. for example promptly for 15 rabbit intravenouss every day that cross limit heritability hyperlipidemia (WHHL), " Social environment influences the progression ofatherosclerosis in the watanabe heritable hyperlipidemic rabbits ", Circulation, 2002; 105, pp.354-9); S.Ojio et al., " Considerable time from theonset of plaque rupture and/or thrombi until the onset of acute myocardialinfarction in humans:coronary angiographic findings within 1 week beforethe onset of infarction ", Circulation, 2000; 102, pp.2063-9; And K.Yokoya etal., " Process of progression of coronary artery lesions from mild or moderatestenosis to moderate or severe stenosis:A study based on four serial coronaryarteriograms per year ", Circulation, 1999; 100, pp.903-9), can go out active aorta speckle at 6 months ages duration like this, and 5 New Zealand white rabbit (NZW) intravenous every day as the contrast of each medicament is used this medicament.Can not use any medicament and investigate 5 other WHHL rabbits, each group is provided the contrast of catching an illness.
For example, most or whole rabbits can be 1 years old age approximately.The nano-particle medicament can be used 5 days altogether by ear vein by the dosage with 1～2mg/kg between the killing period of isoflurane every day.The WHHL rabbit of accepting nano-particle was implemented euthanasia (3 rabbits of each time point) on the 2nd, 3 and 4.The contrast rabbit will be implemented euthanasia on 4th.Before the results aorta, pour into fixing earlier.With the per 5 microns Histological sections that cut into series, and this Histological section is with hematoxylin Yihong, masson trichrome stain, CD68 immunoperoxidase and Prussian blue dyeing.The mode that nano-particle distributes can be relevant with histology's determiner (that is, lipid core and medicated cap 100 thickness) of speckle vulnerability.In addition, 2 millimeters sections of each aorta sample will be accepted the ultramicroscope evaluation, to distribute in position and ultrastructure form and the cell in the cell of accurately determining nanoparticle deposition.
According to another example embodiment of the present invention, the nano-particle of preferably measuring in the animal atheromatous plaque with hyperlipidemia absorbs related optical markings.For example, after implementing euthanasia and before the aortal perfusion of above-mentioned rabbit is fixing, can use the speed from the iliac artery to the aortic arch is that pulling back automatically of 0.5 mm/second carried out optical coherence tomography (OCT) technology and blood vessel microscope imaging.Then can open aorta and reflect confocal microscopy along the length of each blood vessel.For each medicament and time point, can compare with image on the form and on the spectrum from the contrast rabbit from the image of handled rabbit.Can evaluate the quantitative analysis that comprises medicated cap shoulder, medicated cap body in the speckle and be rich in the signal intensity in the purpose zone of nuclear of lipid, to estimate the quantitative distribution of each medicament in atheromatous plaque.The tissue location that has with respect to the unique optical markings that contrasts the rabbit measured value will optionally be adopted and be supplied histology and electron micrology to handle.
According to another example embodiment of the present invention, preferably prove the quantification of the macrophage of nanoparticle label in the body.Can use with the dosage of 2mg/kg 10 WHHL rabbits (1 years old age) and reach the nano-particle metal that high light is learned radiography.For example, can be with 5 of not accepting the nano-particle medicament other WHHL rabbit is with comparing.Best day (determining as above-mentioned) after using nano-particle can carry out example OCT imaging technique and put to death this rabbit.For example, but intramuscular injection is used his life (35mg/kg)/xylazine (7mg/kg) and local anesthetic (lignocaine) of gram to pars inguinalis.
Can be used to monitor narcotic level to rabbit in response to the continuous evaluation of cornea and lower jaw reflection.Can expose and separation left ilium tremulous pulse through the excision program.The 6F introducer can be inserted the left ilium tremulous pulse.0.014 inch guide wire can be probeed into aorta.Under fluoroscopic guidance, OCT conduit (3F) can be by introducer, cross guide wire and probe into aorta.Can use anatomic landmark to carry out the example OCT imaging of aorta and iliac artery, register for image.After imaging, can put to death this animal.Can take out Histological section from the speckle adjacent with the anatomic landmark that is identified, simultaneously under fluoroscopic guidance with the OCT imaging.Can handle tissue by customary mode.Can be in 4 microns sections of OCT image space place cutting-out, also with h and E (H﹠amp; E) and masson trichrome stain dye.In order to observe the situation that exists of macrophage, can use mouse anti rabbit CD68 monoclonal antibody (Dako company).
The immunohistochemistry of preferred epi-position detects and can carry out according to indirect horseradish peroxidase technology.Use digitized histology and OCT technology the two, the measured value of macrophage density can use 500 * 125 microns of being positioned at each speckle center (horizontal * axially) interest region (ROI) and obtaining.The painted area percentage of CD68+ can carry out quantitatively (100 * doubly amplification) like this: promptly, use the interior automatic bimodal colour of corresponding ROI of the slide of digitized immunohistochemical staining to cut apart (automaticbimodal color segmentation).Then the immunohistochemical staining of the OCT signal intensity in each speckle and standard deviation and the slide that obtains from the corresponding position can be used linear regression compare.
The cell-specific laser therapy of image guiding
The cell-specific laser therapy can be used as independent technology/program or combines with imaging or beam split microtechnique/program and carry out, for to the diagnosis of target atheromatous plaque with to the guide of treatment.Can use technology such as laser facula imaging (for example, as shown in Figure 5), blood vessel microscope imaging, fluorescence art, fluorescence spectrum art, time-resolved fluorescence art, OCT, OFDI, SD-OCT, Raman or IR spectrometry, IVUS, the interior MRI of blood vessel to detect harmful speckle and the laser therapy of cell guiding specificity.Example embodiment that is used for image cell guiding specific treatment relates to uses OCT and/or such as OFDI or frequency domain OCT OCT methods of future generation such as (SD-OCT), the speckle that is rich in macrophage for detection carries out targeted therapy.
The conduit that is used for the cell-specific laser therapy
I. the embodiment of single exemplary optical fiber
This example embodiment can comprise the design (Fig. 6) of the independent way of the comprehensive cell-specific laser therapy that is used for not using the image guiding.In this example embodiment, can be coupled to the near-end of optical fiber 600 from the light of pulsed laser source.Optical fiber can be contained in the overcoat 615.Optical fiber connector can be that light beam focuses on and/or light beam redirection mirrors 605, with light 610 is directed and focus on pre-position on the arterial wall.The laser of far-end can be calibrated or be focused on by lens, and these lens can be a micron mirror, GRIN mirror etc.Optical fiber can be arranged at least one direction in direction of rotation 616 or vertical 617 or along scanning light beam on the other direction of blood vessel wall 620.For this embodiment, can treat like this: wherein intravascular space is washed, to keep good beam quality and to avoid treating light by blood scattering and absorption.
In another example embodiment as shown in Figure 7, treatment optical fiber 700 can be arranged to touch or almost touch blood vessel wall 710.Can direction of rotation 716 vertical 717 or other direction at least one direction on scan optical fiber, to treat one section tremulous pulse.In an also example embodiment as shown in Figure 8, treatment optical fiber can be in the air bag 818.Air bag 818 can expand in blood vessel wall 820 zones that needs are handled, and can direction of rotation 816, vertical 817 or other direction at least one direction on scanning optical fiber 800, to handle the zone of being paid close attention to.
Ii. spread the conduit example embodiment
According to of the present invention another example embodiment as shown in Figure 9, can use air bag, diffusion mirror 905 etc. that the light related with the target chromophore 910 is diffused on the large tracts of land of blood vessel wall 920.
Iii. carry out the laser therapy of vascular cell specificity by cooling
Although chromophoric specificity can make selectivity damage the cell of being paid close attention to, and is big inadequately if the absorptance between target and the surrounding tissue differs, the destruction of following of tissue surface then can appear, and cause endothelium destroyed.For fear of this possible adverse effect, during treatment laser emission, cooling salt, water, D can be used in the surface of endothelium
2O, blood or other refrigerative liquid cool off.This program can be kept the existence of endothelium, makes cell-specific laser emission go deep into blood vessel wall safely more simultaneously.Therefore, conduit can be related with the device that washes blood vessel with coolant.In an exemplary embodiment of the present invention, this device can comprise and wherein includes the guide catheter for the treatment of conduit.In another embodiment, the treatment conduit can comprise rinse mouth.In going back an embodiment, conduit can comprise the air bag that fills with described coolant.
Iv. the exemplary catheter embodiment of image guiding
As shown in figure 10, this example embodiment of the present invention can comprise such probe design: it is used for the diagnosis of comprehensive volume and to the screening of target atheromatous plaque, and simultaneously the macrophage in the atheromatous plaque is carried out the cell-specific laser therapy.Exemplary probe 1000 shown in Figure 10 can constitute axial 1003, radially 1005 or other direction at least one direction on scanning pass the luminal surface of tremulous pulse.Can apply treatment laser 1015 and optical diagnostics configuration 1010 (for example, laser facula imaging, vascular microscope imaging, OCT, OFDI, SD-OCT, Raman or IR spectroscopy, fluorescent radiation, fluorescence spectroscopy, time-resolved fluorescence radiation configuration) light beam by same optical fiber or isolating optical fiber.For different diagnosis and treatment optical fiber, each bar optical fiber can have the end mirror of oneself, with optical diagnostics and the treatment beam diameter that produces oneself on target tissue.In one embodiment, optical fiber and end mirror are contained in the actuating sleeve and place sheathed catheter 1020 inside.The near-end of conduit can be coupled to the rotation binding and be installed in mobile retracting on the unit.The rotation of the inner member of conduit and retract and make and to diagnose simultaneously and to treat.In another example embodiment of the present invention, diagnosis and treatment conduit can constitute and touch arterial wall 1025.Can scan fiber along endothelium, so that the cell-specific treatment at contact point place to be provided.
Below explanation and the example flow in Figure 11～13 there is shown some example embodiment according to cell-specific Therapeutic Method of the present invention.For example, Figure 11 shows the example flow diagram according to the example embodiment of endogenous Therapeutic Method of the present invention, wherein can start conduit (step 1100) and conduit is inserted tremulous pulse (step 1105), and the laser emission of suitable wavelength, exposure parameter and power density is imported tremulous pulse (step 1110).Wavelength-selective is to obtain the absorption than big-difference between plaque macrophages and the surrounding tissue.Can select to expose to the open air with power parameter with the thermal confinement of influence to these cells.Before laser emission, can remove or not remove blood.Tremulous pulse can expose one section preset time in light to the open air.Conduit can be at circumference, vertically or to move (step 1115) at least one direction in other direction regional to scan whole treatments.As an alternative or additionally, can not carry out beam flying and make light scattering everywhere in tremulous pulse.In step 1120, can determine whether to have finished example procedure, if do not finish, then repeat this program (step 1122).
Figure 12 shows the flow chart according to the example embodiment of exogenous Therapeutic Method of the present invention, start program in step 1200 wherein, and use exogenous materials (step 1205) such as noble metal nano particles to the patient.After having spent suitable a period of time (step 1210), conduit is inserted tremulous pulse (step 1215), and the laser emission of suitable wavelength, exposure parameter and power density is imported tremulous pulse (step 1225).Select wavelength to obtain the absorption between plaque macrophages and the surrounding tissue than big-difference.Selection exposes to the open air with power parameter with influence the thermal confinement of these cells.Before laser emission, can remove or not remove blood.Tremulous pulse exposes one section preset time in light to the open air.Conduit can be at circumference, vertically or to move (step 1230) at least one direction in other direction regional to scan whole treatments.As an alternative or additionally, can not carry out beam flying and make the scattering everywhere in tremulous pulse of treatment light.Can repeat this program (step 1232).
Figure 13 shows the flow chart according to the example embodiment of general cell-specific Therapeutic Method of the present invention, and it utilizes the image guiding target position to be identified for treating, and/or when definite treatment is finished.This exemplary method can be implemented endogenous absorbent (for example, do not have provide in the box 1307 key element) or exogenous absorbent (for example, having the key element that provides in the box 1307).Program can begin in step 1300, but in step 1305 the administration of exogenous medicament, and can wait for (step 1310).Conduit can be inserted tremulous pulse (step 1315), and from the arterial wall retrieving information to determine whether to dispose treatment laser emission (step 1320).
At the suitable example location place that for example determines by the example diagnostic method, light with suitable wavelengths, expose parameter to the open air and power density is come radiation tube wall (step 1325).Selection exposes to the open air with power parameter with influence the thermal confinement of these cells.Tremulous pulse can expose in light one section preset time to the open air or by feeding back to identical or another example diagnostic method and definite a period of time (step 1330).Conduit can be at circumference, vertically or move at least one direction in other direction to scan whole treatments regional (step 1335).Can repeat this program (step 1332).
The exemplary reference document
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Principle of the present invention below only has been described. Consider teaching herein, the various of above-described embodiment are repaiied It all is obvious changing and be out of shape concerning the ordinary person of this area. Really, implement according to example of the present invention The system and method for example can together use and/or the person implements with following: any OCT system, OFDI system System, SD-OCT system, laser facula imaging (LSI) system or other imaging system, and for example with lower The content that illustrates in the row patent is together used: the international patent application that on September 8th, 2004 submitted to The U.S. Patent application the 11/266th, 779 of submitting in PCT/US2004/029148, on November 2nd, 2005, The U.S. Patent application the 10/501st, 276 of submitting on July 9th, 2004, on January 18th, 2007 submit to U.S. Patent application the 11/624th, 334 and the U.S. Patent application of everyday submitting to September 29 in 2005 10/551,735, its full content is incorporated at this by reference. So it should be noted that the common of this area Personnel can design multiple systems, configuration and method, although their not herein expressly explanations, But embody principle of the present invention and thereby fall in the spirit and scope of the present invention. In addition, as long as herein By reference and expressly do not incorporate existing knowledge into, then expressly incorporate its full content into. Cited above whole Publication is all incorporated its full content by reference into.
Claims (64)
1. equipment comprises:
At least one configuration is used for electromagnetic radiation is sent to anatomical structure, and the described electromagnetic radiation with at least one character is used for:
I. revise at least one feature of at least one first cell; And
Ii. following at least one: (a) make any modification of at least one feature of at least one second cell minimize or (b) revise at least one feature of at least one second cell;
Wherein said first and second cells differ from one another, the described feature of wherein said first and second cells differs from one another, wherein at least one described first cell or described second cell have at least one macrophage characteristic, and wherein described at least one feature of at least one described at least one first cell or described at least one second cell is a temperature.
2. equipment according to claim 1, wherein said at least one character comprise wavelength, mean power, instantaneous power, pulsewidth or interim at least one when always exposing to the open air.
3. equipment according to claim 2, wherein said at least one character comprises wavelength, the absorbing wavelength feature of itself and described at least one first intracellular chemical compound is roughly the same.
4. equipment according to claim 2, wherein said at least one character comprises pulsewidth, it causes described at least one feature roughly to be limited in described at least one first cell.
5. equipment according to claim 2, wherein said at least one character comprises power, it causes described at least one feature irreversibly to destroy at least one part of described at least one first cell.
6. equipment according to claim 1, the temperature that described at least one feature of wherein said at least one first cell damages greater than at least one part to described at least one first cell.
7. equipment according to claim 1, wherein the destruction to described at least one part of described at least one first cell is irreversible.
8. equipment according to claim 1, wherein said at least one first cell is positioned at blood vessel wall.
9. equipment according to claim 8, wherein said blood vessel wall are parts coronarius.
10. equipment according to claim 1, wherein said at least one configuration is located in the conduit.
11. equipment according to claim 1, wherein said at least one macrophage characteristic is the lysosome that comprises at least one lipid.
12. equipment according to claim 11, wherein said at least one lipid comprises at least one low density lipoprotein, LDL (LDL), oxidized ldl, cholesterol or cholesteryl ester.
13. equipment according to claim 1, wherein said at least one macrophage characteristic is the lysosome that comprises downright bad fragment.
14. equipment according to claim 1, wherein said at least one macrophage characteristic is a plurality of lysosomes.
15. equipment according to claim 1, wherein said at least one macrophage characteristic is at least one nano-particle.
16. equipment according to claim 1, wherein said at least one nano-particle is located in the cell.
17. equipment according to claim 16, wherein said at least one nano-particle is located in the lysosome.
18. equipment according to claim 16, wherein the size of single described at least one nano-particle is between 1～20 nanometer.
19. equipment according to claim 16, wherein said at least one nano-particle is by metal, noble metal, ultra-fine paramagnetic iron oxide, gold or silver-colored at least aly constitute.
20. equipment according to claim 16, wherein said at least one nano-particle is administered to object by intravenous.
21. equipment according to claim 16 wherein, when described electromagnetic radiation is on described at least one nano-particle, generates surface plasma.
22. equipment according to claim 1, wherein said at least one first configuration is configured to outwards send electromagnetic radiation from the health of object.
23. equipment according to claim 1, wherein said at least one macrophage characteristic is in fibrous cap.
24. equipment according to claim 1, further comprise at least one second configuration, be configured to be used for to determine with described at least one first cell and described at least one second cell at least one position that is associated, wherein said at least one first dispose and further be configured to be used near transmission electromagnetic radiation described position.
25. equipment according to claim 24, wherein at least one described first cell or described second cell have at least one macrophage characteristic.
26. equipment according to claim 24, wherein described at least one feature of at least one described at least one first cell or described at least one second cell is a temperature.
27. a method comprises:
Electromagnetic radiation is sent to anatomical structure, and the described electromagnetic radiation with at least one character is used for:
I. revise at least one feature of at least one first cell; And
Ii. following at least one: (a) make any modification of at least one feature of at least one second cell minimize or (b) revise at least one feature of at least one second cell;
Wherein said first and second cells differ from one another, the described feature of wherein said first and second cells differs from one another, wherein at least one described first cell or described second cell have at least one macrophage characteristic, and wherein described at least one feature of at least one described at least one first cell or described at least one second cell is a temperature.
28. an equipment comprises:
At least one first configuration is used for electromagnetic radiation is sent to anatomical structure, and the described electromagnetic radiation with at least one character is used for:
I. revise at least one feature of at least one first cell; And
Ii. following at least one: (a) make any modification of at least one feature of at least one second cell minimize or (b) revise at least one feature of at least one second cell, wherein said first and second cells differ from one another, and the described feature of wherein said first and second cells differs from one another; And
At least one second configuration, be used for determining with described at least one first cell and described at least one second cell at least one position that is associated, wherein said at least one first dispose to be further configured and become to be used near transmission electromagnetic radiation described position.
29. equipment according to claim 28, wherein at least one described first cell or described second cell have at least one macrophage characteristic.
30. equipment according to claim 28, wherein described at least one feature of at least one described at least one first cell or described at least one second cell is a temperature.
31. equipment according to claim 28, wherein said at least one second configuration are configured to be used for determine described position based on the image of at least one part of described anatomical structure.
32. equipment according to claim 28, wherein said at least one second configuration comprises at least one in relevant range finding configuration, hot spot analysis configuration, thermal imaging configuration or the spectroscope configuration.
33. equipment according to claim 28, wherein at least one described first cell or described second cell have at least one macrophage characteristic, and described at least one feature of at least one described at least one first cell or described at least one second cell is a temperature.
34. equipment according to claim 33, wherein said at least one character comprise wavelength, mean power, instantaneous power, pulsewidth or interim at least one when always exposing to the open air.
35. equipment according to claim 34, wherein said at least one character comprises wavelength, and the absorbing wavelength feature of itself and the described at least the first intracellular chemical compound is roughly the same.
36. equipment according to claim 34, wherein said at least one character comprises pulsewidth, and it causes described at least one feature roughly to be limited in described at least one first cell.
37. equipment according to claim 34, wherein said at least one character comprises power, and it causes described at least one feature irreversibly to destroy at least one part of described at least one first cell.
38. equipment according to claim 33, the temperature that described at least one feature of wherein said at least one first cell damages greater than at least one part to described at least one first cell.
39. according to the described equipment of claim 38, wherein the destruction to described at least one part of described at least one first cell is irreversible.
40. equipment according to claim 33, wherein said at least one first cell is positioned at blood vessel wall.
41. according to the described equipment of claim 40, wherein said blood vessel wall is a part coronarius.
42. equipment according to claim 33, wherein said at least one configuration is located in the conduit.
45. equipment according to claim 33, wherein said at least one macrophage characteristic is the lysosome that comprises at least one lipid.
46. equipment according to claim 33, wherein said at least one lipid comprises at least one low density lipoprotein, LDL (LDL), oxidized ldl, cholesterol or cholesteryl ester.
47. equipment according to claim 33, wherein said at least one macrophage characteristic is the lysosome that comprises downright bad fragment.
48. equipment according to claim 33, wherein said at least one macrophage characteristic is a plurality of lysosomes.
49. equipment according to claim 33, wherein said at least one macrophage characteristic is at least one nano-particle.
50. equipment according to claim 33, wherein said at least one nano-particle is located in the cell.
51. according to the described equipment of claim 50, wherein said at least one nano-particle is located in the lysosome.
52. according to the described equipment of claim 50, wherein the size of single described at least one nano-particle is between 1～20 nanometer.
53. according to the described equipment of claim 50, wherein said at least one nano-particle is by metal, noble metal, ultra-fine paramagnetic iron oxide, gold or silver-colored at least aly constitute.
54. according to the described equipment of claim 50, wherein said at least one nano-particle is administered to object by intravenous.
55., wherein, when described electromagnetic radiation is on described at least one nano-particle, generate surface plasma according to the described equipment of claim 50.
56. equipment according to claim 33, wherein said at least one first configuration is used for outwards sending electromagnetic radiation from the health of object.
57. equipment according to claim 33, wherein said at least one macrophage characteristic is in fibrous cap.
58. a method comprises:
Electromagnetic radiation is sent to anatomical structure, and the described electromagnetic radiation with at least one character is used for:
I. revise at least one feature of at least one first cell; And
Ii. following at least one: (a) make any modification of at least one feature of at least one second cell minimize or (b) revise at least one feature of at least one second cell, wherein said first and second cells differ from one another, and the described feature of wherein said first and second cells differs from one another; And
Determine with described at least one first cell and described at least one second cell at least one position that is associated, near wherein transmission electromagnetic radiation described position.
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| US77833606P | 2006-03-01 | 2006-03-01 | |
| US60/778,336 | 2006-03-01 | ||
| US60/783,599 | 2006-03-17 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112342181A (en) * | 2020-03-26 | 2021-02-09 | 中国人民解放军总医院第四医学中心 | Non-invasive cell patterning method and system based on numerical control laser radiation |
| CN114569903A (en) * | 2022-01-20 | 2022-06-03 | 重庆医科大学 | Pulse ultrasound-medicine-cooperated external noninvasive therapeutic apparatus and operation method thereof |
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2007
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112342181A (en) * | 2020-03-26 | 2021-02-09 | 中国人民解放军总医院第四医学中心 | Non-invasive cell patterning method and system based on numerical control laser radiation |
| CN112342181B (en) * | 2020-03-26 | 2021-12-24 | 中国人民解放军总医院第四医学中心 | Non-invasive cell patterning method and system based on numerical control laser radiation |
| CN114569903A (en) * | 2022-01-20 | 2022-06-03 | 重庆医科大学 | Pulse ultrasound-medicine-cooperated external noninvasive therapeutic apparatus and operation method thereof |
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