CN101698121A - Conformal ultrasonic system for enforcing medicaments to permeate blood brain barrier - Google Patents
Conformal ultrasonic system for enforcing medicaments to permeate blood brain barrier Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0092—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
Abstract
The invention discloses a system for enforcing medicaments to permeate a blood brain barrier by enforcing the blood brain barrier to be opened. A computer control system adjusts the phase and amplitude of each piezoelectric crystal drive signal to enable the ultrasonic radiation in special power to be generated at a brain lesion, so that the blood brain barrier on the brain lesion is effectively led to be opened, macromolecular medicaments are enforced to permeate the blood brain barrier and the effective medicament concentration is achieved at the lesion; and researches show that when the ultrasonic radiation stops, the blood brain barrier can restore the normal function after a dozen of hours. The system for enforcing medicaments to permeate the blood brain barrier has the advantages of non-invasiveness, controllability, safety, no cytotoxicity and good positioning and targeting characteristics, and can effectively prevent the functions from being interfered when the blood brain barrier is normal and protect the brain environment, and the invention creates a new path for medicament and gene therapies of central nervous system diseases.
Description
Technical field:
The present invention relates to medical instruments field, exactly a kind of medicine that promotes sees through the conformal ultrasonic system of blood brain barrier.
Background technology:
Below from domestic present Research and foreign study present situation two parts prior art related to the present invention is described.
Domestic in striding the research of blood brain barrier drug delivery representational as Tang of The Fourth Military Medical University all the Liu Qiang of hospital etc. to the high molecular weight protein of protein transduction mediation by blood brain barrier effect and research (the contemporary Chinese medical journal that in cerebral tissue, distributes and carry out thereof, 2003,3 (5): 33-35), the Chen of No.1 Military Medical Univ. Yi is recruited the research that high temperature is carried out close-connected influence and molecular mechanism thereof between the blood brain barrier endotheliocyte, Zhao of Hebei Yiling Pharmaceutical Research Institute protects and win to wait the physiological action of having inquired into the short Blood Brain Barrier (BBB) opening of Borneolum Syntheticum, and the Lanzhou medical college is induced research that the rat Blood Brain Barrier (BBB) opening carries out etc. to mannitol.
About ultrasonic domestic not the appearing in the newspapers of research of striding the transmission of blood brain barrier macromolecular drug.But studies have shown that of the focus supersonic high temperature cerebral tumor that people such as Taiwan Win-Li Lin carry out treatment can make the acoustic attenuation minimum of skull under the frequency of suitable ultrasonic window size, optimization and power, and the hot stack minimum arrives the acoustic energy maximum of application site.Frequency band at 0.6-1.2MHz is ultrasonic more satisfactory frequency of passing skull, and its sound energy attenuation is at 52-16Np/m.The ultrasonic treatment that is used for brain diseases through skull of result of study explanation.
External research in this respect is also just at the early-stage.Several pieces of relevant reports only limit to ultrasonic to external blood brain barrier vascular endothelial cell permeability, medicine intake, and synergistic research.More representational be calendar year 2001 Harvard University's medical college Kullervo doctor Hynynen with 0.2W to the ultrasonic experimental study of having carried out opening the blood brain barrier of rabbit of the focusing pulse of 11.5W, with contrast agent and NMR (Nuclear Magnetic Resonance) imaging the result is observed, demonstrated deposition of contrast agent at target site, under low-power, do not have brain tissue injury, drawn the ultrasonic conclusion that can open blood brain barrier under contrast agent.Cho professor C of pharmaceutical college of Colorade USA health sciences center university in 2002 utilizes monolayer calf cerebrovascular endothelial cell, ultrasonic slight fever effect is strengthened the external assessment of medicine absorption having carried out of the permeability and the vascular endothelial cell of blood brain barrier, ultrasonic energy strengthens the medicine intake of blood brain barrier vascular endothelial cell, and can increase the ability of the penetrating blood brain barrier of P glycoprotein (PSC 833), the result shows that ultrasonic is the method for a potential reversible and undamaged increase blood-brain barrier permeability.People such as the Experiment of Applied Physics chamber Mesiwala of Washington, DC university in 2003 studies show that high intensity focused ultrasound can be opened blood brain barrier and not damage the brain structure, can repair voluntarily after 72 hours.2005, humans such as Hynynen are suitable for through the low frequency ultrasound of skull the live body Medulla Leporis seu Oryctolagi being studied, analyzed more biological data, confirmed that further low frequency ultrasound is to opening effective and controlled effect of blood brain barrier, but this experiment is to carry out on the skull bone window of opening, his research does not relate to low frequency ultrasound as yet and passes the fine-focused technology of skull, and to ultrasonic hot stack and thereby the influence to cerebral tissue in skin of head and the contiguous skull that produces when passing skull.
In a word, external correlational study still is in the physical chemical phenomenon observation at present, and the elementary step of striding the mechanism research of blood brain barrier drug delivery, the correlational study report that does not have holonomic system, particularly to various parameters and hot stack problem in the skull ultrasonic transmission process, be used for problems such as the supersonic array of this research and control parameter and all also do not relate to.
Summary of the invention:
The present invention is directed to the existing medicine that promotes and see through the problem that exists in the blood brain barrier method, provide a kind of effective promotion medicine to see through the conformal ultrasonic system of blood brain barrier, utilize native system can pass through to regulate the degree of ultransonic amplitude size regulation and control Blood Brain Barrier (BBB) opening, open the blood brain barrier of specific part by adjusting ultransonic phase place time-delay realization focused sound beam.
The objective of the invention is to be achieved through the following technical solutions: promote medicine to see through the conformal ultrasonic system of blood brain barrier, mainly form that phased array supersonic discharger 7 is by central computer 1 monitoring by central computer 1 and phased array supersonic discharger 7;
Described phased array supersonic discharger 7 is made of some ultrasound emission unit, described ultrasound emission unit is connected to form by Single Chip Microcomputer (SCM) system 2, high frequency pumping unit 3, power amplifier 4, coupling unit 5 and phased array piezoelectricity array element 6, Single Chip Microcomputer (SCM) system 2 control high frequency pumping unit 3 synthetic high_frequency sine wave or high frequency square waves, high_frequency sine wave or high frequency square wave are through power amplifier 4 amplifying powers, and it is ultrasonic to drive phased array piezoelectricity array element 6 emissions that comprise piezoquartz by coupling unit 5;
Described central computer 1 is treated parameter by radioing to Single Chip Microcomputer (SCM) system 2 with ultrasonic radiation, it is ultrasonic that control phased array supersonic discharger 7 produces focal positions, watt level, focal spot size, radiated time is adjustable, realizes the information transmission and central authorities' control in the therapeutic process by central computer 1.
This promotion medicine sees through the blood brain barrier system, also comprise NMR (Nuclear Magnetic Resonance)-imaging aid system 9, described NMR (Nuclear Magnetic Resonance)-imaging aid system 9 comprises MRI discharger, MRI receiving system and MRI signal processing and imaging three parts, with brain spatial positional information and brain functional imaging information, be transferred to central computer 1, the location that is used for the brain lesion in early stage, and the inspection of anaphase effect.
This promotion medicine sees through the blood brain barrier system, also comprises the driver 8 of phased array supersonic discharger 7, and central computer 1 moves phased array ultrasonic transmitter 7 by the driver 8 of controlling phased array supersonic discharger 7 and carries out radiation to the appropriate location.
This promotion medicine sees through the blood brain barrier system, also comprises a circulation water bag 12, by 12 couplings of circulation water bag, reduces Ultrasonic attenuation between phased array supersonic discharger 7 and brain.
It is to produce by digital frequency synthesizer or LC self-oscillation circuit that this promotion medicine sees through the high_frequency sine wave described in the blood brain barrier system.
It is to produce by digital frequency synthesizer that this promotion medicine sees through the high frequency square wave described in the blood brain barrier system.
It is Capacitance Coupled unit or transformer coupled unit that this promotion medicine sees through the coupling unit 5 described in the blood brain barrier system.
It is spherical crowns that this promotion medicine sees through phased array supersonic discharger 7 profiles described in the blood brain barrier system, described ultrasound emission unit is positioned on the evenly spaced concentric circular of this spherical crown spherical distance, enclose the inboard uniform distribution of concentrically ringed spherical crown at each, totally 16 enclose, if interior circle is the 1st circle, the circle of outermost is the 16th circle, then N encloses 4*N ultrasound emission unit of the inboard uniform distribution of concentrically ringed spherical crown, get 32 ultrasound emission unit on the outermost one circle concentric circular, altogether 512 ultrasound emission unit.
This promotion medicine sees through circulation water bag 12 outfans described in the blood brain barrier system and is connected with degassing apparatus 10, temperature controlling instruments 11, the temperature in bubble that produces to eliminate water bag endogenous cause of ill ultrasonic cavitation and the control water bag.
This promotion medicine sees through the emission ultrasonic radiation parameter described in the blood brain barrier system: frequency 1-2MHZ, sound intensity 1-5W/cm
2, emittance 10-20W, pulsewidth 100ms, time 10-30s.
The present invention adopts ultrasonic be a kind of suitable brain shape, can focus on, 512 array element phased array supersonic dischargers produce, ultransonic frequency is 1-2MHz, power controlled is built in 10-20W, radiated time 10-30s, by Single Chip Microcomputer (SCM) system piezoelectricity array element is adopted the excitation of different delayed time time, can make part array element ultrasound wave identical in the phase place in TA zone, then the optimal power in this zone obtains allowed band causes Blood Brain Barrier (BBB) opening.In addition, observe the ultrasonic obvious damage effect of not finding in the radiation dose scope under study for action to brain tissue; And by local these characteristics of enhanced rad of phase array focusing ultrasound, can control the open position of blood brain barrier, avoid when hyperamization brain barrier popularity is open in the previous methods infringement normal cerebral tissue.
Above-mentioned promotion medicine sees through the blood brain barrier system, and after central computer obtained brain lesion locus and phased array elements emission space position by the NMR (Nuclear Magnetic Resonance)-imaging aid system, central computer calculated the space length between each array element and focus; Convert the phase place delay parameter of each array element correspondence again to by central computer so that arrive lesions position ultrasonicly have an optimal power.It is simple to regulate and control radiation parameter during use on computers.Can overcome existing deficiency in the aforementioned prior art, such as making skull lower influence to greatest extent by the phased array supersonic discharger, and can realize that regional area opens blood brain barrier ultrasonic attenuation; Solve the hot stack problem to a certain extent by the circulation water bag.So when reaching the effect that promotes Blood Brain Barrier (BBB) opening, can not cause the damage of extensively open side effect that causes of full brain blood brain barrier and heat effect to normal brain cell by the radiation of this device is ultrasonic.The adjustability of radiation focus point, amount of radiation, radiated time is convenient at various disease, is adapted to different patients, can't concentrate for the medicine that causes because of blood brain barrier and hinder the central nervous system disease of treatment in focus, and its superiority is more apparent outstanding.Confirm that by experiment phased array supersonic radiation method selected in this device can promote the blood brain barrier of brain appointed area noinvasive, safe, controlled, reversibly open to occur really effectively.
Description of drawings
Fig. 1 is the basic block diagram of ultrasonic system in the embodiment of the invention;
Fig. 2 is the model of action figure of ultrasonic system in the embodiment of the invention;
Fig. 3 is a phased array supersonic discharger profile sketch map in the embodiment of the invention;
Fig. 4 is 65 * 65 array element array phase-control focusing wave beam scattergrams, and figure a and figure b adopt two kinds of focusing situations that time-delay obtains, and the peak of two width of cloth figure is obviously different, i.e. both focusing position differences;
Fig. 5 is that the S180 cell is at power 0.7W/cm
2, under the ultrasonication of 8min, the scanning electron microscope analysis result after gene transmits.
The specific embodiment:
Below in conjunction with accompanying drawing the present invention is described in further detail.
As shown in Figure 1, the conformal ultrasonic system that promotes medicine to see through blood brain barrier mainly is made up of central computer 1 and phased array supersonic discharger 7, phased array supersonic discharger 7 is to be made of 512 ultrasound emission unit, and each ultrasound emission unit is connected to form by Single Chip Microcomputer (SCM) system 2, high frequency pumping unit 3, power amplifier 4, coupling unit 5 and phased array piezoelectricity array element 6.Single Chip Microcomputer (SCM) system 2 control high frequency pumping unit 3 synthetic high_frequency sine wave or high frequency square waves, high_frequency sine wave or high frequency square wave can produce by digital frequency synthesizer, also can produce by LC self-oscillation circuit, process power amplifier 4 is high_frequency sine wave or high frequency square wave power amplification, it is ultrasonic to drive phased array piezoelectricity array element 6 emissions that comprise piezoquartz by coupling unit 5, coupling unit 5 can realize by Capacitance Coupled, also can be by transformer coupled realization;
In conjunction with shown in Figure 2, native system also comprises the driver 8 of phased array supersonic discharger 7, and central computer 1 moves phased array ultrasonic transmitter 7 by control driver 8 and carries out radiation to the appropriate location.Native system also comprises NMR (Nuclear Magnetic Resonance)-imaging aid system 9, described NMR (Nuclear Magnetic Resonance)-imaging aid system 9 comprises MRI discharger, MRI receiving system and MRI signal processing and imaging three parts, with brain spatial positional information and brain functional imaging information, be transferred to central computer 1, the location that is used for the brain lesion in early stage, and the inspection of anaphase effect.After central computer 1 obtained brain lesion locus and phased array elements emission space position by NMR (Nuclear Magnetic Resonance)-imaging aid system 9, central computer 1 calculated the space length between each array element and focus; Convert the phase place delay parameter of each array element correspondence again to by central computer 1 so that arrive lesions position ultrasonicly have an optimal power.Native system also comprises a circulation water bag 12, be coupled by circulation water bag 12 between phased array supersonic discharger 7 and brain, to reduce Ultrasonic attenuation, circulation water bag 12 outfans are connected with degassing apparatus 10, temperature controlling instruments 11, the temperature in bubble that produces to eliminate water bag endogenous cause of ill ultrasonic cavitation and the control water bag.
The configuration design of phased array supersonic discharger 7 and concrete working condition are as follows:
As shown in Figure 3, phased array supersonic discharger 7 is that a radius is the spherical crown of 15cm, its aperture radius 11cm, and array element is evenly distributed in the inboard of each circle of spherical crown with the concentric circular form.If a is the angle that departs from the x positive axis on the xy plane, span is 0 to 2 π, and b is the angle of the negative semiaxis of skew z, and span is 0 to π/4, the centre of sphere of spherical crown (0,0, R) locate, then the space coordinates of spherical crown is:
0≤a≤2π，0≤b≤π/4
Array element is designed to the concentric circular form of 16 circles, has 544 array elements, only gets 32 for an outmost circle array element, finally reaches the design of 512 array elements.That gets b is spaced apart π/64, on the i circle a be spaced apart 2 π/(4*i), so just can obtain the space coordinates of 512 array elements, be the profile sketch map of transducer as Fig. 3.If I
(i, j)(i represents that the skew of b measures for i, j) individual array element, and value is 1 to 16, and j represents that the skew of a measures, and value is 0 to 4*i-1, so I to be the
(i, j)Corresponding one by one each array element.When definite focus locus, can obtain the distance D between each array element and the focus
(i, j)
Get min (D)={ D
(i, j)(formula 2)
If launching the ultransonic time from the shortest array element of focus distance is t
0, then the time of each array element time-delay back emission is:
Suppose the focal position (0,0,15) of focus, obtain the space coordinates position of each array element by (formula 1), and then draw the distance of each array element and focus at spherical crown:
By recycle ratio, can draw a min (D)={ D minimum in these 512 distances
(i, j), obtain the time that launch each array element time-delay back according to (formula 3) again:
Finish determining of focus locus by NMR (Nuclear Magnetic Resonance)-imaging aid system 9, the spatial relation of each array element draws in the above, in central computer 1, obtain the calculating of each array element delay time by top algorithm, send to the Single Chip Microcomputer (SCM) system 2 of each array element again by wireless telecommunications handle control parameter, finish 512 array element time-delays separately.As shown in Figure 4, the peak that the focus beam that adopts different delayed time to obtain distributes is obviously different, i.e. both focusing position differences.As seen, as long as we are to the different time time-delay of each array element accurate Calculation, just can produce the focused beam of certain power at place, requirement locus.The ultrasonic radiation parameter is: frequency 1-2MHZ, sound intensity 1-5W/cm
2, emittance 20-200W, pulsewidth 100ms, time 10-30s.
At first allow patient lie low on a bed that can move horizontally, the water bag of hat-shaped on the head band, and then patient sent into the instrument treatment district.
After patient lies low, start the nuclear magnetic resonance, NMR discharger in the NMR (Nuclear Magnetic Resonance)-imaging auxiliary monitoring system 9, receive the brain function image at nuclear magnetic resonance receiver, the brain function information is passed to central computer through NMR signal processing and image-generating unit.
The doctor is checked through lesions position on computers, determines the focus locus by click.
It is ultrasonic to ideal therapentic part emission that driver 8 is used for mobile phased array ultrasonic transmitter 7; Calculate array element on the current ultrasonic probe with respect to the space length of focus by central computer 1 again, and the delay time of each array element correspondence, said above the computational methods.
The doctor is provided with the treatment parameter on computers according to the state of an illness, and watt level, radiation areas size, radiation irradiation time are arranged.
After the treatment parameter setting is intact, by starting ultrasonic button, the relevant control parameter of the single-chip microcomputer 2 of computer by radioing to each array element then, and specified point carried out ultrasonic therapeutic.
After having treated, start NMR (Nuclear Magnetic Resonance)-imaging aid system 9 once more, check therapeutic effect.
Have suffered process degassing apparatus 10 and temperature control device 11 is worked always, guarantee the brain good environment.
Effect is showed experiment two parts in outer experiment of split and the body.
The foundation of external blood brain barrier model realizes with White Rabbit brain micro blood vessel endothelium cell, astrocyte co-cultivation.Studies have shown that under specific ultrasound parameter, ultrasonic wave energy significantly increases the permeability of cell membrane, make the htrb gene medicine can enter cell inner expression, its transfection efficiency is 40%, intracellular gene expression intensity and specific control parameter amount are closely related, drawn under accurate effect yardstick control system and can be used for the conclusion that gene transmits safely, as can be seen from Figure 5, pass through scanning electron microscope, the micropore of the recoverability that is caused by ultrasonication on the S180 cell membrane, promptly ultrasonic because its mechanical performance make on the cell membrane micropore open; By observing, can find tangible micropore healing vestige when being used as with the time in 5 minutes simultaneously, promptly under the ultrasonic radiation of suitable intensity, the cell membrane micropore is reversible; But radiation surpasses 8 minutes action time, and then cell begins mortality, i.e. the permeability of the parameter cell membrane of ultrasonic radiation is particularly important.
Experiment White Rabbit CR in the body, by intravenous injection Azo-Blue solution, the combined with fluorescent reporter gene, determine the site of action and the efficient of striding blood brain barrier of medicine at cerebral tissue, by with the comparison of not using ultransonic matched group, determine that macromolecular drug under the ultrasonication strides the effect intensity of blood brain barrier.Detect brain tissue injury and apoptosis with scanning electron microscope and flow cytometer, analyze the damage situations of cerebral tissue.Wherein, the Azo-Blue in the missing experiment of Azo-Blue is a kind of Powdered dyestuff, goes into behind the blood rapidly almost absolutely and albumin bound.The albumin molecular weight is 67kDa, almost can not see through blood brain barrier under the normal condition.When blood-brain barrier permeability increased, the bonded albumin of Azo-Blue then can enter cerebral tissue by blood brain barrier.During excitation wavelength 550nm, red color visible fluorescence under the fluorescence microscope.
Find that behind the low frequency ultrasound irradiation, White Rabbit brain tissue position Azo-Blue content increases than matched group when adopting the azovan blue penetrant method to detect the variation of permeability of blood brain barrier.
In addition, find by transmission electron microscope observing, behind the ultrasonic irradiation, passing in time, Azo-Blue content has a peak value, but slowly go down in the back.We find microstructural variation by the transmission electron microscope observation blood brain barrier, behind the ultrasonic irradiation, passing in time, the tight connection degree difference of the vascular endothelial cell in the experimental group, meeting is the degree of opening maximum in a period of time, but slowly reduce, do not see the opening between vascular endothelial cell in the matched group.The ultrasonic of the suitable radiation parameter of these presentation of results can cause that the blood brain barrier reversibility of White Rabbit is open.
Experiment shows, under the normal condition, Azo-Blue with after serum albumin combines, because of the albumin molecular weight is bigger, can not see through blood brain barrier as tracer; After the ultrasonic radiation, as seen fluorescence microscope is observed down, during the 30s left and right sides, has tangible blood-brain barrier permeability to increase.Measure radiation simultaneously according to the Azo-Blue content in group White Rabbit cortex Hippocampus, hypothalamus and the cerebellum, with the normal control group tangible increase is arranged relatively, and it is on the low side according to her Wen's content after back 12 hours, and not remarkable with the normal group comparing difference, illustrate that ultrasonic radiation can cause that rat blood-brain barrier permeability reversibility changes.And detecting brain tissue injury and the apoptosis situation is found with scanning electron microscope and flow cytometer, obvious damage situations does not appear in cerebral tissue in the radiation parameter scope that we set.
Ultrasonic system of the present invention can have various deformation, be not limited in above-mentioned major technique approach, as the profile of phased array supersonic discharger can be flat board or other shapes, the ultrasonic radiation mode can be linear scanning or other scan modes, the parameter that radiation is relevant also can be regulated within the specific limits; In addition, also can utilize other method to produce ultrasonic.In a word, all spirit is done according to the present invention any simple modification and equivalent structure transformation all should be encompassed within protection scope of the present invention.
Claims (10)
1. promote that medicine sees through the conformal ultrasonic system of blood brain barrier, it is characterized in that: this system mainly is made up of central computer (1) and phased array supersonic discharger (7), and phased array supersonic discharger (7) is monitored by central computer (1);
Described phased array supersonic discharger (7) is made of some ultrasound emission unit, described ultrasound emission unit is connected to form by Single Chip Microcomputer (SCM) system (2), high frequency pumping unit (3), power amplifier (4), coupling unit (5) and phased array piezoelectricity array element (6), synthetic high_frequency sine wave in Single Chip Microcomputer (SCM) system (2) control high frequency pumping unit (3) or high frequency square wave, high_frequency sine wave or high frequency square wave are through power amplifier (4) amplifying power, and it is ultrasonic to drive phased array piezoelectricity array element (6) emission that comprises piezoquartz by coupling unit (5);
Described central computer (1) is treated parameter by radioing to Single Chip Microcomputer (SCM) system (2) with ultrasonic radiation, it is ultrasonic that control phased array supersonic discharger (7) produces focal position, watt level, focal spot size, radiated time is adjustable, realizes the information transmission and central authorities' control in the therapeutic process by central computer (1).
2. see through the conformal ultrasonic system of blood brain barrier according to the described promotion medicine of claim 1, it is characterized in that: described system also comprises NMR (Nuclear Magnetic Resonance)-imaging aid system (9), described NMR (Nuclear Magnetic Resonance)-imaging aid system (9) comprises MRI discharger, MRI receiving system and MRI signal processing and imaging three parts, with brain spatial positional information and brain functional imaging information, be transferred to central computer (1), the location that is used for the brain lesion in early stage, and the inspection of anaphase effect.
3. see through the conformal ultrasonic system of blood brain barrier according to claim 1 or 2 described promotion medicines, it is characterized in that: described system also comprises the driver (8) of phased array supersonic discharger (7), and central computer (1) carries out radiation by the mobile phased array ultrasonic transmitter of driver (8) (7) of control phased array supersonic discharger (7) to the appropriate location.
4. see through the conformal ultrasonic system of blood brain barrier according to the described promotion medicine of claim 1, it is characterized in that: described system also comprises a circulation water bag (12), be coupled by circulation water bag (12) between phased array supersonic discharger (7) and brain, to reduce Ultrasonic attenuation.
5. see through the conformal ultrasonic system of blood brain barrier according to the described promotion medicine of claim 1, it is characterized in that: described high_frequency sine wave is to produce by digital frequency synthesizer or LC self-oscillation circuit.
6. see through the conformal ultrasonic system of blood brain barrier according to the described promotion medicine of claim 1, it is characterized in that: described high frequency square wave is to produce by digital frequency synthesizer.
7. see through the conformal ultrasonic system of blood brain barrier according to the described promotion medicine of claim 1, it is characterized in that: described coupling unit (5) is Capacitance Coupled unit or transformer coupled unit.
8. see through the conformal ultrasonic system of blood brain barrier according to the described promotion medicine of claim 1, it is characterized in that: described phased array supersonic discharger (7) profile is a spherical crown, described ultrasound emission unit is positioned on the evenly spaced concentric circular of this spherical crown spherical distance, enclose the inboard uniform distribution of concentrically ringed spherical crown at each, totally 16 enclose, if interior circle is the 1st circle, the circle of outermost is the 16th circle, then N encloses 4*N ultrasound emission unit of the inboard uniform distribution of concentrically ringed spherical crown, get 32 ultrasound emission unit on the outermost one circle concentric circular, altogether 512 ultrasound emission unit.
9. see through the conformal ultrasonic system of blood brain barrier according to the described promotion medicine of claim 4, it is characterized in that: described circulation water bag (12) outfan is connected with degassing apparatus (10), temperature controlling instruments (11), the temperature in bubble that produces to eliminate water bag endogenous cause of ill ultrasonic cavitation and the control water bag.
10. see through the conformal ultrasonic system of blood brain barrier according to the described promotion medicine of claim 1, it is characterized in that: described emission ultrasonic radiation parameter is: frequency 1-2MHZ, sound intensity 1-5W/cm
2, emittance 20-200W, pulsewidth 100ms, time 10-30s.
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