Abstract:
The invention concerns a method and device for needle-less delivery of substances into or through natural or artificial biological components such as membranes, organelles, cells, tissues, organs, or creatures, by exposing the said biological components to accelerated substances wherein high impact mechanical movement over short distance is used to create acceleration of substances so to drive substances into or through said natural or artificial biological components, while isolating the biological component from the driving force. The mechanical movement is preferably created by an ultrasonic member having a high repetition rate, and the space between accelerating element and biological target is preferably composed of low density compound. The delivery device can be provided with a unit for supplying substance to be delivered, to the mechanical accelerating element. The device can be constructed either as delivery device for superficial tissues, or as an endoscopes laparoscope-like or catheter-like device for delivery in minimally invasive procedures.

Description:
FIELD OF THE INVENTION  
       [0001]     The present invention concerns a method, device and system for the delivery of accelerated substances, soluble or particulate, to and through biological components such as membranes, organelles, cells, tissues, organs or creatures, using ultrasound as a preferred accelerating agent and while isolating the biological component from the driven force.  
       BACKGROUND OF THE INVENTION  
       [0002]     Needle less delivery of substances such as mechanical stabilizers, drugs, nutrients, gene-carriers, vaccines or metabolites, either as particles or in solution, into natural or artificial biological components, is often faced with difficulties due to mal-penetration attributed to the barriers functioning against undesired penetration of foreign components. Also topical delivery to internal zones of biological components is faced with difficulties associated with mal-permeability of biological component.  
         [0003]     Ionphoresis, high pressure injection, or ultrasound are among the techniques developed for the facilitation of efficient and safe administration of substances into biological components, mostly of superficial zones.  
         [0004]     For example, ultrasound is used for facilitation of transport of various compounds across tissues, typically skin (Mitragotri, M., et al.,  Science,  269:850-853 (1995)).  
         [0005]     The ultrasonic delivery was improved by using ultrasound in conjunction with chemical permeation enhancer and/or iontophoresis (U.S. Pat. No. 5,231,975). Other methods use ultrasonic waves to excite the local nerves, thereby to open the epidermal/dermal junction membrane and the capillary endothelial cell joints, which enables the transfer of drugs through the skin and into the blood stream (U.S. Pat. No. 5,421,816) or delivery through two pulses where the first one enlarges the intercellular spaces and the second one enables delivery thereof (PCT/IL97/00405). Significant problem of the conventional ultrasound, ionphoresis or chemical assisted delivery is that during the process the biological component is constantly exposed to the driven stimulus, such as irradiation.  
         [0006]     It is also desirable to deliver into biological components relatively large amounts of solutions, or complex particles. State-of-the-art ultrasound-facilitated administration methods are unsuitable for administration of said solutions or complex particles, since application of ultrasound pulses, sufficient to drive a small amount of small-sized molecule through a tissue is insufficient to drive large amounts or to drive those complex particles through tissues or biological or artificial membranes. Increase of the duration, or intensity, changes of frequency or of the ultrasound pulses to levels which are presumably sufficient to drive the large amounts of solutions or particles through the tissue or cell membrane in one operation, or a serial of repeated operations, has not been reported probably since it results in irreversible damage to the tissue and in significant cell-death. Similarly, irreversible damage occurs in non-biological membranes of e.g., polyethylene or elastomer (for example those used in implants), when increased intensities or durations of ultrasound irradiation have been used.  
         [0007]     Other devices perform delivery of compounds by employing a pressure enforced from compressed gas reservoir or by gas spring to create sufficient pressure enabling pushing of medication through e.g., the skin tissue (U.S. Pat. No. 6,096,002). Significant problems here include the need of high-pressure gas reservoir, moving pistons, or gas release, which restricts application to only certain external tissues.  
         [0008]     At times, it is desirable to deliver into biological components substances in the form of solutions, or particles, without accompanied energy delivery to the biological component, without gasses flux or moving pistons. It is also desired to do substances administration regardless of their molecular weight, ionic condition, size or polarity.  
         [0009]     It would have been highly desirable to provide a method for a single as well as high repeatability delivery of wide variety of substances to natural or artificial biological components, either superficial or internal, utilizing driving force, while isolating the driving force from the biological components, therefore minimizing the damage to the tissue or cells. It would have further been desirable to provide an ultrasound facilitated method for delivery of solutions or complex particles having a relatively large size and without employing pressure to the compound to be delivered, nor ventilation or energy delivery to the treated area. It is the object of this invention to provide a method and device for multi purposes intra tissual delivery, which avoid limitations of current technologies and reduce their possible side effects.  
       SUMMARY OF THE INVENTION  
       [0010]     In view of the above, the present invention provides a novel method and device allowing the delivery of substances to, into or through biological components that are part of or an entire biological entity. Said biological components might be membranes, organelles, cells, tissues, organs or creatures. This, in accordance with the invention, is achieved by utilizing an ultrasound stimulus, or other energy source capable of producing high acceleration rate over short distance and at high repeatability, to accelerate the substance to be delivered via low density medium and in the direction of the biological component. By accelerating the substance attached to an ultrasonic vibrating element, or other high accelerating means, in a low density medium, it has been found that substances continue to move in direction of acceleration and it was possible to deliver substances while affecting only the attached substance and isolating the biological component from the energy source, therefore enabling substance delivery without energy delivery to the biological component and without causing it energy related damage. The method for the delivery of substances to biological compounds shall be preferably performed via low density medium such as gas or vacuum. The delivery does not involve any gas streaming or moving parts, and is applicable also to internal tissues.  
         [0011]     The method, in accordance with the invention, comprises the step of exposing the substance to be delivered to a high amplitude ultrasound stimulus, being such as to accelerate the ultrasound attached substance, kept at certain distance from the biological component, via low density medium and in the direction of the said biological component. Surface of the ultrasound generating element, might be covered by compounds capable of reducing the surface-tension, therefore enabling easy release of substance to be delivered. Due to the distance filled with low density medium between the energy source and the substance to be delivered on one hand, and the biological component on the other hand, said energy created by the accelerating means is markedly attenuated in the low density medium and essentially do not reach the target biological component. On the other hand, the substance to be delivered is accelerated with minimal friction during delivery and eventually at least part of it reaches and penetrate the biological component. The disconnection between the accelerating agent, for instance the ultrasound, and the biological component, as well as the non pressurized procedure, enable delivery without causing damage to the bulk of said biological component, at high repetition rate and also to internal zones of biological components, as is below explained.  
         [0012]     The method of the present invention may be used for therapeutic and cosmetic purposes, as well as for diagnostic and experimental purposes, according to the type of substance to be delivered, and the relevant biological component.  
         [0013]     By one non limiting embodiment, the substances to be administered may be soluble substances such as various medicaments for therapeutic treatment, anti ageing agents for prevention purposes, toxic compounds for controlled degeneration, growth factors hormones or interleukins for the initiation or cessation of processes, amino acids or proteins or substrate elements to be resources for macromolecules or processes, macromolecules such as DNA molecules or their fragments, for the purpose of gene therapy or genetic manipulation, various dyes for the purpose of diagnosis inside cells, or within a tissue, substances for local anesthesia, substances for topical destruction of biological component, substances for the reduction or acceleration the activity of biological component or of any sub biological component including infectious agents, substances for changing the mechanical or chemical properties of a biological component or any of it&#39;s subunits, and the like.  
         [0014]     By yet another non-limiting embodiment, the substances to be administered are complex particles. The term “particles” or “complex particle” refers generally to a particle having the size of at least 1 nm ranging to tens or hundreds of microns which is usually composed of a single type of molecule, or alternatively several types of molecules. The complex particles are essentially insoluble in the medium in which they are carried. Examples of complex particles are granules of toxic compounds, sensitizers or radioactive compounds, attenuated or killed disease-causing agents or parts thereof such as bacteria, virions, fingi, protozoa or parasites administered for the purpose of vaccination; plasmids containing DNA to be inserted for the purpose of gene-therapy or genetic manipulations; nano-particles with genes or DNA vaccines, nanomachines, nuclei of gametes administered into oocytes for the purpose of fertilization; particles impregnated with medicaments capable of releasing them at a slow rate to the surrounding tissue for the purpose of therapy or controlled immune reduction; particles containing compounds that were coated with a protective coating, for example, in order to form particles having different solubility, to prevent oxidation, to prevent a hygroscopic effect, to increase resistance to heat or to protect the contents of the particle from biological effects (such as degradation); particles comprising a biologically compatible dye for the purpose of tattooing, as for example, in the case of permanent makeup; particles comprising a detectable marker for the purpose of diagnosis, and the like.  
         [0015]     According to another non limiting example, particles might be also inert or other compounds of particular characteristics, accelerated towards biological components at high acceleration rates, from short distance and at certain angle, and affecting by disconnecting, causing destruction and removal of sub-components or layers of said treated biological components.  
         [0016]     Particles or solutions might be also active or inert compounds used for mechanical support or stabilization of biological components. Active or inert particles might be also used for paving of biological components.  
         [0017]     The “biological component” to which the substances are administered, can be any type of membranes, organelles, cells, tissues, organs or creatures. Biological component might therefore refer to eukaryotic or prokaryotic cells, or their sub-components, including cells cultured in a medium. Biological component might further refer to epithelial tissues which may be keratinized epithelial tissues such as skin, or moist-epithelial tissues, for example, the epithelium lining the eyes, digestive tract, respiratory, or reproductive systems. The tissue may also be the moist epithelial tissue covering aquatic creatures such as fish, crustaceans or mollusks at different stages of rearing, including embryonic ones.  
         [0018]     The term “biological component” might also refer to artificial components, being parts of, or replacing parts of, or assisting the activity of, or used as mechanical support for, or used for releasing substances to or through natural membranes, organelles, cells, tissues, organs or creatures. Therefore the term biological component might refer also to elastomer compounds which form part of an implant, or to artificial skin which has been constructed for replacing damaged skin area, to encapsulated cells or artificial tissue constructed for slow release, or similar artificial components, as the case might be.  
         [0019]     The substance accelerating stimuli, created by ultrasound or any other accelerating mean, are applied when the relevant biological component is not in contact with the accelerating stimuli mean, nor in contact with any liquid medium or gel coupling medium that form a bridge between the biological component and the accelerating mean, but remains isolated from the accelerating stimuli when that is being performed. The medium between the stimulating element and the biological component is essentially composed of an ultrasound isolation medium, such as gas or vacuum, and not of ultrasound coupling medium.  
         [0020]     The substance to be administered shall be acoustically coupled to the stimulating element at least during part of the operation period. That is to say that coupling might be on permanent or temporal basis. Temporal coupling might be achieved for instance, during at least part of cycle of the acceleration of the vibrating element towards the substance. The substance may be present in liquid, gel, paste, powder, pellet, solid strip and the like. It might be composed of homogenous materials or alternatively of different compounds mixed together close to the vibrating element before the delivery, or mixed in the space between vibrating element and biological component during delivery, or mixed in the biological component after the delivery.  
         [0021]     According to non-limiting embodiment, more then one compound is delivered to gain the desired effect. This according to the invention can be performed by having same accelerating rates to the different compounds, or alternatively performing different accelerating rates due to substance weight or size, or by delivery from more than one vibrating element and more than one substance-supply sub-devices. When more than one stimulus is being given, the stimuli may be applied one after the other or simultaneously.  
         [0022]     The specific parameters of the stimulus, capable of driving the administered substances into or through said biological components, should be determined empirically, depending among other things on the nature of the biological component, on the nature of the administered substance and on the parameters of the accelerating mean. However, at least one stimuli composed of at least cycle portion shall be given to deliver unit of substance.  
         [0023]     Generally speaking, the driving stimulus has the following parameters: Frequency: At least 1 Hz; Preferably 10 Hz to 30 MHz, more preferably 10 kHz to 3 MHz, most preferably, 20 kHz to 100 kHz. Duration: At least quarter of cycle; Therefore at least 0.025 sec. or 0.75×10 −7  sec for 10 Hz or 30 MHz respectively. Amplitude: At least one micron; Preferably 10 to 10,000 microns, most preferably 20 to 200 microns. Intensity: 0.0001-10,000 W/cm 2 , preferably 0.1-100 W/cm 2 , most preferably 3-50 W/cm 2 . Under preferred embodiment, the ultrasonic force is used to cause acceleration of substance to be delivered to the site of administration in the biological component.  
         [0024]     It shall be understood that also in the ultrasonic range of frequencies, certainly below it, also other means might be used to create the acceleration force. Such means might include any means that can produce high acceleration rates, over short distance of movement and at high repeatability, for instance sonic speakers, electromagnets, motors, motor-coupled ex-centers, liquid-containing pistons and the like.  
         [0025]     Generally speaking, the acceleration rate can be determined as a=ω 2 Asin(ωt), where A is the amplitude of movement in meters, and ω=2πf, where f is the frequency in Hz. For example, when the frequency is 20 kHz, and the amplitude of vibration 100μ (100×10 −6  m), and maximum acceleration is achieved (i.e., sin(ωt)=1) then acceleration of 1,570,000 m/sec 2  or about 160,000 g is achieved and can be utilized for delivery. However, it should be appreciated that there exists a reversal proportion between the parameters. For instance, when higher frequency is used, the amplitude can be reduced to achieve similar acceleration rate. At times that ultrasonic transducer is used to create the acceleration stimulus, the high amplitude is essentially created by amplification of the original amplitude of the piezoelectric crystals, or other source, using a horn or tip preferably designed to be in resonance under operation conditions.  
         [0026]     Occasionally, biological component might pass pre-delivery treatment to increase their susceptibility and the efficiency of delivery. Said treatment might for example include adherence of cells which are the target of delivery under in vitro conditions, or removal of superficial layers of tissue, such as mucus secretions or keratinized epithelium. According to one non limiting embodiment, the pretreatment might be performed with the same delivery device, operated for instance under streaming or cavitation mode. During such pre-treatment process, a coupling medium shall essentially be present between the accelerating element and the biological component. At times, pre-treatment might be carried out also having gas medium between the driving element and the biological component, and acoustic pressure can be performed to achieve desired pre-treatment effect Pre treatment, however, might be carried out also using other methods and devices, not part of the current invention.  
         [0027]     At times, biological components might pass post-delivery treatment. Said post-delivery treatment might be carried out using the same delivery-device, or methods and devices not part of the current invention or their combination. According to non limiting example, post-delivery treatment might include activation when the delivered agents are irradiation-activated substances. According to one embodiment, the agents might be activated by ultrasound, for instance sonosensitizers such as dimethylformamide, N-methylformamide, or dimethylsulfoxide, or activated by light or other energy modalities after delivery. Substances might be also active in nature, for instance radioactive agents, or activated before, or during their delivery due to ultrasound, light irradiation or other stimuli. According to this example, activated substances are being delivered and effect is performed already during their penetration route so that essentially all the region from the site of administration to the region where the substances reached is essentially destroyed.  
         [0028]     According to yet another non-limiting example, post treatment might include controlled degeneration of at least portion of biological component. According to one embodiment, said degeneration is performed after delivery of substances such as vaccines, so creating a biological reservoir for the slow release of substance during normal process of phagocytosis and absorbance of the degenerated tissue. The degeneration might for instance be performed by allowing the accelerating device to touch the biological component for a short period of time, causing friction and degeneration.  
         [0029]     The present invention also concerns a system for use in the above method. In the following the invention will be further illustrated with reference to some non-limiting drawings and examples. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0030]      FIG. 1  shows a schematic drawing of the ultrasound delivery device of the invention:  1 A before operation and  1 B during delivery process.  
         [0031]      FIG. 2  shows a schematic representation of a multi-lobed delivery device used in the system of the invention:  2 A before operation and  2 B during delivery process.  
         [0032]      FIG. 3  shows another schematic drawing of a multi lobed device having another substance-supply unit:  3 A before operation and  3 B during supply of substance to be delivered.  
         [0033]      FIG. 4  shows another schematic drawing of delivery device having another actuating mechanism.  
         [0034]      FIG. 5  shows a schematic drawing of a laparoscope-implanted delivery device.  
         [0035]      FIG. 6  shows another schematic drawing of a laparoscope-implanted delivery device, having particular substance supply method and component.  
         [0036]      FIG. 7  shows a schematic drawing of delivery device, having another substance supply method and a concentration element.  
         [0037]      FIG. 8  shows another schematic drawing of a delivery device, having another substance supply method and a dispersion element.  
         [0038]      FIG. 9  shows yet another schematic drawing of a lateral delivery device. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0039]     In the device for substances delivery to biological components, high accelerartion rates are utilized to enforce substances delivery from accelerating element to or through biological component, while isolating the biological component from the driving force. The energy is essentially utilized to push the substances, and it essentialy does not reach and consequently is not absorbed in the biological component. The resultant delivery is therefore free of side effects related to energy absorbance and can be performed in superficial as well as in deeper parts of biological components.  
         [0040]     A delivery device, in accordance with the invention, functions to deliver solutions as well as particles, yet essentially does not permit the energy to be delivered, therefore prevent the biological component to be affected by the delivery force. As will later be explained, this result is accomplished by drawing continuous vibration and heat away from the biological component.  
         [0041]     The delivery system of the invention generally comprises a control unit, a single or a multi-frequency signal generator, a signal amplifier, a matching unit and at least one transducer which may be attached to an amplitude increasing devices, such as resonator or resonating tip. These elements which increases the amplitude, actually increases also the acceleration rate, having small displacement. The phenomena essentially occur at the distal part of said resonating tip, yet might occur also in other locations according to the planning.  
         [0042]     At times other means to create high acceleration rate over small displacement might be used either with the ultrasonic driving force or together with other means, or as stand alone means. The high amplitude element is however encased in a housing. The system further comprises substance to be delivered, which may be brought manually or automatically to the accelerating edge by supply elements. The system is provided by a spacer enabling keeping the biological component at certain distance from the accelerating element during operation. This distance might be changed, increased or decreased. At times, for instance during post treatment procedure, distance between resonating element and biological component might be reduced to zero. The system is most preferably also provided with vacuum element, or gas delivery system, to apply low viscosity medium between the accelerating element and the biological component. The vacuum device might be used also for the suction of the non delivered substances from site of delivery, for instance at the end of treatment. The system might be provided also, by element for supply of media for pre-treatment, means for activation of delivered substances, or other means as the case might be.  
         [0043]     It is important to note, however, that the system can be operated as stand alone device, for instance during external procedures; It can be further operated as an add-on to other devices, for instance by implanting a high-rate accelerating device, such as resonating transducer, at the distal part of plunger of a gas-spring needle less injection device, or other delivery device, thereby enabling higher acceleration rates to the substances; It can be further operated in laparoscope devices, for delivery to internal biological components, in conjunction with diagnostic element for monitoring the delivery-device location.  
         [0044]     A conceptual model of the delivery device in accordance with the invention, is shown in  FIGS. 1A and 1B . The system operated by electricity, is composed of control unit, a signal generator, a signal amplifier, and matching unit (not shown) which are connected to the said delivery device. The device  100  is encased in housing  10 . It contain a piezoelectric element  44 , transforming the electrical signal to mechanical displacement, and a tip  46  enabling high amplitude at distal end  48 , with still the original high repetition rate. The device contain substance reservoir  26 , linked by tube  28  to pump  34  which delivers said substance via tube  36  and opening  38  to distal end  48 . Element  50  represents the substance accumulated at distal end  48  of the tip  46 . The device is separated to two compartments, by septum  18 . Vacuum pump  20  is having suction activity of air and debris via opening  24  and tube  22 . At the end of the suction activity, the air pressure at space  16  of the septum is lowered. Leakage of gasses from the surroundings is prevented by attaching housing  10  having suction rubber  17  in a shape of circular rim at it&#39;s distal open end, to surface  60  of the biological component. The air pressure at space  14  at the other side of septum  18  can remain without change.  
         [0045]     In practice, as can be shown in fig  1 B, during activation piezoelectric element  44  transform the electrical signal to mechanical displacement. Maximal amplitude of displacement is achieved at the distal end  48  of the tip, which is displaced and accelerated in the general direction of arrow C. The rapid displacement enforces the substance previously attached to end  48  to be detached and move forward. The acceleration and accompanied forces push the substance in the general direction of arrows D,E,F and G between schematic broken lines H and J, into and through surface  60  of the biological component.  
         [0046]     According to the example given is  FIGS. 2A and 2B  a multi lobed device  200  might be used. The device in housing  110  attached to surface  152  of biological component via suction rubber  150 , is composed of a piezoelectric element  130 , guiding horn  134  and distal end composed of several tips  124 ,  126  and  128 . Attached to, or alternatively part of, the distal ends of the tips, for instance end  125  of tip  124 , are small units  124   a ,  126   a  and  128   a , capable of absorbing liquids (for instance firm sponge). Substance is supplied from reservoir  112 , to tube  114  and pump  116 , via tube  120  in space  140 , and further to tube  122  in space  144 . Tube  122  has holes  124   b ,  126   b  and  128   b , in the same number of the tips, and in a location compatible to said tips  124 ,  126  and  128 , respectively. Occasionally, different substances might be delivered from different reservoirs to different tips.  
         [0047]     When pump  116  is activated, holes  124   b ,  126   b  and  128   b  become filled with substance to be delivered. Suction activity performed by vacuum pump  164 , via opening  160  and tube  162 , reduces gas content in compartment  144 . Suction activity might also facilitate the supply of substance from reservoir  112  to the general direction of space  144 , separated from space  140  by septum  142 . The supply is in the general direction of arrow J in  FIG. 2B . It shall be noted that excess of substance in space  144  is carried out via the suction activity into opening  160 , tube  162 , and via pump  164  to tube  166 , filter  168  and back to the reservoir via tube  170 . As demonstrated in  FIG. 2B , during operation distance between tips, for instance tip  124  and its absorbing unit  124   a  on one hand, and holes, for instance  124   b  on the other hand, is diminished. Supplied substance enters absorbing unit  124   a , and similarly enters  126   a  and  128   a , and the accelerating tip  124 , and similarly  126  and  128 , deliver substance towards surface  152  in the general direction of schematic arrows K,L and M.  
         [0048]     It shall be appreciated that as pre-treatment, space  144  might be filled with gassed distilled water, and cavitation performed using irradiation via tips  124 , 126  and  128 . At the end of said pre-treatment water shall be pumped out via suction hole  160 .  
         [0049]      FIG. 3  schematically describes device  300  of the invention. Delivery device is encased in housing  200  attached to the biological component via rubber ring  206 . Piezoelectric transducer  246  is coupled to tips  238  and  238   a  via coupling horn  242 . The transducer is attached to inner wall  257 , separating between spaces  204  and  256 , via attachment unit  252  that also prevents leakage of gasses between spaces. Substance, for instance in the form of particles, is kept in reservoir  208 , from where it can be delivered via tube  212  and pump  216 , to tube  218  and tube compartment  220 . Said tube compartment  220  has hollowed area  228  and a valve  224 . At the distal end of each tip  238  and  238   a , a lattice  232  is present. The tips are partially hollowed; From lattice  232  tube  236  and  236   a  run, via tube  250  into vacuum pump  254 . During supply of substance, or at certain synchronization with supply of substance, suction activity of pump  254 , opens valve  224  to allow particles to be supplied to hollowed area  228 . Substances then are accumulated at lattice  232  and form aggregate  277 . Ultrasonic pulse will deliver particles of aggregate  277  towards and into surface  208  of biological component.  
         [0050]     System  400  of  FIG. 4  describes another non limiting example of a device. According to this embodiment, inside housing  302  attached to biological component  305  via rubber ring  304 , the accelerating element is attached at its proximal end to spring  360 . The accelerating element, composed of proximal ultrasonic transducer  320 , guiding horn  324  and tips  326  and  327 , is attached to inner wall  344  via rings  340  and  340   a , that serve also to prevent gas transfer between compartments. However, operation might be performed also when similar pressure exists in the different compartments. Certain degree of vacuum of space  331  is carried out by suction activity of vacuum pump (not shown), via tube  350  and opening  306 . Supply of substance is carried out from reservoir and pump (not shown) via tube  342 , passing wall  344  via tube  345 , via tube  346  into lattice or absorbent element  314   a  (for particles or solutions respectively) and further via tube  348  to lattice or absorbent  314 . Both  314  and  314   a , and the interconnecting tubes, are located on stab  312  kept at certain distance from surface of biological component  305 , by legs  310  and  310   a.    
         [0051]     During actuation, releasing of spring  360 , causes movement of the accelerating element in the general direction of arrow A, towards lattice/absorbent  314  and  314   a . When distal parts  330  and  330   a  having high accelerating rate, of accelerating element, touches area  314  and  314   a , substance located in said  314  and  314   a  is accelerated and delivered towards surface  305  of biological component in the general direction of schematic arrows B,C,D,B′, C′ and D′. The whole inner construction might be also circular, for instance circular shape of tip, circular shape of lattice or absorbent and so on. The impact of contact between vibrating edges  330  and  330   a , and elements  314  and  314   a  on the other hand, causes the accelerating element to move backwards with spring  360 , new substance is applied to  314  and  314   a , and the procedure is being repeated. At the end of procedure, as post-treatment, edges  330  and  330   a  can be vibrated while attached to surface  305 , thereby causing local destruction at surface  305 . It will be followed by slow release of substances, where the biological component itself serves as reservoir. Post treatment might also for instance include activation of sonosensitizers, previously delivered to biological component.  
         [0052]     It shall be appreciated, that with few modifications, the schematic device described in  FIG. 4  might be also utilized as add-on that significantly improves performance of, for instance gas spring actuated injection devices, of for instance Medi-Ject Cooperation, or Bioject, Inc., Genesis Medical Technologies, Inc., Weston Medical LimitedRymed Technologies, Mycone Dental Supply Co. Ferton Holding and the like. According to a non-limiting embodiment part of the present invention, at the front edge of piston, or gas releasing orifice, or elsewhere, a high accelerating agent such as ultrasonic element of high frequency and relatively high amplitude (preferably tenth of millimeter), or edge of ultrasonic vibrating tip, is placed to further accelerate substances, in addition to the spring or gas pressure originally used.  
         [0053]      FIG. 5  schematically describes device  500  for delivery to internal tissues. The system is composed of control unit, signal generator, amplifier, matching unit and transducer, as well as possibly increasing amplitude element such as tip, all of which are not shown. Movements created by the transducer (not shown) are transferred to the treatment device, via a wave guide  408  in the general direction described by arrow A. The wave guide is designed so its dimensions till ends  413  and  414  enable movement at resonance of distal ends  413  and  414 . Space  440  between wave-guide and wave-guide sleeve  402  is preferably under certain vacuum conditions, as will be further explained below. Tube  420  enters said wave-guide at a point which is preferably a point of minimal movement, for instance zero point. Tube  420  supply the substances from a reservoir (not shown) in the general direction of arrow B, and further via continuation tube  422  in the general direction described by arrow C. Tube  422  might be a hollowed area of a rounded wave guide, and then parts  410  and  411  actually refer to two sides of a cylinder, but it can be also a channel between two separated (and for instance flat), wave guides  410  and  411 . Supplied substances leave tube  422  via opening  426 , reaches reflecting valve  430 , and are reflected and accumulated in lattice, or sponge,  434  and  436  (for particles or liquid), which again might be two sides of a cylindrical component.  
         [0054]     Certain degree of vacuum is created by a pump (not shown). Suction of air, cellular debris or excess of substance is performed from the area between delivery device  500  and internal biological component  470 . Suction is performed via the spaces  442  and  444 , between device laparoscope-wall  406 , and wall  450  of accelerating element of the wave-guide  410  and  411 , in the general direction of schematic arrows F and G. The supply of substances might be via pushing them with a pump via tube  420 , but also by suction activity from the reservoir.  
         [0055]     During activity, while held by handle  400 , and while wall  406  serves as laparoscope guide, delivery device is inserted via surface  466  to desired location, for instance organ  470 . Certain degree of vacuum, according to the needs is performed so that at least space between elements  436  and  434  on one hand, and organ  470  essentially contains no liquid or cellular debris. Substance is delivered to be accumulated in elements  434  and  436 . Accelerating element is operated to create high amplitude repeated movement of ends  413  and  414  of the wave-guide. Substance accumulated in  436  and  434  is accelerated towards and into organ  470  in the general direction of arrows D and E. According to non-limiting example, organ  470  might be a tumor and the substance to be delivered composed of Tumor Necrosis Factor.  
         [0056]     Generally speaking, the suction activity and the accompanied reduction of air pressure, aim at increasing the isolation capabilities of the space between biological component and accelerating element, and concomitantly to reduce friction of the accelerated substance and air. It shall be noted, however that procedure can be performed also via gasses, and other media.  
         [0057]      FIG. 6  schematically describes device  600  for delivery to internal tissues. The system is composed of control unit, signal generator, amplifier, matching unit and transducer, all of which are not shown. Movements of high accelerating rate, created by the transducer (not shown) are transferred in the general direction of schematic arrow A, via wave-guide  506 . Wave guide  506 , is mechanically isolated from sleeve  510  by space  508 , containing gas or slight degree of vacuum. Similar isolation exists also between the other accelerating components, such as tip  514  or delivery distal end  522 , and laparoscope cover  540 . The tip has larger cross section in area  514 , and lower cross section closer to the distal end, at area  516 , and therefore amplitude of movement is increased under the same frequency and acceleration rate is increased. The whole device is designed for activity under resonance, so that area of maximal movement, and maximal accelerating rate, is at distal end  520  of the tip. The space between tip end and lattice wall  528  contain the substance to be delivered.  
         [0058]     At times, a device where the substance fills the wave-guide, might be used. In such case, a liquid substance medium, or gel with appropriate substance to be delivered, is the content of at least last portions of the wave guide, including for instance area  506 ,  514  and  516  and with continuity to the area between tip end  520  and lattice  528 , for instance via openings in tip end  520 . Alternatively, the wave-guide may be composed of solid material, or liquid not relevant for the delivery, and for instance only the space between  520  and  528  with said substance to be delivered.  
         [0059]     During operation, the device held in handle  500 , is inserted via surface  550  of biological component till target  552 , having laparoscope wall  540  as guiding element. During insertion, hollowed grid-like end  538  is in same line as end of wall  540 . When laparoscope wall reaches target  552 , insertion stops. At this stage, pushing of sub-handle  530 , transfer further movement of hollowed grid-like end  538 , via walls of cylinder  534 . Movement of grid-like end  538  might press a bit target  552 , but in addition it increases the distance between lattice  528  on one hand, and hollowed grid-like  538  and target  552  on the other hand. This increase of distance is performed and concomitantly, or shortly after and essentially before the increased distance is filled by liquids, waves are emitted and high acceleration is performed to affect tip end  522 . It further accelerates substance via lattice  528  which might have larger area than tip end  522 , and via hollowed grid-like end  538 , into target  552 , in the general direction of arrows B,C and D. The ultrasonic path might be also constructed in a different way, so having for instance the ultrasonic transducer in handle  500 .  
         [0060]      FIG. 7  schematically describes an example of delivery device  700 , encased in housing  600  which is attached to biological component  670  via suction rubber  680 . Control unit, generating and amplifying elements of the system are not shown. Transducer  640 , might be in housing  600 , yet might be also located elsewhere, with a wave-guide for transferring the movements to the treatment device, subject of this schematic drawing. Septum  608  separated the device to normal pressure zone  610  and low pressure zone  612 , whereas low pressure is created via suction activity employed by pump  660  via opening  668  and tube  664 . Delivered substance might be in encapsulated as upside v-shaped  630 , and brought from reservoir  614  via guiding element  614 , and motor  622 , utilizing arm  624 .  
         [0061]     During operation, mechanical signal given by the transducer, is amplified in amplitude and acceleration rate in tip  644 . Maximal, or at least optimal, acceleration rate is achieved in upside v-shaped tip end  648 . Substance  630   a , or its components, located attached to tip-end  648 , are accelerated in the general direction vectors schematically described as arrows A and B. The vectors created, are being further united and amplified in the general direction of schematic delivery vector E, through surface  670  into the biological component.  
         [0062]      FIG. 8  describes delivery device  800 , encased in housing  700  which is attached to biological component surface  781  via rubber ring  780 . Septum  710 , divides it to space  720  and space  740 , whereas space  740  is preferably having slight vacuum. The accelerating elements of the device is composed of transducer  770 , guiding tip element  774  and distal v-shaped end  776 , having the appropriate acceleration rate. Substance is in a strip form. Bulk of substance  724 , is located in sub-encasing  722 , from where strip  726  is supplied via channel  728 . At least one side of strip  726  contains the substance to be delivered. Strip is forwarded via the space between v-shaped distal end  776  and v-shaped lattice  744 , and further via channel  728   a . The supply of the strip is carried out by pulling activity, performed by motor  784  in casing  786 . It pulls the strip from reservoir  724 , as herein above described and further via tube  788  to reservoir  792  of substance depleted strip, in sub-housing  790 .  
         [0063]     During operation, strip is moving from reservoir  724  to reservoir  792 , partially along accelerating v-shaped end  776 , and substance is accelerated via openings  760  of lattice  744 , in the general direction of arrows A,B,C,D,E and F towards and into surface  781 . Operation can be performed in continuous mode, for instance continuous movement of strip together with continuous activation of accelerating element. Operation can be done also in synchronized mode, for instance movement of strip, activation of acceleration, cessation of activation, movement of strip and so on. Combined mode might be also performed.  
         [0064]     According to a non limiting embodiment, substances attached to strip are inert solid crystals. Their acceleration at certain angle and acceleration rate towards biological component, will cause during impingement energetic impact on surface of biological component and removal of sub components or layers therefrom. Said debris can be further removed, for instance by a suction activity.  
         [0065]      FIG. 9  schematically describes lateral delivery device  900 , the delivery component of delivery system. The device might be cylindrical, encased in cylindrical housing  810  having narrow leading edge  814 . The device  900  according to this non-limiting example is located in lumen  828  of tube-like biological component  824  which might be for instance be vagina or the coronary blood vessels. Leading edge  814 , which essentially is narrow then at least part of other components of the device, widened biological component while being inserted to it, and the biological component is then supported and clasped on the area between rings  818  and  820 .  
         [0066]     The accelerating element is transducer  830 , receiving the electrical signal via cable  831  to create transmission of waves and acceleration of movement. Acceleration of movement is increased via wave guide tip  834 . The general direction of propagation of stimuli is from the transducer  830 , via wave guide tip in the general direction of schematic arrow  888 , reflected from wall  836  in the general direction of schematic arrow  889  and till edge  838  having maximal amplitude and maximal acceleration rate. The surface of the device between rings  818  and  820  is composed of cylindrical lattice cover  842 , and inner to it cylindrical reservoir sheet  840  that contain the substance to be delivered. Said substance might for instance be vaccine for local immunization or the vaginal epithelium, localized immune suppression before introducing an IUD, or substance for after-widening stabilization of the coronary arteries, similar to stents, or compounds for paving the coronary arteries before implantation of stents.  
         [0067]     After the device reaches its place, certain reduction of the atmospheric pressure in space  858  is created, by suction activity via opening  854  of suction tube  852  of guiding element  850 . Stimuli is then created in the transducer, waves are emitted so that edge  838  is accelerated. The acceleration causes delivery of substance from reservoir sheet  840  via opening of lattice  842  and into biological component  824  in the general direction of schematic arrows  890  and  891 . The device might be operated also without lattice  842 , providing that a certain space can be kept between reservoir  840  and biological component  824 . Said space shall preferably be composed of low density medium.  
         [0068]     At times, the delivery device might be operated in such synchronization that substances delivered in a circular way, for instance in direction of arrow  890 , will get harder after delivery for the creation of a solid ring for mechanical support. That way several rings, with possible supportive linking elements, or any other shape performed according to the lattice design and construction, might be created for establishing for instance a new type of in-situ constructed stent for the stabilization of coronary blood vessels, urethra and other vessels.  
         [0069]     During operation, or in synchronic manner, the accelerating device is pulled backwards where transducer  830  is guided along inner wall  856  of guiding element  850 . That way each time is affects and delivers substance from another area of reservoir sheet  840 . According to non limiting embodiment, the transducer is located outside the delivery device, closer to the other system component such as signal generator, control panel or suction pump, and only appropriate wave guide is located in the device to create the delivery.  
         [0070]     It shall be appreciated that also here same device can be used initially to remove portion of tissue, suction for removal of debris, and subsequently the delivery of for instance substances for mechanical support such as for coronary stent or for immunization and the like. The control unit can for example monitor and determine gas pressure in the delivery device, amplitude of vibration, frequency, pulse duration, duty cycle of emitted waves, movement of accelerating element in relation to the biological component or to the supplied substance, rate of supplying the substance and other parameters that might be relevant.  
         [0071]     The description and drawings were given for illustrative and non limiting purposes only. The invention embraces any and all modifications, alternatives or rearrangements of the method and device as defined by the claims, including the use of method and device for non-biological components.