IL294690A - Ultra-wideband micromechanical method for modulation cellular activity - Google Patents

Description

(?MEW OFFICE 12.07.22 RECEIVED הטיש תינבמורקימ ספ-הבחר-הרטלוא היצלודומל לש תוליעפ תירלולס ULTRA-WIDEBAND MICROMECHANICAL METHOD FOR MODULATION CELLULAR ACTIVITY Inventors: Aleksandr Marchenko Rabbi Yehuda Ha'nasi Str. 8, Apt. 114Haifa 3542803, Israel Audrius Miciukevicius c. Imeldo Seris 62, Piso 2,Santa Cruz de Tenerife, 38003, Spain ULTRA-WIDEBAND MICROMECHANICAL METHOD FOR MODULATION CELLULAR ACTIVITY TECHNICAL FIELD The present invention relates to ultra-wideband micromechanical methods of impact, in particular to non-invasive ultra-wideband micromechanical bursts used in research, technological, biological, medical and cosmetic equipment to affect diseased, damaged or altered, including aged or infected, somatic cells and biological tissues in order to enhance and speed up the processes their regeneration and recovery. DEFINITIONS For the purpose of this invention, the following terms employed herein and in the appended claims refer to the following concepts:"Micro-energy modulation impact" - the impact in the treatment area of ultra-wideband micro-energy micromechanical signals with a maximum peak energy of 0.03-0.1 mJ / mm2, and a spatial-peak temporal average intensity of less than hundreds of microwatts per square millimeter [1]."Inducedstem cells" - undifferentiated pluripotent or progenitor stem cells obtained from somatic cells by their reprogramming;"Regenerative Impact" - restoration of diseased or damaged tissues and organs of a biological object using pluripotent and progenitor stem cells, activated, transplanted or transformed [2]; "Regenerative cosmetology" - a technology for rejuvenating (revitalizing) aging skin by activation or transplantation of stem cells, or induced transformation of somatic and progenitor cells into stem cells [3];"Ultra-wideband (UWB) system and signals"- the fractional bandwidth ף and the frequency band ratio b, of signals which correspond to the following values: fh-fi br-1 n = 2 --------- = 2 --------- > 0,2 fh + fi br +l(1), where fh and fi are the upper and lower frequencies of the spectrum of signal at the level - dB, br is the ratio: fh 2+ q br = --------- = --------- > 1,22 f! 2-n (2).

In accordance with the Standards [4-10]and scientific research [11-12]: Fractional Bandwidth ף Band Ratio b rNarrowband 0,00 < ף S 0,01; 1,00 < b r < 1,01, Wideband 0,01 < qs 0,2 1,01 < b r < 1,22 Ultra-wideband 0,2 < q < 2,00 1,22 < b r < ~ "Ultra-wideband Micromechanical Impact Burst (UMI Burst) "- propagating in medium detached ultra-wideband micro-mechanical disturbance of the medium, which differs in spectral and spatial characteristics from known narrowband and wideband ultrasound;"Ispta - narrowband signal intensity" - spatial-peak temporal-average intensity of narrowband signal or the sum of narrowband signals, averaged over the cross section of the ultrasonic beam, impulse rate and overtime."Isptaf intensity of wideband and ultra-wideband signals intensity, in particular, ultra- wideband micro-mechanical impact bursts (UMI Bursts)" - the intensity averaged over cross- section of the burst radiating beam, as well as overtime, impulse rate and over burst spectrum."Vibration modes of an electromechanical transducer" - a set of natural or forced vibrations of a transducer with different physical characteristics, for example: resonance modes - radial R, edge E, angular A, volume V, as well as planar ultra-wideband P - mode - vibration of the surface layer of the transducer; REFERENCES CITED 1. Yegang Chen et al. Role and Mechanism of Micro-energy Treatment in Regenerative Medicine. Translational Andrology and Urology. Feb. 08, 2020 doiorg/10.21037/tau.2020.02.25.2. A. Atala (editor) et al. Principles of Regenerative Medicine, Academic Press, 2019,14pages.3. Sucharita Boddu et al. Regenerative Medicine in Cosmetic Dermatology. Review. Cutis. 2018 Jan; 101(1): 33-36.4. OSD/DARPA, Ultra-Wideband Radar Review Panel, "Arlington, VA, Defense Advanced Research Project Agency (DARPA), 1990.5. US Federal Communication Commission (FCC), Part 15, October 2003, . http://www.fcc.gov/oct/info/rules6. EC 2009 Commission of the European communities Decision 2007/131/EC April 2009.7. International Electrotechnical Commission (IEC), Basic EMC Publication 6100-2-13: "Environment-High-power Electromagnetic (HPEM) Environment-Radiated Conducted". American National Standards Institute (ANSI) ANSIC63.14-1998, American National Standards 8. Dictionary for Technologies of Electromagnetic Compatibility (EMC), Electromagnetic Pulse (EMP), and Electromagnetic Discharge (ESD), October 1998.9. Manual of Regulations and Procedures for Federal Ratio Frequency Management National Telecommunication and Information Administration. Report of May 2003 (rev. September 2004).10. Institute of Electrical and Electronics Engineers (IEEE), IEEE Std 6861997, IEEE Standard Radar Definitions, 16 September 1997.11. Oyan, MJ. et al. "Ultrasound Gates Step Frequency Ground-Penetrating Radar". Geoscience and Remote Sensing, IEEE Transactions, vol. 50, No. 1, pp. 212-22, Jan. 201212. F. Sabath et al. "Definition and Classification of Ultra-Wideband Signals and Devices".Radio Science Bulletin (2005), No 313 pp. 12-20.

BACKGROUND OF THE INVENTION 1. Description of Related Art In regenerative impact, the restoration of degraded, diseased or damaged biological tissues is carried out by transplantation of exogenous stem cells (SC) and activation of endogenous SC [131■ Stem cells originate from two main "sources": tissues of an adult organism and embryos. Scientists are also working on ways to obtain stem cells from other cells using-reprogramming techniques.The sources of exogenous SC for transplantation are embryos, umbilical cord blood, bone marrow and adipose tissue. SC transplantation is widely used, despite the immunogenicity and oncogenicity of exogenous SC (14], SCsarefound in many tissues ofthe body, including the brain, bone marrow, blood and blood vessels, skeletal muscles, skin, and liver. It has been established that such and similar resident endogenous SCs, due to the home effect, can be accumulated in the treatment area and accelerate the regeneration process [15],In regenerative impact-treatment, autologous extracorporeal pluripotent SCs are often used, isolated, for example, from the adipose tissue of the body. They are propagated in an artificial nutrient medium and returned to the body . Disadvantages of the technology for extracorporeal cultivation of autologous SCs are their high cost, incomplete compatibility with resident cells, carcinogenicity arising from accumulated differences in the process of cell reproduction, and the presence of biochemical growth factors necessary for the growing process. It is safest to use your own non-multiplied SCs. They are obtained either from the-bones in the body marrow or with the help of drugs that displace SC into the blood. Using this technology, it is possible to obtain only a small amount of SC [16],In 2006-2012, Yamanaki Shinya and co-author showed [17-18] (John B. Gordon, Shinya Yamanaka. The Nobel Prize in Physiology or Medicine 2012) that in principle, an induced transformation (reprogramming) of any adult somatic cell into a pluripotent young stem cell is possible, and, in the future, its transformation into any specialized cell. Reprogramming took place in the cell culture due to the "cocktail" ofYamanaki-a set of four modified genes implanted into the genome of somatic cell generations of proliferating cells. The long-term consequences of such a transformation for the organism are still insufficiently understood. In addition, the extracorporeal production of modified cells using the Yamanaka technology is still very expensive.Later it was found that somatic cells can be reprogrammed in SC not only biochemically, but also physically. Strong, on the verge of cell death, compression or stretching of adult cells leads to their massive transformation into SC [19], Moreover, the impact of even weak mechanical signals acting on the extracellular matrix also leads to reprogramming, i.e., transformation of a part of cells into SC [20-21], Weak mechanical signals can trigger many chains of informational and biochemical transformations like an avalanche [22], A new scientific discipline called "mechanobiology" has appeared, aimed at studying the control of the properties of cells and tissues under the influence of mechanical forces.Specialists in mechanobiology have established [23-27]: -generation and transmission of mechanical signals occurs at all levels ofthe cell structures. The cell nucleus, including DNA and chromosomes, are sensitive mechanosensors. Mechanical informational signals come from the environment of cells into the intracellular cytoskeleton and along the filaments further into the nucleus. Deformation and conformal transformations of intranuclear structures are triggered, and changes in gene regulation and configuration of epigens are initiated. Mechanical signals in cells control numerous processes, including transformation of the epigenome and migration of methylating markers. Cells also exchange mechanical signals when their membranes are in contact [28].It is obvious that external mechanical signals, similar to the signals of the cells themselves, can effectively influence the processes of their vital activity and transformation. Scientists became interested in the possibility of reprogramming cells by excitation a special type of mechanical vibration - ultrasound [29].The advantage of ultrasound is the non-invasive introduction of therapeutic signals into the body, therefore, changes in cells and tissues occur in their natural environment. There are no chemical factors for reprogramming, which dramatically reduces the risk of developing tumors and immune rejection of "foreign" cells.The new type of ultrasound is needed, in which the mechanobiological effect prevails and are excluded the thermal, acoustochemical, acoustoelectric effects inherent in conventional impact-therapeutic ultrasound.This type of ultrasound was proposed by Duarte L.R. back in 1985 (US 4530360 [30]). To date, in low-intensity ultrasound treatment, narrow-band amplitude-modulated harmonic ultrasound is mainly used with an Intensity of less than 200.0 mW/cm 2, most often 1.0-30.mW/cm 2, with a frequency about of 1.5 MHz. The duration of each ultrasonic pulse is 200 ps, the duty cycle is 0.2. Impact-treatment with such impacted signals came to be called Low Intensity Pulsed Ultrasound Impact (LIPUS).Broadband rate q of LIPUS signals is q < 0.2.

In 1999, Duarte L.R. (US 5904659 [31]) significantly expanded the boundaries of the operating frequencies of signals. The carrier frequency is proposed in the range of 20,0 kHz -10,MHz, the frequency of the modulating signal is from 5.0 Hz to 10.0 kHz, the Ispta intensity (spatial peak temporal average acoustic intensity) is less than 0.1 W/cm 2 (100 mW/cm 2). Broadband rate ף is 0.2 > ון.Already the first clinical applications of LIPUS have shown its effectiveness in the treatment of bone fractures, especially poorly healing ones, as well as in accelerating the healing of soft tissue injuries.It has been clinically shown that LIPUS is a non-invasive method for stimulating tissue and cell bioactivity [32], In US20060241522A1 Chandraratna H. !33] describes a method of therapeutictreatment for ischemia and other cardiovascular disorders. The application of low-intensity ultrasound with frequencies in the range of 40.0 KHz-8.0 MHz, mainly 1.6-4.0 MHz, with an intensity not higher than the intensity of diagnostic ultrasound is claimed.The use of LIPUS in dentistry has proven to be effective. Bone tissue regeneration, treatment of periodontal disease, and acceleration of implantation are clinically indicated [34], Several years ago, the possibility of LIPUS treatment of skin tumors was shown, in particular, basal cell carcinoma, squamous cell carcinoma and melanoma (WO 2015077006, Boer Miriam Sara et al. [35]). Ultrasound was used with frequencies of 27.0 kHz and 2.2 MHz, and intensity in the focal zone of 0.17 W/cm 2 and 5.0 W/cm 2, i.e., LIPUS was combined with low frequency ultrasound.In the invention US 20160067526 [36] there is proposed the use of LIPUS for the treatment and /or prevention of neurodegenerative diseases. A focusing ultrasonic transducer with an operating frequency of 1.0 MHz, which emits pulses with a duration of 50 ms and a duty cycle of 0.05 was used. The intensity of Ispta ultrasound at the surface of the transducer was 1mW/cm 2, and at the focus 528 mW/cm 2. It is stated that ultrasound can be with frequencies from 20.0 kHz to 16.0 MHz, and intensities from 1.0 mW/cm 2 to 1.0 W/cm 2.In US20060241522A1, Chandraratna H. [37], it was shown that LIPUS can also be used for the regeneration of peripheral nerves.Shields in US20070249938 [38] used LIPUS two-frequency sequences for living tissue treatment.

A modification of LIPUS with an intensity increased to 400 mW/cm 2 was proposed by Min et al. for the treatment of edema (US 20100204618 Al [39]). Muckle J. et al in 2010 patented the use of LIPUS for the treatment of connective tissue pathologies, and hence diseases of the musculoskeletal system [40], In 2010, Schwartz D. in patent US2010152626 Al proposes ultrasound treatment of glaucoma [42], Zhou J. et al in 2018 showed that LIPUS protects retinal ganglion cells and reduces the consequences of their injury [42], In 2013, EP Global Communications Inc. (USA) announced advanced technology and device for macular degeneration and retinitis pigmentosa by emitting low intensity ultrasound into the eye for the purpose of regeneration of damaged cells and to possibly stopping the degeneration of existing healthy cells within the macula and the entire retina [43], In 2018 it was found by Zhou L.X. et al. [44], that low-intensity pulsed ultrasound protects retinal ganglion cells from damage to the optic nerve, which can stop the development of glaucoma.The list of the above-mentioned diseases and pathological stages for which LIPUS is effective coincides with the diseases for which stem cell treatment is used [13], Therefore, it is generally accepted that LIPUS, in contrast to classical treatment ultrasound, is a non-invasive method of stem cell mechanotherapy in general and regenerative treatment in particular [25,26, 28], At the same time, despite the significant potential of LIPUS as a unique treatment factor, and for more than 30 years of research, so far in clinics it is used only to accelerate the healing of bones and soft tissues and accelerate the implantation of dental implants.The reason for the limited use of LIPUS is the low efficiency of the treatment of diseases. The main physical characteristics of LIPUS signals - vibration frequency, pulse duration, duty cycle and time of their exposure do not differ from classical treatment ultrasound. Only tens and hundreds of times the intensity of treatment signals were reduced, which, along with a large duty cycle, made it possible to avoid their power manifestations - heating, cavitation, acousto- chemical and acoustoelectric effects, which previously masked the manifestations of the effects of low-intensity signals.

There were many attempts, which have been made to improve the effectiveness of treatment with low-intensity ultrasound signals.In US 5460595 [45] it was proposed by Hall et al. the using of several operating frequencies of classical ultrasound to control the depth of exposure and improve treatment results.Kruglikov I. in DE102011115906A1, 2013, [46] also proposes two or more operating frequencies, which were continuously switched between each other (LDM - Local Dynamic Massage). At the same time, the range of operating frequencies of ultrasound to 16 MHz was expanded.Vortman, K. in WO 2014135987 A2 [47] proposes to optimize the frequency of ultrasound depending on the type of tissue and the depth of the treatment effect.Barthe P. et al. in US 8460193 B2 [48] describe the system and method of ultra-high- frequency ultrasound treatment, considering it possible to increase the frequency of the treatment signal to 500 MHz to emit it deep into the tissues, the authors proposed a "semi- invasive" introduction using a needle emitter.To date, preclinical experiments have shown that LIPUS:- significantly improves the condition of animals after treatment with chronic myocardial ischemia;- improves the condition after acute heart attacks;- prevents muscle wasting caused by diabetes;- improves cognitive functions of the brain while simulating dementia and Alzheimer's disease;- inhibits the proliferation of breast cancer cells and osteosarcoma;- enhances the growth of osteoblasts and fibroblasts;- strengthens cellular immunity;- accelerates the regeneration of peripheral nerves;- reduces and prevents cerebral ischemia and vascular damage in experimental stroke;- forms new blood vessels and stimulates cellular regeneration in the brain; - improves erectile function;- accelerates osteo-integration of orthopedic implants;- accelerates the healing of bone fractures and wounds.These diseases are more effectively treated with autologous stem cell injections.

William Tyler radically improved the LIPUS method of treating many diseases, mainly neurological. Starting from the year 2010 [49]and up to the present time [50-77],many modes of operation and parameters of LIPUS ultrasound have been proposed, firstly in the frequency range from 0.02 to 1.0 MHz, and later to 100 MHz, and Ispta intensity from 0.0001 to about 9mW/cm 2. Different treatment waveforms are applied, such as harmonic signals, and/or any repetitive impulses or their combinations, such as the stimulus waveforms containing one or many ultrasonic frequencies. Periodically repeating waveforms as a single or plurality pulses are also possible. Each impulse includes from 1 to 50,000 acoustic cycles, repeating with frequencies from 0.001 to 100 kHz, that is, it is emitted in the form of a comb spectrum.In other words, W. Tyler proposes a low-intensity ultrasound treatment using one modulated harmonic signal or using multiple signals or using multiple comb signals, or combinations thereof. It is obvious that any finite set of harmonic W. Tyler signals is always narrowband, and, therefore, the broadband ratio 0,2 > ף.W. Tylor uses a patented variety of signaling variants to modulate cellular activity, including nerves and other cells in the human body, namely for changes in:- ion activity;- ion transporter activity;- secreting of signaling molecules;- proliferation of the cells;- differentiating of the cells;- protein transcription of the cells;- protein translation of the cells;- phosphorylation of the cells;- protein structures in the cells or - a combination thereof.Change in cellular activity leads to a change in the physiological and pathological conditions of organs and tissues and treats the following, but not only: Parkinson's disease, Alzheimer's disease, coma, epilepsy, stroke, depression, schizophrenia, neurogenic pain, cognitive / memory dysfunction, diabetics, traumatic brain injury, spinal / cord injuries, migraine, epilepsy.The clinical efficiency of W. Tyler signaling treatment is currently being studied. We are not yet aware of commercially available devices based on patents [49-77] or FDA approval for their use. Considering the absence of fundamental differences between Tyler W. signals from the well-studied and approved for clinical use signals from Duarte L., it can be expected that there are ways to further improvement of the efficiency of low intensity ultrasound.The physical reason for the low clinical efficiency of LIPUS is the discrepancy between the parameters of the ultrasound signal intended to affect cells with those signals that are adequate to the own micromechanical signals of the nuclei of cells, cells and tissues.It is known that the amount of information that can be transmitted from a source to a receiver is proportional to the spectral bandwidth of the signal and the dynamic range of the signal. When passing from several or from a finite set of narrow-band harmonic signals to a continuous band, that is an infinite number of frequencies, it is possibletotransmit a much larger amount of information with better noise immunity. For this reason, at the end of the 70s of the last century, ultra-wideband technology for communications and radars appeared which dramatically improved devices the technical characteristics of the devices [78-79].There have been created radars with the ability to see under ground and through the walls of buildings [11], and noise-immune communication facilities.The miniature radars began to be used in medicine for remote monitoring of respiration and heartbeat of patients (Me Ewan T., US5573012 [80]).Ultra-wideband equipment has appeared for monitoring vital functions of the human body, as well as equipment for cardiological, pneumological and obstetric remote visualization [81].Mahfouz M. et al. in 2011 described a surgical navigation ultra-wideband system for orthopedics [82], To date, the development of ultra-wideband radio-frequency systems for imaging and diagnostics of internal organs is being completed [83], There is known use of ultra-wideband ultrasound in medicine for the purpose of internal organs diagnosing. In ultrasound diagnostics, devices with a frequency band of 3,0-15,0 MHz are already used. Devices with a limiting operating frequency above of 30,0 MHz are under development [84], In [85] it is shown that very short ultra-wideband ultrasonic diagnostic signals in the form of Gaussian monocycles can propagate in biological tissues with attenuation less than mono frequency, which opens up the prospect of further increasing the upper limit of the operating frequencies of ultrasonic medical equipment. 2. The Prior Art Ultra-wideband medical devices began to be developed since 1981 by the author of the present invention, A. Marchenko, after the creation by him broadband (later ultra-wideband) ultrasonic multimode transducers with a transducing efficiency comparable to mono frequency ones (Marchenko A. et al, [86-89]). On their basis, ultra-wideband impact and cosmetology ultrasound devices were created: RU2066215C1, Marchenko A. et al, 1996 [90]and RU2058167C1, Marchenko A. et al., 1996 [91], In 2014, based on the aforementioned multimode transducers, Tereschenko N. et al. patented (Patent UA 91162) an ultra-wideband ultrasound treatment system [92]known for all of us as ultra-wideband impact devices using a band of ultrasonic frequencies from about 1.0 to about 5.0 MHz in the form of frequency-varying harmonic signals or stochastic continuous signals. The ultrasound intensity from 0.1 to 0.6 W/cm 2 was chosen.Limited clinical trials carried out jointly with the author of ultra-wideband technology Marchenko A. at the Kyiv Otorhinolaryngology Institute showed significantly better results in the treatment of chronic tonsillitis compared to classical therapeutic ultrasound [93-94].

Thus, it can be concluded that there are scientific, technical and technological prerequisites for the creation of new ultrasonic/micromechanical signals and devices that provide a stronger and faster course of regenerative processes.12 REFERENCES CITED TO BACKGROUND OF THE INVENTION 13. Nassim Rajabzadeh et al. Stem cell-based regenerative medicine. Stem Cell Investigation. 2019; 6.181 http://dx.doi.Org/10.2.1037/sci.2019.06.04 14. Reisman, M.; Adams, K.T. Stem cell therapy: A look at current research, regulations, and remaining hurdles. PTA Peer Rev. J. Formul Manag 2014, 39, 846-857. 15. De Lucas, B.; Perez, L.M.; Galvez, B.G. Importance and regulation of adult stem cell migration. J. Cell. Mol. Med. 2018, 22, 746-754.16. Fluri D.A. et al. Derivation, expansion and differentiation of induced pluripotent stem cells in continuous suspension cultures. Nat Methods. 2012; 9: 509-516. 17. Takahashi K. Yamanaka S. Induction of Pluripotent Stem Cells from Mouse Embrionic and Adult Fibroblast Cultures by Defined Factors// Cell. -2006, V.126, No 4, pp. 663-676. 18. John B. Gordon, Shinya Yamanaka. The Nobel Prize in Physiology or Medicine 2012. 19. Caizzo M. et al. Generation of Induced Pluripotent Stem Cells in Defined Three-Dimensional Hydrogels. Method Mol. Biol. 2017; 1612:65-78. Doi 10.1007/978-l-4939-7021-6_5.20. Shin J.W, Mooney O.J. Improving Stem Cell Therapeutics with Mechanobiology. In Cell Stem Cell, 2016, Jan. 7,18 (1): 16-19. Doi 10.1016/ j stem 2015.12.007. 21. Lim J. M. et al. Somatic cell transformation into stem cell-like cells induced by different microenvironments. Published online, Sept.2013, . https://doi.org/10.4161/org.26202 22. Haruko Obokata, Charles A. Vacanti et al. Stimulus-Triggered Fate Conversion of Somatic Cells into Pluripotency. 2014. Nature, volume 505, p. 641-647. 23. Sun Y. et al. Mechanics regulates fate decisions of human embryonic stem cells. PL0S one 2012. 7: 637178. 24. Emad Moeendarbary et al. Cell Mechanics: Principles, Practices and Prospects. WIRES Syst Biol Med 2014, 6: 371-3888. Doi: 1002/wsbm.l275. 25. Chenyu Huang et al. Mechanotherapy: Revisiting Physical Therapy and Recruiting Mechanobiology for a New Era in Medicine. Trends Mol Med 2013 September; 19 (9) ,555-564.26. G.V. Shivashankar. Mechanics and Genome Regulation. Academ Press, 2019, 200 p. 27. Kirby TJ. and Lammerding. Emerging Views of the Nucleus as a Cellular Mechanosensor. Nat. Cell. Biol. 2018.20: 373-381. . https://doi.org/10.1038/s-41556-018-0038-y 28. G.V. Shivashankar. Mechanical regulation of genome architecture and cell-fate decisions. Current Opin. Cell Biol.,56, 115-121 (2019). (Singapore). 29. Beatriz de Lucas et al. Ultrasound Therapy: Experiences and Perspectives for Regenerative Medicine. Genes 2020,11m 1086; doi:10.3390/genes 11091086. 30. US 4530360.Duarte L.R. Method for healing bone fractures with ultrasound, 1985. 31. US 5904659. 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SUMMARY OF THE INVENTION The method according to the present invention consists in applying ultra-wideband micromechanical impact bursts (UMI Bursts) for amplification and acceleration of regenerative processes in a human body to all levels of hierarchy of the tissue structures, having dimensions from about 104 mm to about 1.5 mm.In the method, according to the present invention, micromechanical energy is non- invasively transferred to mechanosensitive elements of pathologically altered tissues and adjacent healthy tissues located next to them, in the form of ultra-wideband micromechanical bursts each of which is formed by at least two signals with different complementary spectra.The method according to the present invention includes the use of UMI Bursts, the spectra of which contain an infinite number of frequencies in at least one ultra-wideband frequency range, and have wideband rate of 0.2 them is improved. There is an intensification and acceleration of the processes of physiological and reparative regeneration of degraded, diseased old or damaged tissues of human organs.

The method of non-invasive regenerative ultra-wideband burst (Burst Impact) includes: - generation in one or more ultra-wideband ranges complementary of the main and at least one corrective electrical signal with a broadband rate 0.2<ף;- correction of the spectrum of the main signal by summing with the spectrum of the corrective signal;- ultra-wideband transducing of the corrected electrical signal into an impact UMI Burst;- non-invasive input of UMI Bursts into cells and tissues of the pathology area and surrounding tissues;- transferring the energy of UMI Bursts to a plurality of mechanosensitive elements of the cellular hierarchy resonating at a variety of frequencies to improve the exchange of micromechanical signals between cells and within cells;- strengthening, acceleration and synergy of many processes in tissues and cells aimed at their regeneration;- repeated exposure to bursts for 5-40 days and the accumulation of regeneration factors in pathologically altered, damaged and surrounding tissues to obtain a treatment effect in the regenerative treatment of many pathologies and diseases.According to the basic embodiment of the present method, the main UMI Burst has a first frequency range with the first shape of the frequency spectrum and first intensity, which mainly exerts stress on tissues and intercellular matrix of the treatment area. At the same time at least one second UMI Burst has at least a second shape of the frequency spectrum and second intensity, that when exposed to cells and the intracellular media mainly stimulates the processes of reprogramming, direct reprogramming, differentiation, proliferation, and cell replacement in the treatment area.According to the basic embodiment of the present method, the first UMI Burst is generated at least in the first frequency range, for example, 1,0-10,0 MHz, with a frequency, space and time-averaged intensity in the treatment area of 1,0-300,0 mW/cm 2.This first UMI Burst has a repetition rate of 0.05 -100,0 kHz.19 At least the second UMT Burst is generated in the second frequency range, for example, 10,0 - 50,0 MHz, with an intensity averaged over frequency, space and time in the treatment area is between 0.0001 -300,0 mW/cm 2. This at least the second impact UMI Burst is repeated at a frequency of 0.05-103 kHz.

At least the third UMI Burst is formed in the third frequency range of 50,0-250,0 MHz, and have a frequency, space and time averaged intensity of burst on the body surface of 0,0001- 100,0 MW/cm 2 and into the treatment area of 0.0001-30,0 mW/cm 2. This at least the third UMI Burst has a repetition rate of 0.05-103 kHz.

According to the other embodiment of the present method, the burst frequency spectra shapes of the main generators are selected from shock signals, stress signals as well as from frequency spectra of rectangular, triangular, trapezoidal signals, or their differentials, and/or Frequency spectra of arbitrary signals or their combinations.The frequency spectra of the correction signals of the generators are selected from the differentials of the main signals and/or low-cycle sinusoidal signals, damped sinusoidal signals, damped Sine signals, as well as from Gaussian monocycles and from other known and arbitrary spectra of low-cycle signals or their combinations.According to still other embodiments of the present method, the UMI Bursts have pulse durations of 5.0-100.0 ns or less.According to the still other embodiment of the present method, the sequence of the UMI Bursts is incoherent.According to still other another embodiment of the present method, the sequence of the UMI Bursts is coherent.According to the basic embodiment of the present method, the converting of electrical impulses into ultra-wideband micro-mechanical impact bursts (UMI Bursts) are performed by more than one UWB transducer, coupled to the UWB acoustically transparent protector.

According to the still other embodiment of the present method, the UMI Burst stimulation of the treatment area and surrounding tissues is performed by a multi-element UWB transducer that generates the micromechanical field, which converging, diverging or dynamically changing in space and/or time.Accordingto the still other embodiment of the present method, the UMI Bursts are applied to the body surface through acoustically transparent and acoustically coupled to each other intermediate medium, such as UWB protector, and UWB contact layer or an extended UWB medium placed between the protector and the body surface.According to the still other embodiment of the proposed method, the forms/parameters of the frequency spectra of UMI Bursts, as well as the treatment procedure, control remotely, including photo and video recording of the procedure, its Internet transmission and documentation.Accordingto still other embodiment of the present method, the UMI Bursts are introduced into the treatment area through eye conjunctival surface.According to still other embodiments of the present method, the impact can be interventional and comprise inserting the UMI Bursts into body entity openings, such as nasal cavity, oral cavity, esophagus, rectum, vagina.According of the present method, the UMI Bursts are used in regenerative treatment to treat diseases selected from the group, including at least a stroke, myocardial infarction, ischemia, spinal cord injury, Alzheimer's and Parkinson's diseases, diabetes, some types of cancers, atherosclerosis, varicose, post-traumatic and post-burn scars and wounds.According to the embodiments of the present method, the UMI Bursts are used in regenerative ophthalmology to reduce vision loss, including vision loss due to degradation of the optic nerve or glaucoma.According to the embodiments of the present method, treating UMI Bursts are used in regenerative cosmetology to treat diseases and pathologically altered skin selected from the group, including the signs of skin aging, reduction of scars, acne, wrinkles, post-traumatic and post-surgical seals, melasma, swelling, ptosis.

According to the embodiments of the invention, UMI Burst treatment can be used in combination with ultra-wideband electromagnetic signals, including gigahertz ultra-wideband pulsed radio signals.The foregoing and other features of the present invention are more fully described below and specifically pointed out in the claims, whereas the following description detailing only one illustrative embodiment of the invention, but also indicating only some of the different directions in which the principles of the present invention may be employed.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1. shows the block diagram that illustrates method of ultra-wideband micromechanical regenerative-impact (UMI Burst Impact);FIG. 2. shows the example of formation of a treating UMI Burst, with increasing shape of frequency spectrum by correcting the shape of spectrum of the main signal burst; FIG. 3. shows the block diagram of a 3D system for measuring the spatial and spectral characteristics of UWB ultrasonic/micromechanical fields;FIG. 4. Illustrates the dependence of the intensity averaged over space, time and frequency of ultra-wideband micromechanical impulses with a frequency range of 1.0 - 7.0 MHz on the distance to the transducer, in comparison with narrow-band ultrasonic signals of 1.0, 3.and 5.0 MHz frequencies, and also with ultra-wideband stochastic ultrasonic noise signal with a frequency band of 1.0 - 3.0 MHz. FIG. 5. Illustrates the differences in the impact of ultra-wideband micromechanical bursts (UMI Bursts) with a frequency spectrum range of 1.0-7.0 MHz on the proliferation rate of normal mouse fibroblast cells, in comparison with exposure to narrow-band ultrasound with frequencies of 1.0 MHz, 3.0 MHz and 7.0 MHz.FIG. 6. shows the differences in blast transformation (immune activity) of human T- lymphocytes in normal conditions, compared to LIPUS and UMI Burst exposures.

FIG. 7. shows the differences in dynamics of healing of extensive linear wounds of mice in normal and under LIPUS and UMI Burst influences. FIG. 8. shows a variant of the implementation of a UMI Burst method for reducing an old, rough, extensive scar on the man's face. FIG. 9. showsa variant of the implementation of a UMI Burst method for drastic reduction of long-term dermal hyperpigmentation (dermal melasma) on the on a woman's face and for reduction of deep forehead wrinkles. FIG. 10. Avariant of the implementation of the UMI Burst method in cosmetology is shown. Reduction of deep creases of the skin on the face with quantitative control of the size of creases using the Altera 3D apparatus. FIG. 11. Illustrates the implementation of the proposed UMI Burst method for restoring blood microcirculation in the area of the lower limb with varicose veins.

DETAILED DESCRIPTION Regenerative restoration of cells and tissues occurs at different levels of cellular organization - molecular, ultrastructural, cellular and tissue [13], Cellular regeneration is characteristic for the hematopoietic system, skin epithelium, mucous membranes, connective tissue and bones. Such regeneration occurs due to division and subsequent maturation and renewal of cells. There are two phases of cell regeneration - cell proliferation and differentiation.The combination of cellular and intracellular regeneration occurs mainly during the restoration of the lungs, liver, kidneys, pancreas, endocrine glands, central nervous system.Intracellular regeneration - renewal and restoration of cells - prevails in the processes in the myocardium, skeletal muscles and nervous cells.At the tissue level, in the process of regeneration, the extracellular matrix is renewed, as well as disseminated resident and accumulated pluripotent, and progenitor somatic stem cells are attracted to the treatment area. The stem cells delivered by the blood flow (Homing effect) is involved in the regeneration process.

New cells necessary for regeneration are located in cell niches that are freed from old, diseased and infected cells due to apoptosis - genetically programmed and regulated death by their self-separation into parts that are detected and eliminated by the immune system.All levels of regeneration are characterized by biochemical regeneration, that is, the renewal of the molecular composition of all organs and tissues of the body without exception.

The basis of regenerative processes is the activity of stem cells of different degrees of differentiation, which in the process of regeneration go through the stages of proliferation, differentiation (maturation), reprogramming (obtaining stem cells from any somatic cells), direct reprogramming (dedifferentiation and transformation into a specialized cell without passing through stage of young stem cells) [95].At the tissue level, the processes of formation of new functional areas of tissues, vessels and micro vessels are added and formation of tissue innervation systems and numerous receptors. Numerous biochemical regeneration factors are also involved in regenerative processes.For effective influence on the processes of regeneration, and consequently on a treatment, it is necessary to apply therapeutic factors on many levels of cellular and tissue organization.Known external and internal factors for increasing the efficiency of regeneration, such as biochemical, physical or the introduction of alien or autologous multiplied stem cells into the treatment area, only partially solve the problem of accelerating and enhancing the processes, as well as increasing the effectiveness of safe regenerative therapy.In nowadays, the key role of mechanical / micromechanical signals in controlling the vital processes of intracellular structures, cells and tissues has been established [20-28],The present invention solves the problem of creating micromechanical impact signals capable of stimulating and enhancing regenerative processes at the tissue, cellular and intracellular levels, and a synergistic increase in the effectiveness of non-invasive regenerative therapy.The present invention is implemented into practice with an apparatus having at least one UWB signals generator and at least one UWB signals corrector, as well as one UWB transducer of 24 electrical signals into micromechanical bursts. In addition, the present invention can be implemented by an apparatus having two or more UWB generators, as well as UWB signal correctors and UWB transducers.

Mechanobiology studies show cells and tissues act, sense, decipher and regulate mechanical forces [95]. The effect on tissues and cells of constant or slowly changing forces, as well as mechanical vibrations/ultrasound in detail has been studied [96-101], The action of impulsive mechanical forces, such as shock or stress waves, as well as a special type of low- intensity perturbations of an elastic medium - micromechanical effects (see Definitions) has been intensively studied.The main events that occur when mechanical forces interact with tissues and cells are mechanosensitivity, or the ability of cells and tissues to perceive mechanical forces, and mechanotransduction, or the ability of tissues and cells to convert external mechanical signals into biochemical ones in order to stimulate certain tissue and cellular functions that can change their architecture and properties.

The theoretical explanation of mechanobiology is based on the discovery that the extra- and intracellular skeletons of cells act as a dynamic transducer of external forces, concentrating mechanical disturbances and transmitting them to other molecular components outside and inside the cells.This model of transducing is based on the concept of "tensegrity" - the connection of elements of the extracellular matrix, cytoskeleton and cell structures by tension.Many oscillatory systems with many natural resonant frequencies that transmit and receive micromechanical disturbances to the structures of tissues and cells are formed. [100,101] Each resonant system transmits mechanical signals to higher levels of tissue and cellular organization fortheir conversion into biochemical ones, to activate certain gene programs and trigger cellular responses.Mechanical signals propagate through tissue cells through intercellular interactions, which are regulated by special protein complexes, including epithelial cells, endothelial cells, and non-epithelial cells. Their combination coordinates wound healing, tissue remodeling, and morphogenetic development [20-28]. Through the extracellular matrix, mechanical signals control cell adhesion, cell shape and migration, and the activation of downstream signaling pathways to control gene expression, proliferation, and cell fate (species). The matrix consists mainly of collagen, elastin, laminin and fibronectin.Transmembrane proteins - integrins - transmit mechanical signals into and out of cells and bind the extracellular matrix to the intracellular matrix through their cytoplasmic domains and nanoscale layers, mechanically connecting the domains and the cytoskeleton. The main components of the intracellular matrix are vinculin, paxillin, talin and kinase. The cytoskeleton regulates the propagation of mechanical signals within the cell. It is a dynamic multi resonant structure composed of microfilaments, microtubules and intermediate filaments. Through the cytoskeleton, mechanical signals affect all the basic and specialized functions of cells.From the cytoskeletal fibers, mechanical signals collected by integrins are transmitted to the nuclear nucleoskeleton, causing changes in its structure and spatial organization. The structure of the nucleoskeleton is the main regulator of biochemical and physical connections between the nucleus and the cytoskeleton, through which the regulation of gene geometry and gene expression is carried out. Within the nucleus, there are also other multi-resonance structures that connect the nuclear membrane to the cytoskeleton (the so-called LINC complex). Mechanical signals propagating through the LINC complex cause conformal changes in nuclear proteins and directly affect the structure of chromatin and the reprogramming of gene expression.Thus, biological tissues, cells, extracellular, intracellular, nuclear and intranuclear structures are complex multilevel mechanical pluriresonance systems that conduct mechanical signals inside and outside cells and tissues. It is of fundamental importance that mechanical signals can interact with all levels of the structural hierarchy of cells, radically influencing all processes of their vital activity, including transformation and expression of genes.Well known and widely used single-frequency or narrow-band mechanical/ultrasound signals, for example LIPUS, will not be adequate for effective regenerative therapy.

Ultra-wideband low-intensity micromechanical perturbations of the elastic medium (UMI Bursts) are closer to the own multi-resonant plurioscillations of cell and tissue structures and, therefore, are proposed in the present invention for use in regenerative therapy.Narrowband and ultra-wideband signals differ significantly not only in the frequency band, but also in some other characteristics, for example, information capacity, noise immunity and energy loss (attenuation) during propagation in media.

Information capacity. In narrowband LIPUS technology there is used long pulses with a frequency of 1.5 MHz, with a pulse width of 200 ps, repetitive at a frequency of 1 kHz, with an average spatial and temporal intensity of 1-30 mW / cm 2.Consequently LIPUS bandwidth ratio Hl20.01, LIPUS Band Ratio spectrum width br 1< 0.01, maximum LIPUS spectrum width Fl= 0.MHz, pulse duty cycle Tl = 0.2, maximum dynamic range of LIPUS signals in the treatment area D1 =30.By UMI Burst technology, ultra-wideband bursts of mechanical energy with duration of -100 ns are introduced into the treatment area. Bursts have a continuous spectrum of oscillations in the frequency range Fu 1-250 MHz, repeating with a frequency of up to 103 kHz, with a duty cycle up to Tu = 1,0 at averaged spatial, temporal and frequency intensities of 0.0001 -100 mW / cm 2, with a dynamic range Du = 106.The amount of information V transmitted from the emitter to the treatment area is [102]: V = F • T • D,and Vu / Vi = 2.5 108 Mbps / 0.06 Mbps = 4.1«109 times.Consequently, amount of information transmitted by new impact UMI Burst signals is several billion times greater than by the knownLIPUS signals.

Immunity. Biological tissues are complex structures, within which, when mechanical bursts propagate, there are absorption, scattering on various objects, reflection and re-reflection from internal boundaries and structures, interference of direct and reflected bursts.Due to the long length of LIPUS harmonic pulses, during their propagation, a lot of reflected signals appear, propagating both along the shortest distance and in many other ways. Multiple dynamic interference of the incoming signals inside the treatment area occurs, which 27 significantly changes the amplitudes, phases and shapes of the LIPUS signals, therefore, influencing the treatment results.One of the significant advantages of UMI Bursts is the absence of interference of directly propagating signals with their reflections from internal tissue structures. A short UMI Burst arrives at the structures of biological tissues in the minimum time, providingthe necessary effect, and then leaves the area of influence. Many reflected signals, which are delayed in different ways in time, create some random noise weak signal lagging behind the curative. Thus, the short duration of treating bursts protects them from interference distortions.

Attenuation in an absorbing medium. In [85] it is shown that ultra-wideband ultrasonic low cycle short pulses can propagate in biological tissues with attenuation less than narrowband ones.This effect is widely used in ultrawideband electromagnetic devices. To date, many ultra- wideband radars have been created, which, due to their ultra-wideband, allow one to "see" objects through walls [103], underground [104] or inside the body [105]. In the past few years, new medical devices for remote diagnostics have been created:- breast tumor detection;- bone cancer detection;- brain hemorrhage detection:- body position and localization:- noncontacting medical imaging;- detection of vascular pressure;- blood glucose concentration level measurement;- octretics imaging radar.The use of ultra-wideband ultrasonic signals is also known for treatment purposes (inventions of the author of the present invention [90-91]).One of the most preferred embodiments of the present invention is shown below. The block diagram in FIG. 1 illustrates the method of ultra-wideband micromechanical impact Burst regenerative treatment (UMI Burst treatment), which is implemented using the device 10. The device contains an ultra-wideband main generator 12 and a corrective generator 13, which 28 generate electrical frequency spectrum complementary to spectrum of main generator 12, that together satisfy the value of the (broad band rate) of 0.2 < q < 0.992 and the corresponding frequency band 1 - 250 MHz.Ultra-wideband signals can have one ultra-wide frequency range formed by generators and 13 or at least two ultra-wide frequency ranges, formed by at least the second main generator 14 and the corrective generator 15. The outputs of generators 12 and 13, as well as generators 14 and 15, are connected to the inputs of ultra-wideband spectrum corrector 16. The coordinated operation of generators 12 -15 by controller 18 is controlled, which also performs the functions of a programmer and interface.The corrector performs band-pass filtering of signals in each frequency range, normalization of their amplitudes and synchronous summation in order to obtain at the output frequency spectra with specified characteristics. The output of the spectrum corrector to the input of ultra-wideband amplifier 20 is connected, and the signals from which are fed to ultra- wideband head 21.

Head 21 contains ultra-wideband transducer 22 of electrical pulses into detached bursts of low-intensity micromechanical energy that is ultra-wideband micro-mechanical impact bursts - UMI Bursts. Transducer 22 is equipped with rear 23 and front 24 electrodes connected to amplifier 20. UMI Bursts through ultra-wideband protector 26 of head 21 and, through the conductive UMI Bursts coupling medium, are delivered to the surface of body 28, and then non- invasively injected into treatment area 30 and adjacent tissues 31.To deliver the required amount of energy to the selected treatment area, using controller and functional blocks 12-15,16, 20, 21-26 of device 10, they select the parameters of UMI Bursts and select the shape of the burst emission field of any shape, suitable to the geometrical form of the treatment area, for example, divergent, collinear, converging or a dynamically changing.The energy of UMI Bursts is transmitted to a variety of mechano-sensitive resonant tissue structures, including cellular ensembles 31, extracellular matrix 33, somatic cells 34, progenitor cells 36, pluripotent cells 38, and cell nuclei 40.

The UMI Bursts stimulate and reinforce regenerative processes at various levels of mechano- sensitive tissue structures, including:- apoptosis of deviant cells,- enhancement of many biochemical reactions of tissues and cells that accompany and accelerate regenerative processes,- stress reprogramming of the part of somatic cells into multipotent and progenitor stem cells;- nuclear reprogramming of another part of somatic cells into multipotent and progenitor stem cells;- acceleration and enhancement of natural regeneration.- UMI Bursts promotes accumulation of pluripotent and progenitor stem cells in and around treatment area by multi-day repetitions of UMI Bursts, thereby increasing the effectiveness of treatment.The electrical ultra-wideband frequency spectra of at least main generators 12 and 14 and corresponding to the above electrical signals shapes of frequency spectra are selected from: shock signals, stress signals, as well as from the frequency spectra of rectangular, triangular, trapezoidal signals or their differentials, and / or from the spectra of arbitrary signals or their combinations.The electrical ultra-wideband frequency spectra of corrective signals at least of generators and 15 are selected from the differentials of the signals of main generators 12 and 14, as well as from damped sinusoidal signals, damped Sine signals and from Gaussian monocycles and from all possible spectra of low-cycle signals.The treating UMI bursts are formed in one ultra-wide frequency range at least from the main and corrective signal, for example, for q>0.2, or are formed from several ultra-wideband frequency ranges, from several complementary signals, for example, for q=0.992.The intensity Isptaf of UMI bursts is selected from values within the range from 10 s mW I cm 2 to 102 mW / cm 2׳ at a repetition rate of 0.05 - 5• 102 KHz. The peak value of the burst signal intensity Ipa < 10 W / cm 2 at a repetition rate of up to 100 Hz.

F IG. 2 shows an example of a complementary pair of spectra of treating signal. FIG 2-a - Gaussian monocycle spectrum 42 for the frequency range 0-50 MHz, Fig 2-b) and its corresponding pulse shape 44. In curve 42, after about 20 MHz, the amplitude of the frequency spectrum-decreases significantly with frequency. Corrective spectrum 46 FIG.2-c) is selected in the form of an exponentially damped sinusoid 48 (FIG.2-d). Its frequency spectra increase with frequency after 20 MHz. After spectrum corrector resulting spectrum 50 is shown in FIG.2-e. It has the necessary for UMI Bursts treatment frequency response. FIG. 2-f) shows the complex shape of treatment time-domain pulse 52 after spectrum corrector 16.

In accordance with the method of ultra-wideband micromechanical burst treatment, which is implemented in device 10, exposure to ultra-wideband micro-mechanical bursts initiates and accelerates and intensify many processes that underlie the renewal and regeneration of cells and tissues, including:- reprogramming and transformation of some somatic cells into pluripotent stem and/or progenitor stem cells;- proliferation of a part of somatic cells and acceleration of their division into new mature specialized and stem cells;- change in the state of the extracellular matrix and synergistic acceleration of multilevel reprogramming of somatic cells into stem cells;- accumulation in the treatment area and in the surrounding healthy tissues of scattered "sleeping" and delivered by the bloodstream (homing effect) stem cells;- secretion of biologically active factors and production of proteins that accelerate regeneration processes;- increased apoptosis of pathological cells and acceleration of the release of "niches" for proliferating cells;- proliferation of stem multipotent and progenitor cells, and replacement of damaged and diseased cells with stem cells with their further differentiation into surrounding tissues.

FIGS shows a block diagram of an ultra-wideband experimental facilities based on the certified AIMS III Scanning System (ONDA Corporation, USA).31 Absorption of continuous narrow-band ultrasound of different frequencies, broadband stochastic ultrasound, and ultra-wideband micromechanical impact bursts (UMI Bursts) in water were experimentally compared.The experimental facilities contain ultra-wideband generator 54 connected to ultra- wideband amplifier 56, the signal from which is fed to multimode ultra-wideband transducer 58. Calibrated needle hydrophone 60 and amplifier 62 from Precision Acoustic (UK) in the measurements were used.Experimental ultra-wideband transducer 58 emitted harmonic ultrasound at frequencies of 1.0, or 3.0 or 5.0 MHz (q<0,01, br FIG.4 shows the changes in the intensity of ultrasound/micromechanical signals depending on the distance to transducer 58. The figure shows the curves: 70 -1,0 MHz, 72 - 3,MHz, 74 - 5,0 MHz, 76 - stochastic noise having band 1,0 - 3,0 MHz, 78 - ultra-wideband UMI Burst with a frequency band of 1,0-7,0 MHz.

As can be seen from FIG. 4, the intensities of a monofrequency harmonic signal with a frequency of 5,0 MHz, and stochastic noise of 1,0 - 3,0 MHz, decrease with distance with an attenuation coefficient a = 6.25 dB/cm. Signals reach the equipment noise level at a distance of 2.7 cm from the transducer. Monofrequency harmonic signals with frequencies of 1,0 MHz and 3,0 MHz decrease with distance from attenuation coefficient a =4.5 dB/cm and reach the noise level at a distance of 3.0 cm.Ultra-wideband UMI Bursts with a frequency range of 1,0-7,0 MHz decrease in amplitude with distance from the emitter much more slowly, on average a = 2.8 dB/cm, and reach the same noise level at a distance of 6, 2 cm from the transducer.

Therefore, ultra-wideband signals can affect biological structures not only on the surface of the body, but also in depth.

FIG.5 shows the differences in the impact of ultra-wideband micromechanical bursts (UMI Bursts) with a frequency range of 1.0 - 7.0 MHz on the proliferation rate of normal mouse fibroblast cells, in comparison with exposure to ultrasound with frequencies of 1.0 MHz, 3.0 MHz and 7.0 MHz.

Studies were performed on normal fibroblasts of BALB / c mice (cell line 3T3-A31).Ultrasonic harmonic signals with frequencies of 1,0, 3,0 and 7,0 MHz, as well as UMI bursts with an emission spectrum in the 1,0 - 7,0 MHz band range, were fed to an ultrasound/micromechanical ultra-wideband multimode transducer 22 having the diameter of mm from main 12 and correction 13 outputs of SigLent SDG 6052X generator.The exposure time was 5 min daily for 5 days and beam-average intensity Isptaf of all signals was set at 30 mW / cm 2, which was measured according to [106,107]. Trypan blue dye was used (Hy Clone, USA).An Axiostar Plus binocular microscope (Carl Zeiss, Germany) with a digital camera was used to observe and photo to fix the state of cells. Counting the number of cells in a given volume of the nutrient medium was carried out in the camera Goryaeva (Farmmedteh, Ukraine).hours after the fifth treatment session, the number of live and dead cells and their sums were compared.As seen from FIG.5, 1.0 MHz ultrasound suppresses fibroblast proliferation to 62% of control. Cell apoptosis appears to occur, which confirms the findings of the publication [108], At an ultrasound frequency of 3,0 MHz, the effects of cell proliferation and apoptosis are balanced, and the effect of such ultrasound on proliferation is negligible. At a frequency of ultrasonic irradiation of cells of 7,0 MHz, proliferative processes prevail. On day 6, the number of fibroblasts increased by 20% compared with the control. Fibroblast proliferation is most pronounced when exposed to UMI Bursts with a frequency band of 1,0-7,0 MHz and an intensity of 30 mW / cm 2.The number of cells after exposure to UMI Bursts increased by almost 40%.

Thus, with an increase in the frequency of ultrasound, the proliferation of fibroblast cells increases, and the greatest increase in proliferative activity with UMI Burst exposure is observed.The diagram FIG.6 shows the results of stimulation of cell bioactivity - blast transformation of T-lymphocytes - with LIPUS and UMI Burst exposures.The reaction of blast transformation of T-lymphocytes is an indicator of the of cellular immunity.Ultrasonic LIPUS signals with frequencies of 1,5 MHz, as well as UMI Bursts with a frequency spectrum in the 1,0 - 7,0 MHz band, were fed to ultrasonic/micromechanical ultra- wideband multimode transducer 22having the diameter of 20 mm from master 12and correction 13 outputs of SigLent SDG 6052X generator.The exposure time was 5 min daily for 5 days and beam-average intensity Isptaf of signals was set at 30 mW/cm 2, which was measured according to [107],The intensity of UMI Bursts was set at 30 mW/cm 2 and 1.0 pW/cm 2.To set up the reaction under aseptic conditions, 10 ml of blood from a person from a person's vein was taken into a test tube with heparin (25 U/ml). The contents of the tube were mixed carefully and left for 60 minutes in a thermostat at 37 ° C to precipitate red blood cells. After incubation in a thermostat, the supernatant plasma layer was enriched by leukocytes and was aspirated into a separate sterile tube and the number of leukocytes in 1 ml was determined. Then the suspension of leukocytes with nutrient medium 199 (containing 200 ml of IU of penicillin and 100 IU of streptomycin in 1 ml) was diluted, so that 1 ml contained 1-2 mil of white blood cells, 20% autologous plasma and 80% of the nutrient medium. The prepared leukocyte suspension was poured into sterile 1 ml vials and there was passed some gas mixture containing 5% carbon dioxide. The vials were placed in a thermostat at 37 ° C for 5 days.In the field of view of the optical microscope, there were calculated the percentage of transformed cells visually different from normal cells. FIG.6s hows the results.It is seen the normal blast transformation of leukocytes BTLNORM = 7.4 %.Compared with the control LIPUS has practically no effect on the transformation of lymphocytes, BTLupus=6.9 %.

The UMI Bursts with an intensity of 30 mW / cm 2 increases the BTLumt to 10.6 %, that is, almost one and a half times.The UMI Bursts with a micro intensity of 1,0 pW/ cm 2 increases the BTLmicroumt= 23,5 %, that is more than three times.It can be seen that UMI Bursts are an effective stimulator of the activity of immunocompetent cells.

FIG. 7 compares wound healing in in control group of mice, that is, without exposure and, with ultrasonic LIPUS and micromechanical UMI Burst effects.Studies on 40 mice - female BALB line were performed. Standardized linear wounds mm long and 1.2 mm deep on their backs were inflicted.The animals were divided into 3 groups:- a group with classic LIPUS ultrasound impact with an intensity of lspta=30 mW / cm 2, a pulse filling frequency of 1.5 MHz, a pulse duration of 200 ps, a repetition rate of 1 kHz.- a group with UMI Bursts with a micro intensity of Isptaf = 1 pW / cm 2, and a radiation spectrum of 1 - 7 MHz. and a repetition rate of 1 kHz.Exposure was 5 minutes daily for 9 days until the wounds completely healed in one of the groups.A beam-average intensity of ultrasonic/micromechanical signals Ispta and Isptaf according to [107] were measured. The intensities of UMI bursts at 30 mW/cm 2 and 1.0 pW/cm were set.We used a SigLent SDG 6052X DOS generator from SigLent Technologies Co. The head for emitting LIPUS ultrasonic and ultra-wideband micromechanical UMI Bursts contained a multimode ultra-wideband transducer with a diameter of 20 mm. Ultrasonic oscillations and micromechanical bursts were delivered to the affected area on the back of the mouse through a layer of ultrasonic gel UBQ5000 Ultragel.In the first control group of animals (curve 80), wound healing occurs at the lowest rate, the maximum value of which does not exceed 2.1 mm/day. In the first two days inflammation and edema in this group in the wound area were observed. In the second group of animals after LIPUS exposure (curve 82), inflammation and edema were absent. The healing rate was approximately equal to the healing rate in the control group also is 2.1 mm/day. In the third group of animals, the wounds of which were exposed to UMI bursts (curve 84), the healing rate was significantly higher and reached a value of 3.8 mm/day. Complete healing of wounds in UMI Bursts group was achieved, on day 9 from the start of exposure, when LIPUS treatment was applied, the wound size still was 3 mm on day 9, and in the control group wound size was still mm.Therefore, UMI Bursts may be more effective in promoting wound healing in compare with LIPUS.

FIG. 8 shows a variant of the implementation of the UMI Burst method for reducing an old, rough, extensive scar on the face.The scar of patient Ch., 42 years old man (Kyiv, Ukraine). When he was 3 years old, being hit by the butt of a car door, he was injured. At the age of 42, the length of the scar on the face was 4.1 cm before testing (FIG.8-a).The SigLent SDG 6052X DOS generator from SigLent Technologies Co was used. The head for emitting UMI Bursts contained a multimode ultra-wideband transducer with a diameter of mm. The UMI Bursts to the scar and surrounding skin were delivered through a layer of ultrasonic gel UBQ 5000 Ultragel.The scar treating area was irradiated with UMI Bursts with a frequency band of 1,0 - 7,MHz, intensity Isptaf = 30 mW/cm 2 and a repetition rate of 1 kHz.The exposure was carried out daily for 9 days. The duration of each session was 10 min.FIG.8-a. There is shown on the photo a pronounced scar with traces of surgical intervention before UMI Burst procedures. FIG.8-b)there is a photo ofthe scar after 5 days of daily treatments. The traces of sutured wound are almost invisible. The depth ofthe scar has decreased significantly. FIG.S-c)there is a photo of the scar after 9 days of applying UMI Bursts The scar has drastically decreased and become less noticeable. Its length by about 1 cm was also reduced.There were obtained the regenerative restoration of the skin, similar to the restoration by the stem cell transplantation.36 FIG. 9 shows a variant of the implementation of the UMI Burst method for drastic reduction of long-term dermal hyperpigmentation (dermal melasma) and reduction of deep forehead wrinkles on the face.The UMI Burst signals to the forehead of patient S., 46 years old woman, were applied. To exclude primary biliary cholangitis, hemochromatosis and Addison's disease, before using the UMI Bursts, patient S. underwent the necessary examination in the clinic. According to the conclusion of dermatologists, patient S. had a mixed type of melasma, i.e. both epidermal and dermal. Therefore, the previous long-term treatment was ineffective.A selected area of the skin with age-related changes with the UMI Bursts with a bandwidth of 1,0 - 7,0 MHz, with an intensity of Isptaf = 30 mW/cm 2 and a repetition rate of 1 kHz were irradiated. The exposure was carried out daily for 40 days. The duration of each session was minutes. The micromechanical transducer was moved slowly on the affected area.We used the SigLent SDG 6052X DOS generator from Sigtent Technologies Co. The head for emitting the UMI Bursts contained a multimode ultra-wideband transducer with a diameter of 10 mm. The UMI Bursts to the affected area through a layer of ultrasonic gel UBQ5000 Ultragel were delivered.From the comparison of FIG.9-a) and FIG.9-b) it can be seen that as a result of treatment, the intensity of hyperpigmentation has significantly decreased. The spots are almost imperceptible (visible in the photo only after increasing the contrast of the image FIG.9-b) up to 400%).Intractable deep wrinkles on the forehead also decreased significantly, the skin began to look younger.On FIG. 10the variant of the implementation of the UMI Burst method in cosmetology for correction of nasolabial folds is shown. Quantitative control of the size of creases by using Altera 3D apparatus was made. Testing subject R is a 49 years old woman. 'The UMI Burst exposure was used with a frequency band of 1,0 - 7,0 MHz, with an Isptaf intensity of 30 mW/cm 2 and a repetition rate of 1 kHz. The exposure daily for 14 days was performed. The duration of each session was 10 minutes. The micromechanical head was slowly moved on the affected area.We used the SigLent SDG 6052X DOS generator from SigLent Technologies Co. The head for emitting the UMI Bursts contained a multimode ultra-wideband transducer having diameter of 10 mm. The UMI Bursts were delivered to the treatment area through a layer of ultrasonic gel UBQ 5000 Ultragel. FIG. 10 shows an example of the correction of the nasolabial folds of the woman R., age years.Prior to the UMI Burst exposure, the crease volume measured by the Altera apparatus was 10.29 mm 3.After exposure, the volume of the crease decreased to 3.1 mm3, i.e., by 70%. No filling substances under the room were introduced.The patient was observed by us throughout one year. The effect of improving the appearance was persistent.

FIG. 11 illustrates the implementation of the proposed method for restoring blood microcirculation in the area of the lower limb with varicose veins.The tests were carried out on the volunteer M., 72 years old man.The UMI Burst effect was applied with a frequency band of 1,0-7,0 MHz, with an intensity of Isptaf = 30 mW/cm 2 and a repetition rate of 1 kHz. Exposure daily was carried out for 5 days. The duration of each session was for 10 minutes. The micromechanical transducer was moved slowly on the affected area.We used the SigLent SDG 6052X DDS generator from SigLent Technologies Co. The head for emitting of the UMI bursts contained a multimode ultra-wideband transducer with a diameter of 10 mm. The micromechanical bursts to the treatment area were delivered through a layer of ultrasonic gel UBQ.5000 Ultragel.The appearance of the shin area with hematomas on the photographs of FIG.ll-a) and FIG. 11-b) before and after the UMI Burst treatment is shown. Note that by the time of treatment, hematomas were constantly present in the part of the limb shown in the photographs for more 38 than 4 months, and were accompanied by microcirculatory disorders by periodic severe pain and night cramps of the calf muscles.After the UMI Burst, exposure already on the fourth day the hematoma almost disappeared. There was a slightly noticeable pigmentation of the skin. Periodic pains and night cramps in the limb also ceased. Observation over 1.5 years showed that the treatment effect is persistent, hyperpigmentation in the observed area no longer occurred.Thus, in accordance with the essence of the proposed method of treatment, with some of the above-described embodiments and applications of the ultra-wideband, micromechanical UMI burst regenerative treatment; it is possible to treat skin diseases, injuries, degenerative and traumatic diseases of the musculoskeletal system and blood vessels circulation disorders. It is also possible to treat eye diseases, lesions of the heart to correct the state of the immune system, stimulate the defenses and general endurance, and on this basis, prevent premature aging. The invention can also be applied in field military and sports medicine, aesthetic medicine and cosmetology.

It is obvious that the present invention is not limited to the above-mentioned embodiments, and variations and modifications may be made without departing from the scope of the present invention. It will be appreciated by persons skilled in the art that the present invention is not limited by the drawings and description hereinabove presented. Rather, the invention is defined solely by the claims that follow.

Claims (23)

1.CLAIMS What we claimed is:1. A method of ultra-wideband micromechanical modulating of cellular activity comprising:a) the generation of at least one pair of complementary electrical UWB signals, consisting of a main and correction signals with different distribution of frequency spectra, intended for at least one UWB frequency range of treating signals;b) the correction of UWB frequency spectra of the main signals in at least one frequency range by using bandpass filters as well as summation with the spectra of correcting signals, to obtain ultra-wideband electrical signals with constant, rising or arbitrary shape of the frequency spectrum;c) converting corrected UWB electrical signals by electromechanical transducer into Ultra- wideband Micromechanical Impact Bursts (UMI Bursts);d) delivery of impact UMI Bursts through an acoustically transparent UWB protector and a UWB coupling medium, which conduct UMI Bursts to the surface of object;e) non-invasive injection and delivery of impact UMI Bursts to the treatment area and adjacent to the treatment area of the biological tissues;f) UMI Burst accumulation of pluripotent and progenitor stem cells in and around treatment area by multi-day repetitions of treating by the UMI Bursts;g) transfer of energy of impacted the UMI Bursts to variety of mechanosensitive structures of the biological tissues in the treatment area and adjacent tissues, including cell assemblies, intracellular and extracellular matrices, cells, organelles and cells' nuclei;h) ultra-wideband micromechanical impact burst (UMI Burst) stimulation of regenerative processes at various levels of mechanosensitive tissues and cell structures, including:- stress impact on cells and extracellular matrix to apoptosis stimulation of deviant cells;- stimulation and enhancement of many biochemical reactions of tissues and cells that accompany and accelerate regenerative processes;- stress reprogramming of the part of somatic cells into pluripotent and progenitor stem cells; - nuclear reprogramming of another part of somatic cells into pluripotent and progenitor stem cells,-s timulation, acceleration and enhancement of natural regeneration.

2. The method according to claim 1, in which the first UMI Burst has a first frequency range with a first shape of frequency spectrum, which exerts stress on tissues and intercellular matrix of the treatment area, and wherein at least the second UMI Burst has at least a second frequency range with a second shape of frequency spectrum, that stimulates the processes of reprogramming, direct reprogramming, differentiation, proliferation and cell replacement in the treatment area of diseased or damaged cells with healthy ones.

3. The method according to claim 2, wherein the first of said UMI Bursts is generated at least inside the first frequency range 1,0 - 10,0 MHz, with a frequency, space and time-averaged intensity in the treatment area of 1,0 - 300,0 mW/cm2.

4. The method according to claim 3, wherein the first of said UMI Bursts has a repetition rate of 0.05 -100,0 kHz.

5. The method according to claim 3, wherein at least the second of said UMI Bursts is generated inside the second frequency range of 10,0-50,0 MHz, with an intensity averaged over frequency, space and time in the treatment area of 0.0001 -30,0 mW/cm2.

6. The method according to claim 5, in which at least the second of said UMI Bursts is repeated at a frequency of 0.05 -103 kHz.

7. The method according to claim 2, wherein, at least the third of several UMI Burst is formed inside the third frequency range of 50-250 MHz, and have a frequency, space and time averaged intensity of burst on the body surface of 0,0001-100 MW/cm2 and into the treatment area of 0.0001 - 30 mW/cm2.

8. The method according to claim 7, wherein said at least the third UMI Burst has a repetition rate of 0.05 -103 kHz.

9. The method according to claim 1, in which the frequency spectra of the main signals of the generators are selected from shock signals, stress signals, as well as from the frequency spectra of rectangular, triangular, trapezoidal signals or their differentials, and/or from the frequency spectra of arbitrary signals, ortheir combinations.

10. The method according to claim 1, in which the frequency spectra of the correction signals of the generators are selected from the differentials of the main signals, and/or from low-cycle sinusoidal signals, damped sinusoidal signals, damped Sine signals, as well as from Gaussian monocycles, and from other known and arbitrary spectra of low-cycle signals or their combinations.

11. The method according to claim 1, in which UMI Burst has a pulses duration of 5.0 -100.0 ns.

12. The method according to claim 1, wherein the sequence of UMI Bursts is incoherent.

13. The method according to claim 1, wherein the sequence of UMI Bursts is coherent.

14. The method according to claim 1, in which the transducing of electrical impulses into UMI Bursts perform by more than one UWB transducer, acoustically coupled to the UWB acoustically transparent protector.

15. The method according to claim 14, wherein the UMI Burst stimulation of the treatment area and surrounding tissues is performed by a multi-element UWB transducer that generates the UMI Burst field, converging, diverging or dynamically changing in space and time.

16. The method according to claim 1, wherein said UMI Bursts are applied to the body surface through acoustically transparent and acoustically coupled to each other intermediate medium, such as UWB protector, and UWB contact layer or an extended UWB medium placed between the protector and object's surface.

17. The method according of claims 1 - 16, wherein parameters of the spectra of impact UMI Bursts, as well as the treatment procedure, control remotely, including photo and video recording of the procedure, its Internet transmission and documentation.

18. The method according of claims 1 - 16, wherein said UMI Bursts are introduced into the treatment area through eye conjunctival surface.

19. The method according of claims 1 - 16, wherein the treatment can be interventional and comprise inserting the impact UMI Bursts into body entity openings, such as nasal cavity, oral cavity, esophagus, rectum, vagina.

20. The method according of claims 1 - 16, wherein said UMI Bursts are used in regenerative treatment to treat disease is selected from a group, including at least a stroke, myocardial infarction, ischemia, spinal cord injury, Alzheimer's and Parkinson's diseases, diabetes, some types of cancers, atherosclerosis, varicose, burns, post-traumatic and post-burn scars and wounds.

21. The method according of claims 1 - 16, in which the UMI Bursts are used in regenerative ophthalmology to reduce vision loss, including, at least vision loss due to degradation of the optic nerve including glaucoma.

22. The method according of claims 1 - 16, wherein said UMI Bursts are used in regenerative cosmetology to treat diseases and pathologically altered skin selected from the group, including the signs of skin aging, reduction of scars, acne, wrinkles, post-traumatic and post-surgical seals, melasma, swelling, ptosis.

23. The method according to claim 1, additionally including the use of the UMI Bursts in combination with UWB radio frequency pulse signals of the gigahertz frequency range. Inventors: Aleksandr Marchenko Audrius Miciukevicius