CN114796865A - Flexible implanted electric stimulator driven by ultrasound and control method thereof - Google Patents
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- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
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- A—HUMAN NECESSITIES
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- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
- A61N1/36125—Details of circuitry or electric components
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- A—HUMAN NECESSITIES
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- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
- A61N1/36128—Control systems
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Abstract
The invention discloses an ultrasonic-driven flexible implanted electric stimulator and a control method thereof. The electric stimulator comprises a micro-channel, wherein the micro-channel is annular, and a solution containing free ions is filled in the micro-channel; the inner wall of the micro flow channel is provided with a micro cantilever array; and a conductive film is laid in the micro-channel along the trend of the micro-channel, and a pair of stimulation electrodes are led out of the micro-channel by the conductive film. The invention controls the flow direction and the flow velocity of the solution in the micro-channel by adjusting the frequency and the amplitude of the ultrasonic wave, further controls the magnitude and the polarity of the output voltage of the electric stimulator, and can solve the problem of poor mechanical flexibility of the existing ultrasonic-driven implanted electric stimulator based on a novel ultrasonic transduction mechanism of sound-current-electricity conversion.
Description
Technical Field
The invention particularly relates to an ultrasonic-driven flexible implanted electric stimulator and a control method thereof.
Background
The implantation of an electrical stimulator to a specific part in the body for non-pharmacological electrical stimulation is recognized as an effective therapy for tissue regeneration repair and nerve regulation, and is an important means for treating various chronic diseases in modern medicine.
The traditional implanted electric stimulator relying on long-term energy supply of the large-size battery has the problems that the service life of the battery is limited, secondary operation risks can be caused by battery replacement, and the traditional implanted electric stimulator is large in size, poor in mechanical flexibility, capable of generating a large operation wound surface, difficult to adhere to tissue in a conformal mode, and poor in stability of electric stimulation signal conduction. Meanwhile, the implanted electric stimulator is easy to cause discomfort and physiological rejection of patients, and researches show that the incidence rate of related complications of the electric stimulator capsular bag and the lead is up to 10-20%. Therefore, the research and construction of the small-size flexible implantable electrical stimulator has great significance for reducing the risks of the wound surface of the implantation operation and postoperative complications and improving the stability of electrical stimulation signal conduction.
The ultrasonic wireless energy transmission is an important technical approach for constructing a small-size flexible implanted electric stimulator suitable for deep tissues due to the advantages of short ultrasonic wave length, large tissue penetration depth, no electromagnetic interference, good biological safety and the like. However, the existing ultrasonic energy-supplying implantable electrical stimulator relies on the positive piezoelectric effect to realize ultrasonic energy conversion, needs to use thicker hard piezoelectric ceramics, and seriously affects the mechanical flexibility of the electrical stimulation device. And high-frequency alternating current signals generated by conversion of the positive piezoelectric effect are difficult to be directly used for functional electrical stimulation, signal conditioning is required to be carried out through a hard silicon-based chip, coreless transformation is difficult to be realized, and the mechanical flexibility of an electrical stimulation device is further limited. Therefore, how to innovate the ultrasonic transduction mechanism of the implanted electric stimulator, get rid of the dependence on the hard piezoelectric ceramics and the silicon-based chip, realize the full flexibility of the implanted electric stimulator and the AC/DC multi-mode controllable output in the coreless state is a leading-edge technological problem which needs to be solved urgently by the ultrasonic energy-supply implanted electric stimulator.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, provides an ultrasonic-driven flexible implanted electric stimulator and a control method thereof, and solves the problems that the prior art needs a battery for energy supply, has large device size and adopts a hard piezoelectric ceramic or silicon-based chip to influence the flexibility and the biological safety.
The invention provides an ultrasonic-driven flexible implantable electric stimulator, which comprises a micro-channel, a flexible electrode and a flexible electrode, wherein the micro-channel is used as a channel for circulating and flowing fluid, is annular, and is filled with a solution containing free ions; the inner wall of the micro flow channel is provided with a micro cantilever array; a conductive film is laid in the micro-channel along the trend of the micro-channel and is used for forming better conductive connection so as to realize equipotential at two ends of the film; the conductive film leads out a pair of stimulating electrodes to the outside of the micro-channel and can output an electrical stimulation signal.
The structure of the flexible implantable electric stimulator driven by ultrasound has better mechanical flexibility, can realize bending deformation of more than 90 degrees, and can meet the requirement of conformal attachment with target tissues.
The flexible implantable electric stimulator driven by ultrasound is based on a novel ultrasound transduction mechanism of sound-current-electricity conversion, stable second-order fluid flow is generated under ultrasound excitation due to the coupling interaction of sound wave-micro cantilever array-fluid, so that the fluid in the micro-channel directionally and circularly flows, and the flow direction, the flow velocity and the flow form of the fluid can be cooperatively regulated and controlled with ultrasound frequency through the micro-channel structure design. The shear motion occurs between the solution and the double electric layers formed between the walls of the micro-channels when the solution flows, so that net charges in the diffusion layers flow along with the fluid to generate a flow potential on the stimulation electrodes, and further the application of ultrasonic-driven electrical stimulation is realized.
In a preferred embodiment of the present invention, the conductive film has an upstream end and a downstream end, and the upstream end and the downstream end respectively lead out the stimulation electrodes to the outside of the micro channel. The stimulation electrode is a vital machine interface for implementing electrical stimulation, the voltage at two ends of the stimulation electrode is positively correlated with the flow velocity of fluid, the positive and negative voltages depend on the flow direction of the fluid, the ultrasonic remote regulation and control of the amplitude and the direction of an electrical stimulation signal can be realized through reasonable micro-channel and cantilever beam structural design, and the requirement of functional electrical stimulation on the output of an alternating current/direct current multi-mode electrical signal is met.
In a preferred embodiment of the invention, the microfluidic chip further comprises graphene located on a bottom surface of the microchannel, on which a fluid can flow. The graphene is single-layer or multi-layer graphene. The introduction of graphene materials into the micro-channel can enhance the electrokinetic conversion efficiency and can meet the power consumption requirement of the lowest sub- μ W level of functional electrical stimulation. The thickness, shape and size parameters of the graphene can be adjusted according to parameters of the micro-channel and actual requirements, and the graphene is preferably of a multi-layer graphene structure. The graphene is prepared by CVD and laser reduction of graphene oxide, patterns of the graphene can be controlled by a transfer printing process and a laser scanning process, and the graphene is preferably prepared and pattern defined by the combination of the CVD and the transfer printing process.
In a preferred embodiment of the present invention, the micro-cantilever array is composed of a plurality of obliquely arranged micro-cantilevers, and the micro-cantilevers form an included angle with the inner wall of the micro-channel on a vertical plane, the included angle is 10 ° to 60 °, and the included angle is preferably 30 °. The free end of the micro cantilever beam is of a pointed structure, the angle of the tip is 5-45 degrees, and the angle of the pointed structure is preferably 20 degrees. The micro-cantilever arrays are at least two groups (less than 10 groups) and are arranged on the inner walls of two sides of the micro-channel, and the number of the micro-cantilevers in the unit array is 1-100, preferably 3. The length of the micro-cantilever is 10-999 mu m, the material of the micro-cantilever can be polymer materials such as PDMS and SU-8, the length of the micro-cantilever is preferably 100 mu m, and the material of the micro-cantilever is preferably SU-8.
In a preferred embodiment of the invention, the solution containing free ions comprises NaCl solution, KCl solution or CaCl 2 Solution, preferably 0.6M NaCl solution.
In a preferred embodiment of the present invention, the thickness of the conductive film is 10 to 999nm, the material includes an inert metal such as gold and platinum or a conductive metal oxide such as ITO, the thickness of the conductive film is preferably about 100 nm, and the material is preferably platinum.
In a preferred embodiment of the present invention, the width of the micro flow channel is 10 μm to 9mm, the height of the micro flow channel is 10 μm to 999 μm, the width and the height of the micro flow channel at different positions can be different, the height of the micro flow channel is preferably several tens of micrometers, and the width of the micro flow channel is preferably several hundreds of micrometers.
In a preferred embodiment of the present invention, the thickness of the stimulation electrode is 10 to 999nm, the stimulation electrode can be made of an inert metal material such as gold and platinum, or a conductive metal oxide such as ITO, the thickness of the stimulation electrode is preferably 100 nm, and the metal thin film material is preferably platinum.
In a preferred embodiment of the present invention, in the preferred embodiment of the present invention, the surface of the stimulation electrode is modified with a conductive polymer through biocompatibility, so as to improve the safe injection charge density of the stimulation electrode, and the conductive polymer modified material is preferably graphene-doped PEDOT: PSS conductive polymers.
The invention also provides an ultrasonic-driven flexible implanted electric stimulator which comprises a micro-channel, a micro-cantilever array, a conductive film and a pair of stimulation electrodes, wherein the solution containing free ions in the micro-channel forms a fluid which flows in a directional and circular manner by ultrasonic excitation and generates a flow potential by shearing movement with the micro-cantilever array, and the stimulation electrodes output electric stimulation signals by equipotential conductive connection of the conductive film.
The invention also provides a control method of the ultrasonic-driven flexible implantable electric stimulator, which controls the flow direction and the flow speed of the solution in the micro-channel by adjusting the frequency and the amplitude of ultrasonic waves, and further controls the magnitude and the polarity of the output voltage of the electric stimulator. The flowing direction and speed of the liquid in the micro-channel are controlled by the frequency and amplitude of the ultrasonic wave, clockwise circulating flow and anticlockwise circulating flow can be realized, and the frequency of the ultrasonic wave is preferably between 1 and 5 MHz.
In a preferred embodiment of the present invention, the magnitude and polarity of the output voltage of the electrical stimulator are controlled in cooperation with the ultrasonic excitation conditions by adjusting the type and concentration of the solution containing free ions, adjusting the size of the inner diameter of the micro flow channel, adjusting the size, distribution, number of the micro-cantilever array, or the inclination angle of the micro-cantilever.
Compared with the background technology, the technical scheme has the following advantages:
1. the flexible implanted electric stimulator driven by ultrasound is based on a novel ultrasound transduction mechanism of sound-current-electricity conversion, does not need hard piezoelectric ceramics to carry out ultrasound transduction, and greatly improves the mechanical flexibility of the implanted electric stimulator driven by ultrasound;
2. the invention does not depend on the direct piezoelectric effect to carry out ultrasonic transduction, can obtain direct current output without rectifying by a hard integrated circuit, and can regulate and control the voltage and the polarity in real time by ultrasonic waves;
3. the invention does not depend on the AC/DC multi-mode controllable output of the hard integrated circuit, is beneficial to improving the signal conduction stability and the biological safety of the implanted electric stimulator, and has very wide application prospect in the field of biomedicine.
Drawings
Fig. 1 is a top view of the overall structure of the flexible implantable electrical stimulator driven by ultrasound in example 1.
Fig. 2 is a partial enlarged view of the structure of the ultrasonically driven flexible implantable electrical stimulator in example 1.
Fig. 3 is a left side cross-sectional view of a micro channel in which a group of micro cantilever arrays are positioned in the flexible implantable electrical stimulator driven by ultrasound in example 1.
Fig. 4 is a front cross-sectional view of a micro channel in which a group of micro cantilever arrays are positioned in the flexible implantable electrical stimulator driven by ultrasound in example 1.
Fig. 5 is a schematic diagram of the working principle of the polarity switching of the output voltage of the flexible implantable electrical stimulator driven by ultrasound in embodiment 1.
In the figure: 1-microchannel, 2-metal film, 3-upper side micro cantilever array, 4-graphene, 5-lower stimulation electrode, 6-upper stimulation electrode, 7-lower side micro cantilever array, solid arrow: indicating the direction of fluid flow within the microchannel.
Detailed Description
The following detailed description of embodiments of the invention refers to the accompanying drawings. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
Example 1
An ultrasonically driven flexible implantable electrical stimulator, as shown in fig. 1, may include: the device comprises a micro-channel 1, a metal film 2, an upper micro-cantilever array 3, graphene 4, a lower stimulation electrode 5, an upper stimulation electrode 6 and a lower micro-cantilever array 7.
The micro flow channel 1 is an annular flow channel structure, the solution containing free ions is filled in the micro flow channel 1, and under the excitation of external ultrasonic waves, the liquid can circularly flow in the micro flow channel 1 in a clockwise direction or a counterclockwise direction. The inner wall of the micro-channel 1 is provided with micro-cantilever arrays 3 and 7; a metal film 2 is laid in the micro-channel along the trend thereof, as shown in fig. 1, the metal film 2 is U-shaped and is provided with an upstream end and a downstream end, and the upstream end and the downstream end are respectively led out of stimulation electrodes 5 and 6 to the outside of the micro-channel.
Under ultrasonic excitation, steady second-order fluid flow, namely acoustic flow phenomenon, can be generated due to the coupling interaction of sound wave-micro cantilever array-fluid, so that the fluid flow in the micro-channel can be driven by ultrasonic.
As shown in fig. 2, the upper micro-cantilever array 3 and the lower micro-cantilever array 7 have different cantilever structure size parameters, so that they have different resonant frequencies, and thus the selective excitation of the upper micro-cantilever array 3 and the lower micro-cantilever array 7 can be realized by two ultrasonic frequencies; under the ultrasonic excitation with the frequency same as the resonant frequency of the cantilever beam structure in the upper micro-cantilever array 3, the vibration amplitude of the cantilever beam in the upper micro-cantilever array 3 is much larger than that of the cantilever beam in the lower micro-cantilever array 7; on the contrary, under ultrasonic excitation with the same frequency as the resonant frequency of the cantilever beam structure in the lower micro-cantilever array 7, the vibration amplitude of the cantilever beam in the lower micro-cantilever array 7 is much larger than that of the cantilever beam in the upper micro-cantilever array 3.
The flow direction of the steady-state sound flow generated by the coupling interaction of the sound wave-micro cantilever array-fluid depends on the free end direction of a cantilever beam structure in the cantilever array; because the free ends of the cantilever beam structures in the upper micro-cantilever array 3 and the lower micro-cantilever array 7 point to the left, when the ultrasonic frequency is consistent with the resonance frequency of the cantilever beam in the upper micro-cantilever array 3, the upper micro-cantilever array 3 excites strong sound flow to flow, and liquid is driven to flow in a micro-channel in a counterclockwise circulation manner; when the ultrasonic frequency is consistent with the resonance frequency of the cantilever beams in the lower micro-cantilever array 7, the lower micro-cantilever array 7 excites strong acoustic current to flow, and liquid is driven to flow in the micro-channel in a clockwise circulation mode.
Increasing and decreasing the ultrasonic amplitude with a constant ultrasonic frequency can correspondingly increase and decrease the liquid flow velocity in the microchannel.
The free ends of cantilever beams in the upper micro-cantilever array 3 and the lower micro-cantilever array 7 are both in a pointed structure, and the pointed free ends of the cantilever beam structures can increase the sound flow intensity.
Under the driving of ultrasound, the solution flow and the double electric layers formed between the wall surfaces of the micro-channel 1 generate shearing motion, so that net charges in the fluid diffusion layer flow with the fluid to generate a flow potential on the metal film electrodes at the two ends, and the introduction of graphene 4 (shown in fig. 3 and 4) at the bottom of the micro-channel 1 can greatly enhance the flow potential generated when the fluid flows in the micro-channel 3.
Two ends of the graphene 4 are respectively connected with the metal film 2 and the upper stimulating electrode 6, and two ends of the metal film 2 are respectively connected with upper and lower sides of the graphene; correspondingly, graphene is also arranged at the bottom of the micro channel where the lower micro cantilever array 7 is located, and two ends of the graphene are respectively connected with the metal film 2 and the lower stimulation electrode 5.
The left end of the upper side graphene and the left end of the lower side graphene are equipotential under the connection of the metal thin film 2, and the right end of the upper side graphene and the right end of the lower side graphene can generate a large flowing potential under the flowing of liquid, so that a potential difference exists between the upper stimulating electrode 6 and the lower stimulating electrode 5 which are respectively connected with the upper side graphene and the lower side graphene.
When the structure, the material and the concentration and the components of the solution of the micro-channel are determined, the magnitude of the potential difference between the upper stimulation electrode 6 and the lower stimulation electrode 5 is in positive correlation with the fluid flow speed, so that the magnitude of the potential difference between the upper stimulation electrode 6 and the lower stimulation electrode 5 can be regulated in real time by regulating the ultrasonic excitation amplitude. In this embodiment, the height of the micro flow channel is about 30 μ M, the width of the micro flow channel is about 300. mu.m, PDMS and SU-8 photoresist are used as the materials constituting the micro flow channel, and the solution is 0.6M NaCl solution.
The direction of the potential difference between the upper stimulation electrode 6 and the lower stimulation electrode 5 depends on the liquid flowing direction (solid arrow) in the micro-channel 1, when the ultrasonic frequency is consistent with the resonance frequency of the cantilever beam in the upper micro-cantilever array 3, the upper micro-cantilever array 3 stimulates stronger sound flow to flow, the liquid is driven to flow in the micro-channel in a counterclockwise circulating manner, and the polarity of the output voltage at the two ends of the upper and lower stimulation electrodes is positive; when the ultrasonic frequency is consistent with the resonance frequency of the cantilever beams in the lower micro-cantilever array 7, the lower micro-cantilever array 7 stimulates strong acoustic current to flow, so that the liquid is driven to flow in a clockwise circulation manner in the micro-channel, and the polarity of the output voltage at the two ends of the upper stimulation electrode and the lower stimulation electrode is negative; thus, as shown in fig. 5, switching of the polarity of the output voltage across the stimulation electrodes can be achieved by switching the ultrasound frequency.
In order to improve the safe injection charge density of the stimulation electrode and improve the biological safety of the implanted electric stimulator, the surfaces of the stimulation electrodes 6 and 5 are modified by a conductive polymer in a biocompatible way, and the conductive polymer modified material is preferably graphene doped PEDOT: PSS conductive polymers.
The structure of the flexible implanted electric stimulator driven by ultrasound has better mechanical flexibility, can realize bending deformation of more than 90 degrees, does not depend on alternating current/direct current multi-mode controllable output of a hard integrated circuit, and is favorable for improving the signal conduction stability and biological safety of the implanted electric stimulator.
Example 2
In this embodiment, a control method of the flexible implantable electrical stimulator driven by ultrasound in embodiment 1 is to control the flow direction and flow rate of the solution in the micro channel by adjusting the frequency and amplitude of the ultrasound, so as to control the magnitude and polarity of the output voltage of the electrical stimulator. Meanwhile, the size and polarity of the output voltage of the electric stimulator are controlled by adjusting the type and concentration of the solution containing free ions, adjusting the size of the inner diameter of the micro-flow channel, adjusting the size, distribution and quantity of the micro-cantilever array or the inclination angle of the micro-cantilever and cooperating with the ultrasonic excitation condition.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (14)
1. An ultrasonically driven flexible implantable electrical stimulator characterized by: the device comprises a micro-channel, wherein the micro-channel is annular, and a solution containing free ions is filled in the micro-channel; the inner wall of the micro flow channel is provided with a micro cantilever array; and a conductive film is laid in the micro-channel along the trend of the micro-channel, and a pair of stimulation electrodes are led out of the micro-channel by the conductive film.
2. The ultrasonically driven flexible implantable electrical stimulator of claim 1, wherein: still include graphite alkene, graphite alkene is located the bottom surface of microchannel.
3. The ultrasonically driven flexible implantable electrical stimulator of claim 1, wherein: the conductive film is provided with an upstream end and a downstream end, and the upstream end and the downstream end respectively lead out stimulation electrodes to the outside of the micro-channel.
4. The ultrasonically driven flexible implantable electrical stimulator of claim 1, wherein: the micro-cantilever array is composed of a plurality of obliquely arranged micro-cantilevers, and the micro-cantilevers and the inner wall of the micro-channel form a certain included angle on a vertical surface, wherein the included angle is 10-60 degrees.
5. The ultrasonically driven flexible implantable electrical stimulator of claim 4, wherein: the length of the micro-cantilever is 10-999 mu m.
6. The ultrasonically driven flexible implantable electrical stimulator of claim 4, wherein: the free end of the micro cantilever beam is of a pointed structure, and the angle of the tip of the micro cantilever beam is 5-45 degrees.
7. The ultrasonically driven flexible implantable electrical stimulator of claim 4, wherein: the micro cantilever arrays are at least two groups and are arranged on the inner walls of two sides of the micro flow channel, and the number of the micro cantilevers in the arrays is 1-100.
8. The ultrasonically driven flexible implantable electrical stimulator of claim 1, wherein: the solution containing free ions comprises NaCl solution, KCl solution or CaCl 2 And (3) solution.
9. The ultrasonically driven flexible implantable electrical stimulator of claim 1, wherein: the material of the conductive film includes a metal or a conductive metal oxide.
10. The ultrasonically driven flexible implantable electrical stimulator of claim 1, wherein: the width of the micro-channel is 10-9 mm, the height of the micro-channel is 10-999 μm, the length of the micro-cantilever is 10-999 μm, the thickness of the conductive film is 10-999 nm, and the thickness of the stimulating electrode is 10-999 nm.
11. The ultrasonically driven flexible implantable electrical stimulator of claim 1, wherein: the surface of the stimulating electrode is modified with a conductive polymer through biocompatibility.
12. An ultrasonically driven flexible implantable electrical stimulator characterized by: the micro-channel stimulation device comprises a micro-channel, a micro-cantilever array, a conductive film and a pair of stimulation electrodes, wherein a solution containing free ions in the micro-channel forms a fluid which flows in a directional and circulating manner through ultrasonic excitation and generates a flow potential by shearing movement with the micro-channel, and the stimulation electrodes output an electrical stimulation signal through equipotential conductive connection of the conductive film.
13. The control method of the flexible implanted electric stimulator driven by ultrasound according to any one of claims 1 to 12, wherein: and controlling the flow direction and the flow speed of the solution in the micro-channel by adjusting the frequency and the amplitude of the ultrasonic waves, and further controlling the magnitude and the polarity of the output voltage of the electric stimulator.
14. The control method according to claim 13, characterized in that: the size and polarity of the output voltage of the electric stimulator are controlled by adjusting the type and concentration of the solution containing free ions, the size of a micro-channel, the size, distribution and quantity of a micro-cantilever array or the inclination angle of the micro-cantilever and the ultrasonic excitation condition.
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| WO2017113179A1 (en) * | 2015-12-30 | 2017-07-06 | 深圳先进技术研究院 | Head-mounted ultrasound stimulation device and system |
| CN114220910A (en) * | 2021-12-01 | 2022-03-22 | 华中科技大学 | Ultrasonic-driven flexible piezoelectric device for organism and preparation and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017113179A1 (en) * | 2015-12-30 | 2017-07-06 | 深圳先进技术研究院 | Head-mounted ultrasound stimulation device and system |
| CN114220910A (en) * | 2021-12-01 | 2022-03-22 | 华中科技大学 | Ultrasonic-driven flexible piezoelectric device for organism and preparation and application thereof |
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| 王永兵;张根福;颜国正;姜萍萍;程思漫;: "基于腔内压力评价的植入式结肠电刺激系统设计与动物实验", 生物医学工程与临床, no. 05, 30 July 2012 (2012-07-30), pages 18 - 22 * |
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