WO2021223684A1 - 一种避免活性非消融电极附近组织损伤的装置 - Google Patents

一种避免活性非消融电极附近组织损伤的装置 Download PDF

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WO2021223684A1
WO2021223684A1 PCT/CN2021/091601 CN2021091601W WO2021223684A1 WO 2021223684 A1 WO2021223684 A1 WO 2021223684A1 CN 2021091601 W CN2021091601 W CN 2021091601W WO 2021223684 A1 WO2021223684 A1 WO 2021223684A1
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tissue
ablation
electrode
insert
electrolysis
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PCT/CN2021/091601
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English (en)
French (fr)
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鲁宾斯基·鲍里斯
鲁格纳尼·弗兰克
赵国江
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电冷科学有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/14—Probes or electrodes therefor

Definitions

  • the present application uses a method and device in the field of tissue ablation, especially a device for avoiding tissue damage near the active non-ablative electrode.
  • Thermal methods involving high temperatures generally heat tissue by consuming electrical energy in the tissue at the target site.
  • non-thermal ablation methods there are several methods that also involve the use of electricity, but the dose causes only limited or no thermal damage.
  • These technologies include: various nanosecond pulse electroablation technologies; technologies based on reversible electroporation (reversible permeation of cell membranes with electric fields, such as electrochemical treatment); technology based on irreversible electroporation (irreversible permeation of cell membranes with electric fields), Technology based on tissue ablation and electrolysis products produced on the electrodes.
  • Electrolysis is an electrochemical process in which electrons are transferred between ions through an interface. This process occurs at the interface between an electrical conduit (electrode) that transfers charges through electrons and an electrical conduit (electrolyte) that transfers electrical charges through the movement of ionic species.
  • the method involves passing current through an electrolyte between two electrodes of different polarity immersed in the electrolyte. In this process, positive ions (anions) are drawn into the negative electrode (cathode), and negative ions (cations) are drawn into the positive electrode (anode). At the cathode, electrons are transferred to anions, and at the anode, electrons are absorbed by cations.
  • the schematic diagram of the electrolysis reaction in the salt solution is shown in Figure 2.
  • the electrochemical reaction only occurs at the interface between the electrode and the ionic solution. Although the electrochemical reaction only occurs on the electrode, the ionic products of the electrochemical process on the electrode diffuse out from the electrode into the body of the solution in the solution.
  • the electrolysis reaction is driven by two reactions that occur, one at each electrode. Each reaction creates a potential difference between the electrode and the surrounding electrolyte. In order for the reaction to continue between the two electrodes, there must be an electrically neutral region relative to the potential between the electrodes, as shown in Figure 3. This electrically neutral region forces the entire potential difference to appear on the external electrical load and is an essential part of the electrolysis process. Later, we will show the relevance of this fact to the application.
  • Figure 4 shows that when two electrodes with different polarities are inserted into an ion-conducting biological tissue, an electrolysis process similar to that in a solution occurs in the tissue. Obviously different electrochemical reactions occur at the anode and cathode.
  • the chemicals produced on the electrodes may be toxic to living cells.
  • the formation of Cl2 and the change of pH occur during the electrolysis of salt solutions.
  • the use of electrolysis to ablate bad tissue has been established.
  • a book published in the mid-nineteenth century provides detailed information related to the current practice of using electrolysis to ablate tissue and living cells [17].
  • tissue ablation by electrolysis is performed between two electrodes in contact with the tissue.
  • several excellent papers have been published [18]-[21], [8], [9].
  • the electrochemical reactions on the electrodes produce chemicals that are toxic to cells. These include changes in pH and various chlorines. The electrolysis reaction only occurs on the electrode.
  • the product of the reaction diffuses from one electrode to the other through Brownian motion or electrical diffusion, which is a function of concentration, the potential difference between the electrodes, and the charge.
  • tissue damage spreads outward from the electrode over time.
  • tissue ablation by methods involving full or partial electrolysis There are two important aspects of tissue ablation by methods involving full or partial electrolysis, which are relevant to this application.
  • the electrochemical reaction of electrolysis requires two electrodes with different potentials in the electrolyte solution (tissue).
  • the two electrodes can conduct ionic charges, and the electric potential difference must be generated by the charges to drive the electrolysis reaction.
  • One electrode cannot produce electrolysis.
  • the second particularly relevant fact is that on two electrodes of different polarity, the nature of tissue damage is different [16], [11], [15], [22], [23]. This is to be expected, because different chemicals will be produced on electrodes of different polarities.
  • the present application relates to a situation in which it is desired to perform ablation including electrolysis around only one polarity electrode, so as to avoid damage to tissue near the second polarity electrode.
  • the reason for using electrolysis to cause damage on only one polarity electrode is to ensure precise and controllable treatment, in which the tissue ablation process is only one type, that is, it is produced by one type of electrolysis polarity, and only in one Precisely placed electrodes.
  • This application relates to tissue ablation by electrolysis alone or a combination of electrolysis and other tissue ablation methods, such as cryosurgery, reversible and irreversible electroporation, nanosecond pulses, and radiofrequency.
  • tissue ablation by electrolysis alone or a combination of electrolysis and other tissue ablation methods, such as cryosurgery, reversible and irreversible electroporation, nanosecond pulses, and radiofrequency.
  • a device for avoiding tissue damage near the active non-ablation electrode when a certain electrode is used for tissue ablation is composed of:
  • the insert is in contact with the non-ablation electrode on one side, and the other side is in contact with the tissue, as a separation between the tissue and the insert;
  • c) Choose an insert with a certain thickness.
  • the thickness should be such that during the ablation of the tissue at the electrode, most of the electrolysis products from the inactive electrode will not extend to the tissue on the side of the insert that is in contact with the tissue.
  • the insert is made of gel such as agar or sodium alginate plus saline (preferably normal saline).
  • gel such as agar or sodium alginate plus saline (preferably normal saline).
  • the insert is an insert with a thickness from 1 mm to 40 mm, preferably 5 mm to 20 mm is a better choice
  • the insert is made of pH buffered saline.
  • the insert is made of ion exchange resin.
  • a method for avoiding tissue damage near the active non-ablation electrode when a certain electrode is used for tissue ablation comprising:
  • the ion-conducting tissue protection insert is placed between the active non-ablation electrode and the tissue to be protected, so as not to be affected by the electrolysis product;
  • Figure 1 The macroscopic specimen of the liver after electrolysis.
  • Figure 2 Schematic diagram of the electrolysis process in physiological saline solution.
  • Figure 3 A schematic diagram of the potential distribution of the solution between the anode and the cathode and the position of the neutral potential relative to the anode and the cathode. It is important to note that there must be a neutral potential to react.
  • Fig. 4 A schematic diagram of the potential distribution in the tissue inserted between the anode and the cathode in the tissue and the position of the neutral potential relative to the anode and the cathode.
  • Figure 5 A schematic diagram illustrating the basic principles of this application, for the solid or gel of the ion-conducting insert between the non-ablation electrode and the skin.
  • FIG. 6 A schematic diagram illustrating the basic principle of the present application.
  • the ion conductive insert is an ionic fluid flowing between the non-ablation electrode and the skin.
  • Figure 7 A schematic diagram illustrating the basic principle of the present application, used for the situation where the insert is placed between the non-ablation electrode and the inside of the body.
  • Figure 8 The experiment proves the effectiveness of the insertion between the simulated tissue and the non-ablation electrode during the simulated typical electrolytic ablation process.
  • Figure 9 A photograph showing the experimental assembly. There is a kind of agarose gel that simulates tissue. Insert ablation electrodes. One side of the agarose gel is in contact with the simulated tissue, and the other side is in contact with the non-ablation surface electrode. The dimensions are shown in Figure 8, where the width of the insert is 4 cm.
  • Figure 10 Different views of the experimental setup in Figure 9.
  • FIG. 11 After simulating tissue ablation by electrolysis, the appearance of the experimental system, where the non-ablation electrode is the cathode and the ablation electrode is the anode. Note the pH staining near the electrode. It represents the degree to which the electrode product has penetrated in the tissue simulation and insert. In the insert between the non-ablation electrode and the edge of the tissue, the pH stain (representing the location of the electrolysis product generated on the non-ablation electrode) penetrated only 4 mm from the electrode surface. The stained area near the ablation electrode is oval, with a height of about 4 cm and a width of about 3 cm. These are typical clinical ablation sizes.
  • FIG 12 Experimental results, in which the cryosurgery probe is used as the anode, the non-ablation electrode is used as the cathode, cryosurgery is performed in it for 13 minutes, and then electrolysis is performed for 13 minutes, in which the ablation electrode (cryosurgery probe) is used as the anode . (Side view and top view)
  • Figure 13 The cross-sectional view illustrates the important results of the frozen electrolysis simulation process. It can be seen that the penetration degree of electrolysis products of the non-ablation electrode in the insert is only 5 mm.
  • Figure 14 The overall appearance of the result of repeating the experiment is shown in Figure 12.
  • Figure 15 The cross-sectional view illustrates the important results of the frozen electrolysis simulation process. It can be seen that the penetration degree of electrolysis products of the non-ablation electrode in the insert is only 3 mm.
  • Figure 16 Experimental results of cryo-electroporation, where the ablation electrode is the cathode and the non-ablation electrode is the anode. The results are similar in quality to other experiments with reverse electrode polarity.
  • FIG. 17 Experimental design of the irreversible electroporation protocol.
  • Figure 18 Results of an irreversible electroporation protocol involving electrolysis. Shown is an electroporation electrode that has been electrolytically corroded. There is pH dye staining near the ablation electrode, and there is no pH dye staining in the insert near the non-ablation electrode.
  • Figures 5, 6 and 7 show different possible embodiments of the concept and are introduced here to illustrate the concept.
  • the basic concept is that when the ablation electrode is in contact with the tissue to be ablated, the non-ablative electrode is separated by providing a continuous ion current between the two electrodes so as to contact the tissue while maintaining the contact between the ablation electrode and the tissue.
  • various designs using the same principle are also possible.
  • the second polarity electrode does not directly contact any part of the body or any tissue.
  • the contact between the body or tissue and the non-ablative electrode is made through ion-conducting "inserts.”
  • the size and material of the insert are such that the electrolysis products produced by the contact between the non-ablative electrode and the insert cannot reach the tissue during the period of electrolytic ablation treatment together with the problematic ablation electrode. During the operation, there are several methods to achieve this insertion.
  • the thickness can be evaluated by experiment of electrolytic dose, as described in the following experiment. It can also be analyzed and evaluated by solving the diffusion equation, where the boundary conditions of the inactive electrode are the charge transport and the resulting product amount, as well as the diffusivity values of different species based on the literature. This type of calculation can be found in the electrolytic ablation literature, namely [19], [21]. There are some ways to improve the performance of the protection plug-in. One is to use a pH buffer solution to prepare the gel.
  • the insert when the insert is between the electrode and the skin, the insert can be made with a pH solution compatible with the pH of the skin.
  • a pH compatible with the pH of the tissue can be selected.
  • Another technique is the manufacture of ion exchange resin or polymer inserts.
  • Another technique is to use a perfusion system as an insert, so that the electrolysis product is continuously washed away as it is produced, and replaced with a tissue-compatible pH buffer solution.
  • Another method is to make the interface between the insert and the membrane tissue impermeable to the toxic products of the electrode.
  • Fig. 5 is a schematic diagram of a situation where the ablation polarity electrode is inside the tissue instead of the ablation electrode outside the body.
  • an insert made of ionic substances is placed between the non-ablation electrode and the skin.
  • the insert must be in good electrical contact with the skin and the electrode, and must be wide enough so that the electrolysis product at the non-ablation electrode does not reach the skin during tissue ablation through the ablation electrode.
  • the insert can be made of ion conductive gel, which is placed on the skin at the beginning of the process and removed at the end of the process, thus avoiding all damage to the skin .
  • the gel can be prepared, for example, by performing agar with a pH buffered physiological salt solution. The thickness of the gel is calculated in such a way that during the tissue ablation process involving electrolysis, the electrolysis products cannot spread to the skin.
  • Fig. 6 is a schematic diagram of a situation where the ablation polarity electrode is inside the tissue instead of the ablation electrode outside the body.
  • a catheter for transporting ionic fluid is set between the non-ablation electrode and the skin. Ensure that the fluid is in good electrical contact with the skin and non-ablation electrodes.
  • this can be a plastic box with one side open to the skin and the other side in contact with non-ablation electrodes at the entrance and exit to promote flow.
  • the box can be placed in the opening part in contact with the tissue and sealed around the edge in contact with the tissue to promote blood flow through the catheter level to ensure the ion channel between the non-ablation electrode and the tissue.
  • the flow through the catheter must be large enough so that the electrolysis product at the non-ablation electrode does not reach the skin during tissue ablation through the ablation electrode.
  • the ionic fluid may be pH-buffered physiological saline.
  • Fig. 7 is a schematic diagram of a situation where the ablative polarity electrode is inside the tissue but the ablative electrode is also located in the body.
  • an insert made of ionic substances is placed between the non-ablation electrode and the tissue.
  • the insert must be in good electrical contact with the tissue and the electrode, and must be wide enough so that the electrolysis product at the non-ablation electrode does not reach the skin during tissue ablation through the ablation electrode.
  • the insert can be made of gel, which is placed in the body cavity or cavity formed in the tissue at the beginning of the procedure, and removed at the end of the procedure, thereby avoiding interference. All damage to the organization.
  • the gel can be made, for example, from agar with a pH-buffered physiological saline solution or ion exchange resin.
  • the actual experimental setup is shown in Figure 9.
  • the experimental setup includes an agarose gel simulation of the tissue as shown. All dimensions are shown in Figure 8.
  • a tissue simulation based on physiological saline was prepared. Mix one liter of water with 9 grams of sodium chloride and 7 grams of agarose (UltraPure agarose, Invitrogen). The solution was stirred and heated for 10 minutes, then the heating was stopped. After cooling for five minutes, two pH indicator dyes were added. For the electrolysis analysis near the anode, we add 1ml methyl red 9Sigma Aldrich (St.
  • the ablation electrode is a stainless steel cylinder with an outer diameter of 2.4 mm. In this experiment, it is used as an electrode.
  • the non-ablation electrode is a silver-aluminum sheet used as a cathode. The silver-aluminum sheet is placed on the container wall and is in good contact with the insert. The insert is in good contact with the non-ablation electrode and the tissue analog agarose.
  • This experiment is a typical tissue ablation performed through an electrolysis process, in which the ablation electrode delivers 50 mA through the tissue for 13 minutes, and the simulated tissue is inserted into the non-ablation electrode. Another view of the experimental design is shown in Figure 10.
  • FIG 11 shows the method and way of implementing this application.
  • This treatment plan is typical for electrolysis procedures for tissue ablation.
  • the figure on the right panel shows the overall appearance of the experimental system after tissue ablation through electrolysis.
  • the pH staining near the electrode is of special significance. They indicate the degree to which the electrode product produced on the surface of the electrode has penetrated in the agarose simulation of the tissue and in the agarose insert.
  • the pH stain (representing the location of the electrolysis product generated on the non-ablation electrode) penetrated only 4 mm from the electrode surface. In this experiment, the insert is 4 cm.
  • the interface between the edge of the tissue (skin) and the insert will not be damaged in any way by the electrolysis products at the non-ablation electrode.
  • the stained area near the ablation electrode is oval, with a height of about 4 cm and a width of about 3 cm. These are typical clinical ablation sizes used for electrolytic tissue ablation.
  • the insert eliminates the damage that the non-ablative electrode may cause to the tissue, the fact is that this configuration facilitates the electrolysis process, and the non-ablative electrode does not need to directly contact the tissue, except by facilitating the flow of ions between the electrodes The intermediate.
  • cryoelectrolysis electrolysis is performed after cryosurgery, which is called "cryoelectrolysis".
  • the experimental setup is similar to the previous experiment and the one in Figure 9. The main difference is that we use stainless steel cryosurgical probes (JOHN, FRANCO-SPEC and probes for cryosurgery systems) for the ablation electrodes. Steel cylinder used in previous electrolysis experiments. A typical freezing electrolysis operation was performed, in which freezing was first performed for 13 minutes. Immediately thereafter, an electrolysis process similar to that in the only electrolysis protocol in which only a 50 mA current was delivered between the ablation electrode and the non-ablation electrode for 13 minutes was performed.
  • Figure 12 shows the results of an experiment using a cryosurgery probe as an anode in which cryosurgery was performed for 13 minutes followed by electrolysis for 13 minutes.
  • the stained area near the ablation electrode is oval, 45 mm in height and 33 mm in width. These are the typical clinical ablation sizes expected from the cryo-electrolysis protocol. Although not directly related to this application, it is worth noting that at the outer edge of the ablation area, the staining around the ablation electrode is stronger. This is actually the goal of the freezing electrolysis protocol. In freezing electrolysis, it is desirable to add electrolytic ablation elements to the freezing ablation element at the edge of the frozen lesion, because cells can survive at the edge.
  • the insert eliminates the damage that the non-ablative electrode may cause to the tissue
  • this configuration facilitates the electrolysis process, and the non-ablative electrode does not need to directly contact the tissue, except by facilitating the flow of ions between the electrodes The intermediate.
  • Figures 14 and 15 show the results of repeated freezing electrolysis experiments discussed in Figures 12 and 13. The overall appearance of the result of this process is shown in Figure 14. It shows similar results. In the repeated experiments, the similarity between Fig. 13 and Fig. 15 is that the penetration depth of the electrolysis product from the non-ablation electrode into the insert and the appearance of the ablation area near the ablation electrode are also similar.
  • tissue treatment with irreversible electroporation can also produce electrolysis products.
  • the experimental setup is shown in Figure 17.
  • a 2.4mm steel electroporation probe is used as the ablation anode and is connected to the BTX electroporation power supply.
  • the non-ablation electrode is the electrode that is in contact with the insert and is also connected to the electroporation power source.
  • the loop is closed by agarose gel to form a tissue simulation and insert.
  • the irreversible electroporation scheme consists of sending a series of 198 rectangular electrical pulses at a frequency of 198 Hz and a frequency of 1 Hz.

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Abstract

一种消融不良组织的方法和装置，涉及通过将电极放置到或靠近不良组织的组织消融过程，该组织消融过程至少部分涉及组织与电极之间发生电解反应。电解过程包括电极中的电子与电极周围介质中的离子之间的电荷转移，这些离子将电荷从一个电极传输到另一个电极。电解过程需要两个不同极性的电极和一个离子介质，以促进电极之间的电荷转移。组织消融可以发生在不同极性的两个电极周围。在不同的电极极性下，损伤机理是不同的。通过该方法和装置，可以在涉及电解的过程中仅围绕一个极性的电极诱导组织消融，该过程可以与或不与其他组织消融方式相结合，同时避免第二极性电极周围的组织损伤。

Description

一种避免活性非消融电极附近组织损伤的装置
相关申请的交叉引用
本申请要求在2020年05月02日提交美国专利商标局、申请号为63/019,310、发明名称为“一种避免活性非消融电极附近组织损伤的装置”的美国临时专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本申请通过一种方法和装置在组织消融领域应用，尤其是一种避免活性非消融电极附近组织损伤的装置。
背景技术
在许多医疗手术中，如治疗良性或恶性肿瘤，重要的是能够以控制和集中的方式消融不希望保留的组织，而不影响周围理想的组织。多年来，已经开发了大量的微创方法作为切除手术的替代方法来选择性地破坏不希望保留组织的特定区域。很多技术具有特定的优点和缺点，这些技术被指示和禁止用于各种应用。组织消融的方法大致有两种，热消融和非热消融。热消融方法包括高温和低温。冷冻外科是一种涉及低温的方法。在冷冻外科手术中，冷冻探针被插入到不希望保留的组织中，该组织被冷冻，希望冷冻会破坏组织。涉及高温的热方法通常通过在目标部位的组织中消耗电能来进行组织加热。在非热消融方法中，有几种方法也涉及电的使用，但剂量仅造成有限的或没有热损伤。这些技术包括：各种纳秒脉冲电消融技术；基于可逆电穿孔的技术(具有电场的细胞膜的可逆渗透，如电化学治疗)；基于不可逆电穿孔的技术(具有电场的细胞膜的不可逆渗透)，基于组织消融的技术以及在电极上产生的电解产物。最近，一项涉及上述组织消融方式与电解结合的组织消融治疗专利已经发布(组织消融的方法、系统和设备_使用电解和渗透美国专利：10390874)。例如，提出将冷冻外科与由冷冻外科探针的电解结合起来。另一种组合涉及从相同或不同的电极的电穿孔和电解。
下一节将详细讨论电解过程。然而，在这一阶段应该强调的是，电解在离子溶液中的两个电极之间发生，并且需要至少两个极性不同的电极。两个电极的电化学过程是不 同的，一个在低pH值下发生，另一个在高pH值下发生，它们在不同极性的电极上引起不同的组织损伤模式[16]。图1说明了在阳极和阴极处理的肝脏之间的外观差异。通常，在上述组织消融的所有应用中，单独进行电解或与其他消融技术结合进行电解时，仅使用一种与一种电极极性的事件有关的组织消融方式即可。而不是在两个极性的电极上。当期望一次仅从一个极性电极进行与电解相关的消融时，本申请解决了由于需要两个不同极性的电极以产生电解过程而出现的难题。
电解是一种电化学过程，其中电子通过界面与离子之间转移。该过程发生在通过电子传递电荷的电导管(电极)和通过离子物质的运动传递电荷的电导管(电解质)之间的界面处。该方法涉及使电流通过浸没在电解质中的不同极性的两个电极之间的电解质中。在此过程中，正离子(阴离子)被吸入负极(阴极)，负离子(阳离子)被吸入正极(阳极)。在阴极，电子被传递到阴离子，在阳极，电子被阳离子吸收。盐溶液中的电解反应示意图如图2所示。
电化学反应仅在电极和离子溶液之间的界面发生。尽管电化学反应仅在电极上发生，但电极上电化学过程的离子产物在溶液中从电极向外扩散到溶液的主体中。当每个电极具有不同的电势时，通过发生的两个反应来驱动电解反应，每个电极处的一个。每个反应都会在电极和周围的电解质之间产生电势差。为了使反应在两个电极之间继续进行，相对于电极之间的电势，必须有一个电中性区域，如图3所示。该电中性区域迫使整个电势差出现在外部电负载上并且是电解过程中必不可少的部分。稍后，我们将显示该事实与申请的相关性。图4显示，当在离子导电生物组织中插入两个极性不同的电极时，组织中会发生与溶液中类似的电解过程。显然在阳极和阴极发生不同的电化学反应。
在组织中电解过程中，电极上产生的化学物质可能对活细胞有毒。例如，在盐溶液电解过程中会发生Cl2的生成和pH的变化。已经建立了使用电解消融不良组织的用途。19世纪中叶出版的一本书提供了与当前使用电解消融组织和活细胞的实践相关的详细信息[17]。如图4所示，在与组织接触的两个电极之间进行通过电解进行的组织消融。关于通过电解进行组织消融的基础知识，已发表了几篇优秀论文[18]-[21]，[8]，[9]。简而言之，电极上的电化学反应产生对细胞有毒的化学物质。其中包括pH值的变化和各种氯。电解反应仅在电极上发生。然而，反应的产物通过布朗运动或电扩散从一个电极扩散到另一个电极，这是浓度，电极之间的电势差和电荷的函数。随着有毒物质从电极向 外扩散到组织中，组织损伤随时间从电极向外扩展。通过涉及全部或部分电解的方法进行组织消融有两个重要方面，它们与本申请有关。首先，电解的电化学反应需要在电解质溶液(组织)中具有两个电位不同的电极，该两个电极能够传导离子电荷，必须通过该电荷产生电势差来驱动电解反应。一个电极不能产生电解。第二个特别相关的事实是，在两个不同极性的电极上，组织损伤的性质是不同的[16]，[11]，[15]，[22]，[23]。这是可以预料的，因为在不同极性的电极上会产生不同的化学物质。
发明内容
本申请涉及一种情况，其中希望在仅一个极性电极周围进行包括电解的消融，从而避免在第二极性电极附近损害组织。由于电解剂量必须足够高以确保在组织消融电极处进行所需的组织消融，这一事实使问题变得复杂。使用电解仅在一个极性电极上引起损伤的方案的原因是为了确保精确和可控的治疗，其中组织消融过程仅是一种类型，即由一种类型的电解极性产生，并且仅在一个精确放置的电极。本申请涉及单独通过电解的组织消融或通过电解与其他组织消融方式的组合消融，例如冷冻手术，可逆和不可逆电穿孔，纳秒脉冲，射频。当需要在一个电极(消融电极)上产生组织消融并避免影响另一电极(非消融电极)上的组织时，此处提出的概念对于采用至少两个电极的每种组织消融技术都具有价值。
根据本发明的一个方面，提供了一种在某一电极用于组织消融过程中，避免活性非消融电极附近组织损伤的装置，该装置由：
a)在非消融电极和组织之间分隔的离子导电插入物；
b)插入物与非消融电极一侧接触，另一侧与组织接触，在组织和插入物之间作为分隔；
c)选择具有一定厚度的插入物，其厚度应使得在电极处的组织消融过程中，来自非活性电极的电解产物大部分不会扩展到与组织接触的插入物一侧的组织。
可选地，所述插入物由琼脂或海藻酸纳加盐水(最好是生理盐水)等凝胶制成。
可选地，所述插入物是厚度从1毫米到40毫米的插入物，优选的5毫米到20毫米是更好的选择
可选地，所述插入物由pH缓冲盐水制成。
可选地，所述插入物由离子交换树脂制成。
根据本发明的另一个方面，提供了一种在某一电极用于组织消融过程中，避免活性非消融电极附近组织损伤的方法，该装置：
a)在涉及电解的组织消融过程中，将离子导电的组织保护插入物置于活性非消融电极和要保护的组织之间，以免受到电解产物的影响；
b)以这样的方式选择插入物的厚度和材料：在涉及电解的组织消融过程中，非消融组织电极上产生的电解产物不能一直扩散到插入物与组织接触一侧的组织；
c)在还涉及电解的过程中，在希望消融组织的位置将组织消融电极插入组织中；
d)在电极之间施加电流，直到确定不良组织被消融为止；
e)从需要保护的组织上移除插入物；
f)移除非消融电极和消融电极。
附图说明
图1：肝脏电解处理后的宏观标本。
图2：生理盐水溶液中电解过程的示意图。
图3：溶液在阳极和阴极之间的电势分布以及相对于阳极和阴极的中性电势的位置示意图。重要的是要注意，必须有中性电位才能发生反应。
图4：插入在组织中的阳极和阴极之间的组织中的电势分布以及相对于阳极和阴极的中性电势的位置的示意图。
图5：说明本申请的基本原理的示意图，用于离子导电插入物在非消融电极和皮肤之间的固体或凝胶。
图6：说明本申请的基本原理的示意图，所述离子导电插入物是流动在非消融电极和皮肤之间的离子流体。
图7：说明本申请的基本原理的示意图，用于将插入物放置在非消融电极和身体内部之间的情况。
图8：实验证明了在模拟的典型电解消融过程中，模拟组织和非消融电极之间插入的有效性。
图9：显示实验组装的照片。有一种模拟组织的琼脂糖凝胶，插入消融电极，插入琼脂糖 凝胶的一侧接触模拟组织，另一侧接触非消融表面电极。尺寸如图8所示，这里插入物的宽度为4厘米。
图10：图9中实验设置的不同视图。
图11：在通过电解模拟组织消融后，实验系统的外观，其中非消融电极为阴极，消融电极为阳极。注意电极附近的pH染色。它代表了电极产物在组织模拟和插入物中已穿透的程度。在非消融电极和组织边缘之间的插入物中，pH染色(代表在非消融电极上产生的电解产物的位置)仅从电极表面渗透了4毫米。消融电极附近的染色区域是椭圆形，其高度约为4厘米，宽度约为3厘米。这些是典型的临床消融尺寸。
图12：实验结果，其中冷冻外科手术探针作为阳极，非消融电极作为阴极，在其中进行13分钟的冷冻外科手术，然后进行13分钟的电解，其中消融电极(冷冻外科手术探针)作为阳极。(侧视图和俯视图)
图13：横截面图说明了冷冻电解模拟过程的重要结果。可以看出，插入物中非消融电极的电解产物渗透程度仅为5mm。
图14：重复进行该实验的结果的整体外观如图12所示。
图15：横截面图说明了冷冻电解模拟过程的重要结果。可以看出，插入物中非消融电极的电解产物渗透程度仅为3mm。
图16：冷冻电穿孔的实验结果，其中消融电极为阴极，非消融电极为阳极。结果与反电极极性的其他实验在质量上相似。
图17：不可逆电穿孔协议的实验设计。
图18：涉及电解的不可逆电穿孔协议的结果。显示的是经过电解腐蚀的电穿孔电极，在烧蚀电极附近有pH染料染色，在非消融电极附近的插入物中没有pH染料染色。
具体实施方式
图5、6和7示出了该概念的不同的可能实施例，并且在这里被引入以示出该概念。基本概念是，当消融电极与需要消融的组织接触时，非消融电极通过在两个电极之间提供连续离子流的方式分离，以便与组织接触，同时保持消融电极与组织的接触。非消融电极与用于以足够的距离向组织提供离子流的连续性的装置之间的界面，使得在非消融电极处的电解产物不能到达组织。显然，采用相同原理的各种设计也是可能的。基本概念 是，虽然我们要用于消融的极性电极与要消融的组织接触，但第二极性电极并不与身体或任何组织的任何部位直接接触。为了确保电极之间所需的离子流，身体或组织与非消融电极之间的接触是通过离子导电的“插入物”进行的。插入件的尺寸和材料使得在与问题消融电极一起进行电解消融治疗的时间段内，由非消融电极与插入件接触产生的电解产物不能到达组织。在手术过程当中，有几种方法可以实现这种插入，一种是离子凝胶溶液，其足够宽并且使非消融电极与组织保持足够的距离，以使来自非消融电极的电解产物在形成期间不会扩散到与插入物接触的组织。可以通过电解剂量的实验评估厚度，如以下实验所述。也可以通过求解扩散方程来进行分析评估，其中非活性电极的边界条件是电荷输送和随之产生的产物量，以及基于文献的不同物种的扩散率值。这种类型的计算可以在电解消融文献中找到，即[19]，[21]。有一些方法可以改善保护插件的性能。一种是使用pH缓冲溶液制备凝胶。例如，当插入物在电极和皮肤之间时，可以用与皮肤的pH相容的pH溶液制成插入物。或者，如果插入物在体内，例如在胃肠道内或在血管系统内或在组织内或在肺内，则可以选择与该组织的pH相容的pH。另一种技术是制造离子交换树脂或聚合物的插入物。另一种技术是使用灌注系统作为插入物，以使电解产物在产生时被连续冲洗掉，并用与组织相容的pH缓冲溶液代替。另一种方法是使插入物与膜组织之间的界面不渗透电极的有毒产物。总之，一旦理解了原理，就有许多方法可以实现一种设计，其中阻止非消融电极产生的电解产物到达组织，而同时在电解过程中与组织消融电极一起起作用。
图5是消融极性电极在组织内部而非消融电极在身体外部的情况的示意图。为了确保离子在电极之间的传输，将由离子物质制成的插入物放置在非消融电极和皮肤之间。插入件必须与皮肤和电极良好电接触，并且必须足够宽，以使在非消融电极处的电解产物在通过消融电极进行组织消融的过程中不会到达皮肤。在一个简单的过程中，插入物可以由离子导电凝胶制成，该离子导电凝胶在过程开始时被放置在皮肤上，并在过程结束时被移除，从而避免了对皮肤的所有损害。该凝胶可以例如通过用pH缓冲的生理盐溶液进行琼脂制备。凝胶的厚度以这样的方式计算：在涉及电解的组织消融过程中，电解产物不能扩散到皮肤上。
图6是消融极性电极在组织内部而非消融电极在身体外部的情况的示意图。为了确保离子在电极之间的输送，在非消融电极和皮肤之间设置了用于输送离子流体的导管。确 保流体与皮肤和非消融电极良好电接触。例如，这可以是一个塑料盒，该塑料盒的一侧向皮肤敞开，另一侧与入口和出口处的非消融电极接触，以促进流动。该盒子可以放置在与该组织接触的开口部分，并密封在周围与组织接触的边缘，以促进血流通过导管的水平确保非消融电极和组织之间的离子通道。通过导管的流量必须足够大，以使在非消融电极处的电解产物在通过消融电极进行组织消融的过程中不会到达皮肤。离子流体可以是pH缓冲的生理盐水。
图7是消融性极性电极在组织内部而非消融性电极也位于体内的情况的示意图。为了确保电极之间的离子流动，将由离子物质制成的插入物放置在非消融电极和组织之间。插入物必须与组织和电极良好电接触，并且必须足够宽，以使在非消融电极处的电解产物在通过消融电极进行组织消融的过程中不会到达皮肤。在简单的过程中，插入物可以由凝胶制成，该凝胶在过程开始时被置于体腔内或在组织中形成的腔内，并在过程结束时将其移除，从而避免了对组织的所有损害。凝胶可以例如通过琼脂用pH缓冲的生理盐水溶液或离子交换树脂制成。
实施例：
进行实验以证明图5中所述类型的插入物能够避免在组织中典型的电解消融过程中由非消融电极产生的电解产物到达组织(皮肤)的能力。实验设计的示意图如图8所示。它由生理盐水制成的凝固琼脂凝胶组成，用pH染料模拟组织，以监测电解产物在模拟活性电极的电极附近的传播程度。被插入组织中。组织模拟物的边缘(皮肤)和非消融电极之间的插入物是由琼脂凝胶制成的，带有pH缓冲液和pH染料。实验的目的是表明，在典型的电解消融程序中，插入物可促进电解过程的发生，同时避免非消融电极处的电解产物到达组织(皮肤)。
实际的实验设置如图9所示。该实验设置包括如图所示的组织的琼脂糖凝胶模拟。所有尺寸均如图8所示。如[14]中所述，准备了基于生理盐水的组织模拟。将一升水与9克氯化钠和7克琼脂糖(UltraPure琼脂糖，Invitrogen)混合。将溶液搅拌并加热10分钟，然后停止加热。冷却五分钟后，添加了两种pH指示剂染料。对于阳极附近的电解分析，我们在每100ml琼脂糖溶液中添加1ml甲基红9Sigma Aldrich(美国密苏里州圣路易斯)，对于阴极附近的电解分析，我们使用乙醇中的0.5wt％酚酞溶液(sigma Aldrich)浓度为 每100毫升琼脂糖溶液1毫升)。对于插入物，我们向该溶液中添加了pH缓冲液，每升50ml，pH值为6.86。如图9所示，将凝固的琼脂糖溶液切成一定尺寸并放置在实验装置中。我们对所有实验都使用了相同的实验设置。
电解
在通过电解模拟组织消融的实验中，消融电极是外径为2.4mm的不锈钢圆柱体，在本实验中，它作为电极。非消融电极是用作阴极的银铝片，该银铝片放置在容器壁上并与插入物良好接触。插入物与非消融电极以及组织模拟琼脂糖接触良好。该实验是通过电解过程进行的典型组织消融，其中消融电极将50mA的电流输送通过组织，持续13分钟，并将模拟组织插入到非消融电极中。实验设计的另一个视图如图10所示。
图11展示了实现本申请的方法和方式。该治疗方案对于组织消融的电解程序而言是典型的。该图在右侧面板上显示了通过电解模拟组织消融后实验系统的整体外观。电极附近的pH染色具有特殊意义。它们表示在电极的表面上产生的电极产物在组织的琼脂糖模拟中和在琼脂糖插入物中已渗透的程度。在非消融电极和组织边缘之间的插入物中，pH染色(代表在非消融电极上产生的电解产物的位置)仅从电极表面渗透了4毫米。在此实验中，插入物为4厘米。因此，显然在组织边缘(皮肤)和插入物之间的界面不会受到非消融电极处电解产物的任何损害。消融电极附近的染色区域是椭圆形，其高度约为4厘米，宽度约为3厘米。这些是用于电解组织消融的典型临床消融尺寸。与插入物消除了非消融电极可能对组织造成的损害这一事实一样重要的事实是，这种配置有助于电解过程，并且非消融电极无需直接接触组织，除非通过促进离子在电极之间流动的中间体。
冷冻电解
我们已经进行了几个实验，其中冷冻手术后进行电解，称为“冷冻电解”。实验设置与之前的实验以及图9中的相似。主要区别在于，我们为消融电极使用了插入不锈钢的冷冻外科探针(冷冻外科系统的JOHN，FRANCO-SPEC和探针)。以前的电解实验中使用的钢瓶。进行了典型的冷冻电解操作，其中冻结首先进行13分钟。此后立即进行类似于仅在消融电极和非消融电极之间输送50mA电流13分钟的唯一电解规程中的电解过程的。图12显示了将冷冻外科手术探针用作阳极的实验结果，在该阳极中进行13分钟的冷冻外科手术后再进行13分钟的电解。
详细的信息可以在图13中找到。出现了一些重要的观察结果，以支持我们的申请的价 值。电极附近的pH染色具有特殊意义。它们表示在电极的表面上产生的电极产物在组织的琼脂糖模拟中和在琼脂糖插入物中已渗透的程度。在非消融电极和组织边缘之间的插入物中，pH染色(代表在非消融电极上产生的电解产物的位置)仅从电极表面渗透了5毫米。在此实验中，插入物为4厘米。因此，显然在组织边缘(皮肤)和插入物之间的界面不会受到非消融电极处电解产物的任何损害。消融电极附近的染色区域是椭圆形，高度为45毫米，宽度约为33毫米。这些是从冷冻电解方案中预期得到的典型临床消融尺寸。尽管与本申请没有直接关系，但是值得注意的是，在消融区域的外边缘处，消融电极周围的染色更强。这实际上是冷冻电解规程的目标。在冷冻电解中，希望在冰冻病灶的边缘向冰冻消融元素中添加电解消融元素，因为细胞可以在该边缘处存活。与插入物消除了非消融电极可能对组织造成的损害这一事实一样重要的事实是，这种配置有助于电解过程，并且非消融电极无需直接接触组织，除非通过促进离子在电极之间流动的中间体。
图14、15中显示了重复进行图12和图13中讨论的冷冻电解实验的结果。该过程结果的整体外观如图14所示。它显示了相似的结果。在重复实验中，图13和图15之间类似，电解产物从非消融电极渗透到插入物中的深度以及在消融电极附近的消融区域的外观也相似。
重复与上述讨论类似的实验，这次以消融电极为阴极，非消融电极为阳极。图16显示了结果。可以看出，在这种情况下，pH染料从非消融电极渗入插入件的深度仅为5mm。
电穿孔
据报道，用不可逆电穿孔进行组织处理也可产生电解产物。在这里，我们使用了与以前的实验类似的配置，以观察插入件设计是否还可以消除非消融性电极可能产生的有害影响。实验装置如图17所示。一个2.4mm钢电穿孔探针用作消融阳极，并连接到BTX电穿孔电源。非消融电极是与插入件接触的电极，并且还连接到电穿孔电源。通过琼脂糖凝胶闭合回路，形成组织模拟和插入物。不可逆的电穿孔方案包括以198Hz的频率以1Hz的频率发送一系列198个矩形电脉冲，这些电脉冲的电压为3000V，脉冲长度为99μs。一旦电穿孔程序停止，插入物上就会出现非常浅的染色，该染色很快消失，这可能是由于pH缓冲液的作用。在活性电极附近观察到一些染色，表明存在电解。电穿孔探针上的腐蚀也证明了这一点，所有这些都显示在图18中。图18显示了涉及电解的不可逆电穿孔 方案的结果。结果表明，电穿孔电极已经发生了电解腐蚀，在消融电极附近显示了琼脂糖模拟组织中的pH染料染色，在非消融电极附近的插入物中没有看到pH染料染色。应当注意的是，在操作后不久，插入件就在非消融电极附近被染色，并且染色立即消失了，
这可能是由于pH缓冲液的作用所致。
总之，我们的实验证明了该方法和装置作为消除任何涉及电解的组织消融方案的价值，这种方法是由电解引起的组织消融仅发生在一个极性电极附近而不发生在另一个极性电极附近。这提供了对在期望的消融部位处的组织消融机制的更大控制。
引用：
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Claims (6)

  1. 一种在某一电极用于组织消融过程中，避免活性非消融电极附近组织损伤的装置，该装置由：
    a)在非消融电极和组织之间分隔的离子导电插入物；
    b)插入物与非消融电极一侧接触，另一侧与组织接触，在组织和插入物之间作为分隔；
    c)选择具有一定厚度的插入物，其厚度应使得在电极处的组织消融过程中，来自非活性电极的电解产物大部分不会扩展到与组织接触的插入物一侧的组织。
  2. 根据权利要求1所述的避免活性非消融电极附近组织损伤的装置，其特征在于：所述插入物由琼脂或海藻酸纳加盐水(最好是生理盐水)等凝胶制成。
  3. 根据权利要求1所述的避免活性非消融电极附近组织损伤的装置，其特征在于：所述插入物是厚度从1毫米到40毫米的插入物，优选的5毫米到20毫米是更好的选择。
  4. 根据权利要求1所述的避免活性非消融电极附近组织损伤的装置，其特征在于：所述插入物由pH缓冲盐水制成。
  5. 根据权利要求1所述的避免活性非消融电极附近组织损伤的装置，其特征在于：所述插入物由离子交换树脂制成。
  6. 一种在某一电极用于组织消融过程中，避免活性非消融电极附近组织损伤的方法，该方法：
    a)在涉及电解的组织消融过程中，将离子导电的组织保护插入物置于活性非消融电极和要保护的组织之间，以免受到电解产物的影响；
    b)以这样的方式选择插入物的厚度和材料：在涉及电解的组织消融过程中，非消融组织电极上产生的电解产物不能一直扩散到插入物与组织接触一侧的组织；
    c)在还涉及电解的过程中，在希望消融组织的位置将组织消融电极插入组织中；
    d)在电极之间施加电流，直到确定不良组织被消融为止；
    e)从需要保护的组织上移除插入物；
    f)移除非消融电极和消融电极。
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