JP6594901B2 - パルス電界を使用した細胞の細胞内効果の選択的調節 - Google Patents
パルス電界を使用した細胞の細胞内効果の選択的調節 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- 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
- A61N1/327—Applying electric currents by contact electrodes alternating or intermittent currents for enhancing the absorption properties of tissue, e.g. by electroporation
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- 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
- A61B18/1206—Generators therefor
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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
- A61B18/14—Probes or electrodes therefor
- A61B18/1477—Needle-like probes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
- A61B90/36—Image-producing devices or illumination devices not otherwise provided for
- A61B90/37—Surgical systems with images on a monitor during operation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/06—Electrodes for high-frequency therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/08—Arrangements or circuits for monitoring, protecting, controlling or indicating
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/40—Applying electric fields by inductive or capacitive coupling ; Applying radio-frequency signals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B2017/00017—Electrical control of surgical instruments
- A61B2017/00137—Details of operation mode
- A61B2017/00154—Details of operation mode pulsed
- A61B2017/00172—Pulse trains, bursts, intermittent continuous operation
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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
- A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
- A61B2018/00577—Ablation
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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
- A61B18/1206—Generators therefor
- A61B2018/1246—Generators therefor characterised by the output polarity
- A61B2018/126—Generators therefor characterised by the output polarity bipolar
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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
- A61B18/14—Probes or electrodes therefor
- A61B2018/1405—Electrodes having a specific shape
- A61B2018/1425—Needle
- A61B2018/143—Needle multiple needles
Description
本願は、2014年5月12日出願の米国仮出願第61/992,023号の開示に依拠し、その出願日の優先権及び利益を主張するものであり、その開示全体が、参照により本明細書に組み込まれる。
背景
電気穿孔法に対する二峰性正弦波の効果を調査するために、求心性の核を有する球状細胞に対する周波数ドメイン中のラプラス方程式を解いた解析モデルを実施した(Yao,C.G.,et al.,Study of transmembrane potentials of inner and outer membranes induced by pulsed−electric−field model and simulation.IEEE Trans Plasma Sci,2007.35(5):p.1541−1549)。各細胞領域を誘電率及び導電率の両方によって特徴付け、周波数でのTMP及びnTMP計算精度がMHz範囲であることを確実にする。簡潔に、時間ドメイン中の低周波(250kHz)及び高周波(1MHz)電界を統合し、ラプラス変換をとることによって信号を周波数ドメインに変換し、信号に細胞の幾何学及び誘電特性を表す伝達関数を掛け(Kotnik,T.and D.Miklavcic,Theoretical evaluation of voltage inducement on internal membranes of biological cells exposed to electric fields.Biophysical Journal,2006.90(2):p.480−491)、逆ラプラス変換をとることによって結果を時間ドメインに変換して戻すことによって、解を得た。最適化されたバーストの臨床的有用性を示すために、標準的な技術に従って、無限組織ドメイン中の2つの針電極(φ1mm)に対して、ラプラス方程式を解いた。電極を0.1cm離間し、印加電圧を20kVに設定した。
として決定した。
として決定し、
Claims (26)
- 電気穿孔システムであって、
少なくとも1つの電極と、
前記少なくとも1つの電極に連結され、かつ連続パルス間に遅延を伴う複数の電気パルスを標的領域に印加するように構成される電圧パルス発生器であって、各パルスの長さ及び連続パルス間の前記遅延は、第1の電気穿孔領域及び第2の電気穿孔領域を作り出すように最適化される、電圧パルス発生器と、を備え、
前記第2の電気穿孔領域において、選択された細胞のみが前記複数の電気パルスの影響を受け、
前記複数の電気パルスは、矩形パルス波、ランプ波、指数関数減衰波、または正弦波である電界波形を含み、
前記電界波形は、連続してマイクロ秒オーダのパルスと交互になったナノ秒オーダのパルスを含む、システム。 - 前記電圧パルス発生器は、前記第2の電気穿孔領域内で、癌細胞が細胞分裂の減速または停止によって阻害されるように、複数の電気パルスを印加するように構成される、請求項1に記載のシステム。
- 前記電圧パルス発生器は、前記第2の電気穿孔領域内で、癌細胞が遊走の減速または停止によって阻害されるように、複数の電気パルスを印加するように構成される、請求項1に記載のシステム。
- 前記電圧パルス発生器は、前記第2の電気穿孔領域内で、癌細胞が血液及び栄養素の輸送の低減によって阻害されるように、複数の電気パルスを印加するように構成される、請求項1に記載のシステム。
- 前記電圧パルス発生器は、前記第1の電気穿孔領域内で、癌細胞及び非癌細胞が壊死によって死滅させられるように、複数の電気パルスを印加するように構成される、請求項1に記載のシステム。
- 前記電圧パルス発生器は、前記第2の電気穿孔領域内で、癌細胞がアポトーシスによって死滅させられるように、複数の電気パルスを印加するように構成される、請求項1に記載のシステム。
- 前記電圧パルス発生器は、いくつかの癌細胞及びいくつかの非癌細胞が前記第1の電気穿孔領域内で死滅させられるように、複数の電気パルスを印加するように構成される、請求項1に記載のシステム。
- 前記電圧パルス発生器は、いくつかの癌細胞が前記第2の電気穿孔領域内で死滅させられるか、または阻害され、いくつかの非癌細胞が前記第2の電気穿孔領域内で残されるように、複数の電気パルスを印加するように構成される、請求項1に記載のシステム。
- 前記電圧パルス発生器は、癌細胞及び非癌細胞の両方が、それらの膜内外電位の致死限界値への増加の結果として、前記第1の電気穿孔領域内で死滅させられるように、複数の電気パルスを印加するように構成される、請求項5に記載のシステム。
- 前記電圧パルス発生器は、癌細胞が、それらの核膜内外電位の致死限界値への増加の結果として、前記第2の電気穿孔領域内で死滅させられるように、複数の電気パルスを印加するように構成される、請求項2に記載のシステム。
- 連続パルス間の前記遅延は、各パルスの前記長さよりも大きい、請求項1に記載のシステム。
- 連続パルス間の前記遅延は、各パルスの前記長さの分数である、請求項1に記載のシステム。
- 電気穿孔システムであって、
少なくとも1つの電極と、
前記少なくとも1つの電極に連結され、かつ連続パルス間に遅延を伴う複数の電気パルスを標的領域に印加するように構成される電圧パルス発生器であって、各パルスの長さ及び連続パルス間の前記遅延は、第1の電気穿孔領域及び第2の電気穿孔領域を作り出すように最適化される、電圧パルス発生器と、を備え、
前記第2の電気穿孔領域において、選択された細胞のみが前記複数の電気パルスの影響を受け、
前記複数の電気パルスの影響を受ける前記選択された細胞は癌細胞であり、各パルスの前記長さが、前記癌細胞の細胞膜の充電時間と前記癌細胞の核膜の放電時間とを足した時間に等しい一方で、連続パルス間の前記遅延は、前記癌細胞の前記細胞膜の前記充電時間に等しい、システム。 - 前記複数の電気パルスの影響を受ける前記選択された細胞は癌細胞であり、前記癌細胞の前記細胞膜の前記充電時間及び前記癌細胞の前記核膜の前記放電時間は、数値モデリングにより決定される、請求項13に記載のシステム。
- 前記複数の電気パルスは、単極性または双極性の電界波形を含む、請求項1に記載のシステム。
- 前記電界波形は、第1の周波数調波と第2の周波数調波とを含む重畳二峰性信号であり、前記第2の周波数調波は、前記第1の周波数調波よりも高い周波数を有する、請求項1に記載のシステム。
- 前記電界波形は、非対称である、請求項1に記載のシステム。
- 前記電界波形は、100kHz〜10MHzの範囲内の搬送波周波数を有する、請求項1に記載のシステム。
- 電気穿孔システムであって、
少なくとも1つの電極と、
前記少なくとも1つの電極に連結され、かつ連続パルス間に遅延を伴う複数の電気パルスを標的領域に印加するように構成される電圧パルス発生器であって、各パルスの長さ及び連続パルス間の前記遅延は、第1の電気穿孔領域及び第2の電気穿孔領域を作り出すように最適化される、電圧パルス発生器と、を備え、
前記第2の電気穿孔領域において、選択された細胞のみが前記複数の電気パルスの影響を受け、
前記複数の電気パルスは、矩形パルス波、ランプ波、指数関数減衰波、または正弦波である電界波形を含み、
前記複数の電気パルスの影響を受ける前記選択された細胞は癌細胞であり、前記波形の搬送波周波数またはパルス持続時間は、前記癌細胞のクロスオーバ周波数に基づく、システム。 - 電気穿孔システムであって、
少なくとも1つの電極と、
前記少なくとも1つの電極に連結され、かつ連続パルス間に遅延を伴う複数の電気パルスを標的領域に印加するように構成される電圧パルス発生器であって、各パルスの長さ及び連続パルス間の前記遅延は、第1の電気穿孔領域及び第2の電気穿孔領域を作り出すように最適化される、電圧パルス発生器と、を備え、
前記第2の電気穿孔領域において、選択された細胞のみが前記複数の電気パルスの影響を受け、
前記複数の電気パルスの影響を受ける前記選択された細胞は癌細胞であり、各パルスの前記長さ及び連続パルス間の前記遅延は、前記癌細胞の物理的な核対細胞質のサイズ比に基づき最適化される、システム。 - 前記複数の電気パルスは、双極性方形波であり、各パルスの前記長さは、250ナノ秒〜50マイクロ秒である、請求項1に記載のシステム。
- 細胞を選択的に処置するための電気穿孔システムであって、
少なくとも1つの電極と、
前記少なくとも1つの電極に連結され、かつ細胞を含有する物質に複数の電気パルスを印加するように構成される電圧パルス発生器であって、前記複数の電気パルスは、一種類の細胞の標的細胞を処置し、別の種類の細胞の非標的細胞を残すように選択される周波数、振幅、及びパルス波形を有する、電圧パルス発生器と、を備え、
前記電圧パルス発生器が、前記標的細胞についての核対細胞質比を決定するように構成され、
前記電圧パルス発生器が、前記標的細胞についての前記核対細胞質比に基づき、前記周波数、振幅、及びパルス波形を選択するように構成される、システム。 - 前記核対細胞質比は、前記細胞を含有する物質の生検から採取された細胞から測定される、請求項22に記載のシステム。
- 前記複数の電気パルスは、異なるパルス幅または異なる振幅を有する正パルス及び負パルスを含む、請求項1に記載のシステム。
- 電気穿孔システムであって、
少なくとも1つの電極と、
前記少なくとも1つの電極に連結され、かつ連続パルス間に遅延を伴う複数の電気パルスを標的領域に印加するように構成される電圧パルス発生器であって、各パルスの長さ及び連続パルス間の前記遅延は、第1の電気穿孔領域及び第2の電気穿孔領域を作り出すように最適化される、電圧パルス発生器と、を備え、
前記第2の電気穿孔領域において、選択された細胞のみが前記複数の電気パルスの影響を受け、
前記第2の電気穿孔領域において前記複数の電気パルスの影響を受ける前記選択された細胞は、前記第2の電気穿孔領域において前記複数の電気パルスの影響を受けない細胞より高い核対細胞質比を有する、システム。 - 電気穿孔システムであって、
少なくとも1つの電極と、
前記少なくとも1つの電極に連結され、かつ連続パルス間に遅延を伴う複数の電気パルスを標的領域に印加するように構成される電圧パルス発生器であって、各パルスの長さ及び連続パルス間の前記遅延は、第1の電気穿孔領域及び第2の電気穿孔領域を作り出すように最適化される、電圧パルス発生器と、を備え、
前記第2の電気穿孔領域において、選択された細胞のみが前記複数の電気パルスの影響を受け、
前記電圧パルス発生器は、いくつかの癌細胞が前記第2の電気穿孔領域内で死滅させられるか、または阻害され、いくつかの非癌細胞が前記第2の電気穿孔領域内で残されるように、複数の電気パルスを印加するように構成され、
前記複数の電気パルスは、選択された閾値を超える核対細胞質比を有する細胞に選択的に影響を及ぼす、システム。
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US10471254B2 (en) | 2019-11-12 |
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JP2017518805A (ja) | 2017-07-13 |
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EP3143124A1 (en) | 2017-03-22 |
AU2015259303A1 (en) | 2016-11-10 |
US20190351224A1 (en) | 2019-11-21 |
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US20170266438A1 (en) | 2017-09-21 |
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