201236695 六、發明說明： 【發明所屬之技術領域】 本發明係關於氣泡之使用且更特定言之係關於透過氣泡 之使用成像。 【先前技術】 光聲學係醫學成像的新興領域。由於光聲學依賴經由光 學吸收及隨之發生之加熱/膨脹過程而產生之聲波之偵 測’故該技術與超音波緊密相關。通常，強度經調變之光 源或短脈衝源（即雷射）用作激發源。光通常照射在組織表 面上，但是亦可藉由最小侵入性遞送系統（例如内窺鏡、 導管、光遞送針）從體内遞送。光主要經由光散射穿透組 織’因此照射大體積。光被血液/組織發色團或非目標及 目標外源顯影劑（諸如為此目的而組態之光學染料或奈米 顆粒）吸收。吸收及隨之發生之膨脹產生聲波，即超音波 或聲信號。血管（在腫瘤内具有不同大小及密度以及不同 血氧程度）及周圍組織之光吸收不同。所產生之光學產生 之超音波之所得差異提供成像中所使用之顯影。注意到該 技術在研究領域内迅速流行，主要圍繞一些臨床使用前的 - 工作，諸如小型動物全身成像及監控藥物動力學及腫瘤學 的臨床引用諸如針對乳腺癌或前列腺癌。 但是，Wang等人之共同讓與之名為「ph〇t〇ac〇ustic Imaging Contrast Agent and System for Converting Optical201236695 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to the use of air bubbles and more particularly to the imaging of the use of air bubbles. [Prior Art] An emerging field of photoacoustic medical imaging. This technique is closely related to ultrasound because photoacoustics rely on the detection of sound waves generated by optical absorption and consequent heating/expansion processes. Typically, a modulated source of intensity or a short pulse source (i.e., a laser) is used as the excitation source. Light is typically illuminated on the surface of the tissue, but can also be delivered from the body by a minimally invasive delivery system such as an endoscope, catheter, light delivery needle. Light penetrates the tissue primarily through light scattering' thus illuminating a large volume. Light is absorbed by blood/tissue chromophores or non-target and target exogenous developers, such as optical dyes or nanoparticles configured for this purpose. Absorption and consequent expansion produce sound waves, ie ultrasonic or acoustic signals. Blood vessels (of different sizes and densities in the tumor and different levels of blood oxygen) and light absorption in surrounding tissues are different. The resulting difference in the resulting optically generated ultrasound provides visualization for use in imaging. It is noted that this technology is rapidly gaining popularity in research, mainly around pre-clinical use - such as whole body imaging of small animals and monitoring clinical citing of pharmacokinetics and oncology such as targeting breast or prostate cancer. However, the common name given by Wang et al. is “ph〇t〇ac〇ustic Imaging Contrast Agent and System for Converting Optical
Energy to In-Band Acoustic Emission」之國際公開案 w〇 2009/057021(下文稱作rWang」）（其全文以引用的方式併 160930.doc 201236695 * . 入本文中）說明並於其中藉由圖i(a)、圖i(b)、圖2(a)、圖 2(b)闡釋藉由使用短雷射脈衝照射點式吸收體（諸如pA顯影 劑顆粒）而產生之光聲（PA)信號為寬頻且僅一部分pA信號 旎量落在常規醫學超音波傳感器之接收頻率範圍内❶絕大 部分能量落在該範圍之外，即在更高頻率範圍内。 為解決此問題，Wang將微氣泡及/或奈米氣泡放置為緊 密鄰近PA顯影劑。 特定言之，Wang之各奈米顆粒併入蒸發材料及光吸收 材料。當光吸收材料藉由輻射激發或「活化」時，奈米顆 粒將其蒸發材料蒸發以藉此形成附著之氣泡。 系統宜可調諧使得氣泡再次輻射主要在常規醫學超音波 傳感器之接收頻率範圍内之能量。再次輻射之能量已被放 大且在所有方向上分散，包含在超音波傳感器之方向上。 奈米顆粒在活化前小至足以跨過脈管系統與淋巴系統之 間之邊界。因此，可量測滲透性。亦因此，可使更多人體 結構成像。 形成氣泡之材料及導致氣泡形成之光吸收材料以根據實 施例而不同之方式組合為顆粒或小滴，藉此經由重複膨脹 共同提供一系列氣泡大小及氣泡壽命。 【發明内容】 本發明者已觀察到除上述頻寬失配問題外，一物件（諸 如膀胱、心臟或淋巴結）之習知ΡΑ成像主要僅識別組織邊 界，因為該技術依賴差異光吸收。差異吸收形成組織之各 自差異膨脹。藉由膨脹而在邊界上產生之超音波在背離超 160930.doc 201236695 音波傳感器之邊界之範圍内可能較不明顯。因此，僅聲透 射方向邊界清晰可見。 本文中所提出的是Wang之擴展且關於解決上述問題之 一者或多者。Energy to In-Band Acoustic Emission" International Publication No. 2009/057021 (hereinafter referred to as rWang)) (the entire disclosure of which is hereby incorporated by reference and assigned to (a), Figure i(b), Figure 2(a), Figure 2(b) illustrate photoacoustic (PA) signals generated by irradiating a point absorber (such as pA developer particles) with short laser pulses For broadband and only a portion of the pA signal is within the receiving frequency range of conventional medical ultrasound sensors, most of the energy falls outside this range, ie in the higher frequency range. To solve this problem, Wang places the microbubbles and/or nanobubbles in close proximity to the PA developer. Specifically, each nanoparticle of Wang is incorporated into an evaporation material and a light absorbing material. When the light absorbing material is excited or "activated" by radiation, the nanoparticles scatter their evaporation material to thereby form attached bubbles. The system should be tunable such that the bubble re-radiates energy primarily within the receiving frequency range of conventional medical ultrasound sensors. The energy radiated again has been amplified and dispersed in all directions, including in the direction of the ultrasonic sensor. The nanoparticles are small enough to cross the boundary between the vasculature and the lymphatic system before activation. Therefore, the permeability can be measured. As a result, more human structures can be imaged. The material forming the bubbles and the light absorbing material causing the formation of the bubbles are combined into particles or droplets in a manner different according to the embodiment, thereby providing a series of bubble sizes and bubble life through repeated expansion. SUMMARY OF THE INVENTION The inventors have observed that in addition to the above-described bandwidth mismatch problem, conventional imaging of an object (such as the bladder, heart, or lymph nodes) primarily identifies only tissue boundaries because the technique relies on differential light absorption. Differential absorption forms the individual differential expansion of the tissue. Ultrasonic waves generated at the boundary by expansion may be less noticeable in the range deviating from the boundary of the supersonic sensor. Therefore, only the sound transmission direction boundary is clearly visible. What is proposed herein is an extension of Wang and one or more of the above problems.
如本文中所提出，如Wang之氣泡係定位為緊密鄰近pA 顯影劑（諸如基於染料或奈米結構之PA顯影劑）且同樣在所 有方向上再次輻射聲能。因此，成像之上述角度依賴性類 似地用氣泡填充組織結構協助其等之視覺化而解決，使得 超曰波傳感器可用於基於自氣泡接收之超音波更全面地摘 測結構。 此外，在本提議中，氣泡自由浮動且可預製，在大小及 壽命方面提供更大的靈活性。然而，氣泡仍可用於中繼已 渗透至微氣泡纟大而無法到區域之奈米大小之顆 提供之聲能。對於大小，氣泡之散射截面比其幾何截面大 幾倍（高至1〇6倍），容許緊密圍繞一點式以源之顯影微氣泡 有效攔截待中繼之聲能。 在本發明之-態樣中’成像顯影劑包含氣泡及獨立於氣 泡自由浮動之第一光聲顯影劑。成像顯影劑充當第二 顯影劑^ . 在一相關態樣中，第二光聲顯影劑包含氣泡及處於非活 化狀態之第一光聲顯影劑。 在另一相關態樣中，一方法包含定彳 心饥用於中繼所接收之 聲負b (其係由具有被成像之位置之一源路从、 原發射）之顯影劑。成 像係基於所中繼之能量。源與顯影劑 冉J所包括之氣泡之間存 160930.doc 201236695 在實體間隔。 作為一子態樣’定位包括下列之至少一者·· a)將顯影劑 注入身體組織以與源混合；及b)在體外將顯影劑與源混 合0 在另一子態樣中，源包含光聲顯影劑。 在一不同子態樣中，源具有多個位置。顯影劑包含用於 使多個位置之一者成像之氣泡。 在又一子態樣中，定位包含控制氣泡濃度以使顯影覆蓋 範圍最大化及使多重散射最小化。 在一補充子態樣中，接收自複數個氣泡之一者之超音波 之時間延遲及方向用於定位源之至少一部分。 在又一子態樣中，顯影劑充當複合顯影劑，其中其進一 步包括光聲顯影劑。 在又-子態樣中，複合顯影劑經組態以歸因於氣泡鄰近 光聲顯影劑而充當第二光聲顯影劑。 在一替代態樣中，用於形成第二光聲顯影劑作為混合物 之方法包含結合以混合第-群組與第：群組。第二群組包 含氣泡。第-群組包含第-光聲顯影劑之顆粒。 在一子態樣中，在欲接收混合物之對象之體外執行結 合0 在另版本中，混合之開始發生於對象之體内。 替代態樣之子態樣涉及以^ Jg]卩主、去β 衣戊及以同時達成顯影覆蓋範圍最大化 :使多：散射最小化為目標而在氣泡特定超音波成像之指 導下即時控制成像部位上之第二光聲顯影劑之氣泡之漠 160930.doc 201236695 度。 在一相關版本中，一裝置經組態以定位聲能之一源之一 或多個位置。藉由包含氣泡之顯影劑中繼能量。源與氣泡 之間存在實體間隔。裝置包含用於接收所中繼之能量之一 設備或可與用於接收所中繼之能量之—設備通信地連接。 定位係基於所接收之所中繼之能量。 在一子版本中，裝置所包括之設備包含一超音波傳感器 陣列’該超音波傳感器陣列包括空間分佈之元件且充當成 像陣列。 在替代子版本中，裝置實施為用於通信地連接至設備 之一或多個積體電路。 在又一版本中，一裝置經組態用於使用接收自複數個氣 泡之超音波之時間延遲及方向以定位聲能之一源。氣泡將 =量中繼為待接收之超音波。裝置包含用於接收所中繼之 肊量之-設備或可與用於接收所中繼之能量之一設備通信 地連接。定位係基於所接收之所中繼之能量。 本文所提出的内容可實現為方法、用於執行方法之事物 之組合、用於執行方法之裝置、用於執行裝置之功能性之 電腦程式、用於傳達功能性之信號及/或用於產生信號之 方法。用於產生信號之—方法包括改變施加至下列之至少 2之電流：a)至該裝置之—線輸人端；及b)用於傳輸以 藉由改變產生信號之一天線。 步說明新穎光聲顯影劑技 借助於下列圖式在下文中進_ 術之細節。 160930,doc 201236695 【實施方式】 如圖1藉由闡釋性及非限制性實例所示，一光聲（pA)系 統100包含藉由一電纜連接至一控制單元1〇4之一超音波傳 感器陣列102作為一成像陣列。傳感器陣列1〇2包括空間分 佈之傳感器元件（未展示）。控制單元104可包含作為控制器 106且視需要用於接收控制資訊之控制電子器件形式之一 或多個積體電路（IC)、一天線108及/或一線輸入端11〇。控 制器106可如藉由電纜或無線連接與傳感器陣列1〇2通信地 連接。天線108接收一源天線U2所傳輸之控制資訊。控制 資訊係藉由改變114一電路116之電流而形成◦控制資訊若 饋送至控制單元1 04亦可藉由有線連接而傳達至線輸入端 110 ° 可充當超音波（US)顯影劑123之微氣泡118、120、122在 圖1中展示為在身體組織124中自由浮動。身體組織124可 為一内科病人或更一般而言一人類或動物對象或一樣本之 身體組織。 平均具有從1微米至5微米之直徑之微氣泡通常限制於脈 管系統’但是一些小至足以進入淋巴系統。包括PA顯影劑 或「聲能源」140之奈米顆粒126、128、130、132、134、 136、138小至足以穿過。奈米顆粒126至138可為充當PA顯 影劑之任何已知及適當類型，例如金或碳奈米棒或奈米球 體。 奈米顆粒12 6係展示為在微氣泡118太大而可能無法到達 之組織結構142内。 160930.doc • 10 - 201236695 微氣泡118係定位為與奈米顆粒128相距一實體間隔但與 奈米顆粒128足夠接近使得短pA脈衝在給微氣泡通電前僅 行進短距離。因此’此近接性之衰減損失小。此外，PA脈 衝為寬頻且與將中繼之相對較低聲頻率相比在生物組織中 發生相對較小之聲衰減損失。因此，微氣泡118攔截並再 次輻射聲能’充當一非線性聲能轉換器及一聲信號放大 器。 圖1所示之其他微氣泡12〇、122及其等各自附近之奈米 顆粒130、136(其等為聲能之源140之其他部分，該能量歸 因於電流雷射脈衝之施加而發生）之情況相同。源丨4 〇之至 少一部分將成像。 微氣泡118至122之脈衝回波成像無需依賴來自超音波傳 感器陣列102之脈衝。而是，在光聲學之情況中，原始脈 衝來自可重複發射雷射脈衝之雷射（未展示）。 與光聲學中已使用之脈衝回波成像不同，此處所使用之 脈衝回波成像係基於自氣泡中繼（散射或反射）之超音波且 繼續如下。雷射脈衝導致來自附近之奈米顆粒128、130、 136之聲能之脈動’該脈動接著導致附近之氣泡ns至122 之振盪。振盪傳輸傳感器陣列102所接收之超音波。原始 雷射脈衝以比聲波傳播速度快得多之光速行進。亦假定奈 米顆粒128、130、136可忽略地接近其等之各自微氣泡n8 至122。因此，雷射脈衝與傳感器陣列102之一特定元件之 間之時間延遲或「飛行時間」（TOF)可視覺化為與元件同 心之一部分球面之半徑之量值，微氣泡118至122定位在球 160930.doc 201236695 上之某處。70件之多個元件或所有可具有其等自身針對 I特定微氣泡118至122之球面。相反地微氣泡至⑵ -各者具有其自身之各自球面組，各表面對應於其自身之 疋件。來自與一給定元件相距不同距離之微氣泡之TOF可 由接收時間窗期間所接收之聲壓量值之增大而區分。各自 傳感器疋件之兩個球面相交以形成一曲線且一第三者可與 線相交以形成-點。針對形成自上述球面之各點指派 光J之增量。身體組織中之一些點纟「關注體積」 (VOI) 124因此具有光及逐漸地比其他者多。具有多數光之 點幾何疋值在v〇I中作為微氣泡1〖8至m之位置。總之， /氣包118、120或122分別在奈米顆粒128、130或136之位 置^中繼（散射/反射）來自附近pA源（如pA成像中之）超音波 脈衝’根據非常接近各自微氣泡之附近之奈米顆粒128、 3〇及13 6得知微氣泡118至122之位置。 可再次基於在接收時間窗期間觀察到之聲壓量值之增加 而區刀來自微氣泡118至122之各者之隨後到達之射頻資 料所到達之資料可針對微氣泡未定位為非常靠近奈米顆 粒即相對較大微氣泡無法到達特定組織結構之該等情況指 丁不米顆粒138。在已定位之微氣泡118至122中，半徑分 J反射額外TOF之部分球面可用於同樣地對「遠端」奈米 顆粒138進行二角測距並藉此將其^位。因此，角度144、 146 148及各自實體間隔或等效地TOF 150' 152、154用 於定位遠端奈米顆粒138。角度144至148代表微氣泡11 8至 122將PA顯影劑或「源」l4Q所發射之聲能中繼至傳感器陣 160930.doc •12· 201236695 列102之各自元件之方向》先前判定之至微氣泡118至i22 之TOF 156、158、160亦間接地用於定位。t〇F 156至160 係展示為對應於傳感器陣列102之各自元件，但是可在多 個元件上執行相同分析。 應指出，由於微氣泡118(或120或122)與奈米顆粒138之 間之距離比微氣泡11 8(或120或122)與陣列102之間之距離 小得多，故微氣泡118至122仍充當源140之奈米顆粒138之 聲信號增強器。 注意微氣泡118至122亦可中繼（散射/反射）傳輸自陣列 102(如超音波成像中）之超音波脈衝。因此，可使用例如微 氣泡特定超音波顯影成像來判定微氣泡i丨8至122之位置。 如在超音波顯影成像中微氣泡之定位接著使如在PA成像中 判定之奈米顆粒（諸如奈米顆粒138)之位置容易且精確得 多。此外’若需要’可針對所傳輸之超音波脈衝序列使用 較少寬波束（在限制例中係一非常寬之波束）達成超音波成 像之更同圖框速率。 此外’雖然在實例中使用三個微氣泡丨18至122，但是若 更多者有資料貢獻則可在計算中使用更多者。此外，其他 奈米顆粒126係安置在pa顯影劑140之位置上用於成像。因 此’此等其他奈求顆粒126可同樣經定位以補充微氣泡無 法到達之區域之成像。 因此，當與微氣泡118至122組合時，即使當第一pA顯影 劑140處於未活化狀態時’仍組成第二PA顯影劑162。在 此’即使藉由將第一 PA顯影劑14〇與微氣泡118至m混合 160930.doc •13· 201236695 在一起而使二者結合，第一 PA顯影劑140仍獨立於微氣泡 118至122自由浮動。 待成像部位166上之顯影覆蓋範圍164延伸超過組織結構 142以包含圖1所示之實例中之微氣泡丨丨8至122。 如圖1所示之微氣泡118與12〇之間之聲能之多重散射168 將使成像失真。將藉由在藉由增大濃度而使顯影覆蓋範圍 164最大化的同時降低氣泡濃度而使多重散射168最小化。 在操作中及參考圖2 ’判定醫療超音波應用之接收頻寬 (步驟S204^舉例而言，使更深層損傷成像需要較低超音 波頻率之頻帶而犧牲解析度。相反地，詢問較淺物件可用 包含較咼頻率之頻寬完成。由於氣泡之共振頻率與其大小 成反比例變化，故隨後選擇一系列氣泡大小在超音波傳感 器陣列102之接收頻率範圍内（步驟s2〇8)。 執行以所選氣泡大小混合/施用US顯影劑123(步驟 S212)。 可以許多不同可行方式完成此步驟。 可將例如處於非活化狀態之PA顯影劑或「第一群組」 140與US顯影劑或「第二群組」123混合以形成第二pA顯 影劑162 » 可在臨床檢查期間及/或恰在臨床檢查前執行混合，但 是在本實例之此階段，混合恰在檢查前發生且其可在體内 即在病人或對象體内或體外執行。舉例而言，在稀釋後， 第一群組140與第二群組丨23可填充兩個分開注射泵。可藉 由各泵獨立地控制如藉由靜脈導管（Iv)之輸注而注射各群 160930.doc •14· 201236695 組之時序及速率。兩個泵之輸出混合以形成PA顯影㈣2 且隨後直接或藉由鹽水輸注線間接輸注給病人。輸注可在 成像檢査之前及/或期間發生。可獨立控制各群組、 123之時序及劑量。鑑於結果微氣泡ιΐ8至122接近各自奈 米顆粒126至138 ’混合具有定位us顯影劑123之效果以中 繼源140所發射之所接收之聲能。US顯影劑123在輸注後保 持此定位。 替代地，可用大致在成像檢查前預混合之兩個群組 140、123之組合給病人輸注或注射^在此，亦鑑於微氣泡 118至122結果接近各自奈米顆粒126至138，混合定位超音 波顯影劑123以中_源14〇所發射之所接收之聲能。同樣 地，US顯影劑在輸注後保持此定位。 將一群組140、123系統地輸注至血流，同時將另一群組 直接注射至物件（例如，損傷）使得混合開始在體内發生亦 可行。 作為又一實例，同時或在不同時間將兩個群組l4〇、123 直接注射或輸注至物件中。 在舉例而言腸道成像之情 >兄中病Α或可同時 < 分開吞服 群組140 123兩者。或作為另一實例，可能的是在腎臟之 PA檢查中可透過尿道將群組14〇、注射至腎臟中。 在任何情況中，可針對成像部位166執行混合及/或施用 時序或速率使得顯影覆蓋範圍164最大化，同時使微氣泡 118至122之間之多重散射168最小化。 可藉由超音波顯影劑脈衝回波成像監控部位丨66以偵測 I60930.doc 15 201236695 微氣泡11 8至122何時充分填滿該部位而能進行檢查（步驟 S216)，此時可在該部位上發射雷射脈衝（步驟S22〇) ^藉此 產生之聲能被中繼以供超音波傳感器陣列1〇2接收（步驟 S224)° 可重複完成雷射脈動及接收步驟S220、S224以積累更多 資料用於分析（步驟S228)»視需要，雷射脈動步驟322〇有 時可包含上述微氣泡特定超音波顯影成像作為用於定位微 氣泡118至122之PA成像之替代技術，執行該技術以更新定 位0 當不重複脈動及接收步驟S220、8224時，諸如暫停以檢 查結果（步驟S228)時，或替代地當脈動及接收步驟S22〇、 S224繼續重複時，使用者可在成像指導下即時對混合及/ 或施用時序或速率進行調整以更全面地同時實現顯影°覆蓋 範圍最大化與多重散射最小化之目標(步驟s232)。成像指 導可涉及舉例而言藉由微氣泡特定超音波顯影成像監控成 像部位166處所存在的微氣泡濃度。 隨後，若繼續檢查（步驟S236)，W處理返回至步驟 S220。否則，若不繼續檢査，程序終止。 在-些實施例—氣泡用作光聲顯影劑之部分且在 :用於定位聲能之源之-或多個位置。氣泡(諸：微 氣泡）可用在第一光聲顯+ 第二…“ 顆粒附近，藉此提供 射ϋ 泡可在氣泡之緊鄰附近棚截並再次輕 射藉由第一光聲顯影劑 劑之基於先之活化而發射之聲能。作 ，“米顆粒更深入地滲透至組織結構但是保 160930.doc 201236695 持足夠的緊密鄰近，則可藉由附近氣泡基於一傳感器陣列 所接收之超音波之方向及時間延遲對其等之位置進行三角 測距。 雖然根據本文所提出内容之方法宜應用於提供人類或動 物對象之醫療診斷，但是申請專利範圍之涵蓋範圍之預期 範疇不限於此。更寬泛地說’可設想體内'體外或離體的 增強光聲成像》 所提出的技術可直接應用於心血管成像及腫瘤學，其等 為PA成像之常見目標應用領域。 雖然已在圖式及上述描述中闡釋及描述本發明，但是應 將此闞釋及描述視為闞釋性或例示性而非限制性；本發明 不限於所揭示之實施例。 舉例而言，在上文提出之内容之任意者或所有中，可使 用奈米氣泡來取代微氣泡。 熟習此項技術者藉由研究圖式、揭示内容及隨附申請專 利範圍可在實踐本發明時瞭解及實施所揭示實施例之其他 變動。在申請專利範圍巾’字詞「包括」不排除其他元件 或步驟，且不定冠詞「一」&「一個」不排除複數個。申 請專利範圍中的任何元件符號不得解釋為限制範疇。 電腦程式可瞬時、暫時或在更長時段内儲存在適當電腦 可讀媒體中’諸如光學儲存媒體或固態媒體。此―媒體僅 為暫時性、傳播信號意義上的非暫時性，包含其他形式 之電腦可讀媒體，諸如暫存記憶體、處理器快取記憶體及 160930.doc 201236695 可藉由適當地改變電流形成實現裝置100之上述發明功 能性並用於將其傳達至裝置之信號。信號可藉由裝置輸入 線到達或藉由 一天線無線傳輸。 單個處理器或其他單元可完成申請專利範圍中所述之數 個項目之功能 。某些措施敘述在相互不同的從屬請求項中 之純粹事實並不表示不可有利地使用此等措施之組合。 【圖式簡單說明】 圖1係一例示性光聲系統之一示意及概念圖；及 圖2係圖解說明圖丨之系統之操作之一流程圖。 【主要元件符號說明】 100 光聲（PA)系統 102 超音波傳感器陣列 104 控制單元 106 積體電路 108 天線 110 線輸入端 112 源天線 114 改變 116 電路 118 微氣泡 120 微氣泡 122 微氣泡 123 超音波（US)顯影劑 124 身體組織/關注體積（νοι) 160930.doc -18- 201236695 126 微氣泡/奈米顆粒 128 微氣泡/奈米顆粒 130 微氣泡/奈米顆粒 132 微氣泡/奈米顆粒 134 微氣泡/奈米顆粒 136 微氣泡/奈米顆粒 138 微氣泡/奈米顆粒 140 光聲（PA)顯影劑/聲能源 142 組織結構 144 角度 146 角度 148 角度 150 飛行時間（TOF)/時間延遲 152 飛行時間（TOF)/時間延遲 154 飛行時間（TOF)/時間延遲 156 飛行時間（TOF)/時間延遲 158 飛行時間（TOF)/時間延遲 160 飛行時間（TOF)/時間延遲 162 第二光聲（PA)顯影劑 164 顯影覆蓋範圍 166 待成像部位 168 多重散射 160930.doc -19-As proposed herein, a bubble system such as Wang is positioned in close proximity to a pA developer (such as a PA developer based on a dye or nanostructure) and also radiates acoustic energy again in all directions. Thus, the angular dependence of imaging described above is similarly solved by bubble-filled tissue structures to assist in their visualization, such that the ultra-chopping sensor can be used to more fully extract structures based on ultrasonic waves received from the bubbles. Furthermore, in this proposal, the bubbles are free floating and prefabricated, providing greater flexibility in terms of size and life. However, the bubbles can still be used to relay the acoustic energy provided by the nanometer-sized particles that have penetrated into the microbubbles and are too large to reach the area. For size, the scattering cross section of the bubble is several times larger (up to 1〇6 times) than its geometric cross section, allowing the developing microbubbles to be closely spaced around the point to effectively intercept the acoustic energy to be relayed. In the aspect of the invention, the image forming developer contains bubbles and a first photoacoustic developer which is free to float independently of the bubble. The imaged developer acts as a second developer. In a related aspect, the second photoacoustic developer comprises bubbles and a first photoacoustic developer in an inactive state. In another related aspect, a method includes concentrating the developer for relaying the received acoustic b (which is emitted from the original source with one of the imaged locations). The imaging system is based on the energy relayed. The source and the developer 冉J are included between the bubbles 160930.doc 201236695 at the physical interval. As a sub-state, 'positioning includes at least one of the following: a) injecting the developer into the body tissue to mix with the source; and b) mixing the developer with the source in vitro. In another sub-form, the source comprises Photoacoustic developer. In a different sub-state, the source has multiple locations. The developer contains bubbles for imaging one of a plurality of locations. In yet another sub-portion, positioning includes controlling the bubble concentration to maximize development coverage and minimize multiple scattering. In a complementary sub-state, the time delay and direction of the ultrasonic waves received from one of the plurality of bubbles is used to locate at least a portion of the source. In still another aspect, the developer functions as a composite developer, which further includes a photoacoustic developer. In the yet-sub-situ, the composite developer is configured to act as a second photoacoustic developer due to the bubbles adjacent to the photoacoustic developer. In an alternate aspect, the method for forming a second photoacoustic developer as a mixture comprises combining to mix the first-group and the first:-group. The second group contains bubbles. The first group contains particles of the photo-photoacoustic developer. In a sub-form, the binding is performed outside the subject to receive the mixture. In another version, the onset of mixing occurs within the subject. The sub-situ of the alternative aspect involves the simultaneous control of the imaging site with the aim of maximizing the development coverage by minimizing the scattering: minimizing the scattering to the target and controlling the imaging site under the guidance of bubble-specific ultrasound imaging. The second photoacoustic developer on the bubble of the desert 160930.doc 201236695 degrees. In a related version, a device is configured to locate one or more of the sources of acoustic energy. The energy is relayed by a developer containing bubbles. There is a physical separation between the source and the bubble. The device includes means for receiving one of the relayed devices or may be communicatively coupled to the device for receiving the relayed energy. The positioning is based on the received energy relayed. In a sub-version, the device included in the device comprises an array of ultrasonic sensors. The array of ultrasonic sensors comprises spatially distributed elements and acts as an imaging array. In an alternative sub-version, the apparatus is implemented for communicatively connecting to one or more integrated circuits of the device. In yet another version, a device is configured to use a time delay and direction of ultrasonic waves received from a plurality of bubbles to locate a source of acoustic energy. The bubble relays the amount to the ultrasonic wave to be received. The device includes means for receiving the relayed amount of devices or may be communicatively coupled to one of the devices for receiving the relayed energy. The positioning is based on the received energy relayed. What is presented herein can be implemented as a method, a combination of things for performing the method, a device for performing the method, a computer program for performing the function of the device, a signal for communicating functionality, and/or for generating The method of signal. The method for generating a signal includes changing a current applied to at least 2 of: a) to a line input terminal of the apparatus; and b) an antenna for transmission to change by generating a signal. Steps to illustrate the novel photoacoustic developer technique are described below with the aid of the following figures. 160930, doc 201236695 [Embodiment] As shown in an illustrative and non-limiting example, a photoacoustic (pA) system 100 includes an ultrasonic sensor array connected to a control unit 1〇4 by a cable. 102 acts as an imaging array. The sensor array 1 2 includes a spatially distributed sensor element (not shown). Control unit 104 can include one or more integrated circuits (ICs), an antenna 108, and/or a line input terminal 11 as controller 106 and, if desired, for receiving control information. Controller 106 can be communicatively coupled to sensor array 102, e.g., by a cable or wireless connection. The antenna 108 receives control information transmitted by a source antenna U2. The control information is formed by changing the current of the 114-circuit 116. If the control information is fed to the control unit 104, it can also be transmitted to the line input terminal 110 by a wired connection to serve as the ultrasonic (US) developer 123. Bubbles 118, 120, 122 are shown in FIG. 1 as being free to float in body tissue 124. Body tissue 124 can be a medical patient or, more generally, a human or animal subject or the same body tissue. Microbubbles having an average diameter from 1 micron to 5 microns are typically limited to the vasculature 'but some are small enough to enter the lymphatic system. Nanoparticles 126, 128, 130, 132, 134, 136, 138 comprising PA developer or "sound energy" 140 are small enough to pass through. Nanoparticles 126 through 138 can be of any known and suitable type that acts as a PA developer, such as a gold or carbon nanorod or a nanosphere. The nanoparticle 12 6 series is shown in the structure 142 where the microbubbles 118 are too large to be reached. 160930.doc • 10 - 201236695 The microbubble 118 series is positioned at a physical separation from the nanoparticle 128 but sufficiently close to the nanoparticle 128 that the short pA pulse travels only a short distance before energizing the microbubble. Therefore, the attenuation loss of this proximity is small. In addition, the PA pulse is broadband and relatively less acoustic attenuation losses occur in biological tissue than the relatively lower acoustic frequencies to be relayed. Therefore, the microbubbles 118 intercept and re-radiate the acoustic energy' as a nonlinear acoustic energy converter and an acoustic signal amplifier. The other microbubbles 12 〇, 122 and their respective nearby nanoparticles 130, 136 (which are other parts of the source 140 of acoustic energy, which are generated by the application of a current laser pulse) The same is true. At least a portion of the source 丨4 will be imaged. Pulse echo imaging of microbubbles 118 through 122 does not rely on pulses from the ultrasonic sensor array 102. Rather, in the case of photoacoustics, the original pulse is from a laser (not shown) that can repeatedly emit laser pulses. Unlike pulse echo imaging, which has been used in photoacoustics, the pulse echo imaging used herein is based on ultrasonic waves from bubble relay (scattering or reflection) and continues as follows. The laser pulse causes a pulsation of the acoustic energy from the nearby nanoparticles 128, 130, 136. This pulsation then causes oscillation of the nearby bubbles ns to 122. The ultrasonic waves received by the sensor array 102 are oscillated. The original laser pulse travels at a speed of light that is much faster than the sound wave propagation speed. It is also assumed that the nanoparticles granules 128, 130, 136 are negligibly close to their respective microbubbles n8 to 122. Thus, the time delay or "time of flight" (TOF) between the laser pulse and a particular component of sensor array 102 can be visualized as the magnitude of the radius of a spherical portion of a portion concentric with the component, with microbubbles 118 through 122 positioned at the ball. 160930.doc Somewhere on 201236695. A plurality of 70 or all of the elements may have their own spherical faces for the specific microbubbles 118 to 122. Conversely, the microbubbles to (2) - each have their own respective spherical set, each surface corresponding to its own element. The TOF from microbubbles at different distances from a given component can be distinguished by an increase in the amount of sound pressure received during the reception time window. The two spherical faces of the respective sensor elements intersect to form a curve and a third can intersect the line to form a - point. The increment of the light J is assigned to each point formed from the above spherical surface. Some of the "organic volume" (VOI) 124 in the body tissue has more light and gradually more than others. The point 疋 value with most light points is in v〇I as the position of microbubble 1 from 8 to m. In summary, the air bag 118, 120 or 122 respectively relays (scatters/reflects) the ultrasonic pulse from a nearby pA source (as in pA imaging) at the position of the nanoparticle 128, 130 or 136, according to the very close The positions of the microbubbles 118 to 122 are known by the nanoparticles granules 128, 3 〇 and 13 6 in the vicinity of the bubble. Based on the increase in the amount of sound pressure observed during the reception time window, the data obtained by the subsequent arrival of the radio frequency data from each of the microbubbles 118 to 122 may be positioned very close to the nanobubble for the microbubbles. The granules, i.e., the relatively large microbubbles that are unable to reach a particular tissue structure, refer to the butyl granules 138. In the positioned microbubbles 118 to 122, a portion of the spherical surface of the radius portion J that reflects the additional TOF can be used to equally angularly "distal" the nanoparticle 138 and thereby position it. Thus, angles 144, 146 148 and respective physical spacing or equivalently TOF 150' 152, 154 are used to position distal nanoparticle 138. Angles 144 to 148 represent microbubbles 11 8 to 122 to relay the acoustic energy emitted by the PA developer or "source" l4Q to the direction of the respective components of the sensor array 160930.doc • 12· 201236695 column 102. The TOFs 156, 158, 160 of the bubbles 118 to i22 are also used indirectly for positioning. The t〇F 156 to 160 series are shown as corresponding to the respective elements of the sensor array 102, but the same analysis can be performed on multiple elements. It should be noted that since the distance between the microbubbles 118 (or 120 or 122) and the nanoparticles 138 is much smaller than the distance between the microbubbles 11 8 (or 120 or 122) and the array 102, the microbubbles 118 to 122 Still acts as an acoustic signal booster for the nanoparticle 138 of source 140. Note that the microbubbles 118 through 122 can also relay (scatter/reflect) ultrasonic pulses transmitted from the array 102 (as in ultrasound imaging). Therefore, the position of the microbubbles i 丨 8 to 122 can be determined using, for example, microbubble-specific ultrasonic development imaging. The positioning of the microbubbles as in the ultrasound development imaging then makes the position of the nanoparticles (such as nanoparticles 138) as determined in the PA imaging easier and more precise. In addition, 'if needed' can achieve a more frame rate for ultrasonic imaging using a less wide beam (in the case of a very wide beam in the limiting case) for the transmitted ultrasound pulse sequence. In addition, although three microbubbles 至 18 to 122 are used in the examples, more may be used in the calculation if more data contributions are available. In addition, other nanoparticles 126 are placed at the location of the pa developer 140 for imaging. Thus, these other nemesis particles 126 can likewise be positioned to complement the imaging of areas in which the microbubbles cannot reach. Therefore, when combined with the microbubbles 118 to 122, the second PA developer 162 is formed even when the first pA developer 140 is in an unactivated state. Here, even if the first PA developer 14 is mixed with the microbubbles 118 to m by mixing 160930.doc • 13·201236695, the first PA developer 140 is still independent of the microbubbles 118 to 122. Free floating. The development coverage 164 on the portion to be imaged 166 extends beyond the tissue structure 142 to include the microbubbles 8 to 122 in the example shown in FIG. The multiple scattering 168 of acoustic energy between the microbubbles 118 and 12〇 as shown in Figure 1 will distort the imaging. Multiple scattering 168 will be minimized by reducing the bubble concentration while maximizing development coverage 164 by increasing the concentration. In operation and with reference to Figure 2 'determining the reception bandwidth of the medical ultrasound application (step S204), for example, the deeper damage imaging requires a lower frequency band of the ultrasonic frequency to sacrifice the resolution. Conversely, the shallower object is interrogated. This can be done with a bandwidth that includes a higher frequency. Since the resonant frequency of the bubble varies inversely proportional to its size, a series of bubble sizes are then selected within the receive frequency range of the ultrasonic sensor array 102 (step s2 〇 8). The bubble size is mixed/applied with US Developer 123 (step S212). This step can be accomplished in a number of different possible ways. For example, a PA developer or "first group" 140 in an inactive state can be used with US Developer or "Second. The group "123" is mixed to form a second pA developer 162 » The mixing can be performed during the clinical examination and/or just prior to the clinical examination, but at this stage of the example, the mixing occurs just prior to the examination and it can be in vivo That is, it is performed in vivo or in vitro in the patient or subject. For example, after dilution, the first group 140 and the second group 丨23 can be filled with two separate syringe pumps. The pump independently controls the timing and rate of each group of 160930.doc •14·201236695 by infusion via an intravenous catheter (Iv). The outputs of the two pumps are mixed to form a PA visualization (4) 2 and then infused directly or via saline. The line is indirectly infused to the patient. The infusion can occur before and/or during the imaging examination. The timing and dose of each group, 123 can be independently controlled. Given the results microbubbles ι 8 to 122 close to the respective nanoparticle 126 to 138 'mixed with positioning The effect of the developer 123 is the received acoustic energy emitted by the relay source 140. The US developer 123 maintains this position after the infusion. Alternatively, two groups 140, 123 that are premixed approximately prior to imaging inspection can be used. The combination is infused or injected to the patient. Here, in view of the fact that the microbubbles 118 to 122 result in proximity to the respective nanoparticles 126 to 138, the received acoustic energy emitted by the localized ultrasonic developer 123 in the middle source 14 is mixed. Likewise, the US developer maintains this position after infusion. A group 140, 123 is systematically infused into the bloodstream while another group is injected directly into the item (eg, damage) so that mixing begins In vivo, it can be done. As a further example, two groups of l4〇, 123 can be injected or infused directly into the object at the same time or at different times. For example, in the case of intestinal imaging, the disease may be At the same time < separately swallowing both groups 140 123. Or as another example, it is possible that in the PA examination of the kidney, the group 14 can be injected into the kidney through the urethra. In any case, for imaging The portion 166 performs mixing and/or application timing or rate to maximize the development coverage 164 while minimizing multiple scattering 168 between the microbubbles 118 to 122. The ultrasound monitoring region can be imaged by ultrasonic echo imaging. The detection can be performed by detecting when I60930.doc 15 201236695 microbubbles 11 8 to 122 fully fill the portion (step S216), at which time a laser pulse can be emitted at the portion (step S22〇). The acoustic energy is relayed for reception by the ultrasonic sensor array 1 2 (step S224) ° the laser pulsation can be repeated and the steps S220, S224 can be repeated to accumulate more data for analysis (step S228) » as needed, laser pulsation Step 322 〇 may sometimes include the above-described microbubble-specific ultrasonic development imaging as an alternative technique for locating the microbubbles 118 to 122 for PA imaging, performing the technique to update the positioning 0 when the pulsation is not repeated and the receiving steps S220, 8224 are performed. When paused to check the result (step S228), or alternatively when the pulsation and reception steps S22〇, S224 continue to repeat, the user can instantly adjust the mixing and/or application timing or rate under imaging guidance to more comprehensively At the same time, the goal of maximizing the development coverage and minimizing the multiple scattering is achieved (step s232). Imaging guidance may involve, for example, monitoring the concentration of microbubbles present at the imaging site 166 by microbubble-specific ultrasound imaging imaging. Subsequently, if the inspection is continued (step S236), the W processing returns to step S220. Otherwise, if you do not continue checking, the program terminates. In some embodiments - the bubble is used as part of the photoacoustic developer and at: - a plurality of locations for locating the source of acoustic energy. Bubbles (all: microbubbles) can be used in the first photoacoustic + second ... "particles nearby, thereby providing a blister bubble that can be slanted near the bubble and lighted again by the first photoacoustic developer Acoustic energy emitted based on prior activation. "The rice particles penetrate deeper into the tissue structure but maintain the close proximity of the cells. The supersonic waves received by a nearby sensor array based on a sensor array. The direction and time delay are triangulated for their position. Although the method according to the teachings herein is preferably applied to provide medical diagnosis of a human or animal object, the intended scope of the scope of the patent application is not limited thereto. More broadly, it is conceivable that in vivo or ex vivo enhanced photoacoustic imaging can be directly applied to cardiovascular imaging and oncology, which are common target applications for PA imaging. The present invention has been illustrated and described with respect to the embodiments of the invention, and is not to be construed as limiting. For example, in any or all of the above suggested, nanobubbles can be used in place of microbubbles. Other variations to the disclosed embodiments can be understood and effected in the practice of the invention. The word "comprising" does not exclude other elements or steps, and the indefinite article "a" & "an" does not exclude the plural. Any symbol of a component in the scope of the patent application shall not be construed as limiting. The computer program can be stored in a suitable computer readable medium, such as an optical storage medium or solid state medium, instantaneously, temporarily, or for a longer period of time. This media is only temporary, non-transitory in the sense of a signal, and includes other forms of computer readable media, such as scratch memory, processor cache memory, and 160930.doc 201236695 can be changed by appropriate current Signals are formed that implement the above described inventive functionality of device 100 and are used to communicate it to the device. The signal can be reached by the device input line or wirelessly by an antenna. A single processor or other unit can perform the functions of several items described in the scope of the patent application. The mere fact that certain measures are recited in mutually different dependent claims does not mean that a combination of such measures may not be used. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic and conceptual diagram of an exemplary photoacoustic system; and Fig. 2 is a flow chart illustrating the operation of the system of the diagram. [Major component symbol description] 100 Photoacoustic (PA) system 102 Ultrasonic sensor array 104 Control unit 106 Integrated circuit 108 Antenna 110 Line input terminal 112 Source antenna 114 Change 116 Circuit 118 Microbubble 120 Microbubble 122 Microbubble 123 Ultrasonic (US) Developer 124 Body Tissue/Volume of Interest (νοι) 160930.doc -18- 201236695 126 Microbubbles/Nano Particles 128 Microbubbles/Nano Particles 130 Microbubbles/Nano Particles 132 Microbubbles/Nano Particles 134 Microbubbles/Nano Particles 136 Microbubbles/Nano Particles 138 Microbubbles/Nano Particles 140 Photoacoustic (PA) Developer/Sound Energy 142 Organizational Structure 144 Angle 146 Angle 148 Angle 150 Time of Flight (TOF) / Time Delay 152 Time of Flight (TOF) / Time Delay 154 Time of Flight (TOF) / Time Delay 156 Time of Flight (TOF) / Time Delay 158 Time of Flight (TOF) / Time Delay 160 Time of Flight (TOF) / Time Delay 162 Second Light Sound ( PA) Developer 164 Development coverage 166 Area to be imaged 168 Multiple scattering 160930.doc -19-