應用偽逆矩陣法探討球狀相位陣列式超音波換能器於腦部短時間熱治療之研究

Abstract

研究背景：腦部腫瘤中轉移性腦腫瘤的發生率比任何原發性腦腫瘤都要高(大於50 %)，而其他腫瘤患者在疾病後期常會發生轉移性腦腫瘤，所有死於惡性腫瘤的病人中約有25%的比率被發現有轉移性腦腫瘤，因此轉移性腦腫瘤是腫瘤治療中十分重要的課題。一般而言針對腫瘤的治療手段包括手術切除、使用化療藥物或放射治療。然而當面對腦部腫瘤時，開顱手術困難度高且風險較大，放射治療容易受到病灶於腦中位置以及腫瘤類型影響其治療效果，使用化療藥物時則須面臨藥物難以穿越血腦屏障，不容易抵達目標腫瘤的限制。根據先前研究指出，轉移性腦腫瘤常與周邊血管再重組形成血液腫瘤屏障(blood-tumor barrier, BTB)，若透過熱治療(hyperthermia, HT)則可能經由增加局部血流、改善血管通透性或提升腫瘤氧合作用等途徑，幫助奈米抗癌藥物進入轉移性腦腫瘤進行藥物治療。另外本實驗室研究發現乳癌之轉移性腦腫瘤小鼠模型在透過超音波熱治療後能夠增加血液腫瘤屏障之通透性，有效提升奈米化療藥物在目標積聚與提高小鼠生存率。若能在熱治療同時將熱治療劑量控制在腦組織加熱限制以下，則可以對正常腦組織傷害降到最低。 研究目的：本研究基於超音波熱治療能有效幫助奈米化抗癌藥物進入轉移性腦腫瘤，利用先前建立的陣列式超音波熱治療系統做更進一步的拓展與改進，使用重新設計之超音波熱治療系統參數與治療方式進行超音波聲場模擬與數值分析，希望藉由同時產生多點聚焦讓單次照射下產生大範圍的加熱區域，改善先前系統只有單點小範圍加熱的不足。並採用顱骨形狀較特殊的案例來突顯其對超音波聲場的影響，嘗試藉由相位調控對顱骨像差進行修正以解決臨床上的顱骨個體差異問題。另外，將轉移性腦腫瘤發生在偏離腦部中央位置的情形設計為顱骨偏移問題，並模擬檢視多點聚焦模式在此情形下是否仍能達到熱治療的效果。最後以溫感變色水膠實驗檢視超音波換能器於顱骨仿體下是否能夠達成多點聚焦之大範圍加熱區域作為可行性的驗證。 材料方法：使用頻率為1 MHz之超音波，搭配透過頭部電腦斷層影像重建的顱骨模型，利用行經多層介面之次波源模型以及雷利積分式進行腦部壓力場計算，再將壓力值轉換為腦組織吸收能量以生物熱傳方程式模擬腦部之溫度場及熱劑量分布，評估熱治療之療效。其中精確重建之顱骨能提供超音波聲場準確地計算並對顱骨像差進行相位修正，而多點聚焦則經由偽逆矩陣法計算求得換能器各單元所需振幅與相位值來達成。多點聚焦實驗則以溫感變色水膠作為溫度變化之指標。 研究結果：本研究模擬使用新的超音波換能器參數可以在對顱骨像差相位修正後產生更集中準確的聚焦結果。而在進行多點聚焦模式1、2 (模式1為同時聚焦於位置(2,0,0)、(-2,0,0)；模式2為聚焦於(0,2,0)、(0,-2,0))時，若同樣將最大聲強度限制於 120 W cm-2以下持續加熱180秒，模式1能形成x方向寬度約7 mm、z方向高度約9 mm的41 ℃等溫區域而模式2能形成y方向寬度約6 mm、z方向高度約8 mm的41 ℃等溫區域，兩者最高溫度皆不會超過45 ℃、熱劑量EM43最大值約為6.57分鐘，能控制於腦組織加熱限制以下，確保正常腦組織不會受到傷害。而模擬快速切換多點聚焦模式1、2 (切換頻率5 Hz)時，可以結合兩模式的聚焦結果形成約7 x 6 x 11 mm3的41 ℃等溫區域。關於顱骨偏移問題，溫度場與熱劑量分布顯示雖然最大值可能受到顱骨偏移方向影響而偏向某一側，但仍能維持有效之加熱程度與範圍。在溫感變色水膠實驗中，驗證了本研究之多點聚焦模式可以應用於腦部之大範圍熱治療。 結論：採用面積較小、數目較多的壓電單元且排列方式更緊密的超音波換能器結構參數，結果顯示除了單點聚焦更集中準確、顱骨像差相位修正的效果也更佳，而在多點聚焦模式下也能大幅減少光柵波瓣的產生。使用偽逆矩陣法進行多點聚焦確實能夠搭配顱骨像差修正在腦部進行大範圍熱治療並有效限制熱劑量，降低對正常腦組織的損傷。面對顱骨偏移問題時，雖然可能因為聚焦點間聲強度的落差導致加熱效果不均勻，但仍然能夠形成有效之熱治療範圍與加熱程度。溫感水膠實驗顯示此超音波熱治療架構與模式在腦腫瘤短時間熱治療應用上的可行性。

Background: Brain metastasis tumors are one of the most significant issues in tumor therapy. Brain metastasis tumors are more frequent (>50%) than any other primary brain tumors and the appearance is about 25% of patients dying of cancer. In general, methods of dealing with these tumors include operation, chemotherapy and radiotherapy, but to some certain degree they are restricted to brain tumor’s conditions. According to previous research, brain metastasis tumors tend to remodeling with surrounding blood vessels and form blood-tumor barrier (BTB). Hyperthermia is found to locally enhance the permeability of BTB formed by brain metastasis tumor, which could benefit antitumor nanodrugs delivery. Researches show that focused ultrasound hyperthermia can enhance liposomal doxorubicin delivery and antitumor efficacy for brain metastasis of breast cancers to improve the mouse survival. Purpose: Based on the array ultrasound transducer designed previously, in this study, we developed phase correction method to deal with skull aberration and to make the device actually applicable in clinic. Furthermore, we used new transducer parameters with smaller PZT element’s surface area and larger number of PZT elements to enlarge hyperthermia heating region by multi-foci pseudoinverse technique. When the tumors are not at the center of head, we must assure the multi-foci method still be able to create enough energy to complete the hyperthermia for clinical use. Materials and Methods: In this study, we reconstructed the skull model by head CT images, calculating the pressure field in the brain for 1 MHz ultrasound by multi-layer second source wave model and Rayleigh Integral. According to bio-heat transfer equation, we simulated the temperature field and thermal dose distribution in the brain to evaluate the effect of hyperthermia. The skull aberration correction and multi-foci techniques are introduced to these simulations. Results: The skull aberration correction technique can improve the focusing, producing more precise and accurate focal spots with new transducer parameters. In multi-foci technique, mode 1 (for multi-foci at (2,0,0)、(-2,0,0)) and mode 2 (for multi-foci at (0,2,0)、(0,-2,0)) can create an effective large hyperthermia region. In the case of switching mode 1 and mode 2 (switching rate at 5 Hz) with intensity limited by 150 W cm-2 for 180 seconds, it can create a region of 7 x 6 x 11 mm3 higher than 41 ℃ and the maximum of temperature lower than 45 ℃, thermal dose beneath the brain tolerance limit. For the cases of tumors not located at the center of head, the multi-foci technique can still produce effective heating region to carry out the hyperthermia. The results of experiments show that the techniques in this study can actually form large heating regions under the skull phantom, demonstrating its practicality for clinical use. Conclusion: The transducer with smaller PZT element’s surface area and larger number of PZT elements can not only form accurate focal zone but create large enough and effective heating regions with phase correction and multi-foci techniques. The results show its feasibility and practicality for clinical brain metastasis tumor hyperthermia.