微型化光纖結合光聲薄膜與奈米液滴汽化應用於眼部藥物遞送之可行性研究

Abstract

本研究開發一款可整合於臨床 25-gauge 微針管腔內之微型化光纖式光聲雙模態裝置，旨在建立可於微創介入條件下進行局部能量導引之技術平台。本研究以眼科脈絡膜上腔(suprachoroidal space, SCS)注射作為主要驗證情境，因其雖具靠近後極部之優勢，但藥物仍受外層血–視網膜屏障(outer blood–retinal barrier, oBRB)限制而難以有效滲透；此外，傳統外部激發方式亦常受限於系統體積、對位困難與能量在組織中的衰減，使其在眼內等狹小解剖空間中難以提供穩定且可控的能量作用。基於此，本研究採用光纖作為能量導引介面以縮小系統尺寸並降低對位需求，除可用於眼內治療外，亦具延伸至其他微創介入場景之應用潛力。本研究以 200 μm 光纖端面為基礎，製備具半穿透特性之光聲薄膜，使單一 808 nm 奈秒脈衝雷射激發時可同軸同步產生穿透光與光聲超音波負壓，分別用於光致液滴氣化(optical droplet vaporization, ODV)與聲致液滴氣化(acoustic droplet vaporization, ADV)，以降低傳統雙源系統在空間對位與時序同步上的實作負擔；此外，針對微型化後可能導致之聲壓輸出不足，本研究進一步透過材料工程提升光聲轉換效率，包含調整 PDMS 交聯度至高交聯比例(3:1)並加入 Super P 導電碳黑作為吸光填料，藉由優化薄膜之吸收與透光配置以兼顧光學穿透與聲學輸出，使裝置在 60% 激發條件下可達 2914 mJ/cm² 光通量與 −752 kPa 峰值負壓，且於較低能量條件下仍可穩定觸發奈米液滴氣化。實驗結果顯示，奈米液滴氣化所誘發之瞬態機械效應，能顯著提升高阻力仿體中之藥物傳輸表現，且該增益效果可隨激發參數(如作用時間)進行調控。螢光定量分析進一步指出，藥物釋放量隨激發時間累積而增加，惟擴散增益與介質阻力呈現負相關趨勢。而能量對照組(相同激發條件下但不含奈米液滴、不發生氣化)未能產生相同程度之增益，支持主要效果來自氣化事件所伴隨之機械擾動。此外，活體前導試驗亦初步界定可行之安全操作參數範圍，整體顯示本系統具提升局部遞送效率並支持後續轉譯醫學評估之應用潛力。

This study develops a miniaturized fiber-based photoacoustic dual-mode device that can be integrated within the lumen of a clinical 25-gauge microneedle, aiming to establish a technical platform for localized energy guidance during minimally invasive interventions. The ophthalmic suprachoroidal space (SCS) injection was selected as the primary validation scenario. Although the SCS offers the advantage of proximity to the posterior pole, drug delivery is typically hindered by the outer blood-retinal barrier (oBRB), resulting in limited effective permeability. Furthermore, traditional external excitation methods are often constrained by bulky system dimensions, alignment difficulties, and energy attenuation in tissues, limiting their ability to deliver stable, controllable energy effects in confined anatomical spaces, such as the intraocular environment. To address these challenges, this study employs an optical fiber as an energy guidance interface to minimize system size and reduce alignment requirements. Beyond intraocular therapy, this design has the potential to be extended to other minimally invasive intervention scenarios. Using a 200 μm fiber tip, a semi-transparent photoacoustic film was fabricated, allowing a single 808 nm nanosecond-pulsed laser to coaxially and synchronously generate transmitted light for optical droplet vaporization (ODV) and photoacoustic ultrasonic negative pressure for acoustic droplet vaporization (ADV). This approach significantly reduces the implementation burden regarding spatial alignment and temporal synchronization associated with traditional dual-source systems. To address potential insufficient acoustic pressure output following miniaturization, photoacoustic conversion efficiency was enhanced through materials engineering. By adjusting the polydimethylsiloxane (PDMS) cross-linking ratio to a high proportion (3:1) and incorporating Super P conductive carbon black as a light-absorbing filler, the film's absorption and transmission configuration were optimized to balance optical penetration and acoustic output. Consequently, the device achieved a light fluence of 2914 mJ/cm2 and a peak negative pressure of −752 kPa under 60% excitation conditions, enabling stable triggering of nanodroplet vaporization even at lower energy levels. Experimental results indicated that transient mechanical effects induced by nanodroplet vaporization significantly enhanced drug delivery performance in high-resistance phantoms, with the gain effect being tunable via excitation parameters (e.g., duration). Quantitative fluorescence analysis further revealed that cumulative drug release increased with excitation time; however, the diffusion gain showed a negative correlation with medium resistance. The energy control group (under identical excitation conditions but without nanodroplets/vaporization) failed to achieve a comparable degree of gain, supporting the conclusion that the primary enhancement arises from mechanical perturbations associated with vaporization events. Furthermore, in vivo pilot trials preliminarily defined a feasible range of safe operating parameters. Overall, these results demonstrate the system's potential for enhancing local delivery efficiency and supporting subsequent translational medical evaluations.