Fiberoptic Microneedle Device for Combined Light and Nanomedicine Delivery: Mimicking Nature's Design of a Mosquito

一种名为FMD的光纤微针装置已经发明，它可以显著增强光在组织中的穿透性，从而使结合光和纳米药物输送的微创和更具选择性的光热疗法成为可能。该装置由一个或多个光学透明玻璃纤维(直径约40微米)组成，由新型支撑套圈引导进入患者组织。对于皮肤科应用，该设备可能被放置在患者的皮肤上，机械挤压导致纤维针滑过套圈，无痛地穿透皮肤，类似于蚊子叮咬的动态。纤维尖端可以定位在组织内所需的目标位置(可能有2 mm深)。有些纤维可能是中空的，从而能够输送药物(化疗药物、纳米材料等)。特定的组织区域进行靶向治疗。随后将激光能量施加到固体纤维中，将有效地传输到包含光吸收纳米材料的目标组织，从而导致选择性光热或光化学损伤。为了实现这种用于癌症治疗的设备的临床翻译，必须对其光学、机械和治疗能力进行基本了解。为了展示这项技术的潜力，研究小组在以下三个目标中组织了研究目标：1)机械穿透：设计和制造光纤微针装置(FMD)，并使用白光摄影成像和称重传感器测试评估其穿透体外猪皮肤的性能2)光学/流体输送：设计和制造具有固体核心的单独光纤微针，以输送光和中空核心，以输送含有纳米颗粒的流体，并使用Brightfield和荧光成像评估其光/流体输送性能3)热/治疗：使用热成像和细胞活力分析来评估FMD光输送单独或与纳米颗粒联合使用的光热损伤特异性所有目标都将涉及使用基于细胞的组织代表性模体和体外猪皮肤的实验。每个目标都有相关的里程碑，在本项目的三年中每年都要完成。这项工作的完成将提供必要的初步结果，以推进使用FMD治疗癌症的动物和最终人类临床试验。这项拟议的研究将极大地促进FMD介导的激光癌症治疗的发展，因为它提供了对该技术的光学、机械和治疗能力的理解。使用FMD，纳米颗粒和光可以通过微创光纤微针传递到上皮表面下几毫米处的特定靶点。由于目标组织中的纳米颗粒选择性地吸收光辐射，光剂量可以更精确地传递，减少不必要的附带组织损伤和相关疼痛，并促进更快的伤口愈合。该项目涉及组织力学(针刺)、组织光学(光传输)、纳米材料传输、热产生和传输以及细胞损伤的跨学科实验和建模。这项工作的长期社会影响将是改善癌症患者的生活质量。FMD是一种能够对组织表面下几毫米处的早期、小型上皮癌进行微创检测和治疗的技术，如黑色素瘤、子宫癌和食道癌。癌症的早期发现和治疗是提高存活率和减少发病率的关键。FMD设备的规模适当，可用于早期肿瘤的微创选择性检测和治疗。此外，FMD非常适合输送光敏药物或纳米材料，以增加选择性肿瘤破坏，同时保持周围健康组织的生存能力。这个项目的跨学科性质将为来自不同科学领域的学生提供在实验设计、工程、成像和计算建模方面获得经验的机会。PI致力于通过积极参与多文化学术机会计划(MAOP)和弗吉尼亚理工大学工程多样性促进中心(CEED)等项目，增加工程领域的女性和少数族裔的数量。这项提案的资金将允许招募更多的女性和少数族裔学生在他的生物运输和光学实验室学习。

0933571RylanderA fiberoptic microneedle device, FMD, has been invented that can significantly enhance light penetration in tissue to enable a new regime of minimally-invasive and more selective photothermal therapy combining light and nanomedicine delivery. The device is comprised of one or more optically transparent glass fibers (~40 microns in diameter) which are guided into a patient's tissue by a novel support ferrule. For dermatological applications, the device may be placed against a patient's skin, and mechanical compression causes the fiber needles to slide through the ferrule and painlessly penetrate the skin, similar to the dynamics of a mosquito bite. The fiber tips may be positioned at desirable target positions (potentially 2mm deep) within tissue. Some fibers may be hollow, enabling delivery of drugs (chemotherapeutic agents, nanomaterials etc.) to specific tissue regions for targeted treatment. Subsequent application of laser energy into the solid fibers will be transmitted efficiently to the target tissue containing the light-absorbing nanomaterials, thereby inducing selective photothermal or photochemical damage. To achieve clinical translation of this device for cancer treatment a fundamental understanding of its optical, mechanical, and therapeutic capability must be performed. To demonstrate the potential of this technology the research team has organized the research goals in the following three objectives:1) Mechanical Penetration: Design and fabricate a fiberoptic microneedle device (FMD) and evaluate its performance in penetrating ex vivo porcine skin using white light photographic imaging and load-cell testing2) Optical/Fluid Delivery: Design and fabricate individual fiberoptic microneedles with solid cores to deliver light and hollow cores to deliver fluids containing nanoparticles, and evaluate their light/fluid delivery performance using brightfield and fluorescence imaging3) Thermal/Therapeutic: Evaluate photothermal damage specificity of FMD light delivery alone or in combination with nanoparticles using thermal imaging and cell viability assaysAll objectives will involve experimentation using cell-based tissue representative phantoms and ex vivo porcine skin. Each objective has associated milestones to be completed during each of the three years of this project. Completion of this work will provide preliminary results necessary to move forward with animal and eventually human clinical trials for cancer treatment using the FMD. The proposed research will greatly advance development of FMD-mediated laser cancer therapies by providing an understanding of the optical, mechanical, and therapeutic capabilities of this technology. Using the FMD, nanoparticles and light may be delivered to specific target sites several millimeters beneath an epithelial surface via minimally-invasive fiberoptic microneedles. Due to selective absorption of optical radiation by the nanoparticles in the target tissue, the optical dose can be more precisely delivered, reducing unwanted collateral tissue damage and associated pain, and promoting faster wound healing. This project involves interdisciplinary experimentation and modeling of tissue mechanics (needle penetration), tissue optics (light transport), transport of nanomaterials, heat generation and transport, and cellular injury. Long-range societal impact of this work will be improved quality of life for cancer patients. The FMD is an enabling technology for minimally-invasive detection and treatment of early stage, small epithelial cancers located a few millimeters under the tissue surface, such as melanoma, uterine, and esophageal cancer. Early stage detection and treatment of cancer is the key to enhanced survival and diminished morbidity. The FMD device is appropriately scaled for minimally invasive selective detection and treatment of early stage tumors. Furthermore, the FMD is well suited to deliver photosensitizing drugs or nanomaterials to increase the selective tumor destruction while maintaining the viability of the surrounding healthy tissue. The interdisciplinary nature of this project will provide opportunities for students from different scientific fields to gain experience in experimental design, engineering, imaging, and computational modeling. The PI is devoted to increasing the number of females and minorities within the engineering field through active participation in programs such as Multicultural Academic Opportunities Program (MAOP), and Center for the Enhancement of Engineering Diversity (CEED) at Virginia Tech. Funding from this proposal will allow recruitment of additional female and minority students to study in his biotransport and optics laboratory.