Novel force sensors for in vivo live animal applications

物理力量影响多种细胞功能，从干细胞分化到细胞迁移、恶性肿瘤和伤口愈合。在组织植入物、假体和微创外科手术等医疗应用中，监测内部应力是至关重要的。尽管有明显的需求，但目前可用的力传感技术不足以在处于自然状态的完整组织中进行力传感。本项目提出了一种新型的纳米传感器，能够在活体动物中进行高灵敏的力测量。这种纳米传感器利用特殊的纳米粒子(上转换纳米粒子(UCNPs))，当受到红外线激发时，将发出光带，可以操纵这些光带来测量深部组织中纳米级的力和组织位移。提出的力传感器代表了一种变革性的新技术，它将允许遥感生物组织内的力并生成3D力图，这将对生物学和医学以及广泛的工程应用产生深远的影响。该项目的最终目标是开发一种新的力传感技术，允许在体内对3D体积的生物组织中的局部力进行微创传感。它承诺使用传统的扫描光学显微镜测量1nN范围内的力和低至~1 nm的局部变形。该纳米传感器由上转换纳米粒子(UCNPs)、柔性聚合物和金属纳米结构组成。所提出的比率传感UCNP信号是由红外光激发的，因此不会激发背景自发荧光。通过利用UCNP与金属的短程相互作用，该传感器实现了高灵敏度。上转换发光是一个非线性过程，自然可以获得出色的空间分辨率成像。该研究计划分为三个阶段：(1)纳米传感器的设计和制造，(2)传感器的校准和(3)活体动物皮肤力传感的演示，即充分表征和校准的传感器将被注射到活小鼠的皮下，以测量上皮细胞迁移期间表皮中的机械力。预计这项新技术将能够以极高的力敏感度和空间分辨率生成自然状态下的生物组织的3D力图。该项目的研究目标与教育和外联计划很好地结合在一起。研究生的研究机会将使研究融入教育。研究成果将纳入课程和外联活动。私人投资机构有指导研究生、本科生和鼓励妇女和少数族裔学生参与的记录。PIs积极参与面向普通公众和当地行业的外展计划。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Physical forces impact a wide variety of cell functions ranging from stem cell differentiations to cell migration, malignancy and wound healing. Monitoring internal stresses is of critical importance in medical applications such as tissue implants, prosthetics and minimally invasive surgery. Despite the clear needs, the currently available force-sensing techniques are inadequate for force-sensing in intact tissues in their natural states. This project presents a novel nanosensor capable of highly sensitive force measurements in live animals. The nanosensor makes use of specialized nanoparticles (upconversion nanoparticles (UCNPs)), that, when excited by infrared light, will emit light bands that can be manipulated to measure forces and tissue displacements at the nanoscale in deep tissues. The proposed force sensor represents a transformative new technique that will allow remote sensing of forces inside biological tissues and generate 3D force maps, which will have far-reaching impacts on biology and medicine as well as on a wide range of engineering applications.The ultimate goal of this project is to develop a novel force sensing technique that allows minimally invasive in vivo sensing of local force within a 3D volume of biological tissues. It promises force measurements in the range of 1 nN and local deformation down to ~1 nm using a conventional scanning optical microscope. The nanosensor is composed of upconversion nanoparticles (UCNPs), a flexible polymer and a metal nanostructure. The proposed ratiometric sensing UCNP signal is excited by an infrared light and thus does not excite background autofluorescence. By exploiting the short-range UCNP-metal interaction, the sensor achieves high sensitivity. Upconversion luminescence is a nonlinear process and naturally allows imaging with excellent spatial resolution. The Research Plan is organized under three phases: (1) design and fabrication of the nanosensor, (2) sensor calibration and (3) demonstration of in vivo force sensing in live animal skin, i.e., fully characterized and calibrated sensors will be injected subcutaneously into live mice to measure mechanical forces in the epidermis during epithelial cell migrations. It is expected that this novel technique will be capable of producing 3D force maps of biological tissues in their natural states with extremely high force sensitivity and spatial resolution. The research goals of the project are integrated well with the education and outreach plans. Research opportunities for graduate students will allow research to be integrated into education. Research results will be integrated into courses and outreach activities. The PIs have track records of mentoring graduate students, undergraduate students and encouraging the participation of women and minority students. The PIs are actively engaged in outreach programs to general public and local industry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.