Advanced Techniques for Assessing Osteoarthritis in Rats

描述（由申请人提供）： 这项工作是NIH R01 AR46996“评估软骨修复和保护的新光学模型”的竞争性延续。从软骨移植到药物治疗的各种方式已经证明了作为改变骨关节炎（OA）进展的方法的相当大的前景。这使得人们对评估人类和动物早期OA变化的方法产生了更大的兴趣，这也是NIH提出OA倡议的原因。目前，包括兔、大鼠和狗的动物模型涉及在给定时间点处死动物组并用组织学分析关节变化。这种使用动物模型的方法有几个缺点。首先，不是跟踪给定动物中疾病的时间进程，而是仅在单个时间点获得每只动物的数据。其次，由于仅在一个时间点获得个体数据，因此时间过程研究需要大量动物。因此，由于大量动物的成本和与组织处理相关的成本，实验往往是昂贵的。第三，只有有限数量的给定治疗剂可用。最后，由于在小动物模型中可用于分析的组织量较少，因此通常仅使用大型动物。一种能够在真实的时间内、接近组织学分辨率并且不需要动物处死的情况下识别小动物OA关节变化的技术可能是评估治疗剂功效的有力工具。本提案的目的是继续开发基于成像的动物模型，用于评价旨在治疗OA软骨的治疗方法。具体而言，这项工作的重点是，光学相干断层扫描（OCT），当与OA大鼠模型相结合时，将表现出独特的优势，用于评价潜在的治疗方法。据推测，所提出的模型，除了增加治疗效果的信息，将减少需要被处死的动物的数量，需要处理的组织的数量，以及所需的治疗量。此外，技术进步可以直接转移到人体内应用。 OCT类似于使用红外光而不是声波的超声B模式成像（1，2）。我们已经证明，与以前的工作，OCT可以识别关节软骨的内部微观结构的分辨率高达25倍高于任何临床成像技术。这包括微米尺度的原纤化、软骨宽度和纤维软骨的存在。该提案的假设是，可以大幅改善OCT在前一资助期进行的OA大鼠模型中的应用。该假设将通过OCT技术的进步和使用更类似于人类OA发展的大鼠模型进行测试。这将通过修改OCT系统和所用动物模型来实现。检验该假设的具体目的是： 目标1.修改OCT系统，以更高的灵敏度在早期监测OA。目标2.检查OCT与几种OA大鼠手术模型的结合。3.在OA手术大鼠模型中检查OCT与Microawl治疗技术的组合。4.在OA的外科大鼠模型中检查OCT与药物干预的组合。

DESCRIPTION (provided by applicant): This work is a competing continuation of NIH R01 AR46996, "New Optically Based Model for Assessing Cartilage Repair and Protection". A variety of modalities, ranging from cartilage transplant to Pharmaceuticals, have demonstrated considerable promise as methods for altering the progression of osteoarthritis (OA). This has resulted in heightened interest in methods for assessing early OA changes both in humans and animals and is the reason the NIH has put forward the OA initiative. Currently, animal models including rabbits, rats, and dogs involve sacrificing groups of animals at given time points and analyzing joint changes with histology. This approach to using animal models has several drawbacks. First, rather than following the time course of the disease in a given animal, data for each animal is obtained only at a single time point. Second, since individual data is obtained at only one time point, large numbers of animals are required for time course studies. Therefore, experiments tend to be expensive due to the costs of the large numbers of animal and the cost associated with tissue processing. Third, only limited quantities of the given therapeutic may be available. Finally, large animals are often only used because of the small amount of tissue available for analysis in small animal models. A technology capable of identifying changes in OA joints in small animals in real time, near the resolution of histology, and without the need for animal sacrifice could be a powerful tool for assessing the efficacy of therapeutic agents. The objective of this proposal is the continued development of an imaging based animal model(s) for the evaluation of therapeutics designed to treat OA cartilage. Specifically, the focus of this work is that optical coherence tomography (OCT), when combined with a rat model(s) of OA, will demonstrate unique advantages for the evaluation of potential therapeutics. It is postulated that the proposed model, in addition to increasing information on the efficacy of therapeutics, will reduce the number of animals that need to be sacrificed, the quantity of tissue requiring processing, and the amount of therapeutic needed. Furthermore, technological advances can be directly transferred to in vivo human applications. OCT is analogous to ultrasound B mode imaging using infrared light rather than acoustical waves(1,2). We have demonstrated with previous work that OCT can identify the internal microstructure of articular cartilage at a resolution up to 25X higher than any clinical imaging technology. This has included the micron scale delineation of fibrillations, cartilage width, and the presence of fibrocartilage. The hypothesis of this proposal is that the application of OCT to an OA rat model performed in the previous funding period can be substantially improved. The hypothesis will be tested through both advances in OCT technology and the use of rat models that more closely resembles OA development in humans. This will be achieved through both modifications of the OCT system and the animal model used. The specific aims to test the hypothesis are: Aim 1. Modifying the OCT system to Monitor OA at Earlier Stages and with Greater Sensitivity. Aim 2. Examining the Combination of OCT with Several Surgical Models of OA in the Rat. 3. Examining the Combination of OCT with the Microawl Therapeutic Technique in a Surgical Rat Model of OA. 4. Examining the Combination of OCT with a Pharmaceutical Intervention in Surgical Rat Model of OA.