Advanced Techniques for Assessing Osteoarthritis in Rats

描述(由申请人提供)： 这项工作是NIH R01 AR46996的竞争性延续，“评估软骨修复和保护的新的基于光学的模型”。各种方式，从软骨移植到药物，已经被证明是改变骨关节炎(OA)进展的相当有前途的方法。这导致了人们对评估人类和动物早期OA变化的方法的高度兴趣，这也是NIH提出OA倡议的原因。目前，包括兔、大鼠和狗在内的动物模型包括在给定的时间点处死多组动物，并用组织学分析关节的变化。这种使用动物模型的方法有几个缺点。首先，不是跟踪给定动物的疾病时间进程，而是只在单个时间点获得每种动物的数据。其次，由于个体数据只在一个时间点获得，时间进程研究需要大量的动物。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，可能只有有限数量的特定治疗药物可用。最后，大型动物通常只是因为小动物模型中可用于分析的组织数量较少而使用。一种能够实时识别小动物骨关节炎关节变化的技术，接近组织学的分辨率，并且不需要动物牺牲，可能是评估治疗剂疗效的有力工具。这项建议的目的是继续发展一种基于成像的动物模型(S)，用于评估治疗OA软骨的治疗方法。具体地说，这项工作的重点是光学相干断层扫描(OCT)，当结合一个大鼠模型(S)，将显示出独特的优势，以评估潜在的治疗。据推测，拟议的模型除了增加关于治疗效果的信息外，还将减少需要牺牲的动物数量、需要处理的组织数量和所需的治疗量。此外，技术进步可以直接转化为活体人类应用。 OCT类似于使用红外线而不是声波的B型超声波成像(1，2)。我们以前的工作已经证明，OCT可以识别关节软骨的内部微结构，分辨率高达任何临床成像技术的25倍。这包括微米级的纤维组织描绘、软骨宽度和纤维软骨的存在。这项建议的假设是，OCT在前一个资助期进行的OA大鼠模型中的应用可以得到实质性的改进。这一假说将通过OCT技术的进步和使用更接近人类骨性关节炎发展的大鼠模型来验证。这将通过修改OCT系统和所使用的动物模型来实现。检验这一假设的具体目标是： 目的1.修改OCT系统，以便在早期阶段监测OA，并具有更高的灵敏度。目的2.探讨OCT与几种大鼠骨性关节炎手术模型的联合应用。3.观察OCT与Microawl治疗技术在大鼠骨性关节炎手术模型中的联合应用。4.观察OCT联合药物干预对手术大鼠骨性关节炎模型的影响。

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.