Diagnosis of Crystal-Based Arthropathies via Raman Spectroscopy

通过拉曼光谱诊断晶体关节病

• 批准号: 8187630
• 负责人: Ozan Akkus
• 金额: $ 35.17万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8187630
• 关键词: Adoption; Affect; Aliquot; Arthritis; Aspirate substance; Biomedical Engineering; Calcium Oxalate; Calcium Pyrophosphate; Calcium Pyrophosphate Dihydrate; Chemicals; Clinic; Clinical; Collaborations; Collection; Communities; Complex; Cost Savings; Cystine; Data; Decision Making; Deposition; Deterioration; Devices; Diagnosis; Diagnostic Procedure; Disease; Engineering; Evaluation; Facilities and Administrative Costs; Fever; Filtration; Foundations; Goals; Gold; Gout; Head; Health system; Home environment; Hospitals; Image; Impairment; Inflammatory; Investigation; Joints; Kidney; Lasers; Lead; Letters; Light; Location; Maps; Medical; Methods; Microscope; Microscopic; Modality; Morbidity - disease rate; Pain; Pathology; Patients; Perception; Pharmaceutical Preparations; Photons; Physicians; Preparation; Prevalence; Primary Health Care; Process; Pseudogout; Quality Control; Quality of life; Raman Spectrum Analysis; Reaction; Research; Resort; Resources; Rheumatology; Roentgen Rays; Sampling; Screening procedure; Sensitivity and Specificity; Serum; Signal Transduction; Spottings; Swelling; Symptoms; Syringes; Techniques; Technology; Time; Training; Translating; Urate; Validation; Work; Xanthines; arthropathies; base; calcium phosphate; clinical Diagnosis; clinical practice; clinically relevant; cost; cost effective; improved; instrument; medical specialties; millimeter; novel; patient population; point of care; polarized light; primary care setting; programs; prototype; rheumatologist; tool; user-friendly

DESCRIPTION (provided by applicant): The overall goal of the proposed study is to assess the efficiency of diagnosing crystals leading to inflammation of joints using a cost-efficient device which uses laser light. The study will fabricate the device, collect samples from the clinic and determine the sensitivity of the method in comparison to existing clinical diagnostic methods. PUBLIC HEALTH RELEVANCE: Diagnosis of Crystal-Based Arthropathies via Raman Spectroscopy Extremely painful inflammatory reaction occurs at joints due to presence of monosodium urate monohydrate (MSU, gout) or calcium pyrophosphate dehydrate (CPPD, pseudogout) crystals. Other crystals such as basic calcium phosphates, calcium oxalates, cystine and xanthine are also implicated in creation of arthrogenic conditions. The prevalence of gout in the US alone is 5-6 million. While there are effective drug treatments to counter gouty diseases, suboptimal diagnosis is a barrier to management of gout. Unfortunately, false negative rates (FNRs) of gout is 30%, regardless the diagnosis is reached by microscopic observations of synovial aspirates or by clinical symptoms [8-13]. False negatives result in significant morbidity such as tender and swollen joints, joint degradation, fever, renal impairment and spread of the disease to multiple joints [1-7]. False positives happen up to 20% of the time, lead to inappropriate long-term treatment and delay the treatment of the actual cause [9-11]. The financial resources lost due to misdirected investigation of other causes further exacerbate the picture [14, 15]. Polarized light microscopic analysis (PLM) of synovial aspirates is the gold standard, yet, it is reliable only when conducted by expert operators who are mostly unavailable in community based primary care settings where the majority of gout patients are diagnosed. Therefore, physicians resort to symptom-based diagnosis which lacks reliability [13]. Therefore, there is a clear need for affordable, automated and portable technologies at the primary care setting for reducing the unacceptably high misdiagnosis rate of crystal species in joint spaces. A lower misdiagnosis would impact patients' quality of life as it translates to less suffering, less deterioration of joints and avoidance of incorrect treatments, introducing cost savings. Raman analysis is a promising alternative for diagnosis of crystal species. In Raman spectroscopy, the sample is excited by laser and the reflected photons hold information on the identity and the amount of chemical species in the observed region. Earlier results from our exploratory R21 project demonstrated that Raman spectroscopy can identify crystal species in synovial aspirates at clinically relevant concentrations. Despite this promise, there are no data on the sensitivity and specificity of Raman analysis with respect to PLM from a sufficiently large number of clinical samples. Another barrier in terms of Raman method's acceptance amongst the clinicians is the perception of Raman analysis as a complex method that is implemented by expensive and bulky instruments. If Raman analysis were to be automated to function at an affordable cost- basis, the technique's adoption in the clinical practice would be possible. Our preliminary studies demonstrate the feasibility of detecting crystal species using a low-cost Raman concept, made possible by a convenient sample preparation method that concentrates crystals to sub-millimeter sized spots using a quick syringe- filtration approach. The diagnosis is reached within 15 minutes of sample aspiration. The main objective of the proposed study is to lay the foundation work that will bring Raman to the point of care (clinic, home office, pathology units) as an automated, portable, practical and affordable tool. This objective will be attained by integrating a cost-efficient Raman device and assessing it on a sufficiently large clinical sample set. The ensuing studies will bring together rheumatologists (Henry Ford Hospital and Clarian- Arnett Health System) with biomedical engineers to continue our ongoing collaboration. The first aim will be to translate an already working cost effective Raman prototype concept to a stand-alone portable robust platform (Cost-efficient Automated Raman Device-CARD). Accomplishment of this aim will result in a robust device that will identify the types of crystals in an automated fashion. The second aim will validate and evaluate CARD by assessing its sensitivity and specificity over a clinical patient population. Synovial aspirates from symptomatic patients will be collected and also subjected to standard clinical diagnosis. The sensitivity and specificity of CARD will be compared to those of PLM. High-end Raman microscopic analysis of deposits with a research-grade confocal Raman microscope will also be conducted to definitively prove the clinical need for Raman. X-Ray microdiffraction of microcentrifuged synovial samples will serve as the gold standard for crystal identification. The significance of the proposed study is in its potential to shift the clinical opinion on diagnosis of gout. An affordable, objective and practical Raman modality would lead the clinical practice towards screening of synovial aspirates more extensively and effectively, especially in the community medical practice. Following the validation of CARD over a clinically meaningful patient population, a natural next step to this work would be the assessment of CARD prototypes in multiple primary care locations, hospitals and even office-based programs.

描述（由申请人提供）：拟议的研究的总体目标是评估诊断晶体的效率，该晶体使用使用激光光的经济高效设备来评估关节发炎。该研究将制造设备，从诊所收集样品，并确定该方法与现有临床诊断方法相比的敏感性。 公共卫生相关性：通过拉曼光谱诊断基于晶体的关节炎，由于存在单钠一水合物（MSU，痛风）或焦磷酸钙脱水（CPPD，Pseudogogout）晶体，在关节发生了极度痛苦的炎症反应。其他晶体，例如碱性磷酸钙，草酸钙，半胱氨酸和黄嘌呤也与创造关节性疾病有关。仅在美国，痛风的普遍性就是5-600万。尽管有有效的药物治疗可抵消痛风疾病，但次优诊断是痛风管理的障碍。不幸的是，痛风的假阴性率（FNR）为30％，无论诊断是通过显微镜观察到滑膜抽吸物或临床症状的[8-13]。假阴性导致明显的发病率，例如嫩和肿胀的关节，关节降解，发烧，肾功能障碍以及疾病传播到多个关节[1-7]。假阳性最多发生20％，导致不适当的长期治疗并延迟对实际原因的治疗[9-11]。由于对其他原因的调查误导了进一步加剧了图片[14，15]。滑膜抽吸物的偏振光显微镜分析（PLM）是黄金标准，但是，只有在大多数诊断出大多数痛风患者的基于社区的初级保健环境中，这些专家经营者才能可靠。因此，医生诉诸于缺乏可靠性的基于症状的诊断[13]。因此，在初级保健环境中，显然需要负担得起的，自动化和便携式技术，以降低关节空间中晶体物种的高度误诊率。较低的误诊会影响患者的生活质量，因为它可以减少苦难，关节的恶化和避免不正确的治疗，从而节省成本。 拉曼分析是诊断晶体物种的有希望的替代方法。在拉曼光谱学中，样品被激光激发，并且反射的光子持有有关观测区域化学物种的身份和量的信息。我们的探索性R21项目的早期结果表明，拉曼光谱可以鉴定出在临床相关浓度下滑膜运动中的晶体物种。尽管有这样的承诺，但仍未获得有关拉曼分析对PLM的敏感性和特异性的数据。关于拉曼方法在临床医生中接受的另一个障碍是将拉曼分析视为一种复杂的方法，该方法由昂贵且笨重的仪器实施。如果要自动化拉曼分析以可承受的成本基础运行，则该技术在临床实践中的采用将有可能。我们的初步研究表明，使用低成本的拉曼概念检测晶体物种的可行性，这是通过方便的样品制备方法使晶体浓缩到亚毫米大小的斑点的可行性，使用快速的注射器过滤方法。样本抽吸后的15分钟内达到诊断。 拟议的研究的主要目的是为将拉曼带到护理点（诊所，家庭办公室，病理单位）作为一种自动化，便携式，实用和负担得起的工具的基础工作。将通过整合具有成本效益的拉曼设备并将其评估在足够大的临床样本集上来实现这一目标。随后的研究将使风湿病学家（亨利·福特医院和克利纳特·阿内特卫生系统）与生物医学工程师一起继续我们的持续合作。第一个目的是将已经有效的成本效益的拉曼原型概念转换为独立的便携式稳健平台（具有成本效益的自动化拉曼设备卡）。实现这一目标将导致一个健壮的设备，该设备将以自动化的方式识别晶体的类型。第二个目标将通过评估其对临床患者人群的敏感性和特异性来验证和评估卡。将收集有症状患者的滑膜运动员，并进行标准临床诊断。卡的灵敏度和特异性将与PLM的敏感性和特异性进行比较。还将对具有研究级共焦拉曼显微镜的沉积物进行高端拉曼显微镜分析，以确定证明拉曼的临床需求。微离心的滑膜样品的X射线微屈光度将作为晶体鉴定的金标准。 拟议的研究的意义在于它的潜力转移了临床意见对痛风的诊断。负担得起，客观和实用的拉曼方式将导致临床实践更广泛，有效地筛选滑膜筛选，尤其是在社区医学实践中。在对临床意义的患者人群进行验证后，这项工作的下一步是对多个初级保健，医院甚至基于办公室计划的卡原型的自然下一步。