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）：拟议研究的总体目标是评估使用具有成本效益的激光设备诊断导致关节炎症的晶体的效率。该研究将制造该设备，从诊所收集样本，并与现有的临床诊断方法相比确定该方法的灵敏度。 公共健康相关性：通过拉曼光谱诊断晶体性关节病 由于一水尿酸钠（MSU，痛风）或脱水焦磷酸钙（CPPD，假痛风）晶体的存在，关节处会发生极其痛苦的炎症反应。其他晶体，如碱性磷酸钙、草酸钙、胱氨酸和黄嘌呤也与关节炎病症的产生有关。仅在美国，痛风患病率就有 5-600 万人。虽然有有效的药物治疗来对抗痛风疾病，但不理想的诊断是痛风治疗的障碍。不幸的是，无论是通过滑膜抽吸物的显微镜观察还是通过临床症状进行诊断，痛风的假阴性率 (FNR) 均为 30% [8-13]。假阴性会导致显着的发病率，例如关节压痛和肿胀、关节退化、发烧、肾功能损害以及疾病扩散到多个关节[1-7]。假阳性的发生率高达20%，导致长期治疗不当并延误对实际病因的治疗[9-11]。由于对其他原因的错误调查而造成的财政资源损失进一步加剧了这种情况 [14, 15]。滑膜抽吸物的偏振光显微镜分析 (PLM) 是黄金标准，但只有由专家操作员进行时才可靠，而这些操作员在大多数痛风患者被诊断的社区初级保健机构中大多无法获得。因此，医生采取缺乏可靠性的基于症状的诊断[13]。因此，初级保健机构显然需要负担得起的、自动化和便携式技术，以降低关节空间晶体物质误诊率高得令人无法接受的情况。误诊率降低将影响患者的生活质量，因为这意味着减少痛苦、减少关节恶化并避免不正确的治疗，从而节省成本。 拉曼分析是晶体种类诊断的一种有前途的替代方法。在拉曼光谱中，样品被激光激发，反射的光子保存有关观察区域中化学物质的身份和数量的信息。我们探索性 R21 项目的早期结果表明，拉曼光谱可以识别临床相关浓度的滑液抽吸物中的晶体种类。尽管有这样的希望，但还没有来自足够多的临床样本的 PLM 拉曼分析的敏感性和特异性的数据。临床医生接受拉曼方法的另一个障碍是将拉曼分析视为一种复杂的方法，需要通过昂贵且笨重的仪器来实现。如果拉曼分析能够以可承受的成本实现自动化，那么该技术在临床实践中的采用将是可能的。我们的初步研究证明了使用低成本拉曼概念检测晶体种类的可行性，这是通过一种方便的样品制备方法实现的，该方法使用快速注射器过滤方法将晶体浓缩到亚毫米大小的点。吸取样本后 15 分钟内即可做出诊断。 拟议研究的主要目标是奠定基础，使拉曼成为一种自动化、便携式、实用且价格实惠的工具进入护理点（诊所、家庭办公室、病理科）。这一目标将通过集成具有成本效益的拉曼设备并在足够大的临床样本集上对其进行评估来实现。随后的研究将汇集风湿病学家（亨利·福特医院和Clarian-Arnett Health System）与生物医学工程师，以继续我们正在进行的合作。第一个目标是将已经运行的具有成本效益的拉曼原型概念转化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-CARD）。实现这一目标将产生一种强大的设备，能够以自动方式识别晶体的类型。第二个目标是通过评估 CARD 对临床患者群体的敏感性和特异性来验证和评估 CARD。将收集有症状患者的滑液抽吸物并进行标准临床诊断。 CARD 的敏感性和特异性将与 PLM 进行比较。还将使用研究级共焦拉曼显微镜对沉积物进行高端拉曼显微分析，以明确证明拉曼的临床需求。微量离心滑膜样品的 X 射线微衍射将作为晶体鉴定的金标准。 这项研究的意义在于它有可能改变痛风诊断的临床观点。一种负担得起的、客观的和实用的拉曼模式将引导临床实践更广泛、更有效地筛查滑膜抽吸物，特别是在社区医疗实践中。在对具有临床意义的患者群体验证 CARD 后，这项工作的下一步自然是在多个初级保健地点、医院甚至办公室项目中评估 CARD 原型。