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.
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 . 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.
|Li, Bolan; Singer, Nora G; Yeni, Yener N et al. (2016) A Point-of-Care Raman Spectroscopy-Based Device for the Diagnosis of Gout and Pseudogout: Comparison With the Clinical Standard Microscopy. Arthritis Rheumatol 68:1751-7|
|Unal, Mustafa; Akkus, Ozan (2015) Raman spectral classification of mineral- and collagen-bound water's associations to elastic and post-yield mechanical properties of cortical bone. Bone 81:315-326|
|Yang, Shan; Li, Bolan; Akkus, Anna et al. (2014) Wide-field Raman imaging of dental lesions. Analyst 139:3107-14|
|Li, Bolan; Yang, Shan; Akkus, Ozan (2014) A customized Raman system for point-of-care detection of arthropathic crystals in the synovial fluid. Analyst 139:823-30|
|Yang, Shan; Li, Bolan; Slipchenko, Mikhail N et al. (2013) Laser Wavelength Dependence of Background Fluorescence in Raman Spectroscopic Analysis of Synovial Fluid from Symptomatic Joints. J Raman Spectrosc 44:1089-1095|