Raman spectroscopic platform for transcutaneous monitoring of bone quality

骨质疏松症（OP）是一个全球性的健康问题，具有巨大的社会经济负担。令人震惊的是， 使用标准双能X射线吸收测定法（DXA）进行骨质疏松症筛查的结果非常糟糕， 可预防的脆性骨折的高发病率。我们的长期目标是发展一种无障碍的筛查 一种基于拉曼光谱（RS）的方法，用于在就诊期间早期准确识别高危患者， 初级保健提供者或社区诊所。我们认为，这将增加对金本位制的推荐 DXA诊断和早期干预，以减少可预防的脆性骨折的发生率。我们 先前证明RS检测与以下相关的生化变化的可靠性和灵敏度： 骨疾病的各种小鼠模型，并报告了强大的相关性，拉曼光谱特征与 全骨强度和断裂韧性。我们还开发了仪器和复杂的算法 从覆盖的软组织中减去光学贡献 完整肢体上鼠骨的经皮RS（tRS）。当我们转向扩大我们的仪器， 在人类的诊断测量中，我们正在解决三个重大挑战。第一，制造能力 可靠的经皮骨测量受到来自厚软组织层的信号的阻碍， 覆盖骨头因此，我们确定了指骨和掌骨在手中的解剖部位 适用于tRS测量，这可以通过调整照明源-检测器偏移来实现 建立各种组织的光谱库。第二，目前没有可证明的关联 手部周围骨的RS与脆性骨折的临床相关部位的BMD之间的关系， 如手腕、臀部和脊柱。第三，目前没有证据表明骨的RS可以安全可靠地 用于骨骼健康诊断。在目标1中，我们将调整我们小组的新光谱 解混算法，SOLD，将其应用于最近获得的人尸体手tRS数据集 测量.该适应将解释在200 nm处的拉曼光谱响应中的空间不均匀性。 骨干中段和骨骺区在目标2中，我们将证明tRS之间的诊断关联 尸体手指骨和掌骨的测量与临床相关的腕和髋DXA T评分和腕关节骨折风险。尸体手将从不同性别，年龄， 种族、BMI和DXA BMD和T评分。在目标3中，我们将在50名志愿者中开展一项试验性体内tRS研究， 改进方法学，识别尸体数据差异，并直接进行骨折风险评估 tRS数据。拟议的研究代表了证明概念验证的基本步骤， 经皮拉曼光谱作为骨质疏松症的临床相关诊断和预筛选工具。 该项目的成功完成将为今后的临床研究奠定基础。

Osteoporosis (OP) is a global health concern with enormous socioeconomic burdens. Alarmingly, rates of osteoporosis screening using standard dual-energy x-ray absorptiometry (DXA) are abysmal, which contributes to high rates of preventable fragility fractures. Our long-term objective is to develop an accessible screening method based on Raman spectroscopy (RS) for early, accurate identification of at-risk patients during visits to primary care providers or community clinics. We posit that this would increase referrals for a gold standard DXA diagnosis and earlier interventions to reduce the incidence of preventable fragility fractures. We previously demonstrated the reliability and sensitivity of RS to detect biochemical changes associated with bone diseases in various mouse models and reported robust correlations of Raman spectral features with whole bone strength and fracture toughness. We also developed instrumentation and sophisticated algorithms to subtract optical contributions from overlying soft tissue to enable reliable diagnostically sensitive transcutaneous RS (tRS) of murine bone on intact limbs. As we pivot to scale up our instrumentation to make diagnostic measurements in humans, we are addressing three significant challenges. First, the ability to make reliable transcutaneous bone measurements is hampered by the signal from the thick layers of soft tissues that overlay the bone. Therefore, we identified the phalanges and metacarpals in the hand as anatomical sites suitable for tRS measurements, which can be accomplished by adjusting illumination source-detector offsets and establishing spectral libraries of various tissues. Second, there are no currently demonstrable associations between RS of peripheral bones of the hand and BMD at the clinically relevant sites of fragility fractures such as the wrist, hip, and spine. Third, there is currently no evidence that RS of bone can be safely and reliably acquired in living subjects for bone health diagnosis. In Aim 1, we will adapt our group’s novel spectral unmixing algorithm, SOLD, to apply it to a recently acquired dataset of human cadaver hand tRS measurements. The adaptation will account for spatial heterogeneities in Raman spectral responses at the midshaft versus the epiphyseal regions. In Aim 2 we will demonstrate diagnostic associations between tRS measurements in the phalanges and metacarpals of cadaver hands with clinically relevant wrist and hip DXA T-scores and wrist fracture risk. The cadaver hands will be obtained from donors with different sexes, ages, races, BMI, and DXA BMD and T-scores. In Aim 3, we will launch a pilot in vivo tRS study on 50 volunteers to improve methodology, identify differences from cadaver data, and perform fracture risk estimations directly from the tRS data. The proposed studies represent essential steps to demonstrating proof-of-concept of transcutaneous Raman spectroscopy as a clinically relevant diagnostic and prescreening tool for osteoporosis. Successful completion of the project will lay the foundation for future clinical studies.