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，有着巨大的社会经济负担。令人震惊的是， 使用标准的双能x射线骨密度仪(DXA)筛查骨质疏松的情况很糟糕，这对 可预防的脆性骨折的高比率。我们的长期目标是开发一种无障碍筛查 基于拉曼光谱(RS)的早期准确识别高危患者的方法 初级保健提供者或社区诊所。我们假设，这将增加金本位制的转介 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 以前证明了RS检测与以下疾病相关的生化变化的可靠性和敏感性 不同小鼠模型中的骨骼疾病，并报告了拉曼光谱特征与 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成分以实现可靠的诊断敏感性 小鼠骨在完整肢体的经皮RS(TRS)。随着我们致力于扩大我们的仪器设备，以使 在人类诊断测量方面，我们正在应对三个重大挑战。首先，有能力使 可靠的经皮骨测量受到来自厚层软组织的信号的阻碍 把骨头盖上。因此，我们将手中的指骨和掌骨确定为解剖位置。 适用于TRS测量，可通过调整照明源-探测器偏移量来实现 以及建立各种组织的光谱库。其次，目前还没有可以证明的关联 手部周围骨的RS与脆性骨折临床相关部位的骨密度之间的关系 手腕、臀部和脊椎。第三，目前没有证据表明骨骼RS可以安全可靠地进行 在活体受试者中获得，用于骨健康诊断。在目标1中，我们将改编我们小组的新光谱 分解算法，将其应用于最近获得的人类身体手TRS数据集 测量。这种适应将解释拉曼光谱响应的空间不均一性 骨干中段与骨盆部位的对比。在目标2中，我们将演示TRS之间的诊断关联 临床相关腕部和髋部DXA对身体手指骨和掌骨的测量 T-Score和手腕骨折风险。身体的手将从不同性别，年龄， 种族、BMI和DXA骨密度和T分数。在目标3中，我们将在50名志愿者中启动体内TRS试验研究，以 改进方法，从身体数据中找出差异，并直接进行骨折风险评估 来自TRS的数据。拟议的研究代表了演示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未来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.