Optimized whole-lung mapping of the oxygen concentration in human lungs, using Hy

使用 Hy 优化人肺氧浓度的全肺绘图

• 批准号: 8110656
• 负责人: Iulian Constantin Ruset
• 金额: $ 37.49万
• 依托单位: XEMED, LLC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-22 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110656
• 关键词: Acceleration; Address; Adult; Air; Alveolar; Alveolar wall; Animal Model; Asthma; Biological Markers; Blood; Blood Circulation; Breathing; Calibration; Carbon Dioxide; Cause of Death; Child; Child Care; Childhood; Chronic Obstructive Airway Disease; Clinical; Cystic Fibrosis; Development; Diagnosis; Diagnostic; Diffusion; Dimensions; Discrimination; Disease; Disease Management; Early Diagnosis; Elements; Embolism; Environmental air flow; Equilibrium; Exhalation; Exposure to; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Gases; Goals; Helium; Human; Hypoxemia; Image; Imaging Techniques; Inflammatory; Interstitial Lung Diseases; Intervention; Ionizing radiation; Lung; Lung diseases; Magnetic Resonance Imaging; Maps; Measurement; Measures; Methods; Modality; Modeling; Molecular; Morphologic artifacts; Motion; Noble Gases; Noise; Nuclear; Obstructive Lung Diseases; Oxygen; Patients; Perfusion; Pharmacologic Substance; Phase; Phase II Clinical Trials; Physiologic pulse; Predisposition; Procedures; Production; Protocols documentation; Pulmonology; Radiation; Relaxation; Research; Resolution; Respiratory physiology; Scanning; Scheme; Severities; Sickle Cell Anemia; Signal Transduction; Speed; Staging; Techniques; Technology; Testing; Three-Dimensional Image; Three-Dimensional Imaging; Time; Translating; Variant; Weight; Work; Xenon; base; density; healthy volunteer; image registration; imaging modality; improved; innovation; interstitial; novel; public health relevance; success; tool

DESCRIPTION (provided by applicant): Pulmonary medicine is facing a broad spectrum of unmet clinical needs, mainly for three reasons: (1) Lack of regional and quantitative information about lung function especially in obstructive disease; (2) Lack of a radiation-free diagnostic modality in pediatric lung diseases to initiate treatment at the right time; (3) Lack of a grading scale for inflammatory activity and diffusion barriers in interstitial lung disease. The availability of a safe, affordable, and highly quantitative modality for 3-D imaging of lung function would improve early diagnosis and discrimination of diseases, accelerate testing of therapies by pharmaceutical companies, and assist in personalized disease management and intervention decisions for children and adult patients. Hyperpolarized xenon (HXe) MRI is a leading candidate to address this need. Since the depolarization of HXe atoms in lungs is dominated by the presence of paramagnetic oxygen gas molecules, an imaging sequence that determines the rate of signal loss can be interpreted as a map of the local alveolar oxygen concentration. Our recent hundred-fold improvements in HXe production technology deliver high polarizations of HXe in multi-liter quantities. We have incorporated this technology into a compact platform, delivered it to clinical partners, and operated it remotely over periods of several months. Our xenon-tuned 32-element parallel receive coil with integrated asymmetric birdcage transmit coil achieves highly uniform flip angles with maximal speed-up factors, allowing several 3D images in a single breath hold. Our Phase I project demonstrated feasibility for a robust, quantitative, high resolution protocol by implementing and performing pulse sequences that determine the rate of signal loss of pulmonary HXe, applying novel image registration techniques, and estimating corrections due to loss of HXe into the bloodstream. In this Phase 2 project we propose to establish HXe mapping of local alveolar oxygen as a clinically validated and commercially viable diagnostic protocol. We will implement imaging sequences that reconstruct oxygen-induced signal loss with three state-of-the-art acceleration schemes to compare their resolution, SNR, susceptibility to artifacts, and biomarker accuracy. We will compare these sequences against three truth standards: precisely mixed bags of gas, healthy volunteers performing tidal breathing with their exhaled gases calibrated with gas concentration analysis, and hyperventilated healthy volunteers with exhaled gases calibrated with gas concentration analysis. Comparing measurements after tidal breathing to others after hyperventilating will allow calibration and improvement of our models correcting for <10% xenon signal lost to the bloodstream. Finally we will explore and demonstrate the utility of this protocol in the diagnosis and severity staging of several patients with COPD (ventilation abnormalities), interstitial disease (gas exchange abnormalities), and sickle cell disease (perfusion abnormalities). The US FDA has approved our hyperpolarized xenon for Phase 2 trials in subjects with lung disease. PUBLIC HEALTH RELEVANCE: Pulmonary functional magnetic resonance imaging with hyperpolarized xenon, a technology which recently improved by two orders of magnitude, has the potential to address unmet needs in managing a full range of lung diseases, including COPD, asthma, cystic fibrosis, and interstitial diseases. We propose to develop an innovative, robust, and quantitative probe of regional alveolar oxygen concentration with high resolution in three-dimensions and validate it against truth standards. This non-ionizing, well-tolerated, quick, and affordable imaging modality would provide pulmonologists caring for children through adult patients with maps of the highest measure of lung function: regional oxygen exchange into the bloodstream.

描述（由申请人提供）：肺部医学正面临着各种未满足的临床需求，主要是出于三个原因：（1）缺乏有关肺功能的区域和定量信息，尤其是在阻塞性疾病中； （2）小儿肺部疾病中缺乏无辐射诊断方式，无法在适当的时间开始治疗； （3）缺乏间质性肺部疾病中炎症活性和扩散屏障的评分量表。对于肺功能的3-D成像，可用性，负担得起且高度定量的方式可改善疾病的早期诊断和歧视，加速制药公司对治疗的测试，并协助对儿童和成人患者进行个性化疾病管理和干预决策。超极化氙（HXE）MRI是满足这一需求的领先候选人。由于肺中HXE原子的去极化主要取决于存在顺磁性氧气分子的存在，因此决定信号损失速率的成像序列可以解释为局部肺泡氧浓度的图。我们最近在HXE生产技术方面的一百倍改进提供了HXE的高极化数量。我们将这项技术纳入了一个紧凑的平台，将其交付给临床合作伙伴，并在几个月的时间内远程操作。我们的Xenon调整的32个元素平行接收线圈，其整合的不对称鸟笼发射线圈具有最大的加速因子的高度均匀的翻转角度，从而可以单一呼吸中几个3D图像。我们的I阶段项目通过实施和执行脉冲序列来证明可行性，可行性，以确定肺HXE的信号损失速率，应用新颖的图像注册技术以及由于HXE丢失而导致HXE导致的脉冲序列的可行性。 在此阶段2项目中，我们建议将局部肺泡氧的HXE映射作为临床验证且在商业上可行的诊断方案。我们将实施成像序列，通过三个最先进的加速度方案重建氧诱导的信号损失，以比较其分辨率，SNR，对伪影的易感性以及生物标志物的准确性。我们将将这些序列与三个真实标准进行比较：精确混合的气体，健康的志愿者，通过通过气体浓度分析校准的呼出气体进行潮汐呼吸，以及用气体浓度分析校准的呼出气体过度渗透的健康志愿者。在过度换气后将潮汐呼吸与其他人进行比较，将允许校准和改进我们的模型，以校正失去血液的<10％氙气信号。最后，我们将探索并证明该方案在几名COPD患者（通风异常），间质性疾病（气体交换异常）和镰状细胞疾病（灌注异常）的诊断和严重程度分期中的实用性。美国FDA已批准了我们的超极性氙气，用于肺部疾病受试者的2期试验。 公共卫生相关性：使用超极化氙的肺功能磁共振成像，这项技术最近通过两个数量级改进了该技术，有可能满足不满足的需求，以管理各种肺部疾病，包括COPD，哮喘，囊性纤维化，囊性纤维化和间质疾病。我们建议在三维中以高分辨率进行区域肺泡氧浓度的创新，健壮和定量探针，并根据真实标准进行验证。这种非离子化，耐受性良好，快速和负担得起的成像方式将为肺病学家通过具有最高肺功能量度的成年患者照顾儿童：区域氧气交换到血液中。