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The objective of this Funding Opportunity Announcement (FOA) is to support the development of devices to evaluate dynamic changes in microvascular blood flow and tissue oxygenation.  Devices designed to measure temporal changes in regional perfusion and oxygen delivery following red blood cell transfusion or in peripheral vascular disease are of particular interest.  

This FOA is seeking applications that propose to develop devices capable of analyzing temporal differences in tissue oxygen saturation and microvascular blood flow. Desirable criteria for the successful measurement of tissue oxygenation and/or microcirculation in the context of evaluating the efficacy of blood transfusion, or the natural and treated course of peripheral vascular disease, in clinical research are: utility of the parameter(s) reported in measuring tissue oxygenation; noninvasiveness; capability to make repeated measurements, accuracy and robustness of measurements; ease of use; and reproducibility between operators. Imaging technologies are of interest and will be considered. Successful development of devices that measure oxygenation or microcirculation in cerebral and/or splanchnic tissues are of particular interest.  Minimally invasive methods that require the use of contrast agents and probes may be acceptable and would be dependent on their safety profile.  Development and validation of biomarkers and/or combination of biomarkers that reflect changes in tissue perfusion and oxygenation in the context of blood transfusion are also of interest.


The primary indication for red blood cell (RBC) transfusion is to increase tissue oxygenation in patients with inadequate circulating red cell mass. Oxygen delivery to tissues is partially dependent on hemoglobin concentration along with blood viscosity and homeostatic mechanisms including cardiac output and microvascular blood flow.  In patients with co-morbidities, improvements in global oxygen delivery may not result in improvements in regional perfusion and oxygen delivery.  In addition blood transfusion carries risks.  Two priority research questions in transfusion medicine are: 1) defining and evaluating the extent by which RBC transfusion improves the delivery of oxygen to tissues, especially in moderately anemic, normovolemic subjects who represent a substantial proportion of the transfused patients; and 2) determining if various factors related to a RBC product, such as storage time or differences in manufacturing, affect how transfused RBCs influence microcirculatory flow and tissue oxygenation. 

Clinical researchers have employed two FDA approved, non-invasive methods to assess the effectiveness of a RBC transfusion.  One method is sublingual microscopy, which measures changes in microcirculatory density and flow using sidestream dark field (SDF) imaging.  The other instrumentation is tissue oximetry, which measures changes in tissue oxygenation using near-infrared spectroscopy (NIRS) to assess hemoglobin oxygen saturation in the microcirculation of peripheral tissue(s), usually of the thenar eminence.  These technologies are often selected because they are noninvasive with the capability to make repeated measurements.  The tissues that can be evaluated with these methods are limited. The reproducibility and robustness of measurement provided by these methods can be problematic in the clinical research setting.  Rigorous validation of these technologies for the indicated purpose of measuring effectiveness of a RBC transfusion is also lacking. 

The development of minimally invasive procedures to accurately measure tissue oxygenation and that allow serial testing is also needed in other NHLBI scientific areas. For example, the use of NIRS to measure tissue hemoglobin saturation (StO2) in skeletal muscle in the context of Peripheral Arterial Disease is controversial.  The contribution of myoglobin cannot be excluded and cannot address interactions between microvascular and intracellular oxygen stores.  Measurements can also be influenced due to failure to discriminate between capillary and venous blood and the distribution of oxyhemoglobin and deoxyhemoglobin within the area of measurement.

Scientific Scope

Research examples include but are not limited to:

  • Improvement of the NIRS technique to reduce measurement variability.
  • Improvement or development of new minimally or non-invasive technologies to measure splanchnic tissue oxygenation in neonates, pediatrics and adult populations.
  • Development of new minimally or non-invasive techniques for the measurement of changes in tissue oxygenation related to RBC transfusion.
  • Development of new minimally or non-invasive techniques for the measurement of changes in tissue oxygenation related to monitoring of peripheral arterial disease in the lower limbs for diagnosis
  • Development of new minimally or non-invasive techniques for the measurement of changes in microcirculation related to RBC transfusion.
  • Improvement of sidestream darkfield (SDF) and/or orthogonal polarization spectral (OPS) microscopy techniques to reduce intra- and inter-rater variability for the measurement of changes in microcirculation related to RBC transfusion.
  • Development and validation of biomarkers (or combination of) that reflect changes in tissue  perfusion and oxygenation in the context of blood transfusion and/or peripheral vascular disease.

Areas of research that will not be considered responsive to this FOA include the development of techniques or devices that require more than minimally invasive procedures and/or the use of radioactive probes.

Applicants are strongly encouraged to discuss the proposed approach, concept, or strategy with Scientific/Research staff listed under Agency Contacts, to determine responsiveness to this FOA.

Applicants wishing to submit a Phase I or Fast-Track application can apply to the companion FOA RFA-HL-15-003.

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