SBIR-STTR Award

Over a quarter century of research has significantly improved our understanding of the circulating cardiovascular system and its cellular components. However, study of the parallel lymphatic system has lagged far behind, limiting our understanding of this complex and potentially clinical beneficial network. The lymphatic system is comprised of an extensive network of vessels and nodes that parallel the venous vasculature. Peripheral lymphatic channels combine to form a single thoracic duct that enters the venous system at the confluence of the left internal jugular and subclavian veins. It is known that the lymphatic system plays a number of roles in GI physiology including fluid homeostasis, digestion, and cell mediated immunity. More recent research suggests potentially critical roles in pathophysiological conditions such as diabetes, cancer, cirrhosis, and autoimmune disorders. A significant obstacle in advancing lymphatic research is the ability to safely and easily collect circulating lymph and its cellular components. The majority of studies on circulating lymphatic cells depend on cells collected from peripheral blood, where lymphocytes make up less than 3% of circulating cells. Peripheral blood collection techniques (the predominant type is leukapheresis) are time consuming and expensive. Processing can damage cells, altering their genetic profile and impacting behavior. Because of the complexity and time required, it is difficult to obtain multiple scheduled samples and truly map changes in lymphocyte populations and non-cellular components in real-time. Direct sampling from the lymphatic system requires a complex open surgical cut-down to locate and cannulate the thoracic duct which is not feasible for widespread clinical use, particularly in a research setting. We are proposing a novel sampling method to access and aspirate lymphocytes, fluid, and non-cellular components directly from the thoracic duct. Our approach involves a novel access catheter placed via the central venous system under ultrasound visualization. Catheterization is safe and predictable, leveraging existing central venous access and guidewire techniques. Access would provide an exponentially higher concentration of desirable cell types. This SBIR Phase I project consists of two Specific Aims designed to advance our technology through proof-of-concept design, testing and fabrication, and pilot production. Successful completion of these Aims will place the company in a position to conduct a first-in-human sampling study as part of Phase II. A safe and effective method to collect large quantities of circulating lymphocytes would be of benefit in advancing basic and translational research in gastrointestinal medicine, catalyzing development of new clinical applications in infectious disease, oncology, and fluid management. Once fully realized, this method provides an opportunity to launch a wide range of classification studies to better understand circulating lymphatic cell characteristics and dynamics. Downstream clinical applications may include selective removal of specific T cell phenotypes in GI autoimmune conditions, large volume cell collection for ex-vivo manipulation (ex. CAR T cell therapy, dendritic vaccine development), and removal/manipulation of non-cell components like exosomes, cholesterol, cylomicons, or interstitial fluid.

Public Health Relevance Statement:
Over a quarter century of research has significantly improved our understanding of the circulating cardiovascular system and its cellular components. However, study of the parallel lymphatic system has lagged far behind, limiting our understanding of this complex and potentially clinical beneficial network. While it is known that the lymphatic system plays a number of roles in GI physiology and pathophysiology, a significant remaining obstacle is the ability to safely and easily collect circulating lymph and its cellular components. We are proposing a novel transvascular access device to safely and repeatedly cannulate the thoracic duct. A safe and effective method to access the lymphatic system directly would be of benefit in advancing basic and translational research in gastrointestinal medicine, catalyzing development of new clinical applications in infectious disease, oncology, and fluid management. Once fully realized, this method provides an opportunity to launch a wide range of classification studies to better understand circulating lymphatic cell characteristics and dynamics. Downstream clinical applications may include selective removal of specific T cell phenotypes in GI autoimmune conditions, large volume cell collection for ex-vivo manipulation, and manipulation of non-cell components like exosomes, cholesterol, cylomicons, or interstitial fluid.

Project Terms:
Anatomic Models; Anatomy; Aspirate substance; Autoimmune Diseases; Autoimmune Process; Basic Science; Behavior; biomaterial compatibility; Blood Vessels; brachiocephalic vein; Cardiovascular system; Catheterization; Catheters; cell injury; cell type; Cell Volumes; Cells; Cellular Immunity; Characteristics; Cholesterol; Cirrhosis; Classification; Clinical; clinical application; Clinical Research; Collecting Cell; Collection; Communicable Diseases; Complex; Data; Data Set; design; Development; Devices; Diabetes Mellitus; Digestion; Distal; Evaluation; Excision; exosome; Fatigue; Freezing; Friction; Functional disorder; gastrointestinal; genetic profiling; Homeostasis; Human; Imagery; improved; Intercellular Fluid; Internal jugular vein structure; Joints; Left; Leukapheresis; Libraries; Liquid substance; Lymph; Lymphatic; Lymphatic System; Lymphocyte; Malignant Neoplasms; manufacturing process; Maps; Materials Testing; Mechanics; Medicine; Methods; Modeling; Molds; novel; oncology; Operative Surgical Procedures; Performance; Peripheral; peripheral blood; Peripheral Blood Lymphocyte; Phase; Phenotype; Physiology; Play; Population; Positioning Attribute; pressure; Process; Production; Property; Research; Resistance; response; Role; Sampling; Sampling Studies; Schedule; seal; Shapes; Silicones; Small Business Innovation Research Grant; Solid; Sterilization; Structure of jugular vein; Structure of subclavian vein; T cell therapy; T-Lymphocyte; Techniques; Technology; Tensile Strength; Testing; Thoracic Duct; Time; Torque; Translational Research; Trauma; Ultrasonography; vaccine development; Vacuum; Validation; Variant; Venous; Venous system; Work; X-Ray Computed Tomography

Over a quarter century of research has significantly improved our understanding of the circulating cardiovascular system and its cellular components. However, study of the parallel lymphatic system has lagged far behind, limiting our understanding of this complex and potentially clinical beneficial network. The lymphatic system is comprised of an extensive network of vessels and nodes that parallel the venous vasculature. Peripheral lymphatic channels combine to form a single thoracic duct that enters the venous system at the confluence of the left internal jugular and subclavian veins. It is known that the lymphatic system plays a number of roles in GI physiology including fluid homeostasis, digestion, and cell mediated immunity. More recent research suggests potentially critical roles in pathophysiological conditions such as diabetes, cancer, cirrhosis, and autoimmune disorders. A significant obstacle in advancing lymphatic research is the ability to safely and easily collect circulating lymph and its cellular components. The majority of studies on circulating lymphatic cells depend on cells collected from peripheral blood, where lymphocytes make up less than 3% of circulating cells. Peripheral blood collection techniques (the predominant type is leukapheresis) are time consuming and expensive. Processing can damage cells, altering their genetic profile and impacting behavior. Because of the complexity and time required, it is difficult to obtain multiple scheduled samples and truly map changes in lymphocyte populations and non-cellular components in real-time. Direct sampling from the lymphatic system requires a complex open surgical cut-down to locate and cannulate the thoracic duct which is not feasible for widespread clinical use, particularly in a research setting. We are proposing a novel sampling method to access and aspirate lymphocytes, fluid, and non-cellular components directly from the thoracic duct. Our approach involves a novel access catheter placed via the central venous system under ultrasound visualization. Catheterization is safe and predictable, leveraging existing central venous access and guidewire techniques. Access would provide an exponentially higher concentration of desirable cell types. This Phase II project is divided into two Specific Aims. Our preliminary studies and existing data on lymphatic anatomy and physiology suggests it will be critical in many downstream applications that our device is safe and effective over a dwell time sufficient to collect a sizable number of potentially rare cell types, re- infuse drugs or cells, or monitor the immune system during illness, transplantation, or drug administration. In Aim I we will refine our design to facilitate longer dwell times which permit intermittent, chronic aspiration and infusion. Designs will be validated first in benchtop models and later in a large animal study. In Aim II we will undertake mechanical and biocompatibility testing required for clinical use and FDA approval. Regulatory strategy and planning are included in this approach. Completion of these activities will place the company in a position to move efficiently through regulatory approval and into clinical use.

Thesaurus Terms:
Anatomy; Animal Model; Animal Testing; Animals; Aspirate Substance; Autoimmune Diseases; Autoimmune Process; Base; Basic Science; Behavior; Biomaterial Compatibility; Cardiovascular System; Catheterization; Catheters; Cell Injury; Cell Type; Cell Volumes; Cells; Cellular Immunity; Characteristics; Cholesterol; Chronic; Chylomicrons; Cirrhosis; Classification; Clinical; Clinical Application; Collection; Communicable Diseases; Complex; Data; Design; Development; Device Designs; Device Safety; Devices; Diabetes Mellitus; Digestion; Documentation; Duct (Organ) Structure; Ensure; Equilibrium; Excision; Exosome; Experience; Food, Drug And Cosmetic Act; Functional Disorder; Gastrointestinal; Genetic Profiling; Homeostasis; Human Subject; Imagery; Immune System; Immunologic Monitoring; Improved; Infusion Procedures; Intercellular Fluid; Internal Jugular Vein Structure; Laboratories; Left; Leukapheresis; Liquid Substance; Lymph; Lymphatic; Lymphatic System; Lymphocyte; Malignant Neoplasms; Maps; Mechanics; Medical Device; Medicine; Methods; Modeling; Movement; Multidisciplinary; Novel; Oncology; Operative Surgical Procedures; Outcome; Outpatients; Peripheral; Peripheral Blood; Peripheral Blood Lymphocyte; Pharmaceutical Preparations; Phase; Phenotype; Physiology; Play; Population; Positioning Attribute; Process; Production; Quality Assurance; Research; Research Personnel; Role; Sampling; Schedule; Specialist; Sterility; Structure Of Subclavian Vein; System; T-Lymphocyte; Techniques; Testing; Therapeutic; Thoracic Duct; Time; Translating; Translational Research; Transplantation; Ultrasonography; Venous; Venous System; Work;