SBIR-STTR Award

Disregulated angiogenesis-the growth of new blood-vessels from existing vasculature-plays a central role in more than 70 major health conditions including cancer, cardiovascular disease, and macular degeneration. More than one billion people worldwide are afflicted by angiogenesis-dependent diseases. Therapeutics that target blood-vessel growth promise new possibilities in the treatment of devastating diseases and have vast economic potential. However, progress in translation from basic research into the clinic is slowed by the lack of dependable models for angiogenesis research and drug testing. Presently, none of the existing in-vitro models for the study of angiogenesis integrates most of the critical elements that typify vascular growth in vivo, and none of the existing models includes the growth of capillary sprouts from existing blood vessels under flow- which is by definition the hallmark of angiogenesis. Previously, we have developed tissue-engineering techniques for the creation of microvessels within small fluidic devices. Within these devices, we generate luminally-perfused parent vessels from endothelial cells that subsequently sprout and form anatomizing capillary-like networks in collagen. We now propose to develop this method into an advanced in-vitro angiogenesis model with the following attributes: (1) tissue-engineered parent vessels mimicking architecture and cell composition in vivo, capable of angiogenic sprouting into a surrounding three-dimensional matrix;(2) human-derived cells;(3) direct luminal perfusion of parent vessels and sprouts;(4) tightly-controlled physical and chemical conditions;and (5) a mass produced, disposable fluidic device that can be adapted for the use in existing high-throughput analysis platforms. Aim 1 of the proposed project will be the completion of an optimized design of the fluidic device and the establishment of a system that allows for the tight control of perfusion, temperature, gas concentration and pH within the device. Aim 2 will be to achieve established techniques for the generation of microvasculature with the three structural key components of angiogenesis: endothelial cells, pericytes, and basement membrane. Once feasibility is established, we plan to advance our model into a standardized, easy to use product that can be of significant value in the development of therapies for a range of devastating diseases.

Public Health Relevance:
Disregulated growth of blood vessels is a central element in cancer and other important diseases. More reliable assays and models for the study of vascular growth and the evaluation of therapeutic drugs are necessary to improve clinical results. We propose a new model for the study of vascular functions that closer mimics natural vessels.

Thesaurus Terms:
Advanced Development;Adventitial Cell;Architecture;Assay;Basement Membrane;Basic Research;Basic Science;Bioassay;Biologic Assays;Biological Assay;Blood Vessels;Blood Capillaries;Cancers;Capillaries;Cardiovascular Diseases;Cell Communication;Cell Interaction;Cell-To-Cell Interaction;Cells;Chemicals;Clinic;Clinical;Collagen;Confocal Microscopy;Deposit;Deposition;Development;Devices;Dimensions;Disease;Disorder;Drugs;Economics;Electron Microscopy;Elements;Endothelial Cells;Engineering / Architecture;Event;Future;Gases;Gel;Generalized Growth;Generations;Growth;Hand;Health;Human;Immunofluorescence;Immunofluorescence Immunologic;In Vitro;In Element;Indium;Loinc Axis 4 System;Macular Degeneration;Macular Degenerative Disease;Malignant Neoplasms;Malignant Tumor;Man (Taxonomy);Measurement;Medication;Membrane Proteins;Membrane-Associated Proteins;Methods;Modeling;Modern Man;Morphogenesis;Parents;Performance;Perfusion;Pericapillary Cell;Pericytes;Perivascular Cell;Pharmaceutic Preparations;Pharmaceutical Preparations;Physiologic;Physiological;Plant Embryos;Plant Zygotes;Play;Production;Protein Inhibition;Protocol;Protocols Documentation;Recruitment Activity;Relative;Relative (Related Person);Research;Role;Rouget Cells;Seeds;Study Models;Surface;Surface Proteins;System;Techniques;Temperature;Testing;Time;Tissue Engineering;Tissue Growth;Translations;Umbilical Vein;Angiogenesis;Capillary;Cardiovascular Disorder;Design;Designing;Develop Therapy;Developmental;Disease/Disorder;Drug Detection;Drug Testing;Drug/Agent;Engineered Tissue;Experiment;Experimental Research;Experimental Study;Fluid Flow;High Throughput Analysis;Improved;In Vitro Model;In Vivo;Intervention Development;Macula;Macular;Malignancy;Neoplasm/Cancer;New Growth;Ontogeny;Operation;Pressure;Recruit;Research Study;Seed;Social Role;Therapeutic Evaluation;Therapeutic Target;Therapy Development;Treatment Development;Vascular

Abnormal angiogenesis-the growth of new blood vessels from existing vasculature-plays a central role in more than seventy major health conditions, afflicting over one billion people worldwide. Uncovering the mechanisms that control angiogenesis promises to fuel the discovery of novel therapies targeting cancer, diabetes, macular degeneration and others-but the progress in translation from basic research into the clinic is slowed by the lack of dependable models for angiogenesis research and drug testing. None of the existing in-vitro models includes the growth of capillary sprouts from existing blood vessels under flow-which is, by definition, the hallmark of angiogenesis. To address this need, our company has developed a proprietary technology for the creation of human microvasculature within microfluidic chips. Within these chips, we generate lumenally perfused 'parent' vessels from human endothelial cells that are surrounded by an extracellular-matrix gel. When exposed to vascular growth factors the parent vessels exhibit angiogenic sprouting and grow new capillaries into the surrounding matrix. We plan to commercialize this technology under the name PIVA (Perfused In Vitro Angiogenesis) system. PIVA is envisioned to consist of the following components: (1) disposable microfluidic chips, (2) portable, modular perfusion platforms that can be stacked inside standard cell incubators, (3) scalable meta-modules that can support up to six microfluidic chips, and (4) image analysis software. The meta-module concept will allow users to run 100 or more assays simultaneously per incubator-a throughput capacity that is sufficient for applications in research and drug discovery. During Phase I of thisproject, we established feasibility of the manufacturing techniques, developed the prototype of a pneumatically driven perfusion platform and validated that our angiogenesis model recapitulates features of in vivo microvasculature. Currently, chips and perfusion platforms are tested in more than ten research laboratories throughout the U.S. The goal of Phase II is to finish the development of the PIVA technology to enable a rapid commercial transition into the research market. Aim 1 is to finalize the design of the microfluidic chip, meta-module perfusion platform, and the image analysis software. Aim 2 will focus on defining assay parameters and establishing the metrics for image analysis and methods for downstream analysis. Aim 3 will be to test PIVA on drugs with known anti-angiogenic effects. Once Phase II is completed, the PIVA design will be ready for production transfer within twelve months. Nortis has significant expertisein bringing prototype technologies to market. The commercial launch of the PIVA components will leverage previously validated manufacturing processes as well as operational and business infrastructure to support commercial activities. Phase III funding is lined up in the form of angelinvestments and revenue obtained through sales of existing Nortis products. We believe that PIVA will become an important new tool in angiogenesis research, accelerating the discovery and clinical translation of novel angiogenesis-modulating therapeutics.

Thesaurus Terms:
Address;Advanced Development;Angiogenesis;Animal Testing;Assay Development;Basement Membrane;Basic Science;Biological Assay;Biology;Blood Capillaries;Blood Vessels;Businesses;Capillary;Cell Type;Cells;Clinic;Clinical;Commercialization;Computer Software;Confidence Intervals;Design;Development;Devices;Diabetes Mellitus;Disease;Drug Candidate;Drug Discovery;Drug Testing;Endothelial Cells;Evaluation;Exhibits;Extracellular Matrix;Flexibility;Flow Cytometry;Fluid Flow;Funding;Gel;Goals;Growth;Growth Factor;Harvest;Health;Human;Image Analysis;Imaging Modality;In Vitro;In Vitro Model;In Vivo;Incubators;Investments;Laboratory Research;Legal Patent;Life;Liquid Substance;Macular Degeneration;Malignant Neoplasms;Manufacturing Process;Market Research;Marketing;Measures;Meetings;Methods;Metric;Microfluidics;Modeling;Molecular;Names;New Growth;Novel;Parents;Performance;Perfusion;Pericytes;Pharmaceutical Preparations;Phase;Play;Pressure;Production;Proteins;Protocols Documentation;Prototype;Public Health Relevance;Reporting;Research;Research And Development;Research Infrastructure;Research Personnel;Response;Rna;Role;Running;Sales;Small Business Innovation Research Grant;Source;Success;System;Techniques;Technology;Temperature;Testing;Therapeutic;Time;Tool;Translations;Writing;