SBIR-STTR Award

More than 500,000 U.S. patients have end stage renal disease and over 80% utilize hemodialysis as their renal replacement modality of choice. The Achilles Heel in the care of dialysis patients is the development of a functioning and durable vascular access, preferably an arteriovenous fistula. The annual cost of treating vascular access dysfunction totals over one billion US dollars. This is largely due to the high proportion of arteriovenous fistulas (AVFs) that fail to mature. After creation, sixty percent of AVFs fail to mature successfully for dialysis use, due to early venous neointimal development and inadequate vasodilation. At present, there are no effective therapies to promote vascular access maturation. Endomimetics has developed a nanomatrix coating that mimics the characteristic properties of native endothelium. This nanomatrix can be coated on biocompatible electrospun polycaprolactone (ePCL) sheets that are then wrapped around the dialysis AVF at the time of creation. The coating provides sustained release of nitric oxide (NO) over 2 months, thus recruiting and retaining endothelial cells and endothelial progenitor cells. It also incorporates a endothelial cell adhesive ligand that promotes endothelial cell retention and migration. The sustained release of NO also promotes appropriate vasodilation necessary for healthy AVF maturation. This coating also limits smooth muscle (SMC) proliferation, an additional benefit since SMC proliferation plays a significant role in AVF non-maturation. The nanomatrix coating is a biocompatible peptide based material and is coated on ePCL sheets by simple water evaporation. This coating method minimizes the risk of inflammatory responses. In this Phase I SBIR, we propose to evaluate and optimize the coating for ePCL sheets. This will include evaluation of physical characteristics and assessing effects on endothelial and smooth muscle cell growth. In collaboration with Dr. Lee at the University of Alabama at Birmingham, the efficacy of this coating will be evaluated in an established rodent AVF model, and compared with non-coated ePCL sheets. Development of a coating that promotes AVF maturation may have significant impact in the treatment of patients requiring dialysis. With successful completion of Phase I, we plan to move forward in Phase II to large animal studies.

Public Health Relevance Statement:


Public Health Relevance:
Arterovenousfistula non-maturation occurs in 60% of patients of hemodialysis patients receiving an arteriovenous fistula (AVF). This results in significant morbidity and mortality because of long-term dialysis catheter use. Endomimetics, LLC has developed a novel nanomatrix coating, which, when applied to an electrospun sheet and wrapped around the AVF at time of creation, could promote and enhance healthy AVF maturation and reduce the risk of longer-term complications.

Project Terms:
Address; Adhesions; Adhesives; Affect; Agreement; Alabama; Anastomosis - action; Animals; Arteriovenous fistula; base; Biocompatible; Blood Cells; Blood flow; Blood Vessels; Caring; Catheters; cell growth; Cell Proliferation; Cells; Characteristics; Clinical; clinical care; Collaborations; cost; Data; Development; Dialysis patients; Dialysis procedure; effective therapy; Elements; End stage renal failure; Endothelial Cells; Endothelium; Evaluation; evaporation; Fiber; Fistula; Functional disorder; Hemodialysis; Histologic; Human; Hyperplasia; improved; In Vitro; in vivo; industry partner; Inflammation; Inflammatory Response; innovation; Kidney; Legal patent; Letters; Ligands; Mediating; Methodology; Methods; migration; Modality; Modeling; Morbidity - disease rate; Mortality Vital Statistics; nanofiber; Nitric Oxide; novel; Organic solvent product; Patients; Pattern; Peptides; Phase; phase 1 study; Play; polycaprolactone; Positioning Attribute; Preparation; prevent; Production; Property; public health relevance; quality assurance; Rattus; Recruitment Activity; Research; Research Infrastructure; Resources; Risk; Rodent; Role; scale up; Site; Small Business Innovation Research Grant; Smooth muscle (tissue); Smooth Muscle Myocytes; Stem cells; Therapeutic; Time; Tissues; Ultrasonography; Umbilical vein; United States Food and Drug Administration; Universities; Vascular remodeling; Vasodilation; Venous; Water; Work

More than 500,000 U.S. patients have end stage renal disease and over 80% utilize hemodialysis as their renal replacement modality of choice. The Achilles Heel in the care of dialysis patients is the development of a functioning and durable vascular access, preferably an arteriovenous fistula (AVF). The annual cost of treating vascular access dysfunction totals over one billion US dollars. This is largely due to the high proportion of AVFs that fail to mature. After creation, sixty percent of AVFs fail to mature successfully for dialysis use, due to early venous neointimal development and inadequate vasodilation. At present, there are no effective therapies to promote vascular access maturation. Endomimetics has developed a nitric oxide (NO) releasing nanomatrix gel that mimics the characteristic properties of native endothelium. This nanomatrix can be applied on the dialysis AVF at the time of creation. In our Phase I SBIR, the nanomatrix gel demonstrated release of NO over 30 days, inhibited neointimal hyperplasia, and reduced expression of inflammatory markers in a rat AVF model. The Endomimetics nanomatrix gel is a biocompatible peptide based material and minimizes the risk of inflammatory responses. In this Phase II SBIR, we propose to evaluate the efficacy of the nanomatrix gel for AVF maturation at a clinically relevant time point. Aim 1 will include evaluation of gelation properties, ex vivo blood vessel dilation, and assessment of NO effects on inhibition of inflammation. In collaboration with Dr. Lee at the University of Alabama at Birmingham, Aims 2 and 3 will evaluate the efficacy of the Endomimetics nanomatrix gel in an established rodent AVF model, and in a porcine model. Development of the Endomimetics NO releasing nanomatrix gel that promotes AVF maturation may have significant impact in the treatment of patients requiring dialysis. With successful completion of Phase II, we plan to move forward in discussion with the FDA.

Public Health Relevance Statement:
Arteriovenous fistula non-maturation occurs in 60% of patients of hemodialysis patients receiving an arteriovenous fistula (AVF). This results in significant morbidity and mortality because of long-term dialysis catheter use. Endomimetics, LLC has developed a novel nitric oxide releasing nanomatrix gel, which, when applied at the time of AVF creation, could promote and enhance healthy AVF maturation and reduce the risk of longer-term complications.

Project Terms:
Address; Adhesives; Agreement; Alabama; Anastomosis - action; Animals; Anti-inflammatory; Anti-Inflammatory Agents; Arteriovenous fistula; base; biomaterial compatibility; Blood Vessels; Caring; Catheters; cell motility; Cell Proliferation; Characteristics; Clinical; clinical application; clinical care; clinically relevant; Collaborations; cost; Development; Devices; Dialysis patients; Dialysis procedure; effective therapy; Elements; End stage renal failure; Endothelial Cells; Endothelium; Enzymes; Evaluation; Family suidae; Fistula; Functional disorder; Gel; Hemodialysis; Hyperplasia; improved; In Vitro; in vivo; industry partner; Inflammation; Inflammatory; inflammatory marker; Inflammatory Response; innovation; Kidney; Legal patent; Letters; Ligands; Long-Term Effects; Mediating; Methodology; Modality; Modeling; Molecular Conformation; Morbidity - disease rate; mortality; Nitric Oxide; novel; Operative Surgical Procedures; Patients; Peptides; Phase; phase 1 study; phase 2 study; polycaprolactone; Positioning Attribute; pre-clinical; Preparation; prevent; Production; Property; quality assurance; Rattus; Research; Research Infrastructure; Resources; Risk; risk minimization; Rodent; scale up; Site; Small Business Innovation Research Grant; Smooth Muscle Myocytes; Therapeutic; Time; Tissues; United States; United States Food and Drug Administration; Universities; Vascular remodeling; Vasodilation; Venous; viscoelasticity; Work