SBIR-STTR Award

Current gold standards for hemodialysis access, radial cephalic vein fistulas and autogenous saphenous veins, have significant problems associated with their use. Many patients do not have a healthy vein to spare due to disease progression or prior/future use for a different surgical procedure (i.e. for a distal or coronary bypass). These surgical procedures also require greater time than a prosthetic graft implant due to vein harvesting. Synthetic grafts have issues with patency and inability to provide instant access. Our hypothesis is that the next generation of prosthetic hemodialysis grafts should possess multiple structural and biological properties that mimic some of those processes inherent to native arteries in order to prevent these complications from occurring. The goal of the Phase I study is to develop a first of its kind hemodialysis access graft comprised of polyester (PET) and polyurethane (PU) blend via electrospinning technology (BioAccess). Incorporation of these polymers as this unique blend will impart both strength and compliance to the graft. Specific biologic agents for preventing thrombosis (recombinant hirudin or rHir), infection (Moxifloxacin) and hyperplasia (Paclitaxel), will be blended in the graft. The incorporation of these agents should aid in the healing of the graft by preventing acute thrombosis, chronic infection and stenosis of the conduits during the repeated cannulation of the graft. The specific objectives of our proposed study are to: 1) optimize electrospinning conditions for the nanofibrous BioAccess graft, 2) characterize physical, chemical and surface properties of the graft, 3) evaluate release pharmacokinetics of rHir, Moxifloxacin and Paclitaxel from the BioAccess graft via a stringent washing study and 4) examine antithrombotic, antimicrobial and anti-proliferative properties of the graft using established biologic assays. The overall annual cost of ESRD treatment in the US is $23 billion, which is projected to increase 3.6% every year. About 2 million patients worldwide (355,000, currently in US alone) will receive hemodialysis treatment by 2010. With increasing age of dialysis patients and higher occurrence of diabetes and obesity, there is an urgent need for hemodialysis grafts with immediate access and better healing properties.

Public Health Relevance:
End Stage Renal Disease (ESRD) affects millions of people worldwide with the total cost of treatment in US alone standing at $23 billion. With increasing age, diabetes and obesity associated with the patients, there is a need for better hemodialysis access grafts that provide instant access and faster healing. The goal of this Phase I grant is to develop a novel hemodialysis graft from polyester (PET) and polyurethane (PU) through the process of electrospinning, incorporating antithrombotic (recombinant hirudin), antimicrobial and antineoplastic (Paclitaxel) agents directly into the fibrous (Moxifloxacin) construct. Our hypothesis is that the strength and elasticity of the polymers combined with the synergisticbiological effects of the selected drugs should lead to a synthetic graft with improved healing, better long-term patency and instant access.

Thesaurus Terms:
"1-Leu-2-Thr-63-Desulfohirudin; 1-Cyclopropyl--7-(2,8-Diazabicyclo(4.3.0)Non-8-Yl)-6-Fluoro-8-Methoxy-1,4-Dihydro-4-Oxo-3-Quinolinecarboxylic Acid; Acute; Affect; Age; Anti-Cancer Agents; Anti-Infective Agents; Anti-Infective Drugs; Anti-Infectives; Anti-Tumor Agents; Anti-Tumor Drugs; Anti-Infective Preparation; Antiinfective Drugs; Antiinfectives; Antiinfective Agents; Antineoplastic Agents; Antineoplastic Drugs; Antineoplastics; Antiproliferative Agents; Antiproliferative Drugs; Anzatax; Aortocoronary Bypass; Arteries; Asotax; Assay; Au Element; Autologous; Bioassay; Biologic Assays; Biological; Biological Assay; Bristaxol; Calorimetry, Differential Scanning; Cancer Drug; Cannulations; Catheters; Cephalic Vein; Chemicals; Chemotherapeutic Agents, Neoplastic Disease; Chronic; Constriction, Pathologic; Constriction, Pathological; Coronary Artery Bypass; Coronary Artery Bypass Grafting; Coronary Artery Bypass Surgery; Diabetes Mellitus; Dialysis; Dialysis Patients; Dialysis Procedure; Differential Scanning Calorimetry; Differential Thermal Analysis, Calorimetric; Disease Progression; Distal; Drug Kinetics; Drugs; Esrd; Elasticity; End Stage Renal Failure; End-Stage Kidney Disease; Fistula; Future; Goals; Gold; Grant; Harvest; Healed; Healing Abnormal; Healing Delayed; Health Care Costs; Health Costs; Health Insurance For Aged And Disabled, Title 18; Health Insurance For Aged, Title 18; Health Insurance For Disabled Title 18; Healthcare Costs; Hemodialyses; Hemodialysis; Hemostasis; Hemostatic Function; Hyperplasia; Hyperplastic; Impaired Healing; Impaired Tissue Repair; Impaired Wound Healing; Implant; Individual; Infection; Lead; Legal Patent; Lepirudin; Medicare; Medication; Moxifloxacin; Obesity; Operation; Operative Procedures; Operative Surgical Procedures; Ostamer; Paclitaxel; Paclitaxel (Taxol); Patents; Patients; Pb Element; Pellethane; Permeability; Persons; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacokinetics; Phase; Polyesters; Polyisocyanates; Polymers; Polyurethanes; Porosity; Praxel; Process; Property; Property, Loinc Axis 2; Prosthesis; Prosthetic Device; Prosthetics; Radial; Recombinant Hirudin; Renal Disease, End-Stage; Resistance; Saphenous Vein; Seroma; Stenosis; Structure Of Cephalic Vein; Surface Properties; Surgical; Surgical Interventions; Surgical Procedure; Surgical Sutures; Sutures; Taxol; Taxol (Old Nsc); Taxol A; Taxol Konzentrat; Technology; Testing; Thrombosis; Thrombus; Time; Title 18; Treatment Cost; Tumor-Specific Treatment Agents; Veins; Abnormal Tissue Repair; Adiposity; Aging Population; Anti-Microbial; Anticancer Agent; Anticancer Drug; Antimicrobial; Cephalic Vein; Communicable Disease Control Agent; Coronary Bypass; Corpulence; Corpulency; Corpulentia; Cost; Delayed Wound Healing; Diabetes; Dialysis Therapy; Drug/Agent; Economic Impact; Graft Healing; Healing; Health Insurance For Disabled; Heavy Metal Pb; Heavy Metal Lead; Improved; Nano Fiber; Nanofiber; Nanofibrous; Next Generation; Novel; Obese; Obese People; Obese Person; Obese Population; Phase 1 Study; Prevent; Preventing; Public Health Relevance; Resistant; Seal; Surgery"

Current gold standards for hemodialysis access to treat End-Stage Renal Disease (ESRD), radial cephalic vein fistulas and autogenous saphenous veins, have significant problems associated with their use. The issues range from unavailability of a healthy vein the patient can spare complexity of harvesting and longevity of the surgical procedure to the long time (4-6 months) required for healing of the fistula. Synthetic grafts made of ePTFE and polyurethane (PU) have issues of low patency (20% for 2 years), delayed access time to first puncture (more than 3 weeks), infection, weeping (leading to hematomas/seroma formation) and kinking of the native vein resulting in graft thrombosis. Thus, there is a need to develop an off-the shelf prosthetic graft that would give comparable or higher patency to autologous grafts or fistulas, eliminate/reduce infection, prevent surface thrombus formation inhibit uncontrolled cellular proliferation throughout graft and most importantly, provide instant access to puncture. Research objectives proposed and accomplished in Phase I were: 1) synthesis of a novel nanofibrous bioactive hemodialysis graft (BioAccess) via electrospinning of polyester and polyurethane in combination with antithrombin, antimicrobial and anti-proliferative agents, 2) characterization of the physical and chemical properties of the BioAccess graft, 3) determination of the release pharmacokinetics from the BioAccess graft, and 4) evaluation of the biologic properties of the BioAccess grafts after undergoing stringent wash conditions. The goal of the Phase II study is to assess in vivo the BioAccess grafts (6mm ID) as well as clinically utilized ePTFE grafts in a canine arteriovenous (carotid artery to jugular vein) shunt access model. BioAccess grafts will be evaluated for patency, infection-resistance, gross hematoma formation, surface thrombus formation and hyperplasia formation after being punctured various times for 30 and 60 days. Our hypothesis is that the BioAccess Graft will become the new standard for hemodialysis access by outperforming ePTFE grafts in terms of immediate access, reduced hematoma formation, low incidences of infection and increased primary patency rates. The BioAccess graft will be superior to ePTFE grafts due to its better mechanical compliance in conjunction with localized release of antithrombotic, antimicrobial and anti- proliferative agents, thereby regulating any potential complications directly at the graft surface. The specific objectives for Phase II are to: 1) electrospin BioAccess grafts for implantation studies, qualify physical, chemical and surface properties of BioAccess grafts, 3) confirm biologic properties of BioAccess graft using established assays employed in Phase I, 4) implant BioAccess and control ePTFE grafts into a canine arteriovenous shunt access model for 30 and 60 days in conjunction with numerous needle punctures and 5) macroscopically and histologically analyze explanted BioAccess and ePTFE grafts. The overall annual cost of ESRD treatment in the US is $23 billion, which is projected to increase at an annual rate of 3.6%. About 2 million patients worldwide (355,000 in US alone) currently will receive hemodialysis treatment by 2012. Approximately 140,000 access grafts are currently implanted in the US at a total healthcare cost of $80 million. Temporary catheters are the most expensive of all the ESRD treatments for Medicare, costing about $77,000/person/year, a cost that can be avoided by immediate access through a permanent arteriovenous graft. With the increase in aging population of ESRD patients, higher occurrence of diabetes and obesity, the options for a patient are reduced to immediate hemodialysis. Thus, there is an increasing demand for hemodialysis grafts with immediate access and better healing properties.

Public Health Relevance:
Current gold standards for hemodialysis access to treat End-Stage Renal Disease (ESRD), radial cephalic vein fistulas and autogenous saphenous veins, have significant problems associated with their use. The issues range from unavailability of a healthy vein the patient can spare complexity of harvesting and longevity of the surgical procedure to the long time (4-6 months) required for healing of the fistula. The goal of the Phase II study is to assess in vivo the BioAccess grafts (6mm ID) as well as clinically utilized ePTFE grafts in a canine arteriovenous (carotid artery to jugular vein) shunt access model. BioAccess grafts will be evaluated for patency, infection-resistance, gross hematoma formation, surface thrombus formation and hyperplasia formation after being punctured various times for 30 and 60 days. With the increase in aging population of ESRD patients, higher occurrence of diabetes and obesity, the options for a patient are reduced to immediate hemodialysis. Thus, there is an increasing demand for hemodialysis grafts with immediate access and better healing properties.