PI: Wang, Dongfang

CO-PI: Plunkett, Mark
CO-PI: Zwischenberger, Joseph
Title: STTR: Development of Percutaneous DLC for Total Cava-Pulmonary Assistance
Sponsor: NIH: W-Z Biotech LLC
Abstract: The Fontan procedure is currently standard care for patients with complex single ventricle congenital heart defects. The Fontan procedure involves the creation of a cavopulmonary (CP) shunt connecting the inferior and superior vena cava (IVC and SVC) directly to the right pulmonary artery (RPA), diverting total venous return from the IVC/SVC directly to the PA without entering the right atrium (RA) and right ventricle (RV). The Fontan procedure results in a blood flow pattern of a passively filled pulmonary circulation and a single ventricle to pump blood to the systemic circulation. Although it has improved thousands of patients’ quality of life by increasing arterial O2 saturation, the mortality is reported at 29.1%. Patients with a failing Fontan follow a bimodal distribution with some failing acutely in the early post-operative period and others failing years later. Cavopulmonary assistance (CPA) is highly desired to effectively pump venous blood through the Fontan connection to the pulmonary artery and to reverse the pathophysiology of the failing Fontan circulation. However, there is currently no specific device available for CPA. Our objective in this Phase I STTR is to develop and fabricate a working prototype of a percutaneous double lumen cannula (DLC) for CPA and to test this prototype in our new failing Fontan sheep model. Our ultimate goal is to develop a CPA system that avoids the need for an open surgical procedure or the use of cardiopulmonary bypass (CPB). The enabling technology will be a percutaneous DLC that will drain venous blood from both the IVC and SVC simultaneously and infuse blood directly into the pulmonary artery. Our Specific Aims are: 1) to develop and fabricate a working prototype of a percutaneous DLC to assist failing Fontan circulation, and 2) to test our prototype CPA DLC in our improved failing Fontan sheep model. Our proposed cannula-based CPA will be a “game changer” in the management of failing Fontan physiology.

PI: Zwischenberger, Joseph

CO-PI: Ballard-Croft, Cherry
CO-PI: Wang, Dongfang
Title: Development of a Perfusion-Induced Systemic Hyperthermia Delivery Apparatus
Sponsor: Exatherm LLC
Abstract: Lung cancer is the leading cause of cancer-related deaths in men and women in the United States today (1). The long-term prognosis for patients with advanced stage non-small cell lung cancer (NSCLC), which accounts for 75% of all new lung cancer cases, is dismal with currently available chemotherapy regimens providing only a 9-12 month median survival (2-10). Thus, our long term goal is to develop a more effective treatment for late stage NSCLC. Several studies have shown that regional/local hyperthermia exhibits primary effects on cancer and synergism with various chemotherapy agents (11-16). Hyperthermia also enhances intracellular platinum uptake and inhibits platinum-induced DNA adduct repair, an effect that may be important in reversing cisplatin resistance (17). Thus, concurrent combined use of hyperthermia and chemotherapy has great potential in the treatment of advanced NSCLC. Although clinical efficacy of local/regional hyperthermia plus chemotherapy has been reported in numerous clinical trials (13, 14, 16, 18), clinical data on systemic hyperthermia is very limited (19). Our initial venovenous perfusion-induced systemic-hyperthermia (vv-PISH) system was developed in large animals over a 10 year period then tested in a phase I clinical trial in 10 patients with advanced NSCLC that was unresponsive to chemotherapy. The control group median survival was 87 days, while the hyperthermia group median survival was significantly greater at 450 days (20). Although our vv-PISH system functioned adequately in the phase 1 clinical trial, we encountered several problems. The vv-PISH system required a multi-site venous cannulation, which increased the potential for serious vascular complications. The circuit was also quite complicated with several bulky pumps, a separate dialysis unit, and a non-standard water heater. This complex circuit had a long blood path, which decreased heating efficiency. To compensate, the circuit blood temperature was much higher (46'C) than the hyperthermia target temperature (42'C) which likely resulted in some blood damage. Numerous dialysis problems associated with the charcoal sorbent dialyzer also occurred (20). The goal of this application is to develop a "next generation" vv-PISH system for therapeutic hyperthermia delivery. Our Phase I STIR results showed the feasibility of a simple and inexpensive vv-PISH system in delivering a predictable therapeutic hyperthermia dose. This system included: 1) a non-occlusive peristaltic roller pump (MC3 pump, MC3, Inc., 21,22,22),2) an adult ECMO heat exchanger (23), 3) a hemofilter (24),4) a water heater, and 5) a double lumen cannula (Avalon, Inc., 25). Our vv-PISH system was prototyped and tested in healthy adult swine (n=4) where it safely delivered the hyperthermichyperthermia dose (42°C for 120 minutes). The objective of this Phase II STIR proposal is to establish the feasibility of our finalized vv-PISH circuit to safely deliver therapeutic hyperthermia. The Phase II research will allow us to develop and test a vv-PISH clinical prototype which is a critical step toward FDA approval of this promising new advanced stage NSCLC treatment strategy. The specific aims are as follows: Specific Aim 1: To finalize and produce an integrated, clinical vv-PISH prototype. In this specific aim, our system will be finalized to incorporate the new developments and integrate the "off the shelf" components into a vv-PISH prototype suitable for preclinical and clinical testing. Specifically, we will assemble into a single unit the: 1) peristaltic roller pump (MC3 pump), 2) adult ECMO heat exchanger (ECMOtherm-1i TM), 3) hemofilter (Renaflow II®), 4) water heater (Hemotherm®), and 5) double lumen cannula (Avalon Elite™). Once assembled, we will perform bench testing, including operational limits testing, to confirm that design requirements have been met. Specific Aim 2: To determine the temperature control performance and in vivo safety of the clinical vv-PISH circuit. In this specific aim, we will establish the safety and reproducibility of the vv-PISH circuit in achieving the target therapeutic dose (42°C for 120 minutes) in adult female sheep. To this end, we will examine major organ function during hyperthermia. Adult sheep will also be monitored for five days after hyperthermia administration. Parameters used to assess the safety of the vv-PISH system will include: 1) survival, 2) multiple organ function, and 3) quality of life. This outcomes study is an essential part of the preclinical testing that must precede the clinical trial. Upon completion, a detailed necropsy will examine for end organ damage or emboli. Specific Aim 3: To determine the clinical feasibility of the vv-PISH circuit in a prospective randomized clinical trial. In this specific aim, a prospective randomized phase I clinical trial will be performed to test the clinical feasibility of the vv-PISH circuit. Advanced stage (Ilib or IV) NSCLC patients will be randomized into: 1) standard of care treatment consisting of cisplatin and etoposide chemotherapy with concurrent radiation therapy (n=1 0) and 2) standard of care therapy followed by systemic hyperthermia treatment via our vv-PISH clinical prototype (n=10). Hyperthermia will be given 2-4 weeks after the last chemotherapy dose.

PI: Zwischenberger, Joseph

CO-PI: Ballard-Croft, Cherry
CO-PI: Wang, Dongfang
Title: SBIR: Novel Dense Hollow Fiber for Blood Gas Exchange
Sponsor: Medarray Inc
Abstract: The goal of this project is to determine the performance and durability of MedArray's Silicone Membrane Hollow Fiber (SMHF) gas exchanger. This study will consist of two phases. In phase one, we will test the two-week performance and durability of the SMHF gas exchanger. In phase two, we will test the four-week performance and durability of the SMHF gas exchanger. To test the SMHF gas exchanger, we will use our ambulatory sheep model. In this model, healthy sheep will have an artificial lung circuit applied. This circuit will consist of a double lumen cannula, as exchanger (SMHF), and a blood pump. Parameters to be assessed will include sheep hemodynamics, gas exchanger flow and pressure gradient, blood gases, pump flow, blood trauma, and coagulation level. At conclusion of the experiment, an autopsy will be performed, and the gas exchanger will be examined for thrombi.

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