SBIR-STTR Award

The objective of this proposal is to examine a novel technique called improved Synchronization Modulation Electric Field (i-SMEF) in protection of donor kidneys and improvement of transplanted graft functions. We will apply the i-SMEF on donor kidneys during cold storage and evaluate the transplanted graft function following kidney transplantation in mice. We have developed a novel technique, named i-SMEF, which could not only maintain the pump functions, but also generate ATP molecules. Briefly, on the one hand, i-SMEF maintains Na/K pump activity to actively transport three Na+ out and two K+ ions in by consuming one ATP molecule, on the other hand, the electric field provides energy to the pump molecules so that they can synthesize one ATP in each pumping cycle. Consequently, the ATP net-consumption for the i-SMEF-controlled Na/K pumps is theoretically zero at any pumping rate, in other words, the pump molecules can effectively build up physiological ionic concentration gradients in the situations with a limited or lack of ATP supply, such as in hypoxia. Based on the strong preliminary findings, we propose to test this technique in a mouse kidney transplantation model. We will test our hypothesis that application of the i-SMEF on donor kidneys during cold storage protects against ischemic injury and improves the transplanted graft functions.

Public Health Relevance Statement:
The objective of this proposal is to examine a novel technique called improved Synchronization Modulation Electric Field (i-SMEF) in protection of donor kidneys and improvement of transplanted graft functions.

Project Terms:
Na(+)-K(+)-Exchanging ATPase; Na pump; Na+ K+ ATPase; Potassium ATPase Sodium; Potassium Adenosine Triphosphatase Sodium; Potassium Adenosinetriphosphatase Sodium; Potassium Pump; Sodium Pump; Sodium-Potassium Pump; sodium potassium exchanging ATPase; Active Biological Transport; Active Biologic Transport; Active Transport; Uphill Transport; Body Temperature; Cell membrane; Cytoplasmic Membrane; Plasma Membrane; plasmalemma; Clinical Trials; Creatinine; Cryopreservation; Cryofixation; cold preservation; cold storage; Equilibrium; balance; balance function; Exhibits; Graft Survival; Half-Life; Histology; Incidence; Ions; Ischemia; Kidney; Kidney Urinary System; renal; Kidney Transplantation; Kidney Grafting; Kidney Transplants; Renal Grafting; Renal Transplantation; Renal Transplants; kidney tx; Medical Device; Membrane Potentials; Resting Potentials; Transmembrane Potentials; Mus; Mice; Mice Mammals; Murine; Names; Necrosis; Necrotic; Organ Transplantation; Grafting Procedure; Organ Transplants; organ allograft; organ graft; organ xenograft; Legal patent; Patents; Patients; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Reperfusion Injury; Ischemia-Reperfusion Injury; Reperfusion Damage; Risk Factors; Saline; Saline Solution; Savings; Survival Rate; Testing; Transplantation; transplant; Autologous Transplantation; Autograft; Autotransplant; autologous graft; autotransplantation; Measures; Injury to Kidney; kidney injury; renal injury; Apoptosis; Apoptosis Pathway; Programmed Cell Death; base; Organ; Pump; improved; Procedures; Phase; Physiological; Physiologic; Renal function; kidney function; Hypoxia; Hypoxic; Oxygen Deficiency; electric field; Cardiac Death; Life; Pulse; Physiologic pulse; Hour; Frequencies; Pattern; Techniques; Clampings; Closure by clamp; Cell Volumes; experience; success; novel; Prevention; Devices; ESRD; End-Stage Kidney Disease; End-Stage Renal Disease; End stage renal failure; Seminal; Development; developmental; delayed graft function; Warm Ischemia; pre-clinical; preclinical; design; designing; novel strategies; new approaches; novel approaches; novel strategy; Consumption; Impairment; graft function; Same-sex; transplant model; ischemic injury; ischemia injury; porcine model; pig model; piglet model; swine model

The goals of this Phase II application: 1) determine the translational significance of the i-SMEF (improved Synchronization Modulation Electric Field) in a preclinical animal model using adult Yorkshire pigs with kidney autotransplantation; and 2) determine the optimal parameters of the i-SMEF in protection against ischemic injury of the donor kidneys during cold storage and improvement of the transplanted graft function. In the Phase I proposal, we have developed a novel technique, named i-SMEF (patent pending). The i-SMEF not only controls the Na/K pump activity, but also generates ATP molecules. Briefly, by utilizing the intrinsic dual energy transform functions of the Na/K pumps, we specially designed the i-SMEF to control Na/K pump activity. Meanwhile, the electric field provides adequate energy to the pump molecules so that they can synthesize one ATP molecule for each pumping cycle. Consequently, the i-SMEF can maintain the Na/K pumping activity in situations with an insufficient or lack of ATP supply, such as in hypoxia. Then, we demonstrated that the application of the i-SMEF on the donor kidneys effectively protected transplanted graft functions in a mouse kidney transplantation model. These data have just been published in Science Translational Medicine. In this Phase II proposal, we will examine the translational significance of the i-SMEF by using a preclinical porcine model in adult Yorkshire pigs. To minimize the immunoresponse and focus on the ischemia reperfusion injury, we will use kidney autotransplantation model. Then, we will determine the optimal parameters, including the numbers of electrode pairs, frequency, and voltage. Considering the high similarities in size, anatomy and physiology between human and adult pig kidneys, we believe that the optimal parameters obtained from pigs are readily applicable to humans in the Phase III proposal.

Public Health Relevance Statement:
The goals of this Phase II application are to determine the translational significance of the i-SMEF (improved Synchronization Modulation Electric Field) in a preclinical animal model using adult Yorkshire pigs with kidney autotransplantation. Then, the optimal parameters of the i-SMEF in protection against ischemic injury of the donor kidneys during cold storage and improvement of the transplanted graft function will be determined.

Project Terms:
Adult; 21+ years old; Adult Human; adulthood; Anatomy; Anatomic; Anatomic Sites; Anatomic structures; Anatomical Sciences; Back; Dorsum; Clinical Trials; Creatinine; Cryopreservation; Cryofixation; cold preservation; cold storage; Electrodes; Equipment; Flushing; Goals; Histology; General Hospitals; Human; Modern Man; Investments; Kidney; Kidney Urinary System; renal; Kidney Transplantation; Kidney Grafting; Kidney Transplants; Renal Grafting; Renal Transplantation; Renal Transplants; kidney tx; Medical Device; Mitochondria; mitochondrial; Mus; Mice; Mice Mammals; Murine; Names; Nephrectomy; Patents; Legal patent; Physiology; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma; Production; Publishing; Ischemia-Reperfusion Injury; Reperfusion Damage; Reperfusion Injury; Pigs; Suidae; Swine; porcine; suid; Family suidae; Testing; Tissues; Body Tissues; Transplantation; transplant; Autologous Transplantation; Autograft; Autotransplant; autologous graft; autotransplantation; Universities; Urine; Urine Urinary System; Wisconsin; Measures; Injury to Kidney; kidney injury; renal injury; Injury; injuries; base; Pump; improved; Phase; kidney function; Renal function; Hypoxic; Oxygen Deficiency; Hypoxia; Funding; Immunological response; host response; immune system response; immunoresponse; Immune response; electric field; Hour; Frequencies; cell type; Techniques; success; voltage; Animal Models and Related Studies; model of animal; model organism; Animal Model; novel; Devices; Modeling; Data; Multi-center clinical trial; Multi-site clinical trial; Multicenter clinical trial; Multisite clinical trial; Multi-Institutional Clinical Trial; Seminal; Translational Research; Translational Science; translation research; pre-clinical; preclinical; design; designing; translational medicine; graft function; Secure; LCN2 gene; LCN2; Lipocalin 2; NGAL; Neutrophil Gelatinase-Associated Lipocalin; Oncogenic Lipocalin 24P3; Uterocalin; preservation; transplant model; kidney biopsy; renal biopsy; ischemic injury; ischemia injury; porcine model; pig model; piglet model; swine model