SBIR-STTR Award

Pluromed, Inc. NIH SBIR Phase I Grant Application Internal Polymeric Vessel Occluder for Temporary Vascular Occlusion of the Kidney During Partial Nephrectomy Project Summary/Abstract Nephron-sparing surgery has become more common for the treatment of renal masses. With increasing experience, the need to control intraoperative renal bleeding is increasingly significant. This need is amplified by the trend in urologic surgery towards robotic and minimally invasive techniques where visibility can be severely limited by even small volumes of blood. As a result, many techniques have been developed to achieve hemostasis, including conventional suture repair, tissue sealants, radiofrequency ablation, laser ablation, water dissection, and microwave tissue coagulation. Pluromed has developed a biocompatible gel in which the blood vessel is filled with and occluded by the gel. The gel's working principle is based on the reverse thermosensitive properties of the polymer. At low temperatures, the polymeric solution is a liquid. As the temperature increases to body temperature, the viscosity of the solution rapidly increases several orders of magnitude to the consistency of a hard gel. Cooling the occlusion site, for example by applying ice, lowers the viscosity back to that of a liquid, dissolving the gel in blood and reestablishing blood flow. The gel has been developed for applications in anastomosis such as Off-Pump Bypass surgery (OPCAB), hemodialysis access, and tibial anastomosis. It has been shown to work very gently, neither compromising nor changing the biochemical make-up the arterial wall, as evidenced by measurements of the microvascular reactivity after filling and opening up the blood vessel. The proposal of this Phase I application is to apply the same principle to nephron-sparing surgery. In this approach, the renal artery leading to the diseased kidney is infused with the reverse thermosensitive gel. This has been shown to lead to cessation of blood flow within the renal parenchyma. It appears that, with the appropriate injection rate, the polymer flows downstream to occlude small, intra-renal vessels on both the arterial and venous sides of the circulation. This produces a completely bloodless surgical field, allowing speedy resection. After about 20 minutes the flow gradually resumes, with no apparent adverse consequences to the kidney. Return of blood flow may then be accelerated, if necessary, by cooling the kidney. Initial short-term in-vivo experiments indicate the feasibility of this approach. However, the polymer used in these preliminary experiments has a lower than optimal transition temperature for a solid organ. In a solid organ, such as the kidney, temperatures during the surgery may be higher than in exposed arteries where the company has greater experimental experience. A polymer solution with a higher transition temperature may be superior to the present formulation for solid organ applications. Furthermore, a more extensive animal study is needed to ascertain the relationship between rate/volume of injection and the expected downstream ischemic time. It is also necessary to develop an injection system that does not unduly increase the procedural time by requiring a long dissection of the artery or by requiring additional surgery to repair the artery at the injection site. Delineation of these parameters will allow for chronic animal experiments in Phase II and a clear path forward to subsequent clinical application with the declared involvement of Dr. John A. Libertino, Chairman of the Department of Urology at Lahey Clinic Medical Center. Pluromed, Inc. NIH SBIR Phase I Grant Application Internal Polymeric Vessel Occluder for Temporary Vascular Occlusion of the Kidney During Partial Nephrectomy

Two important advances in the treatment of renal cancer are gaining acceptance; partial nephrectomy is replacing radical nephrectomy for preserving functioning renal tissue, and minimally invasive surgery is replacing open partial nephrectomy. For both, control of intra-operative renal bleeding is essential. Pluromed has developed a family of Rapid Transition Polymers" (RTPs"), reverse thermosensitive polymers which are liquid at low temperatures and rapidly transition to gel as they warm to body temperature. The aqueous polymer is reversible back to a liquid via cooling and is dissolvable. The Company has developed a new RTP, LeGoo-XL", and a technique, Perfusive Hemostasis", which are used to achieve superior hemostasis during partial nephrectomy. By injecting LeGoo-XL into a segmental branch of the renal artery, blood flow is reversibly interrupted to that renal segment destined for resection while normal flow is maintained to uninvolved s commercialization by performing all of the pre-clinical development required in anticipation of a subsequent clinical trial supporting FDA approval. This includes validation and extension of Phase I results, a comparison of LeGoo-XL to standard arterial clamping techniques, an assessment of the safety and biocompatibility of the polymer, and development of a market-ready injection system. Acute and chronic experiments in pigs and calves will be performed. The Specific Aims of this project are: 1. To verify and extend Phase I results in an acute pig study; 2. To compare LeGoo-XL to renal artery clamping in acute and chronic pigs; 3. To study pathology in 6 week survival pigs; 4. To extend results to a second and larger animal model in an acute calf study; 5. To characterize the biocompatibility, toxicity and physiochemistry of LeGoo-XL; 6. To develop a market-ready angiographic injector and system 7. To develop an alternative direct renal artery injection technique upon completion ofinimally invasive techniques in this approach by offering superior hemostasis and allowing surgery on one section of the kidney while maintaining normal flow to the remaining renal tissue.

Public Health Relevance:
Surgically removing only the morbid part of a diseased kidney instead of removing the entire kidney, nephron- sparing surgery, is beneficial for long-term kidney function. The technical hurdles limiting the adoption of this approach are the ability to control bleeding during the surgery and the need to reduce warm ischemia time. A bloodless field is vital to the success of minimally invasive techniques. LeGoo-XL offers superior hemostasis and the ability to temporarily interrupt flow only to that renal segment destined for resection. This approach has the capability to make the surgeon's job easier and the partial nephrectomy procedure shorter while leading to better renal function and outcomes. It has the potential to enable greater adoption of both the partial nephrectomy approach and the use of minimally invasive techniques in this approach.

Public Health Relevance Statement:
Project Narrative Surgically removing only the morbid part of a diseased kidney instead of removing the entire kidney, nephron- sparing surgery, is beneficial for long-term kidney function. The technical hurdles limiting the adoption of this approach are the ability to control bleeding during the surgery and the need to reduce warm ischemia time. A bloodless field is vital to the success of minimally invasive techniques. Le-Goo-XL offers superior hemostasis and the ability to temporarily interrupt flow only to that renal segment destined for resection. This approach has the capability to make the surgeon's job easier and the partial nephrectomy procedure shorter while leading to better renal function and outcomes. It has the potential to enable greater adoption of both the partial nephrectomy approach and the use of minimally invasive techniques in this approach.

NIH Spending Category:
Bioengineering; Diagnostic Radiology; Kidney Disease

Project Terms:
Abscission; Acute; Address; Adoption; Advanced Development; Affect; Angiogram; Angiography; Animal Model; Animal Models and Related Studies; Animals; Arm; Arteries; Back; Behavior; Biocompatible; Bleeding; Blood; Blood Cell Count, White; Blood Vessels; Blood flow; Body Temperature; Buffers; Caliber; Categories; Catheters; Characteristics; Chronic; Clinical Trials; Clinical Trials Design; Clinical Trials, Unspecified; DISSEC; Development; Devices; Diameter; Dissection; Dorsum; Erythrocyte Volume, Packed; Excision; Extirpation; Family; Family suidae; Fluoroscopy; Gel; Generations; Goals; Hand; Hct; Hematocrit; Hematocrit procedure; Hemorrhage; Hemostasis; Hemostatic function; Individual; Injection of therapeutic agent; Injections; Interruption; Jobs; Kidney; Kidney Cancer; Kidney Carcinoma; Laboratories; Leukocyte Count; Leukocyte Number; Liquid substance; Liver; Liver Function Tests; Location; Lung; Lytotoxicity; Marketing; Measures; Methods; Methods and Techniques; Methods, Other; Modeling; Monitor; Nephrectomy; Nephrons; Occupations; Operation; Operative Procedures; Operative Surgical Procedures; Organ; Outcome; Packed Red-Cell Volume; Pathology; Phase; Pigs; Plug-in; Polymers; Post-Operative; Postoperative; Postoperative Period; Preparedness; Pressure; Pressure- physical agent; Procedures; Professional Postions; RDST; Readiness; Removal; Renal Artery; Renal Cancer; Renal Tissue; Renal carcinoma; Renal function; Reperfusion Therapy; Research; Respiratory System, Lung; Reticuloendothelial System, Blood; Safety; Solutions; Specific qualifier value; Specified; Structure of renal artery; Suidae; Surgeon; Surgical; Surgical Interventions; Surgical Procedure; Surgical Removal; Swine; Syringes; System; System, LOINC Axis 4; Techniques; Testing; Time; Toxic effect; Toxicities; Transition Temperature; Upper arm; Urinary System, Kidney; Uriniferous Tube; Validation; Variant; Variation; Venous; Warm Ischemia; White Blood Cell Count procedure; Work; aqueous; biocompatibility; biomaterial compatibility; blood loss; body system, hepatic; clinical applicability; clinical application; clinical investigation; cold temperature; commercialization; cytotoxicity; experiment; experimental research; experimental study; fluid; genotoxicity; in vivo; irritation; kidney function; liquid; low temperature; minimally invasive; model organism; organ system, hepatic; porcine; pre-clinical; preclinical; pressure; prototype; public health relevance; pulmonary; radiologist; renal; renal artery; reperfusion; research study; resection; species difference; success; suid; surgery; vascular