HUN002201S
PROJECT TITLE: DEVELOPMENT OF A BIOENGINEERED THERAPEUTIC DEVICE FOR THE PREVENTION OF LYMPHEDEMA PROJECT START/END DATES: 07/08/2024 Â 06/30/2029 SITE AND PI NAME: FIBRALIGN CORP.,/MICHAEL PAUKSHTO, PHD OVERALL PROJECT OBJECTIVES: OUR PREVIOUS PRECLINICAL DATA SHOWED THAT COLLAGEN CONDUITS RESTORE LYMPH FLOW FROM THE IMPAIRED AREA THROUGH RE-ROUTING LYMPH DRAINAGE TOWARD UNAFFECTED LYMPHATICS, AND PILOT STUDIES OF THE CONDUIT EMPLOYMENT AS AN ADJUNCT THERAPY IN LYMPHEDEMA PATIENTS SHOWED THAT STIMULATION OF CONDUIT-DIRECTED LYMPHATIC REGENERATION CORRELATED WITH CLINICAL IMPROVEMENT. WE FORESEE SIGNIFICANT VALUE IN ADVANCING THIS IMPORTANT TECHNOLOGY FURTHER AND OPTIMIZING THE PROPERTIES OF THE CONDUIT TO MAXIMIZE THEIR THERAPEUTIC EFFECT. WE WILL TEST THE TRANSLATIONAL POTENTIAL OF THIS DEVICE AS AN INTERVENTION THAT CAN PREVENT LYMPHEDEMA DURING CANCER SURGERY, THEREBY PROVIDING SIGNIFICANT BENEFIT TO AT-RISK PATIENTS AND SUBSTANTIAL HEALTHCARE COST SAVINGS. THEREFORE, THE PROPOSED INNOVATIVE STRATEGY AIMS TO OBVIATE LYMPHEDEMA BY ADVANCING THE DEVELOPMENT OF AN OPTIMIZED CONDUIT THAT BRIDGES THE GAP OF SEVERED LYMPHATICS TO PRESERVE LYMPHATIC CONTINUITY, PROMOTE LYMPHANGIOGENESIS, AND REDUCE FIBROTIC REACTION LOCALLY ALONG THE CONDUIT. ACCORDINGLY, THE OBJECTIVES OF THE PROPOSED STUDY ARE TO OPTIMIZE THE STRUCTURAL AND MECHANICAL PROPERTIES OF THE CONDUIT FOR TARGETING LYMPHEDEMA PREVENTION AND. VERIFY ITS EFFICACY AS PREVENTIVE TREATMENT IN MOUSE TAIL AND RAT HINDLIMB LYMPHEDEMA MODELS, AS WELL AS TO REVEAL THE FUNDAMENTAL BIOLOGICAL MECHANISMS UNDERLYING THE PROCESS. IF SUCCESSFUL, THE PROPOSED STUDIES WILL LEAD TO MAXIMUM BENEFIT FOR PREVENTION OF LYMPHEDEMA, AND THE BIOLOGICAL INSIGHTS GAINED FROM THE STUDIES WILL FURTHER INFORM OUR CONDUIT DESIGN STRATEGY. SCOPE OF WORK AND TASKS/SCIENTIFIC GOALS: OPTIMIZATION OF SCAFFOLD MECHANICAL AND STRUCTURAL PROPERTIES AND EVALUATION OF SCAFFOLD ACTIVITY IN VITRO. WE WILL PREPARE VARIOUS CONFIGURATIONS OF NANOFIBRILLAR SCAFFOLDS TO ACHIEVE SPECIFIC STRUCTURAL AND MECHANICAL PROPERTIES SUCH AS: FIBRIL SIZE BY IONIC STRENGTH OF THE COLLAGEN MATERIAL, ELASTIC MODULUS, DEGRADATION RATE BY CROSSLINKING DEGREE, AND POROSITY/CAPILLARITY BY LYOPHILIZATION CONDITIONS. THIS DEVELOPMENT WILL TAKE ADVANTAGE OF FIBRALIGNÂ S ESTABLISHED TECHNOLOGY PLATFORM FOR PROCESSING ATELOCOLLAGEN INTO PRECISE NANOFIBRILLAR SCAFFOLDS AND WILL BE CONDUCTED IN THE COMPANYÂ S EXISTING GMP CLEANROOM FACILITY AND LABS UTILIZING ITS MULTI-STEP FABRICATION PROCESS AND EQUIPMENT DEVELOPED FOR THIS PURPOSE. WE WILL CHARACTERIZE THESE SCAFFOLD CONFIGURATIONS BY AFM, TENSILE STRENGTH, DEGRADATION RATE, WATER UPTAKE AND CAPILLARY FLOW. WE WILL ASSESS THE EFFECT OF THE SCAFFOLD PROPERTIES ON LEC PHENOTYPE, PROLIFERATION AND SPROUTING, AND INTEGRIN SIGNALING. WE WILL DETERMINE THE Â IN-VITRO OPTIMALÂ SCAFFOLD CHARACTERISTICS BASED ON CAPILLARITY AND MAINTENANCE OF LYMPHATIC PHENOTYPE, LYMPHATIC SPROUTING, AND PROPER INTEGRIN SIGNALING INTERACTIONS. IN VIVO ASSESSMENT OF SCAFFOLD FUNCTION IN (1) MOUSE TAIL LYMPHEDEMA MODEL AND (2) RAT HINDLIMB LYMPHEDEMA MODEL. WE WILL SUPPORT EVALUATION OF THE SCAFFOLD CONFIGURATIONS FOR THEIR ABILITY TO ENHANCE LYMPHATIC VESSEL FORMATION IN VIVO FOLLOWING SUBCUTANEOUS IMPLANTATION ACROSS THE DISRUPTED LYMPHATICS IN MOUSE TAIL LYMPHEDEMA MODEL. AFTER IMPLANTATION, LYMPHEDEMA DEVELOPMENT WILL BE TRACED BY MEASURING THE TAIL VOLUME, AND LYMPH FLOW ACROSS THE INJURY SITE WILL BE DETECTED BY ICG IMAGING, UP TO 4 WEEKS POST IMPLANTATION. AT 4 WEEKS POST TRANSPLANTATION, MOUSE TAIL TISSUE WITH THE IMPLANTS WILL BE HARVESTED AND SUBJECTED TO HISTOLOGICAL EVALUATION FOR THE STATUS OF IMPLANT AND LYMPHATIC DENSITY. EXPERIMENTAL GROUP (LYMPHEDEMA SURGERY FOLLOWED BY SCAFFOLD IMPLANTATION, N = 8) WILL BE COMPARED TO CONTROL GROUP (LYMPHEDEMA SURGERY ONLY). WE WILL DETERMINE THE BEST PERFORMING SCAFFOLD BY THE LOWEST TAIL VOLUME AND THE HIGHEST RATE OF RESTORING LYMPH FLOW ACROSS THE INJURY SITE BY ICG IMAGING. EX VIVO, LYMPHATIC REGENERATION WILL BE CHARACTERIZED BY HISTOLOGICAL ANALYSIS OF LYMPHATIC DENSITY. SCAFFOLD PERFORMANCE WILL THEN BE FURTHER EVALUATED UTILIZING A WELL-ESTABLISHED RAT HINDLIMB LYMPHEDEMA MODEL. AFTER RESECTION OF INGUINAL AND POPLITEAL LYMPH NODES, WE WILL IMPLANT SCAFFOLD WITH THE OPTIMIZED PROPERTIES TO BRIDGE ACROSS THE AREA OF DISRUPTED LYMPHATICS. TREATMENT GROUPS WILL CONSIST OF OPTIMALLY ENGINEERED SCAFFOLD, THE LOWEST RANK SCAFFOLD, AND COMPARED TO NO TREATMENT CONTROL GROUP. OVER THE COURSE OF 4 MONTHS, OUTPUTS WILL CONSIST OF QUANTIFICATION OF EDEMA ACCUMULATION BY MICRO COMPUTED TOMOGRAPHY, ICG IMAGING FOR RESTORATION OF LYMPH FLOW AND ITS PATTERN. EX VIVO, LYMPHATIC REGENERATION WILL BE CONFIRMED BY HISTOLOGICAL ANALYSIS OF LYMPHATIC DENSITY.
Fibralign Corporation
Project Grant R01CA285372
$112.3k 9/25/24