Project Grant R43CA291522

PRESSURE-ENHANCED SENSING SURGERY (PRESS) AS A TOOL FOR SURGICAL GUIDANCE. - ABSTRACT SOME SURGERY PROCEDURES CAN BE MADE MORE SPECIFIC THROUGH THE USE OF ADMINISTERED TRACERS THAT ENHANCE THE CONTRAST THROUGH DIGITAL IMAGING OF THE FIELD AT THE TIME, AS DONE WITH X-RAYS OR FLUORESCENCE. TO DATE, NO CONTRAST AGENT HAS EVEN BEEN SHOWN TO ALLOW DYNAMIC IMAGING OF TISSUE FUNCTION, IN A WAY THAT INTERACTS WITH THE SURGEON'S RESECTION. THIS PROJECT WE INTRODUCE A FUNDAMENTALLY NEW TYPE OF CONTRAST, PRESSURE-ENHANCED SENSING SURGERY (PRESS) WHICH IS BASED AROUND A MAJOR DISCOVERY THAT A COMMONLY AVAILABLE HUMAN-USE CONTRAST AGENT CAN BE USED FOR STIMULATING IMMEDIATE FLUORESCENCE WHEN THERE IS HYPOXIA PRESENT. THIS PRESS IMAGING ALLOWS VISUALIZATION OF VASCULAR PATENCY AND DYNAMICS WHILE THE SURGEON PALPATES THE TISSUE, AND COULD BE READILY DEPLOYED TO GUIDE ONCOLOGIC SURGERY. THIS CONTRAST COMES FROM D-AMINOLEVULINIC ACID (ALA) WHICH IS AN FDA CLEARED PRODRUG, THAT IS METABOLIZED INTO THE HEME SYNTHESIS CYCLE IN MOST HUMAN CELLS, BUT PRODUCES PROTOPORPHYRIN IX (PPIX) AS AN INTERMEDIATE SPECIES. PPIX HAS A DELAYED FLUORESCENCE EMISSION THAT HAS NOT WIDELY ACKNOWLEDGED PRIOR TO NOW, BUT IS SIGNIFICANTLY AMPLIFIED BY THE LACK OF OXYGEN AROUND IT, SUCH AS THE MICROREGIONAL HYPOXIA PRESENT THROUGHOUT MOST SOLID CANCERS. THE CORE DISCOVERY LEADING TO THIS PROJECT WAS THAT THE DELAYED FLUORESCENCE SIGNAL OF PPIX, CAN BE EFFECTIVELY IMAGED OVER A FEW MILLISECONDS, AFTER A SHORT, PULSED EXCITATION LIGHT, AND THAT THIS SIGNAL PROVIDES A DIRECT IMAGE INDICATIVE OF A LACK OF OXYGEN INSIDE THE TISSUE. THIS IS AN IDEAL SURGICAL SIGNAL TO HIGHLIGHT HYPOXIC TISSUES AND SO THE APPROACH AND METHOD IS PROTECTED FOR USE BY OUR SYSTEM. WE ADVANCE A FUNDAMENTALLY NEW IMAGING SYSTEM THAT IS TEMPORARILY SEQUENCED WITH PULSED LIGHT FOLLOWED BY THE DELAYED CAPTURE OF EMISSION SIGNAL OVER THE SPAN OF A FEW MILLISECONDS. IMAGING REQUIRES RAPID GATING AND LOW NOISE IN THE CAMERA INTEGRATED WITH AN OPTIMIZED SET OF HARDWARE, EMBEDDED SYSTEM CONTROLS, AND A CUSTOM INTERFACE. IN PHASE I, WE REFINE AN ALPHA PROTOTYPE SYSTEM BASED UPON A CURRENT LABORATORY GRADE SYSTEM AND TEST THE TECHNOLOGICAL FEASIBILITY OF THE PROPOSED DESIGN IN PHANTOMS AND ANIMAL TUMORS. THE WORKS IS BACKED UP BY A NETWORK OF LEADING EXPERTS IN NEUROSURGERY, PHOTODYNAMICS, OXYGEN AND TUMOR BIOLOGY, TO SUPPORT OUR EARLY PHASE TESTING AND GIVE FEEDBACK ON SIGNAL VALIDATION AND UTILITY FOR AN EVENTUAL PHASE II. THE GOAL OF THE PROJECT IS TO DEVELOP A FUNDAMENTALLY NEW SURGICAL IMAGING SYSTEM CAPABLE OF DELAYED FLUORESCENCE IMAGING TO DISPLAY REAL-TIME OXYGENATION MAPS OF TISSUE FOR SURGICAL GUIDANCE, WHILE TAKING ADVANTAGE OF CLINICALLY APPROVED ALA AGENTS. THE TECHNICAL TEAM INVOLVED AT THE COMPANY HAS AN EXPERT KNOWLEDGE OF THE FIELD AND HAS ESTABLISHED SUCCESSFUL COMMERCIAL IMAGING SYSTEMS IN THE PAST. WHEN FULLY DEVELOPED FOR USE BY SURGEONS, PRESS IMAGE GUIDANCE SHOULD BE POISED TO TRANSFORM THE WAY THAT TISSUE IS EVALUATED DURING SURGICAL PROCEDURES.