Project Grant R44TR003968

ADDITIVE MANUFACTURING OF PDMS MICROFLUIDICS - DEVELOPMENT OF NEW THERAPEUTICS OFTEN FAILS IN HUMAN CLINICAL TRIALS DUE TO THE BIOLOGICAL DIFFERENCES BETWEEN HUMANS AND ANIMAL MODELS AND THE INABILITY OF CURRENT IN VITRO MODELS TO ACCURATELY RECAPITULATE THE IN VIVO STATE. AS SUCH, IN VITRO MICROFLUIDIC (MF) MODELS HAVE SEEN SIGNIFICANT GROWTH AND BECOME A KEY TOOL FOR UNDERSTANDING BIOLOGICAL SYSTEMS, AND FOR TESTING AND DEVELOPMENT OF NEW THERAPEUTICS. INNOVATION IN MICROFLUIDICS, HOWEVER, IS LIMITED BY MATERIALS AND MANUFACTURING CHALLENGES ASSOCIATED WITH CONVENTIONAL PROCESSES SUCH AS SOFT LITHOGRAPHY, INJECTION MOLDING, AND MECHANICAL MILLING. ADDITIVE MANUFACTURING (AM), ALSO REFERRED TO AS 3D PRINTING, HAS BEEN HERALDED AS THE SOLUTION TO THESE MANUFACTURING CHALLENGES AND AM ADDITIONALLY OFFERS BROAD DESIGN FREEDOM NOT ACCESSIBLE VIA CONVENTIONAL MANUFACTURING. HOWEVER, AM FACES A CRITICAL HURDLE: THE LIMITED ABILITY TO 3D PRINT CONVENTIONAL (THERMALLY-CURABLE) POLYDIMETHYLSILOXANE (PDMS), THE MOST WIDELY ESTABLISHED R & D MICROFLUIDIC MATERIAL. DESPITE THE POTENTIAL MANUFACTURING AND DESIGN BENEFITS, AM HAS NOT BEEN BROADLY ADOPTED FOR MF PRODUCTION DUE IN LARGE PART TO THE POTENTIAL MATERIAL RISKS. OF THE COMMERCIALLY AVAILABLE AM PROCESSES AND THOSE BEING RESEARCHED, NONE OFFER A CLEAR PATH TO COMMERCIAL 3D PRINTING OF CONVENTIONAL PDMS MF DEVICES. OUR HYPOTHESIS IS: COMBINING THE KNOWLEDGE-BASE AND FAMILIARITY OF CONVENTIONAL PDMS WITH OUR 3D PDMS PROCESS WILL FUNDAMENTALLY CHANGE THE WAY MICROFLUIDICS ARE FABRICATED AND UNLOCK THE DESIGN FREEDOM OF ADDITIVE MANUFACTURING FOR THE MF COMMUNITY, WHICH WILL LEAD TO SIGNIFICANT ADVANCEMENTS OF IN VITRO MF MODELS. BUILDING UPON OUR SUCCESSFUL PHASE I EFFORT - DURING WHICH WE DEMONSTRATED THE ABILITY OF OUR PATENT-PENDING 3D PDMS PROCESS TO 3D PRINT MF DEVICES FROM CONVENTIONAL PDMS - THIS PHASE II EFFORT FOCUSES ON DEVELOPING A PILOT-SCALE COMMERCIAL 3D PDMS SYSTEM AND USING THE 3D PDMS PROCESS TO FABRICATE CUTTING EDGE IN VITRO BLOOD-BRAIN-BARRIER MODELS FOR TESTING BY OUR COLLABORATORS AT VIRGINIA TECH. THEY RECENTLY DEVELOPED A MF BBB MODEL CONTAINING A NANOFIBER BASEMENT MEMBRANE MIMIC WHICH DEMONSTRATES A SUPERIOR ABILITY TO RECAPITULATE THE IN VIVO BBB ARCHITECTURE. IN PHASE II, THE TEAM WILL OPTIMIZE THE ARCHITECTURE OF THE NANOMEMBRANES AND THEN DESIGN AND DEMONSTRATE A COMMERCIALLY PRODUCIBLE 3D PDMS MF NANOMEMBRANE BBB MODEL WITH INTEGRATED ELECTRODES. WE WILL ALSO COLLABORATE WITH THE NADKARNI GROUP AT HARVARD MGH TO CHARACTERIZE THE PDMS CURING KINETICS IN 3D PDMS PRINTING USING LASER SPECKLE RHEOLOGY. AIM 1: OPERATIONAL PILOT-SCALE 3D PDMS SYSTEM. THE OBJECTIVE OF THIS AIM IS TO DESIGN AND A BUILD PILOT-SCALE 3D PDMS SYSTEM. MILESTONE 1A: 3D PDMS SIMULATION & MODEL ACCURATELY PREDICT CURING WITHIN +/-10%; MILESTONE 1A: 3D PDMS SIMULATION MODEL ACCURATELY PREDICTS CURING WITHIN +/-10%; MILESTONE 1B: 3D PDMS UNIT ACHIEVES 200 MM3/HR BUILD RATE FOR MF DEVICE. AIM 2: 3D PRINTED NANOFIBER BLOOD-BRAIN-BARRIER MODEL. THE OBJECTIVE OF THIS AIM IS TO 3D PRINT A HIGHLY REPRODUCIBLE BBB MODEL WHICH INCORPORATES A NANOFIBER MEMBRANE AND INTEGRATED TEER ELECTRODES. MILESTONE 2A: TRANSPORT MASTER CURVES FOR NANOFIBER MEMBRANES DEVELOPED; MILESTONE 2B: OPTIMIZED NANOFIBER BBB MODEL DEMONSTRATED BY A 20% INCREASE IN TEER VALUES FOR A CO- CULTURE SAMPLE AS COMPARED TO A MONOCULTURE SAMPLE. PROJECT SUMMARY/ABSTRACT