1 ENGINEERING THE BIOINTERFACE FOR ENHANCED 2 BIOELECTRODE AND BIOSENSOR PERFORMANCE 3 BY BUDDY D. RATNER 4 5 THE MODERATOR: I'D AGAIN LIKE TO WELCOME 6 YOU TO THE SECOND OF THE SERIES OF TUTORIAL SESSIONS 7 FOR THE NATIONAL ACADEMIES KECK FUTURES INITIATIVE ON 8 SMART PROSTHETICS. IT'S MY PLEASURE TO INTRODUCE OUR 9 SECOND SPEAKER, DR. BUDDY RATNER. HE'S THE DIRECTOR OF 10 THE UNIVERSITY OF WASHINGTON ENGINEERED BIOMATERIALS 11 AND PROFESSOR OF BIOENGINEERING AND CHEMICAL 12 ENGINEERING AT THE UNIVERSITY OF WASHINGTON. HE'LL BE 13 SPEAKING ABOUT ENGINEERING THE BIOINTERFACE FOR 14 ENHANCED BIOELECTRODE AND BIOSENSOR PERFORMANCE. 15 DR. RATNER: GOOD MORNING. PLEASURE TO BE 16 ABLE TO PRESENT SOME PERSPECTIVES, I THINK, FROM COMING 17 IN THE DIRECTION, PERHAPS, THE WAY A BIOENGINEER MIGHT 18 THINK ABOUT THIS INTERFACE. 19 AND LET'S SEE. SO WHAT WE SOMETIMES REFER TO 20 AS THE BIOINTERFACE, IF THIS GREEN DEVICE IN THE CENTER 21 OF THE SLIDE IS SOME EITHER SENSOR OR ELECTRODE AND IT 22 EXISTS IN SOME BIOLOGICAL ENVIRONMENT, I'VE DRAWN IT IN 23 AN AQUEOUS, MAYBE AN OCEANIC ENVIRONMENT, BUT IT COULD 24 JUST AS WELL BE IN A BRAIN OR IN A SOFT TISSUE. AT THE 25 INTERFACE THERE'S SOME VERY INTERESTING EVENTS THAT 1 1 TAKE PLACE. 2 AND THIS SLIDE, IT'S A RATHER LENGTHY SLIDE, 3 BUT IT COVERS, I THINK, THE MAJORITY OF THE WAYS THIS 4 INTERESTING ENVIRONMENT, THE BIOENVIRONMENT, CAN IMPACT 5 SYNTHETIC MATERIALS WE PUT INTO THE BODY. I'M NOT 6 GOING TO ACTUALLY READ EVERY ONE OF THEM. SOME OF THEM 7 ARE FAIRLY OBVIOUS THINGS LIKE WATER ABSORPTION, ALMOST 8 LIKE A SPONGE SWELLING, OR LIPIDS ABSORPTION OR SOME OF 9 THEM OXIDIZE OR HYDROLYZE OR CATALYTICALLY BREAK DOWN. 10 BUT AS WE GET DOWN TOWARDS THE BOTTOM OF THIS LIST, 11 WHERE WE HAVE THINGS LIKE RELEASED MATERIAL STIMULATES 12 INTENSIFIED INFLAMMATORY REACTION, CALCIFICATION AND 13 MINERALIZATION AND ENCAPSULATION, IT'S A MORE COMPLEX 14 BIOLOGICAL PROCESS. THESE ARE GOING TO BE THE ONES 15 THAT I'M GOING TO MAINLY FOCUS ON. 16 THE ITEMS MORE TOWARDS THE TOP OF THE LIST 17 ARE ACTUALLY FAIRLY WELL DEALT WITH FROM THE 18 UNDERSTANDING OF THE MATERIAL -- SCIENCE OF THE 19 MATERIALS, BUT THESE THAT SORT OF TAKE US INTO COMPLEX 20 BIOLOGICAL PROCESSES ARE GOING TO NEED A BIT MORE 21 THOUGHT AND INTRODUCTION. 22 SO THE ELECTRODES AND DEVICES IN THE BODY, BE 23 THEY BIOSENSORS OR IN SOME CASES MEDICAL DEVICES, I 24 THINK, FIT A CATEGORY THAT'S VERY LOOSELY BEEN CALLED 25 BIOMATERIALS. AND IF ONE LOOKS AT THE ORIGIN OF THIS 2 1 MODERN FIELD OF BIOMATERIALS, YOU CAN FIND EXAMPLES OF 2 THE EGYPTIANS HAVING USED MATERIALS IN MEDICINE 3,000 3 YEARS AGO, BUT THE MORE MODERN FIELD, ENZYMES ATTRIBUTE 4 TO THIS EVENT THAT'S SORT OF BEEN ILLUSTRATED IN THIS 5 PARTICULAR PAINTING. THE INDIVIDUAL WHO'S ON THE SLIDE 6 IS DR. HAROLD RIDLEY OR SIR HAROLD RIDLEY. AND RIDLEY 7 WAS AN OPHTHALMOLOGIC SURGEON WHO DEALT WITH A NUMBER 8 OF AVIATORS AFTER WORLD WAR II. AND AN INTERESTING 9 SORT OF MEDICAL EVENT OCCURRED. 10 THE WINDSHIELDS OF THESE FIGHTER PLANES WERE 11 MADE OF A PLASTIC. AND THE MACHINE GUN FIRE IN THE 12 THEATER OVER EUROPE, THE WAR SPACE OVER EUROPE, OFTEN 13 SHATTERED THOSE WINDSHIELDS, AND THE CONSEQUENCE OF 14 THAT SHATTERING WAS, LET'S CALL IT, UNINTENTIONAL 15 IMPLANTATIONS OF SHARDS OF PLASTIC IN THE EYES OF THESE 16 AVIATORS. 17 WELL, YEARS AFTER THE WAR, DR. RIDLEY WAS 18 EXAMINING THE EYES OF THESE AVIATORS, AND HE NOTED 19 SOMETHING THAT WAS QUITE INTERESTING FOR THE TIME. HE 20 NOTICED THE SHARDS SEEMED TO RESIDE IN THE EYE WITHOUT 21 ANY FURTHER REACTION. THEY JUST SEEMED TO BE RATHER 22 INERTLY SITTING THERE. NOW, THE CONVENTIONAL WISDOM AT 23 THE TIME IS IF YOU GOT A SPLINTER IN YOU, YOU'D GET 24 REDNESS, SWELLING, INFECTION, AND RELATED UNPLEASANT 25 CONSEQUENCES, AND YET HERE WERE SHARDS OF MATERIAL IN 3 1 THE EYE THAT SAT THERE FOR YEARS. AND HE CONCLUDED, 2 WELL, PERHAPS THIS MATERIAL THAT THIS WINDSHIELD WAS 3 MADE OF WAS, AND THE WORD -- I DON'T KNOW IF HE USED 4 EXACTLY THIS WORD, BUT I'M SURE THE SORT OF GENERAL 5 THOUGHT WENT THROUGH HIS MIND -- PERHAPS THIS IS 6 BIOCOMPATIBLE. 7 AND PROFESSOR OR DR. RIDLEY ACTUALLY WENT OUT 8 AND PURCHASED A SHEET OF THE SAME MATERIAL THE 9 WINDSHIELDS WERE MADE OUT OF, FABRICATED THE FIRST 10 INTRAOCULAR LENSES THAT ARE USED TO REPLACE THE NATURAL 11 LENS OF THE EYE WHEN IT BECOMES CATARACTOUS, AND REALLY 12 STARTED AN INDUSTRY AND A MEDICAL OR THERAPEUTIC 13 PRACTICE THAT IS IMPACTING ABOUT 10 MILLION EYES PER 14 YEAR AT THE PRESENT TIME. SO JUST BASED UPON THIS 15 CHANCE, BUT CLEVER OBSERVATION, I THINK OUR WHOLE FIELD 16 REALLY MAY HAVE BEEN LAUNCHED. 17 THERE ARE OTHER INDICATIONS TOO, SO JUST 18 POINT OUT THAT THE INTRAOCULAR LENS SHOWN IN THE SLIDE 19 IS FROM A WINDSHIELD. THIS HAS SORT OF LED TO OUR 20 MODERN BIOMATERIALS AND MEDICAL IMPLANT FIELD. AND, 21 AGAIN, I HAVE JUST A FEW DEVICES LISTED HERE. I'M NOT 22 GOING TO DWELL ON THEM, BUT I THINK THE IMPORTANT THING 23 TO NOTE IS THE LARGE NUMBERS PER YEAR. THESE ARE VERY 24 WIDELY USED IN MEDICINE, SURGERY, AND IMPACT MANY 25 PEOPLE. THEY SAVE LIVES AND IMPROVE THE QUALITY OF 4 1 LIFE FOR MILLIONS. 2 SO ALL THESE MATERIALS HAVE A COMMON 3 PROPERTY, AND A WORD THAT'S VERY WIDELY USED, THE WORD 4 IS BIOCOMPATIBILITY AND, IN FACT, THERE WAS A CONSENSUS 5 CONFERENCE THAT TOOK PLACE TO ATTEMPT TO DEFINE THIS 6 WORD "BIOCOMPATIBILITY." AND THE DEFINITION THAT CAME 7 UP FROM THREE DAYS OF SCIENTISTS WRANGLING WITH EACH 8 OTHER OVER THE MEANING OF WORDS WAS THE ABILITY OF A 9 MATERIAL TO PERFORM WITH AN APPROPRIATE HOST RESPONSE 10 IN A SPECIFIC APPLICATION. IT'S ACTUALLY A PERFECTLY 11 ACCURATE DEFINITION AND REALLY DOES DESCRIBE TWO 12 ASPECTS OF THIS, THE FACT WE USE THESE MATERIALS IN SO 13 MANY DIFFERENT APPLICATIONS IN THE BODY AND THEY HAVE 14 TO PERFORM WITH AN APPROPRIATE HOST RESPONSE, THE 15 RESPONSE OF THE BODY. 16 THE PROBLEM WITH THE DEFINITION IS IT REALLY 17 GIVES US NO INSIGHTS INTO WHAT IS BIOCOMPATIBLE. HOW 18 CAN WE TEST IT? HOW CAN WE OPTIMIZE IT? AND, IN FACT, 19 THE WORD HAS BEEN A BIT OVERUSED. THERE WAS A PAPER 20 THAT CAME OUT RECENTLY ON THE BIOCOMPATIBILITY OF 21 SWEETPOTATO AND PEANUT IN HYDROPONIC SYSTEMS. DOESN'T 22 SEEM TO TOO WELL RELATE TO OUR THINKING. AND THEN A 23 COMPANY IS SELLING BIOCOMPATIBLE CHROMATOGRAPHY 24 FITTINGS. SO THERE'S A VERY WIDE SPAN IN THE 25 UNDERSTANDING OF THIS WORD "BIOCOMPATIBILITY." 5 1 SO I'D LIKE TO EXAMINE IT A LITTLE BIT MORE 2 IN CERTAIN DETAIL, AND I HAVE THIS DIAGRAM. AGAIN, 3 IT'S A BIT COMPLICATED, BUT I THINK IT OUTLINES IN A 4 TUTORIAL SENSE THE KEY ELEMENTS THAT WE SEE WHEN A 5 BIOCOMPATIBLE DEVICE OR BIOMATERIAL, AND THAT'S SORT OF 6 INDICATED BY THIS BLUE-GREEN-LIKE STRUCTURE HERE, IS 7 IMPLANTED IN THE BODY. 8 THE IMPLANTATION, OF COURSE, IS IN ITSELF AN 9 INJURY. AND THE FIRST EVENT WE SEE IN SECONDS WHEN 10 THIS IS IMPLANTED IS PROTEIN ADSORPTION. PROTEINS 11 OVERCOAT THE OUTSIDE OF THE MATERIAL. VERY SHORTLY 12 AFTER THAT WE FIND NEUTROPHILS PRESENT AROUND THE 13 MATERIAL. THE NEUTROPHILS ARE BELIEVED TO BE PRIMARILY 14 SEARCHING FOR BACTERIA. IF THIS IS DONE IN A STERILE 15 FIELD, THEY DON'T FIND BACTERIA, THEY'RE PRETTY QUICKLY 16 GONE. BUT SOMEWHAT AFTER THAT, PROBABLY WITHIN MAYBE 17 24 TO 48 HOURS, ONE STARTS SEEING MACROPHAGES AT THE 18 BIOMATERIAL INTERFACE. AND THE MACROPHAGES ATTACH TO 19 THE BIOMATERIAL, AS SEEN DOWN IN NO. 4 HERE. AND WHAT 20 THEY'RE REALLY TRYING TO DO IS BASICALLY INTERROGATE 21 AND DIGEST THIS FOREIGN OBJECT. 22 WHEN THEY FIND THAT THIS IS QUITE 23 INDIGESTIBLE, THEY FUSE AND BEGIN TO SPREAD OVER THE 24 SURFACE OF THE BIOMATERIAL. AND WHAT THEY'RE TRYING TO 25 DO, AGAIN, IS TO ENGULF IT, AND THEY STILL FIND THAT 6 1 THEY'RE INCAPABLE OF BECOMING LARGE ENOUGH TO EAT THE 2 WHOLE BIOMATERIAL, SO THEY CALL IN PERHAPS ANOTHER CELL 3 TYPE, FIBROBLASTS, THAT MAY COME IN. AND THE 4 FIBROBLASTS WILL GENERATE A COLLAGENOUS CAPSULE, A BAG. 5 AND WE CALL IT THE FOREIGN BODY REACTION, AND THAT'S 6 PRETTY UNIVERSALLY SEEN WITH BIOCOMPATIBLE 7 BIOMATERIALS. 8 HERE'S THE REALITY OF THIS. THIS IS A SLIDE 9 FROM ONE OF THE COMPANIES THAT PARTNER WITH OUR 10 NSF-FUNDED ENGINEERING RESEARCH CENTER. THE COMPANY IS 11 CALLED ISENSE, AND THEY'RE INVOLVED IN THE DEVELOPMENT 12 OF A GLUCOSE SENSOR. AND THIS TEFLON DEVICE WE SEE 13 HERE IS A GLUCOSE SENSOR. AND THIS HAS BEEN IMPLANTED 14 SIX WEEKS SUBCUTANEOUSLY IN A RAT. AND WHAT DO WE FIND 15 AT THE END OF SIX WEEKS? IN THIS SCANNING ELECTRON 16 MICROSCOPE VIEW, WE FIND A DENSE FOREIGN BODY CAPSULE. 17 REMEMBER, THIS TEFLON DEVICE HERE IS A GLUCOSE SENSOR. 18 AND GLUCOSE WOULD HAVE TO PENETRATE THROUGH THIS DENSE 19 CAPSULE. IT'S RATHER CHALLENGING TO GET GOOD DIFFUSION 20 THROUGH SUCH A DENSE CAPSULE.