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Conjugated Polymer Materials for Biomedical Devices

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Presentation from the Fall 2020 American Chemical Society meeting, as part of the special symposium in honor of Qinghuang Lin, recipient of the 2020 Roy M. Tess Award from the Polymeric Materials Science and Engineering (PMSE) Division.

Well good morning or good afternoon uh depending on when this is played my name is dave martin and i’m from the university of delaware and it’s my pleasure to be involved in this uh special symposium for the acs fall 2020 meeting in honor of qinghuang lens receiving the roy tess award from the pimsy division so it’s been an unusual time and i’m sorry i

Can’t be there in person uh but i just wanted to congratulate qingwong on this well-deserved award uh he and i have known each other since our days at the university of michigan when ching wong was a graduate student in professor albert e’s lab and i was a relatively young assistant professor at the time and we had a lot of very nice conversations about liquid

Crystalline epoxies that i recall fondly and since that time we’ve uh kept in touch and over the last few years we’ve had a lot of interactions related to pimsey business it’s always been a pleasure to interact with ching wong and to learn about the work that he’s been doing at ibm to look at dna through small holes my own group has been interested in looking at

Conjugated polymers for a number of device applications so that’s what i want to tell you about today we’ve been looking in some detail at a conjugated polythiaphine called pdot which has really become quite popular over recent years and what i want to tell you about today is the newest work we’ve been doing to look at a very interesting copolymer of pdot that

Has a malayamid functionality on it and those of you who are familiar with malayalam chemistry will appreciate that having an alayamid group on a thiophene opens up a whole wide world of new synthetic opportunities for tailoring the properties of these materials all right so let me uh start by saying that everything you’re going to hear about today was done by

Somebody else and it’s really because of these talented graduate students that those of us faculty members get anything done this is particularly true for me over the last year and a half because in february of last year i assumed the position of the associate dean for research and entrepreneurship in the college of engineering at delaware and so it’s just been

That much more difficult for me to really spend time hanging out in the laboratory but these guys are really fantastic let me call out in particular samadhan nagane dr nagane came to delaware in april of last year and really made very rapid progress uh working at the time on a darpa project that we had and since then i’ve been supporting him with discretionary

Funding that has enabled us to create these new monitors that i’m going to be talking about today so he at the moment is back in india he went back to get his wife and family and bring them back to delaware but just around that time the cronus coronavirus hit and so we’ve been doing what we can to work with him and are currently setting up a lab that he can do

Some work in locally in india and then send us samples to characterize in more detail all right so about five years ago i had just finished serving as the material science engineering department chair and in order to rehabilitate my brain i took the time to write a review article um this was unusual in the sense that i’m the sole author on this paper so my

Students uh i i really appreciated again how much work is involved in uh getting all the references together and the figure uh approvals have appeared elsewhere all together and uh anyway uh the work that we’ve been doing in my lab has really been centered around materials that can interface inorganic electronic biomedical devices of various sorts with living

Tissues of various sorts so there are whole number of applications of these devices pacemakers of course deep brain stimulator glucose sensors cochlear implants and even most recently an fda approved retinal implant that is hoping to restore some sense of vision there are also implants that are going into the brain for brain machine interfaces including the

Group at michigan that we were interacting with a lot that makes electrodes go into the outer regions of the cortex and that technology from the center for neural communication technology was spun off into a small company called neural nexus that my colleague daryl kippke is quite involved in there’s also work that’s come out of the university of utah to make

A micro electrode array that’s more of a pin cushion type design um but in all these devices it’s really some kind of an electrode made out of stainless steel gold iridium platinum or a silicon substrate that’s trying to talk to tissue so what we have is an interface where you’ve got an inorganic hard rigid flat crystalline device that’s trying to talk to soft

Squishy organic and wet ionically conductive tissue and so conjugated polymers are very interesting because of the fact that they have physical properties that are intermediate to the two extremes we’re trying to talk to here but in particular they’re very interesting because of the fact that the devices devices talk in solid state by electrons and holes the

Tissue itself talks ionically and so conjugated polymers are nice because they have the ability to conduct charge uh both electronically and ionically so a very interesting because of that now as i mentioned the polymer that has received a lot of attention is this chemically stable polythiaphy called pdot pdot is available commercially from hereas they bought

The technology originally developed from buyer and commercially it’s sold as a suspension so you get it in a bottle and you can cast it as a film my colleagues in france add a cross-linking agent called gox that creates a stable film that then won’t redissolve when it’s implanted into the body we like to use electrochemistry because electrochemistry allows us

To do the oxidation polymerization reaction right on the electrode surface so we can direct where it goes we can tailor the counter ion quite easily and we can then create also very precisely tailored films that have different morphologies by using say dissolvable substrates or different constructs that we grow the polymer around in fact we’ve even done this

Polymerization in living tissue so we’ve grown the polymer in the brain we’ve grown it in hippocampus we’ve grown it in peripheral nerve and that’s one of the other interesting angles that can be explored here now in terms of a materials design problem the con the stability of this molecule comes from the fact that there’s no hydrogens pendant on the conjugated

Backbone and again you get this transport where you have electrons and holes moving along the molecular backbone and then some counter ions that are putting a little bit of charge on the polymer backbone so you get both electron transport and ion transport if you look at the deposition of conjugated polymers onto a device as a function of time this is a particular

Device a michigan style neural electrode 150 micron wide silicon substrate with metal electrodes 40 microns in diameter you send different amounts of charge through it and you will deposit more and more conjugated polymer as more current runs through the electrode if you look at the impedance of these electrodes and we like to look at the impedance as a function

Of frequency do what’s called impedance spectroscopy for biomedical devices the important frequencies are those that are at a thousand hertz and below a neural event is typically one millisecond in length and so if you look at the impedance at 1000 hertz as a function of time you see that it drops dramatically sometimes two orders of magnitude sometimes three

Depending upon the precise conditions and the reason for this you can appreciate just from looking at the scm images in the upper right so the conjugated polymer is not a better conductor than the underlying metal but it has a whole lot of surface area and so we’re creating a thin film that’s essentially acting as my colleague george maliaris likes to call it as

A volumetric capacitor so there’s just lots of room for charge exchange particularly when you’re going to put a device into an ionic solution like a tissue and so you’re pulling cations in and out you’re exchanging that with whole transport in the polymer you exchange holes with electrons at the polymer metal interface and typically these devices are operated at

Zero net voltage so that you’re not doing any electrochemistry so that very dramatic drop in impedance is extremely important for biomedical devices of various sorts it opens up the opportunity for building lots of interesting specialized devices that would do particular things this is just one example from our own group looking at the use of these materials as

Chemical sensors in this case for a growth factor protein called vegf that’s very important for certain eye diseases so this was done in collaboration with reyesi at the mayo clinic and we were able to get very sensitive detection of vegf by using this system where we would measure changes in electrical current in the presence of the jeff so as you can imagine

There’s a lot of commercial interest i just would mention we actually spun a small company off just before i left the university of michigan and formed a company biotechnics the principles there were sarah burns a former post-doc who unfortunately passed away just a couple years ago and jeff hendricks who is a director of engineering the technology for biotechnics

Lived on for 10 years and then was fully acquired by hereas medical components an arm of the hurries company that sells the pdot uh and is now subsumed and it’s behind the firewall so i now no longer have any insight into what’s actually going on in a business sense and no longer a conflict of interest and i would just point out that there are a number of other

People including this gentleman elon musk who has looked at the use of pdot elon’s company neural link is making a brain machine interface technology and one of the critical components to lower the impedance of those electrodes is to electrochemically deposit following procedures we developed p dot coatings onto those electrodes before they’re inserted into

Animals okay so p dot is great but that’s 10 15 years ago technology what’s happened in the meantime well pdot itself has a lot of advantages um but a number of disadvantages one thing is pdot has not yet been approved for use on a particular device although it’s very close in a number of applications let me point out by the way that the fda does not approve

Materials per se they approve devices and so the issue if you have a new material is to get your material approved for use on a particular device there are also a number of other applications uh or i should say limitations uh there aren’t any specific interactions with tissue for normal pdot there are some issues with brittleness and adhesion to substrates the

Normal e dot monomer is relatively cytotoxic and there’s no way of changing the mechanical properties all that much the only reaction that occurs is the polymerization or reaction across the thiophene and so our new monomers have uh addressed all of these different issues so one of the first new monomers that we developed back still at michigan was the carboxylic

Acid functionality so my colleague ginseng kim helped to create this edot acid monomer that we have been examining in some detail since right after i got to delaware i was at the university of santa barbara and met katie feldman who at the time was working with craig hawker she brought in phil ian click chemistry and so we’ve created a whole series of different

Thiol in functionalized click functionalized edots and prodots product having an extra carbon between the two oxygens so it’s propylene dioxy fibrin you can have either one end dangling off or you can have two ends dangling off so this was some work by a subsequent graduate student in way where he had the di-functionalized pro dot and he used different thiols one

Being hydrophobic which shut down the charge one hydrophilic which created a nice wet surface and essentially didn’t change the charge transport much at all and then one that had an electroactive ferrocene and really caused a lot of electrical activity that we could easily see when we did cp so the most recent monomers uh are again uh different uh in the sense

That we’ve made a pita aldehyde dopamine and tyramine but the real important one of all of these is this pdot dot malayamid and so pdot and leomid is very interesting because if you’ve got malayamid you’ve got access to a wide variety of different chemical reactions either with furan’s thiols amines azides or polymerizing the malayamid or the thiophene itself

So you have a whole huge uh laundry list of chemical reactions that you can use to optimize and the malayamate itself can undergo a reaction similar to the thyoline where you have now a thiol on a bioactive molecule and you can click on your bioactive molecule to make a functionalized monomer or you can make the polymer and click it onto the polymer at the end

And again some of the groups we’ve looked at so far include adamantine relatively bulky hydrophobic group a surface active molecule like cholesterol and an amino acid so uh again just to emphasize that this degree of uh processability and synthetic flexibility allows us to consider either making monomers into polymers and then functionalizing the polymer or

Making a monomer and then polymerizing the monomer to make the polymer the preferred route depends on really what application you’re after and what the other limitations are the bio functionalized thiophenes tend to be less cytotoxic but they also tend to be more difficult to polymerize because they become more hydrophilic and so getting the polymer to crash out

Of solution using the electrochemistry that we prefer is more difficult when the monomer becomes more hydrophilic so just some results showing that we’ve obtained the molecules that we’re after here is the synthesis route and the proton nmr that confirms that we’ve made the e dot malayamid here is the synthesis route for putting dopamine on the dopamine itself

An interesting molecule can be used as the precursor for synthetic melanins is found in the body naturally and again the proton nmr confirming that we got it and here’s the e dot cholesterol showing that we’ve made thiafeng with the surface active and potentially liquid crystalline cholesterol unit on the side um just another slide showing that the azide group

Itself can be used and gives you the ability to control cross-linking and then these are optical micrographs showing that we have indeed deposited the polymer on the central electrode here and have measured the impedance spectroscopy and are comparing these results to those of other studies that we’ve done in the past and other materials so you can either lower

The impedance or increase the impedance depending upon what particular application you’re after right now we’re creating a bunch of sensors making organic electrochemical transistors where these new functionalized edots serve as the channel layer of a field effect transistor that’s in contact with the ionic solution following work that uh has gone on elsewhere

Including george malliars jonathan ritnay and others i’ll just conclude by saying we’ve also continuing to do a bunch of tem so my lab is currently actively exploring the use of liquid cell tem especially using an electrochemical cell we can do the polymerization in the transmission electron microscope and here’s an example of p dot and in this case poly dopamine

Growing on an electrode this happens to be a hummingbird uh holder that we are putting into our 200 kv telos all right so this is my conclusion slide we’ve got new monomers we’re characterizing them we’re doing a lot of bioelectronic applications and let me just pause and thank and congratulate thank the organizers who congratulate you on for the award thanks for your attention

Transcribed from video
Conjugated Polymer Materials for Biomedical Devices By David Martin