Material and Device Design Strategies for Suppressing the Foreign Body Response to Implantable Electronics

Implantable medical devices (IMDs) are playing an increasingly important role due to an aging population and the associated increasing prevalence of chronic diseases. However, the foreign body response (FBR) has limited IMDs from realizing their full potential. The FBR is characterized by inflammatory and fibrotic processes that surround the implanted material. Degradative chemicals enzymes produced in the process can damage the implant. Fibrotic encapsulation is particularly detrimental for biosensors and electrophysiological devices because it would impede the diffusion of analytes and ions. Despite this, there seem to be few strategies for suppressing the FBR in the long term. As electronic materials for IMDs, poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) is of interest because it is chemically stable, highly processable, non-cytotoxic, and has good mixed ion-electron conducting properties. Furthermore, PEDOT:PSS can be chemically modified and physically blended with a variety of materials which makes it interesting for generating new strategies for suppressing the FBR to electronic materials. Nonetheless, previous work addressing the FBR against PEDOT:PSS did not place their focus on long-term solutions or did not carry out FBR-specific characterization methods. In Chapter 1 of this dissertation, we introduce FBR and the problems that it causes for IMDs. We will go into the in-depth mechanism of the FBR, at the molecular, cellular, and cellular network level. Then, we will explore the reported material strategies for suppressing the FBR. An overview on conjugated polymers, including PEDOT:PSS, and its role in IMDs will also be discussed.

In Chapter 2, we introduce the zwitterionic PEDOT:PSS hydrogel (ZIPH) which was found to have both good electrical conductivity and good FBR-suppressing properties. Zwitterionic polymers are a class of materials with promising FBR suppressing properties which have been shown to nearly eliminate the FBR for at least a year in mice. We hypothesized that by combining PEDOT:PSS and a zwitterionic polymer into a double-network hydrogel and carefully tuning its phase separation morphology, the conductivity can be increased and the FBR can be suppressed indefinitely. In this chapter, we demonstrate a process for inducing PEDOT:PSS network formation in situ in a zwitterionic hydrogel matrix, which significantly improves its conductivity and reduces FBR-associated fibrosis. Investigation of the mechanism of the FBR suppression revealed that ZIPH is associated with a unique immune response that diverged significantly from its parent materials, PEDOT:PSS and zwitterionic polymer.

In Chapter 3, we sought to demonstrate that the high electrical conductivity and FBR-suppressing properties of ZIPH are advantageous in electrophysiological applications via electrocardiography (ECG) in mice. Device design and a new surface functionalization strategy for substantially enhancing adhesion of ZIPH on plastic substrates are explored. We also discuss the (ECG) recording setup and amplifier design. Finally, we show that ZIPH ECG electrodes have less signal degradation compared to PEDOT:PSS ECG electrodes. Furthermore, ZIPH ECG electrodes have similar signal degradation compared to PEDOT:PSS ECG electrodes with dexamethasone-eluting silicone backings without the side effects associated with dexamethasone. We have successfully demonstrated that the novel approach for designing ZIPH can lead to long-lasting implantable electrophysiological devices. 

In Chapter 4, we take a different approach from previous chapters and confer antifouling properties to PEDOT:PSS by assembling zwitterionic polymer brushes. Because PEDOT:PSS has no useful functional groups for chemical modification and swells easily in water, conventional coating strategies do not work as well. In addition, maintaining a low interfacial impedance is desirable. To solve this, we devised a new coating strategy that involves the electrostatic interaction between PSS and other polyelectrolytes. The coating terminates with a polyzwitterion-polyelectrolyte block copolymer, which demonstrated good antifouling properties. We also use this strategy to coat PEDOT:PSS ECG electrodes, which are implanted in mice for 12 weeks, and demonstrate the strategy can lead to almost no signal loss.