Introduction: Considerable advancements have been made using neural electrodes to minimise the effects of debilitating neural conditions[1],[2]. However, the chronic implantation of these electrodes into the brain has proven to be problematic, with most failing after 5-6 months due to the formation of an inhibitory glial scar[2]-[4]. Researchers at Trinity College Dublin are developing an alternative strategy using highly localized cooling and are collaborating with Harvard-MIT to design a coating with a long term microfluidic drug delivery system. This presentation will discuss our preliminary results on integrating the two systems into a single design to reduce the formation of a glial scar and extend the efficacy of these probes.
Experimental Methods: Required ceramic coating thickness for thermal insulation was modelled in silico and validated with an in vitro model. Microfluidic channels were fabricated in a photocrosslinkable methacryloyl gelatin (GelMA) and polyethylene glycol (PEG) hydrogel and covered with a PDMS membrane with micropores (100μm). The effects of the release of anti-inflammatory drugs or factors such as dexamethasone and cytokine IL4 were tested in vitro on monocytes and astrocytes encapsulated in a brain-like hydrogel model to determine cell behaviour over 4 weeks. Adhesion tests were carried out to ensure the stability of both coatings on a probe surface.
Results and Discussion:
An insulating ceramic coating was designed to allow cooling of brain tissue by 10°C at a depth of up to 10cm and provide easy probe insertion. For the drug delivery system, microfluidic channels of <100µm diameter were successfully created in GelMA/PEG. This hydrogel can be inserted in its thin dry state and allowed to reswell to reduce micromotion. The coupling of GelMA/PEG with a PDMS membrane allowed 4 days of slow steady diffusion of anti-inflammatory cytokines into the in vitro brain model from one infusion (Fig 1). Burst release of small drug like molecules was also minimal. These active particles significantly reduced the presence of inflammatory markers 27E10 in monocytes and GFAP in astrocytes and increased the presence of anti-inflammatory marker CD206 which implies that a larger proportion of monocytes have differentiated into prohealing M2 macrophages because of the anti-inflammatory particles delivered to them(Fig 2). This implies that, in an in vivo environment, chronic drug delivery could potentially reduce the body’s immune response against the implants and ensure they function better during long term implantation.
Conclusion: An insulating ceramic coating was developed to allow cooling of brain tissue by 10°C. The addition of a microfluidic coating to this allowed repeated infusions of anti-inflammatory factors which were shown to reduce the inflammatory response of monocytes and astrocytes in vitro. The mechanical properties of the hydrogel reduced micromotion of the probe and the mechanical mismatch between probe and brain tissue. Further work to miniaturise the system is required before moving to in vivo trials. The combination of our therapeutic cooling with prolonged anti-inflammatory treatment could increase the chronic efficacy of these probes in patients.
This work was funded by the Higher Education Authority (HEA) Ireland (PRTLI5 GREP) and supported by Fulbright Ireland
References:
[1] Massia et al. J Biomed Mater Res 68A, 2004
[2] Polikov et al. J. Neurosc. Methods, 148, 2005
[3] Green et al. Biomaterials, 2008
[4] Yu et al. J Materials Today, 11, 2008