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Objective. In this work, the development of an active high-density transverse intrafascicular micro-electrode (hd-TIME) probe to interface with the peripheral nervous system is presented. Approach. The TIME approach is combined with an active probe chip, resulting in improved selectivity and excellent signal-to-noise ratio. The integrated multiplexing capabilities reduce the number of external electrical connections and facilitate the positioning of the probe during implantation, as the most interesting electrodes of the electrode array can be selected after implantation. The probe chip is packaged using thin-film manufacturing techniques to allow for a minimally invasive electronic package. Special attention is paid to the miniaturization, the mechanical flexibility and the hermetic encapsulation of the device. Main results. A customized probe chip was designed and packaged using a flexible, implantable thin electronic package (FITEP) process platform. The platform is specifically developed for making slim, ultra-compliant, implantable complementary metal-oxide-semiconductor based electronic devices. Multilayer stacks of polyimide films and HfO2/Al2O3/HfO2 layers deposited via atomic layer deposition act as bidirectional diffusion barriers and are key to the hermetic encapsulation. Their efficacy was demonstrated both by water vapor transmission rate tests and accelerated immersion tests in phosphate buffered saline at 60 °C. Using the hd-TIME probe, an innovative implantation method is developed to prevent the fascicles from moving away when the epineurium is pierced. In addition, by transversally implanting the hd-TIME probe in the proximal sciatic nerve of a rat, selective activation within the nerve was demonstrated. Significance. The FITEP process platform can be applied to a broader range of integrated circuits and can be considered as an enabler for other biomedical applications.

Injectable composites for tissue regeneration can be developed by dispersion of inorganic microparticles and cells in a hydrogel phase. In this study, multifunctional carbonate microparticles containing different amounts of calcium, magnesium and zinc were mixed with solutions of gellan gum (GG), an anionic polysaccharide, to form injectable hydrogel-microparticle composites, containing Zn, Ca and Mg. Zn and Ca were incorporated into microparticle preparations to a greater extent than Mg. Microparticle groups were heterogeneous and contained microparticles of differing shape and elemental composition. Zn-rich microparticles were 'star shaped' and appeared to consist of small crystallites, while Zn-poor, Ca- and Mg-rich microparticles were irregular in shape and appeared to contain lager crystallites. Zn-free microparticle groups exhibited the best cytocompatibility and, unexpectedly, Zn-free composites showed the highest antibacterial activity towards methicilin-resistant Staphylococcus aureus. Composites containing Zn-free microparticles were cytocompatible and therefore appear most suitable for applications as an injectable biomaterial. This study proves the principle of creating bi- and tri-elemental microparticles to induce the gelation of GG to create injectable hydrogel-microparticle composites.

Membranes of the autologous blood-derived biomaterial platelet-rich fibrin (PRF) were mineralized enzymatically with calcium phosphate (CaP) by the incorporation of alkaline phosphatase (ALP) followed by incubation for 3 days in solutions of either 0.1 M calcium glycerophosphate (CaGP) or a combination of CaGP and magnesium glycerophosphate (CaGP:MgGP; both 0.05 M), resulting in the formation of two different PRF-mineral composites. Fourier transform infrared spectroscopy, transmission electron microscopy and selected area electron diffraction examinations showed that the CaP formed was amorphous. Inductively coupled plasma optical emission spectroscopy analysis revealed similar amounts of Ca and P in both composite types, while a smaller amount of Mg (Ca:Mg molar ratio = 10) was detected in the composites formed in the CaGP:MgGP solution, which was supported by the results of energy-dispersive x-ray spectroscopy-based elemental mapping. Scanning electron microscopy (SEM) imaging showed that the mineral deposits in PRF incubated in the CaGP:MgGP solution were markedly smaller. The mass percentage attributable to the mineral phase was similar in both composite types. MTT and WST tests with SAOS-2 cells revealed that incubation in the CaGP:MgGP solution had no negative effect on cytocompatibility and cell proliferation compared to the CaGP solution. Cells on all samples displayed a well-spread morphology as revealed by SEM imaging. In conclusion, the incorporation of Mg reduces mineral deposit dimensions and promotes cell proliferation.