Bruton's tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination.

Bruton's tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of BTK inhibition in a model of secondary progressive autoimmune demyelination in Biozzi mice with experimental autoimmune encephalomyelitis (EAE). We show that late in the course of disease, EAE severity could not be reduced with a potent relapse inhibitor, FTY720 (fingolimod), indicating that disease was relapse-independent. During this same phase of disease, treatment with a BTK inhibitor reduced both EAE severity and demyelination compared to vehicle treatment. Compared to vehicle treatment, late therapeutic BTK inhibition resulted in fewer spinal cord-infiltrating myeloid cells, with lower expression of CD86, pro-IL-1ß, CD206, and Iba1, and higher expression of Arg1, in both tissue-resident and infiltrating myeloid cells, suggesting a less inflammatory myeloid cell milieu. These changes were accompanied by decreased spinal cord axonal damage. We show similar efficacy with two small molecule inhibitors, including a novel, highly selective, central nervous system-penetrant BTK inhibitor, GB7208. These results suggest that through lymphoid and myeloid cell regulation, BTK inhibition reduced neurodegeneration and disease progression during secondary progressive EAE.

Precipitation-Printed High-ß Phase Poly(vinylidene fluoride) for Energy Harvesting.

Poly(vinylidene fluoride) (PVDF) possesses outstanding piezoelectric properties, which allows it to be utilized as a functional material. Being a semicrystalline polymer, enhancing the piezoelectric properties of PVDF through the promotion of the polar ß phase is a key research focus. In this research, precipitation printing is demonstrated as a scalable and tailorable approach to additively manufacture complex and bulk 3D piezoelectric energy harvesters with high-ß phase PVDF. The ß-phase fraction of PVDF is improved to 60% through precipitation printing, yielding more than 200% improvement relative to solvent-cast PVDF films. Once the precipitation-printed PVDF is hot-pressed to reduce internal porosity, a significant ferroelectric response with a coercive field of 98 MV m-1 and a maximum remnant polarization of 3.2 µC cm-2 is observed. Moreover, the piezoelectric d33 and d31 coefficients of printed then hot-pressed PVDF are measured to be -6.42 and 1.95 pC N-1, respectively. For energy-harvesting applications, a stretching d31-mode energy harvester is demonstrated to produce a power density of up to 717 µW cm-3, while a printed full-scale heel insole with embedded d33-mode energy harvesting is capable of successfully storing 32.2 µJ into a capacitor when used for 3 min. Therefore, precipitation printing provides a new method for producing high-ß phase PVDF and bulk piezoelectric energy harvesters with the advantages of achieving geometry complexity, fabrication simplicity, and low cost.