TNFR1-mediated senescence and lack of TNFR2-signaling limit human intervertebral disc cell repair in back pain conditions.

Poor intervertebral disc (IVD) healing causes IVD degeneration (IVDD) and progression to herniation and back pain. This study identified distinct roles of TNFα-receptors (TNFRs) in contributing to poor healing in painful IVDD. We first isolated IVDD tissue of back pain subjects and determined the complex pro-inflammatory mixture contained many chemokines for recruiting inflammatory cells. Single-cell RNA-sequencing of human IVDD tissues revealed these pro-inflammatory cytokines were dominantly expressed by a small macrophage-population. Human annulus fibrosus (hAF) cells treated with IVDD-conditioned media (CM) underwent senescence with greatly reduced metabolic rates and limited inflammatory responses. TNFR1 inhibition partially restored hAF cell metabolism sufficiently to enable a robust chemokine and cytokine response to CM. We showed that the pro-reparative TNFR2 was very limited on hIVD cell membranes so that TNFR2 inhibition with blocking antibodies or activation using Atsttrin had no effect on hAF cells with CM challenge. However, TNFR2 was expressed in high levels on macrophages identified in scRNA-seq analyses, suggesting their role in repair responses. Results therefore point to therapeutic strategies for painful IVDD involving immunomodulation of TNFR1 signaling in IVD cells to enhance metabolism and enable a more robust inflammatory response including recruitment or delivery of TNFR2 expressing immune cells to enhance IVD repair.

Implantable Intracranial Pressure Sensor with Continuous Bluetooth Transmission via Mobile Application.

Hydrocephalus is a clinical disorder caused by excessive cerebrospinal fluid (CSF) buildup in the ventricles of the brain, often requiring permanent CSF diversion via an implanted shunt system. Such shunts are prone to failure over time; an ambulatory intracranial pressure (ICP) monitoring device may assist in the detection of shunt failure without an invasive diagnostic workup. Additionally, high resolution, noninvasive intracranial pressure monitoring will help in the study of diseases such as normal pressure hydrocephalus (NPH) and idiopathic intracranial hypertension (IIH). We propose an implantable, continuous, rechargeable ICP monitoring device that communicates via Bluetooth with mobile applications. The design requirements were met at the lower ICP ranges; the obtained error fell within the idealized ±2 mmHg margin when obtaining pressure values at or below 20 mmHg. The error was slightly above the specified range at higher ICPs (±10% from 20-100 mmHg). The system successfully simulates occlusions and disconnections of the proximal and distal catheters, valve failure, and simulation of A and B ICP waves. The mobile application accurately detects the ICP fluctuations that occur in these physiologic states. The presented macro-scale prototype is an ex-vivo model of an implantable, rechargeable ICP monitoring system that has the potential to measure clinically relevant ICPs and wirelessly provide accessible and continuous data to aid in the workup of shunt failure.