Low-intensity pulsed ultrasound stimulation (LIPUS) modulates microglial activation following intracortical microelectrode implantation.

Microglia are important players in surveillance and repair of the brain. Implanting an electrode into the cortex activates microglia, produces an inflammatory cascade, triggers the foreign body response, and opens the blood-brain barrier. These changes can impede intracortical brain-computer interfaces performance. Using two-photon imaging of implanted microelectrodes, we test the hypothesis that low-intensity pulsed ultrasound stimulation can reduce microglia-mediated neuroinflammation following the implantation of microelectrodes. In the first week of treatment, we found that low-intensity pulsed ultrasound stimulation increased microglia migration speed by 128%, enhanced microglia expansion area by 109%, and a reduction in microglial activation by 17%, indicating improved tissue healing and surveillance. Microglial coverage of the microelectrode was reduced by 50% and astrocytic scarring by 36% resulting in an increase in recording performance at chronic time. The data indicate that low-intensity pulsed ultrasound stimulation helps reduce the foreign body response around chronic intracortical microelectrodes.

Dysregulated inflammatory response to urogynecologic meshes in women with diabetes and its implications.

BACKGROUND: Diabetes is an independent risk factor for mesh complications in women undergoing mesh-augmented surgical repairs of stress urinary incontinence and/or pelvic organ prolapse. The underlying mechanism remains unclear. OBJECTIVE: This study aimed to define the diabetes-associated alterations in the host inflammatory response to mesh and correlate them with perioperative glucose management. STUDY DESIGN: Deidentified demographics and medical records of patients who underwent mesh removal and participated in a mesh biorepository study were reviewed (n=200). In patients with diagnosed diabetes (n=25), blood glucose management before initial mesh implantation and before and after mesh removal was assessed by blood glucose and hemoglobin A1c levels. Age- and body mass index-matched tissue samples excised from patients with and without diabetes were examined. Transcriptomic profiles of immune cell markers, immune mediators, key inflammatory regulators, cell senescence, and epigenetic enzymes were determined by multiplex transcriptomic assays (NanoString). Ratios of apoptotic cells to CD68+ macrophages were examined with immunofluorescence. Protein profiles of 12 molecules involved in apoptotic cell clearance were examined with a multiplex protein assay (Luminex). RESULTS: Demographic and clinical characteristics, including duration between mesh implantation and removal, reason for removal, and type of mesh, etc., were comparable between patients with and without diabetes, except for 11.6% higher body mass index in the former (P=.005). In patients with diabetes, suboptimal management of blood glucose following mesh implantation was observed, with 59% of the patients having loosely or poorly controlled glucose before and after the mesh removal. Ongoing chronic inflammatory response was observed in the excised mesh-tissue complexes in both groups, whereas markers for M2 macrophages (Mrc1 [mannose receptor C-type 1]) and helper T cells (Cd4 [CD4 molecule]) were increasingly expressed in the diabetic vs nondiabetic group (P=.023 and .047, respectively). Furthermore, the gene expressions of proinflammatory Ccl24 (C-C motif chemokine ligand 24) and Ccl13 (C-C motif chemokine ligand 13) were upregulated by 1.5- and 1.8-fold (P=.035 and .027, respectively), whereas that of Il1a (interleukin 1 alpha) was paradoxically downregulated by 2.2-fold (P=.037) in the diabetic vs nondiabetic group. Interestingly, strong positive correlations were found between the expression of Ccl13, Setdb2 (SET domain bifurcated histone lysine methyltransferase 2), and M2 macrophage markers, and between the expression of Il1a, Fosl1 (activator protein-1 transcription factor subunit), and dendritic cell markers, suggesting the involvement of macrophages and dendritic cells in the diabetes-dysregulated proinflammatory response. Supportively, apoptotic cell clearance, which is an important function of macrophages, appeared to be impaired in the diabetic group, with a significantly increased protein level of CALR (calreticulin), an "eat-me" signal on the surface of apoptotic cells (P=.031), along with an increase of AXL (AXL receptor tyrosine kinase) (P=.030), which mediates apoptotic cell clearance. CONCLUSION: Diabetes was associated with altered long-term inflammatory response in complicated mesh implantation, particularly involving innate immune cell dysfunction. Suboptimal blood glycemic control following mesh implantation may contribute to this immune dysregulation, necessitating further mechanistic studies.

Low-intensity pulsed ultrasound stimulation (LIPUS) modulates microglial activation following intracortical microelectrode implantation.

Microglia are important players in surveillance and repair of the brain. Their activation mediates neuroinflammation caused by intracortical microelectrode implantation, which impedes the application of intracortical brain-computer interfaces (BCIs). While low-intensity pulsed ultrasound stimulation (LIPUS) can attenuate microglial activation, its potential to modulate the microglia-mediated neuroinflammation and enhance the bio-integration of microelectrodes remains insufficiently explored. We found that LIPUS increased microglia migration speed from 0.59±0.04 to 1.35±0.07 µm/hr on day 1 and enhanced microglia expansion area from 44.50±6.86 to 93.15±8.77 µm 2 /min on day 7, indicating improved tissue healing and surveillance. Furthermore, LIPUS reduced microglial activation by 17% on day 6, vessel-associated microglia ratio from 70.67±6.15 to 40.43±3.87% on day 7, and vessel diameter by 20% on day 28. Additionally, microglial coverage of the microelectrode was reduced by 50% in week 1, indicating better tissue-microelectrode integration. These data reveal that LIPUS helps resolve neuroinflammation around chronic intracortical microelectrodes.