Bioactive Coatings Loaded with Osteogenic Protein for Metallic Implants

Osteoconductive and osteoinductive coatings represent attractive and tunable strategies towards the enhanced biomechanics and osseointegration of metallic implants, providing accurate local modulation of bone-to-implant interface. Composite materials based on polylactide (PLA) and hydroxyapatite (HAp) are proved beneficial substrates for the modulation of bone cells’ development, being suitable mechanical supports for the repair and regeneration of bone tissue. Moreover, the addition of osteogenic proteins represents the next step towards the fabrication of advanced biomaterials for hard tissue engineering applications, as their regulatory mechanisms beneficially contribute to the new bone formation. In this respect, laser-processed composites, based on PLA, Hap, and bone morphogenetic protein 4(BMP4), are herein proposed as bioactive coatings for metallic implants. The nanostructured coatings proved superior ability to promote the adhesion, viability, and proliferation of osteoprogenitor cells, without affecting their normal development and further sustaining the osteogenic differentiation of the cells. Our results are complementary to previous studies regarding the successful use of chemically BMP-modified biomaterials in orthopedic and orthodontic applications.

Peripheral and Central Pain Pathways and Pathophysiology

Pain is an unpleasant sensory experience that may be associated with actual or potential tissue damage. Perception of pain includes 3 aspects: sensory-discriminative (intensity and location), cognitive (bodily sensation), and affective-emotional (suffering). Pain is a complex integration of anatomical pathways, including dorsal root ganglion nociceptive neurons, dorsal horn neurons, spinothalamic and spinobulbar pathways, the thalamus, the cortex, and local modulation. Peripheral and central sensitization may occur after tissue injury. This chapter reviews the peripheral and central processing of pain and concludes with a discussion of pain pathophysiology.

Peripheral NOD-like receptor deficient inflammatory macrophages trigger neutrophil infiltration disrupting daytime locomotion

Inflammation is known to disrupt normal behavior, yet the underlying neuroimmune interactions remain elusive. Here, we investigated whether inappropriate macrophage-evoked inflammation alters CNS control of daily-life animal locomotion using a set of zebrafish mutants selected for specific macrophage dysfunction and microglia deficiency. Large-scale genetic and computational analyses revealed that NOD-like receptor nlrc3l mutants are capable of normal motility and visuomotor response, but preferentially swim less in the daytime, suggesting low motivation rather than physical impairment. Examining their brain activities and structures implicate impaired dopaminergic descending circuits, where neutrophils abnormally infiltrate. Furthermore, neutrophil depletion recovered daytime locomotion. Restoring wild-type macrophages reversed behavioral and neutrophil aberrations, while three other microglia-lacking mutants failed to phenocopy nlrc3l mutants. Overall, we reveal how peripheral inflammatory macrophages with elevated pro-inflammatory cues (including il1b, tnfa, cxcl8a) in the absence of microglia co-opt neutrophils to infiltrate the brain, thereby enabling local modulation of neural circuits affecting spontaneous locomotion.

Spatial regulation of coordinated excitatory and inhibitory synaptic plasticity at dendritic synapses

The induction of synaptic plasticity at an individual dendritic glutamatergic spine can affect neighboring spines. This local modulation generates dendritic plasticity microdomains believed to expand the neuronal computational capacity. Here, we investigate whether local modulation of plasticity can also occur between glutamatergic synapses and adjacent GABAergic synapses. Using MNI-glutamate and DPNI-GABA double uncaging combined with electrophysiology, live-cell imaging and single-particle tracking, we find that the induction of LTP at an individual glutamatergic spine causes the depression of nearby GABAergic inhibitory synapses (within 3 microns), whereas more distant ones are potentiated. Notably, L-type calcium channels and calpain are required for this plasticity spreading. Overall, our data support a model whereby input-specific glutamatergic postsynaptic potentiation induces a spatially-regulated rearrangement of inhibitory synaptic strength in the surrounding area through short-range heterosynaptic interactions. Such local coordination of excitatory and inhibitory synaptic plasticity is expected to profoundly influence dendritic information processing and integration.

Effect Of Local Modulation In Enzymatic Homeostasis On Bone Turnover Marker Dynamics In Blood At Substituting Femur Defects With Vaterite Scaffolds

The goal of this research was the investigation of concentration changes in the blood bone turnover markers during local modulation of enzymatic homeostasis by means of targeted delivery of alkaline phosphatase (ALP) with polycaprolactone (PCL) and vaterite (VT) scaffolds implanted into the femur defects in white rats. Material and Methods ― The tests of PCL/VT/ALP scaffold implantations into the bone defects were performed on 30 white rats, and the serum of intact animals was used as the control. ELISA and multiplex assay were used to find inflammatory and bone turnover markers including monocyte chemoattractant-1, sclerostin, fibroblast growth factor-23, connective tissue growth factor (CTGF), osteoprotegerin, osteocalcin, β-сross laps and the activity of tartrate-resistant acid phosphatase-5b in the blood of experimental animals. The activity of serum ALP was tested with the conventional kinetic method. The morphology of the reparative processes was verified by microscopy of specimens taken from the implantation areas and stained with hematoxylin or eosin. Results ― The PCL/VT/ALP scaffold implantations into the bone defects of white rats caused active osteogenesis along with the steady rise in osteocalcin concentration in blood. ALP activity in the blood did not depend on the exogenous enzyme in the scaffold and rose by the 28th day after the implantations. The targeted ALP delivery into the defect area caused the rise in CTGF concentration as well as the decrease in blood sclerostin within a short time after the implantations. Conclusion ― The modulation of the local enzyme homeostasis by means of the targeted ALP delivery with PCL/VT scaffolds stimulated reparative osteogenesis within a short time after the implantations with no changes to the bloodstream or local inflammatory changes suggesting their biocompatibility and the safety in use.

Modulation of Vascular Function by Perivascular Adipose Tissue: Sex Differences

In addition to the endothelium, the perivascular adipose tissue (PVAT) has been described to be involved in the local modulation of vascular function by synthetizing and releasing vasoactive factors. Under physiological conditions, PVAT has anticontractile and anti-inflammatory effects. However, in the context of hypertension, obesity and type 2 diabetes, the PVAT pattern of anticontractile adipokines is altered, favoring oxidative stress, inflammation and, consequently, vascular dysfunction. Therefore, dysfunctional PVAT has become a target for therapeutic intervention in cardiometabolic diseases. An increasing number of studies have revealed sex differences in PVAT morphology and in the modulatory effects of PVAT on endothelial function and vascular tone. Moreover, distinct mechanisms underlying PVAT dysfunction may account for vascular abnormalities in males and females. Therefore, targeting sex-specific mechanisms of PVAT dysfunction in cardiovascular diseases is an evolving strategy for cardiovascular protection.

Morphometric reconstructions atlas shows insult-driven plasticity in cortical VIP/ChAT interneurons

We developed an automatic morphometric reconstruction pipeline, Pop-Rec, and used it to study the morphologies of cortical cholinergic VIP/ChAT interneurons (VChIs). Cholinergic networks control high cognitive functions, but their local modulation and stress-driven plasticity patterns remained elusive. Reconstructing thousands of local VChIs registered to their exact coordinates in multiple cleared murine cortices highlighted distinct populations of bipolar and multipolar VChIs which differed in their dendritic spatial organization. Following mild unilateral whisker deprivation, Pop-Rec found both ipsi-and contra-lateral VChI dendritic arborization changes. Furthermore, RNA-seq of FACS-sorted VChIs showed differentially expressed dendritic, synapse and axon-modulating transcripts in whisker-deprived mice. Indicating novel steady-state morphological roles, those genes also clustered distinctly in naïve single cell VChIs. This VChIs “morpheome” atlas is the first example of unbiased analysis of neuronal populations and holds the possibility to compare neuronal structure-function relationships across experimental conditions.