piperidines and Foreign-Body-Reaction

Intracranial implants elicit neurodegeneration via the foreign body response (FBR) that includes BBB leakage, macrophage/microglia accumulation, and reactive astrogliosis, in addition to neuronal degradation that limit their useful lifespan. Previously, monocyte chemoattractant protein 1 (MCP-1, also CCL2), which plays an important role in monocyte recruitment and propagation of inflammation, was shown to be critical for various aspects of the FBR in a tissue-specific manner. However, participation of MCP-1 in the brain FBR has not been evaluated. Here we examined the FBR to intracortical silicon implants in MCP-1 KO mice at 1, 2, and 8 weeks after implantation. MCP-1 KO mice had a diminished FBR compared to WT mice, characterized by reductions in BBB leakage, macrophage/microglia accumulation, and astrogliosis, and an increased neuronal density. Moreover, pharmacological inhibition of MCP-1 in implant-bearing WT mice maintained the increased neuronal density. To elucidate the relative contribution of microglia and macrophages, bone marrow chimeras were generated between MCP-1 KO and WT mice. Increased neuronal density was observed only in MCP-1 knockout mice transplanted with MCP-1 knockout marrow, which indicates that resident cells in the brain are major contributors. We hypothesized that these improvements are the result of a phenotypic switch of the macrophages/microglia polarization state, which we confirmed using PCR for common activation markers. Our observations suggest that MCP-1 influences neuronal loss, which is integral to the progression of neurological disorders like Alzheimer's and Parkinson disease, via BBB leakage and macrophage polarization.

Topics: Animals; Benzoxazines; Blood-Brain Barrier; Brain; Cell Survival; Chemokine CCL2; Chronic Disease; Foreign-Body Reaction; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Neurodegenerative Diseases; Neurons; Piperidines; Prostheses and Implants; Receptors, CCR2; Tissue Engineering

Angiogenesis depends on a complex interaction between cellular networks and mediators. The endocannabinoid system and its receptors have been shown to play a role in models of inflammation. Here, we investigated whether blockade of cannabinoid receptors may interfere with inflammatory angiogenesis.. Polyester-polyurethane sponges were implanted in C57Bl/6j mice. Animals received doses (3 and 10 mg/kg/daily, s.c.) of the cannabinoid receptor antagonists SR141716A (CB1) or SR144528 (CB2). Implants were collected at days 7 and 14 for cytokines, hemoglobin, myeloperoxidase, and N-acetylglucosaminidase measurements, as indices of inflammation, angiogenesis, neutrophil and macrophage accumulation, respectively. Histological and morphometric analysis were also performed.. Cannabinoid receptors expression in implants was detected from day 4 after implantation. Treatment with CB1 or CB2 receptor antagonists reduced cellular influx into sponges at days 7 and 14 after implantation, although CB1 receptor antagonist were more effective at blocking leukocyte accumulation. There was a reduction in TNF-α, VEGF, CXCL1/KC, CCL2/JE, and CCL3/MIP-1α levels, with increase in CCL5/RANTES. Both treatments reduced neovascularization. Dual blockade of cannabinoid receptors resulted in maximum inhibition of inflammatory angiogenesis.. Blockade of cannabinoid receptors reduced leukocyte accumulation, inflammation and neovascularization, suggesting an important role of endocannabinoids in sponge-induced inflammatory angiogenesis both via CB1 and CB2 receptors.

Topics: Animals; Camphanes; Cannabinoid Receptor Antagonists; Cytokines; Foreign Bodies; Foreign-Body Reaction; Leukocytes; Male; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Piperidines; Polyesters; Polyurethanes; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Skin

The host foreign body response (FBR) adversely effects the performance of numerous implanted biomaterials especially biosensors, including clinically popular glucose-monitoring sensors. Reactive formation of a fibrous capsule around implanted sensors hinders the transport of essential analytes to the sensor from the surrounding tissue, resulting in loss of glucose response sensitivity and eventual sensor failure. Several strategies have sought to mitigate the foreign body response's effects on CGM sensors through the use of local delivery of pharmaceuticals and biomolecules with limited success. This study describes release of a tyrosine kinase inhibitor - masitinib - from the sensor implant to target tissue resident mast cells as key mediators of the FBR. Model implants are coated with a composite polymer hydrophilic matrix that rapidly dissolves upon tissue implantation to deposit slower-degrading polymer microparticles containing masitinib. Matrix dissolution limits coating interference with sensor function while establishing a local controlled-release delivery depot formulation to alter implant tissue pharmacology and addressing the FBR. Drug efficacy was evaluated in a murine subcutaneous pocket implant model. Drug release extends to more than 30 days in vitro. The resulting FBR in vivo, evaluated by implant capsule thickness and inflammatory cell densities at 14, 21, and 28 days, displays statistically significant reduction in capsule thickness around masitinib-releasing implant sites compared to control implant sites.

Topics: Animals; Benzamides; Biocompatible Materials; Biosensing Techniques; Foreign-Body Reaction; Lactic Acid; Male; Mice; Mice, Inbred C57BL; Piperidines; Polyethylene Glycols; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Prostheses and Implants; Protein Kinase Inhibitors; Pyridines; Thiazoles

Capsular fibrosis is one of the most severe complications that can occur in connection with silicone breast implants. Should this case arise, a periprosthetic deposition of fibroid tissue may evolve. Transforming growth factor (TGF)-beta is one of the most important mediators in relation to such processes.. The chinazolinone derivative halofuginone is a type I collagen synthesis inhibitor that interferes with the TGF-beta signaling pathway. The work at hand examines the local antifibrotic effectiveness of halofuginone lactate, which has been biotechnologically bound to the silicone implant's surface. The experiments in relation to this were conducted in vivo on two groups of seven Sprague-Dawley rats. Group I received untreated silicone implants, and group II received halofuginone-coated silicone implants.. Submusculary embedded halofuginone-coated silicone implants have shown no systemic side effects. The histologic and immunohistologic examinations of the periprostatic capsules revealed a significant decrease of CD68 histiocytes, TGF-beta, fibroblasts, collagen type I and type III, and capsular thickness after a 3-month period.. The results confirmed a decrease in foreign body responses to halofuginone surface-modified silicone implants and mark their potential for obtaining a lessened capsular fibrosis by way of a local antifibrotic effect.

Topics: Animals; Breast Implants; Coated Materials, Biocompatible; Collagen Type I; Disease Models, Animal; Female; Fibrosis; Foreign-Body Reaction; Mammary Glands, Animal; Piperidines; Protein Synthesis Inhibitors; Quinazolinones; Rats; Rats, Sprague-Dawley; Silicon; Treatment Outcome