Intracerebral Implantation of Ionic Synthetic Hydrogels: Effect of Polar Substrata on Astrocytosis and Axons

In previous studies, hyperporous synthetic hydrogels of poly(glyceryl methacrylate) or p(GMA), containing bioadhesive substrates of collagen, were implanted into rat cerebral tissue in order to provide systems of oriented guidance channels for directing the growth of the scar and axons /28/. In the present study, ionic p(GMA)- collagen hydrogels containing polar chemical groups, either basic amino groups or acidic carboxyl groups, were evaluated for their tolerance and their effects on the brain scarring response and axonal reactivity after long-term implantation in the cerebral cortex. In all animals, the implants were well tolerated. Although both types of gels influenced the astroglial reaction near the bioimplant, hydrogels carrying carboxyl groups had the strongest influence on the elongation, the direction and the organization of astrocytic processes so that a glial matrix could form in regions of the gel. Extracellular material (e.g. reticulin) was also deposited into the gels carrying carboxyl groups. Although cortical nerve fibers .in the surrounding tissue showed a regenerative response, extending onto or into the matrices, this behavior seemed to depend more on the organization of the .astrocytic scar imposed by the gel than on the type of gel. We conclude that matrices carrying negatively charged groups influence favorably the astrocytosis and the deposition of connective tissue, and that this approach represents a new avenue in attempting to modulate the brain scar formation

Intracerebral Implantation of Hydrogel-Coupled Adhesion Peptides: Tissue Reaction

Arg-Gly-Asp peptides (RGD) were synthesized and chemically coupled to the bulk of N-(2-hydroxypropyl) methacrylamide-based polymer hydrogels. Fourier Transform Infrared Spectroscopy (FFIR) and amino acid analysis confirmed the peptide coupling to the polymer. Activated and control (unmodified) polymer matrices were stereotaxically implanted in the striata of rat brains, and two months later the brains were processed for immunohistochemistry using antibodies for glial acidic fibrillary protein (GFAP), laminin and neurofilaments. RGD-containing polymer matrices promoted stronger adhesion to the host tissue than the unmodified polymer matrices. In addition, the RGD-grafted polymer implants promoted and supported the growth and spread of GFAP-positive glial tissue onto and into the hydrogels. Neurofilament-positive fibers were also seen running along the surface of the polymer and, in some instances, penetrating the matrix. These findings are discussed in the context of using bioactive polymers as a new approach for promoting tissue repair and axonal regeneration of damaged structures of the central nervous system

Novel hydrogel obtained by chitosan and dextrin-VA co-polymerization

A novel hydrogel was obtained by reticulation of chitosan with dextrin enzymatically linked to vinyl acrylate (dextrin-VA), without cross-linking agents. The hydrogel had a solid-like behaviour with G′ (storage modulus) >> G″ (loss modulus). Glucose diffusion coefficients of 3.9 × 10−6 ± 1.3 × 10−6 cm2/s and 2.9 × 10−6 ± 0.5 × 10−6 cm2/s were obtained for different substitution degrees of the dextrin-VA (20% and 70% respectively). SEM observation revealed a porous structure, with pores ranging from 50 µm to 150 µm

Regioisomeric and substituent effects upon the outcome of the reaction of 1-borodienes with nitrosoarene compounds

A study of the reactivity of 1-borodienes with nitrosoarene compounds has been carried out showing an outcome that differs according to the hybridization state of the boron moiety. Using an sp2 boron substituent, a one-pot hetero-Diels–Alder/ring contraction cascade occurred to afford N-arylpyrroles with low to good yields depending on the electronic properties of the substituents on the borodiene, whereas an sp3 boron substituent led to the formation of stable boro-oxazines with high regioselectivity in most of the cases, in moderate to good yields. 1H and 11B NMR studies on two boro-oxazine regioisomers showed that selective deprotection can be performed. Formation of either the pyrrole or the furan derivative is pH- and regioisomer-structure-dependent. The results obtained, together with previous B3LYP calculations, support mechanistic proposals which suggest that pyrrole, or furan, formation proceeds via oxazine formation, followed by a boryl rearrangement and an intramolecular addition–elimination sequence

An overview of tissue engineering approaches for management of spinal cord injuries

Severe spinal cord injury (SCI) leads to devastating neurological deficits and disabilities, which necessitates spending a great deal of health budget for psychological and healthcare problems of these patients and their relatives. This justifies the cost of research into the new modalities for treatment of spinal cord injuries, even in developing countries. Apart from surgical management and nerve grafting, several other approaches have been adopted for management of this condition including pharmacologic and gene therapy, cell therapy, and use of different cell-free or cell-seeded bioscaffolds. In current paper, the recent developments for therapeutic delivery of stem and non-stem cells to the site of injury, and application of cell-free and cell-seeded natural and synthetic scaffolds have been reviewed

The pathophysiological function of peroxisome proliferator-activated receptor-γ in lung-related diseases

Research into respiratory diseases has reached a critical stage and the introduction of novel therapies is essential in combating these debilitating conditions. With the discovery of the peroxisome proliferator-activated receptor and its involvement in inflammatory responses of cardiovascular disease and diabetes, attention has turned to lung diseases and whether knowledge of this receptor can be applied to therapy of the human airways. In this article, we explore the prospect of peroxisome proliferator-activated receptor-γ as a marker and treatment focal point of lung diseases such as asthma, chronic obstructive pulmonary disorder, lung cancer and cystic fibrosis. It is anticipated that peroxisome proliferator-activated receptor-γ ligands will provide not only useful mechanistic pathway information but also a possible new wave of therapies for sufferers of chronic respiratory diseases

PPARα downregulates airway inflammation induced by lipopolysaccharide in the mouse

BACKGROUND: Inflammation is a hallmark of acute lung injury and chronic airway diseases. In chronic airway diseases, it is associated with profound tissue remodeling. Peroxisome proliferator-activated receptor-α (PPARα) is a ligand-activated transcription factor, that belongs to the nuclear receptor family. Agonists for PPARα have been recently shown to reduce lipopolysaccharide (LPS)- and cytokine-induced secretion of matrix metalloproteinase-9 (MMP-9) in human monocytes and rat mesangial cells, suggesting that PPARα may play a beneficial role in inflammation and tissue remodeling. METHODS: We have investigated the role of PPARα in a mouse model of LPS-induced airway inflammation characterized by neutrophil and macrophage infiltration, by production of the chemoattractants, tumor necrosis factor-α (TNF-α), keratinocyte derived-chemokine (KC), macrophage inflammatory protein-2 (MIP-2) and monocyte chemoattractant protein-1 (MCP-1), and by increased MMP-2 and MMP-9 activity in bronchoalveolar lavage fluid (BALF). The role of PPARα in this model was studied using both PPARα-deficient mice and mice treated with the PPARα activator, fenofibrate. RESULTS: Upon intranasal exposure to LPS, PPARα(-/- )mice exhibited greater neutrophil and macrophage number in BALF, as well as increased levels of TNF-α, KC, MIP-2 and MCP-1, when compared to PPARα(+/+ )mice. PPARα(-/- )mice also displayed enhanced MMP-9 activity. Conversely, fenofibrate (0.15 to 15 mg/day) dose-dependently reduced the increase in neutrophil and macrophage number induced by LPS in wild-type mice. In animals treated with 15 mg/day fenofibrate, this effect was associated with a reduction in TNF-α, KC, MIP-2 and MCP-1 levels, as well as in MMP-2 and MMP-9 activity. PPARα(-/- )mice treated with 15 mg/day fenofibrate failed to exhibit decreased airway inflammatory cell infiltrate, demonstrating that PPARα mediates the anti-inflammatory effect of fenofibrate. CONCLUSION: Using both genetic and pharmacological approaches, our data clearly show that PPARα downregulates cell infiltration, chemoattractant production and enhanced MMP activity triggered by LPS in mouse lung. This suggests that PPARα activation may have a beneficial effect in acute or chronic inflammatory airway disorders involving neutrophils and macrophages

Evaluation of the PPAR-γ agonist pioglitazone in mild asthma: a double-blind randomized controlled trial

Background Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a nuclear receptor that modulates inflammation in models of asthma. To determine whether pioglitazone improves measures of asthma control and airway inflammation, we performed a single-center randomized, double-blind, placebo-controlled, parallel-group trial. Methods Sixty-eight participants with mild asthma were randomized to 12 weeks pioglitazone (30 mg for 4 weeks, then 45 mg for 8 weeks) or placebo. The primary outcome was the adjusted mean forced expiratory volume in one second (FEV1) at 12 weeks. The secondary outcomes were mean peak expiratory flow (PEF), scores on the Juniper Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ), fractional exhaled nitric oxide (FeNO), bronchial hyperresponsiveness (PD20), induced sputum counts, and sputum supernatant interferon gamma-inducible protein-10 (IP-10), vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1), and eosinophil cationic protein (ECP) levels. Study recruitment was closed early after considering the European Medicines Agency’s reports of a potential increased risk of bladder cancer with pioglitazone treatment. Fifty-five cases were included in the full analysis (FA) and 52 in the per-protocol (PP) analysis. Results There was no difference in the adjusted FEV1 at 12 weeks (-0.014 L, 95% confidence interval [CI] -0.15 to 0.12, p = 0.84) or in any of the secondary outcomes in the FA. The PP analysis replicated the FA, with the exception of a lower evening PEF in the pioglitazone group (-21 L/min, 95% CI -39 to -4, p = 0.02). Conclusions We found no evidence that treatment with 12 weeks of pioglitazone improved asthma control or airway inflammation in mild asthma