Release kinetics from nano-inclusion-based and affinity-based hydrogels: A comparative study

In this study, we compare the release mechanisms from nanocomposite hydrogels. Liposomes made of different compositions of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine (DPPC), nanogels made of chitosan-hyaluronic acid association and crosslinked nanogels made of Nisopropylacrylamide (NIPAM) and different ratios of methacrylic acid (MAA) were embedded in acrylamide hydrogels with a model drug, either sulforhodamine B or rhodamine 6G. Liposomes demonstrated the capacity to release their payload over 10 days while NIPAM nanogels and chitosan nanogels released within one or two days. We found that liposomes embedded in hydrogels presented two distinctive release mechanisms, a diffusive burst and a slower “sub-diffusive” release. Both nanogels on the other side presented no observable nor defined affinity-based release mechanism due to presence of salts, completely screening electrostatic interactions. The present work highlights critical points related to the release mechanisms from nanocomposite hydrogels as drug delivery devices or as biomedical tools for tissue engineering or regenerative medicine

Конструкция и дизайн картонной упаковки для обуви на базе предприятия ОАО "Гродненская обувная фабрика "Неман"

Objective— Vascular calcification significantly increases morbidity in life-threatening diseases, and no treatments are available because of lack of understanding of the underlying molecular mechanism. Here, we study the physicochemical details of mineral nucleation and growth in an animal model that faithfully recapitulates medial arterial calcification in humans, to understand how pathological calcification is initiated on the vascular extracellular matrix. Approach and Results— MGP (matrix Gla protein) is a potent mineralization inhibitor. We study the evolution of medial calcification in MGP-deficient mice over the course of 5 weeks using a combination of material science techniques and find that mineral composition and crystallinity evolve over time and space. We show that calcium is adsorbed first and then amorphous calcium phosphate and octacalcium phosphate forms, which then transform into hydroxyapatite and carbonated apatite. These events are repeated after each nucleation event, providing a snapshot of the overall mineral evolution at each time point analyzed. Conclusions— Our results show that an interdisciplinary approach combining animal models and materials science can provide insights into the mechanism of vascular calcification and suggest the importance of analyzing mineral phases, rather than just overall mineralization extent, to diagnose and possibly prevent disease development. </jats:sec

Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia

Abstract Matrix Gla protein (MGP) is a vitamin K-dependent post-translationally modified protein, highly expressed in vascular and cartilaginous tissues. It is a potent inhibitor of extracellular matrix mineralization. Biallelic loss-of-function variants in the MGP gene cause Keutel syndrome, an autosomal recessive disorder characterized by widespread calcification of various cartilaginous tissues and skeletal and vascular anomalies. In this study, we report four individuals from two unrelated families with two heterozygous variants in MGP, both altering the cysteine 19 residue to phenylalanine or tyrosine. These individuals present with a spondyloepiphyseal skeletal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. We investigated the cellular and molecular effects of one of the heterozygous deleterious variants (C19F) using both cell and genetically modified mouse models. Heterozygous ‘knock-in’ mice expressing C19F MGP recapitulate most of the skeletal anomalies observed in the affected individuals. Our results suggest that the main underlying mechanism leading to the observed skeletal dysplasia is endoplasmic reticulum stress-induced apoptosis of the growth plate chondrocytes. Overall, our findings support that heterozygous variants in MGP altering the Cys19 residue cause autosomal dominant spondyloepiphyseal dysplasia, a condition distinct from Keutel syndrome both clinically and molecularly

Lipoprotein(a) Induces Human Aortic Valve Interstitial Cell Calcification

Lipoprotein(a), or Lp(a), significantly increased alkaline phosphatase activity, release of phosphate, calcium deposition, hydroxyapatite, cell apoptosis, matrix vesicle formation, and phosphorylation of signal transduction proteins; increased expression of chondro-osteogenic mediators; and decreased SOX9 and matrix Gla protein (p < 0.001). Inhibition of MAPK38 and GSK3β significantly reduced Lp(a)-induced calcification of human aortic valve interstitial cells (p < 0.001). There was abundant presence of Lp(a) and E06 immunoreactivity in diseased human aortic valves. The present study demonstrates a causal effect for Lp(a) in aortic valve calcification and suggests that interfering with the Lp(a)pathway could provide a novel therapeutic approach in the management of this debilitating disease