scholarly journals Hyaluronan and Elastin-Like Protein (HELP) Gels Significantly Improve Cargo Retention in the Myocardium

2021 ◽  
Author(s):  
Riley A. Suhar ◽  
Vanessa M. Doulames ◽  
Yueming Liu ◽  
Meghan E. Hefferon ◽  
Oscar Figueroa ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Time Window ◽  
Direct Injection ◽  
Clinical Intervention ◽  
Post Injection ◽  
Rat Myocardium ◽  
Covalent Bonds ◽  
Injectable Hydrogels ◽  
Chemically Modified

Heart disease is the leading cause of death globally, and delivery of therapeutic cargo (e.g. cells, proteins, drugs) through direct injection into the myocardium is a promising clinical intervention. However, retention of deliverables to the contracting myocardium is low, with as much as 60 - 90% of payload being lost within 24 hours. Commercially-available injectable hydrogels, including Matrigel, have been hypothesized to increase payload retention, but have not yielded significant improvements in quantified analyses. Here, we assess a recombinant hydrogel composed of chemically modified hyaluronan and elastin-like protein (HELP) as an alternative injectable carrier to increase cargo retention. HELP is crosslinked using dynamic covalent bonds, and tuning the hyaluronan chemistry significantly alters hydrogel mechanical properties including stiffness, stress-relaxation rate, and ease of injectability through a needle or catheter. These materials can be injected even after complete crosslinking, extending the time window for surgical delivery. We show that HELP gels significantly improve in vivo retention of microsphere cargo compared to Matrigel, both 1 day and 7 days post-injection directly into the rat myocardium. These data suggest that HELP gels may assist with the clinical translation of therapeutic cargo designed for delivery into the contracting myocardium by preventing acute cargo loss.

Cocrystal and its Application in the Field of Active Pharmaceutical Ingredients and Food Ingredients

2018 ◽  
Vol 24 (21) ◽  
pp. 2339-2348 ◽  
Author(s):  
Na Wang ◽  
Chuang Xie ◽  
Haijiao Lu ◽  
Nannan Guo ◽  
Yajing Lou ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Clinical Performance ◽  
Chemical Properties ◽  
Drug Dosage ◽  
Active Pharmaceutical Ingredients ◽  
Covalent Bonds ◽  
Food Ingredients ◽  
Pharmaceutical Ingredients ◽  
Processing And Storage

Background: The development of solid drug dosage form and food ingredients is constrained by their low solubility, low dissolution, low bioavailability and poor physicochemical properties. Formation of cocrystal is a novel and promising method to enhance and improve the properties of materials without breaking the covalent bonds. Methods: The goal of this review is to summarize the cocrystals and their applications in the field of Active Pharmaceutical Ingredients (APIs) and food ingredients (AFIs), mainly on the effective improvements of APIs’ and AFIs’ pharmacokinetic, physicochemical and mechanical properties by the formation of cocrystals. Results: After years of research and development on cocrystals in the area of pharmaceutical and food industries, significant progress has been made. Formation of cocrystal is an efficient method for improving the solubility, dissolution rate, permeability and in vivo bioavailability of APIs and AFIs, as well as for enhancing stability and mechanical properties. Conclusion: Cocrystals exhibit complex structures which can conspicuously affect the physical and chemical properties of original substance, with good clinical performance and outstanding stability during processing and storage.

Ultrastructure of melanocyte-keratinocyte interactions and pigment transfer in vitro

1978 ◽  
Vol 36 (2) ◽  
pp. 650-651
Author(s):  
Raul I. Garcia ◽  
Evelyn A. Flynn ◽  
George Szabo
Keyword(s):  
Direct Injection ◽  
Skin Pigmentation ◽  
Freeze Fracture ◽  
Pigment Granule ◽  
Time Lapse ◽  
Ultrastructural Level ◽  
Lanthanum Tracer ◽  
A Cell

Skin pigmentation in mammals involves the interaction of epidermal melanocytes and keratinocytes in the structural and functional unit known as the Epidermal Melanin Unit. Melanocytes(M) synthesize melanin within specialized membrane-bound organelles, the melanosome or pigment granule. These are subsequently transferred by way of M dendrites to keratinocytes(K) by a mechanism still to be clearly defined. Three different, though not necessarily mutually exclusive, mechanisms of melanosome transfer have been proposed: cytophagocytosis by K of M dendrite tips containing melanosomes, direct injection of melanosomes into the K cytoplasm through a cell-to-cell pore or communicating channel formed by localized fusion of M and K cell membranes, release of melanosomes into the extracellular space(ECS) by exocytosis followed by K uptake using conventional phagocytosis. Variability in methods of transfer has been noted both in vivo and in vitro and there is evidence in support of each transfer mechanism. We Have previously studied M-K interactions in vitro using time-lapse cinemicrography and in vivo at the ultrastructural level using lanthanum tracer and freeze-fracture.

Imine Based Self-Healing Hydrogel Triggered by Periodate

2020 ◽  
Author(s):  
Alexis Wolfel ◽  
Cecilia Inés Alvarez Igarzabal ◽  
Marcelo Ricardo Romero
Keyword(s):  
Functional Groups ◽  
Time Window ◽  
Crosslinking Reaction ◽  
Self Healing ◽  
Swelling Properties ◽  
Covalent Bonds ◽  
Smart Systems ◽  
Primary Amino ◽  
Vicinal Diols ◽  
Aldehyde Groups

<p>Design of materials with novel sensitivities and smart behaviour is important for the development of smart systems with automated responsiveness. We have recently reported the synthesis of hydrogels, cross-linked by <i>N,N'</i>-diallyltartardiamide (DAT). The covalent DAT-crosslinking points have vicinal diols which can be easily cleaved with periodate, generating valuable a-oxo-aldehyde functional groups, useful for further chemical modification. Based on those findings, we envisioned that a self-healable hydrogel could be obtained by incorporation of primary amino functional groups, from <a>2-aminoethyl methacrylate </a>hydrochloride (AEMA), coexisting with DAT into the same network. The a-oxo-aldehyde groups generated after the reaction with periodate would arise in the immediate environment of amine groups to form imine cross-links. For this purpose, DAT-crosslinked hydrogels were synthesized and carefully characterized. The cleavage of DAT-crosslinks with periodate promoted changes in the mechanical and swelling properties of the materials. As expected, a self-healing behavior was observed, based on the spontaneous formation of imine covalent bonds. In addition, we surprisingly found a combination of fast vicinal diols cleavage and a low speed self-crosslinking reaction by imine formation. Consequently, it was found a time-window in which a periodate-treated polymer was obtained in a transient liquid state, which can be exploited to choose the final shape of the material, before automated gelling. The singular properties attained on these hydrogels could be useful for developing sensors, actuators, among other smart systems.</p>

Neurotoxicity of Pesticides: The Roadmap for the Cubic Mode of Action

2020 ◽  
Vol 27 (1) ◽  
pp. 54-77 ◽  
Author(s):  
Bogdan Bumbăcilă ◽  
Mihai V. Putz
Keyword(s):  
Biological Activity ◽  
Wiener Index ◽  
Laboratory Animals ◽  
Covalent Bonds ◽  
Organophosphate Compounds ◽  
Sar Studies ◽  
Structure Activity ◽  
Cubic Structure

Pesticides are used today on a planetary-wide scale. The rising need for substances with this biological activity due to an increasing consumption of agricultural and animal products and to the development of urban areas makes the chemical industry to constantly investigate new molecules or to improve the physicochemical characteristics, increase the biological activities and improve the toxicity profiles of the already known ones. Molecular databases are increasingly accessible for in vitro and in vivo bioavailability studies. In this context, structure-activity studies, by their in silico - in cerebro methods, are used to precede in vitro and in vivo studies in plants and experimental animals because they can indicate trends by statistical methods or biological activity models expressed as mathematical equations or graphical correlations, so a direction of study can be developed or another can be abandoned, saving financial resources, time and laboratory animals. Following this line of research the present paper reviews the Structure-Activity Relationship (SAR) studies and proposes a correlation between a topological connectivity index and the biological activity or toxicity made as a result of a study performed on 11 molecules of organophosphate compounds, randomly chosen, with a basic structure including a Phosphorus atom double bounded to an Oxygen atom or to a Sulfur one and having three other simple covalent bonds with two alkoxy (-methoxy or -ethoxy) groups and to another functional group different from the alkoxy groups. The molecules were packed on a cubic structure consisting of three adjacent cubes, respecting a principle of topological efficiency, that of occupying a minimal space in that cubic structure, a method that was called the Clef Method. The central topological index selected for correlation was the Wiener index, since it was possible this way to discuss different adjacencies between the nodes in the graphs corresponding to the organophosphate compounds molecules packed on the cubic structure; accordingly, &quot;three dimensional&quot; variants of these connectivity indices could be considered and further used for studying the qualitative-quantitative relationships for the specific molecule-enzyme interaction complexes, including correlation between the Wiener weights (nodal specific contributions to the total Wiener index of the molecular graph) and the biochemical reactivity of some of the atoms. Finally, when passing from SAR to Q(uantitative)-SAR studies, especially by the present advanced method of the cubic molecule (Clef Method) and its good assessment of the (neuro)toxicity of the studied molecules and of their inhibitory effect on the target enzyme - acetylcholinesterase, it can be seen that a predictability of the toxicity and activity of different analogue compounds can be ensured, facilitating the in vivo experiments or improving the usage of pesticides.

scholarly journals Facile sonochemical-assisted synthesis of orthorhombic phase black phosphorus/rGO hybrids for effective photothermal therapy

Nanophotonics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 3023-3034
Author(s):  
Weiyuan Liang ◽  
Dou Wang ◽  
Xiaohui Ren ◽  
Chenchen Ge ◽  
Hanyue Wang ◽  
...  
Keyword(s):  
Electrode Materials ◽  
Orthorhombic Phase ◽  
Cost Effective ◽  
Black Phosphorus ◽  
Antitumor Effects ◽  
Covalent Bonds ◽  
Preparation Conditions ◽  
Reduced Graphene

AbstractTwo-dimensional black phosphorus (BP) has been demonstrated to be promising in photoelectronic devices, electrode materials, and biomedicine owing to its outstanding properties. However, the application of BP has been hindered by harsh preparation conditions, high costs, and easy degradation in ambient condition. Herein, we report a facile and cost-effective strategy for synthesis of orthorhombic phase BP and a kind of BP-reduced graphene oxide (BP/rGO) hybrids in which BP remains stable for more than 4 weeks ascribed to the formation of phosphorus-carbon covalent bonds between BP and rGO as well as the protection effect of the unique wrinkle morphology of rGO nanosheets. Surface modification BP/rGO hybrids (PEGylated BP/rGO) exhibit excellent photothermal performance with photothermal conversion efficiency as high as 57.79% at 808 nm. The BP/rGO hybrids exhibit enhanced antitumor effects both in vitro and in vivo, showing promising perspectives in biomedicine.

scholarly journals Concomitant control of mechanical properties and degradation in resorbable elastomer-like materials using stereochemistry and stoichiometry for soft tissue engineering

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mary Beth Wandel ◽  
Craig A. Bell ◽  
Jiayi Yu ◽  
Maria C. Arno ◽  
Nathan Z. Dreger ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Drug Delivery ◽  
Soft Tissue ◽  
Tissue Regeneration ◽  
Biological Tissues ◽  
Soft Tissue Regeneration ◽  
Soft Tissue Engineering ◽  
Degradation Properties ◽  
Enhance Cell Adhesion

AbstractComplex biological tissues are highly viscoelastic and dynamic. Efforts to repair or replace cartilage, tendon, muscle, and vasculature using materials that facilitate repair and regeneration have been ongoing for decades. However, materials that possess the mechanical, chemical, and resorption characteristics necessary to recapitulate these tissues have been difficult to mimic using synthetic resorbable biomaterials. Herein, we report a series of resorbable elastomer-like materials that are compositionally identical and possess varying ratios of cis:trans double bonds in the backbone. These features afford concomitant control over the mechanical and surface eroding degradation properties of these materials. We show the materials can be functionalized post-polymerization with bioactive species and enhance cell adhesion. Furthermore, an in vivo rat model demonstrates that degradation and resorption are dependent on succinate stoichiometry in the elastomers and the results show limited inflammation highlighting their potential for use in soft tissue regeneration and drug delivery.

scholarly journals The C-Terminal Domain of LRRK2 with the G2019S Substitution Increases Mutant A53T α-Synuclein Toxicity in Dopaminergic Neurons In Vivo

2021 ◽  
Vol 22 (13) ◽  
pp. 6760
Author(s):  
Noémie Cresto ◽  
Camille Gardier ◽  
Marie-Claude Gaillard ◽  
Francesco Gubinelli ◽  
Pauline Roost ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Alpha Synuclein ◽  
Post Injection ◽  
Terminal Portion ◽  
Contrast Injection ◽  
Neuron Degeneration ◽  
Terminal Domain ◽  
G2019s Mutation ◽  
A53t Mutation

Alpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) play crucial roles in Parkinson’s disease (PD). They may functionally interact to induce the degeneration of dopaminergic (DA) neurons via mechanisms that are not yet fully understood. We previously showed that the C-terminal portion of LRRK2 (ΔLRRK2) with the G2019S mutation (ΔLRRK2G2019S) was sufficient to induce neurodegeneration of DA neurons in vivo, suggesting that mutated LRRK2 induces neurotoxicity through mechanisms that are (i) independent of the N-terminal domains and (ii) “cell-autonomous”. Here, we explored whether ΔLRRK2G2019S could modify α-syn toxicity through these two mechanisms. We used a co-transduction approach in rats with AAV vectors encoding ΔLRRK2G2019S or its “dead” kinase form, ΔLRRK2DK, and human α-syn with the A53T mutation (AAV-α-synA53T). Behavioral and histological evaluations were performed at 6- and 15-weeks post-injection. Results showed that neither form of ΔLRRK2 alone induced the degeneration of neurons at these post-injection time points. By contrast, injection of AAV-α-synA53T alone resulted in motor signs and degeneration of DA neurons. Co-injection of AAV-α-synA53T with AAV-ΔLRRK2G2019S induced DA neuron degeneration that was significantly higher than that induced by AAV-α-synA53T alone or with AAV-ΔLRRK2DK. Thus, mutated α-syn neurotoxicity can be enhanced by the C-terminal domain of LRRK2G2019 alone, through cell-autonomous mechanisms.

scholarly journals Size-based characterization of adalimumab and TNF-α interactions using flow induced dispersion analysis: assessment of avidity-stabilized multiple bound species

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Morten E. Pedersen ◽  
Ragna M. S. Haegebaert ◽  
Jesper Østergaard ◽  
Henrik Jensen
Keyword(s):  
Protein Interactions ◽  
Free Ligand ◽  
Local Environment ◽  
Dispersion Analysis ◽  
Surface Immobilization ◽  
Covalent Bonds ◽  
Essential Information ◽  
Tnf Α

AbstractThe understanding and characterization of protein interactions is crucial for elucidation of complicated biomolecular processes as well as for the development of new biopharmaceutical therapies. Often, protein interactions involve multiple binding, avidity, oligomerization, and are dependent on the local environment. Current analytical methodologies are unable to provide a detailed mechanistic characterization considering all these parameters, since they often rely on surface immobilization, cannot measure under biorelevant conditions, or do not feature a structurally-related readout for indicating formation of multiple bound species. In this work, we report the use of flow induced dispersion analysis (FIDA) for in-solution characterization of complex protein interactions under in vivo like conditions. FIDA is an immobilization-free ligand binding methodology employing Taylor dispersion analysis for measuring the hydrodynamic radius (size) of biomolecular complexes. Here, the FIDA technology is utilized for a size-based characterization of the interaction between TNF-α and adalimumab. We report concentration-dependent complex sizes, binding affinities (Kd), kinetics, and higher order stoichiometries, thus providing essential information on the TNF-α–adalimumab binding mechanism. Furthermore, it is shown that the avidity stabilized complexes involving formation of multiple non-covalent bonds are formed on a longer timescale than the primary complexes formed in a simple 1 to 1 binding event.

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