Design, Synthesis, and Development of 4-[(7-Chloroquinoline-4-yl)amino]phenol as a Potential SARS-CoV-2 Mpro Inhibitor.

A series of chloroquine analogs were designed to search for a less toxic chloroquine derivative as a potential SARS-CoV-2 Mpro inhibitor. Herein, an ANN-based QSAR model was built to predict the IC50 values of each analog using the experimental values of other 4-aminoquinolines as the training set. Subsequently, molecular docking was used to evaluate each analog's binding affinity to Mpro. The analog that showed the greatest affinity and lowest IC50 values was synthesized and characterized for its posterior incorporation into a polycaprolactone-based nanoparticulate system. After characterizing the loaded nanoparticles, an in vitro drug release assay was carried out, and the cytotoxicity of the analog and loaded nanoparticles was evaluated using murine fibroblast (L929) and human lung adenocarcinoma (A549) cell lines. Results show that the synthesized analog is much less toxic than chloroquine and that the nanoparticulate system allowed for the prolonged release of the analog without evidence of adverse effects on the cell lines used; therefore, suggesting that the analog could be a potential therapeutic option for COVID-19.

Adjustable conduits for guided peripheral nerve regeneration prepared from bi-zonal unidirectional and multidirectional laminar scaffold of type I collagen.

Shortness of donor nerves has led to the development of nerve conduits that connect sectioned peripheral nerve stumps and help to prevent the formation of neuromas. Often, the standard diameters of these devices cannot be adapted at the time of surgery to the diameter of the nerve injured. In this work, scaffolds were developed to form filled nerve conduits with an inner matrix with unidirectional channels covered by a multidirectional pore zone. Collagen type I dispersions (5 mg/g and 8 mg/g) were sequentially frozen using different methods to obtain six laminar scaffolds (P1 to P5) formed by a unidirectional (U) pore/channel zone adjacent to a multidirectional (M) pore zone. The physicochemical and microstructural properties of the scaffolds were determined and compared, as well as their biodegradability, residual glutaraldehyde and cytocompatibility. Also, the Young's modulus of the conduits made by rolling up the bizonal scaffolds from the unidirectional to the multidirectional zone was determined. Based on these comparisons, the proliferation and differentiation of hASC were assessed only in the P3 scaffolds. The cells adhered, aligned in the same direction as the unidirectional porous fibers, proliferated, and differentiated into Schwann-like cells. Adjustable conduits made with the P3 scaffold were implanted in rats 10 mm sciatic nerve lesions to compare their performance with that of autologous sciatic nerve grafted lesions. The in vivo results demonstrated that the tested conduit can be adapted to the diameter of the nerve stumps to guide their growth and promote their regeneration.

Evaluation of collagen type I scaffolds including gelatin-collagen microparticles and Aloe vera in a model of full-thickness skin wound.

Research on collagen type I scaffolds with Aloe vera is sparse. The aim of this work was to develop collagen type I scaffolds with gelatin-collagen microparticles and loaded with a dispersion of A. vera, to assess their performance as grafting material for healing of skin wounds. Scaffolds were evaluated in a Cavia porcellus model with full-thickness skin wound and compared with wounds healed by secondary intention (controls). Animals grafted with scaffolds without A. vera and their control wounds were also included in the study. Evaluation of enzymatic degradation and percentage of the scaffolds' free amino groups-as an indirect assessment of their cross-linking-were also carried out because A. vera contains compounds which affect their stability. We found that dispersions of lyophilized A. vera extract loaded on scaffolds do not have cytotoxic potential, and they decrease collagenase degradation of scaffolds in the range of 0.1 to 0.3% w/v in a dose-dependent manner. Only the A. vera dispersion with the highest concentration (0.3% w/v) decreased the percentage of free amino groups, which are the ones involved in the cross-link of collagen fibers. This finding suggests that cross-linking is not the mechanism by which the tested dispersions stabilize the scaffolds. Preclinical, histochemical, and histomorphometric analyses of repaired wound tissue indicate that loading collagen type I scaffolds, including microparticles of gelatin-collagen, with A. vera in the concentrations tested does not improve wound healing. Low biodegradability of the tested scaffolds caused by the inhibition of collagenase activity might account for these results.

Controlled release of an extract of Calendula officinalis flowers from a system based on the incorporation of gelatin-collagen microparticles into collagen I scaffolds: design and in vitro performance.

Aiming to develop biological skin dresses with improved performance in the treatment of skin wounds, acellular collagen I scaffolds were modified with polymeric microparticles and the subsequent loading of a hydroglycolic extract of Calendula officinalis flowers. Microparticles made of gelatin-collagen were produced by a water-in-oil emulsion/cross-linking method. Thereafter, these microparticles were mixed with collagen suspensions at three increasing concentrations and the resulting mixtures lyophilized to make microparticle-loaded porous collagen scaffolds. Resistance to enzymatic degradation, ability to associate with the C. officinalis extract, and the extract release profile of the three gelatin-collagen microparticle-scaffold prototypes were assessed in vitro and compared to collagen scaffolds without microparticles used as control. Data indicated that the incorporation of gelatin-collagen microparticles increased the resistance of the scaffolds to in vitro enzymatic degradation, as well as their association with the C. officinalis flower extract. In addition, a sharp decrease in cytotoxicity, as well as more prolonged release of the extract, was attained. Overall results support the potential of these systems to develop innovative dermal substitutes with improved features. Furthermore, the gelatin-collagen mixture represents a low-cost and scalable alternative with high clinical transferability, especially appealing in developing countries.