A Comprehensive Mechanical Characterization of Subject-Specific 3D Printed Scaffolds Mimicking Trabecular Bone Architecture Biomechanics.

This study presents a polymeric scaffold designed and manufactured to mimic the structure and mechanical compressive characteristics of trabecular bone. The morphological parameters and mechanical behavior of the scaffold were studied and compared with trabecular bone from bovine iliac crest. Its mechanical properties, such as modulus of elasticity and yield strength, were studied under a three-step monotonic compressive test. Results showed that the elastic modulus of the scaffold was 329 MPa, and the one for trabecular bone reached 336 MPa. A stepwise dynamic compressive test was used to assess the behavior of samples under various loading regimes. With microcomputed tomography (µCT), a three-dimensional reconstruction of the samples was obtained, and their porosity was estimated as 80% for the polymeric scaffold and 88% for trabecular bone. The full-field strain distribution of the samples was measured using in situ µCT mechanics and digital volume correlation (DVC). This provided information on the local microdeformation mechanism of the scaffolds when compared to that of the tissue. The comprehensive results illustrate the potential of the fabricated scaffolds as biomechanical templates for in vitro studies. Furthermore, there is potential for extending this structure and fabrication methodology to incorporate suitable biocompatible materials for both in vitro and in vivo clinical applications.

Muscle-like Scaffolds for Biomechanical Stimulation in a Custom-Built Bioreactor.

Tissue engineering aims to develop in-vitro substitutes of native tissues. One approach of tissue engineering relies on using bioreactors combined with biomimetic scaffolds to produce study models or in-vitro substitutes. Bioreactors provide control over environmental parameters, place and hold a scaffold under desired characteristics, and apply mechanical stimulation to scaffolds. Polymers are often used for fabricating tissue-engineering scaffolds. In this study, polycaprolactone (PCL) collagen-coated microfilament scaffolds were cell-seeded with C2C12 myoblasts; then, these were grown inside a custom-built bioreactor. Cell attachment and proliferation on the scaffolds were investigated. A loading pattern was used for mechanical stimulation of the cell-seeded scaffolds. Results showed that the microfilaments provided a suitable scaffold for myoblast anchorage and that the custom-built bioreactor provided a qualified environment for the survival of the myoblasts on the polymeric scaffold. This PCL-based microfilament scaffold located inside the bioreactor proved to be a promising structure for the study of skeletal muscle models and can be used for mechanical stimulation studies in tissue engineering applications.

Evaluation of Biomechanical and Chemical Properties of Gamma-Irradiated Polycaprolactone Microfilaments for Musculoskeletal Tissue Engineering Applications.

An appropriate and reliable sterilization technique is crucial for tissue engineering scaffolds. Skeletal muscle scaffolds are often fabricated using microfilaments of a wide variety of polymers. One method for sterilization is 25 kGy of gamma irradiation. In addition, sterilization through irradiation should administer a dose within a specific range. Radiation directly affects the chemical and mechanical properties of scaffolds. The accuracy and effects of irradiation are often not considered during sterilization procedures; however, these are important since they provide insight on whether the sterilization procedure is reliable and reproducible. This study focused on the chemical and mechanical characterization of 25 kGy gamma-irradiated scaffold. The accuracy and uncertainty of the irradiation procedure were also obtained. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analyses were performed to determine whether the crystallinity of the polymer changed after irradiation and whether gamma rays influenced its thermal properties. The tensile parameters of the microfilaments were analyzed by comparing irradiated and nonirradiated scaffolds to determine whether gamma radiation changed their elastic behavior. Dose distribution and uncertainty were recorded with several dosimeters. The results showed that the irradiation process slightly affected the mechanical parameters of the scaffold; however, it did not modify its crystallinity or thermal properties. The irradiation was uniform, since the measured uncertainty was low. The scaffold was pathogen-free after 7 days; this meant sterilization was achieved. These results indicated that gamma-sterilized scaffolds were a promising material for use as a skeletal muscle analog material for tissue-engineering applications because they can be sterilized with gamma rays without changing their chemical structure and mechanical properties. This study provided the dose distribution measurement and uncertainty calculations for the sterilization procedure.

Crystal Forms of the Antihypertensive Drug Irbesartan: A Crystallographic, Spectroscopic, and Hirshfeld Surface Analysis Investigation.

The design of new pharmaceutical solids with improved physical and chemical properties can be reached through in-detail knowledge of the noncovalent intermolecular interactions between the molecules in the context of crystal packing. Although crystallization from solutions is well-known for obtaining new solids, the effect of some variables on crystallization is not yet thoroughly understood. Among these variables, solvents are noteworthy. In this context, the present study aimed to investigate the effect of ethanol (EtOH), acetonitrile (MeCN), and acetone (ACTN) on obtaining irbesartan (IBS) crystal forms with 2,3-dibromosuccinic acid. Crystal structures were solved by single-crystal diffraction, and the intermolecular interactions were analyzed using the Hirshfeld surfaces analysis. The characterization of physicochemical properties was carried out by powder X-ray diffraction, Fourier transform infrared spectroscopy (FT-IR), thermal analysis, and solution-state NMR techniques. Two different IBS salts were obtained, one from MeCN and ACTN (compound 1) and a different one from EtOH (compound 2). The experimental results were in agreement with the findings obtained through quantum mechanics continuum solvation models. Compound 1 crystallized as a monoclinic system P21/c, whereas compound 2 in a triclinic system P1̅. In both structures, a net of strong hydrogen bonds is present, and their existence was confirmed by the FT-IR results. In addition, the IBS cation acts as a H-bond donor through the N1 and N6 nitrogen atoms which interact with the bromide anion and the water molecule O1W in compound 1. Meanwhile, N1 and N6 nitrogen atoms interact with the oxygen atoms provided by two symmetry-related 2,3-dibromo succinate anions in compound 2. Solution-state NMR data agreed with the protonation of the imidazolone ring in the crystal structure of compound 1. Both salts presented a different thermal behavior not only in melting temperature but also in thermal stability.

Evaluation of Piperine as Natural Coformer for Eutectics Preparation of Drugs Used in the Treatment of Cardiovascular Diseases.

Piperine (PIP) was evaluated as a natural coformer in the preparation of multicomponent organic materials for enhancing solubility and dissolution rate of the poorly water-soluble drugs: curcumin (CUR), lovastatin (LOV), and irbesartan (IBS). A screening based on liquid assisted grinding technique was performed using 1:1 drug-PIP molar ratio mixtures, followed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) analyses. Three eutectic mixtures (EMs) composed of CUR-PIP, LOV-PIP, and IBS-PIP were obtained. Therefore, binary phase and Tamman's diagrams were constructed for each system to obtain the exact eutectic composition, which was 0.41:0.59, 0.29:0.71, and 0.31:0.69 for CUR-PIP, LOV-PIP, and IBS-PIP, respectively. Further, bulk materials of each system were prepared to characterize them through DSC, PXRD fully, Fourier transform infrared spectroscopy (FT-IR), and solution-state nuclear magnetic resonance (NMR) spectroscopy. In addition, the contact angle, solubility, and dissolution rate of each system were evaluated. The preserved characteristic in the PXRD patterns and FT-IR spectra of the bulk material of each system confirmed the formation of EM mixture without molecular interaction in solid-state. The formation of EM resulted in improved aqueous solubility and dissolution rate associated with the increased wettability observed by the decrease in contact angle. In addition, solution NMR analyses of CUR-PIP, LOV-PIP, and IBS-PIP suggested no significant intermolecular interactions in solution between the components of the EM. Hence, this study concludes that PIP could be an effective coformer to improve the solubility and dissolution rate of CUR, LOV, and IBS.

Drug Solubility Enhancement through the Preparation of Multicomponent Organic Materials: Eutectics of Lovastatin with Carboxylic Acids.

Lovastatin (LOV) is a drug used to treat hypercholesterolemia. Recent studies have identified its antioxidant effects and potential use in the treatment of some types of cancer. However, the low bioavailability related to its poor water solubility limits its use in solid oral dosage forms. Therefore, to improve the solubility of LOV three eutectic systems of LOV with the carboxylic acids benzoic (BEN), salicylic (SAL) and cinnamic (CIN) were obtained. Both binary phase and Tammann diagrams were constructed using differential scanning calorimetry (DSC) data of mixtures prepared from 0.1 to 1.0 molar ratios. Binary mixtures and eutectics were prepared by liquid-assisted grinding. The eutectics were further characterized by DSC and powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). The LOV-BEN, LOV-SAL and LOV-CIN system formed a eutectic at an LOV mole fraction of 0.19, 0.60 and 0.14, respectively. The systems exhibited improvements in LOV solubility, becoming more soluble by five-fold in the LOV-SAL system and approximately four-fold in the other two systems. Considering that the solubility enhancements and the carboxylic acids used are generally recognized as safe by the U.S. Food and Drug Administration (FDA), the LOV eutectic systems are promising materials to be used in a solubility enhancement strategy for pharmaceutical product formulation.

The effect of solution environment and the electrostatic factor on the crystallisation of desmotropes of irbesartan.

The experimental conditions necessary for stabilising irbesartan (IBS) tautomers in solution and selectively obtaining the desmotropic crystal forms are presented herein. 1H and 2H tautomers were stabilized in specific solution conditions and the 2H-tetrazole⋯imidazole interaction was confirmed by solution-state NMR. The results showed that highly polar and polarisable solvents (higher values of the electrostatic factor (EF)) lead to the crystallisation of IBS form B. Furthermore, the variations of pH in methanol, in turn, determined the crystallisation of desmotropes A and/or B.

Irbesartan desmotropes: Solid-state characterization, thermodynamic study and dissolution properties.

Irbesartan (IBS) is a tetrazole derivative and antihypertensive drug that has two interconvertible structures, 1H- and 2H-tautomers. The difference between them lies in the protonation of the tetrazole ring. In the solid-state, both tautomers can be isolated as crystal forms A (1H-tautomer) and B (2H-tautomer). Studies have reported that IBS is a polymorphic system and its forms A and B are related monotropically. These reports indicate form B as the most stable and less soluble form. Therefore, the goal of this contribution is to demonstrate through a complete solid-state characterization, thermodynamic study and dissolution properties that the IBS forms are desmotropes that are not related monotropically. However, the intention is also to call attention to the importance of conducting strict chemical and in solid-state quality controls on the IBS raw materials. Hence, powder X-ray diffraction (PXRD) and Raman spectroscopy (RS) at ambient and non-ambient conditions, differential scanning calorimetry (DSC), hot stage microscopy (HSM), Fourier transform infrared (FT-IR) and scanning electron microscopy (SEM) techniques were applied. Furthermore, intrinsic dissolution rate (IDR) and structural stability studies at 98% relative humidity (RH), 25 °C and 40 °C were conducted as well. The results show that in fact, form A is approximately four-fold more soluble than form B. In addition, both IBS forms are stable at ambient conditions. Nevertheless, structural and/or chemical instability was observed in form B at 40 °C and 98% RH. IBS has been confirmed as a desmotropic system rather than a polymorphic one. Consequently, forms A and B are not related monotropically.

Irbesartan desmotropes:Solid-state characterization, thermodynamic study and dissolution properties / 药物分析学报

Irbesartan (IBS) is a tetrazole derivative and antihypertensive drug that has two interconvertible struc-tures, 1H-and 2H-tautomers. The difference between them lies in the protonation of the tetrazole ring. In the solid-state, both tautomers can be isolated as crystal forms A (1H-tautomer) and B (2H-tautomer). Studies have reported that IBS is a polymorphic system and its forms A and B are related monotropically. These reports indicate form B as the most stable and less soluble form. Therefore, the goal of this contribution is to demonstrate through a complete solid-state characterization, thermodynamic study and dissolution properties that the IBS forms are desmotropes that are not related monotropically. However, the intention is also to call attention to the importance of conducting strict chemical and in solid-state quality controls on the IBS raw materials. Hence, powder X-ray diffraction (PXRD) and Raman spectroscopy (RS) at ambient and non-ambient conditions, differential scanning calorimetry (DSC), hot stage microscopy (HSM), Fourier transform infrared (FT-IR) and scanning electron microscopy (SEM) techniques were applied. Furthermore, intrinsic dissolution rate (IDR) and structural stability studies at 98％relative humidity (RH), 25 ?C and 40 ?C were conducted as well. The results show that in fact, form A is approximately four-fold more soluble than form B. In addition, both IBS forms are stable at ambient conditions. Nevertheless, structural and/or chemical instability was observed in form B at 40 ?C and 98％RH. IBS has been confirmed as a desmotropic system rather than a polymorphic one. Consequently, forms A and B are not related monotropically.