-
Acta Biomaterialia Apr 2024Cardiac pacing with temporary epicardial pacing wires (TEPW) is used to treat rhythm disturbances after cardiac surgery. Occasionally, TEPW cannot be mechanically...
Cardiac pacing with temporary epicardial pacing wires (TEPW) is used to treat rhythm disturbances after cardiac surgery. Occasionally, TEPW cannot be mechanically extracted and remain in the thorax, where they may rarely cause serious complications like migration and infection. We aim to develop bioresorbable TEPW that will dissolve over time even if postoperative removal is unsuccessful. In the present study, we demonstrate a completely bioresorbable design using molybdenum (Mo) as electric conductor and the resorbable polymers poly(D, L-lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL) for electrically insulating double-coating. We compared the pacing properties of these Mo TEPW demonstrators to conventional steel TEPW in Langendorff-perfused rat hearts and observed similar functionality. In vitro, static immersion tests in simulated body fluid for up to 28 days elucidated the degradation behaviour of uncoated Mo strands and the influence of polymer coating thereon. Degradation was considerably reduced in double-coated Mo TEPW compared to the uncoated and the PLGA-coated condition. Furthermore, we confirmed good biocompatibility of Mo degradation products in the form of low cytotoxicity in cell cultures of human cardiomyocytes and cardiac fibroblasts. STATEMENT OF SIGNIFICANCE: Temporary pacing wires are routinely implanted on the heart surface to treat rhythm disturbances in the days following cardiac surgery. Subsequently, these wires are to be removed. When removal attempts are unsuccessful, wires are cut at skin level and the remainders are left inside the chest. Retained fragments may migrate within the body or become a centre of infection. These complications may be prevented using resorbable pacing wires. We manufactured completely resorbable temporary pacing wires using molybdenum as electrical conductor and assessed their function, degradation and biological compatibility. Our study represents an important step in the development of a safer approach to the treatment of rhythm disturbances after cardiac surgery.
Topics: Humans; Animals; Rats; Cardiac Pacing, Artificial; Pacemaker, Artificial; Molybdenum; Absorbable Implants; Pericardium
PubMed: 38432350
DOI: 10.1016/j.actbio.2024.02.039 -
European Journal of Pharmaceutics and... Oct 2023Today, macromolecular compounds such as microRNAs (miRNAs) are becoming more and more widespread as leading therapeutics. However, their application is limited mostly...
Today, macromolecular compounds such as microRNAs (miRNAs) are becoming more and more widespread as leading therapeutics. However, their application is limited mostly due to their poor stability, limited cellular uptake, and poor target specificity. Cell-penetrating peptides (CPPs), a group of positively charged peptides, represent a breakthrough as delivery systems for macromolecules. In the present study, we used two types of nanoparticles which differ in the type of CPP used for their manufacturing. The first type is composed of protamine, an arginine rich CPP, which is highly positively charged. The arginine residues are able to form electrostatic interactions with miRNAs, stabilize them, and deliver them to cells. The second type is composed of the N-Ter peptide (also known as MPG), an amphipathic peptide rich in lysine. The positively charged parts of the N-Ter peptide electrostatically stabilize miRNAs, whereas its amphipathic character allows it to successfully traverse cell membranes. We used miRNA-27a, a negative regulator of adipogenesis, to form nanoparticles with the peptides and traced their uptake in 3T3-L1 preadipocytes. Motivated by the lengthy discourse regarding the uptake mechanism of CPPs, the focus of our study was to analyse and understand the internalization of proticles (protamine nanoparticles) and N-Ter complexes. The nanoparticles were characterized regarding size, size distribution, and zeta potential, and their cytotoxicity was tested in 3T3-L1 cells. The uptake studies were performed by varying the experimental conditions such as time, concentration, and temperature, as well as by applying different inhibitors of endocytosis. Furthermore, we assessed the biological effect of miRNA-27a on the pro-adipogenic machinery. The obtained data have shown that protamine and the N-Ter peptide form positively charged nanoparticles through non-covalent complexation. The uptake of proticles and N-Ter complexes was found to be dependent on time, concentration, and temperature, and different uptake pathways were discovered to be involved in the internalization of the different nanoparticles. Furthermore, both types of nanoparticles induced the anti-adipogenic effect of miRNA-27a, demonstrating that this approach can be used as a novel miRNA replacement therapy in the treatment of obesity and obesity-related disorders.
Topics: MicroRNAs; Cell-Penetrating Peptides; Drug Delivery Systems; Endocytosis; Protamines; Arginine
PubMed: 37666365
DOI: 10.1016/j.ejpb.2023.08.019 -
ACS Omega May 2024Lithium carbonate (LiCO) is a critical raw material in cathode material production, a core of Li-ion battery manufacturing. The quality of this material significantly...
Lithium carbonate (LiCO) is a critical raw material in cathode material production, a core of Li-ion battery manufacturing. The quality of this material significantly influences its market value, with impurities potentially affecting Li-ion battery performance and longevity. While the importance of impurity analysis is acknowledged by suppliers and manufacturers of battery materials, reports on elemental analysis of trace impurities in LiCO salt are scarce. This study aims to establish and validate an analytical methodology for detecting and quantifying trace impurities in LiCO salt. Various analytical techniques, including X-ray diffraction (XRD), scanning electron microscopy-energy-dispersive X-ray spectroscopy (SEM-EDX), X-ray photoelectron spectroscopy (XPS), and inductively coupled plasma optical emission spectroscopy (ICP-OES), were employed to analyze synthetic and processed lithium salt. X-ray diffraction patterns of LiCO were collected via step-scanning mode in the 5-80° 2θ range. SEM-EDX was utilized for particle morphology and quantitative impurity analysis, with samples localized on copper tape. XPS equipped with a hemispherical electron analyzer was employed to analyze the surface composition of the salt. For ICP-OES analysis, a known amount of lithium salt was subjected to acid digestion and dilution with ultrapure water. Multielemental standard solutions were prepared, including elements such as Al, Cd, Cu, Fe, Mn, Ni, Pb, Si, Zn, Ca, K, Mg, Na, and S. Results confirmed the presence of the zabuyelite phase in XRD analysis, corresponding to the natural form of lithium carbonate. SEM-EDX mapping revealed impurities of Si and Al, with low relative quantification values of 0.12% and 0.14%, respectively. XPS identified eight potential impurity elements, including S, Cr, Fe, Cl, F, Zn, Mg, and Na, alongside Li, O, and C. Regarding ICP-OES analysis, performance parameters such as linearity, limit of detection (LOD), and quantification (LOQ), variance, and recovery were evaluated for analytical validation. ICP-OES results demonstrated high linearity (>0.99), with LOD and LOQ values ranging from 0.001 to 0.800 ppm and 0.003 to 1.1 ppm, respectively, for different elements. The recovery rate exceeded 90%. In conclusion, the precision of the new ICP-OES methodology renders it suitable for identifying and characterizing LiCO impurities. It can effectively complement solid-state techniques such as XRD, SEM-EDX, and XPS.
PubMed: 38737033
DOI: 10.1021/acsomega.4c00085 -
Polymer Color Intelligence: Effect of Materials, Instruments, and Measurement Techniques - A Review.ACS Omega Jul 2023Transparent polymers and plastics are used to create molded parts and films for many applications. The colors of these products are of great importance for the... (Review)
Review
Transparent polymers and plastics are used to create molded parts and films for many applications. The colors of these products are of great importance for the suppliers, manufacturers, and end-users. However, for simplicity of the processing, the plastics are produced in the form of small pellets or granules. The predictive measurement of the color of such materials is a challenging process and needs consideration of a complex set of factors. A combination of color measurement systems in transmittance and reflectance modes need to be used for such materials, along with the techniques for minimizing the artifacts based on surface texture and particle sizes. This article provides an extensive overview and discussion of the various factors that can affect the perceptive colors and the methods used for the characterization of the colors and minimizing the measuring artifacts.
PubMed: 37426280
DOI: 10.1021/acsomega.2c08252 -
Pharmaceutics Jul 2023Achieving homogeneity and reproducibility in the size, shape, and morphology of active pharmaceutical ingredient (API) particles is crucial for their successful...
Achieving homogeneity and reproducibility in the size, shape, and morphology of active pharmaceutical ingredient (API) particles is crucial for their successful manufacturing and performance. Herein, we describe a new method for API particle engineering using melt-jet printing technology as an alternative to the current solvent-based particle engineering methods. Paracetamol, a widely used API, was melted and jetted as droplets onto various surfaces to solidify and form microparticles. The influence of different surfaces (glass, aluminum, polytetrafluoroethylene, and polyethylene) on particle shape was investigated, revealing a correlation between substrate properties (heat conduction, surface energy, and roughness) and particle sphericity. Higher thermal conductivity, surface roughness, and decreased surface energy contributed to larger contact angles and increased sphericity, reaching a near-perfect micro-spherical shape on an aluminum substrate. The integrity and polymorphic form of the printed particles were confirmed through differential scanning calorimetry and X-ray diffraction. Additionally, high-performance liquid chromatography analysis revealed minimal degradation products. The applicability of the printing process to other APIs was demonstrated by printing carbamazepine and indomethacin on aluminum surfaces, resulting in spherical microparticles. This study emphasizes the potential of melt-jet printing as a promising approach for the precise engineering of pharmaceutical particles, enabling effective control over their physiochemical properties.
PubMed: 37631240
DOI: 10.3390/pharmaceutics15082026 -
Micromachines May 2024Adapting to the growing demand for personalized, small-batch manufacturing, this study explores the development of additively manufactured molds for electroforming...
Adapting to the growing demand for personalized, small-batch manufacturing, this study explores the development of additively manufactured molds for electroforming personalized metal parts. The approach integrates novel multi-level mold design and fabrication techniques, along with the experimental procedures for the electroforming process. This work outlines design considerations and guidelines for effective electroforming in additively manufactured molds, successfully demonstrating the production of composite metal components with multi-level and free-form geometries. By emphasizing cost efficiency and part quality, particularly for limited-thickness metal components, the developed technique offers distinct advantages over existing metal additive manufacturing methods. This approach establishes itself as a flexible and durable method for metal additive manufacturing, expanding the scope of electroforming beyond traditional constraints such as thin-walled hollow structures, 2D components, and nanoscale applications.
PubMed: 38930706
DOI: 10.3390/mi15060734 -
Communications Biology Jan 2024Large-scale manufacturing of induced pluripotent stem cells (iPSCs) is essential for cell therapies and regenerative medicines. Yet, iPSCs form large cell aggregates in...
Large-scale manufacturing of induced pluripotent stem cells (iPSCs) is essential for cell therapies and regenerative medicines. Yet, iPSCs form large cell aggregates in suspension bioreactors, resulting in insufficient nutrient supply and extra metabolic waste build-up for the cells located at the core. Since subtle changes in micro-environment can lead to a heterogeneous cell population, a novel Biological System-of-Systems (Bio-SoS) framework is proposed to model cell-to-cell interactions, spatial and metabolic heterogeneity, and cell response to micro-environmental variation. Building on stochastic metabolic reaction network, aggregation kinetics, and reaction-diffusion mechanisms, the Bio-SoS model characterizes causal interdependencies at individual cell, aggregate, and cell population levels. It has a modular design that enables data integration and improves predictions for different monolayer and aggregate culture processes. In addition, a variance decomposition analysis is derived to quantify the impact of factors (i.e., aggregate size) on cell product health and quality heterogeneity.
Topics: Induced Pluripotent Stem Cells; Analysis of Variance; Bioreactors; Cell Communication; Cell- and Tissue-Based Therapy
PubMed: 38191636
DOI: 10.1038/s42003-023-05653-w -
BMC Health Services Research Sep 2023Many medicine quality problems are detected after they arrive at health facilities. Thus, critically defective medicines that may pose health risks to patients need to...
BACKGROUND
Many medicine quality problems are detected after they arrive at health facilities. Thus, critically defective medicines that may pose health risks to patients need to be withheld or recalled.
AIMS
To investigate the withheld and recalled medicines in relation to the types of defects, their total numbers, therapeutic categories, pharmaceutical dosage forms, and country of manufacturer during the study period.
METHODS
A retrospective review was performed on withheld and recalled medicines published on the publicly available National Medicines Regulatory Authority (NMRA) official website in Sri Lanka between June 2018 and August 2021. Details on substandard medicines (SM) were extracted and documented. Each record of SM was individually reviewed to determine the type of defect, subsequent action taken by NMRA, therapeutic category, pharmaceutical dosage form, and country of manufacturer.
RESULTS
A total of 163 defects were identified in 143 defective medicines, among which the most common types of defects were contamination (n = 59, 36.2%), stability defects (n = 41, 25.2%), packaging and labelling defects (n = 27, 16.6%) and active pharmaceutical ingredient defects (n = 26, 15.9%). Out of 143 total defective medicines identified, anti-infectives accounted for 41.9%, while parenteral preparations (44.0%) were found to be frequently defective. Nearly 70% of the recalled and withheld medicines were of Indian origin, and some manufacturers were identified to be repeatedly involved.
CONCLUSIONS
This study revealed that contamination was the most frequent cause of defective medicines, while parenteral preparations and anti-infectives were the most susceptible pharmaceutical dosage form and therapeutic category found to be substandard, respectively. In addition, the findings show that some manufacturers were accountable for repetitive withholdings and recalls, which reflects the ignorance of quality control measures and weak regulatory inspections as a violation of Good Manufacturing Practice (GMP).
Topics: Humans; Sri Lanka; Retrospective Studies; Commerce; Drug Packaging; Pharmaceutical Preparations
PubMed: 37700302
DOI: 10.1186/s12913-023-09995-3 -
Acta Biomaterialia Nov 2023Hepatic in vitro models that accurately replicate phenotypes and functionality of the human liver are needed for applications in toxicology, pharmacology and...
Hepatic in vitro models that accurately replicate phenotypes and functionality of the human liver are needed for applications in toxicology, pharmacology and biomedicine. Notably, it has become clear that liver function can only be sustained in 3D culture systems at physiologically relevant cell densities. Additionally, drug metabolism and drug-induced cellular toxicity often follow distinct spatial micropatterns of the metabolic zones in the liver acinus, calling for models that capture this zonation. We demonstrate the manufacture of accurate liver microphysiological systems (MPS) via engineering of 3D stereolithography printed hydrogel chips with arrays of diffusion open synthetic vasculature channels at spacings approaching in vivo capillary distances. Chip designs are compatible with seeding of cell suspensions or preformed liver cell spheroids. Importantly, primary human hepatocytes (PHH) and hiPSC-derived hepatocyte-like cells remain viable, exhibit improved molecular phenotypes compared to isogenic monolayer and static spheroid cultures and form interconnected tissue structures over the course of multiple weeks in perfused culture. 3D optical oxygen mapping of embedded sensor beads shows that the liver MPS recapitulates oxygen gradients found in the acini, which translates into zone-specific acet-ami-no-phen toxicity patterns. Zonation, here naturally generated by high cell densities and associated oxygen and nutrient utilization along the flow path, is also documented by spatial proteomics showing increased concentration of periportal- versus perivenous-associated proteins at the inlet region and vice versa at the outlet region. The presented microperfused liver MPS provides a promising platform for the mesoscale culture of human liver cells at phenotypically relevant densities and oxygen exposures. STATEMENT OF SIGNIFICANCE: A full 3D tissue culture platform is presented, enabled by massively parallel arrays of high-resolution 3D printed microperfusion hydrogel channels that functionally mimics tissue vasculature. The platform supports long-term culture of liver models with dimensions of several millimeters at physiologically relevant cell densities, which is difficult to achieve with other methods. Human liver models are generated from seeded primary human hepatocytes (PHHs) cultured for two weeks, and from seeded spheroids of hiPSC-derived human liver-like cells cultured for two months. Both model types show improved functionality over state-of-the-art 3D spheroid suspensions cultured in parallel. The platform can generate physiologically relevant oxygen gradients driven by consumption rather than supply, which was validated by visualization of embedded oxygen-sensitive microbeads, which is exploited to demonstrate zonation-specific toxicity in PHH liver models.
Topics: Humans; Liver; Hepatocytes; Oxygen; Hydrogels
PubMed: 37734628
DOI: 10.1016/j.actbio.2023.09.022 -
APL Bioengineering Dec 2023In tissues and organs, the extracellular matrix (ECM) helps maintain inter- and intracellular architectures that sustain the structure-function relationships defining...
In tissues and organs, the extracellular matrix (ECM) helps maintain inter- and intracellular architectures that sustain the structure-function relationships defining physiological homeostasis. Combining fiber scaffolds and cells to form engineered tissues is a means of replicating these relationships. Engineered tissues' fiber scaffolds are designed to mimic the topology and chemical composition of the ECM network. Here, we asked how cells found in the heart compare in their propensity to align their cytoskeleton and self-organize in response to topological cues in fibrous scaffolds. We studied cardiomyocytes, valvular interstitial cells, and vascular endothelial cells as they adapted their inter- and intracellular architectures to the extracellular space. We used focused rotary jet spinning to manufacture aligned fibrous scaffolds to mimic the length scale and three-dimensional (3D) nature of the native ECM in the muscular, valvular, and vascular tissues of the heart. The representative cardiovascular cell types were seeded onto fiber scaffolds and infiltrated the fibrous network. We measured different cell types' propensity for cytoskeletal alignment in response to fiber scaffolds with differing levels of anisotropy. The results indicated that valvular interstitial cells on moderately anisotropic substrates have a higher propensity for cytoskeletal alignment than cardiomyocytes and vascular endothelial cells. However, all cell types displayed similar levels of alignment on more extreme (isotropic and highly anisotropic) fiber scaffold organizations. These data suggest that in the hierarchy of signals that dictate the spatiotemporal organization of a tissue, geometric cues within the ECM and cellular networks may homogenize behaviors across cell populations and demographics.
PubMed: 38046543
DOI: 10.1063/5.0172423