Search Results (10,064)

Background/Objectives: Dual-modality probes, combining positron emission tomography (PET) with fluorescence imaging (FI) capabilities in a single molecule, are of high relevance for the accurate staging and guided resection of tumours. We herein present a pair of candidates targeting the cholecystokinin-2 receptor (CCK2R), namely [⁶⁸Ga]Ga-CyTMG and [⁶⁸Ga]Ga-CyFMG. In these probes, the SulfoCy5.5 fluorophore and two units of a CCK2R-binding motif are coupled to the chelator acting as a core scaffold, triazacyclononane-phosphinic acid (TRAP), and Fusarinine C (FSC), respectively. Using this approach, we investigated the influence of these chelators on the final properties. Methods: The synthetic strategy to both precursors was based on the stoichiometric conjugation of the components via click chemistry. The characterization in vitro included the evaluation of the CCK2R affinity and internalization in A431-CCK2R cells. Ex vivo biodistribution as well as PET and FI studies were performed in xenografted mice. Results: ⁶⁸Ga labelling was accomplished with high radiochemical yield and purity for both precursors. A CCK2R affinity in the subnanomolar range of the conjugates and a receptor-specific uptake of the radioligands in cells were observed. In A431-CCK2R/A431-mock xenografted mice, the investigated compounds showed specific accumulation in the tumours and reduced off-target uptake compared to a previously developed compound. Higher accumulation and prolonged retention in the kidneys were observed for [⁶⁸Ga]Ga-CyTMG when compared to [⁶⁸Ga]Ga-CyFMG. Conclusions: Despite the promising targeting properties observed, further probe optimization is required to achieve enhanced imaging contrast at early timepoints. Additionally, the results indicate a distinct influence of the chelators in terms of renal accumulation and retention. Full article

Constructing scaffolds with the desired structures and functions is one of the main goals of tissue engineering. Three-dimensional (3D) bioprinting is a promising technology that enables the personalized fabrication of devices with regulated biological and mechanical characteristics similar to natural tissues/organs. To date, 3D bioprinting has been widely explored for biomedical applications like tissue engineering, drug delivery, drug screening, and in vitro disease model construction. Among different bioinks, photocrosslinkable bioinks have emerged as a powerful choice for the advanced fabrication of 3D devices, with fast crosslinking speed, high resolution, and great print fidelity. The photocrosslinkable biomaterials used for light-based 3D printing play a pivotal role in the fabrication of functional constructs. Herein, this review outlines the general 3D bioprinting approaches related to photocrosslinkable biomaterials, including extrusion-based printing, inkjet printing, stereolithography printing, and laser-assisted printing. Further, the mechanisms, advantages, and limitations of photopolymerization and photoinitiators are discussed. Next, recent advances in natural and synthetic photocrosslinkable biomaterials used for 3D bioprinting are highlighted. Finally, the challenges and future perspectives of photocrosslinkable bioinks and bioprinting approaches are envisaged. Full article

The cross-linking process of collagen is one of the more important ways to improve the mineralization ability of collagen. However, the regulatory effect of dynamic cross-linking on biomineralization in vitro remains unclear. Dynamic-cross-linked mineralized collagen under different cross-linking processes, according to the process of cross-linking and mineralization of natural bone, was prepared in this study. Mineralization was performed for 12 h at 4, 8, and 12 h of collagen cross-linking. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) showed the characteristics of dynamic-cross-linked mineralization in terms of morphological transformation and distribution. Fourier transform infrared spectroscopy (FTIR) analysis showed the crystallinity characteristics of the hydroxyapatite (HA) crystal formation. Pre-cross-linked dynamic-cross-linked mineralization refers to the process of cross-linking for a period of time and then side cross-linked mineralization. The mineral content, enzyme stability, and mechanical properties of mineralized collagen were improved through a dynamic cross-linking process of pre-cross-linking. The swelling performance was reduced through the dynamic cross-linking process of pre-cross-linking. This study suggests that the dynamic cross-linking process through pre-cross-linking could make it easier for minerals to permeate and deposit between collagen fibers, improve mineralization efficiency, and, thus, enhance the mechanical strength of biomineralization. This study can provide new ideas and a theoretical basis for designing mineralized collagen scaffolds with better bone repair ability. Full article

3D-printed microporous titanium scaffolds enjoy good biointegration with the residuum’s soft and bone tissues, and they promote excellent biomechanical properties in attached prostheses. Implant-associated infection, however, remains a major clinical challenge. Silver-based implant coatings can potentially reduce bacterial growth and inhibit biofilm formation, thereby reducing the risk of periprosthetic infections. In the current study, a 1-µm thick silver coating was prepared on the surface of a 3D-printed microporous titanium alloy with physical vapor deposition (PVD), with a final silver content of 1.00 ± 02 mg/cm². Cell viability was evaluated with an MTT assay of MC3T3-E1 osteoblasts and human dermal fibroblasts cultured on the surface of the implants, and showed low cytotoxicity for cells during the 14-day follow-up period. Quantitative real-time polymerase chain reaction (RT-PCR) analysis of the relative gene expression of the extracellular matrix components (fibronectin, vitronectin, type I collagen) and cell adhesion markers (α2, α5, αV, β1 integrins) in dermal fibroblasts showed that cell adhesion was not reduced by the silver coating of the microporous implants. An RT-PCR analysis of gene expression related to osteogenic differentiation, including TGF-β1, SMAD4, osteocalcin, osteopontin, and osteonectin in MC3T3-E1 osteoblasts, demonstrated that silver coating did not reduce the osteogenic activity of cells and, to the contrary, enhanced the activity of the TGF-β signaling pathway. For representative sample S5 on day 14, the gene expression levels were 7.15 ± 0.29 (osteonectin), 6.08 ± 0.12 (osteocalcin), and 11.19 ± 0.77 (osteopontin). In conclusion, the data indicate that the silver coating of the microporous titanium implants did not reduce the biointegrative or osteoinductive properties of the titanium scaffold, a finding that argues in favor of applying this coating in designing personalized osseointegrated implants. Full article

Small-molecule probes are powerful tools for studying biological systems and can serve as lead compounds for developing new therapeutics. Especially, nitrogen heterocycles are of considerable importance in the pharmaceutical field. These compounds are found in numerous bioactive structures. Their synthesis often requires several steps or the use of functionalized starting materials. This review describes the use of vicinal diamines generated from modified short peptides to access substituted diaza- and triazacyclic compounds. Small-molecule diaza- and triazacyclic compounds with different substitution patterns and embedded in various molecular frameworks constitute important structure classes in the search for bioactivity. The compounds are designed to follow known drug likeness rules, including “Lipinski’s Rule of Five”. The screening of diazacyclic and traizacyclic libraries has shown the utility of these classes of compounds for the de novo identification of highly active compounds, including antimalarials, antimicrobial compounds, antifibrotic compounds, potent analgesics, and antitumor agents. Examples of the synthesis of diazacyclic and triazacyclic small-molecule libraries from vicinal chiral polyamines generated from modified short peptides and their application for the identification of highly active compounds are described. Full article

Due to the chemical composition and structure of the target tissue, autologous bone grafting remains the gold standard for orthopedic applications worldwide. However, ongoing advancements in alternative grafting materials show that 3D-printed synthetic biomaterials offer many advantages. For instance, they provide high availability, have low clinical limitations, and can be designed with a chemical composition and structure comparable to the target tissue. This study aimed to compare the influences of particle size and sintering temperature on the mechanical properties and biocompatibility of calcium phosphate (CaP) gyroid scaffolds. CaP gyroid scaffolds were fabricated by 3D printing using powders with the same chemical composition but different particle sizes and sintering temperatures. The physicochemical characterization of the scaffolds was performed using X-ray diffractometry, scanning electron microscopy, and microtomography analyses. The immortalized human mesenchymal stem cell line SCP-1 (osteoblast-like cells) and osteoclast-like cells (THP-1 cells) were seeded on the scaffolds as mono- or co-cultures. Bone cell attachment, number of live cells, and functionality were assessed at different time points over a period of 21 days. Improvements in mechanical properties were observed for scaffolds fabricated with narrow-particle-size-distribution powder. The physicochemical analysis showed that the microstructure varied with sintering temperature and that narrow particle size distribution resulted in smaller micropores and a smoother surface. Viable osteoblast- and osteoclast-like cells were observed for all scaffolds tested, but scaffolds produced with a smaller particle size distribution showed less attachment of osteoblast-like cells. Interestingly, low attachment of osteoclast-like cells was observed for all scaffolds regardless of surface roughness. Although bone cell adhesion was lower in scaffolds made with powder containing smaller particle sizes, the long-term function of osteoblast-like and osteoclast-like cells was superior in scaffolds with improved mechanical properties. Full article

Bombyx mori silk fibroin is a promising biopolymer with notable mechanical strength, biocompatibility, and potential for diverse biomedical applications, such as tissue engineering scaffolds, and drug delivery. These properties are intrinsically linked to the structural characteristics of silk fibroin, making it essential to understand its molecular stability under varying environmental conditions. This study employed molecular dynamics simulations to examine the structural stability of silk I and silk II conformations of silk fibroin under changes in temperature (298 K to 378 K) and pressure (0.1 MPa to 700 MPa). Key parameters, including Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and Radius of Gyration (R_g) were analyzed, along with non-bonded interactions such as van der Waals and electrostatic potential energy. Our findings demonstrate that both temperature and pressure exert a destabilizing effect on silk fibroin, with silk I exhibiting a higher susceptibility to destabilization compared to silk II. Additionally, pressure elevated the van der Waals energy in silk I, while temperature led to a reduction. In contrast, electrostatic potential energy remained unaffected by these environmental conditions, highlighting stable long-range interactions throughout the study. Silk II’s tightly packed β-sheet structure offers greater resilience to environmental changes, while the more flexible α-helices in silk I make it more susceptible to structural perturbations. These findings provide valuable insights into the atomic-level behavior of silk fibroin, contributing to a deeper understanding of its potential for applications in environments where mechanical or thermal stress is a factor. The study underscores the importance of computational approaches in exploring protein stability and supports the continued development of silk fibroin for biomedical and engineering applications. Full article

Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare, serious, and pharmacoresistant epileptic disorder often linked to gain-of-function mutations in the KCNT1 gene. KCNT1 encodes the sodium-activated potassium channel known as SLACK, making small molecule inhibitors of SLACK channels a compelling approach to the treatment of EIMFS and other epilepsies associated with KCNT1 mutations. In this manuscript, we describe a hit optimization effort executed within a series of 2-aryloxy-N-(pyrimidin-5-yl)acetamides that were identified via a high-throughput screen. We systematically prepared analogs in four distinct regions of the scaffold and evaluated their functional activity in a whole-cell, automated patch clamp (APC) assay to establish structure-activity relationships for wild-type (WT) SLACK inhibition. Two selected analogs were also profiled for selectivity versus other members of the Slo family of potassium channels, of which SLACK is a member, and versus a panel of structurally diverse ion channels. The same two analogs were evaluated for activity versus the WT mouse channel as well as two clinically relevant mutant human channels. Full article

We have investigated the thermodynamic property modification of ammonia borane via nanoconfinement. Two different mesoporous silica scaffolds, SBA-15 and MCM-41, were used to confine ammonia borane. Using in situ Raman spectroscopy, we examined how pore size influences the phase transition temperature from tetragonal (I4mm) to orthorhombic (Pmn21) for ammonia borane. In bulk ammonia borane, the phase transition occurs at around 217 K; however, confinement in SBA-15 (with ~8 nm pore sizes) reduces this temperature to approximately 195 K, while confinement in MCM-41 (with pore sizes of 2.1–2.7 nm) further lowers it to below 90 K. This suppression of the phase transition as a function of pore size has not been previously studied using Raman spectroscopy. The stability of the I4mm phase at a much lower temperature can be interpreted by incorporating the surface energy terms to the overall free energy of the system in a simple thermodynamic model, which leads to a significant increase in the surface energy when transitioning from the tetragonal phase to the orthorhombic phase. Full article

Ladder oligomers containing calixarene skeletons in the main chain—calix[4]resorcinarene (CRA) ladder macromolecules with open chain and cyclic macromolecules with double ring-like (Noria-type) topologies—bring particular research attention as functional materials with various applications. However, there is still a remarkable lack of studies into the synthesis of fully water-soluble derivatives of these interesting macromolecules. Research on this topic would allow their bio-based research and application niche to be at least revealed. In the present study, a strategy for the synthesis of water-soluble polyglycidol-derivatized calix resorcinarene ladder oligomers with open chain and cyclic structures is introduced. A grafting from approach was used to build branched or linear polyglycidol chains from the ladder scaffolds. The novel structures were synthesized in quantitative yields and fully characterized by NMR, FTIR and UV–vis spectroscopy, gel permeation chromatography, MALDI-TOF mass spectrometry, analytical ultracentrifugation, and static light scattering to obtain the molar mass characteristics and composition. The biocompatibility and toxicity of the two polyglycidol-derivatized oligomers were investigated and the concentration dependence of the survival of three cell lines of human origin determined. The selective apoptosis effect at relatively low dissolve concentrations toward two kinds of cancerous cell lines was found. Full article

The 3D printing of a biomimetic scaffold with a high hydroxyapatite (HA) content (>80%) and excellent mechanical property is a serious challenge because of the difficulty of forming and printing, insufficient cohesion, and low mechanical property of the scaffold. In this study, hydroxyapatite whiskers (HAWs), with their superior mechanical property, biodegradability, and biocompatibility, were used to reinforce spherical HA scaffolds by 3D printing. The compressive strength and energy absorption capacity of HAW-reinforced spherical HA (HAW/HA) scaffolds increased when the HAW/HA ratio increased from 0:10 to 4:6 and then dropped with any further increases in the HAW/HA ratio. Bioceramic content (HAWs and spherical HA) in the scaffolds reached 83%, and the scaffold with a HAW/HA ratio of 4:6 (4-HAW/HA) exhibited an optimum compressive strength and energy absorption capacity. The scaffold using polyvinyl alcohol (PVA) as an additive possessed a good bonding between HA and PVA as well as a higher strength, which allowed the scaffold to bear a higher stress at the same strain. The compressive strength and toughness of the 4-HAW/HA-PVA scaffold were 1.96 and 1.63 times that of the 4-HAW/HA scaffold with hydroxypropyl methyl cellulose (HPMC), respectively. The mechanical property and inorganic components of the biomimetic HAW/HA scaffold were similar to those of human bone, which would make it ideal for repairing bone defects. Full article

Leishmaniasis, a protozoan disease affecting humans, exposes significant shortcomings in current treatments. In continuation to our previous findings on amidoxime-based antileishmanial compounds bearing a 4,5-dihydrofuran scaffold, twelve new amidoxime derivatives substituted at position 3 with an amide bearing a nitrogen heterocycle were synthesized. This series was designed to replace the sulfone and aryl group on a previously reported HIT. The synthesis of these compounds involved the following three-step pathway: manganese (III) acetate-based cyclization of a β-ketoester, followed by amidation with LiHMDS and a final reaction with hydroxylamine. Three of them, containing either bromine, chlorine, or methyl substitutions and featuring a pyridine moiety, showed an interesting toxicity–activity relationship in vitro. They exhibited IC₅₀ values of 15.0 µM, 16.0 µM, and 17.0 µM against the promastigote form of the parasite and IC₅₀ values of 0.5 µM, 0.6 µM, and 0.3 µM against the intracellular amastigote form, respectively. A selectivity index (SI) greater than 300 was established between the cytotoxic concentrations (in murine macrophages) and the effective concentrations (against the intracellular form of Leishmania amazonensis). This SI is at least seventy times higher than that observed for Pentamidine and twenty-five times higher than that observed for the reference HIT, as previously reported. Full article

Obtaining new materials by exploiting the self-assembly of biomolecules is a very challenging field. In recent years, short peptides and nucleic acids have been used as scaffolds to produce supramolecular structures for different applications in the biomedical and technological fields. In this review, we will focus on the self-assembly of peptide nucleic acids (PNAs), their conjugates with peptides, or other molecules. We will describe the physical properties of the assembled systems and, where described, the application they were designed for. Full article

Producing a tissue-engineered pancreas based on a tissue-specific scaffold from a decellularized pancreas, imitating the natural pancreatic tissue microenvironment and the islets of Langerhans, is one of the approaches to treating patients with type 1 diabetes mellitus (T1DM). The aim of this work was to investigate the ability of a fine-dispersed tissue-specific scaffold (DP scaffold) from decellularized human pancreas fragments to support the islets’ survival and insulin-producing function when injected in a streptozotocin-induced diabetic rat model. The developed decellularization protocol allows us to obtain a scaffold with a low DNA content (33 [26; 38] ng/mg of tissue, p < 0.05) and with the preservation of GAGs (0.92 [0.84; 1.16] µg/mg, p < 0.05) and fibrillar collagen (273.7 [241.2; 303.0] µg/mg, p < 0.05). Rat islets of Langerhans were seeded in the obtained scaffolds. The rats with stable T1DM were treated by intraperitoneal injections of rat islets alone and islets seeded on the DP scaffold. The blood glucose level was determined for 10 weeks with a histological examination of experimental animals’ pancreas. A more pronounced decrease in the recipient rats’ glycemia was detected after comparing the islets seeded on the DP scaffold with the control injection (by 71.4% and 51.2%, respectively). It has been shown that the DP scaffold facilitates a longer survival and the efficient function of pancreatic islets in vivo and can be used to engineer a pancreas. Full article

Autologous chondrocyte implantation (ACI) and matrix-induced ACI (MACI) have demonstrated improved clinical outcomes and reduced revision rates for treating osteochondral and chondral defects. However, their ability to achieve lasting, fully functional repair remains limited. To overcome these challenges, scaffold-enhanced ACI, particularly utilizing hydrogel-based biomaterials, has emerged as an innovative strategy. These biomaterials are intended to mimic the biological composition, structural organization, and biomechanical properties of native articular cartilage. This review aims to provide comprehensive and up-to-date information on advancements in hydrogel-enhanced ACI from the past decade. We begin with a brief introduction to cartilage biology, mechanisms of cartilage injury, and the evolution of surgical techniques, particularly looking at ACI. Subsequently, we review the diversity of hydrogel scaffolds currently undergoing development and evaluation in preclinical studies for articular cartilage regeneration, emphasizing chondrocyte-laden hydrogels applicable to ACI. Finally, we address the key challenges impeding effective clinical translation, with particular attention to issues surrounding fixation and integration, aiming to inform and guide the future progression of tissue engineering strategies. Full article