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Collagen is the main protein found in skin, bone, cartilage, ligaments, tendons and connective tissue, and it can exhibit properties ranging from compliant to rigid or form gradients between these states. The collagen family comprises 28 members, each containing at least one triple-helical domain. These proteins play critical roles in maintaining mechanical characteristics, tissue organization, and structural integrity. Collagens regulate cellular processes such as proliferation, migration, and differentiation through interactions with cell surface receptors. Fibrillar collagens, the most abundant extracellular matrix (ECM) proteins, provide organs and tissues with structural stability and connectivity. In the mammalian myocardial interstitium, types I and III collagens are predominant: collagen I is found in organs, tendons, and bones; collagen II is found in cartilage; collagen III is found in reticular fibers; collagen IV is found in basement membranes; and collagen V is found in nails and hair. Recombinant human collagens, particularly in sponge-like porous formats combined with bone morphogenetic proteins, serve as effective scaffolds for bone repair. Due to their biocompatibility and low immunogenicity, collagens are pivotal in tissue engineering applications for skin, bone, and wound regeneration. Recombinant technology enables the production of triple-helical collagens with amino acid sequences identical to human tissue-derived collagens. This review summarizes recent advances in the molecular functions and recombinant expression of human collagens, with a focus on their biomedical applications.

In the present research, the enzyme-facilitated collagen from sea eel (Muraenesox cinereus) swim bladder was isolated, and the collagen characteristics were analyzed. Then, the collagen sponge was prepared and its potential mechanism in promoting skin wound healing in mice was further investigated. Collagen was obtained from the swim bladder of sea eels employing the pepsin extraction technique. Single-factor experiments served as the basis for the response surface method (RSM) to optimize pepsin concentration, solid-liquid ratio, and hydrolysis period. With a pepsin concentration of 2067 U/g, a solid-liquid ratio of 1:83 g/mL, and a hydrolysis period of 10 h, collagen extraction achieved a yield of 93.76%. The physicochemical analysis revealed that the extracted collagen belonged to type I collagen, and the collagen sponge displayed a fibrous structure under electron microscopy. Furthermore, in comparison to the control group, mice treated with collagen sponge dressing exhibited elevated activities of superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (T-AOC), and glutathione peroxidase (GSH-Px), and decreased levels of malondialdehyde (MDA), interleukin (IL)-1β, interleukin (IL)-6, and tumor necrosis factor (TNF)-α. The collagen sponge dressing effectively alleviated inflammation in the wound area, facilitating efficient repair and rapid healing of the skin tissue. During the initial phase of wound healing, the group treated with collagen sponge dressing exhibited an enhancement in the expressions of cluster of differentiation (CD)31, epidermal growth factor (EGF), transforming growth factor (TGF)-β1, and type I collagen, leading to an accelerated rate of wound healing. In addition, this collagen sponge dressing could also downregulate the expressions of CD31, EGF, and type I collagen to prevent scar formation in the later stage. Moreover, this collagen treatment minimized oxidative damage and inflammation during skin wound healing and facilitated blood vessel formation in the wound. Consequently, it exhibits significant potential as an ideal material for the development of a skin wound dressing.

Scanning small‐angle X‐ray scattering (sSAXS) has found multiple applications as a technique to probe the nanostructure in soft tissues and pathologies thereof. However, fresh tissue is fragile and prone to the quick onset of decomposition and autolysis. It lacks the firmness required for uniform and thin sectioning, resulting in the loss of 2D resolution offered by focused X‐ray beams, because the signal would be integrated through thick and/or irregular sections. Tissue processing, that includes fixation and embedding, is used to mitigate these issues but can by itself introduce structural changes in the tissues and impede the correct interpretation of sSAXS data. Here the extent of these structural changes in the SAXS signal caused by common tissue preservation methods on the example of skeletal muscle tissue, consisting of both muscle and surrounding connective tissue, was studied. This can guide an informed choice of preservation method tailored for specific experimental requirements. While some techniques performed better than others, all tissue‐processing methods induced structural changes to a certain degree. The choice of preservation method is therefore a balance between sectioning requirements and type of tissue used, as well as targeted structural information. The effect of tissue‐processing techniques, including fixation and embedding, on the structural information obtained from scanning small‐angle X‐ray scattering of muscle and connective tissue has been studied. This provides a framework for sSAXS users working with soft tissues to make an informed choice on the sample preservation method, tailored to their own requirements.

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy, mainly due to its resistance to chemotherapy and its complex tumour microenvironment characterised by stromal desmoplasia. There is a need for new strategies to improve the delivery of drugs and therapeutic response. Relevant preclinical tumour models are needed to test potential treatments. This paper compared orthotopic and subcutaneous PDAC tumour models and their suitability for drug delivery studies. A novel aspect was the broad range of tumour properties that were studied, including tumour growth, histopathology, functional vasculature, perfusion, immune cell infiltration, biomechanical characteristics, and especially the extensive analysis of the structure and the orientation of the collagen fibres in the two tumour models. The study unveiled new insights into how these factors impact the uptake of a fluorescent model drug, the macromolecule called 800CW. While the orthotopic model offered a more clinically relevant microenvironment, the subcutaneous model offered advantages for drug delivery studies, primarily due to its reproducibility, and it was characterised by a more efficient drug uptake facilitated by its collagen organisation and well-perfused vasculature. The tumour uptake seemed to be influenced mainly by the structural organisation and the alignment of the collagen fibres and perfusion. Recognising the diverse characteristics of these models and their multifaceted impacts on drug delivery is crucial for designing clinically relevant experiments and improving our understanding of pancreatic cancer biology.

Heart valves (HVs) are cardiac structures whose physiological function is to ensure directed blood flow through the heart over the cardiac cycle. While primarily passive structures that are driven by forces exerted by the surrounding blood and heart, this description does not adequately describe their elegant and complex biomechanical function. Moreover, they must replicate their cyclic function over an entire lifetime, with an estimated total functional demand of least 3×109 cycles. As in many physiological systems, one can approach HV biomechanics from a multi-length-scale approach, since mechanical stimuli occur and have biological impact at the organ, tissue and cellular scales. The present review focuses on the functional biomechanics of HVs. Specifically, we refer to the unique aspects of valvular function, and how the mechanical and mechanobiological behaviours of the constituent biological materials (e.g. extracellular matrix proteins and cells) achieve this remarkable feat. While we focus on the work from the authors' respective laboratories, the works of most investigators known to the authors have been included whenever appropriate. We conclude with a summary and underscore important future trends.

The aim of the research was to check whether it is possible to use fragments of type IV collagen to obtain, as a result of self-assembling, stable spatial structures that could be used to prepare new materials useful in regenerative medicine. Collagen IV fragments were obtained by using DMT/NMM/TosO− as a coupling reagent. The ability to self-organize and form stable spatial structures was tested by the CD method and microscopic techniques. Biological studies covered: resazurin assay (cytotoxicity assessment) on BJ, BJ-5TA and C2C12 cell lines; an alkaline version of the comet assay (genotoxicity), Biolegend Legendplex human inflammation panel 1 assay (SC cell lines, assessment of the inflammation activity) and MTT test to determine the cytotoxicity of the porous materials based on collagen IV fragments. It was found that out of the pool of 37 fragments (peptides 1–33 and 2.1–2.4) reconstructing the outer sphere of collagen IV, nine fragments (peptides: 2, 4, 5, 6, 14, 15, 25, 26 and 30), as a result of self-assembling, form structures mimicking the structure of the triple helix of native collagens. The stability of spatial structures formed as a result of self-organization at temperatures of 4 °C, 20 °C, and 40 °C was found. The application of the MST method allowed us to determine the Kd of binding of selected fragments of collagen IV to ITGα1β1. The stability of the spatial structures of selected peptides made it possible to obtain porous materials based on their equimolar mixture. The formation of the porous materials was found for cross-linked structures and the material stabilized only by weak interactions. All tested peptides are non-cytotoxic against all tested cell lines. Selected peptides also showed no genotoxicity and no induction of immune system responses. Research on the use of porous materials based on fragments of type IV collagen, able to form stable spatial structures as scaffolds useful in regenerative medicine, will be continued.

The human ureters have not been thoroughly explored from the biomechanics perspective, despite the wealth of such data for other soft-tissue types. This study was motivated by the need to use relevant biomechanical data from human ureters and microstructure-based material formulations for simulations of ureteral peristalsis and stenting. Our starting choice was the four-fiber family model that has proven its validity as a descriptor of the multiaxial response of cardiovascular tissues. The degree of model complexity, required for rigorous fits to passive quasi-static pressure-diameter-force data at several axial stretches, was systematically investigated. Ureteral segments from sixteen human autopsy subjects were evaluated. A diagonal and axial family model allowed equally-good fits as the full model for all age groups and ureteral regions; considerably better than those allowed by the phenomenological Fung-type model whose root-mean-square error of fitting was three-fold greater. This reduced model mimicked the structure seen in histologic sections, namely plentiful diagonal collagen fibers in the lamina propria and axial fibers in the muscle and adventitia. The paucity of elastin fibers and mixed muscle orientation justified the use of isotropic muscle-dominated matrix with small neo-Hookean parameter values. The significantly thicker lamina propria in the lower than the upper ureter of young subjects (312 ± 27 vs. 232 ± 26 μm; mean ± standard error) corroborated the significant regional differences in diagonal-fiber family parameter values. The significant muscle thickening with age (upper ureter: 373 ± 48 vs. 527 ± 67 μm; middle: 388 ± 29 vs. 575 ± 69 μm; lower: 440 ± 21 vs. 602 ± 71 μm) corroborated the significant age-related increase in axial-fiber family parameter values.

This article presents, for the first time, the results of applying the rheological technique to measure the molecular weights (Mw) and their distributions (MwD) of highly hierarchical biomolecules, such as non-hydrolyzed collagen gels. Due to the high viscosity of the studied gels, the effect of the concentrations on the rheological tests was investigated. In addition, because these materials are highly sensitive to denaturation and degradation under mechanical stress and temperatures close to 40 °C, when frequency sweeps were applied, a mathematical adjustment of the data by machine learning techniques (artificial intelligence tools) was designed and implemented. Using the proposed method, collagen fibers of Mw close to 600 kDa were identified. To validate the proposed method, lower Mw species were obtained and characterized by both the proposed rheological method and traditional measurement techniques, such as chromatography and electrophoresis. The results of the tests confirmed the validity of the proposed method. It is a simple technique for obtaining more microstructural information on these biomolecules and, in turn, facilitating the design of new structural biomaterials with greater added value.

Basal cell carcinoma (BCC) is the most frequent malignant neoplasm in the Caucasian population. There are several therapeutic options for BCC, but surgical excision is considered gold standard treatment. As BCCs often have poorly defined borders, the clinical assessment of the tumor margins can be challenging. Therefore, there is an increasing demand for efficient in vivo imaging techniques for the evaluation of tumor borders prior to and during surgeries. In the near future, nonlinear microscopy techniques might meet this demand. We measured the two-photon excitation fluorescence (TPEF) signal of nicotinamide adenine dinucleotide hydride (NADH) and elastin and second harmonic generation (SHG) signal of collagen on 10 ex vivo healthy control and BCC skin samples and compared the images by different quantitative image analysis methods. These included integrated optical density (IOD) measurements on TPEF and SHG images and application of fast Fourier transform (FFT), CT-FIRE and CurveAlign algorithms on SHG images to evaluate the collagen structure. In the BCC samples, we found significantly lower IOD of both the TPEF and SHG signals and higher collagen orientation index utilizing FFT. CT-FIRE algorithm revealed increased collagen fiber length and decreased fiber angle while CurveAlign detected higher fiber alignment of collagen fibers in BCC. These results are in line with previous findings which describe pronounced changes in the collagen structure of BCC. In the future, these novel image analysis methods could be integrated in handheld nonlinear microscope systems, for sensitive and specific identification of BCC.

Collagens are among proteins that undergo several post-translational modifications, such as prolyl hydroxylation, that occur during elongation of the nascent chains in the endoplasmic reticulum. The major structural collagens, types I, II and III, have large, uninterrupted triple helices, comprising three polyproline II-like chains supercoiled around a common axis. The structure has a requirement for glycine, as every third residue, and is stabilized by the high content of proline and 4-hydroxyproline residues. Action of prolyl hydroxylases is critical. Spontaneous or targeted genetic defects in prolyl hydroxylases can be lethal or result in severe osteogenesis imperfecta. Prolines, as determinants of substrate specificity and susceptibility, also play a role in degradation of collagen by collagenolytic matrix metalloproteinases (MMPs). Targeted mutations in mice in the collagenase cleavage domain have profound effects on collagen turnover and the function of connective tissues. Prolines are thus critical determinants of collagen structure and function.