Tissue Functional Properties Research Articles

Diverse and multifunctional roles for perlecan (HSPG2) in repair of the intervertebral disc.

Perlecan is a widely distributed, modular, and multifunctional heparan sulfate proteoglycan, which facilitates cellular communication with the extracellular environment to promote tissue development, tissue homeostasis, and optimization of biomechanical tissue functions. Perlecan-mediated osmotic mechanotransduction serves to regulate the metabolic activity of cells in tissues subjected to tension, compression, or shear. Perlecan interacts with a vast array of extracellular matrix (ECM) proteins through which it stabilizes tissues and regulates the proliferation or differentiation of resident cell populations. Here we examine the roles of the HS-proteoglycan perlecan in the normal and destabilized intervertebral disc. The intervertebral disc cell has evolved to survive in a hostile weight bearing, acidic, low oxygen tension, and low nutrition environment, and perlecan provides cytoprotection, shields disc cells from excessive compressive forces, and sequesters a range of growth factors in the disc cell environment where they aid in cellular survival, proliferation, and differentiation. The cells in mechanically destabilized connective tissues attempt to re-establish optimal tissue composition and tissue functional properties by changing the properties of their ECM, in the process of chondroid metaplasia. We explore the possibility that perlecan assists in these cell-mediated tissue remodeling responses by regulating disc cell anabolism. Perlecan's mechano-osmotic transductive property may be of potential therapeutic application.

Diffusion tensor imaging identifies atrial regional changes associated with atrial fibrillation remodelling

Abstract Background Structural remodeling in the context of persistent atrial fibrillation (PAF) has been mainly characterized by imaging techniques focused on fibrosis detection. Diffusion tensor imaging (DTI) has demonstrated its direct relationship with histological properties and myocyte organization, which may provide a more complete structural information. However, the potential of DTI in the characterization of the AF-related structural substrate remains unknown. Purposes To evaluate the performance of DTI-derived parameters to characterise the structural remodelling derived from persistent AF and its relationship with specific atrial regions associated with AF maintenance (i.e., driver regions). Methods Two experimental groups of pigs were studied: control (n=7) and PAF (n=10). The PAF swine model was developed using rapid atrial pacing until the animals reached a stage of self-sustained PAF. The AV node was ablated to prevent heart failure due to fast ventricular activation rates. A second lead in the right ventricular was used for ventricular pacing at 60-110 bpm. Animals with PAF were studied after ≥ 6 months in self-sustained persistent AF. AF animals underwent invasive electroanatomical to identify driver regions based on instantaneous frequency modulation maps. After euthanasia, explanted hearts from AF animals and controls underwent DTI including 15 diffusion weighted images with a b-value of 600 s/mm² plus a non-DWI volume (isotropic resolution, 0.6 mm³). DTI images were segmented and divided into 13 atrial anatomical regions. Driver regions in AF animals were also segmented and classified as functional regions of interest (ROIs) (Figure 2B). Afterwards, diffusion tensors were estimated and scalar features were analyzed (Figures 1A and 2A) according to both anatomical and functional ROIs. Results DTI analysis in AF animals revealed region-specific structural remodelling (Figure 1B). Compared to controls, PAF animals showed an increased fractional anisotropy (FA) in both right and left atrial free walls (Figure 1C). Other anatomical regions, such as the superior vena cava (SVC), the coronary sinus (CS) or the left atrium roof developed higher axial diffusivities in AF compared to controls (Figure 1D), without significant alterations in FA (Figure 1C). AF driver regions were frequently located in the CS, the SVC and the LAA (Figure 2C). AF driver ROIs into the CS and the SVC showed intracase increased diffusivities and decreased linear indexes compared to non-driver regions. However, AF driver ROIs in the LAA showed increased intervoxel main eigenvector dispersion in contrast to non-driver ROIs (Figure 2C). Conclusion DTI sequences provide atrial structural information associated with functional tissue properties relevant for AF maintenance.

Constructing epidermal rete ridges using a composite hydrogel to enhance multiple signaling pathways for the maintenance of epidermal stem cell niche.

The undulating microstructure rete ridge (RR) located at the junction between the dermis and epidermis plays a crucial role in improving skin mechanical properties and maintaining skin homeostasis. However, the investigation of RR microstructures is usually neglected in current tissue engineering for skin regeneration. Here, to create an epidermal model with RR microstructures, keratinocytes were cultured on a patterned GelMA-PEGDA hydrogel constructed using molding technology. Furthermore, grafting acryloylated Arg-Gly-Asp (RGD) peptides on the hydrogel surface significantly improved cell adhesion, fusion, and development. RT-PCR, Western blot, and immunofluorescence staining confirmed that cells on RR microstructures exhibited higher gene and protein expression associated with epidermal stem cells. RNA sequencing analysis of cells on RR microstructure showed higher gene expression profiles related to stem cell maintenance, basement membrane formation, and epidermal development. Furthermore, RT-PCR analysis of epidermal models of various dimensions demonstrated that smaller microstructures were more conducive to epidermal stem cell marker gene expression, which is analogous to human skin. Overall, we have successfully developed a method for integrating RR microstructures into an epidermal model that mimics natural skin to maintain epidermal stem cell niche, providing a valuable reference for researching skin regeneration within the fields of tissue engineering and regenerative medicine. STATEMENT OF SIGNIFICANCE: This study presents a method for precisely fabricating microstructures of skin rete ridges using composite hydrogels, thereby creating a skin model that mimics natural human skin. The findings reveal that this microstructure provides a stem cell niche that regulates the pathways and promotes the expression of proteins related to epidermal stem cells. This work advances the functional properties of tissue engineered skin and holds promise for improving the therapeutic efficacy of artificial skin grafts for the skin wounds.

The Glycosaminoglycan Side Chains and Modular Core Proteins of Heparan Sulphate Proteoglycans and the Varied Ways They Provide Tissue Protection by Regulating Physiological Processes and Cellular Behaviour.

This review examines the roles of HS-proteoglycans (HS-PGs) in general, and, in particular, perlecan and syndecan as representative examples and their interactive ligands, which regulate physiological processes and cellular behavior in health and disease. HS-PGs are essential for the functional properties of tissues both in development and in the extracellular matrix (ECM) remodeling that occurs in response to trauma or disease. HS-PGs interact with a biodiverse range of chemokines, chemokine receptors, protease inhibitors, and growth factors in immune regulation, inflammation, ECM stabilization, and tissue protection. Some cell regulatory proteoglycan receptors are dually modified hybrid HS/CS proteoglycans (betaglycan, CD47). Neurexins provide synaptic stabilization, plasticity, and specificity of interaction, promoting neurotransduction, neurogenesis, and differentiation. Ternary complexes of glypican-1 and Robbo-Slit neuroregulatory proteins direct axonogenesis and neural network formation. Specific neurexin-neuroligin complexes stabilize synaptic interactions and neural activity. Disruption in these interactions leads to neurological deficits in disorders of functional cognitive decline. Interactions with HS-PGs also promote or inhibit tumor development. Thus, HS-PGs have complex and diverse regulatory roles in the physiological processes that regulate cellular behavior and the functional properties of normal and pathological tissues. Specialized HS-PGs, such as the neurexins, pikachurin, and Eyes-shut, provide synaptic stabilization and specificity of neural transduction and also stabilize the axenome primary cilium of phototoreceptors and ribbon synapse interactions with bipolar neurons of retinal neural networks, which are essential in ocular vision. Pikachurin and Eyes-Shut interactions with an α-dystroglycan stabilize the photoreceptor synapse. Novel regulatory roles for HS-PGs controlling cell behavior and tissue function are expected to continue to be uncovered in this fascinating class of proteoglycan.

Extracellular matrix biomechanical roles and adaptation in health and disease.

Extracellular matrices (ECMs) are dynamic 3D macromolecular networks that exhibit structural characteristics and composition specific to different tissues, serving various biomechanical and regulatory functions. The interactions between ECM macromolecules such as collagen, elastin, glycosaminoglycans (GAGs), proteoglycans (PGs), fibronectin, and laminin, along with matrix effectors and water, contribute to the unique cellular and tissue functional properties during organ development, tissue homoeostasis, remodeling, disease development, and progression. Cells adapt to environmental changes by adjusting the composition and array of ECM components. ECMs, forming the 3D bioscaffolds of our body, provide mechanical support for tissues and organs and respond to the environmental variables influencing growth and final adult body shape in mammals. Different cell types displaydistinct adaptations to the respective ECM environments. ECMs regulate biological processes by controlling the diffusion of infections and inflammations, sensing and adapting to external stimuli and gravity from the surrounding habitat, and, in the context of cancer, interplaying with and regulating cancer cell invasion and drug resistance. Alterations in the ECM composition in pathological conditions drive adaptive responses of cells and could therefore result in abnormal cell behavior and tissue dysfunction. Understanding the biomechanical functionality, adaptation, and roles of distinct ECMs is essential for research on various pathologies, including cancer progression and multidrug resistance, which is of crucial importance for developing targeted therapies. In this Viewpoint article, we critically present and discuss specific biomechanical functions of ECMs and regulatory adaptation mechanisms in both health and disease, with a particular focus on cancer progression.

High-density Approaches to Ventricular Tachycardia Substrate Ablation

Ventricular tachycardia (VT) ablation is a challenging procedure with significant clinical benefit for patients. The classic VT ablation approach centers on arrhythmia induction and entrainment of tachycardia to identify the critical components of a VT circuit. In the post-coronary reperfusion era, smaller infarct size and subsequently faster VT cycle lengths have led to an increased occurrence of unstable, unmappable VT cases, making the classic approach untenable. While approaches of signal-based substrate modification have shown clinical efficacy in the past, these approaches are sometimes imprecise and require extensive ablation. With the advancement of high-density (HD) mapping technology and recognition of functional tissue properties requisite for VT initiation and propagation, a more finely targeted VT ablation approach may be pursued. Benefits of HD mapping include better tissue and signal characterization, avoidance of ‘perpendicular blinding’ and better identification of VT putative channels. Functional characterization of tissue, such as isochronal late activation mapping or decremental evoked potential mapping, allow for the identification of functional slowing required for VT reentry. Pre-ablative imaging continues to play an increasing role in substrate characterization and pre-operative planning. Using a comprehensive, tailored, substrate-based functional HD VT ablation strategy can allow for safe and effective ablation of even unstable and unmappable VT.

The future of MRI in radiation therapy: Challenges and opportunities for the MR community.

Radiation therapy is a major component of cancer treatment pathways worldwide. The main aim of this treatment is to achieve tumor control through the delivery of ionizing radiation while preserving healthy tissues for minimal radiation toxicity. Because radiation therapy relies on accurate localization of the target and surrounding tissues, imaging plays a crucial role throughout the treatment chain. In the treatment planning phase, radiological images are essential for defining target volumes and organs-at-risk, as well as providing elemental composition (e.g., electron density) information for radiation dose calculations. At treatment, onboard imaging informs patient setup and could be used to guide radiation dose placement for sites affected by motion. Imaging is also an important tool for treatment response assessment and treatment plan adaptation. MRI, with its excellent soft tissue contrast and capacity to probe functional tissue properties, holds great untapped potential for transforming treatment paradigms in radiation therapy. The MR in Radiation Therapy ISMRM Study Group was established to provide a forum within the MR community to discuss the unmet needs and fuel opportunities for further advancement of MRI for radiation therapy applications. During the summer of 2021, the study group organized its first virtual workshop, attended by a diverse international group of clinicians, scientists, and clinical physicists, to explore our predictions for the future of MRI in radiation therapy for the next 25 years. This article reviews the main findings from the event and considers the opportunities and challenges of reaching our vision for the future in this expanding field.

Photoacoustic image synthesis with generative adversarial networks

Photoacoustic tomography (PAT) has the potential to recover morphological and functional tissue properties with high spatial resolution. However, previous attempts to solve the optical inverse problem with supervised machine learning were hampered by the absence of labeled reference data. While this bottleneck has been tackled by simulating training data, the domain gap between real and simulated images remains an unsolved challenge. We propose a novel approach to PAT image synthesis that involves subdividing the challenge of generating plausible simulations into two disjoint problems: (1) Probabilistic generation of realistic tissue morphology, and (2) pixel-wise assignment of corresponding optical and acoustic properties. The former is achieved with Generative Adversarial Networks (GANs) trained on semantically annotated medical imaging data. According to a validation study on a downstream task our approach yields more realistic synthetic images than the traditional model-based approach and could therefore become a fundamental step for deep learning-based quantitative PAT (qPAT).

Radioactive Imagine Agents: 99mTc-Toxicological Study

Radioactive pharmaceutical materials (radiopharmaceuticals) that contain radioactive atom or/ and ion (emits nuclear (α, β, or / and γ) ray according to its energy and half-life duration) companied with organic or inorganic molecule are important materials in nuclear imaging or therapeutically medicine. Many biomolecules labeled with Technetium-99 in relationship to toxicity issues can be transported, distributed, and detected with the computerized algorithm detector depending upon chemical, biological, metabolic, and functional properties of tissue or organ (bone, liver, heart, kidney, and others). According to literatures' review about this subject, this is the first try in Iraq and other countries to study Technetium – radiomolecules with in Silico depending on two approachs. LD50, Class, Polar Surface Area PSA, logP, Hepatotoxicity, Carcinogenity, Immunotoxicity, Mutagenicity, Cytotoxicity, AMES test, Max. tolerated dose (human), hERG I and II inhibitor, Oral Rat Acute (LD50) and Chronic (LOAEL) Toxicity, Hepatotoxicity besides Skin Sensitisation showed that Tc-biomolecules under study are structurally unsafe having toxic response to liver, immune system, cellular components, DNA, and/or cardiac repolarization through hERG inhibition of action. These mainly conclusion notes depended upon Technetium oxidation state, heteroatoms presence, surface properties besides bio-target specifications, concentration, exposure time, genetic factors of human, and health problems.

SIMPA: an open-source toolkit for simulation and image processing for photonics and acoustics.

.SignificanceOptical and acoustic imaging techniques enable noninvasive visualisation of structural and functional properties of tissue. The quantification of measurements, however, remains challenging due to the inverse problems that must be solved. Emerging data-driven approaches are promising, but they rely heavily on the presence of high-quality simulations across a range of wavelengths due to the lack of ground truth knowledge of tissue acoustical and optical properties in realistic settings.AimTo facilitate this process, we present the open-source simulation and image processing for photonics and acoustics (SIMPA) Python toolkit. SIMPA is being developed according to modern software design standards.ApproachSIMPA enables the use of computational forward models, data processing algorithms, and digital device twins to simulate realistic images within a single pipeline. SIMPA’s module implementations can be seamlessly exchanged as SIMPA abstracts from the concrete implementation of each forward model and builds the simulation pipeline in a modular fashion. Furthermore, SIMPA provides comprehensive libraries of biological structures, such as vessels, as well as optical and acoustic properties and other functionalities for the generation of realistic tissue models.ResultsTo showcase the capabilities of SIMPA, we show examples in the context of photoacoustic imaging: the diversity of creatable tissue models, the customisability of a simulation pipeline, and the degree of realism of the simulations.ConclusionsSIMPA is an open-source toolkit that can be used to simulate optical and acoustic imaging modalities. The code is available at: https://github.com/IMSY-DKFZ/simpa, and all of the examples and experiments in this paper can be reproduced using the code available at: https://github.com/IMSY-DKFZ/simpa_paper_experiments.

Tattoo tomography: Freehand 3D photoacoustic image reconstruction with an optical pattern

PurposePhotoacoustic tomography (PAT) is a novel imaging technique that can spatially resolve both morphological and functional tissue properties, such as vessel topology and tissue oxygenation. While this capacity makes PAT a promising modality for the diagnosis, treatment, and follow-up of various diseases, a current drawback is the limited field of view provided by the conventionally applied 2D probes.MethodsIn this paper, we present a novel approach to 3D reconstruction of PAT data (Tattoo tomography) that does not require an external tracking system and can smoothly be integrated into clinical workflows. It is based on an optical pattern placed on the region of interest prior to image acquisition. This pattern is designed in a way that a single tomographic image of it enables the recovery of the probe pose relative to the coordinate system of the pattern, which serves as a global coordinate system for image compounding.ResultsTo investigate the feasibility of Tattoo tomography, we assessed the quality of 3D image reconstruction with experimental phantom data and in vivo forearm data. The results obtained with our prototype indicate that the Tattoo method enables the accurate and precise 3D reconstruction of PAT data and may be better suited for this task than the baseline method using optical tracking.ConclusionsIn contrast to previous approaches to 3D ultrasound (US) or PAT reconstruction, the Tattoo approach neither requires complex external hardware nor training data acquired for a specific application. It could thus become a valuable tool for clinical freehand PAT.

Learned spectral decoloring enables photoacoustic oximetry

The ability of photoacoustic imaging to measure functional tissue properties, such as blood oxygenation sO_2, enables a wide variety of possible applications. sO_2 can be computed from the ratio of oxyhemoglobin HbO_2 and deoxyhemoglobin Hb, which can be distuinguished by multispectral photoacoustic imaging due to their distinct wavelength-dependent absorption. However, current methods for estimating sO_2 yield inaccurate results in realistic settings, due to the unknown and wavelength-dependent influence of the light fluence on the signal. In this work, we propose learned spectral decoloring to enable blood oxygenation measurements to be inferred from multispectral photoacoustic imaging. The method computes sO_2 pixel-wise, directly from initial pressure spectra S_{text {p}_0}(lambda , mathbf {x}), which represent initial pressure values at a fixed spatial location mathbf {x} over all recorded wavelengths lambda. The method is compared to linear unmixing approaches, as well as pO_2 and blood gas analysis reference measurements. Experimental results suggest that the proposed method is able to obtain sO_2 estimates from multispectral photoacoustic measurements in silico, in vitro, and in vivo.

Current Applications of Ultrasound in Fruit and Vegetables Osmotic Dehydration Processes

Ultrasound (US) is a promising technology, which can be used to improve the efficacy of the processes in food technology and the quality of final product. US technique is used, e.g., to support mass and heat transfer processes, such as osmotic dehydration, drying and freezing, as well as extraction, crystallization, emulsification, filtration, etc. Osmotic dehydration (OD) is a well-known process applied in food processing; however, improvements are required due to the long duration of the process. Therefore, many recent studies focus on the development of OD combined with sonication as a pretreatment method and support during the OD process. The article describes the mechanism of the OD process as well as those of US and changes in microstructure caused by sonication. Furthermore, it focuses on current applications of US in fruits and vegetables OD processes, comparison of ultrasound-assisted osmotic dehydration to sonication treatment and synergic effect of US and other innovative technics/treatments in OD (such as innovative osmotic solutions, blanching, pulsed electric field, reduced pressure and edible coatings). Additionally, the physical and functional properties of tissue subjected to ultrasound pretreatment before OD as well as ultrasound-assisted osmotic dehydration are described.

Simultaneous scattering-absorption dual-modal cell imaging in a single shot by a transmission-mode photoacoustic microscope

A microscopy scheme is proposed to simultaneously achieve optical scattering-absorption dual-contrast imaging of a transparent or semi-transparent specimen. This scheme is based on a transmission-mode photoacoustic microscope. We find that two peaks exist in the detected photoacoustic signal. One peak is caused by the optical absorption of the specimen, and the other is related to both the optical scattering and absorption of the specimen. Therefore, both the absorption and scattering information can be simultaneously extracted by analyzing the same photoacoustic signal excited by a single-shot laser pulse. After the microscope is validated by imaging a binary mixture consisting of particles with different optical properties, it successfully acquires dual images of red blood cells with different contrasts. Quantitative analysis reveals that the optical absorption and scattering properties of the specimen can be derived from the two images. The proposed dual-modal imaging method would be useful in revealing the structural and functional properties of tissues at the cell level or the clinical assessment of pathological sections.

Light source calibration for multispectral imaging in surgery

PurposeLive intra-operative functional imaging has multiple potential clinical applications, such as localization of ischemia, assessment of organ transplantation success and perfusion monitoring. Recent research has shown that live monitoring of functional tissue properties, such as tissue oxygenation and blood volume fraction, is possible using multispectral imaging in laparoscopic surgery. While the illuminant spectrum is typically kept constant in laparoscopic surgery and can thus be estimated from preoperative calibration images, a key challenge in open surgery originates from the dynamic changes of lighting conditions.MethodsThe present paper addresses this challenge with a novel approach to light source calibration based on specular highlight analysis. It involves the acquisition of low-exposure time images serving as a basis for recovering the illuminant spectrum from pixels that contain a dominant specular reflectance component.ResultsComprehensive in silico and in vivo experiments with a range of different light sources demonstrate that our approach enables an accurate and robust recovery of the illuminant spectrum in the field of view of the camera, which results in reduced errors with respect to the estimation of functional tissue properties. Our approach further outperforms state-of-the-art methods proposed in the field of computer vision.ConclusionOur results suggest that low-exposure multispectral images are well suited for light source calibration via specular highlight analysis. This work thus provides an important first step toward live functional imaging in open surgery.

Functional MRI Mapping of Human Meniscus Functionality and its Relation to Degeneration

Meniscus pathology may promote early osteoarthritis. This study assessed human meniscus functionality (i.e. its response to loading) ex vivo based on quantitative T1, T1ρ, and T2 mapping as a function of histological degeneration and loading. Forty-five meniscus samples of variable degeneration were harvested from the lateral meniscus body region of 45 patients during total knee arthroplasties. Samples underwent serial mapping on a 3.0-T MRI scanner (Achieva, Philips) using a force-controlled and torque-inducing compressive loading device. Samples were measured at three loading positions, i.e. unloaded, loaded to 2 bar (compression force 37 N) and 4 bar (69 N). Histology (Pauli classification) and biomechanics (Elastic Modulus) served as references. Based on histology, samples were trichotomized as grossly intact (n = 14), mildly degenerative (n = 16), and moderate-to-severely degenerative (n = 15) and analyzed using appropriate parametric and non-parametric tests. For T1, we found loading-induced decreases in all samples, irrespective of degeneration. For T1ρ, zonal increases in intact (apex) and decreases in degenerative samples (base) were found, while for T2, changes were ambiguous. In conclusion, force-controlled loading and serial MR imaging reveal response-to-loading patterns in meniscus. Zonal T1ρ response-to-loading patterns are most promising in differentiating degeneration, while T1 and T2 aren’t clearly related to degeneration.and may provide an imaging-based indication of functional tissue properties.

Keratan Sulphate in the Tumour Environment.

Keratan sulphate (KS) is a bioactive glycosaminoglycan (GAG) of some complexity composed of the repeat disaccharide D-galactose β1→4 glycosidically linked to N-acetyl glucosamine. During the biosynthesis of KS, a family of glycosyltransferase and sulphotransferase enzymes act sequentially and in a coordinated fashion to add D-galactose (D-Gal) then N-acetyl glucosamine (GlcNAc) to a GlcNAc acceptor residue at the reducing terminus of a nascent KS chain to effect chain elongation. D-Gal and GlcNAc can both undergo sulphation at C6 but this occurs more frequently on GlcNAc than D-Gal. Sulphation along the developing KS chain is not uniform and contains regions of variable length where no sulphation occurs, regions which are monosulphated mainly on GlcNAc and further regions of high sulphation where both of the repeat disaccharides are sulphated. Each of these respective regions in the KS chain can be of variable length leading to KS complexity in terms of chain length and charge localization along the KS chain. Like other GAGs, it is these variably sulphated regions in KS which define its interactive properties with ligands such as growth factors, morphogens and cytokines and which determine the functional properties of tissues containing KS. Further adding to KS complexity is the identification of three different linkage structures in KS to asparagine (N-linked) or to threonine or serine residues (O-linked) in proteoglycan core proteins which has allowed the categorization of KS into three types, namely KS-I (corneal KS, N-linked), KS-II (skeletal KS, O-linked) or KS-III (brain KS, O-linked). KS-I to -III are also subject to variable addition of L-fucose and sialic acid groups. Furthermore, the GlcNAc residues of some members of the mucin-like glycoprotein family can also act as acceptor molecules for the addition of D-Gal and GlcNAc residues which can also be sulphated leading to small low sulphation glycoforms of KS. These differ from the more heavily sulphated KS chains found on proteoglycans. Like other GAGs, KS has evolved molecular recognition and information transfer properties over hundreds of millions of years of vertebrate and invertebrate evolution which equips them with cell mediatory properties in normal cellular processes and in aberrant pathological situations such as in tumourogenesis. Two KS-proteoglycans in particular, podocalyxin and lumican, are cell membrane, intracellular or stromal tissue-associated components with roles in the promotion or regulation of tumour development, mucin-like KS glycoproteins may also contribute to tumourogenesis. A greater understanding of the biology of KS may allow better methodology to be developed to more effectively combat tumourogenic processes.

Glycosaminoglycan and Proteoglycan Biotherapeutics in Articular Cartilage Protection and Repair Strategies: Novel Approaches to Visco‐supplementation in Orthobiologics

AbstractThe aim of this study is to review developments in glycosaminoglycan and proteoglycan research relevant to cartilage repair biology and in particular the treatment of osteoarthritis (OA). Glycosaminoglycans decorate a diverse range of extracellular matrix and cell associated proteoglycans conveying structural organization and physico‐chemical properties to tissues. They play key roles mediating cellular interactions with bioactive growth factors, cytokines, and morphogenetic proteins, and structural fibrillar collagens, cell interactive and extracellular matrix proteoglycans, and glycoproteins which define tissue function. Proteoglycan degradation detrimentally affects tissue functional properties. Therapeutic strategies have been developed to counter these degenerative changes. Neo‐proteoglycans prepared from chondroitin sulfate or hyaluronan and hyaluronan or collagen‐binding peptides emulate the interactive, water imbibing, weight bearing, and surface lubricative properties of native proteoglycans. Many neo‐proteoglycans outperform native proteoglycans in terms of water imbibition, matrix stabilization, and resistance to proteolytic degradation. The biospecificity of recombinant proteoglycans however, provides precise attachment to native target molecules. Visco‐supplements augmented with growth factors/therapeutic cells, hyaluronan, and lubricin (orthobiologicals) have the capacity to lubricate and protect cartilage, control inflammation, and promote cartilage repair and regeneration of early cartilage lesions and may represent a more effective therapeutic approach to the treatment of mild to moderate OA and deserve further study.

Towards Patient-Specific Computational Modelling of Articular Cartilage on the Basis of Advanced Multiparametric MRI Techniques

Cartilage degeneration is associated with tissue softening and represents the hallmark change of osteoarthritis. Advanced quantitative Magnetic Resonance Imaging (qMRI) techniques allow the assessment of subtle tissue changes not only of structure and morphology but also of composition. Yet, the relation between qMRI parameters on the one hand and microstructure, composition and the resulting functional tissue properties on the other hand remain to be defined. To this end, a Finite-Element framework was developed based on an anisotropic constitutive model of cartilage informed by sample-specific multiparametric qMRI maps, obtained for eight osteochondral samples on a clinical 3.0 T MRI scanner. For reference, the same samples were subjected to confined compression tests to evaluate stiffness and compressibility. Moreover, the Mankin score as an indicator of histological tissue degeneration was determined. The constitutive model was optimized against the resulting stress responses and informed solely by the sample-specific qMRI parameter maps. Thereby, the biomechanical properties of individual samples could be captured with good-to-excellent accuracy (mean R2 [square of Pearson’s correlation coefficient]: 0.966, range [min, max]: 0.904, 0.993; mean Ω [relative approximated error]: 33%, range [min, max]: 20%, 47%). Thus, advanced qMRI techniques may be complemented by the developed computational model of cartilage to comprehensively evaluate the functional dimension of non-invasively obtained imaging biomarkers. Thereby, cartilage degeneration can be perspectively evaluated in the context of imaging and biomechanics.

Transmission\u2013reflection optoacoustic ultrasound (TROPUS) computed tomography of small animals

Rapid progress in the development of multispectral optoacoustic tomography techniques has enabled unprecedented insights into biological dynamics and molecular processes in vivo and noninvasively at penetration and spatiotemporal scales not covered by modern optical microscopy methods. Ultrasound imaging provides highly complementary information on elastic and functional tissue properties and further aids in enhancing optoacoustic image quality. We devised the first hybrid transmission–reflection optoacoustic ultrasound (TROPUS) small animal imaging platform that combines optoacoustic tomography with both reflection- and transmission-mode ultrasound computed tomography. The system features full-view cross-sectional tomographic imaging geometry for concomitant noninvasive mapping of the absorbed optical energy, acoustic reflectivity, speed of sound, and acoustic attenuation in whole live mice with submillimeter resolution and unrivaled image quality. Graphics-processing unit (GPU)-based algorithms employing spatial compounding and bent-ray-tracing iterative reconstruction were further developed to attain real-time rendering of ultrasound tomography images in the full-ring acquisition geometry. In vivo mouse imaging experiments revealed fine details on the organ parenchyma, vascularization, tissue reflectivity, density, and stiffness. We further used the speed of sound maps retrieved by the transmission ultrasound tomography to improve optoacoustic reconstructions via two-compartment modeling. The newly developed synergistic multimodal combination offers unmatched capabilities for imaging multiple tissue properties and biomarkers with high resolution, penetration, and contrast.