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What's the highest glucose concentration (in mM) anywhere in the human body (tissue, capillaries, tumor microenvironment, etc.)?

What's the highest glucose concentration (in mM) anywhere in the human body (tissue, capillaries, tumor microenvironment, etc.)?


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Glucose blood levels are around 5mM, or 10mM after meals. In capillaries these levels can rise by about 40 %. I haven't found measurements of glucose concentration in tissues, or in extracellular spaces. I'm wondering what's the highest glucose concentration, anywhere in the human body?


Glucose concentration in the blood is a highly regulated biologic variable. From personal laboratory experience, it is very difficult to raise a healthy, non-diabetic individual's blood glucose over about 6.5-7 mM (i.e. 120-130 mg/dl). My best guess at where the highest glucose concentration might be in the body is within the hepatic portal vein that drains the intestines after a high carbohydrate meal. The glucose concentration is probably highest in the prandial state or, in other words, when carbohydrates (i.e. food) is being digested and absorbed by the gastrointestinal tract. Many simple and/or complex carbohydrates are digested to glucose and absorbed through the gastrointestinal tract. Once absorbed the glucose enters the venous mesenteric circulation and then drains into the hepatic portal circulation. This allows high concentrations of glucose and other compounds like amino acids from dietary nutrients to be "buffered" by the liver.

I don't have hard evidence to demonstrate that this is the highest glucose, but I think it's probably a good guess. It is inherently difficult to measure the blood glucose concentration in the portal vein - mostly because it's so difficult to get to that place anatomically during a meal. The dog is probably the most used animal for these types of metabolic studies, because catheters can be placed in the peripheral venous and arterial circulation, as well as in the portal vein and hepatic veins, to measure nutrient uptake by the intestine and nutrient extraction by the liver.

A number of previous studies by Cherrington and colleagues, who have done some of the most comprehensive work in this field, frequently measure glucose concentration and blood flow rates across the liver. In one such paper that is freely available from the American Journal of Physiology by Abumrad et al (1982) entitled, "Absorption and disposition of a glucose load in the conscious dog" you can see from Figure 1 the average plasma glucose concentration in the portal vein from a group of dogs given an oral glucose load of ~40 grams is somewhere in the 250 mg/dl region (i.e. ~14mM). These were otherwise healthy dogs, and similar to healthy humans I would bet the glucose concentration doesn't rise too much further. As you could imagine though, in a diabetic individual who has high peripheral glucose concentrations to start, the portal vein concentration might be expected to be higher. How much higher is another educated guess - maybe 100-200 mg/dl higher on an extreme end (obviously pathologic).

In a healthy human (i.e. non-diabetic) who undergoes a 75-gram oral glucose tolerance test I can't imagine that the portal glucose would go any higher than 300-400 mg/dl (or, 16.5 to 18 mM). But again - these numbers are just educated guesses. This is probably the highest glucose concentration anywhere in the body. Additionally, in diabetic patients the glucose concentrations would be expected to be slightly higher because circulating glucose may be slightly higher, but probably not by too much (definitely not an order of magnitude).


What's the highest glucose concentration (in mM) anywhere in the human body (tissue, capillaries, tumor microenvironment, etc.)? - Biology

Hydrogels are soft biomaterials that can be engineered to mimic many aspects of a tissue structure.

Hydrogel can be formulated into adhesives as wound dressing or bio-sutures.

Hydrogels are platforms to deliver cells into the body for therapy or tissue regeneration.

Hydrogels in bulk form or nano-hydrogels formed into vehicles can deliver immunotherapies-from antibody-based to cell-based for cancer therapy.

Hydrogels can form the scaffold for bio-inspired wearable or implanted devices to operate a vast range of diagnosis to therapeutics.


NORMAL ANGIOGENESIS

The adult vasculature is derived from a network of blood vessels that is initially created in the embryo by vasculogenesis, a process whereby vessels are formed de novo from endothelial cell precursors termed angioblasts (202). During vasculogenesis, angioblasts proliferate and coalesce into a primitive network of vessels known as the primary capillary plexus. The endothelial cell lattice created by vasculogenesis then serves as a scaffold for angiogenesis.

After the primary capillary plexus is formed, it is remodeled by the sprouting and branching of new vessels from preexisting ones in the process of angiogenesis. Most normal angiogenesis occurs in the embryo, where it establishes the primary vascular tree as well as an adequate vasculature for growing and developing organs (73). Angiogenesis occurs in the adult during the ovarian cycle and in physiological repair processes such as wound healing (123). However, very little turnover of endothelial cells occurs in the adult vasculature (48).

Maturation and remodeling of newly formed microvessels is accomplished by the coordination of several diverse processes in the microvasculature (124) that are summarized in Fig.1. For new blood vessel sprouts to form, mural cells (pericytes) must first be removed from the branching vessel. Endothelial cell basement membrane and extracellular matrix are then degraded and remodeled by specific proteases such as matrix metalloproteinases (161), and new matrix synthesized by stromal cells is then laid down. This new matrix, coupled with soluble growth factors, fosters the migration and proliferation of endothelial cells. After sufficient endothelial cell division has occurred, endothelial cells arrest in a monolayer and form a tubelike structure. Mural cells (pericytes in the microvasculature, smooth muscle cells in larger vessels) are recruited to the abluminal surface of the endothelium, and vessels uncovered by pericytes regress. Blood flow is then established in the new vessel.

Fig. 1.Mechanisms of physiological angiogenesis. Normal angiogenesis depends on the coordination of several independent processes. Removal of pericytes from the endothelium and destabilization (1) of the vessel by angiopoietin-2 (Ang2) shift endothelial cells from a stable, growth-arrested state to a plastic, proliferative phenotype. Vascular endothelial growth factor (VEGF)-induced hyperpermeability (2) allows for local extravasation of proteases and matrix components from the bloodstream. Endothelial cells proliferate (3) and migrate (4) through the remodeled matrix (5), and then they form tubes through which blood can flow (6). Mesenchymal cells proliferate and migrate along the new vessel (7) and differentiate into mature pericytes (8). Establishment of endothelial cell quiescence, strengthening of cell-cell contacts, and elaboration of new matrix stabilize the new vessel (9). TGF-β, transforming growth factor-β FGF, fibroblast growth factor EGF, epidermal growth factor PDGF, platelet-derived growth factor TNF-α, tumor necrosis factor-α a, arteriole v, venule. [Adapted from Hughes et al. (108a).]

Under normal circumstances, angiogenesis is a highly ordered process under tight regulation, because it requires inducing quiescent endothelial cells in a monolayer to divide and spread the vascular network only to the extent demanded by the demands of growing tissues. Many positively and negatively acting factors influence angiogenesis among these are soluble polypeptides, cell-cell and cell-matrix interactions, and hemodynamic effects. The soluble growth factors, membrane-bound molecules, and mechanical forces that mediate these signals are summarized in Table1 and are discussed below in terms of their contribution to the mechanism of normal angiogenesis.

Table 1. Factors that regulate normal angiogenesis

vWF, von Willebrand factor VSMA, vascular smooth muscle actin see text for all other definitions.


TUMOR PERFUSION—METHODS AND FINDINGS

Perfusion is central to our understanding of the tumor microenvironment. Perfusion is a complex process that encompasses the delivery of nutrients (primarily oxygen and glucose), their diffusion and convection (if lymphatics are functional) into the tumor parenchyma, and the removal of waste products. The perfusion of tumors can be interrogated with time-dependent delivery of exogenous or endogenous contrast, using contrast agents and spin tagging, respectively. These studies show a spatio-temporal heterogeneity of perfusion in tumors that is consistent with the chaotic vascular architecture.

Dynamic Contrast-Enhanced (DCE)-MRI

The technique of DCE-MRI using bolus injections of contrast agents is the subject of another chapter in this volume (see Padhani et al, this volume) and will not be extensively discussed here. However, it is important to point out that a distinction is made between diffusible and blood pool tracers, since they behave differently and yield different information. Diffusible tracers range from freely diffusible tracers, such as 2 H2O, to small molecular weight contrast agents, such as chelates (DOTA, DTPA, etc.) of gadolinium. Extraction fractions (i.e., the proportion that moves from the vasculature to the interstitium during the first pass) for these agents vary from 0.5 to 1.0, depending on the agent and the vasculature. Additionally, contrast agents affect the spins of blood water, which can freely diffuse into the interstitium and, in some cases, into cells ( 68 , 69 ). Blood pool tracers are usually larger molecules and hence diffuse into the interstitium much more slowly. They are also cleared more slowly, yielding flatter arterial input functions. These slower kinetics allow for higher dynamic range in quantification of vascular leakage and acquisition of much higher-resolution images, which can be important in pathodiagnosis. One facet of vasculature revealed from MRI of macromolecular contrast agents is that regions of high vascular volume are not spatially coincident with regions of high permeability within the same tumor (Fig. 6). Regions of high permeability, which have been associated with necrotic areas, consistently exhibit lower vascular volumes ( 70 ). These findings suggest that the delivery of macromolecular agents to the tumor interstitium will be limited in viable vascular areas, but effective in regions wherein cells are already doomed to die.

Co-registered vascular volume and permeability maps. Triplanar and 3D views of red and green fusion maps of vascular volume and permeability surface area product (PSP). Obtained from an MDA-MB-435 tumor (150 mm 3 ) using multislice quantitative T1 maps obtained before and after injection of albumin-Gd-DTPA. Vascular volume is displayed in red, and PSP in green. The absence of yellow demonstrates that regions of high vascular volume and high PSP are not spatially coincident. (Adapted from Ref. 142 ).

Only diffusible tracers are approved for human use at this time, although a number of blood pool agents are in clinical development. The application of DCE-MRI is of high interest because of its potential to measure tumor responses to anti-angiogenic therapies. This technique was the subject of a recent special issue of NMR in Biomedicine ( 71 ), to which the reader is referred. In brief, DCE MRI data are generally obtained with rapid acquisitions to describe the full time course of enhancement over 2–5 minutes. If the arterial input function is known, the data can be quantitatively analyzed to yield a transfer constant (Ktrans), leakage space (ve), and maximum contrast medium accumulation (MCMA). The Ktrans is most predictive of therapy response ( 72 ). An elegant series of experiments by Dafni and colleagues ( 73 ) has shown that this parameter is related to vascular permeability induced by transient VEGF treatments. Alternatively, without an input function, the area under the curve (AUC) can be used to yield an ad hoc solution that is every bit as robust. Dynamic contrast methods are highly reproducible in static normal organs and are altered with high dynamic range in response to antivascular therapies ( 74 ). The DCE parameters can also be used for diagnostic purposes. In general, tumors that show an elevated Ktrans have a poorer prognosis, yet larger changes in this parameter are associated with better response to therapies. Such methods were first developed in the brain, where motion is not problematic and the low permeability of brain capillaries simplifies analysis ( 75 ). These have since devolved to more difficult sites, such as cancer of the cervix and hepatic lesions ( 76 , 77 ).

Bolus Spin Tagging

Quantitative measurements of blood flow in tumors (in mL 100 g –1 minute –1 ) require a freely diffusible tracer, such as water. Historically this has been measured with deuterium wash-in however, the sensitivity and resolution are too low to discriminate microenvironmental differences. An alternative method is to magnetically tag the water using arterial spin tagging ( 78 ). This method requires a well-defined input artery and dual coils (one for excitation and one for receiving). Quantification also requires relatively high blood flow and/or long T1. It has been successfully applied to brain tumors, which have relatively high blood flow (i.e., 35–85 mL 100 g –1 minute –1 ) to generate high-resolution perfusion maps showing heterogeneities in blood perfusion ( 79 , 80 ).


3D bioprinting of tissues and organs for regenerative medicine ☆

3D bioprinting is a pioneering technology that enables fabrication of biomimetic, multiscale, multi-cellular tissues with highly complex tissue microenvironment, intricate cytoarchitecture, structure-function hierarchy, and tissue-specific compositional and mechanical heterogeneity. Given the huge demand for organ transplantation, coupled with limited organ donors, bioprinting is a potential technology that could solve this crisis of organ shortage by fabrication of fully-functional whole organs. Though organ bioprinting is a far-fetched goal, there has been a considerable and commendable progress in the field of bioprinting that could be used as transplantable tissues in regenerative medicine. This paper presents a first-time review of 3D bioprinting in regenerative medicine, where the current status and contemporary issues of 3D bioprinting pertaining to the eleven organ systems of the human body including skeletal, muscular, nervous, lymphatic, endocrine, reproductive, integumentary, respiratory, digestive, urinary, and circulatory systems were critically reviewed. The implications of 3D bioprinting in drug discovery, development, and delivery systems are also briefly discussed, in terms of in vitro drug testing models, and personalized medicine. While there is a substantial progress in the field of bioprinting in the recent past, there is still a long way to go to fully realize the translational potential of this technology. Computational studies for study of tissue growth or tissue fusion post-printing, improving the scalability of this technology to fabricate human-scale tissues, development of hybrid systems with integration of different bioprinting modalities, formulation of new bioinks with tuneable mechanical and rheological properties, mechanobiological studies on cell-bioink interaction, 4D bioprinting with smart (stimuli-responsive) hydrogels, and addressing the ethical, social, and regulatory issues concerning bioprinting are potential futuristic focus areas that would aid in successful clinical translation of this technology.


3 STRUCTURES AND PROPERTIES

As emerging two-dimensional materials, MXenes show definite properties compared with other materials, such as excellent electronic properties, outstanding optical properties, extraordinary magnetic properties, superior hydrophilic as well as flexible mechanical properties. As we all know, structures are associated with properties, while properties lead to applications. Then the structures and properties will be introduced in the following sections.

3.1 Structures of MXenes

Up to date, the structures of MXenes can be divided into four types: mono-transition metal MXenes, such as Ti2C and Nb4C3 solid solution MXenes, such as (Ti, V)3C2 and (Ti, V)2C ordered double- transition metal (M) MXenes, such as (Cr2V)C2 and (Mo2Ti2)C3 and ordered divacancy such as Mo1.33C and W1.33C [ 36 ] (Figure 3A, B).

In addition to the common two-dimensional structure of MXenes (Figure 4A), there is one-dimensional structure (Figure 4B, C), three-dimensional structure (Figure 4D) and quasi-zero-dimensional structure (Figure 4E). Compared with the two-dimensional structure that has been studied a lot, MXenes of one-dimensional structure have fewer investigations. Zhao et al. constructed Tin+1Cn (n = 1, 2) and V2C nanoribbons to study their properties and two types of armchair and six types of zigzag nanoribbon were considered. All of them possess unique properties, especially manageable magnetism, and some of them have larger band gaps compared with pristine MXenes nanosheets. [ 37 ] Apart from nanoribbon, Pang et al. report a HF-free method that is capable of synthesizing 1D Nb2CTx nanowire with dilute HCl electrolyte in 4 hours [ 38 ] Although two-dimensional MXenes have many advantages, their aggregation and self-restacking are also problems that can be seen usually during the fabrication process. Then some researchers consider assembling 3D architectures with 2D MXene nanosheets to fix problems of restacking for the purpose of larger specific surface area, higher porosity, as well as shorter transport distance of ion and mass over normal 1D and 2D structures. [ 39 ] For example, Li et al. took PS (polystyrene) spheres as a template to fabricate Ti3C2Tx electrodes with a 3D structure. The obtained freestanding and flexible 3D-macroporous Ti3C2Tx (3D M-Ti3C2Tx) film has an open and interconnected structure. The electrical conductivity of the film was about 600 S cm −1 , which is higher than that of 3D graphene film with a similar structure (≈12 S cm –1 ). [ 40 ] And, Shah et al. showed that the Ti3C2Tx nanosheets have the ability to be scrolled, bent, and folded into 3D wrinkled structures after encapsulated with spray-dried droplets. After rehydration, the changes in morphology can be restored to the original state. [ 41 ] Besides, 2D MXene nanosheets can be assembled into 3D porous architectures with other materials such as reduced graphene oxide (rGO), [ 42 ] melamine, [ 43 ] SnS [ 44 ] and so on. These MXenes with 3D structure mostly used for energy storage, such as supercapacitors, lithium-ion batteries, sodium-ion batteries, lithium-sulfur batteries and electrocatalysis. In addition to the above 1D, 2D, 3D structures, there are 2D MXenes-derived QDs (MQDs). Even though in an early stage, they have many advantages such as high electrical conductivity, plentiful active sites, remarkable dispersibility, tunable structure, great hydrophilicity, excellent optical properties, multiple functionalization, and so on. [ 45 ] Thus, they can be used in the fields of sensing, catalysis, energy storage, biomedical science and optoelectronic devices. For example, Guo et al. using hydrothermal treatment to prepare Ti3C2 QDs from Ti3C2 MXenes. When in an aqueous solution, the obtained Ti3C2 QDs showed excellent tolerance to salt, anti-photobleaching and dispersion stability. Moreover, they can determine alkaline phosphatase (ALP) activity with a low limit of detection (0.02 U L −1 ) and monitor the enzyme activity in real-time to identify embryonic stem cells (ESC). [ 46 ] Though so many great achievements, there are still some challenges that need to be noted, such as synthesis methods, properties, functionalized modification, biocompatibility and cytotoxicity of MQDs. Besides, more effort should be devoted to exploring more applications.

3.2 Electrical properties

Compared with other properties, electronic properties have been studied mostly. Interestingly, all bare MXenes monolayers are metallic, while OH, F, O terminations can cause the metal-semiconductors transition. There are some factors that affect the electrical performance of MXenes, such as the preparation process, surface termination, elemental composition, inner structures and surrounding conditions like humidity, pH, temperature and so on. Thus, the electronic properties can be adjusted by the following means: (i) changing the “M” elements, which are mostly related to metallic of MXenes (ii) improving synthesis methods that making fewer defects, such as the use of fluorine-free synthesis (iii) changing the surface groups to tune bandgaps, for example, removing OH-contained groups or adding O-contained groups (iv) increasing the interlayer distance which contributes to the energy density (v) designing new structures. For example, Ran et al. prepared the MXene film electrode through the freeze-drying technique to alleviate its self-restacking and improve the electrochemical performances. Through freeze-drying treatment, the frozen solvent molecules were removed by sublimation, and alleviated the adverse effect of van der Waals forces and enlarging layer space. The obtained freeze-dried MXene (f-MXene) films show unique porous architecture with highly efficient ion diffusion and transport channels. [ 48 ] Benefit from their outstanding electronic properties, MXenes are mostly used in energy store, besides, they can be applicable for biomedical fields. For example, when specific biomolecules are attached to the surface of MXenes, the electrical conductivity of MXenes will be changed to achieve the purpose of biomolecule detection. Also, the electronic properties make them suitable for the manufacture of wearable electronic devices to monitor the body's physiological signals.

3.3 Optical properties

For applications of MXenes, optical properties are also important which include absorption, transmission, photoluminescence, saturation absorption, nonlinear refractive index, scattering, emission, and so on. These properties are highly dependent on their energy structure such as energy band gap, direct/indirect band gap, topological properties, etc, [ 49 ] while the energy band structure of MXenes is mainly affected by surface groups, external electric field, stress, doping, and electronic localization. Noting that, compared with 2D MXenes nanosheets, MQDs have stronger photoluminescence (PL) emission. Because of these properties, MXenes can be applied in many fields like photocatalysis, sensing and biomedical such as photoacoustic imaging, photothermal therapy (PTT), photodynamic treatment (PDT), controlled drug release and biosensing. Since MXenes show strong light absorption in the near infrared region (NIR) with the ability of high photothermal conversion owing to localized surface plasmon resonances, they are often used to ablate tumors in biomedical applications. Because these Ti3C2 MXenes possess not only a high drug loading capacity of 211.8%, but also the characteristics of pH sensitivity and near-infrared laser on-demand trigger drug release, the cooperative treatment of chemotherapy and PTT is achieved. Also, these Ti3C2 MXenes have also proved to be ideal photoacoustic imaging contrast agents, demonstrating the potential for diagnosis, imaging guidance and monitoring during treatment. Thus, MXenes can get the purpose of monitoring the lesion while achieving synergetic treatment. [ 50 ] It is worth mentioning that the optical characteristics can also be adjusted by altering thickness, [ 51 ] intercalation, such as ion intercalation [ 52 ] and molecule intercalation (TMAOH, or NMe4OH), [ 53 ] changing M, which is related to the visible light absorption range, [ 54 ] tuning their surface terminations to adjust the band gaps to fit the UV light, for example, the O-terminated Ti3C2Tx offering the best catalytic activity. [ 45, 55 ]

3.4 Magnetic properties

Compared with the electronic and optical properties, the magnetic properties of MXenes are less studied. When the Stoner criterion I · N (Ef) > 1, the high values of N (Ef) can result in a magnetic instability, making MXenes magnetic. [ 56 ] It is worth noting that Ti2CO2, Zr2CO2, Hf2CO2, Sc2CO2, Sc2C(OH)2, Cr2C(OH)2, Cr2CF2, and Sc2CF2 are considered to be semiconductors and non-magnetic among MXenes. [ 57 ] The magnetic properties of MXenes include ferromagnetic(such as Cr2C [ 58 ] )and antiferromagnetic (such as Ti3C2, Cr2TiC2F2 [ 59 ] ). [ 60 ] Similar to the optical and electrical properties, the magnetic properties of MXenes are also affected by many factors such as the composition of “M” and surface termination. For example, Zhong et al. proposed V2N with the structure of Janus in which one V layer is replaced with Ti/Cr layer. Making use of the first-principles calculations, they showed that although the antiferromagnetic (AFM) ground states are formed, the TiVN and CrVN monolayers possess net magnetic moments of 1.97 and 0.28 mu(B) per formula unit, respectively. In addition, when a considerable strain (-8% to 8%) is applied to the TiVN and CrVN monolayers, their net magnetic moments are also very stable. [ 61 ] Moreover, surface groups are also vital to the magnetic properties of MXenes. The presence of surface terminals causes the magnetism of MXenes to disappear because of the p–d bonds between the M atoms and T groups, which results in a partial depopulation of the near Fermi states, then the value of N (Ef) reduces, except for Cr2C and Cr2N. [ 56 ] Besides, external conditions can also affect the magnetic properties of MXenes. For example, Lv et al. have found that monolayer Ti2C changes from an AFM semiconductor to a ferrimagnetic (FIM) semiconductor, half-metal, magnetic metal, non-magnetic (NM) metal, and NM semiconductor when applying an external electric field. Besides, while the electric field increases beyond a certain value, the magnetic moments of Ti atoms decrease drastically, at this time, the effective masses decrease remarkably, while the conductivity increases. Thus, the magnetic properties can be adjusted through the external electric field. [ 62 ] Importantly, MXenes can also be a promising electromagnetic interference (EMI) shielding material, which is more than 70 dB at merely 0.8 mm in X-band. Not only does the multilayered structure strengthen the internal electromagnetic (EM) attenuation, it also enhances the absorption efficiency apparently. Furthermore, the high electrical conductivity makes the EM reflection on the surface sufficient. [ 63 ] Although MXenes, by virtue of their magnetic properties, have been outstanding contrast agents for bioimaging. The EMI shielding performance of MXenes for biomedical research needs to be developed.

3.5 Hydrophilicity and biocompatibility

Surfaces hydrophilic nature of MXenes was given by the surface terminations including hydroxyl (-OH), oxygen (-O), or fluorine(-F). The contact angle measurements using deionized water on the surface of the cold-pressed MXenes disc found that MXenes have hydrophilicity and good electrical conductivity. [ 17 ] Thus, the hydrophilic properties of MXenes with high conductivity makes them interact with the polymer matrix better, which is beneficial to their use in composite materials. [ 64 ] Besides, hydrophilicity is usually related to biocompatibility. Generally speaking, better biocompatibility makes hydrophilicity higher. Although there are not many studies on the biocompatibility of MXenes, some common Ti-based MXenes are found to be biocompatible such as Ti3AlC2. [ 65 ] Therefore, MXenes, which combine conductivity, hydrophilicity and 2D layered atomic structures, can be promising candidates to manufacture biologically compatible field-effect transistors (FET) to investigate biological events in a speedy, direct, and label-free way. [ 66 ] Noting that their hydrophilic behavior is also beneficial to the surface functionalization and antibacterial activity of MXenes which may facilitate the inactivation of bacteria through direct contact interactions. [ 67 ] In addition, hydrophilicity and large surface area of MXenes make them possess the capacity of drug-loading. As we all know, the hydrophilic property will promote adsorption for polar or ionic molecular. Therefore, another potential application of MXenes is in the environment to adsorb harmful substances.

3.6 Mechanical properties

In addition to the above properties, the mechanical properties of MXenes have aroused great interest, too. The atomic layer thickness of MXenes gives MXenes mechanical flexibility, while MXenes’ mechanical properties depend on their surface terminations (the O-terminated MXenes have very high stiffness, which may be related to the larger lattice parameters) significantly. What's more, the mechanical properties are tested by strain tests, and the resulting elastic constants are used to evaluate the mechanical properties of MXenes. Materials with good mechanical properties can be used in many fields of strain sensors, energy storage, wearable electronics, etc. Thus, it is important to understand the mechanical nature of MXenes under deformation fully. Guo et al. took 2D Tin+1Cn (n = 1, 2 and 3) as examples to study the tensile stress-strain curves of MXenes which were under different loading directions through first-principles calculations systematically. The calculated results showed that 2D Ti2CO2 can sustain larger strains compared with graphene because of the surface functionalizing oxygen. What's more, the collapse of the Ti layer will be retarded by the surface functionalization, and the critical strain of 2D Ti2C increased apparently. Moreover, the critical strains did not change much but Young's modulus decreased slightly with n in Tin+1Cn increasing from 1 to 3. In a word, the surface functionalization can reduce Young's modulus, extend the critical strains to improve their mechanical properties and enhance mechanical flexibility. [ 68 ] And the number of atomic layers is also a factor affecting mechanical properties. Apart from these, the mechanical properties will also be improved after forming a composite material with other materials. For example, Cao et al. combined 2D MXenes with a scale of micro-nano and 1D cellulose nanofibers with strong hydrogen bonds through mesoscopic assembly to obtain a soft actuator with layered gradient structure. The actuator has the advantages of the high tensile strength (237.1 MPa), high Young's modulus (8.5 GPa), and excellent toughness (10.9 MJ m –3 ) with direct and rapid moisture absorption in a single body. [ 69 ] Some flexible wearable sensors can be designed based on the mechanical properties of MXenes. Physical activity deforms these sensors and sends out electrical signals to detect human activity and physiological signal in real time.


GRANTS

We thank the Biotechnology and Biological Sciences Research Council (UK) for International Fellowship no. 1678 to support N. E. Miller's work in Oxford. This study was also funded in part by the project “Hepatic and Adipose Tissue and Functions in the Metabolic Syndrome” (http://www.hepadip.org), which was supported by the European Commission as an Integrated Project under the 6th Framework Programme (Contract LSHM-CT-2005-018734). W. L. Olszewski was in receipt of grant no. N404/07132/2197 from the Ministry of Science and Higher Education, Poland. G. Olivecrona received support from the Swedish Heart and Lung Foundation.


Proliferation, Differentiation, and Gene Expression

Several researchers have examined the effects of 2D and 3D culture methods on the proliferation, differentiation, and gene expression levels of cells (21, 81, 91). Pineda et al. (91) demonstrated that OCT4 in mouse ESCs decreased in both 2D and 3D cultures, showing a loss of pluripotency, whereas NES (ectoderm) and BRACHY-T (mesoderm) markers were shown to increase. However, the ESCs cultured on glass slides (2D) coated with collagen type I had a faster rate of differentiation than in 3D cultures (EBs and GELs). It was also shown that the duration of cell culture and organization of cells affected their differentiation. Based on assessment of GATA4, a potential myocardial transcription factor, it was shown that EB cultures possessed the greatest ability, among these culture types, to support cardiovascular differentiation. Furthermore, neural differentiation was only supported in EB cultures that had been sustained over time (91).

Chitcholtan et al. (21) also showed that some characteristics of tumor cells are not properly modeled in 2D. In all the tumor cells lines that were observed, there were higher proliferation rates in 2D monolayers than in 3D reconstituted basement membrane (rBM) cultures. Although 3D cultures exhibited a reduction in proliferation, there was an increase in β4 and β1 integrins that serve as markers for cell polarization and differentiation. Previous experimentations have shown that 2D cell culture of endometrial cancer cells led to a loss in tissue-specific function and organization. The complexity of studying 3D cultures is highlighted by how different cell lines uptake a ubiquitous energy source, such as glucose. A glucose analog, 2-NBDG, was introduced to both 2D and 3D cultures of KLE, Ish-ikawa, and EN-1078D cells. KLE and Ish-ikawa cells in 3D conformations had a lower influx of 2-NBDG than their counterparts in a 2D conformation. This contrasts with the EN-1078D cell line, which showed higher uptake of 2-NBDG in 3D models compared with 2D. KLE cancer cells had the highest overall rate of 2-NBDG uptake in both 2D and 3D cultures but expressed the lowest levels of cellular proliferation. These findings imply that glucose uptake levels may not impact cell proliferation rates regardless of the culture method (21). Findings such as these demonstrate the challenge in assessing whether 2D or 3D cultures are preferable for cellular proliferation and differentiation, since many of the differences are cell line specific.

Phenotypic expression is also altered depending on the culture method used. Microarray analysis of valvular interstitial cells (VIC), the primary cell type in heart valves, revealed that substrate stiffness can affect the gene expression of cell lines. Cells cultured on stiff, 2D tissue culture polystyrene presented with more gene expression changes than 2D or 3D cultures conducted in less stiff materials such as hydrogels. The Young’s modulus of the material that VIC cells were cultured on impacted the expression of cytoskeletal, contractility, and matrix remodeling genes (81). Additionally, Pineda et al. showed that cells grown in a monolayer expressed higher levels of cytoskeletal elements and extracellular matrix proteins than those grown in 3D cultures (91). The combinations of these factors influences cellular proliferation, differentiation, and gene expression, and makes both 2D and 3D cultures valuable to scientific experimentation.


Preservation of Stem Cell Niche, Regenerative Capacity, and Tissue Repairing

We reported above that the alterations in metabolic conditions characterized by increasing insulin resistance, the decreased oxygen supply, and changes in the local metabolic milieu could altogether stimulate SCs to enter the alternative mesenchymal lineage differentiation pathway and ultimately justify the increase in IMAT. Thus it is becoming more and more evident that the preservation of stem cell niche components is critical for maintaining the regenerative capacity and the muscular lineage orientation of SCs.

Myoblasts harvested from adult skeletal muscle quickly change their fate and their regenerative capacity and lose their self-renewal capacity during in vitro expansion (12, 97, 128) On the contrary, direct implantation of freshly isolated SCs or single fibers with resident SCs is extremely effective to regenerate damaged muscle tissue (14, 27). There is now increasing evidence that cells sense the mechanical properties of their matrix and respond by phenotypic change (37) possibly by differentiating away from their precursor state (e.g., in the case of rigid culture plastic). Support for the importance of the matrix in the stem cell niche also comes from observations that bone marrow integrity during injury accelerates natural healing (102). Not only loss of the matrix context but also loss of the cellular context may cause SC fate change. After muscle injury, macrophages are important for removal of dead cells and the dead parts of muscle fibers. Macrophage infiltration of adipose tissue to remove the dead adipocytes explains the appearance of the “low-grade chronic inflammation” present in obesity and type 2 diabetes (26). Moreover, macrophages also enter the atherosclerotic plaque as foam cells, and also in this case the inflammatory process plays a pathogenetic role in the progression of the arterial wall lesion (21, 71). Macrophages have also been shown to be able to directly stimulate SC proliferation and delay their differentiation. In this context it is important to remind that, although acute inflammation is a trigger for stem cell proliferation, chronic inflammation appears to be detrimental on stem cell recruitment and tissue repair. The vascular microenvironment also plays a crucial role on SC fate control. More than 60% of SCs are located very close to and receive signals from endothelial cells, although they are not in direct contact with them. The number of capillaries per muscle fiber has been shown to correlate to the number of SCs, and loss of capillaries leads to loss of SCs, pointing to some sort of interaction (22). In addition, transwell experiments showed that endothelial cells have a positive effect on myoblast proliferation, which is mediated by growth factors (22). Capillary density, the distance of muscle cells from capillary, and the fiber type play a role in determining the in vivo insulin action in obese subjects (68).


Future Perspectives

Although significant progress has been made toward utilizing EPCs for vascularizing engineered tissues, there is no evidence of EPC integration with tissue niche parenchymal and stromal cells to produce organotypic endothelium in vitro. Contributing to this lack of progress is the common approach to generate vascularized tissues in vitro, which is mixing EPCs or ECs alongside tissue stromal and progenitor cells, utilizing previously optimized growth conditions for the tissue of interest. The fallacy in this concept is the underlying assumption that the growth conditions for avascular tissue development will also promote vasculogenesis and that the angiogenic conditions will not interfere with parenchymal differentiation of tissue progenitor cells.

Organ development is an elaborate feedback control system in which temporally and spatially secreted factors by tissue niche cells provide positive and negative regulation. 205 The use of angiogenic initiators, such as VEGF, can redirect parenchymal progenitor differentiation toward vascular lineages. 215 As a consequence, novel techniques are required to guide orthogonal differentiation of vascular and parenchymal progenitor cells in situ. The use of reductionist, in vitro models utilizing synthetic hydrogels and chemically defined media can provide a translatable platform to probe the intricate relationship among endothelial, stromal, and parenchymal cells. For instance, Lutolf and colleagues demonstrated VEGF could be covalently bound with protease-sensitive peptides within synthetic PEG hydrogels and released by cell-secreted proteases, enabling studies of vascular morphogenesis within a chemically defined microenvironment. 216

In addition to angiocrine factors, angiogenic transcription factors, such as the transcription factor hypoxia-inducible factor 1, could also be identified in reductionist, synthetic hydrogel models of vascular morphogenesis. Activators for the master angiogenic regulators of each tissue niche could then be incorporated within the scaffold to indirectly stimulate the production of angiocrine factors in mural and parenchymal cells surrounding the vascular cells. 37,205 This approach would enable complex angiocrine profile production at physiological concentrations, confined to localized regions, thus eliminating the complexity of releasing multiple angiocrine factors within the scaffold in a temporally and spatially controlled manner. 217–220 As well, clustered regularly interspaced short palindromic repeat-mediated gene activation may be utilized to regulate the angiogenic transcription factors. 221

Also, deriving EPCs and tissue-specific progenitors from mesodermal precursors would closely mimic the process in organ development and eliminate the need for multiple cell isolations. Gerecht, Palecek, and colleagues have provided proof-of-principle for this approach, generating EPCs or organotypic ECs and parenchymal progenitors from hiPSCs. 175,213,222 In addition, inducing EPCs to form macrovasculature within the prevascularized construct could create a vascular axis within the construct, enabling microsurgical connection with the host vasculature and instantly perfusing the scaffold with blood. 46,223 Assisting efforts to advance EPC vascularization research is omnidirectional, direct-contact bioprinting that can recapitulate the distinct 3D hierarchical vascular networks for each tissue, as well as mimic the local matrix microenvironment by finely controlled deposition of biomolecules. 224–226 Thus, combining reductionist in vitro models with recent advances in polymer science, genetic engineering, and 3D bioprinting can provide the sophisticated systems needed to develop the next generation of tissue-engineered models that can further EPC vascularization research.


Watch the video: Στο νοσοκομείο ξεψύχησε 44χρονος υπάλληλος καταστήματος ψιλικών, ο οποίος δέχτηκε επίθεση από ληστή (May 2022).


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