Stages Of Remodeling Research Articles

Association between objectively-measured sleep duration and early cardiac and hepatic imaging changes in adolescents: insights from the EnIGMA study

Abstract Introduction Inadequate sleep duration (SD) has been associated with adverse cardiovascular (CV) events in adults and adiposity in all life stages. Furthermore, previous cross-sectional studies have shown a possible association between self-reported SD and cardiac structural alterations as detected with echocardiography and cardiovascular magnetic resonance (MR), even in young healthy people. However, there is a lack of longitudinal studies demonstrating an association between objectively-measured SD and structural cardiac alterations. Purpose To assess the association between SD and MR-derived cardiac and hepatic parameters in adolescents. Methods This study used longitudinal data collected as part of the SI! Program for Secondary Schools trial in Spain (2017-2021), which enrolled 1326 participants (mean age: 12.5±0.5 years at baseline). Measurements were taken at three different time-points: baseline, 2-year follow-up and 4-year follow-up. SD and physical activity were assessed by accelerometry for seven consecutive days at each follow-up. The participants were offered to undergo a MR scan in the final follow-up as part of the Early imaging markers of unhealthy lifestyles in adolescents (EnIGMA) study. The imaging protocol included a cine SSFP to provide images for chamber size and function, myocardial tagging acquisitions to assess myocardial strain, T1 and T2 mapping sequences to provide precise myocardial relaxation time properties, and a liver mDixonQuant sequence to obtain liver fat content, using a 3-T scanner. The cumulative effect of the independent variable (SD) and the covariates was assessed using the area under the curve (AUC) method, calculating the integral of the curve parameters during the follow-up period for each subject. To facilitate interpretation, AUC values were divided by the years of follow-up. The participants were included in the analysis if they had available data for SD in at least 2 of the 3 time-points. The association between SD and the MR parameters was assessed by linear regression models. Results 109 participants (61 girls [56.0%]; mean age=16.0±0.5 years) were included in this study. Indexed left ventricular (LV) mass, as well as indexed end-diastolic biventricular volumes were higher in boys than in girls (Figure 1). SD AUC (hours/day) was independently and inversely associated with indexed LV mass and liver fat fraction in the unadjusted and adjusted (age, gender, physical activity, body mass index percentile, and systolic and diastolic blood pressure percentiles AUCs) models (Figure 2). There were no significant associations between the SD AUC and other MR-derived parameters. Conclusion Shorter SD is independently associated with initial stages of cardiac remodeling and liver fat accumulation as assessed with state-of-the-art MR as early as in adolescence. Considering these results, health promotion programs should be implemented early in life emphasizing the importance of good sleep habits.Participant characteristicsAssociation between SD and MR

Healing of chronic wounds at the remodeling stage: the ratio of hormonal and immune parameters

Background. Both patients and healthcare systems around the world experience the negative consequences of chronic wounds. Chronic wounds often precede serious events such as amputation and premature death. Objective: to study the relationship between endocrine factors (insulin and cortisol) and bioactive molecules (interferon-γ (IFN-γ) and transforming growth factor-β1 (TGF-β1)), influencing the development of reparative processes of chronic wounds at the remodeling stage in an experiment, and to analyze the features of the histostructure of rat skin in the area of chronic wound healing. Materials and methods. The study was conducted on 12 white rats. Animals were randomized into intact and experimental groups, with 6 participants in each group. Chronic wounds were induced in the experimental group. Rats were euthanized on the 28th day of the experiment. In the blood serum, the insulin, cortisol, IFN-γ, and TGF-β1 levels were determined by enzyme immunoassay. Histological examination was carried out using generally accepted methods. Results. It was shown that the concentrations of insulin, cortisol, and TGF-β1 in animals of the experimental group were almost doubled compared to intact rats. The level of IFN-γ in animals with wounds was 1.2 times lower than in intact rats. Microscopic examination showed that the wounds were at the stage of remodeling. At the same time, signs of inflammation are partially preserved, which may indicate chronicity of the reparative process. Conclusions. Understanding the mechanisms of reparative processes during wound healing will allow for the development of clinical protocols to improve care for patients with injuries.

Dandelion-shaped strontium-gallium microparticles for the hierarchical stimulation and comprehensive regulation of wound healing.

The management of full-thickness skin injuries continues to pose significant challenges. Currently, there is a dearth of comprehensive dressings capable of integrating all stages of wound healing to spatiotemporally regulate biological processes following full-thickness skin injuries. In this study, we report the synthesis of a dandelion-shaped mesoporous strontium-gallium microparticle (GE@SrTPP) achieved through dopamine-mediated strontium ion biomineralization and self-assembly, followed by functionalization with gallium metal polyphenol networks. As a multifunctional wound dressing, GE@SrTPP can release bioactive ions in a spatiotemporal manner akin to dandelion seeds. During the early stages of wound healing, GE@SrTPP demonstrates rapid and effective hemostatic performance while also exhibiting antibacterial properties. In the inflammatory phase, GE@SrTPP promotes M2 polarization of macrophages, suppresses the expression of pro-inflammatory factors, and decreases oxidative stress in wounds. Subsequently, during the stages of proliferation and tissue remodeling, GE@SrTPP facilitates angiogenesis through the activation of the Hypoxia-inducible factor-1α/vascular endothelial growth factor (HIF-1α/VEGF) pathway. Analogous to the dispersion and rooting of dandelion seeds, the root-like new blood vessels supply essential nutrients for wound healing. Ultimately, in a rat chronic wound model, GE@SrTPP achieved successful full-thickness wound repair. In summary, these dandelion-shaped GE@SrTPP microparticles demonstrate comprehensive regulatory effects in managing full-thickness wounds, making them highly promising materials for clinical applications.

Dynamic control of mTORC1 facilitates bone healing in mice

Bone healing requires well-orchestrated sequential actions of osteoblasts and osteoclasts. Previous studies have demonstrated that the mechanistic target of rapamycin complex 1 (mTORC1) plays a critical role in the metabolism of osteoblasts and osteoclasts. However, the role of mTORC1 in bone healing remains unclear. Here, we showed that a dynamic change in mTORC1 activity during the process was essential for proper healing and can be harnessed therapeutically for treatment of bone fractures. Low mTORC1 activity induced by osteoblastic Raptor knockout or rapamycin treatment promoted osteoblast-mediated osteogenesis, thus leading to better bone formation and shorter bone union time. Rapamycin treatment in vitro also revealed that low mTORC1 activity enhanced osteoblast differentiation and maturation. However, rapamycin treatment affected the recruitment of osteoclasts to new bone sites, thus resulting in delayed callus absorption in bone marrow cavity. Mechanistically, decreased mTORC1 activity inhibited the recruitment of osteoclast progenitor cells to healing sites through a decrease in osteoblastic expression of monocyte chemoattractant protein-1, thus inhibiting osteoclast-mediated remodeling. Therefore, normal mTORC1 activity was necessary for bone remodeling stage. Furthermore, through the use of sustained-release materials at the bone defect, we confirmed that localized application of rapamycin in early stages accelerated bone healing without affecting bone remodeling. Together, these findings revealed that the activity of mTORC1 continually changed during bone healing, and staged rapamycin treatment could be used to promote bone healing.

Freestanding Hydrogen-Bonded Organic Framework Membrane for Efficient Wound Healing.

Hydrogen-bonded organic frameworks (HOFs) are emerging as multifunctional materials with exceptional biocompatibility, abundant active sites, and tunable porosity, which are highly beneficial for advanced wound care. However, a significant challenge involves transforming pristine HOFs powders into lightweight, ultrathin, freestanding membranes compatible with soft biological systems. Herein, the study successfully develops shape-adaptive HOF-based matrix membranes (HMMs) using a polymer-assisted liquid-air interface technique. The HMMs conform seamlessly to tissues of different sizes and shapes, effectively stopping bleeding, and provide high water-vapor permeability. Notably, both in vitro and in vivo studies with mice wound models demonstrated that these tissue-conformable HMMs significantly accelerate wound healing by modulating the inflammatory environment of the injured tissue and promoting rapid re-epithelialization. Furthermore, RNA-seq analysis and mechanistic studies revealed that HMMs effectively reduce inflammation and facilitate the tissue transition from the proliferative stage to the remodeling stage of skin development. This work not only opens up new avenues for advanced wound care materials but also establishes a foundation for hybridizing HOFs with polymers for a wide range of potential applications.

Alpha(α)-mangostin (Xanthone of Garcinia mangostana L.): Augmenting Macrophages Activity for an Effective Diabetic Wound Healing

Diabetic wounds are particularly difficult to treat medically because they heal at a slower pace than regular wounds. Macrophages are essential in all stages of normal wound healing, including inflammation, proliferation and rem odelling. When wound healing is affected, macrophages can reduce the level of growth factor and increase the level of interleukin-6 (IL-6), disrupt the balance between tissue inhibitors of metalloproteinase (TIMPs) and matrix metalloproteinase (MMPs), which can slow down healing. Alpha(α)-mangostin, a natural xanthone derived from the pericarp of the mangosteen, has gained considerable attention due to its anti-inflammatory properties, suggesting its potential to promote wound healing. However, its exact role in healing diabetic foot ulcers, common in diabetes, remains unclear. Hence, this study aims to explore how α-mangostin might affect diabetic wound healing by evaluating its impact on PDGF, CTGF, BFGF, VEGF, TGF-β, MMP-9, TIMP-2 and IL-6 secretion in macrophage cells. Human monocytic macrophages (THP-1) were incubated with a 35 mM glucose solution for 72 h to create a glucose-enriched medium. The cells were then incubated with α-mangostin (0.15, 2.5 and 5 µg/mL) together with 35 mM glucose. Carboxymethyl cellulose (CMC) served as positive controls; glucose-enriched media and media-alone served as negative controls. Protein expression was measured using ELISA. α-mangostin (2.5 µg/mL) increased the levels of PDGF and VEGF and decreased the level of MMP-9 compared to glucose controls. There was no significant difference in other growth factors, TIMP-2 and IL-6 protein levels across any of the treatment groups compared to glucose controls. In conclusion, α-mangostin particularly at 2.5 µg/mL demonstrated a significant increase in PDGF and VEGF levels while simultaneously reducing MMP-9 in macrophage cells under glucose-induced conditions. These findings suggest that α-mangostin holds the potential for enhancing the healing of chronic wounds in diabetic conditions. HIGHLIGHTS Treatment of macrophages (THP-1 cells) with 2.5 µg/mL Alpha (α)-mangostin in a high glucose medium led to a significant increase in PDGF and VEGF secretion compared to glucose control. Treatment of the cells with 2.5 µg/mL Alpha (α)-mangostin in a high glucose medium led to a significant reduction of MMP-9 secretion compared to glucose control. There is no significant effects of Alpha (α)-mangostin on IL-6 and TIMP secretion compared to controls This study suggests that Alpha (α)-mangostin may be beneficial in promoting diabetic wound healing via stimulation of PDGF and VEGF secretion and reducing MMP-9 levels. GRAPHICAL ABSTRACT

Utility of ultrasound imaging in monitoring fracture healing in rat femur: Comparison with other imaging modalities

ObjectiveFractures are common injuries and various imaging modalities are employed to diagnose and monitor bone union. However, the follow-up of fracture healing using ultrasound imaging (US) remains a topic of debate. In this study, we analyzed of fracture healing process and compared US and radiological analyses with histological analyses to clarify the characteristics and limitations of each modality. MethodsAn osteotomy model was created using the femur of Wistar rats, and US, radiological (radiography and micro-computed tomography (micro-CT)), and histological analyses were performed. Radiological assessments were conducted for the evaluation of calcified tissue. The gap between the bony callus and cartilaginous callus was measured. ResultsUS effectively captured changes on the fracture surface, potentially reflecting the early healing processes. Both US and radiographic findings showed strong correlation in terms of the decrease in the bony callus gap. US was unable to distinguish cartilaginous callus from the surrounding soft tissue. During the remodeling stage, micro-CT offered a detailed assessment of the internal fracture surface, whereas US was limited to evaluating the outer bone surface and lacked accuracy in visualizing the entire fracture site. Radiography provided a general overview of the fractures. The decrease in the bony callus gap measured using US correlated with the reduction in cartilaginous callus observed histologically. ConclusionThis study demonstrated that US could be a valuable tool for evaluating fracture healing. Combining fracture management with US and radiological examinations may provide a more accurate assessment of healing progress.

Rapid correction of chronic hyperglycemia and bone remodeling, warning against overdoing.

It is widely recognized that chronic hyperglycemia decreases bone quality, although little is known about the impact of the rapid correction of chronic hyperglycemia on the quality of bone remodeling. This spotlight article explores this correlation by focusing on the stages of bone remodeling linked to glucose levels.

In Vitro Wound-Healing Potential of Phenolic and Polysaccharide Extracts of Aloe vera Gel.

The present study aimed to conduct a comparative investigation of the biological properties of phenolic and polysaccharide extracts obtained using an ultrasound-assisted technique from Aloe vera gel and their effects on each stage of the wound healing process in in vitro experimental models. HPLC analysis showed that the phenolic extract contained aloin, ferulic, and caffeic acid, as well as quercetin dihydrate, as major compounds. Capillary zone electrophoresis indicated the prevalence of mannose and glucose in the polysaccharide extract. Cell culture testing revealed the anti-inflammatory properties of the phenolic extract at a concentration of 0.25 mg/mL through significant inhibition of pro-inflammatory cytokines-up to 28% TNF-α and 11% IL-8 secretion-in inflamed THP-1-derived macrophages, while a pro-inflammatory effect was observed at 0.5 mg/mL. The phenolic extract induced 18% stimulation of L929 fibroblast proliferation at a concentration of 0.5 mg/mL, enhanced the cell migration rate by 20%, and increased collagen type I synthesis by 18%. Moreover, the phenolic extract exhibited superior antioxidant properties by scavenging free DPPH (IC50 of 2.50 mg/mL) and ABTS (16.47 mM TE/g) radicals, and 46% inhibition of intracellular reactive oxygen species (ROS) production was achieved. The polysaccharide extract demonstrated a greater increase in collagen synthesis up to 25%, as well as antibacterial activity against Staphylococcus aureus with a bacteriostatic effect at 25 mg/mL and a bactericidal one at 50 mg/mL. All these findings indicate that the phenolic extract might be more beneficial in formulations intended for the initial phases of wound healing, such as inflammation and proliferation, while the polysaccharide extract could be more suitable for use during the remodeling stage. Moreover, they might be combined with other biomaterials, acting as efficient dressings with anti-inflammatory, antioxidant, and antibacterial properties for rapid recovery of chronic wounds.

Vitamin D status in healing of distal humeral fractures: Clinical observations.

Fracture healing is a complex biological process that begins soon after a fracture has occurred. Whereas the role of vitamin D status on the maintenance of bone health is well established, the clinical effects of vitamin D deficiency in the healing of distal humeral fractures are less well explored. This study examines the role of vitamin D serum levels in distal humeral fractures (C2, C3) managed with open reduction and double plate fixation, by comparing its concentration in patients with or without radiographic signs of fracture healing and in control subjects. Our hypothesis is that 6 months from treatment vitamin D levels will be different between the groups of patients. We measured the vitamin D serum level in a cohort of consecutive adult patients aged 30 to 60 years. They included a group of subjects without fractures who were admitted to our clinic in the 6 months preceding the study (controls) and two groups of patients with humeral fractures who at 6-month follow-up showed or failed to show radiological signs of fracture healing. The mean vitamin D concentration was 23.03 μg/L (±5.8) in the group with radiographic signs of fracture healing, 9.30 μg/L (±2.60) in the group with radiographic signs of delayed union and 26.15 μg/L (±11.76 μg/L) in the control group. Significantly different (p < 0.05) concentrations were measured between the fracture groups, between the group with radiographic signs of fracture healing and the control group and between the group with radiographic signs of delayed union and the control group. Vitamin D is primarily involved in the stages of hard callus formation and remodelling. It also has several functions that affect the early stages of fracture healing. Vitamin D influences the cellular process of bone healing, although the underlying mechanism is still partly unclear. It would be useful to determine the vitamin D status of fracture patients at admission and to start supplementation, with periodic checks, to foster the consolidation phase. Although vitamin D is clearly not the only factor influencing the consolidation of a surgically treated distal humerus fracture, its concentration can easily be determined and managed. Our data suggest that vitamin D levels should be determined at admission and that fracture patients with low concentrations should be started on vitamin D supplementation.

Oxygen-Propelled Dual-Modular Microneedles with Dopamine-Enhanced RNA Delivery for Regulating Each Stage of Diabetic Wounds.

Diabetic wounds are characterized by the disruption and cessation of essential healing stages, which include hemostasis, inflammation, proliferation, and remodeling. However, traditional treatments for diabetic wounds concentrate on individual stages of the healing process. Herein, this study utilizes mask-mediated sequential polymerization and varied cross-linking techniques to develop dual-modular microneedles (MNs) with fast- and slow-module, exhibiting varying degradation rates tailored for the full spectrum of diabetic wound healing. First, MNs incorporating calcium ions and dopamine synergistically promote rapid hemostasis. Second, fast-module physically cross-linked MNs rapidly D-mannose/dopamine-enhanced tripolyphosphate-quaternized chitosan (mDTC) nanoparticles (NPs) loaded with microRNA-147 (miRNA-147) to manage inflammation and oxidative stress in diabetic wounds. Additionally, dopamine in these NPs enhances their internalization and safeguards miRNA-147 from oxidative stress and RNase degradation. Finally, slow-module chemically cross-linked MNs facilitate the continuous release of deferoxamine (DFO) and dopamine, accelerating angiogenesis and tissue regeneration during the proliferation and remodeling stages. Manganese/dopamine-enhanced calcium peroxide NPs within the MNs initiate a blast-like generation of oxygen bubbles, not only enhancing the delivery of miRNA-mDTC NPs and DFO but also alleviating tissue hypoxia. Consequently, dual-modular MNs are instrumental in promoting rapid and complete healing of diabetic wounds through all stages of healing.

Abstract Tu004: Global distribution of cardiac exosomes after myocardial infarction

Background: Exosomes’ beneficial effects on the injured hearts show promising results. Understanding the biodistribution and kinetics of cardiac exosomes during myocardial infarction (MI) is crucial for exploring the underlying mechanisms. Aim: We aimed to elucidate dynamic biodistributions of cardiomyocyte-released exosomes in MI hearts at post-MI day 3 and day 14, representing the acute and remodeling stages, respectively. We employed the cardiac exosome reporter mice expressing CD63NanoLuc to track the endogenous cardiac exosomes. Method: The NanoLuc reporter mice underwent MI surgery (n=3-12/group). Reporter expression was induced by tamoxifen injection. To assess post-MI cardiac exosome distribution via circulation, fourteen organs, and plasma exosomes were harvested for luciferase activity quantification at each time point. Bioluminescence analysis was conducted in isolated cardiac fibroblasts, endothelial cells, and leukocytes to profile exosome-mediated paracrine signaling. Result: Plasma exosome luciferase activities were consistent across groups. A decline in bioluminescent levels was observed in all organs at both time points, with significant differences in the pancreas, thyroid, kidney, lung, and thymus (p&lt;0.05). Day 3 post-MI showed increased heart endothelial cell bioluminescence in risk and remote areas (p=0.0007), whereas day 14 showed decreased bioluminescence in cardiac fibroblasts in both areas (p=0.0029 and p=0.0086). Endothelial cells and leukocytes exhibited a ten-fold higher exosome uptake than cardiac fibroblasts. Conclusion: There was a significant decrease in exosome uptake by major organs from the injured heart. Cardiac endothelial cells and fibroblasts demonstrated dynamic exosome uptake changes, with endothelial cells and leukocytes showing notably higher uptake compared to fibroblasts.

Expression of Osteopontin and Gremlin 1 Proteins in Cardiomyocytes in Ischemic Heart Failure.

A relevant role of osteopontin (OPN) and gremlin 1 (Grem1) in regulating cardiac tissue remodeling and formation of heart failure (HF) are documented, with the changes of OPN and Grem1 levels in blood plasma due to acute ischemia, ischemic heart disease-induced advanced HF or dilatative cardiomyopathy being the primary focus in most of these studies. However, knowledge on the early OPN and Grem1 proteins expression changes within cardiomyocytes during remodeling due to chronic ischemia remains insufficient. The aim of this study was to determine the OPN and Grem1 proteins expression changes in human cardiomyocytes at different stages of ischemic HF. A semi-quantitative immunohistochemical analysis was performed in 105 myocardial tissue samples obtained from the left cardiac ventricles. Increased OPN immunostaining intensity was already detected in the stage A HF group, compared to the control group (p < 0.001), and continued to increase in the stage B HF (p < 0.001), achieving the peak of immunostaining in the stages C/D HF group (p < 0.001). Similar data of Grem1 immunostaining intensity changes in cardiomyocytes were documented. Significantly positive correlations were detected between OPN, Grem1 expression in cardiomyocytes and their diameter as well as the length, in addition to positive correlation between OPN and Grem1 expression changes within cardiomyocytes. These novel findings suggest that OPN and Grem1 contribute significantly to reorganization of cellular geometry from the earliest stage of cardiomyocyte remodeling, providing new insights into the ischemic HF pathogenesis.

Sequence analysis of microbiota in clinical human cases with diabetic foot ulcers from China

BackgroundDiabetic foot ulcers (DFU) seriously threaten the health and quality of life of patients. The microbiota is the primary reason for the refractory and high recurrence of DFU. This study aimed to determine the wound microbiota at different DFU stages. MethodsWound samples were collected from 48 patients with DFU and divided into three phases: inflammatory (I, n = 49), proliferation (P, n = 22), and remodeling (R, n = 19). The wound samples obtained at different stages were then subjected to 16S rRNA gene sequencing. The number of operational taxonomic units (OTUs) in the different groups was calculated according to the criterion of 97 % sequence similarity. The diversity of the microbiota differentially presented bacterial taxa at the phylum and genus levels, and important phyla and genera in the different groups were further explored. ResultsAfter sequencing, 3351, 925, and 777 OTUs were observed in groups I, P, and R, respectively, and 175 OTUs overlapped. Compared with the inflammatory stage, the α-diversity of wound microbiota at proliferation and remodeling stages was significantly decreased (P < 0.05). At the phylum level, Firmicutes, Proteobacteria, Actinobacteriota, and Bacteroidota were the dominant phyla, accounting for more than 90 % of all the phyla. At the genus level, Random Forest and linear discriminant analysis effect size analyses showed that Peptoniphilus, Lactobacillus, Prevotella, Veillonella, Dialister, Streptococcus, and Ruminococcus were the signature wound microbiota for the inflammatory stage; Anaerococcus, Ralstonia, Actinomyces, and Akkermansia were important species for the proliferation stage; and the crucial genera for the remodeling stage were Enterobacter, Pseudomonas, Sondgrassella, Bifidobacterium, and Faecalibacterium. ConclusionsThere were significant differences in the composition and structure of the wound microbiota in patients with DFU at different stages, which may lay a foundation for effectively promoting wound healing in DFU.

Poster 367: Nano-Semiconductor Fibers in a Commercial Compression Sleeve Accelerates Healing of Achilles Tendon Injury in a Rat Model

Objectives: Commercial compression sleeves have been promoted to ameliorate pain secondary to arthritis and tendinopathy. The fabric of one particular sleeve is embedded with nano-semiconductor fibers that reflect thermal energy produced by the body at a photonic wavelength mimicking low-level laser therapy. The device is theorized to accelerate the inflammatory stage of tissue healing to reach the proliferation and remodeling stages at faster rates. Previous clinical studies have shown a significant improvement in patient-reported outcomes between patients who did and did not use this sleeve to treat osteoarthritis. The objective of this investigation was to determine if compression sleeves embedded with nano-semiconductor fibers can accelerate Achilles tendon healing in a rabbit model. Methods: Twelve New Zealand White rabbits—under IACUC approval—were administered intratendinous injections of 0.2% collagenase into the right Achilles tendon to simulate an acute tendon injury. Rabbits were divided into three groups: group I received the commercial compression sleeve without nano-semiconductors (n = 4), group II received the sleeve with nano-semiconductors (n = 4), and group III received an alternate sleeve design also with nano-semiconductors (n = 4). Calf circumference measurements and thermal radiation imaging of the right lower leg of each rabbit were collected days 7, 14, 21, and 28 post-injection. Two rabbits from each group were sacrificed at the 14-day and 28-day marks and the right Achilles tendons were harvested. Histological analysis using picrosirius red staining was performed to evaluate tissue organization. A custom MATLAB program (MathWorks, Natick, MA) was used to quantify the collagen fiber dispersion within the Achilles tendon samples. Results: A statistically significant difference in calf circumference was found at the 28-day mark between group I versus groups II and III: group I had an average calf circumference of 5.2 cm while groups II and III had an average calf circumference of 4.85 cm (p = 0.036) and 4.60 cm (p = 0.021) respectively. Additionally, after 28 days, group I demonstrated an average pixel density intensity on thermal radiation imaging of 1,531,192 while groups II and III yielded average pixel density intensities of 1,363,515 (p = 0.008) and 1,335,456 (p = 0.003) respectively. Histological staining showed observable alterations in collagen architecture, with group I displaying widespread disorganization and degradation of type I and type III collagen fibers near the injection site. Groups II and III displayed greater organization at the 28-day mark in comparison to group I, with signs of tissue proliferation and remodeling evident. No statistically significant differences were found between group I versus groups II and III regarding collagen fiber dispersion at both the 2-week mark (p = 0.145, p = 0.236) and the 4-week mark (p = 0.113, p = 0.268), respectively. Conclusions: The nano-semiconductor fibers embedded within a commercial sleeve significantly decreased swelling and temperature of the lower leg 28 days following acute Achilles tendon injury in a rabbit model. Furthermore, histologic analysis demonstrated greater collagen fiber and extracellular matrix organization as well as greater proliferation of type III collagen suggesting a faster transition to the proliferation stage of tissue healing.

Features of the regulation of reparative processes of chronic wounds in response to the effect of photobiomodulation therapy on a wound defect. Photobiomodulation therapy for chronic wounds.

One of the promising methods of influencing the wound process is photobiomodulation (PBM) therapy. The optimal parameters of PBM therapy have not yet been found because the molecular mechanisms of light interaction with tissue are not fully understood. Studying the influence of PBM of various parameters on the regulation of reparative process- es of chronic wounds using the example of indicators of aggregation activity of platelets, platelet-derived growth factor (PDGF), interleukin-8 (IL-8), and amino-terminal propeptide of type III procollagen (PIIINP) at the remodeling stage. And also the study of the structural and functional features of chronic wound heal- ing in an experiment under various parameters of PBM therapy. Experiments were carried out on Wistar rats. Chronic wounds were simulated. Experimental animals were exposed to PBM at a wavelength of 660 nm and an energy density of 1 J/cm2. In serum, PDGF, IL-8, and PIIINP levels were measured by enzyme-linked immunosorbent assay. The functional activity of platelets was measured using the turbidimetric method. Histological analysis was performed. The work noted the dose-dependent effect of PBM using the example of platelet aggregation at the remodeling stage during the healing of chronic wounds. The use of PBM therapy resulted in increased serum PDGF levels. Histological examination data indicate a positive effect of PBM therapy on the wound healing process. The effectiveness of the use of PBM therapy for the healing of chronic wounds to regulate reparative processes has been proven.

Deformable microlaser force sensing

Mechanical forces are key regulators of cellular behavior and function, affecting many fundamental biological processes such as cell migration, embryogenesis, immunological responses, and pathological states. Specialized force sensors and imaging techniques have been developed to quantify these otherwise invisible forces in single cells and in vivo. However, current techniques rely heavily on high-resolution microscopy and do not allow interrogation of optically dense tissue, reducing their application to 2D cell cultures and highly transparent biological tissue. Here, we introduce DEFORM, deformable microlaser force sensing, a spectroscopic technique that detects sub-nanonewton forces with unprecedented spatio-temporal resolution. DEFORM is based on the spectral analysis of laser emission from dye-doped oil microdroplets and uses the force-induced lifting of laser mode degeneracy in these droplets to detect nanometer deformations. Following validation by atomic force microscopy and development of a model that links changes in laser spectrum to applied force, DEFORM is used to measure forces in 3D and at depths of hundreds of microns within tumor spheroids and late-stage Drosophila larva. We furthermore show continuous force sensing with single-cell spatial and millisecond temporal resolution, thus paving the way for non-invasive studies of biomechanical forces in advanced stages of embryogenesis, tissue remodeling, and tumor invasion.

Inflammatory microenvironment regulation and osteogenesis promotion by bone-targeting calcium and magnesium repletion nanoplatform for osteoporosis therapy

Osteoporosis is the most common bone metabolic disease that affects the health of middle-aged and elderly people, which is hallmarked by imbalanced bone remodeling and a deteriorating immune microenvironment. Magnesium and calcium are pivotal matrix components that participate in the bone formation process, especially in the immune microenvironment regulation and bone remodeling stages. Nevertheless, how to potently deliver magnesium and calcium to bone tissue remains a challenge. Here, we have constructed a multifunctional nanoplatform composed of calcium-based upconversion nanoparticles and magnesium organic frameworks (CM-NH2-PAA-Ald, denoted as CMPA), which features bone-targeting and pH-responsive properties, effectively regulating the inflammatory microenvironment and promoting the coordination of osteogenic functions for treating osteoporosis. The nanoplatform can efficaciously target bone tissue and gradually degrade in response to the acidic microenvironment of osteoporosis to release magnesium and calcium ions. This study validates that CMPA possessing favorable biocompatibility can suppress inflammation and facilitate osteogenesis to treat osteoporosis. Importantly, high-throughput sequencing results demonstrate that the nanoplatform exerts a good inflammatory regulation effect through inhibition of the nuclear factor kappa-B signaling pathway, thereby normalizing the osteoporotic microenvironment. This collaborative therapeutic strategy that focuses on improving bone microenvironment and promoting osteogenesis provides new insight for the treatment of metabolic diseases such as osteoporosis.

Primary Atriopathy in Mitral Valve Prolapse: Echocardiographic Evidence and Clinical Implications.

Prominent multi-scallop systolic leaflet displacement toward the left atrium (atrialization) is typically observed in bileaflet mitral valve prolapse (MVP) with mitral annular disjunction. We hypothesized that mitral leaflet atrialization is associated with an underlying left atrial (LA) myopathy characterized by progressive structural and functional abnormalities, irrespective of mitral regurgitation (MR) severity. We identified 334 consecutive patients with MVP, no prior atrial fibrillation, and comprehensive clinical and echocardiographic data. LA function was assessed by LA reservoir strain, LA function index, and LA emptying fraction. We also classified the stage of LA remodeling based on LA enlargement and LA reservoir strain (stage 1: no remodeling; stage 2: mild remodeling; stage 3: moderate remodeling; and stage 4: severe remodeling). The primary end point was the composite risk of sudden arrhythmic death, heart failure hospitalization, or the new onset of atrial fibrillation. Bileaflet MVP with no or mild MR had a lower LA reservoir strain (P=0.04) and LA function index (P<0.001) compared with other MVP subtypes. In multivariable linear regression adjusted for cardiovascular risk factors and MR ≥moderate, bileaflet MVP remained significantly associated with lower LA function parameters (all P<0.05). There was a significant increase in the risk of events as the LA reservoir strain and LA remodeling stage increased (P<0.001). In multivariable analysis, stage 4 of LA remodeling remained significantly associated with a higher risk of events compared with stage 1 (hazard ratio, 6.09 [95% CI, 1.69-21.9]; P=0.006). In a large MVP registry, bileaflet involvement is associated with reduced LA function regardless of MR severity, suggesting a primary atriopathy in this MVP subtype. Abnormal LA function, particularly when assessed through a multiparametric approach, is linked to a higher risk of cardiovascular events and may improve risk stratification in MVP, even in those without significant MR.

The importance of scar border zone size in VT presentation and recurrence in post MI patients

Abstract Introduction Available mapping data in post-myocardial infarction patients describe ventricular tachycardia (VT) re-entry circuit characteristics of slow VT, that are typically related to transmural scars. Fast VTs with cycle lengths close to the refractory period may be related to functional re-entry in the scar border zone. Functional re-entry related border zone VTs may be difficult to control by ablation. Purpose The aims of this study are (1) to describe electroanatomical voltage map (EAVM) characteristics in post myocardial infarction (MI) patients with spontaneous and inducible fast VTs and (2) to assess the relation between scar border zone size and ablation outcomes. Methods Consecutive post-MI patients undergoing VT ablation at a tertiary referral center from January 2012 to November 2018 were included. Fast VT was defined as a VT cycle length (VTCL) = ventricular refractory period + max. 30ms. Areas of scar border zone (using 0.5 – 2.1mV/3.0mV cut-offs (according to LV remodeling stage; LVEF&amp;lt;47% and LV end-systolic volume index of &amp;gt;50 ml/m2)) were measured on the EAVM and correlated with clinical outcomes. Results In total, 138 patients were included (86% male; left ventricular ejection fraction 35±10%; 86% remodeled LV). Twenty-three patients (17%) had ≥1 fast VT (mean VTCL 275±52ms) at presentation, mean VTCL of the remaining patients 397±88ms). The median scar border zone size was 27% [IQR 20-38] of the left ventricular endocardial surface. Patients who presented with a spontaneous fast VT had a larger border zone than patients with slower VT (32% [IQR 28 – 41] vs. 25% [IQR 16 – 36], p=0.01). After ablation, 79 (57%) patients remained inducible for any VT, including 59/79 (75%) for a fast VT (median VTCL fast VT 260ms [IQR 236 -280]). Patients who remained inducible for fast VTs had a larger border zone than patients who remained inducible for slower VTs (35% [IQR 27 – 44] vs. 26% [IQR 20 – 36], p&amp;lt;0.001). During a median follow-up of 26 months [IQR 8 – 47], 45 patients (33%) had a VT recurrence (mean VTCL 357±98ms). Patients with a below median (27%) scar border zone area had a lower VT recurrence rate compared to patients with an above median scar border zone area (recurrence rate: 16/66 (24%) vs. 29/72 (40%), p=0.03). Kaplan-Meier survival analysis showed better free VT survival in the below median border zone patients (Log-rank: p&amp;lt;0.05) (Figure 1). Conclusion Patients who present with spontaneous fast VTs or who remain inducible for fast VTs after ablation have larger scar border zones during EAVM compared to patients with presenting or remaining slower VTs. A larger border zone appeared to be associated with higher VT-recurrence rates. The scar border zone may play an important role as VT substrate for (fast) VTs and may not be easily targeted by current ablation techniques.VT-free survival stratified by median BZ