Injured Site Research Articles

Anti – intercellular adhesion molecule-1(ICAM-1) nanoparticles for damaged endothelium to treat venous thromboembolism

Venous thromboembolism (VTE) is a potentially fatal vascular disease that can be successfully managed to reduce the risk of mortality and impairment. Anticoagulation therapy is frequently recommended for the treatment and prevention of venous thromboembolism. Despite breakthroughs in anticoagulant therapy using parenteral anticoagulant medications and vitamin K antagonists, limits in their usage persist, prompting research into alternative anticoagulants such as factor Xa inhibitors. Of the agents under development, edoxaban shows the most promise due to strong data confirming its therapeutic benefit for VTE. Nanoparticle drug delivery systems (NDDS) are designed technologies that employ nanoparticles to convey therapeutic drugs in a targeted and regulated manner. Intraendothelial transport of therapies in VTE is facilitated by the induction of cell adhesion molecule-mediated endocytosis upon interaction of intercellular adhesion molecule 1 (ICAM-1) on endothelium cells by ICAM-1-targeted carriers. The potential application of NDDS as nanoparticles as anticoagulant agents has been emphasized. There is proof of outstanding efficacy in preventing blood coagulation, dissolving blood clots, and improving in vivo detection of thrombus. These nanoplatforms’ growing evaluations, strong action, enhanced biocompatibility, and lack of problems from excessive bleeding are all positive signs of their possible integration in the clinical treatment of blood coagulation diseases in the future. Additionally, by avoiding biological barriers and enhancing a medication’s therapeutic index, NDDSs offer superior drug delivery to targeted treatment or even directly to the injured site as compared to standard anticoagulants. Emerging scientific and clinical data suggests that NDDS may be a safe, efficacious, and attractive treatment option for a variety of cardiovascular disorders, including thromboembolic syndromes. This study presents an updated knowledge of nanocarriers for thrombosis as well as an outline of recent significant breakthroughs in targeted thrombosis therapy.

Can a complete excision of the injured site of the spinal cord lead to positive results?

Until now, there are no successful ways to restore the damaged spinal cord and its functions in severe spinal cord injury such as spinal cord contusion, rupture or intersection. This is largely due to the lack of treatment methods aimed at the chain of pathogenetic processes occurring in the nervous tissue after injury. The topic of restoration of spinal cord functions is taboo, often undesirable for discussion, and is influenced by clinical stereotypes. The article proposes to consider the method of treatment of spinal cord injury, using modern data, taking into account emerging pathophysiological processes at the site of injury and beyond. The use of new data and achievements of experimental science on severe spinal cord injury can be a serious step towards the development of new methods for the treatment of this pathology.

Synthesis, Characterizations and Optimization of Magnesium Oxide Scaffold for Bone Healing Applications

In this work, the structural properties of Magnesium oxide nanoparticles (MgONPs) are synthesized by a simple chemical technique. X-ray diffraction pattern (XRD) pattern showed the crystalline nature of MgO NPs. The average diameter of MgO NPs calculated by SEM and XRD was around 19 nm. Energy dispersive X-ray spectroscopy (EDS) spectrum and XRD pattern suggested that prepared MgO NPs were highly pure. The viability of cells in a medium containing MgO-AV composite scaffold was nearly equal to that of MgO, AV, and control, with no statistically significant difference (p>0.05). The Runx2-mediated modulation of gene expressions of the bone biomarkers ALP and OCN was investigated to determine the mechanism of scaffold-induced improvement in bone repair. ALP was immunodetected in the injured site of the right femur twenty-one days after the bone defects were created. The implantation of scaffolds into the bone defect region of the left femur, on the other hand, resulted in a noticeable increase in ALP levels. Similarly, OCN was immunodetected in the right femur's bone defect site. The implantation of scaffolds into the bone defect location of the left femur, on the other hand, resulted in a significant increase in OCN levels. The low-level diode laser therapy (LLLT) promotes the partially bony incorporation of the xeno bony implantation with the recipient femoral bone, and can successfully fill the space, and support the weight after removing the internal fixation methods, with no body rejection. The histopathological finding at the end of the 6th week post-operation in treatment groups the trabecular bone is mature and wide with little cavity. The control group showed immature and thin trabecular bone, with large cavities, and an area of connective tissues not organized. At the end of 12th weeks, post-operation the treatment groups revealed mature trabecular bone surrounding the bony device and lamellar bone formation with partial bony incorporation, the lacuna and haversian canals of the bony device filled with osteocyte and blood vessels, while in control groups the trabecula bone not mature, and many lucana and havesan canal still empty in the bony device

The pioneer transcription factor Zelda facilitates the exit from regeneration and restoration of patterning in Drosophila.

For a damaged tissue to regenerate, the injured site must repair the wound, proliferate, and restore the correct patterning and cell types. We found that Zelda, a pioneer transcription factor largely known for its role in embryonic zygotic genome activation, is dispensable for normal wing development but crucial for wing disc patterning during regeneration. Impairing Zelda function during disc regeneration resulted in adult wings with a plethora of cell fate errors, affecting the veins, margins, and posterior compartment identity. Using CUT&RUN, we identified and validated targets of Zelda including the cell fate genes cut, Delta and achaete, which failed to return to their normal expression patterns upon loss of Zelda. In addition, Zelda controls expression of factors previously established to preserve cell fate during regeneration like taranis and osa, which stabilizes engrailed expression during regeneration, thereby preserving posterior identity. Finally, Zelda ensures proper expression of the integrins encoded by multiple edematous wings and myospheroid during regeneration to prevent blisters in the resuting adult wing. Thus, Zelda is crucial for maintaining cell fate and structural architecture of the regenerating tissue.

An injectable refrigerated hydrogel for inducing local hypothermia and neuroprotection against traumatic brain injury in mice

BackgroundHypothermia is a promising therapy for traumatic brain injury (TBI) in the clinic. However, the neuroprotective outcomes of hypothermia-treated TBI patients in clinical studies are inconsistent due to several severe side effects. Here, an injectable refrigerated hydrogel was designed to deliver 3-iodothyronamine (T1AM) to achieve a longer period of local hypothermia for TBI treatment. Hydrogel has four advantages: (1) It can be injected into injured sites after TBI, where it forms a hydrogel and avoids the side effects of whole-body cooling. (2) Hydrogels can biodegrade and be used for controlled drug release. (3) Released T1AM can induce hypothermia. (4) This hydrogel has increased medical value given its simple operation and ability to achieve timely treatment.MethodsPol/T hydrogels were prepared by a low-temperature mixing method and characterized. The effect of the Pol/T hydrogel on traumatic brain injury in mice was studied. The degradation of the hydrogel at the body level was observed with a small animal imager. Brain temperature and body temperature were measured by brain thermometer and body thermometer, respectively. The apoptosis of peripheral nerve cells was detected by immunohistochemical staining. The protective effect of the hydrogels on the blood–brain barrier (BBB) after TBI was evaluated by the Evans blue penetration test. The protective effect of hydrogel on brain edema after injury in mice was detected by Magnetic resonance (MR) in small animals. The enzyme linked immunosorbent assay (ELISA) method was used to measure the levels of inflammatory factors. The effects of behavioral tests on the learning ability and exercise ability of mice after injury were evaluated.ResultsThis hydrogel was able to cool the brain to hypothermia for 12 h while maintaining body temperature within the normal range after TBI in mice. More importantly, hypothermia induced by this hydrogel leads to the maintenance of BBB integrity, the prevention of cell death, the reduction of the inflammatory response and brain edema, and the promotion of functional recovery after TBI in mice. This cooling method could be developed as a new approach for hypothermia treatment in TBI patients.ConclusionOur study showed that injectable and biodegradable frozen Pol/T hydrogels to induce local hypothermia in TBI mice can be used for the treatment of traumatic brain injury.Graphical

Gym and Fitness Injuries amongst those Aged 16–64 in New Zealand: Analysis of Ten Years of Accident Compensation Corporation Injury Claim Data

BackgroundTo provide epidemiological data for minor and moderate-to-serious injury claims for gym and fitness related injuries amongst those aged 16–64 in New Zealand, to inform the development of an injury prevention program.MethodsRetrospective analytical review of gym and fitness related injury entitlement minor and moderate- to-serious Accident Compensation Corporation (ACC) claims from 1 July 2011 to 30 June 2020. Data were analysed by cause of injury, geographical region, sex, age, body site and injury type. Qualitative analysis of free text describing the activity causing the injury was conducted.ResultsOver the ten-year period, 16–64 year olds made 345,254 injury claims, costing ACC NZ$241,298,275 in treatment charges. Soft tissue injuries were the most prevalent making up 96% (331,343) of all claims and 88% (NZ$213,049,197) of the total charges. Strenuous movement with lifting (n = 154,467, 47%), strenuous movement without lifting (n = 84,469, 25%), impact/contact with object (n = 39,610, 12%) and impact/contact with ground (n = 25,351, 8%) were the top four mechanisms resulting in injury, accounting for 92% of soft tissue injuries. Males and females aged 21 to 30 years old were most frequently injured. The four most injured body sites (lower back/spine, shoulder, knee, neck/back of head) accounted for 63% of injuries in females, and 65% in males.ConclusionsThe most common cause of injury from gym and fitness activity claims in 16–64 year olds in New Zealand was lifting/carrying/strain resulting in lower back/spine and shoulder (including clavicle/blade) soft tissue injuries. Soft tissue injuries accounted for 96% of the total claims. Males and females aged 21 to 30 years old were most frequently injured age group.

Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration

Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies, resulting in severe disability. Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation. However, different clusters of macrophages have various functions and receive multiple regulation, which are both still unknown. In our current study, multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury. The transcriptomes of over 74 000 human single cells were profiled. As results, we found that SPP1+ macrophages, RGCC+ endothelial cells, ACKR1+ endothelial cells and ADAM12+ fibroblasts participated in tendon adhesion formation. Interestingly, despite specific fibrotic clusters in tendon adhesion, FOLR2+ macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells. Furthermore, ACKR1 was verified to regulate FOLR2+ macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26RtdTomato mice to lethally irradiated Ackr1−/− mice (Ackr1−/− chimeras; deficient in ACKR1) and control mice (WT chimeras). Compared with WT chimeras, the decline of FOLR2+ macrophages was also observed, indicating that ACKR1 was specifically involved in FOLR2+ macrophages migration. Taken together, our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis, but also uncovered a novel antifibrotic cluster of macrophages and their origin. These results provide potential therapeutic targets against human tendon adhesion.

Innovative Vancomycin-Loaded Hydrogel-Based Systems - New Opportunities for the Antibiotic Therapy.

Surgical site infections pose a significant challenge for medical services. Systemic antibiotics may be insufficient in preventing bacterial biofilm development. With the local administration of antibiotics, it is easier to minimize possible complications, achieve drugs' higher concentration at the injured site, as well as provide their more sustained release. Therefore, the main objective of the proposed herein studies was the fabrication and characterization of innovative hydrogel-based composites for local vancomycin (VAN) therapy. Presented systems are composed of ionically gelled chitosan particles loaded with vancomycin, embedded into biomimetic collagen/chitosan/hyaluronic acid-based hydrogels crosslinked with genipin and freeze-dried to serve in a flake/disc-like form. VAN-loaded carriers were characterized for their size, stability, and encapsulation efficiency (EE) using dynamic light scattering technique, zeta potential measurements, and UV-Vis spectroscopy, respectively. The synthesized composites were tested in terms of their physicochemical and biological features. Spherical structures with sizes of about 200 nm and encapsulation efficiencies reaching values of approximately 60% were obtained. It was found that the resulting particles exhibit stability over time. The antibacterial activity of the developed materials against Staphylococcus aureus was established. Moreover, in vitro cell culture study revealed that the surfaces of all prepared systems are biocompatible as they supported the proliferation and adhesion of the model MG-63 cells. In addition, we have demonstrated significantly prolonged VAN release while minimizing the initial burst effect for the composites compared to bare nanoparticles and verified their desired physicochemical features during swellability, and degradation experiments. It is expected that the developed herein system will enable direct delivery of the antibiotic at an exposed to infections surgical site, providing drugs sustained release and thus will reduce the risk of systemic toxicity. This strategy would both inhibit biofilm formation and accelerate the healing process.

Advances in Material-Assisted Electromagnetic Neural Stimulation.

Bioelectricity plays a crucial role in organisms, being closely connected to neural activity and physiological processes. Disruptions in the nervous system can lead to chaotic ionic currents at the injured site, causing disturbances in the local cellular microenvironment, impairing biological pathways, and resulting in a loss of neural functions. Electromagnetic stimulation has the ability to generate internal currents, which can be utilized to counter tissue damage and aid in the restoration of movement in paralyzed limbs. By incorporating implanted materials, electromagnetic stimulation can be targeted more accurately, thereby significantly improving the effectiveness and safety of such interventions. Currently, there have been significant advancements in the development of numerous promising electromagnetic stimulation strategies with diverse materials. This review provides a comprehensive summary of the fundamental theories, neural stimulation modulating materials, material application strategies, and pre-clinical therapeutic effects associated with electromagnetic stimulation for neural repair. It offers a thorough analysis of current techniques that employ materials to enhance electromagnetic stimulation, as well as potential therapeutic strategies for future applications.

An In Situ-Gelling Conductive Hydrogel for Potential Use in Neural Tissue Engineering.

Cerebral cavitation is usual following acute brain injuries, such as stroke and traumatic brain injuries, as well as after tumor resection. Minimally invasive implantation of an injectable scaffold in the cavity is a promising approach for potential regeneration of tissue loss. This study aimed at designing an in situ-gelling conductive hydrogel containing silk fibroin (SF), brain decellularized extracellular matrix (dECM), and carbon nanotubes (CNT) for potential use in brain tissue regeneration. Two percent w/v SF hydrogels with different concentrations of dECM (0.1%, 0.2%, or 0.3% w/v) and CNTs (0.05%, 0.1%, or 0.25% w/v) were fabricated and characterized. It was observed that with the addition of dECM, the porosity decreased, whereas swelling and electrical conductivity tended to increase. The addition of dECM also led to a faster resorption rate, but no significant change in compressive modulus. Addition of CNTs, on the other hand, led to a denser, stronger, and more regular porous structure, higher swelling ratio, faster gelation time, slower degradation rate, and a significant increase in electrical conductivity. dECM and CNTs combined together resulted in superior porosity, swelling, resorption rate, mechanical properties, and electrical conductivity compared with SF scaffolds containing only dECM or CNTs. Hydrogel samples containing 2% SF, 0.3% dECM, and 0.1% CNTs had a high porosity (58.9%), low swelling ratio (15.9%), high conductivity (2.35 × 10-4 S/m), and moderate degradation rate (37.3% after 21 days), appropriate for neural tissue engineering applications. Cell evaluation studies also showed that the hydrogel systems support the cell adhesion and growth, with no sign of significant cytotoxicity. Impact statement Tissue loss and formation of a fluid-filled cavity following stroke, traumatic brain injury, or brain tumor resection lead to sensorimotor and/or cognitive deficits. The lack of a healthy extracellular matrix in the cavity avoids the endogenous cell migration and axonal sprouting and may also worsen the secondary injuries to peri-lesional tissue. Due to the brain anatomy, simple implantation of tissue engineering scaffolds to the injured site is not possible in many cases. Therefore, the development of injectable scaffolds that support neural growth and differentiation is crucial for tissue repair or limiting the expansion of damage region.

Injectable plant-derived polysaccharide hydrogels with intrinsic antioxidant bioactivity accelerate wound healing by promoting epithelialization and angiogenesis

Skin wound healing is a complex and dynamic process involving hemostasis, inflammatory response, cell proliferation and migration, and angiogenesis. Currently used wound dressings remain unsatisfactory in the clinic due to the lack of adjustable mechanical property for injection operation and bioactivity for accelerating wound healing. In this work, an “all-sugar” hydrogel dressing is developed based on dynamic borate bonding network between the hydroxyl groups of okra polysaccharide (OP) and xyloglucan (XG). Benefiting from the reversible crosslinking network, the resulting composite XG/OP hydrogels exhibited good shear-thinning and fast self-healing properties, which is suitable to be injected at wound beds and filled into irregular injured site. Besides, the proposed XG/OP hydrogels showed efficient antioxidant capacity by scavenging DPPH activity of 73.9 %. In vivo experiments demonstrated that XG/OP hydrogels performed hemostasis and accelerated wound healing with reduced inflammation, enhanced collagen deposition and angiogenesis. This plant-derived dynamic hydrogel offers a facile and effective approach for wound management and has great potential for clinical translation in feature.

Modification of Biodegradable Polymer Nanofibers for Cartilage Tissue Engineering Applications: A Review

Tissue engineering is the use of a combination of cells, engineering and materials methods, and suitable biochemical and physiochemical factors to improve or replace biological functions at the injured site. The designing of a biomaterial that can mimic the three-dimensional tissues in vivo is still challenging. Biodegradable polymers are used for the development of tissue engineering constructs in the form of sponges, films, and macroporous scaffolds, which do not influence cell fate processes such as cell differentiation, migration, and proliferation. Biodegradable polymer nanofibers fabricated by electrospinning have gathered great attention in tissue engineering applications. The electrospun materials have a nanofibrous morphology that is closest to the natural extracellular matrix (ECM). The electrospun material is composed of three-dimensional networks of nanosized fibrous materials that mimic an extracellular matrix such as collagen, elastin, and keratin. These polymers fabricated in the form of fibers in nanosize cause a more favorable microenvironment for cells. We prepared the PLGA/PPG (polylactic-co-glycolic acid/polypropylene glycol) nanofibers by electrospinning technique. PLGA (85:15)/PLGA (75:25) nanofibers are hydrophobic, which can be minimized by the addition of PPG to give better hydrophilicity for cell adhesion for tissue engineering constructs. The morphology of the electrospun fibers of the composite of PLGA and PPG was observed using scanning electron microscopy (SEM). The results proved that the small amount of polypropylene glycol polymer to the polylactic-co-glycolic acid (PLGA 85:15) drastically improves the hydrophilicity of the electrospun nanofibers. The addition of a small amount of hydrophilic polymer to the biodegradable hydrophobic polymer increases the hydrophilic property and can be used for nanofiber-based tissue engineering constructs. In addition, the biomimetic approach for tissue engineering scaffolds for cartilage repair has been discussed.

From Short Circuit to Completed Circuit: Conductive Hydrogel Facilitating Oral Wound Healing.

The primary challenges posed by oral mucosal diseases are their high incidence and the difficulty in managing symptoms. Inspired by the ability of bioelectricity to activate cells, accelerate metabolism, and enhance immunity, a conductive polyacrylamide/sodium alginate crosslinked hydrogel composite containing reduced graphene oxide (PAA-SA@rGO) is developed. This composite possesses antibacterial, anti-inflammatory, and antioxidant properties, serving as a bridge to turn the "short circuit" of the injured site into a "completed circuit," thereby prompting fibroblasts in proximity to the wound site to secrete growth factors and expedite tissue regeneration. Simultaneously, the PAA-SA@rGO hydrogel effectively seals wounds to form a barrier, exhibits antibacterial and anti-inflammatory properties, and prevents foreign bacterial invasion. As the electric field of the wound is rebuilt and repaired by the PAA-SA@rGO hydrogel, a 5 × 5 mm2 wound in the full-thickness buccal mucosa of rats can be expeditiously mended within mere 7 days. The theoretical calculations indicate that the PAA-SA@rGO hydrogel can aggregate and express SOX2, PITX1, and PITX2 at the wound site, which has a promoting effect on rapid wound healing. Importantly, this PAA-SA@rGO hydrogel has a fast curative effect and only needs to be applied for the first three days, which significantly improves patient satisfaction during treatment.

Kupffer cells abrogate homing and repopulation of allogeneic hepatic progenitors in injured liver site

BackgroundAllogeneic hepatocyte transplantation is an emerging approach to treat acute liver defects. However, durable engraftment of the transplanted cells remains a daunting task, as they are actively cleared by the recipient’s immune system. Therefore, a detailed understanding of the innate or adaptive immune cells-derived responses against allogeneic transplanted hepatic cells is the key to rationalize cell-based therapies.MethodsHere, we induced an acute inflammatory regenerative niche (3–96 h) on the surface of the liver by the application of cryo-injury (CI) to systematically evaluate the innate immune response against transplanted allogeneic hepatic progenitors in a sustained micro-inflammatory environment.ResultsThe resulting data highlighted that the injured site was significantly repopulated by alternating numbers of innate immune cells, including neutrophils, monocytes and Kupffer cells (KCs), from 3 to 96 h. The transplanted allo-HPs, engrafted 6 h post-injury, were collectively eliminated by the innate immune response within 24 h of transplantation. Selective depletion of the KCs demonstrated a delayed recruitment of monocytes from day 2 to day 6. In addition, the intrasplenic engraftment of the hepatic progenitors 54 h post-transplantation was dismantled by KCs, while a time-dependent better survival and translocation of the transplanted cells into the injured site could be observed in samples devoid of KCs.ConclusionOverall, this study provides evidence that KCs ablation enables a better survival and integration of allo-HPs in a sustained liver inflammatory environment, having implications for rationalizing the cell-based therapeutic interventions against liver defects.

Amikacin sulphate loaded chitosan-diopside nanoparticles composite scaffold for infectious wound healing

A wound dressing material should inhibit infections that may occur at the wound site, and at the same time, it should enhance the healing process. In this study, we developed an amikacin sulphate (AK) incorporated chitosan (Ch) and Diopside nanoparticles composite dressing (Ch-nDE-AK) for controlling wound infection and healing. The diopside nanoparticles (nDE) were prepared using sol-gel synthesis and characterized using XRD, FT-IR, and FESEM. nDE shows a size range of 142 ± 31 nm through FESEM analysis. Later, the developed composite dressing was characterized using SEM, EDS, and FT-IR analysis. Ch-nDE-AK dressing possesses a porous nature that will aid in easy cell infiltration and proliferation. The swelling studies indicated the expansion capability of the scaffold when applied to the injured site. Ch-nDE-AK scaffold showed a 69.6 ± 8.2 % amikacin sulphate release up to 7 days, which indicates the sustained release of the drug from Ch-nDE-AK scaffold. The drug release data was subjected to various kinetics models and was observed to follow the Higuchi model. The scaffold showed antibacterial activity against ATCC strains of S. aureus and E. coli for 7 days by in vitro. Ch-nDE-AK scaffold also showed antibacterial activity against S. aureus and E. coli clinical strains in vitro. The ex vivo antibacterial study confirmed the antibacterial ability of Ch-nDE-AK scaffold against S. aureus and E. coli. Ch-nDE-AK scaffold also exhibits anti-biofilm activity against S. aureus and E. coli. The Ch-nDE-AK scaffold showed cytocompatibility and cell attachment to fibroblast cells. Additionally, the scratch assay using fibroblast cells confirmed the role of the nDE in the scaffold, helping in cell migration. Thus, the developed Ch-nDE-AK dressing can potentially be used to treat infectious wound healing.

A Combined Treatment of BMP2 and Soluble VEGFR1 for the Enhancement of Tendon-Bone Healing by Regulating Injury-Activated Skeletal Stem Cell Lineage

Background: Bone morphogenetic protein 2 (BMP2) is an appealing osteogenic and chondrogenic growth factor for promoting tendon-bone healing. Recently, it has been reported that soluble vascular endothelial growth factor (VEGF) receptor 1 (sVEGFR1) (a VEGF receptor antagonist) could enhance BMP2-induced bone repair and cartilage regeneration; thus, their combined application may represent a promising treatment to improve tendon-bone healing. Moreover, BMP2 could stimulate skeletal stem cell (SSC) expansion and formation, which is responsible for wounded tendon-bone interface repair. However, whether the codelivery of BMP2 and sVEGFR1 increases tendon enthesis injury–activated SSCs better than does BMP2 alone needs further research. Purpose: To study the effect of BMP2 combined with sVEGFR1 on tendon-bone healing and injury-activated SSC lineage. Study Design: Controlled laboratory study. Methods: A total of 128 C57BL/6 mice that underwent unilateral supraspinatus tendon detachment and repair were randomly assigned to 4 groups: (1) untreated control group; (2) hydrogel group, which received a local injection of the blank hydrogel at the injured site; (3) BMP2 group, which received an injection of hydrogel with BMP2; and (4) BMP2 with sVEGFR1 group, which received an injection of hydrogel with BMP2 and sVEGFR1. Histology, micro–computed tomography, and biomechanical tests were conducted to evaluate tendon-bone healing at 4 and 8 weeks after surgery. In addition, flow cytometry was performed to detect the proportion of SSCs and their downstream differentiated subtypes, including bone, cartilage, and stromal progenitors; osteoprogenitors; and pro-chondrogenic progenitors within supraspinatus tendon enthesis at 1 week postoperatively. Results: The repaired interface in BMP2 with sVEGFR1 group showed a significantly improved collagen fiber continuity, increased fibrocartilage, greater newly formed bone, and elevated mechanical properties compared with the other 3 groups. There were more SSCs; bone, cartilage, and stromal progenitors; osteoprogenitors; and pro-chondrogenic progenitors in the BMP2 with sVEGFR1 group than that in the other groups. Conclusion: Our study suggests that the combined delivery of BMP2 and sVEGFR1 could promote tendon-bone healing and stimulate the expansion of SSCs and their downstream progeny within the injured tendon-bone interface. Clinical Relevance: Combining BMP2 with sVEGFR1 may be a good clinical treatment for wounded tendon enthesis healing.

Renal ischemia and reperfusion impact the purinergic signaling in a vascular bed distant from the injured site

AimsAcute kidney injury (AKI) is a public health problem and represents a risk factor for cardiovascular diseases (CVD) and vascular damage. This study aimed to investigate the impact of AKI on purinergic components in mice aorta. Main methods: The kidney ischemia was achieved by the occlusion of the left kidney pedicle for 60 min, followed by reperfusion for 8 (IR8) and 15 (IR15) days. Renal function was assessed through biochemical assays, while gene expression levels were evaluated by RT-qPCR. Key findings: Analyses of renal parameters showed renal remodeling through mass loss in the left kidney and hypertrophy of the right kidney in the IR15 group. Furthermore, after 15 days, local inflammation was evidenced in the aorta. Moreover, the aorta purinergic components were significantly impacted by the renal ischemia and reperfusion model, with increases in gene expression of the pro-inflammatory purinoceptors P2Y1, P2Y2, P2Y6, and P2X4, potentially contributing to the vessel inflammation. The expression of NTPDase2 and ecto-5′-nucleotidase were also significantly increased in the aorta of the same group. In addition, both ATP and AMP hydrolysis were significantly increased in the aorta from IR15 animals, driving the entire purinergic cascade to the production of the anti-inflammatory adenosine. Significance: In short, this is the first time that inflammation of the aorta due to AKI was shown to have an impact on purinergic signaling components, with emphasis on the adenosinergic pathway. This seems to be closely implicated in the establishment of vascular inflammation in this model of AKI and deserves to be further investigated.

Impaired receptivity of thin endometrium: therapeutic potential of mesenchymal stem cells.

The endometrium is a resilient and highly dynamic tissue, undergoing cyclic renewal in preparation for embryo implantation. Cyclic endometrial regeneration depends on the intact function of several cell types, including parenchymal, endothelial, and immune cells, as well as adult stem cells that can arise from endometrial or extrauterine sources. The ability of the endometrium to undergo rapid, repeated regeneration without scarring is unique to this tissue. However, if this tissue renewal process is disrupted or dysfunctional, women may present clinically with infertility due to endometrial scarring or persistent atrophic/thin endometrium. Such disorders are rate-limiting in the treatment of female infertility and in the success of in vitro fertilization because of a dearth of treatment options specifically targeting the endometrium. A growing number of studies have explored the potential of adult stem cells, including mesenchymal stem cells (MSCs), to treat women with disorders of endometrial regeneration. MSCs are multipotent adult stem cells with capacity to differentiate into cells such as adipocytes, chondrocytes, and osteoblasts. In addition to their differentiation capacity, MSCs migrate toward injured sites where they secrete bioactive factors (e.g. cytokines, chemokines, growth factors, proteins and extracellular vesicles) to aid in tissue repair. These factors modulate biological processes critical for tissue regeneration, such as angiogenesis, cell migration and immunomodulation. The MSC secretome has therefore attracted significant attention for its therapeutic potential. In the uterus, studies utilizing rodent models and limited human trials have shown a potential benefit of MSCs and the MSC secretome in treatment of endometrial infertility. This review will explore the potential of MSCs to treat women with impaired endometrial receptivity due to a thin endometrium or endometrial scarring. We will provide context supporting leveraging MSCs for this purpose by including a review of mechanisms by which the MSC secretome promotes regeneration and repair of nonreproductive tissues.

Antioxidant and anti-inflammatory injectable hydrogel microspheres for in situ treatment of tendinopathy.

Tendinopathy is a common disorder that causes local dysfunction and reduces quality of life. Recent research has indicated that alterations in the inflammatory microenvironment play a vital role in the pathogenesis of tendinopathy. Herein, injectable methacrylate gelatin (GelMA) microspheres (GM) were fabricated and loaded with heparin-dopamine conjugate (HDC) and hepatocyte growth factor (HGF). GM@HDC@HGF were designed to balance the inflammatory microenvironment by inhibiting oxidative stress and inflammation, thereby regulating extracellular matrix (ECM) metabolism and halting tendon degeneration. Combining growth factors with heparin was expected to improve the encapsulation rate and maintain the long-term efficacy of HGF. In addition, the catechol groups on dopamine have adhesion and antioxidant properties, allowing potential attachment at the injured site, and better function synergized with HGF. GM@HDC@HGF injected in situ in rat Achilles tendinopathy (AT) models significantly down-regulated oxidative stress and inflammation, and ameliorated ECM degradation. In conclusion, the multifunctional platform developed presents a promising alternative for the treatment of tendinopathy.

The mitochondria‒paraspeckle axis regulates the survival of transplanted stem cells under oxidative stress conditions.

Rationale: Stem cell-based therapies have emerged as promising tools for tissue engineering and regenerative medicine, but their therapeutic efficacy is largely limited by the oxidative stress-induced loss of transplanted cells at injured tissue sites. To address this issue, we aimed to explore the underlying mechanism and protective strategy of ROS-induced MSC loss. Methods: Changes in TFAM (mitochondrial transcription factor A) signaling, mitochondrial function, DNA damage, apoptosis and senescence in MSCs under oxidative stress conditions were assessed using real-time PCR, western blotting and RNA sequencing, etc. The impact of TFAM or lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) knockdown or overexpression on mitochondrial function, DNA damage repair, apoptosis and senescence in MSCs was also analyzed. The effect of mitochondrion-targeted antioxidant (Mito-TEMPO) on the survival of transplanted MSCs was evaluated in a mouse model of renal ischemia/reperfusion (I/R) injury. Results: Mitochondrial ROS (mtROS) bursts caused defects in TFAM signaling and overall mitochondrial function, which further impaired NEAT1 expression and its mediated paraspeckle formation and DNA repair pathways in MSCs, thereby jointly promoting MSC senescence and death under oxidative stress. In contrast, targeted inhibition of the mtROS bursts is a sufficient strategy for attenuating early transplanted MSC loss at injured tissue sites, and coadministration of Mito-TEMPO improved the local retention of transplanted MSCs and reduced oxidative injury in ischemic kidneys. Conclusions: This study identified the critical role of the mitochondria‒paraspeckle axis in regulating cell survival and may provide insights into developing advanced stem cell therapies for tissue engineering and regenerative medicine.