Platelet membrane-derived biomimetic microbubbles with enhanced targeting ability for the early detection of myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MIRI) is a widely recognized cardiovascular disease that significantly impacts the prognosis of patients undergoing myocardial infarction recanalization. This condition can be fatal and involves complex pathophysiological mechanisms. Early diagnosis of MIRI is crucial to minimize myocardial damage and reducing mortality. Based on the inherent relationship between platelets and MIRI, we developed biomimetic microbubbles coated with platelet membrane (MB-pla) for early identification of MIRI. The MB-pla were prepared through a recombination process involving platelet membrane obtained from rat whole blood and phospholipids, blended in appropriate proportions. By coating the microbubbles with platelet membrane, MB-pla acquired various adhesion molecules, thereby gaining the capability to selectively adhere to damaged endothelial cells in the context of MIRI. In vitro experiments demonstrated that MB-pla exhibited remarkable targeting characteristics, particularly toward type IV collagen and human umbilical vein endothelial cells that had been injured through hypoxia/reoxygenation procedures. In a rat model of MIRI, the signal intensity produced by MB-pla was notably higher than that of control microbubbles. These findings were consistent with results obtained from fluorescence imaging of isolated hearts and immunofluorescence staining of tissue sections. In conclusion, MB-pla has great potential as a non-invasive early detection method for MIRI. Furthermore, this approach can potentially find application in other conditions involving endothelial injury in the future.

Ursolic acid reduces oxidative stress injury to ameliorate experimental autoimmune myocarditis by activating Nrf2/HO-1 signaling pathway.

Background: Oxidative stress is crucial in experimental autoimmune myocarditis (EAM)-induced inflammatory myocardial injury. Ursolic acid (UA) is an antioxidant-enriched traditional Chinese medicine formula. The present study aimed to investigate whether UA could alleviate inflammatory cardiac injury and determine the underlying mechanisms. Methods: Six-week-old male BALB/c mice were randomly assigned to one of the three groups: Sham, EAM group, or UA intervention group (UA group) by gavage for 2 weeks. An EAM model was developed by subcutaneous injection of α-myosin heavy chain derived polypeptide (α-MyHC peptide) into lymph nodes on days 0 and 7. Echocardiography was used to assess cardiac function on day 21. The inflammation level in the myocardial tissue of each group was compared using hematoxylin and eosin staining (HE) of heart sections and Interleukin-6 (IL-6) immunohistochemical staining. Masson staining revealed the degree of cardiac fibrosis. Furthermore, Dihydroethidium staining, Western blot, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) were used to determine the mechanism of cardioprotective effects of UA on EAM-induced cardiac injury, and the level of IL-6, Nrf2, and HO-1. Results: In EAM mice, UA intervention significantly reduced the degree of inflammatory infiltration and myocardial fibrosis while improving cardiac function. Mechanistically, UA reduced myocardial injury by inhibiting oxidative stress (as demonstrated by a decrease of superoxide and normalization of pro- and antioxidant enzyme levels). Interestingly, UA intervention upregulated the expression of antioxidant factors such as Nrf2 and HO-1. In vitro experiments, specific Nrf2 inhibitors reversed the antioxidant and antiapoptotic effects of ursolic acid, which further suggested that the amelioration of EAM by UA was in a Nrf2/HO-1 pathway-dependent manner. Conclusion: These findings indicate that UA is a cardioprotective traditional Chinese medicine formula that reduces EAM-induced cardiac injury by up-regulating Nrf2/HO-1 expression and suppressing oxidative stress, making it a promising therapeutic strategy for the treatment of EAM.

Decreased ventricular systolic function in chemotherapy-naive patients with acute myeloid leukemia: a three-dimensional speckle-tracking echocardiography study.

Background: The relationship between acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) and cardiac function is not well established. This study aimed to evaluate whether AML patients exist early myocardial damages prior to chemotherapy and to investigate its association with cardiovascular biomarkers. Methods: Conventional echocardiography and three-dimensional speckle-tracking strain analysis were performed prospectively in 72 acute leukemia (AL) patients before any chemotherapy therapy (of whom 44 were AML patients, 28 ALL patients). The results were compared with those from 58 control group matched for age and gender. Results: There were no significant differences in conventional biventricular systolic function parameters between AL patients and controls. The left ventricular global longitudinal strain (LVGLS) and right ventricular free wall longitudinal strain (RVFWLS) were significantly lower in AL patients (-23.0 ± 1.4% vs. -24.1 ± 1.3% and -27.9 ± 7.1% vs. -33.0 ± 4.6%, respectively, P < 0.001 for all). Compared with ALL patients, AML patients had lower LVGLS and RVFWLS (-22.7 ± 1.3% vs. -23.5 ± 1.6% and -26.2 ± 7.6% vs. -30.4 ± 5.5%, respectively, P < 0.05 for all). LVGLS was lower in ALL patients compared with controls (-23.5 ± 1.6% vs. -24.7 ± 1.4%, P < 0.05), however, there was no difference in right ventricular systolic function parameters between the two groups. LVGLS in AL patients was independently correlated with left ventricular ejection fraction (LVEF) and the absolute number of circulating lymphocytes. Conclusions: Our findings suggest that baseline myocardial systolic function is lower in AL patients than controls. AML patients had lower baseline LVGLS and RVFWLS than controls and ALL patients. The decreased LVGLS is correlated with LVEF and the absolute number of circulating lymphocytes.

Noninvasive ultrasound stimulation to treat myocarditis through splenic neuro-immune regulation.

BACKGROUND: The cholinergic anti-inflammatory pathway (CAP) has been widely studied to modulate the immune response. Current stimulating strategies are invasive or imprecise. Noninvasive low-intensity pulsed ultrasound (LIPUS) has become increasingly appreciated for targeted neuronal modulation. However, its mechanisms and physiological role on myocarditis remain poorly defined. METHODS: The mouse model of experimental autoimmune myocarditis was established. Low-intensity pulsed ultrasound was targeted at the spleen to stimulate the spleen nerve. Under different ultrasound parameters, histological tests and molecular biology were performed to observe inflammatory lesions and changes in immune cell subsets in the spleen and heart. In addition, we evaluated the dependence of the spleen nerve and cholinergic anti-inflammatory pathway of low-intensity pulsed ultrasound in treating autoimmune myocarditis in mice through different control groups. RESULTS: The echocardiography and flow cytometry of splenic or heart infiltrating immune cells revealed that splenic ultrasound could alleviate the immune response, regulate the proportion and function of CD4+ Treg and macrophages by activating cholinergic anti-inflammatory pathway, and finally reduce heart inflammatory injury and improve cardiac remodeling, which is as effective as an acetylcholine receptor agonists GTS-21. Transcriptome sequencing showed significant differential expressed genes due to ultrasound modulation. CONCLUSIONS: It is worth noting that the ultrasound therapeutic efficacy depends greatly on acoustic pressure and exposure duration, and the effective targeting organ was the spleen but not the heart. This study provides novel insight into the therapeutic potentials of LIPUS, which are essential for its future application.

Bioceramic scaffolds with triply periodic minimal surface architectures guide early-stage bone regeneration.

The pore architecture of porous scaffolds is a critical factor in osteogenesis, but it is a challenge to precisely configure strut-based scaffolds because of the inevitable filament corner and pore geometry deformation. This study provides a pore architecture tailoring strategy in which a series of Mg-doped wollastonite scaffolds with fully interconnected pore networks and curved pore architectures called triply periodic minimal surfaces (TPMS), which are similar to cancellous bone, are fabricated by a digital light processing technique. The sheet-TPMS pore geometries (s-Diamond, s-Gyroid) contribute to a 3‒4-fold higher initial compressive strength and 20%-40% faster Mg-ion-release rate compared to the other-TPMS scaffolds, including Diamond, Gyroid, and the Schoen's I-graph-Wrapped Package (IWP) in vitro. However, we found that Gyroid and Diamond pore scaffolds can significantly induce osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Analyses of rabbit experiments in vivo show that the regeneration of bone tissue in the sheet-TPMS pore geometry is delayed; on the other hand, Diamond and Gyroid pore scaffolds show notable neo-bone tissue in the center pore regions during the early stages (3-5 weeks) and the bone tissue uniformly fills the whole porous network after 7 weeks. Collectively, the design methods in this study provide an important perspective for optimizing the pore architecture design of bioceramic scaffolds to accelerate the rate of osteogenesis and promote the clinical translation of bioceramic scaffolds in the repair of bone defects.

Ultrasonic Microbubble Cavitation Deliver Gal-3 shRNA to Inhibit Myocardial Fibrosis after Myocardial Infarction.

Galectin-3 (Gal-3) participates in myocardial fibrosis (MF) in a variety of ways. Inhibiting the expression of Gal-3 can effectively interfere with MF. This study aimed to explore the value of Gal-3 short hairpin RNA (shRNA) transfection mediated by ultrasound-targeted microbubble destruction (UTMD) in anti-myocardial fibrosis and its mechanism. A rat model of myocardial infarction (MI) was established and randomly divided into control and Gal-3 shRNA/cationic microbubbles + ultrasound (Gal-3 shRNA/CMBs + US) groups. Echocardiography measured the left ventricular ejection fraction (LVEF) weekly, and the heart was harvested to analyze fibrosis, Gal-3, and collagen expression. LVEF in the Gal-3 shRNA/CMB + US group was improved compared with the control group. On day 21, the myocardial Gal-3 expression decreased in the Gal-3 shRNA/CMBs + US group. Furthermore, the proportion of the myocardial fibrosis area in the Gal-3 shRNA/CMBs + US group was 6.9 ± 0.41% lower than in the control group. After inhibition of Gal-3, there was a downregulation in collagen production (collagen I and III), and the ratio of Col I/Col III decreased. In conclusion, UTMD-mediated Gal-3 shRNA transfection can effectively silence the expression of Gal-3 in myocardial tissue, reduce myocardial fibrosis, and protect the cardiac ejection function.

68Ga-FAPI PET visualize heart failure: from mechanism to clinic.

PURPOSE: Heart failure (HF) is a chronic progressive clinical syndrome associated with structural and/or functional heart abnormalities. Active fibroblasts and ventricular remodelling play an essential role in HF progression. 68Ga-labelled fibroblast activation protein (FAP) inhibitor (68Ga-FAPI) binds to FAP. This study aimed to examine the feasibility of using 68Ga-FAPI positron emission tomography (PET)/computed tomography (CT) to visualize changes in cardiac fibrosis and function over time in the HF setting. METHODS: After establishing an isoproterenol (ISO)-induced HF rat model (14 consecutive days of intraperitoneal ISO injections), echocardiography and 68Ga-FAPI PET/CT were performed weekly in experimental and control groups. Rat hearts were examined weekly for biodistribution analysis; autoradiography; and haematoxylin and eosin, FAP immunofluorescence and Masson's trichrome staining analysis. Rat blood was sampled weekly for enzyme-linked immunosorbent assay analysis of various plasma indicators. A preliminary clinical study was also performed in seven HF patients who underwent both 13N-amino (NH3) perfusion and 68Ga-FAPI cardiac PET imaging. RESULTS: In the animal experiments, myocardial 68Ga-FAPI uptake, expression of FAP and myocardial contractility peaked on day 7 after the initial ISO injection. Only slight fibrotic changes were observed on histopathological examination. 68Ga-FAPI uptake and ventricular wall motion decreased over time as cardiac fibrosis and degree of myocardial injury gradually increased. In the human HF patient study, 68Ga-FAPI PET imaging identified varying degrees of 68Ga-FAPI uptake in the myocardium that did not precisely match with 13N-NH3 myocardial perfusion. CONCLUSION: As HF progresses, 68Ga-FAPI uptake is high in the early stages and then gradually decreases. Although preliminary, our findings suggest that 68Ga-FAPI PET can be used to demonstrate active myocardial fibrosis. Active myocardial FAP expression is followed by myocardial remodelling and fibrosis. Detection of early active FAP expression may assist treatment decision making in HF patients. CLINICAL TRIAL REGISTRATION: NCT04982458.

New trends in non-pharmacological approaches for cardiovascular disease: Therapeutic ultrasound.

Significant advances in application of therapeutic ultrasound have been reported in the past decades. Therapeutic ultrasound is an emerging non-invasive stimulation technique. This approach has shown high potential for treatment of various disease including cardiovascular disease. In this review, application principle and significance of the basic parameters of therapeutic ultrasound are summarized. The effects of therapeutic ultrasound in myocardial ischemia, heart failure, myocarditis, arrhythmias, and hypertension are explored, with key focus on the underlying mechanism. Further, the limitations and challenges of ultrasound therapy on clinical translation are evaluated to promote application of the novel strategy in cardiovascular diseases.

Constructing a highly bioactive tendon-regenerative scaffold by surface modification of tissue-specific stem cell-derived extracellular matrix.

Developing highly bioactive scaffold materials to promote stem cell migration, proliferation and tissue-specific differentiation is a crucial requirement in current tissue engineering and regenerative medicine. Our previous work has demonstrated that the decellularized tendon slices (DTSs) are able to promote stem cell proliferation and tenogenic differentiation in vitro and show certain pro-regenerative capacity for rotator cuff tendon regeneration in vivo. In this study, we present a strategy to further improve the bioactivity of the DTSs for constructing a novel highly bioactive tendon-regenerative scaffold by surface modification of tendon-specific stem cell-derived extracellular matrix (tECM), which is expected to greatly enhance the capacity of scaffold material in regulating stem cell behavior, including migration, proliferation and tenogenic differentiation. We prove that the modification of tECM could change the highly aligned surface topographical cues of the DTSs, retain the surface stiffness of the DTSs and significantly increase the content of multiple ECM components in the tECM-DTSs. As a result, the tECM-DTSs dramatically enhance the migration, proliferation as well as tenogenic differentiation of rat bone marrow-derived stem cells compared with the DTSs. Collectively, this strategy would provide a new way for constructing ECM-based biomaterials with enhanced bioactivity for in situ tendon regeneration applications.

Biomechanically and biochemically functional scaffold for recruitment of endogenous stem cells to promote tendon regeneration.

Tendon regeneration highly relies on biomechanical and biochemical cues in the repair microenvironment. Herein, we combined the decellularized bovine tendon sheet (DBTS) with extracellular matrix (ECM) from tendon-derived stem cells (TDSCs) to fabricate a biomechanically and biochemically functional scaffold (tECM-DBTS), to provide a functional and stem cell ECM-based microenvironment for tendon regeneration. Our prior study showed that DBTS was biomechanically suitable to tendon repair. In this study, the biological function of tECM-DBTS was examined in vitro, and the efficiency of the scaffold for Achilles tendon repair was evaluated using immunofluorescence staining, histological staining, stem cell tracking, biomechanical and functional analyses. It was found that tECM-DBTS increased the content of bioactive factors and had a better performance for the proliferation, migration and tenogenic differentiation of bone marrow-derived stem cells (BMSCs) than DBTS. Furthermore, our results demonstrated that tECM-DBTS promoted tendon regeneration and improved the biomechanical properties of regenerated Achilles tendons in rats by recruiting endogenous stem cells and participating in the functionalization of these stem cells. As a whole, the results of this study demonstrated that the tECM-DBTS can provide a bionic microenvironment for recruiting endogenous stem cells and facilitating in situ regeneration of tendons.

Higher Rate of Postoperative Complications in Delayed Achilles Tendon Repair Compared to Early Achilles Tendon Repair: A Meta-Analysis.

BACKGROUND: Some authors found that delayed repair of Achilles tendon ruptures achieved similar functional outcomes when compared with acute repair of Achilles tendon ruptures. The purpose of our study was to compare functional outcomes and complication rates of acute repair to delayed repair after Achilles tendon ruptures. METHODS: PubMed, Embase (Ovid) and the Cochrane Library were searched. RESULTS: For Achilles tendon rupture score (ATRS), the overall result revealed that there was no significant difference in ATRS between acute repair groups and delayed repair groups (P = 0.59). For Tegner scores, Halasi scores and Achilles tendon resting angle (ATRA), there was no significant difference between the two groups (P = 0.28, P = 0.47 and P = 0.68). There was no significant difference in the subjective assessment between acute repair groups and delayed repair groups (P = 0.84). However, delayed repair groups showed a higher incidence of complications than acute repair groups (P = 0.01). Subgroup analyses showed that the mean time from injury to surgery of delayed repair groups affect the pooled result substantially. For mean time less than 28d, there was no difference in the incidence of complications between acute repair groups and delayed repair groups (P = 0.09). However, for mean time more than 28d, delayed repair groups showed a higher incidence of complications than acute repair groups (P = 0.05). CONCLUSION: Our study showed delayed repair could obtain similar functional outcomes and subjective assessment when compared with acute repair. However, the rate of complications after delayed repair was higher than that of early repair. Further high-quality randomized controlled trials (RCT) are needed to evaluate the difference.

Fracture-Dedicated Prosthesis Promotes the Healing Rate of Greater Tuberosity in Reverse Shoulder Arthroplasty: A Meta-Analysis.

Introduction: Reverse shoulder arthroplasty (RSA) is becoming popular in the treatment of complex proximal humeral fractures (PHFs). Greater tuberosity healing may influence functional outcomes and range of motion (ROM) of shoulder after RSA. In addition, the design of prosthesis may impact the healing rate of greater tuberosity. The purpose of this study is to know: (1) does the healing of greater tuberosity affect the functional outcomes and ROM of shoulder? and (2) does the design of prosthesis affect the healing rate of greater tuberosity? Materials and Methods: PubMed, Ovid/Embase, and the Cochrane Library were searched for studies comparing the clinical outcomes between the healed groups and the non-healed groups after RSA. Results: For functional outcomes, the results showed that the healed group had better Constant scores (CSs) (p < 0.0001). For ROM, the healed group showed better flexion (p < 0.0001), abduction (p = 0.02), and external rotation (p < 0.00001) of shoulder. For the design of prosthesis, the mean healing rate of greater tuberosity (82.7%) in patients with fracture-dedicated prosthesis was higher than those (63.0%) in patients with standard prosthesis. Subgroup analyses showed that the CS (p = 0.12) and abduction (p = 0.96) of patients using fracture-dedicated prostheses were not different between the healed groups and the non-healed groups. Meta-regression showed that there was no significant relationship between the design of prosthesis and CS (p = 0.312), flexion (p = 0.422), or external rotation (p = 0.776). Conclusion: Our meta-analysis showed that the healed groups could obtain better functional outcomes and ROM than the non-healed groups. In addition, fracture-dedicated prostheses promoted the healing rate of greater tuberosity. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020157276, PROSPERO: CRD42020157276.

[Research progress of interfacial tissue engineering in rotator cuff repair].

OBJECTIVE: To summarize the research progress of interfacial tissue engineering in rotator cuff repair. METHODS: The recent literature at home and abroad concerning interfacial tissue engineering in rotator cuff repair was analysed and summarized. RESULTS: Interfacial tissue engineering is to reconstruct complex and hierarchical interfacial tissues through a variety of methods to repair or regenerate damaged joints of different tissues. Interfacial tissue engineering in rotator cuff repair mainly includes seed cells, growth factors, biomaterials, oxygen concentration, and mechanical stimulation. CONCLUSION: The best strategy for rotator cuff healing and regeneration requires not only the use of biomaterials with gradient changes, but also the combination of seed cells, growth factors, and specific culture conditions (such as oxygen concentration and mechanical stimulation). However, the clinical transformation of the relevant treatment is still a very slow process.

Hierarchically Demineralized Cortical Bone Combined With Stem Cell-Derived Extracellular Matrix for Regeneration of the Tendon-Bone Interface.

BACKGROUND: Poor healing of the tendon-bone interface after rotator cuff repair is one of the main causes of surgical failure. Previous studies demonstrated that demineralized cortical bone (DCB) could improve healing of the enthesis. PURPOSE: To evaluate the outcomes of hierarchically demineralized cortical bone (hDCB) coated with stem cell-derived extracellular matrix (hDCB-ECM) in the repair of the rotator cuff in a rabbit model. STUDY DESIGN: Controlled laboratory study. METHODS: Tendon-derived stem cells (TDSCs) were isolated, cultured, and identified. Then, hDCB was prepared by the graded demineralization procedure. Finally, hDCB-ECM was fabricated via 2-week cell culture and decellularization, and the morphologic features and biochemical compositions of the hDCB-ECM were evaluated. A total of 24 rabbits (48 samples) were randomly divided into 4 groups: control, DCB, hDCB, and hDCB-ECM. All rabbits underwent bilateral detachment of the infraspinatus tendon, and the tendon-bone interface was repaired with or without scaffolds. After surgery, 8 rabbits were assessed by immunofluorescence staining at 2 weeks, and the others were assessed by micro-computed tomography (CT) examination, immunohistochemical staining, histological staining, and biomechanical testing at 12 weeks. RESULTS: TDSCs were identified to have universal stem cell characteristics including cell markers, clonogenicity, and multilineage differentiation. The hDCB-ECM contained 3 components (bone, partial DCB, and DCB coated with ECM) with a gradient of calcium and phosphorus elements, and the ECM had stromal cell-derived factor 1, biglycan, and fibromodulin. Macroscopic observations demonstrated the absence of infection and rupture around the enthesis. The results of immunofluorescence staining showed that hDCB-ECM promoted stromal cell recruitment. Results of micro-CT analysis, immunohistochemical staining, and histological staining showed that hDCB-ECM enhanced bone and fibrocartilage formation at the tendon-bone interface. Biomechanical analysis showed that the hDCB-ECM group had higher ultimate tensile stress and Young modulus than the DCB group. CONCLUSION: The administration of hDCB-ECM promoted healing of the tendon-bone interface. CLINICAL RELEVANCE: hDCB-ECM could provide useful information for the design of scaffolds to repair the tendon-bone interface, and further studies are needed to determine its effectiveness.

Segmentally Demineralized Cortical Bone With Stem Cell-Derived Matrix Promotes Proliferation, Migration and Differentiation of Stem Cells in vitro.

A recent study has shown that demineralized cortical bone (DCB) did not improve the healing of tendon-bone interface. Considering that there is a gradient of mineral content in the tendon-bone interface, we designed a segmentally demineralized cortical bone (sDCB) scaffold with two different regions: undemineralized cortical bone section within the scaffold (sDCB-B) and complete demineralized cortical bone section within the scaffold (sDCB-D), to mimic the natural structure of the tendon-bone interface. Furthermore, the extracellular matrix (ECM) from tendon-derived stem cells (TDSCs) was used to modify the sDCB-D region of sDCB to construct a novel scaffold (sDCB-ECM) for enhancing the bioactivity of the sDCB-D. The surface topography, elemental distribution, histological structure, and surface elastic modulus of the scaffold were observed using scanning electron microscopy, energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, histological staining and atomic force microscopy. Cell proliferation of bone marrow mesenchymal stem cells (BMSCs) and TDSCs cultured on scaffolds was evaluated using the Cell Counting kit-8, and cell viability was assessed by Live/Dead cell staining. Cell morphology was detected by fluorescent staining. The ability of the scaffolds to recruit stem cells was tested using transwell migration assay. The expression levels of bone-, cartilage- and tendon-related genes and proteins in stem cells were assessed by the polymerase chain reaction and western blotting. Our results demonstrated that there was a gradient of Ca and P elements in sDCB, and TDSC-derived ECM existed on the surface of the sDCB-D region of sDCB. The sDCB-ECM could promote stem cell proliferation and migration. Moreover, the sDCB-B region of sDCB-ECM could stimulate osteogenic and chondrogenic differentiation of BMSCs, and the sDCB-D-ECM region of sDCB-ECM could stimulate chondrogenic and tenogenic differentiation of TDSCs when compared to DCB. Our study indicated that sDCB-ECM might be a potential bioscaffold to enhance the tendon-bone interface regeneration.

Influence of the integrity of tendinous membrane and fascicle on biomechanical characteristics of tendon-derived scaffolds.

The biomechanical characteristics of tendon grafts is essential for tendon reconstructive surgery due to its great role in providing a good mechanical environment for tendon healing and regeneration. In our previous studies, the decellularized tendon slices (DTSs) and decellularized bovine tendon sheets (DBTSs) scaffolds were successfully developed. However, the influence of the integrity of tendinous membrane (endotenon and epitenon) and fascicle on biomechanical characteristics of these two scaffolds was not investigated. In this study, we assessed the integrity of tendinous membrane and fascicle of the tendon derived scaffolds and its effect on the biomechanical characteristics. The results of histological staining indicated that the DBTSs had complete endotenon and epitenon, while DTSs had no epitenon at all, only part of endotenon was remained. Furthermore, the DBTSs, and DTSs with thickness of 900 µm had complete fascicles, while DTSs with thickness less than 600 µm had almost no complete fascicles. The fibrous configuration of epitenon was well-preserved in the surface of the DBTSs but the surface ultrastructure of the DTSs was aligned collagen fibers based on scanning electron microscopy examination. The results of transmission electron microscopy showed that there was no significant difference between the DBTSs and DTSs. Mechanically, the DBTSs and DTSs with thickness of 900 µm showed similar ultimate tensile strength and stiffness to native tendon segments (NTSs). The strain at break and suture retention strength of the DBTSs showed much higher than that of the DTSs (p < 0.05). Additionally, the DBTSs showed higher ultimate load than the DTSs when these scaffolds were sutured with NTSs (p < 0.05) through the modified Kessler technique based on a uniaxial tensile test. This study demonstrated that DTSs may be used as a patch for reinforcing tendon repair, while DBTSs may be used as a bridge for reconstructing tendon defects.

A Stable Large Animal Model for Dural Defect Repair with Biomaterials and Regenerative Medicine.

IMPACT STATEMENT: Using biomaterials and regenerative medicine to repair tissue defects has been a very hot research field, during which the development of stable large animal models with appropriate biotechnology is crucial. Recently, more and more researchers are paying attention to dural defect repair. However, the lack of widely recognized stable large animal models has seriously affected the related further research. In this study, a stable large animal dural defect model is developed exactly for the first time. Therefore, the article would attract considerable attention and be highly cited after publication.

Combined use of Kirschner wires and hinged external fixator for capitellar and trochlear fractures: a minimum 24-month follow-up.

BACKGROUND: Open reduction and internal fixation is the adequate treatment for capitellar and trochlear fractures. Given the low incidence of this type of fractures, it is difficult to constitute a universally accepted method for fixation. Thus, we hypothesised that combined use of Kirschner wires (K-wires), absorbable rods and sutures for fixation and post-operative hinged external fixator for early rehabilitation exercise can restore elbow joint function well. METHODS: This retrospective study included 20 patients with a mean age of 48.3 (range 16-76) years. According to the Dubberley classification, fractures were classified on plain radiographs, computed tomography images and intra-operative findings. All patients were evaluated by the range of motion of the elbow and the Broberg-Morrey score. RESULTS: All fractures had healed without non-union, and the average time was 13.6 (range 8-17) weeks. The mean follow-up was 42.5 (range 24-80) months. The mean flexion was 117.1° (range 90°-135°), and the mean extension was 17.5° (range 0°-45°). The mean pronation was 74.4° (range 45°-85°), and the mean supination was 84.3° (range 60°-90°). The average Broberg-Morrey score was 86.2 (range 68-98) points with 10 excellent, 7 good and 3 fair results. CONCLUSION: K-wires, absorbable rods and sutures combined with hinged external fixator are feasible for fixation of capitellar and trochlear fractures. However, due to the absence of a control group (such as Herbert screw fixation), comparative studies are still needed to demonstrate the safety and reliability of K-wires for fixation.

Nanostructured titanium surfaces fabricated by hydrothermal method: Influence of alkali conditions on the osteogenic performance of implants.

Hydrothermal method is an easy-to-use approach for creating nanostructured surfaces on titanium (Ti). However, whether the alkali conditions of this method influence the osteogenic potential of the modified surfaces remains unknown. In this study, we fabricated nanostructured surfaces, termed the Ti-1, Ti-5, and Ti-10 groups, by using the hydrothermal method in 1 M, 5 M, and 10 M NaOH aqueous solutions, respectively. An untreated Ti surface served as a control. The osteogenic performance of modified surfaces was systemically investigated, including the proliferation and osteogenic differentiation of human osteoblast-like MG63 cells in vitro and the osteointegration of implants in a rabbit femoral condyle defect model. After hydrothermal treatment, the hydrophilicity of modified surfaces was greatly enhanced. The Ti-1 group showed a nanowire-like topography, while the Ti-5 and Ti-10 groups exhibited a nanopetal-like topography with different pore sizes. Compared with the untreated Ti surface, the modified surfaces showed good cytocompatibility and enhanced the osteogenic differentiation of MG-63 cells. Compared with the other modified surfaces, the Ti-5 group was the most favourable for the osteogenic differentiation of cells, showing higher levels of alkaline phosphatase activity, osteogenic gene expression, mineralization and osteoprotegerin secretion. Twelve weeks after implantation at the bone defects, the Ti-5 group showed superior peri-implant bone regeneration and higher peak push-out force than the other groups. Overall, this study revealed the crucial role of alkali conditions of hydrothermal method in modulating the material characteristics of modified surfaces and their osteogenic performance in vitro and in vivo, highlighting the need for optimizing the processing conditions of hydrothermal method for enhanced osteointegration.

Stem Cell Extracellular Matrix-Modified Decellularized Tendon Slices Facilitate the Migration of Bone Marrow Mesenchymal Stem Cells.

It is highly desirable to develop a novel scaffold that can induce stem cell migration in tendon tissue engineering and regeneration. The objective of this study is to assess the effect of stem cell extracellular matrix-modified decellularized tendon slices (ECM-DTSs) on bone marrow mesenchymal stem cells (BMSCs) migration and explore the possible molecular mechanisms. Native ECM produced by BMSCs and tendon-derived stem cells (TDSCs) was deposited on DTSs, denoted as bECM-DTSs and tECM-DTSs, respectively, and the migration of BMSCs treated with the extracts from ECM-DTSs was studied. Almost all the seeded stem cells were removed from the stem cell-DTS composites, while ECM produced by stem cells completely covered the surface of the DTSs. Significantly higher levels of chemokines, including stromal cell-derived factor-1 (SDF-1) and monocyte chemotactic protein-1 (MCP-1) were released by ECM-DTSs than by bare DTSs (p < 0.05), according to ELISA, and tECM-DTSs exhibited the highest release within 72 h. bECM-DTSs and tECM-DTSs markedly improved BMSCs migration compared to bare DTSs, with tECM-DTSs yielding the best recruitment effects. The ECM-DTSs led to early cytoskeletal changes compared to bare DTSs (p < 0.05). Migration-related gene and protein expression was significantly up-regulated in BMSCs treated with ECM-DTSs via the PI3K/AKT signaling pathway (p < 0.05), indicating that ECM-DTSs could enhance BMSCs migration via the PI3K/AKT signal pathway, and the effect of tECM-DTSs on BMSCs migration is superior to that of bECM-DTSs. This may provide the experimental and theoretical evidence for using stem cell-derived ECM-modified scaffold as a novel approach to recruit stem cells.