Intra-articular Histone Deacetylase Inhibitor Microcarrier Delivery to Reduce Osteoarthritis.

The histone deacetylase inhibitor (HDACi) was a milestone in the treatment of refractory T-cell lymphoma. However, the beneficial effects of HDACi have not been appreciated in osteoarthritis (OA). Herein, we implemented a microcarrier system because of the outstanding advantages of controlled and sustained release, biodegradability, and biocompatibility. The poly(d,l-lactide-co-glycolide) (PLGA) microcapsules have a regulated and sustained release profile with a reduced initial burst release, which can improve the encapsulation efficiency of the Chidamide. The emulsion solvent evaporation strategy was used to encapsulate Chidamide in PLGA microcapsules. The encapsulation of Chidamide was established by UV-vis spectra and scanning electron microscopy. Additionally, the inhibition of Tnnt3 and immune stimulation by Chidamide helped to inhibit cartilage destruction and prevent articular cartilage degeneration. Based on the results, the Chidamide in PLGA microcapsules provides a transformative therapeutic strategy for the treatment of osteoarthritis patients to relieve symptoms and protect against cartilage degeneration.

CT and MRI measurements of tibial tubercle lateralization in patients with patellar dislocation were not equivalent but could be interchangeable.

PURPOSE: To compare the values and the relationship of tibial tubercle lateralization measurements between computerized tomography (CT) and magnetic resonance imaging (MRI). METHODS: Sixty patients with patellar dislocation who underwent both CT and MRI of the same knee joint from November 2021 to February 2022 were included in our study. The intraclass correlation coefficient (ICC) and Bland-Altman analysis were performed to evaluate the reliability of tibial tubercle-trochlear groove (TT-TG), tibial tubercle-Roman arch (TT-RA), and tibial tubercle-posterior cruciate ligament (TT-PCL) distance measurements. The values of CT and MRI measurements using the same bony landmarks were compared for the difference. Pearson correlation analysis and linear regression analysis were performed to assess the correlation between CT and MRI measurements. Finally, the estimated values obtained from the regression equation were compared with the actual values obtained from the radiological measurement to evaluate the accuracy of the equations. RESULTS: A total of 60 patients with patellar dislocation who underwent both CT and MRI of the same knee joint were included in this study. The included measurements showed excellent agreement with ICCs > 0.9. TT-TG distance measured on CT (19.5 ± 5.1 mm) had a mean of 7.1 mm higher than that on MRI (12.4 ± 4.7 mm) (P < 0.001). The mean value of TT-RA distance was 22.5 ± 3.7 mm on CT and 16.7 ± 4.9 mm on MRI (P < 0.001), showing a mean difference of 5.8 mm. The values of TT-TG distance measured by CT and MRI were significantly correlated (R = 0.5, P < 0.001). The values of TT-RA distance between these two modalities showed a better correlation than that of TT-TG distance (R = 0.6, P < 0.001). The interchange values of TT-TG distance and TT-RA distance between CT and MRI can be obtained using regression equations (TT-TG distance: y = 0.6x + 12.3; TT-RA distance: y = 0.5x + 14.4). CONCLUSION: The values of tibial tubercle lateralization measured by MRI may be underestimated compared with those measured by CT. Although the values measured on CT and MRI are not equivalent, the value in the other modality can be estimated. Therefore, an additional CT scan for tibial tubercle lateralization evaluation may not be necessary. LEVEL OF EVIDENCE: Level II.

Epigenetics-Based Tumor Cells Pyroptosis for Enhancing the Immunological Effect of Chemotherapeutic Nanocarriers.

Pyroptosis is a lytic and inflammatory form of programmed cell death and could be induced by chemotherapy drugs via caspase-3 mediation. However, the key protein gasdermin E (GSDME, translated by the DFNA5 gene) during the caspase-3-mediated pyroptosis process is absent in most tumor cells because of the hypermethylation of DFNA5 (deafness autosomal dominant 5) gene. Here, we develop a strategy of combining decitabine (DAC) with chemotherapy nanodrugs to trigger pyroptosis of tumor cells by epigenetics, further enhancing the immunological effect of chemotherapy. DAC is pre-performed with specific tumor-bearing mice for demethylation of the DFNA5 gene in tumor cells. Subsequently, a commonly used tumor-targeting nanoliposome loaded with cisplatin (LipoDDP) is used to administrate drugs for activating the caspase-3 pathway in tumor cells and trigger pyroptosis. Experiments demonstrate that the reversal of GSDME silencing in tumor cells is achieved and facilitates the occurrence of pyroptosis. According to the anti-tumor activities, anti-metastasis results, and inhibition of recurrence, this pyroptosis-based chemotherapy strategy enhances immunological effects of chemotherapy and also provides an important insight into tumor immunotherapy.

Chondroprotective Effects of Hyaluronic Acid-Chitosan Nanoparticles Containing Plasmid DNA Encoding Cytokine Response Modifier A in a Rat Knee Osteoarthritis Model.

BACKGROUND/AIMS: Interleukin (IL)-1ß plays an essential role in the pathophysiology of osteoarthritis (OA). Cytokine response modifier A (CrmA) can prevent the generation of active IL-1ß. This study aimed to explore the chondroprotective effects of hyaluronic acid-chitosan nanoparticles containing plasmid DNA encoding CrmA (HA/CS-CrmA) in a rat OA model. METHODS: HA/CS-CrmA nanoparticles were synthesized through the complex coacervation of cationic polymers. The characteristics, toxicity, and transfection of the nanoparticles were investigated. Furthermore, the potential effects of HA/CS-CrmA nanoparticles were evaluated via a rat anterior cruciate ligament transection (ACLT) model of OA. Cartilage damage and synovial inflammation were assessed by safranin O/fast green and hematoxylin and eosin staining. Type II collagen in cartilage was measured by immunohistochemistry, and the expression levels of IL-1ß, matrix metalloproteinase (MMP)-3, and MMP-13 in synovial tissue were detected by western blot. RESULTS: The HA/CS-CrmA nanoparticles, which effectively entrapped plasmid DNA, showed an adequate size (100-300 nm) and a regular spherical shape. The nanoparticles safely transfected synoviocytes and released plasmid DNA in a sustained manner over 3 weeks. Additionally, HA/CS-CrmA nanoparticles significantly inhibited cartilage damage, synovial inflammation, and the loss of type II collagen induced by ACLT. The expression levels of IL-1ß, MMP-3, and MMP-13 in synovial tissue were dramatically down-regulated by HA/CS-CrmA nanoparticles. CONCLUSIONS: These results suggested that HA/CS-CrmA nanoparticles could attenuate cartilage destruction and protect against early OA by inhibiting synovial inflammation via inhibition of IL-1ß generation.

Chitosan/hyaluronic acid/plasmid-DNA nanoparticles encoding interleukin-1 receptor antagonist attenuate inflammation in synoviocytes induced by interleukin-1 beta.

Synovial inflammation mainly resulting from interleukin-1 beta (IL-1ß) plays a crucial role in the early and late stage of osteoarthritis. Recent progress in therapeutic gene delivery systems has led to promising strategies for local sustained target gene expression. The aim of this study was to design a nanoparticle made of chitosan (CS)/hyaluronic acid (HA)/plasmid-DNA (pDNA) encoding IL-1 receptor antagonist gene (pIL-1Ra) and furtherly use it to transfect the primary synoviocytes, and then investigate whether CS/HA/pIL-1Ra nanoparticles could make the synoviocytes overexpress functional IL-1Ra to attenuate inflammation induced by IL-1ß. In this study, CS was modified with HA to generate CS/HA nanoparticles and then combined with pIL-1Ra to form CS/HA/pIL-1Ra nanoparticles. The physicochemical characteristics results showed that CS/HA nanoparticles exhibited an appropriate particle size (144.9 ± 2.8 nm) and positive zeta potential ( + 28 mV). The gel retardation assay revealed that pDNA was effectively protected and released in a sustained manner more than 15 days. Cytotoxicity results showed that CS/HA/pIL-1Ra nanoparticles had a safe range (0-80 µg/ml) for the application to synoviocytes. RT-qPCR and western blot analysis demonstrated that CS/HA/pIL-1Ra nanoparticles were able to increase IL-1Ra expression in primary synoviocytes, and reduce the mRNA and protein levels of matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-13 (MMP-13), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in IL-1ß-induced synoviocytes. Our findings indicated that CS/HA/pIL-1Ra nanoparticles efficiently transfected synoviocytes and attenuated synovitis induced by IL-1ß, which will provide a potential strategy for OA synovitis.

Multi objective optimization and evaluation approach of prefabricated component combination solutions using NSGA-II and simulated annealing optimized projection pursuit method.

As a main carrier mode for the sustainable development of the construction industry in China, prefabricated building may lead to problems such as cost overruns, project delays, and waste of resources due to unreasonable selection of prefabricated components. Therefore, we quantitatively analyze the contribution rate of quality optimization of prefabricated components using QFD-SEM. Under the constraints of prefabrication rate, quality optimization contribution rate, and expected values of various sub-goals, we propose a multi-objective optimization method for prefabricated component combinations based on cost, duration, and carbon emissions. By using NSGA-II to solve the model, we can obtain a set of optimal Pareto solutions for prefabricated component combinations. Based on the optimal Pareto solution set, we establish a multi-objective evaluation model using simulated annealing optimization projection tracing method, and select the optimal prefabricated component combination solution according to the projected eigenvalues of the solutions. An empirical study is conducted using an eleven-story framed building in Shenzhen, Guangdong Province, China as a case study. The results show that: (1) Using this method, optimal solutions can be obtained in an unbounded solution space, with the optimal solution having advantages over both fully cast-in-place and fully prefabricated solutions. Compared to the fully cast-in-place solution, the duration and carbon emissions are reduced by 36.62% and 12.74% respectively, while compared to the fully prefabricated solution, costs are reduced by 4.15%. (2) There is a certain negative correlation between the cost of prefabricated component combinations and duration, carbon emissions, and quality optimization, while there is a certain positive correlation with the prefabrication rate. (3) The size of the optimal projection direction vector based on the optimization objectives indicates that carbon emissions have the greatest impact on the evaluation results of the solutions.

Robust tetra-armed poly (ethylene glycol)-based hydrogel as tissue bioadhesive for the efficient repair of meniscus tears.

Repair and preservation of the injured meniscus has become paramount in clinical practice. However, the complexities of various clinic stitching techniques for meniscus repair pose challenges for grassroots doctors. Hence, there is a compelling interest in innovative therapeutic strategies such as bioadhesives. An ideal bioadhesive must cure quickly in aqueous and blood environments, bind strongly, endure arthroscopic washing pressures, and degrade appropriately for tissue regeneration. Here, we present a tetra-poly (ethylene glycol) (PEG)-based hydrogel bioadhesive, boasting high biocompatibility, ultrafast gelation, facile injectable operation, and favorable mechanical strength. In view of the synergistic effects of chemical anchor and physical chain entanglement to tightly bind the meniscus, a seamless interface was formed between the surrounding meniscal tissues and hydrogels, enabling the longitudinal tear of the meniscus fused in situ to withstand large tensile force with the adhesive strength of 541.5 ± 31.4 kPa and arthroscopic washout resistance of 29.4 kPa. Superior to existing commercial adhesives, ours allows sutureless application and arthroscopic assistance, without requiring specialized clinical skills. This research is expected to significantly impact our understanding of meniscal healing and ultimately promote a simpler process for achieving functional and structural recovery in torn menisci.

Chondrocyte membrane-coated nanoparticles promote drug retention and halt cartilage damage in rat and canine osteoarthritis.

Osteoarthritis (OA) is a chronic joint disease characterized by progressive degeneration of articular cartilage. A challenge in the development of disease-modifying drugs is effective delivery to chondrocytes. The unique structure of the joint promotes rapid clearance of drugs through synovial fluid, and the dense and avascular cartilage extracellular matrix (ECM) limits drug penetration. Here, we show that poly(lactide-co-glycolic acid) nanoparticles coated in chondrocyte membranes (CM-NPs) were preferentially taken up by rat chondrocytes ex vivo compared with uncoated nanoparticles. Internalization of the CM-NPs was mediated primarily by E-cadherin, clathrin-mediated endocytosis, and micropinocytosis. These CM-NPs adhered to the cartilage ECM in rat knee joints in vivo and penetrated deeply into the cartilage matrix with a residence time of more than 34 days. Simulated synovial fluid clearance studies showed that CM-NPs loaded with a Wnt pathway inhibitor, adavivint (CM-NPs-Ada), delayed the catabolic metabolism of rat and human chondrocytes and cartilage explants under inflammatory conditions. In a surgical model of rat OA, drug-loaded CM-NPs effectively restored gait, attenuated periarticular bone remodeling, and provided chondroprotection against cartilage degeneration. OA progression was also mitigated by CM-NPs-Ada in a canine model of anterior cruciate ligament transection. These results demonstrate the feasibility of using chondrocyte membrane-coated nanoparticles to improve the pharmacokinetics and efficacy of anti-OA drugs.

An immunomodulatory polypeptide hydrogel for osteochondral defect repair.

Osteochondral injury is a common and frequent orthopedic disease that can lead to more serious degenerative joint disease. Tissue engineering is a promising modality for osteochondral repair, but the implanted scaffolds are often immunogenic and can induce unwanted foreign body reaction (FBR). Here, we prepare a polypept(o)ide-based PAA-RGD hydrogel using a novel thiol/thioester dual-functionalized hyperbranched polypeptide P(EG3Glu-co-Cys) and maleimide-functionalized polysarcosine under biologically benign conditions. The PAA-RGD hydrogel shows suitable biodegradability, excellent biocompatibility, and low immunogenicity, which together lead to optimal performance for osteochondral repair in New Zealand white rabbits even at the early stage of implantation. Further in vitro and in vivo mechanistic studies corroborate the immunomodulatory role of the PAA-RGD hydrogel, which induces minimum FBR responses and a high level of polarization of macrophages into the immunosuppressive M2 subtypes. These findings demonstrate the promising potential of the PAA-RGD hydrogel for osteochondral regeneration and highlight the importance of immunomodulation. The results may inspire the development of PAA-based materials for not only osteochondral defect repair but also various other tissue engineering and bio-implantation applications.

Pathological Thresholds of Segmental Femoral Torsion in Patients With Patellar Dislocation: Influence on Patellofemoral Malalignment.

Background: Femoral torsion can be evaluated from different femoral segments. The pathological thresholds for femoral torsion of different segments and the influence of segmental femoral torsion on patellofemoral alignment remain unknown. Purpose: To compare femoral torsion between patients with recurrent patellar dislocation and healthy individuals, to determine the statistical physiological range and pathological thresholds of femoral torsion in different segments, and to investigate the influence of femoral torsion on patellofemoral malalignment. Study Design: Cross-sectional study; Level of evidence, 3. Methods: We retrospectively reviewed the records of patients with patellar dislocation who received surgical treatment in our department between 2019 and 2020. Healthy participants were recruited as the control group. The control patients were asymptomatic and had no history of lower extremity disorders. The differences in femoral torsion between the study and control groups were compared. The diagnostic capacity of femoral torsion in different segments and their correlation with patellar tilt were investigated. The mean value and 95% CI of femoral torsion in different segments were established using data from healthy volunteers. Results: A total of 60 patients with patellar dislocation and 100 healthy volunteers were included in this study. The total, mid, and distal femoral torsion values differed significantly between the study and control groups (P < .01). Total femoral torsion had the highest diagnostic value (area under the receiver operating curve = 0.733). Total torsion (r = 0.432; P < .001), mid torsion (r = 0.242; P = .002), and distal torsion (r = 0.324; P < .001) showed significant correlations with patellar tilt. The pathological thresholds of excessive femoral torsion of the total, proximal, mid, and distal femoral segments were 24.73°, 46.68°, -6.55°, and 14.92°, respectively. Conclusion: Patients with patellar dislocation had greater femoral torsion than healthy individuals in multiple femoral segments. Excessive mid, distal, and total torsion was associated with more significant patellar tilt.

Immunomodulatory PEG-CRGD Hydrogels Promote Chondrogenic Differentiation of PBMSCs.

Cartilage damage is a common injury. Currently, tissue engineering scaffolds with composite seed cells have emerged as a promising approach for cartilage repair. Polyethylene glycol (PEG) hydrogels are attractive tissue engineering scaffold materials as they have high water absorption capacity as well as nontoxic and nutrient transport properties. However, PEG is fundamentally bio-inert and lacks intrinsic cell adhesion capability, which is critical for the maintenance of cell function. Cell adhesion peptides are usually added to improve the cell adhesion capability of PEG-based hydrogels. The suitable cell adhesion peptide can not only improve cell adhesion capability, but also promote chondrogenesis and regulate the immune microenvironment. To improve the interactions between cells and PEG hydrogels, we designed cysteine-arginine-glycine-aspartic acid (CRGD), a cell adhesion peptide covalently cross-linked with PEG hydrogels by a Michael addition reaction, and explored the tissue-engineering hydrogels with immunomodulatory effects and promoted chondrogenic differentiation of mesenchymal stem cells (MSCs). The results indicated that CRGD improved the interaction between peripheral blood mesenchymal stem cells (PBMSCs) and PEG hydrogels. PEG hydrogels modified with 1 mM CRGD had the optimal capacity to promote chondrogenic differentiation, and CRGD could induce macrophage polarization towards the M2 phenotype to promote tissue regeneration and repair. PEG-CRGD hydrogels combined with PBMSCs have the potential to be suitable scaffolds for cartilage tissue engineering.

Function and Mechanism of RGD in Bone and Cartilage Tissue Engineering.

Bone and cartilage injury is common, tissue engineered scaffolds are potential means to repair. Because most of the scaffold materials used in bone and cartilage tissue engineering are bio-inert, it is necessary to increase the cellular adhesion ability of during tissue engineering reconstruction. The Arginine - Glycine - Aspartic acid (Arg-Gly-Asp, RGD) peptide family is considered as a specific recognition site for the integrin receptors. Integrin receptors are key regulators of cell-cell and cell-extracellular microenvironment communication. Therefore, the RGD polypeptide families are considered as suitable candidates for treatment of a variety of diseases and for the regeneration of various tissues and organs. Many scaffold material for tissue engineering and has been approved by US Food and Drug Administration (FDA) for human using. The application of RGD peptides in bone and cartilage tissue engineering was reported seldom. Only a few reviews have summarized the applications of RGD peptide with alloy, bone cements, and PCL in bone tissue engineering. Herein, we summarize the application progress of RGD in bone and cartilage tissue engineering, discuss the effects of structure, sequence, concentration, mechanical stimulation, physicochemical stimulation, and time stimulation of RGD peptide on cells differentiation, and introduce the mechanism of RGD peptide through integrin in the field of bone and cartilage tissue engineering.

Scaffold-Based Tissue Engineering Strategies for Osteochondral Repair.

Over centuries, several advances have been made in osteochondral (OC) tissue engineering to regenerate more biomimetic tissue. As an essential component of tissue engineering, scaffolds provide structural and functional support for cell growth and differentiation. Numerous scaffold types, such as porous, hydrogel, fibrous, microsphere, metal, composite and decellularized matrix, have been reported and evaluated for OC tissue regeneration in vitro and in vivo, with respective advantages and disadvantages. Unfortunately, due to the inherent complexity of organizational structure and the objective limitations of manufacturing technologies and biomaterials, we have not yet achieved stable and satisfactory effects of OC defects repair. In this review, we summarize the complicated gradients of natural OC tissue and then discuss various osteochondral tissue engineering strategies, focusing on scaffold design with abundant cell resources, material types, fabrication techniques and functional properties.

Non-depleting reformation of immunosuppressive myeloid cells to broaden the application of anti-PD therapy.

Traditional methods of depleting tumor-associated myeloid cells via chemotherapy can easily lead to the re-recruitment of them, eventually resulting in chemo-resistance and presenting obstacles in immunotherapy. Herein, we report a nano-educator (NE) that when loaded with all trans retinoic acid (ATRA) and anti-PD-1 antibodies (aPD-1) instructs myeloid cells to assist T cells towards revitalizing anti-PD-1 therapy. In vivo, ATRA converts myeloid-derived suppressor cells (MDSCs) into dendritic cells (DCs), which are essential for anti-PD-1 therapy, while intervening in the polarization of macrophages. Furthermore, aPD-1-armed T cells reboot anti-tumor immunity after suppression relief, which exposes tumor-specific antigens and in turn promotes the maturation of transformed DCs. The nano-platform provides shelter for vulnerable immunomodulatory agents and durable drug release to stimulate intensive immune modulation. We established three types of tumor-bearing mice models with different myeloid cell contents to show the spatiotemporal complementarity of ATRA and aPD-1. The NE re-educates the tumor's guard to assist T cells in enhanced immunotherapy, broadening the application of aPD-1 in the treatment of anti-PD-1-resistant tumors.

Construction of chitosan/ZnO nanocomposite film by in situ precipitation.

In the present work, flexible chitosan/ZnO nanocomposite films were prepared by a green and facile method through in situ precipitation of nano-ZnO (nZnO) in the chitosan film. Zn(Ac)2 was added in chitosan solution to provide Zn2+, thus Zn2+ was fixed in the chitosan matrix and converted into nZnO through interaction with NaOH with heating. The structure and properties of the hybrid films were characterized by Field emission scanning electron microscope (FESEM), atomic force microscope (AFM), Fourier transform infra-red (FT-IR), X-ray diffraction (XRD) and tensile testing. The results indicated that there was strong coordination interaction existed between Zn2+ and chitosan matrix for the good dispersion of nZnO in the chitosan film. Furthermore, nZnO distributed evenly in the chitosan and aggregated to form micro-nano-binary hierarchical structure, mimicking lotus leaf structure. Therefore, this work provides an effective way to prepare biocompatible and antibacterial chitosan/ZnO nanocomposite films, showing potential applications in the fields of antibacterial packaging and dressings.

Hyaluronic acid-chitosan nanoparticles encoding CrmA attenuate interleukin-1ß induced inflammation in synoviocytes in vitro.

Osteoarthritis (OA) is a common degenerative joint disease characterized by inflammation of synoviocytes and degradation of cartilage. In the present study, hyaluronic acid/chitosan (HA/CS) nanoparticles were used as a vehicle for gene therapy of OA, and the cytokine response modifier A (CrmA) pDNA was proposed as the target gene. The HA/CS/pCrmA nanoparticles were prepared and the characteristics of the nanoparticles were examined. The nanoparticles were spherical, and the smallest size was obtained with the HA:CS weight ratio of 1:4. The release analysis exhibited a constant release over 29 days. The pDNA was completely combined with HA/CS nanoparticles and the HA/CS nanoparticles protected pDNA from degradation. Subsequently, rat synoviocytes were transfected with HA/CS/pDNA nanoparticles, and the results demonstrated that the HA/CS nanoparticles were able to improve the transfection capacity of pDNA. The cytotoxicity of the HA/CS/pDNA nanoparticles was additionally detected using a MTS assay to ensure that the HA/CS nanoparticle was a safe carrier. To additionally investigate the effects of HA/CS/pCrmA nanoparticles on synoviocytes in OA, the MMP­3 and MMP­13 gene expression levels were detected at the gene and protein expression levels. These results indicated that the HA/CS/pCrmA nanoparticles attenuated interleukin­1ß­mediated inflammation in synoviocytes. It was concluded that the HA/CS/pCrmA nanoparticles may provide a novel approach to the treatment of OA.

Nanoparticles from Cuttlefish Ink Inhibit Tumor Growth by Synergizing Immunotherapy and Photothermal Therapy.

Natural nanoparticles have been extensively studied due to their diverse properties and easy accessibility. Here, the nanoparticles extracted from cuttlefish ink (CINPs) with significant antitumor efficacy are explored. These CINPs, with spherical morphology, good dispersibility, and biocompatibility, are rich in melanin and contain a variety of amino acids and monosaccharides. Through the activation of mitogen-activated protein kinase (MAPK) signaling pathway, CINPs can efficiently reprogram tumor-associated macrophages (TAMs) from immune-suppressive M2-like phenotype to antitumor M1-like phenotype. Besides, under near-infrared (NIR) irradiation, CINPs exhibit high photothermal effect and tumor cell killing ability, which make them a potential candidate in photothermal therapy (PTT) of tumor. In vivo, CINPs can increase the proportion of M1 macrophages and foster the recruitment of cytotoxic T lymphocytes (CTLs) to tumors, leading to reduced primary tumor growth and lung metastasis. In combination with their photothermal effect, which can induce tumor-specific antigens release, CINPs could almost completely inhibit tumor growth accompanied by more active immune responses. Collectively, these CINPs described here can provide both tumor immunotherapy and PTT, implying that CINPs are promising for tumor treatment.