[Biomechanical characteristics of hip prosthesis in hip arthroplasty treating elderly patients with Evans I-III intertrochanteric fracture of femur].

OBJECTIVE: To investigate the feasibility of hip arthroplasty in the treatment of elderly patients with Evans I-III intertrochanteric fracture of femur by analyzing its biomechanics characters. METHODS: We solved the CT digital image files with the graphics processing software Mimics at DICOM 3.0 standard, and reconstructed the three-dimensional entity of femur with CAD modeling software Unigraphics. Then the fracture line was defined in the model as the line between the tip of greater trochanter and inferior margin of small trochanter, above which the upper bone was removed. Afterwards the two prosthesises with different stem lengths (120 mm and 170 mm) were implanted into the fracture model respectively as hip arthroplasty with 3 mm bone cement layer between prosthesis and femur, and the bone defect was repatched with 5 mm bone cement layer. A three-dimensional finite element model was established with finite element analysis software ABAQUS 6.5. We formulated different material parameters under the stress condition standing with single leg to build the stress distribution map of the femur prosthesis, and took 5 loci of region of stress concentration to calculate the mean value of stress. RESULTS: The stress distribution maps of the short and long stem length prothesises were similar. And there were two areas of stress concentration, including the upper portion and the lower portion close to the joint of the prosthesis stem, and the stress concentration in the junction part was obviously between the lower portion and the upper area of the small trachanter. The stress reached the first concentration area at the junction and then gradually reached the second concentration area at the interior terminal of the stem. While the stress gradually increased along the lateral prosthesis stem, and reached the stress concentration area at the end. CONCLUSIONS: The stress distribution maps in the femur prosthesises are similar between hip arthroplasty in the treatment of intertrochanteric fracture of femur and the traditional hip arthroplasty surgery. The peak stress values are higher in the long stem prosthesis in the treatment of intertrochanteric fracture of femur than the short type, while they are under the rupture value of the metal.

Using Platelet-Rich Plasma Hydrogel to Deliver Mesenchymal Stem Cells into Three-Dimensional PLGA Scaffold for Cartilage Tissue Engineering.

The synthetic biodegradable polyester-based rigid porous scaffolds and cell-laden hydrogels have been separately employed as therapeutic modality for cartilage repair. However, the synthetic rigid scaffolds alone may be limited due to the inherent lack of bioactivity for cartilage regeneration, while the hydrogels have insufficient mechanical properties that are not ideal for load-bearing cartilage applications. In the present study, a hybrid construct was designed to merge the advantage of 3D-printed rigid poly(lactic-co-glycolic acid) (PLGA) scaffolds with cell-laden platelet-rich plasma (PRP) hydrogels that can release growth factors to regulate the tissue healing process. PRP hydrogels potentially achieved the effective delivery of mesenchymal stem cells (MSCs) into PLGA scaffolds. This hybrid construct could obtain adequate mechanical properties and independently provide MSCs with appropriate clues for proliferation and differentiation. Real-time gene expression analysis showed that PRP stimulated both chondrogenic and osteogenic differentiation of MSC seeding into PLGA scaffolds. Finally, the hybrid constructs were implanted into rabbits to simultaneously regenerate both articular cartilage and subchondral bone within osteochondral defects. Our findings suggest that this unique hybrid system could be practically applied for osteochondral regeneration due to its capacity for cell transportation, growth factors release, and excellent mechanical strength, which would greatly contribute to the progress of cartilage tissue engineering.

PDCD4 Negatively Regulated Osteogenic Differentiation and Bone Defect Repair of Mesenchymal Stem Cells Through GSK-3ß/ß-Catenin Pathway.

Mesenchymal stem cells (MSCs) have been shown to be involved in bone injury repair. Programmed cell death 4 (PDCD4) is not only a tumor suppressor gene but also plays roles in the regulation of MSC function. The aim of the study was to uncover PDCD4 potential regulatory roles and mechanisms in the osteogenic differentiation and bone defect repair of MSCs. shRNA technique was used to knock down PDCD4 expression in umbilical cord-derived mesenchymal stem cells (shPDCD4-UCMSCs). Their phenotype was characterized by flow cytometry and the differentiation potential was verified. We found that PDCD4 knockdown did not affect the surface molecule expression of UCMSCs, but significantly enhanced their osteogenic differentiation and osteogenesis-related molecule expression. Mechanistically, glycogen synthase kinase-3ß (GSK-3ß) phosphorylation and ß-catenin expression were significantly increased in shPDCD4-UCMSCs during the osteogenic differentiation process. The ß-catenin inhibitor PNU-74654 reversed shPDCD4-increased osteogenesis and osteogenesis-related molecule expression. The results of animal experiments showed that shPDCD4-UCMSCs markedly improved the defect healing in rabbits. Our findings suggest that PDCD4 acts as a negative regulator of MSC osteogenic differentiation through GSK-3ß/ß-catenin pathway. Targeting PDCD4 may be a way to improve MSC-mediated therapeutic effects on bone injury.

Finite element analysis of cemented prostheses for hip replacement in elderly patients with comminuted intertrochanteric fracture.

BACKGROUND: To determine postoperative stress distribution after cemented arthroplasty in elderly patients with comminuted intertrochanteric fracture, and assist in determining a rational prosthetic stem length. METHODS: A three-dimensional (3D) model of intertrochanteric fracture was established using the Mimics and Unigraphics modeling software, which included the 3D model of comminuted intertrochanteric fracture, two long-stem(#4,#5) and one short stem(#3) prostheses, and the mantle layer of cement. The bone defect of the calcar femorale was replaced with a 5-mm thick cement. Then, the 3D finite element model of those materials was established, boundary conditions of force were imposed, and material parameters were set. Accordingly, a finite element analysis was performed to this model in stress. RESULTS: (1) The stress of the femur in the three-stem replacement prosthesis models increased from proximal end to distal end in the same pattern, while a stress concentration region was found at 5 mm from within the distal tip of the short-stem prosthesis (#3), which had a peak value of 67.85 MPa. However, no stress concentration was found on the long-stem prosthesis model. (2) For the short-stem prosthesis, the stress distribution of the cement-prosthesis interface was significantly concentrated in the distal region around the prosthesis end, in which the peak value of the lateral interface exceeded the fatigue strength of the bone cement. However, the biomechanics for the long prosthesis was better appreciated. CONCLUSION: Long prosthesis stems may theoretically be a better option for comminuted intertrochanteric fractures in elderly patients. However, the application of exceedingly long prosthesis stems would not be a better option. KEY WORDS: Comminuted intertrochanteric fracture, Elderly patients Finite element analysis, Prosthetic replacement.

Blocking of checkpoint receptor PD-L1 aggravates osteoarthritis in macrophage-dependent manner in the mice model.

As a chronic degenerative joint disease, osteoarthritis is among the most common diseases all over the world. In osteoarthritis, inflammation plays an important role in the generation of joint symptoms and the development of disease. When the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint is blocked, the antitumor immunity will be enhanced. We aim to illustrate the function of PD-L1 in osteoarthritis. Osteoarthritis in mice was induced by the injection of collagenase or anterior cruciate ligament transection (ACLT). Anti-PD-L1 was employed to block the signal of PD-L1. Knee joints histological sections were stained by Safranin-O. The level of cytokine was checked by enzyme-linked immunosorbent assay (ELISA) and mRNA level was shown by quantitative reverse transcriptase polymerase chain reaction. The blockade of PD-L1 signal up-regulated inflammatory response and promoted the development of osteoarthritis in mice. The inflammatory cytokine interleukin-6 and tumor necrosis factor-α expression were promoted by PD-L1 blocking in macrophages. Osteoarthritis was aggravated when the expression of inflammatory cytokine is elevated in macrophages. Our results indicated that the blockade of PD-L1 signal in macrophages elevates the expression of inflammatory cytokine and promotes the development of osteoarthritis in mice, which could be utilized as a potential diagnostic and therapeutic target for osteoarthritis patients.

Effect of Cross-Linked Hyaluronate Scaffold on Cartilage Repair: An In Vivo Study.

OBJECTIVE: To determine the safety and effectiveness of a cross-linked sodium hyaluronate (CHA) scaffold in cartilage repair. METHODS: Physicochemical properties of the scaffold were determined. The safety and effectiveness of the scaffold for cartilage repair were evaluated in a minipig model of a full-thickness cartilage defect with microfracture surgery. Postoperative observation and hematological examination were used to evaluate the safety of the CHA scaffold implantation. Pathological examination as well as biomechanical testing, including Young's modulus, stress relaxation time, and creep time, were conducted at 6 and 12 months postsurgery to assess the effectiveness of the scaffold for cartilage repair. Furthermore, type II collagen and glycosaminoglycan content were determined to confirm the influence of the scaffold in the damaged cartilage tissue. RESULTS: The results showed that the routine hematological indexes of the experimental animals were within the normal physiological ranges, which confirmed the safety of CHA scaffold implantation. Based on macroscopic observation, it was evident that repair of the defective cartilage in the animal knee joint began during the 6 months postoperation and was gradually enhanced from the central to the surrounding region. The repair smoothness and color of the 12-month cartilage samples from the operation area were better than those of the 6-month samples, and the results for the CHA scaffold implantation group were better than the control group. Greater cell degeneration and degeneration of the adjacent cartilage was found in the implantation group compared with the control group at both 6 and 12 months postoperation, evaluated by O'Driscoll Articular Cartilage Histology Scoring. Implantation with the CHA scaffold matrix promoted cartilage repair and improved its compression capacity. The type II collagen level in the CHA scaffold implantation group tended to be higher than that in the control group at 6 months (2.33 ± 1.50 vs 1.68 ± 0.56) and 12 months postsurgery (3.37 ± 1.70 vs 2.06 ± 0.63). The GAG content in the cartilage of the control group was significantly lower than that of the experimental group (2.17 ± 0.43 vs 3.64 ± 1.17, P = 0.002 at 6 months and 2.27 ± 0.38 vs 4.12 ± 1.02, P = 0.002 at 12 months). Type II collagen and glycosaminoglycan content also demonstrated that CHA was beneficial for the accumulation of both these vital substances in the cartilage tissue. CONCLUSIONS: The CHA scaffold displayed the ability to promote cartilage repair when applied in microfracture surgery, which makes it a promising material for application in the area of cartilage tissue engineering.

Contralateral monoarthritis exacerbated chronic constriction injury-induced pain hypersensitivity through upregulating inducible nitric oxide synthase.

INTRODUCTION: High comorbidity of osteoarthritis (OA) and neuropathic pain has been reported in aged patients. Evidence shows that central sensitization of pain processing occurs in late-phase OA and may facilitate the development of neuropathic pain. Few studies reveal whether acute monoarthritis (MA) aggravates neuropathic pain on the opposite side of the body from the injury. METHODS: To address whether neuropathic pain is affected by contralateral MA through distinct inflammatory pathway, MA was induced by intra-articular injection of complete Freund's adjuvant (CFA) into the right tibiotarsal joint, and neuropathic pain was established by chronic constriction injury (CCI) of the left sciatic nerve. RESULTS: We observed that MA aggravated mechanical allodynia and thermal hyperalgesia in CCI rats. Furthermore, MA affected the other side of the spinal cord in multiple aspects, including the upregulation of iNOS mRNA and the enhancement of forskolin-induced facilitation of excitatory synaptic transmission in the spinal cord dorsal horn substantia gelatinosa neurons. DISCUSSION: Interestingly, intrathecal injection of 1400W, an antagonist of iNOS, attenuated intensity of pain behaviors in CCI rats with contralateral MA to similar levels in CCI rats without MA, and also normalized the facilitatory effect of forskolin on excitatory synaptic transmission in the spinal cord dorsal horn neurons in contralateral MA rats. Therefore, contralateral MA worsened CCI-induced pain hypersensitivity probably through upregulating iNOS and enhancing the facilitation of synaptic transmission following CCI. CONCLUSION: Inhibiting the iNOS might be a potential therapeutic strategy for concurrent OA and neuropathic pain.

Bindarit Attenuates Pain and Cancer-Related Inflammation by Influencing Myeloid Cells in a Model of Bone Cancer.

C-C motif chemokine ligand 2 (CCL2) is a small cytokine that functions in inflammation and cancer development. Bindarit, a CCL2 inhibitor, is a small anti-inflammatory molecule proven safe by phase II trials in type 2 diabetic nephropathy patients. As cancer-related inflammation is a cause of pain, we investigated whether Bindarit suppresses cancer-related inflammation and pain. We established a bone-cancer mouse model by inoculating cancer cells. After applying Bindarit, we preformed pain sensitivity tests and checked cancer development by X-ray. Using flow cytometry and qRT-PCR assays, we assessed the effect of Bindarit on peripheral blood monocyte mobilization and M2 macrophage polarization. We also investigated the targets of Bindarit using western blotting and luciferase assay. Bindarit-treated mice performed better in pain sensitivity tests compare to control mice. X-ray imaging showed that Bindarit-treated mice had fewer cancer cell colonies and smaller overall tumor burden. Bindarit reduced the number of monocytes in peripheral blood and down-regulated the expression of M2 macrophage polarization makers. Bindarit also inhibited IKKß phosphorylation. Bindarit efficiently relieves cancer-related pain and suppresses cancer development. Bindarit inhibits monocyte mobilization in peripheral blood as well as M2 macrophage polarization. IKKß is identified as a target of Bindarit.

Anti-inflammatory effect of hesperidin enhances chondrogenesis of human mesenchymal stem cells for cartilage tissue repair.

BACKGROUND: Articular cartilage diseases are considered a major health problem, and tissue engineering using human mesenchymal stem cells (MSCs) have been shown as a promising solution for cartilage tissue repair. Hesperidin is a flavonoid extract from citrus fruits with anti-inflammatory properties. We aimed to investigate the effect of hesperidin on MSCs for cartilage tissue repair. MSCs were treated by hesperidin, and colony formation and proliferation assays were performed to evaluate self-renewal ability of MSCs. Alcian blue staining and Sox9 expression were measured to evaluate chondrogenesis of MSCs. Secretion of pro-inflammatory cytokines IFN-γ, IL-2, IL-4 and IL-10, and expression of nuclear factor kappa B (NF-κB) subunit p65 were also assessed. RESULTS: Hesperidin improved self-renewal ability and chondrogenesis of MSCs, inhibited secretion of pro-inflammatory cytokines IFN-γ, IL-2, IL-4 and IL-10, and suppressed the expression of p65. Overexpression of p65 was able to reverse the hesperidin inhibited secretions of pro-inflammatory cytokines, and abolish the enhancing effect of hesperidin on chondrogenesis of MSCs. CONCLUSION: Hesperidin could serve as a therapeutic agent to effectively enhance chondrogenesis of human MSCs by inhibiting inflammation to facilitate cartilage tissue repair.

Biomechanical supporting effect of tantalum rods for the femoral head with various sized lesions: a finite-element analysis.

BACKGROUND: Features of necrotic lesions and various interventions could affect the biomechanics of the femoral head. A three-dimensional finite-element analysis was designed to demonstrate necrotic femoral head stress changes with various sizes of necrotic lesions, and evaluate the effect of tantalum rods on preventing femoral head cracking. METHODS: Femoral computed tomography scans were used to build a normal three-dimensional finite-element femoral head model in a computer. Based on the normal model, necrotic models of different lesion diameters (15 mm, 20 mm and 30 mm) were created, as were the repaired models with tantalum rods for each diameter. After a series of meshing and force loading, the von Mises stress distributions, simulating single-legged stance, and stresses on specific points under loaded conditions were determined for each model. RESULTS: Deep exploration into the burdened area of the femoral head indicated that higher stresses to the femoral head were observed with a larger necrotic lesion; the largest stress concentration, 91.3 MPa, was found on the femoral head with a lesion diameter of 30 mm. By contrast, topical stress on the surface of the necrotic regions was lowered following implantation of a tantalum rod, and the changes in stress were significant in models with lesions of 15 mm and 30 mm in diameter, with the best biomechanical benefit from the tantalum rod found with a lesion diameter of 15 mm. CONCLUSIONS: Femoral heads with larger necrotic lesions usually have a higher stress concentration and a higher risk of collapse. Various sized lesions on the femoral head can benefit from the mechanical support offered by the implantation of a tantalum rod; however, femoral heads with smaller sized lesions may benefit more. A thorough evaluation of the lesion size should be conducted prior to the use of tantalum rod implants in the treatment of femoral head necrosis.

Therapeutic effect of an injectable sustained-release sinomenine hydrochloride and sodium hyaluronate compound in a rabbit model of osteoarthritis.

BACKGROUND: While intra-articular injection of sinomenine hydrochloride has a therapeutic effect on osteoarthritis, it has a short half-life, and is thermolabile and photolabile. The aim of this research was to evaluate the sustained-release of sinomenine hydrochloride from an injectable sinomenine hydrochloride and sodium hyaluronate compound (CSSSI) and its therapeutic effect in a rabbit model of osteoarthritis following intra-articular injection. METHODS: An injectable compound consisting of 1% sodium hyaluronate and 2.5% sinomenine hydrochloride was prepared and kept as the experiment group, and 2.5% sinomenine hydrochloride was prepared and kept as the control group. The cumulative mass release was measured at different time points in each group in vitro. Sixty-five male Zelanian rabbits were randomly divided into five groups: 15 (30 knees) each for the control, sodium hyaluronate, sinomenine hydrochloride, and CSSSI groups respectively, and five (10 knees) for the modeling group. Papain was injected into both knees of each rabbit for model establishment. Subsequently, 0.2 ml of the corresponding drugs was injected into the articular cavities of the remaining experiment groups, while the control group was treated with 0.2 ml normal saline. All groups were treated once a week for 4 weeks. Seven days after the last treatment, knees were anatomized to perform pathological observations and Mankin's evaluation of the synovium. Four groups were compared using the SPSS 13.0 software package. RESULTS: In the in vitro sustained-release experiments, 90% of the drug was released in the experiment group 360 minutes following the injection. Comparison of the Mankin's evaluations of the four groups illustrated statistical discrepancies (P < 0.05). In further paired comparisons of the CSSSI group vs. modeling control/sodium hyaluronate/sinomenine hydrochloride groups, statistical significance was uniformly obtained. Moreover, sodium hyaluronate and sinomenine hydrochloride treatments showed significant improvement over the modeling control (P < 0.05), whereas sodium hyaluronate vs. sinomenine hydrochloride comparison failed to reach significance (P > 0.05). CONCLUSIONS: CSSSI has a sustained-release effect on sinomenine hydrochloride. Intra-articular injection of CSSSI was significantly better than the sole sodium hyaluronate or sinomenine hydrochloride for the treatment of osteoarthritis in a rabbit model.