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Background: Our group have developed a new 3D printing cervical composite joint system prosthesis. The corresponding biomechanical effect should be evaluated in the treatment of cervical spondylosis. The purpose of this study was to evaluate the biomechanical properties of the prosthesis using a three-dimensional finite element model.Methods: CT data were extracted by mimics16.0 software to reconstruct the C3-C7 model of cervical spine. The model was divided into three groups: normal cervical spine group, prosthesis implantation group and ACCF group. The three groups of models in six different motion states (flexion, extension, left and right lateral bending, left and right rotation) were simulated by three-dimensional finite element simulation. The RoM of lower cervical vertebra, RoM between each vertebrae, and the stress of intervertebral disc were compared and analyzed. Results: Compared with the normal cervical spine, the RoM of C3-7 in the prosthesis implantation group showed a downward trend in six different motion states, with a decrease range of 5.27%. RoM of each segment in the prosthesis implantation group was decreased, and the decrease range was less than 7.34%. In the six motion states, the stress of each intervertebral disc in the prosthesis implantation group and ACCF group was increased. Compared with the prosthesis implantation group, the stress increased significantly at at the C3-C4 level in ACCF group. Conclusion: The novel 3D printing cervical composite joint system prosthesis can not only retain the range of motion of the cervical spine, but also decrease the stress of the upper adjacent intervertebral disc.

Background Since the first report about nail gun injuries in 1959, there has been an average of approximately 37,000 patients hurt by nail guns and treated in emergency departments. Carotid arterial injury by nail gun has been reported, but vertebral artery damage is extremely rare. Case Description A 42-year-old man was transported to the emergency department after suffering an accidental self-inflicted nail gun injury to the left lateral aspect of his neck. Radiographic imaging of the cervical spine revealed a 3.1-cm metallic nail in the C5 region. A computed tomography (CT) angiogram revealed the nail passing through the left C5 transverse foramen and compressing the left vertebral artery. He was immediately brought to the operating room for removal of the nail. At 1-month follow-up, the patient did not have any neck complaints and postoperative CT angiogram indicated the patient was asymptomatic with no signs of complication or infection. Conclusions Based on our experience and a review of the literature, in terms of treating a nail gun injury to the cervical spine, we would like emphasize that preoperative CT scan or CT angiogram is necessary to assess the location and shape of the nail, especially nails with barbers or washers. Improving awareness of the risk from accidental nail gun trauma may lead to better prevention of this rare but potentially life-threatening injury.

As a chronic inflammatory disease, diabetes mellitus creates a proinflammatory microenvironment around implants, resulting in a high rate of implant loosening or failure in osteological therapies. In this study, macroporous silk gel scaffolds are injected at the bone–implant interface for in situ release of sitagliptin that can regulate macrophage response to create a prohealing microenvironment in diabetes mellitus disease. Notably, it is discovered that sitagliptin induces macrophage polarization to the M2 phenotype and alleviates the impaired behaviors of osteoblasts on titanium (Ti) implants under diabetic conditions in a dose‐dependent manner. The silk gel scaffolds loaded with sitagliptin elicite a stronger recruitment of M2 macrophages to the sites of Ti implants and a significant promotion of osteointegration, as compared to oral sitagliptin administration. The results suggest that injectable silk/sitagliptin gel scaffolds can be utilized to modulate the immune responses at the bone–implant interface, thus enhancing bone regeneration required for successful implantation of orthopedic and dental devices in diabetic patients., A silk gel scaffold loaded with sitagliptin is developed to in situ regulate macrophage polarization from M1 to M2 phenotypes and improve osteointegration of endosseous implants at the bone–implant interface under diabetes conditions. The study provides a new insight into the mechanisms underlying diabetes‐induced implant failure and represents an innovative strategy to promote osteointegration in diabetic patients with hyperglycaemia.

Objective To evaluate the mechanical properties of a new connector rod aiming to preserve implants in revision surgery (RS) for adjacent segment disease, a problematic complication of instrumented spinal fusion, and to assess its clinical applicability. Methods The mechanical properties of the connector-rod construct (implant preservation) and traditional rod construct (implant replacement) were evaluated and compared. Forty-three patients underwent RS for adjacent segment disease in the thoracolumbar spine with implant preservation or replacement, and radiological and clinical outcomes were assessed. Results Mechanical properties in group A were comparable to those in group B. Total mean time from prior surgery to RS was 6.86 ± 1.08 years. Surgical time and blood loss values of group A were 40.14% and 29.29% statistically significantly smaller than values of group B. In group B, 12% (3/25) of patients developed surgical site infections. In both groups, the visual analog scale leg score decreased significantly after RS. Early postoperative (at 1-month and 3-month follow-up) Oswestry Disability Index and visual analog scale back scores of group A were significantly lower than those of group B; the difference in the visual analog scale back score between groups was significant until the 6-month follow-up. No implant failures occurred, and spinal fusion was achieved in all cases. Conclusions The connector rod is considered safe and can reduce the surgical time, blood loss, risk of complications, and medical costs. Better early postoperative clinical outcomes can be achieved with the rod owing to less surgical trauma.

Rationale: Mechanisms underlying the compromised bone formation in type 1 diabetes mellitus (T1DM), which causes bone fragility and frequent fractures, remain poorly understood. Recent advances in organ-specific vascular endothelial cells (ECs) identify type H blood vessel injury in the bone, which actively direct osteogenesis, as a possible player. Methods: T1DM was induced in mice by streptozotocin (STZ) injection in two severity degrees. Bony endothelium, the coupling of angiogenesis and osteogenesis, and bone mass quality were evaluated. Insulin, antioxidants, and NADPH oxidase (NOX) inhibitors were administered to diabetic animals to investigate possible mechanisms and design therapeutic strategies. Results: T1DM in mice led to the holistic abnormality of the vascular system in the bone, especially type H vessels, resulting in the uncoupling of angiogenesis and osteogenesis and inhibition of bone formation. The severity of osteopathy was positively related to glycemic levels. These pathological changes were attenuated by early-started, but not late-started, insulin therapy. ECs in diabetic bones showed significantly higher levels of reactive oxygen species (ROS) and NOX 1 and 2. Impairments of bone vessels and bone mass were effectively ameliorated by treatment with anti-oxidants or NOX2 inhibitors, but not by a NOX1/4 inhibitor. GSK2795039 (GSK), a NOX2 inhibitor, significantly supplemented the insulin effect on the diabetic bone. Conclusions: Diabetic osteopathy could be a chronic microvascular complication of T1DM. The impairment of type H vessels by NOX2-mediated endothelial oxidative stress might be an important contributor that can serve as a therapeutic target for T1DM-induced osteopathy.

STUDY DESIGN: Retrospective observational cohort study. OBJECTIVES: To compare the benefits of long and short fusion treatments, and to identify factors potentially aiding surgeons' decision making about the surgical management of degenerative lumbar scoliosis associated with spinal stenosis (DLSS). SUMMARY OF BACKGROUND DATA: The comparative effectiveness of long and short segment fusion for the treatment of DLSS remains controversial. METHODS: Fifty-three patients with symptomatic DLSS managed by posterior-only fusion surgery were enrolled in this study. Twenty patients underwent short fusion (fewer than two segments), and 33 patients had more than three segments fused. The radiological outcomes were assessed by radiography. Health-related quality of life data, including visual analog scale (VAS) and Oswestry Disability Index (ODI) scores, were collected at all preoperative and follow-up visits. RESULTS: The short and long fusion groups showed significant differences in the change in the Cobb angle (4.2° vs. 11.2°), lumbar lordosis (3.9° vs. 11.5°), and pelvic incidence minus the lumbar lordosis angle (PI - LL; 3.2° vs. 11.2°). Both the short and long fusion achieved significant changes in low back pain and leg pain. Patients with PI -LLs > 10° had more relief of low back pain after long fusion (VAS 4.0 ±â€Š2.0) than after short fusion (VAS 2.6 ±â€Š1.7). Patients with PI - LLs > 10° showed significantly improved walking ability after long fusion (ODI 1.0 ±â€Š0.8). The improvement in standing ability after short fusion was greater when PI - LL ≤ 10°(ODI 0.9 ±â€Š0.6). CONCLUSION: Long segment fusion can relieve low back pain better and improve walking ability when PI-LL is mismatched, whereas short segment fusion is more advantageous in improving standing ability in cases of more balanced sagittal spinopelvic alignment. LEVEL OF EVIDENCE: 3.

Background Clinical evidence indicates that sitagliptin treatment improves bone quality in diabetic patients, but the mechanisms involved remain elusive. Here, we studied the role of angiogenesis with sitagliptin treatment in diabetes-induced poor osteointegration of titanium implants and the underlying mechanisms. Methods In vitro, Human Umbilical Vein Endothelial Cells (HUVECs) incubated on titanium (Ti) surface were subjected to 1) normal milieu (NM); 2) diabetic milieu (DM); 3) DM + sitagliptin; 4) NM + macrophage; 5) DM + macrophage; or 6) DM + macrophage + sitagliptin. Microphage and HUVECs were cultured alone or co-cultured in a Transwell system. In vivo, DM was induced by high-fat diet and administration of streptozotocin (STZ) in rats. Titanium screws were implanted in the femurs of rats in three groups: Control, DM, Sitagliptin-treated DM. Results In vitro, when cells were incubated alone, DM caused M1 polarization of macrophage, evidenced by the increased iNOS and decreased CD206 expressions, and obvious dysfunctions of HUVECs. The DM-induced injury of endothelial cells were significantly worsened when the two cells were co-cultured. The addition of sitagliptin markedly reversed the changes of macrophage but not of HUVECs in DM when cells were cultured alone. When cells co-cultured, however, both the abnormal macrophage polarization and the endothelial impairment in DM was significantly alleviated by sitagliptin. In vivo, compared with normal animals, DM animals showed imbalanced M1/M2 polarization, angiogenesis inhibition and poor bone formation on the bone-implant interface (BII), which were significantly ameliorated by sitagliptin treatment. Conclusion Our results demonstrate macrophage polarization imbalance as a crucial mechanism underlying the impaired angiogenesis and bone healing in diabetes, and provide sitagliptin as a promising novel drug for biomaterial-engineering to improve the osteointegration of titanium implants in diabetic patients.

Hydrogels are widely utilized in regenerative medicine for drug delivery and tissue repair due to their superior biocompatibility and high similarity to the extracellular matrix. For minimally invasive therapies, in situ forming gel scaffolds are desirable, but technical challenges remain to be overcome to achieve the balance between tissue-like strength and cell-sized porosity, especially for intracranial and osteological therapies. Here, a new method-inspired by the liquid crystalline spinning process in natural silk fibers-is reported for preparing injectable silk gel scaffolds with favorable preclinical efficacy and unique characteristics including 1) in situ gelling for minimally invasive surgeries, 2) controllable porosity for efficient cellular infiltration and desirable degradation, 3) resilient and tunable mechanical properties that are compatible with the modulus regime of native soft tissues, and 4) all-aqueous processing that avoids toxic solvents and enables facile loading of bioactive agents. Moreover, hierarchically structured heterogeneous silk gel scaffolds with variable porosity and bioactive agent gradients within 3D matrices can be achieved for sustained drug release and guided tissue regeneration. Preclinical efficacy studies in rodent models show efficient bacterium and glioma inhibition and positive effects on bone regeneration and vascularization.

Clinical evidence indicates the compromised application of titanium implants (TIs) in diabetics, associated with reactive oxygen species (ROS) overproduction at the bone-implant interface. Silk fibroin (SF) has displayed impressive biocompatibility in the application of biomedical material and optimal anti-diabetic effects in oriental medicine. We proposed that SF-coated titanium implants (STIs) could alleviate diabetes-induced compromised osteointegration, which has rarely been reported before. To confirm this hypothesis and explore the underlying mechanisms, rat osteoblasts cultured on 3-dimensional (3D) -printed titanium implants (TIs) and STIs were subjected to normal serum (NS), diabetic serum (DS), DS with N-acetyl-L-cysteine (a ROS inhibitor) or SN50 (an NF-κB inhibitor). An in vivo study was performed on diabetic sheep with TIs or STIs implanted into bone defects on the crista iliaca. The results demonstrated that ROS overproduction induced by diabetes lead to osteoblast dysfunctions and cellular apoptosis on the TI substrate, associated with the activation of an NF-κB signaling pathway in osteoblasts. Importantly, the STI substrate significantly attenuated ROS production and NF-κBp65 phosphorylation, thereby ameliorating the osteoblast biological dysfunctions. These results were further confirmed in vivo by the improved osteointegration of the STIs, as evidenced by Micro-CT and histological examinations compared with those of TIs. These results demonstrated that the ROS-mediated NF-κB signaling pathway played a crucial role in diabetes-induced implant destabilization. Importantly, the SF coating, as a promising material for biomaterial-engineering, markedly improved the clinical treatment effect of TIs under diabetic conditions, possibly associated with the suppression of the NF-κB pathway.

Mechanism underlying the diabetes-induced poor osteointegration of implants remains elusive, making it a challenge to develop corresponding solutions. Here, we studied the role of angiogenesis in the diabetes-induced poor bone repair at the bone-implant interface (BII) and the related mechanisms. In vivo, titanium screws were implanted in the femurs of mice, and, in vitro, vascular endothelial cell (VEC) was cultured on titanium surface. Results showed that, compared with normal milieu (NM), diabetic milieu (DM) led to angiogenesis inhibition around implants which resulted in reduced osteoprogenitors and poor bone formation on BII in vivo. In vitro, DM caused significant increase of NADPH oxidases (NOX), dysfunction of mitochondria and overproduction of reactive oxygen species (ROS) in VEC on titanium surface, inducing obvious cell dysfunction. Both Mito-TEMPO (Mito, a mitochondria-targeted ROS antagonist) and apocynin (APO, a NOX inhibitor) effectively attenuated the oxidative stress and dysfunction of VEC, with the beneficial effects of APO significantly better than those of Mito. Further study showed that the diabetes-induced metabolic disturbance of VEC was significantly related to the increase of advanced glycation end products (AGEs) at the BII. Our results suggested that the AGEs-related and NOX-triggered cellular oxidative stress leads to VEC dysfunction and angiogenesis impairment at the BII, which plays a critical role in the compromised implant osteointegration under diabetic conditions. These demonstrated new insights into the BII in pathological states and also provided NOX and AGEs as promising therapeutic targets for developing novel implant materials to accelerate the angiogenesis and osteointegration of implants in diabetic patients with hyperglycemia. Statement of Significance The high failure rate of bone implants in diabetic patients causes patients terrible pain and limits the clinical application of implant materials. The mechanism underlying this phenomenon needs elucidation so that it would be possible to develop corresponding solutions. Our study demonstrated that the AGEs-related and NOX-triggered oxidative stress of VEC leads to angiogenesis impairment at the bone-implant interface (BII) in diabetes. These are critical mechanisms underlying the compromised implant osteointegration in diabetic hyperglycemia. These provide new insights into the BII in diseased states and also suggest NOX and AGEs as crucial therapeutic targets for developing novel implant materials which could modulate the oxidative stress on BII to get improved osteointegration and reduced implant failure, especially in diabetic patients.

Tantalum (Ta)-coated porous Ti-6A1-4V scaffolds have better bioactivity than Ti-6A1-4V scaffolds; however, their bioperformance as an artificial vertebral body (AVB) is unknown. In the present study, we combined a Ta-coated Ti-6A1-4V scaffold with rabbit bone marrow stromal cells (BMSCs) for tissue-engineered AVB (TEAVB) construction and evaluated the healing and fusion efficacy of this scaffold in lumbar vertebral defects after corpectomy in rabbits. The results showed that BMSCs on the surface of the Ta-coated Ti scaffolds proliferated better than BMSCs on Ti scaffolds. Histomorphometry showed better bone formation when using Ta-coated TEAVBs than that with Ti TEAVBs at both 8 and 12 weeks after implantation. In addition, the vertical and rotational stiffness results showed that, compared with uncoated TEAVBs, Ta-coated TEAVBs enhanced rabbit lumbar vertebral defect repair. Our findings demonstrate that Ta-coated TEAVBs have better healing and fusion efficacy than Ti TEAVBs in rabbit lumbar vertebral defects, which indicates their good prospects for clinical application.

BACKGROUND Our study explored the influences of hydration conditions and loading methods on the mechanical properties of cortical bones and cancellous bones. MATERIAL AND METHODS Elastic modulus and hardness of human cortical bones and cancellous bones that contained different moisture levels (20%, 30%, 40%, 50%, and 60%) were measured with nanoindentation with different peak loads and loading rates. Cortical bones with 20% and 60% moisture were tested with 30 nm, 40 nm, and 50 nm peak loads at 6 nm/s, 8 nm/s, and 10 nm/s loading rates, respectively. Cancellous bones with 5% or 40% moisture percentages were tested with 600 μN, 750 μN, and 1000 μN peak loads at 200 μN/s, 250 μN/s, and 333 μN/s loading rates, respectively. RESULTS Under the same loading condition, specimens with higher moisture contents showed decreased elastic modulus and hardness. Under different loading conditions, the loading modes had little influence on elastic modulus and hardness of cortical bone and cancellous bone with low moisture, but had significant influence on specimens with higher moistures. CONCLUSIONS The elastic modulus and bone hardness were affected by the moisture content and the loading conditions in cortical and cancellous bones with high hydration condition but not in those with low hydration condition.

The diabetes-related high failure risk for endosseous implants needs efficacious methods to improve osteointegration on the bone-implant interface (BII). Poly(lactic-co-glycolic) acid (PLGA) is widely used in tissue engineering but its effects on the BII in diabetes remain unclear. To clarify this issue, 3D-printed porous titanium implants (TI) with and without PLGA coating were fixed in the bone defects of sheep in vivo, and vascular endothelial cells (VEC) and osteoblasts were incubated on the implant surface under normal conditions (NC) and diabetic conditions (DC) in vitro. The results showed that the PLGA coating promoted angiogenesis on the BII and the osteointegration of TI in diabetic sheep. The PLGA coating attenuated the DC-induced dysfunctions of VEC but not of osteoblasts. When VEC and osteoblasts were co-cultured in DC, the PLGA coating showed protective effects on the osteoblasts. Lactic acid (LA) but not glycolic acid (GA), both of which are degradation products of PLGA, induced similar effects to those of PLGA. These results suggest that PLGA coating on TI could promote angiogenesis in diabetes by its degradation production of LA, thus indirectly improving the bone formation on BII. Furthermore, PLGA exerted its effects, at least partially, through inhibiting the pathological effects of advanced glycation end products (AGEs) on the BII. This is the first study of the effects of PLGA on angiogenesis on the BII and the first findings on the inhibitory effects of PLGA on AGEs. Our findings demonstrate that PLGA is a promising interface-modification component for fabricating implants with better angiogenesis and osteointegration on the BII under diabetic conditions. This strategy might be applicable for reducing implant failure in diabetic patients.

Poly(methyl methacrylate) (PMMA), the most common bone cement, has been used as a graft substitute in orthopedic surgeries such as vertebroplasty. However, an undesirable minor crack in the bone-cement interface provoked by shrinkage during polymerization and high elastic modulus of conventional PMMA bone cement dramatically increases the risk of vertebral body refracture postsurgery. Thus, herein, a hydrophilous expandable bone cement was synthesized based on a PMMA commercial cement (Mendec Spine Resin), acrylic acid (AA), and styrene (St). The two synthesized cements (PMMA-PAA, PMMA-PAA-PSt) showed excellent volumetric swelling in vitro and cohesive bone-cement contact in rabbit femur cavity defect. The elastic modulus and compressive strength of the new cements were lower than PMMA. Furthermore, the in vitro analysis indicated that the new cements had lower cytotoxicity than PMMA, including superior proliferation and lower apoptotic rates of Sprague-Dawly rat-derived osteoblasts. Western blotting for protein expression and RT-PCR analysis of osteogenesis-specific genes were conducted on SD rat-derived osteoblasts from both PMMA and new cements films; the results showed that new cements enhanced the expression of osteogenesis-specific genes. Scanning electron microscopy demonstrated improved morphology and attachment of osteoblast on new cement discs compared to the PMMA discs. Additionally, the histological morphologies of the bone-cement interface from the rabbit medial femoral condyle cavity defect model revealed direct and cohesive contact with the bone in the new cement groups in contrast to a minor crack in the PMMA cement group. The sign of a new bone growing into the cement has been found in the new cements after 12 weeks, thereby indicating the osteogenic capacity in vivo. In conclusion, the synthesized hydrophilous expandable bone cements based on PMMA and poly(acrylic acid) (PAA) are promising candidates for vertebroplasty.

Diabetes-induced reactive oxygen species (ROS) overproduction would result in compromised osteointegration of titanium implant (TI) and high rate of implant failure, yet the underlying mechanisms remain elusive. Adiponectin (APN) is a fat-derived adipocytokine with strong antioxidant, mitochondrial-protective and anti-diabetic efficacies. We hypothesized that mitochondrial dysfunction under diabetes may account for the oxidative stress in osteoblasts and titanium-bone interface (TBI) instability, which could be ameliorated by APN. To test this hypothesis, we incubated primary rat osteoblasts on TI and tested the cellular behaviors when subjected to normal milieu (NM), diabetic milieu (DM), DM + APN, DM + AICAR (AMPK activator) and DM + APN + Compound C (AMPK inhibitor). In vivo, APN or APN + Compound C were administered to diabetic db / db mice with TI implanted in their femurs. Results showed that diabetes induced structural damage, dysfunction and content decrease of mitochondria in osteoblasts, which led to ROS overproduction, dysfunction and apoptosis of osteoblasts accompanied by the inhibition of AMPK signaling. APN alleviated the mitochondrial damage by activating AMPK, thus reversing osteoblast impairment and improving the osteointegration of TI evidenced by Micro-CT and histological analysis. Furthermore, AICAR showed beneficial effects similar to APN treatment, while the protective effects of APN were abolished when AMPK activation was blocked by Compound C. This study clarifies mitochondrial dysfunction as a crucial mechanism in the impaired bone healing and implant loosening in diabetes, and provides APN as a novel promising active component for biomaterial-engineering to improve clinical performance of TI in diabetic patients. Statement of Significance The loosening rate of titanium implants in diabetic patients is high. The underlying mechanisms remain elusive and, with the rapid increase of diabetic morbility, efficacious strategies to mitigate this problem have become increasingly important. Our study showed that the mitochondrial impairment and the consequent oxidative stress in osteoblasts at the titanium-bone interface (TBI) play a critical role in the diabetes-induced poor bone repair and implant destabilization, which could become therapeutic targets. Furthermore, adiponectin, a cytokine, promotes the bio-functional recovery of osteoblasts and bone regeneration at the TBI in diabetes. This provides APN as a novel bioactive component used in material-engineering to promote the osteointegration of implants, which could reduce implant failure, especially for diabetic patients.

Magnesium has been investigated as a biodegradable metallic material. Increased concentrations of Mg2+ around magnesium implants due to biodegradation contribute to its satisfactory osteogenic capacity. However, the mechanisms underlying this process remain elusive. We propose that activation of the PI3K/Akt signalling pathway plays a role in the Mg2+-enhanced biological behaviours of osteoblasts. To test this hypothesis, 6, 10 and 18 mM Mg2+ was used to evaluate the stimulatory effect of Mg2+ on osteogenesis, which was assessed by evaluating cell adhesion, cell viability, ALP activity, extracellular matrix mineralisation and RT-PCR. The expression of p-Akt was also determined by western blotting. The results showed that 6 and 10 mM Mg2+ elicited the highest stimulatory effect on cell adhesion, cell viability and osteogenic differentiation as evidenced by cytoskeletal staining, MTT assay results, ALP activity, extracellular matrix mineralisation and expression of osteogenic differentiation-related genes. In contrast, 18 mM Mg2+ had an inhibitory effect on the behaviour of osteoblasts. Furthermore, 10 mM Mg2+ significantly increased the phosphorylation of Akt in osteoblasts. Notably, the aforementioned beneficial effects produced by 10 mM Mg2+ were abolished by blocking the PI3K/Akt signalling pathway through the addition of wortmannin. In conclusion, these results demonstrate that 6 mM and 10 mM Mg2+ can enhance the behaviour of osteoblasts, which is at least partially attributed to activation of the PI3K/Akt signalling pathway. Furthermore, a high concentration (18 mM Mg2+) showed an inhibitory effect on the biological behaviour of osteoblasts. These findings advance the understanding of cellular responses to biodegradable metallic materials and may attract greater clinical interest in magnesium.

Micro-finite element (μFE) models have been widely used to assess the biomechanical properties of trabecular bone. How to choose a proper sample volume of trabecular bone, which could predict the real bone biomechanical properties and reduce the calculation time, was an interesting problem. Therefore, the purpose of this study was to investigate the relationship between different sample volumes and apparent elastic modulus (E) calculated from μFE model. 5 Human lumbar vertebral bodies (L1-L5) were scanned by micro-CT. Cubic concentric samples of different lengths were constructed as the experimental groups and the largest possible volumes of interest (VOI) were constructed as the control group. A direct voxel-to-element approach was used to generate μFE models and steel layers were added to the superior and inferior surface to mimic axial compression tests. A 1% axial strain was prescribed to the top surface of the model to obtain the E values. ANOVA tests were performed to compare the E values from the different VOIs against that of the control group. Nonlinear function curve fitting was performed to study the relationship between volumes and E values. The larger cubic VOI included more nodes and elements, and more CPU times were needed for calculations. E values showed a descending tendency as the length of cubic VOI decreased. When the volume of VOI was smaller than (7.34mm(3)), E values were significantly different from the control group. The fit function showed that E values approached an asymptotic values with increasing length of VOI. Our study demonstrated that apparent elastic modulus calculated from μFE models were affected by the sample volumes. There was a descending tendency of E values as the length of cubic VOI decreased. Sample volume which was not smaller than (7.34mm(3)) was efficient enough and timesaving for the calculation of E.

To assess the survival and the predictors of mortality in patients with severe cervical spinal cord injuries (CSCI).Retrospective study.From January 1, 2010, to May 31, 2018, patients who suffered from severe CSCIs in Western China were enrolled in this study (N=222).Not applicable.Survival rates and mortality risk factors. Measures were calculated by the product-limit method (Kaplan-Meier) and the Cox model.The overall 1-year, 3-year, 5-year, and 8-year postoperative mortalities were 24.4%, 30.6%, 33.3%, 36.2%, and 39.0%, respectively. Most deaths occurred within 36 months after the injury. According to the Cox proportional hazards model, the significant predictors of survival were as follows: (1) age; (2) neurologic level; (3) treatment options (surgical or conservative); (4) ventilator support (P.05). The 8-year mortality for older patients (50y) was 50.2%, which was significantly higher than that for younger patients (32.4%,50y). The risk of death was 2.053 times higher in higher levels of injury (C1-C4) than in lower levels of injury (C5-C8) (P.05). Compared with conservative treatment, patients who received surgical treatment (either anterior or posterior decompression) had a lower risk of death (P.05). No significant difference was detected in the risk of death between early surgery (3d) and mid-term surgery (3-7d) (P.05). However, patients who received late-term surgery (7d) had a higher mortality risk (P.05). The overall 8-year mortality risk of patients who needed ventilator support was much higher than those who did not need ventilator support (P.05).Age, neurologic level, ventilator dependence, treatment options, and timing to surgery were main risk factors for mortality in patients with severe CSCIs. Better understanding of the predictors for survival could possibly contribute to the improvement of survival rates.

A high failure rate of titanium implants in diabetic patients has been indicated in clinical evidences. Excessive oxidative stress at the bone-implant interface plays an important role in the impaired osteointegration under diabetic conditions. While the underlying mechanisms remain unknown and the targeted treatments are urgently needed. Ophiopogonin D (OP-D), isolated from Chinese herbal Radix Ophiopogon japonicus, is generally reported to be a potent antioxidant agent. In the present study, we hypothesized that OP-D exerted promotive effects on osteointegration against oxidative stress, and investigated the underlying mechanisms associated with alteration of Wnt/β-catenin signaling pathway. Rabbit osteoblasts incubated on titanium alloy implant were co-cultured with normal serum (NS), diabetic serum (DS), DS + OP-D, DS + NAC (a potent ROS inhibitor) and DS + OP-D + Dkk1 (a Wnt inhibitor) for examinations of osteoblast behaviors. For in vivo study, titanium alloy implants were implanted into the femoral condyle defects on diabetic rabbits. Results demonstrated that diabetes-induced oxidative stress resulted in osteoblast dysfunctions and apoptotic injury at the bone-implant interface, concomitant with the inactivation of Wnt/β-catenin signaling. Importantly, OP-D administration attenuated oxidative stress, directly reactivating Wnt/β-catenin signaling. Osteoblast dysfunctions were thus reversed as evidenced by improved osteoblast adhesion, proliferation and differentiation, and ameliorated apoptotic injury, exerting similar effects to NAC treatment. In addition, the positive effects afforded by OP-D were confirmed by improved osteointegration and oetogenesis within the titanium alloy implants in vivo by Micro-CT and histological analyses. Furthermore, the pro-osteogenic effects of OP-D were almost completely abolished by the Wnt inhibitor Dkk1. These results demonstrated, for the first time, OP-D administration alleviated the damaged osteointegration of titanium alloy implants under diabetic conditions by means of inhibiting oxidative stress via a Wnt/β-catenin-dependent mechanism. The OP-D administration would become a reliable treatment strategy for implant failure therapy in diabetics due to the optimal anti-oxidative and pro-osteogenic properties.

Chitosan (CS)-based hydroxyapatite (HA) composites have emerged as a novel strategy for promoting bone regeneration. Here nanophase HA/CS composite coated porous titanium implants (nCT) were fabricated and their biological behavior under diabetic conditions was investigated. We proposed that the focal adhesion kinase (FAK)-mediated BMP-2/Smad pathway played a role in mediating the promotive effect of nCTs on osteoblast adhesion and differentiation under diabetes-induced high reactive oxygen species (ROS) condition. To confirm the hypothesis, rat osteoblasts on bare titanium implants (Ti) and nCT were subjected to normal serum (NS), diabetic serum (DS), DS + NAC (a potent ROS inhibitor) and DS + cytochalasin D (an actin polymerization inhibitor). In vivo on diabetic sheep implanted with Ti or nCT showed that diabetes-induced ROS overproduction impaired osteoblast adhesion, evidenced by immunostaining of F-actin and vinculin and morphological observation through inhibition of FAK phosphorylation, which contributed to suppressed BMP-2-dependent Smad1/5/8 phosphorylation. nCT substrate reactivated the FAK-BMP-2/Smad pathway, thus reversing osteoblast dysfunction, which exerted a similar effect to NAC treatment on Ti. These effects were further confirmed by improved osteointegration within nCT in diabetic sheep, evidenced by micro-CT and histological examinations. Our study demonstrated that reactivation of the FAK-BMP-2/Smad pathway was involved in improving osteoblast adhesion and differentiation by nano-HA/CS composite coating, potentially directing biomaterial modification and biofunctionalization under diabetic conditions.

A novel composite scaffold consisting of porous Ti part filled with chitosan/HA sponge was fabricated using a combination of electron beam melting and freeze-drying. The mechanical properties of porous Ti with porosities of ∼60–75% were examined via compressive test. The compression strength values of the samples were ranged from 86.35 (±12.68) – 180.21 (±10.26) MPa and stiffness values were of 2.23 (±0.68) – 5.48 (±0.54) GPa. The microstructure of composite scaffold was characterized using scanning electron microscopy. The chitosan/HA sponge filled in Ti part exhibited highly porous and well-interconnected pore architecture, which is produced to accommodate cells without the need to meet mechanical requirements. The in vitro biocompatibility of the composite scaffolds was investigated using rat osteoblasts. Compared with pure Ti part, composite scaffolds exhibited higher biological activity, such as an improved osteoblast adhesion and morphology, increased proliferation and alkaline phosphatase (ALP) activity. These results suggest that the composite scaffold is potentially useful as a biomedical scaffold for bone repair in load-bearing sites.

Chitosan coated porous titanium alloy implant (CTI) is demonstrated a promising approach to improve osseointegration capacity of pure porous titanium alloy implant (TI). Since chitosan has been demonstrated to exhibit antioxidant activity, we propose CTI may ameliorate the ROS overproduction, thus reverse the poor osseointegration under diabetic conditions, and investigate the underlying mechanisms. Primary rat osteoblasts incubated on the TI and the CTI were subjected to normal serum (NS), diabetic serum (DS), DS + NAC (a potent ROS inhibitor) and DS + LY294002 (a PI3K/AKT-specific inhibitor). In vivo study was performed on diabetic sheep implanted with TI or CTI into the bone defects on crista iliaca. Results showed that diabetes-induced ROS overproduction led to osteoblast dysfunction and apoptosis, concomitant with the inhibition of AKT in osteoblasts on the TI substrate. While CTI stimulated AKT phosphorylation through ROS attenuation, thus reversed osteoblast dysfunction evidenced by improved osteoblast adhesion, increased proliferation and ALP activity, and decreased cytotoxicity and apoptotic rate, which exerted same effect to NAC treatment on the TI. These effects were further confirmed by the improved osseointegration within the CTI in vivo evidenced by Micro-CT and histological examinations. In addition, the aforementioned promotive effects afforded by CTI were abolished by blocking PI3K/AKT pathway with addition of LY294002. These results demonstrate that the chitosan coating markedly ameliorates diabetes-induced impaired bio-performance of TI via ROS-mediated reactivation of PI3K/AKT pathway, which elicits a new surface functionalization strategy for better clinical performance of titanium implant in diabetic patients.

Porous tantalum (Ta), produced via chemical vapor deposition (CVD) of commercially pure Ta onto a vitreous carbon, is currently available for use in orthopedic applications. However, the relatively high manufacturing cost and the incapability to produce customized implant using medical image data have limited its application to gain widespread acceptance. In this study, Ta film was deposited on porous Ti6Al4V scaffolds using CVD technique. Digital microscopy and scanning electron microscopy indicated that the Ta coating evenly covered the entire scaffold structure. X-ray diffraction analysis showed that the coating consisted of α and β phases of Ta. Goat mesenchymal stem cells were seeded and cultured on the Ti6Al4V scaffolds with and without coating. The tetrazolium-based colorimetric assay exhibited better cell adhesion and proliferation on Ta-coated scaffolds compared with uncoated scaffolds. The porous scaffolds were subsequently implanted in goats for 12weeks. Histological analysis revealed similar bone formation around the periphery of the coated and uncoated implants, but bone ingrowth is better within the Ta-coated scaffolds. To demonstrate the ability of producing custom implant for clinical applications via this technology, we designed and fabricated a porous Ti6Al4V scaffold with segmental mandibular shape derived from patient computerized tomography data.

Clinical evidence indicates a high failure rate for titanium implants (TiI) in diabetic patients, involving the overproduction of reactive oxygen species (ROS) at the implant/bone interface. Tantalum coating on titanium (TaTi) has exerted better tissue integration properties than TiI, but its biological performance under diabetic conditions remains elusive. To investigate whether TaTi may ameliorate diabetes-induced implant destabilization and the underlying mechanisms, primary rabbit osteoblasts cultured on 3-dimensional printed TiI and TaTi were exposed to normal serum (NS), diabetic serum (DS), DS+NAC (a potent ROS inhibitor), and DS+SB203580 (a specific p38 MAPK inhibitor). An in vivo study was performed on diabetic sheep implanted with TiI or TaTi. Diabetes induced mitochondrial-derived ROS overproduction and caused cellular dysfunction and apoptosis, together with the activation of p38 MAPK in osteoblasts on TiI surface. Importantly, TaTi significantly attenuated ROS production and p38 MAPK phosphorylation and exerted more osseointegrative cell behavior than TiI, as shown by improved osteoblast adhesion, increased cell proliferation and differentiation and decreased apoptosis. These results were confirmed in vivo by the enhanced bone healing efficacy of TaTi. Moreover, treatment with NAC or SB203580 on TiI not only inhibited the activation of p38 MAPK but also improved cell function and alleviated apoptotic injury, whereas TaTi combined with NAC or SB203580 failed to further improve osteoblast functional recovery compared with TaTi alone. These results demonstrated that the tantalum coating markedly improved diabetes-induced impaired osteogenesis of TiI, which may be attributed to the suppression of the ROS-mediated p38 MAPK pathway.

This study was aimed at elucidating the temporal changes of microarchitectural and mechanical parameters of cancellous bone in the osteoporotic rabbit model induced by ovariectomy (OVX) combined with glucocorticoid (GC) administration. Osteoporotic (OP) group received bilateral OVX combined with injections of GC, while sham group only received sham operation. Cancellous bone quality in vertebrae and femoral condyles in each group was assessed by DXA,μCT, nanoindentation, and biomechanical tests at pre-OVX and 4, 6, and 8 weeks after injection. With regard to femoral condyles, nanoindentation test could detect significant decline in tissue modulus and hardness at 4 weeks. However, BMD and microarchitecture of femoral condylar cancellous bone changed significantly at 6 weeks. In vertebrae, BMD, microarchitecture, nanoindentation, and biomechanical tests changed significantly at 4 weeks. Our data demonstrated that temporal changes of microarchitectural and mechanical parameters of cancellous bone in the osteoporotic rabbit were significant. The temporal changes of cancellous bone in different anatomical sites might be different. The nanoindentation method could detect the changes of bone quality at an earlier stage at both femoral condyle and vertebra in the osteoporotic rabbit model than other methods (μCT, BMD).

Background: The purpose of this study was to evaluate the effectiveness between percutaneous and open pedicle screw fixation for treating thoracolumbar fractures with spinal injuries. Methods: A total of 105 patients with thoracolumbar fractures and spinal injuries were divided into a percutaneous pedicle screw fixation (PPSF) group with 56 patients, who underwent percutaneous pedicle screw fixation, and an open pedicle screw fixation (OPSF) group with 49 patients, who underwent open pedicle screw fixation in accordance with the treatment project. Relative operation indexes, radiologic, and effectiveness parameters were assessed and compared between the 2 groups. Results: Demographic and clinical features including age, body mass index, gender, fracture level, fracture classification, and Frankel grade in both groups were not significantly different (all P >.05). The PPSF group exhibits significantly lower operation time, intraoperative blood loss, postoperative drainage volume, and hospital stay on average compared with the OPSF group (all P .05). Nevertheless, both visual analogue scale (VAS) and Oswestry disability index (ODI) after surgery decreased more substantially in the PPSF group than in the OPSF group (all P .05). Frankel classifications were stimulated in both the groups during the last follow-up period. Conclusion: PPSF has a smaller incision, less intraoperative blood loss, shorter recovery time, higher safety measures on average compared with OPSF with respect to managing thoracolumbar fractures with spinal injuries.

As cortical bone has a hierarchical structure, the macroscopic bone strength may be affected by the alterations of mineral crystal and collagen, which are main components of cortical bone. Limited studies focused on the time related alterations of these two components in osteoporosis, and their contributions to bone mechanics at tissue level and whole-bone level. Therefore, the purpose of this study was to elucidate the time related changes of mineral and collagen in cortical bone of ovariectomized (OVX) rabbits, and to relate these changes to cortical bone nanomechanics and macromechanics. 40 Rabbits (7-month-old) were randomly allocated into two groups (OVX and sham). OVX group received bilateral ovariectomy operation. Sham group received sham-OVX operation. Cortical bone quality of five rabbits in each group were assessed by DXA, μCT, nanoindentation, Fourier transform infrared (FTIR) spectroscopy and biomechanical tests (3-point bending of femoral midshaft) at pre-OVX, 4, 6, and 8 weeks after OVX. As time increased from pre-OVX to 8 weeks, the mineral to matrix ratio decreased with time, while both collagen crosslink ratio and crystallinity increased with time in OVX group. Elastic modulus and hardness measured by nanoindentation, whole-bone strength measured by biomechanical tests all decreased in OVX group with time. Bone material properties measured by FTIR correlated well with nano or whole-bone level mechanics. However, bone mineral density (BMD), structure, tissue-level and whole-bone mechanical properties did not change with age in sham group. Our study demonstrated that OVX could affect the tissue-level mechanics and bone strength of cortical bone. And this influence was attributed to the time related alterations of mineral and collagen properties, which may help us to design earlier interventions and more effective treatment strategies on osteoporosis.

STUDY DESIGN A novel total cervical prosthesis (TCP) for single-level cervical subtotal corpectomy was assessed in a caprine animal model. OBJECTIVES To investigate the radiologic and histomorphometric characteristics of a novel TCP for single-level cervical subtotal corpectomy. SUMMARY OF BACKGROUND Cervical disk replacement has emerged as a promising alternative to arthrodesis in the management of cervical disk herniation. However, they are designed for anterior cervical discectomy, and not suitable for cervical subtotal corpectomy. To solve this problem, our group has developed a novel TCP for single-level cervical subtotal corpectomy. MATERIALS AND METHODS There were 12 adult Shannxi goats (2 y old) used in this study. The goats were divided into 2 groups based on postoperative survival periods of 3 (n=6) and 6 (n=6) months after surgery. Using an anterior surgical approach, a standard anterior C3 vertebra subtotal corpectomy and decompression of the spinal canal were performed, followed by implantation of the TCP device. Then all the goats were killed and underwent radiographic and histologic observations. RESULTS The TCP implant procedures were successfully completed in all 12 goats without incidence of vascular or infectious complications. The range of motion of C2-C3 and C3-C4 segments were preserved in both of the groups. Three-dimensional images of specimens interface indicated confluent interdigitization of trabeculae at the prosthetic endplate-bone interface, without evidence of significant radiolucent lines or gaps. Histomorphometric analysis showed that there were a large number of fibrous tissue and a small amount of cartilage cells between the prostheses and bone in the 3 months' group. In the 6 months' group, part of fibrous tissue has changed into the cartilage tissue. CONCLUSIONS Our data show that this prosthesis can maintain the stability of the cervical spine and retain the activity of the cervical spine in vivo. The findings in this study provide a foundation for ongoing clinical investigations using the TCP.

The purpose of this study was to investigate the therapeutic effects of crocin on ovariectomy-induced osteoporosis in rats. Female Sprague-Dawley rats were randomly assigned to a sham-operated group (sham) and five ovariectomy (OVX) subgroups, that is, OVX with vehicle (OVX), OVX with 17β-estradiol (E2, 25 μg/kg/day), and OVX with graded crocin doses (5, 10, or 20 mg/kg/day). Daily oral administration ofE2or crocin started 4 weeks after OVX and lasted for 16 weeks. Our results showed that crocin dose-dependently inhibited the BMD reduction of L4 vertebrae and femurs caused by OVX and prevented the deterioration of trabecular microarchitecture, which were accompanied by a significant decrease in skeletal remodeling as evidenced by the lower levels of bone turnover markers. Furthermore, crocin reversed the oxidative stress status in both serum and bone tissue. The present study indicates that the administration of crocin at higher doses over a 16-week period can prevent OVX-induced osteoporosis in rats without hyperplastic effects on the uterus, which may, at least partially, be attributed to crocin’s antioxidative property. In brief, crocin is a natural alternative for postmenopausal osteoporosis treatment in elderly women.

Clinical evidence indicates that insulin therapy improves implant survival rates in diabetic patients; however, the mechanisms responsible for this effect are unknown. Here, we test if insulin exerts anti-oxidative effects, thereby improving diabetes-associated impaired osteoblast behavior on titanium implants. To test this hypothesis, we cultured primary rabbit osteoblasts in the presence of titanium implants and studied the impact of treatment with normal serum (NS), diabetic serum (DS), DS + insulin, DS + tempol (a superoxide dismutase mimetic), DS + insulin + tempol, and DS + insulin + wortmannin. We analyzed cell function, apoptosis, and reactive oxygen species (ROS) production in osteoblasts following the various treatments. Treatment with DS induced osteoblast dysfunction, evidenced by impaired cell attachment and morphology, decreased cell proliferation and ALP activity, and decreased expression of osteogenesis-related genes. We also observed a significant increase in apoptosis. Importantly, treatment with DS resulted in increased production of ROS in osteoblasts. In contrast, treatment with insulin inhibited ROS production, alleviated cell dysfunction, and decreased apoptosis of osteoblasts on the implants. Scavenging ROS with tempol also attenuated cell dysfunction. Compared to insulin treatment alone, the combination of insulin and tempol failed to further improve osteoblast functional recovery. Moreover, the anti-oxidative and pro-osteogenic effects afforded by insulin were almost completely abolished by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin. These results demonstrate, for the first time, that insulin treatment alleviates the impaired osteogenesis of titanium implants under diabetic conditions by inhibiting ROS overproduction via a PI3K/Akt-dependent mechanism. Both the anti-oxidative and metabolic properties of insulin should make it a viable therapeutic option to combat diabetic implant failure.

Composited Chitosan/Hydroxyapatite (CS/HA) material coated on titanium surface (cTi) is a promising approach to produce biomaterials with better osseointegration capacity, but its bio-performance under diabetic conditions and the mechanisms involved remain elusive. We propose that the alterations in the Wnt/β-catenin pathway may play a role in mediating the improvement effect of cTi on diabetes-induced impaired implant osteointegration. To confirm the hypothesis, primary rat osteoblasts incubated on Ti and cTi were subjected to normal serum (NS), diabetic serum (DS), DS + Wnt3a (a specific Wnt agonist) and DS + Dkk1 (a specific Wnt antagonist) treatment. In vivo study was performed on diabetic sheep implanted with Ti or cTi into the bone defect on crista iliaca. Results showed that diabetes depressed osteoblast function evidenced by impaired cell adhesion and morphology, decreased cell proliferation and ALP activity, and higher apoptotic rate on Ti. Importantly, both cTi and Wnt3a treatment ameliorated osteoblastic dysfunction and apoptosis under diabetic condition. Implantation with cTi significantly improved osteointegration evidenced by Micro-CT and histological examinations compared with Ti. Moreover, the aforementioned promotive effects afforded by cTi were abolished by blocking Wnt pathway with Dkk1. Our study explicitly demonstrates that CS/HA composite material improves diabetes-induced impaired osteointegration of Ti via the reactivation of Wnt/β-catenin pathway and provides a target point for biomaterial modification to attain better clinical performance in diabetic patients.

Recent clinical studies indicated that angiotensin receptor blockers (ARBs) would decrease the risk of bone fractures in the elderly populations. There is little known about the role of the ARBs in the process of fracture healing. The purpose of the present study was to verify the hypothesis that systemic treatment with telmisartan has the ability to promote fracture healing. In this study, femur fractures were produced in 96 mature male BALB/c mice. Animals were treated with the ARBs telmisartan or vehicle. Fracture healing was analysed after 2, 5 and 10 weeks postoperatively using X-ray, biomechanical testing, histomorphometry, immunohistochemistry and micro-computed tomography (micro-CT). Radiological analysis showed the diameter of the callus in the telmisartan treated animals was significantly increased when compared with that of vehicle treated controls after two weeks of fracture healing. The radiologically observed promotion of callus formation was confirmed by histomorphometric analyses, which revealed a significantly increased amount of bone formation when compared with vehicle-treated controls. Biomechanical testing further showed a significantly greater peak torque at failure, and a higher torsional stiffness in telmisartan-treated animals compared with controls. There was an increased fraction of PCNA-positive cells and VEGF-positive cells in telmisartan-treated group compared with vehicle-treated controls. From the three-dimensional reconstruction of the bony callus, telmisartan-treated group significantly increased the values of BV/TV by 21.7% and CsAr by 26.0% compared to the vehicle-treated controls at 5 weeks post-fracture. In summary, we demonstrate in the current study that telmisartan could promote fracture healing in a mice model via increasing mechanical strength and improving microstructure. The most mechanism is probably by an increase of cell proliferation and neovascularization associated with a decreased VEGF expression in hypertrophic chondrocytes.

Background The basic strategy to construct tissue engineered bone graft (TEBG) is to combine osteoblastic cells with three dimensional (3D) scaffold. Based on this strategy, we proposed the “Totally Vitalized TEBG” (TV-TEBG) which was characterized by abundant and homogenously distributed cells with enhanced cell proliferation and differentiation and further investigated its biological performance in repairing segmental bone defect. Methods In this study, we constructed the TV-TEBG with the combination of customized flow perfusion seeding/culture system and β-tricalcium phosphate (β-TCP) scaffold fabricated by Rapid Prototyping (RP) technique. We systemically compared three kinds of TEBG constructed by perfusion seeding and perfusion culture (PSPC) method, static seeding and perfusion culture (SSPC) method, and static seeding and static culture (SSSC) method for their in vitro performance and bone defect healing efficacy with a rabbit model. Results Our study has demonstrated that TEBG constructed by PSPC method exhibited better biological properties with higher daily D-glucose consumption, increased cell proliferation and differentiation, and better cell distribution, indicating the successful construction of TV-TEBG. After implanted into rabbit radius defects for 12 weeks, PSPC group exerted higher X-ray score close to autograft, much greater mechanical property evidenced by the biomechanical testing and significantly higher new bone formation as shown by histological analysis compared with the other two groups, and eventually obtained favorable healing efficacy of the segmental bone defect that was the closest to autograft transplantation. Conclusion This study demonstrated the feasibility of TV-TEBG construction with combination of perfusion seeding, perfusion culture and RP technique which exerted excellent biological properties. The application of TV-TEBG may become a preferred candidate for segmental bone defect repair in orthopedic and maxillofacial fields.

Clinical evidence indicates that intensive insulin treatment prevents the incidence of multiple organ failures in surgical operation and severe trauma, but the mechanisms involved remain elusive. This study was designed to test the hypothesis that insulin may exert anti-inflammatory and antioxidative effects and thus alleviate cardiac dysfunction after trauma.Prospective, randomized experimental study.Animal research laboratory.Sprague Dawley rats.Anesthetized rats were subjected to 200 revolutions at a rate of 35 rpm in Noble-Collip drum to induce a nonlethal mechanical trauma and were randomized to receive vehicle, insulin, and insulin + wortmannin treatments. An in vitro study was performed on cultured cardiomyocytes subjected to sham-traumatic serum (SS), traumatic serum (TS), SS + tumor necrosis factor (TNF)-α, SS + H2O2, TS + neutralizing anti-TNF-α antibody, or TS + tempol treatments.Immediate cardiac dysfunction occurred 0.5 hr after trauma without significant cardiomyocyte necrosis and apoptosis, while serum TNF-α and cardiac reactive oxygen species (ROS) production was increased. Importantly, incubation of cardiomyocytes with TS or SS + TNF-α significantly increased ROS generation together with dampened cardiomyocyte contractility and Ca transient, all of which were rescued by TNF-α antibody. Administration of insulin inhibited TNF-α and ROS overproduction and alleviated cardiac dysfunction 2 hours after trauma. Scavenging ROS with tempol also attenuated cardiac dysfunction after trauma, whereas insulin combined with tempol failed to further improve cardiac functional recovery compared with insulin treatment alone. Moreover, the aforementioned anti-TNF-α, antioxidative, and cardioprotective effects afforded by insulin were almost abolished by the phosphatidylinositol 3-kinase inhibitor wortmannin.These results demonstrate for the first time that mechanical trauma induces a significant increase in TNF-α and ROS production, resulting in immediate cardiac dysfunction. Early posttrauma insulin treatment alleviates cardiac dysfunction by inhibiting TNF-α-mediated ROS production via a phosphatidylinositol 3-kinase/Akt-dependent mechanism.

Clinical evidence indicates diabetes as a majorrisk factor for titaniumimplant treatment with high failure rates and poor osteointegration, but the underlying mechanism involved remains elusive.We hypothesize that reactive oxygen species (ROS) overproduction may contribute to the impaired osteogenesis of porous titanium implants (pTi) under diabetic conditions. To test this hypothesis, we culturedprimary rabbit osteoblasts onto pTi and studied the cellular performance when subjected to normal serum (NS), diabetic serum (DS), DS + NAC (a potent ROS inhibitor) and NS + H 2 O 2 (an oxidant).In-vivo performance of pTi was investigated by transplanting them intofemoral condyledefects of diabetic rabbits, which received vehicle or NAC treatment respectively.Results showed that diabetic conditions induced significant cellular apoptosis, depressedosteoblast function evidenced by impairedcell attachment and morphology, decreased cell proliferation anddifferentiation, andcompromised in-vivo osteogenesis ofpTi, while cellular ROSgeneration was increased derived from mitochondrial dysfunction. Scavenging ROS with NAC markedly attenuated cell apoptosis and osteoblast dysfunction, and improved bone ingrowth within pTi. Furthermore, treatment withH 2 O 2 exerted similar adverse effect on cellular behavior as diabetes. This study furthers our knowledge on the potential role of ROS overproduction in the diabetes-induced impaired osteogenesis of titanium implants, and indicates anti-oxidative treatment as a promising strategy to promote the treatment efficacy of pTi in diabetic patients.

BACKGROUND: Although three-dimensional (3D) β-tricalcium phosphate (β-TCP) scaffolds serve as promising bone graft substitutes for the segmental bone defect treatment, no consensus has been achieved regarding their optimal 3D architecture. METHODS: In this study, we has systematically compared four types of β-TCP bone graft substitutes with different 3D architectures, including two types of porous scaffolds, one type of tubular scaffolds and one type of solid scaffolds, for their efficacy in treating segmental bone defect in a rabbit model. RESULTS: Our study has demonstrated that when compared to the traditional porous and solid scaffolds, tubular scaffolds promoted significantly higher amount of new bone formation in the defect regions as shown by X-ray, micro CT examinations and histological analysis, restored much greater mechanical properties of the damaged bone evidenced by the biomechanical testing, and eventually achieved the complete union of segmental defect. Moreover, the implantation of tubular scaffolds enhanced the neo-vascularization at the defect region with higher bone metabolic activities than others, as indicated by the bone scintigraphy assay. CONCLUSIONS: This study has further the current knowledge regarding the profound influence of overall 3D architecture of β-TCP scaffolds on their in vivo defect healing performance and illuminated the promising potential use of tubular scaffolds as effective bone graft substitute in treating large segmental bone defects.