Erythropoietin (EPO): EPO-receptor signaling improves early endochondral ossification and mechanical strength in fracture healing

Beyond its role in the regulation of red blood cell proliferation, the glycoprotein erythropoietin (EPO) has been shown to promote cell regeneration and angiogenesis in a variety of different tissues. In addition, EPO has been indicated to share significant functional and structural homologies with the vascular endothelial growth factor (VEGF), a cytokine essential in the process of fracture healing. However, there is complete lack of information on the action of EPO in bone repair and fracture healing. Therefore, we investigated the effect of EPO treatment on bone healing in a murine closed femur fracture model using radiological, histomorphometric, immunohistochemical, biomechanical and protein biochemical analysis. Thirty-six SKH1-hr mice were treated with daily i.p. injections of 5000 U/kg EPO from day 1 before fracture until day 4 after fracture. Controls received equivalent amounts of the vehicle. After 2 weeks of fracture healing, we could demonstrate expression of the EPO-receptor (EPOR) in terminally differentiating chondrocytes within the callus. At this time point EPO-treated animals showed a higher torsional stiffness (biomechanical analysis: 39.6+/-19.4% of the contralateral unfractured femur) and an increased callus density (X-ray analysis (callus density/spongiosa density): 110.5+/-7.1%) when compared to vehicle-treated controls (14.3+/-8.2% and 105.9+/-6.6%; p<0.05). Accordingly, the histomorphometric examination revealed an increased fraction of mineralized bone and osteoid (33.0+/-3.0% versus 28.5+/-3.6%; p<0.05). Of interest, this early effect of the initial 6-day EPO treatment had vanished at 5 weeks after fracture. We conclude that EPO-EPOR signaling is involved in the process of early endochondral ossification, enhancing the transition of soft callus to hard callus.     

The analysis of the unstable tibia fracture treatment applying internal stabilization method

The study included 51 patients with tibia fractures, who underwent percutaneous bone reposition and stabilization with unrimed tibial locking nail. The results obtained using this method were compared with those obtained by standard fracture treatment where flat and anatomic plates were applied (n = 64). In patients who had osteosynthetic material implanted percutaneously (using unrimed tibial locking nail) there was no incidence of post surgical osteitis or any pseudarthrosis. The healing callus of the fracture was of lesser quality and spindle shaped, suggesting that fracture stabilization using this method was less efficient. In patients with fractures stabilized by the open method using flat and anatomic plates (n = 64), we noticed 3.1% (n = 2) cases of osteitis and 4.7% (n = 3) cases of pseudarthrosis. Due to lesser incidence of postoperative osteitis, our method of choice in tibia fractures would be percutaneous stabilization with unrimed tibial locking nail. However, this treatment method has its disadvantages, too. Fracture callus is of lesser quality and it is spindle shaped. Furthermore, there are problems with adequate percutaneous reposition in some cases, as well as necessity for radiological checking.     

Loads acting in an intramedullary nail during fracture healing in the human femur.

The form and function of the musculo-skeletal system is closely related to the forces acting in its components. Significant forces are present in the long bones, but their magnitudes have so far only been estimated from mathematical models. Fracture fixation by means of metal implants provides an opportunity to measure the implant-born forces and to estimate the long bone forces before healing occurs. The load changes during fracture healing may provide additional information. Therefore, a telemetrized, interlocking femoral nail for wireless transmission of forces and moments acting across the fracture site was developed. The design was based on the geometry and material of a 16 mm AO nail with a circular, closed cross-section allowing full protection of the electronic circuits from the body fluids. After careful testing, it was implanted in a 33-year-old patient who had sustained a multifragmentary fracture of the left femur. Measurements at a rate of approx. 0.4 Hz were performed in different patient postures between the 2nd and 26th postoperative week. Significant axial forces and bending moments were measured during several activities such as sitting, unsupported leg elevation and partial weight bearing in a standing position. Forces orthogonal to the nail axis remained small. The reductions of the implant loads due to fracture consolidation were in the order of 50%. Dynamization of the nail did not change the forces. Even though the telemetry system did not allow for dynamic measurements and the results presented here provide data from one subject only, the new information will be useful with respect to implant design, biomechanics of fracture fixation and evaluation of healing progression.     

Method for the evaluation of factors influencing the dislocation stability of total hip endoprotheses]

Dislocation of the artificial joint is a serious complication of total hip replacement. Various factors with an influence on dislocation stability were determined clinically. Our goal was to develop a method for evaluating experimentally the parameters implant design, position and the load situation for their influence on joint stability. With the newly developed testing device the range of motion to impingement and to dislocation can be determined at different implant positions. In addition, the rotational moments on subluxation, i.e. the "levering out" of the femoral head, can be determined. By way of example several hip implants were examined during movements associated with dislocation, e.g. (internal-)rotation in 90 degrees flexion and 0 degrees adduction as well as with (external-)rotation in combination with 10 degrees extension and 15 degrees adduction. Irrespective of implant design and position, the following movement phases can be differentiated: undisturbed motion, impingement, subluxation and, finally, complete dislocation of the head. On the basis of the range of motion of the specific phases, the moments occurring and the direction of dislocation, different implant systems can be compared. In this study the influence of the head diameter on the dislocation stability of the hip endoprosthesis is shown. With the aid of the model presented herein, a data set showing the most favourable and/or most dislocation stable implant position can be acquired for different combinations of the implant components. Additionally, useful information for implant design can be deduced and applied to new developments and/or modifications of existing implant components.     

微创经皮LCP 接骨术治疗老年股骨近端粉碎骨折

目的:本研究通过观察微创锁定钢板接骨术治疗老年股骨近端粉碎骨折临床效果,旨在找出最佳治疗方式。方法:自2007年12月～2010年03月,应用股骨近端锁定加压钢板治疗老年股骨近端粉碎骨折23例。记录术中出血量、手术时间,术后并发症、骨折愈合时间及最后一次随访时功能恢复情况。结果:骨折临床愈合时间为12～28周,平均16周。除1例患者髋内翻畸形,1例锁定加压钢板断裂外,其他患者均达到骨性愈合。结论:股骨近端锁定钢板具有创伤小、固定可靠、骨折愈合快、功能恢复满意的特点,尤其适用于老年股骨近端粉碎骨折。     

A Comparative Analysis of Different Treatments for Distal Femur Fractures using the Finite Element Method

The main objective of this work is the evaluation, by means of the finite element method (FEM) of the mechanical stability and long-term microstructural modifications in bone induced to three different kinds of fractures of the distal femur by three types of implants: the Condyle Plate, the less invasive stabilization system plate (LISS) and the distal femur nail (DFN). The displacement and the stress distributions both in bone and implants and the internal bone remodelling process after fracture and fixation are obtained and analysed by computational simulation. The main conclusions of this work are that distal femoral fractures can be treated correctly with the Condyle Plate, the LISS plate and the DFN. The stresses both in LISS and DFN implant are high especially around the screws. When respect to remodelling, the LISS produces an important resorption in the fractured region, while the other two implants do not strongly modify bone tissue microstructure.     

A comparative analysis of different treatments for distal femur fractures using the finite element method

The main objective of this work is the evaluation, by means of the finite element method (FEM) of the mechanical stability and long-term microstructural modifications in bone induced to three different kinds of fractures of the distal femur by three types of implants: the Condyle Plate, the less invasive stabilization system plate (LISS) and the distal femur nail (DFN). The displacement and the stress distributions both in bone and implants and the internal bone remodelling process after fracture and fixation are obtained and analysed by computational simulation. The main conclusions of this work are that distal femoral fractures can be treated correctly with the Condyle Plate, the LISS plate and the DFN. The stresses both in LISS and DFN implant are high especially around the screws. When respect to remodelling, the LISS produces an important resorption in the fractured region, while the other two implants do not strongly modify bone tissue microstructure.     

Modulation of bone ingrowth of rabbit femur titanium implants by in vivo axial micromechanical loading.

Titanium implants commonly used in orthopedics and dentistry integrate into host bone by a complex and coordinated process. Despite increasingly well illustrated molecular healing processes, mechanical modulation of implant bone ingrowth is poorly understood. The objective of the present study was to determine whether micromechanical forces applied axially to titanium implants modulate bone ingrowth surrounding intraosseous titanium implants. We hypothesized that small doses of micromechanical forces delivered daily to the bone-implant interface enhance implant bone ingrowth. Small titanium implants were placed transcortically in the lateral aspect of the proximal femur in 15 New Zealand White rabbits under general anesthesia and allowed to integrate with the surrounding bone for 6 wk. Micromechanical forces at 200 mN and 1 Hz were delivered axially to the right femur implants for 10 min/day over 12 consecutive days, whereas the left femur implants served as controls. The average bone volume 1 mm from mechanically loaded implants (n = 15) was 73 +/- 12%, which was significantly greater than the average bone volume (52 +/- 21%) of the contralateral controls (n = 15) (P < 0.01). The average number of osteoblast-like cells per endocortical bone surface was 55 +/- 8 cells/mm(2) for mechanically loaded implants, which was significantly greater than the contralateral controls (35 +/- 6 cells/mm(2)) (P < 0.01). Dynamic histomorphometry showed a significant increase in mineral apposition rate and bone-formation rate of mechanically stressed implants (3.8 +/- 1.2 microm/day and 2.4 +/- 1.0 microm(3).microm(-2).day(-1), respectively) than contralateral controls (2.2 +/- 0.92 microm/day and 1.2 +/- 0.60 microm(3).microm(-2).day(-1), respectively; P < 0.01). Collectively, these data suggest that micromechanical forces delivered axially on intraosseous titanium implants may have anabolic effects on implant bone ingrowth.     

逆行可膨胀髓内钉与锁定钢板治疗股骨远端骨折的疗效比较

目的:探讨比较运用逆行可膨胀髓内钉与股骨远端锁定钢板治疗股骨远端33A、33C1型骨折的疗效。方法:对2013年3月至2015年6月收治并符合纳入标准的43例股骨远端33A、33C1型骨折患者进行回顾性研究。按照不同的手术固定方式分为逆行可膨胀髓内钉组(n=18)和锁定钢板组(n=25),记录并比较两组手术时间、失血量、愈合时间及功能结果、术中及术后并发症。结果:所有骨折最终都获得愈合;逆行可膨胀髓内钉组在手术时间及失血量上都显著低于锁定钢板组,两组在愈合时间及功能评定方面无明显差异;5例开放性骨折的患者中1例出现浅表伤口感染,1例患者延迟愈合。结论:股骨远端逆行可膨胀髓内钉在获得与锁定钢板相当的骨折愈合时间及患肢功能的情况下,具有操作简单、手术时间短、失血量少等特点,对于股骨远端33A、33C1型骨折来说是一个较好的选择。     

逆行交锁髓内钉联合单侧骨皮质锁定钢板固定治疗股骨髁上骨不连

目的:探讨逆行交锁髓内钉联合单侧骨皮质钢板固定治疗股骨髁上骨不连的临床疗效。方法:对25例股骨髁上骨不连,均采用逆行交锁髓内钉联合单侧骨皮质钢板固定加自体髂骨植骨治疗。结果:25例获12～24个月随访,平均12个月。4～8个月内均获骨性愈合。结论:应用逆行交锁髓内钉联合单侧骨皮质钢板固定后骨折端可获得坚强内固定,手术操作简便、安全,可早期进行膝关节和股四头肌功能锻炼,是一种治疗股骨髁上骨不连的有效方法。     

扩髓更换髓内钉治疗髓内钉固定后股骨干肥大性骨不连

目的:评价扩髓更换髓内钉治疗髓内钉固定后股骨干肥大性骨不连的临床疗效及手术适应症。方法:自1998年4月至2009年6月采用扩髓更换髓内钉治疗11例髓内钉固定后股骨干肥大性骨不连,其中男9例,女2例,年龄23-61岁。平均36.2岁,骨折部位在股骨上1/3者2例;中1/3者6例;下1/3者3例,原始骨折Winquist-Hansen分型:I型2例,II型3例,III型4例,IV型2例。结果:11例患者均获随访,时间:11～56个月,平均27.4个月,2例患肢短缩1 cm。另4例未获得骨性愈合,3例再次采用附加钢板合并自体髂骨植骨,1例远端锁钉动力化,再次干预后获得骨性愈合,愈合时间6～16个月,平均8.3个月。结论:扩髓更换髓内钉是治疗髓内钉固定后股骨肥大性骨不连的传统方法,基于力学稳定和临床观察,更适用于股骨中段骨不连。     

In-vitro comparison of LC-DCP- and LCP-constructs in the femur of newborn calves - a pilot study

ABSTRACT: BACKGROUND: To compare the biomechanical in-vitro characteristics of limited-contact dynamic compression plate (LC-DCP) and locking compression plate (LCP) constructs in an osteotomy gap model of femoral fracture in neonatal calves. Pairs of intact femurs from 10 calves that had died for reasons unrelated to the study were tested. A 7-hole LC-DCP with six 4.5 mm cortical screws was used in one femur and a 7-hole LCP with four 5.0 mm locking and two 4.5 mm cortical screws was used in the corresponding femur. The constructs were tested to failure by cyclic compression at a speed of 2 mm/s within six increasing force levels. RESULTS: The bone-thread interface was stripped in 21 of 80 cortical screws (26.3%) before a pre-set insertion torque of 3 Nm was achieved. Only 3 corresponding intact pairs of constructs could be statistically compared for relative structural stiffness, actuator excursion and width of the osteotomy gap. Relative structural stiffness was significantly greater, actuator excursion and width of the osteotomy gap were significantly smaller in the LCP constructs. While failure occurred by loosening of the screws in the LC-DCP constructs, locking constructs failed by cutting large holes in the soft distal metaphyseal bone. CONCLUSIONS: An insertion torque sufficient to provide adequate stability in femurs of newborn calves could not be achieved reliably with 4.5 mm cortical screws. Another limiting factor for both constructs was the weak cancellous bone of the distal fracture fragment. LCP constructs were significantly more resistant to compression than LC-DCP constructs.     

Experimental and probabilistic analysis of distal femoral periprosthetic fracture: a comparison of locking plate and intramedullary nail fixation. Part B: probabilistic investigation

The following is Part B of a two-part study. Part A evaluated, biomechanically, intramedullary (IM) nails versus locking plates for fixation of an extra-articular, metaphyseal wedge fracture in synthetic osteoporotic bone. Part B of this study introduces deterministic finite element (FE) models of each construct type in synthetic osteoporotic bone and investigates the probability of periprosthetic fracture of the locking plate compared with the retrograde IM nail using Monte Carlo simulation. Deterministic FE models of the fractured femur implanted with IM nail and locking plate, respectively, were developed and validated using experimental data presented in Part A of this study. The models were validated by comparing the load-displacement curve of the experimental data with the load-displacement curve of the FE simulation with a root-mean square error of less than 3?mm. The validated FE models were then modified by defining the cortical and cancellous bone modulus of elasticity as uncertain variables that could be assumed to vary randomly. Monte Carlo simulation was used to evaluate the probability of fracture (POF) of each fixation. The POF represents the cumulative probability that the predicted shear stresses in the cortical bone will exceed the expected shear strength of the cortical bone. This investigation provides information regarding the significance of post-operative damage accumulation on the POF of the implanted bones when the two fixations are used. The probabilistic analysis found the locking plate fixation to have a higher POF than the IM nail fixation under the applied loading conditions (locking plate 21.8% versus IM nail 0.019%).     

Excessive compression of the human tibio-femoral joint causes ACL rupture

The knee is one of the most frequently injured joints in the human body. A recent study suggests that axial compressive loads on the knee may play a role in injury to the anterior cruciate ligament (ACL) for the flexed knee, because of an approximate 10 degrees posterior tilt in the tibial plateau (J. Orthop. Res. 16 (1998) 122-127). The hypothesis of the current study was that excessive axial compressive loads in the human tibio-femoral (TF) joint would cause relative displacement and rotation of the tibia with respect to the femur, and result in isolated injury to the ACL when the knee is flexed to 60 degrees , 90 degrees or 120 degrees . Sixteen isolated knees from eleven fresh cadaver donors (74.3+/-10.5 yr) were exposed to repetitive TF compressive loads increasing in intensity until catastrophic injury. ACL rupture was documented in 14/16 cases. The maximum TF joint compressive force for ACL failure was 5.1+/-2.1 kN for all flexion angles combined. For the 90 degrees flexed knee, the injury occurred with a relative anterior displacement of 5.4+/-3.8mm, a lateral displacement of 4.1+/-1.4mm, and a 7.8+/-7.0 degrees internal rotation of the tibia with respect to the femur.     

Cyclooxygenase-2 inhibitor inhibits the fracture healing

We investigated the effects of cyclooxigenase-2 (cox-2) on fracture healing. After closed non-displaced fractures were created at the middle of both femoral shafts in 12-week-old Wister rats, a cox-2 specific inhibitor, etodolac (20 mg/day; intra-peritoneal) was administered every day for three weeks (E group). Bone union and callus formation were evaluated by weekly radiographs. Three weeks after surgery, the mechanical strength of the fractured femur was evaluated by a three-point-bending test. These results were compared with those of a vehicle control group (V group). The fracture healing score on radiographs in the E group three weeks after the surgery was 3.3 +/- 0.9, and in the V group it was 5.8 +/- 1.5, indicating that fracture healing was significantly poorer in the E than the V group (p < 0.05). From the three point bending test, the ultimate strength and stiffness of etodolac-treated fractured femurs were shown to be significantly lower than those in vehicle control group (p < 0.05). Mechanically, femurs of etodolac treated rats were weaker than those of control rats. Thus, it was concluded that etodolac, a cox-2 specific inhibitor, inhibited fracture healing.     

An improved murine femur fracture device for bone healing studies

Murine models are commonly used to investigate bone healing and test new treatments before human trials. Our objective was to design an improved murine femur fracture device and determine optimal mass and velocity settings for maximal likelihood of transverse fracture. Fracture reproducibility was maximized using an adjustable kinetic energy level, a novel mouse positioning system and an electromagnet striker release assembly. Sixty wild-type mice of 8-12-week-old male and female with a weight of 26.4+/-6.1g were subjected to an experimental postmortem fracture in the left and right femur (n=120) using variable kinetic energy inputs. A best-fit prediction equation for transverse fracture was developed using multivariate linear regression. Transverse fracture was shown to correlate most highly with kinetic energy with a maximum likelihood at mv2=292 where m is mass (g) and v is velocity (m/s). Model validation with a group of 134 anesthetized C57BL/6 mice resulted in a favorable transverse fracture rate of 85.8%. Simple modifications to existing fracture devices can improve accuracy and reproducibility. The results may assist researchers studying the effects of genetic modifications and novel treatments on boney healing in murine femur fracture models. Maintaining kinetic energy parameters within suggested ranges may also aid in ensuring accuracy and reproducibility.     

近端防旋髓内钉与近端锁定钢板治疗老年股骨转子间不稳定骨折的疗效对比分析

目的:分析对比股骨近端防旋髓内钉(PFNA)与股骨近端锁定钢板(PFLP)治疗老年股骨转子间不稳定骨折的临床疗效。方法:回顾性分析我院骨外科2009年4月至2013年4月收治的老年股骨转子间不稳定骨折患者90例,根据患者手术方式的不同,将其分为PFNA组及PFLP组,各45例。对比分析两组患者术中出血量、手术持续时间及骨折愈合时间术后髋关节功能及内固定并发症情况。结果:PFNA组髋关节功能Harris评分优良率91.11%明显高于PFLP组的71.11%(P0.05);PFNA组比PFLP组骨折愈合时间短、内固定并发症少,比较差异有统计学意义(P0.05)。结论:应用PFNA治疗老年股骨转子间不稳定骨折患者具有骨折愈合时间短、髋关节功能恢复好、术后内固定并发症少的特点,治疗效果较PFLP更满意。     

LOC103691336/miR-138-5p/BMPR2 axis modulates Mg-mediated osteogenic differentiation in rat femoral fracture model and rat primary bone marrow stromal cells

Intramedullary stabilization is frequently used to treat long bone fractures. Since implant removal can become technically very challenging with the potential to cause further tissue damage, biodegradable materials are emerging as alternative options. Magnesium (Mg)-based biodegradable implants have a controllable degradation rate and good tissue compatibility, which makes them attractive for musculoskeletal research. Herein, the degradation of Mg and steel implants, the pathological characteristics and osteoblast differentiation in mice femora were examined. To investigate the molecular mechanism, we analyzed the differentially expressed long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) in Mg-implanted or stain-steel-implanted callus tissues. lncRNA LOC103691336 was upregulated in Mg-implanted tissues and most relevant to BMPR2, a kinase receptor of BMPs with an established role in osteogenesis. The knockdown of LOC103691336 attenuated Mg-mediated osteogenic differentiation. Furthermore, miR-138-5p, previously reported to inhibit osteogenic differentiation, could bind to LOC103691336 and BMPR2 in bone marrow stromal cells (BMSCs). LOC103691336 competed with BMPR2 for miR-138-5p binding in BMSCs to attenuate the inhibitory effect of miR-138-5p on BMPR2 expression. Finally, the effect of LOC103691336 knockdown on Mg-mediated osteogenic differentiation could be attenuated by miR-138-5p inhibition. In conclusion, we provided a novel mechanism of Mg implants mediating the osteogenesis differentiation and demonstrated that Mg implants may be promising for improving fracture healing.     

MIPO技术结合锁定加压钢板、顺行交锁髓内钉及锁定加压钢板治疗肱骨干中段骨折疗效的对比研究

摘要 目的：探讨微创经皮钢板内固定（MIPO）技术结合锁定加压钢板、顺行交锁髓内钉、锁定加压钢板治疗肱骨干中段骨折的疗效。方法：选择2016年2月至2019年2月我院收治的126例肱骨干中段骨折患者，采用随机数字表法将其分为三组，MIPO组（42例）采用MIPO技术结合锁定加压钢板固定治疗，髓内钉组（42例）采用顺行交锁髓内钉固定治疗，钢板组（42例）采用锁定加压钢板固定治疗。所有患者术后随访12个月，比较三组手术时间、术中出血量、术后住院时间、骨折愈合时间、术前和术后第12个月美国加州大学肩关节评分系统（UCLA）评分、Mayo肘关节功能评分（MEPS）、欧洲五维健康量表(EQ-5D)评分以及并发症发生率。结果：MIPO组和髓内钉组的术中出血量与术后住院时间均少于钢板组（P＜0.05），MIPO组和髓内钉组之间无统计学差异（P＞0.05）。MIPO组、钢板组骨折愈合时间短于髓内钉组（P＜0.05），MIPO组、钢板组之间无统计学差异（P＞0.05）。MIPO组、钢板组术后第12个月UCLA评分均高于髓内钉组（P＜0.05），MIPO组、钢板组之间无统计学差异，第12个月MEPS无差异（P＞0.05）。术后第12个月MIPO组、钢板组EQ-5D评分高于髓内钉组（P＜0.05），MIPO组、钢板组之间无统计学差异（P＞0.05）。三组桡神经损伤、肩峰损伤发生率相比较，差异有统计学意义（P＜0.05），桡神经损伤以钢板组发生率最高，肩峰损伤以髓内钉组发生率最高。结论：MIPO技术结合锁定加压钢板具有微创、术后恢复快、对肩关节功能及生活质量的影响较小、术后并发症较少的优势，是肱骨干中段骨折较为理想的治疗方式。     

Experimental study in rat metatarsals to determine whether callus vascularity is an indicator of the mechanical strength of healing fractures

Changes in the mechanical properties and percentage area of blood vessels of healing fracture callus were followed using rat metatarsals. By 24 weeks after fracture the mean ultimate tensile stress and elastic modulus were still less than half that of the contralateral unfractured bone, whereas the mean torsional modulus had almost reached that of the unfractured bone. The percentage area of blood vessels declined from five days post-fracture and showed no changes which coincided with the increases in mechanical strength or moduli. We conclude that studies of vascularity would not justify a prediction of the strength of a healing fracture.