The basic science of peri-implant bone healing

Given the popularity of cementless orthopedic implants, it is imperative for orthopedic surgeons to have a basic understanding of the process of peri-implant bone healing. Contact and distance osteogenesis have been used to explain peri-implant bone healing. In contact osteogenesis, de novo bone forms on the implant surface, while in distance osteogenesis, the bone grows from the old bone surface toward the implant surface in an appositional manner. Contact osteogenesis may lead to bone bonding if the surface of the implant displays the appropriate surface topography. The early stage of peri-implant bone healing is very important and involves the body’s initial response to a foreign material: protein adsorption, platelet activation, coagulation, and inflammation. This results in the formation of a stable fibrin clot that is a depot for growth factors and allows for osteoconduction. Osteoconduction is the migration and differentiation of osteogenic cells, such as pericytes, into osteoblasts. Osteoconduction allows for contact osteogenesis to occur at the implant surface. The late stage of healing involves the remodeling of this woven bone. In many respects, this process is similar to the bone healing occurring at a fracture site.     

Effect of capacitively coupled electric fields on an experimental model of delayed union of fracture

To evaluate the effect of capacitively coupled electric fields (CCEF) on delayed union of fractures, an experimental model of delayed union was produced in the radius of rabbits, and the process of healing was investigated by radiography, bone mineral density (BMD) measured with dual energy x-ray absorptiometry, and histological survey. It was confirmed radiographically and histologically that callus formation was enhanced in the group treated with CCEF. After stimulation, the average BMD increased more than 18% compared with the controls. Our experiment on a delayed union model suggests that CCEF is effective for the treatment of delayed union of fractures.     

Combination of femoral fracture treatment and corrective osteotomy in a child with osteogenesis imperfecta

The main feature of osteogenesis imperfecta is an excessive fragility and deformability of the bones owing to reduced mass and bone quality. This leads to angular deformity and frequent fractures. These fractures usually heal rapidly, and conservative treatment is the norm. In displaced and unstable fractures, elastic intramedullary nailing is a treatment option. We report a case of a 3-year-old child with osteogenesis imperfecta type I who suffered an undisplaced femoral shaft fracture in the presence of a preexisting 32° femoral antecurvation. This deformity greatly increases the risk of a refracture due to the pathological induction of stress risers. Therefore, fracture treatment by unreamed elastic intramedullary nailing was combined with simultaneous correction osteotomy, resulting in anatomic alignment and uncomplicated fracture healing. The single-stage surgical stabilization performed allowed rapid mobilization along with a decreased likelihood of refracture.     

辛伐他汀及淫羊藿提取物促进成骨作用研究进展

骨折临床愈合是一个相对缓慢的过程,由于全身性因素、生物学因素、骨折局部条件及手术的影响等,部分患者可出现骨折延迟愈合和不愈合。辛伐他汀是一种能够降低血清胆固醇和甘油三酯的有效药物,近年来国内外大量实验证明,辛伐他汀能增加骨密度、促进骨生长、有效预防或减少骨质疏松症。淫羊藿是一种传统的补肾阳、强筋骨、祛风湿的中药,近年研究证明其提取物亦具有促进骨形成作用。本文就此二种药物促进骨折愈合研究有关的文献进行综述,进一步分析二者单独及联合应用促进成骨作用的机制。     

方形波电容偶合电场促进骨修复的实验研究

为寻求促进骨组织生长与修复的方法,我们研制了“方形波电容偶合电场(CCEF)骨折治疗仪”,采用新西兰纯种大白兔,手术造成双侧桡骨骨折模型,进行电刺激。通过组织学切片,光学显微镜观察,四环素标记荧光显微镜观察,骨组织形态计量学测定及力学抗折试验。结果表明方形波电容偶合电场的促进成骨作用及骨折愈合抗折强度均明显优于正弦波组和对照组。并对电容偶合电场促进骨生长与修复的机理进行了探讨。     

多种技术联用治疗难治性骨髓炎的疗效分析

目的探讨应用Ilizarov骨搬移技术联合抗生素骨水泥片技术、Masquelet技术(膜诱导技术)等技术治疗长骨慢性骨髓炎的临床疗效。 方法回顾性分析2012年6月至2016年10月,新疆军区总医院创伤骨科联合应用病灶清除、Ilizarov技术、抗生素骨水泥片填充技术、膜诱导成骨技术、远端缓慢回缩技术等技术治疗的20例股骨、胫骨慢性骨髓炎和感染性骨不连患者。纳入标准：慢性骨髓炎合并骨不连或骨缺损的患者;经常规治疗效果差的患者;无影响治疗的合并症;病例资料完整的患者。排除标准：不符合疾病的纳入标准;存在活动性结核、肿瘤等疾病的患者;依从性差、不能按照医生要求调整外固定架的患者。记录上述患者是否需行皮瓣转移手术、带外固定架时间、全负重时间及是否出现复发情况。 结果所有患者均得到随访,随访时间平均(29.2±1.8)个月。均获得了良好的骨性愈合,所治疗患者感染均得到一期愈合,创面无需皮瓣转移或植皮均得到良好闭合,骨搬移结合处愈合良好。患者骨搬移长度平均(7.3±1.8)cm。所有患者未出现神经损伤,其中有两例患者术前存在腓总神经损伤,术后在骨搬移过程中出现不同程度的神经功能恢复。 结论应用Ilizarov的骨搬移和骨延长技术能有效治疗彻底清创后的骨缺损或肢体短缩问题,保证彻底清创、促进局部血运改善、不需要皮瓣覆盖也能愈合创面;抗生素骨水泥片起到占位器和膜诱导作用促进成骨;远端缓慢回缩有利于骨端愈合;多种方法联合应用,有效地提高了难治性骨髓炎的治愈率,是一种安全有效的治疗方法。     

Fracture healing physiology and the quest for therapies for delayed healing and nonunion

Delayed healing and nonunion of fractures represent enormous burdens to patients and healthcare systems. There are currently no approved pharmacological agents for the treatment of established nonunions, or for the acceleration of fracture healing, and no pharmacological agents are approved for promoting the healing of closed fractures. Yet several pharmacologic agents have the potential to enhance some aspects of fracture healing. In preclinical studies, various agents working across a broad spectrum of molecular pathways can produce larger, denser and stronger fracture calluses. However, untreated control animals in most of these studies also demonstrate robust structural and biomechanical healing, leaving unclear how these interventions might alter the healing of recalcitrant fractures in humans. This review describes the physiology of fracture healing, with a focus on aspects of natural repair that may be pharmacologically augmented to prevent or treat delayed or nonunion fractures (collectively referred to as DNFs). The agents covered in this review include recombinant BMPs, PTH/PTHrP receptor agonists, activators of Wnt/β‐catenin signaling, and recombinant FGF‐2. Agents from these therapeutic classes have undergone extensive preclinical testing and progressed to clinical fracture healing trials. Each can promote bone formation, which is important for the stability of bridged calluses, and some but not all can also promote cartilage formation, which may be critical for the initial bridging and subsequent stabilization of fractures. Appropriately timed stimulation of chondrogenesis and osteogenesis in the fracture callus may be a more effective approach for preventing or treating DNFs compared with stimulation of osteogenesis alone. © 2016 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 35:213–223, 2017.

     

Rosiglitazone induces adipogenesis of both marrow and periosteum derived mesenchymal stem cells during endochondral fracture healing

BackgroundType 2 diabetes mellitus (T2DM) afflicts about six percent of the global population, and these patients suffer from a two-fold increased fracture risk. Thiazolidinediones (TZDs), including rosiglitazone, are commonly used medications in T2DM because they have a low incidence of monotherapy failure. It is known that rosiglitazone is associated with secondary osteoporosis, further increasing the fracture risk in an already susceptible population. However, it is not yet understood how rosiglitazone impacts endochondral bone healing after fracture. The aim of this study is to elucidate how rosiglitazone treatment impacts endochondral fracture healing, and how rosiglitazone influences the differentiation of skeletal stem and progenitor cells from the bone marrow and the periosteum.MethodsAn in-vivo mouse femur fracture model was employed to evaluate differences in fracture healing between mice treated with and without rosiglitazone chow. Fracture healing was assessed with histology and micro computed tomography (μCT). In-vitro assays utilized isolated mouse bone marrow stromal cells and periosteal cells to investigate how rosiglitazone impacts the osteogenic capability and adipogenicity of these cells.ResultsThe in-vivo mouse femur fracture model showed that fracture callus in mice treated with rosiglitazone had significantly more adipose content than those of control mice that did not receive rosiglitazone. In addition, μCT analysis showed that rosiglitazone treated mice had significantly greater bone volume, but overall greater porosity when compared to control mice. In-vitro experimentation showed significantly less osteogenesis and more adipogenesis in bone marrow derived progenitor cells that were cultured in osteogenic media. In addition, rosiglitazone treatment alone caused significant increases in adipogenesis in both bone marrow and periosteum derived cells.ConclusionRosiglitazone impairs endochondral fracture healing in mice by increasing adipogenesis and decreasing osteogenesis of both bone marrow and periosteum derived skeletal progenitor cells.     

闭合复位结合锁定加压钢板治疗Barton骨折的临床分析

目的探讨闭合复位结合锁定加压钢板（locking compression plate,LCP）治疗Barton骨折的临床疗效。方法回顾性分析2010年2月至2012年11月收治的71例新鲜Barton骨折患者的临床资料,按照患者治疗方法分为闭合复位结合LCP内固定组33例及常规LCP内固定组38例,应用Gartland功能评分对两组患者的临床疗效作统计分析。结果两组手术均取得成功。平均随访（9.0±2.1）个月,骨折全部愈合,两组Gartland评分差异有统计学意义（P〈0.05）,平均手术时间比较差异有统计学意义（P〈0.05）,术后愈合时间比较差异无统计学意义（P〉0.05）。结论闭合复位结合LCP内固定治疗新鲜Barton骨折取得满意效果,为Barton骨折的治疗提供了一种新的选择。     

Treatment of nonunion with a constant direct current: a totally implantable system

There is now sufficient basic research and clinical experience to establish that electrical stimulation produces osteogenesis. Furthermore, electrical stimulation significantly helps union where impaired bone healing exists. The implanted bone growth stimulator is one effective method of electrical stimulation. It can be used in a wide variety of problems: delayed union and nonunion of bones with or without chronic infection and in failed posterior spinal fusion. Successful treatment of congenital pseudarthrosis of the tibia has been encouraging. The implanted bone growth stimulator technique requires a simple operation with strict adherence to detail. There is minimal postoperative discomfort and a short hospital stay. The average time to union is 16 weeks. The Osteostim can be used in the presence of chronic infection and internal fixation. Above all, the technique does not require any cooperation from the patient. The implanted bone growth stimulator should be accepted as a method of treatment for delayed and nonunion of bones, as it is at least as effective as other more conventional methods of surgical treatment for this situation. It has been proved that electrical stimulation produces osteogenesis. Orthopedic surgeons should no longer be skeptical about this.     

Mitogens are increased in the systemic circulation during bone callus healing.

The influence of mechanical tissue strain caused by flexible fracture fixation on the systemic occurrence of systemic mitogens during callus healing was investigated. For this purpose the mitogenic capacity and growth factor concentration of sera from patients undergoing fracture treatment were determined. Sera from 9 patients whose fractures had been stabilized by external fixation were collected before and during fracture treatment. The sera were added to cell culture media of the osteoblastic cell line SaOS-2. After 5-6 days cell proliferation was measured. Transforming growth factor-beta1 (TGF-beta1) and insulin-like growth factor-I (IGF-I) concentrations were analyzed in serum samples from different healing stages. STATISTICS: paired Wilcoxon-test. Sera from fracture patients decreased SaOS-2 proliferation in the first week after surgery (p<0.05) compared to sera obtained prior to surgery. In the fourth or fifth week proliferation increased significantly (p<0.03). The increased proliferation of the SaOS-2 cells was associated with elevated levels of TGF-beta and IGF-I (p<0.05). The higher mitogenic activity of sera suggests an increased level of circulating mitogens. In a previous study this increase had also been observed in patients during distraction osteogenesis treatment but not in patients with primary bone healing by a stable fixated plate. It is therefore assumed that their release from the fracture site is a consequence of mechanical stimulation by interfragmentary movement of fracture ends.     

Deformation across the zone of callotasis during loading. radiostereometric analysis in a patient with achondroplasia.

The present study demonstrates that high-resolution radiostereometric analysis (RSA) can be used to assess global longitudinal compressive deformation across the callotasis zone during loading. In an achondroplastic patient operated with bifocal lengthening of the tibia by use of the Ilizarov external fixator, the axial compressive intersegmental strain in the proximal lengthening zone under a load of 71% of body weight was 7.7 mm. The proximal lengthening zone was 51.0 mm, and accordingly the overall linear strain across the callotasis was 15.1%. This large strain value found in distraction osteogenesis 6 weeks after end of distraction is not consistent with classical theory of the magnitude of micromotion needed for adequate stimulation of bone formation in fracture healing. The increased axial displacement did not stimulate bone healing and delayed union was observed. This one single observation does not allow for any conclusions to be drawn about the relationship of strain to fracture healing, but further and refined use of the RSA method will certainly improve our understanding of the role of axial strains in distraction osteogenesis.     

微量元素锶与骨质疏松症

随着世界范围内老龄人口的不断增加,骨质疏松症已经成为严重危害中老年人健康的常见病、多发病。骨质疏松症患者不仅易于发生骨折,他们在接受牙种植、人工关节置换等治疗时,还经常存在生物植入材料骨整合不佳、甚至松动脱落的问题,严重限制了中老年患者生活质量的提高。因此,探索各种科学、合理的方法改善骨质疏松症患者的骨代谢状况,预防骨质疏松性骨折的发生,促进骨质疏松性骨折的愈合,改善骨质疏松状态下植入体的骨整合已经成为骨科、矫形外科、口腔颌面外科以及老年医学等多学科领域内亟待解决的难题。近期的研究发现,微量元素锶是一种具有促进成骨和抑制骨吸收双重作用的抗骨质疏松药物,本文就微量元素锶治疗骨质疏松症的研究进展作一综述。     

Effect of Mechanical Strain on Cells Involved in Fracture Healing

Secondary fracture healing is a complex multi‐stage process in which the mechanical environment plays a key role. The use of an appropriate mechanical stimulation such as strain is conducive to tissue formation between fracture ends, thus aiding the healing process. However, if the strain is too large or too small, the biological behavior of the cells involved in bone healing will be affected, resulting in non‐union or delayed healing. In this review, we summarize the current state of knowledge regarding the effect of strain on cells that play a role in the fracture‐healing process. Overall, the related literature suggests that selection of an adequate strain promotes fracture healing through the stimulation of angiogenesis and osteogenesis, along with inhibition of osteoclast differentiation and bone resorption. However, standardized methods for the application of mechanical stimulation are lacking, and a unified consensus on the mechanism by which strain promotes cell differentiation has not yet been reached. These issues, therefore, deserve further investigation.     

Enhancing bone healing during distraction osteogenesis with platelet-rich plasma

Gradual limb lengthening with external fixators using distraction osteogenesis principles is the gold standard for treatment of limb-length discrepancy. However, long treatment time is a major disadvantage of the current lengthening procedures. Efforts to decrease the treatment include biological and biomechanical factors. Injection of platelet-rich plasma (PRP) is a biological method to enhance bone healing during distraction osteogenesis. We hypothesised that PRP can enhance bone healing during limb lengthening. We report our experience with the use of PRP during distraction osteogenesis. This retrospective study included 19 patients divided into the standard group of 10 patients who did not receive PRP and the PRP group of nine patients who received PRP at the end of the distraction phase. The study variables included external fixator time, external fixation index, and complications during treatment. The PRP group had statistically significantly shorter treatment time (p = 0.0412). Injection of PRP into regenerate bone might be an effective method to shorten treatment time during limb lengthening and lead to better functional outcomes and improved patient satisfaction.Level of evidence: Level IV, therapeutic study.     

Effects of electrical stimulation on the biomechanical properties of fracture healing in rabbits

One hundred fifteen white rabbits with an average weight of 2.0 kg were used to study the influence of electrical stimulation on osteogenesis. They were divided into three groups: Group I was electrically stimulated with a constant direct current of 20 microamperes delivered to the fracture site; Group II was the control group having the same protocol as Group I except that the stimulator was not switched on; and Group III was the normal fracture healing group (no introduction of electrodes to the fracture site). Roentgenologic and histologic assessment showed that new bone formation in the electrical stimulation group was more exuberant than those in the other two groups in observation periods from three to eight weeks. However, at 12 weeks no difference was observed among the three groups. Biomechanical analysis showed definite increases in the breaking strength and bending stiffness of the fracture healing tibia in Group I, especially at six weeks after surgery. However, at 12 weeks no significant difference was observed among the three groups. Therefore, electrical stimulation of fracture healing has a positive effect only at the midphase of the healing process, and it does not lead to faster fracture healing.     

Osteoporotic Vertebral Fractures

Abstract Due to a demographic increase in patients with osteoporosis the epidemiology of vertebral fractures changes. Osteoporosis is characterized by low bone density, microarchitectural deterioration of bone tissue and impaired bone strength, which leads to an increased bone fragility and susceptibility to fracture. Asymptomatic vertebral deformity was found to be associated with subsequent risk of symptomatic fractures, particularly vertebral fracture, and increased risk of mortality after a fracture. After the first osteoporotic fracture at any site the risk for further fractures increases dramatically. Osteoporosis represents, besides the origin of such vertebral fractures and impaired bone healing, a problem in osteofixation and implant stability in fracture treatment in orthopedic surgery. Two new treatment strategies of percutaneous vertebro- and kyphoplasty have gained worldwide attention in the treatment of osteoporotic vertebral fracture and short-term observational studies and case-control studies indicate that the results are favorable, regarding both pain relief and functional status. Actually, it cannot be decided whether the internal application of bone cement to the vertebral body is effective in the long run. Special attention has to be given to the underlying osteoporosis in order to reduce the incidence of further fractures in the patients at risk. Diagnosis and treatment of osteoporosis have to be part of the treatment concept of osteoporotic vertebral fractures. Thus, it is important that orthopedic surgeons identify, assess and treat patients with fragility fractures for osteoporosis according to the currently available treatment protocols.     

Femoral nonunion with segmental bone defect treated by distraction osteogenesis with monolateral external fixation

Background

Currently, the common treatment for femoral nonunion with large segmental bone defect is difficult and complex. The effective surgical methods are rare, include vascularized bone grafting, Masquelet technique and Ilizarov distraction osteogenesis. The objective of this study is to investigate the outcomes of segmental femoral defects treated with monolateral external fixation using the distraction osteogenesis.

Methods

We retrospectively analyzed patients with femoral nonunion with segmental bone defects (>?6 cm) between January 2010 and January 2014 in our single trauma center. All patients were treated by distraction osteogenesis with monolateral external fixation. All surgeries were performed by the same surgeon. Bone union, duration of distraction osteogenesis in days, time to consolidation in months, external fixation index (EFI), complications, and additional surgical interventions were recorded postoperatively. The modified Application of Methods of Illizarov (ASAMI) criteria were used to evaluate the operative effectiveness.

Results

Forty-one patients were enrolled in this study for analysis. The length of the bone defect ranged from 6 to 17 cm. All patients eventually achieved healing, and no patient experienced recurrence of infection or newly developed infection. The average time needed for healing was 13 months. In terms of the incidence of complications, 3 cases axial deviations, 5 cases docking site nonunion, 23 cases pin-tract infection, 14 cases knee joint stiffness or their joint mobility declined, 2 cases osteogenesis insufficient in the distraction area,1 case refracture, and 2 cases loose external fixation pins. In terms of the evaluations of fracture healing and function, 30 patients excellent, 6 patients good, 5 patients fair, and 0 patient poor. In terms of postoperative function evaluations, 21 patients excellent, 9 patients good, 7 patients fair, and 4 patients poor.

Conclusion

For patients with femoral nonunion with large segmental bone defects, the monolateral external fixation can provide effective stability, improve compliance, and reduce complications.

     

Sclerostin antibody treatment improves fracture outcomes in a Type I diabetic mouse model

Type 1 diabetes mellitus (T1DM) patients have osteopenia and impaired fracture healing due to decreased osteoblast activity. Further, no adequate treatments are currently available that can restore impaired healing in T1DM; hence a significant need exists to investigate new therapeutics for treatment of orthopedic complications. Sclerostin (SOST), a WNT antagonist, negatively regulates bone formation, and SostAb is a potent bone anabolic agent. To determine whether SOST antibody (SostAb) treatment improves fracture healing in streptozotocin (STZ) induced T1DM mice, we administered SostAb twice weekly for up to 21 days post-fracture, and examined bone quality and callus outcomes at 21 days and 42 days post-fracture (11 and 14 weeks of age, respectively). Here we show that SostAb treatment improves bone parameters; these improvements persist after cessation of antibody treatment. Markers of osteoblast differentiation such as Runx2, collagen I, osteocalcin, and DMP1 were reduced, while an abundant number of SP7/osterix-positive early osteoblasts were observed on the bone surface of STZ calluses. These results suggest that STZ calluses have poor osteogenesis resulting from failure of osteoblasts to fully differentiate and produce mineralized matrix, which produces a less mineralized callus. SostAb treatment enhanced fracture healing in both normal and STZ groups, and in STZ + SostAb mice, also reversed the lower mineralization seen in STZ calluses. Micro-CT analysis of calluses revealed improved bone parameters with SostAb treatment, and the mineralized bone was comparable to Controls. Additionally, we found sclerostin levels to be elevated in STZ mice and β-catenin activity to be reduced. Consistent with its function as a WNT antagonist, SostAb treatment enhanced β-catenin activity, but also increased the levels of SOST in the callus and in circulation. Our results indicate that SostAb treatment rescues the impaired osteogenesis seen in the STZ induced T1DM fracture model by facilitating osteoblast differentiation and mineralization of bone.     

Daily subcutaneous Teriparatide injection increased bone mineral density of newly formed bone after tibia distraction osteogenesis,a randomized study

Long bone defects are often treated by bone segment transport with the Ilizarov method requiring months spent with fixator mounted until bony consolidation of the newly formed bone. Shortening of consolidation would allow earlier fixator removal and earlier return to work. In pre-clinical studies parathyroid hormone, increased bone mineral density and mechanical properties of regenerate bone formed during distraction osteogenesis. Clinical studies showed that Teriparatide accelerated fracture healing in patients with osteoporotic fracture of the pelvis, hip, wrist and shoulder. We hypothesized that rhPTH(1-34) (Teriparatide) administered to patients who had undergone distraction osteogenesis, would increase mineralization of the regenerate formed during the consolidation phase.Sixteen patients with tibial defects after infection, underwent bone segment transport and at the time of docking the transport segment, were randomized to 8 weeks treatment with daily subcutaneous 0.20-μg Teriparatide injection followed by 8 weeks with no treatment, or to 8 weeks with no treatment followed by 8 weeks with daily subcutaneous 0.20 μg Teriparatide injection. Bone mineral density (BMD) of the regenerate was measured at the time of docking, 8 weeks after docking and 16 weeks after docking with DEXA. Functional evaluation was performed after one year. The design was a cross-over study.Overall BMD increased 0.14 g/cm² in 8 weeks without treatment and 0.33 g/cm² under Teriparatide treatment. After adjustment for a potential phase difference, 8 weeks of Teriparatide treatment led to an additional 0.19 g/cm² BMD increase (95%-CI:[0.11,0.28], p < 0.001). The ratio of the BMD increase between the two treatments was 0.33/0.14 = 2.43 (CI: [1.21,3.65]).Teriparatide treatment during the consolidation phase of distraction osteogenesis doubled the mineralization rate of the regenerate when compared to no treatment.