Impaired Bone Healing Research Articles

The development of traumatic temporomandibular joint bony ankylosis: A course similar to the hypertrophic nonunion?

The traumatic temporomandibular joint (TMJ) bony ankylosis has generated great interest in the cranio-maxillofacial surgeons yet remains an enigma, due to its unknown pathogenesis. Organization and ossification of hematoma is the classical hypothesis concerning the underlying pathophysiology, but it could not explain all the unique characters of TMJ bony ankylosis. The previous imaging descriptions about bony ankylosis tend to over-emphasize the obliteration of joint space and the overgrowth of new bone around the joint. Our recent study has found that the radiolucent zone in the bony fusion area indicating impaired bone healing is one of the most important imaging features of bony ankylosis, and this imaging feature is similar to that of hypertrophic nonunion of long bone. We also observe that there is close relationship between the mouth opening and the degree of calcification of radiolucent zone. Therefore, we hypothesize that the development of traumatic TMJ bony ankylosis may be the course of bone healing of two injured articular surfaces under the interference of opening movement, which is similar to the hypertrophic nonunion. Our hypothesis could help to explain some unintelligible characters of bony ankylosis, and deserves further studies.

Dysregulated Bone Wound Repair and Marrow Functions in Senescence Accelerated Mice (SAMP6),

Abstract 3415 Introduction:The Senescence Accelerated-Prone mouse (SAMP6) shows normal growth followed by rapid aging, development of osteopenia and shortened lifespan, compared with control R1 mice. The bone defect has been attributed to reduced osteoblast potential of marrow stromal cells. We compared in vivo repair of tibial bone wounds. We compared in vitro hematopoiesis, irradiation sensitivity, stromal cell biology, and osteoblastogenesis with SamP6 and R1 marrow. We tested the hypothesis that SAMP6 mice have poor healing of osseous wounds and that in vitro properties of SAMP6 marrow are abnormal. Methods:As a model for spontaneous bone repair, a 2-mm unicortical wound was made in each proximal tibia. At intervals, wound diameter was measured on radiographs. Long term bone marrow cultures (LTBMCs) were established from other SAMP6 and R1 mice to measure hematopoiesis and to establish marrow stromal cell lines (MSCLs) for analysis. MSCL gene expression and sensitivity to irradiation were measured; osteoblastogenic potential was determined by culture in osteoblastogenic medium (1% FBS, 10 nM dexamathasone, 5 mM b-glycerophosphate, 50 mg/mL ascorbate-2-phosphate) and gene expression analysis for osteoblast markers alkaline phosphatase (ALP), PTH-receptor-1 (PTHR1), and Osteocalcin (OC). Results:There was a faster rate of closure of the tibial wounds in R1 than in SAMP6 mice; at day 21, wounds in R1 mice were 47% the size of those in SAMP6 mice (p = 0.032). For the first 24 weeks, SAMP6 LTBMCs had significantly greater hematopoiesis than R1, shown by more cobblestone islands (sites of stem cell activity) and by more multilineage colonies from nonadherent cells transferred to semisolid medium. After 24 weeks, however, hematopoiesis ceased in SAMP6 cultures but continued in the SAMR1 cultures for 40 weeks. There was constitutive upregulation of TGF-b, an inhibitor of hematopoiesis, in SAMP6 MSCLs, compared with R1 cells. SAMP6 MSCLs were more sensitive to radiation (Do of 1.5 ± 0.1 Gy), compared with R1 (Do of 4.0 ± 0.4 Gy; p = 0.0080). There was unexpected constitutive expression of ALP, PTHR1, and OC in SAMP6 MSCLs, compared with R1. In osteoblastogenic medium, there was greater expression of osteoblast marker genes in the SAMP6 line compared to R1. Conclusion:SAMP6 showed delayed bone wound repair. Marrow from SAMP6 mice showed shortened in vitro hematopoiesis and greater radiation sensitivity, indicative of greater oxidative stress, but the unexpected finding of constitutive expression of osteoblast genes suggest that in vivo factors are more important than innate cellular defects in marrow to account for impaired bone healing. Acknowledgments:This project was supported by NIAID U191A168021-06 and NIA R21AG034254. Disclosures:No relevant conflicts of interest to declare.

A murine model of neurofibromatosis type 1 tibial pseudarthrosis featuring proliferative fibrous tissue and osteoclast-like cells

Neurofibromatosis type 1 (NF1) is a common genetic condition caused by mutations in the NF1 gene. Patients often suffer from tissue-specific lesions associated with local double-inactivation of NF1. In this study, we generated a novel fracture model to investigate the mechanism underlying congenital pseudarthrosis of the tibia (CPT) associated with NF1. We used a Cre-expressing adenovirus (AdCre) to inactivate Nf1 in vitro in cultured osteoprogenitors and osteoblasts, and in vivo in the fracture callus of Nf1(flox/flox) and Nf1(flox/-) mice. The effects of the presence of Nf1(null) cells were extensively examined. Cultured Nf1(null)-committed osteoprogenitors from neonatal calvaria failed to differentiate and express mature osteoblastic markers, even with recombinant bone morphogenetic protein-2 (rhBMP-2) treatment. Similarly, Nf1(null)-inducible osteoprogenitors obtained from Nf1 MyoDnull mouse muscle were also unresponsive to rhBMP-2. In both closed and open fracture models in Nf1(flox/flox) and Nf1(flox/-) mice, local AdCre injection significantly impaired bone healing, with fracture union being <50% that of wild type controls. No significant difference was seen between Nf1(flox/flox) and Nf1(flox/-) mice. Histological analyses showed invasion of the Nf1(null) fractures by fibrous and highly proliferative tissue. Mean amounts of fibrous tissue were increased upward of 10-fold in Nf1(null) fractures and bromodeoxyuridine (BrdU) staining in closed fractures showed increased numbers of proliferating cells. In Nf1(null) fractures, tartrate-resistant acid phosphatase-positive (TRAP+) cells were frequently observed within the fibrous tissue, not lining a bone surface. In summary, we report that local Nf1 deletion in a fracture callus is sufficient to impair bony union and recapitulate histological features of clinical CPT. Cell culture findings support the concept that Nf1 double inactivation impairs early osteoblastic differentiation. This model provides valuable insight into the pathobiology of the disease, and will be helpful for trialing therapeutic compounds.

Optimisation des traitements orthodontiques chez les patients sous biphosphonates

Bisphosphonates have unique pharmacological characteristics unlike those of any other drug group. Millions of adults take oral bisphosphonates for long-term treatment of osteoporosis and osteopenia; some of these people will most likely also seek orthodontic treatment. Adverse dental effects from bisphosphonates have been reported, including decreased tooth movement, impaired bone healing, and osteonecrosis in the mandible and the maxilla. Osteonecrosis has been rarely observed after bisphosphonate use for osteoporosis. However, adverse drug effects might occur more frequently in orthodontic patients, and they would probably be noted before the end-stage pathology of osteonecrosis. Adverse effects during orthodontic treatment, including decreased tooth movement, could last for years after the drug therapy is stopped. Successful orthodontic treatment requires optimal bone healing to prevent excessive tooth mobility. Bisphosphonates appear to have two bone elimination rates - a fast elimination of weeks from the bone surface and a slow elimination of years after incorporation into the bone structure. This article presents methods to clinically and radiographically monitor orthodontic patients who are taking oral bisphosphonates. Efforts to minimize adverse effects and optimize orthodontic procedures with physician-approved drug holidays are discussed. The orthodontic treatment results of three patients who received bisphosphonate therapy are reported.

Local inhibition of angiogenesis results in an atrophic non-union in a rat osteotomy model

Long bone and in particular tibia fractures frequently fail to heal. A disturbed revascularisation is supposed to be a major cause for impaired bone healing or the development of non-unions. We aim to establish an animal model, which reliably mimics the clinical situation. Human microvascular endothelial cells (HMEC-1) and primary human osteoblast like cells (POBs) were cultured with different angiogenesis-inhibitors (Fumagillin, SU5416, Artesunate and 3,5,4'-Trimethoxystilbene) released out of poly(D,L-Lactide) (PDLLA) coated k-wires and cell activity was determined. Discs containing PDLLA or PDLLA + Fumagillin/Artesunate were placed at the chorionallantoic membrane of hen eggs and the effect on vessel formation and egg vitality was observed. Tibia osteotomy was performed in rats and stabilised with K-wires coated with PDLLA + Fumagillin or with PDLLA only (control group). The healing was compared at different time points to the PDLLA control. Fumagillin and Artesunate inhibited the activity of HMEC-1 with minor effect on POBs. Artesunate caused embryonic death, whereas Fumagillin had no effects on egg vitality, but reduced the blood vessels. In the animal study all rats showed an impaired healing with reduced biomechanical stability. The Fumagillin treated tibiae had a significantly decreased callus size at day 42 and 84, less blood vessels in the early callus, a reduced histological callus size at day 10, 28 and 84, as well as an altered callus composition. This study presents a less vascularised, atrophic, tibia non-union and can be used in further investigations to analyse the pathology of atrophic non-union and to test new interventions.

Cigarette smoking influences the clinical and occupational outcome of patients with tibial shaft fractures

Tibial shaft fracture is one of the most common types of bone fracture in young patients. In this prospective clinical cohort study, we investigated the effects of cigarette smoking on the clinical, functional, psychosocial and occupational outcomes after isolated lower-leg fracture. We examined 85 patients, including 61 men and 24 women, with a collective mean age of 46 years (range: 18–84 years). Thirty-nine patients had never smoked (G1) and 45 patients were current or previous smokers (G2). The G2 group displayed a significantly increased risk for delayed union or nonunion (G1 = 3 patients, G2 = 18 patients; P = 0.0007) and increased time required for fracture healing (mean times: G1 = 11.9 weeks, G2 = 17.4 weeks; p = 0.003) and a markedly increased time out of work (mean times: G1 = 16.1 weeks, G2 = 21.5 weeks; p = 0.1177 (not significant)). The 18 negatively affected patients in G2 displayed a significant increase in the time required for fracture healing and time out of work (26 weeks ( p = 0.02) and 31 weeks ( p = 0.03), respectively). G2 group members had a 3- to 18-fold higher risk of impaired bone healing. The mean Short Form 36 (SF-36) was similar in both groups. The physical-function scores were G1 = 49.6 and G2 = 48.6; the mental scores were G1 = 52.7 and G2 = 52.8. These findings indicate that smoking significantly increases the risk of impaired fracture healing, which has clinical and occupational consequences for the affected patients. Based on our data, we developed a score to estimate the individual risk of impaired fracture healing. These types of patients must be informed and closely monitored to determine the need for timely re-intervention with additional therapy, such as BMP s or ultrasound.

NCPAP Improves the Quality of Life of Siblings with Mandibuloacral Dysplasia

Mandibuloacral dysplasia (MAD; MIM 248370, 608612) is a rare progeroid syndrome with autosomal reces- sive inheritance. It is characterized by mandibular hypoplasia, acroosteolysis, delayed closure of the cranial sutures, skin atrophy with mottled hyperpigmentation, stiff joints, and growth retardation. We here report Japanese female siblings with a severe MAD phenotype. Because of extreme micrognathia and small mouth and nostril, obstructive sleep apnea syn- drome (OSAS) was observed in both sisters and was especially life-threatening in the younger sister. Nasal continuous positive airway pressure (nCPAP), which seemed to be only one therapeutic choice for these sisters since impaired bone healing made oral surgical approach including maxillomandibular advancement surgery inapplicable to these sisters, suc- cessfully alleviated OSAS in both sisters. Since the initiation of nCPAP, the younger sister has gained weight constantly and her developmental milestones have been steadily achieved. We conclude that possible life threatening sleep- disordered breathing in the patients with progeroid syndromes should be properly managed.

Delayed Fracture Healing in Growth Differentiation Factor 5-deficient Mice: A Pilot Study

Growth differentiation factor-5 (GDF-5) is a key regulator of skeletogenesis and bone repair and induces bone formation in spinal fusions and nonunion applications by enhancing chondrocytic and osteocytic differentiation and stimulating angiogenesis. Elucidating the contribution of GDF-5 to fracture repair may support its clinical application in complex fractures. We therefore asked whether the absence of GDF-5 during fracture repair impaired bone healing as assessed radiographically, histologically, and mechanically. In this pilot study, we performed tibial osteotomies on 10-week-old male mice, stabilized by intramedullary and extramedullary nailing. Healing was assessed radiographically and histologically on Days 1 (n = 1 wild-type; n = 5 bp [brachopodism]), 5 (n = 3 wild-type; n = 3 bp), 10 (n = 6 wild-type; n = 3 bp), 14 (n = 6 wild-type; n = 6 bp), 21 (n = 6 wild-type; n = 6 bp), 28 (n = 7 wild-type; n = 6 bp), and 56 (n = 6 wild-type; n = 6 bp) after fracture. After 10 (n = 7 wild-type; n = 7 bp contralateral and n = 3 bp fractured tibiae), 14 (n = 6 wild-type; n = 6 bp), 21 (n = 6 wild-type; n = 6 bp), 28 (n = 6 wild-type; n = 3 bp), and 56 (n = 8 wild-type; n = 6 bp) days, the callus cross-sectional area was calculated. We characterized the mechanical integrity of the healing fracture by yield stress and Young's modulus at 28 (n = 6 wild-type; n = 3 bp) and 56 (n = 8 wild-type; n = 6 bp) days postfracture. The absence of GDF-5 impaired cartilaginous matrix deposition in the callus and reduced callus cross-sectional area. After 56 days, the repaired bp fracture was mechanically comparable to that of controls. Although GDF-5 deficiency did not compromise long-term fracture healing, a delay in cartilage formation and remodeling supports roles for GDF-5 in the early phase of bone repair. Local delivery of GDF-5 to clinically difficult fractures may simulate cartilage formation in the callus and support subsequent remodeling.

Influence of Gender and Fixation Stability on Bone Defect Healing in Middle-aged Rats: A Pilot Study

Gender and stability of fixation independently influence bone regeneration but their combined effects are unclear. In a pilot study we determined the combined influence of gender and fixation stability on the callus of middle-aged rats regarding (1) biomechanical properties; (2) bridging over time; (3) callus formation; and (4) callus size, geometry, mineralization, and microstructure. We osteotomized the left femur of 32 Sprague-Dawley rats (12 months old). Femurs were externally fixed with a gap of 1.5 mm in four groups of eight animals each: female semirigid, male semirigid, female rigid, and male rigid. Qualitative and quantitative in vivo radiographic analyses were performed twice weekly. Six weeks postoperatively, harvested femora were evaluated using micro-CT and biomechanical testing. Torsional stiffness and maximum torque at failure were higher in male and in semirigidly fixed fractures. Radiographic analysis revealed earlier bridging and callus formation in both male groups. Micro-CT analysis showed a larger callus size, altered geometry, and microstructure in males and semirigidly fixed animals, whereas mineralization was similar in all animals. Our data suggest female gender represents an independent risk factor for bone healing in middle-aged rats. Although healing in females was delayed compared with males, they exhibited a similar response (superior callus properties) to a more semirigid fixation. While female gender appears to reflect a risk for impaired bone healing in middle-aged female rats, clinical studies would be required to confirm the finding in humans.

Winkelstabile Implantate zur Osteosynthese nach Korrekturosteotomien in der Kinder- und Neuroorthopädie

Modern locking plates are widely used for the treatment of adult orthopaedic and trauma patients. Sporadic descriptions of their advantages now exist for paediatric trauma patients. Publications concerning their implantation in paediatric orthopaedic and neuroorthopaedic patients are still scarce even though it is well known that the compliance of children and adolescents is limited and that rapid mobilisation is essential for patients with disorders of neurological origin or bone metabolism to avoid developmental setbacks and perioperative fractures. The principle of the locking plate system also described as internal fixateur is based on the thread bolting of the screwheads within the plate. This results in high initial stability and thus high initial loading capacity. Furthermore, it is possible to preserve soft tissue and periosteum which leads to less impaired biological bone healing. Between February 2008 and March 2010 locking plates were used for osteosynthesis in our department in 16 paediatric patients with 20 corrective osteotomies. All patients suffered from either neurological disorders or diseases with alteration of the bone metabolism. The outcome was analysed concerning safety, complications, practicability, mobilisation, consolidation of the osteotomy, loss of correction, as well as complications with the removal of the implants. Seven of the treated patients suffered from neurological disorders such as cerebral palsy or spina bifida, 9 patients had diseases with local or systemic alteration of their bone metabolism such as vitamin D deficiency and phosphate diabetes. The average age of the patients at the time of surgery was 11.18 (5-18) years. Implant-associated complications were not seen in this patient group, especially no implant failures. Mobilisation was achieved without cast treatment with at least partial weight-bearing within the first postoperative week in most cases. Loss of correction or problems with implant removal did not occur. 18 of the 20 osteotomy sites were completely healed at the 12 week follow-up. Locking plates are a safe and effective treatment device not only for adult trauma patients but also for the treatment of children and adolescents. When stabilisation of corrective osteotomies is performed with locking plates especially young patients benefit from this technique since mobilisation can be started earlier as compared to the use of non-angle stable plates or wires and cast immobilisation becomes unneccessary. The surgeon needs to know the range of products to pick the best implant regarding the growing skeleton's special anatomy. When choosing implants for patients with reduced bone density or impaired motor abilities as in cerebral palsy, spina bifida, and other systemic disorders, locking plates have to be taken into account to facilitate mobilisation and to avoid setbacks in motor development as well as pressure ulcers from casts. Clinical studies have to evaluate if early mobilisation combined with shorter inpatient treatment and less time and cost consuming postoperative physiotherapy or rehabilitation justify the use of the more expensive locking plates for the treatment of otherwise healthy patients.

Impaired bone healing in rabbits with steroid-induced osteonecrosis

Corticosteroids are prescribed for the treatment of many medical conditions and their adverse effects on bone, including steroid-associated osteoporosis and osteonecrosis, are well documented. Core decompression is performed to treat osteonecrosis, but the results are variable. As steroids may affect bone turnover, this study was designed to investigate bone healing within a bone tunnel after core decompression in an experimental model of steroid-associated osteonecrosis. A total of five 28-week-old New Zealand rabbits were used to establish a model of steroid-induced osteonecrosis and another five rabbits served as controls. Two weeks after the induction of osteonecrosis, core decompression was performed by creating a bone tunnel 3 mm in diameter in both distal femora of each rabbit in both the experimental osteonecrosis and control groups. An in vivo micro-CT scanner was used to monitor healing within the bone tunnel at four, eight and 12 weeks postoperatively. At week 12, the animals were killed for histological and biomechanical analysis. In the osteonecrosis group all measurements of bone healing and maturation were lower compared with the control group. Impaired osteogenesis and remodelling within the bone tunnel was demonstrated in the steroid-induced osteonecrosis, accompanied by inferior mechanical properties of the bone. We have confirmed impaired bone healing in a model of bone defects in rabbits with pulsed administration of corticosteroids. This finding may be important in the development of strategies for treatment to improve the prognosis of fracture healing or the repair of bone defects in patients receiving steroid treatment.

Impaired bone healing pattern in mice with ovariectomy-induced osteoporosis: A drill-hole defect model

To establish a drill-hole defect model in osteoporotic mouse femur by comparing temporal cortical bone healing pattern between OVX-induced osteoporotic bone and sham-operated bone. 3-month-old female C57BL/6 mice were randomly divided into an ovariectomy group (OVX) and a sham-operated group (Sham). At 6 weeks post-surgery, 7 mice from each group were sacrificed to examine the distal femur and femoral shaft by both micro-CT and mechanical testing for confirming established osteoporosis induced by OVX. In the remaining mice, a cortical bone defect 0.8mm in diameter was created on the mid-diaphysis of the right femur. The local repair process at days 0, 3, 7, 10, 14 and 21 after creation of the drill-hole was in vivo monitored by high-resolution micro-CT scanning. At each time point, each animal was scanned four times and was removed from the scanner between scans to determine reproducibility. Mice were sacrificed at each time point (n=12 at days 0, 3, 7, 10 and 14; n=20 at day 21). Before sacrifice, sera were collected to examine expression of bone formation marker P1NP (procollagen type I N-terminal propeptide) and bone resorption marker CTX (C-terminal telopeptide of type I collagen). After sacrifice, callus samples were collected and subjected to the following analyses: micro-CT-based angiography; histological examination; immunohistochemical staining to determine estrogen receptor expression; quantitative real-time PCR analysis of collagen type I, collagen type II, collagen type X, osteocalcin, tartrate-resistant acid phosphatase, estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta) gene expression; and three-point mechanical testing. At 6 weeks post-surgery, OVX mice had significantly lower bone mass, impaired bone micro architecture and compromised mechanical properties compared to the Sham mice. In vivo micro-CT analysis revealed that the bone volume fraction in the defect region was significantly lower in the OVX group from day 10 to day 21 post-injury as compared to the Sham group, and was significantly lower in the intra-medulla region in the OVX group from day 7 to day 14 as compared to the Sham group, consistent with the histological data. Analysis of bone biochemical markers indicated that circulating P1NP levels normalized by baseline in the OVX mice were significantly lower than in the Sham mice from day 7 to day 10, and that temporal expression of circulating CTX levels normalized by baseline was also lower in the OVX mice as compared to the Sham mice. These results were consistent with quantitative real-time PCR analysis. ER alpha mRNA expression was significantly lower in the OVX mice, whereas ER beta mRNA expression was significantly higher in the OVX mice as compared to the Sham mice at all time points examined, consistent with immunohistochemical staining. The restoration of femoral mechanical property, determined based on ultimate load and energy-to-failure, was significantly lower in the OVX mice than in the Sham mice. In addition, in vivo micro-CT scanning for quantifying new bone formation in the defect site was highly reproducible in this model. The bone healing of the drill-hole defect was impaired in mice with OVX-induced osteoporosis. The present study provides a model to investigate the functional role of specific gene in osteoporotic bone healing and may facilitate development of novel therapeutic strategies for promoting osteoporotic bone healing.

Smoking and impaired bone healing: will activation of cholinergic anti-inflammatory pathway be the bridge?

This review was written to analyse the potential role of the cholinergic anti-inflammatory pathway in smoking-induced impairment of the bone healing process. Literature in PubMed was reviewed by entering the following keywords "smoking AND bone healing", "cholinergic anti-inflammatory pathway AND tumour necrosis factor", "tumour necrosis factor AND bone healing". All the related papers were recruited and carefully selected according to the content of this paper. Literature review indicated that tumour necrosis factor alpha (TNF-α) plays a pivotal role in the fracture healing process. In brief, TNF-α may accelerate the endochondral ossification process by increasing matrix metalloproteinases (MMPs) level, chondrocyte apoptosis, as well as osteoclast formation, therefore reducing the cartilaginous stage leading to the acceleration of fracture healing. Nicotine is the main effective ingredient of tobacco, which has been found to inhibit the secretion of TNF-α through activation of the cholinergic anti-inflammatory pathway. It is reasonable to believe that the nicotine in tobacco at least partly contributes to the delayed fracture healing by inhibiting TNF-α secretion through the activation of the cholinergic anti-inflammatory pathway. An in-depth study of this issue will contribute to the clinical treatment of nonunion, as well as the development of new therapies to accelerate bone healing.

Genetic predisposition to fracture non-union: a case control study of a preliminary single nucleotide polymorphisms analysis of the BMP pathway

BackgroundDespite the known multi-factorial nature of atrophic fracture non-unions, a possible genetic predisposition for the development of this complication after long bone fractures remains unknown. This pilot study aimed to address this issue by performing a preliminary SNP analysis of specific genes known to regulate fracture healing.MethodsA total of fifteen SNPs within four genes of the Bone Morphogenetic Protein (BMP) pathway (BMP-2, BMP-7, NOGGIN and SMAD6) were examined, in 109 randomly selected patients with long bone fractures as a result of motor vehicle accident, fall or direct blow. There were sixty-two patients with atrophic non-union and forty-seven patients (54 fractures) with uneventful fracture union. Overall SNPs frequencies were computed with respect to patient's age, gender, smoking habits, fracture-associated parameters and the use of nonsteroidal anti-inflammatory drugs (NSAIDs), and tested for their association to the impaired bone healing process, using binary logistic regression (STATA 11.1; StataCorp, Texas USA).ResultsStatistical analysis revealed age to be an important covariate in the development of atrophic non-union (p = 0.01, OR 1.05 [per year]), and two specific genotypes (G/G genotype of the rs1372857 SNP, located on NOGGIN and T/T genotype of the rs2053423 SNP, located on SMAD6) to be associated with a greater risk of fracture non-union (p = 0.02, OR 4.56 and p = 0.04, OR 10.27, respectively, after adjustment for age).ConclusionsThis is the first clinical study to investigate the potential existence of genetic susceptibility to fracture non-union. Even though no concrete conclusions can be obtained from this pilot study, our results indicate the existence of a potential genetically predetermined impairment within the BMP signalling cascade, initiated after a fracture and when combined with other risk factors could synergistically increase the susceptibility of a patient to develop non-union. Further research is desirable in order to clarify the genetic component and its role and interaction with other risk factors in the development of atrophic long bone non-union, as simple genetic testing may contribute to the early identification of patients at risk in the future and the on-time intervention at the biologic aspects of bone healing.

Effects of Near Cortical Slotted Holes in Locking Plate Constructs

The development of locked plating has led to substantial improvements in fracture fixation. This is particularly evident in periarticular fractures, in which conventional nonlocking plates are unable to support the articular surface from a single side. Initially, locked plating appeared to be the ideal solution for these situations and reduced the necessity for double plating and secondary bone grafting. However, with increasing use of locked plating, it became evident that the plate-bone interaction is rigid and may lead to impaired bone healing. The near cortical locking holes increased the construct stiffness and appeared to interfere with local healing. Slotted near cortical locking holes might improve this drawback. This review summarizes the current knowledge of the healing process associated with different types of near cortical locking options.

Effect of low intensity pulsed ultrasound (LIPUS) on bone healing around a titanium implant in the tibia of osteoporosis-induced rats

Introduction: Osteoporosis is a major health problem in the elderly that involves changes in the properties of bone as well as impaired bone healing around a titanium implant in both humans and animals. This study examined effect of low intensity pulsed ultrasound (LIPUS) on the bone healing process around a titanium implant in osteoporosis-induced rats. Materials and Methods: Sixteen rats were divided into two groups. A control group with osteoporosis induced by removing both ovaries and an experimental group of rats that were applied with LIPUS after osteoporosis had been induced. A screw type titanium implant (diameter, 2.0 mm: length, 3.5 mm, Cowell-Medi, KOREA) was placed into the tibias of 16 rats. The control and experimental group contained 8 rats each. The rats were sacrificed at 1, 2, 4, and 8 weeks after implantation to examine the histopathology and immunochemistry. Results: The histopathology examination revealed earlier new bone formation in the experimental group than the control group. In particular, at 1 week after implantation, more new bone matrix and collagen were observed around the implant of the experimental group compared to the control group. Immunochemistry analysis showed that the level of OPG expression of the experimental group was higher in the early stages than in the control group. After 8 weeks, the levels of OPG expression were similar in both groups. The expression level of receptor activator of nuclear factor kB ligand (RANKL) was stronger in the experimental group than the control group. After 4 weeks, the level of RANKL expression was similar in both groups. Conclusion: These results suggest that the application of LIPUS to implantation can promote bone healing around titanium in osteoporosis animals.

Experimental blunt chest trauma impairs fracture healing in rats

In poly-traumatic patients a blunt chest trauma is an important trigger of the posttraumatic systemic inflammatory response. There is clinical evidence that fracture healing is delayed in such patients, however, experimental data are lacking. Therefore, we investigated the influence of a thoracic trauma on fracture healing in a rat model. Male Wistar rats received either a blunt chest trauma combined with a femur osteotomy or an isolated osteotomy. A more rigid or a more flexible external fixator was used for fracture stabilization to analyze whether the thoracic trauma influences regular healing and mechanically induced delayed bone healing differently. The blunt chest trauma induced a significant increase of IL-6 serum levels after 6 and 24 h, suggesting the induction of a systemic inflammation, whereas the isolated fracture had no effect. Under a more rigid fixation the thoracic trauma considerably impaired fracture healing after 35 days, reflected by a significantly reduced flexural rigidity (three-point-bending test), as well as a significantly diminished callus volume, moment of inertia, and relative bone surface (µCT analysis). In confirming the clinical evidence, this study reports for the first time that a blunt chest trauma considerably impaired bone healing, possibly via the interaction of the induced systemic inflammation with local inflammatory processes.

Pain Management After Elective Hallux Valgus Surgery

Pain is a common complaint after day surgery, and there is still a controversy surrounding the use of selective cyclooxygenase-2 (COX-2) inhibitors. In the present prospective, randomized, double-blind study we compared pain management with a selective (COX-2) inhibitor (etoricoxib) with pain management using sustained-release tramadol after elective hallux valgus surgery. One hundred ASA 1 to 2 female patients were randomized into 2 groups of 50 patients each; oral etoricoxib 120 mg x 1 x IV + 90 mg x 1 x day V-VII and oral tramadol sustained-release 100 mg x 2 x VII. Pain, pain relief, satisfaction with pain management, and need for rescue medication were evaluated during the first 7 postoperative days. A computed tomography scan evaluating bone healing was performed 12 weeks after surgery. A clinical evaluation of outcome (healing, mobility, and patient-assessed satisfaction) was performed 16 weeks after surgery. Two patients withdrew before discharge from the hospital. Ninety-eight patients, 81 ASA 1 and 17 ASA 2 (82 nonsmokers and 14 smokers), mean age 49 years (19-65), weight 64 (47-83) kg, and height 167 (154-183) cm were evaluated. Overall pain was well managed, but the mean visual analog scale (VAS) was significantly lower among etoricoxib patients evaluated during the entire 7-day period studied (12.5 + or - 8.3 vs. 17.3 + or - 11, P < 0.05). patient's grading of pain relief (92 + or - 12 vs. 85 + or - 15, P < 0.05) and satisfaction with pain medication (47/49 vs. 39/49, P < 0.05) was higher among etoricoxib patients. Patients receiving tramadol reported significantly more side effects. Six patients, all in the tramadol group, discontinued the study because of side effects (P < 0.05). At 14-day follow-up 1 patient in the etoricoxib group and 5 patients in the tramadol group exhibited minor irritation in the wound area. The 12-week computed tomography scan showed good healing in 82 patients, 43 in the etoricoxib group, and 39 in the tramadol group. The study found ongoing healing in 11 patients, 4 in the etoricoxib group and 7 in the tramadol group. The 16-week patient-assessed Health Profile Quality of life revealed high patient satisfaction overall; 47 patients in each study group rated the outcome as satisfactory and the mean change in the patient-assessed quality of life VAS score was 6.2 and 2.6 for the etoricoxib and tramadol groups, respectively. Clinical follow-up at 16 weeks showed high functionality and no signs or symptoms of improper healing in any patient. Etoricoxib was found to be more effective and associated with fewer side effects in comparison with tramadol sustained release as a component of multimodel analgesia after elective hallux valgus surgery. There were no signs of impaired wound or bone healing associated with the use of etoricoxib.

Uncoupled angiogenesis and osteogenesis in nicotine-compromised bone healing

Nicotine is the main chemical component responsible for tobacco addiction. This study aimed to evaluate the influence of nicotine on angiogenesis and osteogenesis and the associated expression of angiogenic and osteogenic mediators during bone healing. Forty-eight adult New Zealand White rabbits were randomly assigned to a nicotine group and a control group. Nicotine pellets (1.5 g, 60-day time release) or placebo pellets were implanted in the neck subcutaneous tissue. The nicotine or placebo exposure time for all the animals was 7 weeks. Unilateral mandibular distraction osteogenesis was performed. Eight animals in each group were euthanized on day 5, day 11 of active distraction, and week 1 of consolidation, respectively. The mandibular samples were subjected to radiographic, histologic, immunohistochemical, and real-time reverse-transcriptase polymerase chain reaction examinations. Nicotine exposure upregulated the expression of hypoxia inducible factor 1alpha and vascular endothelial growth factor and enhanced angiogenesis but inhibited the expression of bone morphogenetic protein 2 and impaired bone healing. The results indicate that nicotine decouples angiogenesis and osteogenesis in this rabbit model of distraction osteogenesis, and the enhanced angiogenesis cannot compensate for the adverse effects of nicotine on bone healing.

BMP‐7–induced ectopic bone formation and fracture healing is impaired by systemic NSAID application in C57BL/6‐mice

Nonsteroidal antiinflammatory drugs (NSAIDs) are known to potentially impair the fracture healing process. The aim of the present study was to determine if the impairment of bone healing by systemic NSAID application is, at least in part, due to an interaction of NSAIDs with the bone anabolic BMP-7 pathway. Therefore, we first analyzed fracture healing in control and diclofenac-treated mice, where we not only found a significant impairment of fracture healing due to diclofenac treatment as assessed by biomechanical testing and microCT imaging, but also found high coexpression of bone morphogenetic protein-7 (BMP-7) and cyclooxygenase-2 (COX-2) within the fracture callus of both groups. To experimentally address the possible interaction between BMP-7 and COX-2, we then induced ectopic bone formation in control (n = 10) and diclofenac-treated mice (n = 10) by application of BMP-7 (recombinant human OP-1, rhOP-1) into the hamstring muscles. After 20 days of treatment, each ectopic bone nodule was analyzed by contact-radiography, microCT, histology, and histomorphometry. Diclofenac application decreased the trabecular number and bone mass in the ectopic bone nodules significantly due to reduced osteoblast number and activity. These data demonstrate that the bone anabolic effect of BMP-7 and fracture healing is impaired by diclofenac application, and suggest that the potential negative impact of NSAIDs on fracture healing is, at least in part, due to interference with BMP-7 signaling.