Proper Bone Healing Research Articles

Three-dimensional customized titanium plate versus conventional titanium miniplate for management of mandibular angle fractures

Background Surgical treatment of mandibular angle fractures using an internal fixation has changed in the last decades to achieve the required rigidity, stability, and immediate restoration of function. Purpose The aim of the study was to evaluate both clinically and radiologically the efficacy of three-dimensional customized titanium plate versus conventional titanium miniplate in the management of mandibular angle fractures. Patients and methods Sixteen adult patients with unilateral mandibular angle fracture indicated for reduction and internal fixation were selected from the Outpatient Clinic, Oral and Maxillofacial Surgery Department, Faculty of Dentistry, Tanta University. Patients were divided into two equal groups according to the type of plating system used in fracture fixation, for group I mandibular angle fractures were fixed with 3-D customized titanium plate while for group II mandibular angle fractures were fixed with single conventional titanium miniplate. Postoperative clinical and radiographic evaluations were performed immediately, one week, two weeks, one month, three months and six months. The postoperative clinical evaluation included presence or absence of infection, position and stability of the mandibular lower border, state of occlusion, maximal mouth opening, sensory nerve function, condition of teeth related to the fracture line and patient's tolerance to the plate. The postoperative radiographic examinations evaluated the accuracy of reduction and bony union by measuring the inter-fragmentary gap and the intergonial distance. Results Uneventful wound healing was obtained in all cases of both groups except case no 4 of group II in which dehiscence and mild infection was happened. Satisfactory occlusion was obtained in all cases of both groups except case no 7 of group II where it had mild occlusal derangement. Other parameters including clinical stability, maximal mouth opening, sensory nerve function, and plate tolerance were comparable in both groups. There were no significant differences between group I and group II regarding inter-fragmentary gap and intergonial distance regarding postoperative radiographs. Conclusion The use of three-dimensional customized titanium plate and conventional titanium miniplate fixation systems provided enough stability for proper bone healing, establishment of optimal occlusion, and early return to normal function.

106. Usage trends and safety profile of recombinant human bone morphogenetic protein-2 for spinal column tumor surgery: a national matched analysis

<h3>BACKGROUND CONTEXT</h3> Achieving arthrodesis after spinal tumor surgery remains a significant challenge. Patients in this vulnerable cohort commonly experience poor bone quality, malnutrition and concurrent use of chemotherapy or radiotherapy—all of which interfere with proper bone formation and healing. To augment fusion efforts, recombinant human bone morphogenetic protein-2 (rhBMP-2) emerged as a powerful osteogenic factor after its FDA approval in 2002 but its use has remained a persistent concern. Although most recent evidence does not seem to suggest significantly increased rates of complications or carcinogenicity due to rhBMP-2 use, these findings remain poorly defined in the spinal oncology subcohort. <h3>PURPOSE</h3> To investigate national rates of rhBMP-2 utilization in spinal tumor surgery and examine its association with postoperative complications, revisions, and carcinogenicity. <h3>STUDY DESIGN/SETTING</h3> Retrospective national database analysis. <h3>PATIENT SAMPLE</h3> All patients diagnosed with primary or metastatic spinal tumors who underwent subsequent surgical intervention involving a spinal fusion recorded in Medicare, Medicaid, and commercial administrate claims databases in PearlDiver from 2005-2020. <h3>OUTCOME MEASURES</h3> Utilization rates; postoperative rates of complications, revisions, and failures; survivorship. <h3>METHODS</h3> Patients were organized into two cohorts according to rhBMP-2 usage and 1:1 matched based on age, gender, and Charlson Comorbidity Index. rhBMP-2 utilization trends were compared via a Pearson correlation across calendar years. Postoperative complications and revisions were examined at 1 month, 3 months, 6 months, and 1 year after spinal fusion. New cancer incidence following spinal tumor surgery was assessed until 5 years postoperatively. Post hoc comparisons were characterized using chi-squared analysis, and threshold for significance was established at P < 0.05. <h3>RESULTS</h3> A total of 11,198 patients underwent fusion surgery after resection of spinal tumors between 2005 and 2020, with 909 cases reporting the use of rhBMP-2 (8.1%). An annualized analysis revealed that the proportion of spine tumor fusion procedures utilizing rhBMP-2 has been significantly decreasing (R2 = 0.859, P < 0.001), with the most recent annual utilization rate at 1.1%. The final matched cohorts each comprised 894 patients. At least 6 months after surgery, significantly increased incidences of surgical site (7.3% vs 1.6%, P = 0.05) and systemic infections (13.8% vs 4.1%, P = 0.01) were observed in patients who underwent fusion with rhBMP-2. Across all time points, no significant differences were observed between the groups in survival, implant removal, or revision rates. In addition, incidence of new cancer diagnoses after fusion surgery was comparable between the two groups. <h3>CONCLUSIONS</h3> rhBMP-2 has been widely used off-label to promote arthrodesis; however. its role in spinal fusion procedures involving spinal tumors remains controversial. This analysis demonstrated significantly declining national utilization rates, and while rhBMP-2 usage was not associated with new cancer incidence postoperatively, its impact on local and metastatic progression remains unknown and requires further investigation. Compared with nonusers, spinal tumor cases utilizing rhBMP-2 sustained greater rates of surgical site and systemic infections. Furthermore, rhBMP-2 usage did not significantly reduce the risk of mortality, implant failure, or reoperation–suggesting it may not be essential to fulfilling the needs of this specific patient population. <h3>FDA DEVICE/DRUG STATUS</h3> BMP-2: not approved for this indication.

Bioengineered Living Bone Grafts-A Concise Review on Bioreactors and Production Techniques In Vitro.

It has been observed that bone fractures carry a risk of high mortality and morbidity. The deployment of a proper bone healing method is essential to achieve the desired success. Over the years, bone tissue engineering (BTE) has appeared to be a very promising approach aimed at restoring bone defects. The main role of the BTE is to apply new, efficient, and functional bone regeneration therapy via a combination of bone scaffolds with cells and/or healing promotive factors (e.g., growth factors and bioactive agents). The modern approach involves also the production of living bone grafts in vitro by long-term culture of cell-seeded biomaterials, often with the use of bioreactors. This review presents the most recent findings concerning biomaterials, cells, and techniques used for the production of living bone grafts under in vitro conditions. Particular attention has been given to features of known bioreactor systems currently used in BTE: perfusion bioreactors, rotating bioreactors, and spinner flask bioreactors. Although bioreactor systems are still characterized by some limitations, they are excellent platforms to form bioengineered living bone grafts in vitro for bone fracture regeneration. Moreover, the review article also describes the types of biomaterials and sources of cells that can be used in BTE as well as the role of three-dimensional bioprinting and pulsed electromagnetic fields in both bone healing and BTE.

Bone regeneration capacity of newly developed spherical magnesium phosphate cement granules

ObjectivesMagnesium phosphate–based cements begin to catch more attention as bone substitute materials and especially as alternatives for the more commonly used calcium phosphates. In bone substitutes for augmentation purposes, atraumatic materials with good biocompatibility and resorbability are favorable. In the current study, we describe the in vivo testing of novel bone augmentation materials in form of spherical granules based on a calcium-doped magnesium phosphate (CaMgP) cement.Materials and methodsGranules with diameters between 500 and 710 μm were fabricated via the emulsification of CaMgP cement pastes in a lipophilic liquid. As basic material, two different CaMgP formulations were used. The obtained granules were implanted into drill hole defects at the distal femoral condyle of 27 New Zealand white rabbits for 6 and 12 weeks. After explantation, the femora were examined via X-ray diffraction analysis, histological staining, radiological examination, and EDX measurement.ResultsBoth granule types display excellent biocompatibility without any signs of inflammation and allow for proper bone healing without the interposition of connective tissue. CaMgP granules show a fast and continuous degradation and enable fully adequate bone regeneration.ConclusionsDue to their biocompatibility, their degradation behavior, and their completely spherical morphology, these CaMgP granules present a promising bone substitute material for bone augmentation procedures, especially in sensitive areas.Clinical relevanceThe mostly insufficient local bone supply after tooth extractions complicates prosthetic dental restoration or makes it even impossible. Therefore, bone augmentation procedures are oftentimes inevitable. Spherical CaMgP granules may represent a valuable bone replacement material in many situations.

Assessing the biomechanical properties of nitinol staples in normal, osteopenic and osteoporotic bone models: A finite element analysis

ObjectiveBone staples are internal fixation devices that are frequently used in the foot, ankle, and hand to provide stabilization. Fixation stability is vital after fusion or fracture surgeries to ensure proper bone healing. Patients undergoing surgeries that require fixation to keep bones aligned and stable may present with diminishing bone mechanical properties, and this may compromise the ability of the fixation hardware to maintain a stable construct. The purpose of this study was to investigate the mechanical performance of shape memory and superelastic nitinol bone staples with different bridge geometries in normal, osteopenic, and osteoporotic bone models. Contact forces and maximum principal stress and strain in the bone were recorded. MethodsFinite element simulations of a bone staple fixation procedure were performed to examine the initial and post-surgery contact force, as well as the maximum principal stress and strain of 15 mm bridge and 20 mm bridge staple-bone constructs. ResultsShape memory nitinol staples exhibited higher contact forces compared to superelastic nitinol staples. Nitinol bone staples with 20 mm bridge lengths displayed higher contact forces and lower stresses in all bone types, as well as lower strains in osteoporotic bone models compared to nitinol staples with a 15 mm bridge length. ConclusionNitinol bone staple constructs with 20 mm bridge length staples provide higher contact forces and display lower stresses in the bone than 15 mm bridge staple-bone constructs, which may be beneficial in bone with diminishing mechanical properties. Both superelastic and shape memory effect nitinol staples provide adequate compression and stress relief. However, if osteopenia is present, shape memory effect nitinol staples with a 20 mm bridge length may provide more stress relief and compression, if the bone anatomy allows.

Case Report: Hand Replantation

BACKGROUND: The upper limb plays a vital role in our daily function; injuries to this vital structure can result in devastating consequences to functional, psychological and social well-being; especially traumatic amputations of the upper limb are challenging to manage and deciding which patients would benefit from limb salvage versus amputation is critical. CASE REPORTS: A 52-year-old male patient, who suffered a traumatic partial amputation in the distal third of his right forearm with an industrial machine, presenting an ulnar and radius fracture, with severe soft tissue injuries, who underwent a replantation surgery after 12 hours of ischemia. EVOLUTION: Patient presented good postsurgical outcome. 24 hours after surgery he presented normal Allen’s test results, adequate temperature, pink coloration, hypoesthesia and 2/5 muscle strength in the injured limb. He was discharged 7 days after surgery with follow-up and rehabilitation prescription. The percutaneous needles were removed 13 weeks after, with proper bone healing of the fracture. 5 months after surgery, he presented a DASH Score of 60.83. CONCLUSION: The replantation field has become very sophisticated in recent years; the decision to perform replantation of the amputated limb must be individualized to each patient, based on several established factors such as the characteristics of the injury, patient related factors, and the functional recovery capacity.

Inhibition of PAD4 mediated neutrophil extracellular traps prevents fibrotic osseointegration failure in a tibial implant murine model : an animal study.

Aseptic loosening is a leading cause of uncemented arthroplasty failure, often accompanied by fibrotic tissue at the bone-implant interface. A biological target, neutrophil extracellular traps (NETs), was investigated as a crucial connection between the innate immune system's response to injury, fibrotic tissue development, and proper bone healing. Prevalence of NETs in peri-implant fibrotic tissue from aseptic loosening patients was assessed. A murine model of osseointegration failure was used to test the hypothesis that inhibition (through Pad4-/- mice that display defects in peptidyl arginine deiminase 4 (PAD4), an essential protein required for NETs) or resolution (via DNase 1 treatment, an enzyme that degrades the cytotoxic DNA matrix) of NETs can prevent osseointegration failure and formation of peri-implant fibrotic tissue. Patient peri-implant fibrotic tissue was analyzed for NETs biomarkers. To enhance osseointegration in loose implant conditions, an innate immune system pathway (NETs) was either inhibited (Pad4-/- mice) or resolved with a pharmacological agent (DNase 1) in a murine model of osseointegration failure. NETs biomarkers were identified in peri-implant fibrotic tissue collected from aseptic loosening patients and at the bone-implant interface in a murine model of osseointegration failure. Inhibition (Pad4-/- ) or resolution (DNase 1) of NETs improved osseointegration and reduced fibrotic tissue despite loose implant conditions in mice. This study identifies a biological target (NETs) for potential noninvasive treatments of aseptic loosening by discovering a novel connection between the innate immune system and post-injury bone remodelling caused by implant loosening. By inhibiting or resolving NETs in an osseointegration failure murine model, fibrotic tissue encapsulation around an implant is reduced and osseointegration is enhanced, despite loose implant conditions. Cite this article: Bone Joint J2021;103-B(7 Supple B):135-144.

Management of large inflammatory dentigerous cysts adapted to the general condition of the patient: Two case reports.

Dentigerous cysts may be of developmental or inflammatory origin. The latter occur in unerupted permanent teeth as a result of inflammation from a preceding non-vital primary tooth or from another source spreading to involve the tooth follicle. This report presents two clinical cases of children with dentigerous cysts of inflammatory origin. Case 1 is a healthy boy (7 years 11 months) referred for a large cystic cavity in the right mandibular premolar region. Extraction of 84 and 85 and marsupialization of the cyst were performed under nitrous sedation. A removable appliance with an acrylic piece fitted into the socket was applied on the same occasion. The in-socket piece was progressively reduced as the cystic cavity was shrinking. After a 20-month follow-up, 44 and 45 are sound and correctly erupted and 46 remains unaffected. Case 2 is an autistic girl (10 years 9 months) with bilateral large odontogenic cysts enclosing the crowns of 35 and 45. Extractions of 75, 85 were performed under general anesthesia, leaving large bone defects. Given the limited compliance of the patient under common dental office circumstances, no appliance was used. Thirteen months after extraction, 35 and 45 are sound, fully erupted and no visible mesial drifting of 36 and 46 occurred. In conclusion, conservative treatment of large inflammatory dentigerous cysts in children gives good results with minimal intervention, ensures physiologic development of teeth and proper bone healing. The general condition of the patient can influence treatment choice. Patients must be followed up until eruption of the displaced permanent teeth and bony consolidation of the cyst.

Animal models for studying metaphyseal bone fracture healing.

An estimated 2 million osteoporotic fractures occur annually in the US, resulting in a dramatic reduction in quality of life for affected patients and a high economic burden for society. Osteoporotic fractures are frequently located in metaphyseal bone regions. They are often associated with healing complications, because of the reduced healing capacity of the diseased bone tissue, the poor primary stability of the fracture fixation in the fragile bone, and the high frequency of comorbidities in these patients. Therefore, osteoporotic fractures require optimised treatment strategies to ensure proper bone healing. Preclinical animal models can help understanding of the underlying mechanisms and development of new therapies. However, whereas diaphyseal fracture models are widely available, appropriate animal models for metaphyseal fracture healing are scarce, although essential for translational research. This review covers large and small animal models for metaphyseal fracture healing. General requirements for suitable animal models are presented, as well as advantages and disadvantages of the current models. Furthermore, differences and similarities between metaphyseal and diaphyseal bone fracture healing are discussed. Both large- and small-animal models are available for studying metaphyseal fracture healing, which mainly differ in fracture location and geometry as well as stabilisation techniques. Most common used fracture sites are distal femur and proximal tibia. Each model found in the literature has certain advantages and disadvantages; however, many lack standardisation resulting in a high variability or poor mimicking of the clinical situation. Therefore, further refinement ofanimal models is needed especially to study osteoporotic metaphyseal fracture healing.

Managing Lymphedema in Fracture Care: Current Concepts and Treatment Principles.

Lymphatic flow plays a notable role in the regulation of bone formation and remodeling. Chronic accumulation of the lymph fluid within tissues may lead to issues with proper bone healing after fractures, emphasizing the importance of proper management of lymphedema after trauma. Many associated risk factors place patients at risk for lymphedema, including previous surgery with nodal dissection, radiation therapy, infection, malignancy, family history of congenital lymphedema, and trauma. The benchmark imaging technique for the diagnosis of lymphedema is lymphoscintigraphy. Other modalities include duplex ultrasonography, CT, and MRI. First-line conservative treatment of lymphedema is compression. Complete decongestive therapy or complex physical therapy, also known as decongestive lymphatic therapy (DLT), has shown positive results in reducing lymphedema. Surgical interventions aim to either reconstruct and restore function of the lymphatic system or debulk and reduce tissues and fluids. Understanding the significance of lymphedema on bone healing and techniques available to recognize it are important factors in preventing delay in diagnosis and ensuring proper management of lymphedema after trauma.

Evaluation of the Effects of Low-Level Laser Therapy on Diabetic Bone Healing.

The aim of the present study was to evaluate the effects of low-level laser therapy (LLLT) and biphasic alloplastic bone graft material on diabetic bone healing. Induction of diabetes was performed in 14 male Sprague-Dawley rats by intraperitoneal injection of a 50 mg/kg dose of streptozotocin. Two bilaterally symmetrical non-critical-sized bone defects were created in the parietal bones in each rat. Right defects were filled with biphasic alloplastic bone graft. Rats were randomly divided into 2 groups, with 1 group receiving 10 sessions of LLLT (GaAlAs, 78.5 J/cm, 100mW, 0.028 cm beam). The LLLT was started immediately after surgery and once every 3 days during postoperative period. At the end of treatment period, new bone formation and osteoblast density were determined using histomorphometry. Empty (control), graft-filled, LLLT-treated and both graft-filled and LLLT-treated bone defects were compared. New bone formation was higher in the graft treatment samples compared with the control (P = 0.009) and laser samples (P = 0.029). In addition, graft-laser combination treatment samples revealed higher bone formation than control (P = 0.008) and laser (P = 0.026) samples. Osteoblast density was significantly higher in the laser treatment (P <0.001), graft treatment (P = 0.001) and graft-laser combination treatment (P <0.001) samples than control samples. In addition, significantly higher osteoblast density was observed in the graft-laser combination treatment samples compared to the graft treatment samples (P = 0.005). The LLLT was effective to stimulate osteoblastogenesis but failed to increase bone formation. Graft augmentation for treatment of bone defects seems essential for proper bone healing in diabetes, regeneration may be supported by the LLLT to enhance osteoblastogenesis.

Thermal Effects in the Ablation of Bovine Cortical Bone with Pulsed Laser Sources.

Lasers have advantages as bone surgical tools over mechanical methods, but two goals should be achieved to assure its use: Similar ablation rates to those obtained with mechanical tools (1 mm3/s at least) and to avoid thermal damage, a condition that can prevent proper bone healing. We present results of cow femoral bone with a 355 nm nanosecond (ns) and a 1064 nm picosecond (ps) pulsed laser sources that allow us to discuss the influence on the process of pulse duration and the selective ablation through high energy absorption (as bone highly absorbs 355 nm radiation). The treated samples were characterized by scanning electron microscopy (SEM) and Raman spectroscopy. The evaluation of the thermal effects produced in the samples shows clear differences between both laser sources: On one hand, the ns laser allows reaching high ablation rates (around 1 mm3/s); Raman spectra show no signal of bone carbonization, but unavoidable thermal effects in the form of melted and solidified material have been observed by electron microscopy in the samples treated with this laser. On the other hand, ablation without any sign of thermal effects is obtained using the ps laser, but with lower ablation rates, (around 0.15 mm3/s).

Efficacy of different fixation techniques in repair of anterior mandibular fractures

Objective: To compare between double straight miniplates, double inverted L- shaped miniplates ,and three dimensional ( 3 D) rectangular miniplate in fixation of anterior mandibular (symphyseal / parasymphyseal area) fractures .Patients and methods: Thirty adult patients with anterior mandibular fractures were included in this study. The patients were divided randomly into three equal groups, group I was treated by superior and inferior straight miniplate while group II was treated by double L- shaped miniplates fixation technique and group III was treated by 3D rectangular miniplate. Postoperative clinical, radiographic evaluation and quantitative measurements were performed.Results: Wound healing was optimal in all cases except two cases in group I and one case in group II. Satisfactory occlusion was obtained in all cases except three cases in group I where it had mild to moderate occlusal derangement. Other parameters including maximal mouth opening, sensory nerve function, and patient's tolerance to the plate were comparable. There were the similarity between the density changes for the three groups as there was highly significant difference in G(I) compared to G(II) at six months, and G(I) compared to G(III) at three and six months also between G (II) compared to G(III) at six months. .Conclusion: Both double L-shaped miniplates and 3D rectangular miniplate provided enough stability for proper bone healing, establishment of optimal occlusion and early return to normal function more than with double straight miniplates. Additionally, there is superiority of 3 D rectangular miniplate over double inverted L- shaped miniplates in these parameters.

Efficacy of open cap splint versus split acrylic splint in management of pediatric mandibular fractures

Objective: This prospective randomized clinical study was designed to evaluate the efficacy of open cap splint versus split acrylic splint in management of pediatric mandibular fractures. Patients and Methods: Twelve pediatric patients with symphysis, parasymphysis, and body of mandibular fractures treated by closed reduction and fixation were randomly selected. They were divided randomly into two equal groups: group (I) patients were treated by open cap splint and group (II) patients were treated by the split acrylic splint. Postoperative clinical ,and radiographic evaluations were performed to assess complications, occlusal stability, pain on a visual analogue scale (VAS), maximum mouth opening, and the overall results of fixation up to 6 months. Results: Fracture healing was optimal in all cases, except two cases in group I presented malunion of the fractured bone. Satisfactory dental occlusion was observed in all cases, except two cases in group I, where they had mild to moderate occlusal derangement. Other parameters including maximal mouth opening, and pain level were comparable. Postoperative radiographic evaluation showed a complete union of the fractured segments at the end of six months in all cases. Conclusion: The results of the current study showed that, the open cap splint and split cap splint provided enough stability for proper bone healing, establishment of optimal occlusion, and early return to normal function with superiority for split cap splint.

Impaired bone healing following treatment of established nonunion correlates with serum cytokine expression.

Delayed union and nonunion are a significant concern in long bone fractures and spinal fusions. Treatment of nonunion often entails multiple revision surgeries that further increase the financial, physical, and emotional burden on patients. The optimal treatment strategy for nonunions remains unclear in many cases, and the risk of complications after revision procedures remains high. This is in part due to our limited understanding of the biological mechanisms that inhibit proper bone healing and lead to nonunion. And yet, few preclinical models directly investigate how healing is impacted after establishment of nonunion, with most instead primarily focusing on treatment immediately after a fresh bone injury. Here, we utilized a critical size femoral defect model in rats where treatment was delayed 8 weeks post-injury, at which time nonunion was established. In this study, acute and delayed treatments with bone morphogenetic protein-2 (BMP-2) were assessed. We found that delayed treatment resulted in decreased bone formation and reduced mechanical strength compared to acute treatment, even when BMP-2 dose was increased by 2.5 times the acute treatment dose. Interestingly, serum cytokine analysis at 12 weeks post-treatment revealed signs of chronic immune dysregulation after delayed treatment. In particular, non-responders (rats that did not exhibit defect bridging) demonstrated higher overall expression of inflammatory cytokines, including TNFα and IL-1β, compared to responders. These findings suggest that re-establishing long-term immune homeostasis may be critical for successful bone healing, particularly after nonunion. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:299-307, 2019.

Bone Flap Technique With Piezosurgery for Impacted Teeth Extraction and Bone Cysts Removal Without Additional Fixation.

To explore a new surgical approach for impacted teeth extraction and cystectomy using piezosurgery that provides proper bone healing in normal anatomical structure without additional fixation and graft materials.In cases with intact and relatively thicker vestibular compact bone, a bone flap design was used with converging osteotomy lines made with piezosurgery tips which allow proper stabilization after enucleation or extraction.Procedure was performed in 10 patients with 9 to 36 months follow-up resulted in satisfactory healing without any complications.Comparing to traditional techniques, effective enucleation and accelerated bone regeneration are achieved, with reduced risk of complications, operation time, and costs.

Effects of systemic erythropoietin treatment and heterogeneous xenograft in combination on bone regeneration of a critical-size defect in an experimental model

The aim of the present study was to evaluate the effects of systemic EPO treatment alone or in combination with xenogenic bone graft augmentation on bone regeneration. Eleven adult male Sprague–Dawley rats were used in the present study. Rats were subjected to bilateral 5 mm critical size bone defects on the parietal bones under general anaesthesia. Right parietal bone defects were augmented with xenogenic bone graft and left parietal bone defect was left empty. Rats were randomly assigned for one of the two groups. One group of rats received (i) vehicle (n = 6) and other group received (ii) EPO (500IU kg/day) (n = 5). EPO treatment was continued for 28 days. Vascularization was analysed by immunohistochemical staining of CD31 (PECAM-1) and new bone formation was histomorphometrically evaluated. Xenogenic graft augmentation enhanced bone formation and vascularization significantly in either vehicle or EPO treated groups (p < 0.05). Histomorphometric results of angiogenesis was similar in the EPO treated group and the control group. However, angiogenesis was significantly higher in the combination of systemic EPO treatment with graft augmentation than graft augmentation alone (p < 0.01). Graft augmentation for treatment of critical size bone defects seems essential for proper bone healing. Results of the present study suggest that EPO potentiates the regenerative processes of augmented bone defects.

The inflammatory phase of fracture healing is influenced by oestrogen status in mice

BackgroundFracture healing is known to be delayed in postmenopausal, osteoporotic females under oestrogen-deficient conditions. Confirming this, experimental studies demonstrated impaired callus formation in ovariectomised animals. Oestrogen-deficiency is known to affect the immune system and the inflammatory response during wound healing. Because a balanced immune response is required for proper bone healing, we were interested to ascertain whether the early immune response after facture is affected by oestrogen depletion.MethodsTo address the above question, female mice received either a bilateral ovariectomy (OVX) or were sham-operated, and femur osteotomy was performed 8 weeks after OVX/sham operation. The effects of OVX on the presence of immune cells and pro-inflammatory cytokines were evaluated by flow cytometry and immunohistochemistry of the fracture calli on days 1 and 3 after fracture.ResultsOne day after fracture, immune cell numbers and populations in the fracture haematoma did not differ between OVX- and sham-mice. However, on day 3 after fracture, OVX-mice displayed significantly greater numbers of neutrophils. Local expression of the oestrogen-responsive and pro-inflammatory cytokine midkine (Mdk) and interleukin-6 (IL-6) expression in the fracture callus were increased in OVX-mice on day 3 after fracture compared with sham-mice, indicating that both factors might be involved in the increased presence of neutrophils. Confirming this, Mdk-antibody treatment decreased the number of neutrophils in the fracture callus and reduced local IL-6 expression in OVX-mice.ConclusionsThese data indicate that oestrogen-deficiency influences the early inflammatory phase after fracture. This may contribute to delayed fracture healing after oestrogen depletion.

Immature myeloid cells are critical for enhancing bone fracture healing through angiogenic cascade

Bone fractures heal with overlapping phases of inflammation, cell proliferation, and bone remodeling. Osteogenesis and angiogenesis work in concert to control many stages of this process, and when one is impaired it leads to failure of bone healing, termed a nonunion. During fracture repair, there is an infiltration of immune cells at the fracture site that not only mediate the inflammatory responses, but we hypothesize they also exert influence on neovasculature. Thus, further understanding the effects of immune cell participation throughout fracture healing will reveal additional knowledge as to why some fractures heal while others form nonunions, and lead to development of novel therapeutics modulating immune cells, to increase fracture healing and prevent nonunions. Using novel femoral segmental and critical-size defect models in mice, we identified a systemic and significant increase in immature myeloid cell (IMC) infiltration during the initial phase of fracture healing until boney union is complete. Using gemcitabine to specifically ablate the IMC population, we confirmed delayed bone healing. Further, adoptive transfer of IMC increased bone growth in a nonunion model, signifying the role of this unique cell population in fracture healing. We also identified IMC post-fracture have the ability to increase endothelial cell migration, and tube formation, signaling the essential communication between the immune system and angiogenesis as a requirement for proper bone healing. Based on this data we propose that IMC may play a significant role in fracture healing and therapeutic targeting of IMC after fracture would minimize the chances of eventual nonunion pathology.

Non-unions treated with bone morphogenic protein 7: introducing the quantitative measurement of human serum cytokine levels as promising tool in evaluation of adjunct non-union therapy.

BackgroundIn this study we sought to determine if application of bone morphogenic protein 7 (BMP-7) promotes physiological bone healing of non-unions and to investigate if serum cytokine analysis may serve as a promising tool in the analysis of adjunct non-union therapy. Therefore we analyzed the influence of BMP-7 application on the serum cytokine expression patterns on patients with impaired bone healing compared to patients that showed proper bone healing.MethodsOur study involved analyzing blood samples from 208 patients with long bone fractures together with patients that subsequently developed non-unions. From this large pool, 15 patients with atrophic non-union were matched to 15 patients with atrophic non-union treated with local application of BMP-7 as well as normal bone healing. Changes in the cytokine expression patterns were monitored during the 1st, 2nd, 4th, 8th, 12th and 52nd week. The patients were followed both clinically and radiologically for the entire duration of the study. Serum cytokine expression levels of transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) were analyzed and compared.ResultsSerum expression of TGF-β were nearly parallel in all three groups, however serum concentrations were significantly higher in patients with proper bone healing and those treated with BMP-7 than in patients with non-unions (p < 0.05). bFGF serum concentrations increased initially in patients with proper bone healing and in those treated with BMP-7. Afterwards, values decreased; bFGF serum concentrations in the BMP-7 group were significantly higher than in the other groups (p < 0.05). PDGF serum concentration levels were nearly parallel in all groups, serum concentrations were significantly higher in patients with proper bone healing and those treated with BMP-7 than in patients with non-unions (p < 0.05).ConclusionTreatment with BMP-7 in patients with former non-unions led to similar cytokine expression patterns after treatment as those found in patients with proper bone healing. Our results suggest that treatment with BMP-7 promote healing of non-unions. Furthermore, quantitative measurement of serum cytokine expression is a promising tool for evaluating the effectiveness of additional non-union therapies such as adjunct application of growth factors.