BOSENTAN, A NON-SPECIFIC ENDOTHELIN ANTAGONIST, STIMULATES FRACTURE HEALING

2007 ◽  
Vol 19 (01) ◽  
pp. 37-46 ◽  
Author(s):  
Hasan H. Muratli ◽  
Feza Korkusuz ◽  
Petek Korkusuz ◽  
Ali Bicimoglu ◽  
Z. Sevim Ercan
Keyword(s):  
Fracture Healing ◽  
Bone Fractures ◽  
Fracture Site ◽  
Controlled Study ◽  
Prostaglandin E ◽  
Matrix Mineralization ◽  
Hind Limbs ◽  
Diaphyseal Bone ◽  
Activity Measurements ◽  
Intramedullary Rod

It is assumed that bosentan, a non-selective ET-1 receptor antagonist, will enhance fracture healing. The aim of this prospective randomized controlled study was to investigate the effects of transcutaneous bosentan administration into diaphyseal bone fractures using radiology, histology, prostaglandin E2 (PGE2) and leukotrien C 4 (LTC4) activity measurements. A closed diaphyseal fracture was created in the hind limbs following intramedullary rod fixation of Guinea pigs. Bosentan was administred by repetitive weekly 0.1 μg transcutaneous injections into the fracture site. The effects of bosentan were evaluated by radiology and histology on weeks 1, 2 and 4, whereas prostaglandin E2 (PGE2)-like and leukotrien C 4 (LTC4)-like activity was assessed on weeks 1 and 2. The radiological degree of union (p = 0.001) at the fracture site and cortex-callus ratio (p = 0.02) was significantly better in the bosentan administered site at week 1 when compared to the control. Histology presented an initial stimulation of bone formation on weeks 1 and 2 in the experimental group. PGE2-like activity was significantly higher (p = 0.002) on week 1 and 2 in the bosentan-administered side. LTC4-like activity remained constant on week one and decreased on week two. Transcutaneous repetitive bosentan administration into the fracture site initially stimulated periosteal bone healing that resulted with extracellular matrix mineralization. The inflammatory mediators PGE2/LTC4 played a significant role in this process.

scholarly journals Gukang Capsule Promotes Fracture Healing by Activating BMP/SMAD and Wnt/β-Catenin Signaling Pathways

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Xue Ma ◽  
Jian Yang ◽  
Ting Liu ◽  
Jing Li ◽  
Yanyu Lan ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Signaling Pathways ◽  
Bone Fractures ◽  
Glycogen Synthase ◽  
Fracture Site ◽  
Bone Morphogenetic Protein 2 ◽  
Radius Fracture ◽  
Smad Signaling ◽  
Alp Activity ◽  
Human Osteosarcoma Cells

Background. Gukang capsule (GKC) is a traditional Chinese medicine formulation which has been used extensively in the clinical treatment of bone fractures. However, the mechanisms underlying its effects on fracture healing remain unclear. Methods. In this study we used a rabbit radius fracture model, and we measured the serum content of bone alkaline phosphatase (ALP), calcium, and phosphorus and examined pathology of the fracture site as indicators of the fracture healing effects of GKC. SaOS-2 human osteosarcoma cells were used to measure (i) ALP activity, (ii) ornithine transcarbamylase (OTC), calcium, and mineralization levels, (iii) the expression of osteogenic-related genes, that is, runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2), collagen I (COL-I), osteopontin (OPN), OTC, and osterix (Osx), and (iv) the expression of key proteins in the Wnt/β-catenin and BMP/SMAD signaling pathways to study the mechanisms by which GKC promotes fracture healing. Results. We found that GKC effectively promotes radius fracture healing in rabbits and enhances ALP activity, increases OTC and calcium levels, and stimulates the formation of mineralized nodules in SaOS-2 cells. Moreover, COL-I, OTC, Osx, BMP2, and OPN expression levels were higher in SaOS-2 cells treated with GKC than control cells. GKC upregulates glycogen synthase kinase 3β (GSK3β) phosphorylation and Smad1/5 and β-catenin protein levels, thereby activating Wnt/β-catenin and BMP/Smad signaling pathways. Inhibitors of the Wnt/β-catenin and BMP/Smad signaling pathways (DKK1 and Noggin, respectively) suppress the osteogenic effects of GKC. Conclusions. GKC promotes fracture healing by activating the Wnt/β-catenin and BMP/Smad signaling pathways and increasing osteoprotegerin (OPG) secretion by osteoblasts (OBs), which prevents receptor activator of nuclear factor kappa B ligand (RANKL) binding to RANK.

Contrast-Enhanced Computed Tomography for Non-Destructive, Quantitative Assessment of the Early Stages of Fracture Healing

2011 ◽  
Author(s):  
C. M. J. De Bakker ◽  
L. N. M. Hayward ◽  
L. C. Gerstenfeld ◽  
M. W. Grinstaff ◽  
E. F. Morgan
Keyword(s):  
Computed Tomography ◽  
Fracture Healing ◽  
Bone Fractures ◽  
The United States ◽  
Fracture Site ◽  
Early Assessment ◽  
Subsequent Formation ◽  
Substantial Impact ◽  
Early Stages ◽  
Enhanced Computed Tomography

Each year in the United States, approximately 600,000 bone fractures show delayed or impaired healing and require subsequent surgical intervention1. Techniques for early identification of these cases are presently lacking but could make substantial impact on reducing the morbidity and costs associated with poor bone healing. A current barrier to early assessment of fracture healing is the difficulty in visualizing the cartilaginous “soft” callus that forms at the fracture site in the early stages of repair. The soft callus serves to partially stabilize the fracture and provides a template for subsequent formation of the bony “hard” callus2. Although measurement or estimation of the size, stiffness, and strength of the hard callus is possible by x-ray or computed tomography (CT)3, no analogous methods have been developed for the soft callus, due to the low radio-opacity of cartilage.

scholarly journals Lithium for Fracture Treatment (LiFT): a double-blind randomised control trial protocol

BMJ Open ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. e031545 ◽  
Author(s):  
Diane Nam ◽  
Phumeena Balasuberamaniam ◽  
Katrine Milner ◽  
Monica Kunz ◽  
Kathak Vachhani ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Bone Fractures ◽  
Fracture Site ◽  
Long Bone ◽  
Randomised Control Trial ◽  
Secondary Outcome ◽  
Double Blind ◽  
Carbonate Group ◽  
Main Trial ◽  
Radiographic Union

IntroductionFracture healing can fail in up to 10% of cases despite appropriate treatment. While lithium has been the standard treatment for bipolar disorder, it may also have a significant impact to increase bone healing in patients with long bone fractures. To translate this knowledge into clinical practice, a randomised clinical trial (RCT) is proposed.Methods and analysisA multicentre double blind, placebo-controlled RCT is proposed to evaluate the efficacy of lithium to increase the rate and predictability of long bone fracture healing in healthy adults compared to lactose placebo treatment. 160 healthy individuals from 18 to 55 years of age presenting with shaft fractures of the femur, tibia/fibula, humerus or clavicle will be eligible. Fractures will be randomised to placebo (lactose) or treatment (300 mg lithium carbonate) group within 2 weeks of the injury. The primary outcome measure will be radiographic union defined as visible callus bridging on three of the four cortices at the fracture site using a validated radiographic union score. Secondary outcome measures will include functional assessment and pain scoring.Ethics and disseminationParticipant confidentiality will be maintained with publication of results. Research Ethics Board Approval: Sunnybrook Research Institute (REB # 356–2016). Health Canada Approval (HC6-24-C201560). Results of the main trial and secondary endpoints will be submitted for publication in a peer-reviewed journal and presented at conferences.Trial registration numberNCT02999022.

Effect of Intramedullary Nailing Patterns On Interfragmentary Strain in a Mouse Femur Fracture: a Parametric Finite Element Analysis

2021 ◽  
Author(s):  
Gregory Lowen ◽  
Katherine Garrett ◽  
Moore-Lotridge Stephanie ◽  
Sasidhar Uppuganti ◽  
Scott A. Guelcher ◽  
...  
Keyword(s):  
Finite Element Analysis ◽  
Finite Element ◽  
Fracture Healing ◽  
Bone Repair ◽  
Bone Fractures ◽  
Fracture Site ◽  
Fracture Repair ◽  
Long Bone ◽  
Design Parameters ◽  
Element Analysis

Abstract Delayed long bone fracture healing and nonunion continue to be a significant socioeconomic burden. While mechanical stimulation is known to be an important determinant of the bone repair process, understanding how the magnitude, mode, and commencement of interfragmentary strain (IFS) affect fracture healing can guide new therapeutic strategies to prevent delayed healing or non-union. Mouse models provide a means to investigate the molecular and cellular aspects of fracture repair, yet there is only one commercially available, clinically-relevant, locking intramedullary nail (IMN) currently available for studying long bone fractures in rodents. Having access to alternative IMNs would allow a variety of mechanical environments at the fracture site to be evaluated, and the purpose of this proof-of-concept finite element analysis study is to identify which IMN design parameters have the largest impact on IFS in a murine transverse femoral osteotomy model. Using the dimensions of the clinically relevant IMN as a guide, the nail material, distance between interlocking screws, and clearance between the nail and endosteal surface were varied between simulations. Of these parameters, changing the nail material from stainless steel (SS) to polyetheretherketone (PEEK) had the largest impact on IFS. Reducing the distance between the proximal and distal interlocking screws substantially affected IFS only when nail modulus was low. Therefore, IMNs with low modulus (e.g., PEEK) can be used alongside commercially available SS nails to investigate the effect of initial IFS or stability on fracture healing with respect to different biological conditions of repair in rodents.

scholarly journals Percutaneous administration of allogeneic bone-forming cells for the treatment of delayed unions of fractures: a pilot study

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marc Jayankura ◽  
Arndt Peter Schulz ◽  
Olivier Delahaut ◽  
Richard Witvrouw ◽  
Lothar Seefried ◽  
...  
Keyword(s):  
Pilot Study ◽  
Adverse Events ◽  
Phase I ◽  
Bone Fractures ◽  
Fracture Site ◽  
Post Treatment ◽  
Long Bone ◽  
Allogeneic Bone ◽  
Hla Antibodies ◽  
Long Bone Fractures

Abstract Background Overall, 5–10% of fractures result in delayed unions or non-unions, causing major disabilities and a huge socioeconomic burden. Since rescue surgery with autologous bone grafts can cause additional challenges, alternative treatment options have been developed to stimulate a deficient healing process. This study assessed the technical feasibility, safety and preliminary efficacy of local percutaneous implantation of allogeneic bone-forming cells in delayed unions of long bone fractures. Methods In this phase I/IIA open-label pilot trial, 22 adult patients with non-infected delayed unions of long bone fractures, which failed to consolidate after 3 to 7 months, received a percutaneous implantation of allogeneic bone-forming cells derived from bone marrow mesenchymal stem cells (ALLOB; Bone Therapeutics) into the fracture site (50 × 106 to 100 × 106 cells). Patients were monitored for adverse events and need for rescue surgery for 30 months. Fracture healing was monitored by Tomographic Union Score (TUS) and modified Radiographic Union Score. The health status was evaluated using the Global Disease Evaluation (GDE) score and pain at palpation using a visual analogue scale. The presence of reactive anti-human leukocyte antigen (HLA) antibodies was evaluated. Results During the 6-month follow-up, three serious treatment-emergent adverse events were reported in two patients, of which two were considered as possibly treatment-related. None of the 21 patients in the per-protocol efficacy population needed rescue surgery within 6 months, but 2/21 (9.5%) patients had rescue surgery within 30 months post-treatment. At 6 months post-treatment, an improvement of at least 2 points in TUS was reached in 76.2% of patients, the GDE score improved by a mean of 48%, and pain at palpation at the fracture site was reduced by an average of 61% compared to baseline. The proportion of blood samples containing donor-specific anti-HLA antibodies increased from 8/22 (36.4%) before treatment to 13/22 (59.1%) at 6 months post-treatment, but no treatment-mediated allogeneic immune reactions were observed. Conclusion This pilot study showed that the percutaneous implantation of allogeneic bone-forming cells was technically feasible and well tolerated in patients with delayed unions of long bone fractures. Preliminary efficacy evidence is supporting the further development of this treatment. Trial registration NCT02020590. Registered on 25 December 2013. ALLOB-DU1, A pilot Phase I/IIa, multicentre, open proof-of-concept study on the efficacy and safetyof allogeneic osteoblastic cells (ALLOB®) implantation in non-infected delayed-union fractures.

scholarly journals Mechanical flexural ex vivo study of osteotomized swine femurs stabilized with two types of polyamide 12 rods

2017 ◽  
Vol 47 (8) ◽  
Author(s):  
Juliana Scarpa da Silveira Almeida ◽  
Débora de Oliveira Garcia ◽  
Renato Camargo Bortholin ◽  
Carlos Amaral Razzino ◽  
Cristiane dos Santos Honsho ◽  
...  
Keyword(s):  
Bone Fractures ◽  
Ex Vivo ◽  
Polymeric Materials ◽  
Fracture Site ◽  
Medullary Canal ◽  
Modulus Of Rupture ◽  
Long Bone ◽  
Bone Implant ◽  
Polyamide 12 ◽  
Implant System

ABSTRACT: Long bone fractures are commonly in surgery routine and several bone imobilization techniques are currently available. Technological progress has enabled to use low cost materials in surgical procedures. Thus, the aim of this study was to evaluate the applicability of polyamide 12 rods, solid and hollow in swine femurs, comparing them through flexion strength. This study had as second aim to fix the locking errors, commom place in interlocking nails, once polyamide 12 allows perforation in any direction by orthopaedic screw. Six groups were used: G1 - eight whole swine femurs; G2 - eight whole swine femurs with drilled medullary canal; G3 - two solid polyamide 12 rods; G4 - two hollow polyamide 12 rods; G5 - eight osteotomized drilled swine femurs with a solid polyamide 12 rod implanted in the medullary canal and locked by four 316L stainless steel screws; and G6 - similar to G5 but using hollow rods instead of solid ones. No significant differences were observed for the modulus of rupture between solid and hollow rods, demonstrating that both rods had similar performances. These results led to the speculation that the addition of other polymers to the hollow rods could increase their strength and thus the bone-implant system. Furthermore, the comparison between G1, G5 and G6 could be analyzed using the finite element method in future. New polymeric materials may be developed based on the data from this study, strengthening the bone-implant system and making possible screws to be placed in any direction, nullifying the detrimental forces on the fracture site.

scholarly journals Development and Biocompatibility Characterization of a BioMEMS Sensor for Monitoring the Progression of Fracture Healing

2009 ◽  
Author(s):  
Brandon G. Santoni ◽  
Rohat Melik ◽  
Emre Unal ◽  
Nihan Kosku Perkgoz ◽  
Debra A. Kamstock ◽  
...  
Keyword(s):  
United States ◽  
Fracture Healing ◽  
Bone Fractures ◽  
Financial Burden ◽  
Early Period ◽  
The United States ◽  
Long Bone ◽  
Extremity Injuries ◽  
Manual Manipulation

Orthopaedic extremity injuries present a large medical and financial burden to the United States and world-wide communities [1]. Approximately six million long bone fractures are reported annually in the United States and approximately 10% of these fractures do not heal properly. Though the exact mechanism of impaired healing is poorly understood, many of these non-unions result when there is a communited condition that does not proceed through a stabilized healing pathway [2]. Currently, clinicians may monitor healing visually by radiographs, or via manual manipulation of the bone at the fracture [3]. Unfortunately, the course of aberrant fracture healing is not easily diagnosed in the early period when standard radiographic information of the fracture is not capable of discriminating the healing pathway. Manual assessment of fracture healing is also an inadequate diagnostic tool in the early stages of healing [4].

scholarly journals Effects of Local Opioid Antagonist on Diabetic Fracture Rat Model

2018 ◽  
Vol 3 (3) ◽  
pp. 2473011418S0017
Author(s):  
Jarrett D. Cain ◽  
Michelle Titunick ◽  
Patricia McLaughlin ◽  
Ian Zagon
Keyword(s):  
Growth Factor ◽  
Fracture Healing ◽  
Bone Healing ◽  
Calcium Sulfate ◽  
Bone Fractures ◽  
Diabetic Rats ◽  
Receptor Expression ◽  
Opioid Antagonist ◽  
Diabetic Patients ◽  
Opioid Growth Factor

Category: Diabetes Introduction/Purpose: Complications associated with the diabetes include increased incidence of fracture healing, delayed fracture healing, delayed osteoblasts cell replication, decreased angiogenesis, migration and/or osteoblast cell differentiation. The cellular events involved in bone healing are adversely affected by diabetes; however, can be modulated by the Opioid Growth Factor (OGF)–OGF receptor (OGFr) is an inhibitory peptide that downregulates DNA synthesis in a tissue nonspecific manner. Diabetes is associated with elevated serum levels of OGF and dysregulation of the OGFr leading to multiple complications related to healing, sensitivity, and regeneration. This study explores the presence and function of the OGF-OGFr axis in bone tissue from type 1 diabetic rats examining intact and fractured femurs during early phases of the repair process Methods: Seven-week-old Sprague Dawley rats were injected with streptozotocin (40mg/kg i.p.) to induce T1D; other rats received buffer only and served as controls. After one month, hyperglycemia rats underwent surgery to produce a fracture at the distal third of the femur. Four diabetic rats received opioid antagoinist (naltrexone) and calcium sulfate and all remaining rats received calcium sulfate with water only. X-rays were taken immediately after surgery and after rats were euthanized on post-surgery; femur and tibia were collected for protein isolation, western blot analysis along with frozen or paraffin-embedded for histological analysis Results: Immunofluorescence indicated approximately 90% increase in opioid growth factor receptor expression in diabetic femurs compared to age-matched normal femurs. Western Blotting also suggested an increase in the receptor protein in diabetic bones relative to normal bone. TRAP staining for osteoclasts was greater in control and opioid antagonist-treated diabetic fractures when compared to the number of osteoclasts in vehicle-treated diabetic fractured femurs. Safranin O stained sections revealed approximately more bone in opioid growth receptor antagonist-treated diabetic bone fractures than in vehicle-treated bone fractures Conclusion: These data support our hypothesis that expression levels of OGFr are dysregulated in the bone of diabetic patients leading to complications in bone healing. Moreover, modulation of the OGF-OGFr pathway with receptor antagonists restored some aspects of bone healing. With further study, these preliminary results support the role of the OGF-OGFr axis in treatment of diabetic bone healing. New therapies to target dysregulation of the OGF-OGFr regulatory pathway in diabetes would provide a safe and effective disease-modifying treatment for delayed bone healing.

A randomized clinical efficacy study targeting mPGES1 or EP4 in dogs with spontaneous osteoarthritis

2019 ◽  
Vol 11 (516) ◽  
pp. eaaw9993
Author(s):  
Carol Robertson-Plouch ◽  
John R. Stille ◽  
Peng Liu ◽  
Claire Smith ◽  
Dorothy Brown ◽  
...  
Keyword(s):  
Posterior Probability ◽  
Brief Pain Inventory ◽  
Repeated Measure ◽  
Controlled Study ◽  
Prostaglandin E ◽  
Double Blind ◽  
Mixed Effect ◽  
Secondary Endpoints ◽  
Efficacy Measures ◽  
The Difference

Canine studies of spontaneous osteoarthritis (OA) pain add valuable data supporting drug treatment mechanisms that may translate to humans. A multicenter, randomized, double-blind, placebo- and active-controlled study was conducted in client-owned dogs with moderate OA pain to evaluate efficacy of LYA, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES1), an EP4 antagonist (LYB), and carprofen, versus placebo. Of 255 dogs screened, 163 were randomized (placebo/LYA/LYB/carprofen: n = 43/39/42/39) and 158 completed treatment. Efficacy versus placebo was assessed using Bayesian mixed-effect model for repeated measure analyses of the Canine Brief Pain Inventory (CBPI) pain interference score (PIS; primary endpoint), pain severity score, and overall impression, as well as the Liverpool Osteoarthritis in Dogs (LOAD) mobility score. The posterior probability that the difference to placebo was <0 at week 2 was 80% for LYA and 54% for LYB for CBPI PIS (both <95% predefined threshold). For secondary endpoints, the posterior probability that the difference to placebo was <0 at week 2 ranged from 89 to 96% for LYA and from 56 to 89% for LYB. The posterior probabilities comparing carprofen to placebo groups were ≥90% for all efficacy endpoints. The proportion of dogs with one or more adverse event was not significantly different from placebo (32.6%) for LYA (35.9%) or carprofen (25.6%), but the rate for LYB (59.5%) was higher versus placebo (P = 0.017). LYA treatment demonstrated consistent improvement in all efficacy measures, suggesting that inhibition of mPGES1 may be an effective treatment for chronic pain associated with OA.

Epoxy-Pin External Skeletal Fixation for Management of Open Bone Fractures in Calves and Foals: A Review of 32 Cases

2019 ◽  
Vol 32 (03) ◽  
pp. 257-268
Author(s):  
Hari Aithal ◽  
Prakash Kinjavdekar ◽  
Abhijit Pawde ◽  
Prasoon Dubey ◽  
Rohit Kumar ◽  
...  
Keyword(s):  
Bone Fractures ◽  
Weight Bearing ◽  
Fracture Site ◽  
Open Fractures ◽  
Adhesive Tape ◽  
Stable Fixation ◽  
Early Weight Bearing ◽  
Pin Fixation ◽  
Bone Fragments ◽  
The Subject

Objective The aim of this study was to evaluate epoxy-pin external skeletal fixation technique for the treatment of open fractures in calves and foals. Study Design Twenty-eight calves and four foals (weighing 45–105 kg) with fractures distal to the stifle or elbow made the subject for the retrospective study. The pins (2.0–3.0-mm Kirschner wires, crossed at 60–90°) were fixed at least at two locations in both proximal and distal bone fragments as per the case situation. The pins in the same plane were bent (∼2 cm from the skin) towards the fracture site or joint and were joined using an adhesive tape (additional pins used when required) to make a temporary scaffold of connecting bars or rings. Thoroughly mixed epoxy putty was applied along the pin scaffold (the epoxy columns were 20–25 mm diameter) and allowed to set for 45 to 60 minutes. All animals were evaluated based on various clinical and radiographic observations made at regular intervals. Results The epoxy-pin fixation was easy to apply and provided stable fixation of bone as indicated by early weight bearing, and fracture healing within 45 to 60 days (17/32 cases). The functional recovery was good to very good in 14 animals and satisfactory in nine cases by 12 months after removal of the fixator. Conclusions The multiplanar epoxy-pin external skeletal fixation provides stable fixation of unstable open fractures distal to the stifle or elbow joint; hence, it can be used to treat a variety of fractures in calves and foals weighing up to approximately 100 kg, especially open infected fractures of lower limb, which are difficult to treat by conventional techniques.

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