Summary. Indomethacin has differential effects on chondrogencic outcome depending on differentiation stage. Introduction. Heterotopic ossification (HO) is the abnormal formation of bone in soft tissues and is a frequent complication of hip replacement surgery. The standard treatment to prevent HO is administration of the NSAID indomethacin. HOs are described to develop via endochondral ossification. As it is currently unknown how indomethacin prevents HO, we aimed to define whether indomethacin might influence HO via impairing the chondrogenic phase of endochondral ossification. Materials. ATDC5, human bone marrow stem cells (hBMSCs) and rabbit periosteal agarose cultures were employed as progenitor cell models; SW1353, human articular chondrocytes and differentiated ATDC5 cells were used as matured chondrocyte cell models. All cells were cultured in the presence of (increasing) concentrations of indomethacin. The action of indomethacin was confirmed by decreased PGE. 2. levels in all experiments, and was determined by specific PGE. 2. ELISA. Gene- and protein expression analyses were employed to determine chondrogenic outcome. Results. A dose-dependent decrease in expression of Col2a1, Col10a1 and GAG content was observed when progenitor ATDC5 cells differentiating in the chondrogenic lineage were treated with increasing concentrations of indomethacin. These results were confirmed on primary hBMSCs and ex vivo periosteal agarose cultures. Even when hypertrophic differentiation of ATDC5 cells was provoked by BMP-2 (30ng/ml) the addition of indomethacin resulted in decreased hypertrophic marker expression. Interestingly, when adult chondrocytes (SW1353 and primary human articular chondrocytes) were treated with indomethacin, a clear increase in Col2a1 expression was observed. Similarly, when ATDC5 cells were differentiated for 10 days to obtain a chondrocyte phenotype and indomethacin was added from this time point onwards, low concentrations of indomethacin also resulted in increased Col2a1 expression. Conclusions. Indomethacin (dose-dependently) prevents chondrogenic and hypertrophic differentiation from progenitor cells. In addition we found thatindomethacin (in low concentrations) is able to increase the chondrogenic phenotype of maturated chondrocytes. Together, these data indicate that indomethacin has differentiation stage-dependent effects on chondrogenic differentiation and part of the HO-preventing action of indomethacin might be contributed to inhibition of chondrogenic differentiation

Heterotopic ossi?cation is the abnormal formation of bone in soft tissues and is a frequent complication of hip replacement surgery. Heterotopic ossi?cations are described to develop via endochondral ossification and standard treatment is administration of indomethacin. It is currently unknown how indomethacin influences heterotopic ossi?cation on a molecular level, therefore we aimed to determine whether indomethacin might influence heterotopic ossi?cation via impairing the chondrogenic phase of endochondral ossification. ATDC5, human bone marrow stem cells (hBMSCs) and rabbit periosteal agarose cultures were employed as progenitor cell models; SW1353, human articular chondrocytes and differentiated ATDC5 cells were used as matured chondrocyte cell models. All cells were cultured in the presence of (increasing) concentrations of indomethacin. The action of indomethacin was confirmed by decreased PGE2 levels in all experiments, and was determined by specific PGE2 ELISA. Gene- and protein expression analyses were employed to determine chondrogenic outcome. Progenitor cell models differentiating in the chondrogenic lineage (ATDC5, primary human bone marrow stem cells and ex vivo periosteal agarose cultures) were treated with increasing concentrations of indomethacin and a dose-dependent decrease in gene- and protein expression of chondrogenic and hypertrophic markers as well as decreased glycosaminoglycan content was observed. Even when hypertrophic differentiation was provoked the addition of indomethacin resulted in decreased hypertrophic marker expression. Interestingly, when mature chondrocytes were treated with indomethacin, a clear increase in collagen type 2 expression was observed. Similarly, when ATDC5 cells and bone marrow stem cells were pre-differentiated to obtain a chondrocyte phenotype and indomethacin was added from this time point onwards, low concentrations of indomethacin also resulted in increased chondrogenic differentiation. Indomethacin induces differential effects on in vitro endochondral ossification, depending on the chondrocyte's differentiation stage, with complete inhibition of chondrogenic differentiation as the most pronounced action. This observation may provide a rationale behind the elusive mode of action of indomethacin in the treatment of heterotopic ossifications

Purpose: Indomethacin may preserve tissue viability in compartment syndrome. The mechanism of improved tissue viability is unclear, but the anti-inflammatory effects may alter the relative contribution of tissue necrosis versus apoptosis to cellular injury. Existing studies have only considered indomethacin administration prior to induction of compartment syndrome. The purpose of this study was to determine the effect of timing of indomethacin administration on muscle damage in compartment syndrome, and to assess apoptosis as a cause of tissue demise. Method: Twenty-four Wistar rats were randomized to elevated intracompartmental pressure (EICP) for either 45 or 90 minutes (30mm Hg). In the 45 min group, indomethacin was withheld (group 1), given prior to induction of EICP (group 2) or given 15 min prior to fasciotomy (group 3). In the 90 min group, indomethacin was withheld (group 4) or provided 30 or 60 minutes prior to fasciotomy (groups 5 and 6). Intravital microscopy and histochemical staining assessed capillary perfusion, cell damage and inflammatory activation within EDL muscle. Apoptosis was assessed using ELISA staining for caspase-3. Groups were compared with one-way ANOVA (p< 0.05). Results: Perfusion improved in indomethacin-treated groups. Nonperfused capillaries decreased from group 1 (50.1±2.5), to groups 2 (38.4±1.8) and 3 (14.13±1.73)(p< 0.0001). Similarly, groups 5 and 6 had 25% fewer non-perfused capillaries compared to group 4 (p< 0.0001). Tissue viability improved in indo-methacin-treated groups. Groups 2 and 3 showed fewer damaged cells (1±0.5% and 8.7±2%) compared to group 1 (20±14%)(p< 0.0001). Groups 5 and 6 showed decreased cell damage (13±1% and 11±1%) compared to group 4 (18±1%) (p< 0.01). Apoptotic activity was present in compartment syndrome. At 30 minutes there were elevated caspase levels in EICP groups (0.47±0.08) compared to controls (0.19±0.02). However, indomethacin treated groups did not differ from controls with regards to caspase levels (p> 0.05). Conclusion: Indomethacin decreased cell damage and improved perfusion in compartment syndrome. The benefits of indomethacin were partially time dependent; some improvement in tissue viability occurred regardless of timing of administration. Although apoptosis was common in compartment syndrome, the protective effect of indomethacin does not appear to be related to apoptosis

Elevated intracompartmental pressure (ICP) results in muscle damage. Previous studies identified severe inflammation associated with elevated ICP. This study was designed to determine whether indomethacin, a potent anti-inflammatory agent, reduces muscle damage secondary to elevated ICP. We hypothesised that administration of indomethacin reduces muscle damage from elevated ICP. Sixteen adult Wistar rats were randomised to four groups. In group One (control), no intervention occurred. Group Two (indo) rats were administered indomethacin (12mg/kg) with no elevation of ICP. Group Three (CS) rats had elevated ICP (30–40mmHg X 45 minutes) using saline injection. Group Four rats (CS/indo) had elevated ICP and indomethacin administration. After forty-five minutes, hindlimb fasciotomy was performed. The extensor digitorum longus muscle was reflected onto an intravital microscope. Capillary perfusion was measured by comparing the number of continuously perfused capillaries to intermittent and non perfused capillaries. Inflammation was determined using the number of activated (rolling and adherent) white blood cells. Muscle cell damage was measured using differential fluorescent staining. Perfusion, inflammation, and muscle damage were compared in all four groups using a one-way ANOVA (p< 0.05). Perfusion: Indomethacin treatment (CS/indo) increased the proportion of intermittently perfused capillaries (39.1 ± 2.2 vs 30.3 ± 2.7) and decreased nonperfused capillaries (38.4 ± 1.8 vs 50.1 ±2.5) compared to CS (p=0.0002). Control and indo groups demonstrated more continuously perfused capillaries compared to CS or CS/indo groups (p< 0.0001). Muscle damage: Indomethacin treatment of elevated ICP reduced the proportion of damaged cells from 0.20 ± 0.14 (CS) to 0.01 ± 0.0.005 (CS/indo, p< 0.0001). There were no differences between CS/indo, control, or indo groups. Inflammation: CS and CS/indo groups demonstrated greater inflammatory activation compared to control and indo groups (p< 0.001). There were no differences in inflammatory activation between CS and CS/indo (p> 0.05). Treatment of elevated ICP with indomethacin improved microvascular perfusion and reduced cell damage. The protective mechanism of indomethacin is unknown, but may be related to an anti-oxidative and vasodilatory effect. Treatment of elevated intracompartmental pressure with indomethacin dramatically reduces muscle damage and may have important future clinical benefit

Purpose: This study was designed to determine whether indomethacin, a potent anti-inflammatory agent, reduces muscle damage secondary to elevated ICP. Method: 16 adult Wistar rats were randomized to 4 groups. In group 1 (control), no intervention occurred. Group 2 (indo) rats were administered indomethacin (12mg/kg) with no elevation of ICP. Group 3 (CS) rats had elevated ICP (30–40mmHg × 45 minutes) using saline injection. Group 4 rats (CS/indo) had elevated ICP and indomethacin administration. After 45 minutes, hindlimb fasciotomy was performed. The extensor digitorum longus muscle was reflected onto an intravital microscope. Capillary perfusion was measured by comparing the number of continuously perfused capillaries to intermittent and non perfused capillaries. Inflammation was determined using the number of activated (rolling and adherent) white blood cells. Muscle cell damage was measured using differential fluorescent staining. Perfusion, inflammation, and muscle damage were compared in all 4 groups using a one-way ANOVA (p< 0.05). Results: Perfusion: Indomethacin treatment (CS/indo) increased the proportion of intermittently perfused capillaries (39.1 ± 2.2 vs 30.3 ± 2.7) and decreased nonperfused capillaries (38.4 ± 1.8 vs 50.1 ±2.5) compared to CS (p=0.0002). Control and indo groups demonstrated more continuously perfused capillaries compared to CS or CS/indo groups (p0.05). Conclusion: Treatment of elevated ICP with indomethacin improved microvascular perfusion and reduced cell damage. The protective mechanism of indomethacin is unknown, but may be related to an anti-oxidative and vasodilatory effect. Treatment of elevated intracompartmental pressure with indomethacin dramatically reduces muscle damage and may have important future clinical benefit. Further research is required to determine the mechanism of action

This study was designed to prospectively evaluate the efficacy of indomethacin as prophylaxis for heterotopic ossification (HO) after operatively treated acetabular fractures. An IRB approved, prospective double blind placebo controlled clinical trial was performed at two level I trauma centres to evaluate the efficacy of indomethacin as prophylaxis for heterotopic ossification after the operative treatment of acetabular fractures. Between January 1, 1999 and May 31, 2003, two hundred and thirty-two patients with acetabular fractures were treated operatively through a posterior approach. Patients with the following conditions were excluded from study participation: age < 18, spinal cord injury, ankylosing spondylitis, burns, gastrointestinal bleed, Glasgow coma scale < 12, cerebrovascular accident, pregnancy and use of other non-steroidal anti-inflammatory drugs. One hundred and fifty-seven eligible patients were identified and one hundred and twenty-five patients were enrolled in the clinical trial. One hundred and seven patients have sufficient follow up to be included in data analysis. All patients underwent operative stabilization of their ace-tabular fractures by either a combined anterior and posterior approach or an isolated posterior Kocher-Lan-genbock approach. After fixation and prior to wound closure, any necrotic gluteus minimus muscle was debrided to viable muscle. Sixty-one patients were randomized to the placebo group and forty-six patients to the indomethacin treatment group. Indomethacin 75 mg SR and the placebo were administered to the patients by the investigational drug pharmacy in a blinded fashion. The medication was taken once daily for six weeks. Patient compliance was measured by obtaining indomethacin serum levels at the first postoperative visit (2 weeks). The extent of HO was evaluated on plain radiographs (AP and Judet) at three months postoperatively. The radiographs were scored for the presence of HO using the Brooker classification as modified by Moed. The data were analyzed two ways: 1) by excluding patients with protocol deviations and 2) by using an intent-to-treat model, where all enrolled subjects with 3 month Brooker scores were included in the analysis, regardless of whether they withdrew or were dropped from the study for clinical reasons. The sample size was estimated to produce a statistical power of 80% to detect a difference of 15% between the two treatment groups with alpha = .05. There were no significant differences with regards to age, sex, body mass index (BMI), ISS (injury severity score) and complications between the two treatment groups. The overall incidence of HO (Brooker I-IV) was 52.8% and the overall incidence of significant HO (Brooker III/IV) was 19.6%. There were four patients with Brooker IV HO. There was no significant difference between the treatment groups in the incidence of HO according to Brooker class (p=0.23). Significant HO (Brooker grades III-IV) occurred in 8 cases (17%) in the indomethacin group and 13 cases (21%) in the placebo group. There was no significant difference in the presence of moderate to severe HO (Brooker III/IV) between the two treatment groups (Fisher’s exact test p=0.81). Eighty-two of one hundred and seven patients enrolled completed the protocol. Twenty-five patients did not complete the treatment protocol for the following reasons: stopped medication due to side effects, did not receive medication at discharge, lost medication, or medication stopped by another physician who did not understand the purpose of the study. Nine patients (8.4%) did not receive the full medication course, sixteen patients (15%) were dropped or withdrew from the study for adverse events or gastrointestinal symptoms. Twelve patients dropped or withdrew from the indomethacin group and three from the placebo group. Forty percent of patients in the indomethacin group had non-detectable serum levels at two weeks. Complications identified in the indomethacin treatment group included deep venous thrombosis (5), wound infection (2), nonunion (1), gastrointestinal bleed (1) and perforated ulcer (1). Complications identified in the placebo group included deep venous thrombosis (6) and wound infection (2). In this prospective randomized study, a placebo provided as effective prophylaxis against the development of heterotopic ossification as indomethacin. More patients withdrew from the indomethacin group for gastrointestinal side effects or adverse events than in the placebo group. Patient compliance with indomethacin was poor with 40% of patients having no detectable indomethacin serum level. Serious gastrointestinal complications (gastrointestinal bleed and perforated ulcer) occurred in two patients treated with indomethacin

Severe heterotopic ossification (grade III and IV) after contemporary total hip arthroplasty (THA) requiring excision is very uncommon. We performed a systematic review of the literature, and report a new case series with operative treatment after primary uncemented THA. A systematic review identified papers describing patients who had excision of heterotopic ossification (HO) after contemporary THA, defined as performed after 1988. Concepts of hip arthroplasty, heterotopic ossification, and surgical excision were searched in MEDLINE, Embase, and Scopus, from database inception to November 2022. Inclusion criteria were: articles that included specific patient data on grade of heterotopic ossification, operative procedure, and prophylaxis. Studies were screened for inclusion by two independent reviewers. Extracted data included demographic data, interval from index surgery to excision, clinical results, and complications. One surgeon performed reoperation for ankylosis of primary THA in three patients with severe pain and deformity. Seven case series or case report studies were included. There were 41 patients, with grade III or IV HO, that had excision, and in five patients, revision of a component was also performed. Perioperative prophylaxis was irradiation alone in 10 patients, irradiation and indomethacin in 10, and indomethacin alone in 21 patients. At a mean follow-up time of 14.8 months, definition of the results was not uniform, and range of motion was improved, but relief of pain was inconsistent. There was one dislocation, one gastrointestinal complication, and two recurrences. Treatment of the three patients, with wide excision of peri-articular bone, selective exchange of components, and peri-operative irradiation prophylaxis, was successful in improving motion and deformity. There is insufficient data on the treatment of severe symptomatic HO after contemporary THA. Prophylaxis with low-dose irradiation was successful to prevent recurrence. Multicenter studies will be needed to determine the optimum timing and prognosis for treatment

The aim was to analyze whether non-steroidal anti-inflammatory drugs (NSAIDs) have an adverse effect on bone healing by evaluating all available human randomized controlled trials (RCTs) on this subject. A systematic search of electronic databases (PubMed, MEDLINE, and Cross-References) was performed to identify RCTs comparing the occurrence of nonunion in patients who received NSAIDs to the control group. Risk of bias of the studies was assessed. Nonunion was the main outcome evaluated, however, regression analysis was used to estimate the relative risk comparing duration and type of NSAIDs. Six RCTs (609 patients) were included. The risk of nonunion was higher in the patients given NSAIDs after the fracture (P-value= 0.0009, relative risk [RR] = 2.9, 95% confidence interval [CI] = 1.6 to 6.3). However, once the studies have been categorized to the duration of NSAIDs, those who received short period of NSAIDs (4 weeks) (P-value = 0.0002, RR = 4.1, CI = 2.1 to 8). Also, indomethacin agent has associated with high nonunion (P-value = 0.0001, RR = 3.9, CI = 2.3 to 13.9) compared to other NSAIDs which did not show a nonunion risk (P-value = 0.24, RR = 2.3, CI = 0.6 to 8.9). Using NSAIDs for long period (> 4 weeks) after fracture is significantly associated with nonunion especially with indomethacin agent. However, short period of NSAIDs (< 2 weeks) did not show the adverse effects of nonunion. Overall, further studies are required to support our conclusion

Summary. The negative impact of NSAIDs on fracture healing appears not to pertain to fractures in cancellous bone. Possibly this is because of a higher prevalence of MSCs in cancellous bone, making recruitment of distant cells via inflammatory signals less important. Introduction. It is well established that cox inhibitors (NSAIDs) impair fracture healing, also in humans. However, as they provide good pain relief it is unclear when to avoid these drugs. The healing process in cortical and cancellous fractures differs regarding progenitor cell sources, and inflammation might be involved in the recruitment of cells from distant sources. We therefore hypothesised that fractures in cancellous bone are less sensitive to reduced inflammation due to cox inhibitors. Methods. Indomethacin was used to study the role of an NSAID on shaft and metaphyseal fracture healing. 40 male 10 week old C57/bl6 mice were used, 20 of which received a stabilised mid-shaft femur fracture, whilst the other 20 received a screw inserted into the cancellous bone of the proximal tibia on one side, and a drill hole in the same area on the contralateral side. Half of the mice received injections of 1 mg/kg bodyweight of Indomethacin, twice daily for 14 days. The other half received saline. The effect of the treatment on the fracture healing was evaluated with mechanical testing, µCT, and histology. Results. Biomechanical testing (pull-out force for the screws) could detect no significant effect of indomethacin on the cancellous fracture healing. A reduction in force by more than 21 % could be excluded with 95 % confidence. The drill holes contained new bone, but µCT of this bone showed no effect of treatment on BMD, BV/TV, trabecular thickness, or trabecular number. Analysis of shaft healing is not yet completed. µCT of the first 12 femurs is available. A difference between the groups was obvious on visual inspection: Blind sorting, based on amount of callus, could identify all 6 indomethacin treated femurs and none of the controls as having an inferior callus response. More data will follow. Discussion/Conclusion. NSAIDs had no visible effect on metaphyseal healing, but a dramatic effect on the shaft fractures. Possibly, prostaglandin signaling is important for recruitment of progenitor cells to the shaft callus, whereas such cells are already present within the metaphyseal marrow

The June 2014 Children’s orthopaedics Roundup. 360 . looks at: plaster wedging in paediatric forearm fractures; the medial approach for DDH; Ponseti – but not as he knew it?; Salter osteotomy more accurate than Pemberton in DDH; is the open paediatric fracture an emergency?; bang up-to-date with femoral external fixation; indomethacin, heterotopic ossification and cerebral palsy hips; lengthening nails for congenital femoral deformities, and is MRI the answer to imaging of the physis?

Introduction: Studies have shown steroidal and non-steroidal anti-inflammatory drugs (NSAIDs) suppress bone remodeling. Previous results have indicated that NSAIDs suppress proliferation and induce cell death in cultured osteoblasts and pluripotent stem cells (D1-cells), suggesting these effects might be one of the mechanisms contributing to their inhibitory effects on bone remodeling in vivo. On the other hand, our previous results indicated that dexamethasone treatment shifts the characteristics of osteogenesis into adipogenesis in D1-cells. However, the influences of NSAID on adipogenesis in pluripotent stem cells have rarely been investigated. In this study, we tested the adipogenesis of D1-cells upon long-term treatment of NSAIDs. NSAID influence on the osteocalcin expressions of D1-cells was also examined. Materials and Methods: The effects of treatments with indomethacin, ketorolac, diclofenac and piroxicam (10. −5. and 10. −4. M) for 2, 4 6 or 8 days were evaluated. Lipid droplets in cultures were detected by oil red staining. Adipsin and osteocalcin mRNA expressions were examined by RT-PCR. Results: In this study, 10. −4. M of NSAID treatment for 4–8 days induced adipogenesis in D1-cells, while shorter duration and lower concentration did not. Mild adipogenesis also occurred in cultures treated with 10. −5. M of indomethacin for 6 or 8 days, revealing the strongest effect among the 4 NSAIDs. Piroxicam revealed less effects on adipogenesis in D1-cells. However, despite 2-days of treatment with 10. −5. M indomethacin, NSAIDs did not affect the expression of osteocalcin either at 10. −5. –10. −4. M or during 2–8 days of treatments. Conclusion: These results suggest that high dose and long term administration of NSAIDs may induce adipogenesis in pluripotent stem cells

Introduction: Increased levels of IL-6 and IL-8 have been found in intervertebral disc (IVD) tissue from patients undergoing fusion for discogenic low back pain. The stimuli that induce these mediators in degenerate discs remain unknown. Impaired diffusion of nutrients and wastes to and from the nucleus pulposus (NP) is believed to be an important factor in the degenerative process. The oxygen tension and pH in the NP of degenerating discs are significantly decreased. Aims: The aims of this study were to (1) demonstrate the ability of porcine NP to respond to a proinflamma-tory stimulus (lipopolysaccharride) in vitro, (2) investigate the effects of pH, pO. 2. and glucose concentration on NP proinflammatory mediator secretion and (3) determine if methylprednisolone or indomethacin can block NP proinflammatory mediator secretion. Methods: IVDs were harvested from 6-month old pigs and dissected under sterile conditions in the laboratory. 200mg samples of NP were cultured under optimal conditions (control), in a 1% O. 2. environment, at pH6 and in culture medium without glucose for 72 hours. Blocking experiments were performed by culturing LPS-stimulated samples with either methylprednisolone or indomethacin for 24 hours. IL-6 and IL-8 levels were estimated by ELISA. Results: Time and dose-response curves were generated for each experiment (results not shown). Results for the optimum dose and at 72 hours incubation were note. Data = mean ± standard deviation. Statistical analysis was by students t test. A significant result between control and stimulated groups is indicated by: * p=0.024m, † p=0.0007 or ‡ p=0.012. Methylprednisolone (2mg/ml) caused a significant (p=0.044) 30-fold reduction in IL-6 production and a significant (p=0.00004) 500-fold reduction in IL-8 levels as compared with nucleus pulposus cultured with 5 μg/ml LPS alone for 24 hours. Addition of 500 μM indomethacin significantly (p=0.04) decreased IL-6 production by a factor of 120 and IL-8 levels by a factor of 50 (p=0.00004). Necrotic cell death, as measured by lactate dehydrogenase (LDH) concentration, was not significant in any of the experiments

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to suppress bone repair and remodeling in vivo. Our previous studies showed that NSAIDs inhibited osteoblast proliferation and induced cell death in fetal rat osteoblast cultures. However, the NSAIDs effects on the functions of human osteoblasts remain unclear. Newly developed selective cyclo-oxygenase 2 (COX-2) inhibitors, celecoxib and refecoxib, have been reported to have lower risk of gastrointestinal complications than traditional nonsteroidal anti-inflammatory drugs. A recent report showed that refecoxib decreased bone ingrowth in an animal study. However, the effects of COX-2 selective inhibitors on human osteoblasts have rarely been investigated. In this study, the effects of steroid, non-selective, and selective COX-2 inhibitors on proliferation, cell cycle kinetics, and cytotoxicity in cultured human osteoblasts were examined. Materials and Methods: Indomethacin,ketorolac,piroxicam, and diclofenac (10. −5. and 10. −4. M); dexamethasone (10. −7. and 10. −6. M); Celecoxib and DFU, an analogue of rofecoxib, (10. −7. –10. −4. M) were tested for 24 or 48 hr in human osteoblast cultures. Results: In this study, we found that a 24 hour treatment of COX-2 selective inhibitors, celecoxib and DFU, significantly inhibited proliferation, arrested cell cycle, and had cytotoxicity in cultured human osteoblasts. However, the inhibitory effect on proliferation could be reversed if these agents were withdrawn for 24 hours. Indomethacin, ketorolac, diclofenac, and piroxicam also significantly inhibited proliferation and arrested cell cycle at the G. 0. /G. 1. phase, but had no cytotoxic effects on human osteoblasts. Discussion: These results suggest that the COX-2 selective and non-selective NSAIDs may affect osteoblastic functions through different mechanisms

Introduction Complex fracture dislocation of the elbow can often be either irreducible or unstable with inability to hold the reduction or delayed subluxation or dislocation. This study looks at the aetiology of the instability, bony and ligamentous, and the results following stabilisation with a combination of internal fixation, ligament repair, radial head arthroplasty and or hinged external fixation. Methods Twenty-one consecutive unstable elbows referred to three tertiary centres were prospectively recruited for this study. All cases had fine-cut CT scans with sagittal, coronal and 3D reconstructions. All elbows were approached using a posterior ‘global’ incision. Ulnar neurolysis was routinely performed. Medial and lateral ligament complexes were inspected and repaired. Internal fixation of the radial head was attempted where indicated, or a radial head arthroplasty was performed. The coronoid-brachialis complex was repaired using pull-through sutures. Elbow stability was tested and a hinged external fixator used where indicated. The fixator was removed at six weeks. Indomethacin prophylaxis against heterotopic ossification was used routinely. Follow-up range of motion, articular congruity and DASH score were assessed at one year. All cases required a repair of the coronoid-brachialis complex. Radial head reconstruction was attempted in four cases, but abandoned in three. The radial head was replaced in 13 cases. A lateral repair alone was required in 12 cases, a medial repair alone in two cases and a combined medial and lateral repair in seven cases. Eighteen cases required a hinged device (nine Compass hinges and nine OpteROM distractors). Results The mean less of extension at one year was 12° (range 0 to 20) and the mean loss of flexion was 14° (range 0 to 20). All cases achieved at least a functional arc of motion from 30° to 130°. Three cases achieved a full range of motion. Despite Indomethacin prophylaxis three cases developed minor heterotopic ossification. The average DASH score was 23. Conclusions If managed appropriately, a very good anatomical and functional outcome can be achieved in difficult unstable elbows post fracture dislocation. Repair of the coronoid-brachialis complex is the key to stability, along with radial head reconstruction or replacement. A hinged external fixation device allows early mobilisation

The incidence of clinically significant (Brooker stage 3–4) heterotopic ossification (HO) after THA is 3–7%. Risk factors include male gender, old age, a history of HO, Paget's disease, post-traumatic arthritis, osteonecrosis and rheumatoid arthritis. Prophylaxis for high-risk patients consists of 1) radiotherapy given as one dose of 7–8 Gy either pre-operatively (<4 hours) or post-operatively (within 72 hours) or 2) NSAIDS. Treatment of clinically significant HO includes intensive physiotherapy during the maturation phase of the disease and surgical excision in conjunction with a combination of radiotherapy and indomethacin once the HO has matured. Less invasive surgical approaches may be associated with a reduced incidence of HO

The incidence of clinically significant (Brooker stage 3–4) heterotopic ossification (HO) after THA is 3–7%. Risk factors include male gender, old age, a history of HO, Paget's disease, post-traumatic arthritis, osteonecrosis and rheumatoid arthritis. Prophylaxis for high-risk patients consists of 1) radiotherapy given as one dose of 7–8 Gy either pre-operatively (< 4 hours) or post-operatively (within 72 hours) or 2) NSAIDS. Treatment of clinically significant HO includes intensive physiotherapy during the maturation phase of the disease and surgical excision in conjunction with a combination of radiotherapy and indomethacin once the HO has matured. Less invasive surgical approaches may be associated with a reduced incidence of HO

Introduction: There is an ever-increasing clinical need for the regeneration and replacement of tissue to replace soft tissue lost due to trauma, disease and cosmetic surgery. A potential alternative to the current treatment modalities is the use of tissue engineering applications using mesenchymal stem cells that have been identified in many tissues including the fat pad. In this study, stem cells isolated from the fat pad were characterised and their differentiation potential assessed. Materials and Methods: The infrapatellar fat pad was obtained from total knee replacement for osteoarthritis. Cells were isolated, expanded and stained for a number of stem cell markers. For adipogenic differentiation, cells were cultured in adipogenic inducing medium (10ug/ml insulin, 1uM dexamthasone, 100uM indomethacin and 500uM 3-isobutyl-1-methyl xanthine). Gene expression analyses and Oil red O staining was performed to assess adipogenesis. Results: Cells at passage 2 stained strongly for CD13, CD29, CD44, CD90 and CD105 (mesenchymal stem cell markers). The cells stained sparsely for 3G5 (peri-cyte marker). On gene expression analyses, the cells cultured under adipogenic conditions had almost a 1,000 fold increase in expression of peroxisome proliferator-activated receptor gamma-2 (PPAR gamma-2) and 1,000,000 fold increase in expression of lipoprotein lipase (LPL). Oil red O staining revealed triglyceride accumulation within typical adipogenic morphology, confirming the adipogenic nature of the observed vacuoles, and showed failure of staining in control cells. Discussion: Fat pad derived stem cells expressed a cell surface epitope profile of mesenchymal stem cells, and exhibited the potential to undergo adipogenic differentiation. Our results show that the human fat pad is a viable potential autogeneic source for mesenchymal stem cells capable of adipogenic differentiation as well as previously documented ostegenic and chondrogenic differentiation. This cell source has potential use in tissue engineering applications

The work of Sloof, Ling and Gie has established allografting as a modern technique in revision total hip arthroplasty. The use of allograft enhances the local bone stock and provides a secure fixation for cemented components. Its association with the problem of heterotopic ossification has not been previously considered. The records and x-rays of 114 patients after revision hip surgery were reviewed. All had been operated upon by three Consultant Orthopaedic Surgeons using standard techniques. 35 patients had undergone revision with impaction allografting of both the femur and acetabulum, 29 had allografting of the femur only, 18 of the acetabulum alone and the final 32 patients (acting as controls) had cemented revision arthroplasty without impaction allografting. Fresh frozen allograft was used in all cases and prepared using a bone mill. No patient was given radiation or Indomethacin after their revision surgery, even if they had pre-existing heterotopic ossification. The immediate pre-operative x-rays and x-rays at least a year post-revision were assessed independently by a musculoskeletal radiologist. He was blinded to the type of revision procedure and graded the heterotopic ossification according to the Brooker Classification. Our results report the incidence of heterotopic ossification after revision hip arthroplasty with fresh frozen allograft when compared with cemented revision arthroplasty from our unit and other studies

There is an ever-increasing clinical need for the regeneration and replacement of tissue to replace soft tissue lost due to trauma, disease and cosmetic surgery. A potential alternative to the current treatment modalities is the use of tissue engineering applications using mesenchymal stem cells that have been identified in many tissue including the infrapatellar fat pad. In this study, stem cells isolated from the infrapatellar fat pad were characterised to ascertain their origin, and allowed to undergo adipogenic differentiation to confirm multilineage differentiation potential. The infrapatellar fat pad was obtained from total knee replacement for osteoarthritis. Cells were isolated and expanded in monolayer culture. Cells at passage 2 stained strongly for CD13, CD29, CD44, CD90 and CD105 (mesenchymal stem cell markers). The cells stained poorly for LNGFR and STRO1 (markers for freshly isolated bone marrow derived stem cells), and sparsely for 3G5 (pericyte marker). Staining for CD34 (haematopoetic marker) and CD56 (neural and myogenic lineage marker) was negative. {BR}For adipogenic differentiation, cells were cultured in adipogenic inducing medium consisting of basic medium with 10ug/ml insulin, 1uM dexamthasone, 100uM indomethacin and 500uM 3-isobutyl-1-methyl xanthine. By day 16, many cells had lipid vacuoles occupying most of the cytoplasm. On gene expression analyses, the cells cultured under adipogenic conditions had almost a 1,000 fold increase in expression of peroxisome proliferator-activated receptor gamma-2 (PPAR gamma-2) and 1,000,000 fold increase in expression of lipoprotein lipase (LPL). Oil red O staining confirmed the adipogenic nature of the observed vacuoles and showed failure of staining in control cells. Our results show that the human infrapatellar fat pad is a viable potential autogeneic source for mesenchymal stem cells capable of adipogenic differentiation as well as previously documented ostegenic and chondrogenic differentiation. This cell source has potential use in tissue engineering applications

There is an ever-increasing clinical need for the regeneration and replacement of tissue to replace soft tissue lost due to trauma, disease and cosmetic surgery. A potential alternative to the current treatment modalities is the use of tissue engineering applications using mesenchymal stem cells that have been identified in many tissue including the infrapatellar fat pad. In this study, stem cells isolated from the infrapatellar fat pad were characterised to ascertain their origin, and allowed to undergo adipogenic differentiation to confirm multilineage differentiation potential. The infrapatellar fat pad was obtained from total knee replacement for osteoarthritis. Cells were isolated and expanded in monolayer culture. Cells at passage 2 stained strongly for CD13, CD29, CD44, CD90 and CD105 (mesenchymal stem cell markers). The cells stained poorly for LNGFR and STRO1 (markers for freshly isolated bone marrow derived stem cells), and sparsely for 3G5 (pericyte marker). Staining for CD34 (haematopoetic marker) and CD56 (neural and myogenic lineage marker) was negative. For adipogenic differentiation, cells were cultured in adipogenic inducing medium consisting of basic medium with 10ug/ml insulin, 1uM dexamthasone, 100uM indomethacin and 500uM 3-isobutyl-1-methyl xanthine. By day 16, many cells had lipid vacuoles occupying most of the cytoplasm. On gene expression analyses, the cells cultured under adipogenic conditions had almost a 1,000 fold increase in expression of peroxisome proliferator-activated receptor gamma-2 (PPAR gamma-2) and 1,000,000 fold increase in expression of lipoprotein lipase (LPL). Oil red O staining confirmed the adipogenic nature of the observed vacuoles and showed failure of staining in control cells. Our results show that the human infrapatellar fat pad is a viable potential autogeneic source for mesenchymal stem cells capable of adipogenic differentiation as well as previously documented ostegenic and chondrogenic differentiation. This cell source has potential use in tissue engineering applications