Introduction and aims: Flanged sockets have been in use since 1976.Experimental evidence has shown that they offer an advantage in terms of cement pressurization at the time of implantation. Radiological demarcation at the cement-bone interface has been shown to be significantly reduced in early radiographs with flanged sockets.The Opera Cup with its contoured flange containing a series of tangential rings was developed in Manchester.We present our early results with this cup.

Method: 140 patients had primary hip arthroplasty performed between July1997 and November 2000.

Ten had bilateral surgery.92 (66%) were female and 48 (34%) were male.The mean age at operation was 58 (range 34–90).The mean length of follow up was 50 months (range 36–76).

Standardised anteroposterior radiographs of the pelvis were compared at one year with the three to six year reviews.Radiological demarcation of the acetabular component was assessed using the Hodgkinson grading system by the senior author.

Results: 150 sockets were reviewed.62% had no demarcation at one year (grade 0).This figure fell to 56% at the three to six year review.Grade 1 changes were seen in 36% at one year rising to 41% at the three to six year review.

92% of sockets showed no increase in demarcation during the review period whilst 3% had developed evidence of radiological loosening with grades 2 to 4.

Conclusion: The development and progression of radiolucent lines are associated with aseptic socket loosening.Our results compare favourably with published studies.Long term follow up is needed to make more accurate comparisons.

Heterotopic ossification (HO) is a well-known complication of traumatic elbow injuries. The reported rates of post-traumatic HO formation vary from less than 5% with simple elbow dislocations, to greater than 50% in complex fracture-dislocations. Previous studies have identified fracture-dislocations, delayed surgical intervention, and terrible triad injuries as risk factors for HO formation. There is, however, a paucity of literature regarding the accuracy of diagnosing post-traumatic elbow HO. Therefore, the purpose of our study was to determine the inter-rater reliability of HO diagnosis using standard radiographs of the elbow at 52 weeks post-injury, as well as to report on the rate of mature compared with immature HO. We hypothesized inter-rater reliability would be poor among raters for HO formation. Prospectively collected data from a large clinical trial was reviewed by three independent reviewers (one senior orthopedic resident, one senior radiology resident, and one expert upper extremity orthopedic surgeon). Each reviewer examined anonymized 52-week post-injury radiographs of the elbow and recorded: 1. the presence or absence of HO, 2. the location of HO, 3. the size of the HO (in cm, if present), and 4. the maturity of the HO formation. Maturity was defined by consensus prior to image review and defined as an area of well-defined cortical and medullary bone outside the cortical borders of the humerus, ulna, or radius. Immature lesions were defined as an area of punctate calcification with an ill-defined cloud-like density outside the cortical borders of the humerus, ulna or radius. Data were collected using a standardized online data collection form (CognizantMD, Toronto, ON, CA). Inter-rater reliability was calculated using Fleiss’ Kappa statistic and a multivariate logistic regression analysis was performed to identify risk factors for HO formation in general, as well as mature HO at 52 weeks post injury. Statistical analysis was performed using RStudio (version1.4, RStudio, Boston, MA, USA). A total of 79 radiographs at the 52-week follow-up were reviewed (54% male, mean age 50, age SD 14, 52% operatively treated). Inter-rater reliability using Fleiss’ Kappa was k= 0.571 (p = 0.0004) indicating moderate inter-rater reliability among the three reviewers. The rate of immature HO at 52 weeks was 56%. The multivariate logistic regression analysis identified male sex as a significant risk factor for HO development (OR 5.29, 1.55-20.59 CI, p = 0.011), but not for HO maturity at 52 weeks. Age, time to surgery, and operative intervention were not found to be significant predictors for either HO formation or maturity of the lesion in this cohort. Our study demonstrates moderate inter-rater reliability in determining the presence of HO at 52 weeks post-elbow injury. There was a high rate (56%) of immature HO at 52-week follow-up. We also report the finding of male sex as a significant risk factor for post traumatic HO development. Future research directions could include investigation into possible male predominance for traumatic HO formation, as well as improving inter-rater reliability through developing a standardized and validated classification system for reporting the radiographic features of HO formation around the elbow

Aims. Acquired heterotopic ossification (HO) is a debilitating disease characterized by abnormal extraskeletal bone formation within soft-tissues after injury. The exact pathogenesis of HO remains unknown. It was reported that BRD4 may contribute to osteoblastic differentiation. The current study aims to determine the role of BRD4 in the pathogenesis of HO and whether it could be a potential target for HO therapy. Methods. Achilles tendon puncture (ATP) mouse model was performed on ten-week-old male C57BL/6J mice. One week after ATP procedure, the mice were given different treatments (e.g. JQ1, shMancr). Achilles tendon samples were collected five weeks after treatment for RNA-seq and real-time quantitative polymerase chain reaction (RT-qPCR) analysis; the legs were removed for micro-CT imaging and subsequent histology. Human bone marrow mesenchymal stem cells (hBMSCs) were isolated and purified bone marrow collected during surgeries by using density gradient centrifugation. After a series of interventions such as knockdown or overexpressing BRD4, Alizarin red staining, RT-qPCR, and Western Blot (Runx2, alkaline phosphatase (ALP), Osx) were performed on hBMSCs. Results. Overexpression of BRD4 enhanced while inhibition of Brd4 suppressed the osteogenic differentiation of hBMSCs in vitro. Overexpression of Brd4 increased the expression of mitotically associated long non-coding RNA (Mancr). Downregulation of Mancr suppressed the osteoinductive effect of BRD4. In vivo, inhibition of BRD4 by JQ1 significantly attenuated pathological bone formation in the ATP model (p = 0.001). Conclusion. BRD4 was found to be upregulated in HO and Brd4-Mancr-Runx2 signalling was involved in the modulation of new bone formation in HO. Cite this article: Bone Joint Res 2021;10(10):668–676

This meta analysis address the relationship between infection developing after total hip arthroplasty (THA) and heterotopic ossification (HO). To identify the gaps in available knowledge, we screened for full-length peer-reviewed research articles listed in PubMed, Embase, and Web of Science over the past 20 years. The following search terms and Boolean operators were used: heterotopic ossification AND infection AND (hip replacement OR hip arthroplasty). The search resulted in the identification of as few as 14 articles describing periprosthetic joint infection (PJI) and HO after THA. Data summarized from 6 studies suitable for further meta-analysis yielded a cumulative sample size of 753 observations, with 186 recorded events of HO. The pooled RR was estimated at 2.22 (95% CI: 1.00 to 4.91, p = 0.0497), suggesting a more than twofold risk of HO compared to the group without PJI. In conclusion, there is a clear association between a higher risk of HO and PJI. Basic research findings support the hypothesis that bacterial pathogen-associated molecular patterns (PAMPs) can lead to osteogenesis through a toll-like receptor (TLR) and nuclear factor kappa B (NF-κB) pathway in the course of HO development. Together, these results suggest that HO prophylaxis should always be prescribed in PJI after THA. Moreover, during revisions following THA for presumed non-septic reasons, the presence of HO warrants consideration for infection, as there is a potential heightened risk of pathologic ossification induced by PAMPs. Keywords: heterotopic ossification; total hip arthroplasty; total hip replacement; periprosthetic joint infection; bacteria. Authors Ł. Pulik and P. Łęgosz contributed equally to this work

Heterotopic ossification (HO) is defined as aberrant bone formation in extraskeletal locations. In this process, local stromal cells of mesenchymal origin abnormally differentiate, resulting in pathologic cartilage and bone matrix deposition. However, the specific cell type and mechanisms beyond this process are not well understood, in part due to the heterogeneity of progenitor cells involved. Here, a combination of single cell RNA sequencing (scRNA-Seq) and lineage tracing, defined the extent to which synovial / tendon sheath progenitor cells contribute to HO. For this purpose, a Tppp3 (tubulin polymerization-promoting protein family member 3) inducible reporter model was used, in combination with either Scx (Scleraxis) or Pdgfra (Platelet derived growth factor receptor alpha) reporter animals. Both arthroplasty-induced and tendon injury-mouse experimental HO models were utilized. ScRNA-Seq of tendon-induced traumatic HO suggested that Tppp3 is a progenitor cell marker for either osteochondral or tendon or cells. After HO induction, Tppp3 reporter+ cell population expanded in number and contributed to cartilage and bone formation in tendon and joint-associated HO. Using double reporter animals, we found that both Pdgfra+Tppp3+ and Pdgfra+Tppp3- progenitor cells produced HO-associated cartilage. Finally, the examination of human samples showed a significant population of TPPP3+ cells overlapping with osteogenic markers in areas of HO. Overall, these results provide novel observations that peritenon and synovial progenitor cells undergo abnormal osteochondral differentiation and contribute to heterotopic bone formation after trauma

Introduction and Objective. Heterotopic ossification is the formation of extraskeletal mineralized tissue commonly associated with either trauma or surgery. While several mouse models have been developed to better characterize the pathologic progression of HO, no model currently exists to study HO of the hip, the most common location of acquired HO in patients. Owing to the unique biological mechanisms underpinning the formation of HO in different tissues, we sought to develop a model to study the post-surgical HO of the hip. Materials and Methods. Wild-type mice C57BL/6J mice were used to study the procedure outcomes, while Pdgfra-CreERT2;mT/mG and Scx-GFP reporter animals were used for the lineage tracing experiments (total n=16 animals, male, 12 weeks old). An anterolateral approach to the hip was performed. Briefly, a 2 cm incision was made centered on the great trochanter and directed proximal to the iliac crest and distally over the lateral shaft of the femur. The joint was then reached following the intermuscular plane between the rectus femoris and gluteus medius muscles. After the joint was exposed, the articular cartilage was removed using a micropower drill with a 1.2 mm reamer. The medius gluteus and superficial fascia were then re-approximated with Vicryl 5-0 suture (Ethicon Inc, Somerville, NJ) and skin was then closed with Ethilon 5-0 suture (Ethicon Inc). Live high resolution XR imaging was performed every 2 wks to assess the skeletal tissues (Faxitron Bioptics, Tucson, AZ). The images were then scored using the Brooker classification. Ex-vivo microCT was conducted using a Skyscan 1275 scanner (Bruker-MicroCT, Kontich, Belgium). 3D reconstruction and analysis was performed using Dragonfly (ORS Inc., Montreal, Canada). For the histological analysis of specimens, Hematoxylin and Eosin (H&E), modified Goldner's Trichrome (GMT) stainings were performed. Reporter activity was assessed using fluorescent imaging. Results. Substantial periarticular heterotopic bone was seen in all cases. A periosteal reaction and an initial formation of calcified tissue within the soft tissue was apparent starting from 4 wks after surgery. By XR, progressive bone formation was observed within the periosteum and intermuscular planes during the subsequent 8 weeks. Stage 1 HO was observed in 12.5% of cases, stage 2 in 62.5% of cases, and stage 3 HO in 25% of cases. 3D microCT reconstructions of the treated hip joints demonstrated significant de novo heterotopic bone in several location which phenocopy human disease. Heterotopic bone was observed in an intracapsular location, periosteal location involving the iliac bone and proximal femur, and intermuscular locations. Histological analyses further confirmed these findings. To assess the cells which gave rise to HO in this model, an inducible PDGFRα and constitutive Scx-GFP reporter mice were used. A dramatic increase in mGFP reporter activity was noted PDGFRα within the HO injury site, including in areas of new cartilage and bone formation. Scx-associated reporter activity increased in the soft tissue and periosteal periacetabular areas of injured hips. Conclusions. HO has a diverse set of pathologies, of which joint associated HO after elective surgery is the most common. Here, we present the first mouse model of hip dislocation and acetabular reaming that mimics elements of human periarticular HO. The diverse locations of HO after acetabular reaming (intracapsular, intermuscular and periosteal) suggests the activation of different and specific HO program after surgery. Such a field effect would be consistent with local trauma and inflammation, which is a well-studied contributor to HO genesis. Not surprisingly, joint-associated HO significantly derives from PDGFRα-expressing cells, which has been shown to similarly give rise to intramuscular and intratendinous HO

Aims. Dystrophic calcification (DC) is the abnormal appearance of calcified deposits in degenerating tissue, often associated with injury. Extensive DC can lead to heterotopic ossification (HO), a pathological condition of ectopic bone formation. The highest rate of HO was found in combat-related blast injuries, a polytrauma condition with severe muscle injury. It has been noted that the incidence of HO significantly increased in the residual limbs of combat-injured patients if the final amputation was performed within the zone of injury compared to that which was proximal to the zone of injury. While aggressive limb salvage strategies may maximize the function of the residual limb, they may increase the possibility of retaining non-viable muscle tissue inside the body. In this study, we hypothesized that residual dead muscle tissue at the zone of injury could promote HO formation. Methods. We tested the hypothesis by investigating the cellular and molecular consequences of implanting devitalized muscle tissue into mouse muscle pouch in the presence of muscle injury induced by cardiotoxin. Results. Our findings showed that the presence of devitalized muscle tissue could cause a systemic decrease in circulating transforming growth factor-beta 1 (TGF-β1), which promoted DC formation following muscle injury. We further demonstrated that suppression of TGF-β signalling promoted DC in vivo, and potentiated osteogenic differentiation of muscle-derived stromal cells in vitro. Conclusion. Taken together, these findings suggest that TGF-β1 may play a protective role in dead muscle tissue-induced DC, which is relevant to understanding the pathogenesis of post-traumatic HO. Cite this article: Bone Joint Res 2020;9(11):742–750

Heterotopic Ossification (HO) is a known complication that can arise after total elbow arthroplasty (TEA). In most cases it is asymptomatic, however, in some patients it can limit range of motion and lead to poor outcomes. The objective of this review was to assess and report incidence, risk factors, prophylaxis, and management of HO after TEA. A systematic search was conducted using MEDLINE, EMBASE, and PubMed to retrieve all relevant studies evaluating occurrence of HO after TEA. The search was performed in duplicate and a quality assessment was performed of all included studies. A total of 1907 studies were retrieved of which 45 studies were included involving 2256 TEA patients. HO was radiographically present in 10% of patients and was symptomatic in 3%. Less than 1% of patients went on to surgical excision of HO, with outcomes following surgery reported as good or excellent as assessed by range of motion and Mayo Elbow Performance Scores (MEPS). TEA due to ankylosis, primary osteoarthritis, and posttraumatic arthritis are more likely to develop symptomatic HO. HO is an uncommon complication following TEA with the majority of patients developing HO being asymptomatic and requiring no surgical management. Routine HO prophylaxis for TEA is not supported by the literature. The effectiveness of prophylaxis in high risk patients is uncertain and future studies are required to clarify its usefulness. The strength of these conclusions are limited by inconsistent reporting in the available literature

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

Heterotopic ossification (HO) is lamellar bone formation that occurs within tissues that do not normally have properties of ossification. The pathoaetiology of HO is poorly understood. We conducted a genome wide association study to better understand the genetic architecture of HO. 891 patients of European descent (410 HO cases) following THA for primary osteoarthritis were recruited from the UK. HO was assessed from plain AP radiographs of the pelvis. Genomic DNA was extracted, genotyped using the Illumina 610 beadchip and referenced using the 1000 Genome Project panel. HO susceptibility case-control analysis and an evaluation of disease severity in those with HO was undertaken using SNPTESTv2.3.0 on>10 million variants. We tested variants most strongly associated with HO in an independent UK THA replication cohort comprising 209 cases and 211 controls. The datasets were meta-analysed using PLINK. In the discovery cohort 70 signals with an index variant at p<9×10–5 were suggestively associated with HO susceptibility. The strongest signal lay just downstream of the gene ARHGAP18 (rs59084763, effect allele frequency (EAF) 0.19, OR1.87 [1.48–2.38], p=2.48×10–8), the second strongest signal lay within the long non-coding (LNC) RNA gene CASC20 (rs11699612, EAF 0.25, OR1.73 [1.1.40–2.16, p=9.3×10–8). In the discovery cohort 73 signals with an index variant at p<9×10–5 were associated with HO severity. At replication, 12 of the leading 14 susceptibility signals showed a concordant direction of allelic effect and 5 replicated at nominal significance. Following meta-analysis, the lead replicating susceptibility signal was the CASC20 variant rs11699612 (p=2.71×10–11). We identify consistent replicating association of variation within the LNC RNA CASC20 with HO susceptibility after THA. Although the function of CASC20 is currently unknown, possible mechanisms include transcriptional, post-transcriptional and epigenetic regulation of downstream target genes. The work presented here provides new avenues for the development of novel predictive and therapeutic approaches towards HO

Electron Microscopy and Synchrotron analysis of Heterotopic Ossification (HO) from blast-related amputees' has shown that HO is bone with a disorganised structure and altered remodelling. This research performs mechanical testing of HO to understand its biomechanical properties in an attempt to create an accurate model to predict its morphological appearance. The hypothesis of this work is that HO is mechanically mediated in its formation. Synchrotron mechanical analysis of HO samples was performed to measure Young's modulus, ultimate strength and density distribution. A novel algorithm based on Wolf's law was implemented in a Finite Element (FE) analysis model of HO to take into account the differing mechanical and biological properties measured and the presence of HO outside the skeletal system. An HO modeling factor, which considers boundary conditions, and regulates recruitment of the soft tissue into bone formation, results in a re-creatable formation of HO within the soft tissues, comparable to the appearance of HO seen in military amputees. The results and model demonstrates that certain types of HO are under the control of endogenous and exogenous mechanical stimulus. HO can thus be mechanically exploited in the casualty management and rehabilitation process to achieve better clinical outcomes

Introduction. Heterotopic Ossification(HO) is a recognized complication following Total Hip Arthroplasty(THA) that can compromise patient outcomes. Our objectives were to report its incidence and risk factors in a modern arthroplasty unit(MAU). Methods. 2305 consecutive primary THAs in 2150 patients(887♂;1263♀) undertaken at a single centre and followed-up for at least one year constituted the study cohort. A retrospective review of patient demographics (age, side, body mass index[BMI], type of anaesthesia, surgical approach, method of fixation, estimated blood loss[EBL] and operative time), serial radiographs and outcome measure (The Oxford hip score[OHS]) were undertaken. All HO were further followed for additional four years to determine the incidence of Revision THA at five years. Descriptive statistics and logistic regression was undertaken to identify the risk factors for HO using Statistical Package(SPSS) version16. Results. The mean age and BMI were 67.9±SD9.9years and 29.7±SD5.5 respectively. The mean operative time and blood loss was 72±SD18minutes. 148 hips in 146 patients(83♂;63♀) had established HO in 6.79% patients(146/2150). The first year incidence of HO was 6.42%(148/2305) and the incidence of severe HO (Brooker's Grade III+IV) was 1.47%(34/2305). We did not find any difference in the incidence of HO for choice of fixation (Cemented[6.9%]; Uncemented[6.7%]; Hybrid[5.6%]). The mean OHS was 42±SD7 and overall satisfaction at one year was 97.5%. There was no difference in OHS between the two groups(p=0.39). Statistically significant risk factors (p=0.0001) on logistical regression were male gender (Odds Ratio[OR]=1.97;95%CI:1.40–2.76) and anterolateral (OR=2.05;95%CI:1.42–2.95) approach. Excision of HO mass and Revision THA was undertaken in two instances by five years. Discussion. Incidence of HO in MAU is lower than previous published literature (10–47%). Uncemented THA. EBL and epidural anaesthetic were not found to be associated with higher incidence of HO as previously reported in the literature. The incidence of Revision THA in HO patients was 1.35% at 5 years

Heterotopic ossification (HO) is the formation of bone at extra-skeletal sites. Genetic diseases, traumatic injuries, or severe burns can induce this pathological condition and can lead to severe immobility. While the mechanisms by which the bony lesions arise are not completely understood, intense inflammation associated with musculoskeletal injury and/or highly invasive orthopaedic surgery is thought to induce HO. The incidence of HO has been reported between 3% and 90% following total hip arthroplasty. While the vast majority of these cases are asymptomatic, some patients will present decreased range of motion and painful swelling around the affected joints leading to severe immobility. In severe cases, ectopic bone formation may be involved in implant failure, leading to costly and painful revision surgery. The effects of surgical-related intraoperative risk factors for the formation of HO can also play a role. Prophylactic radiation therapy, and anti-inflammatory and biphosphonates agents have shown some promise in preventing HO, but their effects are mild to moderate at best and can be complicated with adverse effects. Irradiation around surgery could decrease the incidence of HO. However, high costs and the risk of soft tissue sarcoma inhibit the use of irradiation. Increased trials have demonstrated that nonsteroidal anti-inflammatory drugs (NSAID) are effective for the prevention of HO. However, the risk of gastrointestinal side effects caused by NSAID has drawn the attention of surgeons. The effect of the selective COX-2 inhibitor, celecoxib, is associated with a significant reduction in the incidence of HO in patients undergoing THA. Bone morphogenetic proteins (BMP) such as BMP2 identified another novel druggable target, i.e., the remote application of apyrase (ATP hydrolyzing agent) in the burn site decreased HO formation and mitigated functional impairment later. The question is if apyrase can be safely administered through other, such as systematical, routes. While the systemic treatments have shown general efficacy and are used clinically, there may be great benefit obtained from more localised treatment or from more targeted inhibitors of osteogenesis or chondrogenesis. In the surgical setting, prophylaxis for HO is regularly indicated due to the considerable risk of functional impairment. Heterotopic ossification is a well-known complication of total hip arthroplasty, especially when the direct lateral approach is used. Possible intraoperative risks are the size of incision, approach, duration of surgery and gender that can be associated with higher rates of HO or increase of the severity of HO. Like inflammation and tissue damage/ischemia are likely to be the key in the formation of HO, kindness to the soft tissues, tissue preserving surgery, pulse lavage to remove bone inducing factors and avoiding damage to all tissues should be erased as a comorbidity. Incision length, tissue dissection and subsequent localised trauma and ischemia, blood loss, anesthetic type and length of surgery may all contribute to the local inflammatory response. Data suggest that the surgeon may control the extent and nature of HO formation by limiting the incision length and if possible the length of the operation. Currently resection of HO is generally suggested after complete maturation (between 14–18 months), since earlier intervention is thought to predispose to recurrence. Reliable indicators of maturation of HO are diminishing activity on serial bone scans and/or decreasing levels of alkaline phosphatase. Although usually asymptomatic, heterotopic bone formation can cause major disability consisting of pain and a decreased range of motion in up to 7% of patients undergoing THA. Patients benefit from early resection of the heterotopic ossification with a proper and reliable postoperative strategy to prevent recurrence of HO with clinical implications

Aims

The effects of remnant preservation on the anterior cruciate ligament (ACL) and its relationship with the tendon graft remain unclear. We hypothesized that the co-culture of remnant cells and bone marrow stromal cells (BMSCs) decreases apoptosis and enhances the activity of the hamstring tendons and tenocytes, thus aiding ACL reconstruction.

Heterotopic ossification (HO) is perhaps the single most significant obstacle to independence, functional mobility, and return to duty for combat-injured veterans of Operation Enduring Freedom and Operation Iraqi Freedom. Recent research into the cause(s) of HO has been driven by a markedly higher prevalence seen in these wounded warriors than encountered in previous wars or following civilian trauma. To that end, research in both civilian and military laboratories continues to shed light onto the complex mechanisms behind HO formation, including systemic and wound specific factors, cell lineage, and neurogenic inflammation. Of particular interest, non-invasive in vivo testing using Raman spectroscopy may become a feasible modality for early detection, and a wound-specific model designed to detect the early gene transcript signatures associated with HO is being tested. Through a combined effort, the goals of early detection, risk stratification, and development of novel systemic and local prophylaxis may soon be attainable.

Aims

Pigment epithelium-derived factor (PEDF) is known to induce several types of tissue regeneration by activating tissue-specific stem cells. Here, we investigated the therapeutic potential of PEDF 29-mer peptide in the damaged articular cartilage (AC) in rat osteoarthritis (OA).

Background. Heterotopic ossification (HO) is lamellar bone formation in the soft tissues following trauma or joint replacement for osteoarthritis (OA). A genome wide association study of HO patients after total hip arthroplasty for OA has identified Kinesin Family Member 26B (KIF26B) as a gene associated with HO severity. KIF26B has previously been associated with HO in mice. Hypothesis and aims: We hypothesised that Kif26b regulates the osteogenic trans-differentiation of myoblasts; a possible mechanism of HO. Using an in vitro model, we wished to establish whether Kif26b is involved in HO formation and to explore the molecular mechanism. Methods. We developed CRISPR/Cas9 mediated Kif26b knockout (KO) C2C12 myoblasts. Wild type (WT) and KO cells were transdifferentiated towards an osteogenic lineage using BMP-2 for 24 days. The effect of Kif26b KO on mineralisation was quantified by calcium staining. The mean difference (±SEM) in gene expression between WT and KO lines was compared with ANOVA. Results. qPCR and western blotting confirmed Kif26b knockout. Kif26b deficient cells produced substantially less mineral versus WT in response to BMP-2 (34.71% ±3.62%, n=12, P<0.0001). At day 8 of osteogenic differentiation, loss of Kif26b abrogated Osterix (113.6 ±6.781 n=5, P<0.0001), Osteocalcin (737.9 ±84.25, n=5, P<0.0001) and Alkaline phosphatase (6989 ±365.7, n=5, P<0.0001) expression, and down regulated Runx2 (2.725 ±0.7724, n=5, P<0.0052) and Collagen type I (7.25 ±1.154, n=5, P<0.0001) expression relative to WT. The knockout cells also appeared morphologically different. Compared to WT, the Kif26b KO cells displayed a less osteoblast-like morphology during transdifferentiation. Conclusion. Our findings demonstrate an undescribed function for Kif26b as a critical regulator of pathological ossification, with a putative role in HO pathogenesis after THA

Previous reports of the prevalence of Heterotopic Ossification (HO) in limbs from UK blast-related amputees from Afghanistan, is demonstrated to be 57.1%. With the end of UK military operations in Afghanistan in 2014 the aim of this study is establish the rate of HO, assess causality demographics and ascertain risk factors for the formation of HO during the entire period of operations in Afghanistan. Military databases, case notes and radiographs were scrutinised to quantify and qualify the prevalence and risk factors for the formation of HO. 256 servicemen sustained 398 military trauma related amputations. The overall prevalence of HO was 65.9%. Significant (p<0.05) risks identified for the formation of HO included a blast mechanism of injury, a zone of injury the same as the subsequent amputation, and an increased number of debridements prior to closure. Positive correlation existed between the number of amputations and the presence and grade of HO (p=0.04). HO presents clinical problems to military blast injury patient populations. This study demonstrates that both a blast mechanism of injury and an increased injury load are key factors in the increased prevalence of HO seen in military trauma

Heterotopic ossification (HO) is the formation of lamellar bone in extra-skeletal soft tissues. Its exact pathogenic mechanism remains elusive. Previous studies demonstrate observation only of HO at the microscopic scale. This study uses scanning electron microscopy (SEM), Back-scatter electron (BSE) imaging and mechanical testing to detail the organic and non-organic elements of HO, compared to normal bone, to guide stem cell and bio-modelling research into HO. Samples analysed were 5 military blast related HO patients, 5 control cadaveric samples (age and sex matched). Samples were imaged using SEM, BSE and the I13 beam Synchrotron x-ray diffraction scanner using validated quantitative and qualitative techniques of measurement. Appearances seen in HO compared to normal bone were characterised by the presence of a hyper-vascular network and high lacunae (osteocyte) counts, two distinct zones of bone mineral density distribution, with a tendency for hypermineralisation with kurtosis of the grey scale plots (mineral content as a weight percentage of Ca. 2+. was calibrated to atomic weight of C, Al and HA). Direction of dependence and collagen orientation in HO suggest isotropic properties. This research demonstrates that HO is bone, however its characteristics suggest a high metabolic turnover and disorganised ultra-structure consistent with an inflammatory origin

Introduction: Heterotopic ossification (HO) occurs commonly after total hip arthroplasty (THA). Its severe form can result in impaired range of motion with reduced functional outcome. The rate and severity of HO after hip surface replacement arthroplasty (SRA) have never been well studied. Methods: Two hundred and ten hips (194 patients) were randomized to receive uncemented metal-on-metal THA (103) or metal-on-metal SRA (107). Standard antero-posterior radiographs of the pelvis were assessed for HO by 2 reviewers at the latest follow-up (minimum of 6 months), using Brooker severity grading and Kjaersgaard-Andersen regional classification. Results: Pre-operative and post-operative data were similar for both groups. The incidence of HO was 38.5% in the SRA group compared to 32.6% in the THA group (p=0.5). However, there was a significant difference in severity grades for the 2 groups (chi square, p=0.02). According to Brooker_s classification, nearly half of HO was of grade 2 in SRA and of grade 1 in THA. SRA was associated with significantly higher rates of severe HO (grades 3 and 4) than THA (12.5% vs. 2.2%; p=0.009). Inter-rater agreement for Brooker grading was excellent (Cohen_s kappa, 0.88; p< 0.01). HO in SRA involved both the central and lateral regions in 26% of cases, whereas only 3% of HO in THA showed such a pattern (p=0.025). Risk factors, such as male gender, osteoarthritis, bilateral predilection, and previous history of HO, were observed in both groups. Patients with HO had reduced internal hip rotation (16.4° vs. 22.2°; p=0.02) and a higher incidence of postoperative hip pain (52% vs. 30%; p=0.04), but comparable functional outcome scores. Discussion: The incidence of HO after hip arthroplasty seems to be determined by patient-related factors. However, HO severity appears to be associated with local surgical factors and thereby SRA may result in more severe HO than THA. An extensive surgical approach, additional soft tissue release and the blunt damage occurring in gluteal muscles with SRA may signal the induction of more severe HO. Peri-operative deposition of bone debris derived from femoral head preparation may also play a role by transplanting osteoprogenitor cells. Surgeons must be aware of this risk of severe HO when offering SRA as an alternative treatment to younger patients. Routine prophylaxis with NSAIDs needs to be considered in these patients. A meticulous surgical technique to reduce muscle damage, pulsed lavage to clear bone debris, and debridement of necrotic tissue, may help to decrease the risk of severe HO in SRA