Calcified apoptotic vesicles from PROCR+ fibroblasts initiate heterotopic ossification.

Heterotopic ossification (HO) comprises the abnormal formation of ectopic bone in extraskeletal soft tissue. The factors that initiate HO remain elusive. Herein, we found that calcified apoptotic vesicles (apoVs) led to increased calcification and stiffness of tendon extracellular matrix (ECM), which initiated M2 macrophage polarization and HO progression. Specifically, single-cell transcriptome analyses of different stages of HO revealed that calcified apoVs were primarily secreted by a PROCR+ fibroblast population. In addition, calcified apoVs enriched calcium by annexin channels, absorbed to collagen I via electrostatic interaction, and aggregated to produce calcifying nodules in the ECM, leading to tendon calcification and stiffening. More importantly, apoV-releasing inhibition or macrophage deletion both successfully reversed HO development. Thus, we are the first to identify calcified apoVs from PROCR+ fibroblasts as the initiating factor of HO, and might serve as the therapeutic target for inhibiting pathological calcification.

iMSC-mediated delivery of ACVR2B-Fc fusion protein reduces heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by a gain-of-function mutation in ACVR1, which is a bone morphogenetic protein (BMP) type I receptor. Moreover, it causes progressive heterotopic ossification (HO) in connective tissues. Using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) and mouse models, we elucidated the underlying mechanisms of FOP pathogenesis and identified a candidate drug for FOP. METHODS: In the current study, healthy mesenchymal stem/stromal cells derived from iPSCs (iMSCs) expressing ACVR2B-Fc (iMSCACVR2B-Fc), which is a neutralizing receptobody, were constructed. Furthermore, patient-derived iMSCs and FOP mouse model (ACVR1R206H, female) were used to confirm the inhibitory function of ACVR2B-Fc fusion protein secreted by iMSCACVR2B-Fc on BMP signaling pathways and HO development, respectively. RESULTS: We found that secreted ACVR2B-Fc attenuated BMP signaling initiated by Activin-A and BMP-9 in both iMSCs and FOP-iMSCs in vitro. Transplantation of ACVR2B-Fc-expressing iMSCs reduced primary HO in a transgenic mouse model of FOP. Notably, a local injection of ACVR2B-Fc-expressing iMSCs and not an intraperitoneal injection improved the treadmill performance, suggesting compound effects of ACVR2B-Fc and iMSCs. CONCLUSIONS: These results offer a new perspective for treating FOP through stem cell therapy.

Aspectos clínicos, radiográficos e estratégias terapêuticas da Síndrome de Eagle: revisão de literatura / Clinical, radiographic aspects and therapeutic strategies of Eagle Syndrome: literature review

Objetivo: Este trabalho tem como propósito fornecer uma análise abrangente das características anatômicas, clínicas e radiográficas da Síndrome de Eagle, além de abordar os métodos de diagnóstico e estratégias terapêuticas. Materiais e métodos: Foi realizada uma busca por artigos científicos publicados no período de 2016 a 2024, utilizando as bases de dados Scientific Electronic Library Online (SciELO), US National Library of Medicine (PubMed) e Google Scholar. A coleta de artigos foi realizada nos idiomas inglês e português, utilizando as palavras-chave: "síndrome de eagle", "síndrome estiloide", "síndrome da artéria carótida", "estilalgia", "eagle syndrome", "styloid syndrome", "carotid artery syndrome" e "stylalgia". Conclusão: Os profissionais devem estar atentos à síndrome de Eagle em casos de dor unilateral ao realizar atividades como engolir, bocejar e chorar, sem causa aparente, especialmente em mulheres adultas que não encontram alívio com analgésicos. Devido à frequência de casos assintomáticos, a realização precoce de exames radiológicos desempenha um papel crucial na avaliação diagnóstica. É essencial que profissionais de Otorrinolaringologia, Neurologia e Odontologia estejam cientes dessa síndrome, pois está associada a uma significativa deterioração na qualidade de vida. (AU)

Objective: This work aims to provide a comprehensive analysis of the anatomical, clinical and radiographic characteristics of Eagle Syndrome, in addition to addressing diagnostic methods and therapeutic strategies. Materials and methods: A search was carried out for scientific articles published between 2016 and 2024, using the Scientific Electronic Library Online (SciELO), US National Library of Medicine (PubMed) and Google Scholar databases. Articles were collected in English and Portuguese, using the keywords: "eagle syndrome", "styloid syndrome", "carotid artery syndrome", "stilalgia", "eagle syndrome", "styloid syndrome", "carotid artery syndrome" and "stylalgia". Conclusion: Professionals should be aware of Eagle syndrome in cases of unilateral pain when performing activities such as swallowing, yawning and crying, without an apparent cause, especially in adult women who do not find relief with analgesics. Due to the frequency of asymptomatic cases, early radiological examinations play a crucial role in diagnostic evaluation. It is essential that Otorhinolaryngology, Neurology and Dentistry professionals are aware of this syndrome, as it is associated with a significant deterioration in quality of life. (AU)

Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder with episodic and progressive heterotopic ossification. Tissue trauma is a major risk factor for flareups, heterotopic ossification (HO), and loss of mobility in patients with FOP. The International Clinical Council on FOP generally recommends avoiding surgery in patients with FOP unless the situation is life-threatening, because soft tissue injury can trigger an FOP flareup. Surprisingly little is known about flareups, HO formation, and loss of mobility after fractures of the normotopic (occurring in the normal place, distinct from heterotopic) skeleton when treated nonoperatively in patients with FOP. QUESTIONS/PURPOSES: (1) What proportion of fractures had radiographic evidence of union (defined as radiographic evidence of healing at 6 weeks) or nonunion (defined as the radiographic absence of a bridging callus at 3 years after the fracture)? (2) What proportion of patients had clinical symptoms of an FOP flareup because of the fracture (defined by increased pain or swelling at the fracture site within several days after closed immobilization)? (3) What proportion of patients with fractures had radiographic evidence of HO? (4) What proportion of patients lost movement after a fracture? METHODS: We retrospectively identified 36 patients with FOP from five continents who sustained 48 fractures of the normotopic skeleton from January 2001 to February 2021, who were treated nonoperatively, and who were followed for a minimum of 18 months after the fracture and for as long as 20 years, depending on when they sustained their fracture during the study period. Five patients (seven fractures) were excluded from the analysis to minimize cotreatment bias because these patients were enrolled in palovarotene clinical trials (NCT02190747 and NCT03312634) at the time of their fractures. Thus, we analyzed 31 patients (13 male, 18 female, median age 22 years, range 5 to 57 years) who sustained 41 fractures of the normotopic skeleton that were treated nonoperatively. Patients were analyzed at a median follow-up of 6 years (range 18 months to 20 years), and none was lost to follow-up. Clinical records for each patient were reviewed by the referring physician-author and the following data for each fracture were recorded: biological sex, ACVR1 gene pathogenic variant, age at the time of fracture, fracture mechanism, fracture location, initial treatment modality, prednisone use at the time of the fracture as indicated in the FOP Treatment Guidelines for flare prevention (2 mg/kg once daily for 4 days), patient-reported flareups (episodic inflammatory lesions of muscle and deep soft connective tissue characterized variably by swelling, escalating pain, stiffness, and immobility) after the fracture, follow-up radiographs of the fracture if available, HO formation (yes or no) as a result of the fracture determined at a minimum of 6 weeks after the fracture, and patient-reported loss of motion at least 6 months after and as long as 20 years after the fracture. Postfracture radiographs were available in 76% (31 of 41) of fractures in 25 patients and were independently reviewed by the referring physician-author and senior author for radiographic criteria of fracture healing and HO. RESULTS: Radiographic healing was noted in 97% (30 of 31) of fractures at 6 weeks after the incident fracture. Painless nonunion was noted in one patient who sustained a displaced patellar fracture and HO. In seven percent (three of 41) of fractures, patients reported increased pain or swelling at or near the fracture site within several days after fracture immobilization that likely indicated a site-specific FOP flareup. The same three patients reported a residual loss of motion 1 year after the fracture compared with their prefracture status. HO developed in 10% (three of 31) of the fractures for which follow-up radiographs were available. Patient-reported loss of motion occurred in 10% (four of 41) of fractures. Two of the four patients reported noticeable loss of motion and the other two patients reported that the joint was completely immobile (ankylosis). CONCLUSION: Most fractures treated nonoperatively in individuals with FOP healed with few flareups, little or no HO, and preservation of mobility, suggesting an uncoupling of fracture repair and HO, which are two inflammation-induced processes of endochondral ossification. These findings underscore the importance of considering nonoperative treatment for fractures in individuals with FOP. Physicians who treat fractures in patients with FOP should consult with a member of the International Clinical Council listed in the FOP Treatment Guidelines ( https://www.iccfop.org ). LEVEL OF EVIDENCE: Level IV, therapeutic study.

Pathogenesis of acquired heterotopic ossification: Risk factors, cellular mechanisms, and therapeutic implications.

Heterotopic ossification (HO), including hereditary and acquired HO, is the formation of extraskeletal bone in skeletal muscle and surrounding soft tissues. Acquired HO is often caused by range of motion, explosion injury, nerve injury or burns. Severe HO can lead to pain and limited joint activity, affecting functional rehabilitation and quality of life. Increasing evidence shows that inflammatory processes and mesenchymal stem cells (MSCs) can drive HO. However, explicit knowledge about the specific mechanisms that result in HO and related cell precursors is still limited. Moreover, there are no effective methods to prevent or reduce HO formation. In this review, we provide an update of known risk factors and relevant cellular origins for HO. In particular, we focus on the underlying mechanisms of MSCs in acquired HO, which follow the osteogenic program. We also discuss the latest therapeutic value and implications for acquired HO. Our review highlights the current gaps in knowledge regarding the pathogenesis of acquired HO and identifies potential targets for the prevention and treatment of HO.

Preoperative Arterial Embolization for Heterotopic Ossification of the Hip.

PURPOSE: To investigate the efficacy and safety of preoperative arterial embolization for neurogenic heterotopic ossification (NHO) of the hip. MATERIALS AND METHODS: This single-center retrospective study reviewed outcomes in 16 consecutive patients who had surgical resection of NHO of the hip: 8 of whom underwent preoperative arterial embolization and 8 of whom did not. Both patient cohorts had similar baseline characteristics. A mean of 2.62 ± 1.9 arteries per patient, including the gluteal, lateral circumflex femoral, and deep circumflex iliac branches, were embolized using an n-butyl cyanoacrylate (NBCA)-ethiodized oil mixture. Data from both cohorts regarding intraoperative blood loss, volume of blood transfused, complications, and duration of hospitalization were compared. RESULTS: A mean of 2.6 ± 1.9 arteries were embolized with NBCA-ethiodized oil, mainly the gluteal arteries, lateral circumflex femoral artery, and deep circumflex iliac artery. In the embolization group, mean intraoperative blood loss was 875 mL ± 320, mean number of units of blood used was 0.5 ± 0.7, and mean number of days of hospitalization was 6.4 days ± 1.6. In the control group, mean intraoperative blood loss was 1,350 mL ± 120, mean number of units of blood used was 2 ± 1.1, and average number of days of hospitalization was 11.5 days ± 1.4. The embolization group had a mean reduction in blood loss of 40.7% (P = 0.035), reduction in units of blood administered of 75% (P = 0.021), and reduction in days of hospitalization of 44.7% (P = 0.014). No procedural complications were recorded. CONCLUSIONS: Preoperative arterial embolization is effective and safe in reducing intraoperative blood loss, number of hospitalization days, and need for blood transfusions in surgical resection of NHO of the hip.

Carotid artery type of Eagle syndrome: an uncommon cause of ischemic stroke.

Acute ischemic stroke in patients younger than the age of 50 years is a rare occurrence that results in high mortality and substantial loss of functional years of life. Internal carotid artery dissection (CAD) presents a rare, but serious condition that needs to be fully evaluated and carefully treated, as it may lead to an acute ischemic stroke in all, but mostly in younger patients. A possible cause for CAD, the carotid artery type of Eagle syndrome (ESy), is atypical and underrecognized. In this case report we present a case of a young patient with carotid artery type of ESy, resulting in a severe acute ischemic stroke. Only recognition of such a syndrome in its early symptomatic phase could allow appropriate management to prevent this kind of a deleterious outcome.

The effect of extracorporeal shock wave therapy on large neurogenic heterotopic ossification in a patient with pontine hemorrhage: A case report and literature review.

RATIONALE: Heterotopic ossification (HO), an ectopic bone formation in soft tissue around the joint, is a complication observed in stroke patients. HO around the hip joint causes a reduction in the functional ability of patients by generating pain and limiting range of motion (ROM). In addition, it results in impaired mobility, ultimately affecting quality of life and increasing the mortality of patients. Extracorporeal shock wave therapy (ESWT) has demonstrated efficacy in treating soft tissue inflammation and has been used to reduce patients' pain in HO. However, almost none of the studies reported degradation in the size of HO on images obtained before and after ESWT application. PATIENT CONCERNS AND DIAGNOSIS: We report a case of a 36-year-old man who developed HO around both hip joints 3 months after bilateral pontine hemorrhage. INTERVENTIONS: Seven months after HO development, ESWT was administered to the area of HO every other day for a total of 10 sessions. OUTCOMES: Immediately following treatment, the ROM of both hip joints increased. Thus the patient was able to maintain a sitting posture without having to be bound to the wheelchair. In addition, the tolerable sitting time before groaning increased from less than ten minutes to almost 60 minutes by the end of all ESWT sessions. Unlike other previous reports, a diminished HO size was confirmed by comparing plain X-rays and bone scans obtained before and after treatment sessions. LESSONS: In this case, we report an objective size reduction in HO in radiologic findings after applying ESWT to both hips. ESWT is a safe, easy-to-apply, and noninvasive modality. We would like to emphasize the use of ESWT as a treatment option for HO to decrease the extent of HO, as well as to improve pain, spasticity and function in patients with stroke.

Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery.

Heterotopic ossification is the most disabling feature of fibrodysplasia ossificans progressiva, an ultra-rare genetic disorder for which there is currently no prevention or treatment. Most patients with this disease harbor a heterozygous activating mutation (c.617 G > A;p.R206H) in ACVR1. Here, we identify recombinant AAV9 as the most effective serotype for transduction of the major cells-of-origin of heterotopic ossification. We use AAV9 delivery for gene replacement by expression of codon-optimized human ACVR1, ACVR1R206H allele-specific silencing by AAV-compatible artificial miRNA and a combination of gene replacement and silencing. In mouse skeletal cells harboring a conditional knock-in allele of human mutant ACVR1 and in patient-derived induced pluripotent stem cells, AAV gene therapy ablated aberrant Activin A signaling and chondrogenic and osteogenic differentiation. In Acvr1(R206H) knock-in mice treated locally in early adulthood or systemically at birth, trauma-induced endochondral bone formation was markedly reduced, while inflammation and fibroproliferative responses remained largely intact in the injured muscle. Remarkably, spontaneous heterotopic ossification also substantially decreased in in Acvr1(R206H) knock-in mice treated systemically at birth or in early adulthood. Collectively, we develop promising gene therapeutics that can prevent disabling heterotopic ossification in mice, supporting clinical translation to patients with fibrodysplasia ossificans progressiva.

[Research progress of traumatic heterotopic ossification].

Objective: To review and evaluate the research progress of traumatic heterotopic ossification (HO). Methods: The domestic and foreign related research literature on traumatic HO was widely consulted, and its etiology, pathogenesis, pathological progress, diagnosis, prevention, and treatment were summarized. Results: Traumatic HO is often caused by severe trauma such as joint operation, explosion injury, nerve injury, and burn. At present, it is widely believed that the occurrence of traumatic HO is closely related to inflammation and hypoxia. Oral non-steroidal anti-inflammatory drugs and surgery are the main methods to prevent and treat traumatic HO. Conclusion: Nowadays, the pathogenesis of traumatic HO is still unclear, the efficiency of relevant prevention and treatment measures is low, and there is a lack of specific treatment method. In the future, it is necessary to further study the pathogenesis of traumatic HO and find specific prevention and treatment targets.

Allele-Selective LNA Gapmers for the Treatment of Fibrodysplasia Ossificans Progressiva Knock Down the Pathogenic ACVR1R206H Transcript and Inhibit Osteogenic Differentiation.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by episodic heterotopic ossification. The median life span of people with this disorder is ∼40 years, and currently, there is no effective treatment available. More than 95% of cases are caused by a recurrent mutation (c.617G>A; R206H) of Activin A receptor, type I (ACVR1)/Activin receptor-like kinase-2 (ALK2), a bone morphogenetic protein type I receptor. The mutation renders ACVR1 responsive to activin A, which does not activate wild-type ACVR1. Ectopic activation of ACVR1R206H by activin A induces heterotopic ossification. Since ACVR1R206H is a hyperactive receptor, a promising therapeutic strategy is to decrease the activity of mutated ACVR1. To accomplish this goal, we developed locked nucleic acid (LNA) gapmers. These are short DNA oligonucleotides with LNA modification at both ends. They induce targeted mRNA degradation and specific knockdown of gene expression. We demonstrated that some of these gapmers efficiently knocked down ACVR1R206H expression at RNA levels, while ACVR1WT was mostly unaffected in human FOP fibroblasts. Also, the gapmers suppressed osteogenic differentiation induced by ACVR1R206H and activin A. These gapmers may be promising drug candidates for FOP. This novel strategy will also pave the way for antisense-mediated therapy of other autosomal dominant disorders.

Long-term radial extracorporeal shock wave therapy for neurogenic heterotopic ossification after spinal cord injury: A case report.

Context: Heterotopic ossification is characterized by abnormal growth of bone in soft tissues. Neurogenic heterotopic ossification is also closely related to central nervous system injuries and has been reported to respond to radial extracorporeal shock wave therapy.Findings: In this case, a radial extracorporeal shock wave therapy (five times per week, lasted for almost one year) was applied to a patient with neurogenic heterotopic ossification on the left hip as a result of spinal cord injury. Throughout the treatment session, the heterotopic ossification lesion was gradually diminished, associated with the increase in joint range of motion, pain mitigation and decrease in serum alkaline phosphatase level.Conclusion/clinical relevance: Long-term radial extracorporeal shock wave therapy offers a promising therapeutic alternative for neurogenic heterotopic ossification.

Exosomes for gene therapy effectively inhibit the endothelial-mesenchymal transition in mouse aortic endothelial cells.

BACKGROUND: Heterotopic ossification (HO) can limit joint activity, causes ankylosis and impairs the function and rehabilitation of patients. Endothelial to mesenchymal transition (EndMT) plays an important role in the pathogenesis of HO, and high expression of SMAD7(Mothers Against Decapentaplegic Homolog 7) in endothelial cells can effectively reverse the TGF-ß1 mediated EndMT. This article studied an appropriately engineered exosome with high biocompatibility and good targeting property to administrate SMAD7 gene therapy to inhibit the EndMT. METHODS: Exosomes from mouse aortic endothelial cells were cultured and harvested. DSPE-PEG and antibody CD34 were combined to exosomes to synthesize the endothelial cell targeting exosome vector (Exosome-DSPE-PEG-AbCD34). The biocompatibility, stability, targeting and cell internalization of exosome vector were tested, then the Exosome-DSPE-PEG-AbCD34 was loaded with Smad7 plasmid and administrated to MAECs to examine its therapeutic effect on EndMT of MAEC mediated by TGF-ß1. RESULTS: The Exosome-DSPE-PEG-AbCD34 has no impact on MAEC cell viability at high concentration, and exosome-DSPE-PEG-AbCD34 could be stably stored at 4°C and 37°C for at least 8 days. Exosome-DSPE-PEG-AbCD34 has better targeting property to MAEC cells and can enter into the cells more effectively. The Exosome-DSPE-PEG-AbCD34-Smad7 could significantly increase the level of SMAD7, decrease the expression of TGF-ß1, and effectively reverse the EndMT of MAEC mediated by TGF- ß1 in MAEC cells. CONCLUSIONS: The synthesized Exosome-DSPE-PEG-AbCD34-Smad7 has good biological properties and can effectively reverse the EndMT of MAEC mediated by TGF-ß1. Thus, Exosome-DSPE-PEG-AbCD34-Smad7 may has the potential for the prevention and treatment of HO.

Engineered osteoclasts as living treatment materials for heterotopic ossification therapy.

Osteoclasts (OCs), the only cells capable of remodeling bone, can demineralize calcium minerals biologically. Naive OCs have limitations for the removal of ectopic calcification, such as in heterotopic ossification (HO), due to their restricted activity, migration and poor adhesion to sites of ectopic calcification. HO is the formation of pathological mature bone within extraskeletal soft tissues, and there are currently no reliable methods for removing these unexpected calcified plaques. In the present study, we develop a chemical approach to modify OCs with tetracycline (TC) to produce engineered OCs (TC-OCs) with an enhanced capacity for targeting and adhering to ectopic calcified tissue due to a broad affinity for calcium minerals. Unlike naive OCs, TC-OCs are able to effectively remove HO both in vitro and in vivo. This achievement indicates that HO can be reversed using modified OCs and holds promise for engineering cells as "living treatment agents" for cell therapy.

Burn-induced heterotopic ossification from incidence to therapy: key signaling pathways underlying ectopic bone formation.

Burn injury is one of the potential causes of heterotopic ossification (HO), which is a rare but debilitating condition. The incidence ranges from 3.5 to 5.6 depending on body area. Burns that cover a larger percentage of the total body surface area (TBSA), require skin graft surgeries, or necessitate pulmonary intensive care are well-researched risk factors for HO. Since burns initiate such complex pathophysiological processes with a variety of molecular signal changes, it is essential to focus on HO in the specific context of burn injury to define best practices for its treatment. There are numerous key players in the pathways of burn-induced HO, including neutrophils, monocytes, transforming growth factor-ß1-expressing macrophages and the adaptive immune system. The increased inflammation associated with burn injuries is also associated with pathway activation. Neurological and calcium-related contributions are also known. Endothelial-to-mesenchymal transition (EMT) and vascularization are known to play key roles in burn-induced HO, with hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) as potential initiators. Currently, non-steroidal anti-inflammatory drugs (NSAIDs) and radiotherapy are effective prophylaxes for HO. Limited joint motion, ankylosis and intolerable pain caused by burn-induced HO can be effectively tackled via surgery. Effective biomarkers for monitoring burn-induced HO occurrence and bio-prophylactic and bio-therapeutic strategies should be actively developed in the future.

The Impact of Continuous Passive Motion on Heterotopic Ossification Maturation.

ABSTRACT: Heterotopic ossification is the formation of pathological bone in soft tissues. It is postulated that continuous passive motion is a helpful adjuvant in the halt of the heterotopic ossification progression and the maintenance or increase of the joint mobility. The purpose of this clinical case study is to present the effectiveness of continuous passive motion. A 46-yr-old male patient experiencing right hemiparesis arrived in our rehabilitation department with limitation on passive flexion of the right hip. On x-ray of the pelvis, immature heterotopic bone formation was found. To halt this ongoing process of heterotopic bone formation, a program of continuous passive motion was implemented. In addition, risedronate was administrated. We started the continuous passive motion at 50 degrees of flexion for 30 mins that was increased to 100 degrees for 3 hrs daily. The final range of motion at the hip was: flexion 85 degrees, extension 0 degrees, internal rotation 10 degrees, external rotation 10 degrees, abduction 10 degrees, and adduction 10 degrees. Based on our results, continuous passive motion plays a role in heterotopic ossification maturation. The effectiveness of continuous passive motion implementation against HO should be further investigated for selected cases.

Os Trigonum Syndrome.

This article offers an overview of os trigonum syndrome, complications, operative techniques, and the authors' preferred protocol. Os trigonum is an ossicle like many other ossicles in the foot and ankle. Individuals who require repetitive plantarflexion of the ankle for activity may develop symptoms of an enlarged os trigonum. Usually, symptoms will be isolated to the posteriolateral aspect of the ankle. Because of the normal anatomic route of the flexor hallucis longus tendon, its range of motion may also elicit pain to the posterolateral ankle. Conservative, as well as surgical including both endoscopic and open excision, has been described.

Extracorporeal shock wave therapy to treat neurogenic heterotopic ossification in a patient with spinal cord injury: A case report.

Objective: To evaluate the efficacy and safety of treatment for neurogenic heterotopic ossification (NHO) using extracorporeal shock wave therapy (ESWT) in persons with spinal cord injury (SCI).Design: Single case report.Setting: Department of Physical Medicine and Rehabilitation, Veterans Health Service Medical Center.Participants: A 55-year-old male with cervical SCI, who developed painful NHO around the right hip joint.Interventions: Ultrasound-guided ESWT that used 4,000 shocks at the rate of 3 Hz and the energy flux density between 0.056 and 0.068 mJ/mm2 was applied to the NHO region a total of 7 times, weekly.Outcome Measures: We assessed the treatment outcomes using a visual analog scale (VAS) score, wheelchair sitting time and size of NHO.Result: After 7 weeks of ESWT treatment, his pain reduced from a VAS score of 7-8 to 3 and his wheelchair sitting time increased. However, there was no significant change of size of NHO.Conclusion: The application of ESWT could be a possible alternative to other treatments for NHO in persons with SCI.Clinical Trial Registry Number: 2019-03-003.

Understanding the Implications of the Meniscal Ossicle: Patient Presentation, Treatment, and Outcomes.

The meniscal ossicle is observed in clinical practice, yet there currently is limited information on its potential clinical significance. The purpose of this study was to assess the clinical presentation, imaging findings, and clinical treatment and outcomes of a series of patients identified as having a meniscal ossicle. An institutional database was reviewed to identify knees with a meniscal ossicle. Clinical presentation, magnetic resonance imaging (MRI), treatment, and outcomes were analyzed. Radiographs were graded using Kellgren-Lawrence (KL) scores. MRIs were reviewed for the presence and location of meniscal ossicles and additional knee pathology. Knee arthroplasty rates were recorded with the remaining patients contacted to obtain final International Knee Documentation Committee (IKDC) and Tegner's scores. Failure was defined as conversion to arthroplasty or failing IKDC score (< 75.4). Forty-five meniscal ossicles in 45 patients (26 males and 19 females) with a mean age of 51 years (standard deviation [SD] = 19.0) were included. Pain was the most common presenting symptom (89%). Forty-two patients (93%) had an associated meniscus root tear on MRI. Eighteen percent of patients that did not have an ossicle on initial imaging subsequently developed an ossicle. Mean KL grades progressed significantly from baseline of 1.84 (SD = 1.0) to 2.55 (SD = 0.93 p < 0.01) on final follow-up. Thirty-nine percent of baseline radiographs showed KL grades of less than 2 compared with only 15% of follow-up radiographs (p = 0.04). Mean IKDC score obtained for patients ≤ 60 at an average follow-up of 3.1 years (SD = 3.2) was 65.2 (SD = 19.0). Eight out of 45 patients (18%) had progressed to total knee arthroplasty (TKA) by latest available follow-up. Sixty-two percent of patients met failure criteria at latest available follow-up. The meniscal ossicle is most commonly found in the posterior horn or root of the medial meniscus and is highly suggestive to be sequelae of a posterior root tear. Therefore, the presence of a meniscal ossicle should alert the orthopaedic surgeon to the high likelihood of the patient having a meniscus root tear. These patients have shown to have poor clinical outcomes and worsening arthritis.

A review of the biomarkers and in vivo models for the diagnosis and treatment of heterotopic ossification following blast and trauma-induced injuries.

Heterotopic ossification (HO) is the process of de novo bone formation in non-osseous tissues. HO can occur following trauma and burns and over 60% of military personnel with blast-associated amputations develop HO. This rate is far higher than in other trauma-induced HO development. This suggests that the blast effect itself is a major contributing factor, but the pathway triggering HO following blast injury specifically is not yet fully identified. Also, because of the difficulty of studying the disease using clinical data, the only sources remain the relevant in vivo models. The aim of this paper is first to review the key biomarkers and signalling pathways identified in trauma and blast induced HO in order to summarize the molecular mechanisms underlying HO development, and second to review the blast injury in vivo models developed. The literature derived from trauma-induced HO suggests that inflammatory cytokines play a key role directing different progenitor cells to transform into an osteogenic class contributing to the development of the disease. This highlights the importance of identifying the downstream biomarkers under specific signalling pathways which might trigger similar stimuli in blast to those of trauma induced formation of ectopic bone in the tissues surrounding the site of the injury. The lack of information in the literature regarding the exact biomarkers leading to blast associated HO is hampering the design of specific therapeutics. The majority of existing blast injury in vivo models do not fully replicate the combat scenario in terms of blast, fracture and amputation; these three usually happen in one insult. Hence, this paper highlights the need to replicate the full effect of the blast in preclinical models to better understand the mechanism of blast induced HO development and to enable the design of a specific therapeutic to supress the formation of ectopic bone.