Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: a prospective randomized study versus contralateral arthroplasty at a mean fifteen year follow-up.

PURPOSE: Recently, mesenchymal stem cells (MSCs) have been proposed as potential treatment modalities for knee osteoarthritis. However, indications and long-term results have not been frequently reported. The purpose of this study was to determine whether bone marrow lesion on MRI are predictive of risk progression to total knee arthroplasty during the first ten years after subchondral cell therapy. METHODS: This study included 140 adults aged 65 to 90 years. These 140 patients (mean age 75.4 ± 14.2 years) planned to undergo staged-bilateral total knee arthroplasty (TKA) for medial osteoarthritis, had "comparable" pain in both knees, and accepted randomization of the knees for surgery. They received TKA on one side and a subchondral injection of MSCs (from iliac bone marrow concentrate) on the contralateral knee during the same anaesthetic. The bone marrow graft of 20 cm3 volume (10 cc in the tibia and 10 cc in the femur) contained average 7800 MSCs/mL (range 3120 to 11,560). The baseline volume of bone marrow lesions (BMLs) on the tibia and on the femoral condyle determined on MRI was average 3.4 cm3 (range 0.4 to 6.4 cm3). The risk of subsequent knee arthroplasty due to absence of bone marrow lesions regression as well as osteoarthritis (OA) grade was evaluated with Cox proportional-hazards ratio after control of baseline variables (number of cells injected, age, knee alignment). RESULTS: After treatment with MSCs injection in bone marrow lesions of the subchondral bone, medial femorotibial compartment BML volume experienced regression over 24 months (mean regression 1.5 cm3, range 0.8 to 3.2 cm3). At the most recent follow up (average of 15 years, range 10 to 20 years), a total of 25 (18%) of the 140 patients underwent total knee arthroplasty performed at a mean of ten years (range, 5 to 15 years) after the date of the cell therapy. The overall incidence of knee arthroplasty after cell therapy was 1.19% per person-year which was equivalent to the risk of a revision for a primary TKA in the contralateral knees of the same patient population (21 revisions, corresponding to 1.00% revision per person-year; p = 0.34). After adjusting for confounders, persistent BMLs larger than 3 cm3 after cell therapy was a strong independent risk factor for total knee arthroplasty (hazard ratio HR = 4.42 [95% CI = 2.34 to 7.21]; p < 0.001), regardless of OA grade, with higher risks demonstrated for larger BMLs. Incidence rates of arthroplasty were also higher for young patients and for knees presenting severe malalignment. CONCLUSIONS: This study showed that subchondral bone marrow concentrate (as compared with TKA) had a sufficient effect on pain to postpone or avoid the TKA in the contra lateral joint of patients with bilateral osteoarthritis. Bone marrow lesions were predictive factors for future knee arthroplasty in the knee with subchondral cell therapy at ten years follow-up.

Thoracic computerised tomography scans in one hundred eighteen orthopaedic patients during the COVID-19 pandemic: identification of chest lesions; added values; help in managing patients; burden on the computerised tomography scan department.

PURPOSE: Based on the recent literature, chest computed tomography (CT) examination could aid for management of patients during COVID-19 pandemic. However, the role of chest CT in management of COVID-19 patients is not exactly the same for medical or surgical specialties. In orthopaedic or trauma emergency, abdomen, pelvis, cervical, dorsal, and lumbar spine CT are performed to investigate patients; the result is a thoracic CT scan incorporating usually the thorax; however, information about lung parenchyma can be obtained on this thorax CT, and manifestations of COVID-19 can be diagnosed. The objective of our study was to evaluate this role in orthopedic patients to familiarize orthopaedists with the value and limits of thoracic CT in orthopaedic surgery. MATERIALS AND METHODS: Among the 1397 chest CT scans performed during the pandemic period from 1 March 2020 to 10 May 2020, in two centres with orthopaedic surgery, we selected all the 118 thoracic or chest CT performed for patients who presented to the Emergency Department of the hospital with a diagnosis of trauma for orthopaedic surgical treatment. Thirty-nine of these 118 patients were tested with PCR for the diagnosis of COVID-19 infection. Depending on clinical status (symptomatic or non-symptomatic), the information useful for the orthopaedist surgeon and obtained from the Chest CT scan according to the result of the PCR (gold standard) was graded from 0 (no or low value) to 3 (high value). The potential risks of chest CT as exposure to radiation, and specific pathway were analyzed and discussed. A group of patients treated during a previous similar period (1 March 2018 to 15 April 2018) was used as control for evaluation of the increase of CT scanning during the COVID-19 pandemic. RESULTS: Among the 118 patients with chest CT, there were 16 patients with positive COVID-19 chest CT findings, and 102 patients with negative chest CT scan. With PCR results as reference, the sensitivity, specificity, positive predictive value of chest CT in indicating COVID-19 infection were 81%, 93%, and 86%, respectively (p = 0.001). A useful information for the orthopaedic surgeon (graded as 1 for 71 cases, as 2 for 5 cases, and as 3 for 11 cases) was obtained from 118 chest CT scans for 87 (74%) patients, while the CT was no value in 30 (25%) cases, and negative value in one (1%) case. Roughly 20% of the total number of CT scanner performed over the pandemic period was dedicated to COVID-19, but only 2% were for orthopaedic or trauma patients. However, this was ten times higher than during the previous control period of comparison. CONCLUSION: Although extremely valuable for surgery management, these results should not be overstated. The CT findings studied are not specific for COVID-19, and the positive predictive value of CT will be low unless disease prevalence is high, which was the case during this period.

Autologous bone marrow stromal cells are promising candidates for cell therapy approaches to treat bone degeneration in sickle cell disease.

Osteonecrosis of the femoral head is a frequent complication in adult patients with sickle cell disease (SCD). To delay hip arthroplasty, core decompression combined with concentrated total bone marrow (BM) treatment is currently performed in the early stages of the osteonecrosis. Cell therapy efficacy depends on the quantity of implanted BM stromal cells. For this reason, expanded bone marrow stromal cells (BMSCs, also known as bone marrow derived mesenchymal stem cells) can be used to improve osteonecrosis treatment in SCD patients. In this study, we quantitatively and qualitatively evaluated the function of BMSCs isolated from a large number of SCD patients with osteonecrosis (SCD-ON) compared with control groups (patients with osteonecrosis not related to SCD (ON) and normal donors (N)). BM total nuclear cells and colony-forming efficiency values (CFE) were significantly higher in SCD-ON patients than in age and sex-matched controls. The BMSCs from SCD-ON patients were similar to BMSCs from the control groups in terms of their phenotypic and functional properties. SCD-ON patients have a higher frequency of BMSCs that retain their bone regeneration potential. Our findings suggest that BMSCs isolated from SCD-ON patients can be used clinically in cell therapy approaches. This work provides important preclinical data that is necessary for the clinical application of expanded BMSCs in advanced therapies and medical products.

Minimally invasive anterior lumbar interbody fusion for adult degenerative scoliosis with 1 or 2 dislocated levels.

OBJECT: Frequent complications of posterolateral instrumented fusion have been reported after treatment of degenerative scoliosis in elderly patients. Considering that in some cases, most of the symptomatology of adult degenerative scoliosis (ADS) is a consequence of the segmental instability at the dislocated level, the use of minimally invasive anterior lumbar interbody fusion (ALIF) to manage symptoms can be advocated to reduce surgical morbidity. The purpose of this study was to evaluate the midterm outcomes of 1- or 2-level minimally invasive ALIFs in ADS patients with 1- or 2-level dislocations. METHODS: A total of 47 patients (average age 64 years; range 43-80 years) with 1- or 2-level ALIF performed for ADS (64 levels) in a single institution were included in the study. An independent spine surgeon retrospectively reviewed all the patients' medical records and radiographs to assess operative data and surgery-related complications. Clinical outcome was reported using the Oswestry Disability Index (ODI) and the visual analog scale (VAS) for lumbar and leg pain. Intraoperative data and complications were collected. Fusion and risk for adjacent-level degeneration were assessed. RESULTS: The mean follow-up duration was 3 years (range 1-10 years). ODI, and back and leg pain VAS scores were significantly improved at last follow-up. A majority of patients (74%) had a statistically significant improvement in their ODI score of more than 20 points at latest follow-up and 1 had a worsening of his disability. The mean operating time was 166 minutes (range 70-355 minutes). The mean estimated blood loss was 410 ml (range 50-1700 ml). Six (5 major and 1 minor) surgical complications (12.7% of patients) and 13 (2 major and 11 minor) medical complications (27.7% of patients) occurred without death or wound infection. Fusion was achieved in 46 of 47 patients. Surgery resulted in a slight but significant decrease of the Cobb angle, and improved the pelvic parameters and lumbar lordosis, but had no effect on the global sagittal balance. At latest follow-up, 9 patients (19.1%) developed adjacent-segment disease at a mean of 2 years' delay from the index surgery; 4 were symptomatic but treated medically, and none required iterative surgery. CONCLUSIONS: Single- or 2-level minimally invasive fusion through a minimally invasive anterior approach in some selected cases of ADS produced a good functional outcome with a high fusion rate. They were associated with a significantly lower rate of complications in this study than the historical control.

Ceramic-on-ceramic THA associated with fewer dislocations and less muscle degeneration by preserving muscle progenitors.

BACKGROUND: Dislocation is a common complication after total hip arthroplasty (THA). Although the etiology of dislocation is multifactorial, longer-term changes in muscle such as atrophy may influence the risk of prosthetic dislocation. Biological differences in wear products generated by different bearing surfaces may influence differences in the appearance of periarticular muscle after THA; however, such bearing-associated differences to our knowledge have not been studied in vivo, and few studies have evaluated bearing-associated differences in dislocation risk. QUESTIONS/PURPOSES: (1) Is there a correlation between the postoperative risk of dislocation at revision and the bearing surfaces of the primary arthroplasty? (2) Is there a higher extent of fatty muscle atrophy on CT scan in hips with osteolysis (polyethylene hips) as compared with hips without osteolysis (ceramic-on-ceramic hips)? (3) Are these two abnormalities (bone osteolysis and fatty atrophy) associated with a decrease of mesenchymal stem cells (MSCs) in bone and in muscle? METHODS: We retrospectively evaluated 240 patients (240 hips) who had a THA revision (98% of which, 235 of the 240, were isolated acetabular revisions) and a normal contralateral hip. All patients had received the same implants for the primary arthroplasty (32-mm head) except for bearing surfaces (80 hips with ceramic-on-ceramic, 160 with polyethylene). No differences were noted between the groups in terms of age, sex, body mass index, proportion of patients who had a dislocation after the index arthroplasty but before the revision, and proportion of the patients with stem loosening in addition to acetabular loosening. Indications for revision generally were cup loosening. The revisions in the hips with polyethylene bearings generally had more acetabular bone loss, but the position of the center of the cup and the orientation of the cup were similar after reconstruction in the two groups. Before revision, osteolysis, muscle atrophy, and fatty degeneration were evaluated on CT scan and compared with the contralateral side. Bone muscle progenitors were evaluated by bone marrow MSCs and satellite cells for muscle. At revision, all the hips received the same implants with the same head diameter (32 mm) and a standard liner. Revisions were performed between 1995 and 2005. The followup after revision was at a mean of 14 years (range, 10-20 years) for ceramic revision and 12 years (range, 10-20 years) for polyethylene hips, and there was no differential loss to followup between the groups. RESULTS: More hips with polyethylene liners at the time of index arthroplasty dislocated after revision than did hips with ceramic liners (18% [29 of 160] compared with 1% [one of 80]; odds ratio, 17.5; 95% confidence interval, 2.3363-130.9100; p = 0.005). For the 80 hips with ceramic-on-ceramic, no osteolysis was detected before revision; there was no muscle fatty degeneration of the gluteus muscles on CT scan or histology. For the 160 hips with polyethylene liners, osteolytic lesions on the acetabulum and femur were observed in 100% of the hips. The increased atrophy of the gluteus muscles observed on CT scan correlated with the increase of osteolysis (r = 0.62; p = 0.012). The surgical limbs in the patients with polyethylene hips as compared with ceramic-on-ceramic hips demonstrated a greater reduction in cross-sectional area (respectively, 11.6% compared with 3%; odds ratio, 3.82; p < 0.001) and radiological density (41% [14.1/34.1] compared with 9%; odds ratio, 6.8; p = 0.006) of gluteus muscles when compared with the contralateral normal side. (41% compared with 9%; odds ratio, 6.8; p = 0.006). CONCLUSIONS: Ceramic bearing surfaces were associated with fewer dislocations after revision than polyethylene bearing surfaces. The reasons of the lower rate of dislocation with ceramic-on-ceramic bearings may be related to observed differences in the periarticular muscles (fat atrophy or not) with the two bearing surfaces. LEVEL OF EVIDENCE: Level III, therapeutic study.

Development of a simple procedure for the treatment of femoral head osteonecrosis with intra-osseous injection of bone marrow mesenchymal stromal cells: study of their biodistribution in the early time points after injection.

INTRODUCTION: Osteonecrosis of the femoral head (ONFH) is a degenerative disease progressing to a femoral head (FH) collapse. Injection of osteoprogenitor cells like bone marrow mesenchymal stromal cells (BMSCs) into the FH appears to be a good therapeutic treatment. However, safety and efficacy of BMSCs to treat bone defect are the main preclinical data required for clinical application. Efficacy and the lack of risk of cell transformation after amplification of BMSCs have been extensively described. The main objectives of this study were to develop a simple and usable procedure for clinicians and control its feasibility by evaluating the biodistribution of BMSCs after injection into the FH in a large animal model. The impact of this approach was evaluated on one natural pig ONFH. METHODS: BMSCs were directly injected in the pig FH, and then the biodistribution of grafted cells was detected by quantitative real-time polymerase chain reaction, cytometry, or a combination of classic histology analysis and in situ hybridization (ISH). BMSC efficacy on bone regeneration was evaluated by magnetic resonance imaging (MRI) and histology. RESULTS: After 30-minute and 24-hour follow-up, grafted cells were detected at the injection site and no BMSCs were detected in filter organs or body fluids. The combination of classic histology analysis and ISH showed a good homogeneity of cell distribution in FH. Local delivery of BMSCs onto a bone scaffold associated with bone formation in vivo confirmed the preferential tropism of BMSCs to the bone tissue as well as their efficacy to form bone. Treatment of a natural pig ONFH by autologous BMSCs indicated a beginning of bone healing as early as 2 weeks with a complete healing after 9 weeks. At this stage, MRI and histological analysis were similar to those of a normal FH. CONCLUSIONS: Intra-osseous injection of BMSCs in FH seems to be a good strategy for ONFH treatment as the safety concerning the biodistribution of BMSCs is ensured. Moreover, the efficacy of BMSCs in natural ONFH seems to indicate that this is a promising approach. Altogether, these results constitute the preclinical data necessary for the setup of a clinical application with expanded BMSCs in the context of advanced therapy medicinal products.

Percutaneous injection of bone marrow mesenchymal stem cells for ankle non-unions decreases complications in patients with diabetes.

PURPOSE: Clinical studies in diabetic patients have demonstrated that there is a high incidence of complications in distal tibia and ankle fracture treatments. One strategy to mitigate issues with wound healing and infection in diabetic patients is to use a percutaneous technique in which autologous, bone marrow-derived, concentrated cells are injected at the site of non-unions. METHODS: Eighty-six ankle non-union in diabetic patients were treated with bone marrow mesenchymal stem cells (BM-MSCs) delivered in an autologous bone marrow concentrate (BMC). Clinical outcomes of the 86 diabetic non-union patients treated with BMC were compared with 86 diabetic matched non-unions treated with a standard bone iliac crest autograft. RESULTS: Treatment with BMC promoted non-union healing in 70 among 86 diabetic patients (82.1 %) with a low number of complications. Of the 86 diabetic patients treated with iliac bone graft, 53 (62.3 %) had healing; major complications were observed: 5 amputations, 11 osteonecroses of the fracture wound edge and 17 infections. CONCLUSIONS: In diabetic patients with ankle non-unions, treatment with BM-MSCs from bone marrow concentrate may be preferable in view of the high risks of major complications after open surgery and iliac bone grafting, and improved healing rates compared with standard iliac bone autograft treatment.

Long, titanium, cemented stems decreased late periprosthetic fractures and revisions in patients with severe bone loss and previous revision.

PURPOSE: Long, cementless, femoral stem revisions are being used with increasing frequency. There is a relative lack of studies of late fractures after cementless implants, particularly in those patients who had a previous stem revision and are at higher risk for periprosthetic fracture after revision. In this paper, we review risk factors for periprosthetic fracture and revisions of long, cementless, locked stems and report implant survival compared with conventional, cemented, long-stem hip revision arthroplasties in such a group of patients. METHODS: We used data recorded in our institution. Between 1996 and 2002, 85 cementless femoral stem Aura™ (distal locked stem) prostheses were implanted in 85 patients. Of the 85 revisions with long, cementless stems, 32 were performed after one stem revision, 20 after two stem revisions and 12 after three stem revisions. Between 2003 and 2010, 124 femoral revision stems were performed in 124 patients using an extensively long, titanium femoral stem (Ceraver Osteal™). Kaplan-Meier analysis was used to determine implant survival. The Cox regression model was used to study risk factors for reoperation and revision. RESULTS: The increase in stem length corresponded to a mean of 4.5 ± 2.1 femoral canal diameters and was not significantly different (p = 0.02) between the two groups. Cardiopulmonary distress, intraoperative or postoperative complications were not significantly different between the two groups. There was an overall increased risk of pain, periprosthetic fractures and revision for the cementless prostheses compared with the cemented stems. With regard to thigh pain at the last follow-up, most patients (95 %) reported no pain in the cemented group, while 15 % of the cementless group experienced thigh pain under stress and 6 % had incapacitating pain. In the cemented group, stem re-revision was not required in any hip; there was no periprosthetic fracture; five stems had radiological loosening but in the absence of pain were not revised. Among patients of the cementless group, 21 % sustained failure or revision of their interlocked stem with periprosthetic fractures observed in 15 cases; factors which contributed significantly to a higher risk of fracture included the number of previous revisions; the average time between surgery and failure was 3.2 years after one revision, 2.8 years after two revisions, and 1.6 years after three revisions. CONCLUSIONS: The long, cementless, locked stem showed more early complications compared with recementing of long-stem prosthesis. We therefore recommend the use of cemented long stems in patients with severe bone loss and previous revision.

Osteonecrosis repair with bone marrow cell therapies: state of the clinical art.

INTRODUCTION: Hip osteonecrosis is a pathological condition resulting from cellular impairment due to reduction in osteoblast activity and local mesenchymal stem cell populations. Cell-based therapies might aid in overcoming these deficiencies by providing stem cells and other progenitor cells to potentially improve the local cellular environment in the affected hip. METHODS: A PubMed search, using the search terms "hip osteonecrosis" and "mesenchymal stem cells", was conducted in December 2013. A total of 15 publications were identified and reviewed for clinical outcomes. FINDINGS: Clinical studies of patients with osteonecrosis treated with mesenchymal stem cells showed beneficial effects. No unexpected adverse events were identified in these studies. Core decompression was the usual method for autologous bone marrow cell implantation into the femoral head. However, other methods have been used such as arterial or venous delivery. A rationale for the use of cytotherapy, as well as the different descriptions of the techniques of implantation MSCs (autologous vs. allogenic, concentration vs. expansion), is provided in the context of treating hip osteonecrosis. Current problems and future challenges with cytotherapy and associated techniques are discussed. This article is part of a Special Issue entitled "Stem Cells and Bones".

Full weight bearing and dynamisation with Limmed® locked plate fixation accelerates bone regeneration in the volume of opening wedge high tibial osteotomy.

PURPOSE: The efficacy of immediate full weight bearing in accelerating bone regeneration after medial opening wedge high tibial osteotomy (HTO) was evaluated in patients operated with the Limmed system (locked plate fixation) that allows dynamisation of the site of the osteotomy. METHODS: A case series of 50 consecutive osteotomies performed with Limmed locked plate fixation for medial opening wedge HTO had full weight bearing immediately after the HTO; they were compared to a case-matched control series of 50 HTOs (50 patients) performed using the same implant without locked screws. Radiographs were observed at 30 days and two, three, four, five and six months after surgery. The osteotomy gap was only partially filled by a medial bone substitute leaving the lateral part unfilled. Bone surface areas of osteotomy planes were quantified and opening volumes were determined applying wedge heights. End points for evaluation included radiographic evidence of bone regeneration in the volume created by the opening of the osteotomy. RESULTS: Statistically significant differences were seen between the groups in terms of radiographic union and radiographic stability between the two groups. Patients of the Limmed group reported a shorter time for union (average four weeks difference) without loss of correction during healing. At the radiographic evaluation, there was a significant increase in osseointegration in the group with weight bearing compared to the control group without weight bearing with increased rate of speed to fill the void volume of the osteotomy. The computed tomography scan of the grafted area at four months after surgery showed no significant difference in the quality of the newly formed bone between the two groups. CONCLUSIONS: The Limmed medial opening wedge HTO system with immediate full weight bearing accelerates bone graft substitute osseointegration and bone healing as compared with controls without full weight bearing.

Stand-alone ALIF with integrated intracorporeal anchoring plates in the treatment of degenerative lumbar disc disease: a prospective study on 65 cases.

PURPOSE: ALIF with cages is expected to restore disc height and stabilize the spine promoting fusion, while avoiding damage attributed to rod-pedicle screw fixation. However, it may be related to an increased risk of fusion failure and subsidence. A prospective study was conducted by five investigators across three centers to confirm performance of a PEEK cage for stand-alone ALIF in the treatment of lumbar degenerative disc disease (DDD). METHODS: Sixty-five patients, with back ± leg pain, requiring surgery for DDD, were included. Efficacy and safety were evaluated at 6 weeks, 3, 6, and 12 months post-operatively. Fusion and subsidence were assessed through CT-images at 12-month follow-up. Disc height was measured. Clinical outcomes included back and leg pain (VAS), disability (Oswestry Disability Index), Quality of Life (Short-Form 36), and adverse events. RESULTS: The fusion and the subsidence rates were 96.3 and 2.0 %, respectively. ALIF surgery restored anterior and posterior disc height compared to baseline. There were no device-related serious adverse events, and no revision surgeries. Clinical outcomes improved significantly through 12-month follow-up. CONCLUSION: Safety and efficacy of this stand-alone cage with integrated intracorporeal plates was confirmed through 12 months for treatment of degenerative conditions. The design of the cage and plates may contribute to the decreased subsidence rate observed.

New preclinical porcine model of femoral head osteonecrosis to test mesenchymal stromal cell efficiency in regenerative medicine.

PURPOSE: In order to evaluate new therapeutic approaches to human osteonecrosis of the femoral head (ONFH), this study proposed to improve the existing animal model by developing a new surgically induced pig model. METHODS: First, ONFH was induced with an easy and minimally invasive technique: cryogenic insult with repeated freeze-thaw cycle. Then, to compare and improve the efficacy of this first method, we combined the cryogenic insult to vascular coagulation of the posterior circumflex vessels. RESULTS: Cryoinjury with repeated freeze-thaw cycle alone is sufficient to induce, three weeks postsurgery, a subchondral necrosis as confirmed by magnetic resonance imaging (MRI) and histological analysis. However, a bone regeneration began at four weeks and was complete at eight weeks. To optimise this result, we combined cryoinjury with posterior circumflex vessel coagulation and observed the persistence of ONFH, with progression to collapse at 14 weeks postinduction. CONCLUSIONS: Cryoinjury associated with partial vascular coagulation is sufficient to obtain localised and sustainable necrosis in the subchondral area of the femoral head, reproducing all stages of the human disorder. The co-analysis by MRI and histology allowed us to confirm that the classic T1- and T2-weighted hyposignal regeneration front around a fatty high T1-weighted signal observed by MRI indicate signs of induced osteonecrosis. Our results indicate that our pig model induces all stages of human ONFH, which can be followed by MRI, making it relevant for clinical trials.

Induction of an inflammatory and prodegradative phenotype in autologous fibroblast-like synoviocytes by the infrapatellar fat pad from patients with knee osteoarthritis.

OBJECTIVE: The infrapatellar fat pad (IFP) of the knee joint has an inflammatory phenotype in osteoarthritis (OA). Its close proximity to the synovial membrane suggests that the IFP could be involved in the induction of OA synovitis. This study was undertaken to investigate the response of fibroblast-like synoviocytes (FLS) to autologous IFP and subcutaneous adipose tissue (SCAT) from patients with severe knee OA. METHODS: Samples of IFP, SCAT, and autologous synovial membrane tissue close to the IFP were harvested during surgery from 28 patients with end-stage knee OA. FLS from 14 patients were stimulated with autologous IFP- or SCAT-conditioned medium, and levels of messenger RNA (mRNA) expression and protein release of interleukin-6 (IL-6), IL-8, secretory phospholipase A2 (sPLA2 ), cytosolic PLA2 , cyclooxygenase 2 (COX-2), microsomal prostaglandin E synthase, prostaglandin E2 (PGE2 ), and matrix metalloproteinases (MMPs) 1, 3, 9, and 13 were evaluated. Both IFP- and SCAT-conditioned medium were evaluated by enzyme-linked immunosorbent assay for secretion of IL-6, soluble IL-6 receptor (sIL-6R), IL-8, tumor necrosis factor α (TNFα), PGE2 , IL-1ß, and interferon-γ. In addition, OA FLS were treated with PGE2 receptor antagonists to evaluate the contribution of IFP-derived PGE2 to the inflammatory response of FLS to the IFP. RESULTS: Stimulation of OA FLS with IFP-conditioned medium induced the mRNA expression and protein release of IL-6, IL-8, sPLA2 , COX-2, PGE2 , and MMPs 1, 3, 9, and 13. The extent of stimulation was consistently stronger with IFP-conditioned medium than with SCAT-conditioned medium. Moreover, secretion of IL-6, sIL-6R, IL-8, TNFα, and PGE2 was greater in IFP-conditioned medium than in SCAT-conditioned medium, especially PGE2 , whose secretion was 75-fold stronger in IFP-conditioned medium (P < 0.0001). PGE2 receptor antagonists dose-dependently inhibited the release of IL-6, IL-8, and PGE2 by IFP-stimulated FLS. CONCLUSION: This study showed that the IFP has a potential role in the induction of synovial inflammation in patients with severe knee OA. Furthermore, secretion of PGE2 by the IFP may be involved in the OA inflammatory process.

Bone union rate with recombinant human bone morphogenic protein-2 versus autologous iliac bone in PEEK cages for anterior lumbar interbody fusion.

PURPOSE: Autologous iliac crest bone graft (ICBG) is the gold standard material for spinal fusion. Bone graft substitutes, such as recombinant human bone morphogenic protein 2 (rhBMP-2) have been developed to promote spinal fusion and address morbidity issues related to ICBG harvesting. The objective of this study was to compare bone fusion rates after anterior lumbar interbody fusion (ALIF) between ICBG and rhBMP-2 by examining thin-cut computed tomography (CT) images at the one year follow-up. METHODS: Fifty one patients (62 levels) who underwent single- or two-level ALIF via the video-assisted minimally invasive anterior approach in our institution were assessed. Radiolucent cages were inserted in all cases. Each cage has a middle beam delimiting two chambers. Grafting was performed as follows: one chamber was filled with autologous ICBG, and the other chamber was filled with 6 mg of rhBMP-2. Thin-cut CT-scan multiplanar reconstruction analyses were performed to assess the rate and quality of bone fusion at one year of follow-up. RESULTS: Fusion was observed in 55 levels (88.7 %), with significant differences in fusion rates with rhBMP-2 and ICBG (71 % vs. 88.7 %) (P=0.001). Osteogenesis in the rhBMP-2 chamber had a centripetal pattern in all cases, leaving a central void in 97.7 % of cases representing 38.3 % of the surface of its chamber (range 0-80.3 %). In ICBG chambers, graft resorption was present in 44.4 %, representing 9.8 % of the chamber surface (range 0-52.2 %). CONCLUSION: RhBMP-2 was inferior to ICBG in terms of rate and quality of bone fusion in one- or two-level ALIF.

Morbidity of graft harvesting versus bone marrow aspiration in cell regenerative therapy.

PURPOSE: Using bone marrow mesenchymal stem cells (MSCs) with aspiration from the iliac crest is commonly used in reconstructive orthopaedic surgery. Because bone marrow aspiration is a percutaneous technique, the morbidity as compared with the classical bone graft should be decreased. METHOD: Therefore in a retrospective review of 523 consecutive cases of bone marrow aspiration performed at the Henri Mondor Hospital from 1990 to 2006 for the treatment of fractures, minor and major complications were identified and compared to the number of complications observed during the same period with 435 classical iliac crest bone graft procedures performed for the same indications of treatment of fractures. Minor complications included superficial infections, superficial seromas, and minor haematomas. Major complications included herniation of abdominal contents through massive bone graft donor sites, vascular injuries, deep infections at the donor site, neurologic injuries, deep haematoma formation requiring surgical intervention or transfusion, and iliac wing fractures. RESULT: Bone marrow aspiration decreased significantly the number of complications as compared with harvesting classical iliac crest bone graft that was associated with significant morbidity. Adverse events were significantly lower (p < 0.01) in the 523 procedures with bone marrow aspiration as compared with the 435 bone iliac crest piece harvesting. This was true for anaemia (16 cases versus 87 cases), for early pain (six versus 152), persistent pain (two versus 21), neuralgia (three versus 11), minor complications (ten versus 56), and major complications (three cases versus 22 cases). CONCLUSION: In our series the number of complications with bone marrow aspiration was ten times less than the complications observed with the classical technique of bone piece harvesting from the iliac crest, and the complications were clearly less severe.

Cancer risk is not increased in patients treated for orthopaedic diseases with autologous bone marrow cell concentrate.

BACKGROUND: There is concern that regenerative cell-based therapies could result in increased risk of tumor formation. We investigated the long-term risks for systemic and site-specific cancers in patients who had received autologous bone marrow-derived stromal progenitor cells to treat orthopaedic lesions. METHODS: A total of 1873 patients were treated from 1990 to 2006 with bone marrow-derived concentrated cells. Patients were monitored for cancer incidence from the date of the first operation (1990) until death, or until December 31, 2011. The mean follow-up time was 12.5 years (range, five to twenty-two years). The average number of colony-forming unit fibroblasts returned to the patients was 483,000 fibroblasts (range, 62,000 to 2,095,000 fibroblasts). The primary outcome was to evaluate with radiographs and/or magnetic resonance imaging the risk of tumorigenesis at the cell therapy treatment sites. The secondary outcome was to evaluate the risk of cancer diagnosed in areas other than the treatment site during the follow-up period. The relative risk of cancer was expressed as the ratio of observed and expected number of cases, that is, the standardized incidence ratio, according to the cancer incidence in the French population. RESULTS: No tumor formation was found at the treatment sites on the 7306 magnetic resonance images and 52,430 radiographs among the 1873 patients. Fifty-three cancers were diagnosed in areas other than the treatment site. On the basis of cancer incidence in the general population during the same period, the expected number of cancers was between ninety-seven and 108 for the same age and sex distribution. The range of the standardized incidence ratio for the follow-up period was between 0.49 and 0.54 (95% confidence interval, 0.30 to 0.80). CONCLUSIONS: This study found no increased cancer risk in patients after application of autologous cell-based therapy using bone marrow-derived stromal progenitor cells either at the treatment site or elsewhere in the patients after an average follow-up period of 12.5 years.

Benefits of small volume and small syringe for bone marrow aspirations of mesenchymal stem cells.

PURPOSE: Aspirating bone marrow from the iliac crest using small volumes of 1-4 ml with a 10-ml syringe has been historically proposed for harvesting adult mesenchymal stem cells and described as a standard technique to avoid blood dilution. The disadvantage of repeated small aspirations is that there is a significantly increased time to harvest the bone marrow. However, it is not known if a large volume syringe can improve the rate of bone marrow aspiration without increasing blood dilution, thus reducing the quality of the aspirate. We compared the concentrations of mesenchymal stem cells obtained under normal conditions with two different size syringes. METHODS: Thirty adults (16 men and 14 women with a mean age of 49 ± 14 years) underwent surgery with aspiration of bone marrow from their iliac crest. Bilateral aspirates were obtained from the iliac crest of the same patients with a 10-ml syringe and a 50-ml syringe. Cell analysis determined the frequencies of mesenchymal stem cells (as determined by the number of colonies) from each size of syringe. The cell count, progenitor cell concentration (colonies/ml marrow) and progenitor cell frequency (per million nucleated cells) were calculated. All bone marrow aspirates were harvested by the same surgeon. RESULTS: Aspirates of bone marrow demonstrated greater concentrations of mesenchymal stem cells with a 10-ml syringe compared with matched controls using a 50-ml syringe. Progenitor cell concentrations were on average 300 % higher using a 10-ml syringe than matched controls using a 50-ml syringe (p < 0.01). CONCLUSIONS: In normal human donors, bone marrow aspiration from 30 patients demonstrated a reduced mesenchymal stem cell number in aspirates obtained using a larger volume syringe (50 ml) as compared with a smaller volume syringe (10 ml).

Variation of the impact duration during the in vitro insertion of acetabular cup implants.

The acetabular cup (AC) is an implant impacted into a bone cavity and used for hip prosthesis surgery. Initial stability of the AC is an important factor for long term surgical success. The aim of this study is to determine the variations of the impact duration during AC implant insertion. Twenty-two bone samples taken from bovine femurs were prepared ex vivo for the insertion of an acetabular cup implant, following the surgical procedure used in the clinic. For each bone sample, ten impacts were applied using reproducible mass falls (3.5 kg) in order to insert the AC implant. Each impact duration was recorded using a wide bandwidth force sensor. For all bone samples, the impact duration was shown to first decrease as a function of the impact number, then reaching a stationary value equal in average to 4.2±0.7 ms after an average number of 4.1±1.7 impacts. The impact duration may be related to variations of the bone-implant interface contact rigidity because of an increase the amount of bone tissue in contact with the AC implant. Measurements of impact duration have a good potentiality for clinical application to assist the surgeon during the insertion of the AC implant, providing valuable information on the bone-implant interface contact properties.

Outcome of total knee arthroplasty after high tibial osteotomy: does malalignment jeopardize the results when using a posterior-stabilized arthroplasty?

BACKGROUND: The controversy regarding the outcome of total knee arthroplasties after high tibial osteotomy may relate to malalignment secondary to overcorrection after high tibial osteotomy (HTO) [1, 2] and to the type of arthroplasty itself (posterior-stabilized arthroplasty or posterior cruciate ligament-retaining prosthesis). QUESTIONS/PURPOSE: We asked two questions: (1) Would a posterior-stabilized arthroplasty provide sufficient constrain and improve pain and function in patients with severe malalignment due to a previous HTO? (2) Will malalignment of the previous HTO jeopardize the long-term results of a total knee reconstruction with a posterior-stabilized implant? PATIENTS AND METHODS: We retrospectively reviewed 25 posterior-stabilized TKAs in 25 patients with severe valgus deformity after HTO (ranging from 10° to 20° of valgus) and compared the results with a series of matched 25 posterior-stabilized TKAs in 25 patients with normocorrection after HTO ranging from 5° of valgus to 5° of varus. Clinical, operative, and radiographic data were reviewed. Minimum follow-up was 10 years after the arthroplasty (average, 15 years; range, 10-20 years). RESULTS: All the knees had standard posterior-stabilized total knee arthroplasty implants. Patients with an overcorrected HTO were more likely to require a soft tissue release to balance the knee. However, Average Knee Society and Function Score improved, respectively, from 48 to 85 and from 50 to 90 points in the severely overcorrected group, versus, respectively, 50 to 89 and 52 to 97 in the normocorrected group, but the range of mobility was superior for patients with normal alignment. Fifteen-year survivorship after the arthroplasty comparison showed no significant difference between the two groups (one revision in each group). CONCLUSIONS: Patients with an overcorrected HTO are more likely to require a soft tissue release to balance the knee. However, both groups show improvements in function and pain. With a posterior-stabilized arthroplasty, the degree of deformity has no impact on the longevity of the TKA.

An uncommon case of Mycoplasma hominis infection after total disc replacement.

PURPOSE: Beside mechanical complications, the majority of adverse events after total disc arthroplasty (TDA) are related to the surgical approach. Septic complications are very uncommon and only one previous case has been published. The objective of this article is to describe the clinical circumstances, treatment, and outcomes of septic complication after TDA at L4-L5, involving an uncommon pathogen (Mycoplasma hominis). METHODS: A 38-year-old woman underwent a MobiDisc(®) TDA at L4-L5 level for discogenic pain. One month postoperatively, she complained of acute low back and abdominal pain associated with fever (39 °C). C-reactive protein level was elevated (197 mg/L; normal <5 mg/L) and the white blood cell count was normal (7 × 10(9)/L; normal 4-10 × 10(9)/L). A computerized tomography (CT) showed a left psoas-based retroperitoneal abscess. Treatment consisted of open debridement, drainage and empirical antibiotic therapy. Intraoperative cultures yielded M. hominis after 7 days incubation. Antibiotic therapy was adapted and discontinued after 2 months. The patient had failed to mention earlier that she had been suffering from abnormal vaginal discharge for some time and was using an intrauterine contraceptive device. RESULTS: At 1.5-year follow-up, review confirmed healing of the infection with biological normalization without residual collection, radiolucent lines or osteolysis around the prosthesis at radiographs, CT and MRI. CONCLUSIONS: Mycoplasma hominis can be involved as an extragenital pathogen in musculoskeletal infections. Because its culture and identification are difficult, special media and real-time PCR are required in case of postoperative deep wound infection after anterior lumbar spine surgery, especially in the case of previous genitourinary infections, to decrease the delay in diagnosis and treatment.