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1.  Preconditioning Human Mesenchymal Stem Cells with a Low Concentration of BMP2 Stimulates Proliferation and Osteogenic Differentiation In Vitro 
BioResearch Open Access  2014;3(6):278-285.
Clinical trials using bone morphogenetic protein-2 (BMP2) for bone reconstruction have shown promising results. However, the relatively high concentration needed to be effective raises concerns for efficacy and safety. The aim of this study was to investigate the osteogenic effect of an alternative treatment strategy in which human bone marrow–derived mesenchymal stem cells (hMSCs) are preconditioned with low concentrations of BMP2 for a short time in vitro. hMSCs in suspension were stimulated for 15 min with 10 and 20 ng/mL of BMP2. After the BMP2 was removed, the cells were seeded and cultured in osteogenic medium. The effects of preconditioning were analyzed with regard to proliferation and expression of osteogenic markers at both gene and protein level. The results were compared to those from cultures with continuous BMP2 stimulation. A significant increase in proliferation was seen with both precondition and continuous stimulation with BMP2, with no difference between the treatments. Preconditioning with BMP2 significantly increased gene expression of RUNX2, COLI, ALP, and OC, and protein levels of COLI and ALP. This was not found with continuous stimulation. The role of preconditioning with BMP2 in osteogenesis was validated by findings of increased gene expression of SMAD1 and an increase in dual phosphorylation of ser 463 and ser 465 in the SMAD 1/5/8 pathway. We concluded that preconditioning hMSCs with BMP2 stimulates osteogenesis: proliferation with matrix secretion and matrix maturation of hMSCs. This implies that preconditioning with BMP2 might be more effective at inducing proliferation and osteogenic differentiation of hMSCs than continuous stimulation. Preconditioning with BMP2 could benefit the clinical application of BMP2 since side effects from high-dose treatments could be avoided.
PMCID: PMC4245882  PMID: 25469313
growth factor; stem cells; tissue engineering
2.  Transforaminal lumbar interbody fusion (TLIF) versus posterolateral instrumented fusion (PLF) in degenerative lumbar disorders: a randomized clinical trial with 2-year follow-up 
European Spine Journal  2013;22(9):2022-2029.
The aim of the present study was to analyze outcome, with respect to functional disability, pain, fusion rate, and complications of patients treated with transforaminal lumbar interbody fusion (TLIF) in compared to instrumented poserolateral fusion (PLF) alone, in low back pain. Spinal fusion has become a major procedure worldwide. However, conflicting results exist. Theoretical circumferential fusion could improve functional outcome. However, the theoretical advantages lack scientific documentation.
Prospective randomized clinical study with a 2-year follow-up period. From November 2003 to November 2008 100 patients with severe low back pain and radicular pain were randomly selected for either posterolateral lumbar fusion [titanium TSRH (Medtronic)] or transforaminal lumbar interbody fusion [titanium TSRH (Medtronic)] with anterior intervertebral support by tantalum cage (Implex/Zimmer). The primary outcome scores were obtained using Dallas Pain Questionnaire (DPQ), Oswestry disability Index, SF-36, and low back pain Rating Scale. All measures assessed the endpoints at 2-year follow-up after surgery.
The overall follow-up rate was 94 %. Sex ratio was 40/58. 51 patients had TLIF, 47 PLF. Mean age 49(TLIF)/45(PLF). No statistic difference in outcome between groups could be detected concerning daily activity, work leisure, anxiety/depression or social interest. We found no statistic difference concerning back pain or leg pain. In both the TLIF and the PLF groups the patients had significant improvement in functional outcome, back pain, and leg pain compared to preoperatively. Operation time and blood loss in the TLIF group were significantly higher than in the PLF group (p < 0.001). No statistic difference in fusion rates was detected.
Transforaminal interbody fusion did not improve functional outcome in patients compared to posterolateral fusion. Both groups improved significantly in all categories compared to preoperatively. Operation time and blood loss were significantly higher in the TLIF group.
PMCID: PMC3777065  PMID: 23584162
Prospective; RCT; Lumbar interbody fusion
3.  Failure modes in conservative and surgical management of infectious spondylodiscitis 
European Spine Journal  2012;22(8):1837-1844.
Purpose and methods
We reviewed the management, failure modes, and outcomes of 196 patients treated for infectious spondylodiscitis between January 1, 2000 and December 31, 2010, at the Spinal Unit, Aarhus University Hospital, Aarhus, Denmark. Patients with infectious spondylodiscitis at the site of previous spinal instrumentation, spinal metastases, and tuberculous and fungal spondylodiscitis were excluded.
Mean age at the time of treatment was 59 (range 1–89) years. The most frequently isolated microorganism was Staphylococcus aureus. The lumbosacral spine was affected in 64 % of patients and the thoracic in 21 %. In 24 % of patients, there were neurologic compromise, four had the cauda equina syndrome and ten patients were paraplegic. Ninety-one patients were managed conservatively. Treatment failed in 12 cases, 7 patients required re-admission, 3 in-hospital deaths occurred, and 5 patients died during follow-up. Posterior debridement with pedicle screw instrumentation was performed in 75, without instrumentation in 19 cases. Seven patients underwent anterior debridement alone, and in 16 cases, anterior debridement was combined with pedicle screw instrumentation, one of which was a two-stage procedure. Re-operation took place in 12 patients during the same hospitalization and in a further 12 during follow-up. Two in-hospital deaths occurred, and five patients died during follow-up.
Patients were followed for 1 year after treatment. Eight (9 %) patients treated conservatively had a mild degree of back pain, and one (1 %) patient presented with mild muscular weakness. Among surgically treated patients, 12 (10 %) had only mild neurological impairment, one foot drop, one cauda equine dysfunction, but 4 were paraplegic. Twenty-seven (23 %) complained of varying degrees of back pain.
Conservative measures are safe and effective for carefully selected patients without spondylodiscitic complications. Failure of conservative therapy requires surgery that can guarantee thorough debridement, decompression, restoration of spinal alignment, and correction of instability. Surgeons should master various techniques to achieve adequate debridement, and pedicle screw instrumentation may safely be used if needed.
PMCID: PMC3731482  PMID: 23247861
Infectious spondylodiscitis; Vertebral osteomyelitis; Surgical management; Spine infection; Spondylodiscitis complications
4.  The effect of timing of rehabilitation on physical performance after lumbar spinal fusion: a randomized clinical study 
European Spine Journal  2013;22(8):1884-1890.
The number of patients undergoing lumbar spinal fusion procedures (LSF) has risen in recent years, but only few studies have examined different rehabilitation strategies for this patient group.
To evaluate the impact of initiating rehabilitation either 6 or 12 weeks after a LSF based on the patients’ physical performance using the 6-min walking test (6MWT) and the Åstrand Fitness test (AF-test) as measurement.
A multicentre RCT including 82 patients with degenerative disc diseases undergoing LSF randomly assigned to initiate rehabilitation either 6 or 12 weeks after surgery. Both groups received the same group-based rehabilitation. The main outcome measures were the 6MWT and the AF-test, secondarily questionnaire-based measures. Follow-up at baseline as well as at 3, 6 and 12 months after surgery.
Comparing the two groups no statistically significant difference was found in walking distance or fitness over time. In both groups, the patients achieved an overall increase in walking distance (p < 0.01), but no improvement in fitness. The 6MWT showed significant correlation (−0.37 to −0.59) with the questionnaire-based outcome measures (p < 0.01). The AF-test did not correlate to either the 6MWT or any of the questionnaire-based outcome measures.
No difference was found in the effect of initiating rehabilitation either 6 or 12 weeks after LSF on the patients’ physical performance in terms of fitness and walking distance. The 6MWT showed fair to moderate correlation to the questionnaire-based outcome measures. The AF-test showed no significant independent value, and we question its use in LSF patients.
PMCID: PMC3731483  PMID: 23563500
Spinal fusion; Rehabilitation; Physical performance; Occupational therapy; Physiotherapy
5.  Prevalence of complications in neuromuscular scoliosis surgery: a literature meta-analysis from the past 15 years 
European Spine Journal  2012;22(6):1230-1249.
Our objectives were primarily to review the published literature on complications in neuromuscular scoliosis (NMS) surgery and secondarily, by means of a meta-analysis, to determine the overall pooled rates (PR) of various complications associated with NMS surgery.
PubMed and Embase databases were searched for studies reporting the outcomes and complications of NMS surgery, published from 1997 to May 2011. We focused on NMS as defined by the Scoliosis Research Society’s classification. We measured the pooled estimate of the overall complication rates (PR) using a random effects meta-analytic model. This model considers both intra- and inter-study variation in calculating PR.
Systematic review and meta-analysis were performed for 68 cohort and case–control studies with a total of 15,218 NMS patients. Pulmonary complications were the most reported (PR = 22.71 %) followed by implant complications (PR = 12.51 %), infections (PR = 10.91 %), neurological complications (PR = 3.01 %) and pseudoarthrosis (PR = 1.88 %). Revision, removal and extension of implant had highest PR (7.87 %) followed by malplacement of the pedicle screws (4.81 %). Rates of individual studies have moderate to high variability. The studies were heterogeneous in methodology and outcome types, which are plausible explanations for the variability; sensitivity analysis with respect to age at surgery, sample size, publication year and diagnosis could also partly explain this variability. In regard to surgical complications affiliated with various surgical techniques in NMS, the level of evidence of published literature ranges between 2+ to 2−; the subsequent recommendations are level C.
NMS patients have diverse and high complication rates after scoliosis surgery. High PRs of complications warrant more attention from the surgical community. Although the PR of all complications are affected by heterogeneity, they nevertheless provide valuable insights into the impact of methodological settings (sample size), patient characteristics (age at surgery), and continual advances in patient care on complication rates.
Electronic supplementary material
The online version of this article (doi:10.1007/s00586-012-2542-2) contains supplementary material, which is available to authorized users.
PMCID: PMC3676557  PMID: 23085815
Neuromuscular scoliosis; Complications; Scoliosis surgery; Deformity surgery; Systematic review; Meta-analysis
6.  Long-term health care utilisation and costs after spinal fusion in elderly patients 
European Spine Journal  2012;22(5):977-984.
Spinal fusion surgery rates in the elderly are increasing. Cost effectiveness analyses with relatively short-length follow-up have been performed. But the long-term effects in terms of health care use are largely unknown. The aim of the present study was to describe the long-term consequences of spinal fusion surgery in elderly patients on health care use and costs using a health care system perspective.
194 patients undergoing spinal fusion between 2001 and 2005 (70 men, 124 women) with a mean age of 70 years (range 59–88) at surgery were included. Average length of follow-up was 6.2 years (range 0.3–9.0 years). Data on resource utilisation and costs were obtained from national registers providing complete coverage of all reimbursed contacts with primary- and secondary health care providers. Data were available from 3 years prior fusion surgery until the end of 2009.
Use of hospital-based health care increased in the year prior to and the first year following surgery. Hereafter it normalised to the level of the background population and was mainly composed of diseases unrelated to the spine. In contrast, the use of primary health care appeared to increase immediately after surgery and continued to increase to a level that significantly exceeded that of the background population. It could be demonstrated that the increase was mainly due to an increasing number of general practitioner consultations.
Spinal fusion surgery in older patients does not generate excess hospital-based health care use in the longer term as compared with the background population, but primary care use increases.
PMCID: PMC3657062  PMID: 22907726
Spinal stenosis; Spinal fusion; Elderly; Costs; Health care utilisation
7.  A single topical dose of erythropoietin applied on a collagen carrier enhances calvarial bone healing in pigs 
Acta Orthopaedica  2014;85(2):201-209.
Background and purpose
The osteogenic potency of erythropoietin (EPO) has been documented. However, its efficacy in a large-animal model has not yet been investigated; nor has a clinically safe dosage. The purpose of this study was to overcome such limitations of previous studies and thereby pave the way for possible clinical application. Our hypothesis was that EPO increases calvarial bone healing compared to a saline control in the same subject.
We used a porcine calvarial defect model. In each of 18 pigs, 6 cylindrical defects (diameter: 1 cm; height: 1 cm) were drilled, allowing 3 pairwise comparisons. Treatment consisted of either 900 IU/mL EPO or an equal volume of saline in combination with either autograft, a collagen carrier, or a polycaprolactone (PCL) scaffold. After an observation time of 5 weeks, the primary outcome (bone volume fraction (BV/TV)) was assessed with high-resolution quantitative computed tomography. Secondary outcome measures were histomorphometry and blood samples.
The median BV/TV ratio of the EPO-treated collagen group was 1.06 (CI: 1.02–1.11) relative to the saline-treated collagen group. Histomorphometry showed a similar median effect size, but it did not reach statistical significance. Autograft treatment had excellent healing potential and was able to completely regenerate the bone defect independently of EPO treatment. Bony ingrowth into the PCL scaffold was sparse, both with and without EPO. Neither a substantial systemic effect nor adverse events were observed. The number of blood vessels was similar in EPO-treated defects and saline-treated defects.
Topical administration of EPO on a collagen carrier moderately increased bone healing. The dosing regime was safe, and could have possible application in the clinical setting. However, in order to increase the clinical relevance, a more potent but still clinically safe dose should be investigated.
PMCID: PMC3967265  PMID: 24564750
8.  Description and design considerations of a randomized clinical trial investigating the effect of a multidisciplinary cognitive-behavioural intervention for patients undergoing lumbar spinal fusion surgery 
The ideal rehabilitation strategy following lumbar spinal fusion surgery has not yet been established. This paper is a study protocol, describing the rationale behind and the details of a cognitive-behavioural rehabilitation intervention for lumbar spinal fusion patients based on the best available evidence. Predictors of poor outcome following spine surgery have been identified to provide targets for the intervention, and the components of the intervention were structured in accordance with the cognitive-behavioural model. The study aims to compare the clinical and economical effectiveness of a cognitive-behavioural rehabilitation strategy to that of usual care for patients undergoing lumbar spinal fusion surgery.
The study is a randomized clinical trial including 96 patients scheduled for lumbar spinal fusion surgery due to degenerative disease or spondylolisthesis. Patients were recruited in the period October 2011 to July 2013, and the follow-up period is one year from date of surgery. Patients are allocated on a 1:2 ratio (control: intervention) to either treatment as usual (control group), which implies surgery and the standard postoperative rehabilitation, or in addition to this, a patient education focusing on pain behaviour and pain coping (intervention group). It takes place in a hospital setting, and consists of six group-based sessions, managed by a multidisciplinary team of health professionals.
The primary outcomes are disability (Oswestry Disability Index) and sick leave, while secondary outcomes include coping (Coping Strategies Questionnaire), fear-avoidance belief (Fear Avoidance Belief Questionnaire), pain (Low Back Pain Rating Scale, pain index), mobility during hospitalization (Cumulated Ambulation Score), generic health-related quality of life (EQ-5D) and resource use. Outcomes are measured using self report questionnaires, medical records and national registers.
It is expected that the intervention can provide better functional outcome, less pain and earlier return to work after lumbar spinal fusion surgery. By combining knowledge and evidence from different knowledge areas, the project aims to provide new knowledge that can create greater consistency in patient treatment. We expect that the results can make a significant contribution to development of guidelines for good rehabilitation of patients undergoing lumbar spinal fusion.
Trial registration
Current Controlled Trials ISRCTN42281022.
PMCID: PMC3973885  PMID: 24581321
Spine surgery; Chronic low back pain; Rehabilitation; Cognitive-behavioural therapy; Randomized clinical trial
9.  Short-term alendronate treatment does not maintain a residual effect on spinal fusion with interbody devices and bone graft after treatment withdrawal: an experimental study on spinal fusion in pigs 
European Spine Journal  2012;22(2):287-295.
Whether alendronate treatment has a residual effect on bone ingrowth into porous biomaterial in humans or experimental animals after treatment withdrawal is still unknown. The purpose of this study was to investigate bone ingrowth into porous tantalum and carbon fiber interbody implants after discontinuing alendronate treatment in experimental spinal fusion in pigs.
Twenty-four pigs were randomly divided into two groups of each 12 pigs. The pigs underwent anterior intervertebral lumbar arthrodeses at L2–3, L4–5 and L6–7. Each level was randomly allocated to one of the three implants: a porous tantalum ring with pedicle screw fixation, a porous tantalum ring or a carbon fiber cage with anterior staple fixation. The central hole of implants was packed with an autograft. Alendronate was given orally for the first 3 months to one of the two groups. The pigs were observed for 6 months postoperatively. Histology and micro-CT scans were done at the endpoint.
The spinal fusion rates of each implant showed no differences between two treatment groups. Furthermore, no differences were found between two groups as for bone ingrowth into the central holes of implants and bone–implant interface in each implant, or as for the pores of tantalum implants. Trabecular bone microarchitecture in the central hole of the carbon fiber cage did not differ between two treatment groups.
The application of ALN, with a dose equivalent to that given to humans during the first 3 months after surgery, does not maintain a residual effect on spinal fusion with porous tantalum ring and autograft after treatment withdrawal in a porcine ALIF model.
PMCID: PMC3555615  PMID: 23053753
Alendronate; Residual effect; Tantalum; Pig
10.  Queries Regarding Local Erythropoietin Injection in Tibiofibular Fracture Healing 
Trauma Monthly  2013;18(2):101-102.
PMCID: PMC3860679  PMID: 24350163
Erythropoietin; Fracture Healing; Bone and Bones; Orthopedics; Orthopedic Procedures; Tibia
11.  Degenerative Spondylolisthesis Is Associated with Low Spinal Bone Density: A Comparative Study between Spinal Stenosis and Degenerative Spondylolisthesis 
BioMed Research International  2013;2013:123847.
Spinal stenosis and degenerative spondylolisthesis share many symptoms and the same treatment, but their causes remain unclear. Bone mineral density has been suggested to play a role. The aim of this study was to investigate differences in spinal bone density between spinal stenosis and degenerative spondylolisthesis patients. 81 patients older than 60 years, who underwent DXA-scanning of their lumbar spine one year after a lumbar spinal fusion procedure, were included. Radiographs were assessed for disc height, vertebral wedging, and osteophytosis. Pain was assessed using the Low Back Pain Rating Scale pain index. T-score of the lumbar spine was significantly lower among degenerative spondylolisthesis patients compared with spinal stenosis patients (−1.52 versus −0.52, P = 0.04). Thirty-nine percent of degenerative spondylolisthesis patients were classified as osteoporotic and further 30% osteopenic compared to only 9% of spinal stenosis patients being osteoporotic and 30% osteopenic (P = 0.01). Pain levels tended to increase with poorer bone status (P = 0.06). Patients treated surgically for symptomatic degenerative spondylolisthesis have much lower bone mass than patients of similar age treated surgically for spinal stenosis. Low BMD might play a role in the development of the degenerative spondylolisthesis, further studies are needed to clarify this.
PMCID: PMC3760191  PMID: 24024179
12.  A simple method for deriving functional MSCs and applied for osteogenesis in 3D scaffolds 
Scientific Reports  2013;3:2243.
We describe a simple method for bone engineering using biodegradable scaffolds with mesenchymal stem cells derived from human induced-pluripotent stem cells (hiPS-MSCs). The hiPS-MSCs expressed mesenchymal markers (CD90, CD73, and CD105), possessed multipotency characterized by tri-lineages differentiation: osteogenic, adipogenic, and chondrogenic, and lost pluripotency – as seen with the loss of markers OCT3/4 and TRA-1-81 – and tumorigenicity. However, these iPS-MSCs are still positive for marker NANOG. We further explored the osteogenic potential of the hiPS-MSCs in synthetic polymer polycaprolactone (PCL) scaffolds or PCL scaffolds functionalized with natural polymer hyaluronan and ceramic TCP (PHT) both in vitro and in vivo. Our results showed that these iPS-MSCs are functionally compatible with the two 3D scaffolds tested and formed typically calcified structure in the scaffolds. Overall, our results suggest the iPS-MSCs derived by this simple method retain fully osteogenic function and provide a new solution towards personalized orthopedic therapy in the future.
PMCID: PMC3718204  PMID: 23873182
13.  Dermatan sulphate in methoxy polyethylene glycol-polylactide-co-glycolic acid scaffolds upregulates fibronectin gene expression but has no effect on in vivo osteochondral repair 
International Orthopaedics  2012;36(7):1507-1513.
The purpose of the study was to investigate the effect of dermatan sulphate (DS) addition to biodegradable methoxy polyethylene glycol (MPEG) substituted polylactide-co-glycolic acid (PLGA) scaffolds for cartilage repair in vitro and in vivo.
Human chondrocytes from eight patients undergoing anterior cruciate ligament reconstruction were isolated and cultured in 5% oxygen on MPEG-PLGA scaffolds ± DS for one, three, seven and 14 days. Analyses were performed using quantitative gene expression analysis for chondrogenic and cell attachment markers. An osteochondral drill hole defect was created in the intertrochlear groove of the distal femur in 20 New Zealand white rabbits (defects n = 20). When bleeding was observed, the defects were treated with MPEG-PLGA scaffolds ± DS. Twelve weeks after surgery the rabbits were sacrificed and the defects were analysed using histological grading with O’Driscoll scoring.
DS addition to MPEG-PLGA scaffolds resulted in a significant upregulation of fibronectin gene expression on day 1. No differences were observed in chondrogenic gene expression. There were no differences between the two groups in histological grading (+DS 10.3 and −DS 9.6).
Upregulation of fibronectin in vitro indicating early cell-scaffold interaction and attachment did not result in improved cartilage repair in an osteochondral defect model in rabbits.
PMCID: PMC3385878  PMID: 22262251
14.  Lowest instrumented vertebra selection in Lenke 3C and 6C scoliosis: what if we choose lumbar apical vertebra as distal fusion end? 
European Spine Journal  2011;21(6):1053-1061.
The aim of this study was to investigate whether or not post-op curve behaviour differs due to different choices of lowest instrumented vertebra (LIV) with reference to lumbar apical vertebra (LAV) in Lenke 3C and 6C scoliosis.
We reviewed all the AIS cases surgically treated in our institution from 2002 through 2008. Inclusion criteria were as follows: (1) patients with Lenke 3C or 6C scoliosis who were treated with posterior pedicle screw-only constructs; (2) 2-year radiographic follow-up. All the included patients were categorized into three groups based on the relative position of LIV and LAV: Group A—the LIV was above the LAV; Group B—the LIV was at the LAV; Group C—the LIV was below the LAV. All the radiographic parameters were then compared among the groups. All image data were available in our picture archiving and communication systems. Standing anteroposterior (AP) and lateral digital radiographs were reviewed at four times (pre-op, post-op, 3-month and 2-year). In each standing AP radiograph, centre sacral vertical line (CSVL, the vertical line that bisects the proximal sacrum) was first drawn, followed by measuring T1-CSVL, LIV-CSVL, (LIV + 1)-CSVL, LAV-CSVL and thoracic AV-CSVL distance. In addition, the Cobb angles of major thoracic and lumbar curves were measured at the four times and the correction rates were then calculated.
Of the 278 patients reviewed, 40 met the inclusion criteria; 11 of these were included in Group A (LIV above LAV), another 11 in Group B (LIV at LAV) and the remaining 18 in Group C (LIV below LAV). At 2-year follow-up, the lumbar vertebrae such as LIV, LIV + 1 and LAV were all more deviated than before surgery in Group A (LIV above LAV), whereas in Group B and C (LIV at and below LAV) they were all less deviated than before surgery. No significant differences were found in thoracic or lumbar correction rate, global coronal balance and incidence rate of trunk shift among the three groups.
In conclusion, in Lenke 3C and 6C scoliosis, post-op lumbar curve behaviour differs due to different choices of LIV with reference to LAV, that is, the deviation of lumbar curve improves when the LIV is either at or below the LAV but deteriorates when the LIV is above the LAV. Although the greatest correction occurs when the LIV is below the LAV, choosing LAV as LIV can still be the optimal option in certain cases, since it can yield similar correction while preserving more lumbar mobility and growth potential.
PMCID: PMC3366136  PMID: 22057393
Adolescent idiopathic scoliosis; Lowest instrumented vertebra; Radiographic measurement; Spinal imbalance; Curve behaviour
15.  Extensive fusion for Lenke 3C and 6C scoliosis: a two year radiographic follow-up 
International Orthopaedics  2011;36(4):795-801.
To investigate the correction effectiveness, incidence rate of distal adding on, and post-operative spinal balance in Lenke 3C and 6C AIS treated with extensive fusion using posterior pedicle screw-only constructs.
We reviewed all AIS cases surgically treated in our institution between 2002 and 2008. The inclusion criteria were as follows: (1) Lenke 3C or 6C scoliosis patients who were treated with extensive fusion using posterior pedicle screw-only constructs; (2) minimum two year radiographic follow-up; (3) the lowest instrumented vertebra (LIV) ended at L2, L3 or L4 level. All image data were available in our picture archiving and communication systems (PACSs) , and all radiographic measurements were performed. Standing anteroposterior (AP) and lateral digital radiographs were reviewed at four different time points (pre-op, post-op, three months, and two years). In each standing AP radiograph, CSVL (center sacral vertical line, the vertical line bisecting the proximal sacrum) was first drawn, followed by measurement of the translation (deviation from the CSVL) of some key vertebrae, such as the lowest instrumented vertebra (LIV), LIV + 1 (the first vertebra below LIV), lumbar apical vertebra, thoracic apical vertebra and T1, enabling depiction of how translation of different parts of the spine changes over time. Additionally, the Cobb angles of major thoracic and lumbar curves were measured at the different time points and the correction rate was calculated.
Of the 278 patients reviewed, 25 met the inclusion criteria. Immediately after surgery, satisfactory corrections were achieved from the perspective of not only Cobb angle but also vertebral translation. And the corrections were well retained in the following two years. The incidence rate of distal adding-on was low in this group of patients. In the course of two years following surgery, only six patients had an increase of greater than 5 mm in LIV + 1 translation, and among which only two patients had greater than 10 mm. Regarding global balance, overall, it neither improved nor deteriorated after extensive fusion. Furthermore, trunk shift was found in only three patients at two year follow-up.
In Lenke 3C and 6C scoliosis, extensive fusion can produce satisfactory corrections from the perspectives of both Cobb angle and vertebral translation and rarely causes significant distal adding-on, global imbalance or trunk shift.
PMCID: PMC3311790  PMID: 21842429
16.  The Canadian Occupational Performance Measure’s semi-structured interview: its applicability to lumbar spinal fusion patients. A prospective randomized clinical study 
European Spine Journal  2011;21(1):115-121.
Although lumbar spinal fusion has been performed for more than 70 years, few studies have examined rehabilitation strategies for spinal fusion patients, and there is only sparse information about the patient’s activity level after surgery. The Canadian Occupational Performance Measure (COPM) is a standardized semi-structured interview, developed to identify patients’ problems in relation to activities of daily living (ADL). The COPM has neither been examined in a randomised clinical study nor employed in relation to lumbar spinal fusion patients. We aimed to examine whether or not the use of the semi-structured interview COPM during in-hospital rehabilitation could: (1) identify more ADL-related problems of importance to the patients after discharge from the hospital, (2) enhance the patients’ ADL performance after discharge from hospital
Eighty-seven patients undergoing a lumbar spinal fusion caused by degenerative diseases were randomly assigned to either use of the COPM or to standard treatment.
Results and conclusion
Use of the COPM during hospitalization helped in identifying more ADL problems encountered by patients during the first 3 months post-discharge period as COPM served to identify more treatment goals and plans of action. Use of the COPM had no impact on the patients’ ADL performance, and the difference is so small that COPM may be of little clinical consequence.
PMCID: PMC3252452  PMID: 21863462
Activities of daily living (ADL); Canadian Occupational Performance Measure (COPM); Occupational therapy; Rehabilitation; Lumbar spinal fusion
17.  Fabrication and characterization of a rapid prototyped tissue engineering scaffold with embedded multicomponent matrix for controlled drug release 
Bone tissue engineering implants with sustained local drug delivery provide an opportunity for better postoperative care for bone tumor patients because these implants offer sustained drug release at the tumor site and reduce systemic side effects. A rapid prototyped macroporous polycaprolactone scaffold was embedded with a porous matrix composed of chitosan, nanoclay, and β-tricalcium phosphate by freeze-drying. This composite scaffold was evaluated on its ability to deliver an anthracycline antibiotic and to promote formation of mineralized matrix in vitro. Scanning electronic microscopy, confocal imaging, and DNA quantification confirmed that immortalized human bone marrow-derived mesenchymal stem cells (hMSC-TERT) cultured in the scaffold showed high cell viability and growth, and good cell infiltration to the pores of the scaffold. Alkaline phosphatase activity and osteocalcin staining showed that the scaffold was osteoinductive. The drug-release kinetics was investigated by loading doxorubicin into the scaffold. The scaffolds comprising nanoclay released up to 45% of the drug for up to 2 months, while the scaffold without nanoclay released 95% of the drug within 4 days. Therefore, this scaffold can fulfill the requirements for both bone tissue engineering and local sustained release of an anticancer drug in vitro. These results suggest that the scaffold can be used clinically in reconstructive surgery after bone tumor resection. Moreover, by changing the composition and amount of individual components, the scaffold can find application in other tissue engineering areas that need local sustained release of drug.
PMCID: PMC3418070  PMID: 22904634
nanoclay; chitosan; scaffold; tissue engineering; drug delivery system
18.  Fusion mass bone quality after uninstrumented spinal fusion in older patients 
European Spine Journal  2010;19(12):2200-2208.
Older people are at increased risk of non-union after spinal fusion, but little is known about the factors determining the quality of the fusion mass in this patient group. The aim of this study was to investigate fusion mass bone quality after uninstrumented spinal fusion and to evaluate if it could be improved by additional direct current (DC) electrical stimulation. A multicenter RCT compared 40 and 100 μA DC stimulation with a control group of uninstrumented posterolateral fusion in patients older than 60 years. This report comprised 80 patients who underwent DEXA scanning at the 1 year follow-up. The study population consisted of 29 men with a mean age of 72 years (range 62–85) and 51 women with a mean age of 72 years (range 61–84). All patients underwent DEXA scanning of their fusion mass. Fusion rate was assessed at the 2 year follow-up using thin slice CT scanning. DC electrical stimulation did not improve fusion mass bone quality. Smokers had lower fusion mass BMD (0.447 g/cm2) compared to non-smokers (0.517 g/cm2) (P = 0.086). Women had lower fusion mass BMD (0.460 g/cm2) compared to men (0.552 g/cm2) (P = 0.057). Using linear regression, fusion mass bone quality, measured as BMD, was significantly influenced by gender, age of the patient, bone density of the remaining part of the lumbar spine, amount of bone graft applied and smoking. Fusion rates in this cohort was 34% in the control group and 33 and 43% in the 40 and 100 μA groups, respectively (not significant). Patients classified as fused after 2 years had significant higher fusion mass BMD at 1 year (0.592 vs. 0.466 g/cm2, P = 0.0001). Fusion mass bone quality in older patients depends on several factors. Special attention should be given to women with manifest or borderline osteoporosis. Furthermore, bone graft materials with inductive potential might be considered for this patient population.
PMCID: PMC2997208  PMID: 20429017
Spinal fusion; Randomised clinical trial; Bone mineral density; Electrical stimulation; Bone graft; Age; Smoking
19.  Combined 3D and hypoxic culture improves cartilage-specific gene expression in human chondrocytes 
Acta Orthopaedica  2011;82(2):234-240.
Background and purpose
In vitro expansion of autologous chondrocytes is an essential part of many clinically used cartilage repair treatments. Native chondrocytes reside in a 3-dimensional (3D) network and are exposed to low levels of oxygen. We compared monolayer culture to combined 3D and hypoxic culture using quantitative gene expression analysis.
Cartilage biopsies were collected from the intercondylar groove in the distal femur from 12 patients with healthy cartilage. Cells were used for either monolayer or scaffold culture. The scaffolds were clinically available MPEG-PLGA scaffolds (ASEED). After harvesting of cells for baseline investigation, the remainder was divided into 3 groups for incubation in conditions of normoxia (21% oxygen), hypoxia (5% oxygen), or severe hypoxia (1% oxygen). RNA extractions were performed 1, 2, and 6 days after the baseline time point, respectively. Quantitative RT-PCR was performed using assays for RNA encoding collagen types 1 and 2, aggrecan, sox9, ankyrin repeat domain-37, and glyceraldehyde-3-phosphate dehydrogenase relative to 2 hypoxia-stable housekeeping genes.
Sox9, aggrecan, and collagen type 2 RNA expression increased with reduced oxygen. On day 6, the expression of collagen type 2 and aggrecan RNA was higher in 3D culture than in monolayer culture.
Our findings suggest that there was a combined positive effect of 3D culture and hypoxia on cartilage-specific gene expression. The positive effects of 3D culture alone were not detected until day 6, suggesting that seeding of chondrocytes onto a scaffold for matrix-assisted chondrocyte implantation should be performed earlier than 2 days before implantation.
PMCID: PMC3235297  PMID: 21434761
20.  Alendronate treatment improves bone–pedicle screw interface fixation in posterior lateral spine fusion: An experimental study in a porcine model 
International Orthopaedics  2009;34(3):447-451.
The bone–screw interface has been indicated as the weak link in pedicle screw spine fixation. Bisphosphonate treatment may have the effect of improving bone–screw interface fixation in spine fusion by inhibiting bone resorption. An experimental study was conducted using a porcine model to evaluate the influence of alendronate treatment on bone–pedicle screw interface fixation. Eleven pigs in the treatment group received alendronate 10 mg/day orally for three months postoperatively. The other 11 pigs served as a control group. Posterior lateral fusion with the CD Horizon pedicle screw system was performed with autograft on the lumbar spine on all animals. Biomechanical torsion test and histomorphometric parameters of screw fixation were evaluated three months after the operation. The maximum torque and initial angular stiffness of the treatment group was higher than that of the control group, but there was no statistical significance. The bone–screw contact surface was 23.3 ± 10% for the treatment group and 9.8 ± 5.9% for the control group (P < 0.01). This study indicated that alendronate treatment increased bone purchase of stainless steel screw surfaces.
PMCID: PMC2899306  PMID: 19330331
21.  Use of Carboxymethyl Cellulose and Collagen Carrier with Equine Bone Lyophilisate Suggests Late Onset Bone Regenerative Effect in a Humerus Drill Defect – A Pilot Study in Six Sheep 
We assessed the use of a filler compound together with the osteoinductive demineralized bone matrix (DBM), Colloss E. The filler was comprised of carboxymethyl-cellulose and collagen type 1. The purpose of the study was to see if the filler compound would enhance the bone formation and distribute the osteoinductive stimulus throughout the bone defect. Six sheep underwent a bilateral humerus drill defect. The drill hole was filled with a compound consisting of 100 mg CMC, 100 mg collagen powder, and 1 ccm autologous full blood in one side, and a combination of this filler compound and 20 mg Colloss E in the other. The animals were divided into three groups of two animals and observed for 8, 12 and 16 weeks. Drill holes was evaluated using quantitative computed tomography (QCT), micro computed tomography (µCT) and histomorphometry. Mean total bone mineral density (BMD) of each implantation site was calculated with both QCT and µCT. Bone volume to total volume (BV/TV) was analyzed using µCT and histomorphometry. Although not statistically significant, results showed increased bone BMD after 16 weeks in µCT data and an increased BV/TV after 16 weeks in both µCT and histology. Correlation between QCT and µCT was R2 = 0.804. Correlation between histomorphometry and µCT BV/TV data was R2 = 0.8935 and with an average overrepresentation of 8.2% in histomorphometry. In conclusion the CMC-Collagen + Colloss E filler seems like a viable osteogenic bone filler mid- to long term. A correlation was found between the analytical methods used in this study.
PMCID: PMC2892074  PMID: 20582241
Collagen; histomorphometry; equine bone lyophilisate; cellulose.
22.  Validation of suitable house keeping genes for hypoxia-cultured human chondrocytes 
BMC Molecular Biology  2009;10:94.
Hypoxic culturing of chondrocytes is gaining increasing interest in cartilage research. Culturing of chondrocytes under low oxygen tension has shown several advantages, among them increased synthesis of extracellular matrix and increased redifferentiation of dedifferentiated chondrocytes. Quantitative gene expression analyses such as quantitative real-time PCR (qRT-PCR) are powerful tools in the investigation of underlying mechanisms of cell behavior and are used routinely for differentiation and phenotype assays. However, the genes used for normalization in normoxic cell-cultures might not be suitable in the hypoxic environment. The objective of this study was to determine hypoxia-stable housekeeping genes (HKG) for quantitative real-time PCR (qRT-PCR) in human chondrocytes cultured in 21%, 5% and 1% oxygen by geNorm and NormFinder analyses.
The chondrocytic response to the hypoxic challange was validated by a significant increase in expression of the hypoxia-inducible gene ankyrin repeat 37 as well as SOX9 in hypoxia. When cultured on the 3-dimentional (3D) scaffold TATA-binding protein (TBP) exhibited the highest expression stability with NormFinder while Ribosomal protein L13a (RPL13A) and beta2-microglobulin (B2M) were the most stable using geNorm analysis. In monolayer RPL13A were the most stable gene using NormFinder, while geNorm assessed RPL13A and human RNA polymerase II (RPII) as most stable. When examining the combination of (3D) culturing and monolayer RPL13A and B2M showed the highest expression stability from geNorm analysis while RPL13A also showed the highest expression stability using NormFinder. Often used HKG such as beta actin (ACTB) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were the most unstable genes investigated in all comparisons. The pairwise variations for the two most stable HKG in each group were all below the cut-off value of 0.15, suggesting that the two most stable HKG from geNorm analysis would be sufficient for qRT-PCR.
All data combined we recommend RPL13A, B2M and RPII as the best choice for qRT-PCR analyses when comparing normoxic and hypoxic cultured human chondrocytes although other genes might also be suitable. However, the matching of HKG to target genes by means of a thorough investigation of the stability in each study would always be preferable.
PMCID: PMC2764705  PMID: 19818117
23.  Impact of instrumentation in lumbar spinal fusion in elderly patients 
Acta Orthopaedica  2009;80(4):445-450.
Background and purpose An increasing number of lumbar fusions are performed using allograft to avoid donor-site pain. In elderly patients, fusion potential is reduced and the patient may need supplementary stability to achieve a solid fusion if allograft is used. We investigated the effect of instrumentation in lumbar spinal fusion performed with fresh frozen allograft in elderly patients.
Methods 94 patients, mean age 70 (60–88) years, who underwent posterolateral spinal fusion either non-instrumented (51 patients) or instrumented (43 patients) were followed for 2–7 years. Functional outcome was assessed with the Dallas pain questionnaire (DPQ), the low back pain rating scale pain index (LBPRS), and SF-36. Fusion was assessed using plain radiographs.
Results Instrumented patients had statistically significantly better outcome scores in 6 of 7 parameters. Fusion rate was higher in the instrumented group (81% vs. 68%, p = 0.1). Solid fusion was associated with a better functional outcome at follow-up (significant in 2 of 7 parameters). 15 patients (6 in the non-instrumented group and 9 in the instrumented group) had repeated lumbar surgery after their initial fusion procedure. Functional outcome was poorer in the group with additional spine surgeries (significant in 4 of 7 parameters).
Interpretation Superior outcomes after lumbar spinal fusion in elderly patients can be achieved by use of instrumentation in selected patients. Outcome was better in patients in which a solid fusion was obtained. Instrumentation was associated with a larger number of additional surgeries, which resulted in a lesser degree of improvement. Instrumentation should not be discarded just because of the age of the patient.
PMCID: PMC2823186  PMID: 19626471
24.  The positive effect of posterolateral lumbar spinal fusion is preserved at long-term follow-up: a RCT with 11–13 year follow-up 
European Spine Journal  2007;17(2):272-280.
Introduction Few studies have investigated the long-term effect of posterolateral lumbar spinal fusion on functional outcome. Aim To investigate the long-term result after posterolateral lumbar spinal fusion with and without pedicle screw instrumentation. Methods Questionnaire survey of 129 patients originally randomised to posterolateral lumbar spinal fusion with or without pedicle screw instrumentation. Follow-up included Dallas Pain Questionnaire (DPQ), Oswestry Disability Index (ODI), SF-36 and a question regarding willingness to undergo the procedure again knowing the result as global outcome parameter. Results Follow-up was 83% of the original study population (107 patients). Average follow-up time was 12 years (range 11–13 years). DPQ-scores were significantly lower than preoperatively in both groups (P < 0.005) and no drift towards the preoperative level was seen. No difference between the two groups were observed (instrumented vs. non-instrumented): DPQ Daily Activity mean 37.0 versus 32.0, ODI mean 33.4 versus 30.6, SF-36 PCS mean 38.8 versus 39.8, SF-36 MCS mean 49.0 versus 53.3. About 71% in both groups were answered positively to the global outcome question. Patients who had retired due to low back pain had poorer outcome than patients retired for other reasons, best outcome was seen in patients still at work (P = 0.01 or less in all questionnaires, except SF-36 MCS P = 0.08). Discussion Improvement in functional outcome is preserved for 10 or more years after posterolateral lumbar spinal fusion. No difference between instrumented fusion and non-instrumented fusion was observed. Patients who have to retired due to low back pain have the smallest improvement.
PMCID: PMC2365547  PMID: 17851701
Lumbar spinal fusion; Randomised clinical trial; Outcome
25.  Cost-effectiveness evaluation of an RCT in rehabilitation after lumbar spinal fusion: a low-cost, behavioural approach is cost-effective over individual exercise therapy 
European Spine Journal  2007;17(2):262-271.
Recently, Christensen et al. reported the clinical effects of a low-cost rehabilitation program equally efficient to a relatively intensive program of individual, physiotherapist-guided exercise therapy. Yet, the low-cost approach is not fully supported as an optimal strategy until a full-scale economic evaluation, including extra-hospital effects such as service utilization in the primary health care sector and return-to-work, is conducted. The objective of this study was to conduct such evalution i.e. investigate the cost-effectiveness of (1) a low-cost rehabilitation regimen with a behavioural element and (2) a regimen of individual exercise therapy, both in comparison with usual practice, from a health economic, societal perspective. Study design was a cost-effectiveness evaluation of an RCT with a 2-year follow-up. Ninety patients having had posterolateral or circumferential fusion (indicated by chronic low back pain and localized pathology) were randomized 3 months after their spinal fusion. Validated pain- and disability index scales were applied at baseline and at 2 years postoperative. Costs were measured in a full-scale societal perspective. The probability of the behavioural approach being cost-effective was close to 1 given pain as the prioritized effect measure, and 0.8 to 0.6 (dependent on willingness to pay per effect unit) given disability as the prioritized effect measure. The probability of the exercise therapy approach being cost-effective was modest due to inferior effectiveness. Results proved robust to relevant sensitivity analysis although a differentiated cost-effectiveness ratio between males and females was suspected. In conclusion, a simple behavioural extension, of setting up group meetings for patients, to a regimen with a strict physiotherapeutic focus was found cost-effective, whereas the cost-effectiveness of increasing frequency and guidance of a traditional physiotherapeutic regimen was unlikely in present trial setting.
PMCID: PMC2365542  PMID: 17713794
Rehabilitation; Lumbar spinal fusion; Chronic low back pain; Health economic evaluation; Cost-effectiveness evaluation

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