Hydrogels as extracellular matrices for skeletal tissue engineering: state-of-the-art and novel application in organ printing.

Organ printing, a novel approach in tissue engineering, applies layered computer-driven deposition of cells and gels to create complex 3-dimensional cell-laden structures. It shows great promise in regenerative medicine, because it may help to solve the problem of limited donor grafts for tissue and organ repair. The technique enables anatomical cell arrangement using incorporation of cells and growth factors at predefined locations in the printed hydrogel scaffolds. This way, 3-dimensional biological structures, such as blood vessels, are already constructed. Organ printing is developing fast, and there are exciting new possibilities in this area. Hydrogels are highly hydrated polymer networks used as scaffolding materials in organ printing. These hydrogel matrices are natural or synthetic polymers that provide a supportive environment for cells to attach to and proliferate and differentiate in. Successful cell embedding requires hydrogels that are complemented with biomimetic and extracellular matrix components, to provide biological cues to elicit specific cellular responses and direct new tissue formation. This review surveys the use of hydrogels in organ printing and provides an evaluation of the recent advances in the development of hydrogels that are promising for use in skeletal regenerative medicine. Special emphasis is put on survival, proliferation and differentiation of skeletal connective tissue cells inside various hydrogel matrices.

No evidence for intervention-dependent influence of methodological features on treatment effect.

OBJECTIVES: The goal of this systematic review was to evaluate if the influence of methodological features on treatment effect differs between types of intervention. STUDY DESIGN AND SETTING: MEDLINE, Embase, Web of Science, Cochrane methodology register, and reference lists were searched for meta-epidemiologic studies on the influence of methodological features on treatment effect. Studies analyzing influence of methodological features related to internal validity were included. We made a distinction among surgical, pharmaceutical, and therapeutical as separate types of intervention. Heterogeneity was calculated to identify differences among these types. RESULTS: Fourteen meta-epidemiologic studies were found with 51 estimates of influence of methodological features on treatment effect. Heterogeneity was observed among the intervention types for randomization. Surgical intervention studies showed a larger treatment effect when randomized; this was in contrast to pharmaceutical studies that found the opposite. For allocation concealment and double blinding, the influence of methodological features on the treatment effect was comparable across different types of intervention. For the remaining methodological features, there were insufficient observations. CONCLUSION: The influence of allocation concealment and double blinding on the treatment effect is consistent across studies of different interventional types. The influence of randomization although, may be different between surgical and nonsurgical studies.

Effect of methodological quality measures in spinal surgery research: a metaepidemiological study.

BACKGROUND CONTEXT: Methodological quality measures of trials in meta-analyses have been shown to influence the pooled effect sizes in several medical fields. However, for spinal surgery, influence of quality measures has not been assessed. PURPOSE: The purpose of this study was to analyze the influence of quality measures in studies on effectiveness in spinal surgery. STUDY DESIGN: A metaepidemiological study was performed on meta-analyses within spinal surgery. METHODS: A systematic search was performed in MEDLINE, Cochrane Database, and EMBASE in August 2009. The effect sizes, defined as risk of positive clinical outcome, of trials included in the meta-analyses were assessed. The differences in effect sizes were calculated as risk differences (RDs). Relation of the RDs to potential quality measures such as sponsoring, randomization, allocation concealment, blinding, and study size was assessed with metaregression adjusted for multiple testing. RESULTS: Seven reviews consisting of 118 studies were included. Data provided by the systematic reviews alone were insufficient to analyze the effect of quality measures. Metaregression analysis of 76 of the individual trials reporting clinical outcome, though, showed that sample size, strict randomization, and outcome blinding were significant quality measures influencing study effect. Risk difference of effect from validly randomized studies was higher compared with not validly randomized and comparative observational trials (5.4%; 95% confidence interval [CI], 1.2-9.6; p=.044). Studies with adequate observer blinding showed a 7.2% lower RD (95% CI, 0.8-13.7; p=.049). For each increase of 100 patients, the RD decreased 3.6% (95% CI, 0.5-6.8; p=.098). CONCLUSIONS: Contrary to basic methodological assertions, formal and strict randomization appeared to produce a significantly higher RD in spinal surgery research. Sufficient sample size and observer blinding, on the other hand, led to a lower RD as expected. These findings imply that effect of quality measures assessed in metaepidemiological studies should not be too easily translated to research in spinal surgery.

Spine surgery research: on and beyond current strategies.

BACKGROUND CONTEXT: Systematic reviews of the literature are powerful tools in evidence-based medicine. However, the design and report of systematic reviews in spinal surgery contain many aspects amenable to improvement. PURPOSE: To discuss the issues especially relevant for systematic reviews in spinal surgery. METHODS: From our experience of systematic reviews and meta-analyses of clinical trials in spinal surgery, we infer guidance for the design and execution of systematic literature reviews. RESULTS: There are many difficulties associated with the design as well as conduct of clinical trials and consequently appraising evidence in spinal surgery. New treatments should be compared with the gold standard before other comparisons are investigated. Studies should present data as thoroughly as possible regarding all subgroups and follow-up moments, possibly in supplementary material. To provide the highest level of evidence, systematic reviews should be as rigorously designed as possible. CONCLUSIONS: Gathering information on clinical effectiveness in spinal surgery can be improved both at the clinical study level and at the systematic review level. Alternatives to randomized controlled trials such as comparative studies can be valuable tools on the clinical effectiveness of treatments in spinal surgery. The experience reflected in this article can support the scientific efforts in this field.

Replacement of the medial tibial plateau by a metallic implant in a goat model.

The purposes of the present study were to explore the surgical possibilities for replacement of the medial tibial plateau by a metallic implant in a large animal model and to examine the implications for the opposing cartilage. In six goats, the medial tibial plateau of the right knee was replaced by a cobalt-chromium implant, using polymethylmethacrylate bone cement for fixation. The unoperated left knee served as a control. At 26 weeks after surgery, the animals were killed, and the joints evaluated macroscopically. Cartilage quality was analyzed macroscopically and histologically. Glycosaminoglycan content, synthesis, and release were measured in tissue and medium. All animals were able to move and load the knees without any limitations. Macroscopic articular evaluation scores showed worsening 26 weeks after inserting the implant (p < 0.05). Macroscopic and histologic scores showed more cartilage degeneration of the opposing medial femoral condyle in the experimental knee compared to the control knee (p < 0.05). Higher glycosaminoglycan synthesis was measured at the medial femoral condyle cartilage in the experimental knees (p < 0.05). This study shows that the medial tibial plateau can be successfully replaced by a cobalt-chromium implant in a large animal model. However, considerable femoral cartilage degeneration of the medial femoral condyle was induced, suggesting that care must be taken introducing hemiarthroplasty devices in a human clinical setting for the treatment of postmeniscectomy cartilage degeneration of the medial tibial plateau.

Cartilage damage caused by metal implants applied for the treatment of established localized cartilage defects in a rabbit model.

The purpose of the current study was to investigate the feasibility of the application of defect-size femoral implants in a rabbit model of established cartilage defects and compare this treatment to microfracturing. In 31 New Zealand White rabbits, a medial femoral condyle defect was created in each knee. After 4 weeks, 3 animals were killed for defect baseline values. In the other 28 rabbits, knees were sham-operated, treated with microfracturing, or treated by placing an oxidized zirconium (OxZr) or cobalt-chromium (CoCr) implant (theta articulating surface 3.5 mm; fixating pin of 9.1 mm length). These animals were sacrificed 4 weeks after treatment. Joints were evaluated macroscopically. Implant osseointegration was measured by automated histomorphometry, and cartilage repair was scored microscopically. Cartilage quality was analyzed macroscopically and microscopically. Bone-implant contact was 63.2% +/- 3.2% for CoCr and 62.5% +/- 3.2% for OxZr. Cartilage defects did not show complete healing, nor during subsequent sham-surgery or microfracturing. For all treatments, considerable cartilage damage in the articulating medial tibia, and degeneration of lateral tibial and femoral cartilage was observed (p < 0.05). Both CoCr and OxZr implant-treated defects showed an increase of cartilage degeneration compared to microfracturing and sham-operated defects (p < 0.05). Although only a single short-term follow-up period was investigated in this study, caution is warranted using small metal implants as a treatment for established localized cartilage defects because, even after 4 weeks in this model, the metal implants caused considerable degeneration of the articulating surface.

Quality of life in children with osteogenesis imperfecta treated with oral bisphosphonates (Olpadronate): a 2-year randomized placebo-controlled trial.

UNLABELLED: In this double-blind randomised placebo-controlled trial it was investigated during a two-year follow-up whether oral bisphosphonates (Olpadronate 10 mg/m2/day) influence quality of life in children with osteogenesis imperfecta (OI). Thirty-four children with OI (classified according to Sillence criteria), aged 3 to 18 years of age, with a restricted level of ambulation were included. Randomisation was performed using a list of computer generated random numbers to allocate patients to receive Olpadronate or placebo. Quality of life was measured using self-perception profile for children (SPPC) and health-utility index (HUI). Differences between baseline measurements and measurements at two years follow-up were analysed within the Olpadronate and placebo group using a student's t-test. Differences in HUI and SPPC regression coefficients were analysed by random-effects repeated measures analysis (SAS, Proc Mixed, version 8.2), adjusted for age, gender and type of OI. Within the Olpadronate group there was a significant decrease in pain utility; however, difference in six months' regression coefficients between the placebo and Olpadronate group were not significant. Within the placebo group there was a significant increase in scholastic competence and behavioural conduct. The item behavioural conduct showed a steeper annual regression coefficient favourable for the placebo group. In the other SPPC items none of the annual regression coefficients showed a significant difference between the Olpadronate and the placebo group. CONCLUSION: We found only slight differences in quality of life in favour of the bisphosphonate group. A small but not significant decrease in pain was detected in the bisphosphonate group.

Complications of artificial disc replacement: a report of 27 patients with the SB Charité disc.

Disc prosthesis surgery is rapidly becoming an option in treating patients with symptomatic degenerative disc disease. Only short-term and midterm results are described in the literature. Most operated patients belong to the age group of 30-50 years. In these active patients, complications can be expected to increase with longer follow-up, similar to total joint replacements in the extremities. Reported here is a series of 27 patients from another institution, who presented with unsatisfactory results or complications after SB Charité disc replacement. The objective of this work was to describe the possible short- and long-term unsatisfactory results of disc prosthesis surgery. Twenty-seven patients were seen in a tertiary university referral center with persisting back and leg complaints after having received a Charité disc prosthesis. All patients were operated on in a neighboring hospital. Most patients were operated on at the L4-L5 and /or the L5-S1 vertebral levels. The patients were evaluated with plain radiography, some with flexion-extension x-rays, and most of them with computed tomography scans. The group consisted of 15 women and 12 men. Their mean age was 40 years (range 30-67 years) at the time of operation. The patients presented to us a mean of 53 months (range 11-127 months) following disc replacement surgery. In two patients, an early removal of a prosthesis was required and in two patients a late removal. In 11 patients, a second spinal reconstructive salvage procedure was performed. Mean follow-up for 26 patients with mid- and long-term evaluation was 91 months (range 15-157 months). Early complications were the following: In one patient, an anterior luxation of the prosthesis after 1 week necessitated removal and cage insertion, which failed to unite. In another patient with prostheses at L4-L5 and L5-S1, the prosthesis at L5-S1 dislocated anteriorly after 3 months and was removed after 12 months. Abdominal wall hematoma occurred in four cases. Retrograde ejaculation with loss of libido was seen in one case and erection weakness in another case. A temporary benefit was experienced by 12 patients, while 14 patients reported no benefit at all. Main causes of persistent complaints were degeneration at another level in 14, subsidence of the prosthesis in 16, and facet joint arthrosis in 11. A combination of pathologies was often present. Slow anterior migration was present in two cases, with compression on the iliac vessels in one case. Polyethylene wear was obvious in one patient 12 years after operation. In eight cases, posterior fusion with pedicle screws was required. In two cases, the prosthesis was removed and the segment was circumferentially fused. These procedures resulted in suboptimal long-term results. In this relatively small group of patients operated on with a Charité disc prosthesis, most problems arose from degeneration of other lumbar discs, facet joint arthrosis at the same or other levels, and subsidence of the prosthesis. It is to be expected that many more patients will be seen with late problems some years after this operation as the survivorship will decrease with time.