Jan J. Rongen

Biomaterials in search of a meniscus substitute.

The menisci fulfill key biomechanical functions in the tibiofemoral (knee) joint. Unfortunately meniscal injuries are quite common and most often treated by (partial) meniscectomy. However, some patients experience enduring symptoms, and, more importantly, it leads to an increased risk for symptomatic osteoarthritis. Over the past decades, researchers have put effort in developing a meniscal substitute able to prevent osteoarthritis and treat enduring clinical symptoms. Grossly, two categories of substitutes are observed: First, a resorbable scaffold mimicking biomechanical function which slowly degrades while tissue regeneration and organization is promoted. Second, a non resorbable, permanent implant which mimics the biomechanical function of the native meniscus. Numerous biomaterials with different (material) properties have been used in order to provide such a substitute. Nevertheless, a clinically applicable cartilage protecting material is not yet emerged. In the current review we provide an overview, and discuss, these different materials and extract recommendations regarding material properties for future developmental research.

The protective effect of meniscus allograft transplantation on articular cartilage: a systematic review of animal studies

Despite widespread reporting on clinical results, the effect of meniscus allograft transplantation on the development of osteoarthritis is still unclear. The aim of this study was to systematically review all studies on the effect of meniscus allograft transplantation on articular cartilage in animals. Pubmed and Embase were searched for original articles concerning the effect of meniscus allograft transplantation on articular cartilage compared with both its positive (meniscectomy) and negative (either sham or non-operated) control in healthy animals. Outcome measures related to assessment of damage to articular cartilage were divided in five principal outcome categories. Standardized mean differences (SMD) were calculated and pooled to obtain an overall SMD and 95% confidence interval. 17 articles were identified, representing 14 original animal cohorts with an average timing of data collection of 24 weeks [range 4 weeks; 30 months]. Compared to a negative control, meniscus allograft transplantation caused gross macroscopic (1.45 [0.95; 1.95]), histological (3.43 [2.25; 4.61]) damage to articular cartilage, and osteoarthritic changes on radiographs (3.12 [1.42; 4.82]). Moreover, results on histomorphometrics and cartilage biomechanics are supportive of this detrimental effect on cartilage. On the other hand, meniscus allograft transplantation caused significantly less gross macroscopic (-1.19 [-1.84; -0.54]) and histological (-1.70 [-2.67; -0.74]) damage to articular cartilage when compared to meniscectomy. However, there was no difference in osteoarthritic changes on plain radiographs (0.04 [-0.48; 0.57]), and results on histomorphometrics and biomechanics did neither show a difference in effect between meniscus allograft transplantation and meniscectomy. In conclusion, although meniscus allograft transplantation does not protect articular cartilage from damage, it reduces the extent of it when compared with meniscectomy.

Comparison of Registered and Published Primary Outcomes in Randomized Controlled Trials of Orthopaedic Surgical Interventions

BACKGROUNDnThe selective reporting of a subset of the outcomes that had been originally reported to a registry is a potential threat to the validity of evidence-based medicine. The extent of selective reporting has not been described for randomized controlled trials (RCTs) assessing the effectiveness of orthopaedic surgical interventions. The objective of this study was (1) to determine the percentage of orthopaedic surgical RCTs published in high-impact orthopaedic journals that were reported to have been registered, (2) to evaluate the consistency between the primary outcome measures recorded in the registry and those reported in the article, and (3) to evaluate whether selective reporting favored statistically significant outcomes.nnnMETHODSnWe searched PubMed for articles on RCTs assessing orthopaedic surgical interventions indexed from January 2010 through December 2014 and published in the ten orthopaedic journals with the highest impact factors. For every article in which the authors reported registration of the RCT, we extracted the number and nature of the outcome measures from the article and the corresponding information from the registry. We then evaluated the consistency between the primary outcome measures reported in the registry and those reported in the published article. Moreover, we evaluated whether selective reporting favored statistically significant outcomes.nnnRESULTSnOf the 362 articles on orthopaedic surgical RCTs, ninety (24.9%) reported that the RCT had been registered and thirty-four (37.8%) of the ninety had been registered adequately (registered before the study end with a clear description of the primary outcome measure and its time frame, with no substantial change after the study end). Twenty-six reports were eligible for our evaluation of the consistency between the registered primary outcome measures and those reported in the published article. This analysis identified one or multiple major discrepancies for fourteen articles, eight of which favored statistically significant results.nnnCONCLUSIONSnFew articles on orthopaedic surgical RCTs reported registration of the trial, and even fewer of these trials were registered adequately. Inconsistencies between registered primary outcome measures and those reported in the published articles, as well as selective outcome reporting favoring statistically significant outcomes, were prevalent.nnnCLINICAL RELEVANCEnAlthough trial registration is now the rule, it is currently far from optimal for orthopaedic surgical RCTs, and selective outcome reporting is prevalent. Full involvement of authors, editors, and reviewers is necessary to ensure publication of quality, unbiased results.

Transcranial direct current stimulation does not modulate motor cortex excitability in patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive disease caused by the degeneration of upper and lower motor neurons. The etiology of ALS is unclear, but there is evidence that loss of cortical inhibition could be related to motor neuron degeneration. We sought to determine whether cathodal transcranial direct current stimulation (tDCS) can reduce cortical excitability in patients with ALS.

Increased risk for knee replacement surgery after arthroscopic surgery for degenerative meniscal tears: a multi-center longitudinal observational study using data from the osteoarthritis initiative

OBJECTIVEnThe primary objective was to assess whether patients with knee osteoarthritis and whom undergo arthroscopic meniscectomy have an increased risk for future knee replacement surgery.nnnDESIGNnData used were obtained from the Osteoarthritis Initiative (OAI) study.nnnSETTINGnParticipants were enrolled, in four clinical centers, between February 2004 and May 2006 and were followed up on an annual basis up to and including 108-months from enrollment.nnnPARTICIPANTSn4674 participants (58.4% female), aged 45-79, of all ethnic groups, who had, and those who were at high risk for developing, symptomatic knee osteoarthritis were included, of which 3337 (71.4%) were included in the final follow up visit.nnnMAIN OUTCOME MEASURESnHazard ratio of knee replacement surgery for participants who underwent arthroscopic meniscectomy during follow up compared to propensity score matched participants who did not undergo arthroscopic meniscectomy during follow up.nnnRESULTSn335 participants underwent arthroscopic meniscectomy during follow up, of which 63 (18.8%) underwent knee replacement surgery in the same knee. Of the 335 propensity score matched participants 38 (11.1%) underwent knee replacement surgery during follow up. Results from the Cox-proportional hazards model demonstrated that the hazard ratio of knee replacement surgery was 3.03 (95% CI (1.67-5.26)) for participants who underwent arthroscopic meniscectomy relative to the propensity score matched participants who did not undergo arthroscopic meniscectomy.nnnCONCLUSIONSnIn patients with knee osteoarthritis arthroscopic knee surgery with meniscectomy is associated with a three fold increase in the risk for future knee replacement surgery.

Cumulative effect of 5 daily sessions of theta burst stimulation on corticospinal excitability in amyotrophic lateral sclerosis

Introduction: Excitotoxicity plays an important role in the pathogenesis of the preferential motor neuron death observed in amyotrophic lateral sclerosis (ALS). Continuous theta burst stimulation (cTBS) by transcranial magnetic stimulation has an inhibitory effect on corticospinal excitability (CSE). We characterized the neurophysiological changes induced by cTBS in ALS. Methods: The patients received 5 daily sessions of cTBS. CSE was assessed at baseline and after each session of cTBS. Results: The amplitude of a single pulse motor evoked potential was significantly decreased (34%) over the days. The amplitude returned to baseline a week after the last session. The resting motor threshold increased significantly, whereas intracortical inhibition and facilitation did not change over the sessions. Conclusions: Daily cTBS has a cumulative depressing effect on CSE in patients with ALS. These results suggest that modulation of CSE in ALS is possible, but repetitive sessions are needed to maintain the effect. Muscle Nerve 48:733–738, 2013

Meniscus surgery is still widely performed in the treatment of degenerative meniscus tears in The Netherlands

PurposeStudies have demonstrated rising incidences of meniscus procedures for degenerative meniscus tears in several countries, despite accumulating evidence that questions the efficacy of the treatment. It is not clear if this rise in incidences also applies to the practice of arthroscopic surgery in the Netherlands. The objective of this study was, therefore, to evaluate the number of meniscal surgeries performed in the Netherlands between 2005 and 2014.MethodsWe used registry-based data on meniscal surgeries that originated from Dutch national hospital basic care registrations from 2005 to 2014. Poisson regression models were used to test differences in incidences of meniscus surgeries performed in the Netherlands between 2005 and 2014, and to find out if changes in incidences over this period differed for younger and older patients.ResultsThe number of meniscus surgeries was highest in patients aged 40–65 years, who accounted for half of the total number of meniscal surgeries. The incidences of meniscus surgeries decreased from 2005 to 2014 (pu2009<u20090.001); this decrease was observed in all age groups, although the decrease in incidences was more pronounced for younger patients (aged less than 40 years) compared to middle-aged and older patients (aged 40 years and older) (pu2009<u20090.001).ConclusionsThe implementation of a nationwide guideline for arthroscopic procedures for meniscus tears may have contributed to a decrease in incidences of meniscus procedures. Despite accumulating evidence that questions the rationalisation and effectiveness of the treatment, meniscus surgery is still widely performed in the treatment of degenerative meniscus tears in the Netherlands, demonstrating a delay in the dissemination, acceptance, and implementation of clinical evidence in the practice of arthroscopic surgery in the Netherlands.Level of evidenceII.

Degradation behavior of, and tissue response to photo-crosslinked poly(trimethylene carbonate) networks

Photo-crosslinked networks prepared from three-armed methacrylate functionalized PTMC oligomers (PTMC-tMA macromers) are attractive materials for developing an anatomically correct meniscus scaffold. In this study, we evaluated cell specific biocompatibility, in vitro and in vivo degradation behavior of, and tissue response to, such PTMC networks. By evaluating PTMC networks prepared from PTMC-tMA macromers of different molecular weights, we were able to assess the effect of macromer molecular weight on the degradation rate of the PTMC network obtained after photo-crosslinking. Three photo-crosslinked networks with different crosslinking densities were prepared using PTMC-tMA macromers with molecular weights 13.3, 17.8, and 26.7 kg/mol. Good cell biocompatibility was demonstrated in a proliferation assay with synovium derived cells. PTMC networks degraded slowly, but statistically significant, both in vitro as well as subcutaneously in rats. Networks prepared from macromers with higher molecular weights demonstrated increased degradation rates compared to networks prepared from initial macromers of lowest molecular weight. The degradation process took place via surface erosion. The PTMC networks showed good tissue tolerance during subcutaneous implantation, to which the tissue response was characterized by the presence of fibrous tissue and encapsulation of the implants. Concluding, we developed cell and tissue biocompatible, photo-crosslinked PTMC networks using PTMC-tMA macromers with relatively high molecular weights. These photo-crosslinked PTMC networks slowly degrade by a surface erosion process. Increasing the crosslinking density of these networks decreases the rate of surface degradation.

Societal and Economic Effect of Meniscus Scaffold Procedures for Irreparable Meniscus Injuries

Background: Meniscus scaffolds are currently evaluated clinically for their efficacy in preventing the development of osteoarthritis as well as for their efficacy in treating patients with chronic symptoms. Procedural costs, therapeutic consequences, clinical efficacy, and future events should all be considered to maximize the monetary value of this intervention. Purpose: To examine the socioeconomic effect of treating patients with irreparable medial meniscus injuries with a meniscus scaffold. Study Design: Economic and decision analysis; Level of evidence, 2. Methods: Two Markov simulation models for patients with an irreparable medial meniscus injury were developed. Model 1 was used to investigate the lifetime cost-effectiveness of a meniscus scaffold compared with standard partial meniscectomy by the possibility of preventing the development of osteoarthritis. Model 2 was used to investigate the short-term (5-year) cost-effectiveness of a meniscus scaffold compared with standard partial meniscectomy by alleviating clinical symptoms, specifically in chronic patients with previous meniscus surgery. For both models, probabilistic Monte Carlo simulations were applied. Treatment effectiveness was expressed as quality-adjusted life-years (QALYs), while costs (estimated in euros) were assessed from a societal perspective. We assumed €20,000 as a reference value for the willingness to pay per QALY. Next, comprehensive sensitivity analyses were performed to identify the most influential variables on the cost-effectiveness of meniscus scaffolds. Results: Model 1 demonstrated an incremental cost-effectiveness ratio of a meniscus scaffold treatment of €54,463 per QALY (€5991/0.112). A threshold analysis demonstrated that a meniscus scaffold should offer a relative risk reduction of at least 0.34 to become cost-effective, assuming a willingness to pay of €20,000. Decreasing the costs of the meniscus scaffold procedure by 33% (€10,160 instead of €15,233; an absolute change of €5073) resulted in an incremental cost-effectiveness ratio of €7876 per QALY. Model 2 demonstrated an incremental cost-effectiveness ratio of a meniscus scaffold treatment of €297,727 per QALY (€9825/0.033). On the basis of the current efficacy data, a meniscus scaffold provides a relative risk reduction of “limited benefit” postoperatively of 0.37 compared with standard treatment. A threshold analysis revealed that assuming a willingness to pay of €20,000, a meniscus scaffold would not be cost-effective within a period of 5 years. Most influential variables on the cost-effectiveness of meniscus scaffolds were the cost of the scaffold procedure, cost associated with osteoarthritis, and quality of life before and after the scaffold procedure. Conclusion: Results of the current health technology assessment emphasize that the monetary value of meniscus scaffold procedures is very much dependent on a number of influential variables. Therefore, before implementing the technology in the health care system, it is important to critically assess these variables in a relevant context. The models can be improved as additional clinical data regarding the efficacy of the meniscus scaffold become available.

Arthroscopic meniscectomy for degenerative meniscal tears reduces knee pain but is not cost-effective in a routine health care setting: a multi-center longitudinal observational study using data from the osteoarthritis initiative

OBJECTIVESnIt is disputed whether arthroscopic meniscectomy is an (cost-) effective treatment for degenerative meniscus tears in day-to-day clinical practice. The objective of this study was to assess the cost-effectiveness of arthroscopic meniscectomy in subjects with knee osteoarthritis, in routine clinical practice, while taking into account the increased risk for future knee replacement surgery. We compared cost-effectiveness of arthroscopic meniscectomy compared to no surgery.nnnDESIGNnWe used a state transition (Markov) simulation model to evaluate the cost-effectiveness of arthroscopic meniscectomy compared to no surgery in subjects with knee osteoarthritis (age range 45-79 years). Data used in the preparation of the current study were obtained from the Osteoarthritis Initiative (AOI) database. We applied a 9 years time horizon (which is equal to the current OAI study follow up period), and evaluated cost-effectiveness from a societal perspective. The main outcome measure was the incremental cost-effectiveness ratio (Euros per quality adjusted life-year (QALY) gained).nnnRESULTSnArthroscopic meniscectomy was associated with 8.09 (SDxa0±xa00.07) QALYs at a cost of € 21,345 (SDxa0±xa0841), whereas the no surgery was associated with 8.05 (SDxa0±xa00.07) QALYs at a cost of € 16,284 (SDxa0±xa0855). For arthroscopic meniscectomy, the incremental cost per QALY gained was € 150,754.nnnCONCLUSIONSnIn day-to-day clinical practice, arthroscopic meniscectomy in subjects with knee osteoarthritis is associated with € 150,754 per QALY gained, which exceeds the generally accepted willingness to pay (WTP) (range € 20,000-€ 80,000).