Joint homeostasis in tissue engineering for cartilage repair

Traumatic joint damage, articular cartilage and the research into methods of restoring the articulation are not new topics of interest. For centuries, clinicians have recognized the importance of cartilage damage and sought ways of learning about the normal form and function of hyaline cartilage as well as the process of degradation and restoration. Unfortunately, only some of the real problems have been solved partially, while a lot of basic knowledge has been available for centuries. More recently, tissue engineering was introduced as a method of restoring tissue or organ function, and has already been applied to cartilage repair. The possibility of modulating cells and tissues and applying this novel capability towards the restoration of musculoskeletal function provides great promise and opportunity for progress in orthopedics and traumatology. Currently, various strategies have been introduced for tissue engineering in cartilage repair, but so far no solid foundation for full clinical implementation has been established. Therefore, the general aim of this thesis is to investigate influences on cartilage tissue engineering and to identify areas where the outcome can be improved. Given the history of the field of musculoskeletal research, it is important to realize the relativity of individual contributions and the constraints on real progress of scientific knowledge in time. No clearer can this be illustrated than by offering the reader insight in the historically available knowledge. As early as in old Egyptian civilization, descriptions of cartilage as a tissue and the relevance of articular degradation as a disease have been found. Scholars such as Aristoteles, Hippocrates and Leonardo da Vinci already contributed to these investigations, but were also the first to suggest that If one way be better than another, that you may be sure is Nature s way (Aristotle, 4th century B.C.) and Human ingenuity makes inventions but none as beautiful, simple or to more purpose than Nature (Leonardo da Vinci, 15th century). One of the first literature contributions on cartilage biology by the British surgeon William Hunter is a historic hallmark paper, which demonstrates the value and bright practical insight of (almost) forgotten knowledge, and provides the reader of this thesis with a solid grasp of what is important to orthopedic surgeons who perform their research in the field of cartilage repair and surgical intervention. Hunter s description of cartilage biology, though not as detailed as our current knowledge, is accurate, relevant and clear. The clinical problem colorfully described by Hunter remains largely unsolved, although we have fortunately progressed beyond the point at which our patients submit unhappily to extirpation, a doubtful remedy, or wear out a painful though probably short life

Validation of the Knee Injury and Osteoarthritis Outcome Score (KOOS) for the treatment of focal cartilage lesions

SummaryObjectiveTo validate the Knee Injury and Osteoarthritis Outcome Score (KOOS) for the treatment of focal cartilage lesions.MethodsA total of 40 patients (mean age 35±12 years,) treated for a focal cartilage lesion in the knee were included in this study. Test–retest data were collected with an intermediate period of 2 days. Patients were asked to complete the Dutch KOOS and complementary questionnaires [short form-36 (SF-36), Lysholm, EuroQol-5D (EQ-5D)] to evaluate the clinimetric properties of the KOOS in terms of internal consistency (Cronbach's alpha), reliability [intra-class-correlation (ICC) and Bland and Altman plots], construct validity (Spearman's rank correlation), floor and ceiling effects and responsiveness.ResultsThe Cronbach's alpha of the KOOS subdomains and total score ranged from 0.74 to 0.96. The overall ICC of the KOOS was 0.97 while the subscales ranged from 0.87 to 0.95. The Bland and Altman plots showed a small individual variance between the two assessments in time. Spearman's rank correlations between the subscales of the KOOS and representative subscales of the SF-36, Lysholm and EQ-5D were high to moderate ranging from 0.43 to 0.70. We observed no floor effect while the largest observed ceiling effect was 10.3%. The responsiveness was moderate to large with the effect size ranging from 0.70 to 1.32 and the standardized response mean 0.61 to 0.87.ConclusionThis study illustrates the validity and reliability of the KOOS in measuring the clinical condition of patients after treatment of focal cartilage lesions. This study provides a basis for the use of the KOOS for future clinical research in cartilage repair

dGEMRIC as a tool for measuring changes in cartilage quality following high tibial osteotomy:A feasibility study

SummaryObjectiveThe high tibial osteotomy (HTO) is an effective strategy for treatment of painful medial compartment knee osteoarthritis. Effects on cartilage quality are largely unknown. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) enables non-invasive assessment of cartilage glycosaminoglycan content. This study aimed to evaluate if dGEMRIC could detect relevant changes in cartilage glycosaminoglycan content following HTO.DesignTen patients with medial compartment osteoarthritis underwent a dGEMRIC scan prior to HTO, and after bone healing and subsequent hardware removal. A dGEMRIC index (T1Gd) was used for changes in cartilage glycosaminoglycan content, a high T1Gd indicating a high glycosaminoglycan content and vice versa. Radiographic analysis included mechanical axis and tibial slope measurement. Clinical scores [Knee Osteoarthritis Outcome Scale (KOOS), visual analogue score (VAS) for pain, Knee Society Clinical Rating System (KSCRS)] before, 3 and 6 months after HTO and after hardware removal were correlated to T1Gd changes.ResultsOverall a trend towards a decreased T1Gd, despite HTO, was observed. Before and after HTO, lateral femoral condyle T1Gd was higher than medial femoral condyle (MFC) T1Gd and tibial cartilage T1Gd was higher than that of femoral cartilage (P < 0.001). The MFC had the lowest T1Gd before and after HTO. Clinical scores all improved significantly (P < 0.01), KOOS Symptoms and QOL were moderately related to changes in MFC T1Gd.ConclusionsdGEMRIC effectively detected differences in cartilage quality within knee compartments before and after HTO, but no changes due to HTO were detected. Hardware removal post-HTO seems essential for adequate T1Gd interpretation. T1Gd was correlated to improved clinical scores on a subscore level only. Longer follow-up after HTO may reveal lasting changes.ClinicalTrials.gov registration ID: NCT01269944

Knee Images Digital Analysis (KIDA): a novel method to quantify individual radiographic features of knee osteoarthritis in detail

SummaryObjectiveRadiography is still the golden standard for imaging features of osteoarthritis (OA), such as joint space narrowing, subchondral sclerosis, and osteophyte formation. Objective assessment, however, remains difficult. The goal of the present study was to evaluate a novel digital method to analyse standard knee radiographs.MethodsStandardized radiographs of 20 healthy and 55 OA knees were taken in general practise according to the semi-flexed method by Buckland-Wright. Joint Space Width (JSW), osteophyte area, subchondral bone density, joint angle, and tibial eminence height were measured as continuous variables using newly developed Knee Images Digital Analysis (KIDA) software on a standard PC.Two observers evaluated the radiographs twice, each on two different occasions. The observers were blinded to the source of the radiographs and to their previous measurements. Statistical analysis to compare measurements within and between observers was performed according to Bland and Altman. Correlations between KIDA data and Kellgren & Lawrence (K&L) grade were calculated and data of healthy knees were compared to those of OA knees.ResultsIntra- and inter-observer variations for measurement of JSW, subchondral bone density, osteophytes, tibial eminence, and joint angle were small. Significant correlations were found between KIDA parameters and K&L grade. Furthermore, significant differences were found between healthy and OA knees.ConclusionIn addition to JSW measurement, objective evaluation of osteophyte formation and subchondral bone density is possible on standard radiographs. The measured differences between OA and healthy individuals suggest that KIDA allows detection of changes in time, although sensitivity to change has to be demonstrated in long-term follow-up studies

Cytokine profiles in the joint depend on pathology, but are different between synovial fluid, cartilage tissue and cultured chondrocytes

__Introduction:__ This study aimed to evaluate whether profiles of several soluble mediators in synovial fluid and cartilage tissue are pathology-dependent and how their productio

Mitochondrial transport from mesenchymal stromal cells to chondrocytes increases DNA content and proteoglycan deposition In vitro in 3D cultures

Objective: Allogeneic mesenchymal stromal cells (MSCs) are used in the 1-stage treatment of articular cartilage defects. The aim of this study is to investigate whether transport of mitochondria exists between chondrocytes and MSCs and to investigate whether the transfer of mitochondria to chondrocytes contributes to the mechanism of action of MSCs. Design: Chondrocytes and MSCs were stained with MitoTracker, and CellTrace was used to distinguish between cell types. The uptake of fluorescent mitochondria was measured in cocultures using flow cytometry. Transport was visualized using fluorescence microscopy. Microvesicles were isolated and the presence of mitochondria was assessed. Mitochondria were isolated from MSCs and transferred to chondrocytes using MitoCeption. Pellets of chondrocytes, chondrocytes with transferred MSC mitochondria, and cocultures were cultured for 28 days. DNA content and proteoglycan content were measured. Mitochondrial DNA of cultured pellets and of repair cartilage tissue was quantified. Results: Mitochondrial transfer occurred bidirectionally within the first 4 hours until 16 hours of coculture. Transport took place via tunneling nanotubes, direct cell-cell contact, and extracellular vesicles. After 28 days of pellet culture, DNA content and proteoglycan deposition were higher in chondrocyte pellets to which MSC mitochondria were transferred than the control groups. No donor mitochondrial DNA was traceable in the biopsies, whereas an increase in MSC mitochondrial DNA was seen in the pellets. Conclusions: These results suggest that mitochondrial transport plays a role in the chondroinductive effect of MSCs on chondrocytes in vitro. However, in vivo no transferred mitochondria could be traced back after 1 year.Molecular Technology and Informatics for Personalised Medicine and Healt

Interleukin-6 is elevated in synovial fluid of patients with focal cartilage defects and stimulates cartilage matrix production in an in vitro regeneration model

Introduction: This study aimed to determine whether, as in osteoarthritis, increased levels of interleukin-6 (IL-6) are present in the synovial fluid of patients with symptomatic cartilage defects and whether this IL-6 affects cartilage regeneration as well as the cartilage in the degenerated knee.Methods: IL-6 concentrations were determined by ELISA in synovial fluid and in conditioned media of chondrocytes regenerating cartilage. Chondrocytes were obtained from donors with symptomatic cartilage defects, healthy and osteoarthritic donors. The effect of IL-6 on cartilage regeneration and on metabolism of the resident cartilage in the knee was studied by both inhibition of endogen

In patients eligible for meniscal surgery who first receive physical therapy, multivariable prognostic models cannot predict who will eventually undergo surgery

Purpose Although physical therapy is the recommended treatment in patients over 45 years old with a degenerative meniscal tear, 24% still opt for meniscal surgery. The aim was to identify those patients with a degenerative meniscal tear who will undergo surgery following physical therapy. Methods The data for this study were generated in the physical therapy arm of the ESCAPE trial, a randomized clinical trial investigating the effectiveness of surgery versus physical therapy in patients of 45-70 years old, with a degenerative meniscal tear. At 6 and 24 months patients were divided into two groups: those who did not undergo surgery, and those who did undergo surgery. Two multivariable prognostic models were developed using candidate predictors that were selected from the list of the patients' baseline variables. A multivariable logistic regression analysis was performed with backward Wald selection and a cut-off of p < 0.157. For both models the performance was assessed and corrected for the models' optimism through an internal validation using bootstrapping technique with 500 repetitions. Results At 6 months, 32/153 patients (20.9%) underwent meniscal surgery following physical therapy. Based on the multivariable regression analysis, patients were more likely to opt for meniscal surgery within 6 months when they had worse knee function, lower education level and a better general physical health status at baseline. At 24 months, 43/153 patients (28.1%) underwent meniscal surgery following physical therapy. Patients were more likely to opt for meniscal surgery within 24 months when they had worse knee function and a lower level of education at baseline at baseline. Both models had a low explained variance (16 and 11%, respectively) and an insufficient predictive accuracy. Conclusion Not all patients with degenerative meniscal tears experience beneficial results following physical therapy. The non-responders to physical therapy could not accurately be predicted by our prognostic models.Orthopaedics, Trauma Surgery and Rehabilitatio

Cell therapy, biomaterials and other options may enhance cartilage repair

There are several articular cartilage repair techniques being used, including microfracture, autologous chondrocyte implantation and mosaicplasty, and orthopaedic surgeons have found they offer some improvement for patients, overall. The physicians who spoke with Orthopaedics Today Europe discussed indications for the major techniques currently used worldwide and noted that results of each approach are somewhat mixed. From their comments it seems that orthopaedic clinicians and researchers are divided over which cartilage repair approaches are optimal and whether developments being worked on now will deliver on the promise of improved outcomes in the future