Publications by authors named "Harrie Weinans"

148 Publications

3D-printed saw guides for lower arm osteotomy, a comparison between a synthetic CT and CT-based workflow.

3D Print Med 2021 Apr 29;7(1):13. Epub 2021 Apr 29.

Department of Orthopedics, University Medical Center Utrecht, HP:05-228, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Background: Three-dimensional (3D)-printed saw guides are frequently used to optimize osteotomy results and are usually designed based on computed tomography (CT), despite the radiation burden, as radiation-less alternatives like magnetic resonance imaging (MRI) have inferior bone visualization capabilities. This study investigated the usability of MR-based synthetic-CT (sCT), a novel radiation-less bone visualization technique for 3D planning and design of patient-specific saw guides.

Methods: Eight human cadaveric lower arms (mean age: 78y) received MRI and CT scans as well as high-resolution micro-CT. From the MRI scans, sCT were generated using a conditional generative adversarial network. Digital 3D bone surface models based on the sCT and general CT were compared to the surface model from the micro-CT that was used as ground truth for image resolution. From both the sCT and CT digital bone models saw guides were designed and 3D-printed in nylon for one proximal and one distal bone position for each radius and ulna. Six blinded observers placed these saw guides as accurately as possible on dissected bones. The position of each guide was assessed by optical 3D-scanning of each bone with positioned saw guide and compared to the preplanning. Eight placement errors were evaluated: three translational errors (along each axis), three rotational errors (around each axis), a total translation (∆T) and a total rotation error (∆R).

Results: Surface models derived from micro-CT were on average smaller than sCT and CT-based models with average differences of 0.27 ± 0.30 mm for sCT and 0.24 ± 0.12 mm for CT. No statistically significant positioning differences on the bones were found between sCT- and CT-based saw guides for any axis specific translational or rotational errors nor between the ∆T (p = .284) and ∆R (p = .216). On Bland-Altman plots, the ∆T and ∆R limits of agreement (LoA) were within the inter-observer variability LoA.

Conclusions: This research showed a similar error for sCT and CT digital surface models when comparing to ground truth micro-CT models. Additionally, the saw guide study showed equivalent CT- and sCT-based saw guide placement errors. Therefore, MRI-based synthetic CT is a promising radiation-less alternative to CT for the creation of patient-specific osteotomy surgical saw guides.
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http://dx.doi.org/10.1186/s41205-021-00103-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082893PMC
April 2021

Use of Therapeutic Pathogen Recognition Receptor Ligands for Osteo-Immunomodulation.

Materials (Basel) 2021 Feb 27;14(5). Epub 2021 Feb 27.

Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.

Therapeutic pathogen recognition receptor (PRR) ligands are reaching clinical practice following their ability to skew the immune response in a specific direction. We investigated the effects of various therapeutic PRR ligands on bone cell differentiation and inflammation. Following stimulation, alkaline phosphatase (ALP) activity (Day 10), osteocalcin, osteonectin expression (Day 14), and calcium deposition (Day 21) were quantified in bone marrow-derived human mesenchymal stem cells (hMSCs). The osteoclastogenic response was determined by measuring tartrate-resistant acid phosphate (TRAP) activity in human monocytes. TNF-α, IL-6, IL-8, and IL-10 expressions were measured by enzyme-linked immunosorbent assay as an indicator of the ligands' inflammatory properties. We found that nucleic acid-based ligands Poly(I:C) and CpG ODN C increased early ALP activity in hMSCs by 4-fold without affecting osteoclast formation. These ligands did not enhance expression of the other, late osteogenic markers. MPLA, Curdlan, and Pam3CSK4 did not affect osteogenic differentiation, but inhibited TRAP activity in monocytes, which was associated with increased expression of all measured cytokines. Nucleic acid-based ligands are identified as the most promising osteo-immunomodulators, as they favor early osteogenic differentiation without inducing an exaggerated immune-cell mediated response or interfering in osteoclastogenesis and thus can be potentially harnessed for multifunctional coatings for bone biomaterials.
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http://dx.doi.org/10.3390/ma14051119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957819PMC
February 2021

Scoring Osteoarthritis Reliably in Large Joints and the Spine Using Whole-Body CT: OsteoArthritis Computed Tomography-Score (OACT-Score).

J Pers Med 2020 Dec 22;11(1). Epub 2020 Dec 22.

Department of Radiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands.

A standardized method to assess structural osteoarthritis (OA) burden thorough the body lacks from literature. Such a method can be valuable in developing personalized treatments for OA. We developed a reliable scoring system to evaluate OA in large joints and the spine-the OsteoArthritis Computed Tomography (OACT) score, using a convenience sample of 197 whole-body low-dose non-contrast CTs. An atlas, containing example images as reference points for training and scoring, are presented. Each joint was graded between 0-3. The total OA burden was calculated by summing scores of individual joints. Intra- and inter-observer reliability was tested 25 randomly selected scans ( = 600 joints). Intra-observer reliability and inter-observer reliability between three observers was assessed using intraclass correlation coefficient (ICC) and square-weighted kappa statistics. The square-weighted kappa for intra-observer reliability for OACT-score at joint-level ranged from 0.79 to 0.95; the ICC for the total OA grade was 0.97 (95%-CI, 0.94 to 0.99). Square-weighted kappa for interobserver reliability ranged from 0.48 to 0.95; the ICC for the total OA grade was 0.95 (95%-CI, 0.90 to 0.98). The OACT score, a new reproducible CT-based grading system reflecting OA burden in large joints and the spine, has a satisfactory reproducibility. The atlas can be used for research purposes, training, educational purposes and systemic grading of OA on CT-scans.
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http://dx.doi.org/10.3390/jpm11010005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822205PMC
December 2020

The Effect of Postural Pelvic Dynamics on the Three-dimensional Orientation of the Acetabular Cup in THA Is Patient Specific.

Clin Orthop Relat Res 2021 Mar;479(3):561-571

T. E. Snijders, A. de Gast, Clinical Orthopedic Research Center midden-Nederland, Diakonessenhuis, Zeist, the Netherlands.

Background: Sagittal pelvic dynamics mainly consist of the pelvis rotating anteriorly or posteriorly while the hips flexes, and this affects the femoroacetabular or THA configuration. Thus far, it is unknown how the acetabular cup of the THA in the individual patient reorients with changing sagittal pelvic dynamics.

Questions/purposes: The aim of this study was to validate a method that establishes the three-dimensional (3-D) acetabular cup orientation with changing sagittal pelvic dynamics and describe these changes during functional pelvic dynamics.

Methods: A novel trigonometric mathematical model, which was incorporated into an easy-to-use tool, was tested. The model connected sagittal tilt, transverse version, and coronal inclination of the acetabular cup during sagittal pelvic tilt. Furthermore, the effect of sagittal pelvic tilt on the 3-D reorientation of acetabular cups was simulated for cups with different initial positions. Twelve pelvic CT images of patients who underwent THA were taken and rotated around the hip axis to different degrees of anterior and posterior sagittal pelvic tilt (± 30°) to simulate functional pelvic tilt in various body positions. For each simulated pelvic tilt, the transverse version and coronal inclination of the cup were manually measured and compared with those measured in a mathematical model in which the 3-D cup positions were calculated. Next, this model was applied to different acetabular cup positions to simulate the effect of sagittal pelvic dynamics on the 3-D orientation of the acetabular cup in the coronal and transverse plane. After pelvic tilt was applied, the intraclass correlation coefficients of 108 measured and calculated coronal and transverse cup orientation angles were 0.963 and 0.990, respectively, validating the clinical use of the mathematical model.

Results: The changes in 3-D acetabular cup orientation by functional pelvic tilt differed substantially between cups with different initial positions; the change in transverse version was much more pronounced in cups with low coronal inclination (from 50° to -29°) during functional pelvic tilt than in cups with a normal coronal inclination (from 39° to -11°) or high coronal inclination (from 31° to 2°). However, changes in coronal inclination were more pronounced in acetabular cups with high transverse version.

Conclusion: Using a simple algorithm to determine the dynamic 3-D reorientation of the acetabular cup during functional sagittal pelvic tilt, we demonstrated that the 3-D effect of functional pelvic tilt is specific to the initial acetabular cup orientation and thus per THA patient.

Clinical Relevance: Future studies concerning THA (in)stability should not only include the initial acetabular cup orientation, but also they need to incorporate the effect of sagittal pelvic dynamics on the individual 3-D acetabular cup orientation. Clinicians can also use the developed tool, www.3d-hip.com, to calculate the acetabular cup's orientation in other instances, such as for patients with spinopelvic imbalance.
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http://dx.doi.org/10.1097/CORR.0000000000001489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899699PMC
March 2021

Unravelling the knee-hip-spine trilemma from the CHECK study.

Bone Joint J 2020 Sep;102-B(9):1261-1267

Department of Orthopedics, University Medical Center Utrecht, Utrecht, Netherlands.

Aims: The aetiologies of common degenerative spine, hip, and knee pathologies are still not completely understood. Mechanical theories have suggested that those diseases are related to sagittal pelvic morphology and spinopelvic-femoral dynamics. The link between the most widely used parameter for sagittal pelvic morphology, pelvic incidence (PI), and the onset of degenerative lumbar, hip, and knee pathologies has not been studied in a large-scale setting.

Methods: A total of 421 patients from the Cohort Hip and Cohort Knee (CHECK) database, a population-based observational cohort, with hip and knee complaints < 6 months, aged between 45 and 65 years old, and with lateral lumbar, hip, and knee radiographs available, were included. Sagittal spinopelvic parameters and pathologies (spondylolisthesis and degenerative disc disease (DDD)) were measured at eight-year follow-up and characteristics of hip and knee osteoarthritis (OA) at baseline and eight-year follow-up. Epidemiology of the degenerative disorders and clinical outcome scores (hip and knee pain and Western Ontario and McMaster Universities Osteoarthritis Index) were compared between low PI (< 50°), normal PI (50° to 60°), and high PI (> 60°) using generalized estimating equations.

Results: Demographic details were not different between the different PI groups. L4 to L5 and L5 to S1 spondylolisthesis were more frequently present in subjects with high PI compared to low PI (L4 to L5, OR 3.717; p = 0.024 vs L5 to S1 OR 7.751; p = 0.001). L5 to S1 DDD occurred more in patients with low PI compared to high PI (OR 1.889; p = 0.010), whereas there were no differences in L4 to L5 DDD among individuals with a different PI. The incidence of hip OA was higher in participants with low PI compared to normal (OR 1.262; p = 0.414) or high PI (OR 1.337; p = 0.274), but not statistically different. The incidence of knee OA was higher in individuals with a high PI compared to low PI (OR 1.620; p = 0.034).

Conclusion: High PI is a risk factor for development of spondylolisthesis and knee OA. Low pelvic incidence is related to DDD, and may be linked to OA of the hip. Level of Evidence: 1b Cite this article: 2020;102-B(9):1261-1267.
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http://dx.doi.org/10.1302/0301-620X.102B9.BJJ-2019-1315.R2DOI Listing
September 2020

Effects of human articular cartilage constituents on simultaneous diffusion of cationic and nonionic contrast agents.

J Orthop Res 2021 04 28;39(4):771-779. Epub 2020 Aug 28.

Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.

Contrast-enhanced computed tomography is an emerging diagnostic technique for osteoarthritis. However, the effects of increased water content, as well as decreased collagen and proteoglycan concentrations due to cartilage degeneration, on the diffusion of cationic and nonionic agents, are not fully understood. We hypothesize that for a cationic agent, these variations increase the diffusion rate while decreasing partition, whereas, for a nonionic agent, these changes increase both the rate of diffusion and partition. Thus, we examine the diffusion of cationic and nonionic contrast agents within degraded tissue in time- and depth-dependent manners. Osteochondral plugs (N = 15, d = 8 mm) were extracted from human cadaver knee joints, immersed in a mixture of cationic CA4+ and nonionic gadoteridol contrast agents, and imaged at multiple time-points, using the dual-contrast method. Water content, and collagen and proteoglycan concentrations were determined using lyophilization, infrared spectroscopy, and digital densitometry, respectively. Superficial to mid (0%-60% depth) cartilage CA4+ partitions correlated with water content (R < -0.521, P < .05), whereas in deeper (40%-100%) cartilage, CA4+ correlated only with proteoglycans (R > 0.671, P < .01). Gadoteridol partition correlated inversely with collagen concentration (0%-100%, R < -0.514, P < .05). Cartilage degeneration substantially increased the time for CA4+ compared with healthy tissue (248 ± 171 vs 175 ± 95 minute) to reach the bone-cartilage interface, whereas for gadoteridol the time (111 ± 63 vs 179 ± 163 minute) decreased. The work clarifies the diffusion mechanisms of two different contrast agents and presents depth and time-dependent effects resulting from articular cartilage constituents. The results will inform the development of new contrast agents and optimal timing between agent administration and joint imaging.
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http://dx.doi.org/10.1002/jor.24824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048551PMC
April 2021

Cohort profile: The Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) study: a 2-year, European, cohort study to describe, validate and predict phenotypes of osteoarthritis using clinical, imaging and biochemical markers.

BMJ Open 2020 07 28;10(7):e035101. Epub 2020 Jul 28.

Rheumatology and Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands.

Purpose: The Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) consortium intends to prospectively describe in detail, preselected patients with knee osteoarthritis (OA), using conventional and novel clinical, imaging, and biochemical markers, to support OA drug development.

Participants: APPROACH is a prospective cohort study including 297 patients with tibiofemoral OA, according to the American College of Rheumatology classification criteria. Patients were (pre)selected from existing cohorts using machine learning models, developed on data from the CHECK cohort, to display a high likelihood of radiographic joint space width (JSW) loss and/or knee pain progression.

Findings To Date: Selection appeared logistically feasible and baseline characteristics of the cohort demonstrated an OA population with more severe disease: age 66.5 (SD 7.1) vs 68.1 (7.7) years, min-JSW 2.5 (1.3) vs 2.1 (1.0) mm and Knee injury and Osteoarthritis Outcome Score pain 31.3 (19.7) vs 17.7 (14.6), except for age, all: p<0.001, for selected versus excluded patients, respectively. Based on the selection model, this cohort has a predicted higher chance of progression.

Future Plans: Patients will visit the hospital again at 6, 12 and 24 months for physical examination, pain and general health questionnaires, collection of blood and urine, MRI scans, radiographs of knees and hands, CT scan of the knee, low radiation whole-body CT, HandScan, motion analysis and performance-based tests.After two years, data will show whether those patients with the highest probabilities for progression experienced disease progression as compared to those wit lower probabilities (model validation) and whether phenotypes/endotypes can be identified and predicted to facilitate targeted drug therapy.

Trial Registration Number: NCT03883568.
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http://dx.doi.org/10.1136/bmjopen-2019-035101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389775PMC
July 2020

Dual contrast in computed tomography allows earlier characterization of articular cartilage over single contrast.

J Orthop Res 2020 10 25;38(10):2230-2238. Epub 2020 Jun 25.

Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.

Cationic computed tomography contrast agents are more sensitive for detecting cartilage degeneration than anionic or non-ionic agents. However, osteoarthritis-related loss of proteoglycans and increase in water content contrarily affect the diffusion of cationic contrast agents, limiting their sensitivity. The quantitative dual-energy computed tomography technique allows the simultaneous determination of the partitions of iodine-based cationic (CA4+) and gadolinium-based non-ionic (gadoteridol) agents in cartilage at diffusion equilibrium. Normalizing the cationic agent partition at diffusion equilibrium with that of the non-ionic agent improves diagnostic sensitivity. We hypothesize that this sensitivity improvement is also prominent during early diffusion time points and that the technique is applicable during contrast agent diffusion. To investigate the validity of this hypothesis, osteochondral plugs (d = 8 mm, N = 33), extracted from human cadaver (n = 4) knee joints, were immersed in a contrast agent bath (a mixture of CA4+ and gadoteridol) and imaged using the technique at multiple time points until diffusion equilibrium. Biomechanical testing and histological analysis were conducted for reference. Quantitative dual-energy computed tomography technique enabled earlier determination of cartilage proteoglycan content over single contrast. The correlation coefficient between human articular cartilage proteoglycan content and CA4+ partition increased with the contrast agent diffusion time. Gadoteridol normalized CA4+ partition correlated significantly (P < .05) with Mankin score at all time points and with proteoglycan content after 4 hours. The technique is applicable during diffusion, and normalization with gadoteridol partition improves the sensitivity of the CA4+ contrast agent.
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http://dx.doi.org/10.1002/jor.24774DOI Listing
October 2020

Multi-classifier prediction of knee osteoarthritis progression from incomplete imbalanced longitudinal data.

Sci Rep 2020 05 21;10(1):8427. Epub 2020 May 21.

School of Computing Science, Newcastle University, 1 Science Square, Newcastle, NE4 5TG, UK.

Conventional inclusion criteria used in osteoarthritis clinical trials are not very effective in selecting patients who would benefit from a therapy being tested. Typically majority of selected patients show no or limited disease progression during a trial period. As a consequence, the effect of the tested treatment cannot be observed, and the efforts and resources invested in running the trial are not rewarded. This could be avoided, if selection criteria were more predictive of the future disease progression. In this article, we formulated the patient selection problem as a multi-class classification task, with classes based on clinically relevant measures of progression (over a time scale typical for clinical trials). Using data from two long-term knee osteoarthritis studies OAI and CHECK, we tested multiple algorithms and learning process configurations (including multi-classifier approaches, cost-sensitive learning, and feature selection), to identify the best performing machine learning models. We examined the behaviour of the best models, with respect to prediction errors and the impact of used features, to confirm their clinical relevance. We found that the model-based selection outperforms the conventional inclusion criteria, reducing by 20-25% the number of patients who show no progression. This result might lead to more efficient clinical trials.
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http://dx.doi.org/10.1038/s41598-020-64643-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242357PMC
May 2020

Bone Regeneration in Critical-Sized Bone Defects Treated with Additively Manufactured Porous Metallic Biomaterials: The Effects of Inelastic Mechanical Properties.

Materials (Basel) 2020 Apr 24;13(8). Epub 2020 Apr 24.

Department of Orthopaedics, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.

Additively manufactured (AM) porous metallic biomaterials, in general, and AM porous titanium, in particular, have recently emerged as promising candidates for bone substitution. The porous design of such materials allows for mimicking the elastic mechanical properties of native bone tissue and showed to be effective in improving bone regeneration. It is, however, not clear what role the other mechanical properties of the bulk material such as ductility play in the performance of such biomaterials. In this study, we compared the bone tissue regeneration performance of AM porous biomaterials made from the commonly used titanium alloy Ti6Al4V-ELI with that of commercially pure titanium (CP-Ti). CP-Ti was selected because of its high ductility as compared to Ti6Al4V-ELI. Critical-sized (6 mm diameter) femoral defects in rats were treated with implants made from both Ti6Al4V-ELI and CP-Ti. Bone regeneration was assessed up to 11 weeks using micro-CT scanning. The regenerated bone volume was assessed ex vivo followed by histology and biomechanical testing to assess osseointegration of the implants. The bony defects treated with AM CP-Ti implants generally showed higher volumes of regenerated bone as compared to those treated with AM Ti6Al4V-ELI. The torsional strength of the two titanium groups were similar however, and both considerably lower than those measured for intact bony tissue. These findings show the importance of material type and ductility of the bulk material in the ability for bone tissue regeneration of AM porous biomaterials.
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http://dx.doi.org/10.3390/ma13081992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215733PMC
April 2020

Long-term outcomes of the hip shelf arthroplasty in adolescents and adults with residual hip dysplasia: a systematic review.

Acta Orthop 2020 08 2;91(4):383-389. Epub 2020 Apr 2.

Department of Orthopedics, University Medical Center Utrecht, Utrecht.

Background and purpose - The shelf arthroplasty was the regular treatment for residual hip dysplasia before it was substituted by the peri-acetabular osteotomy. Yet, evidence regarding the survival of shelf arthroplasty surgery has never been systematically documented. Hence, we investigated the survival time of the shelf procedure until revision to THA in patients with primary hip dysplasia. Factors that influenced survival and complications were also examined, along with the accuracy of correcting radiographic parameters to characterize dysplasia.Material and methods - The inclusion criteria were studies of human adolescents and adults (> 16 years) with primary or congenital hip dysplasia who were treated with a shelf arthroplasty procedure. Data were extracted concerning patient characteristics, survival time, complications, operative techniques, and accuracy of correcting radiographic parameters.Results - Our inclusion criteria were applicable to 9 studies. The average postoperative Center-Edge Angle and Acetabular Head Index were mostly within target range, but large variations were common. Kaplan-Meier curves (endpoint: conversion to THA) varied between 37% at 20 years' follow-up and 72% at 35 years' follow-up. Clinical failures were commonly associated with pain and radiographic osteoarthritis. Only minor complications were reported with incidences between 17% and 32%.Interpretation - The shelf arthroplasty is capable of restoring normal radiographic hip parameters and is not associated with major complications. When carefully selected on minimal osteoarthritic changes, hip dysplasia patients with a closed triradiate cartilage may benefit from the shelf procedure with satisfactory survival rates. The importance of the shelf arthroplasty in relation to peri-acetabular osteotomies needs to be further (re)explored.
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http://dx.doi.org/10.1080/17453674.2020.1747210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023942PMC
August 2020

Effect of unfocused extracorporeal shockwave therapy on bone mineral content of twelve distal forearms of postmenopausal women: a clinical pilot study.

Arch Osteoporos 2019 11 26;14(1):113. Epub 2019 Nov 26.

Department of Orthopaedics, Elisabeth-TweeSteden Hospital, Tilburg, The Netherlands.

Extracorporeal shockwave therapy showed a pronounced effect on bone mass in previous animal studies. We showed in this pilot study that a single treatment with unfocused shockwave therapy in unselected patients does not show side effects. Although our study did not show any effect of shockwave on BMD, the limited sample size does not definitively exclude this and a study with 174 subjects per group would be needed to show an effect size of 0.3 with a power of 80%.

Purpose: Unfocused extracorporeal shockwave therapy might stimulate bone formation to reduce the fracture risk. In this study, we assessed the safety of unfocused extracorporeal shockwave therapy and its effects on bone mass.

Methods: A clinical pilot study with twelve female patients free of bone disease undergoing elective surgery of the lower extremity or elective spinal surgery under general anesthesia received 3.000 electrohydraulic-generated unfocused extracorporeal shockwaves (energy flux density 0.3 mJ/mm) to one distal forearm. The contralateral forearm served as a control. We examined the effect on bone mass with the use of repeated dual energy X-ray absorptiometry measurements and we measured patient discomfort around the therapy.

Results: No difference in bone mineral content and density was measured 6 and 12 weeks after therapy. shockwave therapy occasionally caused transient erythema or mild hematoma, but no discomfort in daily life or (late) adverse events.

Conclusions: Unfocused extracorporeal shockwave therapy is a safe treatment, but no increase in bone mass on the forearm was found at 0.3 mJ/mm energy flux density. In this study, we were not able to demonstrate that a single treatment with unfocused shockwave therapy in unselected patients had any effect in terms of bone mineral density (BMD) or bone mineral content (BMC). A power analysis indicated that 174 patients per group are required to show an effect size of 0.3 with a power of 80%.
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http://dx.doi.org/10.1007/s11657-019-0650-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877705PMC
November 2019

Deep learning-based MR-to-CT synthesis: The influence of varying gradient echo-based MR images as input channels.

Magn Reson Med 2020 04 8;83(4):1429-1441. Epub 2019 Oct 8.

Image Sciences Institute, University Medical Center Utrecht, Utrecht, Netherlands.

Purpose: To study the influence of gradient echo-based contrasts as input channels to a 3D patch-based neural network trained for synthetic CT (sCT) generation in canine and human populations.

Methods: Magnetic resonance images and CT scans of human and canine pelvic regions were acquired and paired using nonrigid registration. Magnitude MR images and Dixon reconstructed water, fat, in-phase and opposed-phase images were obtained from a single T -weighted multi-echo gradient-echo acquisition. From this set, 6 input configurations were defined, each containing 1 to 4 MR images regarded as input channels. For each configuration, a UNet-derived deep learning model was trained for synthetic CT generation. Reconstructed Hounsfield unit maps were evaluated with peak SNR, mean absolute error, and mean error. Dice similarity coefficient and surface distance maps assessed the geometric fidelity of bones. Repeatability was estimated by replicating the training up to 10 times.

Results: Seventeen canines and 23 human subjects were included in the study. Performance and repeatability of single-channel models were dependent on the TE-related water-fat interference with variations of up to 17% in mean absolute error, and variations of up to 28% specifically in bones. Repeatability, Dice similarity coefficient, and mean absolute error were statistically significantly better in multichannel models with mean absolute error ranging from 33 to 40 Hounsfield units in humans and from 35 to 47 Hounsfield units in canines.

Conclusion: Significant differences in performance and robustness of deep learning models for synthetic CT generation were observed depending on the input. In-phase images outperformed opposed-phase images, and Dixon reconstructed multichannel inputs outperformed single-channel inputs.
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http://dx.doi.org/10.1002/mrm.28008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972695PMC
April 2020

Contrast enhanced computed tomography for real-time quantification of glycosaminoglycans in cartilage tissue engineered constructs.

Acta Biomater 2019 12 30;100:202-212. Epub 2019 Sep 30.

Department of Orthopedics, University Medical Centre Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands; Department of Biomechanical Engineering, Delft University of Technology, Mekelweg 2, 2628 CD Delft, The Netherlands. Electronic address:

Tissue engineering and regenerative medicine are two therapeutic strategies to treat, and to potentially cure, diseases affecting cartilaginous tissues, such as osteoarthritis and cartilage defects. Insights into the processes occurring during regeneration are essential to steer and inform development of the envisaged regenerative strategy, however tools are needed for longitudinal and quantitative monitoring of cartilage matrix components. In this study, we introduce a contrast-enhanced computed tomography (CECT)-based method using a cationic iodinated contrast agent (CA4+) for longitudinal quantification of glycosaminoglycans (GAG) in cartilage-engineered constructs. CA4+ concentration and scanning protocols were first optimized to ensure no cytotoxicity and a facile procedure with minimal radiation dose. Chondrocyte and mesenchymal stem cell pellets, containing different GAG content were generated and exposed to CA4+. The CA4+ content in the pellets, as determined by micro computed tomography, was plotted against GAG content, as measured by 1,9-dimethylmethylene blue analysis, and showed a high linear correlation. The established equation was used for longitudinal measurements of GAG content over 28 days of pellet culture. Importantly, this method did not adversely affect cell viability or chondrogenesis. Additionally, the CA4+ distribution accurately matched safranin-O staining on histological sections. Hence, we show proof-of-concept for the application of CECT, utilizing a positively charged contrast agent, for longitudinal and quantitative imaging of GAG distribution in cartilage tissue-engineered constructs. STATEMENT OF SIGNIFICANCE: Tissue engineering and regenerative medicine are promising therapeutic strategies for different joint pathologies such as cartilage defects or osteoarthritis. Currently, in vitro assessment on the quality and composition of the engineered cartilage mainly relies on destructive methods. Therefore, there is a need for the development of techniques that allow for longitudinal and quantitative imaging and monitoring of cartilage-engineered constructs. This work harnesses the electrostatic interactions between the negatively-charged glycosaminoglycans (GAGs) and a positively-charged contrast agent for longitudinal and non-destructive quantification of GAGs, providing valuable insight on GAG development and distribution in cartilage engineered constructs. Such technique can advance the development of regenerative strategies, not only by allowing continuous monitoring but also by serving as a pre-implantation screening tool.
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http://dx.doi.org/10.1016/j.actbio.2019.09.014DOI Listing
December 2019

Local controlled release of corticosteroids extends surgically induced joint instability by inhibiting tissue healing.

Br J Pharmacol 2019 10 8;176(20):4050-4064. Epub 2019 Oct 8.

Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands.

Background And Purpose: Corticosteroids are intra-articularly injected to relieve pain in joints with osteoarthritis (OA) or acute tissue damage such as ligament or tendon tears, despite its unverified contraindication in unstable joints. Biomaterial-based sustained delivery may prolong reduction of inflammatory pain, while avoiding harmful peak drug concentrations.

Experimental Approach: The applicability of prolonged corticosteroid exposure was examined in a rat model of anterior cruciate ligament and medial meniscus transection (ACLT + pMMx) with ensuing degenerative changes.

Key Results: Intra-articular injection of a bolus of the corticosteroid triamcinolone acetonide (TAA) resulted in enhanced joint instability in 50% of the joints, but neither instability-induced OA cartilage degeneration, synovitis, nor the OA-related bone phenotype was affected. However, biomaterial microsphere-based extended TAA release enhanced instability in 94% of the animals and induced dystrophic calcification and exacerbation of cartilage degeneration. In healthy joints, injection with TAA releasing microspheres had no effect at all. In vitro, TAA inhibited cell migration out of joint tissue explants, suggesting inhibited tissue healing in vivo as mechanisms for enhanced instability and subsequent cartilage degeneration.

Conclusions And Implications: We conclude that short-term TAA exposure has minor effects on surgically induced unstable joints, but its extended presence is detrimental by extending instability and associated joint degeneration through compromised healing. This supports a contraindication of prolonged corticosteroid exposure in tissue damage-associated joint instability, but not of brief exposure.
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http://dx.doi.org/10.1111/bph.14817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811746PMC
October 2019

Challenges in the design and regulatory approval of 3D-printed surgical implants: a two-case series.

Lancet Digit Health 2019 08 23;1(4):e163-e171. Epub 2019 Jul 23.

Department of Orthopaedics, University Medical Centre Utrecht, Utrecht, Netherlands.

Background: Additive manufacturing or three-dimensional (3D) printing of metal implants can provide novel solutions for difficult-to-treat conditions, yet legislation concerning patient-specific implants complicates the implementation of these techniques in daily practice. In this Article, we share our acquired knowledge of the logistical and legal challenges associated with the use of patient-specific 3D-printed implants to treat spinal instabilities.

Methods: Two patients with semiurgent cases of spinal instability presented to our hospital in the Netherlands. In case 1, severe kyphotic deformity of the thoracic spine due to neurofibromatosis type 1 had led to incomplete paralysis, and a strong metallic strut extending from C6 to T11 was deemed necessary to provide long-term anterior support. In case 2, the patient presented with progressive paralysis caused by cervicothoracic dissociation due to vanishing bone disease. As the C5-T1 vertebral bodies had mostly vanished, an implant spanning the anterior spine from C4 to T2 was required. Because of the complex and challenging nature of both cases, conventional approaches were deemed inadequate; instead, patient-specific implants were designed with use of CT scans and computer-aided design software, and 3D printed in titanium with direct metal printing. For each implant, to ensure patient safety, a comprehensive technical file (describing the clinical substantiation, technical and design considerations, risk analysis, manufacturing process, and labelling) was produced in collaboration with a university department certified for the development and manufacturing of medical devices. Because the implants were categorised as custom-made or personalised devices under the EU Medical Device Regulation, the usual procedures for review and approval of medical devices by a notified body were not required. Finite-element analyses, compression strength tests, and cadaveric experiments were also done to ensure the devices were safe to use.

Findings: The planning, design, production, and insertion of the 3D-printed personalised implant took around 6 months in the first patient, but, given the experience from the first case, only took around 6 weeks in the second patient. In both patients, the surgeries went as planned and good positioning of each implant was confirmed. Both patients were discharged home within 1 week after the surgery. In the first patient, a fatigue fracture occured in one of the conventional posterior fusion rods after 10 months, which we repaired, without any deformation of the spine or signs of failure of the personalised implant observed. No other adverse events occurred up to 25 months of follow-up in case 1 and 6 months of follow-up in case 2.

Interpretation: Patient-specific treatment approaches incorporating 3D-printed implants can be helpful in carefully selected cases when conventional methods are not an option. Comprehensive and efficient interactions between medical engineers and physicians are essential to establish well designed frameworks to navigate the logistical and regulatory aspects of technology development to ensure the safety and legal validity of patient-specific treatments. The framework described here could encourage physicians to treat (once untreatable) patients with novel personalised techniques.

Funding: Interreg VA Flanders-The Netherlands programme, Applied and Engineering Sciences research programme, the Netherlands Organisation for Scientific Research, and the Dutch Arthritis Foundation VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/S2589-7500(19)30067-6DOI Listing
August 2019

A Novel Treatment for Anterior Shoulder Instability: A Biomechanical Comparison Between a Patient-Specific Implant and the Latarjet Procedure.

J Bone Joint Surg Am 2019 Jul;101(14):e68

Departments of Orthopaedics (K.W., T.G., H.W., R.M.C., and B.C.H.v.d.W.) and Anatomy (R.L.A.W.B.), University Medical Centre Utrecht, Utrecht, the Netherlands.

Background: Anterior glenohumeral instability with >20% glenoid bone loss is a disorder that can be treated with the Latarjet stabilizing procedure; however, complications are common. The purposes of this study were to (1) evaluate the effect of an anatomic-specific titanium implant produced by 3-dimensional (3D) printing as a treatment option for recurrent shoulder instability with substantial glenoid bone loss and (2) compare the use of that implant with the Latarjet procedure.

Methods: Ten fresh-frozen cadaveric shoulders (mean age at the time of death, 78 years) were tested in a biomechanical setup with the humerus in 30° of abduction and in neutral rotation. The shoulders were tested under 5 different conditions: (1) normal situation, (2) creation of an anterior glenoid defect, (3) implantation of an anatomic-specific titanium implant produced by 3D printing, and the Latarjet procedure (4) with and (5) without 10 N of load attached to the conjoined tendon. In each condition, the humerus was translated 10 mm anteriorly relative to the glenoid, and the maximum peak translational force that was necessary for this translation was measured.

Results: After creation of the glenoid defect, the mean translational peak force decreased by 30% ± 6% compared with that for the normal shoulder. After restoration of the original glenoid anatomy, the translational force needed to dislocate the humeral head from the glenoid significantly increased compared with that in the defect condition-to 119% ± 16% of normal (p < 0.01) with the 3D-printed anatomic-specific implant and to 121% ± 48% of normal (p < 0.01) following the Latarjet procedure. No significant differences in mean translational force were found between the anatomic-specific implant and the Latarjet procedure (p = 0.72).

Conclusions: The mean translational peak force needed to dislocate the humerus 10 mm anteriorly on the glenoid was higher after glenoid restoration with the 3D-printed anatomic-specific implant compared with when the glenoid had a 20% surface defect but also compared with when the glenoid was intact. No differences in mean translational peak force were found between the 3D-printed anatomic-specific glenoid implant and the Latarjet procedure, although there was less variability in the 3D-implant condition.

Clinical Relevance: Novel 3D-printing technology could provide a reliable patient-specific alternative to solve problems related to traditional treatment methods for shoulder instability.
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http://dx.doi.org/10.2106/JBJS.18.00892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6641476PMC
July 2019

[Applications of 3D printing in medicine; 5 years later].

Ned Tijdschr Geneeskd 2019 05 22;163. Epub 2019 May 22.

UMC Utrecht, afd. Orthopedie, Utrecht.

5 years ago, we described the emergence of 3D printing in medicine. It was about 3D printing of anatomical structures, patient-specific drilling guides, cutting templates and implants and printing of living cells, growth factors and biomaterials ('bioprinting'). Surgeons are increasingly making use of 3D printing possibilities in preparation of surgeries on patients with complicated anatomies. Using tangible 3D models, it is easier for surgeons to prepare for surgeries and discussions with patients. They can also use 3D models as a tool to help with the training of young surgeons. Permanent titanium implants are increasingly being printed. Bioprinting is still in its infancy and there are no direct clinical applications yet. As we already predicted 5 years ago, many hurdles still have to be taken before broad clinical application of bioprinted products will become a reality.
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May 2019

Increased TGF-β and BMP Levels and Improved Chondrocyte-Specific Marker Expression In Vitro under Cartilage-Specific Physiological Osmolarity.

Int J Mol Sci 2019 Feb 13;20(4). Epub 2019 Feb 13.

Laboratory for Experimental Orthopedics, Department of Orthopaedic Surgery, Maastricht University Medical Centre+, 6229 HX Maastricht, The Netherlands.

During standard expansion culture (i.e., plasma osmolarity, 280 mOsm) human articular chondrocytes dedifferentiate, making them inappropriate for autologous chondrocyte implantation to treat cartilage defects. Increasing the osmolarity of culture media to physiological osmolarity levels of cartilage (i.e., 380 mOsm), increases collagen type II () expression of human articular chondrocytes , but the underlying molecular mechanism is not fully understood. We hypothesized that TGF-β superfamily signaling may drive expression of under physiological osmolarity culture conditions. Human articular chondrocytes were cultured in cytokine-free medium of 280 or 380 mOsm with or without siRNA mediated TGF-β2 knockdown (RNAi). Expression of TGF-β isoforms, and collagen type II was evaluated by RT-qPCR and immunoblotting. TGF-β2 protein secretion was evaluated using ELISA and TGF-β bioactivity was determined using an established reporter assay. Involvement of BMP signaling was investigated by culturing human articular chondrocytes in the presence or absence of BMP inhibitor dorsomorphin and BMP bioactivity was determined using an established reporter assay. Physiological cartilage osmolarity (i.e., physosmolarity) most prominently increased TGF-β2 mRNA expression and protein secretion as well as TGF-β bioactivity. Upon TGF-β2 isoform-specific knockdown, gene expression of chondrocyte marker was induced. TGF-β2 RNAi under physosmolarity enhanced TGF-β bioactivity. BMP bioactivity increased upon physosmotic treatment, but was not related to TGF-β2 RNAi. In contrast, dorsomorphin inhibited mRNA expression in human articular chondrocytes independent of the osmotic condition. Our data suggest a role for TGF-β superfamily member signaling in physosmolarity-induced mRNA expression of collagen type II. As physosmotic conditions favor the expression of independent of our manipulations, contribution of other metabolic, post-transcriptional or epigenetic factors cannot be excluded in the underlying complex and interdependent regulation of marker gene expression. Dissecting these molecular mechanisms holds potential to further improve future cell-based chondral repair strategies.
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http://dx.doi.org/10.3390/ijms20040795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412363PMC
February 2019

Three-dimensional analysis of shape variations and symmetry of the fibula, tibia, calcaneus and talus.

J Anat 2019 01 4;234(1):132-144. Epub 2018 Nov 4.

Department of Biomechanical Engineering, Delft University of Technology (TU Delft), Delft, The Netherlands.

The bones forming the talocrural joint (TCJ) and subtalar joint (STJ) are often assumed to be bilaterally symmetric. Therefore, the contralateral limb (i.e. the fibula, tibia, calcaneus and talus) is used as a template or an intra-subject control in clinical and research practice. However, the validity of the symmetry assumption is controversial, because insufficient information is available on the shape variations and bilateral (a)symmetry of the fibula, tibia, calcaneus and talus. Using three-dimensional spatially dense sampled representations of bone shapes extracted from bilateral computed tomography scans of 66 individuals (55 male, mean age: 61 ± 10 years; 11 female, mean age: 53 ± 15 years), we analyzed whether: (i) similar shape patterns exist in the left and right bones of the same type; (ii) gender has an effect on bone shape variations; (iii) intra-subject shape variation is smaller than that of inter-subject for a given shape variance direction. For the first set of analyses, all left and right instances of the same type of bone were considered as two separate groups, and statistically compared with each other on multiple aspects including group location (central tendency), variance-covariance scale (dispersion) and orientation (covariance structure) using distance-based permutational tests. For the second and third sets of analyses, all left and right bones of the same type were pooled into one group, and shape variations in the TCJ and STJ bones were extracted using principal component analysis. The effects of gender on age-adjusted bone shape differences were assessed using an analysis of covariance. Moreover, intra-class correlation was employed to evaluate intra- and inter-subject bone shape variations. For each bone type, both sides had similar shape patterns (P -values > 0.05). After Bonferroni adjustment, gender led to shape differences, which were mainly in the lateral and medial condyles of the tibia (P = 0.003), the length and height of the calcaneus (P < 0.001), the posterior and anterior talar articular surfaces of the calcaneus (P = 0.001), and in the posterior aspect of the talus (P = 0.001). Intra-subject shape variations in the tibial tuberosity together with the diameter of the tibia, and the curvature of the fibula shaft and the diameter of the fibula were as high as those of inter-subject. This result suggests that the shape symmetry assumption could be violated for some specific shape variations in the fibula and tibia.
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http://dx.doi.org/10.1111/joa.12900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284442PMC
January 2019

Chronic kidney failure mineral bone disorder leads to a permanent loss of hematopoietic stem cells through dysfunction of the stem cell niche.

Sci Rep 2018 10 18;8(1):15385. Epub 2018 Oct 18.

Department of Immunohematology and Blood transfusion, Leiden University Medical Center, Leiden, The Netherlands.

In chronic kidney disease (CKD), endothelial injury, is associated with disease progression and an increased risk for cardiovascular complications. Circulating cells with vascular reparative functions are hematopoietic and also reduced in CKD. To explore the mechanistic basis behind these observations, we have investigated hematopoietic stem cell (HSC) homeostasis in a mouse model for non-progressive CKD-mineral and bone disorder with experimentally induced chronic renal failure (CRF). In mice subjected to 12 weeks of CRF, bone marrow HSC frequencies were decreased and transplantation of bone marrow cells from CRF donors showed a decrease in long-term HSC repopulation compared to controls. This loss was directly associated with a CRF-induced defect in the HSC niche affecting the cell cycle status of HSC and could not be restored by the PTH-reducing agent cinacalcet. In CRF, frequencies of quiescent (G0) HSC were decreased coinciding with an increase in hematopoietic progenitor cells (HPC) in the S-and G2-phases of cell cycle. Moreover, in CRF mice, HSC-niche supporting macrophages were decreased compared to controls concomitant to impaired B lymphopoiesis. Our data point to a permanent loss of HSC and may provide insight into the root cause of the loss of homeostatic potential in CKD.
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http://dx.doi.org/10.1038/s41598-018-33979-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194087PMC
October 2018

Direct covalent attachment of silver nanoparticles on radical-rich plasma polymer films for antibacterial applications.

J Mater Chem B 2018 Oct 6;6(37):5845-5853. Epub 2018 Aug 6.

School of Aerospace, Mechanical and Mechatronic Engineering, University of Sydney, Sydney, NSW 2006, Australia.

Prevention and treatment of biomaterial-associated infections (BAI) are imperative requirements for the effective and long-lasting function of orthopedic implants. Surface-functionalization of these materials with antibacterial agents, such as antibiotics, nanoparticles and peptides, is a promising approach to combat BAI. The well-known silver nanoparticles (AgNPs) in particular, although benefiting from strong and broad-range antibacterial efficiency, have been frequently associated with mammalian cell toxicity when physically adsorbed on biomaterials. The majority of irreversible immobilization techniques employed to fabricate AgNP-functionalized surfaces are based on wet-chemistry methods. However, these methods are typically substrate-dependent, complex, and time-consuming. Here we present a simple and dry strategy for the development of polymeric coatings used as platforms for the direct, linker-free covalent attachment of AgNPs onto solid surfaces using ion-assisted plasma polymerization. The resulting coating not only exhibits long-term antibiofilm efficiency against adherent Staphylococcus aureus (S. aureus), but also enhances osteoblast adhesion and proliferation. High resolution X-ray photoelectron spectroscopy (XPS), before and after sodium dodecyl sulfate (SDS) washing, confirms covalent bonding. The development of such silver-functionalized surfaces through a simple, plasma-based process holds great promise for the fabrication of implantable devices with improved tissue-implant integration and reduced biomaterial associated infections.
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http://dx.doi.org/10.1039/c8tb01363bDOI Listing
October 2018

Early Signs of Bone and Cartilage Changes Induced by Treadmill Exercise in Rats.

JBMR Plus 2018 May 31;2(3):134-142. Epub 2018 Jan 31.

Department of Orthopaedics University Medical Center Utrecht Utrecht The Netherlands.

This study aims to investigate the earliest alterations of bone and cartilage tissues as a result of different exercise protocols in the knee joint of Wistar rats. We hypothesize that pretraining to a continuous intense running protocol would protect the animals from cartilage degeneration. Three groups of animals were used: (i) an adaptive (pretraining) running group that ran for 8 weeks with gradually increasing velocity and time of running followed by a constant running program (6 weeks of 1.12 km/hour running per day); (ii) a non-adaptive running (constant running) group that initially rested for 8 weeks followed by 6 weeks of constant running; and (iii) a non-running (control) group. At weeks 8, 14, and 20 bone and cartilage were analyzed. Both running groups developed mild symptoms of cartilage irregularities, such as chondrocyte hypertrophy and cell clustering in different cartilage zones, in particular after the adaptive running protocol. As a result of physical training in the adaptive running exercise a dynamic response of bone was detected at week 8, where bone growth was enhanced. Conversely, the thickness of epiphyseal trabecular and subchondral bone (at week 14) was reduced due to the constant running in the period between 8 and 14 weeks. Finally, the intermediate differences between the two running groups disappeared after both groups had a resting period (from 14 to 20 weeks). The adaptive running group showed an increase in aggrecan gene expression and reduction of MMP2 expression after the initial 8 weeks running. Thus, the running exercise models in this study showed mild bone and cartilage/chondrocyte alterations that can be considered as early-stage osteoarthritis. The pretraining adaptive protocol before constant intense running did not protect from mild cartilage degeneration. © 2017 The Authors. is published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124204PMC
May 2018

Multi-scale imaging techniques to investigate solute transport across articular cartilage.

J Biomech 2018 09 22;78:10-20. Epub 2018 Jun 22.

Department of Orthopedics, UMC Utrecht, Heidelberglaan100, 3584CX Utrecht, The Netherlands; Department of Biomechanical Engineering, Faculty of Mechanical, Maritime, and Materials Engineering, Delft University of Technology (TU Delft), Mekelweg 2, 2628 CD Delft, The Netherlands; Department of Rheumatology, UMC Utrecht, Heidelberglaan100, 3584CX Utrecht, The Netherlands. Electronic address:

As articular cartilage is an avascular tissue, the transport of nutrients and cytokines through the tissue is essential for the health of cells, i.e. chondrocytes. Transport of specific contrast agents through cartilage has been investigated to elucidate cartilage quality. In laboratory, pre-clinical and clinical studies, imaging techniques such as magnetic imaging resonance (MRI), computed tomography (CT) and fluorescent microscopy have been widely employed to visualize and quantify solute transport in cartilage. Many parameters related to the physico-chemical properties of the solute, such as molecular weight, net charge and chemical structure, have a profound effect on the transport characteristics. Information on the interplay of the solute parameters with the imaging-dependent parameters (e.g. resolution, scan and acquisition time) could assist in selecting the most optimal imaging systems and data analysis tools in a specific experimental set up. Here, we provide a comprehensive review of various imaging systems to investigate solute transport properties in articular cartilage, by discussing their potentials and limitations. The presented information can serve as a guideline for applications in cartilage imaging and therapeutics delivery and to improve understanding of the set-up of solute transport experiments in articular cartilage.
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http://dx.doi.org/10.1016/j.jbiomech.2018.06.012DOI Listing
September 2018

Comparison of polyetheretherketone versus silicon nitride intervertebral spinal spacers in a caprine model.

J Biomed Mater Res B Appl Biomater 2019 04 9;107(3):688-699. Epub 2018 Aug 9.

Department of Orthopedic Surgery, Clinical Orthopedic Research Center midden-Nederland (CORCmN), Diakonessenhuis, Utrecht, The Netherlands.

Polyetheretherketone (PEEK) is commonly used as a spinal spacer for intervertebral fusion surgery. Unfortunately, PEEK is bioinert and does not effectively osseointegrate into living bone. In contrast, comparable spacers made of silicon nitride (Si N ) possess a surface nanostructure and chemistry that encourage appositional bone healing. This observational study was designed to compare the outcomes of these two biomaterials when implanted as spacers in an adult caprine model. Lumbar interbody fusion surgeries were performed at two adjacent levels in eight adult goats using implants of PEEK and Si N . At six-months after surgery, the operative and adjacent spinal segments were extracted and measured for bone fusion, bone volume, bone-implant contact (BIC) and soft-tissue implant contact (SIC) ratios, and biodynamic stability. The null hypothesis was that no differences in these parameters would be apparent between the two groups. Fusion was observed in seven of eight implants in each group with greater bone formation in the Si N group (52.6%) versus PEEK (27.9%; p = 0.2). There were no significant differences in BIC ratios between PEEK and Si N , and the biodynamic stability of the two groups was also comparable. The results suggest that Si N spacers are not inferior to PEEK and they may be more effective in promoting arthrodesis. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 00B: 000-000, 2018. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 688-699, 2019.
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http://dx.doi.org/10.1002/jbm.b.34162DOI Listing
April 2019

In vivo pharmacokinetics of celecoxib loaded endcapped PCLA-PEG-PCLA thermogels in rats after subcutaneous administration.

Eur J Pharm Biopharm 2018 Oct 31;131:170-177. Epub 2018 Jul 31.

Department of Orthopaedics and Department of Rheumatology, UMC Utrecht, The Netherlands; Department of Biomechanical Engineering, TU Delft, The Netherlands.

Injectable thermogels based on poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-lactide) (PCLA-PEG-PCLA) containing an acetyl- or propyl endcap and loaded with celecoxib were developed for local drug release. The aim of this study was to determine the effects of the composition of the celecoxib/PCLA-PEG-PCLA formulation on their in vivo drug release characteristics. Furthermore, we want to obtain insight into the in vitro-in vivo correlation. Different formulations were injected subcutaneously in rats and blood samples were taken for a period of 8 weeks. Celecoxib half-life in blood increased from 5 h for the bolus injection of celecoxib to more than 10 days for the slowest releasing gel formulation. Sustained release of celecoxib was obtained for at least 8 weeks after subcutaneous administration. The release period was prolonged from 3 to 6-8 weeks by increasing the injected volume from 100 to 500 µL, which also led to higher serum concentrations in time. Propyl endcapping of the polymer also led to a prolonged release compared to the acetyl endcapped polymer (49 versus 21 days) and at equal injected dose of the drug in lower serum concentrations. Increasing the celecoxib loading from 10 mg/mL to 50 mg/mL surprisingly led to prolonged release (28 versus 56 days) as well as higher serum concentrations per time point, even when corrected for the higher dose applied. The in vivo release was about twice as fast compared to the in vitro release for all formulations. Imaging of organs of mice, harvested 15 weeks after subcutaneous injection with polymer solution loaded with infrared-780 labelled dye showed no accumulation in any of these harvested organs except for traces in the kidneys, indicating renal clearance. Due to its simplicity and versatility, this drug delivery system has great potential for designing an injectable to locally treat osteoarthritis, and to enable tuning the gel to meet patient-specific needs.
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http://dx.doi.org/10.1016/j.ejpb.2018.07.026DOI Listing
October 2018

Degradation, Intra-Articular Biocompatibility, Drug Release, and Bioactivity of Tacrolimus-Loaded Poly(d-l-lactide-PEG)--poly(l-lactide) Multiblock Copolymer-Based Monospheres.

ACS Biomater Sci Eng 2018 Jul 23;4(7):2390-2403. Epub 2018 May 23.

Department of Orthopaedics and Department of Rheumatology, UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

The aim of this study was to develop a formulation with a sustained intra-articular release of the anti-inflammatory drug tacrolimus. Drug release kinetics from the prepared tacrolimus loaded monodisperse biodegradable microspheres based on poly(d-l-lactide-PEG)--poly(l-lactide) multiblock copolymers were tunable by changing polymer composition, particularly hydrophobic-hydrophilic block ratio. The monospheres were 30 μm and released the drug, depending on the formulation, in 7 to >42 days. The formulation exhibiting sustained release for 1 month was selected for further in vivo evaluation. Rat knees were injected with three different doses of tacrolimus (10 wt %) loaded monospheres (2.5, 5.0, and 10 mg), contralateral control knees with saline. Micro-CT and histology showed no negative changes on cartilage, indicating good biocompatibility. Minor osteophyte formation was seen in a dose dependent fashion, suggesting local drug release and therapeutic action thereof. To investigate in vivo drug release, tacrolimus monospheres were injected into horse joints, after which multiple blood and synovial fluid samples were taken. Sustained intra-articular release was seen during the entire four-week follow-up, with negligible systemic drug concentrations (<1 ng/mL), confirming the feasibility of local intra-articular drug delivery without provoking systemic effects. Intra-articular injection of unloaded monospheres led to a transient inflammatory reaction, measured by total synovial leucocyte count (72 h). This reaction was significantly lower in joints injected with tacrolimus loaded monospheres, showing not only the successful local tacrolimus delivery but also local anti-inflammatory action. This local anti-inflammatory potential without systemic side-effects can be beneficial in the treatment of inflammatory joint diseases, among which is osteoarthritis.
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http://dx.doi.org/10.1021/acsbiomaterials.8b00116DOI Listing
July 2018

Unfocused shockwaves for osteoinduction in bone substitutes in rat cortical bone defects.

PLoS One 2018 3;13(7):e0200020. Epub 2018 Jul 3.

Department of Orthopaedics, University Medical Centre Utrecht, Utrecht, the Netherlands.

Bone substitutes are frequently used in clinical practice but often exhibit limited osteoinductivity. We hypothesized that unfocused shockwaves enhance the osteoinductivity of bone substitutes and improve osteointegration and angiogenesis. Three different bone substitutes, namely porous tricalcium phosphate, porous hydroxyapatite and porous titanium alloy, were implanted in a critical size (i.e. 6-mm) femoral defect in rats. The femora were treated twice with 1500 shockwaves at 2 and 4 weeks after surgery and compared with non-treated controls. The net volume of de novo bone in the defect was measured by microCT-scanning during 11-weeks follow-up. Bone ingrowth and angiogenesis in the bone substitutes was examined at 5 and 11 weeks using histology. It was shown that hydroxyapatite and titanium both had an increase of bone ingrowth with more bone in the shockwave group compared to the control group, whereas resorption was seen in tricalcium phosphate bone substitutes over time and this was insensitive to shockwave treatment. In conclusion, hydroxyapatite and titanium bone substitutes favour from shockwave treatment, whereas tricalcium phosphate does not. This study shows that osteoinduction and osteointegration of bone substitutes can be influenced with unfocused shockwave therapy, but among other factors depend on the type of bone substitute, likely reflecting its mechanical and biological properties.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200020PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029785PMC
January 2019

Lack of consensus on optimal acetabular cup orientation because of variation in assessment methods in total hip arthroplasty: a systematic review.

Hip Int 2019 Jan 17;29(1):41-50. Epub 2018 May 17.

1 Clinical Orthopedic Research Centre - mN, Zeist, Utrecht, The Netherlands.

Introduction:: Dislocation is 1 of the main reasons for revision of total hip arthroplasty but dislocation rates have not changed in the past decades, compromising patients' well-being. Acetabular cup orientation plays a key role in implant stability and has been widely studied. This article investigates whether there is a consensus on optimal cup orientation, which is necessary when using a navigation system.

Methods:: A systematic search of the literature in the PubMed, Embase and Cochrane databases was performed (March 2017) to identify articles that investigated the direct relationship between cup orientation and dislocation, including a thorough evaluation of postoperative cup orientation assessment methods.

Results:: 28 relevant articles evaluating a direct relation between dislocation and cup orientation could not come to a consensus. The key reason is a lack of uniformity in the assessment of cup orientation. Cup orientation is assessed with different imaging modalities, different methodologies, different definitions for inclination and anteversion, several reference planes and distinct patient positions.

Conclusions:: All available studies lack uniformity in cup orientation assessment; therefore it is impossible to reach consensus on optimal cup orientation. Using navigation systems for placement of the cup is inevitably flawed when using different definitions in the preoperative planning, peroperative placement and postoperative evaluation. Further methodological development is required to assess cup orientation. Consequently, the postoperative assessment should be uniform, thus differentiating between anterior and posterior dislocation, use the same definitions for inclination and anteversion with the same reference plane and with the patient in the same position.
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http://dx.doi.org/10.1177/1120700018759306DOI Listing
January 2019

Anterior longitudinal ligament in diffuse idiopathic skeletal hyperostosis: Ossified or displaced?

J Orthop Res 2018 09 24;36(9):2491-2496. Epub 2018 May 24.

Department of Orthopedic Surgery, University Medical Center Utrecht, Utrecht University, Box 85500, 3508 GA, Utrecht, The Netherlands.

Diffuse idiopathic skeletal hyperostosis (DISH) is often theorized to be an ossification of the anterior longitudinal ligament (ALL). Using computed tomography (CT) imaging and cryomacrotome sectioning, we investigated the spatial relationship between the ALL and newly formed bone in DISH to test this hypothesis. In the current study, four human cadaveric spines diagnosed with DISH using CT imaging were frozen and sectioned using a cryomacrotome. Photographs were obtained of the specimen at 125 µm intervals. Manual segmentations of the ALL on cryomacrotome photographs were projected onto the three-dimensional reconstructed CT scans. The presence and location of newly formed bone were assessed in relationship to the location of the ALL. The ALL could be identified and segmented on the photographs at all levels. The ALL was located at the midline at levels where no new bone had formed. At the locations where new bone had abundantly formed, the ALL was displaced towards to the contralateral side and not replaced by bony tissue. The displacement of the-morphologically normal appearing-ALL away from the newly formed bone implies that newly formed bone in DISH may not originate from the ALL. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society J Orthop Res 36:2491-2496, 2018.
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http://dx.doi.org/10.1002/jor.24020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175084PMC
September 2018