Moyo Kruyt - Academia.edu (original) (raw)
Papers by Moyo Kruyt
European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society, Jan 28, 2016
In vivo evaluation of scoliosis treatment using a novel approach in which two posterior implants ... more In vivo evaluation of scoliosis treatment using a novel approach in which two posterior implants are implanted: XSLAT (eXtendable implant correcting Scoliosis in LAT bending) and XSTOR (eXtendable implant correcting Scoliosis in TORsion). The highly flexible and extendable implants use only small, but continuous lateral forces (XSLAT) and torques (XSTOR), thereby allowing growth and preventing fusion. Since (idiopathic) scoliosis does not occur spontaneously in animals, the device was used to induce a spinal deformity rather than correct it. Six of each implants were tested for their ability to induce scoliotic deformations in 12 growing pigs. Each implant spanned six segments and was attached to three vertebrae using sliding anchors. Radiological and histological assessments were done throughout the 8-week study. In all animals, the intended deformation was accomplished. Average Cobb angles were 19° for XSLAT and 6° for XSTOR. Average apical spinal torsion was 0° for XSLAT and 9° f...
Biomaterials, Apr 30, 2007
Despite decades of extensive research, the application of cell-based bone tissue engineering in c... more Despite decades of extensive research, the application of cell-based bone tissue engineering in clinically relevant models remains challenging. To improve effectiveness, a better understanding of how the technique should work is crucial. In the current study, we investigated the onset time, rate, location and direction of bone formation in ectopically and orthotopically implanted clinically sized tissue-engineered constructs to gain insight the mechanism behind it. Bone marrow stromal cells (BMSCs) were obtained from 10 goats, culture expanded and cryopreserved. Porous biphasic calcium phosphate (BCP) disks of 17 mm  6 mm were per-operatively seeded with BMSCs or left empty. Both conditions were implanted intramuscularly and in bilateral critical-sized iliac wing defects. Fluorochromes were administered at 3, 5 and 7 weeks and samples were retrieved after 9 weeks. Histology showed abundant and homogeneous bone formation throughout the intramuscular BMSC samples and little bone in the controls. Histomorphometry and measurements of the fluorochrome labels of the ectopical BMSC samples indicated that osteogenesis started at the periphery and subsequent osteoconduction filled the whole scaffold within 7 weeks. In the orthotopically implanted disks, there was good integration with the surrounding bone, but minimal bone in the center of the implants, in both conditions. Bone was only derived from the interface with the surrounding bone, there was no early bone at the surfaces in contact to soft tissue as was seen in the ectopical samples. Apparently cell survival was minimal and insufficient for relevant additional bone formation. However, the speed of integration with surrounding bone and subsequent bone apposition on the BMSC-seeded orthotopic scaffolds were found to be significantly enhanced, which may be relevant especially in challenging environments. r
Transplantation, Feb 1, 2004
Little is known about the specific mechanisms that make autologous graft bone (AG) superior to th... more Little is known about the specific mechanisms that make autologous graft bone (AG) superior to the current alternatives. A potential mechanism is the active bone formation by the osteoprogenitor cells within the AG. However, whether these cells survive the transplantation is questionable, especially in nonvascularized, clinically sized grafts. In the present study, we investigated the role of viability in AG implanted ectopically and orthotopically in the goat. Eight goats were operated on twice. At the first operation, pieces of vital or devitalized autologous cortical bone were implanted in the paraspinal muscles. Eight weeks later, corticocancellous plugs were taken from the femoral condyles, morselized, and reimplanted as either vital or devitalized orthotopic grafts. The goats received fluorochrome labels at 5, 7, and 9 weeks after the first operation. At 12 weeks, the goats were killed, and the samples were examined histologically. Ectopically, new bone had formed in both the vital and devitalized grafts. In the vital grafts, all three fluorochrome labels were present, indicating an early osteogenic mechanism. Within the devitalized grafts, only the 9-week label was observed. Histomorphometry indicated significantly more new bone in the vital grafts (10.3% vs. 1.7% in the devitalized grafts, P <0.01). Orthotopically, both vital and devitalized grafts showed new bone. Again, graft viability was advantageous in terms of new bone formation (14.5% vs. 9.3%, P <0.02). The cells inside the autologous bone transplants most likely survived transplantation and were capable of initiating and sustaining new bone formation.
A 34-year-old woman with a known congenital pain-insensitivity syndrome presented because of incr... more A 34-year-old woman with a known congenital pain-insensitivity syndrome presented because of increasing weakness and sensory loss in her right leg. The cause was a rapidly progressive partial caudal compression syndrome in the absence ofknown prior trauma. Radiology revealed a lumbar Charcot spine, i.e. total destruction of the spine with compression of the dural sac. Emergency surgery included opening of the lumbar canal and spondylodesis. Postoperatively, there was almost full neurological recovery. In the pathogenesis the absence of protective pain sensation combined with trophic degeneration due to neurovascular dysregulation may play a role.
Nederlands tijdschrift voor geneeskunde, Jan 7, 2007
A 34-year-old woman with a known congenital pain-insensitivity syndrome presented because of incr... more A 34-year-old woman with a known congenital pain-insensitivity syndrome presented because of increasing weakness and sensory loss in her right leg. The cause was a rapidly progressive partial caudal compression syndrome in the absence ofknown prior trauma. Radiology revealed a lumbar Charcot spine, i.e. total destruction of the spine with compression of the dural sac. Emergency surgery included opening of the lumbar canal and spondylodesis. Postoperatively, there was almost full neurological recovery. In the pathogenesis the absence of protective pain sensation combined with trophic degeneration due to neurovascular dysregulation may play a role.
Bulletin of the World Health Organization, 1999
The article reports the results of a study to determine the true outcome of 8 months of treatment... more The article reports the results of a study to determine the true outcome of 8 months of treatment received by smear-positive pulmonary tuberculosis (PTB) patients who had been registered as defaulters in the Queen Elizabeth Central Hospital (QECH) and Mlambe Mission Hospital (MMH), Blantyre, Malawi. The treatment outcomes were documented from the tuberculosis registers of all patients registered between 1 October 1994 and 30 September 1995. The true treatment outcome for patients who had been registered as defaulters was determined by making personal inquiries at the treatment units and the residences of patients or relatives and, in a few cases, by writing to the appropriate postal address. Interviews were carried out with patients who had defaulted and were still alive and with matched, fully compliant PTB patients who had successfully completed the treatment to determine the factors associated with defaulter status. Of the 1099 patients, 126 (11.5%) had been registered as default...
Tissue Engineering Part A, 2015
Treatment and reconstruction of large bone defects, delayed unions and non-unions is challenging ... more Treatment and reconstruction of large bone defects, delayed unions and non-unions is challenging and has resulted in an ongoing search for novel tissue-engineered therapies. Bone morphogenetic protein-2 (BMP-2) gene therapy is a promising strategy to provide a sustained production of BMP-2 locally. Alginate polymer based non-viral gene therapy with BMP-2 plasmid DNA (pBMP-2) in constructs with multipotent mesenchymal stromal cells (MSCs) has resulted in prolonged gene expression and bone formation in vivo. To further translate this technology towards larger animal models, important issues remain to be investigated, such as the necessity of seeded cells as a target for gene therapy. For that purpose, a large animal-screening model in an orthotopic location, with fully separated chambers, was investigated. Four cylinder shaped implants were placed in the iliac crests of ten goats. Polycaprolactone tubes around each implant allowed bone ingrowth from the underlying bone and bone marrow and ensured separation of the experimental conditions. An empty tube showed low levels of spontaneous bone ingrowth and implantation of autologous bone indicated proper bone function with respect to remodeling and resorption. Control ceramic scaffolds were compared to scaffolds containing pBMP-2 either or not combined with seeded MSCs. Fluorochrome incorporation, evaluated at three, six and nine weeks and histomorphometry at twelve weeks after implantation revealed clear differences between the groups, with pBMP-2 combined with MSCs being most effective. BMP-2 protein was demonstrated in a variety of bone-residing cells through immunohistochemistry. Further analysis indicated that multinucleated giant cells might have an important role in transgene expression. Taken together, this work introduces a large animal model for studying bone formation at multiple sites simultaneously in an orthotopic location. The model appeared robust, showed no neighboring effects and demonstrated effectivity of combined cell-and gene therapy.
Transplantation, 2004
Little is known about the specific mechanisms that make autologous graft bone (AG) superior to th... more Little is known about the specific mechanisms that make autologous graft bone (AG) superior to the current alternatives. A potential mechanism is the active bone formation by the osteoprogenitor cells within the AG. However, whether these cells survive the transplantation is questionable, especially in nonvascularized, clinically sized grafts. In the present study, we investigated the role of viability in AG implanted ectopically and orthotopically in the goat. Eight goats were operated on twice. At the first operation, pieces of vital or devitalized autologous cortical bone were implanted in the paraspinal muscles. Eight weeks later, corticocancellous plugs were taken from the femoral condyles, morselized, and reimplanted as either vital or devitalized orthotopic grafts. The goats received fluorochrome labels at 5, 7, and 9 weeks after the first operation. At 12 weeks, the goats were killed, and the samples were examined histologically. Ectopically, new bone had formed in both the vital and devitalized grafts. In the vital grafts, all three fluorochrome labels were present, indicating an early osteogenic mechanism. Within the devitalized grafts, only the 9-week label was observed. Histomorphometry indicated significantly more new bone in the vital grafts (10.3% vs. 1.7% in the devitalized grafts, P <0.01). Orthotopically, both vital and devitalized grafts showed new bone. Again, graft viability was advantageous in terms of new bone formation (14.5% vs. 9.3%, P <0.02). The cells inside the autologous bone transplants most likely survived transplantation and were capable of initiating and sustaining new bone formation.
Spine, 2013
Study Design. Systematic literature review.
JIMD Reports, 2012
Hurler syndrome (MPS-IH) is a rare autosomal recessive lysosomal storage disease. Besides a varie... more Hurler syndrome (MPS-IH) is a rare autosomal recessive lysosomal storage disease. Besides a variety of other features, Hurler syndrome is characterized by a range of skeletal abnormalities known as dysostosis multiplex. Despite the successful effect of haematopoietic stem cell transplantation on the other features, dysostosis remains a disabling symptom of the disease. This study analyzed the status and development of the orthopaedic manifestations of 14 Dutch Hurler patients after stem cell transplantation.Data were obtained retrospectively by reviewing patients' charts, radiographs and MRIs. Existing methods to measure the deficiencies were modified to optimally address the dysostosis. These measurements were done by two of the authors independently. The odontoïd/body ratio, kyphotic angle, scoliotic angle and parameters for hip dysplasia and genu valgum were measured and plotted against age. The degree of progression was determined. The intraclass correlation coefficient (ICC) was calculated to determine the reliability of the measurements.All patients showed hypoplasia of the odontoïd, which significantly improved during growth. Kyphosis in the thoracolumbar area was present in 13 patients and proved to be progressive. Scoliosis was observed in eight patients. Hip dysplasia was present in all patients and showed no tendency of improvement. In all but one patient, knee valgus remained more than two standard deviations above normal.Dysostosis remains a major problem after haematopoietic stem cell transplantation in Hurler patients. Moreover, except for dens hypoplasia, it appears to be progressive and therefore surgical interventions may be necessary in the majority of these patients.
Tissue Engineering, 2008
ABSTRACT
Tissue Engineering Part A, 2010
The aim of this study was to investigate the effect of implant location on bone formation in goat... more The aim of this study was to investigate the effect of implant location on bone formation in goats using autologous bone marrow-derived stromal cells in porous calcium phosphate scaffolds. Intramuscular locations were compared to posterolateral spine fusion locations in eight goats. As scaffolds, we used biphasic calcium phosphate porous blocks of 5 x 5 x 5 mm. Cell-seeded implants were compared to empty controls. Bone marrow-derived stromal cells were seeded at 8 million cells per cm(3) scaffold and cultured for 1 week. The follow-up time was 12 weeks. Fluorochromes were administered intravenously at 4, 6, and 8 weeks. Ectopic implants showed 21 +/- 3.6% bone formation for the cell seeded and 2.0 +/- 3.0% for the controls (p < 0.001). Paraspinal implants, however, showed 0.10 +/- 0.13% in the cell seeded compared to 0.023 +/- 0.027% in the control group (p = 0.09). A benefit of the cells was only found in the area closest to the paraspinal muscles (p < 0.01). Bone formation in the control samples was of later onset compared to the cell-seeded implants. In conclusion, cell-based bone tissue engineering in an ectopic environment was clearly effective. Similar constructs implanted in a posterolateral spine fusion location hardly showed any effect.
Tissue Engineering Part A, 2008
After decades of research, relatively little is known about the role of bone marrow stromal cells... more After decades of research, relatively little is known about the role of bone marrow stromal cells (BMSCs) for bone tissue engineering. Although homogeneous cell seeding is regarded optimal, cell survival in large constructs is unlikely, except for the very periphery. Also no minimal and optimal BMSC densities have been identified. An interesting development is the use of allogeneic BMSCs. These have not yet been compared directly to autologous BMSCs. Culture-expanded BMSCs of 10 Dutch milk goats were cryopreserved and peroperatively seeded on 7 mm cubic scaffolds of 65% porous biphasic calcium phosphate (BCP). A range of BMSC densities (per cm3 scaffold) were prepared of 8E2 (= 8 x 10(2)), 8E3, 8E4, 8E5, 8E6 (considered the standard), and 1.6E7. Each goat received a control without cells, the six densities, and an 8E6 allogeneic BMSCs construct intramuscularly. After 3, 5, and 7 weeks, fluorochrome markers were administrated. At 9 weeks, implants were retrieved. The BCP scaffolds appeared to be autoinductive as the controls (without BMSCs) showed some bone. Early bone formation (before 3 weeks) appeared only at the peripheral 2mm of the BMSC-seeded constructs; the later 5- and 9-week labels were found more centrally, suggesting bone migration to the center. There was a minimum of 8E4 and optimum of 8E6 BMSCs/cm3. Allogeneic cells yielded comparable new bone.
Tissue Engineering, 2003
Bone tissue engineering has the potential to provide us with an autologous bone substitute. Despi... more Bone tissue engineering has the potential to provide us with an autologous bone substitute. Despite extensive research to optimize the technique, little is known about the survival and function of the cells after implantation. To monitor the cells, in vivo labeling is the method of choice. In this study we investigated the use of the fluorescent membrane marker chloromethyl-benzamidodialkylcarbocyanine (CM-Dil) to label cells used in bone tissue engineering. When applying label concentrations up to 50 microM, cells could be labeled efficiently without negative effects on cell vitality, proliferation, or bone-forming capacity. Porous hydroxyapatite scaffolds were seeded with labeled cells, and up to 6 weeks after implantation in nude mice cells could be traced inside tissue-engineered bone. However, contrary to other reports concerning intramembranous labels, transfer of the label from labeled to unlabeled cells was detected. Transfer occurred both in vitro and in vivo between vital cells and between dead and living cells. To determine when in vivo label transfer happened, devitalized, labeled constructs were implanted for various time periods in nude mice. The presence of vital labeled cells inside these constructs, when evaluated at different implantation periods, indicated transfer of the label. Transfer occurred at 7 days postimplantation when 40 microM label was applied, whereas 10 microM labeled constructs showed transfer 10 days after implantation. These findings indicate that CM-Dil label is useful for in vivo tracing of cells for follow-up periods up to 10 days. This makes the label particularly useful for cell survival studies in tissue-engineered implants.
The Spine Journal, 2012
BACKGROUND CONTEXT: Methodological quality measures of trials in meta-analyses have been shown to... more BACKGROUND CONTEXT: Methodological quality measures of trials in meta-analyses have been shown to influence the pooled effect sizes in several medical fields. However, for spinal surgery, influence of quality measures has not been assessed. PURPOSE: The purpose of this study was to analyze the influence of quality measures in studies on effectiveness in spinal surgery. STUDY DESIGN: A metaepidemiological study was performed on meta-analyses within spinal surgery. METHODS: A systematic search was performed in MEDLINE, Cochrane Database, and EMBASE in August 2009. The effect sizes, defined as risk of positive clinical outcome, of trials included in the meta-analyses were assessed. The differences in effect sizes were calculated as risk differences (RDs). Relation of the RDs to potential quality measures such as sponsoring, randomization, allocation concealment, blinding, and study size was assessed with metaregression adjusted for multiple testing. RESULTS: Seven reviews consisting of 118 studies were included. Data provided by the systematic reviews alone were insufficient to analyze the effect of quality measures. Metaregression analysis of 76 of the individual trials reporting clinical outcome, though, showed that sample size, strict randomization, and outcome blinding were significant quality measures influencing study effect. Risk difference of effect from validly randomized studies was higher compared with not validly randomized and comparative observational trials (5.4%; 95% confidence interval [CI], 1.2-9.6; p5.044). Studies with adequate observer blinding showed a 7.2% lower RD (95% CI, 0.8-13.7; p5.049). For each increase of 100 patients, the RD decreased 3.6% (95% CI, 0.5-6.8; p5.098). CONCLUSIONS: Contrary to basic methodological assertions, formal and strict randomization appeared to produce a significantly higher RD in spinal surgery research. Sufficient sample size and observer blinding, on the other hand, led to a lower RD as expected. These findings imply that effect of quality measures assessed in metaepidemiological studies should not be too easily translated to research in spinal surgery. Ó
The Spine Journal, 2012
BACKGROUND CONTEXT: Systematic reviews of the literature are powerful tools in evidencebased medi... more BACKGROUND CONTEXT: Systematic reviews of the literature are powerful tools in evidencebased medicine. However, the design and report of systematic reviews in spinal surgery contain many aspects amenable to improvement. PURPOSE: To discuss the issues especially relevant for systematic reviews in spinal surgery. METHODS: From our experience of systematic reviews and meta-analyses of clinical trials in spinal surgery, we infer guidance for the design and execution of systematic literature reviews. RESULTS: There are many difficulties associated with the design as well as conduct of clinical trials and consequently appraising evidence in spinal surgery. New treatments should be compared with the gold standard before other comparisons are investigated. Studies should present data as thoroughly as possible regarding all subgroups and follow-up moments, possibly in supplementary material. To provide the highest level of evidence, systematic reviews should be as rigorously designed as possible. CONCLUSIONS: Gathering information on clinical effectiveness in spinal surgery can be improved both at the clinical study level and at the systematic review level. Alternatives to randomized controlled trials such as comparative studies can be valuable tools on the clinical effectiveness of treatments in spinal surgery. The experience reflected in this article can support the scientific efforts in this field. Ó
Journal of Clinical Epidemiology, 2013
Objectives: The goal of this systematic review was to evaluate if the influence of methodological... more Objectives: The goal of this systematic review was to evaluate if the influence of methodological features on treatment effect differs between types of intervention.
Journal of Biomedical Materials Research, 2004
Successful bone-tissue engineering (TE) has been reported for various strategies to combine cells... more Successful bone-tissue engineering (TE) has been reported for various strategies to combine cells with a porous scaffold. In particular, the period after seeding until implantation of the constructs may vary between hours and several weeks. Differences between these strategies can be reduced to (a) the presence of extracellular matrix, (b) the differentiation status of the cells, and (c) the presence of residual potentially immunogenic serum proteins. These parameters are investigated in two types of calcium phosphate scaffolds in a goat model of ectopic bone formation. Culture-expanded bone-marrow stromal cells from eight goats were seeded onto two types of hydroxyapatite granules: HA60/400 (60% porosity, 400-m average pore size) and HA70/800. Scaffolds seeded with cells and control scaffolds were cultured for 6 days in medium containing autologous or semisynthetic serum, in the presence or absence of dexamethasone. Other scaffolds were seeded with cells just before implantation in medium with or without serum. All conditions were implanted autologously in the paraspinal muscles. After 12 weeks, bone had formed in 87% of all TE constructs, as demonstrated by histology. Histomorphometry indicated significantly more bone in the HA70/800 scaffolds. Furthermore, a significant advantage in bone formation was found when the constructs had been cultured for 6 days. In conclusion, both scaffold characteristics (porosity) and TE strategy (culturing of the constructs) were demonstrated to be important for bone TE.
European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society, Jan 28, 2016
In vivo evaluation of scoliosis treatment using a novel approach in which two posterior implants ... more In vivo evaluation of scoliosis treatment using a novel approach in which two posterior implants are implanted: XSLAT (eXtendable implant correcting Scoliosis in LAT bending) and XSTOR (eXtendable implant correcting Scoliosis in TORsion). The highly flexible and extendable implants use only small, but continuous lateral forces (XSLAT) and torques (XSTOR), thereby allowing growth and preventing fusion. Since (idiopathic) scoliosis does not occur spontaneously in animals, the device was used to induce a spinal deformity rather than correct it. Six of each implants were tested for their ability to induce scoliotic deformations in 12 growing pigs. Each implant spanned six segments and was attached to three vertebrae using sliding anchors. Radiological and histological assessments were done throughout the 8-week study. In all animals, the intended deformation was accomplished. Average Cobb angles were 19° for XSLAT and 6° for XSTOR. Average apical spinal torsion was 0° for XSLAT and 9° f...
Biomaterials, Apr 30, 2007
Despite decades of extensive research, the application of cell-based bone tissue engineering in c... more Despite decades of extensive research, the application of cell-based bone tissue engineering in clinically relevant models remains challenging. To improve effectiveness, a better understanding of how the technique should work is crucial. In the current study, we investigated the onset time, rate, location and direction of bone formation in ectopically and orthotopically implanted clinically sized tissue-engineered constructs to gain insight the mechanism behind it. Bone marrow stromal cells (BMSCs) were obtained from 10 goats, culture expanded and cryopreserved. Porous biphasic calcium phosphate (BCP) disks of 17 mm  6 mm were per-operatively seeded with BMSCs or left empty. Both conditions were implanted intramuscularly and in bilateral critical-sized iliac wing defects. Fluorochromes were administered at 3, 5 and 7 weeks and samples were retrieved after 9 weeks. Histology showed abundant and homogeneous bone formation throughout the intramuscular BMSC samples and little bone in the controls. Histomorphometry and measurements of the fluorochrome labels of the ectopical BMSC samples indicated that osteogenesis started at the periphery and subsequent osteoconduction filled the whole scaffold within 7 weeks. In the orthotopically implanted disks, there was good integration with the surrounding bone, but minimal bone in the center of the implants, in both conditions. Bone was only derived from the interface with the surrounding bone, there was no early bone at the surfaces in contact to soft tissue as was seen in the ectopical samples. Apparently cell survival was minimal and insufficient for relevant additional bone formation. However, the speed of integration with surrounding bone and subsequent bone apposition on the BMSC-seeded orthotopic scaffolds were found to be significantly enhanced, which may be relevant especially in challenging environments. r
Transplantation, Feb 1, 2004
Little is known about the specific mechanisms that make autologous graft bone (AG) superior to th... more Little is known about the specific mechanisms that make autologous graft bone (AG) superior to the current alternatives. A potential mechanism is the active bone formation by the osteoprogenitor cells within the AG. However, whether these cells survive the transplantation is questionable, especially in nonvascularized, clinically sized grafts. In the present study, we investigated the role of viability in AG implanted ectopically and orthotopically in the goat. Eight goats were operated on twice. At the first operation, pieces of vital or devitalized autologous cortical bone were implanted in the paraspinal muscles. Eight weeks later, corticocancellous plugs were taken from the femoral condyles, morselized, and reimplanted as either vital or devitalized orthotopic grafts. The goats received fluorochrome labels at 5, 7, and 9 weeks after the first operation. At 12 weeks, the goats were killed, and the samples were examined histologically. Ectopically, new bone had formed in both the vital and devitalized grafts. In the vital grafts, all three fluorochrome labels were present, indicating an early osteogenic mechanism. Within the devitalized grafts, only the 9-week label was observed. Histomorphometry indicated significantly more new bone in the vital grafts (10.3% vs. 1.7% in the devitalized grafts, P <0.01). Orthotopically, both vital and devitalized grafts showed new bone. Again, graft viability was advantageous in terms of new bone formation (14.5% vs. 9.3%, P <0.02). The cells inside the autologous bone transplants most likely survived transplantation and were capable of initiating and sustaining new bone formation.
A 34-year-old woman with a known congenital pain-insensitivity syndrome presented because of incr... more A 34-year-old woman with a known congenital pain-insensitivity syndrome presented because of increasing weakness and sensory loss in her right leg. The cause was a rapidly progressive partial caudal compression syndrome in the absence ofknown prior trauma. Radiology revealed a lumbar Charcot spine, i.e. total destruction of the spine with compression of the dural sac. Emergency surgery included opening of the lumbar canal and spondylodesis. Postoperatively, there was almost full neurological recovery. In the pathogenesis the absence of protective pain sensation combined with trophic degeneration due to neurovascular dysregulation may play a role.
Nederlands tijdschrift voor geneeskunde, Jan 7, 2007
A 34-year-old woman with a known congenital pain-insensitivity syndrome presented because of incr... more A 34-year-old woman with a known congenital pain-insensitivity syndrome presented because of increasing weakness and sensory loss in her right leg. The cause was a rapidly progressive partial caudal compression syndrome in the absence ofknown prior trauma. Radiology revealed a lumbar Charcot spine, i.e. total destruction of the spine with compression of the dural sac. Emergency surgery included opening of the lumbar canal and spondylodesis. Postoperatively, there was almost full neurological recovery. In the pathogenesis the absence of protective pain sensation combined with trophic degeneration due to neurovascular dysregulation may play a role.
Bulletin of the World Health Organization, 1999
The article reports the results of a study to determine the true outcome of 8 months of treatment... more The article reports the results of a study to determine the true outcome of 8 months of treatment received by smear-positive pulmonary tuberculosis (PTB) patients who had been registered as defaulters in the Queen Elizabeth Central Hospital (QECH) and Mlambe Mission Hospital (MMH), Blantyre, Malawi. The treatment outcomes were documented from the tuberculosis registers of all patients registered between 1 October 1994 and 30 September 1995. The true treatment outcome for patients who had been registered as defaulters was determined by making personal inquiries at the treatment units and the residences of patients or relatives and, in a few cases, by writing to the appropriate postal address. Interviews were carried out with patients who had defaulted and were still alive and with matched, fully compliant PTB patients who had successfully completed the treatment to determine the factors associated with defaulter status. Of the 1099 patients, 126 (11.5%) had been registered as default...
Tissue Engineering Part A, 2015
Treatment and reconstruction of large bone defects, delayed unions and non-unions is challenging ... more Treatment and reconstruction of large bone defects, delayed unions and non-unions is challenging and has resulted in an ongoing search for novel tissue-engineered therapies. Bone morphogenetic protein-2 (BMP-2) gene therapy is a promising strategy to provide a sustained production of BMP-2 locally. Alginate polymer based non-viral gene therapy with BMP-2 plasmid DNA (pBMP-2) in constructs with multipotent mesenchymal stromal cells (MSCs) has resulted in prolonged gene expression and bone formation in vivo. To further translate this technology towards larger animal models, important issues remain to be investigated, such as the necessity of seeded cells as a target for gene therapy. For that purpose, a large animal-screening model in an orthotopic location, with fully separated chambers, was investigated. Four cylinder shaped implants were placed in the iliac crests of ten goats. Polycaprolactone tubes around each implant allowed bone ingrowth from the underlying bone and bone marrow and ensured separation of the experimental conditions. An empty tube showed low levels of spontaneous bone ingrowth and implantation of autologous bone indicated proper bone function with respect to remodeling and resorption. Control ceramic scaffolds were compared to scaffolds containing pBMP-2 either or not combined with seeded MSCs. Fluorochrome incorporation, evaluated at three, six and nine weeks and histomorphometry at twelve weeks after implantation revealed clear differences between the groups, with pBMP-2 combined with MSCs being most effective. BMP-2 protein was demonstrated in a variety of bone-residing cells through immunohistochemistry. Further analysis indicated that multinucleated giant cells might have an important role in transgene expression. Taken together, this work introduces a large animal model for studying bone formation at multiple sites simultaneously in an orthotopic location. The model appeared robust, showed no neighboring effects and demonstrated effectivity of combined cell-and gene therapy.
Transplantation, 2004
Little is known about the specific mechanisms that make autologous graft bone (AG) superior to th... more Little is known about the specific mechanisms that make autologous graft bone (AG) superior to the current alternatives. A potential mechanism is the active bone formation by the osteoprogenitor cells within the AG. However, whether these cells survive the transplantation is questionable, especially in nonvascularized, clinically sized grafts. In the present study, we investigated the role of viability in AG implanted ectopically and orthotopically in the goat. Eight goats were operated on twice. At the first operation, pieces of vital or devitalized autologous cortical bone were implanted in the paraspinal muscles. Eight weeks later, corticocancellous plugs were taken from the femoral condyles, morselized, and reimplanted as either vital or devitalized orthotopic grafts. The goats received fluorochrome labels at 5, 7, and 9 weeks after the first operation. At 12 weeks, the goats were killed, and the samples were examined histologically. Ectopically, new bone had formed in both the vital and devitalized grafts. In the vital grafts, all three fluorochrome labels were present, indicating an early osteogenic mechanism. Within the devitalized grafts, only the 9-week label was observed. Histomorphometry indicated significantly more new bone in the vital grafts (10.3% vs. 1.7% in the devitalized grafts, P <0.01). Orthotopically, both vital and devitalized grafts showed new bone. Again, graft viability was advantageous in terms of new bone formation (14.5% vs. 9.3%, P <0.02). The cells inside the autologous bone transplants most likely survived transplantation and were capable of initiating and sustaining new bone formation.
Spine, 2013
Study Design. Systematic literature review.
JIMD Reports, 2012
Hurler syndrome (MPS-IH) is a rare autosomal recessive lysosomal storage disease. Besides a varie... more Hurler syndrome (MPS-IH) is a rare autosomal recessive lysosomal storage disease. Besides a variety of other features, Hurler syndrome is characterized by a range of skeletal abnormalities known as dysostosis multiplex. Despite the successful effect of haematopoietic stem cell transplantation on the other features, dysostosis remains a disabling symptom of the disease. This study analyzed the status and development of the orthopaedic manifestations of 14 Dutch Hurler patients after stem cell transplantation.Data were obtained retrospectively by reviewing patients' charts, radiographs and MRIs. Existing methods to measure the deficiencies were modified to optimally address the dysostosis. These measurements were done by two of the authors independently. The odontoïd/body ratio, kyphotic angle, scoliotic angle and parameters for hip dysplasia and genu valgum were measured and plotted against age. The degree of progression was determined. The intraclass correlation coefficient (ICC) was calculated to determine the reliability of the measurements.All patients showed hypoplasia of the odontoïd, which significantly improved during growth. Kyphosis in the thoracolumbar area was present in 13 patients and proved to be progressive. Scoliosis was observed in eight patients. Hip dysplasia was present in all patients and showed no tendency of improvement. In all but one patient, knee valgus remained more than two standard deviations above normal.Dysostosis remains a major problem after haematopoietic stem cell transplantation in Hurler patients. Moreover, except for dens hypoplasia, it appears to be progressive and therefore surgical interventions may be necessary in the majority of these patients.
Tissue Engineering, 2008
ABSTRACT
Tissue Engineering Part A, 2010
The aim of this study was to investigate the effect of implant location on bone formation in goat... more The aim of this study was to investigate the effect of implant location on bone formation in goats using autologous bone marrow-derived stromal cells in porous calcium phosphate scaffolds. Intramuscular locations were compared to posterolateral spine fusion locations in eight goats. As scaffolds, we used biphasic calcium phosphate porous blocks of 5 x 5 x 5 mm. Cell-seeded implants were compared to empty controls. Bone marrow-derived stromal cells were seeded at 8 million cells per cm(3) scaffold and cultured for 1 week. The follow-up time was 12 weeks. Fluorochromes were administered intravenously at 4, 6, and 8 weeks. Ectopic implants showed 21 +/- 3.6% bone formation for the cell seeded and 2.0 +/- 3.0% for the controls (p < 0.001). Paraspinal implants, however, showed 0.10 +/- 0.13% in the cell seeded compared to 0.023 +/- 0.027% in the control group (p = 0.09). A benefit of the cells was only found in the area closest to the paraspinal muscles (p < 0.01). Bone formation in the control samples was of later onset compared to the cell-seeded implants. In conclusion, cell-based bone tissue engineering in an ectopic environment was clearly effective. Similar constructs implanted in a posterolateral spine fusion location hardly showed any effect.
Tissue Engineering Part A, 2008
After decades of research, relatively little is known about the role of bone marrow stromal cells... more After decades of research, relatively little is known about the role of bone marrow stromal cells (BMSCs) for bone tissue engineering. Although homogeneous cell seeding is regarded optimal, cell survival in large constructs is unlikely, except for the very periphery. Also no minimal and optimal BMSC densities have been identified. An interesting development is the use of allogeneic BMSCs. These have not yet been compared directly to autologous BMSCs. Culture-expanded BMSCs of 10 Dutch milk goats were cryopreserved and peroperatively seeded on 7 mm cubic scaffolds of 65% porous biphasic calcium phosphate (BCP). A range of BMSC densities (per cm3 scaffold) were prepared of 8E2 (= 8 x 10(2)), 8E3, 8E4, 8E5, 8E6 (considered the standard), and 1.6E7. Each goat received a control without cells, the six densities, and an 8E6 allogeneic BMSCs construct intramuscularly. After 3, 5, and 7 weeks, fluorochrome markers were administrated. At 9 weeks, implants were retrieved. The BCP scaffolds appeared to be autoinductive as the controls (without BMSCs) showed some bone. Early bone formation (before 3 weeks) appeared only at the peripheral 2mm of the BMSC-seeded constructs; the later 5- and 9-week labels were found more centrally, suggesting bone migration to the center. There was a minimum of 8E4 and optimum of 8E6 BMSCs/cm3. Allogeneic cells yielded comparable new bone.
Tissue Engineering, 2003
Bone tissue engineering has the potential to provide us with an autologous bone substitute. Despi... more Bone tissue engineering has the potential to provide us with an autologous bone substitute. Despite extensive research to optimize the technique, little is known about the survival and function of the cells after implantation. To monitor the cells, in vivo labeling is the method of choice. In this study we investigated the use of the fluorescent membrane marker chloromethyl-benzamidodialkylcarbocyanine (CM-Dil) to label cells used in bone tissue engineering. When applying label concentrations up to 50 microM, cells could be labeled efficiently without negative effects on cell vitality, proliferation, or bone-forming capacity. Porous hydroxyapatite scaffolds were seeded with labeled cells, and up to 6 weeks after implantation in nude mice cells could be traced inside tissue-engineered bone. However, contrary to other reports concerning intramembranous labels, transfer of the label from labeled to unlabeled cells was detected. Transfer occurred both in vitro and in vivo between vital cells and between dead and living cells. To determine when in vivo label transfer happened, devitalized, labeled constructs were implanted for various time periods in nude mice. The presence of vital labeled cells inside these constructs, when evaluated at different implantation periods, indicated transfer of the label. Transfer occurred at 7 days postimplantation when 40 microM label was applied, whereas 10 microM labeled constructs showed transfer 10 days after implantation. These findings indicate that CM-Dil label is useful for in vivo tracing of cells for follow-up periods up to 10 days. This makes the label particularly useful for cell survival studies in tissue-engineered implants.
The Spine Journal, 2012
BACKGROUND CONTEXT: Methodological quality measures of trials in meta-analyses have been shown to... more BACKGROUND CONTEXT: Methodological quality measures of trials in meta-analyses have been shown to influence the pooled effect sizes in several medical fields. However, for spinal surgery, influence of quality measures has not been assessed. PURPOSE: The purpose of this study was to analyze the influence of quality measures in studies on effectiveness in spinal surgery. STUDY DESIGN: A metaepidemiological study was performed on meta-analyses within spinal surgery. METHODS: A systematic search was performed in MEDLINE, Cochrane Database, and EMBASE in August 2009. The effect sizes, defined as risk of positive clinical outcome, of trials included in the meta-analyses were assessed. The differences in effect sizes were calculated as risk differences (RDs). Relation of the RDs to potential quality measures such as sponsoring, randomization, allocation concealment, blinding, and study size was assessed with metaregression adjusted for multiple testing. RESULTS: Seven reviews consisting of 118 studies were included. Data provided by the systematic reviews alone were insufficient to analyze the effect of quality measures. Metaregression analysis of 76 of the individual trials reporting clinical outcome, though, showed that sample size, strict randomization, and outcome blinding were significant quality measures influencing study effect. Risk difference of effect from validly randomized studies was higher compared with not validly randomized and comparative observational trials (5.4%; 95% confidence interval [CI], 1.2-9.6; p5.044). Studies with adequate observer blinding showed a 7.2% lower RD (95% CI, 0.8-13.7; p5.049). For each increase of 100 patients, the RD decreased 3.6% (95% CI, 0.5-6.8; p5.098). CONCLUSIONS: Contrary to basic methodological assertions, formal and strict randomization appeared to produce a significantly higher RD in spinal surgery research. Sufficient sample size and observer blinding, on the other hand, led to a lower RD as expected. These findings imply that effect of quality measures assessed in metaepidemiological studies should not be too easily translated to research in spinal surgery. Ó
The Spine Journal, 2012
BACKGROUND CONTEXT: Systematic reviews of the literature are powerful tools in evidencebased medi... more BACKGROUND CONTEXT: Systematic reviews of the literature are powerful tools in evidencebased medicine. However, the design and report of systematic reviews in spinal surgery contain many aspects amenable to improvement. PURPOSE: To discuss the issues especially relevant for systematic reviews in spinal surgery. METHODS: From our experience of systematic reviews and meta-analyses of clinical trials in spinal surgery, we infer guidance for the design and execution of systematic literature reviews. RESULTS: There are many difficulties associated with the design as well as conduct of clinical trials and consequently appraising evidence in spinal surgery. New treatments should be compared with the gold standard before other comparisons are investigated. Studies should present data as thoroughly as possible regarding all subgroups and follow-up moments, possibly in supplementary material. To provide the highest level of evidence, systematic reviews should be as rigorously designed as possible. CONCLUSIONS: Gathering information on clinical effectiveness in spinal surgery can be improved both at the clinical study level and at the systematic review level. Alternatives to randomized controlled trials such as comparative studies can be valuable tools on the clinical effectiveness of treatments in spinal surgery. The experience reflected in this article can support the scientific efforts in this field. Ó
Journal of Clinical Epidemiology, 2013
Objectives: The goal of this systematic review was to evaluate if the influence of methodological... more Objectives: The goal of this systematic review was to evaluate if the influence of methodological features on treatment effect differs between types of intervention.
Journal of Biomedical Materials Research, 2004
Successful bone-tissue engineering (TE) has been reported for various strategies to combine cells... more Successful bone-tissue engineering (TE) has been reported for various strategies to combine cells with a porous scaffold. In particular, the period after seeding until implantation of the constructs may vary between hours and several weeks. Differences between these strategies can be reduced to (a) the presence of extracellular matrix, (b) the differentiation status of the cells, and (c) the presence of residual potentially immunogenic serum proteins. These parameters are investigated in two types of calcium phosphate scaffolds in a goat model of ectopic bone formation. Culture-expanded bone-marrow stromal cells from eight goats were seeded onto two types of hydroxyapatite granules: HA60/400 (60% porosity, 400-m average pore size) and HA70/800. Scaffolds seeded with cells and control scaffolds were cultured for 6 days in medium containing autologous or semisynthetic serum, in the presence or absence of dexamethasone. Other scaffolds were seeded with cells just before implantation in medium with or without serum. All conditions were implanted autologously in the paraspinal muscles. After 12 weeks, bone had formed in 87% of all TE constructs, as demonstrated by histology. Histomorphometry indicated significantly more bone in the HA70/800 scaffolds. Furthermore, a significant advantage in bone formation was found when the constructs had been cultured for 6 days. In conclusion, both scaffold characteristics (porosity) and TE strategy (culturing of the constructs) were demonstrated to be important for bone TE.