Bone regeneration is one of the major focus points in the field of regenerative medicine. A well-known stimulus of bone formation is bone morphogenetic protein-2 (BMP-2), which has already been ...extensively used in clinical applications. We investigated the possibility of achieving osteogenic differentiation both in vitro and in vivo as a result of prolonged presence of BMP-2 using plasmid DNA-based gene therapy. By delivering BMP-2 cDNA in an alginate hydrogel, a versatile formulation is developed. High transfection efficiencies of up to 95% were obtained in both human multipotent stromal cells (MSCs) and MG-63 cells using naked DNA in vitro. Over a period of 5 weeks, an increasing amount of biologically active BMP-2 was released from the cells and remained present in the gel. In vivo, transfected cells were found after both two and six weeks implantation in naked mice, even in groups without seeded cells, thus indicating in vivo transfection of endogenous cells. The protein levels were effective in inducing osteogenic differentiation in vitro, as seen by elevated alkaline phosphatase (ALP) production and in vivo, as demonstrated by the production of collagen I and osteocalcin in a mineralised alginate matrix. We conclude that BMP-2 cDNA incorporated in alginate hydrogel appears to be a promising new strategy for minimal-invasive delivery of growth factors in bone regeneration.
DISH is a condition characterized by flowing ossifications of the spine with or without ossifications of entheses elsewhere in the body. Studies on the prevalence and pathogenesis of DISH use a ...variety of partly overlapping combinations of classification criteria, making meaningful comparisons across the literature difficult. The aim of this study was to systematically summarize the available criteria to support the development of a more uniform set of diagnostic/classification criteria.
A search was performed in Pubmed, Embase, Cochrane Library and Web of Science using the term DISH and its synonyms. Articles were included when two independent observers agreed that the articles proposed a new set of classification criteria for DISH. All retrieved articles were evaluated for methodological quality, and the presented criteria were extracted.
A total of 24 articles met the inclusion criteria. In all articles, spinal hyperostosis was required for the diagnosis of DISH. Peripheral, extraspinal manifestations were included as a (co-)requirement for the diagnosis DISH in five articles. Most discrepancies revolved around the threshold for the number of vertebral bodies affected and to defining different developmental phases of DISH. More than half of the retrieved articles described a dichotomous set of criteria and did not consider the progressive character of DISH.
This systematic review summarizes the available different classification criteria for DISH, which highlights the lack of consensus on the diagnosis of (early) DISH. Consensus criteria, including consecutive phases of new bone formation that characterize DISH, can be developed based upon established diagnostic/classification criteria.
Summary Background In degenerative intervertebral discs (IVDs) collagen type X expression and calcifications have been demonstrated, resembling advanced osteoarthritis (OA), which is associated with ...hypertrophic differentiation, characterized by the production of collagen type X, Runt-related transcription factor 2 (Runx2), osteoprotegerin (OPG), alkaline phosphatase (ALP) and calcifications. Objective The aim of this study was to determine if hypertrophic differentiation occurs during IVD degeneration. Methods IVDs from all Thompson degeneration grades were prepared for histology, extraction of nucleus pulposus (NP) and annulus fibrosis (AF) tissue ( N = 50) and micro-CT ( N = 27). The presence of collagen type X, OPG and Runx2 was determined by immunohistochemistry, with OPG levels also determined by Enzyme-linked immunosorbent assay (ELISA). The presence of calcification was determined by micro-CT, von Kossa and Alizarin Red staining. Results Immunohistochemical staining for collagen type X, OPG, Runx2 appeared more intense in the NP of degenerative compared to healthy IVD samples. OPG levels correlated significantly with degeneration grade (NP: P < 0.000; AF: P = 0.002) and the number of microscopic calcifications (NP: P = 0.002; AF: P = 0.008). The extent of calcifications on micro-CT also correlated with degeneration grade (NP: P < 0.001, AF: P = 0.001) as did von Kossa staining (NP: P = 0.015, AF: P = 0.016). ALP staining was only incidentally seen in the transition zone of grades IV and V degenerated IVDs. Conclusion This study for the first time demonstrates that hypertrophic differentiation occurs during IVD degeneration, as shown by an increase in OPG levels, the presence of ALP activity, increased immunopositivity of Runx2 and collagen type X.
Immune cells and their soluble factors regulate skeletal cells during normal bone regeneration and pathological bone formation. Bacterial infections can trigger immune responses that activate ...pro-osteogenic pathways, but these are usually overshadowed by osteolysis and concerns of systemic inflammation. The aim of this study was to determine whether the transient local inflammatory reaction to non-viable bacterial immune agonists could lead to favourable new bone formation. In a series of rabbit studies, as proof-of-concept, how tibial intramedullary injection of viable or killed bacterial species affected bone remodelling and new bone formation was determined. Application of killed bacteria led to considerable new bone formation after 4 weeks, without the prolonged systemic inflammation and exaggerated bone lysis seen with active infection. The osteo-immunomodulatory effects of various species of killed bacteria and the dose response relationship were subsequently screened in ectopically-implanted ceramic scaffolds. Histomorphometry after 8 weeks showed that a relatively low dose of killed bacteria enhanced ectopic bone induction. Moreover, lipoteichoic acid - the bacterial cell-wall derived toll-like-receptor (TLR)-2 activator - was identified as an osteo-stimulatory factor. Collectively, the data indicated that bacterial stimuli could be harnessed to stimulate osteogenesis, which occurs through a synergy with osteoinductive signals. This finding holds promise for the use of non-viable bacteria, bacterial antigens, or their simplified analogues as immuno-modulatory bone regenerating tools in bone biomaterials.
Interleukin 17 (IL-17) stimulates the osteogenic differentiation of progenitor cells in vitro through a synergy with bone morphogenetic protein (BMP)-2. This study investigates whether the diverse ...responses mediated by IL-17 in vivo also lead to enhanced BMP-2-induced bone formation. Since IL-17 is known to induce osteoclastogenesis, we studied the interactions between IL-17 and BMP-2 in ceramic scaffolds either or not carrying a coating with the bisphosphonate zoledronic acid (ZOL). Histological evaluation revealed that IL-17 alone did not induce any osteoclasts at day 10. On the other hand, BMP-2 clearly stimulated early tissue ingrowth and osteoclastogenesis. Both of these processes were blocked in presence of ZOL. IL-17 signaling restored early vascularized connective tissue formation and osteoclastogenesis induced by BMP-2 in ZOL-coated scaffolds. After 12 weeks, the bone volume induced by co-delivery of BMP-2 and IL-17 was doubled as compared to that induced by BMP-2 alone. We conclude that IL-17 has osteo-stimulatory effects through a synergy with bone-inductive BMP-2. Although local and single application of IL-17 does not mediate osteoclast formation, it could promote other processes involved in bone formation such as connective tissue ingrowth. The use of IL-17 may contribute to the development of improved bone graft substitutes.
Purpose
En bloc
sacrectomy is a demanding surgical procedure to remove tumors from the sacrum. Comprehensive data on readmissions for complications endured months to years after initial discharge are ...scant. The purpose of this study is to present the long-term complications, readmissions and secondary interventions for patients having undergone
en bloc
sacrectomy.
Methods
Patients were included if
en bloc
sacrectomy and follow-up were conducted in the authors institution. Correspondence from all specialties involved in the treatment of patients was retrieved. Predefined parameters were scored and assigned to five distinct phases: diagnostic phase; surgery; postoperative period to 1 year after surgery; second year after surgery until follow-up and last follow-up.
Results
Sixteen patients underwent anterior–posterior
en bloc
sacrectomy for a locally aggressive tumor (
n
= 2); malignant tumor (
n
= 13) or solitary metastasis (
n
= 1). The type of resection was low (
n
= 1); middle (
n
= 3); high (
n
= 4); total (
n
= 3) and hemisacrectomy (
n
= 5). The median surgical duration was 12.7 h and median blood lost was 12 l. A total of 73 major complications (average per patient 5; median 4; range 0–12) were recorded and 73 secondary interventions (average per patient 5; median 5; range 0–11) were performed in the first year postsurgery. From the second year until follow-up complications and secondary interventions markedly decreased. At final follow-up (65–266 months), considerable morbidity was found for the eleven patients still alive.
Conclusions
En bloc
sacrectomy is a procedure with a high rate of major complications, regardless of tumor histology, often necessitating readmissions and secondary interventions. Long-term survival is associated with considerable morbidity and extensive preoperative counseling should be conducted to discuss the risks and outcome of the procedure.
In this paper the rationale for total disc replacement is discussed, and the authors suggest seven requirements that should be met before the implantation of these devices can be accepted as regular ...procedures. In an attempt to answer the questions raised, a systematic literature search was performed. The search yielded no controlled trials and nine case series with a total of 564 arthroplasties in 411 patients. The devices used were SB Charité in eight and Acroflex in one study. The percentage results classified as "good" or "excellent" in the studies varied from 50 to 81%. Complications were observed in 3-50% of the patients. Twenty-two of the operated levels were fused either spontaneously or after additional surgery. A meta-analysis to compare the results with other treatments could not be performed due to the lack of comparative studies. Despite the fact that these devices have been implanted for almost 15 years, on the basis of this literature survey there are currently insufficient data to assess the performance of total disc replacement adequately. There is no evidence that disc replacement reliably, reproducibly, and over longer periods of time fulfils the three primary aims of clinical efficacy, continued motion, and few adjacent segment degenerative problems. Total disc replacement seems to be associated with a high rate of re-operations, and the potential problems that may occur with longer follow-up have not been addressed. Therefore, total disc replacements should be considered experimental procedures and should only be used in strict clinical trials.
Introduction
The aim of this proof of concept human cadaver study was to quantify the effect of a bilateral extending pelvic osteotomy (BEPO) on pelvic incidence (PI) as a potential alternative for a ...pedicle subtraction osteotomy (PSO) in patients with severe spinal sagittal malalignment.
Materials and methods
10 fresh frozen human cadavers were treated with the BEPO technique. CT images were made before and after the osteotomy and pure sagittal images were created on which PI was measured.
Results
The mean pre-osteotomy PI was 47.9° (range 36.4–63.9) and the mean post-osteotomy PI was 36.5° (range 22.1–54.4). The mean correction was − 10.4° with a range of − 8.4° to − 17.3° (
p
= 0.03), which resulted in a mean decrease of 23% in the PI (range 16–42).
Conclusions
There was a feasible and effective correction of PI using the BEPO technique on the os ilium. This was a preliminary cadaveric study. No conclusions could be made on global sagittal alignment. We postulate that an extending osteotomy of the ilium could be a potential alternative for a PSO reducing the complexity of spine surgery in patients with severe spinal sagittal malalignment.
Objective To review suitable measures of patient-assessed outcome of surgery for spinal metastases, and suggest the Health-Related Quality of Life measures that are useful and practical for this ...group of patients. Methods Surgery for metastatic spinal tumors is becoming more common, but the impact of surgery on the patient, as determined by patient-assessed outcome measures, is not well known. The authors of this article include members of the Global Spine Tumour Study Group: an international group of spinal surgeons who are studying the techniques and outcomes of surgery for spinal tumors. During the development of a research database for the study of patients undergoing surgery for spinal metastases, the different outcome measures were discussed by a panel of spinal surgeons, and quality of life measures were chosen for inclusion, based on expert opinion and literature review. Results Several different measures are available to assess outcome after spinal surgery for metastatic disease, each with specific advantages and limitations, which are discussed. Our position is to use the EuroQoL EQ-5D questionnaire, because of its simplicity and reliability. Conclusions We recommend the use of the EQ-5D measure in research for assessment of patient-centered outcomes and calculation of cost effectiveness of surgery for spinal metastases. Routine use of the measure in clinical practice is also encouraged, because it is a simple and quick method to assess overall clinical outcome.
PDF
