[Show abstract][Hide abstract] ABSTRACT: Study Design Literature review. Objective The aim of this review is to highlight challenges in the development of a comprehensive surgical algorithm to accompany the AOSpine Thoracolumbar Spine Injury Classification System. Methods A narrative review of the relevant spine trauma literature was undertaken with input from the multidisciplinary AOSpine International Trauma Knowledge Forum. Results The transitional areas of the spine, in particular the cervicothoracic junction, pose unique challenges. The upper thoracic vertebrae have a transitional anatomy with elements similar to the subaxial cervical spine. When treating these fractures, the surgeon must be aware of the instability due to the junctional location of these fractures. Additionally, although the narrow spinal canal makes neurologic injuries common, the small pedicles and the inability to perform an anterior exposure make decompression surgery challenging. Similarly, low lumbar fractures and fractures at the lumbosacral junction cannot always be treated in the same manner as fractures in the more cephalad thoracolumbar spine. Although the unique biomechanical environment of the low lumbar spine makes a progressive kyphotic deformity less likely because of the substantial lordosis normally present in the low lumbar spine, even a fracture leading to a neutral alignment may dramatically alter the patient's sagittal balance. Conclusion Although the new AOSpine Thoracolumbar Spine Injury Classification System was designed to be a comprehensive thoracolumbar classification, fractures at the cervicothoracic junction and the lumbosacral junction have properties unique to these junctional locations. The specific characteristics of injuries in these regions may alter the most appropriate treatment, and so surgeons must use clinical judgment to determine the optimal treatment of these complex fractures.
Global Spine Journal 08/2015; 5(4). DOI:10.1055/s-0035-1549035
[Show abstract][Hide abstract] ABSTRACT: Bone morphogenetic protein-2 (BMP-2) gene delivery has shown to induce bone formation in vivo in cell-based tissue engineering. In addition, the chemoattractant stromal cell-derived factor-1α (SDF-1α, also known as CXCL12) is known to recruit multipotent stromal cells towards its release site where it enhances vascularisation and possibly contributes to osteogenic differentiation. To investigate potential cooperative behaviour for bone formation, we investigated combined release of BMP-2 and SDF-1α on ectopic bone formation in mice. Multipotent stromal cell-seeded and cell-free constructs with BMP-2 plasmid DNA and /or SDF-1α loaded onto gelatin microparticles, were implanted subcutaneously in mice for a period of 6 weeks. Histological analysis and histomorphometry revealed that the onset of bone formation and the formed bone volume were both enhanced by the combination of BMP-2 and SDF-1α compared to controls in cell-seeded constructs. Samples without seeded multipotent stromal cells failed to induce any bone formation. We conclude that the addition of stromal cell-derived factor-1α to a cell-seeded alginate based bone morphogenetic protein-2 plasmid DNA construct has an additive effect on bone formation and can be considered a promising combination for bone regeneration.
European cells & materials 07/2015; 30:1-11. · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several inflammatory processes underlie excessive bone formation, including chronic inflammation of the spine, acute infections, or periarticular ossifications after trauma. This suggests that local factors in these conditions have osteogenic properties. Mesenchymal stem cells (MSCs) and their differentiated progeny contribute to bone healing by synthesizing extracellular matrix and inducing mineralization. Due to the variation in experimental designs used in vitro, there is controversy about the osteogenic potential of proinflammatory factors on MSCs. Our goal was to determine the specific conditions allowing the pro-osteogenic effects of distinct inflammatory stimuli. Human bone marrow MSCs were exposed to tumor necrosis factor alpha (TNF-α) and lipopolysaccharide (LPS). Cells were cultured in growth medium or osteogenic differentiation medium. Alternatively, bone morphogenetic protein 2 (BMP-2) was used as osteogenic supplement to simulate the conditions in vivo. Alkaline phosphatase activity and calcium deposition were indicators of osteogenicity. To elucidate lineage commitment-dependent effects, MSCs were pre-differentiated prior treatment. Our results show that TNF-α and LPS do not affect the expression of osteogenic markers by MSCs in the absence of an osteogenic supplement. In osteogenic differentiation medium or together with BMP-2 however, these mediators highly stimulated their alkaline phosphatase activity and subsequent matrix mineralization. In pre-osteoblasts, matrix mineralization was significantly increased by these mediators, but irrespective of the culture conditions. Our study shows that inflammatory factors potently enhance the osteogenic capacity of MSCs. These properties may be harnessed in bone regenerative strategies. Importantly, the commitment of MSCs to the osteogenic lineage greatly enhances their responsiveness to inflammatory signals.
PLoS ONE 07/2015; 10(7):e0132781. DOI:10.1371/journal.pone.0132781 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: International validation studyObjective. To investigate the influence of the spine surgeons' level of experience on the intraobserver reliability of the novel AOSpine Thoracolumbar Spine Injury Classification system, and the appropriate classification according to this system.
Wide variability has been demonstrated for intraobserver reliability of the AOSpine classification system. The spine surgeons' level of experience may play a crucial role in the appropriate classification of thoracolumbar fractures, and the degree of reproducibility of the same observer on separate occasions. However, this has not been previously investigated.
After a training on the classification system, high quality CT images together with clinical data from 25 patients with thoracolumbar fractures were independently assessed by 100 spine surgeons from across the world on two different occasions, one month apart from each other. The spine surgeons were allocated to a subgroup, according to their years of experience. Intraobserver reliability was calculated for each individual surgeon and for each subgroup, using the Kappa statistics (κ). Descriptive statistics was used to describe any differences between the subgroups. Analysis of any misclassifications was performed by calculating sensitivity and specificity estimates.
Almost all surgeons demonstrated at least moderate intraobserver reliability. All surgeon subgroups demonstrated substantial reliability (κ = 0.67-0.69) for fracture subtype grading, and almost all subgroups demonstrated excellent reliability (κ = 0.79-0.83) for fracture morphology type regardless of subtype identified. In general, the fractures were most frequently misclassified by the most experienced surgeons. No major differences were observed among the subgroups when comparing the sensitivity and specificity rates.
This international study demonstrated that the spine surgeons' level of experience does not substantially influence the classification and intraobserver reliability of the recently described AOSpine Thoracolumbar Spine Injury Classification System.
[Show abstract][Hide abstract] ABSTRACT: Conflicts of interest arising from ties between pharmaceutical industry and physicians are common and may bias research. The extent to which these ties exist among editorial board members of medical journals is not known. This study aims to determine the prevalence and financial magnitude of potential conflicts of interest among editorial board members of five leading spine journals. The editorial boards of: The Spine Journal; Spine; European Spine Journal; Journal of Neurosurgery: Spine; and Journal of Spinal Disorders & Techniques were extracted on January 2013 from the journals' websites. Disclosure statements were retrieved from the 2013 disclosure index of the North American Spine Society; the program of the 20th International Meeting on Advanced Spine Techniques; the program of the 48th Annual Meeting of the Scoliosis Research Society; the program of the AOSpine global spine congress; the presentations of the 2013 Annual Eurospine meeting; and the disclosure index of the American Academy of Orthopaedic Surgeons. Names of the editorial board members were compared with the individuals who completed a disclosure for one of these indexes. Disclosures were extracted when full names matched. Two hundred and ten (29%) of the 716 identified editorial board members reported a potential conflict of interest and 154 (22%) reported nothing to disclose. The remaining 352 (49%) editorial board members had no disclosure statement listed for one of the indexes. Eighty-nine (42%) of the 210 editorial board members with a potential conflict of interest reported a financial relationship of more than $10,000 during the prior year. This finding confirms that potential conflicts of interest exist in editorial boards which might influence the peer review process and can result in bias. Academia and medical journals in particular should be aware of this and strive to improve transparency of the review process. We emphasize recommendations that contribute to achieving this goal.
PLoS ONE 06/2015; 10(6):e0127362. DOI:10.1371/journal.pone.0127362 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The goal of the current study is to establish a surgical algorithm to accompany the AOSpine thoracolumbar spine injury classification system.
A survey was sent to AOSpine members from the six AO regions of the world, and surgeons were asked if a patient should undergo an initial trial of conservative management or if surgical management was warranted. The survey consisted of controversial injury patterns. Using the results of the survey, a surgical algorithm was developed.
The AOSpine Trauma Knowledge forum defined that the injuries in which less than 30 % of surgeons would recommend surgical intervention should undergo a trial of non-operative care, and injuries in which 70 % of surgeons would recommend surgery should undergo surgical intervention. Using these thresholds, it was determined that injuries with a thoracolumbar AOSpine injury score (TL AOSIS) of three or less should undergo a trial of conservative treatment, and injuries with a TL AOSIS of more than five should undergo surgical intervention. Operative or non-operative treatment is acceptable for injuries with a TL AOSIS of four or five.
The current algorithm uses a meaningful injury classification and worldwide surgeon input to determine the initial treatment recommendation for thoracolumbar injuries. This allows for a globally accepted surgical algorithm for the treatment of thoracolumbar trauma.
European Spine Journal 05/2015; DOI:10.1007/s00586-015-3982-2 · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Empirical cross-sectional multicenter study.
To identify the most commonly experienced problems by patients with traumatic spinal column injuries, excluding patients with complete paralysis.
There is no disease or condition-specific outcome instrument available that is designed or validated for patients with spine trauma, contributing to the present lack of consensus and ongoing controversies in the optimal treatment and evaluation of many types of spine injuries. Therefore, AOSpine Knowledge Forum Trauma started a project to develop such an instrument using the International Classification of Functioning, Disability and Health (ICF) as its basis.
Patients with traumatic spinal column injuries, within 13 months after discharge from hospital were recruited from 9 trauma centers in 7 countries, representing 4 AOSpine International world regions. Health professionals collected the data using the general ICF Checklist. The responses were analyzed using frequency analysis. Possible differences between the world regions and also between the subgroups of potential modifiers were analyzed using descriptive statistics and Fisher exact test.
In total, 187 patients were enrolled. A total of 38 (29.7%) ICF categories were identified as relevant for at least 20% of the patients. Categories experienced as a difficulty/impairment were most frequently related to activities and participation (n = 15), followed by body functions (n = 6), and body structures (n = 5). Furthermore, 12 environmental factors were considered to be a facilitator in at least 20% of the patients.
Of 128 ICF categories of the general ICF Checklist, 38 ICF categories were identified as relevant. Loss of functioning and limitations in daily living seem to be more relevant for patients with traumatic spinal column injuries rather than pain during this time frame. This study creates an evidence base to define a core set of ICF categories for outcome measurement in adult spine trauma patients.
[Show abstract][Hide abstract] ABSTRACT: Study Design. Survey of spine surgeons. Objective. To develop a validated regional and global injury severity scoring system for thoracolumbar trauma. Summary of Background Data. The AOSpine Thoracolumbar Spine Injury Classification System was recently published and combines elements of both the Magerl system and the Thoracolumbar Injury Classification System; however, the injury severity of each fracture has yet to be established. Methods. A survey was sent to 100 AOSpine members from all 6 AO regions of the world (North America, South America, Europe, Africa, Asia, and the Middle East). Each respondent was asked to numerically grade the severity of each variable of the AOSpine Thoracolumbar Spine Injury Classification System including the morphology, neurological grade, and patient specific modifiers. A grade of zero was considered to be not severe at all, and a grade of 100 was the most severe injury possible. Results. Seventy-four AOSpine surgeons from all 6 AO regions of the world numerically graded the severity of each variable of the AOSpine Thoracolumbar Spine Injury Classification System to establish the injury severity score. The reported fracture severity increased significantly (P < 0.0001) as the subtypes of fracture type A and type B increased, and a significant difference (P < 0.0001) in severity was established for burst fractures with involvement of 2 versus 1 endplates. Finally, no regional or experiential difference in severity or classification was identified. Conclusion. Development of a globally applicable injury severity scoring system for thoracolumbar trauma is possible. This study demonstrates no regional or experiential difference in perceived severity or thoracolumbar spine trauma. The AOSpine Thoracolumbar Spine Injury Classification System provides a logical approach to assessing these injuries and enables rational strategies for treatment. Level of Evidence: 4
[Show abstract][Hide abstract] ABSTRACT: Study Design Survey of spine surgeons. Objective To determine the reliability with which international spine surgeons identify a posterior ligamentous complex (PLC) injury in a patient with a compression-type vertebral body fracture (type A). Methods A survey was sent to all AOSpine members from the six AO regions of the world. The survey consisted of 10 cases of type A fractures (2 subtype A1, 2 subtype A2, 3 subtype A3, and 3 subtype A4 fractures) with appropriate imaging (plain radiographs, computed tomography, and/or magnetic resonance imaging), and the respondent was asked to identify fractures with a PLC disruption, as well as to indicate if the integrity of the PLC would affect their treatment recommendation. Results Five hundred twenty-nine spine surgeons from all six AO regions of the world completed the survey. The overall interobserver reliability in determining the integrity of the PLC was slight (kappa = 0.11). No substantial regional or experiential difference was identified in determining PLC integrity or its absence; however, a regional difference was identified (p < 0.001) in how PLC integrity influenced the treatment of type A fractures. Conclusion The results of this survey indicate that there is only slight international reliability in determining the integrity of the PLC in type A fractures. Although the biomechanical importance of the PLC is not in doubt, the inability to reliably determine the integrity of the PLC may limit the utility of the M1 modifier in the AOSpine Thoracolumbar Spine Injury Classification System.
Global Spine Journal 03/2015; 5(5). DOI:10.1055/s-0035-1549034
[Show abstract][Hide abstract] ABSTRACT: This project describes a morphology-based subaxial cervical spine traumatic injury classification system. Using the same approach as the thoracolumbar system, the goal was to develop a comprehensive yet simple classification system with high intra- and interobserver reliability to be used for clinical and research purposes.
A subaxial cervical spine injury classification system was developed using a consensus process among clinical experts. All investigators were required to successfully grade 10 cases to demonstrate comprehension of the system before grading 30 additional cases on two occasions, 1 month apart. Kappa coefficients (κ) were calculated for intraobserver and interobserver reliability.
The classification system is based on three injury morphology types similar to the TL system: compression injuries (A), tension band injuries (B), and translational injuries (C), with additional descriptions for facet injuries, as well as patient-specific modifiers and neurologic status. Intraobserver and interobserver reliability was substantial for all injury subtypes (κ = 0.75 and 0.64, respectively).
The AOSpine subaxial cervical spine injury classification system demonstrated substantial reliability in this initial assessment, and could be a valuable tool for communication, patient care and for research purposes.
[Show abstract][Hide abstract] ABSTRACT: 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.
Tissue Engineering Part A 02/2015; 21(9-10). DOI:10.1089/ten.TEA.2014.0593 · 4.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Study Design. Validation study.Objective. To investigate the most valid, reliable, and comprehensible response scale for spinal trauma patients to compare their current level of function and health with their pre-injury state.Summary of Background Data. In the context of a main project of the AOSpine Knowledge Forum Trauma to develop a disease specific outcome instrument for adult spinal trauma patients, the need to identify a response scale that uniquely reflects the degree to which a spine trauma patient has returned to his or her pre-injury state is crucial.Methods. In the first phase, three different question formats and three different response formats were investigated in a questionnaire, which was administered twice. Based on the results of the first phase, in the second phase a modified questionnaire was administered once to a second group of patients to investigate five different response formats: 0-10 Numeric Rating Scale (NRS-11), 0-100 Numeric Rating Scale (NRS-101), Visual Analog Scale (VAS), Verbal Rating Scale (VRS), and Adjective Scale (AS). All patients were interviewed in a semi-structured fashion to identify their preferences. Multiple statistical analyses were performed: test-retest reliability, internal consistency, and discriminant validity.Results. Twenty eligible patients were enrolled in the first phase and 59 in the second phase. The initial phase revealed the highest preference for one specific question format (60.0% and 86.7% after the first and second administration of the questionnaire, respectively). The second phase showed the VRS as the most preferred response format (35.6%). The semi-structured interviews revealed that overall, a subgroup of patients preferred a verbal response format (42.4%), and another group a numerical response format (49.1%). The statistical analysis showed good to excellent psychometric properties for all formats.Conclusions. The most preferred question and response formats were identified for use in a disease specific outcome instrument for spinal trauma patients.
[Show abstract][Hide abstract] ABSTRACT: International web-based survey.
To identify the most relevant aspects of human function and health status from the perspective of health care professionals involved in the treatment of spinal trauma patients.
There is no universally accepted outcome instrument available that is specifically designed or validated for spinal trauma patients, contributing to controversies related to the optimal treatment and evaluation of many types of spinal injuries. Therefore, the AOSpine Knowledge Forum Trauma aims to develop such an instrument using the International Classification of Functioning, Disability, and Health (ICF) as its basis.
Experts from the 5 AOSpine International world regions were asked to give their opinion on the relevance of a compilation of 143 ICF categories for spinal trauma patients on a 3-point scale: "not relevant," "probably relevant," or "definitely relevant." The responses were analyzed using frequency analysis. Possible differences in responses between the 5 world regions were analyzed with the Fisher exact test and descriptive statistics.
Of the 895 invited AOSpine International members, 150 (16.8%) participated in this study. A total of 13 (9.1%) ICF categories were identified as definitely relevant by more than 80% of the participants. Most of these categories were related to the ICF component "activities and participation" (n = 8), followed by "body functions" (n = 4), and "body structures" (n = 1). Only some minor regional differences were observed in the pattern of answers.
More than 80% of an international group of health care professionals experienced in the clinical care of adult spinal trauma patients indicated 13 of 143 ICF categories as definitely relevant to measure outcomes after spinal trauma. This study creates an evidence base to define a core set of ICF categories for outcome measurement in adult spinal trauma patients.Level of Evidence: N/A.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
European Spine Journal 12/2014; DOI:10.1007/s00586-014-3729-5 · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose To present a unique case of multilevel vertebral osteomyelitis after Lemierre syndrome. Methods A previously healthy 27-year-old man presented in the Emergency Department in septic shock because of Lemierre syndrome for which he was subsequently treated with intravenous benzylpenicillin for 2 months. Two and a half months later, the patient was readmitted with severe back pain without neurological deficits or fever. Imaging revealed an extensive vertebral osteomyelitis of the complete thoracic, lumbar and sacral spine. Results Although the blood cultures obtained at the initial admission for Lemierre syndrome revealed Fusobacterium species and Streptococcus milleri, the cultures from the spinal biopsies remained negative. Histology of the spinal biopsies showed a purulent sclerosing osteomyelitis. The patient was successfully treated with intravenous piperacillin and tazobactam. Despite persisting back pain, no recurrence of infection was seen at 3 years of follow-up. Conclusion Lemierre syndrome and an extensive thoracolumbosacral vertebral osteomyelitis are rare but serious infections. Clinicians must maintain a high index of suspicion for infectious metastases leading to vertebral osteomyelitis when a patient presents with back pain after an episode of life-threatening septicaemia caused by Lemierre syndrome.
European Spine Journal 09/2014; 24(S4). DOI:10.1007/s00586-014-3576-4 · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To develop a bio-assay for measuring long-term bioactivity of released anti-inflammatory compounds and to test the bioactivity of celecoxib (CXB) and triamcinolone acetonide (TA) released from a new PLGA-based microsphere platform.
Human osteoarthritic chondrocytes were plated according to standardized procedures after batch-wise harvest and cultured for 3 days to prevent cell confluency and changes in cell behaviour. Prostaglandin E2 (PGE2) production stimulated by TNFα was used as a parameter of inflammation. A novel microsphere platform based on PTE-functionalised PLGA was used to incorporate CXB and TA. Loaded microspheres were added to transwells overlying the cells, with transfer of the wells to new cell cultures every 3 days. Inhibition of PGE2 production was determined over a period of 21 days.
PLGA(75:25)-PTE microspheres were prepared and loaded with CXB and TA at 86 and 97% loading efficiency, respectively. In the bioactivity assay, PGE2 levels induced by TNFα were reduced to an average of 30% using microspheres loaded with 0.1 nmol CXB per transwell; with microspheres loaded with 0.1 nmol TA, PGE2 production was initially reduced to 3% and gradually recovered to 30% reduction. At 1 nmol loading, PGE2 was inhibited to 0-7% for CXB-loaded microspheres, and 0-28% for TA-loaded microspheres.
We present a novel sustained release bioactivity assay which provides an essential link between in vitro buffer-based release kinetics and in vivo application. Novel PLGA-based microspheres loaded with TA and CXB showed efficient anti-inflammatory effects over time.
Pharmaceutical Research 08/2014; 32(2). DOI:10.1007/s11095-014-1495-z · 3.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bone defect healing is highly dependent on the simultaneous stimulation of osteogenesis and vascularization. In bone regenerative strategies, combined seeding of multipotent stromal cells (MSCs) and endothelial progenitor cells (EPCs) proves their mutual stimulatory effects. Here, we investigated whether stromal cell-derived factor-1α (SDF-1α) stimulates vascularization by EPCs and whether SDF-1α could replace seeded cells in ectopic bone formation. Late EPCs of goat origin were characterized for their endothelial phenotype and showed to be responsive to SDF-1α in in vitro migration assays. Subsequently, subcutaneous implantation of Matrigel plugs that contained both EPCs and SDF-1α showed more tubule formation than constructs containing either EPCs or SDF-1α. Addition of either EPCs or SDF-1α to MSC-based constructs showed even more elaborate vascular networks after 1 week in vivo, with SDF-1α/MSC laden groups showing more prominent interconnected networks than EPC/MSC laden groups. The presence of abundant mouse specific CD31/PECAM-1 expression in these constructs confirmed ingrowth of murine vessels and discriminated between angiogenesis and vessel networks formed by seeded goat cells. Importantly, implantation of EPC/MSC or SDF-1α/MSC constructs resulted in indistinguishable ectopic bone formation. In both groups, bone onset was apparent at week 3 of implantation. Taken together, we demonstrated that SDF-1α stimulated the migration of EPCs in vitro and vascularization in vivo. Furthermore, SDF-1α addition was as effective as EPCs in inducing the formation of vascularized ectopic bone based on MSC seeded constructs, suggesting a cell replacement role for SDF-1α. These results hold promise for the design of larger cm-scale cell free vascular bone grafts.
Stem Cells and Development 07/2014; 23(24). DOI:10.1089/scd.2013.0560 · 3.73 Impact Factor