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Autologous mesenchymal stromal cells embedded in tricalcium phosphate for posterolateral spinal fusion: results of a prospective phase I/II clinical trial with long-term follow-up.

ABSTRACT: BACKGROUND:Posterolateral spinal fusion with autologous bone graft is considered the "gold standard" for lumbar degenerative disc disease (DDD) when surgical treatment is indicated. The potential role of mesenchymal stromal cells (MSCs) to replace the bone graft in this setting has not been fully addressed. OBJECTIVE:To analyze the safety, feasibility and potential clinical efficacy of the implantation of autologous MSCs embedded with tricalcium phosphate as a therapeutic alternative to bone graft in patients with DDD during posterolateral spine fusion. STUDY DESIGN:Phase I/II single-arm prospective clinical trial. METHODS:Eleven patients with monosegmental DDD at L4-L5 or L5-S1 level were included. Autologous bone marrow-derived MSC were expanded in our Good Manufacturing Practice (GMP) Facility and implanted during spinal surgery embedded in a tricalcium phosphate carrier. Monitoring of patients included a postoperative period of 12?months with four visits (after the 1st, 3rd, 6th, and 12th?month), with clinical and radiological assessment that included the visual analog scale (VAS), the Oswestry disability index (ODI), the Short-Form Health Survey (SF-36), the vertebral fusion grade observed through a simple Rx, and the evaluation of possible complications or adverse reactions. In addition, all patients were further followed up to 5?years for outcome. RESULTS:Median age of patients included was 44?years (range 30-58?years), and male/female ratio was (6/5) L4-L5 and L5-S1 DDD was present five and six patients, respectively. Autologous MSCs were expanded in all cases. There were no adverse effects related to cell implantation. Regarding efficacy, both VAS and ODI scores improved after surgery. Radiologically, 80% of patients achieved lumbar fusion at the end of the follow-up. No adverse effects related to the procedure were recorded. CONCLUSIONS:The use of autologous MSCs for spine fusion in patients with monosegmental degenerative disc disease is feasible, safe, and potentially effective. TRIAL REGISTRATION:no. EudraCT: 2010-018335-17 ; code Identifier: NCT01513694 ( clinicaltrials.gov ).

SUBMITTER: Blanco JF

PROVIDER: S-EPMC6387529 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Autologous mesenchymal stromal cells embedded in tricalcium phosphate for posterolateral spinal fusion: results of a prospective phase I/II clinical trial with long-term follow-up.

Blanco Juan F JF Villarón Eva M EM Pescador David D da Casa Carmen C Gómez Victoria V Redondo Alba M AM López-Villar Olga O López-Parra Miriam M Muntión Sandra S Sánchez-Guijo Fermín F

Stem cell research & therapy 20190222 1

<h4>Background</h4>Posterolateral spinal fusion with autologous bone graft is considered the "gold standard" for lumbar degenerative disc disease (DDD) when surgical treatment is indicated. The potential role of mesenchymal stromal cells (MSCs) to replace the bone graft in this setting has not been fully addressed.<h4>Objective</h4>To analyze the safety, feasibility and potential clinical efficacy of the implantation of autologous MSCs embedded with tricalcium phosphate as a therapeutic alternat ...[more]

PMID: 30795797

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Project description:Despite considerable research effort, there is a significant need for safe agents that stimulate bone formation. Treatment of large or complex bone defects remains a challenge. Implantation of small molecule-induced human bone marrow-derived mesenchymal stromal cells (hBMSCs) on an appropriate tricalcium phosphate (TCP) scaffold offers a robust system for noninvasive therapy for spinal fusion. To show the efficacy of this approach, we identified a small molecule curcuminoid that when combined with TCP ceramic in the presence of hBMSCs selectively induced growth of bone cells: after 8- or 25-day incubations, alkaline phosphatase was elevated. Treatment of hBMSCs with curcuminoid 1 and TCP ceramic increased osteogenic target gene expression (i.e., Runx2, BMP2, Osteopontin, and Osteocalcin) over time. In the presence of curcuminoid 1 and TCP ceramic, osteogenesis of hBMSCs, including proliferation, differentiation, and mineralization, was observed. No evidence of chondrogenic or adipogenic potential using this protocol was observed. Transplantation of curcuminoid 1-treated hBMSC/TCP mixtures into the spine of immunodeficient rats showed that it achieved spinal fusion and provided greater stability of the spinal column than untreated hBMSC-TCP implants or TCP alone implants. On the basis of histological analysis, greater bone formation was associated with curcuminoid 1-treated hBMSC implants manifested as contiguous growth plates with extensive hematopoietic territories. Stimulation of hBMSCs by administration of small molecule curcuminoid 1 in the presence of TCP ceramic afforded an effective noninvasive strategy that increased spinal fusion repair and provided greater stability of the spinal column after 8 weeks in immunodeficient rats. Impact statement Bone defects only slowly regenerate themselves in humans. Current procedures to restore spinal defects are not always effective. Some have side effects. In this article, a new method to produce bone growth within 8 weeks in rats is presented. In the presence of tricalcium phosphate ceramic, curcuminoid-1 small molecule-stimulated human bone marrow-derived mesenchymal stromal cells showed robust bone cell growth in vitro. Transplantation of this mixture into the spine showed efficient spinal fusion in rats. The approach presented herein provides an efficient biocompatible scaffold for delivery of a potentially clinically useful system that could be applicable in patients.

Project description:Remodeling of the human bony skeleton is constantly occurring with up to 10% annual bone volume turnover from osteoclastic and osteoblastic activity. A shift toward resorption can result in osteoporosis and pathologic fractures, while a shift toward deposition is required after traumatic, or surgical injury. Spinal fusion represents one such state, requiring a substantial regenerative response to immobilize adjacent vertebrae through bony union. Autologous bone grafts were used extensively prior to the advent of advanced therapeutics incorporating exogenous growth factors and biomaterials. Besides cost constraints, these applications have demonstrated patient safety concerns. This study evaluated the regenerative ability of a nanostructured, magnesium-doped, hydroxyapatite/type I collagen scaffold (MHA/Coll) augmented by autologous platelet-rich plasma (PRP) in an orthotopic model of posterolateral lumbar spinal fusion. After bilateral decortication, rabbits received either the scaffold alone (Group 1) or scaffold with PRP (Group 2) to the anatomic right side. Bone regeneration and fusion success compared to internal control were assessed by DynaCT with 3-D reconstruction at 2, 4, and 6 weeks postoperatively followed by comparative osteogenic gene expression and representative histopathology. Both groups formed significantly more new bone volume than control, and Group 2 subjects produced significantly more trabecular and cortical bone than Group 1 subjects. Successful fusion was seen in one Group 1 animal (12.5%) and 6/8 Group 2 animals (75%). This enhanced effect by autologous PRP treatment appears to occur via astounding upregulation of key osteogenic genes. Both groups demonstrated significant gene upregulation compared to vertebral bone controls for all genes. Group 1 averaged 2.21-fold upregulation of RUNX2 gene, 3.20-fold upregulation of SPARC gene, and 3.67-fold upregulation of SPP1 gene. Depending on anatomical subgroup (cranial, mid, caudal scaffold portions), Group 2 had significantly higher average expression of all genes than both control and Group 1-RUNX2 (8.23-19.74 fold), SPARC (18.67-55.44 fold), and SPP1 (46.09-90.65 fold). Our data collectively demonstrate the osteoinductive nature of a nanostructured MHA/Coll scaffold, a beneficial effect of augmentation with autologous PRP, and an ability to achieve clinical fusion when applied together in an orthotopic model. This has implications both for future study and biomedical innovation of bone-forming therapeutics.

Project description:STUDY DESIGN:Two-year clinical and radiographic follow-up of a double-blind, multicenter, randomized, intra-patient controlled, non-inferiority trial comparing a bone graft substitute (AttraX Putty) with autograft in instrumented posterolateral fusion (PLF) surgery. OBJECTIVES:The aim of this study was to compare PLF rates between 1 and 2 years of follow-up and between graft types, and to explore the role of bone grafting based on the location of the PLF mass. SUMMARY OF BACKGROUND DATA:There are indications that bony fusion proceeds over time, but it is unknown to what extent this can be related to bone grafting. METHODS:A total of 100 adult patients underwent a primary, single- or multilevel, thoracolumbar PLF. After instrumentation and preparation for grafting, the randomized allocation side of AttraX Putty was disclosed. The contralateral posterolateral gutters were grafted with autograft. At 1-year follow-up, and in case of no fusion at 2 years, the fusion status of both sides of each segment was blindly assessed on CT scans. Intertransverse and facet fusion were scored separately. Difference in fusion rates after 1 and 2 years and between grafts were analyzed with a Generalized Estimating Equations (GEE) model (P?<?0.05). RESULTS:The 2-year PLF rate (66 patients) was 70% at the AttraX Putty and 68% at the autograft side, compared to 55% and 52% after 1 year (87 patients). GEE analysis demonstrated a significant increase for both conditions (odds ratio 2.0, 95% confidence interval 1.5-2.7, P?<?0.001), but no difference between the grafts (P?=?0.595). Ongoing bone formation was only observed between the facet joints. CONCLUSION:This intra-patient controlled trial demonstrated a significant increase in PLF rate between 1 and 2 years after instrumented thoracolumbar fusion, but no difference between AttraX Putty and autograft. Based on the location of the PLF mass, this increase is most likely the result of immobilization instead of grafting. LEVEL OF EVIDENCE:1.

Dataset Information

Autologous mesenchymal stromal cells embedded in tricalcium phosphate for posterolateral spinal fusion: results of a prospective phase I/II clinical trial with long-term follow-up.

Publications

Autologous mesenchymal stromal cells embedded in tricalcium phosphate for posterolateral spinal fusion: results of a prospective phase I/II clinical trial with long-term follow-up.

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