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1
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Wang D, Qi G, Zhang M, Carlson B, Gernon M, Burton D, Sun XS, Wang J. Peptide Hydrogel for Sustained Release of Recombinant Human Bone Morphogenetic Protein-2 In Vitro. J Funct Biomater 2024; 15:369. [PMID: 39728169 DOI: 10.3390/jfb15120369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/18/2024] [Accepted: 12/03/2024] [Indexed: 12/28/2024] Open
Abstract
This study aimed to investigate the impact of varying the formulation of a specific peptide hydrogel (PepGel) on the release kinetics of rhBMP-2 in vitro. Three PepGel formulations were assessed: (1) 50% v/v (peptides volume/total volume) PepGel, where synthetic peptides were mixed with crosslinking reagents and rhBMP-2 solution; (2) 67% v/v PepGel; (3) 80% v/v PepGel. Each sample was loaded with 12 µg of rhBMP-2 and incubated in PBS. Released rhBMP-2 was quantified by ELISA at 1 h, 6 h, and 1, 2, 4, 7, 10, 14, and 21 days. To explore how PepGel formulations influence rhBMP-2 release, the gel porosities, swelling ratios, and mechanical properties of the three PepGel formulations were quantitatively analyzed. The results showed that rhBMP-2 encapsulated with 50% v/v PepGel exhibited a sustained release over the 21-day experiment, while the 67% and 80% v/v PepGels demonstrated significantly lower rhBMP-2 release rates compared to the 50% formulation after day 7. Higher histological porosity of PepGel was significantly correlated with increased rhBMP-2 release rates. Conversely, the swelling ratio and elastic modulus of the 50% v/v PepGel were significantly lower than that of the 67% and 80% v/v formulations. In conclusion, this study indicates that varying the formulation of crosslinked PepGel can control rhBMP-2 release rates in vitro by modulating gel porosity, swelling ratio, and mechanical properties. Encapsulation with 50% v/v PepGel offers a sustained rhBMP-2 release pattern in vitro; if replicated in vivo, this could mitigate the adverse effects associated with burst release of rhBMP-2 in clinical applications.
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Affiliation(s)
- Dalin Wang
- Department of Orthopedic Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Guangyan Qi
- Department of Biological and Agricultural Engineering, Kansas State University, Seaton Hall, 919 Mid-Campus Drive North, Manhattan, KS 66506, USA
| | - Mingcai Zhang
- Department of Orthopedic Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Brandon Carlson
- Department of Orthopedic Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Matthew Gernon
- Department of Orthopedic Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Douglas Burton
- Department of Orthopedic Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Xiuzhi Susan Sun
- Department of Biological and Agricultural Engineering, Kansas State University, Seaton Hall, 919 Mid-Campus Drive North, Manhattan, KS 66506, USA
| | - Jinxi Wang
- Department of Orthopedic Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
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Von Benecke JP, Tarsitano E, Zimmermann LMA, Shakesheff KM, Walsh WR, Bae HW. A Narrative Review on Recombinant Human Bone Morphogenetic Protein 2: Where Are We Now? Cureus 2024; 16:e67785. [PMID: 39188335 PMCID: PMC11346822 DOI: 10.7759/cureus.67785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/25/2024] [Indexed: 08/28/2024] Open
Abstract
Spinal fusion is a prevalent surgical intervention for degenerative spinal diseases, with increasing demand driven by ageing populations. The coexistence of multiple chronic conditions, termed multimorbidity, often complicates surgical outcomes, making advanced bone grafts crucial for successful fusions. This paper reviews the development, clinical application, and controversies surrounding the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion surgeries. A comprehensive narrative review was conducted, focusing on literature from January 1980 to January 2024, sourced from PubMed and Google Scholar. Studies included those examining rhBMP-2 specifically in spinal fusion contexts, excluding other bone morphogenetic proteins (BMPs) and non-spinal applications. This review presents an overarching synopsis of rhBMP-2, its development history and clinical efficacy, the emergence of side effects, and evolving patterns of clinical use. As discussed in this review, clinical practice has adjusted usage and dosages to mitigate adverse effects, yet the need for safer delivery mechanisms persists. rhBMP-2 remains a potent osteoinductive agent with comparable fusion success, as measured by radiographic fusion and good clinical outcomes, to autologous grafts but poses unique risks. This review sets out how further research is essential to optimise the delivery of rhBMP-2 to reduce side effects. Enhanced understanding and innovation of spatio-temporal presentation relative to endogenous BMP could significantly improve patient outcomes in spinal fusion surgeries. The review contributes to the growing body of literature on the use of rhBMP-2 in spine surgery and discusses changing patterns of clinical use over time.
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Affiliation(s)
| | | | | | | | - William R Walsh
- School of Clinical Medicine, Prince of Wales Clinical School, University of New South Wales, Syndey, AUS
| | - Hyun W Bae
- Orthopaedics, Cedars-Sinai Medical Center, Los Angeles, USA
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3
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Fujibayashi S, Takemoto M, Ishii K, Funao H, Isogai N, Otsuki B, Shimizu T, Nakamura T, Matsuda S. Multicenter Prospective Study of Lateral Lumbar Interbody Fusions Using Bioactive Porous Titanium Spacers without Bone Grafts. Asian Spine J 2022; 16:890-897. [PMID: 36470243 PMCID: PMC9827197 DOI: 10.31616/asj.2021.0354] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/08/2021] [Indexed: 12/07/2022] Open
Abstract
STUDY DESIGN Prospective multicenter clinical study. PURPOSE To evaluate the efficacy of bioactive surface treatment for porous titanium spacers without bone graft for lateral lumbar interbody fusion (LLIF) through clinical and radiological examinations. OVERVIEW OF LITERATURE LLIF is a minimally invasive spinal fusion procedure. To achieve bony union, a substantial volume of grafted bone is typically packed into the cage; however, this is related to donor site morbidities-one of the disadvantages of LLIF. METHODS For this prospective multicenter study, 40 patients were followed up through radiologic and clinical examinations for at least 1 year postoperatively. All surgical procedures were either single- or double-level LLIF using bioactive porous titanium spacers without bone grafts. RESULTS Four patients were excluded from the study owing to aggravation from other comorbidities. Another 36 patients, including 26 and 10 with single- and double-level LLIFs, respectively, participated in the follow-up. The mean age at the time of surgery was 63.7 years. The mean operating time was 50.5 minutes per level. The mean estimated intraoperative blood loss was 11.6 mL per level. Clinical scores improved in all cases and were maintained throughout the follow-up period. The intervertebral bony union rates were 67.4% and 84.8% at 6 and 12 months, respectively. Endplate cyst signs were observed in 13.0% and 8.7% of patients at 6 and 12 months, respectively. Fused segmental angles were maintained throughout the follow-up period, indicating no cage subsidence. CONCLUSIONS Single- and double-level LLIFs using bioactive porous titanium spacers without bone grafts were found to be minimally invasive, resulting in clinical and imaging results comparable with conventional procedures. Therefore, this type of implant may be an option for minimally invasive spinal fusion surgery.
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Affiliation(s)
- Shunsuke Fujibayashi
- Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto,
Japan
| | - Mitsuru Takemoto
- Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto,
Japan,Department of Orthopaedic Surgery, Kyoto City Hospital, Kyoto,
Japan
| | - Ken Ishii
- Department of Orthopaedic Surgery, International University of Health and Welfare Mita Hospital, Tokyo,
Japan,Department of Orthopaedic Surgery, School of Medicine, International University of Health and Welfare, Narita,
Japan
| | - Haruki Funao
- Department of Orthopaedic Surgery, International University of Health and Welfare Mita Hospital, Tokyo,
Japan,Department of Orthopaedic Surgery, School of Medicine, International University of Health and Welfare, Narita,
Japan
| | - Norihiro Isogai
- Department of Orthopaedic Surgery, International University of Health and Welfare Mita Hospital, Tokyo,
Japan
| | - Bungo Otsuki
- Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto,
Japan
| | - Takayoshi Shimizu
- Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto,
Japan
| | - Takashi Nakamura
- Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto,
Japan
| | - Shuichi Matsuda
- Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto,
Japan
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Cleemann R, Sorensen M, West A, Soballe K, Bechtold JE, Baas J. Augmentation of implant surfaces with BMP-2 in a revision setting : effects of local and systemic bisphosphonate. Bone Joint Res 2021; 10:488-497. [PMID: 34346256 PMCID: PMC8414437 DOI: 10.1302/2046-3758.108.bjr-2020-0280.r1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
AIMS We wanted to evaluate the effects of a bone anabolic agent (bone morphogenetic protein 2 (BMP-2)) on an anti-catabolic background (systemic or local zoledronate) on fixation of allografted revision implants. METHODS An established allografted revision protocol was implemented bilaterally into the stifle joints of 24 canines. At revision surgery, each animal received one BMP-2 (5 µg) functionalized implant, and one raw implant. One group (12 animals) received bone graft impregnated with zoledronate (0.005 mg/ml) before impaction. The other group (12 animals) received untreated bone graft and systemic zoledronate (0.1 mg/kg) ten and 20 days after revision surgery. Animals were observed for an additional four weeks before euthanasia. RESULTS No difference was detected on mechanical implant fixation (load to failure, stiffness, energy) between local or systemic zoledronate. Addition of BMP-2 had no effect on implant fixation. In the histomorphometric evaluation, implants with local zoledronate had more area of new bone on the implant surface (53%, p = 0.025) and higher volume of allograft (65%, p = 0.007), whereas implants in animals with systemic zoledronate had the highest volume of new bone (34%, p = 0.003). Systemic zoledronate with BMP-2 decreased volume of allograft by 47% (p = 0.017). CONCLUSION Local and systemic zoledronate treatment protects bone at different stages of maturity; local zoledronate protects the allograft from resorption and systemic zoledronate protects newly formed bone from resorption. BMP-2 in the dose evaluated with experimental revision implants was not beneficial, since it significantly increased allograft resorption without a significant compensating anabolic effect. Cite this article: Bone Joint Res 2021;10(8):488-497.
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Affiliation(s)
- Rasmus Cleemann
- Orthopedics, Zealand University Hospital Koge, Køge, Denmark.,Orthopedic Research Laboratory, Aarhus University Hospital, Aarhus, Denmark.,Orthopedics, Elective Surgery Center - Silkeborg Regional Hospital, Silkeborg, Denmark
| | - Mette Sorensen
- Orthopedic Research Laboratory, Aarhus University Hospital, Aarhus, Denmark.,Orthopedics, Aalborg University Hospital, Aalborg, Denmark
| | - Andreas West
- Orthopedics, Regionshospitalet Horsens, Horsens, Denmark
| | - Kjeld Soballe
- Orthopedic Research Laboratory, Aarhus University Hospital, Aarhus, Denmark.,Orthopedics, Aarhus University Hospital Skejby, Aarhus, Denmark
| | - Joan E Bechtold
- Department of Orthopedic Surgery, Hennepin Healthcare Research Institute, Minneapolis Medical Research Foundation, Orthopedic Biomechanics Laboratory, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jorgen Baas
- Orthopedic Research Laboratory, Aarhus University Hospital, Aarhus, Denmark.,Orthopedics, Aarhus University Hospital Skejby, Aarhus, Denmark
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Barker AJ, Arthur A, DeNichilo MO, Panagopoulos R, Gronthos S, Anderson PJ, Zannettino AC, Evdokiou A, Panagopoulos V. Plant-derived soybean peroxidase stimulates osteoblast collagen biosynthesis, matrix mineralization, and accelerates bone regeneration in a sheep model. Bone Rep 2021; 14:101096. [PMID: 34136591 PMCID: PMC8178086 DOI: 10.1016/j.bonr.2021.101096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 04/29/2021] [Accepted: 05/21/2021] [Indexed: 02/08/2023] Open
Abstract
Bone defects arising from fractures or disease represent a significant problem for surgeons to manage and are a substantial economic burden on the healthcare economy. Recent advances in the development of biomaterial substitutes provides an attractive alternative to the current "gold standard" autologous bone grafting. Despite on-going research, we are yet to identify cost effective biocompatible, osteo-inductive factors that stimulate controlled, accelerated bone regeneration.We have recently reported that enzymes with peroxidase activity possess previously unrecognised roles in extracellular matrix biosynthesis, angiogenesis and osteoclastogenesis, which are essential processes in bone remodelling and repair. Here, we report for the first time, that plant-derived soybean peroxidase (SBP) possesses pro-osteogenic ability by promoting collagen I biosynthesis and matrix mineralization of human osteoblasts in vitro. Mechanistically, SBP regulates osteogenic genes responsible for inflammation, extracellular matrix remodelling and ossification, which are necessary for normal bone healing. Furthermore, SBP was shown to have osteo-inductive properties, that when combined with commercially available biphasic calcium phosphate (BCP) granules can accelerate bone repair in a critical size long bone defect ovine model. Micro-CT analysis showed that SBP when combined with commercially available biphasic calcium phosphate (BCP) granules significantly increased bone formation within the defects as early as 4 weeks compared to BCP alone. Histomorphometric assessment demonstrated accelerated bone formation prominent at the defect margins and surrounding individual BCP granules, with evidence of intramembranous ossification. These results highlight the capacity of SBP to be an effective regulator of osteoblastic function and may be beneficial as a new and cost effective osteo-inductive agent to accelerate repair of large bone defects.
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Affiliation(s)
- Alexandra J. Barker
- Musculoskeletal Biology Research Laboratory, Clinical and Health Sciences, University of South Australia, Adelaide, Australia
| | - Agnes Arthur
- Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Mark O. DeNichilo
- Centre for Cancer Biology, University of South Australia, Adelaide, Australia
| | - Romana Panagopoulos
- Breast Cancer Research Unit, School of Medicine, Discipline of Surgery and Orthopaedics, Basil Hetzel Institute, University of Adelaide, Adelaide, Australia
| | - Stan Gronthos
- Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Peter J. Anderson
- Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
- Centre for Cancer Biology, University of South Australia, Adelaide, Australia
- Australian Craniofacial Unit, Women's and Children's Hospital, Department of Paediatrics and Dentistry, University of Adelaide, Adelaide, Australia
- Central Adelaide Local Health Network, Adelaide, Australia
| | - Andrew C.W. Zannettino
- Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, Australia
- Department of Haematology, Royal Adelaide Hospital, Adelaide, Australia
- Central Adelaide Local Health Network, Adelaide, Australia
| | - Andreas Evdokiou
- Breast Cancer Research Unit, School of Medicine, Discipline of Surgery and Orthopaedics, Basil Hetzel Institute, University of Adelaide, Adelaide, Australia
| | - Vasilios Panagopoulos
- Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
- Breast Cancer Research Unit, School of Medicine, Discipline of Surgery and Orthopaedics, Basil Hetzel Institute, University of Adelaide, Adelaide, Australia
- Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, Australia
- Corresponding author at: Myeloma Research Laboratory, Level 5 South, South Australian Health and Medical Research Institute, Adelaide SA 500, Australia.
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Wu C, Shao X, Lin X, Gao W, Fang Y, Wang J. Surface modification of titanium with collagen/hyaluronic acid and bone morphogenetic protein 2/7 heterodimer promotes osteoblastic differentiation. Dent Mater J 2020; 39:1072-1079. [PMID: 33028783 DOI: 10.4012/dmj.2019-249] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The aim of this study was to evaluate the effects of a collagen/hyaluronic acid coating without or with incorporated heterodimeric bone morphogenetic protein 2/7 (BMP2/7) on in-vitro osteoblastic differentiation on titanium discs. The multilayer collagen/hyaluronic acid coatings without or without incorporated BMP2/7 were deposited on titanium discs via a layer-by-layer technique. The effects of the coatings were evaluated by assessing the alkaline phosphatase (ALP) activity (an early osteoblastic differentiation marker) and the osteocalcin expression (a late osteoblastic differentiation marker). The expression levels of the osteoblastic genes, such as alkaline phosphatase 2 (AKP2) and osteocalcin (OC) were detected using real-time RT-PCR. ALP activity and OC expression were significantly increased when cells were cultured with collagen/hyaluronic acid+BMP2/7 heterodimer (p<0.05). The same result was found in cells with the expression of a BMP2/7 fusion gene, OC and AKP2. These results indicated that collagen/hyaluronic acid+BMP2/7 heterodimer-coated discs might have the potential to greatly enhance osseointegration than a either BMP2 or BMP7 solution or a mixture of BMP2 and BMP7 BMP2/7.
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Affiliation(s)
- Chengzhong Wu
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Wenzhou Medical University
| | - Xia Shao
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Wenzhou Medical University
| | - Xianglin Lin
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Wenzhou Medical University
| | - Weijin Gao
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Wenzhou Medical University
| | - Yiming Fang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Wenzhou Medical University
| | - Jingxiao Wang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Wenzhou Medical University
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7
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Okada R, Kaito T, Ishiguro H, Kushioka J, Otsuru S, Kanayama S, Bal Z, Kitaguchi K, Hashimoto K, Makino T, Takenaka S, Sakai Y, Yoshikawa H. Assessment of effects of rhBMP-2 on interbody fusion with a novel rat model. Spine J 2020; 20:821-829. [PMID: 31901554 DOI: 10.1016/j.spinee.2019.12.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 12/19/2019] [Accepted: 12/20/2019] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT The effects of using off-label recombinant human bone morphogenetic protein (rhBMP)-2 for interbody fusion are controversial. Although animal models of posterolateral fusion are well-established, establishing animal models to validate the safety and efficacy of interbody fusion is difficult, which may contribute to the inconsistent clinical results. PURPOSE To develop a novel animal model of interbody fusion in rat coccygeal vertebrae without destroying bony endplates. STUDY DESIGN An experimental animal study. METHODS Forty-five male Sprague-Dawley rats underwent coccygeal interbody fusion without violating vertebral endplates. The animals were divided into three different groups based on the materials that were implanted into the interbody space (1) allogeneic iliac bone (IB) alone (IB group), (2) IB and 3 µg of rhBMP-2 (BMP low-dose group), or (3) IB and 10 µg of rhBMP-2 (BMP high-dose group). Fusion rates were investigated using microcomputed tomography 6 weeks after the operation. The incidence of adverse events, including soft-tissue swelling, delayed wound healing, osteolysis, and ectopic bone formation were evaluated. The total number of adverse events (using the adverse event score) in each group and the swelling ratio (calculated using the surgical site tissue volume [TV; TV on postoperative day 1/preoperative TV]) were also evaluated. RESULTS The fusion rates in the BMP low- and high-dose groups (33.3% and 46.7%) were not significantly different, but both were significantly higher than that in the IB group (0%) (p=.042 and .006, respectively). Significant differences in the incidence of osteolysis, adverse event scores, and swelling ratios were observed only between the BMP high-dose and IB groups (p=.043, .006 and .014, respectively). CONCLUSIONS We developed a novel rat model of interbody fusion in which the vertebral endplates were not violated, reflecting the normal clinical setting. rhBMP-2 use increased the fusion rate, but a higher dose of rhBMP-2 did not lead to a higher fusion rate than that for low-dose rhBMP-2; conversely, it led to an increase in the occurrence of adverse events. CLINICAL SIGNIFICANCE This novel rat model of coccygeal interbody fusion that preserved bony endplates has clinical significance for validating the effectiveness of biologics or bone graft substitutes before clinical trial.
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Affiliation(s)
- Rintaro Okada
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan
| | - Takashi Kaito
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.
| | - Hiroyuki Ishiguro
- Department of Orthopedic Surgery, National Hospital Organization, Osaka National Hospital, Osaka, Japan
| | - Junichi Kushioka
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan
| | - Satoru Otsuru
- Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Sadaaki Kanayama
- Department of Orthopedic Surgery, Ikeda Municipal Hospital, Ikeda, Osaka, Japan
| | - Zeynep Bal
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan
| | - Kazuma Kitaguchi
- Department of Orthopedic Surgery, Toyonaka Municipal Hospital, Toyonaka, Osaka, Japan
| | | | - Takahiro Makino
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan
| | - Shota Takenaka
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan
| | - Yusuke Sakai
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan
| | - Hideki Yoshikawa
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan
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8
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Ion R, Necula MG, Mazare A, Mitran V, Neacsu P, Schmuki P, Cimpean A. Drug Delivery Systems Based on Titania Nanotubes and Active Agents for Enhanced Osseointegration of Bone Implants. Curr Med Chem 2020; 27:854-902. [PMID: 31362646 DOI: 10.2174/0929867326666190726123229] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 01/16/2019] [Accepted: 05/04/2019] [Indexed: 12/31/2022]
Abstract
TiO2 nanotubes (TNTs) are attractive nanostructures for localized drug delivery. Owing to their excellent biocompatibility and physicochemical properties, numerous functionalizations of TNTs have been attempted for their use as therapeutic agent delivery platforms. In this review, we discuss the current advances in the applications of TNT-based delivery systems with an emphasis on the various functionalizations of TNTs for enhancing osteogenesis at the bone-implant interface and for preventing implant-related infection. Innovation of therapies for enhancing osteogenesis still represents a critical challenge in regeneration of bone defects. The overall concept focuses on the use of osteoconductive materials in combination with the use of osteoinductive or osteopromotive factors. In this context, we highlight the strategies for improving the functionality of TNTs, using five classes of bioactive agents: growth factors (GFs), statins, plant derived molecules, inorganic therapeutic ions/nanoparticles (NPs) and antimicrobial compounds.
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Affiliation(s)
- Raluca Ion
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Madalina Georgiana Necula
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Anca Mazare
- University of Erlangen-Nuremberg, Department of Materials Science, Erlangen, Germany
| | - Valentina Mitran
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Patricia Neacsu
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Patrik Schmuki
- University of Erlangen-Nuremberg, Department of Materials Science, Erlangen, Germany
| | - Anisoara Cimpean
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
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9
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Atienza-Roca P, Kieser DC, Cui X, Bathish B, Ramaswamy Y, Hooper GJ, Clarkson AN, Rnjak-Kovacina J, Martens PJ, Wise LM, Woodfield TBF, Lim KS. Visible light mediated PVA-tyramine hydrogels for covalent incorporation and tailorable release of functional growth factors. Biomater Sci 2020; 8:5005-5019. [DOI: 10.1039/d0bm00603c] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
PVA-Tyr hydrogel facilitated covalent incorporation can control release of pristine growth factors while retaining their native bioactivity.
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Affiliation(s)
- Pau Atienza-Roca
- Department of Orthopaedic Surgery
- University of Otago Christchurch
- Christchurch 8011
- New Zealand
| | - David C. Kieser
- Department of Orthopaedic Surgery
- University of Otago Christchurch
- Christchurch 8011
- New Zealand
| | - Xiaolin Cui
- Department of Orthopaedic Surgery
- University of Otago Christchurch
- Christchurch 8011
- New Zealand
| | - Boushra Bathish
- Department of Orthopaedic Surgery
- University of Otago Christchurch
- Christchurch 8011
- New Zealand
| | - Yogambha Ramaswamy
- School of Biomedical Engineering
- University of Sydney
- Sydney 2006
- Australia
| | - Gary J. Hooper
- Department of Orthopaedic Surgery
- University of Otago Christchurch
- Christchurch 8011
- New Zealand
| | - Andrew N. Clarkson
- Department of Anatomy
- Brain Health Research Centre and Brain Research New Zealand
- University of Otago
- Dunedin 9054
- New Zealand
| | | | - Penny J. Martens
- Graduate School of Biomedical Engineering
- UNSW Sydney
- Sydney 2052
- Australia
| | - Lyn M. Wise
- Department of Pharmacology and Toxicology
- University of Otago
- New Zealand
| | - Tim B. F. Woodfield
- Department of Orthopaedic Surgery
- University of Otago Christchurch
- Christchurch 8011
- New Zealand
| | - Khoon S. Lim
- Department of Orthopaedic Surgery
- University of Otago Christchurch
- Christchurch 8011
- New Zealand
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10
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Kakuta A, Tanaka T, Chazono M, Komaki H, Kitasato S, Inagaki N, Akiyama S, Marumo K. Effects of micro-porosity and local BMP-2 administration on bioresorption of β-TCP and new bone formation. Biomater Res 2019; 23:12. [PMID: 31372237 PMCID: PMC6660686 DOI: 10.1186/s40824-019-0161-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 07/17/2019] [Indexed: 01/19/2023] Open
Abstract
Background It has been reported that the microporous structure of calcium phosphate (CaP) ceramics is important to osteoconduction. Bone morphogenetic protein-2 (BMP-2) has been shown to be a promising alternative to bone grafting and a therapeutic agent promoting bone regeneration when delivered locally. The aim of this study was to evaluate the effects of micro-porosity within beta-tricalcium phosphate (β-TCP) cylinders and local BMP-2 administration on β-TCP resorption and new bone formation. Methods Bilateral cylindrical bone defects were created in rabbit distal femora, and the defects were filled with β-TCP. Rabbits were divided into 3 groups; defects were filled with a β-TCP cylinder with a total of approximately 60% porosity (Group A: 13.4% micro- and 46.9% macropore, Group B: 38.5% micro- and 20.3% macropore, Group C: the same micro- and macro-porosity as in group B supplemented with BMP-2). Rabbits were sacrificed 4, 8, 12, and 24 weeks postoperatively. Results The number of TRAP-positive cells and new bone formation in group B were significantly greater than those in group A at every period. The amount of residual β-TCP in group C was less than that in group B at all time periods, resulting in significantly more new bone formation in group C at 8 and 12 weeks. The number of TRAP-positive cells in group C was maximum at 4 weeks. Conclusions These results suggest that the amount of submicron microporous structure and local BMP-2 administration accelerated both osteoclastic resorption of β-TCP and new bone formation, probably through a coupling-like phenomenon between resorption and new bone formation.
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Affiliation(s)
- Atsuhito Kakuta
- 1Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-0003 Japan
| | - Takaaki Tanaka
- 1Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-0003 Japan.,Department of Orthopaedic Surgery, NHO Utsunomiya National Hospital, 2160 Shimo-Okamoto, Utsunomiya City, Tochigi 329-1193 Japan
| | - Masaaki Chazono
- 1Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-0003 Japan.,Department of Orthopaedic Surgery, NHO Utsunomiya National Hospital, 2160 Shimo-Okamoto, Utsunomiya City, Tochigi 329-1193 Japan
| | - Hirokazu Komaki
- 1Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-0003 Japan
| | - Seiichiro Kitasato
- 1Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-0003 Japan
| | - Naoya Inagaki
- 1Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-0003 Japan
| | - Shoshi Akiyama
- 1Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-0003 Japan
| | - Keishi Marumo
- 1Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-0003 Japan
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11
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Injectable chitosan/β-glycerophosphate hydrogels with sustained release of BMP-7 and ornidazole in periodontal wound healing of class III furcation defects. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 99:919-928. [DOI: 10.1016/j.msec.2019.02.024] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 01/21/2019] [Accepted: 02/06/2019] [Indexed: 12/11/2022]
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12
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Miao C, Qin D, Cao P, Lu P, Xia Y, Li M, Sun M, Zhang W, Yang F, Zhang Y, Tang S, Liu T, Liu F. BMP2/7 heterodimer enhances osteogenic differentiation of rat BMSCs via ERK signaling compared with respective homodimers. J Cell Biochem 2019; 120:8754-8763. [PMID: 30485526 DOI: 10.1002/jcb.28162] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Accepted: 11/05/2018] [Indexed: 01/24/2023]
Abstract
Bone morphogenetic protein (BMP)2/7 heterodimer shows greater efficacy in enhancing bone regeneration. However, the precise mechanism and the role of mitogen-activated protein kinase (MAPK) signaling network in BMP2/7-driven osteogenesis remain ambiguous. In this study, we evaluated the effects of BMP2/7 heterodimers on osteoblastic differentiation in rat bone marrow mesenchymal stem cells (BMSCs), with the aim to elaborate how MAPKs might be involved in this cellular process by treatment of rat BMSCs with BMP2/-7 with a special signal-pathway inhibitor. We found that BMP2/7 heterodimer induced a much stronger osteogenic response in rat BMSCs compared with either homodimer. Most interestingly, extracellular signal-regulated kinase (ERK) demonstrated a highly sustained phosphorylation and activation in the BMP2/7 heterodimer treatment groups, and inhibition of ERK cascades using U0126 special inhibitor that significantly reduced the activity of ALP and calcium mineralization to a substantial degree in rat BMSCs treated with BMP2/7 heterodimers. Collectively, we demonstrate that BMP2/7 heterodimer shows a potent ability to stimulate osteogenesis in rat BMSCs. The activated ERK signaling pathway involved in this process may contribute partially to an increased osteogenic potency of heterodimeric BMP2/7 growth factors.
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Affiliation(s)
- Chunlei Miao
- Division of Plastic Surgery, Institute of Plastic and Reconstructive Surgery, Hospital for Plastic Surgery, Weifang Medical University, Weifang, Shandong, China
| | - Dengke Qin
- Department of Plastic and Cosmetic Surgery, HuaDong Hospital, Fudan University, Shanghai, China
| | - Peigang Cao
- Department of Stomatology, Weifang People's hospital, Weifang, Shandong, China
| | - Ping Lu
- Department of Obstetrics and Gynecology, Zhucheng People's Hospital, Zhucheng, Shandong, China
| | - Yutong Xia
- Department of Plastic and Cosmetic Surgery, HuaDong Hospital, Fudan University, Shanghai, China.,Department of Academic Support, Shanghai Pinghe School, Shanghai, China
| | - Mengjiao Li
- Division of Plastic Surgery, Institute of Plastic and Reconstructive Surgery, Hospital for Plastic Surgery, Weifang Medical University, Weifang, Shandong, China
| | - Miao Sun
- Division of Plastic Surgery, Institute of Plastic and Reconstructive Surgery, Hospital for Plastic Surgery, Weifang Medical University, Weifang, Shandong, China
| | - Wei Zhang
- Division of Plastic Surgery, Institute of Plastic and Reconstructive Surgery, Hospital for Plastic Surgery, Weifang Medical University, Weifang, Shandong, China
| | - Fanghong Yang
- Department of Stomatology, Weifang People's hospital, Weifang, Shandong, China
| | - Yingjie Zhang
- Division of Research & Development, Eugenom Inc, San Diego, CA
| | - Shengjian Tang
- Division of Plastic Surgery, Institute of Plastic and Reconstructive Surgery, Hospital for Plastic Surgery, Weifang Medical University, Weifang, Shandong, China
| | - Tianyi Liu
- Department of Plastic and Cosmetic Surgery, HuaDong Hospital, Fudan University, Shanghai, China
| | - Fangjun Liu
- Division of Plastic Surgery, Institute of Plastic and Reconstructive Surgery, Hospital for Plastic Surgery, Weifang Medical University, Weifang, Shandong, China
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13
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Sebastian AS, Wanderman NR, Currier BL, Pichelmann MA, Treder VM, Fogelson JL, Clarke MJ, Nassr AN. Prospective Evaluation of Radiculitis following Bone Morphogenetic Protein-2 Use for Transforaminal Interbody Arthrodesis in Spine Surgery. Asian Spine J 2019; 13:544-555. [PMID: 30866616 PMCID: PMC6680045 DOI: 10.31616/asj.2018.0277] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 12/13/2018] [Indexed: 11/30/2022] Open
Abstract
Study Design Prospective observational cohort study. Purpose This study aims to evaluate the safety and efficacy of bone morphogenetic protein-2 (BMP-2) in transforaminal lumbar interbody fusion (TLIF) with regard to postoperative radiculitis. Overview of Literature Bone morphogenetic protein (BMP) is being used increasingly as an alternative to iliac crest autograft in spinal arthrodesis. Recently, the use of BMP in TLIF has been examined, but concerns exist that the placement of BMP close to the nerve roots may cause postoperative radiculitis. Furthermore, prospective studies regarding the use of BMP in TLIF are lacking. Methods This prospective study included 77 patients. The use of BMP-2 was determined individually, and demographic and operative characteristics were recorded. Leg pain was assessed using the Visual Analog Scale (VAS) for pain and the Sciatica Bothersome Index (SBI) with several secondary outcome measures. The outcome data were collected at each follow-up visit. Results Among the 77 patients, 29 were administered with BMP. Postoperative leg pain significantly improved according to VAS leg and SBI scores for the entire cohort, and no clinically significant differences were observed between the BMP and control groups. The VAS back, Oswestry Disability Index, and Short-Form 36 scores also significantly improved. A significantly increased 6-month fusion rate was noted in the BMP group (82.8% vs. 55.3%), but no significant differences in fusion rate were observed at the 12- and 24-month follow-up. Heterotopic ossification was observed in seven patients: six patients and one patient in the BMP and control groups, respectively (20.7% vs. 2.1%). However, no clinical effect was observed. Conclusions In this prospective observational trial, the use of BMP in TLIF did not lead to significant postoperative radiculitis, as measured by VAS leg and SBI scores. Back pain and other functional outcome scores also improved, and no differences existed between the BMP and control groups. The careful use of BMP in TLIF appears to be both safe and effective.
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Affiliation(s)
| | | | | | | | - Vickie M Treder
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | | | | | - Ahmad N Nassr
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
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14
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Hu T, Naidu M, Yang Z, Lam WM, Kumarsing RA, Ren X, Ng F, Wang M, Liu L, Tan KC, Kwok KT, Goodman SB, Goh JCH, Wong HK. Bone Regeneration by Controlled Release of Bone Morphogenetic Protein-2: A Rabbit Spinal Fusion Chamber Molecular Study. Tissue Eng Part A 2019; 25:1356-1368. [PMID: 30727849 DOI: 10.1089/ten.tea.2018.0281] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been widely used in spine fusion surgery. However, high doses of rhBMP-2 delivered with absorbable collagen sponge (ACS) have led to inflammation-related adverse conditions. Polyelectrolyte complex (PEC) control release carrier can substantially reduce the rhBMP-2 dose and complication without compromising fusion. The molecular events underlying controlled release and their effects on spinal fusion remain unknown. In this study, a rabbit interbody spinal fusion chamber was designed to provide a controlled environment for profiling molecular events during the fusion process. Study groups included Group 1, PEC with 100 μg rhBMP-2; Group 2, ACS with 100 μg rhBMP-2; Group 3, ACS with 300 μg rhBMP-2; Group 4, autologous bone graft; and Group 5, empty chamber. Manual palpation, microcomputed tomography, and histological analysis showed that Group 1 and 3 achieved bone fusion, while the other groups showed no signs of fusion. Gene expression profiling showed robust induction of osteogenic markers in Groups 1 and 3, with modulated early induction of inflammatory genes in the PEC group. Delivery of 100 μg rhBMP-2 with ACS (Group 2) resulted in less upregulation of osteogenic genes, increased inflammatory genes expression, and upregulation of osteoclastic genes compared to Group 1. These results suggest that the manner of BMP-2 release at the interbody spinal defect site could dictate the balance of in-situ osteogenic and antiosteogenic activities, affecting fusion outcomes. The molecular evidence supports PEC for sustained release of BMP-2 for spinal interbody fusion, and the feasibility of employing this novel interbody spinal fusion chamber for future molecular studies. Impact Statement A radiolucent rabbit interbody spinal fusion chamber was developed to study the molecular events during spinal fusion process. The gene expression profile suggests that control release of bone morphogenetic protein-2 (BMP-2) resulted in lower inflammatory and osteoclastic activities, but elicited higher osteogenic activities, while burst release of BMP-2 resulted in predominantly inflammation and osteoclastogenesis with minimum osteogenic activity. This study provides the molecular evidence that underscores the regeneration outcomes from the two different BMP-2 delivery systems. This spinal fusion chamber could be used for future molecular studies to optimize carrier design for spinal fusion.
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Affiliation(s)
- Tao Hu
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Mathanapriya Naidu
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore.,NUS Tissue Engineering Program (NUSTEP), National University of Singapore, Singapore, Singapore
| | - Zheng Yang
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore.,NUS Tissue Engineering Program (NUSTEP), National University of Singapore, Singapore, Singapore
| | - Wing Moon Lam
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore.,NUS Tissue Engineering Program (NUSTEP), National University of Singapore, Singapore, Singapore
| | - Ramruttun Amit Kumarsing
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Xiafei Ren
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Felly Ng
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Ming Wang
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Ling Liu
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Kim Cheng Tan
- School of Engineering, Temasek Polytechnic, Singapore, Singapore
| | - Kai Thong Kwok
- School of Engineering, Temasek Polytechnic, Singapore, Singapore
| | - Stuart B Goodman
- Department of Orthopaedic Surgery, Stanford University Medical Center, Stanford, California
| | - James Cho-Hong Goh
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore.,NUS Tissue Engineering Program (NUSTEP), National University of Singapore, Singapore, Singapore.,Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore, Singapore
| | - Hee-Kit Wong
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore.,NUS Tissue Engineering Program (NUSTEP), National University of Singapore, Singapore, Singapore
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15
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Abstract
Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor-β family of ligands. BMPs exhibit widespread utility and pleiotropic, context-dependent effects, and the strength and duration of BMP pathway signaling is tightly regulated at numerous levels via mechanisms operating both inside and outside the cell. Defects in the BMP pathway or its regulation underlie multiple human diseases of different organ systems. Yet much remains to be discovered about the BMP pathway in its original context, i.e., the skeleton. In this review, we provide a comprehensive overview of the intricacies of the BMP pathway and its inhibitors in bone development, homeostasis, and disease. We frame the content of the review around major unanswered questions for which incomplete evidence is available. First, we consider the gene regulatory network downstream of BMP signaling in osteoblastogenesis. Next, we examine why some BMP ligands are more osteogenic than others and what factors limit BMP signaling during osteoblastogenesis. Then we consider whether specific BMP pathway components are required for normal skeletal development, and if the pathway exerts endogenous effects in the aging skeleton. Finally, we propose two major areas of need of future study by the field: greater resolution of the gene regulatory network downstream of BMP signaling in the skeleton, and an expanded repertoire of reagents to reliably and specifically inhibit individual BMP pathway components.
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Affiliation(s)
- Jonathan W Lowery
- Division of Biomedical Science, Marian University College of Osteopathic Medicine , Indianapolis, Indiana ; and Department of Developmental Biology, Harvard School of Dental Medicine , Boston, Massachusetts
| | - Vicki Rosen
- Division of Biomedical Science, Marian University College of Osteopathic Medicine , Indianapolis, Indiana ; and Department of Developmental Biology, Harvard School of Dental Medicine , Boston, Massachusetts
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16
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Toth JM, Wang M, Patel CK, Arora A. Early term effects of rhBMP-2 on pedicle screw fixation in a sheep model: histomorphometric and biomechanical analyses. JOURNAL OF SPINE SURGERY 2018; 4:534-545. [PMID: 30547116 DOI: 10.21037/jss.2018.06.19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Background The effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) on pedicle screw pullout force and its potential to improve spinal fixation have not previously been investigated. rhBMP-2 on an absorbable collagen sponge (ACS) carrier was delivered in and around cannulated and fenestrated pedicle screws in a sheep lumbar spine instability model. Two control groups (empty screw and ACS with buffer) were also evaluated. We hypothesized that rhBMP-2 could stimulate bone growth in and around the cannulated and fenestrated pedicle screws to improve early bone purchase. Methods Eight skeletally mature sheep underwent destabilizing laminectomies at L2-L3 and L4-L5 followed by stabilization with pedicle screw and rod constructs. An ACS carrier was used to deliver 0.15 mg of rhBMP-2 within and around the cannulated and fenestrated titanium pedicle screws. Biomechanics and histomorphometry were used to evaluate the early term results at 6 and 12 postoperative weeks. Results rhBMP-2 was unable to improve bony purchase of the cannulated and fenestrated pedicle screws compared to both control groups. Although rhBMP-2 groups had pullout forces that were less than both control groups, both rhBMP-2 groups had pullout force values exceeding 2,000 N, which was comparable to previously published results for unmodified pedicle screws. Significant differences in the percentages of bone in peri-screw tissues was not observed amongst the four treatment groups. Microradiography and quantitative histomorphometry showed that at 6 weeks, rhBMP-2 induced peri-screw remodeling regions containing peri-implant bone which was hypodense with respect to surrounding native trabeculae. A moderate correlation between biomechanical pullout variables and histomorphometry data was observed. Conclusions The design of the cannulated and fenestrated pedicle screw was able to facilitate new bone formation to achieve high pullout forces. However, delivery of rhBMP-2 should be carefully controlled to prevent excessive bone remodeling which could cause early screw loosening.
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Affiliation(s)
- Jeffrey M Toth
- Department of Orthopaedic Surgery, The Medical College of Wisconsin Inc., Milwaukee, WI, USA.,Orthopaedic & Rehabilitation Engineering Center and Graduate Program in Dental Biomaterials, Marquette University, Milwaukee, WI, USA
| | - Mei Wang
- Department of Orthopaedic Surgery, The Medical College of Wisconsin Inc., Milwaukee, WI, USA.,Orthopaedic & Rehabilitation Engineering Center and Graduate Program in Dental Biomaterials, Marquette University, Milwaukee, WI, USA
| | - Chetan K Patel
- Spine Health Institute, Florida Hospital Medical Group, Altamonte Springs, FL, USA
| | - Akshi Arora
- Orthopaedic & Rehabilitation Engineering Center and Graduate Program in Dental Biomaterials, Marquette University, Milwaukee, WI, USA
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17
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Nune KC, Misra RDK, Bai Y, Li S, Yang R. Interplay of topographical and biochemical cues in regulating osteoblast cellular activity in BMP-2 eluting three-dimensional cellular titanium alloy mesh structures. J Biomed Mater Res A 2018; 107:49-60. [DOI: 10.1002/jbm.a.36520] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 06/22/2018] [Accepted: 07/31/2018] [Indexed: 01/05/2023]
Affiliation(s)
- Krishna Chaitanya Nune
- Biomaterials and Biomedical Engineering Research Laboratory, Department of Metallurgical, Materials, and Biomedical Engineering; The University of Texas at El Paso; 500 W. University Avenue, El Paso, Texas, 79968
| | - R. Devesh Kumar Misra
- Biomaterials and Biomedical Engineering Research Laboratory, Department of Metallurgical, Materials, and Biomedical Engineering; The University of Texas at El Paso; 500 W. University Avenue, El Paso, Texas, 79968
| | - Yun Bai
- Shenyang National Laboratory for Materials Science; Institute of Metal Research, Chinese Academy of Sciences; 72 Wenhua Road, Shenyang, 110016 China
| | - Shujun Li
- Shenyang National Laboratory for Materials Science; Institute of Metal Research, Chinese Academy of Sciences; 72 Wenhua Road, Shenyang, 110016 China
| | - Rui Yang
- Shenyang National Laboratory for Materials Science; Institute of Metal Research, Chinese Academy of Sciences; 72 Wenhua Road, Shenyang, 110016 China
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18
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Nguyen J, Weidner H, Schell LM, Sequeira L, Kabrick R, Dharmadhikari S, Coombs H, Duncan RL, Wang L, Nohe A. Synthetic Peptide CK2.3 Enhances Bone Mineral Density in Senile Mice. ACTA ACUST UNITED AC 2018; 6. [PMID: 30294717 PMCID: PMC6173331 DOI: 10.4172/2572-4916.1000190] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Background: Osteoporosis is a silent disease caused by low bone mineral density that results in bone fractures in 1 out of 2 women and 1 in 4 men over the age of 50. Although several treatments for osteopenia and osteoporosis are available, they have severe side effects and new treatments are desperately needed. Current treatments usually target osteoclasts and inhibit their activity or differentiation. Treatments that decrease osteoclast differentiation and activity but enhance osteogenesis and osteoblast activity are not available. We recently developed a peptide, CK2.3, that induces bone formation and increases bone mineral density as demonstrated by injection over the calvaria of 6 to 9-day-old mice and tail vein injection of 8-week-old mice. CK2.3 also decreased osteoclast formation and activity. However, these studies raise questions: does CK2.3 induce similar results in old mice and if so, what is the effective CK2.3 concentration and, is the bone mineral density of vertebrae of the spinal column increased as well? Methods: CK2.3 was systematically injected into the tail vein of female 6-month old mice with various concentrations of CK2.3: 0.76 μg/kg, 2.3 μg/kg, or 6.9 μg/kg per mice. Mice were sacrificed one week, two weeks, and four weeks after the first injection. Their spines and femurs were collected and analyzed for bone formation. Results: Femur and lumbar spine analyses found increased bone mineral density (BMD) and mineral apposition rate, with greater stiffness observed in femoral samples four weeks after the first injection. Histochemistry showed that osteoclastogenesis was suppressed in CK2.3 treated senile mice. Conclusions: For the first time, this study showed the increase of lumbar spine BMD by CK2.3. Moreover, it showed that enhancement of femur BMD was accompanied by increased femur stiffness only at medium concentration of CK2.3 four weeks after the first injection indicating the maintenance of bone’s structural integrity by CK2.3.
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Affiliation(s)
- John Nguyen
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Hilary Weidner
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Lora M Schell
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Linda Sequeira
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Ryan Kabrick
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | | | | | - Randall L Duncan
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Liyun Wang
- Department of Mechanical Engineering, University of Delaware, Newark, DE 19716, USA
| | - Anja Nohe
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
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19
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Cleemann R, Sorensen M, Bechtold JE, Soballe K, Baas J. Healing in peri-implant gap with BMP-2 and systemic bisphosphonate is dependent on BMP-2 dose-A canine study. J Orthop Res 2018; 36:1406-1414. [PMID: 28976594 DOI: 10.1002/jor.23766] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 09/22/2017] [Indexed: 02/04/2023]
Abstract
The bone-implant interface of cementless orthopedic implants can be described as a series of uneven sized gaps with discontinuous areas of direct bone-implant contact. Bridging these voids and crevices by addition of an anabolic stimulus to increase new bone formation can potentially improve osseointegration of implants. Bone morphogenetic protein 2 (BMP-2) stimulates osteoblast formation to increase new bone formation but also indirectly stimulates osteoclast activity. In this experiment, we investigate the hypothesis that osseointegration, defined as mechanical push-out and histomorphometry, depends on the dose of BMP-2 when delivered as an anabolic agent with systemic administration of the anti-resorptive agent zoledronate to curb an increase in osteoclast activity. Four porous coated titanium implants (one with each of three doses of surface-applied BMP-2 (15 µg; 60 µg; 240 µg) and untreated) surrounded by a 0.75 mm empty gap, were inserted into the distal femurs of each of twelve canines. Zoledronate IV (0.1 mg/kg) was administered 10 days into the observation period of 4 weeks. Bone-implant specimens were evaluated by mechanical push-out test and histomorphometry. The 15 µg implants had the best fixation on all mechanical parameters and largest surface area covered with new bone compared to the untreated, 60 and 240 µg implants, as well as the highest volume of new bone in the implant gap compared to 60 and 240 µg implants. The results in a canine implant model demonstrated that a narrow range of BMP-2 doses have opposite effects in bridging an empty peri-implant gap with bone, when combined with systemic zoledronate. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1406-1414, 2018.
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Affiliation(s)
- Rasmus Cleemann
- Orthopaedic Research Laboratory, Aarhus University Hospital, Denmark.,Elective Surgery Center, Silkeborg Regional Hospital, Silkeborg, Denmark
| | - Mette Sorensen
- Department of Orthopaedic Surgery, Regional Hospital Viborg, Viborg, Denmark
| | - Joan E Bechtold
- University of Minnesota Department of Orthopaedic Surgery, Minneapolis Medical Research Foundation, Minneapolis, Minnesota
| | - Kjeld Soballe
- Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus, Denmark
| | - Jorgen Baas
- Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus, Denmark
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20
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Cleemann R, Bechtold JE, Sorensen M, Soballe K, Baas J. Dose-Dependent Resorption of Allograft by rhBMP-2 Uncompensated by New Bone Formation-A Canine Study With Implants and Zoledronate. J Arthroplasty 2018; 33:1215-1221.e1. [PMID: 29248483 DOI: 10.1016/j.arth.2017.11.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 10/26/2017] [Accepted: 11/07/2017] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Impacted bone allograft is used to restore lost bone in total joint arthroplasties. Bone morphogenetic proteins (BMPs) can induce new bone formation to improve allograft incorporation, but they simultaneously invoke a seemingly dose-dependent allograft resorption mediated by osteoclasts. Bisphosphonates effectively inhibit osteoclast activity. Predicting allograft resorption when augmented with bone morphogenetic protein 2 (BMP-2), we intended to investigate whether a balanced bone metabolism was achievable within a range of BMP-2 doses with systemic zoledronate treatment. METHODS Implants were coated with 1 of 3 BMP-2 doses (15 μg, 60 μg, and 240 μg) or left untreated. Implants were surrounded by a 2.5-mm gap filled with impacted morselized allograft. Each of the 12 dogs included received 1 of each implant (15 μg, 60 μg, 240 μg, and untreated), 2 in each proximal humerus. During the 4-week observation period, zoledronate intravenous (0.1 mg/kg) was administered to all animals 10 days after surgery as anticatabolic treatment. Implant osseointegration was evaluated by histomorphometry and mechanical push-out tests. RESULTS Untreated implants had the best mechanical fixation and superior retention of allograft as compared to any of the BMP-2 implants. Both mechanical implant fixation and retention of allograft decreased significantly with BMP-2 dose increments. Surprisingly, there was no difference among the treatment groups in the amount of new bone. CONCLUSION The use of BMP-2 to augment impaction-grafted implants cannot be recommended even when combined with systemic zoledronate.
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Affiliation(s)
- Rasmus Cleemann
- Orthopaedic Research Laboratory, Aarhus University Hospital, Aarhus, Denmark; Elective Surgery Center, Silkeborg Regional Hospital, Silkeborg, Denmark
| | - Joan E Bechtold
- Department of Orthopaedic Surgery, University of Minnesota, Minneapolis Medical Research Foundation, Minneapolis, Minnesota
| | - Mette Sorensen
- Department of Orthopaedic Surgery, Viborg Regional Hospital, Viborg, Denmark
| | - Kjeld Soballe
- Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus, Denmark
| | - Jorgen Baas
- Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus, Denmark
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Growth Factor Delivery Systems for Tissue Engineering and Regenerative Medicine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1078:245-269. [PMID: 30357627 DOI: 10.1007/978-981-13-0950-2_13] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Growth factors (GFs) are often a key component in tissue engineering and regenerative medicine approaches. In order to fully exploit the therapeutic potential of GFs, GF delivery vehicles have to meet a number of key design criteria such as providing localized delivery and mimicking the dynamic native GF expression levels and patterns. The use of biomaterials as delivery systems is the most successful strategy for controlled delivery and has been translated into different commercially available systems. However, the risk of side effects remains an issue, which is mainly attributed to insufficient control over the release profile. This book chapter reviews the current strategies, chemistries, materials and delivery vehicles employed to overcome the current limitations associated with GF therapies.
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Kang DG, Hsu WK, Lehman RA. Complications Associated With Bone Morphogenetic Protein in the Lumbar Spine. Orthopedics 2017; 40:e229-e237. [PMID: 27992640 DOI: 10.3928/01477447-20161213-06] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 05/24/2016] [Indexed: 02/03/2023]
Abstract
Complications associated with the use of recombinant human bone morphogenetic protein in the lumbar spine include retrograde ejaculation, ectopic bone formation, vertebral osteolysis and subsidence, postoperative radiculitis, and hematoma and seroma. These complications are controversial and remain widely debated. This article discusses the reported complications and possible implications for the practicing spine surgeon. Understanding the complications associated with the use of recombinant human bone morphogenetic protein and the associated controversies allows for informed decision making by both the patient and the surgeon. [Orthopedics. 2017; 40(2):e229-e237.].
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TSG-6 secreted by mesenchymal stem cells suppresses immune reactions influenced by BMP-2 through p38 and MEK mitogen-activated protein kinase pathway. Cell Tissue Res 2017; 368:551-561. [PMID: 28247086 DOI: 10.1007/s00441-017-2581-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 12/26/2016] [Indexed: 12/31/2022]
Abstract
Bone morphogenetic protein 2 (BMP-2) has a critical function in bone and cartilage development and in repairing damaged organs and tissue. However, clinical use of BMP-2 at doses of 0.5-1 mg/ml for orthopedics has been associated with severe postoperative swelling requiring emergency surgical intervention. We determined whether a high concentration of BMP-2 induces inflammatory responses in macrophages and the suppression of osteogenesis in hMSCs. We obtained human periodontal ligament stem cells and bone marrow stem cells from the maxilla, i.e., human mesenchymal stem cells (hMSCs), from the periodontal ligament of extracted third molar teeth and from the bone marrow of the maxilla, respectively. Osteogenic differentiation was measured by alkaline phosphatase activity and alizarin red S staining. Proteins were assessed by flow cytometry, enzyme-linked immunosorbent assay, Western blot and immunocytochemistry. Changes of gene expression were measured by reverse transcription plus the polymerase chain reaction (RT-PCR) and real-time PCR. A high BMP-2 concentration inhibited the early stages of osteogenesis in hMSCs. Co-culturing THP-1 cells (human monocytic cells) with hMSCs reduced the late stages of osteogenesis compared with those seen in hMSCs alone. In addition, high-dose BMP-2 induced the expression of inflammatory cytokines in THP-1 cells and the expression of the anti-inflammatory cytokine tumor-necrosis-factor-α-inducible gene 6 protein (TSG-6) in hMSCs. Consistent with the anti-inflammatory effects of hMSCs when co-cultured with THP-1 cells, interleukin-1β expression was downregulated by TSG-6 treatment of THP-1 cells. Our findings suggest that a high BMP-2 concentration triggers inflammation that causes inflammatory cytokine release from THP-1 cells, leading to the suppression of osteogenesis, whereas TSG-6 secreted by hMSCs suppresses inflammatory reactions through p38 and ERK in the mitogen-activated protein kinase pathway.
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Bae HW, Patel VV, Sardar ZM, Badura JM, Pradhan BB, Seim HB, Turner AS, Toth JM. Transient Local Bone Remodeling Effects of rhBMP-2 in an Ovine Interbody Spine Fusion Model. J Bone Joint Surg Am 2016; 98:2061-2070. [PMID: 28002369 DOI: 10.2106/jbjs.16.00345] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a powerful osteoinductive morphogen capable of stimulating the migration of mesenchymal stem cells (MSCs) to the site of implantation and inducing the proliferation and differentiation of these MSCs into osteoblasts. Vertebral end-plate and vertebral body resorption has been reported after interbody fusion with high doses of rhBMP-2. In this study, we investigated the effects of 2 rhBMP-2 doses on peri-implant bone resorption and bone remodeling at 7 time points in an end-plate-sparing ovine interbody fusion model. METHODS Twenty-one female sheep underwent an end-plate-sparing discectomy followed by interbody fusion at L2-L3 and L4-L5 using a custom polyetheretherketone (PEEK) interbody fusion device. The PEEK interbody device was filled with 1 of 2 different doses of rhBMP-2 on an absorbable collagen sponge (ACS): 0.13 mg (1×) or 0.90 mg (7×). Bone remodeling and interbody fusion were assessed via high-resolution radiography and histological analyses at 1, 2, 3, 4, 8, 12, and 20 weeks postoperatively. RESULTS Peri-implant bone resorption peaked between 3 and 8 weeks in both the 1× and the 7× rhBMP-2/ACS-dose group. Osteoclastic activity and corresponding peri-implant bone resorption was dose-dependent, with moderate-to-marked resorption at the 7×-dose level and less resorption at the 1×-dose level. Both dose (p < 0.0007) and time (p < 0.0025) affected bone resorption significantly. Transient bone-resorption areas were fully healed by 12 weeks. Osseous bridging was seen at all but 1 spinal level at 12 and at 20 weeks. CONCLUSIONS In the ovine end-plate-sparing interbody fusion model, rhBMP-2 dose-dependent osteoclastic resorption is a transient phenomenon that peaks at 4 weeks postoperatively. CLINICAL RELEVANCE Using the U.S. Food and Drug Administration (FDA)-approved rhBMP-2 concentration and matching the volume of rhBMP-2/ACS with the volume of desired bone formation within the interbody construct may limit the occurrence of transient bone resorption.
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Affiliation(s)
- Hyun W Bae
- 1Spine Center, Department of Surgery (H.W.B.), Cedars-Sinai Medical Center (Z.M.S.), Los Angeles, California 2Department of Orthopaedic and Spine Surgery, University of Colorado Health Sciences Center, Aurora, Colorado 3Medtronic Sofamor Danek, Inc., Memphis, Tennessee 4Risser Orthopaedic Group, Pasadena, California 5Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado 6Department of Orthopaedic Surgery, The Medical College of Wisconsin, Milwaukee, Wisconsin
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Kesireddy V, Kasper FK. Approaches for building bioactive elements into synthetic scaffolds for bone tissue engineering. J Mater Chem B 2016; 4:6773-6786. [PMID: 28133536 PMCID: PMC5267491 DOI: 10.1039/c6tb00783j] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Bone tissue engineering (BTE) is emerging as a possible solution for regeneration of bone in a number of applications. For effective utilization, BTE scaffolds often need modifications to impart biological cues that drive diverse cellular functions such as adhesion, migration, survival, proliferation, differentiation, and biomineralization. This review provides an outline of various approaches for building bioactive elements into synthetic scaffolds for BTE and classifies them broadly under two distinct schemes; namely, the top-down approach and the bottom-up approach. Synthetic and natural routes for top-down approaches to production of bioactive constructs for BTE, such as generation of scaffold-extracellular matrix (ECM) hybrid constructs or decellularized and demineralized scaffolds, are provided. Similarly, traditional scaffold-based bottom-up approaches, including growth factor immobilization or peptide-tethered scaffolds, are provided. Finally, a brief overview of emerging bottom-up approaches for generating biologically active constructs for BTE is given. A discussion of the key areas for further investigation, challenges, and opportunities is also presented.
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Affiliation(s)
- Venu Kesireddy
- Department of Orthodontics, The University of Texas Health Science Center at Houston, School of Dentistry
| | - F. Kurtis Kasper
- Department of Orthodontics, The University of Texas Health Science Center at Houston, School of Dentistry
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Slowly Delivered Icariin/Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells to Promote the Healing of Calvarial Critical-Size Bone Defects. Stem Cells Int 2016; 2016:1416047. [PMID: 27721833 PMCID: PMC5040948 DOI: 10.1155/2016/1416047] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 08/04/2016] [Accepted: 08/11/2016] [Indexed: 11/17/2022] Open
Abstract
Bone tissue engineering technique is a promising strategy to repair large-volume bone defects. In this study, we developed a 3-dimensional construct by combining icariin (a small-molecule Chinese medicine), allogeneic bone marrow-derived mesenchymal stem cells (BMSCs), and a siliceous mesostructured cellular foams-poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (SMC-PHBHHx) composite scaffold. We hypothesized that the slowly released icariin could significantly promote the efficacy of SMC-PHBHHx/allogeneic BMSCs for repairing critical-size bone defects in rats. In in vitro cellular experiments, icariin at optimal concentration (10-6 mol/L) could significantly upregulate the osteogenesis- and angiogenesis-related genes and proteins, such as Runx2, ALP, osteocalcin, vascular endothelial growth factors, and fibroblast growth factors, as well as the mineralization of BMSCs. Icariin that was adsorbed onto the SMC-PHBHHx scaffold showed a slow release profile within a 2-week monitoring span. Eight weeks after implantation in calvarial critical-size bone defects, the constructs with icariin were associated with significantly higher bone volume density, trabecular thickness, trabecular number, and significantly lower trabecular separation than the constructs without icariin. Histomorphometric analysis showed that icariin was also associated with a significantly higher density of newly formed blood vessels. These data suggested a promising application potential of the icariin/SMC-PHBHHx/allogeneic BMSCs constructs for repairing large-volume bone defects in clinic.
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Heparin-Based Polyelectrolyte Complex Enhances the Therapeutic Efficacy of Bone Morphogenetic Protein-2 for Posterolateral Fusion in a Large Animal Model. Spine (Phila Pa 1976) 2016; 41:1199-1207. [PMID: 26953670 DOI: 10.1097/brs.0000000000001543] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN The study was based on porcine posterolateral fusion model. OBJECTIVE The study aims to prove that polyelectrolyte complex (PEC) carrier could enhance the efficacy and safety profile of bone morphogenetic protein-2 (BMP-2). SUMMARY OF BACKGROUND DATA BMP-2 was introduced to enhance posterolateral fusion; however, extremely high doses of this molecule were often used which contributed to various complications. This was attributed to the poor modulation capacity of the traditional carrier absorbable collagen sponge (ACS). To reduce the efficacious dose of BMP-2 and its associated complications, heparin-based PEC was introduced. METHODS L3/L4 and L5/L6 two-level posterolateral spinal fusion was performed on six pigs using two doses of BMP-2 with PEC or ACS: (1) PEC with 800 μg BMP-2 (n = 2); (2) PEC with 400 μg BMP-2 (n = 2); (3) ACS with 800 μg BMP-2 (n = 1); (4) ACS with 400 μg of BMP-2 (n = 1). The construct was loaded into a rigid bioabsorbable cage for implantation. Fusion rate and quality were assessed 2 months after operation. RESULTS Manual palpation revealed successful fusion in all groups. Radiological fusion score of PEC groups was, however, higher than that of ACS groups. The newly formed bone in PEC groups appeared to be well integrated into the native bone with no overgrowth into the adjacent structure. On comparison, in ACS groups, large gaps were observed between the newly formed bone and the fusion bed with heterotopic ossification into the psoas muscle. The microarchitecture on the newly formed bone in PEC groups was superior to that in ACS groups, which was demonstrated by higher three-dimensional parameters. CONCLUSION The present study demonstrated that BMP-2 delivered by PEC induced successful posterolateral fusion in porcine model. The efficacy of BMP-2 was improved and bony overgrowth was reduced. The microarchitecture of BMP-2-induced bone tissue was also enhanced by PEC. LEVEL OF EVIDENCE N/A.
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Assessment of a polyelectrolyte multilayer film coating loaded with BMP-2 on titanium and PEEK implants in the rabbit femoral condyle. Acta Biomater 2016; 36:310-22. [PMID: 26965394 DOI: 10.1016/j.actbio.2016.03.010] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 02/29/2016] [Accepted: 03/06/2016] [Indexed: 01/14/2023]
Abstract
UNLABELLED The aim of this study was to evaluate the osseointegration of titanium implants (Ti-6Al-4V, noted here TA6V) and poly(etheretherketone) PEEK implants induced by a BMP-2-delivering surface coating made of polyelectrolyte multilayer films. The in vitro bioactivity of the polyelectrolyte film-coated implants was assessed using the alkaline phosphatase assay. BMP-2-coated TA6V and PEEK implants with a total dose of 9.3μg of BMP-2 were inserted into the femoral condyles of New Zealand white rabbits and compared to uncoated implants. Rabbits were sacrificed 4 and 8weeks after implantation. Histomorphometric analyses on TA6V and PEEK implants and microcomputed tomography on PEEK implants revealed that the bone-to-implant contact and bone area around the implants were significantly lower for the BMP-2-coated implants than for the bare implants. This was confirmed by scanning electron microscopy imaging. This difference was more pronounced at 4weeks in comparison to the 8-week time point. However, bone growth inside the hexagonal upper hollow cavity of the screws was higher in the case of the BMP-2 coated implants. Overall, this study shows that a high dose of BMP-2 leads to localized and temporary bone impairment, and that the dose of BMP-2 delivered at the surface of an implant needs to be carefully optimized. STATEMENT OF SIGNIFICANCE The presentation of growth factors from material surfaces currently presents significant challenges in academia, clinics and industry. Applying osteoinductive factors to different types of implants, made of metals or polymers, may improve bone repair in difficult situations. Here, we show the effects of an osteoinductive coating made of polyelectrolyte multilayer films on two widely used materials, titanium TA6V alloys and PEEK implants, which were implanted in the rabbit femoral condyle. We show that a too high dose of BMP-2 delivered from the screw surface has a negative short-term effect on bone regeneration in close vicinity of the screw surface. In contrast, bone formation was increased at early times in the empty spaces around the screw. These results highlight the need for future dose-dependence studies on bone formation in response to osteoinductive coatings.
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Complications of Anterior and Posterior Cervical Spine Surgery. Asian Spine J 2016; 10:385-400. [PMID: 27114784 PMCID: PMC4843080 DOI: 10.4184/asj.2016.10.2.385] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 06/07/2015] [Accepted: 06/08/2015] [Indexed: 02/03/2023] Open
Abstract
Cervical spine surgery performed for the correct indications yields good results. However, surgeons need to be mindful of the many possible pitfalls. Complications may occur starting from the anaesthestic procedure and patient positioning to dura exposure and instrumentation. This review examines specific complications related to anterior and posterior cervical spine surgery, discusses their causes and considers methods to prevent or treat them. In general, avoiding complications is best achieved with meticulous preoperative analysis of the pathology, good patient selection for a specific procedure and careful execution of the surgery. Cervical spine surgery is usually effective in treating most pathologies and only a reasonable complication rate exists.
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Lu H, Liu Y, Guo J, Wu H, Wang J, Wu G. Biomaterials with Antibacterial and Osteoinductive Properties to Repair Infected Bone Defects. Int J Mol Sci 2016; 17:334. [PMID: 26950123 PMCID: PMC4813196 DOI: 10.3390/ijms17030334] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 02/23/2016] [Accepted: 02/29/2016] [Indexed: 12/16/2022] Open
Abstract
The repair of infected bone defects is still challenging in the fields of orthopedics, oral implantology and maxillofacial surgery. In these cases, the self-healing capacity of bone tissue can be significantly compromised by the large size of bone defects and the potential/active bacterial activity. Infected bone defects are conventionally treated by a systemic/local administration of antibiotics to control infection and a subsequent implantation of bone grafts, such as autografts and allografts. However, these treatment options are time-consuming and usually yield less optimal efficacy. To approach these problems, novel biomaterials with both antibacterial and osteoinductive properties have been developed. The antibacterial property can be conferred by antibiotics and other novel antibacterial biomaterials, such as silver nanoparticles. Bone morphogenetic proteins are used to functionalize the biomaterials with a potent osteoinductive property. By manipulating the carrying modes and release kinetics, these biomaterials are optimized to maximize their antibacterial and osteoinductive functions with minimized cytotoxicity. The findings, in the past decade, have shown a very promising application potential of the novel biomaterials with the dual functions in treating infected bone defects. In this review, we will summarize the current knowledge of novel biomaterials with both antibacterial and osteoinductive properties.
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Affiliation(s)
- Haiping Lu
- School of Stomatology, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Yi Liu
- Department of Oral Implantology and Prosthetic Dentistry, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, MOVE Research Institute, Amsterdam 1081LA, The Netherlands.
| | - Jing Guo
- School of Stomatology, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Huiling Wu
- The First Affiliated Hospital, Medical School, Zhejiang University, Hangzhou 310003, China.
| | - Jingxiao Wang
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, China.
| | - Gang Wu
- Department of Oral Implantology and Prosthetic Dentistry, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, MOVE Research Institute, Amsterdam 1081LA, The Netherlands.
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Bougioukli S, Jain A, Sugiyama O, Tinsley BA, Tang AH, Tan MH, Adams DJ, Kostenuik PJ, Lieberman JR. Combination therapy with BMP-2 and a systemic RANKL inhibitor enhances bone healing in a mouse critical-sized femoral defect. Bone 2016; 84:93-103. [PMID: 26723577 PMCID: PMC4903101 DOI: 10.1016/j.bone.2015.12.052] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 12/08/2015] [Accepted: 12/22/2015] [Indexed: 11/26/2022]
Abstract
Recombinant human BMP-2 (rhBMP-2) is a potent osteoinductive agent, but has been associated not only with bone formation, but also osteoclastogenesis and bone resorption. Osteoprotegerin (OPG) is a RANKL inhibitor that blocks differentiation and function of osteoclasts. We hypothesized that the combination of local BMP-2 (recombinant protein or a product of gene therapy) plus systemic OPG-Fc is more effective than BMP-2 alone in promoting bone repair. To test this hypothesis we used a mouse critical-sized femoral defect model. Col2.3eGFP (osteoblastic marker) male mice were treated with rhBMP-2 (group I), rhBMP-2 and systemic OPG (group II), rhBMP-2 and delayed administration of OPG (group III), mouse BM cells transduced with a lentiviral vector containing the BMP-2 gene (LV-BMP-2; group IV), LV-BMP-2 and systemic OPG (group V), a carrier alone (group VI) and administration of OPG alone (group VII). All bone defects treated with BMP-2 (alone or combined with OPG) healed, whereas minimal bone formation was noted in animals treated with the carrier alone or OPG alone. MicroCT analysis showed that bone volume (BV) in rhBMP-2+OPG and LV-BMP-2+OPG groups was significantly higher compared to rhBMP-2 alone (p<0.01) and LV-BMP-2 alone (p<0.001). Similar results were observed in histomorphometry, with rhBMP-2 alone defects exhibiting significantly lower bone area (B.Ar) compared to rhBMP-2+OPG defects (p<0.005) and LV-BMP-2 defects having a significantly lower B.Ar compared to all BMP-2+OPG treated groups (p≤0.01). TRAP staining demonstrated a major osteoclast response in the groups that did not receive OPG (rhBMP-2, LV-BMP-2 and sponge alone) beginning as early as 7days post-operatively. In conclusion, we demonstrated that locally delivered BMP-2 (recombinant protein or gene therapy) in combination with systemically administered OPG improved bone healing compared to BMP-2 alone in a mouse critical-sized bone defect. These data indicate that osteoclasts can diminish healing responses to BMP-2 and that RANKL inhibition may thus accentuate BMP-2 efficacy.
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Affiliation(s)
- Sofia Bougioukli
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Ashish Jain
- Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, University of Connecticut Health, Farmington, CT, USA
| | - Osamu Sugiyama
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Brian A Tinsley
- Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, University of Connecticut Health, Farmington, CT, USA
| | - Amy H Tang
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Matthew H Tan
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Douglas J Adams
- Department of Orthopaedic Surgery, UConn Musculoskeletal Institute, University of Connecticut Health, Farmington, CT, USA
| | - Paul J Kostenuik
- Phylon Pharma Services, Newbury Park, CA, USA; Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Jay R Lieberman
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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Hutchens SA, Campion C, Assad M, Chagnon M, Hing KA. Efficacy of silicate-substituted calcium phosphate with enhanced strut porosity as a standalone bone graft substitute and autograft extender in an ovine distal femoral critical defect model. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2016; 27:20. [PMID: 26684617 DOI: 10.1007/s10856-015-5559-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 08/14/2015] [Indexed: 06/05/2023]
Abstract
A synthetic bone graft substitute consisting of silicate-substituted calcium phosphate with increased strut porosity (SiCaP EP) was evaluated in an ovine distal femoral critical sized metaphyseal defect as a standalone bone graft, as an autologous iliac crest bone graft (ICBG) extender (SiCaP EP/ICBG), and when mixed with bone marrow aspirate (SiCaP EP/BMA). Defects were evaluated after 4, 8, and 12 weeks with radiography, decalcified paraffin-embedded histopathology, non-decalcified resin-embedded histomorphometry, and mechanical indentation testing. All test groups exhibited excellent biocompatibility and osseous healing as evidenced by an initial mild inflammatory response followed by neovascularization, bone growth, and marrow infiltration throughout all SiCaP EP-treated defects. SiCaP EP/ICBG produced more bone at early time points, while all groups produced similar amounts of bone at later time points. SiCaP EP/ICBG likewise showed more favorable mechanical properties at early time points, but was equivalent to SiCaP EP and SiCaP EP/BMA at later time points. This study demonstrates that SiCaP EP is efficacious as a standalone bone graft substitute, mixed with BMA, and as an autograft extender.
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Affiliation(s)
- Stacy A Hutchens
- Baxter Healthcare Corporation, One Baxter Pkwy, Deerfield, IL, 60015, USA.
| | - Charlie Campion
- Baxter Healthcare Corporation, One Baxter Pkwy, Deerfield, IL, 60015, USA
| | - Michel Assad
- Orthopedics and Biomaterials Laboratory, AccelLAB Inc., Boisbriand, QC, Canada
| | - Madeleine Chagnon
- Orthopedics and Biomaterials Laboratory, AccelLAB Inc., Boisbriand, QC, Canada
| | - Karin A Hing
- Institute of Bioengineering, School of Engineering and Materials Science at Queen Mary University of London, London, E1 4NS, UK
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Extracellular calcium-binding peptide-modified ceramics stimulate regeneration of calvarial bone defects. Tissue Eng Regen Med 2015; 13:57-65. [PMID: 30603385 DOI: 10.1007/s13770-015-9066-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 08/24/2015] [Accepted: 08/27/2015] [Indexed: 12/26/2022] Open
Abstract
Secreted protein, acidic, cysteine-rich (SPARC)-related modular calcium binding 1 (SMOC1) has been implicated in the regulation of osteogenic differentiation of human bone marrow mesenchymal stem cells (BMSCs). In this study, we found that a peptide (16 amino acids in length), which is located in the extracellular calcium (EC) binding domain of SMOC1, stimulated osteogenic differentiation of human BMSCs in vitro and calvarial bone regeneration in vivo. Treatment of BMSCs with SMOC1-EC peptide significantly stimulated their mineralization in a dose-dependent manner without changing their rate of proliferation. The expression of osteogenic differentiation marker genes, including type 1 collagen and osteocalcin, also increased in a dose-dependent manner. To examine the effect of the SMOC1-EC peptide on bone formation in vivo, the peptide was covalently immobilized onto hydroxyapatite/β-tricalcium phosphate (HA/β-TCP) particles. X-ray photoelectron spectroscopy analysis showed that the peptide was successfully immobilized onto the surface of HA/β-TCP. Implantation of the SMOC1-EC peptide-immobilized HA/β-TCP particles into mouse calvarial defects and subsequent analyses using microcomputed tomography and histology showed significant bone regeneration compared with that of calvarial defects implanted with unmodified HA/β-TCP particles. Collectively, our data suggest that a peptide derived from the EC domain of SMOC1 induces osteogenic differentiation of human BMSCs in vitro and efficiently enhances bone regeneration in vivo.
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Chang CH, Yeh SY, Lee BH, Chen CJ, Su CT, Lin YT, Liu CL, Chen HY. Osteogenic Surface Modification Based on Functionalized Poly-P-Xylylene Coating. PLoS One 2015; 10:e0137017. [PMID: 26379273 PMCID: PMC4574780 DOI: 10.1371/journal.pone.0137017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 08/10/2015] [Indexed: 11/22/2022] Open
Abstract
The biotechnology to immobilize biomolecules on material surfaces has been developed vigorously due to its high potentials in medical applications. In this study, a simple and effective method was designed to immobilize biomolecules via amine-N-hydroxysuccinimide (NHS) ester conjugation reaction using functionalized poly-p-xylylene coating on material surfaces. The NHS ester functionalized coating is synthesized via chemical vapor deposition, a facile and solvent-less method, creating a surface which is ready to perform a one-step conjugation reaction. Bone morphogenetic protein 2 (BMP-2) is immobilized onto material surfaces by this coating method, forming an osteogenic environment. The immobilization process is controlled at a low temperature which does not damage proteins. This modified surface induces differentiation of preosteoblast into osteoblast, manifested by alkaline phosphatase (ALP) activity assay, Alizarin Red S (ARS) staining and the expression of osteogenic gene markers, Alpl and Bglap3. With this coating technology, immobilization of growth factors onto material surface can be achieved more simply and more effectively.
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Affiliation(s)
- Chih-Hao Chang
- Department of Orthopedics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Shu-Yun Yeh
- Department of Chemical Engineering, National Taiwan University, Taipei, Taiwan
| | - Bing-Heng Lee
- Department of Orthopedics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chia-Jie Chen
- Department of Orthopedics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chiao-Tzu Su
- Department of Chemical Engineering, National Taiwan University, Taipei, Taiwan
| | - Yen-Ting Lin
- Department of Chemical Engineering, National Taiwan University, Taipei, Taiwan
| | - Chien-Lin Liu
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan and School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Hsien-Yeh Chen
- Department of Chemical Engineering, National Taiwan University, Taipei, Taiwan
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Polyelectrolyte Complex Carrier Enhances Therapeutic Efficiency and Safety Profile of Bone Morphogenetic Protein-2 in Porcine Lumbar Interbody Fusion Model. Spine (Phila Pa 1976) 2015; 40:964-73. [PMID: 25893351 DOI: 10.1097/brs.0000000000000935] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Porcine lumbar interbody fusion model. OBJECTIVE This study evaluates the effect of polyelectrolyte complex (PEC) carrier in enhancing the therapeutic efficiency and safety profile of bone morphogenetic protein-2 (BMP-2) in a large animal model. SUMMARY OF BACKGROUND DATA Extremely large amounts of BMP-2 are administered to achieve consistent spinal fusion, which has led to complications. Heparin-modified PEC carrying reduced BMP-2 doses of 0.5 μg was demonstrated to achieve consistent spinal fusion with reduction of complications in rodent model. The purpose of this study was to evaluate whether PEC could improve the therapeutic efficiency of BMP-2 in porcine model. METHODS Three-segment (L3-L6) anterior lumbar interbody fusions with instrumentation were performed on 6 pigs using 3 different doses of BMP-2, namely, (1) 50 μg, (2) 150 μg, and (3) 300 μg. The BMP-2 was delivered using heparin-modified alginate microbeads loaded into biodegradable cage. Fusion performance was evaluated after 3 months. RESULTS Manual palpation and micro-computed tomography showed consistent fusion in all experimental groups. Heterotopic bone formation beyond the cage implant area was more evident in group 2 and group 3 than in group 1. Similarly, superior bone microstructure was observed in the new bone with the lowered BMP-2 dose. Biomechanical evaluation revealed enhanced stiffness of the operated segments compared with nonoperated segments (P < 0.05). Mechanical stability was maintained despite dose reduction of BMP-2. Although the mineral apposition rate was higher in group 3, unsatisfactory bony microstructure with decreased trabecular number was observed in group 3 compared with group 1. CONCLUSION PEC carrying low doses of BMP-2 achieved consistent interbody fusion. We observed dose-related reduction in heterotopic ossification without compromising the stability of the fused segments. PEC carrier reduces the efficacious doses of BMP-2. This could enhance the safety profile of BMP-2 and reduce dose- and carrier-related complications. LEVEL OF EVIDENCE N/A.
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Hunziker EB, Lippuner K, Keel MJ, Shintani N. Age-Independent Cartilage Generation for Synovium-Based Autologous Chondrocyte Implantation. Tissue Eng Part A 2015; 21:2089-98. [DOI: 10.1089/ten.tea.2014.0599] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Affiliation(s)
- Ernst B. Hunziker
- Departments of Osteoporosis, Orthopaedic Surgery and Clinical Research, Center of Regenerative Medicine for Skeletal Tissues, Inselspital, University of Bern, Bern, Switzerland
| | - Kurt Lippuner
- Departments of Osteoporosis, Orthopaedic Surgery and Clinical Research, Center of Regenerative Medicine for Skeletal Tissues, Inselspital, University of Bern, Bern, Switzerland
| | - Marius J.B. Keel
- Departments of Osteoporosis, Orthopaedic Surgery and Clinical Research, Center of Regenerative Medicine for Skeletal Tissues, Inselspital, University of Bern, Bern, Switzerland
| | - Nahoko Shintani
- Departments of Osteoporosis, Orthopaedic Surgery and Clinical Research, Center of Regenerative Medicine for Skeletal Tissues, Inselspital, University of Bern, Bern, Switzerland
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Sayama C, Willsey M, Chintagumpala M, Brayton A, Briceño V, Ryan SL, Luerssen TG, Hwang SW, Jea A. Routine use of recombinant human bone morphogenetic protein-2 in posterior fusions of the pediatric spine and incidence of cancer. J Neurosurg Pediatr 2015; 16:4-13. [PMID: 25860984 DOI: 10.3171/2014.10.peds14199] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECT The aim of this study was to determine the safety of recombinant human bone morphogenetic protein-2 (rhBMP-2) use in posterior instrumented fusions in the pediatric population, focusing on cancer risk. In a previous study, the authors reported the short-term (mean follow-up of 11 months) safety and efficacy of rhBMP-2 in the pediatric age group. The present study reports their results with a minimum of 24 months' follow-up. METHODS The authors retrospectively reviewed 57 consecutive cases involving pediatric patients who underwent posterior occiptocervical, cervical, thoracic, lumbar, or lumbosacral spine fusion from October 1, 2007, to June 30, 2011, at Texas Children's Hospital. Seven cases were excluded from further analysis because of loss to follow-up. Three patients died during the follow-up period and were placed in a separate cohort. RESULTS The patients' average age at the time of surgery was 11 years, 4 months (range 9 months to 20 years). The mean duration of follow-up was 48.4 months (range 24-70 months). Cancer status was determined at the most recent encounter with the patient and/or caretaker(s) in person, or in telephone follow-up. Twenty-four or more months after administration of rhBMP-2, there were no cases of new malignancy, degeneration, or metastasis of existing tumors. The cause of death of the patients who died during the study period was not related to BMP or to the development, degeneration, or metastasis of cancer. CONCLUSIONS Despite the large number of adult studies reporting increased cancer risk associated with BMP use, the authors' outcomes with rhBMP-2 in the pediatric population suggest that it is a safe adjunct to posterior spine fusions of the occipitocervical, cervical, thoracic, lumbar, and lumbosacral spine. There were no new cases of cancer, or degeneration or metastasis of existing malignancies in this series.
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Affiliation(s)
- Christina Sayama
- Neuro-Spine Program, Division of Pediatric Neurosurgery, and.,Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
| | - Matthew Willsey
- Neuro-Spine Program, Division of Pediatric Neurosurgery, and.,Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
| | - Murali Chintagumpala
- Neuro-oncology Program, Division of Hematology-Oncology, Department of Pediatrics, Texas Children's Hospital; and
| | - Alison Brayton
- Neuro-Spine Program, Division of Pediatric Neurosurgery, and.,Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
| | - Valentina Briceño
- Neuro-Spine Program, Division of Pediatric Neurosurgery, and.,Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
| | - Sheila L Ryan
- Neuro-Spine Program, Division of Pediatric Neurosurgery, and.,Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
| | - Thomas G Luerssen
- Neuro-Spine Program, Division of Pediatric Neurosurgery, and.,Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
| | - Steven W Hwang
- Division of Pediatric Neurosurgery, Floating Children's Hospital; and.,Department of Neurosurgery, Tufts University, Boston, Massachusetts
| | - Andrew Jea
- Neuro-Spine Program, Division of Pediatric Neurosurgery, and.,Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
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Pobloth AM, Duda GN, Giesecke MT, Dienelt A, Schwabe P. High-dose recombinant human bone morphogenetic protein-2 impacts histological and biomechanical properties of a cervical spine fusion segment: results from a sheep model. J Tissue Eng Regen Med 2015; 11:1514-1523. [PMID: 26053675 DOI: 10.1002/term.2049] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 03/20/2015] [Accepted: 04/29/2015] [Indexed: 11/11/2022]
Abstract
The 'off-label' use of high-dose recombinant human bone morphogenetic protein-2 (rhBMP-2) in lumbar and cervical fusion leads to heterotopic bone formation and vertebral osteolysis. These radiographically assessed side-effects in patients were frequently associated with an over-dosage of BMP-2. However, little is so far known about the histological, functional or biomechanical tissue consequences of over-dosage of rhBMP-2 in these specific clinical situations. We hypothesized that a high dose of rhBMP-2 in cervical spinal fusion could induce substantial alterations in bone, leading to mechanical impairment. An anterior cervical spinal fusion (C3-C4 ACDF) model in 16 sheep (aged > 2.5 years; n = 8/group) was used to quantify the consequences of a high rhBMP-2 dose (6 mg rhBMP-2) on fusion tissue compared to the 'gold standard' of autologous, cancellous bone graft. The fusion site was assessed by radiography after 0, 8 and 12 weeks. Biomechanical non-destructive testing and (immuno)histological and histomorphometrical analyses were performed 12 weeks postoperatively. Although high-dose rhBMP-2 treatment led to an advanced radiological fusion result compared to autograft treatment, heterotopic bone formation and vertebral bone resorption were induced simultaneously. Histological evaluation unveiled highly active bone-forming processes ventral to the fusion segment after 12 weeks, while radiolucent areas showed still a partial loss of regular trabecular structure, with rare signs of remodelling and restoration. Despite qualitative alteration of the trabecular bone structure within the fusion site, the massive anterior heterotopic bone formation led to a substantial increase in mechanical stiffness compared to the autograft group. Copyright © 2015 John Wiley & Sons, Ltd.
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Affiliation(s)
- Anne-Marie Pobloth
- Julius Wolff Institute and Centre for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Germany.,Berlin-Brandenburg Centre for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Germany
| | - Georg N Duda
- Julius Wolff Institute and Centre for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Germany.,Berlin-Brandenburg Centre for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Germany
| | - Moritz T Giesecke
- Centre for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Germany
| | - Anke Dienelt
- Julius Wolff Institute and Centre for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Germany.,Berlin-Brandenburg Centre for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Germany
| | - Philipp Schwabe
- Centre for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Germany
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Novel Protamine-Based Polyelectrolyte Carrier Enhances Low-Dose rhBMP-2 in Posterolateral Spinal Fusion. Spine (Phila Pa 1976) 2015; 40:613-21. [PMID: 25705961 DOI: 10.1097/brs.0000000000000841] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A rodent posterolateral spinal fusion model. OBJECTIVE This study evaluated a protamine-based polyelectrolyte complex (PEC) developed to use heparin in enhancing the biological activity of low-dose recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion. SUMMARY OF BACKGROUND DATA rhBMP-2 is commonly regarded as the most potent bone-inducing molecule. However, poor pharmacokinetics and short in vivo half-life means that large amounts of the bioactive growth factor are required for consistent clinical outcomes. This has been associated with a number of adverse tissue reactions including seroma and heterotopic ossification. Glycosaminoglycans including heparin are known to stabilize rhBMP-2 bioactivity. Previous studies with poly-L-lysine (PLL) and heparin-based PEC carriers amplified the therapeutic efficacy of low-dose BMP-2. However, questions remained on the eventual clinical applicability of relatively cytotoxic PLL. In the present study, a protamine-based PEC carrier was designed to further enhance the safety and efficacy of BMP-2 by delivering lower dose within the therapeutic window. METHODS A polyelectrolyte shell was deposited on the surface of alginate microbead templates using the polycation (protamine)/polyanion (heparin) layer-by-layer polyelectrolyte self-assembly protocol. rhBMP-2 was loaded onto the outermost layer via heparin affinity binding. Loading and release of rhBMP-2 were evaluated in vitro. The bone-inductive ability of 20-fold reduction of rhBMP-2 with the different carrier vehicle was evaluated using a posterolateral spinal fusion model in rats. RESULTS In vitro uptake and release analysis, protamine-based PEC showed higher uptake and significantly enhanced control release than PLL-based PEC (P < 0.05). In vivo implantation with protamine-based and PLL-based PEC showed better fusion performances than absorbable collagen sponge-delivered same dose of rhBMP-2, and negative control group through manual palpation, micro-computed tomography, and histological analyses. CONCLUSION Solid posterolateral spinal fusion was achieved with 20-fold reduction of rhBMP-2 when delivered using protamine-based PEC carrier in the rat posterolateral spinal fusion model. LEVEL OF EVIDENCE N/A.
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Taniyama T, Masaoka T, Yamada T, Wei X, Yasuda H, Yoshii T, Kozaka Y, Takayama T, Hirano M, Okawa A, Sotome S. Repair of osteochondral defects in a rabbit model using a porous hydroxyapatite collagen composite impregnated with bone morphogenetic protein-2. Artif Organs 2015; 39:529-35. [PMID: 25865039 DOI: 10.1111/aor.12409] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Articular cartilage has a limited capacity for spontaneous repair, and an effective method to repair damaged articular cartilage has not yet been established. The purpose of this study was to evaluate the effect of transplantation of porous hydroxyapatite collagen (HAp/Col) impregnated with bone morphogenetic protein-2 (BMP-2). To evaluate the characteristics of porous HAp/Col as a drug delivery carrier of recombinant human BMP-2 (rhBMP-2), the rhBMP-2 adsorption capacity and release kinetics of porous HAp/Col were analyzed. Porous HAp/Col impregnated with different amounts of rhBMP-2 (0, 5, and 25 μg) was implanted into osteochondral defects generated in the patellar groove of Japanese white rabbits to evaluate the effect on osteochondral defect regeneration. At 3, 6, 12, and 24 weeks after operation, samples were harvested and subjected to micro-computed tomography analysis and histological evaluation of articular cartilage and subchondral bone repair. The adsorption capacity was 329.4 μg of rhBMP-2 per cm(3) of porous HAp/Col. Although 36% of rhBMP-2 was released within 24 h, more than 50% of the rhBMP-2 was retained in the porous HAp/Col through the course of the experiment. Defects treated with 5 μg of rhBMP-2 showed the most extensive subchondral bone repair and the highest histological regeneration score, and differences against the untreated defect group were significant. The histological regeneration score of defects treated with 25 μg of rhBMP-2 increased up to 6 weeks after implantation, but then decreased. Porous HAp/Col, therefore, is an appropriate carrier for rhBMP-2. Implantation of porous HAp/Col impregnated with rhBMP-2 is effective for rigid subchondral bone repair, which is important for the repair of the smooth articular surface.
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Affiliation(s)
- Takashi Taniyama
- Department of Orthopaedic and Spinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomokazu Masaoka
- Department of Orthopaedic and Spinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tsuyoshi Yamada
- Department of Orthopaedic and Spinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Xuetao Wei
- Department of Orthopaedic and Spinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroaki Yasuda
- Department of Orthopaedic and Spinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshitaka Yoshii
- Department of Orthopaedic and Spinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yuko Kozaka
- HOYA Technosurgical Corporation, Tokyo, Japan
| | | | | | - Atsushi Okawa
- Department of Orthopaedic and Spinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinichi Sotome
- Department of Orthopaedic Research and Development, Tokyo Medical and Dental University, Tokyo, Japan
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Kwon TK, Song JM, Kim IR, Park BS, Kim CH, Cheong IK, Shin SH. Effect of recombinant human bone morphogenetic protein-2 on bisphosphonate-treated osteoblasts. J Korean Assoc Oral Maxillofac Surg 2014; 40:291-6. [PMID: 25551094 PMCID: PMC4279973 DOI: 10.5125/jkaoms.2014.40.6.291] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 09/02/2014] [Indexed: 11/15/2022] Open
Abstract
Objectives Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a side effect of bisphophonate therapy that has been reported in recent years. Osteoclastic inactivity by bisphosphonate is the known cause of BRONJ. Bone morphogenetic protein-2 (BMP-2) plays an important role in the development of bone. Recombinant human BMP-2 (rhBMP-2) is potentially useful as an activation factor for bone repair. We hypothesized that rhBMP-2 would enhance the osteoclast-osteoblast interaction related to bone remodeling. Materials and Methods Human fetal osteoblast cells (hFOB 1.19) were treated with 100 µM alendronate, and 100 ng/mL rhBMP-2 was added. Cells were incubated for a further 48 hours, and cell viability was measured using an MTT assay. Expression of the three cytokines from osteoblasts, receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and macrophage colony-stimulating factor (M-CSF), were analyzed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Results Cell viability was decreased to 82.75%±1.00% by alendronate and then increased to 110.43%±1.35% after treatment with rhBMP-2 (P<0.05, respectively). OPG, RANKL, and M-CSF expression were all decreased by alendronate treatment. RANKL and M-CSF expression were increased, but OPG was not significantly affected by rhBMP-2. Conclusion rhBMP2 does not affect OPG gene expression in hFOB, but it may increase RANKL and M-CSF gene expression.
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Affiliation(s)
- Taek-Kyun Kwon
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Jae-Min Song
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea
| | - In-Ryoung Kim
- Department of Oral Anatomy and Cell Biology, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Bong-Soo Park
- Department of Oral Anatomy and Cell Biology, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Chul-Hoon Kim
- Department of Dentistry, Dong-A University Hospital, Busan, Korea
| | - In-Kyo Cheong
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Sang-Hun Shin
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea
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Liporace FA, Breitbart EA, Yoon RS, Doyle E, Paglia DN, Lin S. The effect of locally delivered recombinant human bone morphogenetic protein-2 with hydroxyapatite/tri-calcium phosphate on the biomechanical properties of bone in diabetes-related osteoporosis. J Orthop Traumatol 2014; 16:151-9. [PMID: 25421865 PMCID: PMC4441641 DOI: 10.1007/s10195-014-0327-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 11/07/2014] [Indexed: 01/05/2023] Open
Abstract
Background Recombinant human bone morphogenetic protein-2 (rhBMP-2) is particularly effective in improving osteogenesis in patients with diminished bone healing capabilities, such as individuals with type 1 diabetes mellitus (T1DM) who have impaired bone healing capabilities and increased risk of developing osteoporosis. This study measured the effects of rhBMP-2 treatment on osteogenesis by observing the dose-dependent effect of localized delivery of rhBMP-2 on biomechanical parameters of bone using a hydroxyapatite/tri-calcium phosphate (HA/TCP) carrier in a T1DM-related osteoporosis animal model. Materials and methods Two different doses of rhBMP-2 (LD low dose, HD high dose) with a HA/TCP carrier were injected into the femoral intramedullary canal of rats with T1DM-related osteoporosis. Two more diabetic rat groups were injected with saline alone and with HA/TCP carrier alone. Radiographs and micro-computed tomography were utilized for qualitative assessment of bone mineral density (BMD). Biomechanical testing occurred at 4- and 8-week time points; parameters tested included torque to failure, torsional rigidity, shear stress, and shear modulus. Results At the 4-week time point, the LD and HD groups both exhibited significantly higher BMD than controls; at the 8-week time point, the HD group exhibited significantly higher BMD than controls. Biomechanical testing revealed dose-dependent, higher trends in all parameters tested at the 4- and 8-week time points, with minimal significant differences. Conclusions Groups treated with rhBMP-2 demonstrated improved bone mineral density at both 4 and 8 weeks compared to control saline groups, in addition to strong trends towards improvement of intrinsic and extrinsic biomechanical properties when compared to control groups. Data revealed trends toward dose-dependent increases in peak torque, torsional rigidity, shear stress, and shear modulus 4 weeks after rhBMP-2 treatment. Level of evidence Not applicable.
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Affiliation(s)
- Frank A Liporace
- Division of Orthopaedic Trauma, Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, 301 E 17th Street, Suite 1402, New York, NY, 10003, USA,
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Lam SK, Sayama C, Harris DA, Briceño V, Luerssen TG, Jea A. Nationwide practice patterns in the use of recombinant human bone morphogenetic protein-2 in pediatric spine surgery as a function of patient-, hospital-, and procedure-related factors. J Neurosurg Pediatr 2014; 14:476-85. [PMID: 25171721 DOI: 10.3171/2014.7.peds1499] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECT Current national patterns as a function of patient-, hospital-, and procedure-related factors, and complication rates in the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) as an adjunct to the practice of pediatric spine surgery have scarcely been investigated. METHODS The authors conducted a cross-sectional study using data from the Healthcare Cost and Utilization Project Kids' Inpatient Database. Univariate and multivariate logistic regression were used to calculate unadjusted and adjusted odds ratios and 95% confidence intervals, and p values < 0.05 were considered to be statistically significant. RESULTS The authors identified 9538 hospitalizations in pediatric patients 20 years old or younger who had undergone spinal fusion in the US in 2009; 1541 of these admissions were associated with rhBMP-2 use. By multivariate logistic regression, the following factors were associated with rhBMP-2 use: patient age 15-20 years; length of hospital stay (adjusted odds ratio [aOR] 1.01, p = 0.017); insurance status (private [aOR 1.49, p < 0.001] compared with Medicaid); hospital type (nonchildren's hospital); region (Midwest [aOR 2.49, p = 0.008] compared with Northeast); spinal refusion (aOR 2.20, p < 0.001); spinal fusion approach/segment (anterior lumbar [aOR 1.73, p < 0.001] and occipitocervical [aOR 1.86, p = 0.013] compared with posterior lumbar); short segment length (aOR 1.42, p = 0.016) and midlength (aOR 1.44, p = 0.005) compared with long; and preoperative diagnosis (Scheuermann kyphosis [aOR 1.56, p < 0.017] and spondylolisthesis [aOR 1.93, p < 0.001]). CONCLUSIONS Use of BMP in pediatric spine procedures now comprises more than 10% of pediatric spinal fusion. Patient-related (age, insurance type, diagnosis); hospital-related (children's hospital vs general hospital, region in the US); and procedure-related (redo fusion, anterior vs posterior approach, spinal levels, number of levels fused) factors are associated with the variation in BMP use in the US.
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Affiliation(s)
- Sandi K Lam
- Neuro-Spine Program, Division of Pediatric Neurosurgery, Texas Children's Hospital, and Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
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Exaggerated inflammatory environment decreases BMP-2/ACS-induced ectopic bone mass in a rat model: implications for clinical use of BMP-2. Osteoarthritis Cartilage 2014; 22:1186-96. [PMID: 24981632 DOI: 10.1016/j.joca.2014.06.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 06/09/2014] [Accepted: 06/13/2014] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Numerous recent reports have observed a low osteoinductive efficacy property of bone morphogenetic protein-2 (BMP-2) and disappointing long-term outcomes in clinical cases. An alternative hypothesis, that these observations are caused by an exaggerated inflammatory environment, needs experimental evidence. METHOD Thirty-seven Sprague Dawley (SD) rats were administrated with Lipopolysaccharide (LPS) injections and BMP-2/absorbable collagen sponge (ACS) implantation to respectively mimic pre-operative and post-operative inflammatory responses. Blood samples and BMP-2/ACS implants were analyzed by enzyme-linked immunosorbent assay (ELISA), real-time polymerase chain reaction (PCR), micro-computed tomography (μCT) and histological examination. RESULTS LPS injections and BMP-2/ACS implantation provoked a significant elevation of inflammatory cytokines in serum and an obvious infiltration of inflammatory cells around BMP-2/ACS implants. The bone volume, mineral content and mineral density of the BMP-2/ACS implants from LPS-injected rats were significantly decreased, indicating that attenuated BMP-2-induced bone mass might be associated with down-regulated bone formation activity and up-regulated bone resorption activity. Furthermore, histological examination of the rhBMP-2/ACS implants showed a decreased expression of osteocalcin (OCN) and an increased number of osteoclasts in LPS-injected rats at 8 weeks; the expression level of bone turnover markers in serum and BMP-2/ACS implants revealed inhibited osteoblastogenesis activity and activated osteoclastogenesis activity in LPS-injected rats. Among the top three elevated pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) showed a suppressive effect on BMP-2-induced osteoblastic differentiation in vitro. CONCLUSION These data indicate that an exaggerated inflammatory environment may decrease BMP-2/ACS-induced bone mass in vivo by suppressing BMP-2-induced osteoblastic differentiation and by increasing the number or activity of osteoclasts. The negative role of exaggerated inflammation deserves consideration for future clinical use of BMP-2 in inducing bone regeneration.
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BMP-functionalised coatings to promote osteogenesis for orthopaedic implants. Int J Mol Sci 2014; 15:10150-68. [PMID: 24914764 PMCID: PMC4100145 DOI: 10.3390/ijms150610150] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Revised: 05/13/2014] [Accepted: 05/22/2014] [Indexed: 12/19/2022] Open
Abstract
The loss of bone integrity can significantly compromise the aesthetics and mobility of patients and can be treated using orthopaedic implants. Over the past decades; various orthopaedic implants; such as allografts; xenografts and synthetic materials; have been developed and widely used in clinical practice. However; most of these materials lack intrinsic osteoinductivity and thus cannot induce bone formation. Consequently; osteoinductive functionalisation of orthopaedic implants is needed to promote local osteogenesis and implant osteointegration. For this purpose; bone morphogenetic protein (BMP)-functionalised coatings have proven to be a simple and effective strategy. In this review; we summarise the current knowledge and recent advances regardingBMP-functionalised coatings for orthopaedic implants.
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Sun SX, Guo HH, Zhang J, Yu B, Sun KN, Jin QH. BMP-2 and titanium particles synergistically activate osteoclast formation. ACTA ACUST UNITED AC 2014; 47:461-9. [PMID: 24820069 PMCID: PMC4086172 DOI: 10.1590/1414-431x20132966] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Accepted: 11/25/2013] [Indexed: 02/06/2023]
Abstract
A previous study showed that BMP-2 (bone morphogenetic protein-2) and wear debris can
separately support osteoclast formation induced by the receptor activator of NF-κB
ligand (RANKL). However, the effect of BMP-2 on wear debris-induced osteoclast
formation is unclear. In this study, we show that neither titanium particles nor
BMP-2 can induce osteoclast formation in RAW 264.7 mouse leukemic monocyte macrophage
cells but that BMP-2 synergizes with titanium particles to enhance osteoclast
formation in the presence of RANKL, and that at a low concentration, BMP-2 has an
optimal effect to stimulate the size and number of multinuclear osteoclasts,
expression of osteoclast genes, and resorption area. Our data also clarify that the
effects caused by the increase in BMP-2 on phosphorylated SMAD levels such as c-Fos
expression increased throughout the early stages of osteoclastogenesis. BMP-2 and
titanium particles stimulate the expression of p-JNK, p-P38, p-IkB, and P50 compared
with the titanium group. These data suggested that BMP-2 may be a crucial factor in
titanium particle-mediated osteoclast formation.
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Affiliation(s)
- S X Sun
- Department of Orthopedics, Affiliated Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, China
| | - H H Guo
- Ningxia Medical University, Ningxia Hui Autonomous Region, China
| | - J Zhang
- Institute of Pathology, Xi'an Jiaotong University, Xi'an Shaanxi, China
| | - B Yu
- Ningxia Medical University, Ningxia Hui Autonomous Region, China
| | - K N Sun
- Department of Orthopedics, Affiliated Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, China
| | - Q H Jin
- Department of Orthopedics, Affiliated Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, China
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The effect of dose on rhBMP-2 signaling, delivered via collagen sponge, on osteoclast activation and in vivo bone resorption. Biomaterials 2014; 35:1869-81. [DOI: 10.1016/j.biomaterials.2013.11.029] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 11/08/2013] [Indexed: 12/31/2022]
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Fakhry M, Hamade E, Badran B, Buchet R, Magne D. Molecular mechanisms of mesenchymal stem cell differentiation towards osteoblasts. World J Stem Cells 2013; 5:136-148. [PMID: 24179602 PMCID: PMC3812518 DOI: 10.4252/wjsc.v5.i4.136] [Citation(s) in RCA: 183] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 08/01/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
Bone is a dynamic tissue that is constantly renewed by the coordinated action of two cell types, i.e., the bone-resorbing osteoclasts and the bone-forming osteoblasts. However, in some circumstances, bone regeneration exceeds bone self repair capacities. This is notably often the case after bone fractures, osteolytic bone tumor surgery, or osteonecrosis. In this regard, bone tissue engineering with autologous or allogenic mesenchymal stem cells (MSCs) is been widely developed. MSCs can be isolated from bone marrow or other tissues such as adipose tissue or umbilical cord, and can be implanted in bone defects with or without prior amplification and stimulation. However, the outcome of most pre-clinical studies remains relatively disappointing. A better understanding of the successive steps and molecular mechanisms involved in MSC-osteoblastic differentiation appears to be crucial to optimize MSC-bone therapy. In this review, we first present the important growth factors that stimulate osteoblastogenesis. Then we review the main transcription factors that modulate osteoblast differentiation, and the microRNAs (miRs) that inhibit their expression. Finally, we also discuss articles dealing with the use of these factors and miRs in the development of new bone MSC therapy strategies. We particularly focus on the studies using human MSCs, since significant differences exist between osteoblast differentiation mechanisms in humans and mice for instance.
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Dumas JE, Prieto EM, Zienkiewicz KJ, Guda T, Wenke JC, Bible J, Holt GE, Guelcher SA. Balancing the rates of new bone formation and polymer degradation enhances healing of weight-bearing allograft/polyurethane composites in rabbit femoral defects. Tissue Eng Part A 2013; 20:115-29. [PMID: 23941405 DOI: 10.1089/ten.tea.2012.0762] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
There is a compelling clinical need for bone grafts with initial bone-like mechanical properties that actively remodel for repair of weight-bearing bone defects, such as fractures of the tibial plateau and vertebrae. However, there is a paucity of studies investigating remodeling of weight-bearing bone grafts in preclinical models, and consequently there is limited understanding of the mechanisms by which these grafts remodel in vivo. In this study, we investigated the effects of the rates of new bone formation, matrix resorption, and polymer degradation on healing of settable weight-bearing polyurethane/allograft composites in a rabbit femoral condyle defect model. The grafts induced progressive healing in vivo, as evidenced by an increase in new bone formation, as well as a decrease in residual allograft and polymer from 6 to 12 weeks. However, the mismatch between the rates of autocatalytic polymer degradation and zero-order (independent of time) new bone formation resulted in incomplete healing in the interior of the composite. Augmentation of the grafts with recombinant human bone morphogenetic protein-2 not only increased the rate of new bone formation, but also altered the degradation mechanism of the polymer to approximate a zero-order process. The consequent matching of the rates of new bone formation and polymer degradation resulted in more extensive healing at later time points in all regions of the graft. These observations underscore the importance of balancing the rates of new bone formation and degradation to promote healing of settable weight-bearing bone grafts that maintain bone-like strength, while actively remodeling.
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Affiliation(s)
- Jerald E Dumas
- 1 Department of Chemical and Biomolecular Engineering, Vanderbilt University , Nashville, Tennessee
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Zarrinkalam MR, Schultz CG, Ardern DW, Vernon-Roberts B, Moore RJ. Recombinant human bone morphogenetic protein-type 2 (rhBMP-2) enhances local bone formation in the lumbar spine of osteoporotic sheep. J Orthop Res 2013; 31:1390-7. [PMID: 23737220 DOI: 10.1002/jor.22387] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Accepted: 04/25/2013] [Indexed: 02/04/2023]
Abstract
The failure of orthopedic implants in osteoporotic patients is attributed to the lack of sufficient bone stock and regenerative capacity but most treatments for osteoporosis fail to address this issue. rhBMP-2 is known to promote bone formation under normal conditions but has not been used clinically in the osteoporotic condition. Osteoporosis was induced in 19 ewes using ovariectomy, low calcium diet, and steroid injection. After induction, the steroid was withdrawn and pellets containing inert carrier with rhBMP-2 in either slow or fast-release formulation were implanted into the lumbar vertebrae of each animal. After 2, 3, and 6 months the spines were harvested and assessed for changes in BMD and histomorphometric indices. BMD did not change after cessation of steroid treatment. After 2 months BV/TV increased in the vicinity of the pellets containing the fast-release rhBMP-2 and was sustained for the duration of the study. Focal voids surrounding all implants, particularly the slow-release formulation, were observed initially but resolved with time. Increased BV/TV adjacent to rhBMP-2 pellets suggests it could be used for localized treatment of osteoporosis. Refinement of the delivery system and supplementary treatments may be necessary to overcome the initial catabolic effects of rhBMP-2.
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Affiliation(s)
- Mohammad Reza Zarrinkalam
- The Adelaide Centre for Spinal Research, Surgical Pathology, SA Pathology, Frome Road, Adelaide, South Australia, 5000, Australia.
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