|
1
|
Wu H, Li S, Wang W, Li J, Zhang W. Demineralized bone matrix combined with concentrated growth factors promotes intervertebral fusion in a novel rat extreme lateral interbody fusion model. J Orthop Surg Res 2025; 20:529. [PMID: 40426199 PMCID: PMC12117761 DOI: 10.1186/s13018-025-05954-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2025] [Accepted: 05/22/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND Whether demineralized bone matrix (DBM) combined with concentrated growth factors (CGF) can accelerate intervertebral fusion remains uncertain. This study developed a novel rat model for extreme lateral interbody fusion (XLIF) and evaluated the fusion outcomes of DBM combined with CGF using imaging and histological analysis. METHODS A total of 70 male SD rats (3 months old, average body weight 300 ± 50 g) were included in this study. Among them, 10 rats were used for the anatomical study of the lumbar spine. The remaining 48 rats were randomly divided into four groups (n = 12 per group): Group A (control), Group B (titanium plate fixation), Group C (DBM + titanium plate fixation), and Group D (DBM + CGF + titanium plate fixation). The remaining 12 rats were used as donors to prepare fresh CGF. Eight weeks after surgery, the rats were euthanized and lumbar spine specimens were collected, with interbody fusion evaluated by manual palpation. Subsequently, specimens from groups B, C, and D were analyzed by micro-CT and histological examinations to comprehensively assess the fusion outcome. RESULTS The anatomical and surgical techniques for the rat XLIF model are described. Titanium plates (7 mm × 2.5 mm × 0.8 mm) and screws (3 mm × 1 mm) were designed based on the anatomical measurements. In Group A, spontaneous fusion occurred in 1 case; the remaining 11 cases showed intervertebral mobility. In Group B, 3 cases achieved fusion; in Group C, 8 cases; and in Group D, 11 cases. Micro-CT revealed fusion index scores (FIS) of 2.21 ± 0.51 for Group B, 3.62 ± 0.67 for Group C, and 4.57 ± 0.56 for Group D. Histological examination showed limited bone formation in Group B, with fibrous connective tissue filling the intervertebral space. Group C showed more bone formation, but some cartilage and fibrous tissue remained. Group D demonstrated abundant new bone formation and robust histological fusion, with substantial bridging between vertebrae. CONCLUSION The rat XLIF model for interbody fusion has been successfully established and validated. Using this model, it was preliminarily demonstrated that DBM combined with CGF can effectively promote intervertebral fusion in rats.
Collapse
Affiliation(s)
- Han Wu
- Department of Spine Surgery, The Third Hospital of Hebei Medical University, 139 Ziqiang Street, Shijiazhuang, Hebei, 050031, China
| | - Shaorong Li
- Department of Spine Surgery, The Third Hospital of Hebei Medical University, 139 Ziqiang Street, Shijiazhuang, Hebei, 050031, China
| | - WeiJian Wang
- Department of Spine Surgery, The Third Hospital of Hebei Medical University, 139 Ziqiang Street, Shijiazhuang, Hebei, 050031, China
| | - Jiaqi Li
- Department of Spine Surgery, The Third Hospital of Hebei Medical University, 139 Ziqiang Street, Shijiazhuang, Hebei, 050031, China
| | - Wei Zhang
- Department of Spine Surgery, The Third Hospital of Hebei Medical University, 139 Ziqiang Street, Shijiazhuang, Hebei, 050031, China.
| |
Collapse
|
|
2
|
Gamada H, Funayama T, Setojima Y, Ogata Y, Sunami T, Sakashita K, Okuwaki S, Miura K, Noguchi H, Takahashi H, Yamazaki M, Koda M. Posterior fixation without debridement for pyogenic spondylodiscitis can promote infection control: initial evaluation of a pyogenic spondylodiscitis posterior fixation rat model. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2025:10.1007/s00586-025-08750-y. [PMID: 40029355 DOI: 10.1007/s00586-025-08750-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 10/24/2024] [Accepted: 02/14/2025] [Indexed: 03/05/2025]
Abstract
PURPOSE Pyogenic spondylodiscitis is a significant health concern, particularly in older individuals. Minimally invasive surgical techniques, such as posterior fixation, are promising for infection control; however, their mechanisms remain unclear. This study aimed to clarify how posterior fixation promotes infection control in an animal model. METHODS Thirty female Wistar rats were used to create a pyogenic spondylodiscitis model by injecting methicillin-sensitive Staphylococcus aureus into the intervertebral space between the 6th and 7th coccygeal vertebrae. Three days post-injection, rats were divided into fixation and control groups. The fixation group underwent posterior fixation with an external fixator, whereas the control group underwent screw insertion alone. Bone destruction was assessed via microcomputed tomography on postoperative days (POD) 7, 14, and 21. Immunohistochemistry for cathepsin K and receptor activator of nuclear factor-kappa B ligand (RANKL) was performed on POD 7 samples to assess osteoclast activity. RESULTS The fixation group showed less bone destruction than the control group at POD 14 (35% vs. 56%, p = 0.0007) and POD 21 (30% vs. 52%, p < 0.0001). The cathepsin K-positive area was significantly reduced in the fixation group (p = 0.027). RANKL expression was localized within the intervertebral disc in the fixation group, whereas RANKL was strongly expressed on the bone surface adjacent to the disc in control. The RANKL-positive area was also reduced in the fixation group (p = 0.041). CONCLUSIONS Our combined model of pyogenic spondylodiscitis and posterior fixation supports the theory that posterior fixation stability suppresses RANKL and osteoclast expression, promoting infection control.
Collapse
Affiliation(s)
- Hisanori Gamada
- Department of Orthopaedic Surgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Ibaraki, Japan
| | - Toru Funayama
- Department of Orthopaedic Surgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Ibaraki, Japan.
| | - Yusuke Setojima
- Department of Orthopaedic Surgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Ibaraki, Japan
| | - Yosuke Ogata
- Department of Orthopaedic Surgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Ibaraki, Japan
| | - Takahiro Sunami
- Department of Orthopaedic Surgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Ibaraki, Japan
| | - Kotaro Sakashita
- Department of Orthopaedic Surgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Ibaraki, Japan
| | - Shun Okuwaki
- Department of Orthopaedic Surgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Ibaraki, Japan
| | - Kousei Miura
- Department of Orthopaedic Surgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Ibaraki, Japan
| | - Hiroshi Noguchi
- Department of Orthopaedic Surgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Ibaraki, Japan
| | - Hiroshi Takahashi
- Department of Orthopaedic Surgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Ibaraki, Japan
| | - Masashi Yamazaki
- Department of Orthopaedic Surgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Ibaraki, Japan
| | - Masao Koda
- Department of Orthopaedic Surgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Ibaraki, Japan
| |
Collapse
|
|
3
|
Yoshizato H, Morimoto T, Nonaka T, Otani K, Kobayashi T, Nakashima T, Hirata H, Tsukamoto M, Mawatari M. Animal Model for Anterior Lumbar Interbody Fusion: A Literature Review. Spine Surg Relat Res 2024; 8:373-382. [PMID: 39131411 PMCID: PMC11310536 DOI: 10.22603/ssrr.2023-0262] [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] [Received: 10/24/2023] [Accepted: 12/22/2023] [Indexed: 08/13/2024] Open
Abstract
Lumbar interbody fusion (LIF) is a surgical procedure for treating lumbar spinal stenosis and deformities. It removes a spinal disc and insert a cage or bone graft to promote solid fusion. Extensive research on LIF has been supported by numerous animal studies, which are being developed to enhance fusion rates and reduce the complications associated with the procedure. In particular, the anterior approach is significant in LIF research and regenerative medicine studies concerning intervertebral discs, as it utilizes the disc and the entire vertebral body. Several animal models have been used for anterior LIF (ALIF), each with distinct characteristics. However, a comprehensive review of ALIF models in different animals is currently lacking. Medium-sized and large animals, such as dogs and sheep, have been employed as ALIF models because of their suitable spine size for surgery. Conversely, small animals, such as rats, are rarely employed as ALIF models because of anatomical challenges. However, recent advancements in surgical implants and techniques have gradually allowed rats in ALIF models. Ambitious studies utilizing small animal ALIF models will soon be conducted. This review aims to review the advantages and disadvantages of various animal models, commonly used approaches, and bone fusion rate, to provide valuable insights to researchers studying the spine.
Collapse
Affiliation(s)
- Hiromu Yoshizato
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Tadatsugu Morimoto
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Toshihiro Nonaka
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Koji Otani
- Department of Orthopedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | | | - Takema Nakashima
- Department of Orthopaedic Surgery, JCHO Saga Central Hospital, Saga, Japan
| | - Hirohito Hirata
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Masatsugu Tsukamoto
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Masaaki Mawatari
- Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| |
Collapse
|
|
4
|
Gantenbein B, Oswald KAC, Erbach GF, Croft AS, Bermudez-Lekerika P, Strunz F, Bigdon SF, Albers CE. The bone morphogenetic protein 2 analogue L51P enhances spinal fusion in combination with BMP2 in an in vivo rat tail model. Acta Biomater 2024; 177:148-156. [PMID: 38325708 DOI: 10.1016/j.actbio.2024.01.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 12/31/2023] [Accepted: 01/24/2024] [Indexed: 02/09/2024]
Abstract
Bone morphogenic protein 2 (BMP2) is known to induce osteogenesis and is applied clinically to enhance spinal fusion despite adverse effects. BMP2 needs to be used in high doses to be effective due to the presence of BMP2 inhibitors. L51P is a BMP2 analogue that acts by inhibition of BMP2 inhibitors. Here, we hypothesized that mixtures of BMP2 and L51P could achieve better spinal fusion outcomes regarding ossification. To test whether mixtures of both cytokines are sufficient to improve ossification, 45 elderly Wistar rats (of which 21 were males) were assigned to seven experimental groups, all which received spinal fusion surgery, including discectomy at the caudal 4-5 level using an external fixator and a porous β-tricalcium phosphate (βTCP) carrier. These βTCP carriers were coated with varying concentrations of BMP2 and L51P. X-rays were taken immediately after surgery and again six and twelve weeks post-operatively. Histological sections and µCT were analyzed after twelve weeks. Spinal fusion was assessed using X-ray, µCT and histology according to the Bridwell scale by voxel-based quantification and a semi-quantitative histological score, respectively. The results were congruent across modalities and revealed high ossification for high-dose BMP2 (10 µg), while PBS induced no ossification. Low-dose BMP2 (1 µg) or 10 µg L51P alone did not induce relevant bone formation. However, all combinations of low-dose BMP2 with L51P (1 µg + 1/5/10 µg) were able to induce similar ossificationas high-dose BMP2. These results are of high clinical relevance, as they indicate L51P is sufficient to increase the efficacy of BMP2 and thus lower the required dose for spinal fusion. STATEMENT OF SIGNIFICANCE: Spinal fusion surgery is frequently applied to treat spinal pathologies. Bone Morphogenic Protein-2 (BMP2) has been approved by the U .S. Food and Drug Administration (FDA-) and by the "Conformité Européenne" (CE)-label. However, its application is expensive and high concentrations cause side-effects. This research targets the improvement of the efficacy of BMP2 in spinal fusion surgery.
Collapse
Affiliation(s)
- Benjamin Gantenbein
- Department of Orthopaedic Surgery and Traumatology, Inselspital, Bern University Hospital, Medical Faculty, University of Bern, Bern, Switzerland; Tissue Engineering for Orthopaedics & Mechanobiology, Bone & Joint Program, Department for BioMedical Research (DBMR), Medical Faculty, University of Bern, Bern, Switzerland.
| | - Katharina A C Oswald
- Department of Orthopaedic Surgery and Traumatology, Inselspital, Bern University Hospital, Medical Faculty, University of Bern, Bern, Switzerland
| | - Georg F Erbach
- Department of Orthopaedic Surgery and Traumatology, Inselspital, Bern University Hospital, Medical Faculty, University of Bern, Bern, Switzerland
| | - Andreas S Croft
- Tissue Engineering for Orthopaedics & Mechanobiology, Bone & Joint Program, Department for BioMedical Research (DBMR), Medical Faculty, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, Bern, Switzerland
| | - Paola Bermudez-Lekerika
- Tissue Engineering for Orthopaedics & Mechanobiology, Bone & Joint Program, Department for BioMedical Research (DBMR), Medical Faculty, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, Bern, Switzerland
| | - Franziska Strunz
- Tissue Engineering for Orthopaedics & Mechanobiology, Bone & Joint Program, Department for BioMedical Research (DBMR), Medical Faculty, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, Bern, Switzerland
| | - Sebastian F Bigdon
- Department of Orthopaedic Surgery and Traumatology, Inselspital, Bern University Hospital, Medical Faculty, University of Bern, Bern, Switzerland
| | - Christoph E Albers
- Department of Orthopaedic Surgery and Traumatology, Inselspital, Bern University Hospital, Medical Faculty, University of Bern, Bern, Switzerland
| |
Collapse
|
|
5
|
Nielsen JJ, Low SA, Chen C, Li X, Mbachu E, Trigg L, Sun S, Tremby M, Hadap R, Low PS. Targeted Delivery of Abaloparatide to Spinal Fusion Site Accelerates Fusion Process in Rats. Biomedicines 2024; 12:612. [PMID: 38540225 PMCID: PMC10967909 DOI: 10.3390/biomedicines12030612] [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] [Received: 02/02/2024] [Revised: 02/28/2024] [Accepted: 03/01/2024] [Indexed: 11/11/2024] Open
Abstract
Spinal fusions are performed to treat congenital skeletal malformations, spondylosis, degenerative disk diseases, and other pathologies of the vertebrae that can be resolved by reducing motion between neighboring vertebrae. Unfortunately, up to 100,000 fusion procedures fail per year in the United States, suggesting that efforts to develop new approaches to improve spinal fusions are justified. We have explored whether the use of an osteotropic oligopeptide to target an attached bone anabolic agent to the fusion site might be exploited to both accelerate the mineralization process and improve the overall success rate of spinal fusions. The data presented below demonstrate that subcutaneous administration of a modified abaloparatide conjugated to 20 mer of D-glutamic acid not only localizes at the spinal fusion site but also outperforms the standard of care (topically applied BMP2) in both speed of mineralization (p < 0.05) and overall fusion success rate (p < 0.05) in a posterior lateral spinal fusion model in male and female rats, with no accompanying ectopic mineralization. Because the bone-localizing conjugate can be administered ad libitum post-surgery, and since the procedure appears to improve on standard of care, we conclude that administration of a bone-homing anabolic agent for improvement of spinal fusion surgeries warrants further exploration.
Collapse
Affiliation(s)
- Jeffery J. Nielsen
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA;
- Novosteo Inc., West Lafayette, IN 47906, USA
| | - Stewart A. Low
- Novosteo Inc., West Lafayette, IN 47906, USA
- Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
| | | | - Xinlan Li
- Novosteo Inc., West Lafayette, IN 47906, USA
| | | | - Lina Trigg
- Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Siyuan Sun
- Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Madeline Tremby
- Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Rahul Hadap
- Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Philip S. Low
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA;
- Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
| |
Collapse
|
|
6
|
Heumann M, Benneker LM, Constant C, Ernst M, Richards RG, Wilke HJ, Gueorguiev B, Windolf M. Decreasing implant load indicates spinal fusion when measured continuously. J Biomech 2024; 163:111929. [PMID: 38218695 DOI: 10.1016/j.jbiomech.2024.111929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/26/2023] [Accepted: 01/03/2024] [Indexed: 01/15/2024]
Abstract
Reliable and timely assessment of bone union between vertebrae is considered a key challenge after spinal fusion surgery. Recently, a novel sensor concept demonstrated the ability to objectively assess posterolateral fusion based on continuous implant load monitoring. The aim of this study was to investigate systematically the concept in a mono-segmental fusion model using an updated sensor setup. Three sheep underwent bilateral facetectomy at level L2-L3 and L4-L5. The segments were stabilized using two unconnected pedicle-screw-rod constructs per level. Sensing devices were attached to the rods between each pedicle screw pair and the loads were continuously monitored over 16 weeks. After euthanasia, the spines were biomechanically tested for their range of motion and high-resolution CT scans were performed to confirm the fusion success. After an initial increase in implant load until reaching a maximum (100 %) at approximately week 4, eleven out of twelve sensors measured a constant decrease in implant load to 52 ± 9 % at euthanasia. One sensor measurement was compromised by newly forming bone growing against the sensor clamp. Bridging bone at each facet and minor remnant segmental motion (<0.7°) confirmed the fusion of all motion segments. Data obtained by continuous measurement of implant loading of spinal screw-rod constructs enables objective monitoring of spinal fusion progression. The sensor concept provides valuable real-time information, offering quantifiable data as an alternative to traditional imaging techniques. However, the design of the current sensor concept needs to be matured, tailored to, and validated for the human spine.
Collapse
Affiliation(s)
- Maximilian Heumann
- AO Research Institute Davos, Davos, Switzerland; Institute of Orthopaedic Research and Biomechanics, Trauma Research Center Ulm, Ulm University, Ulm, Germany.
| | | | | | | | | | - Hans-Joachim Wilke
- Institute of Orthopaedic Research and Biomechanics, Trauma Research Center Ulm, Ulm University, Ulm, Germany
| | | | | |
Collapse
|
|
7
|
McClendon MT, Ji W, Greene AC, Sai H, Sangji MH, Sather NA, Chen CH, Lee SS, Katchko K, Jeong SS, Kannan A, Weiner J, Cook R, Driscoll A, Lubbe R, Chang K, Haleem M, Chen F, Qiu R, Chun D, Stock SR, Hsu WK, Hsu EL, Stupp SI. A supramolecular polymer-collagen microparticle slurry for bone regeneration with minimal growth factor. Biomaterials 2023; 302:122357. [PMID: 37879188 PMCID: PMC10897953 DOI: 10.1016/j.biomaterials.2023.122357] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 10/05/2023] [Accepted: 10/15/2023] [Indexed: 10/27/2023]
Abstract
Recombinant bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive growth factor that can promote bone regeneration for challenging skeletal repair and even for ectopic bone formation in spinal fusion procedures. However, serious clinical side effects related to supraphysiological dosing highlight the need for advances in novel biomaterials that can significantly reduce the amount of this biologic. Novel biomaterials could not only reduce clinical side effects but also expand the indications for use of BMP-2, while at the same time lowering the cost of such procedures. To achieve this objective, we have developed a slurry containing a known supramolecular polymer that potentiates BMP-2 signaling and porous collagen microparticles. This slurry exhibits a paste-like consistency that stiffens into an elastic gel upon implantation making it ideal for minimally invasive procedures. We carried out in vivo evaluation of the novel biomaterial in the rabbit posterolateral spine fusion model, and discovered efficacy at unprecedented ultra-low BMP-2 doses (5 μg/implant). This dose reduces the growth factor requirement by more than 100-fold relative to current clinical products. This observation is significant given that spinal fusion involves ectopic bone formation and the rabbit model is known to be predictive of human efficacy. We expect the novel biomaterial can expand BMP-2 indications for difficult cases requiring large volumes of bone formation or involving patients with underlying conditions that compromise bone regeneration.
Collapse
Affiliation(s)
- Mark T McClendon
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States
| | - Wei Ji
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States
| | - Allison C Greene
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States; Department of Orthopaedic Surgery, Northwestern University, Chicago, IL, 60611, United States
| | - Hiroaki Sai
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States
| | - M Hussain Sangji
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States; Department of Biomedical Engineering, Northwestern University, Evanston, IL, 60208, United States
| | - Nicholas A Sather
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States
| | - Charlotte H Chen
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States
| | - Sungsoo S Lee
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States
| | - Karina Katchko
- Department of Orthopaedic Surgery, Northwestern University, Chicago, IL, 60611, United States
| | - Soyeon Sophia Jeong
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States; Department of Orthopaedic Surgery, Northwestern University, Chicago, IL, 60611, United States
| | - Abhishek Kannan
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States; Department of Orthopaedic Surgery, Northwestern University, Chicago, IL, 60611, United States
| | - Joseph Weiner
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States; Department of Orthopaedic Surgery, Northwestern University, Chicago, IL, 60611, United States
| | - Ralph Cook
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States; Department of Orthopaedic Surgery, Northwestern University, Chicago, IL, 60611, United States
| | - Adam Driscoll
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States; Department of Orthopaedic Surgery, Northwestern University, Chicago, IL, 60611, United States
| | - Ryan Lubbe
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States; Department of Orthopaedic Surgery, Northwestern University, Chicago, IL, 60611, United States
| | - Kevin Chang
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States; Department of Orthopaedic Surgery, Northwestern University, Chicago, IL, 60611, United States
| | - Meraaj Haleem
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States; Department of Orthopaedic Surgery, Northwestern University, Chicago, IL, 60611, United States
| | - Feng Chen
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States
| | - Ruomeng Qiu
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States; Department of Chemistry, Northwestern University, Evanston, IL, 60208, United States
| | - Danielle Chun
- Department of Orthopaedic Surgery, Northwestern University, Chicago, IL, 60611, United States
| | - Stuart R Stock
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL, 60611, United States
| | - Wellington K Hsu
- Department of Orthopaedic Surgery, Northwestern University, Chicago, IL, 60611, United States
| | - Erin L Hsu
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States; Department of Orthopaedic Surgery, Northwestern University, Chicago, IL, 60611, United States
| | - Samuel I Stupp
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, 60611, United States; Department of Biomedical Engineering, Northwestern University, Evanston, IL, 60208, United States; Department of Chemistry, Northwestern University, Evanston, IL, 60208, United States; Department of Materials Science and Engineering, Northwestern University, Evanston, IL, 60208, United States; Department of Medicine, Northwestern University, Chicago, IL, 60611, United States.
| |
Collapse
|
|
8
|
Sheng XQ, Yang Y, Ding C, Wang BY, Hong Y, Meng Y, Liu H. Uncovertebral Joint Fusion Versus End Plate Space Fusion in Anterior Cervical Spine Surgery: A Prospective Randomized Controlled Trial. J Bone Joint Surg Am 2023; 105:1168-1174. [PMID: 37228228 DOI: 10.2106/jbjs.22.01375] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
BACKGROUND The uncovertebral joint is a potential region for anterior cervical fusion. Currently, we are aware of no clinical trials on human uncovertebral joint fusion (UJF). The purpose of this study was to compare the time it took to achieve osseous union/fusion and the clinical efficacy of UJF to end plate space fusion (ESF)-i.e., traditional anterior cervical discectomy and fusion (ACDF)-in anterior cervical surgery. METHODS Patients with single-level cervical spondylosis were recruited from April 2021 through October 2022 and randomly divided into the UJF and ESF groups, with 40 patients in each group. Autologous iliac bone was used for bone grafting in both groups. The primary outcome was the early fusion rate at 3 months postoperatively. Secondary outcomes included the prevalence of complications and patient-reported outcome measures (PROMs), including the Japanese Orthopaedic Association (JOA) score, Neck Disability Index (NDI), and visual analog scale (VAS) scores for arm and neck pain. RESULTS A total of 74 patients (92.5%) with an average age of 49.8 years (range, 26 to 65 years) completed the trial and were included in the analysis. There was no significant difference between the 2 groups at baseline. The operative duration and intraoperative blood loss were also comparable between the 2 groups. The fusion rate in the UJF group was significantly higher than that in the ESF group at 3 months (66.7% compared with 13.2%, p < 0.0001) and 6 months (94.1% compared with 66.7%, p = 0.006) after the operation. No significant difference was found in the fusion rate between the 2 groups 12 months postoperatively. Overall, the PROMs significantly improved after surgery in both groups and did not differ significantly between the groups at any follow-up time point. The prevalence of complications was not significantly different between the 2 groups. CONCLUSIONS In our study of anterior cervical fusion surgery, we found that the early fusion rate after UJF was significantly higher than that after ESF. LEVEL OF EVIDENCE Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.
Collapse
Affiliation(s)
- Xia-Qing Sheng
- Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Yi Yang
- Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Chen Ding
- Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Bei-Yu Wang
- Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Ying Hong
- Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
- Department of Anesthesia and Operation Center, West China School of Nursing, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Yang Meng
- Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Hao Liu
- Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| |
Collapse
|
|
9
|
Daldal I, Senkoylu A, Degim IT, Ilbasmıs Tamer S, Omeroglu S, Akarca Dizakar SO, Celik HH, Uzuner MB, Kurtoglu A, Yapar D, Yapar A. The combined use of carbon nanotubes with synthetic ceramics enhances posterolateral fusion: an experimental study in a rat spinal fusion model. Spine Deform 2023; 11:805-814. [PMID: 36750546 DOI: 10.1007/s43390-023-00659-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 01/29/2023] [Indexed: 02/09/2023]
Abstract
PURPOSE The aim of the present study was to evaluate the effectiveness of carbon nanotubes (CNTs)/ HA-tricalcium phosphate (TCP) composite in a posterolateral spinal fusion model. METHODS At first, CNTs and CNTs/HA-TCP composites were prepared. Twenty adult male Sprague Dawley rats were randomized into four groups with five rats in each group. Decortication was carried out in standard manner in all animals. Group 1 (only decortication), group 2 (CNTs), group 3 (HA-TCP) and group 4 (CNTs/HA-TCP) were formed. Eight weeks later, all animals were killed and obtained fusion segments were evaluated by manual palpation, histomorphometry and micro-computed tomography (mCT). RESULTS In all evaluations, highest fusion values were obtained in Group 4. In mCT investigations, bone volume/ tissue volume (BV/TV) ratio was found to be significantly higher in composite group (group 4) only compared to ceramic group (group 3) (p < 0.001). Although in Group 2, in which only CNTs were used, the ratio was found to be statistically significantly higher than group 1(p < 0.001), the difference was not considered as significant in terms of fusion and in addition in group 2, CNTs were completely surrounded by fibrous tissue, i.e., no bone formation was observed. CONCLUSIONS The CNTs/HA-TCP composite is a promising synthetic bone graft substitute for spinal fusion. Although CNTs are inadequate in producing spinal fusion when they are used alone, due to their high biocompatibility due to their high biocompatibility, and multiple effect on bone regeneration, they seem to increase fusion rates significantly when they are used in combination with ceramic-based synthetic grafts.
Collapse
Affiliation(s)
- Ismail Daldal
- Department of Orthopedics and Traumatology, Medicana İnternational İstanbul Hospital, İstanbul, Turkey
| | - Alpaslan Senkoylu
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Ismail Tuncer Degim
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Biruni University, Istanbul, Turkey
| | - Sibel Ilbasmıs Tamer
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Ankara, Turkey
| | - Suna Omeroglu
- Department of Histology and Embryology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | | | - Hakan Hamdi Celik
- Department of Anatomy, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Muhammet Bora Uzuner
- Department of Anatomy, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Alper Kurtoglu
- Sakarya University Training and Research Hospital, Sakarya, Turkey
| | - Dilek Yapar
- Department of Public Health, Ministry of Health, Antalya, Turkey
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Akdeniz University, Antalya, Turkey
| | - Aliekber Yapar
- Department of Orthopedics and Traumatology, Antalya Training and Research Hospital, Antalya, Turkey.
| |
Collapse
|
|
10
|
Duits A, Salvatori D, Schouten J, van Urk P, Gaalen SV, Ottink K, Öner C, Kruyt M. Preclinical model for lumbar interbody fusion in small ruminants: Rationale and guideline. J Orthop Translat 2023; 38:167-174. [DOI: 10.1016/j.jot.2022.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 09/27/2022] [Accepted: 10/10/2022] [Indexed: 11/18/2022] Open
|
|
11
|
Terhune EA, Monley AM, Cuevas MT, Wethey CI, Gray RS, Hadley-Miller N. Genetic animal modeling for idiopathic scoliosis research: history and considerations. Spine Deform 2022; 10:1003-1016. [PMID: 35430722 DOI: 10.1007/s43390-022-00488-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 02/19/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE Idiopathic scoliosis (IS) is defined as a structural lateral spinal curvature ≥ 10° in otherwise healthy children and is the most common pediatric spinal deformity. IS is known to have a strong genetic component; however, the underlying etiology is still largely unknown. Animal models have been used historically to both understand and develop treatments for human disease, including within the context of IS. This intended audience for this review is clinicians in the fields of musculoskeletal surgery and research. METHODS In this review article, we synthesize current literature of genetic animal models of IS and introduce considerations for researchers. RESULTS Due to complex genetic and unique biomechanical factors (i.e., bipedalism) hypothesized to contribute to IS in humans, scoliosis is a difficult condition to replicate in model organisms. CONCLUSION We advocate careful selection of animal models based on the scientific question and introduce gaps and limitations in the current literature. We advocate future research efforts to include animal models with multiple characterized genetic or environmental perturbations to reflect current understanding of the human condition.
Collapse
Affiliation(s)
- Elizabeth A Terhune
- Department of Orthopedics, University of Colorado Anschutz Medical Campus, 12800 E 19th Ave., P18-3105, MS 8343, Aurora, CO, 80045, USA
| | - Anna M Monley
- Department of Orthopedics, University of Colorado Anschutz Medical Campus, 12800 E 19th Ave., P18-3105, MS 8343, Aurora, CO, 80045, USA.,Musculoskeletal Research Center, Children's Hospital Colorado, Aurora, CO, 80045, USA
| | - Melissa T Cuevas
- Department of Orthopedics, University of Colorado Anschutz Medical Campus, 12800 E 19th Ave., P18-3105, MS 8343, Aurora, CO, 80045, USA
| | - Cambria I Wethey
- Department of Orthopedics, University of Colorado Anschutz Medical Campus, 12800 E 19th Ave., P18-3105, MS 8343, Aurora, CO, 80045, USA
| | - Ryan S Gray
- Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, 78712, USA
| | - Nancy Hadley-Miller
- Department of Orthopedics, University of Colorado Anschutz Medical Campus, 12800 E 19th Ave., P18-3105, MS 8343, Aurora, CO, 80045, USA. .,Musculoskeletal Research Center, Children's Hospital Colorado, Aurora, CO, 80045, USA.
| |
Collapse
|
|
12
|
Laubach M, Kobbe P, Hutmacher DW. Biodegradable interbody cages for lumbar spine fusion: Current concepts and future directions. Biomaterials 2022; 288:121699. [PMID: 35995620 DOI: 10.1016/j.biomaterials.2022.121699] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/14/2022] [Accepted: 07/22/2022] [Indexed: 11/16/2022]
Abstract
Lumbar fusion often remains the last treatment option for various acute and chronic spinal conditions, including infectious and degenerative diseases. Placement of a cage in the intervertebral space has become a routine clinical treatment for spinal fusion surgery to provide sufficient biomechanical stability, which is required to achieve bony ingrowth of the implant. Routinely used cages for clinical application are made of titanium (Ti) or polyetheretherketone (PEEK). Ti has been used since the 1980s; however, its shortcomings, such as impaired radiographical opacity and higher elastic modulus compared to bone, have led to the development of PEEK cages, which are associated with reduced stress shielding as well as no radiographical artefacts. Since PEEK is bioinert, its osteointegration capacity is limited, which in turn enhances fibrotic tissue formation and peri-implant infections. To address shortcomings of both of these biomaterials, interdisciplinary teams have developed biodegradable cages. Rooted in promising preclinical large animal studies, a hollow cylindrical cage (Hydrosorb™) made of 70:30 poly-l-lactide-co-d, l-lactide acid (PLDLLA) was clinically studied. However, reduced bony integration and unfavourable long-term clinical outcomes prohibited its routine clinical application. More recently, scaffold-guided bone regeneration (SGBR) with application of highly porous biodegradable constructs is emerging. Advancements in additive manufacturing technology now allow the cage designs that match requirements, such as stiffness of surrounding tissues, while providing long-term biomechanical stability. A favourable clinical outcome has been observed in the treatment of various bone defects, particularly for 3D-printed composite scaffolds made of medical-grade polycaprolactone (mPCL) in combination with a ceramic filler material. Therefore, advanced cage design made of mPCL and ceramic may also carry initial high spinal forces up to the time of bony fusion and subsequently resorb without clinical side effects. Furthermore, surface modification of implants is an effective approach to simultaneously reduce microbial infection and improve tissue integration. We present a design concept for a scaffold surface which result in osteoconductive and antimicrobial properties that have the potential to achieve higher rates of fusion and less clinical complications. In this review, we explore the preclinical and clinical studies which used bioresorbable cages. Furthermore, we critically discuss the need for a cutting-edge research program that includes comprehensive preclinical in vitro and in vivo studies to enable successful translation from bench to bedside. We develop such a conceptual framework by examining the state-of-the-art literature and posing the questions that will guide this field in the coming years.
Collapse
Affiliation(s)
- Markus Laubach
- Australian Research Council (ARC) Training Centre for Cell and Tissue Engineering Technologies, Queensland University of Technology (QUT), Brisbane, QLD, 4000 Australia; Australian Research Council (ARC) Training Centre for Multiscale 3D Imaging, Modelling, and Manufacturing (M3D Innovation), Queensland University of Technology, Brisbane, QLD 4000, Australia; Centre for Biomedical Technologies, School of Mechanical, Medical and Process Engineering, Queensland University of Technology, Brisbane, QLD 4059, Australia; Department of Orthopaedics, Trauma and Reconstructive Surgery, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany.
| | - Philipp Kobbe
- Department of Orthopaedics, Trauma and Reconstructive Surgery, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany
| | - Dietmar W Hutmacher
- Australian Research Council (ARC) Training Centre for Cell and Tissue Engineering Technologies, Queensland University of Technology (QUT), Brisbane, QLD, 4000 Australia; Australian Research Council (ARC) Training Centre for Multiscale 3D Imaging, Modelling, and Manufacturing (M3D Innovation), Queensland University of Technology, Brisbane, QLD 4000, Australia; Centre for Biomedical Technologies, School of Mechanical, Medical and Process Engineering, Queensland University of Technology, Brisbane, QLD 4059, Australia; Max Planck Queensland Center for the Materials Science of Extracellular Matrices, Queensland University of Technology, Brisbane, QLD 4000, Australia.
| |
Collapse
|
|
13
|
Laratta JL, Vivace BJ, López-Peña M, Guzón FM, Gonzalez-Cantalpeidra A, Jorge-Mora A, Villar-Liste RM, Pino-Lopez L, Lukyanchuk A, Taghizadeh EA, Pino-Minguez J. 3D-printed titanium cages without bone graft outperform PEEK cages with autograft in an animal model. Spine J 2022; 22:1016-1027. [PMID: 34906741 DOI: 10.1016/j.spinee.2021.12.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 11/29/2021] [Accepted: 12/06/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Modernization of 3D printing has allowed for the production of porous titanium interbody cages (3D-pTi) which purportedly optimize implant characteristics and increase osseointegration; however, this remains largely unstudied in vivo. PURPOSE To compare osseointegration of three-dimensional (3D) titanium cages without bone graft and Polyether-ether-ketone (PEEK) interbody cages with autologous iliac crest bone graft (AICBG). STUDY DESIGN Animal study utilizing an ovine in vivo model of lumbar fusion. METHODS Interbody cages of PEEK or 3D-pTi supplied by Spineart SA (Geneva, Switzerland) were implanted in seven living sheep at L2-L3 and L4-L5, leaving the intervening disc space untreated. Both implant materials were used in each sheep and randomized to the aforementioned disc spaces. Computed tomography (CT) was obtained at 4 weeks and 8 weeks. MicroCT and histological sections were obtained to evaluate osseointegration. RESULTS MicroCT demonstrated osseous in-growth of native cancellous bone in the trabecular architecture of the 3D-pTi interbody cages and no interaction between the PEEK cages with the surrounding native bone. Qualitative histology revealed robust osseointegration in 3D-pTi implants and negligible osseointegration with localized fibrosis in PEEK implants. Evidence of intramembranous and endochondral ossification was apparent with the 3D-pTi cages. Quantitative histometric bone implant contact demonstrated significantly more contact in the 3D-pTi implants versus PEEK (p<.001); region of interest calculations also demonstrated significantly greater osseous and cartilaginous interdigitation at the implant-native bone interface with the 3D-pTi cages (p=.008 and p=.015, respectively). CONCLUSIONS 3D-pTi interbody cages without bone graft outperform PEEK interbody cages with AICBG in terms of osseointegration at 4 and 8 weeks postoperatively in an ovine lumbar fusion model. CLINICAL SIGNIFICANCE 3D-pTi interbody cages demonstrated early and robust osseointegration without any bone graft or additive osteoinductive agents. This may yield early stability in anterior lumbar arthrodesis and potentially bolster the rate of successful fusion. This could be of particular advantage in patients with spinal neoplasms needing post-ablative arthrodesis, where local autograft use would be ill advised.
Collapse
Affiliation(s)
- Joseph L Laratta
- Department of Orthopaedic Surgery, University of Louisville School of Medicine, Louisville, KY, USA
| | - Bradley J Vivace
- Department of Orthopaedic Surgery, University of Louisville School of Medicine, Louisville, KY, USA.
| | - Mónica López-Peña
- University of Santiago de Compostela, School of Veterinary Medicine, Santiago de Compostela, Galicia, Spain
| | - Fernando Muñoz Guzón
- University of Santiago de Compostela, School of Veterinary Medicine, Santiago de Compostela, Galicia, Spain
| | | | - Alberto Jorge-Mora
- Santiago de Compostela University Hospital, Department of Orthopaedic Surgery, Santiago de Compostela, Galicia, Spain
| | - Rosa Maria Villar-Liste
- Fundación IDIS. Santiago de Compostela University Hospital, Santiago de Compostela, Galicia, Spain
| | - Laura Pino-Lopez
- Fundación IDIS. Santiago de Compostela University Hospital, Santiago de Compostela, Galicia, Spain
| | | | | | - Jesús Pino-Minguez
- Santiago de Compostela University Hospital, Department of Orthopaedic Surgery, Santiago de Compostela, Galicia, Spain
| |
Collapse
|
|
14
|
Slot EMH, Boer B, Redegeld S, Thoor S, Moayeri N, Slooff W, Schaafsma IA, Meij B, Doormaal TPC. Spinal fixation after laminectomy in pigs prevents postoperative spinal cord injury. Animal Model Exp Med 2022; 5:153-160. [PMID: 35234366 PMCID: PMC9043715 DOI: 10.1002/ame2.12213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 01/06/2022] [Accepted: 01/07/2022] [Indexed: 11/16/2022] Open
Abstract
Background A safe, effective, and ethically sound animal model is essential for preclinical research to investigate spinal medical devices. We report the initial failure of a porcine spinal survival model and a potential solution by fixating the spine. Methods Eleven female Dutch Landrace pigs underwent a spinal lumbar interlaminar decompression with durotomy and were randomized for implantation of a medical device or control group. Magnetic resonance imaging (MRI) was performed before termination. Results Neurological deficits were observed in 6 out of the first 8 animals. Three of these animals were terminated prematurely because they reached the predefined humane endpoint. Spinal cord compression and myelopathy was observed on postoperative MRI imaging. We hypothesized postoperative spinal instability with epidural hematoma, inherent to the biology of the model, and subsequent spinal cord injury as a potential cause. In the subsequent 3 animals, we fixated the spine with Lubra plates. All these animals recovered without neurological deficits. The extent of spinal cord compression on MRI was variable across animals and did not seem to correspond well with neurological outcome. Conclusion This study shows that in a porcine in vivo model of interlaminar decompression and durotomy, fixation of the spine after lumbar interlaminar decompression is feasible and may improve neurological outcomes. Additional research is necessary to evaluate this hypothesis.
Collapse
Affiliation(s)
- Emma M. H. Slot
- Department of Neurology and Neurosurgery University Medical Center Utrecht Utrecht The Netherlands
| | - Bart Boer
- Department of Neurosurgery Elizabeth TweeSteden Hospital Tilburg The Netherlands
| | | | - Sander Thoor
- Brain Technology Institute Utrecht The Netherlands
| | - Nizar Moayeri
- Department of Neurology and Neurosurgery University Medical Center Utrecht Utrecht The Netherlands
| | - Willem‐Bart Slooff
- Department of Neurology and Neurosurgery University Medical Center Utrecht Utrecht The Netherlands
| | - Irene A. Schaafsma
- Department of Clinical Sciences Faculty of Veterinary Medicine Utrecht University Utrecht The Netherlands
| | - Björn Meij
- Department of Clinical Sciences Faculty of Veterinary Medicine Utrecht University Utrecht The Netherlands
| | - Tristan P. C. Doormaal
- Department of Neurology and Neurosurgery University Medical Center Utrecht Utrecht The Netherlands
- Department of Neurosurgery Clinical Neuroscience Center University Hospital Zurich Zurich Switzerland
| |
Collapse
|
|
15
|
Establishment of a Novel Method for Spinal Discectomy Surgery in Elderly Rats in an In Vivo Spinal Fusion Model. Methods Protoc 2021; 4:mps4040079. [PMID: 34842793 PMCID: PMC8628999 DOI: 10.3390/mps4040079] [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] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/22/2021] [Accepted: 10/29/2021] [Indexed: 11/18/2022] Open
Abstract
The rat model is a common model for intervertebral disc (IVD) and spinal research. However, complications remain challenging. Standard Operating Procedures (SOPs) are validated methods to minimize complications and improve safety and quality of studies. However, a SOP for rat spinal fusion surgery has been missing until now. Therefore, the aim of the study was to develop a SOP for spinal tail disc surgery in elderly Wistar rats (419.04 ± 54.84 g). An initial preoperative, intraoperative, and postoperative surgical setup, including specific anaesthesia and pain management protocols, was developed. Anaesthesia was induced by subcutaneous injection of a pre-mixture of fentanyl, midazolam, and medetomidin with the addition of 0.5% isoflurane in oxygen and caudal epidural analgesia. The surgery itself consisted of the fixation of a customized external ring fixator with ⌀ 0.8 mm Kirschner wires at the proximal rat tail and a discectomy and replacement with bone morphogenetic protein coated beta-tricalcium-phosphate carrier. The postoperative setup included heating, analgesia with buprenorphine, and meloxicam, as well as special supplementary food. Anaesthesia, surgery, and pain management were sufficient. In the presented optimized SOP, no animals developed any complications. A SOP for spinal surgery in elderly rats in an in vivo spinal fusion model was developed successfully. This novel protocol can improve transparency, reproducibility, and external validity in experimental rat spinal surgery experiments.
Collapse
|
|
16
|
Shen YW, Yang Y, Liu H, Wu TK, Ma LT, Chen L, Hu LY, Ding C, Rong X, Wang BY, Meng Y, Hong Y. Preliminary results in anterior cervical discectomy and fusion with the uncovertebral joint fusion cage in a goat model. BMC Musculoskelet Disord 2021; 22:628. [PMID: 34273965 PMCID: PMC8286593 DOI: 10.1186/s12891-021-04412-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 05/28/2021] [Indexed: 02/08/2023] Open
Abstract
Objective To preliminarily evaluate the safety and efficacy of the uncovertebral joint fusion cage in a goat model of cervical spine interbody fusion. Methods Twenty-four healthy adult goats were randomly assigned to one of the two following groups: Group A, goats were implanted with an uncovertebral joint fusion cage combined with a local autograft and Group B, goats were implanted with a non-profile cage filled with a local autograft. The goats were prospectively evaluated for 24 weeks and then were sacrificed for evaluation. X-rays, CT and micro-CT scanning, and undecalcified bone histological analysis were used for the evaluation of fusion. Results 75.0% (9/12) of the goats in Group A were evaluated as having fusion at 12 weeks, compared to 41.7% (5/12) in Group B. 83.3% (10/12) of the goats in Group A were evaluated as having fusion at 24 weeks compared to 58.3% (7/12) in Group B. The fusion grading scores in Group A were significantly higher than that in Group B both at 12 weeks and 24 weeks (P < 0.05). Micro-CT scanning and undecalcified bone histological analysis showed that new bone formation can be obviously found in the bilateral uncovertebral joint. The bone volume fraction (BV/ TV) in Group A (23.59 ± 4.43%) was significantly higher than Group B (16.16 ± 4.21%), with P < 0.05. Conclusions Preliminary results of this study demonstrated that uncovertebral joint fusion cage is effective for achieving early bone formation and fusion without increase of serious complications.
Collapse
Affiliation(s)
- Yi-Wei Shen
- Department of Orthopedic surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Rd, Chengdu, 610041, China
| | - Yi Yang
- Department of Orthopedic surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Rd, Chengdu, 610041, China
| | - Hao Liu
- Department of Orthopedic surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Rd, Chengdu, 610041, China.
| | - Ting-Kui Wu
- Department of Orthopedic surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Rd, Chengdu, 610041, China
| | - Li-Tai Ma
- Department of Orthopedic surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Rd, Chengdu, 610041, China
| | - Lin Chen
- Department of Orthopedic surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Rd, Chengdu, 610041, China
| | - Ling-Yun Hu
- Department of Orthopedic surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Rd, Chengdu, 610041, China
| | - Chen Ding
- Department of Orthopedic surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Rd, Chengdu, 610041, China
| | - Xin Rong
- Department of Orthopedic surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Rd, Chengdu, 610041, China
| | - Bei-Yu Wang
- Department of Orthopedic surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Rd, Chengdu, 610041, China
| | - Yang Meng
- Department of Orthopedic surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Rd, Chengdu, 610041, China
| | - Ying Hong
- Department of Operation Room and Anesthesia Center, West China Hospital, Sichuan University, No. 37 Guo Xue Rd, Chengdu, 610041, China
| |
Collapse
|
|
17
|
Arlt H, Besschetnova T, Ominsky MS, Fredericks DC, Lanske B. Effects of systemically administered abaloparatide, an osteoanabolic PTHrP analog, as an adjuvant therapy for spinal fusion in rats. JOR Spine 2021; 4:e1132. [PMID: 33778406 PMCID: PMC7984001 DOI: 10.1002/jsp2.1132] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/26/2020] [Accepted: 11/04/2020] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Abaloparatide is a parathyroid hormone receptor agonist that increases bone formation and reduces vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis. Animal studies indicate abaloparatide stimulates vertebral bone formation and enhances bony bridging and biomechanical stability of fracture calluses. AIMS The current study is evaluating the potential utility for abaloparatide as an adjunct therapy for spinal fusions. MATERIAL AND METHODS The effects of 14 or 28 days of daily subcutaneous injections of abaloparatide (20 μg/kg/d) or vehicle were evaluated in 32 male Sprague-Dawley rats starting 1 day after noninstrumented posterolateral fusion (PLF) with bone autograft. Fusion mass microarchitecture was analyzed by micro-computed tomography (micro-CT) and serum markers of bone formation and bone resorption were evaluated. Motion segments were scored in a blinded manner as fused or unfused by postmortem radiography and manual palpation. RESULTS Abaloparatide-treated rats showed higher bone formation (serum osteocalcin) at day 14 and 28 compared with vehicle controls, without increases in the bone resorption marker serum TRACP-5b. Micro-CT showed greater trabecular number in fusion masses from the abaloparatide group vs vehicle controls at day 14. Manual palpation and radiography indicated no fusions in either group at day 14, whereas 25% of vehicle-treated rats and 50% of abaloparatide-treated rats had bilateral fusion at day 28. DISCUSSION AND CONCLUSION In summary, this rat PLF model showed that abaloparatide treatment was associated with higher levels of the bone formation marker osteocalcin, improved fusion mass architecture, and a non- significant 2-fold higher fusion rate compared with vehicle.
Collapse
Affiliation(s)
- Heike Arlt
- Research & DevelopmentRadius Health, Inc.WalthamMassachusettsUSA
| | | | | | - Douglas C. Fredericks
- Department of Orthopedics and RehabilitationUniversity of Iowa Hospitals and ClinicsIowa CityIowaUSA
| | - Beate Lanske
- Research & DevelopmentRadius Health, Inc.WalthamMassachusettsUSA
| |
Collapse
|
|
18
|
Abedi A, Formanek B, Russell N, Vizesi F, Boden SD, Wang JC, Buser Z. Examination of the Role of Cells in Commercially Available Cellular Allografts in Spine Fusion: An in Vivo Animal Study. J Bone Joint Surg Am 2020; 102:e135. [PMID: 33079897 DOI: 10.2106/jbjs.20.00330] [Citation(s) in RCA: 4] [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
BACKGROUND Despite the extensive use of cellular bone matrices (CBMs) in spine surgery, there is little evidence to support the contribution of cells within CBMs to bone formation. The objective of this study was to determine the contribution of cells to spinal fusion by direct comparisons among viable CBMs, devitalized CBMs, and cell-free demineralized bone matrix (DBM). METHODS Three commercially available grafts were tested: a CBM containing particulate DBM (CBM-particulate), a CBM containing DBM fibers (CBM-fiber), and a cell-free product with DBM fibers only (DBM-fiber). CBMs were used in viable states (CBM-particulatev and CBM-fiberv) and devitalized (lyophilized) states (CBM-particulated and CBM-fiberd), resulting in 5 groups. Viable cell counts and bone morphogenetic protein-2 (BMP-2) content on enzyme-linked immunosorbent assay (ELISA) within each graft material were measured. A single-level posterolateral lumbar fusion was performed on 45 athymic rats with 3 lots of each product implanted into 9 animals per group. After 6 weeks, fusion was assessed using manual palpation, micro-computed tomography (μ-CT), and histological analysis. RESULTS The 2 groups with viable cells were comparable with respect to cell counts, and pairwise comparisons showed no significant differences in BMP-2 content across the 5 groups. Manual palpation demonstrated fusion rates of 9 of 9 in the DBM-fiber specimens, 9 of 9 in the CBM-fiberd specimens, 8 of 9 in the CBM-fiberv specimens, and 0 of 9 in both CBM-particulate groups. The μ-CT maturity grade was significantly higher in the DBM-fiber group (2.78 ± 0.55) compared with the other groups (p < 0.0001), while none of the CBM-particulate samples demonstrated intertransverse fusion in qualitative assessments. The viable and devitalized samples in each CBM group were comparable with regard to fusion rates, bone volume fraction, μ-CT maturity grade, and histological features. CONCLUSIONS The cellular component of 2 commercially available CBMs yielded no additional benefits in terms of spinal fusion. Meanwhile, the groups with a fiber-based DBM demonstrated significantly higher fusion outcomes compared with the CBM groups with particulate DBM, indicating that the DBM component is probably the key determinant of fusion. CLINICAL RELEVANCE Data from the current study demonstrate that cells yielded no additional benefit in spinal fusion and emphasize the need for well-designed clinical studies on cellular graft materials.
Collapse
Affiliation(s)
- Aidin Abedi
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Blake Formanek
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California
| | | | | | - Scott D Boden
- Department of Orthopedic Surgery, Emory University, Atlanta, Georgia
| | - Jeffrey C Wang
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Zorica Buser
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California
| |
Collapse
|
|
19
|
Patel VV, Wuthrich ZR, Ortega A, Ferguson VL, Lindley EM. Recombinant Human Bone Morphogenetic Protein-2 Improves Spine Fusion in a Vitamin D-Deficient Rat Model. Int J Spine Surg 2020; 14:694-705. [PMID: 33077435 DOI: 10.14444/7101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND The effects of vitamin D deficiency on spinal fusion are not well studied, nor are approaches to overcoming deficiency-related detrimental effects. The purpose of this study was to (1) evaluate the effects of vitamin D deficiency on spine fusion in a rat model, and (2) determine whether recombinant human bone morphogenetic protein-2 (rhBMP-2) can improve outcomes in deficient rats. METHODS Sprague-Dawley rats were assigned to a vitamin D group: vitamin D sufficient (14), vitamin D deficient (16), vitamin D postoperative rescue (15). Posterolateral fusion was performed at L3-4 and L5-6, with one level receiving rhBMP-2 and the other allograft. Following 6 weeks, the spines were harvested for micro-computed tomography (micro-CT) and histological analyses. Fusion was assessed via manual palpation and micro-CT assessment. Micro-CT images were analyzed for bone microarchitecture in intact L5 vertebral bodies and within fused bone masses treated with rhBMP-2. RESULTS There were no significant effects of vitamin D status on fusion assessments. However, the microarchitecture of native bone in the intact L5 vertebral bodies of vitamin D-sufficient rats showed significantly greater trabecular thickness (P < .001) and bone volume fraction (P < .001), with decreased trabecular spacing (P < .001), than that of vitamin D-deficient rats. Fusion masses of rhBMP-2 levels also showed significant effects of vitamin D supplementation on both bone volume fraction and trabecular thickness. Histological analysis confirmed that robust bone formation was observed in rhBMP-2-treated fusions, but not in fusion levels treated with allograft. CONCLUSIONS Overall, vitamin D deficiency decreased trabecular bone microarchitecture, and treatment with rhBMP-2 improved outcomes across all vitamin D groups. CLINICAL RELEVANCE Given the prevalence of vitamin D deficiency in spine surgery patients, vitamin D supplementation may be a cost-effective method for reducing the risk of pseudoarthrosis.
Collapse
Affiliation(s)
- Vikas V Patel
- Department of Orthopedics, Divisions of Spine Surgery and Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Zachary R Wuthrich
- Department of Orthopedics, Divisions of Spine Surgery and Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Alicia Ortega
- Department of Mechanical Engineering, University of Colorado Boulder, Boulder, Colorado
| | - Virginia L Ferguson
- Department of Mechanical Engineering, University of Colorado Boulder, Boulder, Colorado
| | - Emily M Lindley
- Department of Orthopedics, Divisions of Spine Surgery and Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| |
Collapse
|
|
20
|
Injection of Calcium Phosphate Apatitic Cement/Blood Composites in Intervertebral Fusion Cages: A Simple and Efficient Alternative to Autograft Leading to Enhanced Spine Fusion. Spine (Phila Pa 1976) 2020; 45:E1288-E1295. [PMID: 32694485 DOI: 10.1097/brs.0000000000003598] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
|
|
21
|
Wang JC, Yoon ST, Brodke DS, Park JB, Hsieh P, Meisel HJ, Buser Z. Development of AOSpine BOnE (Bone Osteobiologics and Evidence) Classification. Global Spine J 2020; 10:871-874. [PMID: 32905732 PMCID: PMC7485069 DOI: 10.1177/2192568219880176] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
STUDY DESIGN Classification development. OBJECTIVES The aim of our study was to develop a 3-tier classification for the levels of evidence for osteobiologics and provide a description of the principles by which osteobiologics can be evaluated. BOnE (Bone Osteobiologics and Evidence) classification evaluates each osteobiologic based on the available evidence, and if the published evidence is based on clinical, in vivo or in vitro studies. METHODS The process of establishing the BOnE classification included 5 face-to-face meetings and 2 web calls among members of the AOSpine Knowledge Forum Degenerative. RESULTS The 3 levels of evidence were determined based on the type of data on osteobiologics: level A for human studies, level B for animal studies, and level C for in vitro studies, with level A being the highest level of evidence. Each level was organized into 4 subgroups (eg, A1, A2, A3, and A4). CONCLUSIONS The use and the variety of osteobiologics for spine fusion has dramatically increased over the past few decades; however, literature on their effectiveness is inconclusive. Several prior systematic reviews developed by AOSpine Knowledge Forum Degenerative reported low level of evidence primarily due to the high risk of bias, small sample size, lack of control groups, and limited patient-reported outcomes. BOnE classification will provide a universal platform for research studies and journal publications to classify a new or an existing product and will allow for creating decision-making algorithms for surgical planning.
Collapse
Affiliation(s)
| | | | | | - Jong-Beom Park
- Uijongbu St. Mary’s Hospital, The Catholic University of Korea, Uijongbu, Korea
| | - Patrick Hsieh
- University of Southern California, Los Angeles, CA, USA
| | | | - Zorica Buser
- University of Southern California, Los Angeles, CA, USA,Zorica Buser, Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, 1450 San Pablo St, HC4 - #5400A, Los Angeles, CA 90033, USA.
| |
Collapse
|
|
22
|
Holmes C, Elder BD, Ishida W, Perdomo-Pantoja A, Locke J, Cottrill E, Lo SFL, Witham TF. Comparing the efficacy of syngeneic iliac and femoral allografts with iliac crest autograft in a rat model of lumbar spinal fusion. J Orthop Surg Res 2020; 15:410. [PMID: 32933551 PMCID: PMC7490887 DOI: 10.1186/s13018-020-01936-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 08/31/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Despite widespread use of femoral-sourced allografts in clinical spinal fusion procedures and the increasing interest in using femoral reamer-irrigator-aspirator (RIA) autograft in clinical bone grafting, few studies have examined the efficacy of femoral grafts compared to iliac crest grafts in spinal fusion. The objective of this study was to directly compare the use of autologous iliac crest with syngeneic femoral and iliac allograft bone in the rat model of lumbar spinal fusion. METHODS Single-level bilateral posterolateral intertransverse process lumbar spinal fusion surgery was performed on Lewis rats divided into three experimental groups: iliac crest autograft, syngeneic iliac crest allograft, and syngeneic femoral allograft bone. Eight weeks postoperatively, fusion was evaluated via microCT analysis, manual palpation, and histology. In vitro analysis of the colony-forming and osteogenic capacity of bone marrow cells derived from rat femurs and hips was also performed to determine whether there was a correlation with the fusion efficacy of these graft sources. RESULTS Although no differences were observed between groups in CT fusion mass volumes, iliac allografts displayed an increased number of radiographically fused fusion masses and a higher rate of bilateral fusion via manual palpation. Histologically, hip-derived grafts showed better integration with host bone than femur derived ones, likely associated with the higher concentration of osteogenic progenitor cells observed in hip-derived bone marrow. CONCLUSIONS This study demonstrates the feasibility of using syngeneic allograft bone in place of autograft bone within inbred rat fusion models and highlights the need for further study of femoral-derived grafts in fusion.
Collapse
Affiliation(s)
- Christina Holmes
- Department of Chemical and Biomedical Engineering, Florida A&M University-Florida State University College of Engineering, Tallahassee, FL, USA.
- Department of Neurosurgery, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
| | | | - Wataru Ishida
- Department of Neurosurgery, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | | | - John Locke
- Department of Neurosurgery, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Ethan Cottrill
- Department of Neurosurgery, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Sheng-Fu L Lo
- Department of Neurosurgery, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Timothy F Witham
- Department of Neurosurgery, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| |
Collapse
|
|
23
|
Abstract
STUDY DESIGN This study was a multi-endpoint analysis of bone graft substitutes implanted as a standalone graft in a clinically relevant Ovine model of instrumented posterolateral spinal fusion (PLF). OBJECTIVE The objective of this study was to obtain high-quality evidence on the efficacy of commercial bone graft substitutes compared with autograft in instrumented PLF using a state-of-the-art model with a complete range of assessment techniques. SUMMARY OF BACKGROUND DATA Preclinical and clinical data on the quality of spinal fusions obtained with bone graft substitutes are often limited. Calcium phosphates with submicron topography have shown promising results in PLF, as these are able to induce bone formation in tissues distant from the host bone, which facilitates bony union. METHODS Nine female, skeletally mature sheep (4-5 y) underwent posterior pedicle screw/rods instrumented PLF at L2-L3 and L4-L5 using the following bone graft materials as a standalone graft per spinal segment: (1) biphasic calcium phosphate with submicron topography (BCP<µm), (2) 45S5 Bioglass (BG), and (3) collagen-β-tricalcium phosphate with a 45S5 Bioglass adjunct (TCP/BG). Autograft bone (AB) was used as a positive control treatment. Twelve weeks after implantation, the spinal segments were evaluated by fusion assessment (manual palpation, x-ray, micro-computed tomography, and histology), fusion mass volume quantification (micro-computed tomography), range of motion (ROM) testing, histologic evaluation, and histomorphometry. RESULTS Fusion assessment revealed equivalence between AB and BCP<µm by all fusion assessment methods, whereas BG and TCP/BG led to significantly inferior results. Fusion mass volume was highest for BCP<µm, followed by AB, BG, and TCP/BG. ROM testing determined equivalence for spinal levels treated with AB and BCP<µm, while BG and TCP/BG exhibited higher ROM. Histologic evaluation revealed substantial bone formation in the intertransverse regions for AB and BCP<µm, whereas BG and TCP/BG grafts contained fibrous tissue and minimal bone formation. Histologic observations were supported by the histomorphometry data. CONCLUSIONS This study reveals clear differences in efficacy between commercially available bone graft substitutes, emphasizing the importance of clinically relevant animal models with multiendpoint analyses for the evaluation of bone graft materials. The results corroborate the efficacy of calcium phosphate with submicron topography, as this was the only material that showed equivalent performance to autograft in achieving spinal fusion.
Collapse
|
|
24
|
de Lacerda Schickert S, van den Beucken JJ, Leeuwenburgh SC, Jansen JA. Pre-Clinical Evaluation of Biological Bone Substitute Materials for Application in Highly Loaded Skeletal Sites. Biomolecules 2020; 10:E883. [PMID: 32526829 PMCID: PMC7356650 DOI: 10.3390/biom10060883] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 05/31/2020] [Accepted: 06/02/2020] [Indexed: 12/27/2022] Open
Abstract
The development of bone substitute materials (BSMs) intended for load-bearing bone defects is highly complicated, as biological and mechanical requirements are often contradictory. In recent years, biological BSMs have been developed which allow for a more efficient integration of the material with the surrounding osseous environment and, hence, a higher mechanical stability of the treated defect. However, while these materials are promising, they are still far from ideal. Consequently, extensive preclinical experimentation is still required. The current review provides a comprehensive overview of biomechanical considerations relevant for the design of biological BSMs. Further, the preclinical evaluation of biological BSMs intended for application in highly loaded skeletal sites is discussed. The selected animal models and implantation site should mimic the pathophysiology and biomechanical loading patterns of human bone as closely as possible. In general, sheep are among the most frequently selected animal models for the evaluation of biomaterials intended for highly loaded skeletal sites. Regarding the anatomical sites, segmental bone defects created in the limbs and spinal column are suggested as the most suitable. Furthermore, the outcome measurements used to assess biological BSMs for regeneration of defects in heavily loaded bone should be relevant and straightforward. The quantitative evaluation of bone defect healing through ex vivo biomechanical tests is a valuable addition to conventional in vivo tests, as it determines the functional efficacy of BSM-induced bone healing. Finally, we conclude that further standardization of preclinical studies is essential for reliable evaluation of biological BSMs in highly loaded skeletal sites.
Collapse
Affiliation(s)
| | | | | | - John A. Jansen
- Department of Dentistry—Regenerative Biomaterials, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Philips van Leydenlaan 25, 6525EX Nijmegen, The Netherlands; (S.d.L.S.); (J.J.J.P.v.d.B.); (S.C.G.L.)
| |
Collapse
|
|
25
|
Virk SS, Aurand A, Bertone AL, Hussein H, Kaido M, Marras WS, Khan SN. Assessment of a rabbit posterolateral spinal fusion using movement between vertebrae: a modification of the palpation exam for quantifying fusions. JOURNAL OF SPINE SURGERY 2019; 5:215-222. [PMID: 31380475 DOI: 10.21037/jss.2019.04.08] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Manual palpation of rabbit spine levels has been used to assess fusion status. This method of testing is subject to inter-observer differences in assessment. We attempted to quantify fusion based on the amount of movement between rabbit vertebrae at the level of fusion. Methods Rabbits were divided into three groups. The first underwent a sham surgery; the second underwent a unilateral spinal fusion; and the third underwent a bilateral spinal fusion. All groups were sacrificed at either 5- or 10-week post-procedure. Each spine was tested for fusion using standard manual palpation techniques. The spines were also placed on a specially designed apparatus and moved through 10°, 20°, and 30° of extension/flexion. Results Out of 10 rabbits, 2 underwent sham surgery, 2 underwent a fusion procedure at L4-L5 and 6 underwent a fusion at L5-L6. We only included rabbits that underwent a L5-L6 fusion surgery. Our apparatus did not always rotate the spine the intended amount with up to 30% error. When rabbits graded as fused were compared to sham rabbits, there was a trend towards reduction in percent of overall measured angle within the fused group as compared to the sham group (8.77% vs. 13.84%, P=0.14). Conclusions Our model attempted to quantify the amount of displacement between vertebrae during the manual palpation exam. There is a trend towards reduced measured angle between vertebrae between fused and non-fused spines and no statistically significant difference in overall measured angle between unilaterally and bilaterally fused spines.
Collapse
Affiliation(s)
- Sohrab S Virk
- Department of Orthopaedics, Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Alex Aurand
- Biodynamics Laboratory, Spine Research Institute, Department of Integrated Systems Engineering, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA
| | - Alicia L Bertone
- Comparative Orthopedic Research Laboratory, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA
| | - Hayam Hussein
- Comparative Orthopedic Research Laboratory, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA
| | - Mari Kaido
- Comparative Orthopedic Research Laboratory, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA
| | - William S Marras
- Biodynamics Laboratory, Spine Research Institute, Department of Integrated Systems Engineering, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA
| | - Safdar N Khan
- Department of Orthopaedics, Ohio State University Wexner Medical Center, Columbus, OH, USA
| |
Collapse
|
|
26
|
Cho PG, Ji GY, Ha Y, Lee HY, Shin DA. Effect of the type of electrical stimulation on spinal fusion in a rat posterolateral spinal fusion model. Spine J 2019; 19:1106-1120. [PMID: 30584910 DOI: 10.1016/j.spinee.2018.12.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 12/19/2018] [Accepted: 12/19/2018] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Posterolateral fusion (PLF) with autogenous iliac bone graft is one of the most common surgical procedures for lumbar spinal disease. However, its limited success demands new biologically competent graft enhancers or substitutes. Although the use of direct current (DC) electrical stimulation has been shown to increase rate of successful spinal fusions, little is known about the effect of the type of current in DC stimulation. PURPOSE To evaluate the effects of various DC stimulators on the strength and success rate of posterolateral fusion facilitated by using a nitinol mesh container, in rats. STUDY DESIGN This was an experimental animal study. METHODS A conductive, tubular nitinol mesh container was used to carry small pieces of bone grafts. The nitinol mesh container received electrical stimulation via a lead that connected the container to different types of DC stimulators. Sixty male Sprague-Dawley rats were divided into three groups (N=20 in each): a control group that underwent PLF with a nitinol container filled with autograft, a constant DC group that received a nitinol container and constant DC (100 μA), and a pulsed DC group that received a nitinol container and pulsed DC (100 μA, 100 Hz, 200 μs). The rats underwent PLF between L4 and L5, and transverse processes were grafted with bilateral iliac grafts. A stimulator was implanted subcutaneously. The rats were sacrificed 8 weeks postsurgery, and lumbar spines were removed. Spinal fusion was evaluated by microcomputed tomography, manual testing, biomechanical testing, histologic examination, and molecular analysis. RESULTS All animals in the DC stimulation groups displayed solid fusion, whereas only 70% of control animals showed solid fusion. Radiographic images, biomechanical testing, histologic examination, and molecular analysis revealed improved fusion in the order control group<constant DC group<pulsed DC group. The volume of new bone mass was significantly higher in the pulsed DC group (p<.05). Fusion was more solid in the pulsed DC group than in control group (p<.05). The pulsed DC group displayed the lowest inflammatory responses. CONCLUSIONS Pulsed DC electrical stimulation is efficacious in improving both strength and fusion rate in a rat spinal fusion model. In addition, tubular nitinol mesh, made of conductive suture, appears useful for holding small pieces of bone grafts and maintaining a good environment for bone fusion. CLINICAL RELEVANCE Pulsed DC electrical stimulation may be potentially useful to increase the fusion rate after spinal fusion in humans. Future research is required to evaluate the safety and efficacy of tubular nitinol mesh and pulsed DC electrical stimulation in humans.
Collapse
Affiliation(s)
- Pyung Goo Cho
- Department of Neurosurgery, Bundang Jesaeng Hospital, Seongnam si, Republic of Korea
| | - Gyu Yeol Ji
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yoon Ha
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hye Yeong Lee
- Spine and Spinal Cord Institute, Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dong Ah Shin
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
| |
Collapse
|
|
27
|
Cottrill E, Ahmed AK, Lessing N, Pennington Z, Ishida W, Perdomo-Pantoja A, Lo SF, Howell E, Holmes C, Goodwin CR, Theodore N, Sciubba DM, Witham TF. Investigational growth factors utilized in animal models of spinal fusion: Systematic review. World J Orthop 2019; 10:176-191. [PMID: 31041160 PMCID: PMC6475812 DOI: 10.5312/wjo.v10.i4.176] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 01/03/2019] [Accepted: 01/26/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Over 400000 Americans annually undergo spinal fusion surgeries, yet up to 40% of these procedures result in pseudoarthrosis even with iliac crest autograft, the current “gold standard” treatment. Tissue engineering has the potential to solve this problem via the creation of bone grafts involving bone-promoting growth factors (e.g., bone morphogenetic protein 2). A broad assessment of experimental growth factors is important to inform future work and clinical potential in this area. To date, however, no study has systematically reviewed the investigational growth factors utilized in preclinical animal models of spinal fusion.
AIM To review all published studies assessing investigational growth factors for spinal fusion in animal models and identify promising agents for translation.
METHODS We conducted a systematic review of the literature using PubMed, Embase, Cochrane Library, and Web of Science databases with searches run on May 29th, 2018. The search query was designed to include all non-human, preclinical animal models of spinal fusion reported in the literature without a timespan limit. Extracted data for each model included surgical approach, level of fusion, animal species and breed, animal age and sex, and any other relevant characteristics. The dosages/sizes of all implant materials, spinal fusion rates, and follow-up time points were recorded. The data were analyzed and the results reported in tables and text. PRISMA guidelines were followed for this systematic review.
RESULTS Twenty-six articles were included in this study, comprising 14 experimental growth factors: AB204 (n = 1); angiopoietin 1 (n = 1); calcitonin (n = 3); erythropoietin (n = 1); basic fibroblast growth factor (n = 1); growth differentiation factor 5 (n = 4), combined insulin-like growth factor 1 + transforming growth factor beta (n = 4); insulin (n = 1); NELL-1 (n = 5); noggin (n = 1); P-15 (n = 1); peptide B2A (n = 2); and secreted phosphoprotein 24 (n = 1). The fusion rates of the current gold standard treatment (autologous iliac crest bone graft, ICBG) and the leading clinically used growth factor (BMP-2) ranged widely in the included studies, from 0-100% for ICBG and from 13%-100% for BMP-2. Among the identified growth factors, calcitonin, GDF-5, NELL-1, and P-15 resulted in fusion rates of 100% in some cases. In addition, six growth factors - AB204, angiopoietin 1, GDF-5, insulin, NELL-1, and peptide B2A - resulted in significantly enhanced fusion rates compared to ICBG, BMP-2, or other internal control in some studies. Large heterogeneity in animal species, fusion method, and experimental groups and time points was observed across the included studies, limiting the direct comparison of the growth factors identified herein.
CONCLUSION Several promising investigational growth factors for spinal fusion have been identified herein; directly comparing the fusion efficacy and safety of these agents may inform clinical translation.
Collapse
Affiliation(s)
- Ethan Cottrill
- Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, MD 21287, United States
| | - A Karim Ahmed
- Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, MD 21287, United States
| | - Noah Lessing
- Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, MD 21287, United States
| | - Zachary Pennington
- Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, MD 21287, United States
| | - Wataru Ishida
- Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, MD 21287, United States
| | | | - Sheng-fu Lo
- Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, MD 21287, United States
| | - Elizabeth Howell
- Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, United States
| | - Christina Holmes
- Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, MD 21287, United States
| | - C Rory Goodwin
- Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, United States
| | - Nicholas Theodore
- Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, MD 21287, United States
| | - Daniel M Sciubba
- Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, MD 21287, United States
| | - Timothy F Witham
- Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, MD 21287, United States
| |
Collapse
|
|
28
|
Engineered periosteum-bone biomimetic bone graft enhances posterolateral spine fusion in a rabbit model. Spine J 2019; 19:762-771. [PMID: 30266454 DOI: 10.1016/j.spinee.2018.09.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Revised: 09/22/2018] [Accepted: 09/24/2018] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Bone marrow derived mesenchymal stem cells (BMSCs) and periosteum-derived cells (PDCs) have shown great viability in terms of osteogenic potential and have been considered the major cellular source for skeletal tissue engineering. Using a PDCs-impregnated cell sheet to surround a BMSCs-impregnated tricalcium phosphate (TCP) scaffold might create a periosteum-bone biomimetic bone graft substitute to enhance spine fusion. PURPOSE The purpose of this study was to determine the feasibility of using this newly tissue-engineered biomimetic bone graft for posterolateral spine fusion. STUDY DESIGN/SETTING This study design was based on an animal model using adult male New Zealand White rabbits. METHODS New Zealand White rabbits underwent operation and were divided into three groups based on the experimental material implanted in the bilateral L4-L5 intertransverse space. Group 1 was BMSCs-free TCP wrapped in a PDCs-free cell sheet. Group 2 was BMSCs-loaded-TCP wrapped in a PDCs-free cell sheet. Group 3 was BMSCs-loaded-TCP wrapped in a PDCs-loaded cell sheet. After 12 weeks, six rabbits from each group were euthanized for computed tomography scanning, manual palpation, biomechanical testing, and histology. Each group had 12 radiographic fusion areas for analysis because the right and left intertransverse fusion areas were collected separately. RESULTS Radiographic union of 12 fusion areas for groups 1, 2, and 3 was 0, 3, and 9, respectively. Group 3 had significantly higher fusion success than groups 1 and 2 (p<.001). Solid fusion of six fusion segments in each group by manual palpation was 0, 1, and 5, accordingly. Group 3 had a higher successful solid fusion rate than groups 1 and 2 (p=.005). The average maximal torques at failure were 727±136 N mm, 627±91 N mm, and 882±195 N mm for groups 1, 2, and 3, accordingly. The maximal torque was significantly higher in group 3 than in group 2 (p=.028). Histological evaluation verified that new bone regeneration were greater in the group 3 samples. CONCLUSIONS The results indicated the potential of using a PDCs-impregnated cell sheet to surround the BMSCs-impregnated TCP scaffold for creating a periosteum-bone biomimetic bone graft substitute to enhance bone regeneration and posterolateral fusion success.
Collapse
|
|
29
|
Wang L, Wang Y, Shi L, Liu P, Kang J, He J, Liu Y, Li D. Can the sheep model fully represent the human model for the functional evaluation of cervical interbody fusion cages? Biomech Model Mechanobiol 2018; 18:607-616. [PMID: 30570674 DOI: 10.1007/s10237-018-1104-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 11/24/2018] [Indexed: 12/01/2022]
Abstract
Sheep model is the most favourable choice for animal study for functional evaluation of the cervical fusion prostheses before clinical application; however, significantly large differences between sheep and human existed in terms of morphological characteristics and daily-activity motions. Questions should be raised as whether the differences between the two species have influence on the reliability of sheep model. Finite element models (FEM) of the cervical spinal system were built to characterize the differences between the two species with respect to the range of motion (ROM) and biomechanical behaviour, and experimental cadaver tests on both species were employed for validation purposes. Results indicate that sheep model represents the worst-case scenario of the human model with exaggerated stresses (up to 3 times more) and ROM (up to 10 times more). Moreover, sheep model is very sensitive to the variation of prostheses design, whilst human model does not, which denotes that the sheep model provides a rather amplified effect of a certain design for its biomechanical performance. Therefore, caution needs to be taken when sheep models were used as the animal model for functional evaluation over various design, and the FEM built in this study can be employed as an effective methodology for performance evaluation of cage prostheses of cervical spine.
Collapse
Affiliation(s)
- Ling Wang
- School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.,State Key Laboratory for Manufacturing System Engineering, School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Yingying Wang
- School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.,State Key Laboratory for Manufacturing System Engineering, School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Lei Shi
- Department of Orthopedics, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Peng Liu
- Department of Orthopedics, Honghui Hospital, Xi'an, China
| | - Jianfeng Kang
- School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.,State Key Laboratory for Manufacturing System Engineering, School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Jiankang He
- School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.,State Key Laboratory for Manufacturing System Engineering, School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Yaxiong Liu
- School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.,State Key Laboratory for Manufacturing System Engineering, School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Dichen Li
- School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China. .,State Key Laboratory for Manufacturing System Engineering, School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.
| |
Collapse
|
|
30
|
Kersten RFMR, Wu G, Pouran B, van der Veen AJ, Weinans HH, de Gast A, Öner FC, van Gaalen SM. Comparison of polyetheretherketone versus silicon nitride intervertebral spinal spacers in a caprine model. J Biomed Mater Res B Appl Biomater 2018; 107:688-699. [PMID: 30091515 DOI: 10.1002/jbm.b.34162] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 04/22/2018] [Accepted: 04/29/2018] [Indexed: 12/17/2022]
Abstract
Polyetheretherketone (PEEK) is commonly used as a spinal spacer for intervertebral fusion surgery. Unfortunately, PEEK is bioinert and does not effectively osseointegrate into living bone. In contrast, comparable spacers made of silicon nitride (Si3 N4 ) possess a surface nanostructure and chemistry that encourage appositional bone healing. This observational study was designed to compare the outcomes of these two biomaterials when implanted as spacers in an adult caprine model. Lumbar interbody fusion surgeries were performed at two adjacent levels in eight adult goats using implants of PEEK and Si3 N4 . At six-months after surgery, the operative and adjacent spinal segments were extracted and measured for bone fusion, bone volume, bone-implant contact (BIC) and soft-tissue implant contact (SIC) ratios, and biodynamic stability. The null hypothesis was that no differences in these parameters would be apparent between the two groups. Fusion was observed in seven of eight implants in each group with greater bone formation in the Si3 N4 group (52.6%) versus PEEK (27.9%; p = 0.2). There were no significant differences in BIC ratios between PEEK and Si3 N4 , and the biodynamic stability of the two groups was also comparable. The results suggest that Si3 N4 spacers are not inferior to PEEK and they may be more effective in promoting arthrodesis. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 00B: 000-000, 2018. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 688-699, 2019.
Collapse
Affiliation(s)
- Roel F M R Kersten
- Department of Orthopedic Surgery, Clinical Orthopedic Research Center midden-Nederland (CORCmN), Diakonessenhuis, Utrecht, The Netherlands.,Department of Orthopedic Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Gang Wu
- Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit (VU), Amsterdam, The Netherlands
| | - Behdad Pouran
- Department of Orthopedic Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.,Department of Biomechanical Engineering, Faculty of Mechanical, Maritime, and Materials Engineering, Delft University of Technology (TU Delft), Delft, The Netherlands
| | - Albert J van der Veen
- Department of Physics and Medical Technology, VU University Medical Center, Amsterdam, The Netherlands
| | - Harrie H Weinans
- Department of Orthopedic Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.,Department of Biomechanical Engineering, Faculty of Mechanical, Maritime, and Materials Engineering, Delft University of Technology (TU Delft), Delft, The Netherlands
| | - Arthur de Gast
- Department of Orthopedic Surgery, Clinical Orthopedic Research Center midden-Nederland (CORCmN), Diakonessenhuis, Utrecht, The Netherlands
| | - F Cumhur Öner
- Department of Orthopedic Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Steven M van Gaalen
- Department of Orthopedic Surgery, Clinical Orthopedic Research Center midden-Nederland (CORCmN), Diakonessenhuis, Utrecht, The Netherlands
| |
Collapse
|
|
31
|
Ledet EH, Sanders GP, DiRisio DJ, Glennon JC. Load-sharing through elastic micro-motion accelerates bone formation and interbody fusion. Spine J 2018; 18:1222-1230. [PMID: 29452282 PMCID: PMC6008179 DOI: 10.1016/j.spinee.2018.02.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 01/06/2018] [Accepted: 02/01/2018] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Achieving a successful spinal fusion requires the proper biological and biomechanical environment. Optimizing load-sharing in the interbody space can enhance bone formation. For anterior cervical discectomy and fusion (ACDF), loading and motion are largely dictated by the stiffness of the plate, which can facilitate a balance between stability and load-sharing. The advantages of load-sharing may be substantial for patients with comorbidities and in multilevel procedures where pseudarthrosis rates are significant. PURPOSE We aimed to evaluate the efficacy of a novel elastically deformable, continuously load-sharing anterior cervical spinal plate for promotion of bone formation and interbody fusion relative to a translationally dynamic plate. STUDY DESIGN/SETTING An in vivo animal model was used to evaluate the effects of an elastically deformable spinal plate on bone formation and spine fusion. METHODS Fourteen goats underwent an ACDF and received either a translationally dynamic or elastically deformable plate. Animals were followed up until 18 weeks and were evaluated by plain x-ray, computed tomography scan, and undecalcified histology to evaluate the rate and quality of bone formation and interbody fusion. RESULTS Animals treated with the elastically deformable plate demonstrated statistically significantly superior early bone formation relative to the translationally dynamic plate. Trends in the data from 8 to 18 weeks postoperatively suggest that the elastically deformable implant enhanced bony bridging and fusion, but these enhancements were not statistically significant. CONCLUSIONS Load-sharing through elastic micro-motion accelerates bone formation in the challenging goat ACDF model. The elastically deformable implant used in this study may promote early bony bridging and increased rates of fusion, but future studies will be necessary to comprehensively characterize the advantages of load-sharing through micro-motion.
Collapse
Affiliation(s)
- Eric H. Ledet
- ReVivo Medical, 33 Old Niskayuna Road, Loudonville, NY 12211,Rensselaer Polytechnic Institute, Department of Biomedical Engineering, 110 8 Street, Troy, NY 12180,Stratton VA Medical Center, R&D Service, 113 Holland Avenue, Albany, NY, 12208
| | | | - Darryl J. DiRisio
- ReVivo Medical, 33 Old Niskayuna Road, Loudonville, NY 12211,Albany Medical College, Department of Neurosurgery, 47 New Scotland Avenue, Albany, NY 12208
| | - Joseph C. Glennon
- Veterinary Specialties Referral Center, 1641 Main Street, Pattersonville, NY 12137
| |
Collapse
|
|
32
|
Thermo-sensitive injectable glycol chitosan-based hydrogel for treatment of degenerative disc disease. Carbohydr Polym 2018; 184:342-353. [PMID: 29352928 DOI: 10.1016/j.carbpol.2018.01.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 12/23/2017] [Accepted: 01/02/2018] [Indexed: 11/21/2022]
Abstract
The use of injectable hydrogel formulations have been suggested as a promising strategy for the treatment of degenerative disc disease to both restore the biomechanical function and reduce low back pain. In this work, a new thermo-sensitive injectable hydrogels with tunable thermo-sensitivity and enhanced stability were developed with N-hexanoylation of glycol chitosan (GC) for treatment of degenerative disc disease, and their physico-chemical and biological properties were evaluated. The sol-gel transition temperature of the hydrogels was controlled in a range of 23-56 °С, depending on the degree of hexanoylation and the polymer concentration. In vitro and in vivo tests showed no cytotoxicity and no adverse effects in a rat model. The hydrogel filling of the defective IVD site in an ex vivo porcine model maintained its stability for longer than 28 days. These results suggest that the hydrogel can be used as an alternative material for treatment of disc herniation.
Collapse
|
|
33
|
Duarte RM, Varanda P, Reis RL, Duarte ARC, Correia-Pinto J. Biomaterials and Bioactive Agents in Spinal Fusion. TISSUE ENGINEERING PART B-REVIEWS 2017; 23:540-551. [DOI: 10.1089/ten.teb.2017.0072] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Rui M. Duarte
- School of Medicine, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Orthopedic Surgery Department, Hospital de Braga, Braga, Portugal
| | - Pedro Varanda
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Orthopedic Surgery Department, Hospital de Braga, Braga, Portugal
| | - Rui L. Reis
- ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal
- 3B's Research Group—Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Barco, Portugal
| | - Ana Rita C. Duarte
- ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal
- 3B's Research Group—Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Barco, Portugal
| | - Jorge Correia-Pinto
- School of Medicine, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Pediatric Surgery Department, Hospital de Braga, Braga, Portugal
| |
Collapse
|
|
34
|
In vivo experimental study of anterior cervical fusion using bioactive polyetheretherketone in a canine model. PLoS One 2017; 12:e0184495. [PMID: 28886118 PMCID: PMC5590956 DOI: 10.1371/journal.pone.0184495] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 08/24/2017] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Polyetheretherketone (PEEK) is a widely accepted biomaterial, especially in the field of spinal surgery. However, PEEK is not able to directly integrate with bone tissue, due to its bioinertness. To overcome this drawback, various studies have described surface coating approaches aimed at increasing the bioactivity of PEEK surfaces. Among those, it has been shown that the recently developed sol-gel TiO2 coating could provide PEEK with the ability to bond with bone tissue in vivo without the use of a bone graft. OBJECTIVE This in vivo experimental study using a canine model determined the efficacy of bioactive TiO2-coated PEEK for anterior cervical fusion. METHODS Sol-gel-derived TiO2 coating, which involves sandblasting and acid treatment, was used to give PEEK bone-bonding ability. The cervical interbody spacer, which was designed to fit the disc space of a beagle, was fabricated using bioactive TiO2-coated PEEK. Both uncoated PEEK (control) and TiO2-coated PEEK spacers were implanted into the cervical intervertebral space of beagles (n = 5 for each type). After the 3-month survival period, interbody fusion success was evaluated based on μ-CT imaging, histology, and manual palpation analyses. RESULTS Manual palpation analyses indicated a 60% (3/5 cases) fusion (no gap between bone and implants) rate for the TiO2-coated PEEK group, indicating clear advantage over the 0% (0/5 cases) fusion rate for the uncoated PEEK group. The bony fusion rate of the TiO2-coated PEEK group was 40% according to μCT imaging; however, it was 0% of for the uncoated PEEK group. Additionally, the bone-implant contact ratio calculated using histomorphometry demonstrated a better contact ratio for the TiO2-coated PEEK group than for the uncoated PEEK group (mean, 32.6% vs 3.2%; p = 0.017). CONCLUSIONS The TiO2-coated bioactive PEEK implant demonstrated better fusion rates and bone-bonding ability than did the uncoated PEEK implant in the canine anterior cervical fusion model. Bioactive PEEK, which has bone-bonding ability, could contribute to further improvements in clinical outcomes for spinal interbody fusion.
Collapse
|
|
35
|
Zapata-Cornelio FY, Day GA, Coe RH, Sikora SNF, Wijayathunga VN, Tarsuslugil SM, Mengoni M, Wilcox RK. Methodology to Produce Specimen-Specific Models of Vertebrae: Application to Different Species. Ann Biomed Eng 2017; 45:2451-2460. [PMID: 28744839 PMCID: PMC5622177 DOI: 10.1007/s10439-017-1883-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 07/07/2017] [Indexed: 11/23/2022]
Abstract
Image-based continuum-level finite element models have been used for bones to evaluate fracture risk and the biomechanical effects of diseases and therapies, capturing both the geometry and tissue mechanical properties. Although models of vertebrae of various species have been developed, an inter-species comparison has not yet been investigated. The purpose of this study was to derive species-specific modelling methods and compare the accuracy of image-based finite element models of vertebrae across species. Vertebral specimens were harvested from porcine (N = 12), ovine (N = 13) and bovine (N = 14) spines. The specimens were experimentally loaded to failure and apparent stiffness values were derived. Image-based finite element models were generated reproducing the experimental protocol. A linear relationship between the element grayscale and elastic modulus was calibrated for each species matching in vitro and in silico stiffness values, and validated on independent sets of models. The accuracy of these relationships were compared across species. Experimental stiffness values were significantly different across species and specimen-specific models required species-specific linear relationship between image grayscale and elastic modulus. A good agreement between in vitro and in silico values was achieved for all species, reinforcing the generality of the developed methodology.
Collapse
Affiliation(s)
- Fernando Y Zapata-Cornelio
- School of Mechanical Engineering, Institute of Medical and Biological Engineering, University of Leeds, Leeds, LS2 9JT, UK.
| | - Gavin A Day
- School of Mechanical Engineering, Institute of Medical and Biological Engineering, University of Leeds, Leeds, LS2 9JT, UK
| | - Ruth H Coe
- School of Mechanical Engineering, Institute of Medical and Biological Engineering, University of Leeds, Leeds, LS2 9JT, UK
| | - Sebastien N F Sikora
- School of Mechanical Engineering, Institute of Medical and Biological Engineering, University of Leeds, Leeds, LS2 9JT, UK
| | - Vithanage N Wijayathunga
- School of Mechanical Engineering, Institute of Medical and Biological Engineering, University of Leeds, Leeds, LS2 9JT, UK
| | - Sami M Tarsuslugil
- School of Mechanical Engineering, Institute of Medical and Biological Engineering, University of Leeds, Leeds, LS2 9JT, UK
| | - Marlène Mengoni
- School of Mechanical Engineering, Institute of Medical and Biological Engineering, University of Leeds, Leeds, LS2 9JT, UK
| | - Ruth K Wilcox
- School of Mechanical Engineering, Institute of Medical and Biological Engineering, University of Leeds, Leeds, LS2 9JT, UK
| |
Collapse
|
|
36
|
Abstract
STUDY DESIGN Surgical approach development in an animal model, and a prospective study comparing clinical outcomes between novel and conventional approaches in thoracolumbar burst fracture fixation. OBJECTIVE To investigate the feasibility of a less-invasive retroperitoneal approach to the lumbar spine in a sheep model and to compare the clinical outcomes of anterior reconstruction in the treatment of thoracolumbar burst fractures using novel and conventional approaches. SUMMARY OF BACKGROUND DATA The anterior retroperitoneal lumbar approach is well established for anterior lumbar surgical procedures in both humans and animal models. However, potential concerns include the increased risk of complications such as soft-tissue trauma, and extended periods of rehabilitation postoperatively. MATERIALS AND METHODS A less-invasive retroperitoneal approach was designed in a sheep model with minimal soft-tissue dissection to keep the abdominal and paravertebral muscles intact. Eight sheep underwent anterior lumbar interbody fusion using this approach. In the clinical study, 48 patients with thoracolumbar burst fractures underwent anterior decompression and reconstruction. The less-invasive approach and conventional approach were applied in 12 and 36 cases, respectively. The clinical outcomes during the minimum 12-month follow-up of the 2 groups were compared. RESULTS With the less-invasive approach, anterior lumbar interbody fusion was accomplished in all sheep, and no surgical complications were observed. In the clinical study, operation time, blood loss, and duration of hospitalization were comparable between 2 groups. Using the less-invasive approach decreased the length of incision, 3-day postoperative visual analogue scale score, postoperative independent standing, and narcotic-dependent duration. No surgical complications were observed in either group. CONCLUSIONS Our results and early experience suggests that the less-invasive retroperitoneal approach is safe and effective for anterior lumbar surgery. Compared with the conventional approach, significantly better postoperative rehabilitation and abdominal muscle preservation were seen with this novel approach.
Collapse
|
|
37
|
Rajiv S, Drilling A, Bassiouni A, Harding M, James C, Robinson S, Moratti S, Wormald PJ. Chitosan Dextran gel as an anti adhesion agent in a postlaminectomy spinal sheep model. J Clin Neurosci 2017; 40:153-156. [DOI: 10.1016/j.jocn.2017.02.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 02/07/2017] [Indexed: 10/20/2022]
|
|
38
|
Multifidus Muscle Atrophy Not Observed Following Two-segment Anterior Interbody Fusion: A Rabbit Model Study With a 12-Month Follow-up. Spine (Phila Pa 1976) 2017; 42:711-717. [PMID: 27683975 DOI: 10.1097/brs.0000000000001917] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Experimental study evaluated magnetic resonance imaging (MRI) and histologic changes in the multifidus muscle after anterior spinal fusion. OBJECTIVE To determine the effect of spinal fusion on the multifidus muscle in an anterior rabbit model through the use of MRI and histologic evaluation. SUMMARY OF BACKGROUND DATA Retraction and splitting approach are known to be important factors in postoperative injury and atrophy of the multifidus muscle. The effect and possible mechanism of spinal fusion as an independent factor remains unknown. METHODS Thirty-six New Zealand white rabbits were divided into two groups. Animals in the fusion group underwent two-level anterior spinal fusion whereas those in the control group underwent similar surgery without spinal fusion. The status of the multifidus muscle was evaluated with MRI and histological analysis at preoperative, 3 weeks, 6 weeks, 3 months, 6 months, and 12 months postoperatively. RESULTS All rabbits in the fusion group achieved solid fusion. The mean T1-weighted and T2-weighted signal intensity ratios of gross multifidus to psoas muscles were all approximately 1.0 postoperatively, with no remarkable difference between the groups. The mean lesser diameter of myofibrils in either group did not significantly differ between the preoperative and postoperative specimens. There was no significant fibrotic change or fatty degeneration for either group. Decrease in acetylcholine activity or granular degeneration of the neuromuscular junction were not observed, and normal shape and size were found in nearly all samples at all time points in both groups (P > 0.05). CONCLUSION After two-segment anterior spinal fusion, multifidus atrophy was not observed throughout a 12-month follow up. The rabbit model of anterior fusion is better suited to study the effect of fusion alone on the status of the multifidus muscle. LEVEL OF EVIDENCE 3.
Collapse
|
|
39
|
Kim KH, Park JY, Park HS, Kim KS, Chin DK, Cho YE, Kuh SU. The Influences of Different Ratios of Biphasic Calcium Phosphate and Collagen Augmentation on Posterior Lumbar Spinal Fusion in Rat Model. Yonsei Med J 2017; 58:407-414. [PMID: 28120573 PMCID: PMC5290022 DOI: 10.3349/ymj.2017.58.2.407] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 10/12/2016] [Accepted: 10/31/2016] [Indexed: 11/27/2022] Open
Abstract
PURPOSE To determine the influence of different ratios of hydroxyapatite (HA)/beta tricalcium phosphate (β-TCP) and collagen augmentation for posterior lumbar fusion in a rat model. MATERIALS AND METHODS We generated a posterior lumbar fusion model in 50 rats and divided it into five groups of equal number as follows; 1) autologous bone graft as group A, 2) 70% HA+30% β-TCP as group B, 3) 70% HA+30% β-TCP+collagen as group C, 4) 30% HA+70% β-TCP as group D, and 5) 30% HA+70% β-TCP+collagen as group E. Rats were euthanized at 12 weeks after surgery and fusion was assessed by manual palpation, quantitative analysis using microCT and histology. RESULTS The score of manual palpation was significantly higher in group C than group E (3.1±1.1 vs. 1.8±0.8, p=0.033). However, in terms of microCT analysis, group D showed significantly higher scores than group B (5.5±0.8 vs. 3.1±1.1, p=0.021). According to quantitative volumetric analysis, 30% HA+70% β-TCP groups (group D and E) showed significantly reduced fusion mass at 12 weeks after surgery (123±14.2, 117±46.3 vs. 151±27.3, p=0.008, 0.003, respectively). Collagen augmentation groups revealed superior results in terms of both microCT score and histologic grade. CONCLUSION A 7:3 HA/β-TCP ratio with collagen augmentation rather than a 3:7 HA/β-TCP ratio could be a more favorable graft substitute for lumbar spinal fusion. There was positive role of collagen as an adjunct for spinal bone fusion process.
Collapse
Affiliation(s)
- Kyung Hyun Kim
- Department of Neurosurgery, Spine and Spinal Cord Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jeong Yoon Park
- Department of Neurosurgery, Spine and Spinal Cord Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Hyo Suk Park
- Department of Neurosurgery, Spine and Spinal Cord Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Keun Su Kim
- Department of Neurosurgery, Spine and Spinal Cord Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Dong Kyu Chin
- Department of Neurosurgery, Spine and Spinal Cord Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Yong Eun Cho
- Department of Neurosurgery, Spine and Spinal Cord Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Uk Kuh
- Department of Neurosurgery, Spine and Spinal Cord Institute, Yonsei University College of Medicine, Seoul, Korea.
| |
Collapse
|
|
40
|
Khoshakhlagh P, Rabiee SM, Kiaee G, Heidari P, Miri AK, Moradi R, Moztarzadeh F, Ravarian R. Development and characterization of a bioglass/chitosan composite as an injectable bone substitute. Carbohydr Polym 2017; 157:1261-1271. [DOI: 10.1016/j.carbpol.2016.11.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 10/27/2016] [Accepted: 11/02/2016] [Indexed: 11/27/2022]
|
|
41
|
Virk SS, Coble D, Bertone AL, Hussein HH, Khan SN. Experimental Design and Surgical Approach to Create a Spinal Fusion Model in a New Zealand White Rabbit (Oryctolagus cuniculus). J INVEST SURG 2016; 30:226-234. [PMID: 27739917 DOI: 10.1080/08941939.2016.1235748] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
There are several animal models routinely used for study of the spinal fusion process and animal selection largely depends on the scientific question to be answered. This review outlines the advantages and disadvantages of various animal models used to study spinal fusion and describes the New Zealand White (NSW) rabbit which is the most popular preclinical model to study spinal fusion. We outline critical steps required in planning and performing spinal fusion surgery in this model. This includes determination of the required animal number to obtain statistical significance, an outline of appropriate technique for posterolateral fusion and other components of completing a study. As advances in drug delivery move forward and our understanding of the cascade of gene expression occurring during the fusion process grows, performing and interpreting preclinical animal models will be vital to validating new therapies to enhance spinal fusion.
Collapse
Affiliation(s)
- Sohrab S Virk
- a Department of Orthopaedics , Ohio State University Wexner Medical Center , Columbus , Ohio , USA
| | - Dondrae Coble
- b Office of Research, College of Veterinary Medicine, The Ohio State University , Columbus , Ohio , USA
| | - Alicia L Bertone
- a Department of Orthopaedics , Ohio State University Wexner Medical Center , Columbus , Ohio , USA.,c Comparative Orthopedic Research Laboratory, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University , Columbus , Ohio , USA
| | - Hayam Hamaz Hussein
- c Comparative Orthopedic Research Laboratory, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University , Columbus , Ohio , USA
| | - Safdar N Khan
- a Department of Orthopaedics , Ohio State University Wexner Medical Center , Columbus , Ohio , USA
| |
Collapse
|
|
42
|
Jakus AE, Rutz AL, Jordan SW, Kannan A, Mitchell SM, Yun C, Koube KD, Yoo SC, Whiteley HE, Richter CP, Galiano RD, Hsu WK, Stock SR, Hsu EL, Shah RN. Hyperelastic “bone”: A highly versatile, growth factor–free, osteoregenerative, scalable, and surgically friendly biomaterial. Sci Transl Med 2016; 8:358ra127. [DOI: 10.1126/scitranslmed.aaf7704] [Citation(s) in RCA: 251] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Accepted: 08/16/2016] [Indexed: 12/22/2022]
|
|
43
|
Ishida W, Elder BD, Holmes C, Lo SFL, Witham TF. Variables Affecting Fusion Rates in the Rat Posterolateral Spinal Fusion Model with Autogenic/Allogenic Bone Grafts: A Meta-analysis. Ann Biomed Eng 2016; 44:3186-3201. [PMID: 27473706 DOI: 10.1007/s10439-016-1701-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 07/21/2016] [Indexed: 01/14/2023]
Abstract
The rat posterolateral spinal fusion model with autogenic/allogenic bone graft (rat PFABG) has been increasingly utilized as an experimental model to assess the efficacy of novel fusion treatments. The objective of this study was to investigate the reliability of the rat PFABG model and examine the effects of different variables on spinal fusion. A web-based literature search from January, 1970 to September, 2015, yielded 26 studies, which included 40 rat PFABG control groups and 449 rats. Data regarding age, weight, sex, and strain of rats, graft volume, graft type, decorticated levels, surgical approach, institution, the number of control rats, fusion rate, methods of fusion assessment, and timing of fusion assessment were collected and analyzed. The primary outcome variable of interest was fusion rate, as evaluated by manual palpation. Fusion rates varied widely, from 0 to 96%. The calculated overall fusion rate was 46.1% with an I 2 value of 62.4, which indicated moderate heterogeneity. Weight >300 g, age >14 weeks, male rat, Sprague-Dawley strain, and autogenic coccyx grafts increased fusion rates with statistical significance. Additionally, an assessment time-point ≥8 weeks had a trend towards statistical significance (p = 0.070). Multi-regression analysis demonstrated that timing of assessment and age as continuous variables, as well as sex as a categorical variable, can predict the fusion rate with R 2 = 0.82. In an inter-institution reliability analysis, the pooled overall fusion rate was 50.0% [44.8, 55.3%], with statistically significant differences among fusion outcomes at different institutions (p < 0.001 and I 2 of 72.2). Due to the heterogeneity of fusion outcomes, the reliability of the rat PFABG model was relatively limited. However, selection of adequate variables can optimize its use as a control group in studies evaluating the efficacy of novel fusion therapies.
Collapse
Affiliation(s)
- Wataru Ishida
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA
| | - Benjamin D Elder
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA.
| | - Christina Holmes
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA
| | - Sheng-Fu L Lo
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA
| | - Timothy F Witham
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA
| |
Collapse
|
|
44
|
Koerner JD, Vives MJ, O'Connor JP, Chirichella P, Breitbart EA, Chaudhary SB, Uko L, Subramanian S, Fritton JC, Benevenia J, Lin SS. Zinc has insulin-mimetic properties which enhance spinal fusion in a rat model. Spine J 2016; 16:777-83. [PMID: 26850174 DOI: 10.1016/j.spinee.2016.01.190] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 12/17/2015] [Accepted: 01/22/2016] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Previous studies have found that insulin or insulin-like growth factor treatment can stimulate fracture healing in diabetic and normal animal models, and increase fusion rates in a rat spinal fusion model. Insulin-mimetic agents, such as zinc, have demonstrated antidiabetic effects in animal and human studies, and these agents that mimic the effects of insulin could produce the same beneficial effects on bone regeneration and spinal fusion. PURPOSE The purpose of this study was to analyze the effects of locally applied zinc on spinal fusion in a rat model. STUDY DESIGN/SETTING Institutional Animal Care and Use Committee-approved animal study using Sprague-Dawley rats was used as the study design. METHODS Thirty Sprague-Dawley rats (450-500 g) underwent L4-L5 posterolateral lumbar fusion (PLF). After decortication and application of approximately 0.3 g of autograft per side, one of three pellets were added to each site: high-dose zinc calcium sulfate (ZnCaSO4), low-dose ZnCaSO4 (half of the high dose), or a control palmitic acid pellet (no Zn dose). Systemic blood glucose levels were measured 24 hours postoperatively. Rats were sacrificed after 8weeks and the PLFs analyzed qualitatively by manual palpation and radiograph review, and quantitatively by micro-computed tomography (CT) analysis of bone volume and trabecular thickness. Statistical analyses with p-values set at .05 were accomplished with analysis of variance, followed by posthoc tests for quantitative data, or Mann-Whitney rank tests for qualitative assessments. RESULTS Compared with controls, the low-dose zinc group demonstrated a significantly higher manual palpation grade (p=.011), radiographic score (p=.045), and bone formation on micro-CT (172.9 mm(3) vs. 126.7 mm(3) for controls) (p<.01). The high-dose zinc also demonstrated a significantly higher radiographic score (p=.017) and bone formation on micro-CT (172.7 mm(3) vs. 126.7 mm(3)) (p<.01) versus controls, and was trending toward higher manual palpation scores (p=.058). CONCLUSIONS This study demonstrates the potential benefit of a locally applied insulin-mimetic agent, such as zinc, in a rat lumbar fusion model. Previous studies have demonstrated the benefits of local insulin application in the same model, and it appears that zinc has similar effects.
Collapse
Affiliation(s)
- John D Koerner
- Department of Orthopaedics, Rutgers University, New Jersey Medical School, 90 Bergen St, Suite 7300, Newark, NJ 07101, USA.
| | - Michael J Vives
- Department of Orthopaedics, Rutgers University, New Jersey Medical School, 90 Bergen St, Suite 7300, Newark, NJ 07101, USA
| | - J Patrick O'Connor
- Department of Orthopaedics, Rutgers University, New Jersey Medical School, 90 Bergen St, Suite 7300, Newark, NJ 07101, USA
| | - Paul Chirichella
- Department of Orthopaedics, Rutgers University, New Jersey Medical School, 90 Bergen St, Suite 7300, Newark, NJ 07101, USA
| | - Eric A Breitbart
- Department of Orthopaedics, Rutgers University, New Jersey Medical School, 90 Bergen St, Suite 7300, Newark, NJ 07101, USA
| | - Saad B Chaudhary
- Department of Orthopaedics, Rutgers University, New Jersey Medical School, 90 Bergen St, Suite 7300, Newark, NJ 07101, USA
| | - Linda Uko
- Department of Orthopaedics, Rutgers University, New Jersey Medical School, 90 Bergen St, Suite 7300, Newark, NJ 07101, USA
| | - Sangeeta Subramanian
- Department of Orthopaedics, Rutgers University, New Jersey Medical School, 90 Bergen St, Suite 7300, Newark, NJ 07101, USA
| | - J C Fritton
- Department of Orthopaedics, Rutgers University, New Jersey Medical School, 90 Bergen St, Suite 7300, Newark, NJ 07101, USA
| | - Joseph Benevenia
- Department of Orthopaedics, Rutgers University, New Jersey Medical School, 90 Bergen St, Suite 7300, Newark, NJ 07101, USA
| | - Sheldon S Lin
- Department of Orthopaedics, Rutgers University, New Jersey Medical School, 90 Bergen St, Suite 7300, Newark, NJ 07101, USA
| |
Collapse
|
|
45
|
Bobyn JD, Little DG, Gray R, Schindeler A. Animal models of scoliosis. J Orthop Res 2015; 33:458-67. [PMID: 25492698 DOI: 10.1002/jor.22797] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 12/03/2014] [Indexed: 02/04/2023]
Abstract
Multiple techniques designed to induce scoliotic deformity have been applied across many animal species. We have undertaken a review of the literature regarding experimental models of scoliosis in animals to discuss their utility in comprehending disease aetiology and treatment. Models of scoliosis in animals can be broadly divided into quadrupedal and bipedal experiments. Quadrupedal models, in the absence of axial gravitation force, depend upon development of a mechanical asymmetry along the spine to initiate a scoliotic deformity. Bipedal models more accurately mimic human posture and consequently are subject to similar forces due to gravity, which have been long appreciated to be a contributing factor to the development of scoliosis. Many effective models of scoliosis in smaller animals have not been successfully translated to primates and humans. Though these models may not clarify the aetiology of human scoliosis, by providing a reliable and reproducible deformity in the spine they are a useful means with which to test interventions designed to correct and prevent deformity.
Collapse
Affiliation(s)
- Justin D Bobyn
- Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia
| | | | | | | |
Collapse
|
|
46
|
Bigham-Sadegh A, Karimi I, Oryan A, Mahmoudi E, Shafiei-Sarvestani Z. Spinal fusion with demineralized calf fetal growth plate as novel biomaterial in rat model: a preliminary study. Int J Spine Surg 2015; 8:14444-1005. [PMID: 25694913 PMCID: PMC4325481 DOI: 10.14444/1005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Background Spinal fusions are being performed for various pathologies of the spine such as degenerative diseases, deformities, tumors and fractures. Recently, other bone substitutes such as demineralized bone matrix (DBM) have been developed for spinal fusion. Therefore, this study was conducted to evaluate the intertransverse posterolateral fusion with the Bovine fetal growth plate (DCFGP) and compare it with commercial DBM in rat model. Methods A total of 16 mature male rats (aged 4 months and weighing 200-300 g) were randomly divided in two groups. After a skin incision on posterolateral site, two separate fascial incisions were made 3 mm from the midline. A muscle-splitting approach was used to expose the transverse processes of L4 and L5. Group I (n = 8) underwent with implanted Bovine fetal growth plate among decorticated transverse processes. In group II (n = 8) commercial DBM was placed in the same manner. Fusion was evaluated by manual palpation, radiographical, gross and histopathological analysis. Results The manual palpation, radiological, gross and histopathological findings indicate high potential of the DCFGP in spinal fusion. At the 42nd postoperative day, new bone formation as evidenced by a bridge between L4 and L5 was visualized in all rats implanted with DCFGP and commercial DBM. The newly formed bone tissue was observed in all implanted areas on the 42nd day after operation in the two groups. Conclusions The spinal fusion of the animals of both groups demonstrated more advanced osteogenic potential and resulted in proper fusion of the transverse process of lumbar vertebra.
Collapse
Affiliation(s)
- Amin Bigham-Sadegh
- Department of Veterinary Surgery and Radiology, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran
| | - Iraj Karimi
- Department of Veterinary Pathobiology, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran
| | - Ahmad Oryan
- Department of Veterinary Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Elena Mahmoudi
- Department of Veterinary Surgery, School of Veterinary Medicine, Tehran University, Tehran, Iran
| | - Zahra Shafiei-Sarvestani
- Department of Veterinary Surgery and Radiology, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran
| |
Collapse
|
|
47
|
Abstract
Chronic low back pain (LBP) is a prevalent global problem, which is often correlated with degenerative disc disease. The development and use of good, relevant animal models of the spine may improve treatment options for this condition. While no animal model is capable of reproducing the exact biology, anatomy, and biomechanics of the human spine, the quality of a particular animal model increases with the number of shared characteristics that are relevant to the human condition. The purpose of this study was to investigate the camelid (specifically, alpaca and llama) cervical spine as a model of the human lumbar spine. Cervical spines were obtained from four alpacas and four llamas and individual segments were used for segmental flexibility/biomechanics and/or morphology/anatomy studies. Qualitative and quantitative data were compared for the alpaca and llama cervical spines, and human lumbar specimens in addition to other published large animal data. Results indicate that a camelid cervical intervertebral disc (IVD) closely approximates the human lumbar disc with regard to size, spinal posture, and biomechanical flexibility. Specifically, compared with the human lumbar disc, the alpaca and llama cervical disc size are approximately 62%, 83%, and 75% with regard to area, depth, and width, respectively, and the disc flexibility is approximately 133%, 173%, and 254%, with regard to range of motion (ROM) in axial-rotation, flexion-extension, and lateral-bending, respectively. These results, combined with the clinical report of disc degeneration in the llama lower cervical spine, suggest that the camelid cervical spine is potentially well suited for use as an animal model in biomechanical studies of the human lumbar spine.
Collapse
|
|
48
|
Han X, Zhang W, Gu J, Zhao H, Ni L, Han J, Zhou Y, Gu Y, Zhu X, Sun J, Hou X, Yang H, Dai J, Shi Q. Accelerated postero-lateral spinal fusion by collagen scaffolds modified with engineered collagen-binding human bone morphogenetic protein-2 in rats. PLoS One 2014; 9:e98480. [PMID: 24869484 PMCID: PMC4037187 DOI: 10.1371/journal.pone.0098480] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 05/04/2014] [Indexed: 11/18/2022] Open
Abstract
Bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive cytokine that plays a critical role in bone regeneration and repair. However, its distribution and side effects are major barriers to its success as therapeutic treatment. The improvement of therapy using collagen delivery matrices has been reported. To investigate a delivery system on postero-lateral spinal fusion, both engineered human BMP-2 with a collagen binding domain (CBD-BMP-2) and collagen scaffolds were developed and their combination was implanted into Sprague-Dawley (SD) rats to study Lumbar 4–5 (L4–L5) posterolateral spine fusion. We divided SD rats into three groups, the sham group (G1, n = 20), the collagen scaffold-treated group (G2, n = 20) and the BMP-2-loaded collagen scaffolds group (G3, n = 20). 16 weeks after surgery, the spines of the rats were evaluated by X-radiographs, high-resolution micro-computed tomography (micro-CT), manual palpation and hematoxylin and eosin (H&E) staining. The results showed that spine L4–L5 fusions occurred in G2(40%) and G3(100%) group, while results from the sham group were inconsistent. Moreover, G3 had better results than G2, including higher fusion efficiency (X score, G2 = 2.4±0.163, G3 = 3.0±0, p<0.05), higher bone mineral density (BMD, G2: 0.3337±0.0025g/cm3, G3: 0.4353±0.0234g/cm3. p<0.05) and more bone trabecular formation. The results demonstrated that with site-specific collagen binding domain, a dose of BMP-2 as low as 0.02mg CBD-BMP-2/cm3 collagen scaffold could enhance the posterolateral intertransverse process fusion in rats. It suggested that combination delivery could be an alternative in spine fusion with dramatically decreased side effects caused by high dose of BMP-2.
Collapse
Affiliation(s)
- Xinglong Han
- Orthopedic Department, the First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Wen Zhang
- Orthopedic Institute of Soochow University, Suzhou, P.R. China
| | - Jun Gu
- Orthopedic Department, the Second Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Huan Zhao
- Orthopedic Department, the First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Li Ni
- Orthopedic Department, the First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Jiajun Han
- Orthopedic Department, the First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Yun Zhou
- Orthopedic Department, the First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Yannan Gu
- Orthopedic Department, the First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Xuesong Zhu
- Orthopedic Department, the First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Jie Sun
- Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, P.R. China
| | - Xianglin Hou
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, P.R. China
| | - Huilin Yang
- Orthopedic Department, the First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Jianwu Dai
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, P.R. China
- * E-mail: (QS); (JD)
| | - Qin Shi
- Orthopedic Department, the First Affiliated Hospital of Soochow University, Suzhou, P.R. China
- * E-mail: (QS); (JD)
| |
Collapse
|
|
49
|
Yamaguchi T, Inoue N, Sah RL, Lee YP, Taborek AP, Williams GM, Moseley TA, Bae WC, Masuda K. Micro-computed tomography-based three-dimensional kinematic analysis during lateral bending for spinal fusion assessment in a rat posterolateral lumbar fusion model. Tissue Eng Part C Methods 2014; 20:578-87. [PMID: 24199634 DOI: 10.1089/ten.tec.2013.0439] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Rat posterolateral lumbar fusion (PLF) models have been used to assess the safety and effectiveness of new bone substitutes and osteoinductive growth factors using palpation, radiography, micro-computed tomography (μCT), and histology as standard methods to evaluate spinal fusion. Despite increased numbers of PLF studies involving alternative bone substitutes and growth factors, the quantitative assessment of treatment efficacy during spinal motion has been limited. The purpose of this study was to evaluate the effect of spinal fusion on lumbar spine segment stability during lateral bending using a μCT-based three-dimensional (3D) kinematic analysis in the rat PLF model. Fourteen athymic male rats underwent PLF surgery at L4/5 and received bone grafts harvested from the ilium and femurs of syngeneic rats (Isograft, n=7) or no graft (Sham, n=7). At 8 weeks after the PLF surgery, spinal fusion was assessed by manual palpation, plain radiography, μCT, and histology. To determine lumbar segmental motions at the operated level during lateral bending, 3D kinematic analysis was performed. The Isograft group, but not the Sham group, showed spinal fusion on manual palpation (6/7), solid fusion mass in radiographs (6/7), as well as bone bridging in μCT and histological images (5/7). Compared to the Sham group, the Isograft group revealed limited 3D lateral bending angular range of motion and lateral translation during lateral bending at the fused segment where disc height narrowing was observed. This μCT-based 3D kinematic analysis can provide a quantitative assessment of spinal fusion in a rat PLF model to complement current gold standard methods used for efficacy assessment of new therapeutic approaches.
Collapse
Affiliation(s)
- Tomonori Yamaguchi
- 1 Department of Orthopaedic Surgery, School of Medicine, University of California , San Diego, La Jolla, California
| | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Ghodasra JH, Daley EL, Hsu EL, Hsu WK. Factors influencing arthrodesis rates in a rabbit posterolateral spine model with iliac crest autograft. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2013; 23:426-34. [PMID: 24166021 DOI: 10.1007/s00586-013-3074-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Revised: 10/12/2013] [Accepted: 10/13/2013] [Indexed: 12/01/2022]
Abstract
PURPOSE The rabbit posterolateral intertransverse spine arthrodesis model has been widely used to evaluate spinal biologics. However, to date, the validity and reproducibility of performance of iliac crest bone graft, the most common and critical control group, has not been firmly established. We evaluated original research publications that utilized this model, identified which experimental conditions affected fusion rates, and developed an algorithm to predict fusion rates for future study designs. METHODS A MEDLINE search was performed for publications through December, 2011 that utilized this model to evaluate fusion rates elicited by iliac crest autograft. All study parameters were recorded, and logistic regression analyses were performed to determine the effects of these variables on fusion rates as determined by either manual palpation or radiographs. RESULTS Seventy studies with 959 rabbits in 102 groups met the inclusion criteria. Excluding studies that measured fusion at 4 or fewer weeks or intentionally tried to decrease the fusion rate, the overall fusion rate for autograft was 58.3 ± 16.3 % (mean ± SD) as determined by manual palpation and 66.4 ± 17.8 % by plain radiographs. Regression analysis demonstrated a difference between these outcome measures with a trend towards significance (p = 0.09). Longer time points and larger volumes of autograft resulted in significantly greater reported fusion rates (p < 0.0001 and p < 0.05, respectively). Neither strain, age, weight, nor vertebral level significantly affected fusion rates. CONCLUSIONS Although experimental conditions varied across studies, time point evaluation and autograft volume significantly affected fusion rates. Despite some variability demonstrated across certain studies, we demonstrated that when the time point and volume of autograft were controlled for, the iliac crest control group of the rabbit posterolateral spinal arthrodesis model is both reliable and predictably affected by different experimental conditions.
Collapse
Affiliation(s)
- Jason H Ghodasra
- Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., 76-143 CHS, Los Angeles, CA, 90095, USA,
| | | | | | | |
Collapse
|