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Yang L, Bhujel B, Hou Y, Luo J, An SB, Han I, Lee KB. Effective Modulation of Inflammation and Oxidative Stress for Enhanced Regeneration of Intervertebral Discs Using 3D Porous Hybrid Protein Nanoscaffold. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2303021. [PMID: 37327108 PMCID: PMC10907067 DOI: 10.1002/adma.202303021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 06/11/2023] [Indexed: 06/18/2023]
Abstract
Degeneration of fibrocartilaginous tissues is often associated with complex pro-inflammatory factors. These include reactive oxygen species (ROS), cell-free nucleic acids (cf-NAs), and epigenetic changes in immune cells. To effectively control this complex inflammatory signaling, it developed an all-in-one nanoscaffold-based 3D porous hybrid protein (3D-PHP) self-therapeutic strategy for treating intervertebral disc (IVD) degeneration. The 3D-PHP nanoscaffold is synthesized by introducing a novel nanomaterial-templated protein assembly (NTPA) strategy. 3D-PHP nanoscaffolds that avoid covalent modification of proteins demonstrate inflammatory stimuli-responsive drug release, disc-mimetic stiffness, and excellent biodegradability. Enzyme-like 2D nanosheets incorporated into nanoscaffolds further enabled robust scavenging of ROS and cf-NAs, reducing inflammation and enhancing the survival of disc cells under inflammatory stress in vitro. Implantation of 3D-PHP nanoscaffolds loaded with bromodomain extraterminal inhibitor (BETi) into a rat nucleotomy disc injury model effectively suppressed inflammation in vivo, thus promoting restoration of the extracellular matrix (ECM). The resulting regeneration of disc tissue facilitated long-term pain reduction. Therefore, self-therapeutic and epigenetic modulator-encapsulated hybrid protein nanoscaffold shows great promise as a novel approach to restore dysregulated inflammatory signaling and treat degenerative fibrocartilaginous diseases, including disc injuries, providing hope and relief to patients worldwide.
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Affiliation(s)
- Letao Yang
- Shanghai Tongji Hospital, School of Life Science and Technologies, Tongji University, Shanghai, 200065, China
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Basanta Bhujel
- Department of Neurosurgery, CHA University School of Medicine, CHA Bundang Medical Center, 59 Yaptap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea
| | - Yannan Hou
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Jeffrey Luo
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Seong Bae An
- Department of Neurosurgery, CHA University School of Medicine, CHA Bundang Medical Center, 59 Yaptap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea
| | - Inbo Han
- Department of Neurosurgery, CHA University School of Medicine, CHA Bundang Medical Center, 59 Yaptap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea
| | - Ki-Bum Lee
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
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Alini M, Diwan AD, Erwin WM, Little CB, Melrose J. An update on animal models of intervertebral disc degeneration and low back pain: Exploring the potential of artificial intelligence to improve research analysis and development of prospective therapeutics. JOR Spine 2023; 6:e1230. [PMID: 36994457 PMCID: PMC10041392 DOI: 10.1002/jsp2.1230] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 08/31/2022] [Accepted: 09/11/2022] [Indexed: 02/03/2023] Open
Abstract
Animal models have been invaluable in the identification of molecular events occurring in and contributing to intervertebral disc (IVD) degeneration and important therapeutic targets have been identified. Some outstanding animal models (murine, ovine, chondrodystrophoid canine) have been identified with their own strengths and weaknesses. The llama/alpaca, horse and kangaroo have emerged as new large species for IVD studies, and only time will tell if they will surpass the utility of existing models. The complexity of IVD degeneration poses difficulties in the selection of the most appropriate molecular target of many potential candidates, to focus on in the formulation of strategies to effect disc repair and regeneration. It may well be that many therapeutic objectives should be targeted simultaneously to effect a favorable outcome in human IVD degeneration. Use of animal models in isolation will not allow resolution of this complex issue and a paradigm shift and adoption of new methodologies is required to provide the next step forward in the determination of an effective repairative strategy for the IVD. AI has improved the accuracy and assessment of spinal imaging supporting clinical diagnostics and research efforts to better understand IVD degeneration and its treatment. Implementation of AI in the evaluation of histology data has improved the usefulness of a popular murine IVD model and could also be used in an ovine histopathological grading scheme that has been used to quantify degenerative IVD changes and stem cell mediated regeneration. These models are also attractive candidates for the evaluation of novel anti-oxidant compounds that counter inflammatory conditions in degenerate IVDs and promote IVD regeneration. Some of these compounds also have pain-relieving properties. AI has facilitated development of facial recognition pain assessment in animal IVD models offering the possibility of correlating the potential pain alleviating properties of some of these compounds with IVD regeneration.
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Affiliation(s)
| | - Ashish D. Diwan
- Spine Service, Department of Orthopedic Surgery, St. George & Sutherland Campus, Clinical SchoolUniversity of New South WalesSydneyNew South WalesAustralia
| | - W. Mark Erwin
- Department of SurgeryUniversity of TorontoOntarioCanada
| | - Chirstopher B. Little
- Raymond Purves Bone and Joint Research LaboratoryKolling Institute, Sydney University Faculty of Medicine and Health, Northern Sydney Area Health District, Royal North Shore HospitalSt. LeonardsNew South WalesAustralia
| | - James Melrose
- Raymond Purves Bone and Joint Research LaboratoryKolling Institute, Sydney University Faculty of Medicine and Health, Northern Sydney Area Health District, Royal North Shore HospitalSt. LeonardsNew South WalesAustralia
- Graduate School of Biomedical EngineeringThe University of New South WalesSydneyNew South WalesAustralia
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Šećerović A, Ristaniemi A, Cui S, Li Z, Soubrier A, Alini M, Ferguson SJ, Weder G, Heub S, Ledroit D, Grad S. Toward the Next Generation of Spine Bioreactors: Validation of an Ex Vivo Intervertebral Disc Organ Model and Customized Specimen Holder for Multiaxial Loading. ACS Biomater Sci Eng 2022; 8:3969-3976. [PMID: 35977717 PMCID: PMC9472220 DOI: 10.1021/acsbiomaterials.2c00330] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
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A new generation of bioreactors with integrated six degrees
of
freedom (6 DOF) aims to mimic more accurately the natural intervertebral
disc (IVD) load. We developed and validated in a biological and mechanical
study a specimen holder and corresponding ex vivo IVD organ model
according to the bioreactor requirements for multiaxial loading and
a long-term IVD culture. IVD height changes and cell viability were
compared between the 6 DOF model and the standard 1 DOF model throughout
the 3 weeks of cyclic compressive loading in the uniaxial bioreactor.
Furthermore, the 6 DOF model and holder were loaded for 9 days in
the multiaxial bioreactor under development using the same conditions,
and the IVDs were evaluated for cell viability. The interface of the
IVD model and specimen holder, enhanced with fixation screws onto
the bone, was tested in compression, torsion, lateral bending, and
tension. Additionally, critical motions such as tension and bending
were assessed for a combination of side screws and top screws or side
screws and adhesive. The 6 DOF model loaded in the uniaxial bioreactor
maintained similar cell viability in the IVD regions as the 1 DOF
model. The viability was high after 2 weeks throughout the whole IVD
and reduced by more than 30% in the inner annulus fibrous after 3
weeks. Similarly, the IVDs remained highly viabile when cultured in
the multiaxial bioreactor. In both models, IVD height changes after
loading were in the range of typical physiological conditions. When
differently directed motions were applied, the holder-IVD interface
remained stable under hyper-physiological loading levels using a side
screw approach in compression and torsion and the combination of side
and top screws in tension and bending. We thus conclude that the developed
holding system is mechanically reliable and biologically compatible
for application in a new generation of multiaxial bioreactors.
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Affiliation(s)
- Amra Šećerović
- AO Research Institute Davos, Clavadelerstrasse 8, Davos 7270, Switzerland
| | - Aapo Ristaniemi
- AO Research Institute Davos, Clavadelerstrasse 8, Davos 7270, Switzerland
| | - Shangbin Cui
- AO Research Institute Davos, Clavadelerstrasse 8, Davos 7270, Switzerland.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Zhen Li
- AO Research Institute Davos, Clavadelerstrasse 8, Davos 7270, Switzerland
| | - Astrid Soubrier
- AO Research Institute Davos, Clavadelerstrasse 8, Davos 7270, Switzerland
| | - Mauro Alini
- AO Research Institute Davos, Clavadelerstrasse 8, Davos 7270, Switzerland
| | | | - Gilles Weder
- CSEM, Swiss Center for Electronics and Microtechnology, Rue Jaquet-Droz 1, Neuchatel 2002, Switzerland
| | - Sarah Heub
- CSEM, Swiss Center for Electronics and Microtechnology, Rue Jaquet-Droz 1, Neuchatel 2002, Switzerland
| | - Diane Ledroit
- CSEM, Swiss Center for Electronics and Microtechnology, Rue Jaquet-Droz 1, Neuchatel 2002, Switzerland
| | - Sibylle Grad
- AO Research Institute Davos, Clavadelerstrasse 8, Davos 7270, Switzerland
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Wang Y, Kang J, Guo X, Zhu D, Liu M, Yang L, Zhang G, Kang X. Intervertebral Disc Degeneration Models for Pathophysiology and Regenerative Therapy -Benefits and Limitations. J INVEST SURG 2021; 35:935-952. [PMID: 34309468 DOI: 10.1080/08941939.2021.1953640] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Aim:This review summarized the recent intervertebral disc degeneration (IDD) models and described their advantages and potential disadvantages, aiming to provide an overview for the current condition of IDD model establishment and new ideas for new strategies development of the treatment and prevention of IDD.Methods:The database of PubMed was searched up to May 2021 with the following search terms: nucleus pulposus, annulus fibrosus, cartilage endplate, intervertebral disc(IVD), intervertebral disc degeneration, animal model, organ culture, bioreactor, inflammatory reaction, mechanical stress, pathophysiology, epidemiology. Any IDD model-related articles were collected and summarized.Results:The best IDD model should have the features of repeatability, measurability and controllability. There are a lot of aspects to be considered in the selection of animals. Mice, rats and rabbits are low-cost and easy to access. However, their IVD size and shape are more different from human anatomy than pigs, cattle, sheep and goats. Organ culture models and animal models are two options in model establishment for IDD. The IVD organ culture model can put the studying variables into the controllable system for transitional research. Unlike the animal model, the organ culture model can only be used to evaluate the short-term effects and it is not applicable in simulating the complex process of IDD. Similarly, the animal models induced by different methods also have their advantages and disadvantages. For studying the mechanism of IDD and the corresponding treatment and prevention strategies, the selection of model should be individualized based on the purpose of each study.Conclusions:Various models have different characteristics and scope of application due to their different rationales and methods of construction. Currently, there is no experimental model that can perfectly mimic the degenerative process of human IVD. Personalized selection of appropriate model based on study purpose and experimental designing can enhance the possibility to obtain reliable and real results.
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Affiliation(s)
- Yidian Wang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R. China
| | - Jihe Kang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R. China
| | - Xudong Guo
- The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R. China
| | - Daxue Zhu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R. China
| | - Mingqiang Liu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R. China
| | - Liang Yang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R. China
| | - Guangzhi Zhang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R. China
| | - Xuewen Kang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R. China.,Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, P.R. China.,The International Cooperation Base of Gansu Province for The Pain Research in Spinal Disorders, Gansu, P.R. China
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Lee NN, Salzer E, Bach FC, Bonilla AF, Cook JL, Gazit Z, Grad S, Ito K, Smith LJ, Vernengo A, Wilke H, Engiles JB, Tryfonidou MA. A comprehensive tool box for large animal studies of intervertebral disc degeneration. JOR Spine 2021; 4:e1162. [PMID: 34337336 PMCID: PMC8313180 DOI: 10.1002/jsp2.1162] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 05/25/2021] [Accepted: 05/26/2021] [Indexed: 12/12/2022] Open
Abstract
Preclinical studies involving large animal models aim to recapitulate the clinical situation as much as possible and bridge the gap from benchtop to bedside. To date, studies investigating intervertebral disc (IVD) degeneration and regeneration in large animal models have utilized a wide spectrum of methodologies for outcome evaluation. This paper aims to consolidate available knowledge, expertise, and experience in large animal preclinical models of IVD degeneration to create a comprehensive tool box of anatomical and functional outcomes. Herein, we present a Large Animal IVD Scoring Algorithm based on three scales: macroscopic (gross morphology, imaging, and biomechanics), microscopic (histological, biochemical, and biomolecular analyses), and clinical (neurologic state, mobility, and pain). The proposed algorithm encompasses a stepwise evaluation on all three scales, including spinal pain assessment, and relevant structural and functional components of IVD health and disease. This comprehensive tool box was designed for four commonly used preclinical large animal models (dog, pig, goat, and sheep) in order to facilitate standardization and applicability. Furthermore, it is intended to facilitate comparison across studies while discerning relevant differences between species within the context of outcomes with the goal to enhance veterinary clinical relevance as well. Current major challenges in pre-clinical large animal models for IVD regeneration are highlighted and insights into future directions that may improve the understanding of the underlying pathologies are discussed. As such, the IVD research community can deepen its exploration of the molecular, cellular, structural, and biomechanical changes that occur with IVD degeneration and regeneration, paving the path for clinically relevant therapeutic strategies.
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Affiliation(s)
- Naomi N. Lee
- Thompson Laboratory for Regenerative OrthopaedicsUniversity of MissouriColumbiaMissouriUSA
| | - Elias Salzer
- Orthopaedic Biomechanics, Department of Biomedical EngineeringEindhoven University of TechnologyEindhovenThe Netherlands
| | - Frances C. Bach
- Department of Clinical Sciences, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Andres F. Bonilla
- Preclinical Surgical Research Laboratory, Department of Clinical SciencesColorado State UniversityColoradoUSA
| | - James L. Cook
- Thompson Laboratory for Regenerative OrthopaedicsUniversity of MissouriColumbiaMissouriUSA
| | - Zulma Gazit
- Department of SurgeryCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | | | - Keita Ito
- Orthopaedic Biomechanics, Department of Biomedical EngineeringEindhoven University of TechnologyEindhovenThe Netherlands
| | - Lachlan J. Smith
- Departments of Neurosurgery and Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Andrea Vernengo
- AO Research Institute DavosDavosSwitzerland
- Department of Chemical EngineeringRowan UniversityGlassboroNew JerseyUSA
| | - Hans‐Joachim Wilke
- Institute of Orthopaedic Research and BiomechanicsUniversity Hospital UlmUlmGermany
| | - Julie B. Engiles
- Department of Pathobiology, New Bolton Center, School of Veterinary MedicineUniversity of PennsylvaniaKennett SquarePennsylvaniaUSA
| | - Marianna A. Tryfonidou
- Department of Clinical Sciences, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
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Mengoni M, Zapata-Cornelio FY, Wijayathunga VN, Wilcox RK. Experimental and Computational Comparison of Intervertebral Disc Bulge for Specimen-Specific Model Evaluation Based on Imaging. Front Bioeng Biotechnol 2021; 9:661469. [PMID: 34124021 PMCID: PMC8193738 DOI: 10.3389/fbioe.2021.661469] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/27/2021] [Indexed: 11/13/2022] Open
Abstract
Finite element modelling of the spinal unit is a promising preclinical tool to assess the biomechanical outcome of emerging interventions. Currently, most models are calibrated and validated against range of motion and rarely directly against soft-tissue deformation. The aim of this contribution was to develop an in vitro methodology to measure disc bulge and assess the ability of different specimen-specific modelling approaches to predict disc bulge. Bovine bone-disc-bone sections (N = 6) were prepared with 40 glass markers on the intervertebral disc surface. These were initially magnetic resonance (MR)-imaged and then sequentially imaged using peripheral-qCT under axial compression of 1 mm increments. Specimen-specific finite-element models were developed from the CT data, using three different methods to represent the nucleus pulposus geometry with and without complementary use of the MR images. Both calibrated specimen-specific and averaged compressive material properties for the disc tissues were investigated. A successful methodology was developed to quantify the disc bulge in vitro, enabling observation of surface displacement on qCT. From the finite element model results, no clear advantage was found in using geometrical information from the MR images in terms of the models' ability to predict stiffness or disc bulge for bovine intervertebral disc.
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Affiliation(s)
- Marlène Mengoni
- School of Mechanical Engineering, Institute of Medical and Biological Engineering, University of Leeds, Leeds, United Kingdom
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A Hyaluronan and Platelet-Rich Plasma Hydrogel for Mesenchymal Stem Cell Delivery in the Intervertebral Disc: An Organ Culture Study. Int J Mol Sci 2021; 22:ijms22062963. [PMID: 33803999 PMCID: PMC7999916 DOI: 10.3390/ijms22062963] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/11/2021] [Accepted: 03/13/2021] [Indexed: 12/18/2022] Open
Abstract
The purpose of the present pilot study was to evaluate the effect of a hydrogel composed of hyaluronic acid (HA) and platelet-rich plasma (PRP) as a carrier for human mesenchymal stem cells (hMSCs) for intervertebral disc (IVD) regeneration using a disc organ culture model. HA was mixed with batroxobin (BTX) and PRP to form a hydrogel encapsulating 1 × 106 or 2 × 106 hMSCs. Bovine IVDs were nucleotomized and filled with hMSCs suspended in ~200 μL of the PRP/HA/BTX hydrogel. IVDs collected at day 0 and nucleotomized IVDs with no hMSCs and/or hydrogel alone were used as controls. hMSCs encapsulated in the hydrogel were also cultured in well plates to evaluate the effect of the IVD environment on hMSCs. After 1 week, tissue structure, scaffold integration, hMSC viability and gene expression of matrix and nucleus pulposus (NP) cell markers were assessed. Histological analysis showed a better preservation of the viability of the IVD tissue adjacent to the gel in the presence of hMSCs (~70%) compared to the hydrogel without hMSCs. Furthermore, disc morphology was maintained, and the hydrogel showed signs of integration with the surrounding tissues. At the gene expression level, the hydrogel loaded with hMSCs preserved the normal metabolism of the tissue. The IVD environment promoted hMSC differentiation towards a NP cell phenotype by increasing cytokeratin-19 (KRT19) gene expression. This study demonstrated that the hydrogel composed of HA/PRP/BTX represents a valid carrier for hMSCs being able to maintain a good cell viability while stimulating cell activity and NP marker expression.
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Techens C, Palanca M, Éltes PE, Lazáry Á, Cristofolini L. Testing the impact of discoplasty on the biomechanics of the intervertebral disc with simulated degeneration: An in vitro study. Med Eng Phys 2020; 84:51-59. [PMID: 32977922 DOI: 10.1016/j.medengphy.2020.07.024] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 07/21/2020] [Accepted: 07/26/2020] [Indexed: 11/18/2022]
Abstract
Percutaneous Cement Discoplasty has recently been developed to relieve pain in highly degenerated intervertebral discs presenting a vacuum phenomenon in patients that cannot undergo major surgery. Little is currently known about the biomechanical effects of discoplasty. This study aimed at investigating the feasibility of modelling empty discs and subsequent discoplasty surgery and measuring their impact over the specimen geometry and mechanical behaviour. Ten porcine lumbar spine segments were tested in flexion, extension, and lateral bending under 5.4 Nm (with a 200 N compressive force and a 27 mm offset). Tests were performed in three conditions for each specimen: with intact disc, after nucleotomy and after discoplasty. A 3D Digital Image Correlation (DIC) system was used to measure the surface displacements and strains. The posterior disc height, range of motion (ROM), and stiffness were measured at the peak load. CT scans were performed to confirm that the cement distribution was acceptable. Discoplasty recovered the height loss caused by nucleotomy (p = 0.04) with respect to the intact condition, but it did not impact significantly either the ROM or the stiffness. The strains over the disc surface increased after nucleotomy, while discoplasty concentrated the strains on the endplates. In conclusion, this preliminary study has shown that discoplasty recovered the intervertebral posterior height, opening the neuroforamen as clinically observed, but it did not influence the spine mobility or stiffness. This study confirms that this in vitro approach can be used to investigate discoplasty.
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Affiliation(s)
- Chloé Techens
- Department of Industrial Engineering, School of Engineering and Architecture, Alma Mater Studiorum - Università di Bologna, Viale Risorgimento, 2, Bologna 40136, Italy
| | - Marco Palanca
- Department of Industrial Engineering, School of Engineering and Architecture, Alma Mater Studiorum - Università di Bologna, Viale Risorgimento, 2, Bologna 40136, Italy
| | - Peter Endre Éltes
- R&D Department of National Center for Spinal Disorders, Budapest, Hungary
| | - Áron Lazáry
- R&D Department of National Center for Spinal Disorders, Budapest, Hungary
| | - Luca Cristofolini
- Department of Industrial Engineering, School of Engineering and Architecture, Alma Mater Studiorum - Università di Bologna, Viale Risorgimento, 2, Bologna 40136, Italy.
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Vadalà G, De Salvatore S, Ambrosio L, Russo F, Papalia R, Denaro V. Robotic Spine Surgery and Augmented Reality Systems: A State of the Art. Neurospine 2020; 17:88-100. [PMID: 32252158 PMCID: PMC7136092 DOI: 10.14245/ns.2040060.030] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 02/24/2020] [Indexed: 12/26/2022] Open
Abstract
Instrumented spine procedures have been performed for decades to treat a wide variety of spinal disorders. New technologies have been employed to obtain a high degree of precision, to minimize risks of damage to neurovascular structures and to diminish harmful exposure of patients and the operative team to ionizing radiations. Robotic spine surgery comprehends 3 major categories: telesurgical robotic systems, robotic-assisted navigation (RAN) and virtual augmented reality (AR) systems, including AR and virtual reality. Telesurgical systems encompass devices that can be operated from a remote command station, allowing to perform surgery via instruments being manipulated by the robot. On the other hand, RAN technologies are characterized by the robotic guidance of surgeon-operated instruments based on real-time imaging. Virtual AR systems are able to show images directly on special visors and screens allowing the surgeon to visualize information about the patient and the procedure (i.e., anatomical landmarks, screw direction and inclination, distance from neurological and vascular structures etc.). The aim of this review is to focus on the current state of the art of robotics and AR in spine surgery and perspectives of these emerging technologies that hold promises for future applications.
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Affiliation(s)
- Gianluca Vadalà
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Sergio De Salvatore
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Luca Ambrosio
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Fabrizio Russo
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Rocco Papalia
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Vincenzo Denaro
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
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Interaction between Mesenchymal Stem Cells and Intervertebral Disc Microenvironment: From Cell Therapy to Tissue Engineering. Stem Cells Int 2019; 2019:2376172. [PMID: 32587618 PMCID: PMC7294366 DOI: 10.1155/2019/2376172] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 07/20/2019] [Accepted: 08/19/2019] [Indexed: 12/13/2022] Open
Abstract
Low back pain (LBP) in one of the most disabling symptoms affecting nearly 80% of the population worldwide. Its primary cause seems to be intervertebral disc degeneration (IDD): a chronic and progressive process characterized by loss of viable cells and extracellular matrix (ECM) breakdown within the intervertebral disc (IVD) especially in its inner region, the nucleus pulposus (NP). Over the last decades, innovative biological treatments have been investigated in order to restore the original healthy IVD environment and achieve disc regeneration. Mesenchymal stem cells (MSCs) have been widely exploited in regenerative medicine for their capacity to be easily harvested and be able to differentiate along the osteogenic, chondrogenic, and adipogenic lineages and to secrete a wide range of trophic factors that promote tissue homeostasis along with immunomodulation and anti-inflammation. Several in vitro and preclinical studies have demonstrated that MSCs are able to acquire a NP cell-like phenotype and to synthesize structural components of the ECM as well as trophic and anti-inflammatory mediators that may support resident cell activity. However, due to its unique anatomical location and function, the IVD presents distinctive features: avascularity, hypoxia, low glucose concentration, low pH, hyperosmolarity, and mechanical loading. Such conditions establish a hostile microenvironment for both resident and exogenously administered cells, which limited the efficacy of intradiscal cell therapy in diverse investigations. This review is aimed at describing the characteristics of the healthy and degenerated IVD microenvironment and how such features influence both resident cells and MSC viability and biological activity. Furthermore, we focused on how recent research has tried to overcome the obstacles coming from the IVD microenvironment by developing innovative cell therapies and functionalized bioscaffolds.
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Wangler S, Menzel U, Li Z, Ma J, Hoppe S, Benneker LM, Alini M, Grad S, Peroglio M. CD146/MCAM distinguishes stem cell subpopulations with distinct migration and regenerative potential in degenerative intervertebral discs. Osteoarthritis Cartilage 2019; 27:1094-1105. [PMID: 31002939 DOI: 10.1016/j.joca.2019.04.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 03/06/2019] [Accepted: 04/03/2019] [Indexed: 02/02/2023]
Abstract
OBJECTIVE This study aimed to characterize the mesenchymal stem cell (MSC) subpopulation migrating towards a degenerated intervertebral disc (IVD) and to assess its regenerative potential. DESIGN Based on initial screening for migration towards C-C motif chemokine ligand 5 (CCL5), the migration potential of CD146+ and CD146- mesenchymal stem cells (MSCs) was evaluated in vitro and in a degenerated organ culture model (degeneration by high-frequency loading in a bioreactor). Discogenic differentiation potential of CD146+ and CD146- MSCs was investigated by in vitro pellet culture assay with supplementation of growth and differentiation factor-6 (GDF6). Furthermore, trypsin degenerated IVDs were treated by either homing or injection of CD146+ or CD146- MSCs and glycosaminoglycan synthesis was evaluated by Sulphur 35 incorporation after 35 days of culture. RESULTS Surface expression of CD146 led to a higher number of migrated MSCs both in vitro and in organ culture. CD146+ and CD146- pellets responded with a similar up-regulation of anabolic markers. A higher production of sulfated glycosaminoglycans (sGAG)/DNA was observed for CD146+ pellets, while in organ cultures, sGAG synthesis rate was higher for IVDs treated with CD146- MSCs by either homing or injection. CONCLUSIONS The CD146+ MSC subpopulation held greater migration potential towards degenerative IVDs, while the CD146- cells induced a stronger regenerative response in the resident IVD cells. These findings were independent of the application route (injection vs migration). From a translational point of view, our data suggests that CD146+ MSCs may be suitable for re-population, while CD146- MSCs may represent the primary choice for stimulation of endogenous IVD cells.
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Affiliation(s)
- S Wangler
- AO Research Institute Davos, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland.
| | - U Menzel
- AO Research Institute Davos, Switzerland.
| | - Z Li
- AO Research Institute Davos, Switzerland.
| | - J Ma
- AO Research Institute Davos, Switzerland.
| | - S Hoppe
- Inselspital, University of Bern, Switzerland.
| | | | - M Alini
- AO Research Institute Davos, Switzerland.
| | - S Grad
- AO Research Institute Davos, Switzerland.
| | - M Peroglio
- AO Research Institute Davos, Switzerland.
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12
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Huang YC, Hu Y, Li Z, Luk KDK. Biomaterials for intervertebral disc regeneration: Current status and looming challenges. J Tissue Eng Regen Med 2018; 12:2188-2202. [PMID: 30095863 DOI: 10.1002/term.2750] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 05/21/2018] [Accepted: 07/13/2018] [Indexed: 12/19/2022]
Abstract
A biomaterial-based strategy is employed to regenerate the degenerated intervertebral disc, which is considered a major generator of neck and back pain. Although encouraging enhancements in the anatomy and kinematics of the degenerative disc have been gained by biomaterials with various formulations in animals, the number of biomaterials tested in humans is rare. At present, most studies that involve the use of newly developed biomaterials focus on regeneration of the degenerative disc, but not pain relief. In this review, we summarise the current state of the art in the field of biomaterial-based regeneration or repair for the nucleus pulposus, annulus fibrosus, and total disc transplantation in animals and humans, and we then provide essential suggestions for the development and clinical translation of biomaterials for disc regeneration. It is important for researchers to consider the commonly neglected issues instead of concentrating solely on biomaterial development and fabrication.
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Affiliation(s)
- Yong-Can Huang
- Shenzhen Engineering Laboratory of Orthopaedic Regenerative Technologies, Orthopaedic Research Center, Peking University Shenzhen Hospital, Shenzhen, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong, China
- Shenzhen Key Laboratory of Spine Surgery, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Yong Hu
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong, China
| | - Zhen Li
- AO Research Institute Davos, Davos, Switzerland
| | - Keith D K Luk
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong, China
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13
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D'Este M, Eglin D, Alini M. Lessons to be learned and future directions for intervertebral disc biomaterials. Acta Biomater 2018; 78:13-22. [PMID: 30092378 DOI: 10.1016/j.actbio.2018.08.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 07/16/2018] [Accepted: 08/04/2018] [Indexed: 02/07/2023]
Abstract
Biomaterials science has achieved significant advancements for the replacement, repair and regeneration of intervertebral disc tissues. However, the translation of this research to the clinic presents hurdles. The goal of this paper is to identify strategies to recapitulate the intrinsic complexities of the intervertebral disc, to highlight the unresolved issues in basic knowledge hindering the clinical translation, and finally to report on the emerging technologies in the biomaterials field. On this basis, we identify promising research directions, with the hope of stimulating further debate and advances for resolving clinical problems such as cervical and low back pain using biomaterial-based approaches. STATEMENT OF SIGNIFICANCE Although not life-threatening, intervertebral disc disorders have enormous impact on life quality and disability. Disc function within the human body is mainly mechanical, and therefore the use of biomaterials to rescue disc function and alleviate pain is logical. Despite intensive research, the clinical translation of biomaterial-based therapies is hampered by the intrinsic complexity of this organ. After decades of development, artificial discs or tissue replacements are still niche applications given their issues of integration and displacement with detrimental consequences. The struggles of biological therapies and tissue engineering are therefore understandable. However, recent advances in biomaterial science give new hope. In this paper we identify the most promising new directions for intervertebral disc biomaterials.
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14
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Sloan SR, Lintz M, Hussain I, Hartl R, Bonassar LJ. Biologic Annulus Fibrosus Repair: A Review of Preclinical In Vivo Investigations. TISSUE ENGINEERING PART B-REVIEWS 2018; 24:179-190. [PMID: 29105592 DOI: 10.1089/ten.teb.2017.0351] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Lower back pain, the leading cause of workplace absences and disability, is often attributed to intervertebral disc degeneration, in which nucleus pulposus (NP) herniates through lesions in the annulus fibrosus (AF) and impinges on the spinal cord and surrounding nerves. Surgeons remove extruded NP via discectomy when indicated by local/radicular pain supported by radiographic evidence; however, current interventions do not alter the underlying disease or seal the AF. The reported rates of recurrent herniation or pain following discectomy cases range from 5% to 25%, which has pushed spine research in recent years toward annular repair and closure strategies. Synthetic implants designed to mechanically seal the AF have been subject to large animal and clinical trials, with limited success in preventing recurrent herniation. Like gold standard interventions, purely mechanical devices fail to promote tissue integration, long-term healing, or restore native biomechanical function to the spine. Biological repair strategies utilizing principles of tissue engineering have demonstrated success in overcoming the inadequacies of current interventions and mechanical implants, yet, none has reached clinical or proof-of-concept trials in humans. In this review, we will discuss annular repair strategies promoting biological healing that have been implemented in small and large animal models in vivo, and ways to enhance the efficacy of these treatments.
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Affiliation(s)
- Stephen R Sloan
- 1 Meinig School of Biomedical Engineering, Cornell University , Ithaca, New York
| | - Marianne Lintz
- 1 Meinig School of Biomedical Engineering, Cornell University , Ithaca, New York
| | - Ibrahim Hussain
- 2 Department of Neurological Surgery, Weill Cornell Brain and Spine Center , New York-Presbyterian Hospital, New York, New York
| | - Roger Hartl
- 2 Department of Neurological Surgery, Weill Cornell Brain and Spine Center , New York-Presbyterian Hospital, New York, New York
| | - Lawrence J Bonassar
- 1 Meinig School of Biomedical Engineering, Cornell University , Ithaca, New York.,3 Sibley School of Mechanical and Aerospace Engineering, Cornell University , Ithaca, New York
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Wang Y, Yi XD, Li CD. The influence of artificial nucleus pulposus replacement on stress distribution in the cartilaginous endplate in a 3-dimensional finite element model of the lumbar intervertebral disc. Medicine (Baltimore) 2017; 96:e9149. [PMID: 29390319 PMCID: PMC5815731 DOI: 10.1097/md.0000000000009149] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE This study aimed to investigate the effects involved with the artificial nucleus pulposus (NP) replacement on stress distribution of the cartilaginous endplate (CEP) in a 3-dimensional lumbar intervertebral disc (IVD) model using a finite element (FE) analysis. METHODS A healthy male volunteer was recruited for the purposes of the study and a spiral computed tomography scan was subsequently conducted to obtain the data information in relation to the L4/5 motion segment. An FE model of the L4/5 motion segment constructed, on the basis of which degenerative IVD, IVD with NP removal, and IVD with NP replacement were in turn built. The stress distribution of the CEP and bulging of IVD were estimated using various motion states, including axial loading, forward flexion, backward extension, left axial rotation, and right axial rotation. RESULTS Under different motion states, the vertebral stress was higher in the degenerative IVD, the IVD with NP removal, and the IVD with NP replacement, in comparison to that of the normal IVD. Furthermore, a higher vertebral stress was detected in the degenerative IVD than the IVD with NP removal and the IVD with NP replacement. An even distribution of vertebral stress was observed in the IVD model with an artificial NP replacement, while the vertebral stress and bulging displacement were lower than after NP removal. Our findings provided confirmation that stress of the CEP was consistent with the vertebral stress. CONCLUSION This study provided evidence suggesting that NP replacement, vertebral stress, and bulging displacement are lower than that of degenerative IVD and IVD with NP removal under different motion states.
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Vadalà G, Russo F, Musumeci M, D'Este M, Cattani C, Catanzaro G, Tirindelli MC, Lazzari L, Alini M, Giordano R, Denaro V. Clinically relevant hydrogel-based on hyaluronic acid and platelet rich plasma as a carrier for mesenchymal stem cells: Rheological and biological characterization. J Orthop Res 2017; 35:2109-2116. [PMID: 28019703 DOI: 10.1002/jor.23509] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 12/20/2016] [Indexed: 02/04/2023]
Abstract
Intervertebral disc regeneration is quickly moving towards clinical applications. However, it is still missing an ideal injectable hydrogel to support mesenchymal stem cells (MSC) delivery. Herein, a new injectable hydrogel composed of platelet rich plasma (PRP) and hyaluronic acid (HA) blended with batroxobin (BTX) as gelling agent, was designed to generate a clinically relevant cell carrier for disc regeneration. PRP/HA/BTX blend was tested for rheological properties. Amplitude sweep, frequency sweep, and rotational measurements were performed and viscoelastic properties were evaluated. Human MSC encapsulated in PRP/HA/BTX hydrogel were cultured in both growing medium and medium with or without TGF-β1 up to day 21. The amount of glycosaminoglycan was evaluated. Quantitative gene expression evaluation for collagen type II, aggrecan, and Sox 9 was also performed. Rheological tests showed that the hydrogel jellifies in 15 min 20°C and in 3 min at 37°C. Biological test showed that MSCs cultured in the hydrogel maintain high cell viability and proliferation. Human MSC within the hydrogel cultured with or without TGF-β1 showed significantly higher GAG production compared to control medium. Moreover, MSCs in the hydrogel underwent differentiation to chondrocyte-like cells with TGF-β1, as shown by histology and gene expression analysis. This novel hydrogel improves viability and proliferation of MSCs supporting the differentiation process toward chondrocyte-like cells. Rheology tests showed optimal gelation kinetics at room temperature for manipulation and faster gelation after transplantation (37°C). The clinical availability of all components of the hydrogel will allow a rapid translation of this regenerative approach into the clinical scenario. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2109-2116, 2017.
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Affiliation(s)
- Gianluca Vadalà
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128 Rome, Italy.,Cell Factory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122, Milan, Italy
| | - Fabrizio Russo
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128 Rome, Italy
| | - Maria Musumeci
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128 Rome, Italy
| | | | - Caterina Cattani
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128 Rome, Italy
| | - Giuseppina Catanzaro
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128 Rome, Italy
| | | | - Lorenza Lazzari
- Cell Factory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122, Milan, Italy
| | - Mauro Alini
- AO Research Institute Davos, Davos, Switzerland
| | - Rosaria Giordano
- Cell Factory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122, Milan, Italy
| | - Vincenzo Denaro
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128 Rome, Italy
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Le Fournier L, Fusellier M, Halgand B, Lesoeur J, Gauthier O, Menei P, Montero-Menei C, Guicheux J, Clouet J. The transpedicular surgical approach for the development of intervertebral disc targeting regenerative strategies in an ovine 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 2017; 26:2072-2083. [DOI: 10.1007/s00586-017-5199-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Revised: 04/24/2017] [Accepted: 06/16/2017] [Indexed: 12/29/2022]
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18
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Peroglio M, Douma LS, Caprez TS, Janki M, Benneker LM, Alini M, Grad S. Intervertebral disc response to stem cell treatment is conditioned by disc state and cell carrier: An ex vivo study. J Orthop Translat 2017; 9:43-51. [PMID: 29662798 PMCID: PMC5822953 DOI: 10.1016/j.jot.2017.03.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 03/10/2017] [Accepted: 03/13/2017] [Indexed: 12/26/2022] Open
Abstract
In vitro and in vivo studies evidenced that mesenchymal stem cells (MSCs) contribute to intervertebral disc (IVD) regeneration by differentiation towards the disc phenotype and matrix synthesis and/or by paracrine signalling to endogenous cells, thereby promoting a healthier disc phenotype in degenerative discs. The aim of this study was to investigate IVD response to human MSC (hMSC) treatment based on the disc degenerative state and hMSC carrier. Bovine caudal IVDs with endplates were cultured in a bioreactor under simulated physiological (0.1 Hz load and sufficient glucose) or degenerative (10 Hz load and limited glucose) conditions for 7 days. Discs were partially nucleotomised, restored with hMSCs in either fibrin gel or saline solution and cultured under physiological conditions for 7 days. Controls included fibrin and saline without hMSCs. Cell viability, histology, disc height, and gene expression analyses were performed to evaluate regeneration. hMSCs in fibrin were viable and homogenously distributed following 7 days of culture under dynamic loading in partially nucleotomised discs. IVD response to hMSCs was conditioned by both disc degenerative state and hMSC carrier. The effect of the regenerative treatment was stronger on simulated-degenerative discs than on simulated-physiological discs. hMSCs in fibrin induced a superior anabolic response in degenerative IVDs compared with fibrin alone, thus suggesting an added value of the cellular therapy compared with an acellular solution. When comparing fibrin and saline as a hMSC carrier, a significantly higher anabolic response was observed in IVDs treated with hMSCs in fibrin. Moreover, it was found that the degenerative state of the disc influenced hMSC differentiation. Indeed, a significantly higher expression of specific discogenic markers (ACAN and CA12) was observed in hMSCs implanted into physiological discs than in those implanted into degenerative discs. In conclusion, host disc cells and donor hMSC response depend on the degenerative state of the host disc and carrier used for hMSC delivery, and these two aspects need to be considered for a successful translation of hMSC therapies for the treatment of IVD degeneration.
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Affiliation(s)
| | | | | | | | | | - Mauro Alini
- AO Research Institute Davos, Davos, Switzerland
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19
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Russo F, Hartman RA, Bell KM, Vo N, Sowa GA, Kang JD, Vadalà G, Denaro V. Biomechanical Evaluation of Transpedicular Nucleotomy With Intact Annulus Fibrosus. Spine (Phila Pa 1976) 2017; 42:E193-E201. [PMID: 28207656 DOI: 10.1097/brs.0000000000001762] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Biomechanical testing of partially nucleotomized ovine cadaveric spines. OBJECTIVE To explore how the nucleus pulposus (NP) affects the biomechanical behavior of the intervertebral disc (IVD) by performing a partial nucleotomy via the transpedicular approach. SUMMARY OF BACKGROUND DATA Mechanical loading represents a crucial part of IVD homeostasis. However, traditional regenerative strategies require violation of the annulus fibrosus (AF) resulting in significant alteration of joint mechanics. The transpedicular nucleotomy represents a suitable method to create a cavity into the NP, as a model to study IVD regeneration with intact AF. METHODS A total of 30 ovine-lumbar- functional spinal units (FSUs) (L1-L6) randomly assigned to 5 groups: control; transpedicular tunnel (TT); TT + polymethylmethacrylate (PMMA) to repair the bone tunnel; nucleotomy; nucleotomy + PMMA. Flexion/extension, lateral-bending, and axial-rotation were evaluated under adaptive displacement control. Axial compression was applied for 15 cycles of preconditioning followed by 1 hour of constant compression. Viscoelastic behavior was modeled and parameterized. RESULTS TT has minimal effects on rotational biomechanics. The nucleotomy increases ROM and neutral zone (NZ) displacement width whereas decreasing NZ stiffness. TT + PMMA has small effects in terms of ROM. Nucleotomy + PMMA brings ROM back to the control, increases NZ stiffness, and decreases NZ displacement width. The nucleotomy tends to increase the rate of early creep. TT reduces early and late damping. The use of PMMA increased late elastic stiffness (S2) and reduced viscous damping (η2) culminating in faster resolution of creep. CONCLUSION Biomechanical properties of NP are crucial for IVD repair. This study demonstrated that TT does not affect rotational stability whereas partial nucleotomy with intact AF induce rotational instability, highlighting the central role of NP in early stages of IDD. Therefore, this model represents a successful platform to validate and optimize disc regeneration strategies. LEVEL OF EVIDENCE N/A.
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Affiliation(s)
- Fabrizio Russo
- Department of Orthopedic and Traumatology, University Campus BioMedico of Rome, Rome, Italy
| | - Robert A Hartman
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, USA
| | - Kevin M Bell
- Ferguson Laboratory for Orthopedic and Spine Research, University of Pittsburgh, Pittsburgh, PA
| | - Nam Vo
- Ferguson Laboratory for Orthopedic and Spine Research, University of Pittsburgh, Pittsburgh, PA
| | - Gwendolyn A Sowa
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, USA
| | - James D Kang
- Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
| | - Gianluca Vadalà
- Department of Orthopedic and Traumatology, University Campus BioMedico of Rome, Rome, Italy
| | - Vincenzo Denaro
- Department of Orthopedic and Traumatology, University Campus BioMedico of Rome, Rome, Italy
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Casaroli G, Villa T, Bassani T, Berger-Roscher N, Wilke HJ, Galbusera F. Numerical Prediction of the Mechanical Failure of the Intervertebral Disc under Complex Loading Conditions. MATERIALS (BASEL, SWITZERLAND) 2017; 10:E31. [PMID: 28772392 PMCID: PMC5344546 DOI: 10.3390/ma10010031] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 12/06/2016] [Accepted: 12/20/2016] [Indexed: 11/16/2022]
Abstract
Finite element modeling has been widely used to simulate the mechanical behavior of the intervertebral disc. Previous models have been generally limited to the prediction of the disc behavior under simple loading conditions, thus neglecting its response to complex loads, which may induce its failure. The aim of this study was to generate a finite element model of the ovine lumbar intervertebral disc, in which the annulus was characterized by an anisotropic hyperelastic formulation, and to use it to define which mechanical condition was unsafe for the disc. Based on published in vitro results, numerical analyses under combined flexion, lateral bending, and axial rotation with a magnitude double that of the physiological ones were performed. The simulations showed that flexion was the most unsafe load and an axial tensile stress greater than 10 MPa can cause disc failure. The numerical model here presented can be used to predict the failure of the disc under all loading conditions, which may support indications about the degree of safety of specific motions and daily activities, such as weight lifting.
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Affiliation(s)
- Gloria Casaroli
- Laboratory of Biological Structure Mechanics (LaBS), Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, 20133 Milan, Italy.
| | - Tomaso Villa
- Laboratory of Biological Structure Mechanics (LaBS), Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, 20133 Milan, Italy.
- IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy.
| | - Tito Bassani
- IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy.
| | - Nikolaus Berger-Roscher
- Institute of Orthopedic Research and Biomechanics, Trauma Research Center Ulm (ZTF), Ulm University, D-89081 Ulm, Germany.
| | - Hans-Joachim Wilke
- Institute of Orthopedic Research and Biomechanics, Trauma Research Center Ulm (ZTF), Ulm University, D-89081 Ulm, Germany.
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Mesenchymal Stem/Stromal Cells seeded on cartilaginous endplates promote Intervertebral Disc Regeneration through Extracellular Matrix Remodeling. Sci Rep 2016; 6:33836. [PMID: 27652931 PMCID: PMC5031983 DOI: 10.1038/srep33836] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 09/05/2016] [Indexed: 12/11/2022] Open
Abstract
Intervertebral disc (IVD) degeneration is characterized by significant biochemical and histomorphological alterations, such as loss of extracellular matrix (ECM) integrity, by abnormal synthesis of ECM main components, resultant from altered anabolic/catabolic cell activities and cell death. Mesenchymal Stem/Stromal Cell (MSC) migration towards degenerated IVD may represent a viable strategy to promote tissue repair/regeneration. Here, human MSCs (hMSCs) were seeded on top of cartilaginous endplates (CEP) of nucleotomized IVDs of bovine origin and cultured ex vivo up to 3 weeks. hMSCs migrated from CEP towards the lesion area and significantly increased expression of collagen type II and aggrecan in IVD, namely in the nucleus pulposus. Concomitantly, hMSCs stimulated the production of growth factors, promoters of ECM synthesis, such as fibroblast growth factor 6 (FGF-6) and 7 (FGF-7), platelet-derived growth factor receptor (PDGF-R), granulocyte-macrophage colony-stimulating factor (GM-CSF) and insulin-like growth factor 1 receptor (IGF-1sR). Overall, our results demonstrate that CEP can be an alternative route to MSC-based therapies for IVD regeneration through ECM remodeling, thus opening new perspectives on endogenous repair capacity through MSC recruitment.
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22
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Vadalà G, Russo F, Ambrosio L, Loppini M, Denaro V. Stem cells sources for intervertebral disc regeneration. World J Stem Cells 2016; 8:185-201. [PMID: 27247704 PMCID: PMC4877563 DOI: 10.4252/wjsc.v8.i5.185] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 12/18/2015] [Accepted: 02/16/2016] [Indexed: 02/06/2023] Open
Abstract
Intervertebral disc regeneration field is rapidly growing since disc disorders represent a major health problem in industrialized countries with very few possible treatments. Indeed, current available therapies are symptomatic, and surgical procedures consist in disc removal and spinal fusion, which is not immune to regardable concerns about possible comorbidities, cost-effectiveness, secondary risks and long-lasting outcomes. This review paper aims to share recent advances in stem cell therapy for the treatment of intervertebral disc degeneration. In literature the potential use of different adult stem cells for intervertebral disc regeneration has already been reported. Bone marrow mesenchymal stromal/stem cells, adipose tissue derived stem cells, synovial stem cells, muscle-derived stem cells, olfactory neural stem cells, induced pluripotent stem cells, hematopoietic stem cells, disc stem cells, and embryonic stem cells have been studied for this purpose either in vitro or in vivo. Moreover, several engineered carriers (e.g., hydrogels), characterized by full biocompatibility and prompt biodegradation, have been designed and combined with different stem cell types in order to optimize the local and controlled delivery of cellular substrates in situ. The paper overviews the literature discussing the current status of our knowledge of the different stem cells types used as a cell-based therapy for disc regeneration.
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