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Łuczak JW, Palusińska M, Matak D, Pietrzak D, Nakielski P, Lewicki S, Grodzik M, Szymański Ł. The Future of Bone Repair: Emerging Technologies and Biomaterials in Bone Regeneration. Int J Mol Sci 2024; 25:12766. [PMID: 39684476 DOI: 10.3390/ijms252312766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/20/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
Bone defects and fractures present significant clinical challenges, particularly in orthopedic and maxillofacial applications. While minor bone defects may be capable of healing naturally, those of a critical size necessitate intervention through the use of implants or grafts. The utilization of traditional methodologies, encompassing autografts and allografts, is constrained by several factors. These include the potential for donor site morbidity, the restricted availability of suitable donors, and the possibility of immune rejection. This has prompted extensive research in the field of bone tissue engineering to develop advanced synthetic and bio-derived materials that can support bone regeneration. The optimal bone substitute must achieve a balance between biocompatibility, bioresorbability, osteoconductivity, and osteoinductivity while simultaneously providing mechanical support during the healing process. Recent innovations include the utilization of three-dimensional printing, nanotechnology, and bioactive coatings to create scaffolds that mimic the structure of natural bone and enhance cell proliferation and differentiation. Notwithstanding the advancements above, challenges remain in optimizing the controlled release of growth factors and adapting materials to various clinical contexts. This review provides a comprehensive overview of the current advancements in bone substitute materials, focusing on their biological mechanisms, design considerations, and clinical applications. It explores the role of emerging technologies, such as additive manufacturing and stem cell-based therapies, in advancing the field. Future research highlights the need for multidisciplinary collaboration and rigorous testing to develop advanced bone graft substitutes, improving outcomes and quality of life for patients with complex defects.
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Affiliation(s)
- Julia Weronika Łuczak
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postępu 36A, 05-552 Magdalenka, Poland
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Ciszewskiego 8, Bldg. 23, 02-786 Warsaw, Poland
| | - Małgorzata Palusińska
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postępu 36A, 05-552 Magdalenka, Poland
| | - Damian Matak
- European Biomedical Institute, 05-410 Jozefów, Poland
| | - Damian Pietrzak
- Division of Parasitology and Parasitic Diseases, Department of Preclinical Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-786 Warsaw, Poland
| | - Paweł Nakielski
- Department of Biosystems and Soft Matter, Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawińskiego 5B, 02-106 Warsaw, Poland
| | - Sławomir Lewicki
- Institute of Outcomes Research, Maria Sklodowska-Curie Medical Academy, Pl. Żelaznej Bramy 10, 00-136 Warsaw, Poland
| | - Marta Grodzik
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Ciszewskiego 8, Bldg. 23, 02-786 Warsaw, Poland
| | - Łukasz Szymański
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Postępu 36A, 05-552 Magdalenka, Poland
- European Biomedical Institute, 05-410 Jozefów, Poland
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Salim NV, Madhan B, Glattauer V, Ramshaw JAM. Comprehensive review on collagen extraction from food by-products and waste as a value-added material. Int J Biol Macromol 2024; 278:134374. [PMID: 39098671 DOI: 10.1016/j.ijbiomac.2024.134374] [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: 02/24/2024] [Revised: 07/18/2024] [Accepted: 07/30/2024] [Indexed: 08/06/2024]
Abstract
The consumption of animal products has witnessed a significant increase over the years, leading to a growing need for industries to adopt strict waste control measures to mitigate environmental impacts. The disposal of animal waste in landfill can result in diverse and potentially hazardous decomposition by-products. Animal by-products, derived from meat, poultry, seafood and fish industries, offer a substantial raw material source for collagen and gelatin production due to their high protein content. Collagen, being a major protein component of animal tissues, represents an abundant resource that finds application in various chemical and material industries. The demand for collagen-based products continues to grow, yet the availability of primary material remains limited and insufficient to meet projected needs. Consequently, repurposing waste materials that contain collagen provides an opportunity to meet this need while at the same time minimizing the amount of waste that is dumped. This review examines the potential to extract value from the collagen content present in animal-derived waste and by-products. It provides a systematic evaluation of different species groups and discusses various approaches for processing and fabricating repurposed collagen. This review specifically focuses on collagen-based research, encompassing an examination of its physical and chemical properties, as well as the potential for chemical modifications. We have detailed how the research and knowledge built on collagen structure and function will drive the new initiatives that will lead to the development of new products and opportunities in the future. Additionally, it highlights emerging approaches for extracting high-quality protein from waste and discusses efforts to fabricate collagen-based materials leading to the development of new and original products within the chemical, biomedical and physical science-based industries.
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Affiliation(s)
- Nisa V Salim
- School of Engineering, Swinburne University of Technology, Hawthorne, Victoria 3122, Australia.
| | - Balaraman Madhan
- Centre for Academic and Research Excellence, CSIR-Central Leather Research Institute, Sardar Patel Road, Adyar, Chennai 600 020, India
| | | | - John A M Ramshaw
- School of Engineering, Swinburne University of Technology, Hawthorne, Victoria 3122, Australia
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De Lauretis A, Øvrebø Ø, Romandini M, Lyngstadaas SP, Rossi F, Haugen HJ. From Basic Science to Clinical Practice: A Review of Current Periodontal/Mucogingival Regenerative Biomaterials. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308848. [PMID: 38380549 PMCID: PMC11077667 DOI: 10.1002/advs.202308848] [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: 11/17/2023] [Revised: 01/23/2024] [Indexed: 02/22/2024]
Abstract
Periodontitis is a dysbiosis-driven inflammatory disease affecting the tooth-supporting tissues, characterized by their progressive resorption, which can ultimately lead to tooth loss. A step-wise therapeutic approach is employed for periodontitis. After an initial behavioral and non-surgical phase, intra-bony or furcation defects may be amenable to regenerative procedures. This review discusses the regenerative technologies employed for periodontal regeneration, highlighting the current limitations and future research areas. The search, performed on the MEDLINE database, has identified the available biomaterials, including biologicals (autologous platelet concentrates, hydrogels), bone grafts (pure or putty), and membranes. Biologicals and bone grafts have been critically analyzed in terms of composition, mechanism of action, and clinical applications. Although a certain degree of periodontal regeneration is predictable in intra-bony and class II furcation defects, complete defect closure is hardly achieved. Moreover, treating class III furcation defects remains challenging. The key properties required for functional regeneration are discussed, and none of the commercially available biomaterials possess all the ideal characteristics. Therefore, research is needed to promote the advancement of more effective and targeted regenerative therapies for periodontitis. Lastly, improving the design and reporting of clinical studies is suggested by strictly adhering to the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement.
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Affiliation(s)
- Angela De Lauretis
- Department of Biomaterials, Institute of Clinical Dentistry, Faculty of DentistryUniversity of OsloOslo0455Norway
- Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”Politecnico di MilanoMilan20133Italy
| | - Øystein Øvrebø
- Department of Biomaterials, Institute of Clinical Dentistry, Faculty of DentistryUniversity of OsloOslo0455Norway
- Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”Politecnico di MilanoMilan20133Italy
| | - Mario Romandini
- Department of Periodontology, Institute of Clinical Dentistry, Faculty of DentistryUniversity of OsloOslo0455Norway
| | - Ståle Petter Lyngstadaas
- Department of Biomaterials, Institute of Clinical Dentistry, Faculty of DentistryUniversity of OsloOslo0455Norway
| | - Filippo Rossi
- Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”Politecnico di MilanoMilan20133Italy
| | - Håvard Jostein Haugen
- Department of Biomaterials, Institute of Clinical Dentistry, Faculty of DentistryUniversity of OsloOslo0455Norway
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Ren J, Li Z, Liu W, Fan Y, Qi L, Li S, Kong C, Zou H, Liu Z. Demineralized bone matrix for repair and regeneration of maxillofacial defects: A narrative review. J Dent 2024; 143:104899. [PMID: 38428719 DOI: 10.1016/j.jdent.2024.104899] [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: 01/08/2024] [Revised: 02/14/2024] [Accepted: 02/23/2024] [Indexed: 03/03/2024] Open
Abstract
OBJECTIVES Demineralized bone matrix (DBM) is a well-established bone graft material widely accepted by dentists and the public for its favorable osteoconductivity and osteoinductive potential. This article aimed to provide a narrative review of the current therapeutic applications and limitations of DBM in maxillofacial bone defects. STUDY SELECTION, DATA, AND SOURCES Randomized controlled trials, prospective or retrospective clinical studies, case series and reports, and systematic reviews. MEDLINE, PubMed, and Google Scholar were searched using keywords. CONCLUSIONS Some evidence supported the therapeutic application of DBM in periodontal intrabony defects, maxillary sinus lifts, ridge preservation, ridge augmentation, alveolar cleft repair, orthognathic surgery, and other regional maxillofacial bone defects. However, the limitations of DBM should be considered when using it, including potential low immunogenicity, instability of osteoinductive potential, handling of the graft material, and patient acceptance. CLINICAL SIGNIFICANCE With the increasing demand for the treatment of maxillofacial bone defects, DBM is likely to play a greater role as a promising bone graft material. Safe and effective combination treatment strategies and how to maintain a stable osteoinductive potential will be the future challenges of DBM research.
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Affiliation(s)
- Jiwei Ren
- Hospital of Stomatology, Jilin University, China
| | - Zhiwei Li
- Hospital of Stomatology, Jilin University, China
| | - Wantong Liu
- Hospital of Stomatology, Jilin University, China
| | - Yixin Fan
- Hospital of Stomatology, Jilin University, China
| | - Le Qi
- Hospital of Stomatology, Jilin University, China
| | - Sining Li
- Hospital of Stomatology, Jilin University, China
| | - Chen Kong
- Hospital of Stomatology, Jilin University, China
| | - He Zou
- Hospital of Stomatology, Jilin University, China
| | - Zhihui Liu
- Hospital of Stomatology, Jilin University, China.
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Söhling N, Heilani M, Fremdling C, Schaible A, Schröder K, Brune JC, Eras V, Nau C, Marzi I, Henrich D, Verboket RD. One Stage Masquelets Technique: Evaluation of Different Forms of Membrane Filling with and without Bone Marrow Mononuclear Cells (BMC) in Large Femoral Bone Defects in Rats. Cells 2023; 12:cells12091289. [PMID: 37174689 PMCID: PMC10177115 DOI: 10.3390/cells12091289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/23/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
The classic two-stage masquelet technique is an effective procedure for the treatment of large bone defects. Our group recently showed that one surgery could be saved by using a decellularized dermis membrane (DCD, Epiflex, DIZG). In addition, studies with bone substitute materials for defect filling show that it also appears possible to dispense with the removal of syngeneic cancellous bone (SCB), which is fraught with complications. The focus of this work was to clarify whether the SCB can be replaced by the granular demineralized bone matrix (g-DBM) or fibrous demineralized bone matrix (f-DBM) demineralized bone matrix and whether the colonization of the DCD and/or the DBM defect filling with bone marrow mononuclear cells (BMC) can lead to improved bone healing. In 100 Sprague Dawley rats, a critical femoral bone defect 5 mm in length was stabilized with a plate and then encased in DCD. Subsequently, the defect was filled with SCB (control), g-DBM, or f-DBM, with or without BMC. After 8 weeks, the femurs were harvested and subjected to histological, radiological, and biomechanical analysis. The analyses showed the incipient bony bridging of the defect zone in both groups for g-DBM and f-DBM. Stability and bone formation were not affected compared to the control group. The addition of BMCs showed no further improvement in bone healing. In conclusion, DBM offers a new perspective on defect filling; however, the addition of BMC did not lead to better results.
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Affiliation(s)
- Nicolas Söhling
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany
| | - Myriam Heilani
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany
| | - Charlotte Fremdling
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany
| | - Alexander Schaible
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany
| | - Katrin Schröder
- Center of Physiology, Cardiovascular Physiology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany
| | - Jan C Brune
- German Institute for Cell and Tissue Replacement (DIZG, gemeinnützige GmbH), 12555 Berlin, Germany
| | - Volker Eras
- German Institute for Cell and Tissue Replacement (DIZG, gemeinnützige GmbH), 12555 Berlin, Germany
| | - Christoph Nau
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany
| | - Ingo Marzi
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany
| | - Dirk Henrich
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany
| | - René D Verboket
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany
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Kellaway SC, Roberton V, Jones JN, Loczenski R, Phillips JB, White LJ. Engineered neural tissue made using hydrogels derived from decellularised tissues for the regeneration of peripheral nerves. Acta Biomater 2023; 157:124-136. [PMID: 36494008 DOI: 10.1016/j.actbio.2022.12.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/10/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022]
Abstract
Engineered neural tissue (EngNT) promotes in vivo axonal regeneration. Decellularised materials (dECM) are complex biologic scaffolds that can improve the cellular environment and also encourage positive tissue remodelling in vivo. We hypothesised that we could incorporate a hydrogel derived from a decellularised tissue (dECMh) into EngNT, thereby providing an alternative to the currently used purified collagen I hydrogel for the first time. Decellularisation was carried out on bone (B-ECM), liver (LIV-ECM), and small intestinal (SIS-ECM) tissues and the resultant dECM was biochemically and mechanically characterised. dECMh differed in mechanical and biochemical properties that likely had an effect on Schwann cell behaviour observed in metabolic activity and contraction profiles. Cellular alignment was observed in tethered moulds within the B-ECM and SIS-ECM derived hydrogels only. No difference was observed in dorsal root ganglia (DRG) neurite extension between the dECMh groups and collagen I groups when applied as a coverslip coating, however, when DRG were seeded atop EngNT constructs, only the B-ECM derived EngNT performed similarly to collagen I derived EngNT. B-ECM EngNT further exhibited similar axonal regeneration to collagen I EngNT in a 10 mm gap rat sciatic nerve injury model after 4 weeks. Our results have shown that various dECMh can be utilised to produce EngNT that can promote neurite extension in vitro and axonal regeneration in vivo. STATEMENT OF SIGNIFICANCE: Nerve autografts are undesirable due to the sacrifice of a patient's own nerve tissue to repair injuries. Engineered neural tissue (EngNT) is a type of living artificial tissue that has been developed to overcome this. To date, only a collagen hydrogel has been shown to be effective in the production and utilisation of EngNT in animal models. Hydrogels may be made from decellularised extracellular matrix derived from many tissues. In this study we showed that hydrogels from various tissues may be used to create EngNT and one was shown to comparable to the currently used collagen based EngNT in a rat sciatic nerve injry model.
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Affiliation(s)
- Simon C Kellaway
- Centre for Nerve Engineering, University College London, UK; Division of Regenerative Medicine and Cellular Therapies, School of Pharmacy, Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK; Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK; Biodiscovery Institute, University of Nottingham, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
| | - Victoria Roberton
- Centre for Nerve Engineering, University College London, UK; Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK
| | - Joshua N Jones
- Division of Regenerative Medicine and Cellular Therapies, School of Pharmacy, Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK; Biodiscovery Institute, University of Nottingham, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
| | - Rabea Loczenski
- Division of Regenerative Medicine and Cellular Therapies, School of Pharmacy, Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK; Biodiscovery Institute, University of Nottingham, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
| | - James B Phillips
- Centre for Nerve Engineering, University College London, UK; Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK
| | - Lisa J White
- Division of Regenerative Medicine and Cellular Therapies, School of Pharmacy, Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK; Biodiscovery Institute, University of Nottingham, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
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Bari TJ, Hansen LV, Dahl B, Gehrchen M. Use of demineralized cortical fibers is associated with reduced risk of pseudarthrosis after pedicle subtraction osteotomy for adult spinal deformity. Spine Deform 2022; 10:657-667. [PMID: 34807398 DOI: 10.1007/s43390-021-00444-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 11/10/2021] [Indexed: 11/24/2022]
Abstract
PURPOSE To assess the effect of demineralized cortical fibers (DCF) on postoperative pseudarthrosis requiring revision surgery in patients undergoing pedicle subtraction osteotomy (PSO) for adult spinal deformity (ASD). METHODS The use of DCF was introduced across all procedures in 2017 and subsequent patients undergoing PSO surgery were prospectively and consecutively registered. Following sample-size estimation, a retrospective cohort was also registered undergoing the same procedure immediately prior to the implementation of DCF. The non-DCF group underwent surgery with ABG. Minimum follow-up was 2 years in both groups. The main outcome was postoperative pseudarthrosis, either CT-verified or verified intraoperatively during revision surgery due to rod breakage and assessed using Kaplan-Meier survival analyses. RESULTS A total of 48 patients were included in the DCF group and 76 in the non-DCF group. The DCF group had more frequently undergone previous spine surgery (60% vs 36%) and had shorter follow-up (32 ± 2 vs 40 ± 7 months). Pseudarthrosis occurred in 7 (15%) patients in the DCF group and 31 (41%) in the non-DCF group, corresponding to a relative risk increase of 2.6 (95%CI 1.3-2.4, P < 0.01). 1-KM survival analyses, taking time to event into account and thus the difference in follow-up, also showed increased pseudarthrosis in the non-DCF group (log-rank P = 0.022). Similarly, multivariate logistic regression adjusted for age, instrumented levels and sacral fusion was also with significantly increased odds of pseudarthrosis in the non-DCF group (OR: 4.3, 95%CI: 1.7-11.3, P < 0.01). CONCLUSION We found considerable and significant reductions in pseudarthrosis following PSO surgery with DCF compared to non-DCF. LEVEL OF EVIDENCE III.
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Affiliation(s)
- Tanvir Johanning Bari
- Spine Unit, Department of Orthopedic Surgery, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark.
| | - Lars Valentin Hansen
- Spine Unit, Department of Orthopedic Surgery, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Benny Dahl
- Department of Orthopedics and Scoliosis Surgery, Texas Children's Hospital and Baylor College of Medicine, 6621 Fannin St, Houston, TX, 77030, USA
| | - Martin Gehrchen
- Spine Unit, Department of Orthopedic Surgery, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark
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Moss SM, Ortiz-Hernandez M, Levin D, Richburg CA, Gerton T, Cook M, Houlton JJ, Rizvi ZH, Goodwin PC, Golway M, Ripley B, Hoying JB. A Biofabrication Strategy for a Custom-Shaped, Non-Synthetic Bone Graft Precursor with a Prevascularized Tissue Shell. Front Bioeng Biotechnol 2022; 10:838415. [PMID: 35356783 PMCID: PMC8959609 DOI: 10.3389/fbioe.2022.838415] [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: 12/17/2021] [Accepted: 02/08/2022] [Indexed: 11/13/2022] Open
Abstract
Critical-sized defects of irregular bones requiring bone grafting, such as in craniofacial reconstruction, are particularly challenging to repair. With bone-grafting procedures growing in number annually, there is a reciprocal growing interest in bone graft substitutes to meet the demand. Autogenous osteo(myo)cutaneous grafts harvested from a secondary surgical site are the gold standard for reconstruction but are associated with donor-site morbidity and are in limited supply. We developed a bone graft strategy for irregular bone-involved reconstruction that is customizable to defect geometry and patient anatomy, is free of synthetic materials, is cellularized, and has an outer pre-vascularized tissue layer to enhance engraftment and promote osteogenesis. The graft, comprised of bioprinted human-derived demineralized bone matrix blended with native matrix proteins containing human mesenchymal stromal cells and encased in a simple tissue shell containing isolated, human adipose microvessels, ossifies when implanted in rats. Ossification follows robust vascularization within and around the graft, including the formation of a vascular leash, and develops mechanical strength. These results demonstrate an early feasibility animal study of a biofabrication strategy to manufacture a 3D printed patient-matched, osteoconductive, tissue-banked, bone graft without synthetic materials for use in craniofacial reconstruction. The bone fabrication workflow is designed to be performed within the hospital near the Point of Care.
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Affiliation(s)
- Sarah M. Moss
- Advanced Solutions Life Sciences, Louisville, KY, United States
| | - Monica Ortiz-Hernandez
- Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
- Department of Radiology, University of Washington School of Medicine, Seattle, WA, United States
| | - Dmitry Levin
- Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
- Department of Radiology, University of Washington School of Medicine, Seattle, WA, United States
| | - Chris A. Richburg
- Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
| | - Thomas Gerton
- Advanced Solutions Life Sciences, Louisville, KY, United States
| | - Madison Cook
- Advanced Solutions Life Sciences, Louisville, KY, United States
| | - Jeffrey J. Houlton
- Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
- Department of Radiology, University of Washington School of Medicine, Seattle, WA, United States
| | - Zain H. Rizvi
- Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
- Department of Radiology, University of Washington School of Medicine, Seattle, WA, United States
| | | | - Michael Golway
- Advanced Solutions Life Sciences, Louisville, KY, United States
| | - Beth Ripley
- Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
- Department of Radiology, University of Washington School of Medicine, Seattle, WA, United States
| | - James B. Hoying
- Advanced Solutions Life Sciences, Louisville, KY, United States
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9
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Mu P, Feng J, Hu Y, Xiong F, Ma X, Tian L. Botanical Drug Extracts Combined With Biomaterial Carriers for Osteoarthritis Cartilage Degeneration Treatment: A Review of 10 Years of Research. Front Pharmacol 2022; 12:789311. [PMID: 35173609 PMCID: PMC8841352 DOI: 10.3389/fphar.2021.789311] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
Osteoarthritis (OA) is a long-term chronic arthrosis disease which is usually characterized by pain, swelling, joint stiffness, reduced range of motion, and other clinical manifestations and even results in disability in severe cases. The main pathological manifestation of OA is the degeneration of cartilage. However, due to the special physiological structure of the cartilage, once damaged, it is unable to repair itself, which is one of the challenges of treating OA clinically. Abundant studies have reported the application of cartilage tissue engineering in OA cartilage repair. Among them, cell combined with biological carrier implantation has unique advantages. However, cell senescence, death and dedifferentiation are some problems when cultured in vitro. Botanical drug remedies for OA have a long history in many countries in Asia. In fact, botanical drug extracts (BDEs) have great potential in anti-inflammatory, antioxidant, antiaging, and other properties, and many studies have confirmed their effects. BDEs combined with cartilage tissue engineering has attracted increasing attention in recent years. In this review, we will explain in detail how cartilage tissue engineering materials and BDEs play a role in cartilage repair, as well as the current research status.
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Affiliation(s)
- Panyun Mu
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jie Feng
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yimei Hu
- Department of Orthopedics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Yimei Hu,
| | - Feng Xiong
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xu Ma
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Linling Tian
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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10
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Anti-Inflammatory Activity of a Demineralized Bone Matrix: An In Vitro Pilot Study. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12020876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Demineralized bone matrix (DBM) is commonly used for the reconstruction of bone defects. Early graft consolidation involves a transient inflammatory process. It is, however, unclear whether DBM can modulate this process. To test this possibility, we prepared acid lysates of demineralized ground cortical (DGC) and moldable demineralized fibers (MDF). Murine RAW 264.7 and primary bone marrow macrophages were exposed to acid lysates of DGC and MFD prior to provoking an inflammatory response with lipopolysaccharide (LPS). Similarly, murine ST2 mesenchymal cells were exposed to DGC and MFD with and without interleukin 1β (IL1) and TNFα. We show here that acid lysates of DGC and MFD reduced the expression of IL1 and IL6 in RAW 264.7 macrophages, as determined by RT-PCR and, for IL6, by immunoassay. This response was confirmed with primary macrophages. Likewise, desalted acid lysates exert anti-inflammatory properties on RAW 264.7 cells and in ST2 cells, the forced expression of IL6, inducible nitric oxide synthase (iNOS) and chemokine ligand 5 (CCL5) was reduced. These in vitro findings suggest that DGC and MFD lower the inflammation-induced expression of inflammatory mediators in murine cell-based bioassays.
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Trivedi T, Guise TA. Systemic effects of abnormal bone resorption on muscle, metabolism, and cognition. Bone 2022; 154:116245. [PMID: 34718221 DOI: 10.1016/j.bone.2021.116245] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 10/21/2021] [Accepted: 10/25/2021] [Indexed: 12/11/2022]
Abstract
Skeletal tissue is dynamic, undergoing constant remodeling to maintain musculoskeletal integrity and balance in the human body. Recent evidence shows that apart from maintaining homeostasis in the local microenvironment, the skeleton systemically affects other tissues. Several cancer-associated and noncancer-associated bone disorders can disrupt the physiological homeostasis locally in the bone microenvironment and indirectly contribute to dysregulation of systemic body function. The systemic effects of bone on the regulation of distant organ function have not been widely explored. Recent evidence suggests that bone can interact with skeletal muscle, pancreas, and brain by releasing factors from mineralized bone matrix. Currently available bone-targeting therapies such as bisphosphonates and denosumab inhibit bone resorption, decrease morbidity associated with bone destruction, and improve survival. Bisphosphonates have been a standard treatment for bone metastases, osteoporosis, and cancer treatment-induced bone diseases. The extraskeletal effects of bisphosphonates on inhibition of tumor growth are known. However, our knowledge of the effects of bisphosphonates on muscle weakness, hyperglycemia, and cognitive defects is currently evolving. To be able to identify the molecular link between bone and distant organs during abnormal bone resorption and then treat these abnormalities and prevent their systemic effects could improve survival benefits. The current review highlights the link between bone resorption and its systemic effects on muscle, pancreas, and brain.
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Affiliation(s)
- Trupti Trivedi
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Theresa A Guise
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
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12
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Peng Y, Li J, Lin H, Tian S, Liu S, Pu F, Zhao L, Ma K, Qing X, Shao Z. Endogenous repair theory enriches construction strategies for orthopaedic biomaterials: a narrative review. BIOMATERIALS TRANSLATIONAL 2021; 2:343-360. [PMID: 35837417 PMCID: PMC9255795 DOI: 10.12336/biomatertransl.2021.04.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 11/19/2021] [Indexed: 02/06/2023]
Abstract
The development of tissue engineering has led to new strategies for mitigating clinical problems; however, the design of the tissue engineering materials remains a challenge. The limited sources and inadequate function, potential risk of microbial or pathogen contamination, and high cost of cell expansion impair the efficacy and limit the application of exogenous cells in tissue engineering. However, endogenous cells in native tissues have been reported to be capable of spontaneous repair of the damaged tissue. These cells exhibit remarkable plasticity, and thus can differentiate or be reprogrammed to alter their phenotype and function after stimulation. After a comprehensive review, we found that the plasticity of these cells plays a major role in establishing the cell source in the mechanism involved in tissue regeneration. Tissue engineering materials that focus on assisting and promoting the natural self-repair function of endogenous cells may break through the limitations of exogenous seed cells and further expand the applications of tissue engineering materials in tissue repair. This review discusses the effects of endogenous cells, especially stem cells, on injured tissue repairing, and highlights the potential utilisation of endogenous repair in orthopaedic biomaterial constructions for bone, cartilage, and intervertebral disc regeneration.
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Affiliation(s)
- Yizhong Peng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Jinye Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Hui Lin
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Shuo Tian
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Sheng Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Feifei Pu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Lei Zhao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Kaige Ma
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiangcheng Qing
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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13
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Jin YZ, Zheng GB, Lee JH, Han SH. Comparison of demineralized bone matrix and hydroxyapatite as carriers of Escherichia coli recombinant human BMP-2. Biomater Res 2021; 25:25. [PMID: 34344483 PMCID: PMC8330053 DOI: 10.1186/s40824-021-00225-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/15/2021] [Indexed: 11/10/2022] Open
Abstract
Background Autograft has been widely used in various orthopedic and dental surgery for its superior osteogenicity, osteoinductivity and osteoconductivity. But the available volume of the autograft is limited and the efficacy of it is highly affected by the condition of the patients. Therefore, growth factors such as Escherichia coli bone morphogenetic protein-2 (ErhBMP-2) has been widely used in some countries and regions with various carriers that could affect the effects of the growth factors. Demineralized bone matrix (DBM) has been widely used as a bone graft substitute and growth factor carrier, but its effect as a carrier of ErhBMP-2 was less investigated. Materials and methods Rat calvaria defect model was used in this study. We implanted ErhBMP-2 with DBM or hydroxyapatite (HA) as a carrier in 8 mm calvaria defect and compared their bone regeneration effect in 4th week and 8th week after implantation with micro-CT and histology. The data was analyzed with one-way ANOVA method with Bonferroni post-hoc analysis. Result The group with DBM as the carrier showed significantly higher bone volume and bone thickness than the groups with HA as the carrier in both weeks. And the histology sections showed less adipose tissue formed in the groups with DBM as the carrier. Conclusion DBM could be a better carrier for ErhBMP-2 than HA.
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Affiliation(s)
- Yuan-Zhe Jin
- Department of Orthopedic Surgery, College of Medicine, Seoul National University, Seoul, 03080, South Korea.,The First Hospital of Jilin University, Changchun City, 130021, China
| | - Guang-Bin Zheng
- Department of Orthopaedics, Taizhou Hospial of Zhejiang Province, Linhai, 317000, Zhejiang, China
| | - Jae Hyup Lee
- Department of Orthopedic Surgery, College of Medicine, Seoul National University, Seoul, 03080, South Korea. .,Department of Orthopedic Surgery, SMG-SNU Boramae Medical Center, 39 Boramae Gil, Dongjak-Gu, Seoul, 156-707, South Korea. .,Department of Orthopaedic Surgery, Seoul National University, College of Medicine, Institute of Medical and Biological Engineering, Seoul National University Medical Research Centre, SMG-SNU Boramae Medical Centre, Boramae-ro 5-gil 20, Dongjak-gu, Seoul, 07061, South Korea.
| | - Shi-Huan Han
- Department of Orthopedic Surgery, College of Medicine, Seoul National University, Seoul, 03080, South Korea.,Department of Orthopedic Surgery, YanBian University Hospital, Yanji, 133000, Jilin Province, China
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Kim S, Fan J, Lee CS, Chen C, Lee M. Sulfonate Hydrogel-siRNA Conjugate Facilitates Osteogenic Differentiation of Mesenchymal Stem Cells by Controlled Gene Silencing and Activation of BMP Signaling. ACS APPLIED BIO MATERIALS 2021; 4:5189-5200. [PMID: 34661086 DOI: 10.1021/acsabm.1c00369] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hydrogels have been widely used in bone tissue engineering due to their tunable characteristics that allow facile modifications with various biochemical properties to support cell growth and guide proper cell functions. Herein, we report a design of hydrogel-siRNA conjugate that facilitates osteogenesis via gene silencing and activation of bone morphogenetic protein (BMP) signaling. A sulfonate hydrogel is prepared by modifying chitosan with sulfoacetic acid to mimic a natural sulfated polysaccharide and to provide a hydrogel surface that enables BMP binding. Then, siRNA targeting noggin, an endogenous extracellular antagonist of BMP signaling, is covalently conjugated to the sulfonate hydrogel by visible blue light crosslinking. The sulfonate hydrogel-siRNA conjugate is efficient to bind BMPs and also successfully prolongs the release of siRNA for sustained noggin suppression, thereby resulting in significantly increased osteogenic differentiation. Lastly, demineralized bone matrix (DBM) is incorporated into the sulfonate hydrogel-siRNA conjugate, wherein the DBM incorporation induces noggin expression via a negative feedback mechanism that regulates BMP signaling in DBM. However, simultaneous delivery of siRNA downregulates noggin thus facilitating endogenous BMP activity and enhancing the osteogenic efficacy of DBM. These findings support a promising hydrogel RNA silencing platform for bone tissue engineering applications.
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Affiliation(s)
- Soyon Kim
- Division of Advanced Prosthodontics, University of California, Los Angeles, USA
| | - Jiabing Fan
- Division of Advanced Prosthodontics, University of California, Los Angeles, USA
| | - Chung-Sung Lee
- Division of Advanced Prosthodontics, University of California, Los Angeles, USA
| | - Chen Chen
- Division of Advanced Prosthodontics, University of California, Los Angeles, USA
| | - Min Lee
- Division of Advanced Prosthodontics, University of California, Los Angeles, USA.,Department of Bioengineering, University of California, Los Angeles, USA
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15
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Roy S, Mukherjee P, Das PK, Ghosh PR, Datta P, Kundu B, Nandi SK. Local delivery systems of morphogens/biomolecules in orthopedic surgical challenges. MATERIALS TODAY COMMUNICATIONS 2021; 27:102424. [DOI: 10.1016/j.mtcomm.2021.102424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Verboket RD, Irrle T, Busche Y, Schaible A, Schröder K, Brune JC, Marzi I, Nau C, Henrich D. Fibrous Demineralized Bone Matrix (DBM) Improves Bone Marrow Mononuclear Cell (BMC)-Supported Bone Healing in Large Femoral Bone Defects in Rats. Cells 2021; 10:1249. [PMID: 34069404 PMCID: PMC8158746 DOI: 10.3390/cells10051249] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/12/2021] [Accepted: 05/17/2021] [Indexed: 12/13/2022] Open
Abstract
Regeneration of large bone defects is a major objective in trauma surgery. Bone marrow mononuclear cell (BMC)-supported bone healing was shown to be efficient after immobilization on a scaffold. We hypothesized that fibrous demineralized bone matrix (DBM) in various forms with BMCs is superior to granular DBM. A total of 65 male SD rats were assigned to five treatment groups: syngenic cancellous bone (SCB), fibrous demineralized bone matrix (f-DBM), fibrous demineralized bone matrix densely packed (f-DBM 120%), DBM granules (GDBM) and DBM granules 5% calcium phosphate (GDBM5%Ca2+). BMCs from donor rats were combined with different scaffolds and placed into 5 mm femoral bone defects. After 8 weeks, bone mineral density (BMD), biomechanical stability and histology were assessed. Similar biomechanical properties of f-DBM and SCB defects were observed. Similar bone and cartilage formation was found in all groups, but a significantly bigger residual defect size was found in GDBM. High bone healing scores were found in f-DBM (25) and SCB (25). The application of DBM in fiber form combined with the application of BMCs shows promising results comparable to the gold standard, syngenic cancellous bone. Denser packing of fibers or higher amount of calcium phosphate has no positive effect.
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Affiliation(s)
- René D. Verboket
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (T.I.); (Y.B.); (A.S.); (I.M.); (C.N.); (D.H.)
| | - Tanja Irrle
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (T.I.); (Y.B.); (A.S.); (I.M.); (C.N.); (D.H.)
| | - Yannic Busche
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (T.I.); (Y.B.); (A.S.); (I.M.); (C.N.); (D.H.)
| | - Alexander Schaible
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (T.I.); (Y.B.); (A.S.); (I.M.); (C.N.); (D.H.)
| | - Katrin Schröder
- Center of Physiology, Cardiovascular Physiology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany;
| | - Jan C. Brune
- German Institute for Cell- and Tissue Replacement (DIZG, gemeinnützige GmbH), 12555 Berlin, Germany;
| | - Ingo Marzi
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (T.I.); (Y.B.); (A.S.); (I.M.); (C.N.); (D.H.)
| | - Christoph Nau
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (T.I.); (Y.B.); (A.S.); (I.M.); (C.N.); (D.H.)
| | - Dirk Henrich
- Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; (T.I.); (Y.B.); (A.S.); (I.M.); (C.N.); (D.H.)
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17
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Shepard NA, Rush AJ, Scarborough NL, Carter AJ, Phillips FM. Demineralized Bone Matrix in Spine Surgery: A Review of Current Applications and Future Trends. Int J Spine Surg 2021; 15:113-119. [PMID: 34376500 DOI: 10.14444/8059] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Graft augmentation for spinal fusion is an area of continued interest, with a wide variety of available products lacking clear recommendations regarding appropriate use. While iliac crest autograft has long been considered the "gold standard", suboptimal fusion rates along with harvest-related concerns continue to drive the need for graft alternatives. There are now multiple options of products with various characteristics that are available. These include demineralized bone matrix (DBM) and demineralized bone fibers (DBF), which have been used increasingly to promote spine fusion. The purpose of this review is to provide an updated narrative on the use of DBM/DBF in spine surgery. METHODS Literature review. RESULTS The clinical application of DBM in spine surgery has evolved since its introduction in the mid-1900s. Early preclinical studies demonstrated its effectiveness in promoting fusion. When used in the cervical, thoracic, and lumbar spine, more recent clinical data suggest similar rates of fusion compared with autograft, although clinical studies are primarily limited to level III or IV evidence with few level I studies. However, significant variability in surgical technique and type of product used in the literature limits its interpretation and overall application. CONCLUSIONS DBM and DBF are bone graft options in spine surgery. Most commonly used as graft extenders, they have the ability to increase the volume of traditional grafting techniques while potentially inducing new bone formation. While the literature supports good fusion rates when used in the lumbar spine and when used with adjuvant cages or additional grafting techniques in the cervical spine, care should be taken when using as a stand-alone product. As new literature emerges, DBM and DBF can be a useful method in a surgeon's armamentarium for fusion-based procedures.
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Affiliation(s)
- Nicholas A Shepard
- Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, Illinois
| | - Augustus J Rush
- Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, Illinois
| | | | | | - Frank M Phillips
- Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, Illinois
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18
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Lo WC, Tsai LW, Yang YS, Chan RWY. Understanding the Future Prospects of Synergizing Minimally Invasive Transforaminal Lumbar Interbody Fusion Surgery with Ceramics and Regenerative Cellular Therapies. Int J Mol Sci 2021; 22:3638. [PMID: 33807361 PMCID: PMC8037583 DOI: 10.3390/ijms22073638] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/22/2021] [Accepted: 03/26/2021] [Indexed: 12/14/2022] Open
Abstract
Transforaminal lumber interbody fusion (TLIF) is the last resort to address the lumber degenerative disorders such as spondylolisthesis, causing lower back pain. The current surgical intervention for these abnormalities includes open TLIF. However, in recent years, minimally invasive TLIF (MIS-TLIF) has gained a high momentum, as it could minimize the risk of infection, blood loss, and post-operative complications pertaining to fusion surgery. Further advancement in visualizing and guiding techniques along with grafting cage and materials are continuously improving the safety and efficacy of MIS-TLIF. These assistive techniques are also playing a crucial role to increase and improve the learning curve of surgeons. However, achieving an appropriate output through TLIF still remains a challenge, which might be synergized through 3D-printing and tissue engineering-based regenerative therapy. Owing to their differentiation potential, biomaterials such as stem/progenitor cells may contribute to restructuring lost or damaged tissues during MIS-TLIF, and this therapeutic efficacy could be further supplemented by platelet-derived biomaterials, leading to improved clinical outcomes. Thus, based on the above-mentioned strategies, we have comprehensively summarized recent developments in MIS-TLIF and its possible combinatorial regenerative therapies for rapid and long-term relief.
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Affiliation(s)
- Wen-Cheng Lo
- Department of Surgery, Division of Neurosurgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (Y.-S.Y.); (R.W.Y.C.)
- Department of Neurosurgery, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Taipei Neuroscience Institute, Taipei Medical University, Taipei 11031, Taiwan
| | - Lung-Wen Tsai
- Department of Medical Education and Research, Taipei Medical University Hospital, Taipei 11031, Taiwan;
| | - Yi-Shan Yang
- Department of Surgery, Division of Neurosurgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (Y.-S.Y.); (R.W.Y.C.)
- Department of Neurosurgery, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Taipei Neuroscience Institute, Taipei Medical University, Taipei 11031, Taiwan
| | - Ryan Wing Yuk Chan
- Department of Surgery, Division of Neurosurgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (Y.-S.Y.); (R.W.Y.C.)
- Department of Neurosurgery, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Taipei Neuroscience Institute, Taipei Medical University, Taipei 11031, Taiwan
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19
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TGF-β Activity of a Demineralized Bone Matrix. Int J Mol Sci 2021; 22:ijms22020664. [PMID: 33440877 PMCID: PMC7827646 DOI: 10.3390/ijms22020664] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/04/2021] [Accepted: 01/07/2021] [Indexed: 12/25/2022] Open
Abstract
Allografts consisting of demineralized bone matrix (DBM) are supposed to retain the growth factors of native bone. However, it is not clear if transforming growth factor β1 (TGF-β1) is maintained in the acid-extracted human bone. To this aim, the aqueous solutions of supernatants and acid lysates of OraGRAFT® Demineralized Cortical Particulate and OraGRAFT® Prime were prepared. Exposing fibroblasts to the aqueous solution caused a TGF-β receptor type I kinase-inhibitor SB431542-dependent increase in interleukin 11 (IL11), NADPH oxidase 4 (NOX4), and proteoglycan 4 (PRG4) expression. Interleukin 11 expression and the presence of TGF-β1 in the aqueous solutions were confirmed by immunoassay. Immunofluorescence further confirmed the nuclear translocation of Smad2/3 when fibroblasts were exposed to the aqueous solutions of both allografts. Moreover, allografts released matrix metalloprotease-2 activity and blocking proteases diminished the cellular TGF-β response to the supernatant. These results suggest that TGF-β is preserved upon the processing of OraGRAFT® and released by proteolytic activity into the aqueous solution.
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20
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Abstract
The shortcomings of autografts and allografts in bone defect healing have prompted researchers to develop suitable alternatives. Numerous biomaterials have been developed as bone graft substitutes each with their own advantages and disadvantages. However, in order to test if these biomaterials provide an adequate replacement of the clinical standard, a clinically representative animal model is needed to test their efficacy. In this chapter, we describe a mouse model that establishes a critical sized defect in the mid-diaphysis of the femur to evaluate the performance of bone graft substitutes. This is achieved by performing a femoral ostectomy and stabilization utilizing a femoral plate and titanium screws. The resulting defect enables the bone regenerative potential of bone graft substitutes to be investigated. Lastly, we provide instruction on assessing the torsional strength of the healed femurs to quantitatively evaluate the degree of healing as a primary outcome measure.
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Affiliation(s)
- Ryan P Trombetta
- Orthopedic Trauma Department, US Army Institute for Surgical Research, San Antonio, TX, USA
| | - Emma K Knapp
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
| | - Hani A Awad
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA.
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21
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Chen C, Rehnama M, Kim S, Lee CS, Zhang X, Aghaloo T, Fan J, Lee M. Enhanced Osteoinductivity of Demineralized Bone Matrix with Noggin Suppression in Polymer Matrix. Adv Biol (Weinh) 2021; 5:e202000135. [PMID: 33585837 PMCID: PMC7877805 DOI: 10.1002/adbi.202000135] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Demineralized bone matrix (DBM), a potential alternative to autologous bone-graft, has been increasingly used for clinical bone repair; however, its application in larger defects isn't successful partly due to the rapid dispersion of DBM particles and relatively lower osteoinductivity. Here, a novel strategy is created to complement the osteoinductivity of DBM by incorporating DBM in biopolymer hydrogel combined with the abrogation of BMP antagonism. Combined treatment of DBM + noggin-suppression displays increased osteogenic potency of human bone marrow mesenchymal stem cells (hBMSCs) in vitro. Injectable chitosan (MeGC)-based hydrogel with heparinization (Hep-MeGC) is further developed to localize and stabilize DBM. Noggin-suppression reveals the significant increase in osteogenesis of hBMSCs in the photopolymerizable Hep-MeGC hydrogels with the encapsulation of DBM. Moreover, the combination of DBM + noggin-suppression in the injectable Hep-MeGC hydrogel displays a robust bone healing in mouse critical-sized calvarial defects in vivo. The mechanistic analysis demonstrates that noggin-suppression increased DBM osteoinductivity by stimulating endogenous BMP/Smad signals. These results have shown promise in DBM's ability as a prominent bone grafting material while being coupled with gene editing mechanism and a localizing three-dimensional scaffold. Together, this approach poses a significant increase in the efficiency of DBM-mediated craniofacial bone repair and dental osteointegration.
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Affiliation(s)
- Chen Chen
- Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1668, USA
| | - Matthew Rehnama
- Division of Advanced Prosthodontics, University of California, Los Angeles, UCLA School of Dentistry, 10833 Le Conte Avenue, Los Angeles, CA 90095-1668, USA
| | - Soyon Kim
- Division of Advanced Prosthodontics, University of California, Los Angeles, UCLA School of Dentistry, 10833 Le Conte Avenue, Los Angeles, CA 90095-1668, USA
| | - Chung-Sung Lee
- Division of Advanced Prosthodontics, University of California, Los Angeles, UCLA School of Dentistry, 10833 Le Conte Avenue, Los Angeles, CA 90095-1668, USA
| | - Xiao Zhang
- Division of Advanced Prosthodontics, University of California, Los Angeles, UCLA School of Dentistry, 10833 Le Conte Avenue, Los Angeles, CA 90095-1668, USA
| | - Tara Aghaloo
- Division of Diagnostic and Surgical Sciences, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, California 90095, United States
| | - Jiabing Fan
- Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1668, USA
| | - Min Lee
- Division of Advanced Prosthodontics, School of Dentistry, Department of Bioengineering, University of California, Los Angeles, UCLA School of Dentistry, 10833 Le Conte Avenue, Los Angeles, CA 90095-1668, USA
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22
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Abdel-Aziz A, Waly MR, Abdel-Aziz MA, Sherif MM, Elhaddad H, Mostafa Zaky Abdelrazek BH. Economic Reliable Technique for Tunnel Grafting Using Iliac Crest Bone Graft in Two-Staged Revision Anterior Cruciate Ligament Surgery. Arthrosc Tech 2020; 9:e1917-e1925. [PMID: 33381401 PMCID: PMC7768218 DOI: 10.1016/j.eats.2020.08.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 08/16/2020] [Indexed: 02/03/2023] Open
Abstract
Revision anterior cruciate ligament surgery is a technically demanding procedure. Mal-positioned tunnels together with bone loss and its management are some of the difficulties and challenges faced. Two-staged procedures have successfully been used to tackle those challenges. We present a technique that is safe, reliable, reproducible, and economic in the management of bone defects faced in anterior cruciate ligament revision surgery by using iliac crest bone graft. Preoperative assessment of tunnel position and size is done by computed tomography. Tri-cortical iliac crest bone graft is harvested through a trap door. It is then shaped to fit the tunnels to be filled. It is tapered at the advancing end to facilitate introduction. Mounted on a passing pin and a drill bit, the graft is arthroscopically introduced into the femoral and tibial tunnels. The second stage is performed after the graft has incorporated, as seen on postoperative computed tomography, done at approximately 3 months after the first stage. Iliac crest provides a natural abundant reservoir for bone graft and has all the advantages of being an autograft. With good meticulous technique, complications can be avoided with less donor-site morbidity. This technique is safe, reliable, and reproducible. It provides an ample amount of graft and harvest does not rely on implants; hence, it is economic.
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Affiliation(s)
- Ahmed Abdel-Aziz
- Trauma and Orthopaedics, Kasr-Alainy Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Refaat Waly
- Trauma and Orthopaedics, Kasr-Alainy Faculty of Medicine, Cairo University, Cairo, Egypt,Address correspondence to Mohamed Refaat Waly, M.Sc., M.D., Lecturer of Trauma and Orthopaedics, Kasr-Alainy Faculty of Medicine, Cairo University, Mathaf El-Manial St., Cairo, Egypt, 11553.
| | - Mahmoud Ahmed Abdel-Aziz
- Trauma and Orthopaedics, Kasr-Alainy Faculty of Medicine, Cairo University, Cairo, Egypt,Student Hospital, Cairo University, Cairo, Egypt
| | | | - Hazem Elhaddad
- Trauma and Orthopaedics, Kasr-Alainy Faculty of Medicine, Cairo University, Cairo, Egypt,Cairo Fatemic Hospital, Cairo, Egypt
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Shang F, Yu Y, Liu S, Ming L, Zhang Y, Zhou Z, Zhao J, Jin Y. Advancing application of mesenchymal stem cell-based bone tissue regeneration. Bioact Mater 2020; 6:666-683. [PMID: 33005830 PMCID: PMC7509590 DOI: 10.1016/j.bioactmat.2020.08.014] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 08/07/2020] [Accepted: 08/15/2020] [Indexed: 12/11/2022] Open
Abstract
Reconstruction of bone defects, especially the critical-sized defects, with mechanical integrity to the skeleton is important for a patient's rehabilitation, however, it still remains challenge. Utilizing biomaterials of human origin bone tissue for therapeutic purposes has provided a facilitated approach that closely mimics the critical aspects of natural bone tissue with regard to its properties. However, not only efficacious and safe but also cost-effective and convenient are important for regenerative biomaterials to achieve clinical translation and commercial success. Advances in our understanding of regenerative biomaterials and their roles in new bone formation potentially opened a new frontier in the fast-growing field of regenerative medicine. Taking inspiration from the role and multicomponent construction of native extracellular matrix (ECM) for cell accommodation, the ECM-mimicking biomaterials and the naturally decellularized ECM scaffolds were used to create new tissues for bone restoration. On the other hand, with the going deep in understanding of mesenchymal stem cells (MSCs), they have shown great promise to jumpstart and facilitate bone healing even in diseased microenvironments with pharmacology-based endogenous MSCs rescue/mobilization, systemic/local infusion of MSCs for cytotherapy, biomaterials-based approaches, cell-sheets/-aggregates technology and usage of subcellular vesicles of MSCs to achieve scaffolds-free or cell-free delivery system, all of them have been shown can improve MSCs-mediated regeneration in preclinical studies and several clinical trials. Here, following an overview discussed autogenous/allogenic and ECM-based bone biomaterials for reconstructive surgery and applications of MSCs-mediated bone healing and tissue engineering to further offer principles and effective strategies to optimize MSCs-based bone regeneration.
Focusing on MSCs based bone regeneration. Discussed cytotherapy, cell-free therapies and cell-aggregates technology in detail. Stating the approaches of MSCs in diseased microenvironments.
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Affiliation(s)
- Fengqing Shang
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Department of Stomatology, The 306th Hospital of PLA, Beijing, 100101, China
| | - Yang Yu
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong, 250012, China
| | - Shiyu Liu
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Leiguo Ming
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Yongjie Zhang
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Zhifei Zhou
- Department of Stomatology, General Hospital of Tibetan Military Command, Lhasa, 850000, China
| | - Jiayu Zhao
- Bureau of Service for Veteran Cadres of PLA in Beijing, Beijing, 100001, China
| | - Yan Jin
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Corresponding author.
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Abstract
Nonunions represent a very heterogeneous, rare and sometimes very complex disease picture. The causes, localization and degree of expression show a very high variability, which makes it difficult to establish uniform treatment standards. Nevertheless, the process of bone healing is subject to some essential factors, which should be ensured for a successful treatment. Over the years these factors have been better researched and were taken into consideration for the diamond concept, which was first published by Giannoudis et al. in 2007. This provides the physician with a concept that does not neglect the heterogeneity of the disease picture and is an aid to decision making for the treatment regimen in individual cases in order to guarantee the best biological and mechanical conditions. The diamond concept is nowadays widely used and many studies have already demonstrated a successful application. It must be understood as a framework, in which the various treatment options available (bone substitute materials, mesenchymal stem cells, osteosynthesis procedures etc.) are incorporated into the individual factors and therefore provides the physician with a certain freedom of choice in the selection of tools. Additionally, it is not a rigid corset and subject to medical scientific progress in its factors, so that it is exciting to see which new developments will be incorporated in the future.
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First Human Leucocyte Antigen (HLA) Response and Safety Evaluation of Fibrous Demineralized Bone Matrix in a Critical Size Femoral Defect Model of the Sprague-Dawley Rat. MATERIALS 2020; 13:ma13143120. [PMID: 32668732 PMCID: PMC7412543 DOI: 10.3390/ma13143120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/10/2020] [Accepted: 07/10/2020] [Indexed: 12/31/2022]
Abstract
Treatment of large bone defects is one of the great challenges in contemporary orthopedic and traumatic surgery. Grafts are necessary to support bone healing. A well-established allograft is demineralized bone matrix (DBM) prepared from donated human bone tissue. In this study, a fibrous demineralized bone matrix (f-DBM) with a high surface-to-volume ratio has been analyzed for toxicity and immunogenicity. f-DBM was transplanted to a 5-mm, plate-stabilized, femoral critical-size-bone-defect in Sprague-Dawley (SD)-rats. Healthy animals were used as controls. After two months histology, hematological analyses, immunogenicity as well as serum biochemistry were performed. Evaluation of free radical release and hematological and biochemical analyses showed no significant differences between the control group and recipients of f-DBM. Histologically, there was no evidence of damage to liver and kidney and good bone healing was observed in the f-DBM group. Reactivity against human HLA class I and class II antigens was detected with mostly low fluorescence values both in the serum of untreated and treated animals, reflecting rather a background reaction. Taken together, these results provide evidence for no systemic toxicity and the first proof of no basic immunogenic reaction to bone allograft and no sensitization of the recipient.
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26
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Azab E, Chandler KB, Uda Y, Sun N, Hussein A, Shuwaikan R, Lu V, Costello CE, McComb ME, Divieti Pajevic P. Osteocytes control myeloid cell proliferation and differentiation through Gsα-dependent and -independent mechanisms. FASEB J 2020; 34:10191-10211. [PMID: 32557809 DOI: 10.1096/fj.202000366r] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 05/07/2020] [Accepted: 05/16/2020] [Indexed: 01/19/2023]
Abstract
Osteocytes, the bone cells embedded in the mineralized matrix, control bone modeling, and remodeling through direct contact with adjacent cells and via paracrine and endocrine factors that affect cells in the bone marrow microenvironment or distant organs. Osteocytes express numerous G protein-coupled receptors (GPCRs) and thus mice lacking the stimulatory subunit of G-protein (Gsα) in osteocytes (Dmp1-GsαKO mice) have abnormal myelopoiesis, osteopenia, and reduced adipose tissue. We previously reported that the severe osteopenia and the changes in adipose tissue present in these mice were mediated by increased sclerostin, which suppress osteoblast functions and promote browning of white adipocytes. Inversely, the myeloproliferation was driven by granulocyte colony-stimulating factor (G-CSF) and administration of neutralizing antibodies against G-CSF only partially restored the myeloproliferation, suggesting that additional osteocyte-derived factors might be involved. We hypothesized that osteocytes secrete Gsα-dependent factor(s) which regulate the myeloid cells proliferation. To identify osteocyte-secreted proteins, we used the osteocytic cell line Ocy454 expressing or lacking Gsα expression (Ocy454-Gsαcont and Ocy454-GsαKO ) to delineate the osteocyte "secretome" and its regulation by Gsα. Here we reported that factors secreted by osteocytes increased the number of myeloid colonies and promoted macrophage proliferation. The proliferation of myeloid cells was further promoted by osteocytes lacking Gsα expression. Myeloid cells can differentiate into bone-resorbing osteoclasts, therefore, we hypothesized that osteocyte-secreted factors might also regulate osteoclastogenesis in a Gsα-dependent manner. Conditioned medium (CM) from Ocy454 (both Gsαcont and GsαKO ) significanlty increased the proliferation of bone marrow mononuclear cells (BMNC) and, at the same time, inhibited their differentiation into mature osteoclasts via a Gsα-dependent mechanism. Proteomics analysis of CM from Ocy454 Gsαcont and GsαKO cells identified neuropilin-1 (Nrp-1) and granulin (Grn) as osteocytic-secreted proteins upregulated in Ocy454-GsαKO cells compared to Ocy454-Gsαcont , whereas semaphorin3A was significantly suppressed. Treatment of Ocy454-Gsαcont cells with recombinant proteins or knockdown of Nrp-1 and Grn in Ocy454-GsαKO cells partially rescued the inhibition of osteoclasts, demonstrating that osteocytes control osteoclasts differentiation through Nrp-1 and Grn which are regulated by Gsα signaling.
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Affiliation(s)
- Ehab Azab
- Department of Translational Dental Medicine, Henry M. Goldman School of Dental Medicine, Boston University, Boston, MA, USA
| | - Kevin Brown Chandler
- Center for Biomedical Mass Spectrometry, School of Medicine, Boston University, Boston, MA, USA
| | - Yuhei Uda
- Department of Translational Dental Medicine, Henry M. Goldman School of Dental Medicine, Boston University, Boston, MA, USA
| | - Ningyuan Sun
- Department of Translational Dental Medicine, Henry M. Goldman School of Dental Medicine, Boston University, Boston, MA, USA
| | - Amira Hussein
- Department of Orthopedics, School of Medicine, Boston University, Boston, MA, USA
| | - Raghad Shuwaikan
- Department of Translational Dental Medicine, Henry M. Goldman School of Dental Medicine, Boston University, Boston, MA, USA
| | - Veronica Lu
- Department of Translational Dental Medicine, Henry M. Goldman School of Dental Medicine, Boston University, Boston, MA, USA
| | - Catherine E Costello
- Center for Biomedical Mass Spectrometry, School of Medicine, Boston University, Boston, MA, USA
| | - Mark E McComb
- Center for Biomedical Mass Spectrometry, School of Medicine, Boston University, Boston, MA, USA
| | - Paola Divieti Pajevic
- Department of Translational Dental Medicine, Henry M. Goldman School of Dental Medicine, Boston University, Boston, MA, USA
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Abstract
PURPOSE OF REVIEW Biologic bone graft materials continue to be an important component of various spinal fusion procedures. Given the known risks and morbidity of harvesting iliac crest bone graft, the historical gold standard for spinal fusion, these biologic materials serve the purpose of improving both the efficacy and safety of spinal fusion procedures. Recent advances in biomedical and materials sciences have enabled the design of many novel materials that have shown promise as effective bone graft materials. This review will discuss current research pertaining to several of these materials, including functionalized peptide amphiphiles and other nanocomposites, novel demineralized bone matrix applications, 3D-printed materials, and Hyperelastic Bone®, among others. RECENT FINDINGS Recent investigation has demonstrated that novel technologies, including nanotechnology and 3D printing, can be used to produce biomaterials with significant osteogenic potential. Notably, peptide amphiphile nanomaterials functionalized to bind BMP-2 have demonstrated significant bone regenerative capacity in a pre-clinical rodent posterolateral lumbar fusion (PLF) model. Additionally, 3D-printed Hyperelastic Bone® has demonstrated promising bone regenerative capacity in several in vivo animal models. Composite materials such as TrioMatrix® (demineralized bone matrix, hydroxyapatite, and nanofiber-based collagen scaffold) have also demonstrated significant osteogenic potential in both in vitro and in vivo settings. Advances in materials science and engineering have allowed for the design and implementation of several novel biologic materials, including nanocomposites, 3D-printed materials, and various biologic composites. These materials provide significant bone regenerative capacity and have the potential to be alternatives to other bone graft materials, such as autograft and BMP-2, which have known complications.
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Affiliation(s)
- Mark A Plantz
- Department of Orthopaedic Surgery, Northwestern University - Feinberg School of Medicine, 676 N. St. Clair St. #1350, Chicago, IL, 60611, USA
| | - Wellington K Hsu
- Department of Orthopaedic Surgery, Northwestern University - Feinberg School of Medicine, 676 N. St. Clair St. #1350, Chicago, IL, 60611, USA
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Kim S, Fan J, Lee CS, Chen C, Bubukina K, Lee M. Heparinized chitosan stabilizes the bioactivity of BMP-2 and potentiates the osteogenic efficacy of demineralized bone matrix. J Biol Eng 2020; 14:6. [PMID: 32165922 PMCID: PMC7059291 DOI: 10.1186/s13036-020-0231-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 02/25/2020] [Indexed: 12/23/2022] Open
Abstract
Background Demineralized bone matrix (DBM), an allograft bone processed to better expose osteoinductive factors such as bone morphogenetic proteins (BMPs), is increasingly used for clinical bone repair. However, more extensive use of DBM is limited by its unpredictable osteoinductivity and low bone formation capacity. Commercial DBM products often employ polymeric carriers to enhance handling properties but such carriers generally do not possess bioactive functions. Heparin is a highly sulfated polysaccharide and is shown to form a stable complex with growth factors to enhance their bioactivities. In this study, a new heparinized synthetic carrier for DBM is developed based on photocrosslinking of methacrylated glycol chitosan and heparin conjugation. Results Heparinized chitosan exerts protective effects on BMP bioactivity against physiological stressors related to bone fracture healing. It also enhances the potency of BMPs by inhibiting the activity of BMP antagonist, noggin. Moreover, heparinized chitosan is effective to deliver bone marrow stromal cells and DBM for enhanced osteogenesis by sequestering and localizing the cell-produced or DBM-released BMPs. Conclusions This research suggests an essential approach of developing a new hydrogel carrier to stabilize the bioactivity of BMPs and improve the clinical efficacy of current bone graft therapeutics for accelerated bone repair.
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Affiliation(s)
- Soyon Kim
- 1Division of Advanced Prosthodontics, University of California, Los Angeles, USA
| | - Jiabing Fan
- 1Division of Advanced Prosthodontics, University of California, Los Angeles, USA
| | - Chung-Sung Lee
- 1Division of Advanced Prosthodontics, University of California, Los Angeles, USA
| | - Chen Chen
- 1Division of Advanced Prosthodontics, University of California, Los Angeles, USA
| | - Ksenia Bubukina
- 1Division of Advanced Prosthodontics, University of California, Los Angeles, USA
| | - Min Lee
- 1Division of Advanced Prosthodontics, University of California, Los Angeles, USA.,2Department of Bioengineering, University of California, Los Angeles, USA
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Friend or Foe? Essential Roles of Osteoclast in Maintaining Skeletal Health. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4791786. [PMID: 32190665 PMCID: PMC7073503 DOI: 10.1155/2020/4791786] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 01/27/2020] [Indexed: 02/08/2023]
Abstract
Heightened activity of osteoclast is considered to be the culprit in breaking the balance during bone remodeling in pathological conditions, such as osteoporosis. As a “foe” of skeletal health, many antiosteoporosis therapies aim to inhibit osteoclastogenesis. However, bone remodeling is a dynamic process that requires the subtle coordination of osteoclasts and osteoblasts. Severe suppression of osteoclast differentiation will impair bone formation because of the coupling effect. Thus, understanding the complex roles of osteoclast in maintaining proper bone remodeling is highly warranted to develop better management of osteoporosis. This review aimed to determine the varied roles of osteoclasts in maintaining skeletal health and to highlight the positive roles of osteoclasts in maintaining normal bone remodeling. Generally, osteoclasts interact with osteocytes to initiate targeted bone remodeling and have crosstalk with mesenchymal stem cells and osteoblasts via secreted factors or cell-cell contact to promote bone formation. We believe that a better outcome of bone remodeling disorders will be achieved when proper strategies are made to coordinate osteoclasts and osteoblasts in managing such disorders.
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Salem HS, Axibal DP, Wolcott ML, Vidal AF, McCarty EC, Bravman JT, Frank RM. Two-Stage Revision Anterior Cruciate Ligament Reconstruction: A Systematic Review of Bone Graft Options for Tunnel Augmentation. Am J Sports Med 2020; 48:767-777. [PMID: 31116949 DOI: 10.1177/0363546519841583] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND No consensus is available regarding the optimal choice of bone graft material for bone tunnel augmentation in revision anterior cruciate ligament (ACL) surgery. PURPOSE To compare the outcomes of different bone graft materials for staged revision ACL reconstruction. STUDY DESIGN Systematic review. METHODS A systematic review using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was performed. PubMed, EMBASE, and the Cochrane Library were queried through use of the terms anterior cruciate ligament and revision to identify all studies reporting outcomes of bone tunnel grafting in 2-stage revision ACL reconstruction. Data extracted included indications for 2-stage surgery, surgical technique, graft material, time between surgeries, rehabilitation protocols, physical examination findings, patient-reported outcomes, and radiographic and histologic findings. RESULTS The analysis included 7 studies with a total of 234 patients. The primary outcome in 2 studies was graft incorporation (mean follow-up, 8.8 months), whereas the other 5 studies reported clinical outcomes with follow-up mean ± SD of 4.2 ± 2.1 years. The indication for bone grafting and between-stage protocol varied among studies. Autograft was used in 4 studies: iliac crest bone autograft (ICBG, n = 3) and tibial bone autograft (TBA, n = 1). In 2 studies, the authors investigated the outcomes of allograft: allograft bone matrix (ABM) and allograft bone chips (AC). Finally, 1 study compared ICBG to a synthetic bone substitute. Radiographic evaluation of bone graft integration after the first stage was reported in 4 studies, with an average duration of 4.9 months. In 4 studies, the authors reported the time interval between first and second surgeries, with an average of 6.1 months for ICBG compared with 8.7 months for allogenic and synthetic grafts. Revision ACL graft failure rates were reported by 5 studies, including 1 study with ABM (6.1%), 1 study with AC (8.3%), 1 study with TBA (0%), and 2 studies with ICBG (0% and 2%). CONCLUSION The indications for staged ACL reconstruction and the rehabilitation protocol between stages need to be clearly established. The available data indicate that autograft for bone tunnel grafting in 2-stage ACL revision may be associated with a lower risk of revision ACL reconstruction graft failure compared with allograft bone.
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Affiliation(s)
- Hytham S Salem
- University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Derek P Axibal
- University of Colorado School of Medicine, Aurora, Colorado, USA
| | | | - Armando F Vidal
- University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Eric C McCarty
- University of Colorado School of Medicine, Aurora, Colorado, USA
| | | | - Rachel M Frank
- University of Colorado School of Medicine, Aurora, Colorado, USA
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31
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Liu L, Lam WMR, Naidu M, Yang Z, Wang M, Ren X, Hu T, Kumarsing R, Ting K, Goh JCH, Wong HK. Synergistic Effect of NELL-1 and an Ultra-Low Dose of BMP-2 on Spinal Fusion. Tissue Eng Part A 2019; 25:1677-1689. [PMID: 31337284 DOI: 10.1089/ten.tea.2019.0124] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Bone morphogenetic protein 2 (BMP-2) is widely used in spinal fusion but it can cause adverse effects such as ectopic bone and adipose tissue in vivo. Neural epidermal growth factor like-like molecule-1 (NELL-1) has been shown to suppress BMP-2-induced adverse effects. However, no optimum carriers that control both NELL-1 and BMP-2 releases to elicit long-term bioactivity have been developed. In this study, we employed polyelectrolyte complex (PEC) as a control release carrier for NELL-1 and BMP-2. An ultra-low dose of BMP-2 synergistically functioned with NELL-1 on bone marrow mesenchymal stem cells osteogenic differentiation with greater mineralization in vitro. The osteoinductive ability of NELL-1 and an ultra-low dose of BMP-2 in PEC was investigated in rat posterolateral spinal fusion. Our results showed increased fusion rate, bone architecture, and improved bone stiffness at 8 weeks after surgery in the combination groups compared with NELL-1 or BMP-2 alone. Moreover, the formation of ectopic bone and adipose tissue was negligible in all the PEC groups. In summary, dual delivery of NELL-1 and an ultra-low dose of BMP-2 in the PEC control release carrier has greater fusion efficiency compared with BMP-2 alone and could potentially be a better alternative to the currently used BMP-2 treatments for spinal fusion. Impact Statement In this study, polyelectrolyte complex was used to absorb neural epidermal growth factor like-like molecule-1 (NELL-1) and bone morphogenetic protein 2 (BMP-2) to achieve controlled dual release. The addition of NELL-1 significantly reduced the effective dose of BMP-2 to 2.5% of its conventional dose in absorbable collagen sponge, to produce solid spinal fusion without significant adverse effects. This study was the first to identify the efficacy of combination NELL-1 and BMP-2 in a control release carrier in spinal fusion, which could be potentially used clinically to increase fusion rate and avoid the adverse effects commonly associated with conventional BMP-2.
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Affiliation(s)
- Ling Liu
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Wing Moon Raymond Lam
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Mathanapriya Naidu
- Cancer Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Zheng Yang
- NUS Tissue Engineering Program (NUSTEP), Life Science Institute, National University of Singapore, Singapore, Singapore
| | - Ming Wang
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Xiafei Ren
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Tao Hu
- Department of Spine Surgery, Shanghai East Hospital, Shanghai, China
| | - Ramruttun Kumarsing
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Kang Ting
- Section of Orthodontics, School of Dentistry, Dental and Craniofacial Research Institute, University of California Los Angeles, Los Angeles, California
| | - James Cho-Hong Goh
- NUS Tissue Engineering Program (NUSTEP), Life Science Institute, National University of Singapore, Singapore, Singapore.,Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore, Singapore
| | - Hee-Kit Wong
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,NUS Tissue Engineering Program (NUSTEP), Life Science Institute, National University of Singapore, Singapore, Singapore
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Lin K, Sheikh R, Romanazzo S, Roohani I. 3D Printing of Bioceramic Scaffolds-Barriers to the Clinical Translation: From Promise to Reality, and Future Perspectives. MATERIALS (BASEL, SWITZERLAND) 2019; 12:E2660. [PMID: 31438561 PMCID: PMC6747602 DOI: 10.3390/ma12172660] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 08/17/2019] [Accepted: 08/19/2019] [Indexed: 12/11/2022]
Abstract
In this review, we summarize the challenges of the three-dimensional (3D) printing of porous bioceramics and their translational hurdles to clinical applications. The state-of-the-art of the major 3D printing techniques (powder-based and slurry-based), their limitations and key processing parameters are discussed in detail. The significant roadblocks that prevent implementation of 3D printed bioceramics in tissue engineering strategies, and medical applications are outlined, and the future directions where new research may overcome the limitations are proposed. In recent years, there has been an increasing demand for a nanoscale control in 3D fabrication of bioceramic scaffolds via emerging techniques such as digital light processing, two-photon polymerization, or large area maskless photopolymerization. However, these techniques are still in a developmental stage and not capable of fabrication of large-sized bioceramic scaffolds; thus, there is a lack of sufficient data to evaluate their contribution. This review will also not cover polymer matrix composites reinforced with particulate bioceramics, hydrogels reinforced with particulate bioceramics, polymers coated with bioceramics and non-porous bioceramics.
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Affiliation(s)
- Kang Lin
- Biomaterials Design and Tissue Engineering Lab, School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia
| | - Rakib Sheikh
- Biomaterials Design and Tissue Engineering Lab, School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia
| | - Sara Romanazzo
- Biomaterials Design and Tissue Engineering Lab, School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia
| | - Iman Roohani
- Biomaterials Design and Tissue Engineering Lab, School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
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Jin YZ, Zheng GB, Lee JH. Escherichia coli BMP-2 showed comparable osteoinductivity with Chinese hamster ovary derived BMP-2 with demineralized bone matrix as carrier. Growth Factors 2019; 37:85-94. [PMID: 30947586 DOI: 10.1080/08977194.2019.1596905] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Escherichia coli bone morphogenetic protein-2 (ErhBMP-2) had a larger yield but less osteoinductivity than Chinese hamster ovary cell bone morphogenetic protein-2 (CrhBMP-2). Since the release profile of rhBMP-2 affects its osteoinductivity, an appropriate carrier could improve the effect of ErhBMP-2. Demineralized bone matrix (DBM) was one of the most widely used bone substitutes, but few studies evaluated the osteoinductivity of ErhBMP-2 while it was carried by DBM. Therefore, we compared the osteoinductivity of ErhBMP-2 with CrhBMP-2 with DBM as the carrier of each. In vitro results showed ErhBMP-2 had slightly less osteoinductivity than CrhBMP-2. However, with DBM as the carrier, ErhBMP-2 induced significantly more bone regeneration in rat calvaria defects. Therefore, ErhBMP-2 might have comparable osteoinductivity with CrhBMP-2 while carried by DBM.
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Affiliation(s)
- Yuan-Zhe Jin
- a Department of Orthopedic Surgery, College of Medicine, Seoul National University , Seoul , South Korea
| | - Guang-Bin Zheng
- b Department of Orthopaedics, Taizhou Hospial of Zhejiang Province , Zhejiang , China
| | - Jae Hyup Lee
- a Department of Orthopedic Surgery, College of Medicine, Seoul National University , Seoul , South Korea
- c Department of Orthopedic Surgery, SMG-SNU Boramae Medical Center , Seoul , South Korea
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Li G, Li P, Chen Q, Thu HE, Hussain Z. Current Updates on Bone Grafting Biomaterials and Recombinant Human Growth Factors Implanted Biotherapy for Spinal Fusion: A Review of Human Clinical Studies. Curr Drug Deliv 2019; 16:94-110. [PMID: 30360738 DOI: 10.2174/1567201815666181024142354] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 08/01/2018] [Accepted: 10/18/2018] [Indexed: 01/16/2023]
Abstract
BACKGROUND Owing to their great promise in the spinal surgeries, bone graft substitutes have been widely investigated for their safety and clinical potential. By the current advances in the spinal surgery, an understanding of the precise biological mechanism of each bone graft substitute is mandatory for upholding the induction of solid spinal fusion. OBJECTIVE The aim of the present review is to critically discuss various surgical implications and level of evidence of most commonly employed bone graft substitutes for spinal fusion. METHOD Data was collected via electronic search using "PubMed", "SciFinder", "ScienceDirect", "Google Scholar", "Web of Science" and a library search for articles published in peer-reviewed journals, conferences, and e-books. RESULTS Despite having exceptional inherent osteogenic, osteoinductive, and osteoconductive features, clinical acceptability of autografts (patient's own bone) is limited due to several perioperative and postoperative complications i.e., donor-site morbidities and limited graft supply. Alternatively, allografts (bone harvested from cadaver) have shown great promise in achieving acceptable bone fusion rate while alleviating the donor-site morbidities associated with implantation of autografts. As an adjuvant to allograft, demineralized bone matrix (DBM) has shown remarkable efficacy of bone fusion, when employed as graft extender or graft enhancer. Recent advances in recombinant technologies have made it possible to implant growth and differentiation factors (bone morphogenetic proteins) for spinal fusion. CONCLUSION Selection of a particular bone grafting biotherapy can be rationalized based on the level of spine fusion, clinical experience and preference of orthopaedic surgeon, and prevalence of donor-site morbidities.
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Affiliation(s)
- Guanbao Li
- Department of Minimally Invasive Spine Surgery, Yulin City Orthopaedic Hospital of Traditional Chinese Medicine and Western Medicine, NO.597, Jiaoyu Road, Yulin, Guangxi, 537000, China
| | - Pinquan Li
- Department of Minimally Invasive Spine Surgery, Yulin City Orthopaedic Hospital of Traditional Chinese Medicine and Western Medicine, NO.597, Jiaoyu Road, Yulin, Guangxi, 537000, China
| | - Qiuan Chen
- Department of Minimally Invasive Spine Surgery, Yulin City Orthopaedic Hospital of Traditional Chinese Medicine and Western Medicine, NO.597, Jiaoyu Road, Yulin, Guangxi, 537000, China
| | - Hnin Ei Thu
- Department of Pharmacology and Dental Therapeutics, Faculty of Dentistry, Lincoln University College, Jalan Stadium, SS 7/15, Kelana Jaya, 47301 Petaling Jaya, Selangor, Malaysia
| | - Zahid Hussain
- Department of Pharmaceutics, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, Bandar Puncak Alam 42300, Selangor, Malaysia
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Abstract
In New Zealand, oncoplastic surgery is common, but partial breast reconstruction presents challenges for radiation therapy targeting. Tissue rearrangement creates ambiguity when targeting the tumor bed, with resultant overestimation of treatment volumes. Thus, adoption of advanced methods of radiation therapy have been hindered. This pilot study describes use of a novel three-dimensional implant that provides a scaffolding for tissue ingrowth during partial breast reconstruction and delineates the tumor bed more precisely to assist radiation planning and mammographic surveillance. After informed consent, 15 women were implanted with the three-dimensional bioabsorbable implant. The device was sutured to the tumor bed during lumpectomy, and tissue flaps were mobilized and attached to the implant. Visualization of the marker and radiation treatment volumes were recorded and compared. The implant provided volume replacement and helped to maintain breast contour. Cosmetic outcomes were excellent; no device- or radiation-related complications occurred. One patient had a postoperative hematoma that resolved after percutaneous drainage; there were no postoperative infections. Three-year follow-up shows no tumor recurrences and no untoward effects. When compared to conventional radiation targeting, use of the implant showed that a greater than 50 percent reduction in treatment volume was possible in some cases. Three-year mammograms show no significant artifact, normal tissue ingrowth, and minimal fibrosis. This study describes a method of oncoplastic breast reconstruction using an implantable device that marks the site of tumor excision and provides for volume replacement with tissue ingrowth. Patients tolerated it well, and radiation therapy planning, positioning, and treatment were facilitated.
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Abstract
Supplemental Digital Content is available in the text. Background: The aim of this study was to evaluate freeze-dried cortical allograft bone for nasal dorsal augmentation. The 42-month report on 18 patients was published in 2009 in Plastic and Reconstructive Surgery with 89 percent success at level II evidence, and this article is the 10-year comprehensive review of 62 patients. Methods: All grafts met standards recommended by the American Association of Tissue Banks, the U.S. Food and Drug Administration, and the Centers for Disease Control and Prevention. Objective evaluation of the persistence of graft volume was obtained by cephalometric radiography, cone beam volumetric computed tomography, and computed tomography at up to 10 years. Vascularization and incorporation of new bone elements within the grafts were demonstrated by fluorine-18 sodium fluoride positron emission tomography at up to 10 years. Subjective estimation of graft volume persisting up to 10 years was obtained by patient response to a query conducted by an independent surveyor. Results: The authors report objective proof of persistence of volume alone or combined with proof of neovascularization in 16 of 19 allografts. The authors report the patient’s subjective opinion of volume persistence in 37 of 43 grafts. The dorsal augmentation was assessed overall to be successful in 85 percent of 62 patients evaluated between 1 and 10 years, with a mean of 4.7 years. Conclusions: Freeze-dried allograft bone is a safe and equal alternative for dorsal augmentation without donor-site morbidity. Further studies are needed to (1) confirm these findings for young patients needing long-term reconstruction, and (2) partially demineralize allograft bone to allow carving with a scalpel. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.
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Chramiec A, Vunjak-Novakovic G. Tissue engineered models of healthy and malignant human bone marrow. Adv Drug Deliv Rev 2019; 140:78-92. [PMID: 31002835 PMCID: PMC6663611 DOI: 10.1016/j.addr.2019.04.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 02/14/2019] [Accepted: 04/14/2019] [Indexed: 12/20/2022]
Abstract
Tissue engineering is becoming increasingly successful in providing in vitro models of human tissues that can be used for ex vivo recapitulation of functional tissues as well as predictive testing of drug efficacy and safety. From simple tissue models to microphysiological platforms comprising multiple tissue types connected by vascular perfusion, these "tissues on a chip" are emerging as a fast track application for tissue engineering, with great potential for modeling diseases and supporting the development of new drugs and therapeutic targets. We focus here on tissue engineering of the hematopoietic stem and progenitor cell compartment and the malignancies that can develop in the human bone marrow. Our overall goal is to demonstrate the utility and interconnectedness of improvements in bioengineering methods developed in one area of bone marrow studies for the remaining, seemingly disparate, bone marrow fields.
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Aquino-Martínez R, Monroe DG, Ventura F. Calcium mimics the chemotactic effect of conditioned media and is an effective inducer of bone regeneration. PLoS One 2019; 14:e0210301. [PMID: 30608979 PMCID: PMC6319750 DOI: 10.1371/journal.pone.0210301] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 12/18/2018] [Indexed: 12/22/2022] Open
Abstract
Background After bone resorption, ions and degraded organic components are co-released into the extracellular space. Ions and growth factors, although different in their biological nature, induce a common and coordinated chemotactic effect. Conditioned media has been used successfully in bone regeneration by promoting endogenous cell recruitment. Likewise, calcium alone act as a paracrine chemotactic signal, inducing the host’s undifferentiated progenitor cell infiltration into the implanted biomaterials. The aim of the present study was to compare the chemotactic effect of calcium and conditioned media in primary calvarial cells. Methods The chemotactic cell response was evaluated in vitro using an agarose spot and a wound healing assay. In addition, we used a calvarial bone explant model ex-vivo. The healing potential was also tested through an in vivo model, a critical-size calvarial bone defect in mice. For the in vivo experiment, cell-free calcium-containing or conditioned media-containing scaffolds were implanted, and MSC’s seeded scaffolds were used as positive control. After seven weeks post-implantation, samples were retrieved, and bone regeneration was evaluated by μCT and histological analysis. Osteogenic gene expression was evaluated by qPCR. Results We found that chemotactic cell migration in response to either calcium or conditioned media was equivalent in vitro and ex vivo. Accordingly, μCT analysis showed that bone regeneration induced by the MSC’s seeded scaffolds was similar to that obtained with cell-free calcium or conditioned media-containing scaffolds. Pre-treatment with SB202190, a highly selective p38 inhibitor, abrogated the chemotactic effect induced by conditioned media. In contrast, p38 activity was not essential for the calcium-induced chemotaxis. Moreover, BAPTA-AM treatment, a cytosolic calcium chelator, decreased the chemotactic effect and the expression of key osteogenic genes induced by calcium or conditioned media. Conclusion We show that calcium ions alone not only mimic the conditioned media chemotactic effect, but also induce an osteogenic effect similar to that produced by transplanted MSC’s in vivo. Furthermore, the chemotactic effect induced by conditioned media is calcium and p38 dependent. The rise in cytosolic calcium might integrate the different signaling pathways triggered by conditioned media and extracellular Ca2+. This calcium-driven in situ bone regeneration is a promising and convenient alternative to promote endogenous cell recruitment into the injured bone site. This pre-clinical cell-free and growth factor-free approach might avoid the disadvantages of the ex vivo cell manipulation.
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Affiliation(s)
- Rubén Aquino-Martínez
- Departament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain
- Department of Medicine, Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN, United States of America
| | - David G. Monroe
- Department of Medicine, Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN, United States of America
| | - Francesc Ventura
- Departament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain
- * E-mail:
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Essex AL, Pin F, Huot JR, Bonewald LF, Plotkin LI, Bonetto A. Bisphosphonate Treatment Ameliorates Chemotherapy-Induced Bone and Muscle Abnormalities in Young Mice. Front Endocrinol (Lausanne) 2019; 10:809. [PMID: 31803146 PMCID: PMC6877551 DOI: 10.3389/fendo.2019.00809] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 11/04/2019] [Indexed: 12/14/2022] Open
Abstract
Chemotherapy is frequently accompanied by several side effects, including nausea, diarrhea, anorexia and fatigue. Evidence from ours and other groups suggests that chemotherapy can also play a major role in causing not only cachexia, but also bone loss. This complicates prognosis and survival among cancer patients, affects quality of life, and can increase morbidity and mortality rates. Recent findings suggest that soluble factors released from resorbing bone directly contribute to loss of muscle mass and function secondary to metastatic cancer. However, it remains unknown whether similar mechanisms also take place following treatments with anticancer drugs. In this study, we found that young male CD2F1 mice (8-week old) treated with the chemotherapeutic agent cisplatin (2.5 mg/kg) presented marked loss of muscle and bone mass. Myotubes exposed to bone conditioned medium from cisplatin-treated mice showed severe atrophy (-33%) suggesting a bone to muscle crosstalk. To test this hypothesis, mice were administered cisplatin in combination with an antiresorptive drug to determine if preservation of bone mass has an effect on muscle mass and strength following chemotherapy treatment. Mice received cisplatin alone or combined with zoledronic acid (ZA; 5 μg/kg), a bisphosphonate routinely used for the treatment of osteoporosis. We found that cisplatin resulted in progressive loss of body weight (-25%), in line with reduced fat (-58%) and lean (-17%) mass. As expected, microCT bone histomorphometry analysis revealed significant reduction in bone mass following administration of chemotherapy, in line with reduced trabecular bone volume (BV/TV) and number (Tb.N), as well as increased trabecular separation (Tb.Sp) in the distal femur. Conversely, trabecular bone was protected when cisplatin was administered in combination with ZA. Interestingly, while the animals exposed to chemotherapy presented significant muscle wasting (~-20% vs. vehicle-treated mice), the administration of ZA in combination with cisplatin resulted in preservation of muscle mass (+12%) and strength (+42%). Altogether, these observations support our hypothesis of bone factors targeting muscle and suggest that pharmacological preservation of bone mass can benefit muscle mass and function following chemotherapy.
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Affiliation(s)
- Alyson L. Essex
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Fabrizio Pin
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Joshua R. Huot
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Lynda F. Bonewald
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, United States
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, United States
- Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN, United States
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- IUPUI Center for Cachexia Research, Innovation and Therapy, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Lilian I. Plotkin
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, United States
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Andrea Bonetto
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, United States
- Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN, United States
- IUPUI Center for Cachexia Research, Innovation and Therapy, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Otolaryngology – Head & Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- *Correspondence: Andrea Bonetto
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Kankala RK, Lu FJ, Liu CG, Zhang SS, Chen AZ, Wang SB. Effect of Icariin on Engineered 3D-Printed Porous Scaffolds for Cartilage Repair. MATERIALS (BASEL, SWITZERLAND) 2018; 11:E1390. [PMID: 30096899 PMCID: PMC6119946 DOI: 10.3390/ma11081390] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 08/02/2018] [Accepted: 08/06/2018] [Indexed: 12/21/2022]
Abstract
In recent times, cartilage defects have been the most common athletic injuries, often leading to dreadful consequences such as osteoarthritis, pain, joint deformities, and other symptoms. It is also evident that damage to articular cartilage is often difficult to recover or self-heal because of poor vascular, nervous, and lymphatic supplies. Moreover, cartilage cells have poor regeneration ability and high maturity. Inspired by these facts and the rapid advances in the field of tissue engineering (TE), we fabricated highly porous three-dimensional (3D) scaffold architectures based on cell-responsive polymeric inks, i.e., sodium alginate and gelatin (SA-Gel, 1:3 ratio), by a novel 3D printing method. Moreover, the effect of various processing parameters was systematically investigated. The printed scaffolds of polymer composites gels with excellent transparency, moderate viscosity, and excellent fluid properties showed good surface morphology, better thermal stability and swelling effect, and unique interconnected porous architectures at the optimized operating parameters. In vitro cell proliferation experiments of these cytocompatible scaffolds showed the excellent adhesion rate and growth behavior of chondrocytes. In addition, the porous architectures facilitated the efficient distribution of cells with only a few remaining on the surface, which was confirmed by confocal laser scanning microscopic (CLSM) observations. Icariin (ICA) addition at a concentration of 10 μg/mL further significantly enhanced the proliferation of chondrocytes. We envision that these cell-responsive polymeric inks in the presence of growth regulators like ICA may have potential in engineering complex tissue constructs toward diverse applications in TE.
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Affiliation(s)
- Ranjith Kumar Kankala
- Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China.
- Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen 361021, China.
| | - Feng-Jun Lu
- Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China.
| | - Chen-Guang Liu
- Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China.
| | - Shan-Shan Zhang
- Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China.
| | - Ai-Zheng Chen
- Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China.
- Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen 361021, China.
| | - Shi-Bin Wang
- Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China.
- Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen 361021, China.
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Ramis JM, Calvo J, Matas A, Corbillo C, Gayà A, Monjo M. Enhanced osteoinductive capacity and decreased variability by enrichment of demineralized bone matrix with a bone protein extract. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2018; 29:103. [PMID: 29956013 DOI: 10.1007/s10856-018-6115-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 06/20/2018] [Indexed: 06/08/2023]
Abstract
Osteoinductive capacity of demineralized bone matrix (DBM) is sometimes insufficient or shows high variability between different batches of DBM. Here, we tried to improve its osteoinductive activity by alkali-urea or trypsin treatment but this strategy was unsuccessful. Then, we tested the enrichment of DBM with a bone protein extract (BPE) containing osteogenic growth factors comparing two sources: cortical bone powder and DBM. The osteoinductive capacity (alkaline phosphatase activity) of the obtained BPEs was evaluated in vitro in C2C12 cells. Specific protein levels present in the different BPE was determined by enzyme-linked immunosorbent assay or by a multiplex assay. BPE from cortical bone powder showed a lack of osteoinductive effect, in agreement with the low content on osteoinductive factors. In contrast, BPE from DBM showed osteoinductive activity but also high variability among donors. Thus, we decided to enrich DBM with BPE obtained from a pool of DBM from different donors. Following this strategy, we achieved increased osteoinductive activity and lower variability among donors. In conclusion, the use of a BPE obtained from a pool of demineralized bone to enrich DBM could be used to increase its osteoinductive effect and normalize the differences between donors.
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Affiliation(s)
- Joana M Ramis
- Group of Cell Therapy and Tissue Engineering Group, Research Institute on Health Sciences (IUNICS), University of the Balearic Islands, 07122, Palma, Spain
- Balearic Islands Health Research Institute (IdISBa), 07010, Palma, Spain
- Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, 07122, Palma, Spain
| | - Javier Calvo
- Group of Cell Therapy and Tissue Engineering Group, Research Institute on Health Sciences (IUNICS), University of the Balearic Islands, 07122, Palma, Spain
- Balearic Islands Health Research Institute (IdISBa), 07010, Palma, Spain
- Fundació Banc de Sang i Teixits de les Illes Balears (FBSTIB), 07004, Palma, Spain
| | - Aina Matas
- Group of Cell Therapy and Tissue Engineering Group, Research Institute on Health Sciences (IUNICS), University of the Balearic Islands, 07122, Palma, Spain
- Balearic Islands Health Research Institute (IdISBa), 07010, Palma, Spain
| | - Cristina Corbillo
- Fundació Banc de Sang i Teixits de les Illes Balears (FBSTIB), 07004, Palma, Spain
| | - Antoni Gayà
- Group of Cell Therapy and Tissue Engineering Group, Research Institute on Health Sciences (IUNICS), University of the Balearic Islands, 07122, Palma, Spain
- Balearic Islands Health Research Institute (IdISBa), 07010, Palma, Spain
- Fundació Banc de Sang i Teixits de les Illes Balears (FBSTIB), 07004, Palma, Spain
| | - Marta Monjo
- Group of Cell Therapy and Tissue Engineering Group, Research Institute on Health Sciences (IUNICS), University of the Balearic Islands, 07122, Palma, Spain.
- Balearic Islands Health Research Institute (IdISBa), 07010, Palma, Spain.
- Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, 07122, Palma, Spain.
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Gong M, Chi C, Ye J, Liao M, Xie W, Wu C, Shi R, Zhang L. Icariin-loaded electrospun PCL/gelatin nanofiber membrane as potential artificial periosteum. Colloids Surf B Biointerfaces 2018; 170:201-209. [PMID: 29909312 DOI: 10.1016/j.colsurfb.2018.06.012] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 05/16/2018] [Accepted: 06/08/2018] [Indexed: 02/06/2023]
Abstract
Due to the significant role of the periosteum in bone regeneration, we hypothesised that using a specially engineered artificial periosteum could lead to an enhancement in osteogenesis in bone grafts. Herein, we describe our work aimed at fabricating an electrospun fibrous membrane as an artificial periosteum that exhibits flexibility, permeability and osteoinduction. This membrane was designed to cover the complex surface of bone grafts to facilitate and accelerate bone regeneration. The traditional Chinese medicine icariin (ICA) was subsequently introduced into poly (ε-caprolactone) (PCL) /gelatin nanofibers to fabricate an artificial periosteum for the first time. The effects of ICA content on morphology, physical properties, drug release profile, in vitro degradability, biocompatibility and osteogenic differentiation properties were investigated. The ICA-loaded electrospun membranes showed significant improvement in hydrophilicity, high mechanical strength, appropriate degradation rates and excellent biocompatibility. Furthermore, clear enhancement in alkaline phosphatase (ALP) activity, as well as an increase in osteocalcin (OCN) and type collagen I (COL I) expression in MC3T3-E1 cells were detected. Furthermore, we observed clear calcium deposition content in MC3T3-E1 cells cultured on ICA-loaded fibrous matrix. The membrane loaded with 0.05 wt.% ICA displayed properties contributing to cell attachment, proliferation and differentiation. These results indicate the huge potential of this ICA-loaded PCL/gelatin electrospun membrane as a biomimetic artificial periosteum to accelerate bone regeneration.
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Affiliation(s)
- Min Gong
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, PR China; State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029, PR China
| | - Cheng Chi
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, PR China; State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029, PR China
| | - Jingjing Ye
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, PR China; State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029, PR China
| | - Meihong Liao
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, PR China; State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029, PR China
| | - Wenqi Xie
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, PR China; State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029, PR China
| | - Chengai Wu
- Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Beijing 100035, PR China
| | - Rui Shi
- Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Beijing 100035, PR China.
| | - Liqun Zhang
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, PR China; State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029, PR China.
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Klar RM. The Induction of Bone Formation: The Translation Enigma. Front Bioeng Biotechnol 2018; 6:74. [PMID: 29938204 PMCID: PMC6002665 DOI: 10.3389/fbioe.2018.00074] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 05/22/2018] [Indexed: 11/25/2022] Open
Abstract
A paradigmatic shift in the way of thinking is what bone tissue engineering science requires to decrypt the translation conundrum from animal models into human. The deductive work of Urist (1965), who discerned the principle of bone induction from the pioneering works of Senn, Huggins, Lacroix, Levander, and other bone regenerative scientists, provided the basis that has assisted future bone tissue regenerative scientists to extend the bone tissue engineering field and its potential uses for bone regenerative medicine in humans. However, major challenges remain that are preventing the formation of bone by induction clinically. Growing experimental evidence is indicating that bone inductive studies are non-translatable from animal models into a clinical environment. This is preventing bone tissue engineering from reaching the next phase in development. Countless studies are trying to discern how the formation of bone by induction functions mechanistically, so as to try and solve this enigmatic problem. However, are the correct questions being asked? Why do bone inductive animal studies not translate into humans? Why do bone induction principles not yield the same extent of bone formation as an autogenous bone graft? What are bone tissue engineering scientists missing? By critically re-assessing the past and present discoveries of the bone induction field, this review article attempts to re-discover the field of bone formation by induction, identifying some key features that may have been missed. These include a detailed library of all proteins in bones and their arrangement in the 3D superstructure of the bone together with some other important criteria not considered by tissue engineering scientists. The review therefore not only re-iterates possible avenues of research that need to be re-explored but also seeks to guide present and future scientists in how they assess their own research in light of experimental design and results. By addressing these issues bone formation by induction without autografts might finally become clinically viable.
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Affiliation(s)
- Roland M. Klar
- Laboratory of Biomechanics and Experimental Orthopaedics, Department of Orthopaedic Surgery, Physical Medicine and Rehabilitation, University Hospital of Munich (LMU), Munich, Germany
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Gugala Z, Olmsted-Davis EA, Xiong Y, Davis EL, Davis AR. Trauma-Induced Heterotopic Ossification Regulates the Blood-Nerve Barrier. Front Neurol 2018; 9:408. [PMID: 29922221 PMCID: PMC5996108 DOI: 10.3389/fneur.2018.00408] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 05/17/2018] [Indexed: 01/12/2023] Open
Abstract
De novo bone formation can occur in soft tissues as a result of traumatic injury. This process, known as heterotopic ossification (HO), has recently been linked to the peripheral nervous system. Studies suggest that HO may resemble neural crest-derived bone formation and is activated through the release of key bone matrix proteins leading to opening of the blood-nerve barrier (BNB). One of the first steps in this process is the activation of a neuro-inflammatory cascade, which results in migration of chondro-osseous progenitors, and other cells from both the endoneurial and perineurial regions of the peripheral nerves. The perineurial cells undergo brown adipogenesis, to form essential support cells, which regulate expression and activation of matrix metallopeptidase 9 (MMP9) an essential regulatory protein involved in opening the BNB. However, recent studies suggest that, in mice, a key bone matrix protein, bone morphogenetic protein 2 (BMP2) is able to immediately cross the BNB to activate signaling in specific cells within the endoneurial compartment. BMP signaling correlates with bone formation and appears critical for the induction of HO. Surprisingly, several other bone matrix proteins have also been reported to regulate the BNB, leading us to question whether these matrix proteins are important in regulating the BNB. However, this temporary regulation of the BNB does not appear to result in degeneration of the peripheral nerve, but rather may represent one of the first steps in innervation of the newly forming bone.
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Affiliation(s)
- Zbigniew Gugala
- Department of Orthopedic Surgery and Rehabilitation, University of Texas Medical Branch, Galveston, TX, United States
| | - Elizabeth A. Olmsted-Davis
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, United States
- Department of Pediatrics – Section Hematology/Oncology, Baylor College of Medicine, Houston, TX, United States
- Department of Orthopedic Surgery, Baylor College of Medicine, Houston, TX, United States
| | - Yuqing Xiong
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, United States
| | - Eleanor L. Davis
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, United States
| | - Alan R. Davis
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, United States
- Department of Pediatrics – Section Hematology/Oncology, Baylor College of Medicine, Houston, TX, United States
- Department of Orthopedic Surgery, Baylor College of Medicine, Houston, TX, United States
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Chen Y, Ye SH, Sato H, Zhu Y, Shanov V, Tiasha T, D'Amore A, Luketich S, Wan G, Wagner WR. Hybrid scaffolds of Mg alloy mesh reinforced polymer/extracellular matrix composite for critical-sized calvarial defect reconstruction. J Tissue Eng Regen Med 2018; 12:1374-1388. [DOI: 10.1002/term.2668] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 02/07/2018] [Accepted: 04/11/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Yingqi Chen
- McGowan Institute for Regenerative Medicine; University of Pittsburgh; Pittsburgh PA USA
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, College of Materials Science and Engineering; Southwest Jiaotong University; Chengdu China
| | - Sang-Ho Ye
- McGowan Institute for Regenerative Medicine; University of Pittsburgh; Pittsburgh PA USA
| | - Hideyoshi Sato
- McGowan Institute for Regenerative Medicine; University of Pittsburgh; Pittsburgh PA USA
| | - Yang Zhu
- McGowan Institute for Regenerative Medicine; University of Pittsburgh; Pittsburgh PA USA
| | - Vesselin Shanov
- College of Engineering and Applied Science; University of Cincinnati; Cincinnati OH USA
| | - Tarannum Tiasha
- College of Engineering and Applied Science; University of Cincinnati; Cincinnati OH USA
| | - Antonio D'Amore
- McGowan Institute for Regenerative Medicine; University of Pittsburgh; Pittsburgh PA USA
| | - Samuel Luketich
- McGowan Institute for Regenerative Medicine; University of Pittsburgh; Pittsburgh PA USA
| | - Guojiang Wan
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, College of Materials Science and Engineering; Southwest Jiaotong University; Chengdu China
| | - William R. Wagner
- McGowan Institute for Regenerative Medicine; University of Pittsburgh; Pittsburgh PA USA
- Department of Surgery; University of Pittsburgh; Pittsburgh PA USA
- Department of Chemical Engineering; University of Pittsburgh; Pittsburgh PA USA
- Department of Bioengineering; University of Pittsburgh; Pittsburgh PA USA
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Haumer A, Bourgine PE, Occhetta P, Born G, Tasso R, Martin I. Delivery of cellular factors to regulate bone healing. Adv Drug Deliv Rev 2018; 129:285-294. [PMID: 29357301 DOI: 10.1016/j.addr.2018.01.010] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 01/08/2018] [Accepted: 01/13/2018] [Indexed: 02/06/2023]
Abstract
Bone tissue has a strong intrinsic regenerative capacity, thanks to a delicate and complex interplay of cellular and molecular processes, which tightly involve the immune system. Pathological settings of anatomical, biomechanical or inflammatory nature may lead to impaired bone healing. Innovative strategies to enhance bone repair, including the delivery of osteoprogenitor cells or of potent cytokines/morphogens, indicate the potential of 'orthobiologics', but are not fully satisfactory. Here, we review different approaches based on the delivery of regenerative cues produced by cells but in cell-free, possibly off-the-shelf configurations. Such strategies exploit the paracrine effect of the secretome of mesenchymal stem/stromal cells, presented in soluble form, shuttled through extracellular vesicles, or embedded within the network of extracellular matrix molecules. In addition to osteoinductive molecules, attention is given to factors targeting the resident immune cells, to reshape inflammatory and immunity processes from scarring to regenerative patterns.
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Affiliation(s)
- Alexander Haumer
- Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland; Department of Biomedical Engineering, University of Basel, Switzerland.
| | - Paul Emile Bourgine
- Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland; Department of Biomedical Engineering, University of Basel, Switzerland.
| | - Paola Occhetta
- Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland; Department of Biomedical Engineering, University of Basel, Switzerland.
| | - Gordian Born
- Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland; Department of Biomedical Engineering, University of Basel, Switzerland.
| | - Roberta Tasso
- Ospedale Policlinico San Martino-IST, IRCCS per l'Oncologia, Genova, Italy
| | - Ivan Martin
- Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland; Department of Biomedical Engineering, University of Basel, Switzerland.
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47
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Le BQ, Nurcombe V, Cool SM, van Blitterswijk CA, de Boer J, LaPointe VLS. The Components of Bone and What They Can Teach Us about Regeneration. MATERIALS (BASEL, SWITZERLAND) 2017; 11:E14. [PMID: 29271933 PMCID: PMC5793512 DOI: 10.3390/ma11010014] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 12/20/2017] [Accepted: 12/21/2017] [Indexed: 12/18/2022]
Abstract
The problem of bone regeneration has engaged both physicians and scientists since the beginning of medicine. Not only can bone heal itself following most injuries, but when it does, the regenerated tissue is often indistinguishable from healthy bone. Problems arise, however, when bone does not heal properly, or when new tissue is needed, such as when two vertebrae are required to fuse to stabilize adjacent spine segments. Despite centuries of research, such procedures still require improved therapeutic methods to be devised. Autologous bone harvesting and grafting is currently still the accepted benchmark, despite drawbacks for clinicians and patients that include limited amounts, donor site morbidity, and variable quality. The necessity for an alternative to this "gold standard" has given rise to a bone-graft and substitute industry, with its central conundrum: what is the best way to regenerate bone? In this review, we dissect bone anatomy to summarize our current understanding of its constituents. We then look at how various components have been employed to improve bone regeneration. Evolving strategies for bone regeneration are then considered.
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Affiliation(s)
- Bach Quang Le
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #6-06 Immunos, Singapore 138648, Singapore.
| | - Victor Nurcombe
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #6-06 Immunos, Singapore 138648, Singapore.
| | - Simon McKenzie Cool
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #6-06 Immunos, Singapore 138648, Singapore.
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore 119288, Singapore.
| | - Clemens A van Blitterswijk
- Department of Complex Tissue Regeneration, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
| | - Jan de Boer
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
| | - Vanessa Lydia Simone LaPointe
- Department of Complex Tissue Regeneration, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
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48
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Collignon AM, Lesieur J, Vacher C, Chaussain C, Rochefort GY. Strategies Developed to Induce, Direct, and Potentiate Bone Healing. Front Physiol 2017; 8:927. [PMID: 29184512 PMCID: PMC5694432 DOI: 10.3389/fphys.2017.00927] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 10/31/2017] [Indexed: 12/19/2022] Open
Abstract
Bone exhibits a great ability for endogenous self-healing. Nevertheless, impaired bone regeneration and healing is on the rise due to population aging, increasing incidence of bone trauma and the clinical need for the development of alternative options to autologous bone grafts. Current strategies, including several biomolecules, cellular therapies, biomaterials, and different permutations of these, are now developed to facilitate the vascularization and the engraftment of the constructs, to recreate ultimately a bone tissue with the same properties and characteristics of the native bone. In this review, we browse the existing strategies that are currently developed, using biomolecules, cells and biomaterials, to induce, direct and potentiate bone healing after injury and further discuss the biological processes associated with this repair.
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Affiliation(s)
- Anne-Margaux Collignon
- EA 2496 Orofacial Pathologies, Imaging and Biotherapies, Dental School Faculty, Life Imaging Platform (PIV), University Paris Descartes, Montrouge, France.,Department of Odontology, University Hospitals PNVS, Assistance Publique Hopitaux De Paris, Paris, France
| | - Julie Lesieur
- EA 2496 Orofacial Pathologies, Imaging and Biotherapies, Dental School Faculty, Life Imaging Platform (PIV), University Paris Descartes, Montrouge, France
| | - Christian Vacher
- EA 2496 Orofacial Pathologies, Imaging and Biotherapies, Dental School Faculty, Life Imaging Platform (PIV), University Paris Descartes, Montrouge, France.,Department of Maxillofacial Surgery, Beaujon Hospital, Assistance Publique Hopitaux De Paris, Paris, France
| | - Catherine Chaussain
- EA 2496 Orofacial Pathologies, Imaging and Biotherapies, Dental School Faculty, Life Imaging Platform (PIV), University Paris Descartes, Montrouge, France.,Department of Odontology, University Hospitals PNVS, Assistance Publique Hopitaux De Paris, Paris, France
| | - Gael Y Rochefort
- EA 2496 Orofacial Pathologies, Imaging and Biotherapies, Dental School Faculty, Life Imaging Platform (PIV), University Paris Descartes, Montrouge, France
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49
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Barreto R, Kitase Y, Matsumoto T, Pin F, Colston KC, Couch KE, O'Connell TM, Couch ME, Bonewald LF, Bonetto A. ACVR2B/Fc counteracts chemotherapy-induced loss of muscle and bone mass. Sci Rep 2017; 7:14470. [PMID: 29089584 PMCID: PMC5665981 DOI: 10.1038/s41598-017-15040-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 10/20/2017] [Indexed: 01/06/2023] Open
Abstract
Chemotherapy promotes the development of cachexia, a debilitating condition characterized by muscle and fat loss. ACVR2B/Fc, an inhibitor of the Activin Receptor 2B signaling, has been shown to preserve muscle mass and prolong survival in tumor hosts, and to increase bone mass in models of osteogenesis imperfecta and muscular dystrophy. We compared the effects of ACVR2B/Fc on muscle and bone mass in mice exposed to Folfiri. In addition to impairing muscle mass and function, Folfiri had severe negative effects on bone, as shown by reduced trabecular bone volume fraction (BV/TV), thickness (Tb.Th), number (Tb.N), connectivity density (Conn.Dn), and by increased separation (Tb.Sp) in trabecular bone of the femur and vertebra. ACVR2B/Fc prevented the loss of muscle mass and strength, and the loss of trabecular bone in femurs and vertebrae following Folfiri administration. Neither Folfiri nor ACVR2B/Fc had effects on femoral cortical bone, as shown by unchanged cortical bone volume fraction (Ct.BV/TV), thickness (Ct.Th) and porosity. Our results suggest that Folfiri is responsible for concomitant muscle and bone degeneration, and that ACVR2B/Fc prevents these derangements. Future studies are required to determine if the same protective effects are observed in combination with other anticancer regimens or in the presence of cancer.
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Affiliation(s)
- Rafael Barreto
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Yukiko Kitase
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Tsutomu Matsumoto
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Fabrizio Pin
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Kyra C Colston
- Indianapolis Project STEM, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Katherine E Couch
- Indianapolis Project STEM, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Thomas M O'Connell
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,Department of Otolaryngology - Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,IUPUI Center for Cachexia Research Innovation and Therapy, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Marion E Couch
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,Department of Otolaryngology - Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,IUPUI Center for Cachexia Research Innovation and Therapy, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Lynda F Bonewald
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,IUPUI Center for Cachexia Research Innovation and Therapy, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Andrea Bonetto
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. .,Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. .,Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. .,Department of Otolaryngology - Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. .,Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. .,IUPUI Center for Cachexia Research Innovation and Therapy, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
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50
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Janko M, Sahm J, Schaible A, Brune JC, Bellen M, Schroder K, Seebach C, Marzi I, Henrich D. Comparison of three different types of scaffolds preseeded with human bone marrow mononuclear cells on the bone healing in a femoral critical size defect model of the athymic rat. J Tissue Eng Regen Med 2017; 12:653-666. [PMID: 28548246 DOI: 10.1002/term.2484] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 05/12/2017] [Accepted: 05/19/2017] [Indexed: 12/15/2022]
Abstract
Large bone defects often pose major difficulties in orthopaedic surgery. The application of long-term cultured stem cells combined with a scaffold lead to a significant improvement of bone healing in recent experiments but is strongly restricted by European Union law. Bone marrow mononuclear cells (BMC), however, can be isolated and transplanted within a few hours and have been proven effective in experimental models of bone healing. The effectivity of the BMC-supported therapy might be influenced by the type of scaffold. Hence, we compared three different scaffolds serving as a carrier for BMC in a rat femoral critical size defect with regard to the osteogenic activity in the defect zone. Human demineralized bone matrix (DBM), bovine cancellous bone hydroxyapatite ceramic (BS), or β-tricalcium phosphate (β-TCP) were seeded with human BMC and hereafter implanted into critically sized bone defects of male athymic nude rats. Autologous bone served as a control. Gene activity was measured after 1 week, and bone formation was analysed histologically and radiologically after 8 weeks. Generally, regenerative gene expression (BMP2, RUNX2, VEGF, SDF-1, and RANKL) as well as bony bridging and callus formation was observed to be most pronounced in defects filled with autologous bone, followed in descending order by DBM, β-TCP, and BS. Although DBM was superior in most aspects of bone regeneration analysed in comparison to β-TCP and BS, the level of autologous bone could not be attained.
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Affiliation(s)
- Maren Janko
- Department of Trauma, Hand, and Reconstructive Surgery, Hospital of the Goethe University, Frankfurt, Germany
| | - Julian Sahm
- Department of Trauma, Hand, and Reconstructive Surgery, Hospital of the Goethe University, Frankfurt, Germany
| | - Alexander Schaible
- Department of Trauma, Hand, and Reconstructive Surgery, Hospital of the Goethe University, Frankfurt, Germany
| | - Jan C Brune
- German Institute for Cell and Tissue Replacement gGmbH (DIZG), Berlin, Germany
| | - Marlene Bellen
- Department of Trauma, Hand, and Reconstructive Surgery, Hospital of the Goethe University, Frankfurt, Germany
| | - Katrin Schroder
- Center of Physiology, Cardiovascular Physiology, Hospital of the Goethe University, Frankfurt, Germany
| | - Caroline Seebach
- Department of Trauma, Hand, and Reconstructive Surgery, Hospital of the Goethe University, Frankfurt, Germany
| | - Ingo Marzi
- Department of Trauma, Hand, and Reconstructive Surgery, Hospital of the Goethe University, Frankfurt, Germany
| | - Dirk Henrich
- Department of Trauma, Hand, and Reconstructive Surgery, Hospital of the Goethe University, Frankfurt, Germany
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