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Malige A, Gates C, Cook JL. Mesenchymal stem cells in orthopaedics: A systematic review of applications to practice. J Orthop 2024; 58:1-9. [PMID: 39035449 PMCID: PMC11254590 DOI: 10.1016/j.jor.2024.06.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Accepted: 06/20/2024] [Indexed: 07/23/2024] Open
Abstract
Background Mesenchymal stem cells (MSCs) have alluring interest for clinical use in orthopaedics based on their therapeutic potential through directed pluripotent differentiation. While many studies and reviews have discussed the importance of this approach, few have reduced it to practice using reproducible criteria. This study was designed to systematically review and synthesize current evidence regarding clinical use of clearly defined MSCs in orthopaedics. Methods Studies of any level of evidence and sample size, regardless of MSC source, orthopaedic pathology, and patient population, were reviewed. In vitro and animal studies, and articles written in a language other than English, were excluded. Studies were then screened for final inclusion based on documented MSC verification using testing of the therapeutic cellular population for at least one of the following phenotypic markers: CD 73, CD 90, and CD 105. In addition, therapeutic cellular populations could not have higher percentages of CD34, CD45, CD14, HLA-DR, CD11b, or CD19 markers compared to the aforementioned markers. From each studies' results, sample size, procedural methods, radiographic outcomes, clinical outcomes, patient-report outcomes (PROs), and adverse events were tabulated. Results Overall, 43 studies were included. Twenty-three studies (53.5 %) derived their MSCs from iliac crest bone marrow while 12 (27.9 %) studied adipose-derived MSCs. Included studies explored MSC use in Osteoarthritis, Cartilage Defects, Osteonecrosis, Bone Defects and Nonunions, Spine, and Other. MSC use in all pathologies led to improvement of studied radiographic, clinical, and patient-reported outcomes. Conclusions Mesenchymal stem cells have proven to have successful and safe uses in multiple orthopaedic applications, including treating chondral defects, osteoarthritis, and osteonecrosis. A stringent and reproducible process for evaluating obtained human stem cells using CD markers for clinical use is necessary to both evaluate previous studies and continue to evaluate for future uses. Level of evidence Level V.
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Affiliation(s)
- Ajith Malige
- Kerlan Jobe Orthopedic Clinic, 6801 Park Terrace, Suite 500, Los Angeles, CA, 90045, USA
| | - Carson Gates
- University of Missouri Department of Orthopaedic Surgery, Columbia, MO, USA
| | - James L. Cook
- University of Missouri Department of Orthopaedic Surgery, Columbia, MO, USA
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Oladele IO, Adekola SA, Agbeboh NI, Isola-Makinde BA, Adewuyi BO. Synthesis and Application of Sustainable Tricalcium Phosphate Based Biomaterials From Agro-Based Materials: A Review. Biomed Eng Comput Biol 2024; 15:11795972241293525. [PMID: 39524096 PMCID: PMC11544672 DOI: 10.1177/11795972241293525] [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: 07/24/2024] [Accepted: 10/07/2024] [Indexed: 11/16/2024] Open
Abstract
Trends in health care delivery systems have shifted as a result of the modern uses of biomaterials in medicine. Contrary to traditional medicine, modern healthcare are now useful in solving problems that were considered impossible some years back. One of the most significant factors to the most recent advancements in implant development has been the use of calcium based materials in the creation of necessary implants in the form of soft and hard tissues. With the advent of naturally sourced materials in the manufacturing of biomaterials, lots of attention are now focused on the different sources of agro-based resources that can be used for the product developments. These agro-based materials are now been considered for sustainable and ecological purposes in several areas of applications globally in the recent times. Hence, the review was carried out with focus on the sources, relevance, processing techniques and applications of tricalcium phosphate based biomaterials in modern day healthcare delivery. This review provides a historical and prospective picture of the crucial functions that materials based on tricalcium phosphate will play in fulfilling human requirements for medication.
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Affiliation(s)
- Isiaka Oluwole Oladele
- Department of Metallurgical and Materials Engineering, Federal University of Technology, Akure, Ondo, Nigeria
| | - Samson Ademola Adekola
- Department of Metallurgical and Materials Engineering, Federal University of Technology, Akure, Ondo, Nigeria
- Biomedical Engineering Department, Achievers University Owo, Ondo Sate, Nigeria
| | - Newton Itua Agbeboh
- Department of Metallurgical and Materials Engineering, Federal University of Technology, Akure, Ondo, Nigeria
- Department of Mechanical and Mechatronics Engineering, Federal University Otuoke, Otuoke, Bayelsa State, Nigeria
| | | | - Benjamin Omotayo Adewuyi
- Department of Metallurgical and Materials Engineering, Federal University of Technology, Akure, Ondo, Nigeria
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Hisamatsu D, Ikeba A, Yamato T, Mabuchi Y, Watanabe M, Akazawa C. Optimization of transplantation methods using isolated mesenchymal stem/stromal cells: clinical trials of inflammatory bowel diseases as an example. Inflamm Regen 2024; 44:37. [PMID: 39152520 PMCID: PMC11328379 DOI: 10.1186/s41232-024-00350-5] [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: 04/24/2024] [Accepted: 07/26/2024] [Indexed: 08/19/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are distributed in various tissues and are used in clinical applications as a source of transplanted cells because of their easy harvestability. Although MSCs express numerous cell-surface antigens, single-cell analyses have revealed a highly heterogeneous cell population depending on the original tissue and donor conditions, including age and interindividual differences. This heterogeneity leads to differences in their functions, such as multipotency and immunomodulatory effects, making it challenging to effectively treat targeted diseases. The therapeutic efficacy of MSCs is controversial and depends on the implantation site. Thus, there is no established recipe for the transplantation of MSCs (including the type of disease, type of origin, method of cell culture, form of transplanted cells, and site of delivery). Our recent preclinical study identified appropriate MSCs and their suitable transplantation routes in a mouse model of inflammatory bowel disease (IBD). Three-dimensional (3D) cultures of MSCs have been demonstrated to enhance their properties and sustain engraftment at the lesion site. In this note, we explore the methods of MSC transplantation for treating IBDs, especially Crohn's disease, from clinical trials published over the past decade. Given the functional changes in MSCs in 3D culture, we also investigate the clinical trials using 3D constructs of MSCs and explore suitable diseases that might benefit from this approach. Furthermore, we discuss the advantages of the prospective isolation of MSCs in terms of interindividual variability. This note highlights the need to define the method of MSC transplantation, including interindividual variability, the culture period, and the transplantation route.
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Affiliation(s)
- Daisuke Hisamatsu
- Intractable Disease Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Akimi Ikeba
- Intractable Disease Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Taku Yamato
- Intractable Disease Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Yo Mabuchi
- Intractable Disease Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
- Department of Clinical Regenerative Medicine, Fujita Medical Innovation Center, Fujita Health University, Tokyo, Japan
| | - Mamoru Watanabe
- Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Chihiro Akazawa
- Intractable Disease Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
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Brown MG, Brady DJ, Healy KM, Henry KA, Ogunsola AS, Ma X. Stem Cells and Acellular Preparations in Bone Regeneration/Fracture Healing: Current Therapies and Future Directions. Cells 2024; 13:1045. [PMID: 38920674 PMCID: PMC11201612 DOI: 10.3390/cells13121045] [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: 03/30/2024] [Revised: 05/25/2024] [Accepted: 06/12/2024] [Indexed: 06/27/2024] Open
Abstract
Bone/fracture healing is a complex process with different steps and four basic tissue layers being affected: cortical bone, periosteum, fascial tissue surrounding the fracture, and bone marrow. Stem cells and their derivatives, including embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, hematopoietic stem cells, skeletal stem cells, and multipotent stem cells, can function to artificially introduce highly regenerative cells into decrepit biological tissues and augment the healing process at the tissue level. Stem cells are molecularly and functionally indistinguishable from standard human tissues. The widespread appeal of stem cell therapy lies in its potential benefits as a therapeutic technology that, if harnessed, can be applied in clinical settings. This review aims to establish the molecular pathophysiology of bone healing and the current stem cell interventions that disrupt or augment the bone healing process and, finally, considers the future direction/therapeutic options related to stem cells and bone healing.
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Affiliation(s)
- Marcel G. Brown
- Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Department of Orthopaedic Surgery and Rehabilitation, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Davis J. Brady
- Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Kelsey M. Healy
- Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Kaitlin A. Henry
- Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Department of Orthopaedic Surgery and Rehabilitation, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Ayobami S. Ogunsola
- Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Department of Orthopaedic Surgery and Rehabilitation, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Xue Ma
- Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Department of Orthopaedic Surgery and Rehabilitation, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
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Quek J, Vizetto-Duarte C, Teoh SH, Choo Y. Towards Stem Cell Therapy for Critical-Sized Segmental Bone Defects: Current Trends and Challenges on the Path to Clinical Translation. J Funct Biomater 2024; 15:145. [PMID: 38921519 PMCID: PMC11205181 DOI: 10.3390/jfb15060145] [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: 04/24/2024] [Revised: 05/18/2024] [Accepted: 05/24/2024] [Indexed: 06/27/2024] Open
Abstract
The management and reconstruction of critical-sized segmental bone defects remain a major clinical challenge for orthopaedic clinicians and surgeons. In particular, regenerative medicine approaches that involve incorporating stem cells within tissue engineering scaffolds have great promise for fracture management. This narrative review focuses on the primary components of bone tissue engineering-stem cells, scaffolds, the microenvironment, and vascularisation-addressing current advances and translational and regulatory challenges in the current landscape of stem cell therapy for critical-sized bone defects. To comprehensively explore this research area and offer insights for future treatment options in orthopaedic surgery, we have examined the latest developments and advancements in bone tissue engineering, focusing on those of clinical relevance in recent years. Finally, we present a forward-looking perspective on using stem cells in bone tissue engineering for critical-sized segmental bone defects.
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Affiliation(s)
- Jolene Quek
- Developmental Biology and Regenerative Medicine Programme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore; (J.Q.); (C.V.-D.)
| | - Catarina Vizetto-Duarte
- Developmental Biology and Regenerative Medicine Programme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore; (J.Q.); (C.V.-D.)
| | - Swee Hin Teoh
- Centre for Advanced Medical Engineering, College of Materials Science and Engineering, Hunan University, Changsha 410012, China
| | - Yen Choo
- Developmental Biology and Regenerative Medicine Programme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore; (J.Q.); (C.V.-D.)
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Rodham P, Khaliq F, Giannoudis V, Giannoudis PV. Cellular therapies for bone repair: current insights. J Orthop Traumatol 2024; 25:28. [PMID: 38789881 PMCID: PMC11132192 DOI: 10.1186/s10195-024-00768-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 05/01/2024] [Indexed: 05/26/2024] Open
Abstract
Mesenchymal stem cells are core to bone homeostasis and repair. They both provide the progenitor cells from which bone cells are formed and regulate the local cytokine environment to create a pro-osteogenic environment. Dysregulation of these cells is often seen in orthopaedic pathology and can be manipulated by the physician treating the patient. This narrative review aims to describe the common applications of cell therapies to bone healing whilst also suggesting the future direction of these techniques.
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Affiliation(s)
- Paul Rodham
- Academic Department of Trauma and Orthopaedics, School of Medicine, University of Leeds, Leeds, UK
| | - Farihah Khaliq
- Academic Department of Trauma and Orthopaedic Surgery, School of Medicine, University of Leeds, Leeds, UK
| | - Vasileos Giannoudis
- Academic Department of Trauma and Orthopaedics, School of Medicine, University of Leeds, Leeds, UK
| | - Peter V Giannoudis
- Academic Department of Trauma and Orthopaedics, School of Medicine, University of Leeds, Leeds, UK.
- NIHR Leeds Biomedical Research Centre, Chapel Allerton Hospital, Leeds, UK.
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Theodosaki AM, Tzemi M, Galanis N, Bakopoulou A, Kotsiomiti E, Aggelidou E, Kritis A. Bone Regeneration with Mesenchymal Stem Cells in Scaffolds: Systematic Review of Human Clinical Trials. Stem Cell Rev Rep 2024; 20:938-966. [PMID: 38407793 PMCID: PMC11087324 DOI: 10.1007/s12015-024-10696-5] [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] [Accepted: 02/12/2024] [Indexed: 02/27/2024]
Abstract
The aim of the study is to determine the effectiveness of stem cells in scaffolds in the treatment of bone deficits, in regard of bone regeneration, safety, rehabilitation and quality of life in humans. The systematic review was conducted in accordance with PRISMA 2020. A systematic search was conducted in three search engines and two registries lastly in 29-9-2022.for studies of the last 15 years. The risk of bias was assessed with RoB-2, ROBINS- I and NIH Quality of Before-After (Pre-Post) Studies with no Control group. The certainty of the results was assessed with the GRADE assessment tool. Due to heterogeneity, the results were reported in tables, graphs and narratively. The study protocol was published in PROSPERO with registration number CRD42022359049. Of the 10,091 studies retrieved, 14 were meeting the inclusion criteria, and were qualitatively analyzed. 138 patients were treated with mesenchymal stem cells in scaffolds, showing bone healing in all cases, and even with better results than the standard care. The adverse events were mild in most cases and in accordance with the surgery received. When assessed, there was a rehabilitation of the deficit and a gain in quality of life was detected. Although the heterogeneity between the studies and the small number of patients, the administration of mesenchymal stem cells in scaffolds seems safe and effective in the regeneration of bone defects. These results pave the way for the conduction of more clinical trials, with greater number of participants, with more standardized procedures.
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Affiliation(s)
- Astero Maria Theodosaki
- Research Methodology in Medicine and Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
- Regenerative Medicine Center, Basic and Translational Research Unit (BTRU) of Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, 54636, Greece.
- Postgraduate program of Research Methodology in Medicine and Health Sciences, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
- , Thessaloniki, Greece.
| | - Maria Tzemi
- Research Methodology in Medicine and Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Postgraduate program of Research Methodology in Medicine and Health Sciences, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikiforos Galanis
- School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
- 1st Orthopaedic Department, George Papanikolaou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Athina Bakopoulou
- Department of Prosthodontics, Faculty of Dentistry, Aristotle University of Thessaloniki, University Campus, Dentistry Building, 54124, Thessaloniki, Greece
- Regenerative Medicine Center, Basic and Translational Research Unit (BTRU) of Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, 54636, Greece
| | - Eleni Kotsiomiti
- Department of Prosthodontics, Faculty of Dentistry, Aristotle University of Thessaloniki, University Campus, Dentistry Building, 54124, Thessaloniki, Greece
| | - Eleni Aggelidou
- Department of Physiology and Pharmacology, Faculty of Medicine, Aristotle University of Thessaloniki, University Campus, 54006, Thessaloniki, Greece
- Regenerative Medicine Center, Basic and Translational Research Unit (BTRU) of Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, 54636, Greece
| | - Aristeidis Kritis
- Department of Physiology and Pharmacology, Faculty of Medicine, Aristotle University of Thessaloniki, University Campus, 54006, Thessaloniki, Greece
- Regenerative Medicine Center, Basic and Translational Research Unit (BTRU) of Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, 54636, Greece
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Wang Y, Mou Q, Yi H, Meng Z. Transient Fever: The Sole Treatment-Related Adverse Event Associated with Mesenchymal Stromal Cells and Solid Clues from the Real World. Curr Stem Cell Res Ther 2024; 19:1263-1285. [PMID: 37909436 DOI: 10.2174/011574888x179799231023060734] [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: 06/30/2023] [Revised: 08/12/2023] [Accepted: 08/24/2023] [Indexed: 11/03/2023]
Abstract
BACKGROUND The number of trials investigating mesenchymal stromal cells (MSCs) soars within 3 years which urges a study analysing emerging MSC treatment-related adverse events. AIM To assess the safety of MSC therapy and provide solid evidence for clinical translation of MSC. METHODS A meta-analysis of randomized clinical trials (RCTs) published up to April 20th, 2023 was performed. Odds ratio (OR) and 95% confidential intervals (CIs) were used to display pooled results. RESULTS 152 randomized clinical trials (RCTs) that incorporated 9228 individuals treated with MSCs from autologous or allogenic adipose tissue, bone marrow, Wharton's Jelly, and placenta tissue were included in the analysis. We discovered appropriate 21 MSC treatment-related adverse events (TRAEs), of which fever [OR, 1.61, 95% CI: 1.22-2.11, p<0.01] was the sole event that was closely associated with MSC therapy. MSCs also trended to lower the incidence rate of tachycardia [OR, 0.83, 95% CI: 0.64-1.09, p=0.14] and fatigue [OR, 0.18, 95% CI: 0.61-1.07, p=0.18]. A separate analysis of studies with long-term follow-up (more than 1 year) demonstrated the close relationship between MSCs and fever [OR, 1.75, 95% CI: 1.26-2.24, p<0.01]. The rest TRAEs did not associate themselves with MSC therapy. Dose-response was also conducted for fever, linearity was discovered between MSCs from allogeneic tissue and Wharton's Jelly and fever. CONCLUSION To date, our results suggest that fever is the only AE closely associated with MSCs.
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Affiliation(s)
- Yang Wang
- Department of Orthopedics, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Number, 250, Changgang East Road, Haizhu District, Guangzhou, Guangdong Province, China
| | - Qiuying Mou
- Clinical Medicine College, Guangdong Pharmaceutical University, Number, 280, Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou, Guangdong Province, China
| | - Hanxiao Yi
- Department of Radiotherapy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Number, 600, Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
| | - Zilu Meng
- Department of Maxillofacial Surgery, The First Affiliated Hospital of Guangdong Pharmaceutical University, China
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Chopra H, Cao C, Sommer C, Dahlkemper A, Sugai J, Sherley JL, Kaigler D. Quantification of the Culture Stability of Stem Cell Fractions from Oral-Derived, Human Mesenchymal Stem Cell Preparations: A Significant Step toward the Clinical Translation of Cell Therapies. Cells 2023; 12:2703. [PMID: 38067131 PMCID: PMC10705797 DOI: 10.3390/cells12232703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/09/2023] [Accepted: 11/16/2023] [Indexed: 12/18/2023] Open
Abstract
A continuing limitation and major challenge in the development and utilization of predictable stem cell therapies (SCTs) is the determination of the optimal dosages of stem cells. Herein, we report the quantification of stem cell fractions (SCF) of human mesenchymal stem cell (MSC) preparations derived from oral tissues. A novel computational methodology, kinetic stem cell (KSC) counting, was used to quantify the SCF and specific cell culture kinetics of stem cells in oral alveolar bone-derived MSC (aBMSCs) from eight patients. These analyses established, for the first time, that the SCF within these heterogeneous, mixed-cell populations differs significantly among donors, ranging from 7% to 77% (ANOVA p < 0.0001). Both the initial SCF of aBMSC preparations and changes in the level of the SCF with serial culture over time showed a high degree of inter-donor variation. Hence, it was revealed that the stability of the SCF of human aBMSC preparations during serial cell culture shows inter-donor variation, with some patient preparations exhibiting sufficient stability to support the long-term net expansion of stem cells. These findings provide important insights for the clinical-scale expansion and biomanufacturing of MSCs, which can facilitate establishing more effective and predictable outcomes in clinical trials and treatments employing SCT.
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Affiliation(s)
- Hitesh Chopra
- Kaigler Lab of Stem Cell Science and Tissue Regeneration, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA; (H.C.); (C.C.); (C.S.); (A.D.); (J.S.)
| | - Chen Cao
- Kaigler Lab of Stem Cell Science and Tissue Regeneration, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA; (H.C.); (C.C.); (C.S.); (A.D.); (J.S.)
| | - Celia Sommer
- Kaigler Lab of Stem Cell Science and Tissue Regeneration, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA; (H.C.); (C.C.); (C.S.); (A.D.); (J.S.)
| | - Alex Dahlkemper
- Kaigler Lab of Stem Cell Science and Tissue Regeneration, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA; (H.C.); (C.C.); (C.S.); (A.D.); (J.S.)
| | - James Sugai
- Kaigler Lab of Stem Cell Science and Tissue Regeneration, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA; (H.C.); (C.C.); (C.S.); (A.D.); (J.S.)
| | | | - Darnell Kaigler
- Kaigler Lab of Stem Cell Science and Tissue Regeneration, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA; (H.C.); (C.C.); (C.S.); (A.D.); (J.S.)
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
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Cabrera-Pérez R, Ràfols-Mitjans A, Roig-Molina Á, Beltramone S, Vives J, Batlle-Morera L. Human Wharton's jelly-derived mesenchymal stromal cells promote bone formation in immunodeficient mice when administered into a bone microenvironment. J Transl Med 2023; 21:802. [PMID: 37950242 PMCID: PMC10638709 DOI: 10.1186/s12967-023-04672-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 10/29/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Wharton's Jelly (WJ) Mesenchymal Stromal Cells (MSC) have emerged as an attractive allogeneic therapy for a number of indications, except for bone-related conditions requiring new tissue formation. This may be explained by the apparent recalcitrance of MSC,WJ to differentiate into the osteogenic lineage in vitro, as opposed to permissive bone marrow (BM)-derived MSCs (MSC,BM) that readily commit to bone cells. Consequently, the actual osteogenic in vivo capacity of MSC,WJ is under discussion. METHODS We investigated how physiological bone environments affect the osteogenic commitment of recalcitrant MSCs in vitro and in vivo. To this end, MSC of BM and WJ origin were co-cultured and induced for synchronous osteogenic differentiation in vitro using transwells. For in vivo experiments, immunodeficient mice were injected intratibially with a single dose of human MSC and bone formation was evaluated after six weeks. RESULTS Co-culture of MSC,BM and MSC,WJ resulted in efficient osteogenesis in both cell types after three weeks. However, MSC,WJ failed to commit to bone cells in the absence of MSC,BM's osteogenic stimuli. In vivo studies showed successful bone formation within the medullar cavity of tibias in 62.5% of mice treated with MSC, WJ. By contrast, new formed trabeculae were only observed in 25% of MSC,BM-treated mice. Immunohistochemical staining of human COXIV revealed the persistence of the infused cells at the site of injection. Additionally, cells of human origin were also identified in the brain, heart, spleen, kidney and gonads in some animals treated with engineered MSC,WJ (eMSC,WJ). Importantly, no macroscopic histopathological alterations, ectopic bone formation or any other adverse events were detected in MSC-treated mice. CONCLUSIONS Our findings demonstrate that in physiological bone microenvironment, osteogenic commitment of MSC,WJ is comparable to that of MSC,BM, and support the use of off-the-shelf allogeneic MSC,WJ products in bone repair and bone regeneration applications.
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Affiliation(s)
- Raquel Cabrera-Pérez
- Servei de Teràpia Cel·lular i Avançada, Blood and Tissue Bank (BST), 08005, Barcelona, Catalonia, Spain
- Musculoskeletal Tissue Engineering Group, Vall d'Hebron Research Institute (VHIR) and Universitat Autònoma de Barcelona (UAB), 08035, Barcelona, Catalonia, Spain
| | - Alexis Ràfols-Mitjans
- Centre for Genomic Regulation (CRG), Genomic Regulation, Stem Cells and Cancer Program, The Barcelona Institute of Science and Technology, 08003, Barcelona, Catalonia, Spain
| | - Ángela Roig-Molina
- Musculoskeletal Tissue Engineering Group, Vall d'Hebron Research Institute (VHIR) and Universitat Autònoma de Barcelona (UAB), 08035, Barcelona, Catalonia, Spain
| | - Silvia Beltramone
- Centre for Genomic Regulation (CRG), Genomic Regulation, Stem Cells and Cancer Program, The Barcelona Institute of Science and Technology, 08003, Barcelona, Catalonia, Spain
| | - Joaquim Vives
- Servei de Teràpia Cel·lular i Avançada, Blood and Tissue Bank (BST), 08005, Barcelona, Catalonia, Spain.
- Musculoskeletal Tissue Engineering Group, Vall d'Hebron Research Institute (VHIR) and Universitat Autònoma de Barcelona (UAB), 08035, Barcelona, Catalonia, Spain.
- Medicine Department, Universitat Autònoma de Barcelona (UAB), 08193, Barcelona, Catalonia, Spain.
| | - Laura Batlle-Morera
- Centre for Genomic Regulation (CRG), Genomic Regulation, Stem Cells and Cancer Program, The Barcelona Institute of Science and Technology, 08003, Barcelona, Catalonia, Spain.
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Re F, Borsani E, Rezzani R, Sartore L, Russo D. Bone Regeneration Using Mesenchymal Stromal Cells and Biocompatible Scaffolds: A Concise Review of the Current Clinical Trials. Gels 2023; 9:gels9050389. [PMID: 37232981 DOI: 10.3390/gels9050389] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/27/2023] [Accepted: 05/03/2023] [Indexed: 05/27/2023] Open
Abstract
Bone regenerative medicine is a clinical approach combining live osteoblast progenitors, such as mesenchymal stromal cells (MSCs), with a biocompatible scaffold that can integrate into host bone tissue and restore its structural integrity. Over the last few years, many tissue engineering strategies have been developed and thoroughly investigated; however, limited approaches have been translated to clinical application. Consequently, the development and clinical validation of regenerative approaches remain a centerpiece of investigational efforts towards the clinical translation of advanced bioengineered scaffolds. The aim of this review was to identify the latest clinical trials related to the use of scaffolds with or without MSCs to regenerate bone defects. A revision of the literature was performed in PubMed, Embase, and Clinicaltrials.gov from 2018 up to 2023. Nine clinical trials were analyzed according to the inclusion criteria: six presented in the literature and three reported in Clinicaltrials.gov. Data were extracted covering background trial information. Six of the clinical trials added cells to scaffolds, while three used scaffolds alone. The majority of scaffolds were composed of calcium phosphate ceramic alone, such as β-tricalcium phosphate (TCP) (two clinical trials), biphasic calcium phosphate bioceramic granules (three clinical trials), and anorganic bovine bone (two clinical trials), while bone marrow was the primary source of the MSCs (five clinical trials). The MSC expansion was performed in GMP facilities, using human platelet lysate (PL) as a supplement without osteogenic factors. Only one trial reported minor adverse events. Overall, these findings highlight the importance and efficacy of cell-scaffold constructs in regenerative medicine under different conditions. Despite the encouraging clinical results obtained, further studies are needed to assess their clinical efficacy in treating bone diseases to optimize their application.
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Affiliation(s)
- Federica Re
- Unit of Blood Diseases and Cell Therapies, Department of Clinical and Experimental Sciences, University of Brescia, "ASST-Spedali Civili" Hospital of Brescia, 25123 Brescia, Italy
- Centro di Ricerca Emato-Oncologica AIL (CREA), ASST Spedali Civili, 25123 Brescia, Italy
| | - Elisa Borsani
- Division of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
- Interdepartmental University Center of Research "Adaption and Regeneration of Tissues and Organs (ARTO)", University of Brescia, 25123 Brescia, Italy
| | - Rita Rezzani
- Division of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
- Interdepartmental University Center of Research "Adaption and Regeneration of Tissues and Organs (ARTO)", University of Brescia, 25123 Brescia, Italy
| | - Luciana Sartore
- Department of Mechanical and Industrial Engineering, Materials Science and Technology Laboratory, University of Brescia, 25123 Brescia, Italy
| | - Domenico Russo
- Unit of Blood Diseases and Cell Therapies, Department of Clinical and Experimental Sciences, University of Brescia, "ASST-Spedali Civili" Hospital of Brescia, 25123 Brescia, Italy
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12
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Sparks DS, Savi FM, Dlaska CE, Saifzadeh S, Brierly G, Ren E, Cipitria A, Reichert JC, Wille ML, Schuetz MA, Ward N, Wagels M, Hutmacher DW. Convergence of scaffold-guided bone regeneration principles and microvascular tissue transfer surgery. SCIENCE ADVANCES 2023; 9:eadd6071. [PMID: 37146134 PMCID: PMC10162672 DOI: 10.1126/sciadv.add6071] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
A preclinical evaluation using a regenerative medicine methodology comprising an additively manufactured medical-grade ε-polycaprolactone β-tricalcium phosphate (mPCL-TCP) scaffold with a corticoperiosteal flap was undertaken in eight sheep with a tibial critical-size segmental bone defect (9.5 cm3, M size) using the regenerative matching axial vascularization (RMAV) approach. Biomechanical, radiological, histological, and immunohistochemical analysis confirmed functional bone regeneration comparable to a clinical gold standard control (autologous bone graft) and was superior to a scaffold control group (mPCL-TCP only). Affirmative bone regeneration results from a pilot study using an XL size defect volume (19 cm3) subsequently supported clinical translation. A 27-year-old adult male underwent reconstruction of a 36-cm near-total intercalary tibial defect secondary to osteomyelitis using the RMAV approach. Robust bone regeneration led to complete independent weight bearing within 24 months. This article demonstrates the widely advocated and seldomly accomplished concept of "bench-to-bedside" research and has weighty implications for reconstructive surgery and regenerative medicine more generally.
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Affiliation(s)
- David S Sparks
- Centre for Biomedical Technologies, School of Mechanical, Medical, and Process Engineering, Faculty of Engineering, Queensland University of Technology, Brisbane, QLD, Australia
- Department of Plastic and Reconstructive Surgery, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
- Southside Clinical Division, School of Medicine, University of Queensland, Woolloongabba, QLD, Australia
| | - Flavia M Savi
- Centre for Biomedical Technologies, School of Mechanical, Medical, and Process Engineering, Faculty of Engineering, Queensland University of Technology, Brisbane, QLD, Australia
- ARC Training Centre for Multiscale 3D Imaging, Modelling, and Manufacturing, Queensland University of Technology, Brisbane, QLD, Australia
| | - Constantin E Dlaska
- Centre for Biomedical Technologies, School of Mechanical, Medical, and Process Engineering, Faculty of Engineering, Queensland University of Technology, Brisbane, QLD, Australia
| | - Siamak Saifzadeh
- Centre for Biomedical Technologies, School of Mechanical, Medical, and Process Engineering, Faculty of Engineering, Queensland University of Technology, Brisbane, QLD, Australia
- ARC Training Centre for Multiscale 3D Imaging, Modelling, and Manufacturing, Queensland University of Technology, Brisbane, QLD, Australia
- Medical Engineering Research Facility, Queensland University of Technology, Chermside, QLD, Australia
| | - Gary Brierly
- Centre for Biomedical Technologies, School of Mechanical, Medical, and Process Engineering, Faculty of Engineering, Queensland University of Technology, Brisbane, QLD, Australia
| | - Edward Ren
- Centre for Biomedical Technologies, School of Mechanical, Medical, and Process Engineering, Faculty of Engineering, Queensland University of Technology, Brisbane, QLD, Australia
| | - Amaia Cipitria
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
- Biodonostia Health Research Institute, San Sebastian, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Johannes C Reichert
- Department of Orthopaedics and Orthopaedic Surgery, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, Greifswald, Germany
| | - Marie-Luise Wille
- Centre for Biomedical Technologies, School of Mechanical, Medical, and Process Engineering, Faculty of Engineering, Queensland University of Technology, Brisbane, QLD, Australia
- ARC Training Centre for Multiscale 3D Imaging, Modelling, and Manufacturing, Queensland University of Technology, Brisbane, QLD, Australia
| | - Michael A Schuetz
- Centre for Biomedical Technologies, School of Mechanical, Medical, and Process Engineering, Faculty of Engineering, Queensland University of Technology, Brisbane, QLD, Australia
- ARC Training Centre for Multiscale 3D Imaging, Modelling, and Manufacturing, Queensland University of Technology, Brisbane, QLD, Australia
- Jamieson Trauma Institute, Royal Brisbane Hospital, Herston, QLD, Australia
| | - Nicola Ward
- Department of Orthopaedics, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - Michael Wagels
- Department of Plastic and Reconstructive Surgery, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
- Southside Clinical Division, School of Medicine, University of Queensland, Woolloongabba, QLD, Australia
- Australian Centre for Complex Integrated Surgical Solutions (ACCISS), Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - Dietmar W Hutmacher
- Centre for Biomedical Technologies, School of Mechanical, Medical, and Process Engineering, Faculty of Engineering, Queensland University of Technology, Brisbane, QLD, Australia
- ARC Training Centre for Multiscale 3D Imaging, Modelling, and Manufacturing, Queensland University of Technology, Brisbane, QLD, Australia
- ARC Training Centre for Additive Biomanufacturing, Queensland University of Technology, Kelvin Grove, QLD, Australia
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13
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Comba LC, Bellato E, Colombero D, Mattei L, Marmotti A, Castoldi F. Revision of Total Hip Arthroplasty with Acetabular Bone Defects: Are Biological Grafts Really Better than Synthetic Bone Graft Substitutes? THE ARCHIVES OF BONE AND JOINT SURGERY 2022; 10:568-575. [PMID: 36032645 PMCID: PMC9382253 DOI: 10.22038/abjs.2021.53380.2666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 12/13/2021] [Indexed: 01/24/2023]
Abstract
BACKGROUND Acetabular aseptic loosening due to bone defect in total hip arthroplasty revisions is a great challenge and several solutions have been proposed, but a broadly accepted consensus in the literature has not been reached yet. The aim of this study is to compare the clinical and radiographic results of acetabular bone defects treatment with biological-only graft or with a mixture of bone graft substitute and biological graft. METHODS 33 patients had revision hip arthroplasty using impaction grafting with biological-only graft (21 patients, Group A) or a 1/3 mixture of allograft and tricalcium phosphate bone graft substitute (12 patients, Group B). Patients were reassessed at a minimum of one year after surgery with new x-rays and the Harris Hip Score (HHS). RESULTS Survivorship of bone graft was 86% in Group A and 100% in Group B at a mean follow-up of 35 months. No statistical difference between the two groups was found in terms of implants survivorship (P=0.28), clinical (P=0.08) or radiographic (P=0.27) outcomes. CONCLUSION In our experience the use of tricalcium phosphate bone graft substitutes in combination with allo and autograft provides good outcomes, low risk of failure and great clinical and radiographic results. Further investigations on larger samples are needed to impact clinical practice.
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Affiliation(s)
| | - Enrico Bellato
- San Luigi Gonzaga Hospital, University of Turin Medical School, Orbassano, Turin, Italy
| | - Danilo Colombero
- San Luigi Gonzaga Hospital, University of Turin Medical School, Orbassano, Turin, Italy
| | | | - Antongiulio Marmotti
- San Luigi Gonzaga Hospital, University of Turin Medical School, Orbassano, Turin, Italy
| | - Filippo Castoldi
- San Luigi Gonzaga Hospital, University of Turin Medical School, Orbassano, Turin, Italy
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14
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Lalzawmliana V, Mukherjee P, Roy S, Roy M, Nandi SK. Ceramic Biomaterials in Advanced Biomedical Applications. FUNCTIONAL BIOMATERIALS 2022:371-408. [DOI: 10.1007/978-981-16-7152-4_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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15
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Chun YS, Lee DH, Won TG, Kim Y, Shetty AA, Kim SJ. Current Modalities for Fracture Healing Enhancement. Tissue Eng Regen Med 2021; 19:11-17. [PMID: 34665454 DOI: 10.1007/s13770-021-00399-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 09/04/2021] [Accepted: 09/09/2021] [Indexed: 01/14/2023] Open
Abstract
Previously, most fractures have been treated through bone reduction and immobilization. With an increase in the patients' need for an early return to their normal function, development in surgical techniques and materials have accelerated. However, delayed union or non-union of the fracture site sometimes inhibits immediate return to normal life. To enhance fracture healing, diverse materials and methods have been developed. This is a review on the current modalities of fracture healing enhancement, which aims to provide a comprehensive knowledge regarding fracture healing for researchers and health practitioners.
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Affiliation(s)
- You Seung Chun
- Department of Orthopedic Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 271, Cheonbo-ro, Uijeongbu-si, Gyeonggi-do, Republic of Korea
| | - Dong Hwan Lee
- Department of Orthopedic Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 271, Cheonbo-ro, Uijeongbu-si, Gyeonggi-do, Republic of Korea
| | - Tae Gu Won
- Department of Orthopedic Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 271, Cheonbo-ro, Uijeongbu-si, Gyeonggi-do, Republic of Korea
| | - Yuna Kim
- Department of Orthopedic Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 271, Cheonbo-ro, Uijeongbu-si, Gyeonggi-do, Republic of Korea
| | - Asode Ananthram Shetty
- Faculty of Medicine, Health and Social Care, Canterbury Christ Church University, 30 Pembroke Court, Chatham Maritime, Kent, ME4 4UF, UK
| | - Seok Jung Kim
- Department of Orthopedic Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 271, Cheonbo-ro, Uijeongbu-si, Gyeonggi-do, Republic of Korea.
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16
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Girón J, Kerstner E, Medeiros T, Oliveira L, Machado GM, Malfatti CF, Pranke P. Biomaterials for bone regeneration: an orthopedic and dentistry overview. Braz J Med Biol Res 2021; 54:e11055. [PMID: 34133539 PMCID: PMC8208772 DOI: 10.1590/1414-431x2021e11055] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 04/23/2021] [Indexed: 12/14/2022] Open
Abstract
Because bone-associated diseases are increasing, a variety of tissue engineering approaches with bone regeneration purposes have been proposed over the last years. Bone tissue provides a number of important physiological and structural functions in the human body, being essential for hematopoietic maintenance and for providing support and protection of vital organs. Therefore, efforts to develop the ideal scaffold which is able to guide the bone regeneration processes is a relevant target for tissue engineering researchers. Several techniques have been used for scaffolding approaches, such as diverse types of biomaterials. On the other hand, metallic biomaterials are widely used as support devices in dentistry and orthopedics, constituting an important complement for the scaffolds. Hence, the aim of this review is to provide an overview of the degradable biomaterials and metal biomaterials proposed for bone regeneration in the orthopedic and dentistry fields in the last years.
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Affiliation(s)
- J Girón
- Laboratório de Hematologia e Células Tronco, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.,Programa de Pós-graduação em Fisiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - E Kerstner
- Programa de Pós-graduação em Engenharia de Minas, Metalúrgica e de Materiais, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - T Medeiros
- Laboratório de Hematologia e Células Tronco, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.,Programa de Pós-graduação em Fisiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - L Oliveira
- Laboratório de Hematologia e Células Tronco, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - G M Machado
- Programa de Gradução em Odontologia, Universidade Luterana do Brasil, Canoas, RS, Brasil
| | - C F Malfatti
- Programa de Pós-graduação em Engenharia de Minas, Metalúrgica e de Materiais, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - P Pranke
- Laboratório de Hematologia e Células Tronco, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.,Programa de Pós-graduação em Fisiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.,Instituto de Pesquisa com Células Tronco, Porto Alegre, RS, Brasil
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17
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Petronis S, Jakusonoka R, Linovs V, Jumtins A. Filling Bone Defects after Hip Arthroplasty Revision Using Hydroxyapatite/β-tricalcium Phosphate: A Case Report with Long-term Result. J Orthop Case Rep 2021; 11:5-9. [PMID: 35437485 PMCID: PMC9009477 DOI: 10.13107/jocr.2021.v11.i06.2234] [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] [Indexed: 12/16/2022] Open
Abstract
Introduction: The increasing number of primary total hip replacements means that there is an increased need for hip arthroplasty revisions. The periprosthetic fractures which cause bone defects can occur during removal of the femoral component and healing of these fractures can be delayed. In femoral bone defects during revisions, there are no metal augments for filling these defects. Case Report: Fifty-nine-year-old female presented with infected loosening of the left hip non-cemented endoprosthesis 5 years after surgery. The patient underwent removal of endoprosthesis. In 2 months, re-implantation of non-cemented endoprosthesis was performed and biphasic calcium phosphate (BCP) ceramic granules with hydroxyapatite/β-tricalcium phosphate (HAp/β-TCP) were implanted in the femoral bone defects. Eleven months following the arthroplasty patient had periprosthetic fracture of the distal third of the left femur. The osteosynthesis was performed and BCP ceramic granules with HAp/β-TCP were used to fill the bone defect. Long-term follow-up showed very good functional outcome and bone defect healing. Conclusion: The BCP ceramic granules with HAp/β-TCP material adjusted to the bone defect anatomy, showed effective femoral bone defect and periprosthetic fracture healing in a patient with hip arthroplasty revision and periprosthetic fracture.
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Affiliation(s)
- Sandris Petronis
- Department of Orthopaedics, Riga Stradins University, Riga, Latvia.,Department of Orthopaedics, Riga Second Hospital, Riga, Latvia
| | - Ruta Jakusonoka
- Department of Orthopaedics, Riga Stradins University, Riga, Latvia
| | - Viktors Linovs
- Department of Radiology, Riga Second Hospital, Riga, Latvia
| | - Andris Jumtins
- Department of Orthopaedics, Riga Stradins University, Riga, Latvia
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18
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Meng QS, Liu J, Wei L, Fan HM, Zhou XH, Liang XT. Senescent mesenchymal stem/stromal cells and restoring their cellular functions. World J Stem Cells 2020; 12:966-985. [PMID: 33033558 PMCID: PMC7524698 DOI: 10.4252/wjsc.v12.i9.966] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/23/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) have various properties that make them promising candidates for stem cell-based therapies in clinical settings. These include self-renewal, multilineage differentiation, and immunoregulation. However, recent studies have confirmed that aging is a vital factor that limits their function and therapeutic properties as standardized clinical products. Understanding the features of senescence and exploration of cell rejuvenation methods are necessary to develop effective strategies that can overcome the shortage and instability of MSCs. This review will summarize the current knowledge on characteristics and functional changes of aged MSCs. Additionally, it will highlight cell rejuvenation strategies such as molecular regulation, non-coding RNA modifications, and microenvironment controls that may enhance the therapeutic potential of MSCs in clinical settings.
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Affiliation(s)
- Qing-Shu Meng
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
| | - Jing Liu
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
| | - Lu Wei
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
| | - Hui-Min Fan
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
- Department of Heart Failure, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiao-Hui Zhou
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiao-Ting Liang
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China.
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19
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Carluccio M, Ziberi S, Zuccarini M, Giuliani P, Caciagli F, Di Iorio P, Ciccarelli R. Adult mesenchymal stem cells: is there a role for purine receptors in their osteogenic differentiation? Purinergic Signal 2020; 16:263-287. [PMID: 32500422 DOI: 10.1007/s11302-020-09703-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 05/04/2020] [Indexed: 02/06/2023] Open
Abstract
The role played by mesenchymal stem cells (MSCs) in contributing to adult tissue homeostasis and damage repair thanks to their differentiation capabilities has raised a great interest, mainly in bone regenerative medicine. The growth/function of these undifferentiated cells of mesodermal origin, located in specialized structures (niches) of differentiated organs is influenced by substances present in this microenvironment. Among them, ancestral and ubiquitous molecules such as adenine-based purines, i.e., ATP and adenosine, may be included. Notably, extracellular purine concentrations greatly increase during tissue injury; thus, MSCs are exposed to effects mediated by these agents interacting with their own receptors when they act/migrate in vivo or are transplanted into a damaged tissue. Here, we reported that ATP modulates MSC osteogenic differentiation via different P2Y and P2X receptors, but data are often inconclusive/contradictory so that the ATP receptor importance for MSC physiology/differentiation into osteoblasts is yet undetermined. An exception is represented by P2X7 receptors, whose expression was shown at various differentiation stages of bone cells resulting essential for differentiation/survival of both osteoclasts and osteoblasts. As well, adenosine, usually derived from extracellular ATP metabolism, can promote osteogenesis, likely via A2B receptors, even though findings from human MSCs should be implemented and confirmed in preclinical models. Therefore, although many data have revealed possible effects caused by extracellular purines in bone healing/remodeling, further studies, hopefully performed in in vivo models, are necessary to identify defined roles for these compounds in favoring/increasing the pro-osteogenic properties of MSCs and thereby their usefulness in bone regenerative medicine.
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Affiliation(s)
- Marzia Carluccio
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy.,StemTeCh Group, Via L. Polacchi, 66100, Chieti, Italy
| | - Sihana Ziberi
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy.,StemTeCh Group, Via L. Polacchi, 66100, Chieti, Italy
| | - Mariachiara Zuccarini
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy
| | - Patricia Giuliani
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy
| | - Francesco Caciagli
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy
| | - Patrizia Di Iorio
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy
| | - Renata Ciccarelli
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy. .,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy. .,StemTeCh Group, Via L. Polacchi, 66100, Chieti, Italy.
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20
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Xu GP, Zhang XF, Sun L, Chen EM. Current and future uses of skeletal stem cells for bone regeneration. World J Stem Cells 2020; 12:339-350. [PMID: 32547682 PMCID: PMC7280866 DOI: 10.4252/wjsc.v12.i5.339] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 04/07/2020] [Accepted: 04/18/2020] [Indexed: 02/06/2023] Open
Abstract
The postnatal skeleton undergoes growth, modeling, and remodeling. The human skeleton is a composite of diverse tissue types, including bone, cartilage, fat, fibroblasts, nerves, blood vessels, and hematopoietic cells. Fracture nonunion and bone defects are among the most challenging clinical problems in orthopedic trauma. The incidence of nonunion or bone defects following fractures is increasing. Stem and progenitor cells mediate homeostasis and regeneration in postnatal tissue, including bone tissue. As multipotent stem cells, skeletal stem cells (SSCs) have a strong effect on the growth, differentiation, and repair of bone regeneration. In recent years, a number of important studies have characterized the hierarchy, differential potential, and bone formation of SSCs. Here, we describe studies on and applications of SSCs and/or mesenchymal stem cells for bone regeneration.
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Affiliation(s)
- Guo-Ping Xu
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Xiang-Feng Zhang
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Lu Sun
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, MA 02115, United States
| | - Er-Man Chen
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
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Gu Y, Zhang J, Zhang X, Liang G, Xu T, Niu W. Three-dimensional Printed Mg-Doped β-TCP Bone Tissue Engineering Scaffolds: Effects of Magnesium Ion Concentration on Osteogenesis and Angiogenesis In Vitro. Tissue Eng Regen Med 2019; 16:415-429. [PMID: 31413945 PMCID: PMC6675836 DOI: 10.1007/s13770-019-00192-0] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 04/07/2019] [Accepted: 04/17/2019] [Indexed: 12/14/2022] Open
Abstract
Background Three-dimensional (3D) printed bone tissue engineering scaffolds have been widely used in research and clinical applications. β-TCP is a biomaterial commonly used in bone tissue engineering to treat bone defects, and its multifunctionality can be achieved by co-doping different metal ions. Magnesium doping in biomaterials has been shown to alter physicochemical properties of cells and enhance osteogenesis. Methods A series of Mg-doped TCP scaffolds were manufactured by using cryogenic 3D printing technology and sintering. The characteristics of the porous scaffolds, such as microstructure, chemical composition, mechanical properties, apparent porosity, etc., were examined. To further study the role of magnesium ions in simultaneously inducing osteogenesis and angiogenesis, human bone marrow mesenchymal stem cells (hBMSCs) and human umblical vein endothelial cells (HUVECs) were cultured in scaffold extracts to investigate cell proliferation, viability, and expression of osteogenic and angiogenic genes. Results The results showed that Mg-doped TCP scaffolds have the advantages of precise design, interconnected porous structure, and similar compressive strength to natural cancellous bone. hBMSCs and HUVECs exhibit high proliferation rate, cell morphology and viability in a certain amount of Mg2+. In addition, this concentration of magnesium can also increase the expression levels of osteogenic and angiogenic biomarkers. Conclusion A certain concentration of magnesium ions plays an important role in new bone regeneration and reconstruction. It can be used as a simple and effective method to enhance the osteogenesis and angiogenesis of bioceramic scaffolds, and support the development of biomaterials and bone tissue engineering scaffolds.
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Affiliation(s)
- Yifan Gu
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, 232 Waihuan East Road, Guangzhou, 510006 China
- Orthopedics Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 111 Dade Road, Guangzhou, 510120 China
| | - Jing Zhang
- Medprin Regenerative Medical Technologies Co., Ltd, Guangzhou, 510663 China
- East China Institute of Digital Medical Engineering, Shangrao, 334000 China
| | - Xinzhi Zhang
- East China Institute of Digital Medical Engineering, Shangrao, 334000 China
| | - Guiping Liang
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, 232 Waihuan East Road, Guangzhou, 510006 China
- Orthopedics Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 111 Dade Road, Guangzhou, 510120 China
| | - Tao Xu
- East China Institute of Digital Medical Engineering, Shangrao, 334000 China
- Department of Mechanical Engineering, Biomanufacturing Center, Tsinghua University, Beijing, 100084 China
- Department of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, 518055 China
| | - Wei Niu
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, 232 Waihuan East Road, Guangzhou, 510006 China
- Orthopedics Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 111 Dade Road, Guangzhou, 510120 China
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22
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Yao X, Jing X, Guo J, Sun K, Deng Y, Zhang Y, Guo F, Ye Y. Icariin Protects Bone Marrow Mesenchymal Stem Cells Against Iron Overload Induced Dysfunction Through Mitochondrial Fusion and Fission, PI3K/AKT/mTOR and MAPK Pathways. Front Pharmacol 2019; 10:163. [PMID: 30873034 PMCID: PMC6403125 DOI: 10.3389/fphar.2019.00163] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 02/11/2019] [Indexed: 12/26/2022] Open
Abstract
Iron overload has been reported to contribute to bone marrow mesenchymal stem cells (BMSCs) damage, but the precise mechanism still remains elusive. Icariin, a major bioactive monomer belonging to flavonoid glucosides isolated from Herba Epimedii, has been shown to protect cells from oxidative stress induced apoptosis. The aim of this study was to investigate whether icariin protected against iron overload induced dysfunction of BMSCs and its underlying mechanism. In this study, we found that iron overload induced by 100 μM ferric ammonium citrate (FAC) caused apoptosis of BMSCs, promoted cleaved caspase-3 and BAX protein expressions while inhibited Bcl-2 protein expression, which effects were significantly attenuated by icariin treatment. In addition, iron overload induced significant depolarization of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) generation and inhibition of mitochondrial fusion/fission, which effects were also attenuated by icariin treatment. Meanwhile, we found that iron overload induced by 100 μM FAC significantly inhibited mitochondrial fission protein FIS1 and fusion protein MFN2 expressions, inhibited DRP1 and Cytochrome C protein translocation from the cytoplasm to mitochondria. Icariin at concentration of 1 μM was able to promote mitochondrial fission protein FIS1 and fusion protein MFN2 expressions, and increase DRP1 and cytochrome C protein translocation from the cytoplasm to mitochondria. Further, osteogenic differentiation and proliferation of BMSCs was significantly inhibited by iron overload, but icariin treatment rescued both osteogenic differentiation and proliferation of BMSCs. Further studies showed that icariin attenuated iron overload induced inactivation of the PI3K/AKT/mTOR pathway and activation of the ERK1/2 and JNK pathways. In summary, our study indicated that icariin was able to protect against iron overload induced dysfunction of BMSCs. These effects were potentially related to the modulation of mitochondrial fusion and fission, activation of the PI3K/AKT/mTOR pathway and inhibition of ERK1/2 and JNK pathways.
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Affiliation(s)
- Xudong Yao
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xingzhi Jing
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiachao Guo
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Sun
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Deng
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Zhang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fengjing Guo
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaping Ye
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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23
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Ottensmeyer PF, Witzler M, Schulze M, Tobiasch E. Small Molecules Enhance Scaffold-Based Bone Grafts via Purinergic Receptor Signaling in Stem Cells. Int J Mol Sci 2018; 19:E3601. [PMID: 30441872 PMCID: PMC6274752 DOI: 10.3390/ijms19113601] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 11/08/2018] [Accepted: 11/09/2018] [Indexed: 12/15/2022] Open
Abstract
The need for bone grafts is high, due to age-related diseases, such as tumor resections, but also accidents, risky sports, and military conflicts. The gold standard for bone grafting is the use of autografts from the iliac crest, but the limited amount of accessible material demands new sources of bone replacement. The use of mesenchymal stem cells or their descendant cells, namely osteoblast, the bone-building cells and endothelial cells for angiogenesis, combined with artificial scaffolds, is a new approach. Mesenchymal stem cells (MSCs) can be obtained from the patient themselves, or from donors, as they barely cause an immune response in the recipient. However, MSCs never fully differentiate in vitro which might lead to unwanted effects in vivo. Interestingly, purinergic receptors can positively influence the differentiation of both osteoblasts and endothelial cells, using specific artificial ligands. An overview is given on purinergic receptor signaling in the most-needed cell types involved in bone metabolism-namely osteoblasts, osteoclasts, and endothelial cells. Furthermore, different types of scaffolds and their production methods will be elucidated. Finally, recent patents on scaffold materials, as wells as purinergic receptor-influencing molecules which might impact bone grafting, are discussed.
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Affiliation(s)
- Patrick Frank Ottensmeyer
- Department of Natural Sciences, Bonn-Rhine-Sieg University of Applied Sciences, D-53359 Rheinbach, Germany.
| | - Markus Witzler
- Department of Natural Sciences, Bonn-Rhine-Sieg University of Applied Sciences, D-53359 Rheinbach, Germany.
| | - Margit Schulze
- Department of Natural Sciences, Bonn-Rhine-Sieg University of Applied Sciences, D-53359 Rheinbach, Germany.
| | - Edda Tobiasch
- Department of Natural Sciences, Bonn-Rhine-Sieg University of Applied Sciences, D-53359 Rheinbach, Germany.
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