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Kang WY, Jung S, Jeong H, Woo HM, Kang MH, Bae H, Cha JM. Effect of Mechanical Environment Alterations in 3D Stem Cell Culture on the Therapeutic Potential of Extracellular Vesicles. Biomater Res 2025; 29:0189. [PMID: 40416939 PMCID: PMC12099057 DOI: 10.34133/bmr.0189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/13/2025] [Accepted: 03/20/2025] [Indexed: 05/27/2025] Open
Abstract
Stem-cell-derived extracellular vesicles (EVs) have emerged as a promising therapeutic option, addressing the limitations of conventional stem cell therapies. However, the variability and poorly defined therapeutic contents of EVs produced under standard 2-dimensional culture conditions present challenges for their clinical application. In this study, we investigated how the therapeutic properties of mesenchymal stem cell (MSC)-derived EVs can be enhanced by culturing MSCs within 3-dimensional hydrogels that have tunable mechanical properties. Our results demonstrate that different mechanical cues from the culture environment can induce specific gene expression changes in MSCs without compromising their inherent characteristics. Furthermore, EVs derived from these MSCs exhibited distinct angiogenic and immunomodulatory activities, which were dependent on the mechanical properties of the hydrogels used. A comprehensive analysis of the cytokines and microRNAs present in the EVs provided additional validation of these findings. By utilizing a noninvasive culture method that eliminates the need for genetic modification or exogenous biochemical supplementation, our approach presents a novel platform for the tailored production of EVs, thereby enhancing their therapeutic potential in regenerative medicine.
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Affiliation(s)
- Wu Young Kang
- Department of Biomedical & Robotics Engineering, College of Engineering,
Incheon National University, Incheon 22012, Republic of Korea
- 3D Stem Cell Bioengineering Laboratory, Research Institute for Engineering and Technology,
Incheon National University, Incheon 22012, Republic of Korea
| | - Sunyoung Jung
- Department of Biomedical & Robotics Engineering, College of Engineering,
Incheon National University, Incheon 22012, Republic of Korea
- Department of BioMedical Sciences,
Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Hyundoo Jeong
- Department of Biomedical & Robotics Engineering, College of Engineering,
Incheon National University, Incheon 22012, Republic of Korea
| | - Hyun-Myung Woo
- Department of Biomedical & Robotics Engineering, College of Engineering,
Incheon National University, Incheon 22012, Republic of Korea
| | - Min-Ho Kang
- Department of BioMedical-Chemical Engineering (BMCE),
The Catholic University of Korea, Bucheon 14662, Republic of Korea
- Department of Biotechnology,
The Catholic University of Korea, Bucheon 14662, Republic of Korea
| | - Hojae Bae
- Department of Stem Cell and Regenerative Biotechnology, KU Convergence Science and Technology Institute,
Konkuk University, Seoul 05029, Republic of Korea
- Institute of Advanced Regenerative Science,
Konkuk University, Seoul 05029, Republic of Korea
| | - Jae Min Cha
- Department of Biomedical & Robotics Engineering, College of Engineering,
Incheon National University, Incheon 22012, Republic of Korea
- 3D Stem Cell Bioengineering Laboratory, Research Institute for Engineering and Technology,
Incheon National University, Incheon 22012, Republic of Korea
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Kim JW, Chung DY, Liu FY, Huang Y, Fridayana FR, Vo MN, Cho KS, Ryu JK, Kwon MH, Yin GN. Bone morphogenetic protein 2 rescues neurogenic abnormalities and angiogenic factors in mice with bilateral cavernous nerve injury. J Sex Med 2025:qdaf091. [PMID: 40349205 DOI: 10.1093/jsxmed/qdaf091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 03/25/2025] [Accepted: 04/07/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Bone morphogenetic protein 2 (BMP2), a key isoform within the bone morphogenetic protein family, plays a critical role in promoting angiogenesis and peripheral nerve regeneration, but its specific role in neurogenic erectile dysfunction (ED) remains unclear. AIM This study aimed to explore the therapeutic efficacy of exogenous recombinant BMP2 protein administration in restoring erectile function in a mouse model of cavernous nerve injury (CNI)-induced ED. METHODS Twelve-week-old male C57BL/6 mice were used to evaluate BMP2 expression and erectile function following CNI. Western blotting and immunofluorescence staining were employed to assess BMP2 levels in corpus cavernosum tissues from both sham-operated and CNI-induced ED mice. Erectile function was measured through electrical stimulation of bilateral cavernous nerves, with subsequent intracavernous pressure parameter recordings. Mechanistic investigations included immunofluorescence staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and western blot analysis. Additionally, ex vivo neurite outgrowth assays were conducted using dorsal root ganglia (DRG) and major pelvic ganglia (MPG) tissues. OUTCOMES In vivo intracavernous pressure, neurovascular regeneration, proliferation, apoptosis, ex vivo neurite sprouting, and survival signaling were measured. RESULTS Bone morphogenetic protein 2 expression was significantly decreased in the corpus cavernosum of CNI mice. Exogenous administration of recombinant BMP2 protein effectively enhanced erectile function in CNI mice, likely through the restoration of endothelial cells, smooth muscle cells, pericytes, and neuronal cells within the corpus cavernosum. Immunofluorescence staining and western blot analysis demonstrated that BMP2 treatment promoted angiogenesis by increasing endothelial cell proliferation and reducing apoptosis in the corpus cavernosum. Furthermore, ex vivo assays revealed that BMP2 promoted neurite sprouting in DRG and MPG tissues exposed to lipopolysaccharide. Mechanistic studies further indicated that BMP2 increased the expression of neurotrophic factors and VEGF, activating the AKT/eNOS signaling pathway. CLINICAL IMPLICATIONS Bone morphogenetic protein 2 may be used as a strategy to treat neurogenic ED or other neurovascular diseases. STRENGTHS AND LIMITATIONS Bone morphogenetic protein 2 has dual roles in vascular and neuronal development. Our study focused on broadly evaluating the role of BMP2 in neurogenic ED. Future studies will evaluate the nerve regeneration effects and novel signaling pathways of BMP2 in a sciatic nerve injury mouse model. In view of its properties as an angiogenic factor, its dose concentration should be strictly controlled to avoid potential side effects. CONCLUSIONS The exogenous administration of recombinant BMP2 protein significantly improved erectile function in CNI mice, suggesting BMP2 as a promising therapeutic candidate for neurogenic ED.
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Affiliation(s)
- Jong Won Kim
- Department of Urology, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 22332, Republic of Korea
| | - Doo Yong Chung
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 22332, Republic of Korea
| | - Fang-Yuan Liu
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 22332, Republic of Korea
| | - Yan Huang
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 22332, Republic of Korea
- Program in Biomedical Science & Engineering, Inha University, Incheon 22332, Republic of Korea
| | - Fitri Rahma Fridayana
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 22332, Republic of Korea
- Program in Biomedical Science & Engineering, Inha University, Incheon 22332, Republic of Korea
| | - Minh Nhat Vo
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 22332, Republic of Korea
| | - Kang Su Cho
- Department of Urology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea
| | - Ji-Kan Ryu
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 22332, Republic of Korea
- Program in Biomedical Science & Engineering, Inha University, Incheon 22332, Republic of Korea
| | - Mi-Hye Kwon
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 22332, Republic of Korea
| | - Guo Nan Yin
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 22332, Republic of Korea
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Kotsifaki A, Kalouda G, Maroulaki S, Foukas A, Armakolas A. The Genetic and Biological Basis of Pseudoarthrosis in Fractures: Current Understanding and Future Directions. Diseases 2025; 13:75. [PMID: 40136615 PMCID: PMC11941250 DOI: 10.3390/diseases13030075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 02/27/2025] [Accepted: 02/27/2025] [Indexed: 03/27/2025] Open
Abstract
Pseudoarthrosis-the failure of normal fracture healing-remains a significant orthopedic challenge affecting approximately 10-15% of long bone fractures, and is associated with significant pain, prolonged disability, and repeated surgical interventions. Despite extensive research into the pathophysiological mechanisms of bone healing, diagnostic approaches remain reliant on clinical findings and radiographic evaluations, with little innovation in tools to predict or diagnose non-union. The present review evaluates the current understanding of the genetic and biological basis of pseudoarthrosis and highlights future research directions. Recent studies have highlighted the potential of specific molecules and genetic markers to serve as predictors of unsuccessful fracture healing. Alterations in mesenchymal stromal cell (MSC) function, including diminished osteogenic potential and increased cellular senescence, are central to pseudoarthrosis pathogenesis. Molecular analyses reveal suppressed bone morphogenetic protein (BMP) signaling and elevated levels of its inhibitors, such as Noggin and Gremlin, which impair bone regeneration. Genetic studies have uncovered polymorphisms in BMP, matrix metalloproteinase (MMP), and Wnt signaling pathways, suggesting a genetic predisposition to non-union. Additionally, the biological differences between atrophic and hypertrophic pseudoarthrosis, including variations in vascularity and inflammatory responses, emphasize the need for targeted approaches to management. Emerging biomarkers, such as circulating microRNAs (miRNAs), cytokine profiles, blood-derived MSCs, and other markers (B7-1 and PlGF-1), have the potential to contribute to early detection of at-risk patients and personalized therapeutic approaches. Advancing our understanding of the genetic and biological underpinnings of pseudoarthrosis is essential for the development of innovative diagnostic tools and therapeutic strategies.
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Affiliation(s)
- Amalia Kotsifaki
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.K.); (G.K.); (S.M.)
| | - Georgia Kalouda
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.K.); (G.K.); (S.M.)
| | - Sousanna Maroulaki
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.K.); (G.K.); (S.M.)
| | - Athanasios Foukas
- Third Department of Orthopaedic Surgery, “KAT” General Hospital of Athens, 2, Nikis Street, 14561 Kifissia, Greece;
| | - Athanasios Armakolas
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.K.); (G.K.); (S.M.)
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Li X, Si Y, Liang J, Li M, Wang Z, Qin Y, Sun L. Enhancing bone regeneration and immunomodulation via gelatin methacryloyl hydrogel-encapsulated exosomes from osteogenic pre-differentiated mesenchymal stem cells. J Colloid Interface Sci 2024; 672:179-199. [PMID: 38838627 DOI: 10.1016/j.jcis.2024.05.209] [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: 04/22/2024] [Revised: 05/13/2024] [Accepted: 05/27/2024] [Indexed: 06/07/2024]
Abstract
Mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as promising candidates for cell-free therapy in tissue regeneration. However, the native osteogenic and angiogenic capacities of MSC-Exos are often insufficient to repair critical-sized bone defects, and the underlying immune mechanisms remain elusive. Furthermore, achieving sustained delivery and stable activity of MSC-Exos at the defect site is essential for optimal therapeutic outcomes. Here, we extracted exosomes from osteogenically pre-differentiated human bone marrow mesenchymal stem cells (hBMSCs) by ultracentrifugation and encapsulated them in gelatin methacryloyl (GelMA) hydrogel to construct a composite scaffold. The resulting exosome-encapsulated hydrogel exhibited excellent mechanical properties and biocompatibility, facilitating sustained delivery of MSC-Exos. Osteogenic pre-differentiation significantly enhanced the osteogenic and angiogenic properties of MSC-Exos, promoting osteogenic differentiation of hBMSCs and angiogenesis of human umbilical vein endothelial cells (HUVECs). Furthermore, MSC-Exos induced polarization of Raw264.7 cells from a pro-inflammatory phenotype to an anti-inflammatory phenotype under simulated inflammatory conditions, thereby creating an immune microenvironment conducive to osteogenesis. RNA sequencing and bioinformatics analysis revealed that MSC-Exos activate the p53 pathway through targeted delivery of internal microRNAs and regulate macrophage polarization by reducing DNA oxidative damage. Our study highlights the potential of osteogenic exosome-encapsulated composite hydrogels for the development of cell-free scaffolds in bone tissue engineering.
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Affiliation(s)
- Xiaorong Li
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
| | - Yunhui Si
- School of Biomedical Engineering, Sun Yat-sen University, Shenzhen 518107, China.
| | - Jingxian Liang
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
| | - Mengsha Li
- School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510006, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China
| | - Zhiwei Wang
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China
| | - Yinying Qin
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
| | - Litao Sun
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China.
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Yu Y, Chen R, Chen X, Wang J, Liu C. Regulating the bioactivity of non-glycosylated recombinant human bone morphogenetic protein-2 to enhance bone regeneration. Bioact Mater 2024; 38:169-180. [PMID: 38711759 PMCID: PMC11070760 DOI: 10.1016/j.bioactmat.2024.04.018] [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: 11/29/2023] [Revised: 04/15/2024] [Accepted: 04/16/2024] [Indexed: 05/08/2024] Open
Abstract
Recombinant human bone morphogenetic protein-2 (rhBMP-2) is the predominant growth factor that effectively induces osteogenic differentiation in orthopedic procedures. However, the bioactivity and stability of rhBMP-2 are intrinsically associated with its sequence, structure, and storage conditions. In this study, we successfully determined the amino acid sequence and protein secondary structure model of non-glycosylated rhBMP-2 expressed by an E. coli expression system through X-ray crystal structure analysis. Furthermore, we observed that acidic storage conditions enhanced the proliferative and osteoinductive activity of rhBMP-2. Although the osteogenic activity of non-glycosylated rhBMP-2 is relatively weaker compared to glycosylated rhBMP-2; however, this discrepancy can be mitigated by incorporating exogenous chaperone molecules. Overall, such information is crucial for rationalizing the design of stabilization methods and enhancing the bioactivity of rhBMP-2, which may also be applicable to other growth factors.
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Affiliation(s)
- Yuanman Yu
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Key Laboratory for Ultrafine Materials of Ministry of Education, Engineering Research Center for Biomedical Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Rui Chen
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Key Laboratory for Ultrafine Materials of Ministry of Education, Engineering Research Center for Biomedical Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Xinye Chen
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Jing Wang
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Key Laboratory for Ultrafine Materials of Ministry of Education, Engineering Research Center for Biomedical Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Changsheng Liu
- Key Laboratory for Ultrafine Materials of Ministry of Education, Engineering Research Center for Biomedical Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, PR China
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Chandran M, Akesson KE, Javaid MK, Harvey N, Blank RD, Brandi ML, Chevalley T, Cinelli P, Cooper C, Lems W, Lyritis GP, Makras P, Paccou J, Pierroz DD, Sosa M, Thomas T, Silverman S. Impact of osteoporosis and osteoporosis medications on fracture healing: a narrative review. Osteoporos Int 2024; 35:1337-1358. [PMID: 38587674 PMCID: PMC11282157 DOI: 10.1007/s00198-024-07059-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 03/06/2024] [Indexed: 04/09/2024]
Abstract
Antiresorptive medications do not negatively affect fracture healing in humans. Teriparatide may decrease time to fracture healing. Romosozumab has not shown a beneficial effect on human fracture healing. BACKGROUND Fracture healing is a complex process. Uncertainty exists over the influence of osteoporosis and the medications used to treat it on fracture healing. METHODS Narrative review authored by the members of the Fracture Working Group of the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF), on behalf of the IOF and the Société Internationale de Chirurgie Orthopédique et de Traumatologie (SICOT). RESULTS Fracture healing is a multistep process. Most fractures heal through a combination of intramembranous and endochondral ossification. Radiographic imaging is important for evaluating fracture healing and for detecting delayed or non-union. The presence of callus formation, bridging trabeculae, and a decrease in the size of the fracture line over time are indicative of healing. Imaging must be combined with clinical parameters and patient-reported outcomes. Animal data support a negative effect of osteoporosis on fracture healing; however, clinical data do not appear to corroborate with this. Evidence does not support a delay in the initiation of antiresorptive therapy following acute fragility fractures. There is no reason for suspension of osteoporosis medication at the time of fracture if the person is already on treatment. Teriparatide treatment may shorten fracture healing time at certain sites such as distal radius; however, it does not prevent non-union or influence union rate. The positive effect on fracture healing that romosozumab has demonstrated in animals has not been observed in humans. CONCLUSION Overall, there appears to be no deleterious effect of osteoporosis medications on fracture healing. The benefit of treating osteoporosis and the urgent necessity to mitigate imminent refracture risk after a fracture should be given prime consideration. It is imperative that new radiological and biological markers of fracture healing be identified. It is also important to synthesize clinical and basic science methodologies to assess fracture healing, so that a convergence of the two frameworks can be achieved.
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Affiliation(s)
- M Chandran
- Osteoporosis and Bone Metabolism Unit, Department of Endocrinology, Singapore General Hospital, DUKE NUS Medical School, Singapore, Singapore.
| | - K E Akesson
- Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University, Department of Orthopedics, Skåne University Hospital, Malmö, Sweden
| | - M K Javaid
- NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK
| | - N Harvey
- MRC Lifecourse Epidemiology Centre, University of Southampton, NIHR Southampton Biomedical Research Centre, University of Southampton, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - R D Blank
- Garvan Institute of Medical Research, Medical College of Wisconsin, Darlinghurst, NSW, Australia
- Medical College of Wisconsin, Milwaukee, WI, USA
| | - M L Brandi
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Largo Palagi 1, Florence, Italy
| | - T Chevalley
- Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - P Cinelli
- Department of Trauma Surgery, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - C Cooper
- MRC Lifecourse Epidemiology Centre, University of Southampton, NIHR Southampton Biomedical Research Centre, University of Southampton, University Hospitals Southampton NHS Foundation Trust, Southampton, UK
- NIHR Oxford Biomedical Research Unit, University of Oxford, Oxford, UK
| | - W Lems
- Department of Rheumatology, Amsterdam UMC, Location VUmc, Amsterdam, The Netherlands
| | - G P Lyritis
- Hellenic Osteoporosis Foundation, Athens, Greece
| | - P Makras
- Department of Medical Research, 251 Hellenic Air Force & VA General Hospital, Athens, Greece
| | - J Paccou
- Department of Rheumatology, MABlab ULR 4490, CHU Lille, Univ. Lille, 59000, Lille, France
| | - D D Pierroz
- International Osteoporosis Foundation, Nyon, Switzerland
| | - M Sosa
- University of Las Palmas de Gran Canaria, Investigation Group on Osteoporosis and Mineral Metabolism, Canary Islands, Spain
| | - T Thomas
- Department of Rheumatology, North Hospital, CHU Saint-Etienne and INSERM U1059, University of Lyon-University Jean Monnet, Saint‑Etienne, France
| | - S Silverman
- Cedars-Sinai Medical Center and Geffen School of Medicine UCLA, Los Angeles, CA, USA
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Wang H, Li X, Xuan M, Yang R, Zhang J, Chang J. Marine biomaterials for sustainable bone regeneration. GIANT 2024; 19:100298. [DOI: 10.1016/j.giant.2024.100298] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Shim GJ, Lee CO, Lee JT, Jung HM, Kwon TG. Potentiating effect of AMD3100 on bone morphogenetic protein-2 induced bone regeneration. Maxillofac Plast Reconstr Surg 2024; 46:22. [PMID: 38884872 PMCID: PMC11183024 DOI: 10.1186/s40902-024-00431-y] [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: 05/08/2024] [Accepted: 06/10/2024] [Indexed: 06/18/2024] Open
Abstract
BACKGROUND AMD3100, a CXCR4 antagonist, is currently prescribed for activating the mobilization of hematopoietic stem cells. Recently, AMD3100 was shown to potentiate bone morphogenetic protein-2 (BMP-2)-induced bone formation by stimulating the trafficking of mesenchymal cells. However, optimization of the strategic combination of AMD3100 and BMP-2 has not yet been clearly established. The purpose of this study was to evaluate the effect of AMD3100 on BMP-2-induced bone regeneration in vitro and in a mouse calvarial defect healing model. METHODS In vitro osteoblastic differentiation and cell migration after sequential treatments with AMD3100 and BMP-2 were analyzed by alkaline phosphatase (ALP) activity, ALP staining, and calcium accumulation. Migration capacity was evaluated after treating mesenchymal cells with AMD3100 and/or BMP-2. A critical-size calvarial defect model was used to evaluate bone formation after sequential or continuous treatment with AMD3100 and BMP-2. The degree of bone formation in the defect was analyzed using micro-computed tomography (micro-CT) and histological staining. RESULTS Compared with single treatment using either AMD3100 or BMP-2 alone, sequential treatment with AMD3100 followed by BMP-2 on mesenchymal cells increased osteogenic differentiation. Application of AMD3100 and subsequent BMP-2 significantly activated cell migration on mesenchymal cell than BMP-2 alone or AMD3100 alone. Micro-CT and histomorphometric analysis showed that continuous intraperitoneal (IP) injection of AMD3100 resulted significantly increased new bone formation in BMP-2 loaded scaffold in calvarial defect than control groups without AMD3100 IP injection. Additionally, both single IP injection of AMD3100 and subsequent BMP-2 injection to the scaffold in calvarial defect showed pronounced new bone formation compared to continuous BMP-2 treatment without AMD3100 treatment. CONCLUSION Our data suggest that single or continuous injection of AMD3100 can potentiate BMP-2-induced osteoblastic differentiation and bone regeneration. This strategic combination of AMD3100 and BMP-2 may be a promising therapy for bone regeneration.
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Affiliation(s)
- Gyu-Jo Shim
- Department of Oral & Maxillofacial Surgery, School of Dentistry, Kyungpook National University, and Institute for Translational Research in Dentistry, Kyungpook National University, Daegu, Republic of Korea
| | - Chung O Lee
- Department of Oral & Maxillofacial Surgery, School of Dentistry, Kyungpook National University, and Institute for Translational Research in Dentistry, Kyungpook National University, Daegu, Republic of Korea
| | - Jung-Tae Lee
- Department of Oral & Maxillofacial Surgery, School of Dentistry, Kyungpook National University, and Institute for Translational Research in Dentistry, Kyungpook National University, Daegu, Republic of Korea
| | - Hong-Moon Jung
- Department of Radiologic Technology, Daegu Health College, Daegu, Republic of Korea
| | - Tae-Geon Kwon
- Department of Oral & Maxillofacial Surgery, School of Dentistry, Kyungpook National University, and Kyungpook National University Institute for Translational Research in Dentistry, 2177 Dalgubeol-daero, Jung-Gu, Daegu, 41940, Republic of Korea.
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Okada K, Niwa Y, Fukuhara K, Ohira T, Mizukami Y, Kawao N, Matsuo O, Kaji H. Plasminogen activator inhibitor-1 is involved in glucocorticoid-induced decreases in angiogenesis during bone repair in mice. J Bone Miner Metab 2024; 42:282-289. [PMID: 38704516 DOI: 10.1007/s00774-024-01510-w] [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: 12/27/2023] [Accepted: 03/25/2024] [Indexed: 05/06/2024]
Abstract
INTRODUCTION Glucocorticoids delay fracture healing and induce osteoporosis. Angiogenesis plays an important role in bone repair after bone injury. Plasminogen activator inhibitor-1 (PAI-1) is the principal inhibitor of plasminogen activators and an adipocytokine that regulates metabolism. However, the mechanisms by which glucocorticoids delay bone repair remain unclear. MATERIALS AND METHODS Therefore, we herein investigated the roles of PAI-1 and angiogenesis in glucocorticoid-induced delays in bone repair after femoral bone injury using PAI-1-deficient female mice intraperitoneally administered dexamethasone (Dex). RESULTS PAI-1 deficiency significantly attenuated Dex-induced decreases in the number of CD31-positive vessels at damaged sites 4 days after femoral bone injury in mice. PAI-1 deficiency also significantly ameliorated Dex-induced decreases in the number of CD31- and endomucin-positive type H vessels and CD31-positive- and endomucin-negative vessels at damaged sites 4 days after femoral bone injury. Moreover, PAI-1 deficiency significantly mitigated Dex-induced decreases in the expression of vascular endothelial growth factor as well as hypoxia inducible factor-1α, transforming growth factor-β1, and bone morphogenetic protein-2 at damaged sites 4 days after femoral bone injury. CONCLUSION The present results demonstrate that Dex-reduced angiogenesis at damaged sites during the early bone-repair phase after femoral bone injury partly through PAI-1 in mice.
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Affiliation(s)
- Kiyotaka Okada
- Department of Arts and Science, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
| | - Yuto Niwa
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
| | - Kazusa Fukuhara
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
| | - Takashi Ohira
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
| | - Yuya Mizukami
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
| | - Naoyuki Kawao
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
| | - Osamu Matsuo
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan
| | - Hiroshi Kaji
- Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan.
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Abdollahi F, Saghatchi M, Paryab A, Malek Khachatourian A, Stephens ED, Toprak MS, Badv M. Angiogenesis in bone tissue engineering via ceramic scaffolds: A review of concepts and recent advancements. BIOMATERIALS ADVANCES 2024; 159:213828. [PMID: 38479240 DOI: 10.1016/j.bioadv.2024.213828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 03/08/2024] [Accepted: 03/08/2024] [Indexed: 04/05/2024]
Abstract
Due to organ donor shortages, long transplant waitlists, and the complications/limitations associated with auto and allotransplantation, biomaterials and tissue-engineered models are gaining attention as feasible alternatives for replacing and reconstructing damaged organs and tissues. Among various tissue engineering applications, bone tissue engineering has become a promising strategy to replace or repair damaged bone. We aimed to provide an overview of bioactive ceramic scaffolds in bone tissue engineering, focusing on angiogenesis and the effect of different biofunctionalization strategies. Different routes to angiogenesis, including chemical induction through signaling molecules immobilized covalently or non-covalently, in situ secretion of angiogenic growth factors, and the degradation of inorganic scaffolds, are described. Physical induction mechanisms are also discussed, followed by a review of methods for fabricating bioactive ceramic scaffolds via microfabrication methods, such as photolithography and 3D printing. Finally, the strengths and weaknesses of the commonly used methodologies and future directions are discussed.
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Affiliation(s)
- Farnoosh Abdollahi
- Department of Dentistry, Kashan University of Medical Science, Kashan, Iran
| | - Mahshid Saghatchi
- School of Metallurgy & Materials Engineering, Iran University of Science and Technology, Tehran, Iran
| | - Amirhosein Paryab
- Department of Materials Science & Engineering, Sharif University of Technology, Tehran, Iran
| | | | - Emma D Stephens
- Department of Biomedical Engineering, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada
| | - Muhammet S Toprak
- Department of Applied Physics, Biomedical and X-ray Physics, KTH Royal Institute of Technology, SE 10691 Stockholm, Sweden
| | - Maryam Badv
- Department of Biomedical Engineering, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada; Libin Cardiovascular Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada
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11
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Chantiri M, Nammour S, El Toum S, Zeinoun T. Histological and Immunohistochemical Evaluation of Rh-BMP2: Effect on Gingival Healing Acceleration and Proliferation of Human Epithelial Cells. Life (Basel) 2024; 14:459. [PMID: 38672730 PMCID: PMC11051349 DOI: 10.3390/life14040459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/12/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024] Open
Abstract
This study aims to histologically and immunohistochemically evaluate the effect recombinant human bone morphogenetic protein (rh-BMP2) injected in gingival tissue has on the acceleration of the epithelial migration from the wound edges and epithelial cell proliferation after implant surgery. MATERIAL AND METHODS The study includes 20 patients who underwent bilateral implant surgeries in the premolar-molar region of the mandible, followed by guided bone regeneration. Each patient received an implant in both locations, but rh-BMP2 was only on the right side. At 9 days from the surgery, a gingival biopsy was performed 3 mm distally to the last implant. In total, 20 samples were collected from the left side (control group #1) and 20 from right (test group #1). This was repeated at a 4-month interval during healing abutment placements. Tissues were processed and stained with hematoxylin-eosin and then immunohistochemically for the expression of Ki-67 and further histological examination. RESULT Complete closure of the epithelium with new cell formation was observed in the 55% test group and 20% control group after 9 days. At 4 months, although 100% samples of all groups had complete epithelial closure, the test group showed that the epithelial cells were more organized and mature due to the increased number of blood vessels. The average number of new epithelial cells was 17.15 ± 7.545 and 16.12 ± 7.683 cells per mm in test group, respectively, at 9 days and 4 months and 10.99 ± 5.660 and 10.95 ± 5.768 in control groups. CONCLUSION Evident from histological observations, rh-BMP-2 can accelerate the closure of gingival wounds, the healing process of epithelial gingival tissue, and the formation of epithelial cells in patients undergoing dental implant treatment.
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Affiliation(s)
- Mansour Chantiri
- Department of Periodontology, Faculty of Dental Medicine, Lebanese University, Beirut 27798, Lebanon;
| | - Samir Nammour
- Department of Dental Sciences, Faculty of Medicine, University of Liege, 4000 Liege, Belgium;
| | - Sami El Toum
- Department of Oral Medicine and Maxillofacial Radiology, Faculty of Dental Medicine, Lebanese University, Beirut 27798, Lebanon;
| | - Toni Zeinoun
- Department of Oral and Maxillo-Facial Surgery, Faculty of Dental Medicine, Lebanese University, Beirut 27798, Lebanon
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12
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Lang A, Benn A, Collins JM, Wolter A, Balcaen T, Kerckhofs G, Zwijsen A, Boerckel JD. Endothelial SMAD1/5 signaling couples angiogenesis to osteogenesis in juvenile bone. Commun Biol 2024; 7:315. [PMID: 38480819 PMCID: PMC10937971 DOI: 10.1038/s42003-024-05915-1] [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: 02/22/2023] [Accepted: 02/13/2024] [Indexed: 03/17/2024] Open
Abstract
Skeletal development depends on coordinated angiogenesis and osteogenesis. Bone morphogenetic proteins direct bone formation in part by activating SMAD1/5 signaling in osteoblasts. However, the role of SMAD1/5 in skeletal endothelium is unknown. Here, we found that endothelial cell-conditional SMAD1/5 depletion in juvenile mice caused metaphyseal and diaphyseal hypervascularity, resulting in altered trabecular and cortical bone formation. SMAD1/5 depletion induced excessive sprouting and disrupting the morphology of the metaphyseal vessels, with impaired anastomotic loop formation at the chondro-osseous junction. Endothelial SMAD1/5 depletion impaired growth plate resorption and, upon long-term depletion, abrogated osteoprogenitor recruitment to the primary spongiosa. Finally, in the diaphysis, endothelial SMAD1/5 activity was necessary to maintain the sinusoidal phenotype, with SMAD1/5 depletion inducing formation of large vascular loops and elevated vascular permeability. Together, endothelial SMAD1/5 activity sustains skeletal vascular morphogenesis and function and coordinates growth plate remodeling and osteoprogenitor recruitment dynamics in juvenile mouse bone.
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Affiliation(s)
- Annemarie Lang
- Departments of Orthopaedic Surgery and Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, 10117, Germany.
- Centre for Translational Bone, Joint and Soft Tissue Research, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden (TUD), Fetscherstrasse 74, Dresden, 01307, Germany.
| | - Andreas Benn
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, 3000, Belgium
- VIB-KU Leuven Center for Brain & Disease Research, KU Leuven, Leuven, 3000, Belgium
| | - Joseph M Collins
- Departments of Orthopaedic Surgery and Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Angelique Wolter
- Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, 10117, Germany
- Department of Veterinary Medicine, Institute of Animal Welfare, Animal Behavior and Laboratory Animal Science, Freie Universität Berlin, Berlin, 14163, Germany
| | - Tim Balcaen
- Institute of Mechanics, Materials and Civil Engineering, Biomechanics lab, UCLouvain, Louvain-la-Neuve, 1348, Belgium
- Institute of Experimental and Clinical Research, Pole of Morphology, UCLouvain, Brussels, 1200, Belgium
- KU Leuven, Department of Chemistry, Sustainable Chemistry for Metals and Molecules, Leuven, 3000, Belgium
| | - Greet Kerckhofs
- Institute of Mechanics, Materials and Civil Engineering, Biomechanics lab, UCLouvain, Louvain-la-Neuve, 1348, Belgium
- Institute of Experimental and Clinical Research, Pole of Morphology, UCLouvain, Brussels, 1200, Belgium
- Department of Materials Engineering, KU Leuven, Heverlee, 3001, Belgium
- Division for Skeletal Tissue Engineering, Prometheus, KU Leuven, Leuven, 3000, Belgium
| | - An Zwijsen
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, 3000, Belgium
| | - Joel D Boerckel
- Departments of Orthopaedic Surgery and Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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13
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Sun J, Wu Q, Wei Y, Zhao W, Lv H, Peng W, Zheng J, Chen Y, Wang Z, Pan Y, Xue Y. Agaricus bisporus-Derived Glucosamine Hydrochloride Regulates VEGF through BMP Signaling to Promote Zebrafish Vascular Development and Impairment Repair. Life (Basel) 2023; 13:2330. [PMID: 38137931 PMCID: PMC10745105 DOI: 10.3390/life13122330] [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: 08/30/2023] [Revised: 12/01/2023] [Accepted: 12/05/2023] [Indexed: 12/24/2023] Open
Abstract
Glucosamine hydrochloride (GAH) is a natural component of glycoproteins present in almost all human tissues and participates in the construction of human tissues and cell membranes. GAH has a wide range of biological activities, particularly in anti-inflammatory and osteogenic damage repair. At present, little is known about how GAH functions in angiogenesis. To determine the role of GAH on vascular development and impairment repair, we used the inhibitors VRI, DMH1, and dorsomorphin (DM) to construct vascular-impaired models in Tg(kdrl: mCherry) transgenic zebrafish. We then treated with GAH and measured its repair effects on vascular impairment through fluorescence intensity, mRNA, and protein expression levels of vascular-specific markers. Our results indicate that GAH promotes vascular development and repairs impairment by regulating the vascular endothelial growth factor (VEGF) signaling pathway through modulation of bone morphogenetic protein (BMP) signaling. This study provides an experimental basis for the development of GAH as a drug to repair vascular diseases.
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Affiliation(s)
- Jiarui Sun
- The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China; (J.S.); (Q.W.); (Y.W.); (W.Z.); (H.L.); (W.P.); (J.Z.); (Y.C.); (Z.W.)
- Fujian Fungal Active Substance Engineering Technology Center, Zhangzhou 363000, China
| | - Qici Wu
- The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China; (J.S.); (Q.W.); (Y.W.); (W.Z.); (H.L.); (W.P.); (J.Z.); (Y.C.); (Z.W.)
- Fujian Fungal Active Substance Engineering Technology Center, Zhangzhou 363000, China
| | - Yuxin Wei
- The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China; (J.S.); (Q.W.); (Y.W.); (W.Z.); (H.L.); (W.P.); (J.Z.); (Y.C.); (Z.W.)
- Fujian Fungal Active Substance Engineering Technology Center, Zhangzhou 363000, China
| | - Wei Zhao
- The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China; (J.S.); (Q.W.); (Y.W.); (W.Z.); (H.L.); (W.P.); (J.Z.); (Y.C.); (Z.W.)
- Fujian Fungal Active Substance Engineering Technology Center, Zhangzhou 363000, China
| | - Haokun Lv
- The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China; (J.S.); (Q.W.); (Y.W.); (W.Z.); (H.L.); (W.P.); (J.Z.); (Y.C.); (Z.W.)
- Fujian Fungal Active Substance Engineering Technology Center, Zhangzhou 363000, China
| | - Wei Peng
- The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China; (J.S.); (Q.W.); (Y.W.); (W.Z.); (H.L.); (W.P.); (J.Z.); (Y.C.); (Z.W.)
- Fujian Fungal Active Substance Engineering Technology Center, Zhangzhou 363000, China
| | - Jiayi Zheng
- The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China; (J.S.); (Q.W.); (Y.W.); (W.Z.); (H.L.); (W.P.); (J.Z.); (Y.C.); (Z.W.)
- Fujian Fungal Active Substance Engineering Technology Center, Zhangzhou 363000, China
| | - Yixuan Chen
- The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China; (J.S.); (Q.W.); (Y.W.); (W.Z.); (H.L.); (W.P.); (J.Z.); (Y.C.); (Z.W.)
- Fujian Fungal Active Substance Engineering Technology Center, Zhangzhou 363000, China
| | - Zhengsen Wang
- The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China; (J.S.); (Q.W.); (Y.W.); (W.Z.); (H.L.); (W.P.); (J.Z.); (Y.C.); (Z.W.)
- Fujian Fungal Active Substance Engineering Technology Center, Zhangzhou 363000, China
| | - Yutian Pan
- The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China; (J.S.); (Q.W.); (Y.W.); (W.Z.); (H.L.); (W.P.); (J.Z.); (Y.C.); (Z.W.)
- Fujian Fungal Active Substance Engineering Technology Center, Zhangzhou 363000, China
| | - Yu Xue
- The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China; (J.S.); (Q.W.); (Y.W.); (W.Z.); (H.L.); (W.P.); (J.Z.); (Y.C.); (Z.W.)
- Fujian Fungal Active Substance Engineering Technology Center, Zhangzhou 363000, China
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14
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Chantiri M, Nammour S, El Toum S, Zeinoun T. Effect of rh-BMP-2 in the Initiation of Neovascularization in Human Gingival Tissue: A Split-Mouth Clinical Study. Life (Basel) 2023; 13:2298. [PMID: 38137899 PMCID: PMC10744365 DOI: 10.3390/life13122298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 11/28/2023] [Accepted: 12/01/2023] [Indexed: 12/24/2023] Open
Abstract
The aim of this study is to evaluate the effect on the initiation of new blood vessel formation of rh-BMP-2 administration in the human gingival tissue during bone regeneration surgery. MATERIAL AND METHODS The randomized controlled clinical trial included twenty patients with bilateral partial edentulous of the mandibular premolar and molar region. Each patient received one implants on each side. Only one side received a 0.25 µg injection of rhBMP-2 into the gingival flap and grafted material during guided bone regeneration (GBR) for dental implantation. And the other side received GBR without injection. Three samples were collected from each patient as follows: one from the anterior area of the mandible (control group #1) collected at the time of all implant surgeries, and the two other samples during the placement of healing abutments at 4 months of follow-up, from treated side with rh-BMP-2 (test group) and untreated ones (control group #2). A total of 60 gingival samples were collected. Samples were stained with hematoxylin-eosin, and immunohistochemistry was performed with a vascular endothelial growth factor marker. The number of new vessels in each sample was counted. RESULT Statistical analyses showed a significantly higher number of new vessels in the gingival tissue of the test group. CONCLUSIONS Rh-BMP-2 injections into the gingival flap significantly improved new blood vessel formation.
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Affiliation(s)
- Mansour Chantiri
- Department of Periodontology, Faculty of Dental Medicine, Lebanese University, Beirut 27798, Lebanon;
| | - Samir Nammour
- Department of Dental Sciences, Faculty of Medicine, University of Liege, 4000 Liege, Belgium
| | - Sami El Toum
- Department of Oral Medicine and Maxillofacial Radiology, Faculty of Dental Medicine, Lebanese University, Beirut 27798, Lebanon;
| | - Toni Zeinoun
- Department of Oral and Maxillofacial Surgery, Faculty of Dental Medicine, Lebanese University, Beirut 27798, Lebanon;
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15
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Kuroyanagi G, Kamiya N, Yamaguchi R, Kim HK. Interleukin-6 receptor blockade improves bone healing following ischemic osteonecrosis in adolescent mice. OSTEOARTHRITIS AND CARTILAGE OPEN 2023; 5:100386. [PMID: 37600923 PMCID: PMC10432805 DOI: 10.1016/j.ocarto.2023.100386] [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: 10/19/2022] [Accepted: 07/13/2023] [Indexed: 08/22/2023] Open
Abstract
Objective Juvenile ischemic osteonecrosis (JIO) of the femoral head is one of the most serious hip disorders causing a permanent deformity of the femoral head in childhood. We recently reported that interleukin 6 (IL-6) is significantly increased in the hip synovial fluid of patients with JIO and that articular chondrocytes are primary source of IL-6. Adolescent JIO is particularly challenging to treat and has poor outcome. This study determined if IL-6 receptor blockade prevents bone loss and improves the bone healing in adolescent JIO. Method Adolescent mice (12-week-old) surgically induced with JIO were treated with either saline or MR16-1, an IL-6 receptor blocker. Results Micro-CT assessment showed significantly increased bone volume (p < 0.001, Cohen's d = 2.0) and trabecular bone thickness (p < 0.001, d = 2.3) after the MR16-1 treatment. Histomorphometric assessment showed significantly increased osteoblast number (p < 0.01, d = 2.3), bone formation rate (p < 0.01, d = 4.3), and mineral apposition rate (p < 0.01, d = 4.1) after the MR16-1 treatment. The number of osteoclasts was unchanged. Histologic assessment showed significantly increased revascularization (p < 0.01) and restoration of the necrotic marrow with new hematopoietic bone marrow (p < 0.01). Vascular endothelial growth factor (VEGF) expression was increased in the revascularized area and the articular cartilage, and in the cultured chondrocytes treated with IL-6 receptor inhibitor. Conclusion IL-6 blockade in adolescent mice with JIO enhanced bone formation and revascularization. The findings suggest IL-6 receptor blocker as a potential medical therapy for adolescent JIO.
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Affiliation(s)
- Gen Kuroyanagi
- Center for Excellence in Hip, Scottish Rite for Children, Dallas, TX 75219, USA
- Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Nobuhiro Kamiya
- Center for Excellence in Hip, Scottish Rite for Children, Dallas, TX 75219, USA
- Faculty of Budo and Sport Studies, Tenri University, Nara 6320071, Japan
| | - Ryosuke Yamaguchi
- Center for Excellence in Hip, Scottish Rite for Children, Dallas, TX 75219, USA
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Harry K.W. Kim
- Center for Excellence in Hip, Scottish Rite for Children, Dallas, TX 75219, USA
- Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390-8883, USA
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16
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Gadre S, M M, Chakraborty G, Rayrikar A, Paul S, Patra C, Patra M. Development of a Highly In Vivo Efficacious Dual Antitumor and Antiangiogenic Organoiridium Complex as a Potential Anti-Lung Cancer Agent. J Med Chem 2023; 66:13481-13500. [PMID: 37784224 DOI: 10.1021/acs.jmedchem.3c00704] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2023]
Abstract
While the phenomenal clinical success of blockbuster platinum (Pt) drugs is highly encouraging, the inherent and acquired resistance and dose-limiting side effects severely limit their clinical application. To find a better alternative with translational potential, we synthesized a library of six organo-IrIII half-sandwich [(η5-CpX)Ir(N∧N)Cl]+-type complexes. In vitro screening identified two lead candidates [(η5-CpXPh)Ir(Ph2Phen)Cl]+ (5, CpXPh = tetramethyl-phenyl-cyclopentadienyl and Ph2Phen = 4,7-diphenyl-1,10-phenanthroline) and [(η5-CpXBiPh)Ir(Ph2Phen)Cl]+ (6, CpXBiPh = tetramethyl-biphenyl-cyclopentadienyl) with nanomolar IC50 values. Both 5 and 6 efficiently overcame Pt resistance and presented excellent cancer cell selectivity in vitro. Potent antiangiogenic properties of 6 were demonstrated in the zebrafish model. Satisfyingly, 6 and its nanoliposome Lipo-6 presented considerably higher in vivo antitumor efficacy as compared to cisplatin, as well as earlier reported IrIII half-sandwich complexes in mice bearing the A549 non-small lung cancer xenograft. In particular, complex 6 is the first example of this class that exerted dual in vivo antiangiogenic and antitumor properties.
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Affiliation(s)
- Shubhankar Gadre
- Medicinal Chemistry and Cell Biology Laboratory, Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai, Maharashtra 400005, India
| | - Manikandan M
- Medicinal Chemistry and Cell Biology Laboratory, Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai, Maharashtra 400005, India
| | - Gourav Chakraborty
- Department of Developmental Biology, Agharkar Research Institute, G G Agarkar Road, Pune, Maharashtra 411004, India
| | - Amey Rayrikar
- Department of Developmental Biology, Agharkar Research Institute, G G Agarkar Road, Pune, Maharashtra 411004, India
| | - Subhadeep Paul
- Medicinal Chemistry and Cell Biology Laboratory, Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai, Maharashtra 400005, India
| | - Chinmoy Patra
- Department of Developmental Biology, Agharkar Research Institute, G G Agarkar Road, Pune, Maharashtra 411004, India
| | - Malay Patra
- Medicinal Chemistry and Cell Biology Laboratory, Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai, Maharashtra 400005, India
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17
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Saberi A, Kouhjani M, Mohammadi M, Hosta-Rigau L. Novel scaffold platforms for simultaneous induction osteogenesis and angiogenesis in bone tissue engineering: a cutting-edge approach. J Nanobiotechnology 2023; 21:351. [PMID: 37770928 PMCID: PMC10536787 DOI: 10.1186/s12951-023-02115-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 09/15/2023] [Indexed: 09/30/2023] Open
Abstract
Despite the recent advances in the development of bone graft substitutes, treatment of critical size bone defects continues to be a significant challenge, especially in the elderly population. A current approach to overcome this challenge involves the creation of bone-mimicking scaffolds that can simultaneously promote osteogenesis and angiogenesis. In this context, incorporating multiple bioactive agents like growth factors, genes, and small molecules into these scaffolds has emerged as a promising strategy. To incorporate such agents, researchers have developed scaffolds incorporating nanoparticles, including nanoparticulate carriers, inorganic nanoparticles, and exosomes. Current paper provides a summary of the latest advancements in using various bioactive agents, drugs, and cells to synergistically promote osteogenesis and angiogenesis in bone-mimetic scaffolds. It also discusses scaffold design properties aimed at maximizing the synergistic effects of osteogenesis and angiogenesis, various innovative fabrication strategies, and ongoing clinical studies.
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Affiliation(s)
- Arezoo Saberi
- Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Kouhjani
- Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Marzieh Mohammadi
- Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Leticia Hosta-Rigau
- DTU Health Tech, Centre for Nanomedicine and Theranostics, Technical University of Denmark, Produktionstorvet, Building 423, 2800, Kgs. Lyngby, Denmark.
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18
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Jennissen HP. Camouflaged angiogenic BMP-2 functions exposed by pico-paracrine biohybrids. Front Bioeng Biotechnol 2023; 11:1226649. [PMID: 37744249 PMCID: PMC10513495 DOI: 10.3389/fbioe.2023.1226649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 06/22/2023] [Indexed: 09/26/2023] Open
Abstract
The constant release of human bone morphogenetic protein 2 (rhBMP-2) in the picomolar range (Pico-Stat) from PDLLA-biohybrids led to the detection of intrinsic novel pro- and anti-angiogenic functions of this cytokine. As integrant part in this perspective of previous work, first evidence for the binding of rhBMP-2, as an inverse agonist, to allosteric angiogenic receptors in cocultures of human endothelial cells is reported.
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Affiliation(s)
- Herbert P. Jennissen
- Institute of Physiological Chemistry, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
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19
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Fan S, Sun X, Su C, Xue Y, Song X, Deng R. Macrophages-bone marrow mesenchymal stem cells crosstalk in bone healing. Front Cell Dev Biol 2023; 11:1193765. [PMID: 37427382 PMCID: PMC10327485 DOI: 10.3389/fcell.2023.1193765] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 06/14/2023] [Indexed: 07/11/2023] Open
Abstract
Bone healing is associated with many orthopedic conditions, including fractures and osteonecrosis, arthritis, metabolic bone disease, tumors and periprosthetic particle-associated osteolysis. How to effectively promote bone healing has become a keen topic for researchers. The role of macrophages and bone marrow mesenchymal stem cells (BMSCs) in bone healing has gradually come to light with the development of the concept of osteoimmunity. Their interaction regulates the balance between inflammation and regeneration, and when the inflammatory response is over-excited, attenuated, or disturbed, it results in the failure of bone healing. Therefore, an in-depth understanding of the function of macrophages and bone marrow mesenchymal stem cells in bone regeneration and the relationship between the two could provide new directions to promote bone healing. This paper reviews the role of macrophages and bone marrow mesenchymal stem cells in bone healing and the mechanism and significance of their interaction. Several new therapeutic ideas for regulating the inflammatory response in bone healing by targeting macrophages and bone marrow mesenchymal stem cells crosstalk are also discussed.
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Affiliation(s)
- Siyu Fan
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xin Sun
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Chuanchao Su
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Yiwen Xue
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xiao Song
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Runzhi Deng
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
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20
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Irfan D, Ahmad I, Patra I, Margiana R, Rasulova MT, Sivaraman R, Kandeel M, Mohammad HJ, Al-Qaim ZH, Jawad MA, Mustafa YF, Ansari MJ. Stem cell-derived exosomes in bone healing: focusing on their role in angiogenesis. Cytotherapy 2023; 25:353-361. [PMID: 36241491 DOI: 10.1016/j.jcyt.2022.08.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 12/12/2022]
Abstract
Fractures in bone, a tissue critical in protecting other organs, affect patients' quality of life and have a heavy economic burden on societies. Based on regenerative medicine and bone tissue engineering approaches, stem cells have become a promising and attractive strategy for repairing bone fractures via differentiation into bone-forming cells and production of favorable mediators. Recent evidence suggests that stem cell-derived exosomes could mediate the therapeutic effects of their counterpart cells and provide a cell-free therapeutic strategy in bone repair. Since bone is a highly vascularized tissue, coupling angiogenesis and osteogenesis is critical in bone fracture healing; thus, developing therapeutic strategies to promote angiogenesis will facilitate bone regeneration and healing. To this end, stem cell-derived exosomes with angiogenic potency have been developed to improve fracture healing. This review summarizes the effects of stem cell-derived exosomes on the repair of bone tissue, focusing on the angiogenesis process.
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Affiliation(s)
- Daniyal Irfan
- School of Management, Guangzhou University, Guangzhou, China
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | | | - Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Depok, Indonesia; Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Depok, Indonesia; Dr Soetomo General Academic Hospital, Surabaya, Indonesia.
| | | | - R Sivaraman
- Department of Mathematics, Dwaraka Doss Goverdhan Doss Vaishnav College, University of Madras, Chennai, India
| | - Mahmoud Kandeel
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia; Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelshikh University, Kafrelshikh, Egypt.
| | | | | | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
| | - Mohammad Javed Ansari
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
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21
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Breulmann FL, Hatt LP, Schmitz B, Wehrle E, Richards RG, Della Bella E, Stoddart MJ. Prognostic and therapeutic potential of microRNAs for fracture healing processes and non-union fractures: A systematic review. Clin Transl Med 2023; 13:e1161. [PMID: 36629031 PMCID: PMC9832434 DOI: 10.1002/ctm2.1161] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Approximately 10% of all bone fractures result in delayed fracture healing or non-union; thus, the identification of biomarkers and prognostic factors is of great clinical interest. MicroRNAs (miRNAs) are known to be involved in the regulation of the bone healing process and may serve as functional markers for fracture healing. AIMS AND METHODS This systematic review aimed to identify common miRNAs involved in fracture healing or non-union fractures using a qualitative approach. A systematic literature search was performed with the keywords 'miRNA and fracture healing' and 'miRNA and non-union fracture'. Any original article investigating miRNAs in fracture healing or non-union fractures was screened. Eventually, 82 studies were included in the qualitative analysis for 'miRNA and fracture healing', while 19 were selected for the 'miRNA and fracture non-union' category. RESULTS AND CONCLUSIONS Out of 151 miRNAs, miR-21, miR-140 and miR-214 were the most investigated miRNAs in fracture healing in general. miR-31-5p, miR-221 and miR-451-5p were identified to be regulated specifically in non-union fractures. Large heterogeneity was detected between studies investigating the role of miRNAs in fracture healing or non-union in terms of patient population, sample types and models used. Nonetheless, our approach identified some miRNAs with the potential to serve as biomarkers for non-union fractures, including miR-31-5p, miR-221 and miR-451-5p. We provide a discussion of involved pathways and suggest on alignment of future research in the field.
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Affiliation(s)
- Franziska Lioba Breulmann
- AO Research Institute DavosDavos PlatzSwitzerland
- Department of Orthopedic Sports MedicineKlinikum Rechts der IsarTechnical University of MunichMunichGermany
| | - Luan Phelipe Hatt
- AO Research Institute DavosDavos PlatzSwitzerland
- Institute for BiomechanicsETH ZürichZurichSwitzerland
| | - Boris Schmitz
- Department of Rehabilitation SciencesFaculty of HealthUniversity of Witten/HerdeckeWittenGermany
- DRV Clinic KönigsfeldCenter for Medical RehabilitationEnnepetalGermany
| | - Esther Wehrle
- AO Research Institute DavosDavos PlatzSwitzerland
- Institute for BiomechanicsETH ZürichZurichSwitzerland
| | - Robert Geoff Richards
- AO Research Institute DavosDavos PlatzSwitzerland
- Faculty of MedicineMedical Center‐Albert‐Ludwigs‐University of FreiburgAlbert‐Ludwigs‐University of FreiburgFreiburgGermany
| | | | - Martin James Stoddart
- AO Research Institute DavosDavos PlatzSwitzerland
- Faculty of MedicineMedical Center‐Albert‐Ludwigs‐University of FreiburgAlbert‐Ludwigs‐University of FreiburgFreiburgGermany
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22
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Huyut Z, Bakan N, Yıldırım S, Akbay Hİ, Huyut MT, Ahlatçı A, Uçar B. Can zaprinast and avanafil induce the levels of angiogenesis, bone morphogenic protein 2, 4 and 7 in kidney of ovariectomised rats? Arch Physiol Biochem 2022; 128:945-950. [PMID: 32207349 DOI: 10.1080/13813455.2020.1740743] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE This study investigated effects of zaprinast and avanafil on angiogenesis, vascular endothelial growth factor (VEGF), bone morphogenic protein (BMP) 2, 4 and 7. METHODS Female rats were randomly divided into four groups (n = 6). Sham; abdomen was approximately 2 cm opened and closed. Ovariectomised (OVX); abdomen was opened 2 cm and the ovaries were cut. OVX + zaprinast and OVX + avanafil groups; after the same procedure with OVX, 10 mg/kg zaprinast and avanafil were orally administered for 2 month, respectively. Angiogenesis and the levels of VEGF, BMP2, 4 and 7 were determined. RESULTS VEGF, BMP2, 4 and 7 levels in OVX + zaprinast and especially OVX + avanafil groups were higher than the sham and OVX (p < .05). However, only VEGF and BMP2 levels in OVX + zaprinast group were significant according to sham (p < .05). Also, angiogenesis in OVX + zaprinast and OVX + avanafil groups was dominant according to sham and OVX (p < .05). CONCLUSIONS Zaprinast and avanafil induced BMP2, 4 and 7 levels synergistically with increased VEGF and angiogenesis in renal tissue.
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Affiliation(s)
- Zübeyir Huyut
- Department of Biochemistry, Medical Faculty, Van Yuzuncu Yıl University, Van, Turkey
| | - Nuri Bakan
- Department of Biochemistry, Medical Faculty, Ataturk University, Erzurum, Turkey
| | - Serkan Yıldırım
- Department of Pathology, Faculty of Veterinary, Ataturk University, Erzurum, Turkey
| | - Halil İbrahim Akbay
- Department of Biochemistry, Medical Faculty, Van Yuzuncu Yıl University, Van, Turkey
| | - Mehmet Tahir Huyut
- Deparment of Biostatistics, Medical Faculty, Erzincan Binali Yıldırım University, Erzincan, Turkey
| | - Adem Ahlatçı
- Vocational School of Health Services, Van Yuzuncu Yıl University, Van, Turkey
| | - Bünyamin Uçar
- Department of Biochemistry, Medical Faculty, Van Yuzuncu Yıl University, Van, Turkey
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23
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Huyut Z, Alp HH, Bakan N, Yıldırım S, Şekeroğlu MR. Stimulating effects of vardenafil, tadalafil, and udenafil on vascular endothelial growth factor, angiogenesis, vitamin D 3, bone morphogenic proteins in ovariectomized rats. Arch Physiol Biochem 2022; 128:1121-1127. [PMID: 32314927 DOI: 10.1080/13813455.2020.1755695] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
OBJECTIVE This study investigated the effect of vardenafil, tadalafil, and udenafil from phosphodiesterase-5 inhibitors (PDE-5Is) on bone morphogenic-protein (BMP)2 and 4 levels, along with angiogenesis in ovariectomized rat's kidney. METHOD Rats were randomly divided into five groups (n = 10). Sham: abdomen was opened, and closed. OVX: ovaries were removed. OVX + vardenafil, OVX + tadalafil, and OVX + udenafil groups: ovaries were removed and closed, and after 6 months from postoperative, 10 mg/kg of vardenafil, tadalafil, and udenafil were administrated as daily a single-dose for 60 days, respectively. Histopathologic and immunohistochemical examinations were performed for angiogenesis, and biochemical analysis for vascular endothelial growth-factor (VEGF), VitaminD3, BMP2 and 4 levels in rat's kidney. RESULTS VEGF, BMP2 and 4, VitaminD3, and angiogenesis were high in the all inhibitor groups compared with the sham and OVX (p < .05). However, BMP4 levels were only high in the OVX + tadalafil group (p < .05). CONCLUSION The results indicated that vardenafil, udenafil, and especially tadalafil increased VEGF, BMP2, and VitaminD3 levels.
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Affiliation(s)
- Zübeyir Huyut
- Medical Faculty, Department of Biochemistry, Van Yuzuncu Yıl University, Van, Turkey
| | - Hamit Hakan Alp
- Medical Faculty, Department of Biochemistry, Van Yuzuncu Yıl University, Van, Turkey
| | - Nuri Bakan
- Medical Faculty, Department of Biochemistry, Ataturk University, Erzurum, Turkey
| | - Serkan Yıldırım
- Faculty of Veterinary, Department of Pathology, Ataturk University, Erzurum, Turkey
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Menger MM, Laschke MW, Nussler AK, Menger MD, Histing T. The vascularization paradox of non-union formation. Angiogenesis 2022; 25:279-290. [PMID: 35165821 PMCID: PMC9249698 DOI: 10.1007/s10456-022-09832-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 11/21/2021] [Indexed: 01/01/2023]
Abstract
Despite major research efforts to elucidate mechanisms of non-union formation, failed fracture healing remains a common complication in orthopedic surgery. Adequate vascularization has been recognized as a crucial factor for successful bone regeneration, as newly formed microvessels guarantee the supply of the callus tissue with vital oxygen, nutrients, and growth factors. Accordingly, a vast number of preclinical studies have focused on the development of vascularization strategies to stimulate fracture repair. However, recent evidence suggests that stimulation of blood vessel formation is an oversimplified approach to support bone regeneration. This review discusses the role of vascularization during bone regeneration and delineates a phenomenon, for which we coin the term "the vascularization paradox of non-union-formation". This view is based on the results of a variety of experimental studies that suggest that the callus tissue of non-unions is indeed densely vascularized and that pro-angiogenic mediators, such as vascular endothelial growth factor, are sufficiently expressed at the facture site. By gaining further insights into the molecular and cellular basis of non-union vascularization, it may be possible to develop more optimized treatment approaches or even prevent the non-union formation in the future.
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Affiliation(s)
- Maximilian M Menger
- Department of Trauma and Reconstructive Surgery, BG Trauma Center Tuebingen, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany.
- Institute for Clinical & Experimental Surgery, Saarland University, 66421, Homburg/Saar, Germany.
| | - Matthias W Laschke
- Institute for Clinical & Experimental Surgery, Saarland University, 66421, Homburg/Saar, Germany
| | - Andreas K Nussler
- Department of Trauma and Reconstructive Surgery, BG Trauma Center Tuebingen, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany
- Department of Trauma and Reconstructive Surgery, BG Trauma Center Tuebingen, Siegfried Weller Institute for Trauma Research, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany
| | - Michael D Menger
- Institute for Clinical & Experimental Surgery, Saarland University, 66421, Homburg/Saar, Germany
| | - Tina Histing
- Department of Trauma and Reconstructive Surgery, BG Trauma Center Tuebingen, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany
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Rodrigues BM, Mathias LS, Deprá IDC, Cury SS, de Oliveira M, Olimpio RMC, De Sibio MT, Gonçalves BM, Nogueira CR. Effects of Triiodothyronine on Human Osteoblast-Like Cells: Novel Insights From a Global Transcriptome Analysis. Front Cell Dev Biol 2022; 10:886136. [PMID: 35784485 PMCID: PMC9248766 DOI: 10.3389/fcell.2022.886136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/06/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Thyroid hormones play a significant role in bone development and maintenance, with triiodothyronine (T3) particularly being an important modulator of osteoblast differentiation, proliferation, and maintenance. However, details of the biological processes (BPs) and molecular pathways affected by T3 in osteoblasts remain unclear.Methods: To address this issue, primary cultures of human adipose-derived mesenchymal stem cells were subjected to our previously established osteoinduction protocol, and the resultant osteoblast-like cells were treated with 1 nm or 10 nm T3 for 72 h. RNA sequencing (RNA-Seq) was performed using the Illumina platform, and differentially expressed genes (DEGs) were identified from the raw data using Kallisto and DESeq2. Enrichment analysis of DEGs was performed against the Gene Ontology Consortium database for BP terms using the R package clusterProfiler and protein network analysis by STRING.Results: Approximately 16,300 genes were analyzed by RNA-Seq, with 343 DEGs regulated in the 1 nm T3 group and 467 upregulated in the 10 nm T3 group. Several independent BP terms related to bone metabolism were significantly enriched, with a number of genes shared among them (FGFR2, WNT5A, WNT3, ROR2, VEGFA, FBLN1, S1PR1, PRKCZ, TGFB3, and OSR1 for 1nM T3; and FZD1, SMAD6, NOG, NEO1, and ENG for 10 nm T3). An osteoblast-related search in the literature regarding this set of genes suggests that both T3 doses are unfavorable for osteoblast development, mainly hindering BMP and canonical and non-canonical WNT signaling.Conclusions: Therefore, this study provides new directions toward the elucidation of the mechanisms of T3 action on osteoblast metabolism, with potential future implications for the treatment of endocrine-related bone pathologies.
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Affiliation(s)
- Bruna Moretto Rodrigues
- Department of Internal Medicine, Medical School Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | - Lucas Solla Mathias
- Department of Internal Medicine, Medical School Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | - Igor de Carvalho Deprá
- Department of Internal Medicine, Medical School Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | - Sarah Santiloni Cury
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, Brazil
| | - Miriane de Oliveira
- Department of Internal Medicine, Medical School Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | | | - Maria Teresa De Sibio
- Department of Internal Medicine, Medical School Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | - Bianca Mariani Gonçalves
- Department of Internal Medicine, Medical School Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | - Célia Regina Nogueira
- Department of Internal Medicine, Medical School Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
- *Correspondence: Célia Regina Nogueira,
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26
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Sharma T, Kapoor A, Mandal CC. Duality of bone morphogenetic proteins in cancer: A comprehensive analysis. J Cell Physiol 2022; 237:3127-3163. [DOI: 10.1002/jcp.30785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/06/2022] [Accepted: 04/29/2022] [Indexed: 11/06/2022]
Affiliation(s)
- Tanu Sharma
- Department of Biochemistry, School of Life Sciences Central University of Rajasthan Ajmer Rajasthan India
| | - Anmol Kapoor
- Department of Biochemistry, School of Life Sciences Central University of Rajasthan Ajmer Rajasthan India
| | - Chandi C. Mandal
- Department of Biochemistry, School of Life Sciences Central University of Rajasthan Ajmer Rajasthan India
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Zhang CL, Song DJ, Zhang LD, Liu L, Zhu BL. Research on Mechanism of Nanometric Bone Pulp Activated with Double Gene as Bone Morphogenetic Protein 1 and Vascular Endothelial Growth Factor for Improving the Strength of Centrum in Osteoporosis. J Biomed Nanotechnol 2022; 18:1035-1043. [PMID: 35854465 DOI: 10.1166/jbn.2022.3312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The aim of this study was assessing the mechanism of nanometric bone pulp activated with double gene as bone morphogenetic protein 1 (BMP-1) and vascular endothelial growth factor (VEGF) in improving the strength of centrum in osteoporosis (OP). The model of nanometric bone pulp activated with BMP-1 and VEGF double gene was established and validated. Under maximum condition of load and collapsed fragments, the model was analyzed through biomechanical test. The conditions for ALP, BGP, MLL and BMD in the model were also analyzed, and three-dimensional structural transformation was analyzed. Western blot and qRT-PCR were used to detect the effect of adding or not adding dual gene activated nano-bone stickers on OC-specific protein and mRNA; ELISA kits were used to detect the changes of RANKL pathway RANKL, OPG and TRACP5b. The maximum conformed quality and condensed intensity were strengthened with the nanometric bone pulp activated with BMP-1 and VEGF double gene. The maximum load in centrum was extremely elevated in the model, and the condition of ALP and its effect on bone was partly improved in the model. The precision and efficiency in the quality of BMD were continuously decreased. The BMD and MLF were strengthened notably in the model, and their effect on the bone was extremely improved. There was tight displayed model of trabecular in centrum and porosity was also continuously reduced. After adding the double-gene activated nano-bone stickers, the results from qRTPCR and Western blot showed that the changes of osteoclast-related genes and protein expressions were significantly down-regulated. The nanometric bone pulp activated with BMP-1 and VEGF double gene was one of ideal filled criterion. The BMD and bone strength were also elevated.
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Affiliation(s)
- Cheng-Liang Zhang
- Department of Orthopedics, The Affiliated Shuyang Hospital of Xuzhou Medical University, Shuyang County, Jiangsu Province, 223600, China
| | - Da-Jiang Song
- Department of Orthopedics, The Affiliated Shuyang Hospital of Xuzhou Medical University, Shuyang County, Jiangsu Province, 223600, China
| | - Li-Dong Zhang
- Department of Orthopedics, The Affiliated Shuyang Hospital of Xuzhou Medical University, Shuyang County, Jiangsu Province, 223600, China
| | - Lei Liu
- Department of Orthopedics, The Affiliated Shuyang Hospital of Xuzhou Medical University, Shuyang County, Jiangsu Province, 223600, China
| | - Bao-Lin Zhu
- Department of Orthopedics, The Affiliated Shuyang Hospital of Xuzhou Medical University, Shuyang County, Jiangsu Province, 223600, China
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Lin Z, Zhang X, Fritch MR, Li Z, Kuang B, Alexander PG, Hao T, Cao G, Tan S, Bruce KK, Lin H. Engineering pre-vascularized bone-like tissue from human mesenchymal stem cells through simulating endochondral ossification. Biomaterials 2022; 283:121451. [DOI: 10.1016/j.biomaterials.2022.121451] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 01/28/2022] [Accepted: 02/27/2022] [Indexed: 01/12/2023]
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Bioactive gelatin cryogels with BMP‐2 biomimetic peptide and VEGF: A potential scaffold for synergistically induced osteogenesis. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2021.10.070] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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30
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Wu S, Chen Z, Yu X, Duan X, Chen J, Liu G, Gong M, Xing F, Sun J, Huang S, Zhou X. A sustained release of BMP2 in urine-derived stem cells enhances the osteogenic differentiation and the potential of bone regeneration. Regen Biomater 2022; 9:rbac015. [PMID: 35529046 PMCID: PMC9070791 DOI: 10.1093/rb/rbac015] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 01/25/2022] [Accepted: 01/30/2022] [Indexed: 02/05/2023] Open
Abstract
Cell-based tissue engineering is one of the optimistic approaches to replace current treatments for bone defects. Urine-derived stem cells (USCs) are obtained non-invasively and become one of the promising seed cells for bone regeneration. An injectable BMP2-releasing chitosan microspheres/type I collagen hydrogel (BMP2-CSM/Col I hydrogel) was fabricated. USCs proliferated in a time-dependent fashion, spread with good extension and interconnected with each other in different hydrogels both for 2D and 3D models. BMP2 was released in a sustained mode for more than 28 days. Sustained-released BMP2 increased the ALP activities and mineral depositions of USCs in 2D culture, and enhanced the expression of osteogenic genes and proteins in 3D culture. In vivo, the mixture of USCs and BMP2-CSM/Col I hydrogels effectively enhanced bone regeneration, and the ratio of new bone volume to total bone volume was 38% after 8 weeks of implantation. Our results suggested that BMP2-CSM/Col I hydrogels promoted osteogenic differentiation of USCs in 2D and 3D culture in vitro and USCs provided a promising cell source for bone tissue engineering in vivo. As such, USCs-seeded hydrogel scaffolds are regarded as an alternative approach in the repair of bone defects.
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Affiliation(s)
- Shuang Wu
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610000, China
| | - Zhao Chen
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610000, China
| | - Xi Yu
- Rehabilitation Medicine Center, West China Hospital, Sichuan University, Chengdu, 610000, China
| | - Xin Duan
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610000, China
| | - Jialei Chen
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610000, China
| | - Guoming Liu
- Department of Orthopedics, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Min Gong
- Department of Orthopedics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, China
| | - Fei Xing
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610000, China
| | - Jiachen Sun
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610000, China
| | - Shishu Huang
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610000, China
| | - Xiang Zhou
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610000, China
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31
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Guerrero J, Dasen B, Frismantiene A, Pigeot S, Ismail T, Schaefer DJ, Philippova M, Resink TJ, Martin I, Scherberich A. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:213-229. [PMID: 35259280 PMCID: PMC8929526 DOI: 10.1093/stcltm/szab021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 10/31/2021] [Indexed: 11/24/2022] Open
Abstract
Cells of the stromal vascular fraction (SVF) of human adipose tissue have the capacity to generate osteogenic grafts with intrinsic vasculogenic properties. However, cultured adipose-derived stromal cells (ASCs), even after minimal monolayer expansion, lose osteogenic capacity in vivo. Communication between endothelial and stromal/mesenchymal cell lineages has been suggested to improve bone formation and vascularization by engineered tissues. Here, we investigated the specific role of a subpopulation of SVF cells positive for T-cadherin (T-cad), a putative endothelial marker. We found that maintenance during monolayer expansion of a T-cad-positive cell population, composed of endothelial lineage cells (ECs), is mandatory to preserve the osteogenic capacity of SVF cells in vivo and strongly supports their vasculogenic properties. Depletion of T-cad-positive cells from the SVF totally impaired bone formation in vivo and strongly reduced vascularization by SVF cells in association with decreased VEGF and Adiponectin expression. The osteogenic potential of T-cad-depleted SVF cells was fully rescued by co-culture with ECs from a human umbilical vein (HUVECs), constitutively expressing T-cad. Ectopic expression of T-cad in ASCs stimulated mineralization in vitro but failed to rescue osteogenic potential in vivo, indicating that the endothelial nature of the T-cad-positive cells is the key factor for induction of osteogenesis in engineered grafts based on SVF cells. This study demonstrates that crosstalk between stromal and T-cad expressing endothelial cells within adipose tissue critically regulates osteogenesis, with VEGF and adiponectin as associated molecular mediators.
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Affiliation(s)
- Julien Guerrero
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Boris Dasen
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Agne Frismantiene
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Sebastien Pigeot
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Tarek Ismail
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland
| | - Dirk J Schaefer
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland
| | - Maria Philippova
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Therese J Resink
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Ivan Martin
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Arnaud Scherberich
- Corresponding author: Arnaud Scherberich, Department of Biomedicine, Hebelstrasse 20, University Hospital Basel, 4031 Basel, Switzerland. Tel: +41 061 328 73 75;
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Wang Z, Liu Y, Zhang J, Lin M, Xiao C, Bai H, Liu C. Mechanical loading alleviated the inhibition of β2-adrenergic receptor agonist terbutaline on bone regeneration. FASEB J 2021; 35:e22033. [PMID: 34739146 DOI: 10.1096/fj.202101045rr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 10/19/2021] [Accepted: 10/22/2021] [Indexed: 12/14/2022]
Abstract
The long-term use of adrenergic medication in treating various conditions, such as asthma, increases the chances of bone fracture. Dynamic mechanical loading at a specific time is a method for improving bone quality and promoting healing. Therefore, we hypothesized that precisely controlling the mechanical environment can contribute to the alleviation of the negative effects of chronic treatment with the common asthma drug terbutaline, which is a β2-adrenergic receptor agonist that facilitates bone homeostasis and defect repair through its anabolic effect on osteogenic cells. Our in vitro results showed that terbutaline can directly inhibit osteogenesis by impairing osteogenic differentiation and mineralization. Chronic treatment in vivo was simulated by administering terbutaline to C57BL/6J mice for 4 weeks before bone defect surgery and mechanical loading. We utilized a stabilized tibial defect model, which allowed the application of anabolic mechanical loading. During homeostasis, chronic terbutaline treatment reduced the bone formation rate, the fracture toughness of long bones, and the concentrations of bone formation markers in the sera. During defect repair, terbutaline decreased the bone volume, type H vessel, and total blood vessel volume. Terbutaline treatment reduced the number of osteogenic cells. Periostin, which was secreted mainly by Prrx1+ osteoprogenitors and F4/80+ macrophages, was inhibited by treating the bone defect with terbutaline. Interestingly, controlled mechanical loading facilitated the recovery of bone volume and periostin expression and the number of osteogenic cells within the defect. In conclusion, mechanical loading can rescue negative effects on new bone accrual and repair induced by chronic terbutaline treatment.
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Affiliation(s)
- Ziyan Wang
- Department of Biomedical Engineering, College of Engineering, Southern University of Science and Technology, Shenzhen, China
| | - Yang Liu
- Department of Biomedical Engineering, College of Engineering, Southern University of Science and Technology, Shenzhen, China
| | - Jianing Zhang
- Department of Biomedical Engineering, College of Engineering, Southern University of Science and Technology, Shenzhen, China
| | - Minmin Lin
- Department of Biomedical Engineering, College of Engineering, Southern University of Science and Technology, Shenzhen, China
| | - Chufan Xiao
- Department of Biomedical Engineering, College of Engineering, Southern University of Science and Technology, Shenzhen, China
| | - Haoying Bai
- Department of Biomedical Engineering, College of Engineering, Southern University of Science and Technology, Shenzhen, China
| | - Chao Liu
- Department of Biomedical Engineering, College of Engineering, Southern University of Science and Technology, Shenzhen, China
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Zhu G, Zhang T, Chen M, Yao K, Huang X, Zhang B, Li Y, Liu J, Wang Y, Zhao Z. Bone physiological microenvironment and healing mechanism: Basis for future bone-tissue engineering scaffolds. Bioact Mater 2021; 6:4110-4140. [PMID: 33997497 PMCID: PMC8091181 DOI: 10.1016/j.bioactmat.2021.03.043] [Citation(s) in RCA: 206] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/19/2021] [Accepted: 03/28/2021] [Indexed: 02/06/2023] Open
Abstract
Bone-tissue defects affect millions of people worldwide. Despite being common treatment approaches, autologous and allogeneic bone grafting have not achieved the ideal therapeutic effect. This has prompted researchers to explore novel bone-regeneration methods. In recent decades, the development of bone tissue engineering (BTE) scaffolds has been leading the forefront of this field. As researchers have provided deep insights into bone physiology and the bone-healing mechanism, various biomimicking and bioinspired BTE scaffolds have been reported. Now it is necessary to review the progress of natural bone physiology and bone healing mechanism, which will provide more valuable enlightenments for researchers in this field. This work details the physiological microenvironment of the natural bone tissue, bone-healing process, and various biomolecules involved therein. Next, according to the bone physiological microenvironment and the delivery of bioactive factors based on the bone-healing mechanism, it elaborates the biomimetic design of a scaffold, highlighting the designing of BTE scaffolds according to bone biology and providing the rationale for designing next-generation BTE scaffolds that conform to natural bone healing and regeneration.
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Affiliation(s)
- Guanyin Zhu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Tianxu Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Miao Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Ke Yao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Xinqi Huang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Bo Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Yazhen Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Jun Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Yunbing Wang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610041, PR China
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
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Dong H, Zhu T, Zhang M, Wang D, Wang X, Huang G, Wang S, Zhang M. Polymer Scaffolds-Enhanced Bone Regeneration in Osteonecrosis Therapy. Front Bioeng Biotechnol 2021; 9:761302. [PMID: 34631688 PMCID: PMC8498195 DOI: 10.3389/fbioe.2021.761302] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 09/09/2021] [Indexed: 12/12/2022] Open
Abstract
Osteonecrosis without effective early treatment eventually leads to the collapse of the articular surface and causes arthritis. For the early stages of osteonecrosis, core decompression combined with bone grafting, is a procedure worthy of attention and clinical trial. And the study of bone graft substitutes has become a hot topic in the area of osteonecrosis research. In recent years, polymers have received more attention than other materials due to their excellent performance. However, because of the harsh microenvironment in osteonecrosis, pure polymers may not meet the stringent requirements of osteonecrosis research. The combined application of polymers and various other substances makes up for the shortcomings of polymers, and to meet a broad range of requirements for application in osteonecrosis therapy. This review focuses on various applying polymers in osteonecrosis therapy, then discusses the development of biofunctionalized composite polymers based on the polymers combined with different bioactive substances. At the end, we discuss their prospects for translation to clinical practice.
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Affiliation(s)
- Hengliang Dong
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Tongtong Zhu
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Mingran Zhang
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Dapeng Wang
- Department of Orthopedics, Siping Central Hospital, Siping, China
| | - Xukai Wang
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Guanning Huang
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Shuaishuai Wang
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Minglei Zhang
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
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Redenski I, Guo S, Machour M, Szklanny A, Landau S, Kaplan B, Lock RI, Gabet Y, Egozi D, Vunjak‐Novakovic G, Levenberg S. Engineered Vascularized Flaps, Composed of Polymeric Soft Tissue and Live Bone, Repair Complex Tibial Defects. ADVANCED FUNCTIONAL MATERIALS 2021; 31:2008687. [DOI: 10.1002/adfm.202008687] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Indexed: 02/05/2023]
Affiliation(s)
- Idan Redenski
- Department of Biomedical Engineering Technion—Israel Institute of Technology Haifa 32000 Israel
| | - Shaowei Guo
- Department of Biomedical Engineering Technion—Israel Institute of Technology Haifa 32000 Israel
- The First Affiliated Hospital Shantou University Medical College Shantou 515000 China
| | - Majd Machour
- Department of Biomedical Engineering Technion—Israel Institute of Technology Haifa 32000 Israel
| | - Ariel Szklanny
- Department of Biomedical Engineering Technion—Israel Institute of Technology Haifa 32000 Israel
| | - Shira Landau
- Department of Biomedical Engineering Technion—Israel Institute of Technology Haifa 32000 Israel
| | - Ben Kaplan
- Department of Biomedical Engineering Technion—Israel Institute of Technology Haifa 32000 Israel
| | - Roberta I. Lock
- Department of Biomedical Engineering Columbia University New York NY 10032 USA
| | - Yankel Gabet
- Department of Anatomy and Anthropology Sackler Faculty of Medicine Tel‐Aviv University Tel‐Aviv 6997801 Israel
| | - Dana Egozi
- Department of Plastic and Reconstructive Surgery Kaplan Hospital Rehovot and the Hebrew University Jerusalem 7661041 Israel
| | | | - Shulamit Levenberg
- Department of Biomedical Engineering Technion—Israel Institute of Technology Haifa 32000 Israel
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Singh R, Bhalla AS, Manchanda S, Roychoudhury A. Multidetector computed tomography in preoperative planning for temporomandibular joint ankylosis: A pictorial review and proposed structured reporting format. Imaging Sci Dent 2021; 51:313-321. [PMID: 34621659 PMCID: PMC8479430 DOI: 10.5624/isd.20210027] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 04/18/2021] [Accepted: 04/21/2021] [Indexed: 11/25/2022] Open
Abstract
Ankylosis of the temporomandibular joint (TMJ) is a disabling disease resulting from fibrous or bony fusion of the mandibular condyle and the glenoid fossa. Early diagnosis and surgical treatment are essential to prevent facial deformity and other complications. Conventional radiography has limitations in demonstrating the true extent of ankylosis. It is important for surgeons to be aware of the size and degree of bony ankylosis in order to perform complete resection of the ankylotic mass. In addition, a detailed evaluation of the relationship with adjacent vital structures such as the internal maxillary artery, inferior alveolar nerve canal, external auditory canal, and skull base are crucial to avoid iatrogenic injury. Multidetector computed tomography (MDCT) is the current imaging modality of choice for preoperative assessments. Herein, the authors propose a structured CT reporting template for TMJ ankylosis to strengthen the value of the preoperative imaging report and to reduce the rates of intraoperative complications and recurrence.
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Affiliation(s)
- Rashmi Singh
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Ashu Seith Bhalla
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Smita Manchanda
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Ajoy Roychoudhury
- Department of Oral and Maxillofacial Surgery, All India Institute of Medical Sciences, New Delhi, India
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Datta S, Rameshbabu AP, Bankoti K, Jana S, Roy S, Sen R, Dhara S. Microsphere embedded hydrogel construct - binary delivery of alendronate and BMP-2 for superior bone regeneration. J Mater Chem B 2021; 9:6856-6869. [PMID: 34396378 DOI: 10.1039/d1tb00255d] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Biomimetic delivery of osteoinductive growth factors via an osteoconductive matrix is an interesting approach for stimulating bone regeneration. In this context, the bone extracellular matrix (ECM) has been explored as an optimal delivery system, since it releases growth factors in a spatiotemporal manner from the matrix. However, a bone ECM hydrogel alone is weak, unstable, and prone to microbial contamination and also has been reported to have significantly reduced bone morphogenic protein-2 (BMP-2) post decellularization. In the present work, a microsphere embedded osteoinductive decellularized bone ECM/oleoyl chitosan based hydrogel construct (BOC) was developed as a matrix allowing dual delivery of an anti-resorptive drug (alendronate, ALN, via the microspheres) and BMP-2 (via the hydrogel) for a focal tibial defect in a rabbit model. The synthesized gelatin microspheres (GMs) were spherical in shape with diameter ∼32 μm as assessed by SEM analysis. The BOC construct showed sustained release of ALN and BMP-2 under the studied conditions. Interestingly, amniotic membrane-derived stem cells (HAMSCs) cultivated on the hydrogel construct demonstrated excellent biocompatibility, cell viability, and active proliferation potential. Additionally, cell differentiation on the constructs showed an elevated expression of osteogenic genes in an RT-PCR study along with enhanced mineralized matrix deposition as demonstrated by alkaline phosphatase (ALP) assay and alizarin red assay. The hydrogel construct was witnessed to have improved neo-vascularization potential in a chick chorioalantoic membrane (CAM) assay. Also, histological and computed tomographic findings evidenced enhanced bone regeneration in the group treated with the BOC/ALN/BMP hydrogel construct in a rabbit tibial defect model. To conclude, the developed multifunctional hydrogel construct acts as an osteoinductive and osteoconductive platform facilitating controlled delivery of ALN and BMP-2, essential for stimulating bone tissue regeneration.
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Affiliation(s)
- Sayanti Datta
- Biomaterials and Tissue Engineering Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur - 721302, India.
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Kauffmann P, Raschke D, Tröltzsch M, Santander P, Brockmeyer P, Schliephake H. The use of rhBMP2 for augmentation of established horizontal/vertical defects may require additional use of rhVEGF to achieve significant bone regeneration: An in vivo experimental study. Clin Oral Implants Res 2021; 32:1228-1240. [PMID: 34352150 DOI: 10.1111/clr.13820] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 02/08/2021] [Accepted: 04/07/2021] [Indexed: 11/28/2022]
Abstract
AIM To test the hypothesis that the use of rhBMP2 in established defects requires additional growth factors such as rhVEGF to accomplish effective bone repair. MATERIALS AND METHODS Horizontal/vertical defects of 2 cm length and 1 cm height were created bilaterally in the alveolar crest of the maxillae of 18 minipigs together with the extraction of all premolar teeth and one molar tooth on both sides. After 3 months of healing, defects were augmented with 0.5 g particulate PDLLA/CaCO3 composite loaded with 400 µg rhBMP2/50 µg rhVEGF165 on one side and 800 µg rhBMP2 on the other in 12 test animals, whereas defects in six control animals were sham operated and left unfilled on one side and augmented with blank carriers on the other. After 4 and 13 weeks, the animals were evaluated each for area of new bone formation (mm²) and bone density (area %). RESULTS Augmentations with carriers loaded with 800 g µrhBMP2 failed to induce significantly more bone than in the augmentations with unloaded carrier after 4 and 13 weeks (p = .1000, p = .381). Augmentations with carriers loaded with 400 µg rhBMP2 and 50 µg erhVEGF165 resulted in significantly increased bone formation after 13 weeks (p = .024) compared to blank carriers. Soft tissue in augmentations with combined rhBMP2/rhVEGF165 loading exhibited numerous microvessels compared to soft tissue in augmentations with rhBMP2. CONCLUSIONS It is concluded that effective bone regeneration in augmentations of established alveolar ridge defects may require the application of rhVEGF additionally to rhBMP2.
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Affiliation(s)
- Philipp Kauffmann
- Department for Oral & Maxillofacial Surgery, Universitätsmedizin Goettingen, Goettingen, Germany
| | - David Raschke
- Department for Oral & Maxillofacial Surgery, Universitätsmedizin Goettingen, Goettingen, Germany
| | - Markus Tröltzsch
- Private Office Ansbach, Germany & Department for Oral & Maxillofacial Surgery, Universitätsmedizin Goettingen, Goettingen, Germany
| | - Petra Santander
- Department of Orthodontics, Universitätsmedizin Göttingen, Goettingen, Germany
| | - Phillip Brockmeyer
- Department for Oral & Maxillofacial Surgery, Universitätsmedizin Goettingen, Goettingen, Germany
| | - Henning Schliephake
- Department for Oral & Maxillofacial Surgery, Universitätsmedizin Goettingen, Goettingen, Germany
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Macías I, Alcorta-Sevillano N, Infante A, Rodríguez CI. Cutting Edge Endogenous Promoting and Exogenous Driven Strategies for Bone Regeneration. Int J Mol Sci 2021; 22:7724. [PMID: 34299344 PMCID: PMC8306037 DOI: 10.3390/ijms22147724] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 12/11/2022] Open
Abstract
Bone damage leading to bone loss can arise from a wide range of causes, including those intrinsic to individuals such as infections or diseases with metabolic (diabetes), genetic (osteogenesis imperfecta), and/or age-related (osteoporosis) etiology, or extrinsic ones coming from external insults such as trauma or surgery. Although bone tissue has an intrinsic capacity of self-repair, large bone defects often require anabolic treatments targeting bone formation process and/or bone grafts, aiming to restore bone loss. The current bone surrogates used for clinical purposes are autologous, allogeneic, or xenogeneic bone grafts, which although effective imply a number of limitations: the need to remove bone from another location in the case of autologous transplants and the possibility of an immune rejection when using allogeneic or xenogeneic grafts. To overcome these limitations, cutting edge therapies for skeletal regeneration of bone defects are currently under extensive research with promising results; such as those boosting endogenous bone regeneration, by the stimulation of host cells, or the ones driven exogenously with scaffolds, biomolecules, and mesenchymal stem cells as key players of bone healing process.
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Affiliation(s)
- Iratxe Macías
- Stem Cells and Cell Therapy Laboratory, BioCruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain; (I.M.); (N.A.-S.)
| | - Natividad Alcorta-Sevillano
- Stem Cells and Cell Therapy Laboratory, BioCruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain; (I.M.); (N.A.-S.)
- University of Basque Country UPV/EHU, 48940 Leioa, Spain
| | - Arantza Infante
- Stem Cells and Cell Therapy Laboratory, BioCruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain; (I.M.); (N.A.-S.)
| | - Clara I. Rodríguez
- Stem Cells and Cell Therapy Laboratory, BioCruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain; (I.M.); (N.A.-S.)
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Huang TY, Shahrousvand M, Hsu YT, Su WT. Polycaprolactone/Polyethylene Glycol Blended with Dipsacus asper Wall Extract Nanofibers Promote Osteogenic Differentiation of Periodontal Ligament Stem Cells. Polymers (Basel) 2021; 13:polym13142245. [PMID: 34301001 PMCID: PMC8309225 DOI: 10.3390/polym13142245] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/03/2021] [Accepted: 07/06/2021] [Indexed: 02/06/2023] Open
Abstract
Dipsacus asper wall (DA) is an ancient Chinese medicinal material that has long been used to maintain the health of human bones. The present study aimed to evaluate the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) of Dipsacus asper wall extracts (DAE). Microwave-assisted alcohol extraction of 100 mesh DA powder under optimal conditions can obtain 58.66% (w/w) yield of the crude extract. PDLSCs have excellent differentiation potential. PDLSCs treated with DA extract (DAE) underwent osteogenesis, exhibiting a higher expression of the Col-1, ALP, Runx2, and OCN genes, and had a 1.4-fold increase in mineralization, demonstrating the potential of DAE to promote osteogenic differentiation. After the addition of PI3K inhibitor LY294002, the expression of osteogenic genes was significantly inhibited, confirming that PI3K is an important pathway for DAE to induce osteogenesis. Mix DAE with polycaprolactone/polyethylene glycol (PCL/PEO) to obtain nanofibers with a diameter of 488 nm under optimal electrospinning conditions. The physical property analysis of nanofibers with and without DAE includes FTIR, mechanical strength, biodegradability, swelling ratio and porosity, and cell compatibility. When cells induced by nanofibers with or without DAE, the mineralization of PDLSCs cultured on PCL/PEO/DAE was 2.6-fold higher than that of PCL/PEO. The results of the study confirm that both DAE and PCL/PEO nanofibers have the effect of promoting osteogenic differentiation. In order to obtain the best induction effect, the optimal amount of DAE can be discussed in future research.
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Affiliation(s)
- Te-Yang Huang
- Department of Orthopedic Surgery, Mackay Memorial Hospital, Taipei 104217, Taiwan;
| | - Mohsen Shahrousvand
- Department of Caspian Faculty of Engineering, University of Tehran, Tehran 1417935840, Iran;
| | - Yu-Teng Hsu
- Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei 106344, Taiwan;
| | - Wen-Ta Su
- Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei 106344, Taiwan;
- Correspondence: ; Tel.: +886-2-27712171 (ext. 2554)
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Eriksson E, Björkenheim R, Strömberg G, Ainola M, Uppstu P, Aalto-Setälä L, Leino VM, Hupa L, Pajarinen J, Lindfors N. S53P4 bioactive glass scaffolds induce BMP expression and integrative bone formation in a critical-sized diaphysis defect treated with a single-staged induced membrane technique. Acta Biomater 2021; 126:463-476. [PMID: 33774197 DOI: 10.1016/j.actbio.2021.03.035] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/25/2021] [Accepted: 03/17/2021] [Indexed: 02/07/2023]
Abstract
Critical-sized diaphysis defects are complicated by inherent sub-optimal healing conditions. The two-staged induced membrane technique has been used to treat these challenging defects since the 1980's. It involves temporary implantation of a membrane-inducing spacer and subsequent bone graft defect filling. A single-staged, graft-independent technique would reduce both socio-economic costs and patient morbidity. Our aim was to enable such single-staged approach through development of a strong bioactive glass scaffold that could replace both the spacer and the graft filling. We constructed amorphous porous scaffolds of the clinically used bioactive glass S53P4 and evaluated them in vivo using a critical-sized defect model in the weight-bearing femur diaphysis of New Zealand White rabbits. S53P4 scaffolds and standard polymethylmethacrylate spacers were implanted for 2, 4, and 8 weeks. Induced membranes were confirmed histologically, and their osteostimulative activity was evaluated through RT-qPCR of bone morphogenic protein 2, 4, and 7 (BMPs). Bone formation and osseointegration were examined using histology, scanning electron microscopy, energy-dispersive X-ray analysis, and micro-computed tomography imaging. Scaffold integration, defect union and osteosynthesis were assessed manually and with X-ray projections. We demonstrated that S53P4 scaffolds induce osteostimulative membranes and produce osseointegrative new bone formation throughout the scaffolds. We also demonstrated successful stable scaffold integration with early defect union at 8 weeks postoperative in critical-sized segmental diaphyseal defects with implanted sintered amorphous S53P4 scaffolds. This study presents important considerations for future research and the potential of the S53P4 bioactive glass as a bone substitute in large diaphyseal defects. STATEMENT OF SIGNIFICANCE: Surgical management of critical-sized diaphyseal defects involves multiple challenges, and up to 10% result in delayed or non-union. The two-staged induced membrane technique is successfully used to treat these defects, but it is limited by the need of several procedures and bone graft. Repeated procedures increase costs and morbidity, while grafts are subject to donor-site complications and scarce availability. To transform this two-staged technique into one graft-independent procedure, we developed amorphous porous scaffolds sintered from the clinically used bioactive glass S53P4. This work constitutes the first evaluation of such scaffolds in vivo in a critical-sized diaphyseal defect in the weight-bearing rabbit femur. We provide important knowledge and prospects for future development of sintered S53P4 scaffolds as a bone substitute.
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Novais A, Chatzopoulou E, Chaussain C, Gorin C. The Potential of FGF-2 in Craniofacial Bone Tissue Engineering: A Review. Cells 2021; 10:932. [PMID: 33920587 PMCID: PMC8073160 DOI: 10.3390/cells10040932] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/10/2021] [Accepted: 04/15/2021] [Indexed: 12/21/2022] Open
Abstract
Bone is a hard-vascularized tissue, which renews itself continuously to adapt to the mechanical and metabolic demands of the body. The craniofacial area is prone to trauma and pathologies that often result in large bone damage, these leading to both aesthetic and functional complications for patients. The "gold standard" for treating these large defects is autologous bone grafting, which has some drawbacks including the requirement for a second surgical site with quantity of bone limitations, pain and other surgical complications. Indeed, tissue engineering combining a biomaterial with the appropriate cells and molecules of interest would allow a new therapeutic approach to treat large bone defects while avoiding complications associated with a second surgical site. This review first outlines the current knowledge of bone remodeling and the different signaling pathways involved seeking to improve our understanding of the roles of each to be able to stimulate or inhibit them. Secondly, it highlights the interesting characteristics of one growth factor in particular, FGF-2, and its role in bone homeostasis, before then analyzing its potential usefulness in craniofacial bone tissue engineering because of its proliferative, pro-angiogenic and pro-osteogenic effects depending on its spatial-temporal use, dose and mode of administration.
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Affiliation(s)
- Anita Novais
- Pathologies, Imagerie et Biothérapies Orofaciales, Université de Paris, URP2496, 1 rue Maurice Arnoux, 92120 Montrouge, France; (A.N.); (E.C.); (C.C.)
- AP-HP Département d’Odontologie, Services d’odontologie, GH Pitié Salpêtrière, Henri Mondor, Paris Nord, Hôpital Rothschild, Paris, France
| | - Eirini Chatzopoulou
- Pathologies, Imagerie et Biothérapies Orofaciales, Université de Paris, URP2496, 1 rue Maurice Arnoux, 92120 Montrouge, France; (A.N.); (E.C.); (C.C.)
- AP-HP Département d’Odontologie, Services d’odontologie, GH Pitié Salpêtrière, Henri Mondor, Paris Nord, Hôpital Rothschild, Paris, France
- Département de Parodontologie, Université de Paris, UFR Odontologie-Garancière, 75006 Paris, France
| | - Catherine Chaussain
- Pathologies, Imagerie et Biothérapies Orofaciales, Université de Paris, URP2496, 1 rue Maurice Arnoux, 92120 Montrouge, France; (A.N.); (E.C.); (C.C.)
- AP-HP Département d’Odontologie, Services d’odontologie, GH Pitié Salpêtrière, Henri Mondor, Paris Nord, Hôpital Rothschild, Paris, France
| | - Caroline Gorin
- Pathologies, Imagerie et Biothérapies Orofaciales, Université de Paris, URP2496, 1 rue Maurice Arnoux, 92120 Montrouge, France; (A.N.); (E.C.); (C.C.)
- AP-HP Département d’Odontologie, Services d’odontologie, GH Pitié Salpêtrière, Henri Mondor, Paris Nord, Hôpital Rothschild, Paris, France
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Kim J, Lee G, Chang WS, Ki SH, Park JC. Comparison and Contrast of Bone and Dentin in Genetic Disorder, Morphology and Regeneration: A Review. J Bone Metab 2021; 28:1-10. [PMID: 33730779 PMCID: PMC7973397 DOI: 10.11005/jbm.2021.28.1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 12/18/2020] [Indexed: 01/08/2023] Open
Abstract
The bone and dentin have distinct healing processes. The healing process of bones is regenerative, as newly formed tissues are morphologically and functionally similar to the original bone structures. In contrast, the healing process of dentin is reparative due to its failure to replicate some of its key morphological features. In this review, we compare and contrast the healing processes of bone and dentin. We describe how distinct morphological and physiological structures of the 2 tissues translate into different signaling molecules, growth factors, and matrix protein secretion.
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Affiliation(s)
- Jaehyun Kim
- College of Dental Medicine, Columbia University, New York, USA
| | - Gayeong Lee
- College of Dental Medicine, Columbia University, New York, USA
| | - Woo Sung Chang
- College of Dental Medicine, Columbia University, New York, USA
| | - Si Hyoung Ki
- Laboratory for the Study of Regenerative Dental Medicine, Department of Oral Histology-Developmental Biology & Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea
| | - Joo-Cheol Park
- Laboratory for the Study of Regenerative Dental Medicine, Department of Oral Histology-Developmental Biology & Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea
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44
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Passos LSA, Nunes MCP, Aikawa E. Rheumatic Heart Valve Disease Pathophysiology and Underlying Mechanisms. Front Cardiovasc Med 2021; 7:612716. [PMID: 33537348 PMCID: PMC7848031 DOI: 10.3389/fcvm.2020.612716] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 12/21/2020] [Indexed: 12/27/2022] Open
Abstract
Rheumatic heart valve disease (RHVD) is a post-infectious sequel of acute rheumatic fever resulting from an abnormal immune response to a streptococcal pharyngitis that triggers valvular damage. RHVD is the leading cause of cardiovascular death in children and young adults, mainly in women from low and middle-income countries. It is known that long-term inflammation and high degree of fibrosis leads to valve dysfunction due to anatomic disruption of the valve apparatus. However, since public and private investments in RHVD studies are practically inexistent the number of publications is scarce. This disease shows different natural history and clinical presentations as compared to other degenerative heart valve diseases. Although more than five decades passed after the pioneering studies on the pathogenesis of RHVD, it is still unclear how self-tolerance mechanisms fail in this disease, and how humoral and cellular inflammatory responses are interconnected. Despite that pathological mechanisms have been already proposed for RHVD, none of them are able to explain the preferential involvement of the mitral valve. This review focuses on pathophysiology and underlying mechanisms of RHVD.
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Affiliation(s)
- Livia S A Passos
- The Center for Excellence in Vascular Biology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States
| | - Maria Carmo P Nunes
- Hospital das Clínicas e Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Elena Aikawa
- The Center for Excellence in Vascular Biology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States.,Department of Human Pathology, Sechenov First Moscow State Medical University, Moscow, Russia
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45
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Alekseeva LI, Byalovsky YY, Zagorodny NV, Ivanova GE, Karateev DE, Konchugova TV, Rakitina IS, Strakhov MA. [Pathophysiological mechanisms of the therapeutic action of alternating electromagnetic fields in the treatment of osteoarticular pathology]. VOPROSY KURORTOLOGII, FIZIOTERAPII, I LECHEBNOI FIZICHESKOI KULTURY 2021; 98:80-90. [PMID: 34223758 DOI: 10.17116/kurort20219803180] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Treatment of osteoarticular pathology with an alternating electromagnetic field (AEMF) is used today as a promising, non-invasive and safe strategy of physiotherapy. It has been shown that the action of alternating electromagnetic fields on the musculoskeletal system triggers signaling cascades that effectively contribute to the restoration of bone and articular tissue. The pathophysiological mechanisms underlying the cellular and subcellular effects of stimulation by an alternating electromagnetic field during the restoration of bone and articular tissue are considered. It was pointed out the several key signaling pathways involved in the restoration of bone and articular tissue under the influence of electromagnetic fields with an analysis of the potential for therapeutic application of electromagnetic fields alone or in combination with other available therapies.
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Affiliation(s)
- L I Alekseeva
- V.A. Nasonova Research Institute of Rheumatology, Moscow, Russia
| | | | - N V Zagorodny
- N.N. Priorov Central Research Institute of Traumatology and Orthopedics, Moscow, Russia
| | - G E Ivanova
- N.I. Pirogov Russian National Research Medical University, Moscow, Russia
| | - D E Karateev
- M.F. Vladimirsky Moscow Regional Research and Clinical Institute, Moscow, Russia
| | - T V Konchugova
- National Medical Research Center for Rehabilitation and Balneology, Moscow, Russia
- I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | | | - M A Strakhov
- N.I. Pirogov Russian National Research Medical University, Moscow, Russia
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46
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Damia C, Magnaudeix A, Laverdet B. Chemical Functionalization of Calcium Phosphate Bioceramic Surfaces. ENCYCLOPEDIA OF MATERIALS: TECHNICAL CERAMICS AND GLASSES 2021:716-731. [DOI: 10.1016/b978-0-12-803581-8.12108-3] [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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Abstract
This chapter provides an overview of the growth factors active in bone regeneration and healing. Both normal and impaired bone healing are discussed, with a focus on the spatiotemporal activity of the various growth factors known to be involved in the healing response. The review highlights the activities of most important growth factors impacting bone regeneration, with a particular emphasis on those being pursued for clinical translation or which have already been marketed as components of bone regenerative materials. Current approaches the use of bone grafts in clinical settings of bone repair (including bone grafts) are summarized, and carrier systems (scaffolds) for bone tissue engineering via localized growth factor delivery are reviewed. The chapter concludes with a consideration of how bone repair might be improved in the future.
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48
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Cohen DJ, Ferrara L, Stone MB, Schwartz Z, Boyan BD. Cell and Tissue Response to Polyethylene Terephthalate Mesh Containing Bone Allograft in Vitro and in Vivo. Int J Spine Surg 2020; 14:S121-S132. [PMID: 33122180 PMCID: PMC7735465 DOI: 10.14444/7135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Extended polyethylene terephthalate mesh (PET, Dacron) can provide containment of compressed particulate allograft and autograft. This study assessed if PET mesh would interfere with osteoprogenitor cell migration from vertebral plates through particulate graft, and its effect on osteoblast differentiation or the quality of bone forming within fusing vertebra during vertebral interbody fusion. METHODS The impact of PET mesh on the biological response of normal human osteoblasts (NHOst cells) and bone marrow stromal cells (MSCs) to particulate bone graft was examined in vitro. Cells were cultured on rat bone particles +/- mesh; proliferation and osteoblast differentiation were assessed. The interface between the vertebral endplate, PET mesh, and newly formed bone within consolidated allograft contained by mesh was examined in a sheep model via microradiographs, histology, and mechanical testing. RESULTS Growth on bone particles stimulated proliferation and early differentiation of NHOst cells and MSCs, but delayed terminal differentiation. This was not negatively impacted by mesh. New bone formation in vivo was not prevented by use of a PET mesh graft containment device. Fusion was improved in sites containing allograft/demineralized bone matrix (DBM) versus autograft and was further enhanced when stabilized using pedicle screws. Only sites treated with allograft/DBM+screws exhibited greater percent bone ingrowth versus discectomy or autograft. These results were mirrored biomechanically. CONCLUSIONS PET mesh does not negatively impact cell attachment to particulate bone graft, proliferation, or initial osteoblast differentiation. The results demonstrated that bone growth occurs from vertebral endplates into graft material within the PET mesh. This was enhanced by stabilization with pedicle screws leading to greater bone ingrowth and biomechanical stability across the fusion site. CLINICAL RELEVANCE The use of extended PET mesh allows containment of bone graft material during vertebral interbody fusion without inhibiting migration of osteoprogenitor cells from vertebral end plates in order to achieve fusion. LEVEL OF EVIDENCE 5.
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Affiliation(s)
- D Joshua Cohen
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia
| | - Lisa Ferrara
- OrthoKinetic Technologies, Southport, North Carolina
| | | | - Zvi Schwartz
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia
- Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Barbara D Boyan
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia
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Santos LF, Sofia Silva A, Mano JF. Complex-shaped magnetic 3D cell-based structures for tissue engineering. Acta Biomater 2020; 118:18-31. [PMID: 33039596 DOI: 10.1016/j.actbio.2020.10.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/02/2020] [Accepted: 10/06/2020] [Indexed: 12/21/2022]
Abstract
The use of cells as building blocks for tissue engineering purposes has been a matter of research in the recent years. Still, the fabrication of complex-shaped 3D-like constructs using living-based materials is hampered through the difficulty in recapitulating the mechanical properties of the native tissues. In an attempt to develop robust tissue-like constructs, it is herein proposed the fabrication of complex-shaped magnetic cell sheets (CSs) with improved mechanical properties for bone TE. Hence, magnetic CSs with versatile shapes and enhanced mechanical performance are fabricated using a pre-osteoblast cell line (MC3T3-E1) through an universal approach that relies on the design of the substrate, cell density and magnetic force. Results show that such magnetic CSs exhibit a Young's modulus similar to those encountered in the soft tissues. The construction of stratified CSs is also explored using MC3T3-E1 and adipose-derived stromal cells (ASCs). The role of the pre-osteoblast cell line on ASCs osteogenesis is herein investigated for the first time in layered scaffold-free structures. After 21 days, the level of osteogenic markers in the heterotypic CS (MC3T3-E1:ASCs) is significantly higher than in the homotypic one (ASCs:ASCs), even in the absence of osteogenic differentiation factors. These evidences open new prospects for the creation of mechanically robust, complex, higher-ordered and completely functional 3D cell-based materials that better resemble the native environment of in vivo tissues.
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Repair of Bone Defects With Endothelial Progenitor Cells and Bone Marrow-Derived Mesenchymal Stem Cells With Tissue-Engineered Bone in Rabbits. Ann Plast Surg 2020; 85:430-436. [PMID: 32931683 DOI: 10.1097/sap.0000000000002454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE This study aimed to investigate the repair of bone defects in rabbits with tissue-engineered bones using cocultured endothelial progenitor cells (EPCs) and bone marrow mesenchymal stem cells (BMSCs) as seeding cells. METHODS Endothelial progenitor cells and BMSCs were isolated and purified from the peripheral blood and bone marrow, respectively, of New Zealand rabbits. The third passage of BMSCs was cultured alone or with EPCs. Cells were characterized using specific markers and then seeded on partially deproteinized biologic bones from pigs as a scaffold. The engineered bones were used to repair bone defects in rabbits. Hematoxylin and eosin and Masson staining were performed to examine vascularization and osteogenesis in the engineered bone. RESULTS The cocultured EPCs and BMSCs grew well on the surface of the scaffold. Compared with monocultured BMSCs, cocultured EPCs and BMSCs promoted the formation of blood vessels and bone on the scaffold, in addition to accelerating the repair of bone defects. The collagen content was significantly increased in the scaffold with cocultured EPCs and BMSCs, compared with the scaffold seeded with mono-cultured BMSCs. CONCLUSIONS Tissue-engineered bones seeded with cocultured EPCs and BMSCs may be used effectively for the repair of bone defects.
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