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1
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Yang S, Xue B, Zhang Y, Wu H, Yu B, Li S, Ma T, Gao X, Hao Y, Guo L, Liu Q, Gao X, Yang Y, Wang Z, Qin M, Tian Y, Fu L, Zhou B, Li L, Li J, Gong S, Xia B, Huang J. Engineered Extracellular Vesicles from Antler Blastema Progenitor Cells: A Therapeutic Choice for Spinal Cord Injury. ACS NANO 2025; 19:5995-6013. [PMID: 39841785 PMCID: PMC11841045 DOI: 10.1021/acsnano.4c10298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 01/07/2025] [Accepted: 01/07/2025] [Indexed: 01/24/2025]
Abstract
Deer antler blastema progenitor cells (ABPCs) are promising for regenerative medicine due to their role in annual antler regeneration, the only case of complete organ regeneration in mammals. ABPC-derived signals show great potential for promoting regeneration in tissues with limited natural regenerative ability. Our findings demonstrate the capability of extracellular vesicles from ABPCs (EVsABPC) to repair spinal cord injury (SCI), a condition with low regenerative capacity. EVsABPC significantly enhanced the proliferation of neural stem cells (NSCs) and activated neuronal regenerative potential, resulting in a 5.2-fold increase in axonal length. Additionally, EVsABPC exhibited immunomodulatory effects, shifting macrophages from M1 to M2. Engineered with activated cell-penetrating peptides (ACPPs), EVsABPC significantly outperformed EVs from rat bone marrow stem cells (EVsBMSC) and neural stem cells (EVsNSC), promoting a 1.3-fold increase in axonal growth, a 30.6% reduction in neuronal apoptosis, and a 2.6-fold improvement in motor function recovery. These findings support ABPC-derived EVs as a promising therapeutic candidate for SCI repair.
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Affiliation(s)
- Shijie Yang
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
- Department
of Neurosurgery, The Second Affiliated Hospital
of Xi’an Jiao Tong University, Xi’an 710004, P.R. China
| | - Borui Xue
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
- Air
Force 986(th) Hospital, The Fourth Military
Medical University, Xi’an 710001, P.R. China
| | - Yongfeng Zhang
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
- Department
of Neurosurgery, The Second Affiliated Hospital
of Xi’an Jiao Tong University, Xi’an 710004, P.R. China
| | - Haining Wu
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
| | - Beibei Yu
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
- Department
of Neurosurgery, The Second Affiliated Hospital
of Xi’an Jiao Tong University, Xi’an 710004, P.R. China
| | - Shengyou Li
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
| | - Teng Ma
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
| | - Xue Gao
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
| | - Yiming Hao
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
| | - Lingli Guo
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
| | - Qi Liu
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
| | - Xueli Gao
- School
of
Ecology and Environment, Northwestern Polytechnical
University, Xi’an 710072, P.R. China
| | - Yujie Yang
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
| | - Zhenguo Wang
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
| | - Mingze Qin
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
| | - Yunze Tian
- Department
of Thoracic Surgery, Second Affiliated Hospital
of Xi’an Jiao Tong University, Xi’an 710004, P.R. China
| | - Longhui Fu
- Department
of Neurosurgery, The Second Affiliated Hospital
of Xi’an Jiao Tong University, Xi’an 710004, P.R. China
| | - Bisheng Zhou
- Department
of Neurosurgery, The Second Affiliated Hospital
of Xi’an Jiao Tong University, Xi’an 710004, P.R. China
| | - Luyao Li
- Department
of Neurosurgery, The Second Affiliated Hospital
of Xi’an Jiao Tong University, Xi’an 710004, P.R. China
| | - Jianzhong Li
- Department
of Thoracic Surgery, Second Affiliated Hospital
of Xi’an Jiao Tong University, Xi’an 710004, P.R. China
| | - Shouping Gong
- Department
of Neurosurgery, The Second Affiliated Hospital
of Xi’an Jiao Tong University, Xi’an 710004, P.R. China
- Xi’an
Medical University, Xi’an 710021, P.R. China
| | - Bing Xia
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
| | - Jinghui Huang
- Department
of Orthopaedics, Xijing Hospital, The Fourth
Military Medical University, Xi’an 710032, P.R. China
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Somasundaram S, D F, Genasan K, Kamarul T, Raghavendran HRB. Implications of Biomaterials and Adipose-Derived Stem Cells in the Management of Calvarial Bone Defects. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2024. [DOI: 10.1007/s40883-024-00358-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 08/25/2024] [Accepted: 09/13/2024] [Indexed: 01/03/2025]
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Chen CF, Chou YS, Lee TM, Fu YC, Ou SF, Chen SH, Lee TC, Wang YH. The Uniform Distribution of Hydroxyapatite in a Polyurethane Foam-Based Scaffold (PU/HAp) to Enhance Bone Repair in a Calvarial Defect Model. Int J Mol Sci 2024; 25:6440. [PMID: 38928145 PMCID: PMC11203484 DOI: 10.3390/ijms25126440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/03/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
Polyurethane (PU) is a promising material for addressing challenges in bone grafting. This study was designed to enhance the bone grafting capabilities of PU by integrating hydroxyapatite (HAp), which is known for its osteoconductive and osteoinductive potential. Moreover, a uniform distribution of HAp in the porous structure of PU increased the effectiveness of bone grafts. PEG/APTES-modified scaffolds were prepared through self-foaming reactions. A uniform pore structure was generated during the spontaneous foaming reaction, and HAp was uniformly distributed in the PU structure (PU15HAp and PU30HAp) during foaming. Compared with the PU scaffolds, the HAp-modified PU scaffolds exhibited significantly greater protein absorption. Importantly, the effect of the HAp-modified PU scaffold on bone repair was tested in a rat calvarial defect model. The microstructure of the newly formed bone was analyzed with microcomputed tomography (μ-CT). Bone regeneration at the defect site was significantly greater in the HAp-modified PU scaffold group than in the PU group. This innovative HAp-modified PU scaffold improves current bone graft materials, providing a promising avenue for improved bone regeneration.
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Affiliation(s)
- Chiu-Fang Chen
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan;
| | - Ya-Shuan Chou
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (Y.-S.C.); (T.-C.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Tzer-Min Lee
- Institute of Oral Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan;
- School of Dentistry, National Cheng Kung University, Tainan 701, Taiwan
| | - Yin-Chih Fu
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (Y.-S.C.); (T.-C.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80145, Taiwan
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Shih-Fu Ou
- Department of Mold and Die Engineering, National Kaohsiung University of Science and Technology, Kaohsiung 807, Taiwan;
| | - Szu-Hsien Chen
- Institute of Polymer Science and Engineering, College of Engineering, National Taiwan University, Taipei 106216, Taiwan;
| | - Tien-Ching Lee
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (Y.-S.C.); (T.-C.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80145, Taiwan
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Yan-Hsiung Wang
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan;
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (Y.-S.C.); (T.-C.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
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Dousti M, Golmohamadpour A, Hami Z, Jamalpoor Z. Ca-AlN MOFs-loaded chitosan/gelatin scaffolds; a dual-delivery system for bone tissue engineering applications. NANOTECHNOLOGY 2024; 35:145101. [PMID: 37992401 DOI: 10.1088/1361-6528/ad0ef4] [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: 05/09/2023] [Accepted: 11/22/2023] [Indexed: 11/24/2023]
Abstract
Creating a scaffold for bone tissue engineering that is bioactive and capable of acting as a local-dual delivery system, releasing bioactive molecules and regulating the bone remodeling process to achieve balanced bone resorption and formation, is a significant challenge. The objective of this research is to create a composite scaffold using chitosan/gelatin (CHS/Gel) and the calcium (Ca)-alendronate (ALN) metal-organic frameworks (MOFs). The scaffold will act as a dual-delivery system, releasing Ca ions and ALN to regulate bone formation. Ca-ALN MOF nanoparticles (NPs) were prepared in mild conditions and studied by FTIR, XRD, FESEM, and TGA. Ca-ALN NPs-loaded CHS/Gel scaffolds were opportunely fabricated through freeze-drying approach. Physicochemical features of the scaffolds after incorporating NPs equated by CHS/Gel scaffold changed, therefore, the attendance of NPs caused a decreasing porosity, decreased swelling, and low rate of degradation. The release profile results showed that the NPs-loaded CHS/Gel scaffolds were able to simultaneously release ALN and Ca ions due to the decomposition of NPs. Additionally, the loading of NPs in the CHS/Gel scaffold led to an increment in alkaline phosphatase (ALP) activity and the quantity of deposited Ca along with osteogenesis gene markers. These findings suggest that the NPs-loaded CHS/Gel scaffold has the potential to enhance the differentiation of human adipose tissue-derived mesenchymal stem cells, making it a promising approach for bone repair.
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Affiliation(s)
- Mahdi Dousti
- Trauma and Surgery Research Center, Aja University of Medical Sciences, Tehran, Iran
| | | | - Zahra Hami
- Toxicology Research Center, Aja University of Medical Sciences, Tehran, Iran
| | - Zahra Jamalpoor
- Trauma and Surgery Research Center, Aja University of Medical Sciences, Tehran, Iran
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Zhang P, Qi J, Zhang R, Zhao Y, Yan J, Gong Y, Liu X, Zhang B, Wu X, Wu X, Zhang C, Zhao B, Li B. Recent advances in composite hydrogels: synthesis, classification, and application in the treatment of bone defects. Biomater Sci 2024; 12:308-329. [PMID: 38108454 DOI: 10.1039/d3bm01795h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Bone defects are often difficult to treat due to their complexity and specificity, and therefore pose a serious threat to human life and health. Currently, the clinical treatment of bone defects is mainly surgical. However, this treatment is often more harmful to patients and there is a potential risk of rejection and infection. Hydrogels have a unique three-dimensional structure that can accommodate a variety of materials, including particles, polymers and small molecules, making them ideal for treating bone defects. Therefore, emerging composite hydrogels are considered one of the most promising candidates for the treatment of bone defects. This review describes the use of different types of composite hydrogel in the treatment of bone defects. We present the basic concepts of hydrogels, different preparation techniques (including chemical and physical crosslinking), and the clinical requirements for hydrogels used to treat bone defects. In addition, a review of numerous promising designs of different types of hydrogel doped with different materials (e.g., nanoparticles, polymers, carbon materials, drugs, and active factors) is also highlighted. Finally, the current challenges and prospects of composite hydrogels for the treatment of bone defects are presented. This review will stimulate research efforts in this field and promote the application of new methods and innovative ideas in the clinical field of composite hydrogels.
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Affiliation(s)
- Pengfei Zhang
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, School and Hospital of Stomatology, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
| | - Jin Qi
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, School and Hospital of Stomatology, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
| | - Ran Zhang
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, School and Hospital of Stomatology, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
| | - Yifan Zhao
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, School and Hospital of Stomatology, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
| | - Jingyu Yan
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, School and Hospital of Stomatology, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
| | - Yajuan Gong
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, School and Hospital of Stomatology, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
| | - Xiaoming Liu
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, School and Hospital of Stomatology, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
| | - Binbin Zhang
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, School and Hospital of Stomatology, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
| | - Xiao Wu
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, School and Hospital of Stomatology, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
| | - Xiuping Wu
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, School and Hospital of Stomatology, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
| | - Cheng Zhang
- Jiangsu Key Laboratory of Micro and Nano Heat Fluid Flow Technology and Energy Application, School of Physical Science and Technology, Suzhou University of Science and Technology, Suzhou, Jiangsu 215009, China
| | - Bing Zhao
- Heilongjiang Provincial Key Laboratory of Surface Active Agent and Auxiliary, Chemistry and Chemical Engineering Institute, Qiqihar University, Qiqihar 161006, China
| | - Bing Li
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, School and Hospital of Stomatology, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
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Lee CY, Nedunchezian S, Lin SY, Su YF, Wu CW, Wu SC, Chen CH, Wang CK. Bilayer osteochondral graft in rabbit xenogeneic transplantation model comprising sintered 3D-printed bioceramic and human adipose-derived stem cells laden biohydrogel. J Biol Eng 2023; 17:74. [PMID: 38012588 PMCID: PMC10680339 DOI: 10.1186/s13036-023-00389-x] [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: 08/08/2023] [Accepted: 11/06/2023] [Indexed: 11/29/2023] Open
Abstract
Reconstruction of severe osteochondral defects in articular cartilage and subchondral trabecular bone remains a challenging problem. The well-integrated bilayer osteochondral graft design expects to be guided the chondrogenic and osteogenic differentiation for stem cells and provides a promising solution for osteochondral tissue repair in this study. The subchondral bone scaffold approach is based on the developed finer and denser 3D β-tricalcium phosphate (β-TCP) bioceramic scaffold process, which is made using a digital light processing (DLP) technology and the novel photocurable negative thermo-responsive (NTR) bioceramic slurry. Then, the concave-top disc sintered 3D-printed bioceramic incorporates the human adipose-derived stem cells (hADSCs) laden photo-cured hybrid biohydrogel (HG + 0.5AFnSi) comprised of hyaluronic acid methacryloyl (HAMA), gelatin methacryloyl (GelMA), and 0.5% (w/v) acrylate-functionalized nano-silica (AFnSi) crosslinker. The 3D β-TCP bioceramic compartment is used to provide essential mechanical support for cartilage regeneration in the long term and slow biodegradation. However, the apparent density and compressive strength of the 3D β-TCP bioceramics can be obtained for ~ 94.8% theoretical density and 11.38 ± 1.72 MPa, respectively. In addition, the in vivo results demonstrated that the hADSC + HG + 0.5AFnSi/3D β-TCP of the bilayer osteochondral graft showed a much better osteochondral defect repair outcome in a rabbit model. The other word, the subchondral bone scaffold of 3D β-TCP bioceramic could accelerate the bone formation and integration with the adjacent host cancellous tissue at 12 weeks after surgery. And then, a thicker cartilage layer with a smooth surface and uniformly aligned chondrocytes were observed by providing enough steady mechanical support of the 3D β-TCP bioceramic scaffold.
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Affiliation(s)
- Chih-Yun Lee
- Ph.D. Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Swathi Nedunchezian
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Sung-Yen Lin
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Departments of Orthopaedics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Department of Orthopaedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Department of Orthopaedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, 80145, Taiwan
| | - Yu-Feng Su
- Faculty of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80756, Taiwan
- Department of Surgery, Division of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Che-Wei Wu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Shun-Cheng Wu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Department of Nursing, Asia University, Taichung, 41354, Taiwan
| | - Chung-Hwan Chen
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Departments of Orthopaedics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Department of Orthopaedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Department of Orthopaedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, 80145, Taiwan
- Ph.D. Program in Biomedical Engineering, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Chih-Kuang Wang
- Ph.D. Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
- Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
- Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
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Zhang J, Bai H, Bai M, Wang X, Li Z, Xue H, Wang J, Cui Y, Wang H, Wang Y, Zhou R, Zhu X, Xu M, Zhao X, Liu H. Bisphosphonate-incorporated coatings for orthopedic implants functionalization. Mater Today Bio 2023; 22:100737. [PMID: 37576870 PMCID: PMC10413202 DOI: 10.1016/j.mtbio.2023.100737] [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: 03/20/2023] [Revised: 06/06/2023] [Accepted: 07/19/2023] [Indexed: 08/15/2023] Open
Abstract
Bisphosphonates (BPs), the stable analogs of pyrophosphate, are well-known inhibitors of osteoclastogenesis to prevent osteoporotic bone loss and improve implant osseointegration in patients suffering from osteoporosis. Compared to systemic administration, BPs-incorporated coatings enable the direct delivery of BPs to the local area, which will precisely enhance osseointegration and bone repair without the systemic side effects. However, an elaborate and comprehensive review of BP coatings of implants is lacking. Herein, the cellular level (e.g., osteoclasts, osteocytes, osteoblasts, osteoclast precursors, and bone mesenchymal stem cells) and molecular biological regulatory mechanism of BPs in regulating bone homeostasis are overviewed systematically. Moreover, the currently available methods (e.g., chemical reaction, porous carriers, and organic material films) of BP coatings construction are outlined and summarized in detail. As one of the key directions, the latest advances of BP-coated implants to enhance bone repair and osseointegration in basic experiments and clinical trials are presented and critically evaluated. Finally, the challenges and prospects of BP coatings are also purposed, and it will open a new chapter in clinical translation for BP-coated implants.
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Affiliation(s)
- Jiaxin Zhang
- Orthopedic Institute of Jilin Province, Orthopedic Medical Center, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Haotian Bai
- Orthopedic Institute of Jilin Province, Orthopedic Medical Center, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Miao Bai
- Department of Ocular Fundus Disease, Ophthalmology Center, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Xiaonan Wang
- Orthopedic Institute of Jilin Province, Orthopedic Medical Center, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - ZuHao Li
- Orthopedic Institute of Jilin Province, Orthopedic Medical Center, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Haowen Xue
- Orthopedic Institute of Jilin Province, Orthopedic Medical Center, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Jincheng Wang
- Orthopedic Institute of Jilin Province, Orthopedic Medical Center, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Yutao Cui
- Orthopedic Institute of Jilin Province, Orthopedic Medical Center, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Hui Wang
- Orthopedic Institute of Jilin Province, Orthopedic Medical Center, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Yanbing Wang
- Orthopedic Institute of Jilin Province, Orthopedic Medical Center, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Rongqi Zhou
- Orthopedic Institute of Jilin Province, Orthopedic Medical Center, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Xiujie Zhu
- Orthopedic Institute of Jilin Province, Orthopedic Medical Center, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Mingwei Xu
- Orthopedic Institute of Jilin Province, Orthopedic Medical Center, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Xin Zhao
- Orthopedic Institute of Jilin Province, Orthopedic Medical Center, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - He Liu
- Orthopedic Institute of Jilin Province, Orthopedic Medical Center, The Second Hospital of Jilin University, Changchun 130041, PR China
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Xu W, Yang Y, Li N, Hua J. Interaction between Mesenchymal Stem Cells and Immune Cells during Bone Injury Repair. Int J Mol Sci 2023; 24:14484. [PMID: 37833933 PMCID: PMC10572976 DOI: 10.3390/ijms241914484] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/13/2023] [Accepted: 09/19/2023] [Indexed: 10/15/2023] Open
Abstract
Fractures are the most common large organ trauma in humans. The initial inflammatory response promotes bone healing during the initial post-fracture phase, but chronic and persistent inflammation due to infection or other factors does not contribute to the healing process. The precise mechanisms by which immune cells and their cytokines are regulated in bone healing remain unclear. The use of mesenchymal stem cells (MSCs) for cellular therapy of bone injuries is a novel clinical treatment approach. Bone progenitor MSCs not only differentiate into bone, but also interact with the immune system to promote the healing process. We review in vitro and in vivo studies on the role of the immune system and bone marrow MSCs in bone healing and their interactions. A deeper understanding of this paradigm may provide clues to potential therapeutic targets in the healing process, thereby improving the reliability and safety of clinical applications of MSCs to promote bone healing.
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Affiliation(s)
| | | | - Na Li
- Shaanxi Centre of Stem Cells Engineering & Technology, College of Veterinary Medicine, Northwest A&F University, Yangling, Xianyang 712100, China; (W.X.); (Y.Y.)
| | - Jinlian Hua
- Shaanxi Centre of Stem Cells Engineering & Technology, College of Veterinary Medicine, Northwest A&F University, Yangling, Xianyang 712100, China; (W.X.); (Y.Y.)
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9
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Kim HS, Jang J, Oh JS, Lee EJ, Han CM, Shin US. Injectable remodeling hydrogels derived from alendronate-tethered alginate calcium complex for enhanced osteogenesis. Carbohydr Polym 2023; 303:120473. [PMID: 36657863 DOI: 10.1016/j.carbpol.2022.120473] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/28/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
A combination of hydrogel materials, and therapeutic agents have been actively reported to facilitate bone defect healing. However, conventionally hydrogels using cross-linker would result in low stability of the hydrogel itself, loss of agents during cross-linking, and complexity of use. In this study, alendronate was tethered to an AlA to improve its bone healing and drug-loading stability. AlA was further functionalized with Ca2+ (AlACa). A mixture of AlACa and alginate formed AlAA hydrogel. The gelation time of AlAA was sufficient for injecting into the defect site. The hydrogel stiffness was controlled, while the stress-relaxation time was fixed. In vitro cell tests demonstrated that the AlAA promoted proliferation and differentiation behaviors. In particular, AlAA showed the best mechanical stiffness with appropriate stress-relaxation and cellular behavior, indicating that it would be beneficial as a scaffold in the bone tissue engineering field.
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Affiliation(s)
- Han-Sem Kim
- Department of Nano-biomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea; Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Republic of Korea
| | - JunHwee Jang
- Department of Nano-biomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea
| | - Jun-Sung Oh
- Department of Nano-biomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea
| | - Eun-Jung Lee
- Department of Nano-biomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea
| | - Cheol-Min Han
- Department of Carbon and Nano Materials Engineering, Jeonju University, Jeonju 55069, Republic of Korea.
| | - Ueon Sang Shin
- Department of Nano-biomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea; Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Republic of Korea.
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10
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Ahmadi A, Mazloomnejad R, Kasravi M, Gholamine B, Bahrami S, Sarzaeem MM, Niknejad H. Recent advances on small molecules in osteogenic differentiation of stem cells and the underlying signaling pathways. Stem Cell Res Ther 2022; 13:518. [PMID: 36371202 PMCID: PMC9652959 DOI: 10.1186/s13287-022-03204-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/09/2022] [Indexed: 11/15/2022] Open
Abstract
Bone-related diseases are major contributors to morbidity and mortality in elderly people and the current treatments result in insufficient healing and several complications. One of the promising areas of research for healing bone fractures and skeletal defects is regenerative medicine using stem cells. Differentiating stem cells using agents that shift cell development towards the preferred lineage requires activation of certain intracellular signaling pathways, many of which are known to induce osteogenesis during embryological stages. Imitating embryological bone formation through activation of these signaling pathways has been the focus of many osteogenic studies. Activation of osteogenic signaling can be done by using small molecules. Several of these agents, e.g., statins, metformin, adenosine, and dexamethasone have other clinical uses but have also shown osteogenic capacities. On the other hand, some other molecules such as T63 and tetrahydroquinolines are not as well recognized in the clinic. Osteogenic small molecules exert their effects through the activation of signaling pathways known to be related to osteogenesis. These pathways include more well-known pathways including BMP/Smad, Wnt, and Hedgehog as well as ancillary pathways including estrogen signaling and neuropeptide signaling. In this paper, we review the recent data on small molecule-mediated osteogenic differentiation, possible adjunctive agents with these molecules, and the signaling pathways through which each small molecule exerts its effects.
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Affiliation(s)
- Armin Ahmadi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, P.O. Box: 1985711151, Tehran, Iran
| | - Radman Mazloomnejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, P.O. Box: 1985711151, Tehran, Iran
| | - Mohammadreza Kasravi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, P.O. Box: 1985711151, Tehran, Iran
| | - Babak Gholamine
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, P.O. Box: 1985711151, Tehran, Iran
| | - Soheyl Bahrami
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Research Center, Vienna, Austria
| | - Mohammad Mahdi Sarzaeem
- Department of Orthopedic Surgery, Imam Hossein Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, P.O. Box: 1985711151, Tehran, Iran.
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11
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Zhao M, Chen G, Zhang S, Chen B, Wu Z, Zhang C. A bioactive poly(ether-ether-ketone) nanocomposite scaffold regulates osteoblast/osteoclast activity for the regeneration of osteoporotic bone. J Mater Chem B 2022; 10:8719-8732. [PMID: 36239238 DOI: 10.1039/d2tb01387h] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Due to the lower regeneration capacity of the osteoporotic bone, the treatment of osteoporotic defects is extremely challenging in clinics. In this study, strontium-doped bioactive glass nanoparticles loaded with sodium alendronate (ALN), namely A-SrBG, were incorporated into the poly(ether-ether-ketone) matrix to fabricate a bioactive composite scaffold (ASP), which was expected to both inhibit bone resorption and promote bone regeneration. The results showed that such a composite scaffold with interconnected macropores (200-400 μm) could release Ca2+, Sr2+, and ALN in vitro. The proliferation, alkaline phosphatase (ALP) activity, expression of osteogenesis-related genes, and formation of calcified nodules of rat bone marrow stromal cells (rBMSCs) were clearly evidenced, and the reduction in the proliferation, tartrate-resistant acid phosphatase (TRAP) activity, cell fusion, and expression of osteoclastogenesis-related genes of osteoclasts was observed as well. In the presence of the ASP scaffold, enhanced osteogenesis along with inhibiting osteoclastogenesis was observed by modulating the osteoprotegerin (OPG)/receptor activator for nuclear factor κB ligand (RANKL) ratio. The efficacy of the composite scaffold in the regeneration of osteoporotic critical-sized cranial defect in a rat model was evaluated. Therefore, the bioactive composite scaffold with excellent biocompatibility and osteogenic potential could be a promising material for the repair of osteoporotic bone defects.
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Affiliation(s)
- Mengen Zhao
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
| | - Guo Chen
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Shixiong Zhang
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
| | - Bin Chen
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Zhaoying Wu
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
| | - Chao Zhang
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
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12
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Chang S, Li C, Xu N, Wang J, Jing Z, Cai H, Tian Y, Wang S, Liu Z, Wang X. A sustained release of alendronate from an injectable tetra-PEG hydrogel for efficient bone repair. Front Bioeng Biotechnol 2022; 10:961227. [PMID: 36177182 PMCID: PMC9513246 DOI: 10.3389/fbioe.2022.961227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 07/04/2022] [Indexed: 01/07/2023] Open
Abstract
Significant efforts on construction of smart drug delivery for developing minimally invasive gelling system to prolong local delivery of bisphosphonates are considered as promising perspectives for the bone-related diseases, which provide the hydrogels with unique bioactivities for bone repair in clinic. Herein, we have constructed an alendronate (ALN)-conjoined injectable tetra-PEG hydrogel with excellent biocompatibility, uniform network, and favorable mechanical properties in one-pot strategy. In views of the quick ammonolysis reaction between N-hydroxysuccinimide (NHS)-ester of tetra-PEG-SG and amine groups of tetra-PEG-NH2 polymer and ALN molecules, the uniform networks were formed within seconds along with the easy injection, favorable biocompatibility and mechanical properties for hydrogel scaffolds. On account of the simultaneous physical encapsulation and chemical linkage of the ALN within the hydrogels, the ALN-conjoined tetra-PEG hydrogel exhibited a sustained drug release delivery that could persistently and effectively facilitate viability, growth, proliferation, and osteogenesis differentiation of stem cells, thereby allowing the consequent adaptation of hydrogels into the bone defects with irregular shapes, which endowed the ALN-conjoined tetra-PEG hydrogel with depot formulation capacity for governing the on-demand release of ALN drugs. Consequently, the findings imply that these drug-based tetra-PEG hydrogels mediate optimal release of therapeutic cargoes and effective promotion of in situ bone regeneration, which will be broadly utilized as therapeutic scaffolds in tissue engineering and regenerative medicine.
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Affiliation(s)
- Shuai Chang
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Peking University Third Hospital, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Peking University Third Hospital, Beijing, China
| | - Chao Li
- Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
- Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital, Beijing, China
| | - Nanfang Xu
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Peking University Third Hospital, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Peking University Third Hospital, Beijing, China
| | - Jiedong Wang
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Peking University Third Hospital, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Peking University Third Hospital, Beijing, China
| | - Zehao Jing
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Peking University Third Hospital, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Peking University Third Hospital, Beijing, China
| | - Hong Cai
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Peking University Third Hospital, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Peking University Third Hospital, Beijing, China
| | - Yun Tian
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Peking University Third Hospital, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Peking University Third Hospital, Beijing, China
| | - Shaobo Wang
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Peking University Third Hospital, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Peking University Third Hospital, Beijing, China
| | - Zhongjun Liu
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Peking University Third Hospital, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Peking University Third Hospital, Beijing, China
- *Correspondence: Zhongjun Liu, ; Xing Wang,
| | - Xing Wang
- Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- *Correspondence: Zhongjun Liu, ; Xing Wang,
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13
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Tang G, Zhu L, Wang W, Zuo D, Shi C, Yu X, Chen R. Alendronate-functionalized double network hydrogel scaffolds for effective osteogenesis. Front Chem 2022; 10:977419. [PMID: 36059871 PMCID: PMC9428824 DOI: 10.3389/fchem.2022.977419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 07/12/2022] [Indexed: 11/16/2022] Open
Abstract
Development of artificial bone substitutes mimicking the extracellular matrix is a promising strategy for bone repair and regeneration. In views of the actual requirement of biomechanics, biodegradability, and bioactivity, herein, a double-network (DN) hydrogel was constructed by interspersing a methacrylated gelatin (GelMA) network into alendronate (ALN)-modified oxidized alginate (OSA) network via Schiff base reaction and photo-crosslinking process to promote in situ bone regeneration. This GelMA@OSA-ALN DN hydrogel possessed favorable network and pores, good biocompatibility, and enhanced biomechanics. Notably, the introduction of Schiff base furnished the ND hydrogel scaffold with pH-responsive biodegradation and sustained ALN drug release delivery, which could provide effective bioactivity, upregulate osteogenesis-related genes, and promote the cell viability, growth, proliferation, and osteogenesis differentiation for bone regeneration. Therefore, we provide a new insight to develop functional DN hydrogel scaffold toward governing the on-demand drug release and achieving the stem cell therapy, which will be developed into the minimally invasive gelling system to prolong local delivery of bisphosphonates for the bone-related diseases.
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Affiliation(s)
- Guoke Tang
- Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai, China
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Liang Zhu
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Weiheng Wang
- Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Dongqing Zuo
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Changgui Shi
- Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Xiaojie Yu
- Department of Orthopedics, Hunan Aerospace Hospital, Changsha, Hunan, China
| | - Rui Chen
- Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai, China
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14
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Anabolic Effects of a Novel Simvastatin Derivative on Treating Rat Bone Defects. Biomedicines 2022; 10:biomedicines10081915. [PMID: 36009462 PMCID: PMC9405916 DOI: 10.3390/biomedicines10081915] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/14/2022] [Accepted: 08/05/2022] [Indexed: 11/17/2022] Open
Abstract
Large bone defects may develop fracture nonunion, leading to disability and psychosocial burdens. Bone grafting with anabolic agents is a good autografting alternative. Simvastatin, as a cholesterol-lowering agent worldwide, is proven to enhance osteogenesis. Considering its dose-dependent adverse effects, we developed a simvastatin derivative, named KMUHC-01, which has bone anabolic capacity and lower cytotoxicity than simvastatin. We hypothesize that KMUHC-01 could help bone formation in bone-defect animal models. We used rat models of critical calvarial and long-bone defects to evaluate the effects of KMUHC-01 and simvastatin on biological changes at the bone defect through histology, immunohistology, and mechanical testing using three-point bending and evaluated the new bone formation microstructure through microcomputed tomography analysis. The newly formed bone microstructure at the calvarial defect site showed a significantly improved trabecular bone volume in the KMUHC-01 1-μM group compared with that in the control and simvastatin groups. The biomechanical study revealed a significantly increased maximal strength in the KMUHC-01 1-μM group compared with that in the control group. KUMHC-01, as a simvastatin derivative, showed a great anabolic effect in promoting bone defect healing. However, further studies will be conducted to prove the bioavailability and bone-forming efficacy of KMUHC-01 via systemic administration.
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15
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A Novel Cell Delivery System Exploiting Synergy between Fresh Titanium and Fibronectin. Cells 2022; 11:cells11142158. [PMID: 35883601 PMCID: PMC9317518 DOI: 10.3390/cells11142158] [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: 06/09/2022] [Revised: 07/03/2022] [Accepted: 07/06/2022] [Indexed: 12/10/2022] Open
Abstract
Delivering and retaining cells in areas of interest is an ongoing challenge in tissue engineering. Here we introduce a novel approach to fabricate osteoblast-loaded titanium suitable for cell delivery for bone integration, regeneration, and engineering. We hypothesized that titanium age influences the efficiency of protein adsorption and cell loading onto titanium surfaces. Fresh (newly machined) and 1-month-old (aged) commercial grade 4 titanium disks were prepared. Fresh titanium surfaces were hydrophilic, whereas aged surfaces were hydrophobic. Twice the amount of type 1 collagen and fibronectin adsorbed to fresh titanium surfaces than aged titanium surfaces after a short incubation period of three hours, and 2.5-times more fibronectin than collagen adsorbed regardless of titanium age. Rat bone marrow-derived osteoblasts were incubated on protein-adsorbed titanium surfaces for three hours, and osteoblast loading was most efficient on fresh titanium adsorbed with fibronectin. The number of osteoblasts loaded using this synergy between fresh titanium and fibronectin was nine times greater than that on aged titanium with no protein adsorption. The loaded cells were confirmed to be firmly attached and functional. The number of loaded cells was strongly correlated with the amount of protein adsorbed regardless of the protein type, with fibronectin simply more efficiently adsorbed on titanium surfaces than collagen. The role of surface hydrophilicity of fresh titanium surfaces in increasing protein adsorption or cell loading was unclear. The hydrophilicity of protein-adsorbed titanium increased with the amount of protein but was not the primary determinant of cell loading. In conclusion, the osteoblast loading efficiency was dependent on the age of the titanium and the amount of protein adsorption. In addition, the efficiency of protein adsorption was specific to the protein, with fibronectin being much more efficient than collagen. This is a novel strategy to effectively deliver osteoblasts ex vivo and in vivo using titanium as a vehicle.
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16
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Ionic Cross-Linkable Alendronate-Conjugated Biodegradable Polyurethane Films for Potential Guided Bone Regeneration. Macromol Res 2022. [DOI: 10.1007/s13233-022-0014-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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17
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Cell-Based Double-Screening Method to Identify a Reliable Candidate for Osteogenesis-Targeting Compounds. Biomedicines 2022; 10:biomedicines10020426. [PMID: 35203635 PMCID: PMC8962348 DOI: 10.3390/biomedicines10020426] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 02/05/2022] [Accepted: 02/07/2022] [Indexed: 01/15/2023] Open
Abstract
Small-molecule compounds strongly affecting osteogenesis can form the basis of effective therapeutic strategies in bone regenerative medicine. A cell-based high-throughput screening system might be a powerful tool for identifying osteoblast-targeting candidates; however, this approach is generally limited with using only one molecule as a cell-based sensor that does not always reflect the activation of the osteogenic phenotype. In the present study, we used the MC3T3-E1 cell line stably transfected with the green fluorescent protein (GFP) reporter gene driven by a fragment of type I collagen promoter (Col-1a1GFP-MC3T3-E1) to evaluate a double-screening system to identify osteogenic inducible compounds using a combination of a cell-based reporter assay and detection of alkaline phosphatase (ALP) activity. Col-1a1GFP-MC3T3-E1 cells were cultured in an osteogenic induction medium after library screening of 1280 pharmacologically active compounds (Lopack1280). After 7 days, GFP fluorescence was measured using a microplate reader. After 14 days of osteogenic induction, the cells were stained with ALP. Library screening using the Col-1a1/GFP reporter and ALP staining assay detected three candidates with significant osteogenic induction ability. Furthermore, leflunomide, one of the three detected candidates, significantly promoted new bone formation in vivo. Therefore, this double-screening method could identify candidates for osteogenesis-targeting compounds more reliably than conventional methods.
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18
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Drug-Releasing Gelatin Coating Reinforced with Calcium Titanate Formed on Ti–6Al–4V Alloy Designed for Osteoporosis Bone Repair. COATINGS 2022. [DOI: 10.3390/coatings12020139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Ti–6Al–4V alloy has been widely used in the orthopedic and dental fields owing to its high mechanical strength and biocompatibility. However, this alloy has a poor bone-bonding capacity, and its implantation often causes loosening. Osteoporosis increases with the aging of the population, and bisphosphonate drugs such as alendronate and minodronate (MA) are used for the medical treatment. Reliable and multifunctional implants showing both bone bonding and drug releasing functions are desired. In this study, we developed a novel organic-inorganic composite layer consisting of MA-containing gelatin and calcium-deficient calcium titanate (cd–CT) with high bone-bonding and scratch resistance on Ti–6Al–4V alloy. The alloy with the composite layer formed apatite within 7 days in a simulated body fluid and exhibited high scratch resistance of an approximately 50 mN, attributable to interlocking with cd ± CT. Although the gelatin layer almost completely dissolved in phosphate-buffered saline within 6 h, its dissolution rate was significantly suppressed by a subsequent thermal crosslinking treatment. The released MA was estimated at more than 0.10 μmol/L after 7 days. It is expected that the Ti alloy with the MA-containing gelatin and cd–CT composite layer will be useful for the treatment of osteoporosis bone.
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19
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Lee S, Chae DS, Song BW, Lim S, Kim SW, Kim IK, Hwang KC. ADSC-Based Cell Therapies for Musculoskeletal Disorders: A Review of Recent Clinical Trials. Int J Mol Sci 2021; 22:10586. [PMID: 34638927 PMCID: PMC8508846 DOI: 10.3390/ijms221910586] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 01/04/2023] Open
Abstract
Recently published clinical trials involving the use of adipose-derived stem cells (ADSCs) indicated that approximately one-third of the studies were conducted on musculoskeletal disorders (MSD). MSD refers to a wide range of degenerative conditions of joints, bones, and muscles, and these conditions are the most common causes of chronic disability worldwide, being a major burden to the society. Conventional treatment modalities for MSD are not sufficient to correct the underlying structural abnormalities. Hence, ADSC-based cell therapies are being tested as a form of alternative, yet more effective, therapies in the management of MSDs. Therefore, in this review, MSDs subjected to the ADSC-based therapy were further categorized as arthritis, craniomaxillofacial defects, tendon/ligament related disorders, and spine disorders, and their brief characterization as well as the corresponding conventional therapeutic approaches with possible mechanisms with which ADSCs produce regenerative effects in disease-specific microenvironments were discussed to provide an overview of under which circumstances and on what bases the ADSC-based cell therapy was implemented. Providing an overview of the current status of ADSC-based cell therapy on MSDs can help to develop better and optimized strategies of ADSC-based therapeutics for MSDs as well as help to find novel clinical applications of ADSCs in the near future.
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Affiliation(s)
- Seahyoung Lee
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Dong-Sik Chae
- Department of Orthopedic Surgery, International St. Mary’s Hospital, Catholic Kwandong University, Gangneung 210-701, Korea;
| | - Byeong-Wook Song
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Soyeon Lim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Sang Woo Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Il-Kwon Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
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20
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Le Q, Madhu V, Hart JM, Farber CR, Zunder ER, Dighe AS, Cui Q. Current evidence on potential of adipose derived stem cells to enhance bone regeneration and future projection. World J Stem Cells 2021; 13:1248-1277. [PMID: 34630861 PMCID: PMC8474721 DOI: 10.4252/wjsc.v13.i9.1248] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 05/22/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023] Open
Abstract
Injuries to the postnatal skeleton are naturally repaired through successive steps involving specific cell types in a process collectively termed “bone regeneration”. Although complex, bone regeneration occurs through a series of well-orchestrated stages wherein endogenous bone stem cells play a central role. In most situations, bone regeneration is successful; however, there are instances when it fails and creates non-healing injuries or fracture nonunion requiring surgical or therapeutic interventions. Transplantation of adult or mesenchymal stem cells (MSCs) defined by the International Society for Cell and Gene Therapy (ISCT) as CD105+CD90+CD73+CD45-CD34-CD14orCD11b-CD79αorCD19-HLA-DR- is being investigated as an attractive therapy for bone regeneration throughout the world. MSCs isolated from adipose tissue, adipose-derived stem cells (ADSCs), are gaining increasing attention since this is the most abundant source of adult stem cells and the isolation process for ADSCs is straightforward. Currently, there is not a single Food and Drug Administration (FDA) approved ADSCs product for bone regeneration. Although the safety of ADSCs is established from their usage in numerous clinical trials, the bone-forming potential of ADSCs and MSCs, in general, is highly controversial. Growing evidence suggests that the ISCT defined phenotype may not represent bona fide osteoprogenitors. Transplantation of both ADSCs and the CD105- sub-population of ADSCs has been reported to induce bone regeneration. Most notably, cells expressing other markers such as CD146, AlphaV, CD200, PDPN, CD164, CXCR4, and PDGFRα have been shown to represent osteogenic sub-population within ADSCs. Amongst other strategies to improve the bone-forming ability of ADSCs, modulation of VEGF, TGF-β1 and BMP signaling pathways of ADSCs has shown promising results. The U.S. FDA reveals that 73% of Investigational New Drug applications for stem cell-based products rely on CD105 expression as the “positive” marker for adult stem cells. A concerted effort involving the scientific community, clinicians, industries, and regulatory bodies to redefine ADSCs using powerful selection markers and strategies to modulate signaling pathways of ADSCs will speed up the therapeutic use of ADSCs for bone regeneration.
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Affiliation(s)
- Quang Le
- Department of Orthopaedic Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, United States
| | - Vedavathi Madhu
- Orthopaedic Surgery Research, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Joseph M Hart
- Department of Orthopaedic Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, United States
| | - Charles R Farber
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, United States
- Departments of Public Health Sciences and Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, United States
| | - Eli R Zunder
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, United States
| | - Abhijit S Dighe
- Department of Orthopaedic Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, United States
| | - Quanjun Cui
- Department of Orthopaedic Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, United States
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21
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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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22
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Choi S, Jo HS, Song H, Kim HJ, Oh JK, Cho JW, Park K, Kim SE. Multifunctional Tannic Acid-Alendronate Nanocomplexes with Antioxidant, Anti-Inflammatory, and Osteogenic Potency. NANOMATERIALS 2021; 11:nano11071812. [PMID: 34361198 PMCID: PMC8308329 DOI: 10.3390/nano11071812] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/07/2021] [Accepted: 07/09/2021] [Indexed: 12/12/2022]
Abstract
In the current study, we fabricated tannic acid-alendronate (TA-ALN) nanocomplexes (NPXs) via self-assembly. These TA-ALNs were characterized by dynamic light scattering, zeta potential, transmission electron microscopy, and FT-IR spectroscopy. The TA-ALNs were evaluated for antioxidant, anti-inflammatory, and osteogenesis-accelerating abilities in osteoblast-like cells (MC3T3-E1 cells). All TA-ALNs displayed nano-sized beads that were circular in form. Treatment with TA-ALN (1:0.1) efficiently removed reactive oxygen species in cells and protected osteoblast-like cells from toxic hydrogen peroxide conditions. Moreover, TA-ALN (1:0.1) could markedly decrease the mRNA levels of pro-inflammatory mediators in lipopolysaccharide-stimulated cells. Furthermore, cells treated with TA-ALN (1:1) exhibited not only significantly greater alkaline phosphatase activity and calcium collection, but also outstandingly higher mRNA levels of osteogenesis-related elements such as collagen type I and osteocalcin. These outcomes indicate that the prepared TA-ALNs are excellent for antioxidant, anti-inflammatory, and osteogenic acceleration. Accordingly, TA-ALN can be used latently for bone renovation and regeneration in people with bone fractures, diseases, or disorders.
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Affiliation(s)
- Somang Choi
- Department of Orthopedic Surgery and Nano-Based Disease Control Institute, Korea University Guro Hospital, #148, Gurodong-ro, Guro-gu, Seoul 08308, Korea; (S.C.); (H.-S.J.); (H.-J.K.); (J.-K.O.)
| | - Han-Saem Jo
- Department of Orthopedic Surgery and Nano-Based Disease Control Institute, Korea University Guro Hospital, #148, Gurodong-ro, Guro-gu, Seoul 08308, Korea; (S.C.); (H.-S.J.); (H.-J.K.); (J.-K.O.)
| | - Heegyeong Song
- Department of Systems Biotechnology, Chung-Ang University, Anseong 17546, Korea;
| | - Hak-Jun Kim
- Department of Orthopedic Surgery and Nano-Based Disease Control Institute, Korea University Guro Hospital, #148, Gurodong-ro, Guro-gu, Seoul 08308, Korea; (S.C.); (H.-S.J.); (H.-J.K.); (J.-K.O.)
| | - Jong-Keon Oh
- Department of Orthopedic Surgery and Nano-Based Disease Control Institute, Korea University Guro Hospital, #148, Gurodong-ro, Guro-gu, Seoul 08308, Korea; (S.C.); (H.-S.J.); (H.-J.K.); (J.-K.O.)
| | - Jae-Woo Cho
- Department of Orthopedic Surgery and Nano-Based Disease Control Institute, Korea University Guro Hospital, #148, Gurodong-ro, Guro-gu, Seoul 08308, Korea; (S.C.); (H.-S.J.); (H.-J.K.); (J.-K.O.)
- Correspondence: (J.-W.C.); (K.P.); (S.-E.K.); Tel.: +82-2-2626-1869 (J.-W.C.); +82-31-670-3357 (K.P.); +82-2-6738-4514 (S.-E.K.)
| | - Kyeongsoon Park
- Department of Systems Biotechnology, Chung-Ang University, Anseong 17546, Korea;
- Correspondence: (J.-W.C.); (K.P.); (S.-E.K.); Tel.: +82-2-2626-1869 (J.-W.C.); +82-31-670-3357 (K.P.); +82-2-6738-4514 (S.-E.K.)
| | - Sung-Eun Kim
- Department of Orthopedic Surgery and Nano-Based Disease Control Institute, Korea University Guro Hospital, #148, Gurodong-ro, Guro-gu, Seoul 08308, Korea; (S.C.); (H.-S.J.); (H.-J.K.); (J.-K.O.)
- Correspondence: (J.-W.C.); (K.P.); (S.-E.K.); Tel.: +82-2-2626-1869 (J.-W.C.); +82-31-670-3357 (K.P.); +82-2-6738-4514 (S.-E.K.)
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23
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Wu SC, Chang CH, Chang LH, Wu CW, Chen JW, Chen CH, Lin YS, Chang JK, Ho ML. Simvastatin Enhances the Chondrogenesis But Not the Osteogenesis of Adipose-Derived Stem Cells in a Hyaluronan Microenvironment. Biomedicines 2021; 9:biomedicines9050559. [PMID: 34067739 PMCID: PMC8156330 DOI: 10.3390/biomedicines9050559] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/11/2021] [Accepted: 05/14/2021] [Indexed: 11/16/2022] Open
Abstract
Directing adipose-derived stem cells (ADSCs) toward chondrogenesis is critical for ADSC-based articular cartilage regeneration. Simvastatin (SIM) was reported to promote both chondrogenic and osteogenic differentiation of ADSCs by upregulating bone morphogenetic protein-2 (BMP-2). We previously found that ADSC chondrogenesis is initiated and promoted in a hyaluronan (HA) microenvironment (HAM). Here, we further hypothesized that SIM augments HAM-induced chondrogenesis but not osteogenesis of ADSCs. ADSCs were treated with SIM in a HAM (SIM plus HAM) by HA-coated wells or HA-enriched fibrin (HA/Fibrin) hydrogel, and chondrogenic differentiation of ADSCs was evaluated. SIM plus HAM increased chondrogenesis more than HAM or SIM alone, including cell aggregation, chondrogenic gene expression (collagen type II and aggrecan) and cartilaginous tissue formation (collagen type II and sulfated glycosaminoglycan). In contrast, SIM-induced osteogenesis in ADSCs was reduced in SIM plus HAM, including mRNA expression of osteogenic genes, osteocalcin and alkaline phosphatase (ALP), ALP activity and mineralization. SIM plus HAM also showed the most effective increases in the mRNA expression of BMP-2 and transcription factors of SOX-9 and RUNX-2 in ADSCs, while these effects were reversed by CD44 blockade. HAM suppressed the levels of JNK, p-JNK, P38 and p-P38 in ADSCs, and SIM plus HAM also decreased SIM-induced phosphorylated JNK and p38 levels. In addition, SIM enhanced articular cartilage regeneration, as demonstrated by implantation of an ADSCs/HA/Fibrin construct in an ex vivo porcine articular chondral defect model. The results from this study indicate that SIM may be an enhancer of HAM-initiated MSC-based chondrogenesis and avoid osteogenesis.
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Affiliation(s)
- Shun-Cheng Wu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Post-Baccalaureate Program in Nursing, Asia University, Taichung 41354, Taiwan
| | - Chih-Hsiang Chang
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
| | - Ling-Hua Chang
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
| | - Che-Wei Wu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
| | - Jhen-Wei Chen
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
| | - Chung-Hwan Chen
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
- Department of Orthopaedics, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Division of Adult Reconstruction Surgery, Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
| | - Yi-Shan Lin
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
| | - Je-Ken Chang
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
- Department of Orthopaedics, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Correspondence: (J.-K.C.); (M.-L.H.)
| | - Mei-Ling Ho
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Correspondence: (J.-K.C.); (M.-L.H.)
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24
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Mende W, Götzl R, Kubo Y, Pufe T, Ruhl T, Beier JP. The Role of Adipose Stem Cells in Bone Regeneration and Bone Tissue Engineering. Cells 2021; 10:cells10050975. [PMID: 33919377 PMCID: PMC8143357 DOI: 10.3390/cells10050975] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/19/2021] [Accepted: 04/20/2021] [Indexed: 02/07/2023] Open
Abstract
Bone regeneration is a complex process that is influenced by tissue interactions, inflammatory responses, and progenitor cells. Diseases, lifestyle, or multiple trauma can disturb fracture healing, which might result in prolonged healing duration or even failure. The current gold standard therapy in these cases are bone grafts. However, they are associated with several disadvantages, e.g., donor site morbidity and availability of appropriate material. Bone tissue engineering has been proposed as a promising alternative. The success of bone-tissue engineering depends on the administered cells, osteogenic differentiation, and secretome. Different stem cell types offer advantages and drawbacks in this field, while adipose-derived stem or stromal cells (ASCs) are in particular promising. They show high osteogenic potential, osteoinductive ability, and immunomodulation properties. Furthermore, they can be harvested through a noninvasive process in high numbers. ASCs can be induced into osteogenic lineage through bioactive molecules, i.e., growth factors and cytokines. Moreover, their secretome, in particular extracellular vesicles, has been linked to fracture healing. The aim of this review is a comprehensive overview of ASCs for bone regeneration and bone tissue engineering.
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Affiliation(s)
- Wolfgang Mende
- Hand Surgery-Burn Center, Department of Plastic Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany
| | - Rebekka Götzl
- Hand Surgery-Burn Center, Department of Plastic Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany
| | - Yusuke Kubo
- Department of Anatomy and Cell Biology, RWTH Aachen University Hospital, 52074 Aachen, Germany
| | - Thomas Pufe
- Department of Anatomy and Cell Biology, RWTH Aachen University Hospital, 52074 Aachen, Germany
| | - Tim Ruhl
- Hand Surgery-Burn Center, Department of Plastic Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany
| | - Justus P Beier
- Hand Surgery-Burn Center, Department of Plastic Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany
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25
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Le J, Zhongqun L, Zhaoyan W, Yijun S, Yingjin W, Yaojie W, Yanan J, Zhanrong J, Chunyang M, Fangli G, Nan X, Lingyun Z, Xiumei W, Qiong W, Xiong L, Xiaodan S. Development of methods for detecting the fate of mesenchymal stem cells regulated by bone bioactive materials. Bioact Mater 2021; 6:613-626. [PMID: 33005826 PMCID: PMC7508719 DOI: 10.1016/j.bioactmat.2020.08.035] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/11/2020] [Accepted: 08/11/2020] [Indexed: 01/07/2023] Open
Abstract
The fate of mesenchymal stem cells (MSCs) is regulated by biological, physical and chemical signals. Developments in biotechnology and materials science promoted the occurrence of bioactive materials which can provide physical and chemical signals for MSCs to regulate their fate. In order to design and synthesize materials that can precisely regulate the fate of MSCs, the relationship between the properties of materials and the fate of mesenchymal stem cells need to be clarified, in which the detection of the fate of mesenchymal stem cells plays an important role. In the past 30 years, a series of detection technologies have been developed to detect the fate of MSCs regulated by bioactive materials, among which high-throughput technology has shown great advantages due to its ability to detect large amounts of data at one time. In this review, the latest research progresses of detecting the fate of MSCs regulated by bone bioactive materials (BBMs) are systematically reviewed from traditional technology to high-throughput technology which is emphasized especially. Moreover, current problems and the future development direction of detection technologies of the MSCs fate regulated by BBMs are prospected. The aim of this review is to provide a detection technical framework for researchers to establish the relationship between the properties of BMMs and the fate of MSCs, so as to help researchers to design and synthesize BBMs better which can precisely regulate the fate of MSCs.
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Affiliation(s)
- Jiang Le
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
| | - Liu Zhongqun
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
| | - Wang Zhaoyan
- MOE Key Laboratory of Bioinformatics, Tsinghua University, Beijing, 100084, People's Republic of China
- Center for Synthetic and Systems Biology, Tsinghua University, Beijing, 100084, People's Republic of China
- School of Life Sciences, Tsinghua University, Beijing, 100084, People's Republic of China
| | - Su Yijun
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
| | - Wang Yingjin
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
| | - Wei Yaojie
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
| | - Jiang Yanan
- Key Lab of Advanced Technologies of Materials of Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, People's Republic of China
| | - Jia Zhanrong
- Key Lab of Advanced Technologies of Materials of Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, People's Republic of China
| | - Ma Chunyang
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
| | - Gang Fangli
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
| | - Xu Nan
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
| | - Zhao Lingyun
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
| | - Wang Xiumei
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
| | - Wu Qiong
- MOE Key Laboratory of Bioinformatics, Tsinghua University, Beijing, 100084, People's Republic of China
- Center for Synthetic and Systems Biology, Tsinghua University, Beijing, 100084, People's Republic of China
- School of Life Sciences, Tsinghua University, Beijing, 100084, People's Republic of China
| | - Lu Xiong
- Key Lab of Advanced Technologies of Materials of Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, People's Republic of China
| | - Sun Xiaodan
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, People's Republic of China
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26
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Zeng Y, Zhou M, Mou S, Yang J, Yuan Q, Guo L, Zhong A, Wang J, Sun J, Wang Z. Sustained delivery of alendronate by engineered collagen scaffold for the repair of osteoporotic bone defects and resistance to bone loss. J Biomed Mater Res A 2020; 108:2460-2472. [PMID: 32419333 DOI: 10.1002/jbm.a.36997] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 04/09/2020] [Accepted: 04/19/2020] [Indexed: 12/17/2022]
Abstract
Researches of biomaterials for osteoporotic bone defects focus on the improvement of its anti-osteoporosis ability, due to osteoporosis is a kind of systemic and long-range bone metabolism disorder. Nevertheless, how to steadily deliver anti-osteoporosis drugs in osteoporotic bone defects is rarely studied. Reported evidences have shown that alendronate (Aln) is known to not only restrain osteoclasts from mediating bone resorption but also stimulate osteoblasts to regenerate bone tissue. Here, we developed an engineered implantable scaffold that could sustainably release Aln for osteoporotic bone defects. Briefly, Aln was added into 2% collagen (Col) solution to form a 5 mg/ml mixture. Then the mixture was filled into pre-designed round models (diameter: 5 mm, height: 2 mm) and crosslinked to obtain engineered Col-Aln scaffolds. The release kinetics showed that Aln was released at an average rate of 2.99 μg/d in the initial 8 days and could sustainably release for 1 month. To detect the repair effects of the Col-Aln scaffolds for osteoporotic defects, the Col and Col-Aln scaffolds were implanted into 5 mm cranial defects in ovariectomized rats. After 3 months, the cranial defects implanted with Col-Aln scaffolds achieved more bone regeneration in defect area (11.74 ± 3.82%) than Col scaffold (5.12 ± 1.15%) (p < .05). Moreover, ovariectomized rats in Col-Aln scaffold group possessed more trabecular bone in femur metaphysis than Col scaffold group as analyzed by Micro-CT. This study demonstrated the engineered Col-Aln scaffold has the potential to repair osteoporotic bone defects and resist bone loss in osteoporosis.
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Affiliation(s)
- Yuyang Zeng
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, China
| | - Muran Zhou
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, China
| | - Shan Mou
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, China
| | - Jie Yang
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, China
| | - Quan Yuan
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, China
| | - Liang Guo
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, China
| | - Aimei Zhong
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, China
| | - Jiecong Wang
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, China
| | - Jiaming Sun
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, China
| | - Zhenxing Wang
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, China
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27
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Lee J, Lee S, Ahmad T, Madhurakkat Perikamana SK, Lee J, Kim EM, Shin H. Human adipose-derived stem cell spheroids incorporating platelet-derived growth factor (PDGF) and bio-minerals for vascularized bone tissue engineering. Biomaterials 2020; 255:120192. [PMID: 32559565 DOI: 10.1016/j.biomaterials.2020.120192] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 04/06/2020] [Accepted: 06/09/2020] [Indexed: 12/12/2022]
Abstract
Stem cells with mineralized materials have been used for bone regeneration; however, engineering the complex vascularized structure of the natural bone remains a challenge. Here, we developed platelet-derived growth factor (PDGF) and bio-mineral coated fibers which were then assembled with human adipose-derived stem cells (hADSCs) to form spheroids as building blocks for vascularized bone regeneration. The PDGF incorporated within the spheroid increased the proliferation of hADSCs, which was characterized by Ki-67 staining and DNA contents. Furthermore, the PDGF enhanced not only osteogenic differentiation, but also endothelial differentiation of hADSCs; the cells within the spheroids showed significantly greater gene expression by 2.46 ± 0.14 fold for osteocalcin (OCN) and by 12.85 ± 3.36 fold for von Willebrand factor (vWF) than those without PDGF. Finally, at two months following transplantation of PDGF-incorporated spheroids onto in vivo mouse calvarial defect, the regenerated bone area (42.48 ± 10.84%) was significantly enhanced and the greatest number of capillaries and arterioles with indication of transplanted hADSCs were observed. Moreover, millimeter-scale in vitro tissue prepared by fused assembly of the spheroids exhibited greater mRNA expression-associated to endothelial lineage. Taken together, these findings indicate that stem cell spheroids incorporating PDGF and bio-minerals could be used as a module for successful vascularized bone regeneration.
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Affiliation(s)
- Jinkyu Lee
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea
| | - Sangmin Lee
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea
| | - Taufiq Ahmad
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea
| | - Sajeesh Kumar Madhurakkat Perikamana
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea
| | - Jinki Lee
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea
| | - Eun Mi Kim
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea
| | - Heungsoo Shin
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, 04763, Republic of Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul, 04763, Republic of Korea; Institute of Nano Science and Technology, Hanyang University, Seoul, 04763, Republic of Korea.
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Moradikhah F, Doosti-Telgerd M, Shabani I, Soheili S, Dolatyar B, Seyedjafari E. Microfluidic fabrication of alendronate-loaded chitosan nanoparticles for enhanced osteogenic differentiation of stem cells. Life Sci 2020; 254:117768. [PMID: 32407840 DOI: 10.1016/j.lfs.2020.117768] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/30/2020] [Accepted: 05/06/2020] [Indexed: 01/05/2023]
Abstract
AIMS In this study, we used a cross-junction microfluidic device for preparation of alendronate-loaded chitosan nanoparticles with desired characteristics to introduce a suitable element for bone tissue engineering scaffolds. MAIN METHODS By controlling the reaction condition in microfluidic device, six types of alendronate-loaded chitosan nanoparticles were fabricated which had different physical properties. Hydrodynamic diameter of synthetized particles was evaluated by dynamic light scattering (102 to 215 nm). Nanoparticle morphology was determined by SEM and AFM images. The osteogenic effects of prepared selected nanoparticles on human adipose stem cells (hA-MSCs) were evaluated by assessment of alkaline phosphatase (ALP) activity, calcium deposition, ALP and osteopontin gene expression. KEY FINDINGS The highest loading efficiency percentage (%LE) was %32.42 ± 2.02. Based on MTT assessment, two samples which had no significant cytotoxicity were chosen for further studies (particle sizes and %LE were 142 ± 6.1 nm, 198 ± 16.56 nm, %16.76 ± 3.91 and %32.42 ± 2.02, respectively). In vitro release behavior of nanoparticles displayed pH responsive characteristics. Significant faster release was seen in acidic pH = 5.8 than neutral pH = 7.4. The selected nanoparticles demonstrated higher ALP activity at 14 days in comparison to selected blank sample and osteogenic differentiation media (ODM) and a downregulation at 21 days in comparison to 14 days. Calcium content assay at 21 days displayed significant differences between alendronate-loaded nanoparticles and ODM. ALP and osteopontin mRNA expression was significantly higher than the cells cultured in ODM at 14 and 21 days. SIGNIFICANCE We concluded that our prepared nanoparticles significantly enhanced osteogenic differentiation of hA-MSCs and can be a suitable compartment of bone tissue engineering scaffolds.
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Affiliation(s)
- Farzad Moradikhah
- Department of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran
| | - Mehdi Doosti-Telgerd
- Department of Pharmaceutical Biomaterials, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Iman Shabani
- Department of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran.
| | - Shima Soheili
- Department of Polymer and Color Engineering, Amirkabir University of Technology, Tehran, Iran
| | - Banafsheh Dolatyar
- Department of Cell and Developmental Biology, School of Biological Sciences, College of Science, University of Tehran, Tehran, Iran
| | - Ehsan Seyedjafari
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
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Chen S, Guo R, Xie C, Liang Q, Xiao X. Biomimetic mineralization of nanocrystalline hydroxyapatites on aminated modified polylactic acid microspheres to develop a novel drug delivery system for alendronate. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 110:110655. [DOI: 10.1016/j.msec.2020.110655] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 12/25/2019] [Accepted: 01/06/2020] [Indexed: 12/15/2022]
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Wang C, Ye X, Zhao Y, Bai L, He Z, Tong Q, Xie X, Zhu H, Cai D, Zhou Y, Lu B, Wei Y, Mei L, Xie D, Wang M. Cryogenic 3D printing of porous scaffolds for in situ delivery of 2D black phosphorus nanosheets, doxorubicin hydrochloride and osteogenic peptide for treating tumor resection-induced bone defects. Biofabrication 2020; 12:035004. [PMID: 31952065 DOI: 10.1088/1758-5090/ab6d35] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Tumor resection is widely used to prevent tumor growth. However, the defected tissue at the original tumor site also causes tissue or organ dysfunction which lowers the patient's life quality. Therefore, regenerating the tissue and preventing tumor recurrence are highly important. Herein, according to the concept of 'first kill and then regenerate', a versatile scaffold-based tissue engineering strategy based on cryogenic 3D printing of water-in-oil polyester emulsion inks, containing multiple functional agents, was developed, in order to realize the elimination of tumor cells with recurrence suppression and improved tissue regeneration sequentially. To illustrate our strategy, water/poly(lactic-co-glycolic acid)/dichloromethane emulsions containing β-tricalcium phosphate (β-TCP), 2D black phosphorus (BP) nanosheets, low-dose doxorubicin hydrochloride (DOX) and high-dose osteogenic peptide were cryogenically 3D printed into hierarchically porous and mechanically strong nanocomposite scaffolds, with multiple functions to treat bone tumor, resection-induced tissue defects. Prompt tumor ablation and long-term suppression of tumor recurrence could be achieved due to the synergistic effects of photothermotherapy and chemotherapy, and improved bone regeneration was obtained eventually due to the presence of bony environment and sustained peptide release. Notably, BP nanosheets in scaffolds significantly reduced the long-term toxicity phenomenon of released DOX during in vivo bone regeneration. Our study also provides insights for the design of multi-functional tissue engineering scaffolds for treating other tumor resection-induced tissue defects.
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Affiliation(s)
- Chong Wang
- College of Mechanical Engineering, Dongguan University of Technology, Dongguan, Guangdong, People's Republic of China
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Boda SK, Wang H, John JV, Reinhardt RA, Xie J. Dual Delivery of Alendronate and E7-BMP-2 Peptide via Calcium Chelation to Mineralized Nanofiber Fragments for Alveolar Bone Regeneration. ACS Biomater Sci Eng 2020; 6:2368-2375. [PMID: 33455340 DOI: 10.1021/acsbiomaterials.0c00145] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The fixation and stability of dental implants is governed by the quality of the underlying alveolar bone. The current study investigates if the dual delivery of calcium chelating bone therapeutics from mineralized nanofiber fragments can help regenerate alveolar bone in vivo. Alendronate (ALN) or/and bone morphogenetic protein-2-mimicking peptide conjugated to a heptaglutamate moiety (E7-BMP-2) were incorporated onto mineralized nanofiber fragments of polylactide-co-glycolide-collagen-gelatin (PCG in 2:1:1 weight ratios) via calcium coupling/chelation. Two mg of the single-loaded (ALN) and coloaded (ALN + E7-BMP-2) mineralized nanofiber PCG grafts was filled into critical-sized (2 mm diameter × 2 mm depth) alveolar bone defects in rat maxillae and let heal for 4 weeks. X-ray microcomputed tomography analysis of the retrieved maxillae revealed significantly elevated new bone formation parameters for the ALN and ALN + E7-BMP-2 groups compared with the unfilled defect controls. However, no significant differences between the single and coloaded nanofiber grafts were noted. Furthermore, the histopathological analysis of the tissue sections divulged islands of new bone tissue in the ALN and ALN + E7-BMP-2 groups, whereas the control defect was covered with gingival tissue. Together, the presented strategy using mineralized nanofiber fragments in the sustained delivery of dual calcium chelating therapeutics could have potential applications in enhancing bone regeneration.
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Affiliation(s)
- Sunil Kumar Boda
- Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.,Minnesota Dental Research Center for Biomaterials and Biomechanics (MDRCBB), Department of Restorative Sciences, School of Dentistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Hongjun Wang
- Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Johnson V John
- Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Richard A Reinhardt
- Department of Surgical Specialties, College of Dentistry, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Jingwei Xie
- Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
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Vieira JS, Cunha EJ, de Souza JF, Chaves LHK, de Souza JL, Giovanini AF. Alendronate disturbs femoral growth due to changes during immunolocalization of transforming growth factor-β1 and bone morphogenetic protein-2 in epiphyseal plate. World J Exp Med 2020; 10:1-9. [PMID: 31942441 PMCID: PMC6960019 DOI: 10.5493/wjem.v10.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 11/26/2019] [Accepted: 12/15/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The epiphyseal growth plate is an important anatomical segment localized on the ends of a long bone. Despite the abovementioned atractive reasons for alendronate’s use, few data on the effect of alendronate during epiphyseal growth exist.
AIM Verify the effect of alendronate on the growth epiphyseal plate, and compare its effect with the size of the femur during the double-staining of the immunolocalization of transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-2 (BMP2) in endochondral ossifing in specimens that have received alendronate.
METHODS Forty newborn rats were randomly divided into two groups: a control group (were given applications of 1 mg/kg physiologic saline) and a group that received Alendronate (a dose of 2.5 mg/kg). These groups were then divided into two subgroups for euthanasia in two and 12 d of life. After euthanasia, the femurs were removed, and the femoral bones were measured linearly between the apex of the greater trochanter until the lower intercondylar midlle face to verify the probable bone growth between 3 and 12 d in control and alednroanto treated rats. Posteriorly, the surgical pieces were also sent to the histopathology laboratory to produce histological slides. The obtained slides were stained with hematoxylin and eosin to measure each of the cartilage zones in endochondral development. and other slides were immunohistochemically tested for anti- TGF-β1 and BMP-2 antibodies to investigate the immunolocalization of these proteins in the epiphyseal plaque area.
RESULTS On the third day, some diferences between the control group and specimens treated with alendronate were verified. Macroscopiccaly, we found similarities in size between the femoral bones when we compared the control group with the specimens that received alendronate. On the 12th day, the bone size of the mice receiving the drug was significantly smaller than those of the control group. These results coincide with changes in the TGF-β1 and BMP-2 expression. In the specimens that received alendronate, the TGF-β1 was expressed in some sites of trabecular bone that was neoformed, peripherally to the bone marrow area. The BMP-2 was also positive in proliferative chondrocytes and hypertrofic chondrocytes. On the 12th day, all layers of chondrocytes exhibited positivity for BMP-2 in the specimens that received alendronate. In the interface between the trabecular bone and cartilage, an area of disorganized bone deposition was evident. Neoformed bone also appeared to be different at 12 d. In the control group, BMP-2 was positive in an intense area of bone trabeculae, whereas the alendronate-treated group showed TGF-β1 positive trabeculae and a greater bone area.
CONCLUSION Alendronate alters the immunolocalization of TGF-β1 and BMP-2 simultaneously, a condition that changes the usual histological aspects of the cartilage zone and impairs epiphysis growth and femur growth.
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Recent Advances of Biphasic Calcium Phosphate Bioceramics for Bone Tissue Regeneration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1250:177-188. [PMID: 32601945 DOI: 10.1007/978-981-15-3262-7_12] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Biphasic calcium phosphate bioceramics consist of an intimate mixture of hydroxyapatite (HA) and beta-tricalcium phosphate (β-TCP) in varying ratios. Due to their biocompatibility, osteoconductivity, and safety in in vitro, in vivo, and clinical models, they have become promising bone substitute biomaterials and are recommended for use as alternatives for or as additives in bone tissue regeneration in various orthopedic and dental applications. Many studies have demonstrated the potential uses of BCP bioceramics as scaffolds for tissue engineering. Here, we highlight the recent advances in the uses of BCP bioceramics and functionalized BCPs for bone tissue regeneration.
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Cui Y, Zhu T, Li D, Li Z, Leng Y, Ji X, Liu H, Wu D, Ding J. Bisphosphonate-Functionalized Scaffolds for Enhanced Bone Regeneration. Adv Healthc Mater 2019; 8:e1901073. [PMID: 31693315 DOI: 10.1002/adhm.201901073] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/28/2019] [Indexed: 12/11/2022]
Abstract
The local sustained release of bioactive substances are attracting increasing attention in bone tissue engineering, which is beneficial to bone tissue formation and helps to improve the bone ingrowth ability of a scaffold. Bisphosphonates (BPs), as a representative kind of osteoclast inhibitors, are proven to possess excellent osteogenic induction capability. Accordingly, various physical and chemical strategies are developed to functionalize bone tissue scaffolds with BPs to achieve controlled release profiles. Compared with traditional treatment modalities, local release of BPs from these composite scaffolds will contribute to continuous bone integration without the risk of many complications. This review explores the molecular mechanisms of BPs on bone metabolism and analyzes the appropriate concentrations of BPs that promote bone regeneration. The advanced BP loading strategies, implant modification technologies, and BP-loaded composite scaffolds based on different matrices are summarized. Finally, the latest advances and the future development of BP-modified scaffolds for enhanced bone regeneration are discussed. This article provides leading-edge design strategies of the BP-functionalized bone engineering scaffolds for improved bone repairability.
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Affiliation(s)
- Yutao Cui
- Department of OrthopedicsThe Second Hospital of Jilin University Changchun 130041 P. R. China
| | - Tongtong Zhu
- Department of OrthopedicsChina‐Japan Union Hospital of Jilin University Changchun 130033 P. R. China
| | - Di Li
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of Sciences Changchun 130022 P. R. China
| | - Zuhao Li
- Department of OrthopedicsThe Second Hospital of Jilin University Changchun 130041 P. R. China
| | - Yi Leng
- Department of OrthopedicsThe Second Hospital of Jilin University Changchun 130041 P. R. China
| | - Xuan Ji
- Department of StomatologyThe Second Hospital of Jilin University Changchun 130041 P. R. China
| | - He Liu
- Department of OrthopedicsThe Second Hospital of Jilin University Changchun 130041 P. R. China
| | - Dankai Wu
- Department of OrthopedicsThe Second Hospital of Jilin University Changchun 130041 P. R. China
| | - Jianxun Ding
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of Sciences Changchun 130022 P. R. China
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The effect of two locally administered anti-resorptive agents on bone regeneration in a rat fibula model: Alendronate and 15-deoxy-Δ12,14-prostaglandin J2. J Craniomaxillofac Surg 2019; 47:1758-1766. [DOI: 10.1016/j.jcms.2018.04.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 03/29/2018] [Accepted: 04/19/2018] [Indexed: 11/17/2022] Open
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Li Y, Kong N, Li Z, Tian R, Liu X, Liu G, Wang K, Yang P. Bone marrow macrophage M2 polarization and adipose-derived stem cells osteogenic differentiation synergistically promote rehabilitation of bone damage. J Cell Biochem 2019; 120:19891-19901. [PMID: 31338874 DOI: 10.1002/jcb.29297] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 06/27/2019] [Indexed: 12/11/2022]
Abstract
By differentiating into and the balance being regulated between M1 (pro-inflammatory) and M2 (anti-inflammatory) heterogeneous populations, macrophages play critical roles during the host immune response in various physiological contexts in both health and diseases. Besides regulating innate and adaptive immune capacity, macrophages are also decisively involved in tissue homeostasis. However, how resident macrophages are regulated after tissue damages is still far from elucidation. In the present study, we found that adipose-derived stem cells (ADSCs) apparently promote bone defect rehabilitation in vivo via skewing differentiation of bone marrow-derived macrophage (BMDMs) towards anti-inflammatory M2 macrophages. In vitro data demonstrated that although ADSCs have the potential to differentiate to osteoblasts and adipose cells by using standard tissue culture-differentiating conditions, these mesenchymal progenitors are mainly regulated to differentiate into osteoblasts with overexpressed runt-related transcription factor 2, osteoprotegerin, osterix, and downregulated receptor activator of nuclear factor κB ligand in the presence of BMDMs-conditioned medium. Whereas BMDMs are polarized toward M2 macrophages with higher levels of arginase 1 and mannose receptor, but lower levels of inducible nitric oxide synthase and tumor necrosis factor-α when cocultured with ADSCs. In short, all these findings collectively demonstrated that ADSCs and resident host cells can synergistically contribute to the bony repair through mutual regulation of their differentiation and cytokine secretion.
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Affiliation(s)
- Yiyang Li
- Department of Bone and Joint Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, Shannxi Province, 710004, China
| | - Ning Kong
- Department of Bone and Joint Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, Shannxi Province, 710004, China
| | - Zhe Li
- Department of Bone and Joint Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, Shannxi Province, 710004, China
| | - Run Tian
- Department of Bone and Joint Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, Shannxi Province, 710004, China
| | - Xiaohui Liu
- Department of Bone and Joint Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, Shannxi Province, 710004, China
| | - Guanzhi Liu
- Department of Bone and Joint Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, Shannxi Province, 710004, China
| | - Kunzheng Wang
- Department of Bone and Joint Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, Shannxi Province, 710004, China
| | - Pei Yang
- Department of Bone and Joint Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, Shannxi Province, 710004, China
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Koulouktsi C, Nanaki S, Barmpalexis P, Kostoglou M, Bikiaris D. Preparation and characterization of Alendronate depot microspheres based on novel poly(-ε-caprolactone)/Vitamin E TPGS copolymers. INTERNATIONAL JOURNAL OF PHARMACEUTICS-X 2019; 1:100014. [PMID: 31517279 PMCID: PMC6733287 DOI: 10.1016/j.ijpx.2019.100014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 04/18/2019] [Accepted: 04/21/2019] [Indexed: 12/12/2022]
Abstract
In the present study, new aledronate (AL) loaded microspheres were prepared with the use of polycaprolactone (PCL)/Vitamin E d-ɑ-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) copolymers. Specifically, PCL-TPGS copolymers, prepared at several PCL to TPGS ratios (namely, 90/10, 80/20, 70/30 and 60/40 w/w) via a ring opening polymerization process, were characterized by intrinsic viscosity, proton nuclear magnetic resonance (1H NMR), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and enzymatic hydrolysis. Results showed that as TPGS content increases the intrinsic viscosity of the copolymer (and hence, the viscosity-average molecular weight) is decreasing, while FTIR analysis showed the formation of hydrogen bonds between the —C
Created by potrace 1.16, written by Peter Selinger 2001-2019
]]>O of PCL and the —OH of TPGS. Additionally, XRD analysis indicated that the prepared copolymers were semi-crystalline in nature, while enzymatic hydrolysis studies showed that increasing TGPS content led to increasing copolymer hydrolysis. In the following step, AL drug-loaded microspheres were prepared via single emulsification process. Scanning electron microscopy (SEM) revealed the formation of coarse drug-loaded microspheres with particle size close to 5 μm, while XRD analysis showed that the API was amorphously dispersed only in the cases of high TPGS content. Furthermore, FTIR analysis showed that the API did not interact with the copolymer components, while in vitro drug release studies showed that increasing PCL content led to decreasing API release rate. Finally, analysis of the drug release profiles suggested that the API release mechanism was solely governed by the polymer matrix erosion.
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Affiliation(s)
- Christina Koulouktsi
- Laboratory of Polymer Chemistry and Technology, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
| | - Stavroula Nanaki
- Laboratory of Polymer Chemistry and Technology, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
| | - Panagiotis Barmpalexis
- Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
| | - Margaritis Kostoglou
- Laboratory of General and Inorganic Chemical Technology, Department of Chemistry, Aristotle University of Thessaloniki, GR-541 24 Thessaloniki, Greece
| | - Dimitrios Bikiaris
- Laboratory of Polymer Chemistry and Technology, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
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Histologic and Radiographic Characteristics of Bone Filler Under Bisphosphonates. J Craniofac Surg 2019; 30:1085-1088. [PMID: 30908448 DOI: 10.1097/scs.0000000000005517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Dental implants and bone augmentation are well-established procedures used for oral rehabilitation. There is an increasing interest in biological mediators used topically for prevention of bone resorption maybe enhancement of osseointegration of dental implants. The purpose of the manuscript is to describe preliminarily the effect of bisphosphonates on the ossification pattern of bone grafts in a rat model. MATERIAL AND METHODS Twenty Wistar-derived male rats were divided into 2 groups study and control. Bone substitute was added to mandibular defects and was covered by a resorbable collagen membrane. In the study group, the membrane was soaked with bisphosphonates suspension. In the control group, the membrane was soaked with saline solution. Radiographic and histomorphometric evaluation were performed. RESULTS Radiographically, it was found that bone density was significantly higher in the study group. Histomorphometric analysis revealed a trend of higher bone volume fraction along with reduced bone substitute volume fraction in the study group, and increased number of osteoclasts and blood vessels in the control group. CONCLUSIONS Within the limitations of our study it was found that there is a trend of increasing bone quantity and radiographic bone density by application of bisphosphonates.
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Zoledronate Enhances Osteocyte-Mediated Osteoclast Differentiation by IL-6/RANKL Axis. Int J Mol Sci 2019; 20:ijms20061467. [PMID: 30909508 PMCID: PMC6471260 DOI: 10.3390/ijms20061467] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 03/15/2019] [Accepted: 03/21/2019] [Indexed: 12/13/2022] Open
Abstract
Bisphosphonates are one of the most widely used synthetic pyrophosphate analogues for the treatment of bone resorbing diseases such as osteoporosis, multiple myeloma, and bone metastases. Although the therapeutic usefulness of bisphosphonates mainly depends on their anti-osteoclastogenic effect, a severe side-effect of bisphosphonates called bisphosphonate-related osteonecrosis of the jaw (BRONJ) could not be explained by the anti-osteoclastogenic effect of bisphosphonates. In the present study, we have evaluated the changes in osteoclastogenesis- or osteoblastogenesis-supporting activities of osteocytes induced by bisphosphonates. Zoledronate, a nitrogen-containing bisphosphonate, markedly increased both the receptor activator of nuclear factor kB ligand (RANKL) as well as sclerostin in osteocyte-like MLO-Y4 cells, which were functionally revalidated by osteoclast/osteoblast generating activities of the conditioned medium obtained from zoledronate-treated MLO-Y4 cells. Of note, the zoledronate treatment-induced upregulation of the RANKL expression was mediated by autocrine interleukin-6 (IL-6) and subsequent activation of the signal transducer and activator of transcription 3 (STAT3) pathway. These results were evidenced by the blunted RANKL expression in the presence of a Janus activated kinase (JAK2)/STAT3 inhibitor, AG490. Also, the osteoclastogenesis-supporting activity was significantly decreased in zoledronate-treated MLO-Y4 cells in the presence of IL-6 neutralizing IgG compared to that of the control IgG. Thus, our results show previously unanticipated effects of anti-bone resorptive bisphosphonate and suggest a potential clinical importance of osteocytes in BRONJ development.
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O'Neill E, Rajpura K, Carbone EJ, Awale G, Kan HM, Lo KWH. Repositioning Tacrolimus: Evaluation of the Effect of Short-Term Tacrolimus Treatment on Osteoprogenitor Cells and Primary Cells for Bone Regenerative Engineering. Assay Drug Dev Technol 2019; 17:77-88. [DOI: 10.1089/adt.2018.876] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Edward O'Neill
- Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
- The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
- Division of Endocrinology, Department of Medicine, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
| | - Komal Rajpura
- Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
- The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
- Connecticut Institute for Clinical and Translational Science, University of Connecticut Health Center, Farmington, Connecticut
| | - Erica J. Carbone
- Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
- The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
- Division of Endocrinology, Department of Medicine, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
- UConn Stem Cell Institute, University of Connecticut Health Center, Farmington, Connecticut
| | - Guleid Awale
- Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
- The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
| | - Ho-Man Kan
- Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
- The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
- Department of Orthopaedic Surgery, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
| | - Kevin W.-H. Lo
- Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
- The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
- Division of Endocrinology, Department of Medicine, University of Connecticut Health Center, School of Medicine, Farmington, Connecticut
- Connecticut Institute for Clinical and Translational Science, University of Connecticut Health Center, Farmington, Connecticut
- UConn Stem Cell Institute, University of Connecticut Health Center, Farmington, Connecticut
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Giannasi C, Niada S, Farronato D, Lombardi G, Manfredi B, Farronato G, Brini AT. Nitrogen Containing Bisphosphonates Impair the Release of Bone Homeostasis Mediators and Matrix Production by Human Primary Pre-Osteoblasts. Int J Med Sci 2019; 16:23-32. [PMID: 30662325 PMCID: PMC6332484 DOI: 10.7150/ijms.27470] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 10/11/2018] [Indexed: 12/22/2022] Open
Abstract
Bisphosphonates (BPs) represent the first-line treatment for a wide array of bone disorders. Despite their well-known action on osteoclasts, the effects they induce on osteoblasts are still unclear. In order to shed light on this aspect we evaluated the impact of two nitrogen containing bisphosphonates, Alendronate (ALN) and Zoledronate (ZOL), on human primary pre-osteoblasts. At first, we showed an inhibitory effect on cell viability and alkaline phosphatase activity starting from µM concentrations of both drugs. In addition, an inhibitory trend on mineralized nodules deposition was observed. Then low doses of both ALN and ZOL rapidly increased the release of the pro-inflammatory mediators TNFα and IL-1β, while increased DKK-1 and Sclerostin, both inhibitors of osteoblastogenesis. Finally, ALN and 10-7M ZOL decreased the expression of type I Collagen and Osteopontin, while both drugs slightly stimulated SPARC production. With these results, we would like to suggest a direct inhibitory action on bone-forming cells by nitrogen containing bisphosphonates.
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Affiliation(s)
- Chiara Giannasi
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.,IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | | | - Davide Farronato
- Department of Medicine and Surgery, Insubria University, Varese, Italy
| | | | - Barbara Manfredi
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
| | - Giampietro Farronato
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.,IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Anna Teresa Brini
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.,IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
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42
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Zhu B, Xu W, Liu J, Ding J, Chen X. Osteoinductive Agents-Incorporated Three-Dimensional Biphasic Polymer Scaffold for Synergistic Bone Regeneration. ACS Biomater Sci Eng 2018; 5:986-995. [PMID: 33405789 DOI: 10.1021/acsbiomaterials.8b01371] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Large-scale bone defects are difficult to be regenerated entirely in the clinical practice. Bone tissue engineering has drawn more attention as an alternative to bone grafting owing to its convenience and flexibility. However, the low bioactivity of scaffolds and adverse effects of growth factors have hindered its practical application. Herein, the properties of poly(lactic-co-glycolic acid) (PLGA) scaffold, including hydrophilicity and mechanical strength, were improved by a gelatin coating incorporated with two small molecules, alendronate (ALD) and naringin (NG). Interestingly, these two drugs demonstrated a synergistic effect for the repair of rat calvarial defect, as ALD had an inhibitory impact on osteoclast activity and NG had an osteogenic effect on mesenchymal stem cells. From the results of histopathological staining and microcomputed tomography, the PLGA scaffold incorporated with gelatin, ALD, and NG (PLGA+Gelatin/ALD/NG) almost completely repaired the rat calvarial defect with physiological integrity at 16 weeks. In all, this biphasic scaffold can be a promising alternative to the conventional scaffold for clinical application.
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Affiliation(s)
- Bitao Zhu
- Department of Bone and Joint Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130041, P.R. China.,Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, P.R. China
| | - Weiguo Xu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, P.R. China.,Jilin Biomedical Polymers Engineering Laboratory, 5625 Renmin Street, Changchun 130022, P.R. China
| | - Jianguo Liu
- Department of Bone and Joint Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130041, P.R. China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, P.R. China.,Jilin Biomedical Polymers Engineering Laboratory, 5625 Renmin Street, Changchun 130022, P.R. China
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, P.R. China.,Jilin Biomedical Polymers Engineering Laboratory, 5625 Renmin Street, Changchun 130022, P.R. China
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43
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Wang CZ, Wang YH, Lin CW, Lee TC, Fu YC, Ho ML, Wang CK. Combination of a Bioceramic Scaffold and Simvastatin Nanoparticles as a Synthetic Alternative to Autologous Bone Grafting. Int J Mol Sci 2018; 19:ijms19124099. [PMID: 30567319 PMCID: PMC6321089 DOI: 10.3390/ijms19124099] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 11/28/2018] [Accepted: 12/14/2018] [Indexed: 01/01/2023] Open
Abstract
The fragile nature of porous bioceramic substitutes cannot match the toughness of bone, which limits the use of these materials in clinical load-bearing applications. Statins can enhance bone healing, but it could show rhabdomyolysis/inflammatory response after overdosing. In this study, the drug-containing bone grafts were developed from poly(lactic acid-co-glycolic acid)-polyethylene glycol (PLGA-PEG) nanoparticles encapsulating simvastatin (SIM) (SIM-PP NPs) loaded within an appropriately mechanical bioceramic scaffold (BC). The combination bone graft provides dual functions of osteoconduction and osteoinduction. The mechanical properties of the bioceramic are enhanced mainly based on the admixture of a combustible reverse-negative thermoresponsive hydrogel (poly(N-isopropylacrylamide base). We showed that SIM-PP NPs can increase the activity of alkaline phosphatase and osteogenic differentiation of bone marrow stem cells. To verify the bone-healing efficacy of this drug-containing bone grafts, a nonunion radial endochondral ossification bone defect rabbit model (N = 3/group) and a nonunion calvarial intramembranous defect Sprague Dawley (SD) rat model (N = 5/group) were used. The results indicated that SIM-PP NPs combined with BC can improve the healing of nonunion bone defects of the radial bone and calvarial bone. Therefore, the BC containing SIM-PP NPs may be appropriate for clinical use as a synthetic alternative to autologous bone grafting that can overcome the problem of determining the clinical dosage of simvastatin drugs to promote bone healing.
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Affiliation(s)
- Chau-Zen Wang
- Orthopedic Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Physiology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
| | - Yan-Hsiung Wang
- Orthopedic Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- School of Dentistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Che-Wei Lin
- Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Tien-Ching Lee
- Orthopedic Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Yin-Chih Fu
- Orthopedic Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Orthopedics, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung 812, Taiwan.
| | - Mei-Ling Ho
- Orthopedic Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Physiology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
| | - Chih-Kuang Wang
- Orthopedic Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
- Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
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Wu R, Ruan J, Sun Y, Liu M, Sha Z, Fan C, Wu Q. Long non-coding RNA HIF1A-AS2 facilitates adipose-derived stem cells (ASCs) osteogenic differentiation through miR-665/IL6 axis via PI3K/Akt signaling pathway. Stem Cell Res Ther 2018; 9:348. [PMID: 30545407 PMCID: PMC6293597 DOI: 10.1186/s13287-018-1082-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 10/10/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022] Open
Abstract
Background This study was aimed to investigate the role and specific molecular mechanism of HIF1A-AS2/miR-665/IL6 axis in regulating osteogenic differentiation of adipose-derived stem cells (ASCs) via the PI3K/Akt signaling pathway. Methods RNAs’ expression profile in normal/osteogenic differentiation-induced ASCs (osteogenic group) was from the Gene Expression Omnibus database. The analysis was carried out using Bioconductor of R. Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes dataset were applied to identify up- and downregulated signaling pathways. Co-expression network of specific lncRNAs and mRNAs was structured by Cytoscape, while binding sites amongst lncRNA, mRNA, and miRNA were predicted by TargetScan and miRanda. ASCs were derived from human adipose tissue and were authenticated by flow cytometry. ASC cell function was surveyed by alizarin red and alkaline phosphatase (ALP) staining. Molecular mechanism of HIF1A-AS2/miR-665/IL6 axis was investigated by RNAi, cell transfection, western blot, and qRT-PCR. RNA target relationships were validated by dual-luciferase assay. Results HIF1A-AS2 and IL6 were highly expressed while miR-665 was lowly expressed in induced ASCs. HIF1A-AS2 and IL6 improved the expression level of osteoblast markers Runx2, Osterix, and Osteocalcin and also accelerated the formation of calcium nodule and ALP activity, yet miR-665 had opposite effects. HIF1A-AS2 directly targeted miR-665, whereas miR-665 repressed IL6 expression. Moreover, the HIF1A-AS2/miR-665/IL6 regulating axis activated the PI3K/Akt signaling pathway. Conclusions LncRNA HIF1A-AS2 could sponge miR-665 and hence upregulate IL6, activate the PI3K/Akt signaling pathway, and ultimately promote ASC osteogenic differentiation. Electronic supplementary material The online version of this article (10.1186/s13287-018-1082-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ruoyu Wu
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Jihao Ruan
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600 Yishan Road, Xuhui District, Shanghai, 200233, China
| | - Yongjin Sun
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Mengyu Liu
- Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Zhuang Sha
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Cunyi Fan
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600 Yishan Road, Xuhui District, Shanghai, 200233, China.
| | - Qingkai Wu
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600 Yishan Road, Xuhui District, Shanghai, 200233, China. .,Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
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45
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Hyaluronan microenvironment enhances cartilage regeneration of human adipose-derived stem cells in a chondral defect model. Int J Biol Macromol 2018; 119:726-740. [DOI: 10.1016/j.ijbiomac.2018.07.054] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 06/28/2018] [Accepted: 07/11/2018] [Indexed: 12/22/2022]
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46
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Turnbull G, Clarke J, Picard F, Riches P, Jia L, Han F, Li B, Shu W. 3D bioactive composite scaffolds for bone tissue engineering. Bioact Mater 2018; 3:278-314. [PMID: 29744467 PMCID: PMC5935790 DOI: 10.1016/j.bioactmat.2017.10.001] [Citation(s) in RCA: 627] [Impact Index Per Article: 89.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 10/31/2017] [Accepted: 10/31/2017] [Indexed: 12/13/2022] Open
Abstract
Bone is the second most commonly transplanted tissue worldwide, with over four million operations using bone grafts or bone substitute materials annually to treat bone defects. However, significant limitations affect current treatment options and clinical demand for bone grafts continues to rise due to conditions such as trauma, cancer, infection and arthritis. Developing bioactive three-dimensional (3D) scaffolds to support bone regeneration has therefore become a key area of focus within bone tissue engineering (BTE). A variety of materials and manufacturing methods including 3D printing have been used to create novel alternatives to traditional bone grafts. However, individual groups of materials including polymers, ceramics and hydrogels have been unable to fully replicate the properties of bone when used alone. Favourable material properties can be combined and bioactivity improved when groups of materials are used together in composite 3D scaffolds. This review will therefore consider the ideal properties of bioactive composite 3D scaffolds and examine recent use of polymers, hydrogels, metals, ceramics and bio-glasses in BTE. Scaffold fabrication methodology, mechanical performance, biocompatibility, bioactivity, and potential clinical translations will be discussed.
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Affiliation(s)
- Gareth Turnbull
- Department of Biomedical Engineering, Wolfson Building, University of Strathclyde, 106 Rottenrow, Glasgow, G4 0NW, United Kingdom
- Department of Orthopaedic Surgery, Golden Jubilee National Hospital, Agamemnon St, Clydebank, G81 4DY, United Kingdom
| | - Jon Clarke
- Department of Orthopaedic Surgery, Golden Jubilee National Hospital, Agamemnon St, Clydebank, G81 4DY, United Kingdom
| | - Frédéric Picard
- Department of Biomedical Engineering, Wolfson Building, University of Strathclyde, 106 Rottenrow, Glasgow, G4 0NW, United Kingdom
- Department of Orthopaedic Surgery, Golden Jubilee National Hospital, Agamemnon St, Clydebank, G81 4DY, United Kingdom
| | - Philip Riches
- Department of Biomedical Engineering, Wolfson Building, University of Strathclyde, 106 Rottenrow, Glasgow, G4 0NW, United Kingdom
| | - Luanluan Jia
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Soochow University, Suzhou, Jiangsu, PR China
| | - Fengxuan Han
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Soochow University, Suzhou, Jiangsu, PR China
| | - Bin Li
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Soochow University, Suzhou, Jiangsu, PR China
| | - Wenmiao Shu
- Department of Biomedical Engineering, Wolfson Building, University of Strathclyde, 106 Rottenrow, Glasgow, G4 0NW, United Kingdom
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Miron RJ, Zhang Y. Autologous liquid platelet rich fibrin: A novel drug delivery system. Acta Biomater 2018; 75:35-51. [PMID: 29772345 DOI: 10.1016/j.actbio.2018.05.021] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 04/24/2018] [Accepted: 05/14/2018] [Indexed: 02/07/2023]
Abstract
There is currently widespread interest within the biomaterial field to locally deliver biomolecules for bone and cartilage regeneration. Substantial work to date has focused on the potential role of these biomolecules during the healing process, and the carrier system utilized is a key factor in their effectiveness. Platelet rich fibrin (PRF) is a naturally derived fibrin scaffold that is easily obtained from peripheral blood following centrifugation. Slower centrifugation speeds have led to the commercialization of a liquid formulation (liquid-PRF) resulting in an upper plasma layer composed of liquid fibrinogen/thrombin prior to clot formation that remains in its liquid phase for approximately 15 min until injected into bodily tissues. Herein, we introduce the use of liquid PRF as an advanced local delivery system for small and large biomolecules. Potential target molecules including large (growth factors/cytokines and morphogenetic/angiogenic factors), as well as small (antibiotics, peptides, gene therapy and anti-osteoporotic) molecules are considered potential candidates for enhanced bone/cartilage tissue regeneration. Furthermore, liquid-PRF is introduced as a potential carrier system for various cell types and nano-sized particles that are capable of limiting/by-passing the immune system and minimizing potential foreign body reactions within host tissues following injection. STATEMENT OF SIGNIFICANCE There is currently widespread interest within the biomaterial field to locally deliver biomolecules for bone and cartilage regeneration. This review article focuses on the use of a liquid version of platelet rich fibrin (PRF) composed of liquid fibrinogen/thrombin as a drug delivery system. Herein, we introduce the use of liquid PRF as an advanced local delivery system for small and large biomolecules including growth factors, cytokines and morphogenetic/angiogenic factors, as well as antibiotics, peptides, gene therapy and anti-osteoporotic molecules as potential candidates for enhanced bone/cartilage tissue regeneration.
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Enhancement of chondrogenesis of adipose-derived stem cells in HA-PNIPAAm-CL hydrogel for cartilage regeneration in rabbits. Sci Rep 2018; 8:10526. [PMID: 30002442 PMCID: PMC6043528 DOI: 10.1038/s41598-018-28893-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 06/18/2018] [Indexed: 02/06/2023] Open
Abstract
Injectable thermoresponsive hydrogels have the advantages of effective cell delivery and minimal invasion for tissue engineering applications. In this study, we investigated the chondroinductive potential of newly developed hyaluronic acid (HA)-modified thermoresponsive poly(N-isopropylacrylamide) (HA-PNIPAAm-CL) hydrogels on enhancing rabbit ADSC (rADSC) chondrogenesis in vitro and in the synovial cavity of rabbit. The HA-mixed PNIPAAm (HA-PNIPAAm-CP) and HA-cross-linked PNIPAAm (HA-PNIPAAm-CL) were fabricated using physical interaction and chemical cross-linking methods, respectively. The in vitro results showed that, compared to unmodified PNIPAAm, both HA-modified hydrogels significantly increased cell viability, chondrogenic marker gene (aggrecan and type II collagen) expression and sulfide glycosaminoglycan (sGAG) formation in embedded rADSCs. However, HA-PNIPAAm-CL showed the highest rADSC viability and chondrogenesis. The chondrogenic effects of HA-modified hydrogels on rADSCs were confirmed in vivo by the intraarticular injection of hydrogel-embedded rADSC constructs into rabbit synovial cavities for 3 weeks and tracing with CM-DiI labeling. Neocartilage formation in the hydrogels was determined by histomorphological staining of GAG and type II collagen. In vivo injected rADSC/HA-PNIPAAm-CL constructs showed more hyaline cartilage formation than that of rADSC/HA-PNIPAAm-CP and rADSC/PNIPAAm constructs in the synovial cavity of rabbit. These results suggest that the HA-PNIPAAm-CL provides a suitable microenvironment to enhance ADSC chondrogenesis for articular cartilage tissue engineering applications.
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49
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Kwak EJ, Cha IH, Nam W, Yook JI, Park YB, Kim HJ. Effects of locally administered rhBMP-2 and bisphosphonate on bone regeneration in the rat fibula. Oral Dis 2018; 24:1042-1056. [DOI: 10.1111/odi.12864] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 02/23/2018] [Accepted: 03/16/2018] [Indexed: 12/25/2022]
Affiliation(s)
- E-J Kwak
- Department of Oral and Maxillofacial Surgery; College of Dentistry; Yonsei University; Seoul Korea
| | - I-H Cha
- Department of Oral and Maxillofacial Surgery; College of Dentistry; Yonsei University; Seoul Korea
| | - W Nam
- Department of Oral and Maxillofacial Surgery; College of Dentistry; Yonsei University; Seoul Korea
| | - JI Yook
- Department of Oral Pathology; College of Dentistry; Yonsei University; Seoul Korea
| | - Y-B Park
- Department of Prosthodontics; College of Dentistry; Yonsei University; Seoul Korea
| | - HJ Kim
- Department of Oral and Maxillofacial Surgery; College of Dentistry; Yonsei University; Seoul Korea
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50
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Wu SC, Chen CH, Wang JY, Lin YS, Chang JK, Ho ML. Hyaluronan size alters chondrogenesis of adipose-derived stem cells via the CD44/ERK/SOX-9 pathway. Acta Biomater 2018; 66:224-237. [PMID: 29128538 DOI: 10.1016/j.actbio.2017.11.025] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 11/02/2017] [Accepted: 11/07/2017] [Indexed: 12/23/2022]
Abstract
Hyaluronan (HA) is a natural linear polymer that is one of the main types of extracellular matrix during the early stage of chondrogenesis. We found that the chondrogenesis of adipose-derived stem cells (ADSCs) can be initiated and promoted by the application of HA to mimic the chondrogenic niche. The aim of this study is to investigate the optimal HA molecular weight (Mw) for chondrogenesis of ADSCs and the detailed mechanism. In this study, we investigated the relationships among HA Mw, CD44 clustering, and the extracellular signal-regulated kinase (ERK)/SOX-9 pathway during chondrogenesis of ADSCs. Human ADSCs (hADSCs) and rabbit ADSCs (rADSCs) were isolated and expanded. Chondrogenesis was induced in rADSCs by culturing cells in HA-coated wells (HA Mw: 80 kDa, 600 kDa and 2000 kDa) and evaluated by examining cell aggregation, chondrogenic gene expression (collagen type II and aggrecan) and sulfated glycosaminoglycan (sGAG) deposition in vitro. Cartilaginous tissue formation in vivo was confirmed by implanting HA/rADSCs into joint cavities. CD44 clustering, ERK phosphorylation, SOX-9 expression and SOX-9 phosphorylation in cultured hADSCs were further evaluated. Isolated and expanded rADSCs showed multilineage potential and anchorage-independent growth properties. Cell aggregation, chondrogenic gene expression, and sGAG deposition increased with increasing HA Mw in rADSCs. The 2000 kDa HA had the most pronounced chondrogenic effect on rADSCs in vitro, and implanted 2000 kDa HA/rADSCs exhibited marked cartilaginous tissue formation in vivo. CD44 clustering and cell aggregation of hADSCs were enhanced by an increase in HA Mw. In addition, higher HA Mws further enhanced CD44 clustering, ERK phosphorylation, and SOX-9 expression and phosphorylation in hADSCs. Inhibiting CD44 clustering in hADSCs reduced HA-induced chondrogenic gene expression. Inhibiting ERK phosphorylation also simultaneously attenuated HA-induced SOX-9 expression and phosphorylation and chondrogenic gene expression in hADSCs. Our results indicate that HA initiates ADSC chondrogenesis and that higher Mw HAs exhibit stronger effects, with 2000 kDa HA having the strongest effect. These effects may be mediated through increased CD44 clustering and the ERK/SOX-9 signaling pathway. STATEMENT OF SIGNIFICANCE HA-based biomaterials have been studied in stem cell-based articular cartilage tissue engineering. However, little is known about the optimal HA size for stem cell chondrogenesis and the mechanism of how HA size modulates stem cell chondrogenesis. Accordingly, we used HAs with various Mws (80-2000 kDa) as culture substrates and tested their chondrogenic effect on ADSCs. Our results demonstrated that HAs with a Mw of 2000 kDa showed the optimal effect for chondrogenesis of ADSCs. Moreover, we found that HA size can regulate ADSC chondrogenesis via the CD44/ERK/SOX-9 pathway. This finding provides new information regarding the biochemical control of chondrogenesis by HA substrates that may add value to the development of HA-based biomaterials for articular cartilage regeneration.
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Affiliation(s)
- Shun-Cheng Wu
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Hwan Chen
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Orthopaedics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Adult Reconstruction Surgery, Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jyun-Ya Wang
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Shan Lin
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Je-Ken Chang
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Orthopaedics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Adult Reconstruction Surgery, Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Mei-Ling Ho
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
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