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Augustine R, Gezek M, Nikolopoulos VK, Buck PL, Bostanci NS, Camci-Unal G. Stem Cells in Bone Tissue Engineering: Progress, Promises and Challenges. Stem Cell Rev Rep 2024; 20:1692-1731. [PMID: 39028416 DOI: 10.1007/s12015-024-10738-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2024] [Indexed: 07/20/2024]
Abstract
Bone defects from accidents, congenital conditions, and age-related diseases significantly impact quality of life. Recent advancements in bone tissue engineering (TE) involve biomaterial scaffolds, patient-derived cells, and bioactive agents, enabling functional bone regeneration. Stem cells, obtained from numerous sources including umbilical cord blood, adipose tissue, bone marrow, and dental pulp, hold immense potential in bone TE. Induced pluripotent stem cells and genetically modified stem cells can also be used. Proper manipulation of physical, chemical, and biological stimulation is crucial for their proliferation, maintenance, and differentiation. Stem cells contribute to osteogenesis, osteoinduction, angiogenesis, and mineralization, essential for bone regeneration. This review provides an overview of the latest developments in stem cell-based TE for repairing and regenerating defective bones.
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Affiliation(s)
- Robin Augustine
- Department of Radiology, Stanford Medicine, Stanford University, Palo Alto, CA, 94304, USA
- Department of Chemical Engineering, University of Massachusetts, Lowell, MA, 01854, USA
| | - Mert Gezek
- Department of Chemical Engineering, University of Massachusetts, Lowell, MA, 01854, USA
- Biomedical Engineering and Biotechnology Graduate Program, University of Massachusetts, Lowell, MA, 01854, USA
| | | | - Paige Lauren Buck
- Department of Chemical Engineering, University of Massachusetts, Lowell, MA, 01854, USA
- Biomedical Engineering and Biotechnology Graduate Program, University of Massachusetts, Lowell, MA, 01854, USA
| | - Nazli Seray Bostanci
- Department of Chemical Engineering, University of Massachusetts, Lowell, MA, 01854, USA
- Biomedical Engineering and Biotechnology Graduate Program, University of Massachusetts, Lowell, MA, 01854, USA
| | - Gulden Camci-Unal
- Department of Chemical Engineering, University of Massachusetts, Lowell, MA, 01854, USA.
- Department of Surgery, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
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Zhao F, Qiu Y, Liu W, Zhang Y, Liu J, Bian L, Shao L. Biomimetic Hydrogels as the Inductive Endochondral Ossification Template for Promoting Bone Regeneration. Adv Healthc Mater 2024; 13:e2303532. [PMID: 38108565 DOI: 10.1002/adhm.202303532] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 12/10/2023] [Indexed: 12/19/2023]
Abstract
Repairing critical size bone defects (CSBD) is a major clinical challenge and requires effective intervention by biomaterial scaffolds. Inspired by the fact that the cartilaginous template-based endochondral ossification (ECO) process is crucial to bone healing and development, developing biomimetic biomaterials to promote ECO is recognized as a promising approach for repairing CSBD. With the unique highly hydrated 3D polymeric network, hydrogels can be designed to closely emulate the physiochemical properties of cartilage matrix to facilitate ECO. In this review, the various preparation methods of hydrogels possessing the specific physiochemical properties required for promoting ECO are introduced. The materiobiological impacts of the physicochemical properties of hydrogels, such as mechanical properties, topographical structures and chemical compositions on ECO, and the associated molecular mechanisms related to the BMP, Wnt, TGF-β, HIF-1α, FGF, and RhoA signaling pathways are further summarized. This review provides a detailed coverage on the materiobiological insights required for the design and preparation of hydrogel-based biomaterials to facilitate bone regeneration.
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Affiliation(s)
- Fujian Zhao
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, P. R. China
| | - Yonghao Qiu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, P. R. China
| | - Wenjing Liu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, P. R. China
| | - Yanli Zhang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, P. R. China
| | - Jia Liu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, P. R. China
| | - Liming Bian
- School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 511442, P. R. China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, P. R. China
- Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou, 510006, P. R. China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou, 510006, P. R. China
| | - Longquan Shao
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, P. R. China
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Guangzhou, 510515, P. R. China
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Cárdenas-Aguazaco W, Lara-Bertrand AL, Prieto-Abello L, Barreto-López N, Camacho B, Silva-Cote I. Exploring calcium-free alternatives in endochondral bone repair tested on In vivo trials - A review. Regen Ther 2024; 26:145-160. [PMID: 38872977 PMCID: PMC11169084 DOI: 10.1016/j.reth.2024.05.017] [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: 03/28/2024] [Revised: 05/10/2024] [Accepted: 05/26/2024] [Indexed: 06/15/2024] Open
Abstract
Bone repair via endochondral ossification is a complex process for the critical size reparation of bone defects. Tissue engineering strategies are being developed as alternative treatments to autografts or allografts. Most approaches to bone regeneration involve the use of calcium composites. However, exploring calcium-free alternatives in endochondral bone repair has emerged as a promising way to contribute to bone healing. By analyzing researches from the last ten years, this review identifies the potential benefits of such alternatives compared to traditional calcium-based approaches. Understanding the impact of calcium-free alternatives on endochondral bone repair can have profound implications for orthopedic and regenerative medicine. This review evaluates the efficacy of calcium-free alternatives in endochondral bone repair through in vivo trials. The findings may guide future research to develop innovative strategies to improve endochondral bone repair without relying on calcium. Exploring alternative approaches may lead to the discovery of novel therapies that improve bone healing outcomes.
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Affiliation(s)
- William Cárdenas-Aguazaco
- Unidad de Ingeniería Tisular, Instituto Distrital de Ciencia, Biotecnología e Innovación en Salud-IDCBIS, Colombia
| | - Adriana Lorena Lara-Bertrand
- Unidad de Ingeniería Tisular, Instituto Distrital de Ciencia, Biotecnología e Innovación en Salud-IDCBIS, Colombia
| | - Leonardo Prieto-Abello
- Unidad de Ingeniería Tisular, Instituto Distrital de Ciencia, Biotecnología e Innovación en Salud-IDCBIS, Colombia
| | - Nicolás Barreto-López
- Unidad de Ingeniería Tisular, Instituto Distrital de Ciencia, Biotecnología e Innovación en Salud-IDCBIS, Colombia
| | - Bernardo Camacho
- Unidad de Ingeniería Tisular, Instituto Distrital de Ciencia, Biotecnología e Innovación en Salud-IDCBIS, Colombia
| | - Ingrid Silva-Cote
- Unidad de Ingeniería Tisular, Instituto Distrital de Ciencia, Biotecnología e Innovación en Salud-IDCBIS, Colombia
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Tateiwa D, Iwamoto M, Kodama J, Ukon Y, Hirai H, Ikuta M, Kitahara T, Furuichi T, Bun M, Otsuru S, Okada S, Kaito T. A synthetic retinoic acid receptor γ antagonist (7C)-loaded nanoparticle enhances bone morphogenetic protein-induced bone regeneration in a rat spinal fusion model. Spine J 2024; 24:899-908. [PMID: 38092193 PMCID: PMC11610515 DOI: 10.1016/j.spinee.2023.11.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 10/19/2023] [Accepted: 11/27/2023] [Indexed: 12/25/2023]
Abstract
BACKGROUND CONTEXT Bone morphogenetic proteins (BMPs) have potent osteoinductivity and have been applied clinically for challenging musculoskeletal conditions. However, the supraphysiological doses of BMPs used in clinical settings cause various side effects that prevent widespread use, and therefore the BMP dosage needs to be reduced. PURPOSE To address this problem, we synthesized 7C, a retinoic acid receptor γ antagonist-loaded nanoparticle (NP), and investigated its potential application in BMP-based bone regeneration therapy using a rat spinal fusion model. STUDY DESIGN An experimental animal study. METHODS Fifty-three male 8-week-old Sprague-Dawley rats underwent posterolateral spinal fusion and were divided into the following five treatment groups: (1) no recombinant human (rh)BMP-2 and blank-NP (Control), (2) no rhBMP-2 and 1 μg 7C-NP (7C group), (3) low-dose rhBMP-2 (0.5 μg) and 1 μg blank-NP (L-BMP group), (4) low-dose rhBMP-2 (0.5 μg) and 1 μg 7C-NP (L-BMP + 7C group), and (5) high-dose rhBMP-2 (5.0 μg) and 1 μg blank-NP (H-BMP group). Micro-computed tomography and histologic analysis were performed 2 and 6 weeks after the surgery. RESULTS The spinal fusion rates of the Control and 7C groups were both 0%, and those of the L-BMP, L-BMP + 7C, and H-BMP groups were 55.6%, 94.4%, and 100%, respectively. The L-BMP + 7C group markedly promoted cartilaginous tissue formation during BMP-induced endochondral bone formation that resulted in a significantly better spinal fusion rate and bone formation than in the L-BMP group. Although spinal fusion was slower in the L-BMP + 7C group, the L-BMP + 7C group formed a spinal fusion mass with better bone quality than the spinal fusion mass in the H-BMP group. CONCLUSIONS The combined use of 7C-NP with rhBMP-2 in a rat posterolateral lumbar fusion model increased spinal fusion rate and new bone volume without deteriorating the quality of newly formed bone. CLINICAL SIGNIFICANCE 7C-NP potentiates BMP-2-induced bone regeneration and has the potential for efficient bone regeneration with low-dose BMP-2, which can reduce the dose-dependent side effects of BMP-2 in clinical settings.
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Affiliation(s)
- Daisuke Tateiwa
- Department of Orthopaedic Surgery, Osaka General Medical Center, 3-1-56, Mandaihigashi, Sumiyoshi, Osaka, Japan
| | - Masahiro Iwamoto
- Department of Orthopaedic, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD, USA
| | - Joe Kodama
- Department of Orthopaedic, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD, USA
| | - Yuichiro Ukon
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Hiromasa Hirai
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Masato Ikuta
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Takayuki Kitahara
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Takuya Furuichi
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Masayuki Bun
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Satoru Otsuru
- Department of Orthopaedic, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD, USA
| | - Seiji Okada
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Takashi Kaito
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
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Jeyachandran D, Murshed M, Haglund L, Cerruti M. A Bioglass-Poly(lactic-co-glycolic Acid) Scaffold@Fibrin Hydrogel Construct to Support Endochondral Bone Formation. Adv Healthc Mater 2023; 12:e2300211. [PMID: 37462089 PMCID: PMC11468889 DOI: 10.1002/adhm.202300211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 06/21/2023] [Accepted: 07/05/2023] [Indexed: 07/29/2023]
Abstract
Bone tissue engineering using stem cells to build bone directly on a scaffold matrix often fails due to lack of oxygen at the injury site. This may be avoided by following the endochondral ossification route; herein, a cartilage template is promoted first, which can survive hypoxic environments, followed by its hypertrophy and ossification. However, hypertrophy is so far only achieved using biological factors. This work introduces a Bioglass-Poly(lactic-co-glycolic acid@fibrin (Bg-PLGA@fibrin) construct where a fibrin hydrogel infiltrates and encapsulates a porous Bg-PLGA. The hypothesis is that mesenchymal stem cells (MSCs) loaded in the fibrin gel and induced into chondrogenesis degrade the gel and become hypertrophic upon reaching the stiffer, bioactive Bg-PLGA core, without external induction factors. Results show that Bg-PLGA@fibrin induces hypertrophy, as well as matrix mineralization and osteogenesis; it also promotes a change in morphology of the MSCs at the gel/scaffold interface, possibly a sign of osteoblast-like differentiation of hypertrophic chondrocytes. Thus, the Bg-PLGA@fibrin construct can sequentially support the different phases of endochondral ossification purely based on material cues. This may facilitate clinical translation by decreasing in-vitro cell culture time pre-implantation and the complexity associated with the use of external induction factors.
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Affiliation(s)
| | - Monzur Murshed
- Faculty of DentistryDepartment of Medicineand Shriners Hospital for ChildrenMcGill UniversityMontrealQuebecH4A 0A9Canada
| | - Lisbet Haglund
- Experimental SurgeryMcGill UniversityMontrealH3G 2M1Canada
| | - Marta Cerruti
- Department of Mining and Materials EngineeringMcGill UniversityMontrealH3A 0C1Canada
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6
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Kang Z, Wu B, Zhang L, Liang X, Guo D, Yuan S, Xie D. Metabolic regulation by biomaterials in osteoblast. Front Bioeng Biotechnol 2023; 11:1184463. [PMID: 37324445 PMCID: PMC10265685 DOI: 10.3389/fbioe.2023.1184463] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 05/19/2023] [Indexed: 06/17/2023] Open
Abstract
The repair of bone defects resulting from high-energy trauma, infection, or pathological fracture remains a challenge in the field of medicine. The development of biomaterials involved in the metabolic regulation provides a promising solution to this problem and has emerged as a prominent research area in regenerative engineering. While recent research on cell metabolism has advanced our knowledge of metabolic regulation in bone regeneration, the extent to which materials affect intracellular metabolic remains unclear. This review provides a detailed discussion of the mechanisms of bone regeneration, an overview of metabolic regulation in bone regeneration in osteoblasts and biomaterials involved in the metabolic regulation for bone regeneration. Furthermore, it introduces how materials, such as promoting favorable physicochemical characteristics (e.g., bioactivity, appropriate porosity, and superior mechanical properties), incorporating external stimuli (e.g., photothermal, electrical, and magnetic stimulation), and delivering metabolic regulators (e.g., metal ions, bioactive molecules like drugs and peptides, and regulatory metabolites such as alpha ketoglutarate), can affect cell metabolism and lead to changes of cell state. Considering the growing interests in cell metabolic regulation, advanced materials have the potential to help a larger population in overcoming bone defects.
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Affiliation(s)
- Zhengyang Kang
- Department of Orthopedics, The Second People’s Hospital of Panyu Guangzhou, Guangzhou, China
- Department of Joint Surgery and Sports Medicine, Center for Orthopedic Surgery, Orthopedic Hospital of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Bin Wu
- Department of Orthopedics, The Second People’s Hospital of Panyu Guangzhou, Guangzhou, China
| | - Luhui Zhang
- Department of Joint Surgery and Sports Medicine, Center for Orthopedic Surgery, Orthopedic Hospital of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Xinzhi Liang
- Department of Joint Surgery and Sports Medicine, Center for Orthopedic Surgery, Orthopedic Hospital of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Dong Guo
- Department of Joint Surgery and Sports Medicine, Center for Orthopedic Surgery, Orthopedic Hospital of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Shuai Yuan
- Department of Joint Surgery and Sports Medicine, Center for Orthopedic Surgery, Orthopedic Hospital of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Denghui Xie
- Department of Joint Surgery and Sports Medicine, Center for Orthopedic Surgery, Orthopedic Hospital of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
- Guangxi Key Laboratory of Bone and Joint Degeneration Diseases, Youjiang Medical University For Nationalities, Baise, China
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7
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You Q, Lu M, Li Z, Zhou Y, Tu C. Cell Sheet Technology as an Engineering-Based Approach to Bone Regeneration. Int J Nanomedicine 2022; 17:6491-6511. [PMID: 36573205 PMCID: PMC9789707 DOI: 10.2147/ijn.s382115] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 11/12/2022] [Indexed: 12/24/2022] Open
Abstract
Bone defects that are congenital or the result of infection, malignancy, or trauma represent a challenge to the global healthcare system. To address this issue, multiple research groups have been developing novel cell sheet technology (CST)-based approaches to promote bone regeneration. These methods hold promise for use in regenerative medicine because they preserve cell-cell contacts, cell-extracellular matrix interactions, and the protein makeup of cell membranes. This review introduces the concept and preparation system of the cell sheet (CS), explores the application of CST in bone regeneration, highlights the current states of the bone regeneration via CST, and offers perspectives on the challenges and future research direction of translating current knowledge from the lab to the clinic.
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Affiliation(s)
- Qi You
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China,Sichuan Model Worker and Craftsman Talent Innovation Research Studio, Chengdu, Sichuan Province, People’s Republic of China
| | - Minxun Lu
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China,Sichuan Model Worker and Craftsman Talent Innovation Research Studio, Chengdu, Sichuan Province, People’s Republic of China
| | - Zhuangzhuang Li
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China,Sichuan Model Worker and Craftsman Talent Innovation Research Studio, Chengdu, Sichuan Province, People’s Republic of China
| | - Yong Zhou
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China,Sichuan Model Worker and Craftsman Talent Innovation Research Studio, Chengdu, Sichuan Province, People’s Republic of China
| | - Chongqi Tu
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China,Sichuan Model Worker and Craftsman Talent Innovation Research Studio, Chengdu, Sichuan Province, People’s Republic of China,Correspondence: Chongqi Tu; Yong Zhou, Department of Orthopedics, West China Hospital, Sichuan University, No. 37, Guoxuexiang, Chengdu, 610041, Sichuan Province, People’s Republic of China, Email ;
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Advances in bone regeneration with growth factors for spinal fusion: A literature review. NORTH AMERICAN SPINE SOCIETY JOURNAL 2022; 13:100193. [PMID: 36605107 PMCID: PMC9807829 DOI: 10.1016/j.xnsj.2022.100193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/13/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
Bone tissue is regenerated via the spatiotemporal involvement of various cytokines. Among them, the bone morphogenetic protein (BMP), which plays a vital role in the bone regeneration process, has been applied clinically for the treatment of refractory orthopedic conditions. Although BMP therapy using a collagen carrier has shown efficiency in bone regeneration over the last two decades, a major challenge-considerable side effects associated with the acute release of high doses of BMPs-has also been revealed. To improve BMP efficiency, the development of new carriers and biologics that can be used in conjunction with BMPs is currently underway. In this review, we describe the current status and future prospects of bone regeneration therapy, with a focus on BMPs. Furthermore, we outline the characteristics and molecular signaling pathways involving BMPs, clinical applications of BMPs in orthopedics, clinical results of BMP use in human spinal surgeries, drugs combined with BMPs to provide synergistic effects, and novel BMP carriers.
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Shi J, Dai W, Gupta A, Zhang B, Wu Z, Zhang Y, Pan L, Wang L. Frontiers of Hydroxyapatite Composites in Bionic Bone Tissue Engineering. MATERIALS (BASEL, SWITZERLAND) 2022; 15:ma15238475. [PMID: 36499970 PMCID: PMC9738134 DOI: 10.3390/ma15238475] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/21/2022] [Accepted: 11/25/2022] [Indexed: 05/31/2023]
Abstract
Bone defects caused by various factors may cause morphological and functional disorders that can seriously affect patient's quality of life. Autologous bone grafting is morbid, involves numerous complications, and provides limited volume at donor site. Hence, tissue-engineered bone is a better alternative for repair of bone defects and for promoting a patient's functional recovery. Besides good biocompatibility, scaffolding materials represented by hydroxyapatite (HA) composites in tissue-engineered bone also have strong ability to guide bone regeneration. The development of manufacturing technology and advances in material science have made HA composite scaffolding more closely related to the composition and mechanical properties of natural bone. The surface morphology and pore diameter of the scaffold material are more important for cell proliferation, differentiation, and nutrient exchange. The degradation rate of the composite scaffold should match the rate of osteogenesis, and the loading of cells/cytokine is beneficial to promote the formation of new bone. In conclusion, there is no doubt that a breakthrough has been made in composition, mechanical properties, and degradation of HA composites. Biomimetic tissue-engineered bone based on vascularization and innervation show a promising future.
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Affiliation(s)
- Jingcun Shi
- Department of Oral and Maxillofacial Surgery—Head & Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai 200011, China
- Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, National Center for Stomatology, Shanghai 200011, China
| | - Wufei Dai
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- Shanghai Tissue Engineering Key Laboratory, Shanghai Research Institute of Plastic and Reconstructive Surgey, Shanghai 200011, China
| | - Anand Gupta
- Department of Dentistry, Government Medical College & Hospital, Chandigarh 160017, India
| | - Bingqing Zhang
- Department of Oral and Maxillofacial Surgery—Head & Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai 200011, China
- Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, National Center for Stomatology, Shanghai 200011, China
| | - Ziqian Wu
- Department of Oral and Maxillofacial Surgery—Head & Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai 200011, China
- Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, National Center for Stomatology, Shanghai 200011, China
| | - Yuhan Zhang
- Department of Oral and Maxillofacial Surgery—Head & Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai 200011, China
- Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, National Center for Stomatology, Shanghai 200011, China
| | - Lisha Pan
- College of Stomatology, Shanghai Jiao Tong University, Shanghai 200011, China
- Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, National Center for Stomatology, Shanghai 200011, China
| | - Lei Wang
- Department of Oral and Maxillofacial Surgery—Head & Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai 200011, China
- Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, National Center for Stomatology, Shanghai 200011, China
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10
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Yao Y, Jiang Y, Song J, Wang R, Li Z, Yang L, Wu W, Zhang L, Peng Q. Exosomes as Potential Functional Nanomaterials for Tissue Engineering. Adv Healthc Mater 2022:e2201989. [PMID: 36253093 DOI: 10.1002/adhm.202201989] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 09/14/2022] [Indexed: 11/10/2022]
Abstract
Exosomes are cell-derived extracellular vesicles of 40-160 nm diameter, which carry numerous biomolecules and transmit information between cells. They are used as functional nanomaterials with great potential in biomedical areas, such as active agents and delivery systems for advanced drug delivery and disease therapy. In recent years, potential applications of exosomes in tissue engineering have attracted significant attention, and some critical progress has been made. This review gives a complete picture of exosomes and their applications in the regeneration of various tissues, such as the central nervous systems, kidney, bone, cartilage, heart, and endodontium. Approaches employed for modifying exosomes to equip them with excellent targeting capacity are summarized. Furthermore, current concerns and future outlook of exosomes in tissue engineering are discussed.
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Affiliation(s)
- Yang Yao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Block 3, Renmin Road South, Chengdu, 610041, P. R. China
| | - Yuhuan Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Block 3, Renmin Road South, Chengdu, 610041, P. R. China
| | - Jialu Song
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Block 3, Renmin Road South, Chengdu, 610041, P. R. China
| | - Ruojing Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Block 3, Renmin Road South, Chengdu, 610041, P. R. China
| | - Zhaoping Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Block 3, Renmin Road South, Chengdu, 610041, P. R. China
| | - Lei Yang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Block 3, Renmin Road South, Chengdu, 610041, P. R. China
| | - Weimin Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Block 3, Renmin Road South, Chengdu, 610041, P. R. China
| | - Luyue Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Block 3, Renmin Road South, Chengdu, 610041, P. R. China
| | - Qiang Peng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Block 3, Renmin Road South, Chengdu, 610041, P. R. China
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11
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Therapeutic Efficacy of Adipose-Derived Stem Cells Versus Bone Marrow Stromal Cells for Irradiated Mandibular Fracture Repair. Ann Plast Surg 2022; 89:459-464. [PMID: 36149985 DOI: 10.1097/sap.0000000000003301] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Mesenchymal stem cells have immense potential in applications of bone healing and regeneration. However, few studies have evaluated the therapeutic efficacy of adipose-derived stem cells (ASCs) and bone marrow stromal cells (BMSCs) in irradiated bone. The purpose of this study is to compare the ability of ASCs versus BMSCs to enhance healing outcomes in a murine model of irradiated mandibular fracture repair. METHODS Forty-eight isogenic male Lewis rats underwent radiation therapy followed by mandibular osteotomy with intraoperative placement of either ASCs or BMSCs. Animals were killed on postoperative day 40. Mandibles were analyzed for union rate, biomechanical strength, vascularity, and mineralization. Groups were compared at P < 0.05 significance. RESULTS The ASC and BMSC groups demonstrated 92% and 75% union rates. Compared with the BMSC group, the ASC group demonstrated a trending increase in maximum load ( P = 0.095) on biomechanical strength analysis and a significant increase in vessel number ( P = 0.001), vessel thickness ( P = 0.035), and vessel volume fraction ( P = 0.007) on micro-computed tomography angiography analysis. No significant differences in bone mineralization were identified on micro-computed tomography analysis. CONCLUSION This study demonstrates the superior therapeutic efficacy of ASCs over BMSCs in irradiated fracture healing as evidenced by union rate, vascular morphometry, and a trend in biomechanical strength. We posit that the robust vascular response induced by ASCs better recapitulates the sequence and synchronicity of physiologic bone healing compared with BMSCs, thereby improving the reliability of irradiated fracture repair.
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12
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Khalil AS, Hellenbrand D, Reichl K, Umhoefer J, Filipp M, Choe J, Hanna A, Murphy WL. A Localized Materials-Based Strategy to Non-Virally Deliver Chondroitinase ABC mRNA Improves Hindlimb Function in a Rat Spinal Cord Injury Model. Adv Healthc Mater 2022; 11:e2200206. [PMID: 35882512 PMCID: PMC10031873 DOI: 10.1002/adhm.202200206] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 07/14/2022] [Indexed: 01/27/2023]
Abstract
Spinal cord injury often results in devastating consequences for those afflicted, with very few therapeutic options. A central element of spinal cord injuries is astrogliosis, which forms a glial scar that inhibits neuronal regeneration post-injury. Chondroitinase ABC (ChABC) is an enzyme capable of degrading chondroitin sulfate proteoglycan (CSPG), the predominant extracellular matrix component of the glial scar. However, poor protein stability remains a challenge in its therapeutic use. Messenger RNA (mRNA) delivery is an emerging gene therapy technology for in vivo production of difficult-to-produce therapeutic proteins. Here, mineral-coated microparticles as an efficient, non-viral mRNA delivery vehicles to produce exogenous ChABC in situ within a spinal cord lesion are used. ChABC production reduces the deposition of CSPGs in an in vitro model of astrogliosis, and direct injection of these microparticles within a glial scar forces local overexpression of ChABC and improves recovery of motor function seven weeks post-injury.
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Affiliation(s)
- Andrew S. Khalil
- Department of Biomedical EngineeringUniversity of Wisconsin‐MadisonMadisonWI53705USA
- Department of Orthopedics and RehabilitationUniversity of Wisconsin‐MadisonMadisonWI53705USA
- Present address:
Whitehead Institute for Biomedical ResearchCambridgeMA02142USA
- Present address:
The Wyss Institute for Biologically Inspired EngineeringBostonMA02115USA
| | - Daniel Hellenbrand
- Department of NeurosurgeryUniversity of Wisconsin‐Madison School of Medicine and Public HealthMadisonWI53705USA
| | - Kaitlyn Reichl
- Department of Biomedical EngineeringUniversity of Wisconsin‐MadisonMadisonWI53705USA
- Present address:
Virginia Commonwealth University School of MedicineRichmondVA23298USA
| | - Jennifer Umhoefer
- Department of BiologyUniversity of Wisconsin‐MadisonMadisonWI53705USA
- Present address:
Biomedical Sciences ProgramUniversity of CaliforniaSan FranciscoCA94143USA
| | - Mallory Filipp
- Department of NeurosurgeryUniversity of Wisconsin‐Madison School of Medicine and Public HealthMadisonWI53705USA
- Present address:
Driskill Graduate ProgramNorthwestern University Feinberg School of MedicineChicagoIL60611USA
| | - Joshua Choe
- Department of Biomedical EngineeringUniversity of Wisconsin‐MadisonMadisonWI53705USA
- Department of Orthopedics and RehabilitationUniversity of Wisconsin‐MadisonMadisonWI53705USA
- Medical Scientist Training ProgramUniversity of Wisconsin‐Madison School of Medicine and Public HealthMadisonWI53705USA
| | - Amgad Hanna
- Department of NeurosurgeryUniversity of Wisconsin‐Madison School of Medicine and Public HealthMadisonWI53705USA
| | - William L. Murphy
- Department of Biomedical EngineeringUniversity of Wisconsin‐MadisonMadisonWI53705USA
- Department of Orthopedics and RehabilitationUniversity of Wisconsin‐MadisonMadisonWI53705USA
- Department of Materials Science and EngineeringUniversity of Wisconsin‐MadisonMadisonWI53705USA
- Forward BIO InstituteUniversity of Wisconsin‐MadisonMadisonWI53705USA
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13
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Lin Z, Zhang X, Fritch MR, Li Z, Kuang B, Alexander PG, Hao T, Cao G, Tan S, Bruce KK, Lin H. Engineering pre-vascularized bone-like tissue from human mesenchymal stem cells through simulating endochondral ossification. Biomaterials 2022; 283:121451. [DOI: 10.1016/j.biomaterials.2022.121451] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 01/28/2022] [Accepted: 02/27/2022] [Indexed: 01/12/2023]
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Zhu L, Liu Y, Wang A, Zhu Z, Li Y, Zhu C, Che Z, Liu T, Liu H, Huang L. Application of BMP in Bone Tissue Engineering. Front Bioeng Biotechnol 2022; 10:810880. [PMID: 35433652 PMCID: PMC9008764 DOI: 10.3389/fbioe.2022.810880] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 03/01/2022] [Indexed: 01/15/2023] Open
Abstract
At present, bone nonunion and delayed union are still difficult problems in orthopaedics. Since the discovery of bone morphogenetic protein (BMP), it has been widely used in various studies due to its powerful role in promoting osteogenesis and chondrogenesis. Current results show that BMPs can promote healing of bone defects and reduce the occurrence of complications. However, the mechanism of BMP in vivo still needs to be explored, and application of BMP alone to a bone defect site cannot achieve good therapeutic effects. It is particularly important to modify implants to carry BMP to achieve slow and sustained release effects by taking advantage of the nature of the implant. This review aims to explain the mechanism of BMP action in vivo, its biological function, and how BMP can be applied to orthopaedic implants to effectively stimulate bone healing in the long term. Notably, implantation of a system that allows sustained release of BMP can provide an effective method to treat bone nonunion and delayed bone healing in the clinic.
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Affiliation(s)
- Liwei Zhu
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
- Orthopaedic Research Institute of Jilin Province, Changchun, China
| | - Yuzhe Liu
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
| | - Ao Wang
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
| | - Zhengqing Zhu
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
| | - Youbin Li
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
| | - Chenyi Zhu
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
| | - Zhenjia Che
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
| | - Tengyue Liu
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
| | - He Liu
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
- Orthopaedic Research Institute of Jilin Province, Changchun, China
- *Correspondence: He Liu, ; Lanfeng Huang,
| | - Lanfeng Huang
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: He Liu, ; Lanfeng Huang,
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15
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Effect of Urolithin A on Bone Repair in Mice with Bone Defects. Tissue Eng Regen Med 2021; 19:151-159. [PMID: 34694576 DOI: 10.1007/s13770-021-00382-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/28/2021] [Accepted: 08/03/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Bone defect difficult to manage clinically and it is a big challenge to repair it. Secondary metabolites source from herb has shown potential for the treatment of bone defect. METHODS Mesenchymal stem cells (MSCs) were isolated from mice and incubated with urolithin A (UA) (10, 25, and 50 µg/mL). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was performed to estimate apoptosis and mineralisation was evaluated by alkaline phosphatase assay and alizarin red S staining. A middle femoral defect was induced in mice and bone tissue was prepared for endochondral ossification by treating with UA. The effect of UA was estimated by determining markers of osteoblast proliferation in serum and micro-computed tomography to analyse bone defects. RESULTS UA enhanced mineralisation of MSCs and osteogenic gene markers in MSCs in vitro. Also, the bone defect score and bone mineral density were improved by UA. Moreover, UA ameliorated the altered Wnt3a protein and histopathological changes in bone defect mice. CONCLUSION Presented report conclude that UA enhances osteoblast proliferation in bone-defect mice by activating the Wnt pathway.
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Cyclic Tensile Stress to Rat Thoracolumbar Ligamentum Flavum Inducing the Ossification of Ligamentum Flavum: An In Vivo Experimental Study. Spine (Phila Pa 1976) 2021; 46:1129-1138. [PMID: 34384088 DOI: 10.1097/brs.0000000000004087] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Western blot, reverse transcription-polymerase chain reaction (RT-PCR), radiological, and histological analyses of the rat ossification of ligamentum flavum (OLF) induced by cyclic tensile stress. OBJECTIVE The aim of this study was to induce the OLF using cyclic tensile stress to rat thoracolumbar ligamentum flavum, and to investigate the possible molecular mechanism of tension-induced OLF. SUMMARY OF BACKGROUND DATA Tensile stress has been considered as an important factor leading to the OLF. So far, however, no OLF induced by tension has been reported. METHODS Forty rats were randomly divided into five equal groups. For control groups, the blank and anesthesia groups were not subjected to tension. For experimental groups, the 4-, 8-, and 12-week groups were subjected to cyclic tensile stress of ligamentum flavum after abdominal anesthesia for 4 weeks, 8 weeks, and 12 weeks, respectively, using an original stress apparatus for rats. The radiological and morphological changes of rat spine, as well as the protein and mRNA expressions of CD44, bone morphogenetic protein-2 (BMP-2), integrin β3, collagen protein type I (COL1), osteopontin (OPN), runt-related transcription factor 2 (RUNX-2), and vascular endothelial growth factor (VEGF), were concerned. RESULTS The micro-CT showed OLF in the 4-, 8-, and 12-week group. The axial maximum occupied area of ossifications was 1.42 mm2, 3.35 mm2, and 7.28 mm2, respectively. In histopathology, chondrocytes proliferated in the experimental model; woven bone arose in the 8- and 12-week groups, and was more noticeable in the 12-week group. According to western blot and RT-PCR, the expressions of seven osteogenesis-related molecules were all increased in three experimental groups. CONCLUSION Cyclic tensile stress to the ligamentum flavum in rats can induce the OLF, and the longer the duration, the more visible the osteogenesis. The upregulation and synergism of osteogenesis-related molecules may contribute to the OLF induced by tensile stress.Level of Evidence: N/A.
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Wong SA, Hu DP, Slocum J, Lam C, Nguyen M, Miclau T, Marcucio RS, Bahney CS. Chondrocyte-to-osteoblast transformation in mandibular fracture repair. J Orthop Res 2021; 39:1622-1632. [PMID: 33140859 PMCID: PMC8451921 DOI: 10.1002/jor.24904] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 10/01/2020] [Accepted: 10/31/2020] [Indexed: 02/04/2023]
Abstract
The majority of fracture research has been conducted using long bone fracture models, with significantly less research into the mechanisms driving craniofacial repair. However, craniofacial bones differ from long bones in both their developmental mechanism and embryonic origin. Thus, it is possible that their healing mechanisms could differ. In this study we utilize stabilized and unstabilized mandible fracture models to investigate the pathways regulating repair. Whereas fully stable trephine defects in the ramus form bone directly, mechanical motion within a transverse fracture across the same anatomical location promoted robust cartilage formation before boney remodeling. Literature investigating long bone fractures show chondrocytes are a direct precursor of osteoblasts during endochondral repair. Lineage tracing with Aggrecan-CreERT2 ::Ai9 tdTomato mice demonstrated that mandibular callus chondrocytes also directly contribute to the formation of new bone. Furthermore, immunohistochemistry revealed that chondrocytes located at the chondro-osseous junction expressed Sox2, suggesting that plasticity of these chondrocytes may facilitate this chondrocyte-to-osteoblast transformation. Based on the direct role chondrocytes play in bone repair, we tested the efficacy of cartilage grafts in healing critical-sized mandibular defects. Whereas empty defects remained unbridged and filled with fibrous tissue, cartilage engraftment produced bony-bridging and robust marrow cavity formation, indicating healthy vascularization of the newly formed bone. Engrafted cartilage directly contributed to new bone formation since a significant portion of the newly formed bone was graft/donor-derived. Taken together these data demonstrate the important role of chondrocyte-to-osteoblast transformation during mandibular endochondral repair and the therapeutic promise of using cartilage as a tissue graft to heal craniofacial defects.
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Affiliation(s)
- Sarah A. Wong
- Department of Orthopaedic Surgery, Orthopaedic Trauma InstituteUniversity of California2550 23rd Street Building 9, 3rd FloorSan FranciscoCalifornia94110USA,Oral and Craniofacial Sciences Program, School of DentistryUniversity of CaliforniaSan FranciscoCaliforniaUSA
| | - Diane P. Hu
- Department of Orthopaedic Surgery, Orthopaedic Trauma InstituteUniversity of California2550 23rd Street Building 9, 3rd FloorSan FranciscoCalifornia94110USA
| | - Joshua Slocum
- Department of Orthopaedic Surgery, Orthopaedic Trauma InstituteUniversity of California2550 23rd Street Building 9, 3rd FloorSan FranciscoCalifornia94110USA
| | - Charles Lam
- Department of Orthopaedic Surgery, Orthopaedic Trauma InstituteUniversity of California2550 23rd Street Building 9, 3rd FloorSan FranciscoCalifornia94110USA
| | - Michael Nguyen
- Department of Orthopaedic Surgery, Orthopaedic Trauma InstituteUniversity of California2550 23rd Street Building 9, 3rd FloorSan FranciscoCalifornia94110USA,Oral and Craniofacial Sciences Program, School of DentistryUniversity of CaliforniaSan FranciscoCaliforniaUSA
| | - Theodore Miclau
- Department of Orthopaedic Surgery, Orthopaedic Trauma InstituteUniversity of California2550 23rd Street Building 9, 3rd FloorSan FranciscoCalifornia94110USA
| | - Ralph S. Marcucio
- Department of Orthopaedic Surgery, Orthopaedic Trauma InstituteUniversity of California2550 23rd Street Building 9, 3rd FloorSan FranciscoCalifornia94110USA,Oral and Craniofacial Sciences Program, School of DentistryUniversity of CaliforniaSan FranciscoCaliforniaUSA
| | - Chelsea S. Bahney
- Department of Orthopaedic Surgery, Orthopaedic Trauma InstituteUniversity of California2550 23rd Street Building 9, 3rd FloorSan FranciscoCalifornia94110USA,Steadman Philippon Research InstituteCenter for Regenerative Sports Medicine181 W Meadows DriveVailColorado81657USA
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18
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Kim HD, Hong X, An YH, Park MJ, Kim DG, Greene AK, Padwa BL, Hwang NS, Lin RZ, Melero-Martin JM. A Biphasic Osteovascular Biomimetic Scaffold for Rapid and Self-Sustained Endochondral Ossification. Adv Healthc Mater 2021; 10:e2100070. [PMID: 33882194 PMCID: PMC8273143 DOI: 10.1002/adhm.202100070] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/23/2021] [Indexed: 12/14/2022]
Abstract
Regeneration of large bones remains a challenge in surgery. Recent developmental engineering efforts aim to recapitulate endochondral ossification (EO), a critical step in bone formation. However, this process entails the condensation of mesenchymal stem cells (MSCs) into cartilaginous templates, which requires long-term cultures and is challenging to scale up. Here, a biomimetic scaffold is developed that allows rapid and self-sustained EO without initial hypertrophic chondrogenesis. The design comprises a porous chondroitin sulfate cryogel decorated with whitlockite calcium phosphate nanoparticles, and a soft hydrogel occupying the porous space. This composite scaffold enables human endothelial colony-forming cells (ECFCs) and MSCs to rapidly assemble into osteovascular niches in immunodeficient mice. These niches contain ECFC-lined blood vessels and perivascular MSCs that differentiate into RUNX2+ OSX+ pre-osteoblasts after one week in vivo. Subsequently, multiple ossification centers are formed, leading to de novo bone tissue formation by eight weeks, including mature human OCN+ OPN+ osteoblasts, collagen-rich mineralized extracellular matrix, hydroxyapatite, osteoclast activity, and gradual mechanical competence. The early establishment of blood vessels is essential, and grafts that do not contain ECFCs fail to produce osteovascular niches and ossification centers. The findings suggest a novel bioengineering approach to recapitulate EO in the context of human bone regeneration.
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Affiliation(s)
- Hwan D. Kim
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
- Department of Polymer Science and Engineering, Korea National University of Transportation, Chungju, 27469, Republic of Korea (H.D.K current address)
| | - Xuechong Hong
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Young-Hyeon An
- School of Chemical and Biological Engineering, BioMAX Institute, Institute of Chemical Processes, Institute of Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Mihn Jeong Park
- School of Chemical and Biological Engineering, BioMAX Institute, Institute of Chemical Processes, Institute of Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Do-Gyoon Kim
- Division of Orthodontics, College of Dentistry, The Ohio State University, Columbus, OH 43210, USA
| | - Arin K. Greene
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
- Department of Plastic and Oral Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Bonnie L. Padwa
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
- Department of Plastic and Oral Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Nathaniel S. Hwang
- School of Chemical and Biological Engineering, BioMAX Institute, Institute of Chemical Processes, Institute of Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Ruei-Zeng Lin
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Juan M. Melero-Martin
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Cambridge, MA 02138, USA
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Micic M, Antonijevic D, Milutinovic-Smiljanic S, Trisic D, Colovic B, Kosanovic D, Prokic B, Vasic J, Zivkovic S, Milasin J, Danilovic V, Djuric M, Jokanovic V. Developing a novel resorptive hydroxyapatite-based bone substitute for over-critical size defect reconstruction: physicochemical and biological characterization and proof of concept in segmental rabbit's ulna reconstruction. ACTA ACUST UNITED AC 2021; 65:491-505. [PMID: 32335536 DOI: 10.1515/bmt-2019-0218] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 12/09/2019] [Indexed: 01/19/2023]
Abstract
The aim of this study was to develop novel hydroxyapatite (HAP)-based bioactive bone replacement materials for segmental osteotomy reconstruction. Customized three-dimensional (3D) bone construct was manufactured from nanohydroxyapatite (nHAP) with poly(lactide-co-glycolide) (PLGA) coating using 3D models derived from the computed tomography (CT) scanning of the rabbit's ulna and gradient 3D printing of the bone substitute mimicking the anatomical shape of the natural bone defect. Engineered construct revealed adequate micro-architectural design for successful bone regeneration having a total porosity of 64% and an average pore size of 256 μm. Radiography and micro-CT analysis depicted new bone apposition through the whole length of the reconstructed ulna with a small area of non-resorbed construct in the central area of defect. Histological analysis revealed new bone formation with both endochondral and endesmal type of ossification. Immunohistochemistry analysis depicted the presence of bone formation indicators - bone morphogenetic protein (BMP), osteocalcin (OCN) and osteopontin (OPN) within newly formed bone. Manufactured personalized construct acts as a "smart" responsive biomaterial capable of modulating the functionality and potential for the personalized bone reconstruction on a clinically relevant length scale.
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Affiliation(s)
- Milutin Micic
- Laboratory for Anthropology, Institute for Anatomy, School of Medicine, University of Belgrade, Dr Subotica No. 4, 11000 Belgrade, Serbia
| | - Djordje Antonijevic
- Laboratory for Anthropology, Institute for Anatomy, School of Medicine, University of Belgrade, Dr Subotica No. 4, 11000 Belgrade, Serbia.,Laboratory for Atomic Physics, Institute for Nuclear Sciences Vinca, Mike Alasa 12-14, 11000 Belgrade, Serbia.,School of Dental Medicine, University of Belgrade, Dr. Subotica No. 8, 11000 Belgrade, Serbia
| | | | - Dijana Trisic
- School of Dental Medicine, University of Belgrade, Dr. Subotica No. 8, 11000 Belgrade, Serbia
| | - Bozana Colovic
- Laboratory for Atomic Physics, Institute for Nuclear Sciences Vinca, Mike Alasa 12-14, 11000 Belgrade, Serbia
| | - Dejana Kosanovic
- Institute for Virology, Vaccine and Sera "Torlak", University of Belgrade, Vojvode Stepe No. 458, 11000 Belgrade, Serbia
| | - Bogomir Prokic
- School of Veterinary Medicine, University of Belgrade, Bulevar Oslobodjenja No. 18, 11000 Belgrade, Serbia
| | - Jugoslav Vasic
- School of Veterinary Medicine, University of Belgrade, Bulevar Oslobodjenja No. 18, 11000 Belgrade, Serbia
| | - Slavoljub Zivkovic
- School of Dental Medicine, University of Belgrade, Dr. Subotica No. 8, 11000 Belgrade, Serbia
| | - Jelena Milasin
- School of Dental Medicine, University of Belgrade, Dr. Subotica No. 8, 11000 Belgrade, Serbia
| | - Vesna Danilovic
- School of Dental Medicine, University of Belgrade, Dr. Subotica No. 8, 11000 Belgrade, Serbia
| | - Marija Djuric
- Laboratory for Anthropology, Institute for Anatomy, School of Medicine, University of Belgrade, Dr Subotica No. 4, 11000 Belgrade, Serbia
| | - Vukoman Jokanovic
- Laboratory for Atomic Physics, Institute for Nuclear Sciences Vinca, University of Belgrade, 11000 Belgrade, Serbia.,Albos d.o.o., 11000 Belgrade, Serbia
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20
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McMillan A, Nguyen MK, Huynh CT, Sarett SM, Ge P, Chetverikova M, Nguyen K, Grosh D, Duvall CL, Alsberg E. Hydrogel microspheres for spatiotemporally controlled delivery of RNA and silencing gene expression within scaffold-free tissue engineered constructs. Acta Biomater 2021; 124:315-326. [PMID: 33465507 DOI: 10.1016/j.actbio.2021.01.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 01/08/2021] [Accepted: 01/12/2021] [Indexed: 12/18/2022]
Abstract
Delivery systems for controlled release of RNA interference (RNAi) molecules, including small interfering (siRNA) and microRNA (miRNA), have the potential to direct stem cell differentiation for regenerative musculoskeletal applications. To date, localized RNA delivery platforms in this area have focused predominantly on bulk scaffold-based approaches, which can interfere with cell-cell interactions important for recapitulating some native musculoskeletal developmental and healing processes in tissue regeneration strategies. In contrast, scaffold-free, high density human mesenchymal stem cell (hMSC) aggregates may provide an avenue for creating a more biomimetic microenvironment. Here, photocrosslinkable dextran microspheres (MS) encapsulating siRNA-micelles were prepared via an aqueous emulsion method and incorporated within hMSC aggregates for localized and sustained delivery of bioactive siRNA. siRNA-micelles released from MS in a sustained fashion over the course of 28 days, and the released siRNA retained its ability to transfect cells for gene silencing. Incorporation of fluorescently labeled siRNA (siGLO)-laden MS within hMSC aggregates exhibited tunable siGLO delivery and uptake by stem cells. Incorporation of MS loaded with siRNA targeting green fluorescent protein (siGFP) within GFP-hMSC aggregates provided sustained presentation of siGFP within the constructs and prolonged GFP silencing for up to 15 days. This platform system enables sustained gene silencing within stem cell aggregates and thus shows great potential in tissue regeneration applications. STATEMENT OF SIGNIFICANCE: This work presents a new strategy to deliver RNA-nanocomplexes from photocrosslinked dextran microspheres for tunable presentation of bioactive RNA. These microspheres were embedded within scaffold-free, human mesenchymal stem cell (hMSC) aggregates for sustained gene silencing within three-dimensional cell constructs while maintaining cell viability. Unlike exogenous delivery of RNA within culture medium that suffers from diffusion limitations and potential need for repeated transfections, this strategy provides local and sustained RNA presentation from the microspheres to cells in the constructs. This system has the potential to inhibit translation of hMSC differentiation antagonists and drive hMSC differentiation toward desired specific lineages, and is an important step in the engineering of high-density stem cell systems with incorporated instructive genetic cues for application in tissue regeneration.
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Papantoniou I, Nilsson Hall G, Loverdou N, Lesage R, Herpelinck T, Mendes L, Geris L. Turning Nature's own processes into design strategies for living bone implant biomanufacturing: a decade of Developmental Engineering. Adv Drug Deliv Rev 2021; 169:22-39. [PMID: 33290762 PMCID: PMC7839840 DOI: 10.1016/j.addr.2020.11.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 11/20/2020] [Accepted: 11/29/2020] [Indexed: 12/14/2022]
Abstract
A decade after the term developmental engineering (DE) was coined to indicate the use of developmental processes as blueprints for the design and development of engineered living implants, a myriad of proof-of-concept studies demonstrate the potential of this approach in small animal models. This review provides an overview of DE work, focusing on applications in bone regeneration. Enabling technologies allow to quantify the distance between in vitro processes and their developmental counterpart, as well as to design strategies to reduce that distance. By embedding Nature's robust mechanisms of action in engineered constructs, predictive large animal data and subsequent positive clinical outcomes can be gradually achieved. To this end, the development of next generation biofabrication technologies should provide the necessary scale and precision for robust living bone implant biomanufacturing.
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Affiliation(s)
- Ioannis Papantoniou
- Institute of Chemical Engineering Sciences, Foundation for Research and Technology - Hellas (FORTH), Stadiou street, 26504 Patras, Greece; Skeletal Biology & Engineering Research Center, KU Leuven, Herestraat 49 (813), 3000 Leuven, Belgium; Prometheus, The KU Leuven R&D Division for Skeletal Tissue Engineering, Herestraat 49 (813), 3000 Leuven, Belgium.
| | - Gabriella Nilsson Hall
- Skeletal Biology & Engineering Research Center, KU Leuven, Herestraat 49 (813), 3000 Leuven, Belgium; Prometheus, The KU Leuven R&D Division for Skeletal Tissue Engineering, Herestraat 49 (813), 3000 Leuven, Belgium.
| | - Niki Loverdou
- Prometheus, The KU Leuven R&D Division for Skeletal Tissue Engineering, Herestraat 49 (813), 3000 Leuven, Belgium; GIGA in silico medicine, University of Liège, Avenue de l'Hôpital 11 (B34), 4000 Liège, Belgium; Biomechanics Section, KU Leuven, Celestijnenlaan 300C (2419), 3001 Leuven, Belgium.
| | - Raphaelle Lesage
- Prometheus, The KU Leuven R&D Division for Skeletal Tissue Engineering, Herestraat 49 (813), 3000 Leuven, Belgium; Biomechanics Section, KU Leuven, Celestijnenlaan 300C (2419), 3001 Leuven, Belgium.
| | - Tim Herpelinck
- Skeletal Biology & Engineering Research Center, KU Leuven, Herestraat 49 (813), 3000 Leuven, Belgium; Prometheus, The KU Leuven R&D Division for Skeletal Tissue Engineering, Herestraat 49 (813), 3000 Leuven, Belgium.
| | - Luis Mendes
- Skeletal Biology & Engineering Research Center, KU Leuven, Herestraat 49 (813), 3000 Leuven, Belgium; Prometheus, The KU Leuven R&D Division for Skeletal Tissue Engineering, Herestraat 49 (813), 3000 Leuven, Belgium.
| | - Liesbet Geris
- Skeletal Biology & Engineering Research Center, KU Leuven, Herestraat 49 (813), 3000 Leuven, Belgium; GIGA in silico medicine, University of Liège, Avenue de l'Hôpital 11 (B34), 4000 Liège, Belgium; Prometheus, The KU Leuven R&D Division for Skeletal Tissue Engineering, Herestraat 49 (813), 3000 Leuven, Belgium; Biomechanics Section, KU Leuven, Celestijnenlaan 300C (2419), 3001 Leuven, Belgium.
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22
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Scaffold-free human mesenchymal stem cell construct geometry regulates long bone regeneration. Commun Biol 2021; 4:89. [PMID: 33469154 PMCID: PMC7815708 DOI: 10.1038/s42003-020-01576-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 11/27/2020] [Indexed: 12/19/2022] Open
Abstract
Biomimetic bone tissue engineering strategies partially recapitulate development. We recently showed functional restoration of femoral defects using scaffold-free human mesenchymal stem cell (hMSC) condensates featuring localized morphogen presentation with delayed in vivo mechanical loading. Possible effects of construct geometry on healing outcome remain unclear. Here, we hypothesized that localized presentation of transforming growth factor (TGF)-β1 and bone morphogenetic protein (BMP)-2 to engineered hMSC tubes mimicking femoral diaphyses induces endochondral ossification, and that TGF-β1 + BMP-2-presenting hMSC tubes enhance defect healing with delayed in vivo loading vs. loosely packed hMSC sheets. Localized morphogen presentation stimulated chondrogenic priming/endochondral differentiation in vitro. Subcutaneously, hMSC tubes formed cartilage templates that underwent bony remodeling. Orthotopically, hMSC tubes stimulated more robust endochondral defect healing vs. hMSC sheets. Tissue resembling normal growth plate was observed with negligible ectopic bone. This study demonstrates interactions between hMSC condensation geometry, morphogen bioavailability, and mechanical cues to recapitulate development for biomimetic bone tissue engineering. Herberg et al. previously showed functional healing of femoral defects using scaffold-free human mesenchymal stem cell (hMSC) condensates with localized morphogen presentation. In this study, they report the importance of the tubular geometry of MSC condensates in long bone regeneration. Unlike loosely packed hMSC sheets, only hMSC tubes induced regenerate tissue partially resembling normal growth plate.
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23
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Sun L, Ma Y, Niu H, Liu Y, Yuan Y, Liu C. Recapitulation of In Situ Endochondral Ossification Using an Injectable Hypoxia‐Mimetic Hydrogel. ADVANCED FUNCTIONAL MATERIALS 2021; 31. [DOI: 10.1002/adfm.202008515] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Indexed: 01/06/2025]
Abstract
AbstractDue to the limited ability for perfusion, traditional intramembranous ossification (IMO) often fails to recapitulate the natural regeneration process of most long bones and craniofacial bones. Alternatively, endochondral ossification (ECO) strategy has emerged and has been evidenced to circumvent the drawbacks in the routine application of IMO. Here, an injectable, poly(glycerol sebacate)‐co‐poly (ethylene glycol)/polyacrylic acid (PEGS/PAA) hydrogels are successfully developed to induce a hypoxia‐mimicking environment and subsequently recapitulate ECO via in situ iron chelation. With the incorporation of PAA, these hydrogels present remarkable viscoelasticity and high efficacy of iron ion‐chelating after injection, giving rise to the activation of HIF‐1α signaling pathway and suppression of inflammatory responses, and thereby improving chondrogenic differentiation in the early stage and facilitating vascularization in the later stage, which consequently trigger typical ECO. More importantly, through sustained and stable expression of HIF‐1α regulated by PEGS/PAA hydrogels throughout the regeneration, a harmonious chondrogenic/osteogenic balance can be struck and thereby accelerating the progress of ECO compared to the PEGS. The findings provide an efficient strategy to achieve in situ ECO via biomaterial‐based iron ion‐chelating and ensuing hypoxia‐mimicking, representing a novel and promising concept for future application in bone regeneration.
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Affiliation(s)
- Lili Sun
- Key Laboratory for Ultrafine Materials of Ministry of Education and School of Materials Science and Engineering East China University of Science and Technology Shanghai 200237 P. R. China
- Engineering Research Center for Biomedical Materials of Ministry of Education East China University of Science and Technology Shanghai 200237 P. R. China
| | - Yifan Ma
- Key Laboratory for Ultrafine Materials of Ministry of Education and School of Materials Science and Engineering East China University of Science and Technology Shanghai 200237 P. R. China
- Engineering Research Center for Biomedical Materials of Ministry of Education East China University of Science and Technology Shanghai 200237 P. R. China
| | - Haoyi Niu
- Key Laboratory for Ultrafine Materials of Ministry of Education and School of Materials Science and Engineering East China University of Science and Technology Shanghai 200237 P. R. China
- Engineering Research Center for Biomedical Materials of Ministry of Education East China University of Science and Technology Shanghai 200237 P. R. China
| | - Yutong Liu
- Key Laboratory for Ultrafine Materials of Ministry of Education and School of Materials Science and Engineering East China University of Science and Technology Shanghai 200237 P. R. China
- Engineering Research Center for Biomedical Materials of Ministry of Education East China University of Science and Technology Shanghai 200237 P. R. China
| | - Yuan Yuan
- Key Laboratory for Ultrafine Materials of Ministry of Education and School of Materials Science and Engineering East China University of Science and Technology Shanghai 200237 P. R. China
- Engineering Research Center for Biomedical Materials of Ministry of Education East China University of Science and Technology Shanghai 200237 P. R. China
| | - Changsheng Liu
- Key Laboratory for Ultrafine Materials of Ministry of Education and School of Materials Science and Engineering East China University of Science and Technology Shanghai 200237 P. R. China
- Engineering Research Center for Biomedical Materials of Ministry of Education East China University of Science and Technology Shanghai 200237 P. R. China
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24
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Zhang X, Liu Y, Clark KL, Padget AM, Alexander PG, Dai J, Zhu W, Lin H. Mesenchymal stem cell-derived extracellular matrix (mECM): a bioactive and versatile scaffold for musculoskeletal tissue engineering. ACTA ACUST UNITED AC 2020; 16:012002. [PMID: 32906098 DOI: 10.1088/1748-605x/abb6b3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Mesenchymal stem cell-derived extracellular matrix (mECM) has received increased attention in the fields of tissue engineering and scaffold-assisted regeneration. mECM exhibits many unique characteristics, such as robust bioactivity, biocompatibility, ease of use, and the potential for autologous tissue engineering. As the use of mECM has increased in musculoskeletal tissue engineering, it should be noted that mECM generated from current methods has inherited insufficiencies, such as low mechanical properties and lack of internal architecture. In this review, we first summarize the development and use of mECM as a scaffold for musculoskeletal tissue regeneration and highlight our current progress on moving this technology toward clinical application. Then we review recent methods to improve the properties of mECM that will overcome current weaknesses. Lastly, we propose future studies that will pave the road for mECM application in regenerating tissues in humans.
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Affiliation(s)
- Xiurui Zhang
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America. Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, People's Republic of China. These authors contributed equally to this work
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25
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Mohamed-Ahmed S, Yassin MA, Rashad A, Espedal H, Idris SB, Finne-Wistrand A, Mustafa K, Vindenes H, Fristad I. Comparison of bone regenerative capacity of donor-matched human adipose-derived and bone marrow mesenchymal stem cells. Cell Tissue Res 2020; 383:1061-1075. [PMID: 33242173 PMCID: PMC7960590 DOI: 10.1007/s00441-020-03315-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 09/28/2020] [Indexed: 12/22/2022]
Abstract
Adipose-derived stem cells (ASC) have been used as an alternative to bone marrow mesenchymal stem cells (BMSC) for bone tissue engineering. However, the efficacy of ASC in bone regeneration in comparison with BMSC remains debatable, since inconsistent results have been reported. Comparing ASC with BMSC obtained from different individuals might contribute to this inconsistency in results. Therefore, this study aimed to compare the bone regenerative capacity of donor-matched human ASC and BMSC seeded onto poly(l-lactide-co-ε-caprolactone) scaffolds using calvarial bone defects in nude rats. First, donor-matched ASC and BMSC were seeded onto the co-polymer scaffolds to evaluate their in vitro osteogenic differentiation. Seeded scaffolds and scaffolds without cells (control) were then implanted in calvarial defects in nude rats. The expression of osteogenesis-related genes was examined after 4 weeks. Cellular activity was investigated after 4 and 12 weeks. Bone formation was evaluated radiographically and histologically after 4, 12, and 24 weeks. In vitro, ASC and BMSC demonstrated mineralization. However, BMSC showed higher alkaline phosphatase activity than ASC. In vivo, human osteogenesis–related genes Runx2 and collagen type I were expressed in defects with scaffold/cells. Defects with scaffold/BMSC had higher cellular activity than defects with scaffold/ASC. Moreover, bone formation in defects with scaffold/BMSC was greater than in defects with scaffold/ASC, especially at the early time-point. These results suggest that although ASC have the potential to regenerate bone, the rate of bone regeneration with ASC may be slower than with BMSC. Accordingly, BMSC are more suitable for bone regenerative applications.
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Affiliation(s)
- Samih Mohamed-Ahmed
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Bergen, Norway.
| | - Mohammed A Yassin
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Bergen, Norway
| | - Ahmad Rashad
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Bergen, Norway
| | - Heidi Espedal
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Shaza B Idris
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Bergen, Norway
| | - Anna Finne-Wistrand
- Department of Fibre and Polymer Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Kamal Mustafa
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Bergen, Norway
| | - Hallvard Vindenes
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Bergen, Norway.,Department for Plastic, Hand and Reconstructive Surgery, National Fire Damage Center, Bergen, Norway
| | - Inge Fristad
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Bergen, Norway
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26
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Abstract
Compared with non-degradable materials, biodegradable biomaterials play an increasingly important role in the repairing of severe bone defects, and have attracted extensive attention from researchers. In the treatment of bone defects, scaffolds made of biodegradable materials can provide a crawling bridge for new bone tissue in the gap and a platform for cells and growth factors to play a physiological role, which will eventually be degraded and absorbed in the body and be replaced by the new bone tissue. Traditional biodegradable materials include polymers, ceramics and metals, which have been used in bone defect repairing for many years. Although these materials have more or fewer shortcomings, they are still the cornerstone of our development of a new generation of degradable materials. With the rapid development of modern science and technology, in the twenty-first century, more and more kinds of new biodegradable materials emerge in endlessly, such as new intelligent micro-nano materials and cell-based products. At the same time, there are many new fabrication technologies of improving biodegradable materials, such as modular fabrication, 3D and 4D printing, interface reinforcement and nanotechnology. This review will introduce various kinds of biodegradable materials commonly used in bone defect repairing, especially the newly emerging materials and their fabrication technology in recent years, and look forward to the future research direction, hoping to provide researchers in the field with some inspiration and reference.
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Affiliation(s)
- Shuai Wei
- Tianjin Hospital, Tianjin University, No. 406 Jiefang South Road, Tianjin, 300211 China
| | - Jian-Xiong Ma
- Tianjin Hospital, Tianjin University, No. 406 Jiefang South Road, Tianjin, 300211 China
| | - Lai Xu
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, No. 19 Qixiu Road, Chongchuan District, Nantong, 226001 China
| | - Xiao-Song Gu
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, No. 19 Qixiu Road, Chongchuan District, Nantong, 226001 China
| | - Xin-Long Ma
- Tianjin Hospital, Tianjin University, No. 406 Jiefang South Road, Tianjin, 300211 China
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27
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Ko FC, Sumner DR. How faithfully does intramembranous bone regeneration recapitulate embryonic skeletal development? Dev Dyn 2020; 250:377-392. [PMID: 32813296 DOI: 10.1002/dvdy.240] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 07/19/2020] [Accepted: 08/13/2020] [Indexed: 02/06/2023] Open
Abstract
Postnatal intramembranous bone regeneration plays an important role during a wide variety of musculoskeletal regeneration processes such as fracture healing, joint replacement and dental implant surgery, distraction osteogenesis, stress fracture healing, and repair of skeletal defects caused by trauma or resection of tumors. The molecular basis of intramembranous bone regeneration has been interrogated using rodent models of most of these conditions. These studies reveal that signaling pathways such as Wnt, TGFβ/BMP, FGF, VEGF, and Notch are invoked, reminiscent of embryonic development of membranous bone. Discoveries of several skeletal stem cell/progenitor populations using mouse genetic models also reveal the potential sources of postnatal intramembranous bone regeneration. The purpose of this review is to compare the underlying molecular signals and progenitor cells that characterize embryonic development of membranous bone and postnatal intramembranous bone regeneration.
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Affiliation(s)
- Frank C Ko
- Department of Cell & Molecular Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - D Rick Sumner
- Department of Cell & Molecular Medicine, Rush University Medical Center, Chicago, Illinois, USA
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28
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Zhang M, Shi J, Xie M, Wen J, Niibe K, Zhang X, Luo J, Yan R, Zhang Z, Egusa H, Jiang X. Recapitulation of cartilage/bone formation using iPSCs via biomimetic 3D rotary culture approach for developmental engineering. Biomaterials 2020; 260:120334. [PMID: 32862124 DOI: 10.1016/j.biomaterials.2020.120334] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 07/13/2020] [Accepted: 08/15/2020] [Indexed: 12/21/2022]
Abstract
The recapitulation of cartilage/bone formation via guiding induced pluripotent stem cells (iPSCs) differentiation toward chondrogenic mesoderm lineage is an ideal approach to investigate cartilage/bone development and also for cartilage/bone regeneration. However, current induction protocols are time-consuming and complicated to follow. Here, we established a rapid and efficient approach that directly induce iPSCs differentiation toward chondrogenic mesoderm lineage by regulating the crucial Bmp-4 and FGF-2 signaling pathways using a 3D rotary suspension culture system. The mechanical stimulation from 3D rotary suspension accelerates iPSCs differentiation toward mesodermal and subsequent chondrogenic lineage via the Bmp-4-Smad1 and Tgf-β-Smad2/3 signaling pathways, respectively. The scaffold-free homogenous cartilaginous pellets or hypertrophic cartilaginous pellets derived from iPSCs within 28 days were capable of articular cartilage regeneration or vascularized bone regeneration via endochondral ossification in vivo, respectively. This biomimetic culture approach will contribute to research related to cartilage/bone development, regeneration, and hence to therapeutic applications in cartilage-/bone-related diseases.
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Affiliation(s)
- Maolin Zhang
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China; Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-Ku, Sendai, Miyagi, 980-8575, Japan
| | - Junfeng Shi
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Ming Xie
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Jin Wen
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Kunimichi Niibe
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-Ku, Sendai, Miyagi, 980-8575, Japan
| | - Xiangkai Zhang
- Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Jiaxin Luo
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Ran Yan
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Zhiyuan Zhang
- Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Hiroshi Egusa
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-Ku, Sendai, Miyagi, 980-8575, Japan.
| | - Xinquan Jiang
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China.
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29
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McDermott AM, Herberg S, Mason DE, Collins JM, Pearson HB, Dawahare JH, Tang R, Patwa AN, Grinstaff MW, Kelly DJ, Alsberg E, Boerckel JD. Recapitulating bone development through engineered mesenchymal condensations and mechanical cues for tissue regeneration. Sci Transl Med 2020; 11:11/495/eaav7756. [PMID: 31167930 DOI: 10.1126/scitranslmed.aav7756] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 05/13/2019] [Indexed: 01/08/2023]
Abstract
Large bone defects cannot form a callus and exhibit high complication rates even with the best treatment strategies available. Tissue engineering approaches often use scaffolds designed to match the properties of mature bone. However, natural fracture healing is most efficient when it recapitulates development, forming bone via a cartilage intermediate (endochondral ossification). Because mechanical forces are critical for proper endochondral bone development and fracture repair, we hypothesized that recapitulating developmental mechanical forces would be essential for large bone defect regeneration in rats. Here, we engineered mesenchymal condensations that mimic the cellular organization and lineage progression of the early limb bud in response to local transforming growth factor-β1 presentation from incorporated gelatin microspheres. We then controlled mechanical loading in vivo by dynamically tuning fixator compliance. Mechanical loading enhanced mesenchymal condensation-induced endochondral bone formation in vivo, restoring functional bone properties when load initiation was delayed to week 4 after defect formation. Live cell transplantation produced zonal human cartilage and primary spongiosa mimetic of the native growth plate, whereas condensation devitalization before transplantation abrogated bone formation. Mechanical loading induced regeneration comparable to high-dose bone morphogenetic protein-2 delivery, but without heterotopic bone formation and with order-of-magnitude greater mechanosensitivity. In vitro, mechanical loading promoted chondrogenesis and up-regulated pericellular matrix deposition and angiogenic gene expression. In vivo, mechanical loading regulated cartilage formation and neovascular invasion, dependent on load timing. This study establishes mechanical cues as key regulators of endochondral bone defect regeneration and provides a paradigm for recapitulating developmental programs for tissue engineering.
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Affiliation(s)
- Anna M McDermott
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.,Department of Mechanical Engineering, Trinity Center for Bioengineering, Trinity College Dublin, Dublin D02 PN40, Ireland
| | - Samuel Herberg
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Devon E Mason
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Joseph M Collins
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.,Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Hope B Pearson
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, USA
| | - James H Dawahare
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Rui Tang
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Amit N Patwa
- Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA
| | - Mark W Grinstaff
- Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA
| | - Daniel J Kelly
- Department of Mechanical Engineering, Trinity Center for Bioengineering, Trinity College Dublin, Dublin D02 PN40, Ireland
| | - Eben Alsberg
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA. .,Department of Orthopaedic Surgery, Case Western Reserve University, Cleveland, OH 44106, USA.,National Center for Regenerative Medicine, Division of General Medical Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Joel D Boerckel
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. .,Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.,Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
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30
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Altamirano DE, Noller K, Mihaly E, Grayson WL. Recent advances toward understanding the role of transplanted stem cells in tissue-engineered regeneration of musculoskeletal tissues. F1000Res 2020; 9:F1000 Faculty Rev-118. [PMID: 32117568 PMCID: PMC7029752 DOI: 10.12688/f1000research.21333.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/10/2020] [Indexed: 01/16/2023] Open
Abstract
Stem cell-based tissue engineering is poised to revolutionize the treatment of musculoskeletal injuries. However, in order to overcome scientific, practical, and regulatory obstacles and optimize therapeutic strategies, it is essential to better understand the mechanisms underlying the pro-regenerative effects of stem cells. There has been an attempted paradigm shift within the last decade to think of transplanted stem cells as "medicinal" therapies that orchestrate healing on the basis of their secretome and immunomodulatory profiles rather than acting as bona fide stem cells that proliferate, differentiate, and directly produce matrix to form de novo tissues. Yet the majority of current bone and skeletal muscle tissue engineering strategies are still premised on a direct contribution of stem cells as building blocks to tissue regeneration. Our review of the recent literature finds that researchers continue to focus on the quantification of de novo bone/skeletal muscle tissue following treatment and few studies aim to address this mechanistic conundrum directly. The dichotomy of thought is reflected in the diversity of new advances ranging from in situ three-dimensional bioprinting to a focus on exosomes and extracellular vesicles. However, recent findings elucidating the role of the immune system in tissue regeneration combined with novel imaging platform technologies will have a profound impact on our future understanding of how stem cells promote healing following biomaterial-mediated delivery to defect sites.
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Affiliation(s)
- Dallas E. Altamirano
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Kathleen Noller
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Duke University Medical School, Duke University, Durham, NC, 27710, USA
| | - Eszter Mihaly
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Warren L. Grayson
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Department of Materials Science & Engineering, Johns Hopkins University School of Engineering, Baltimore, MD, 21231, USA
- Institute for NanoBioTechnology, Johns Hopkins University School of Engineering, Baltimore, MD, 21231, USA
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31
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García‐García P, Ruiz M, Reyes R, Delgado A, Évora C, Riancho JA, Rodríguez‐Rey JC, Pérez‐Campo FM. Smurf1 Silencing Using a LNA-ASOs/Lipid Nanoparticle System to Promote Bone Regeneration. Stem Cells Transl Med 2019; 8:1306-1317. [PMID: 31631568 PMCID: PMC6877774 DOI: 10.1002/sctm.19-0145] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 09/17/2019] [Indexed: 12/19/2022] Open
Abstract
Despite the great advance of bone tissue engineering in the last few years, repair of bone defects remains a major problem. Low cell engraftment and dose-dependent side effects linked to the concomitant administration of bone morphogenetic proteins (BMPs) are the main problems currently hindering the clinical use of mesenchymal stem cell (MSC)-based therapies in this field. We have managed to bypass these drawbacks by combining the silencing the Smurf1 ubiquitin ligase in MSCs with the use of a scaffold that sustainably releases low doses of BMP-2. In this system, Smurf1 silencing is achieved by using GapmeRs, a clinically safe method that avoids the use of viral vectors, facilitating its translation to the clinic. Here, we show that a single transient transfection with a small quantity of a Smurf1-specific GapmeR is able to induce a significant level of silencing of the target gene, enough to prime MSCs for osteogenic differentiation. Smurf1 silencing highly increases MSCs responsiveness to BMP-2, allowing a dramatic reduction of the dose needed to achieve the desired therapeutic effect. The combination of these primed cells with alginate scaffolds designed to sustainably and locally release low doses of BMP-2 to the defect microenvironment is able to induce the formation of a mature bone matrix both in an osteoporotic rat calvaria system and in a mouse ectopic model. Importantly, this approach also enhances osteogenic differentiation in MSCs from osteoporotic patients, characterized by a reduced bone-forming potential, even at low BMP doses, underscoring the regenerative potential of this system. Stem Cells Translational Medicine 2019;8:1306&1317.
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Affiliation(s)
- Patricia García‐García
- Department of Chemical Engineering and Pharmaceutical TechnologyInstitute of Biomedical Technologies (ITB), University of La LagunaLa LagunaSpain
| | - Mario Ruiz
- Department of Molecular Biology, Faculty of MedicineUniversity of Cantabria, IDIVALSantanderSpain
| | - Ricardo Reyes
- Department of Biochemistry, Microbiology, Cellular Biology and GeneticsInstitute of Biomedical Technologies (ITB), University of La LagunaLa LagunaSpain
| | - Araceli Delgado
- Department of Chemical Engineering and Pharmaceutical TechnologyInstitute of Biomedical Technologies (ITB), University of La LagunaLa LagunaSpain
| | - Carmen Évora
- Department of Chemical Engineering and Pharmaceutical TechnologyInstitute of Biomedical Technologies (ITB), University of La LagunaLa LagunaSpain
| | - José Antonio Riancho
- Department of Internal Medicine, Hospital U M ValdecillaUniversity of Cantabria, IDIVALSantanderSpain
| | | | - Flor María Pérez‐Campo
- Department of Molecular Biology, Faculty of MedicineUniversity of Cantabria, IDIVALSantanderSpain
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Whitehead J, Kothambawala A, Leach JK. Morphogen Delivery by Osteoconductive Nanoparticles Instructs Stromal Cell Spheroid Phenotype. ADVANCED BIOSYSTEMS 2019; 3:1900141. [PMID: 32270027 PMCID: PMC7141413 DOI: 10.1002/adbi.201900141] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Indexed: 01/04/2023]
Abstract
Mesenchymal stem/stromal cells (MSCs) exhibit a rapid loss in osteogenic phenotype upon removal of osteoinductive cues, as commonly occurs during transplantation. Osteogenic differentiation can be more effectively but not fully maintained by aggregating MSCs into spheroids. Therefore, the development of effective strategies that prolong the efficacy of inductive growth factors would be advantageous for advancing cell-based therapies. To address this challenge, osteoinductive bone morphogenetic protein-2 (BMP-2) was adsorbed to osteoconductive hydroxyapatite (HA) nanoparticles for incorporation into MSC spheroids. MSC induction was evaluated in osteogenic conditions and retention of the osteogenic phenotype in the absence of other osteogenic cues. HA was more uniformly incorporated into spheroids at lower concentrations, while BMP-2 dosage was dependent upon initial morphogen concentration. MSC spheroids containing BMP-2-loaded HA nanoparticles exhibited greater alkaline phosphatase (ALP) activity and more uniform spatial expression of osteocalcin compared to spheroids with uncoated HA nanoparticles. Spheroids cultured in media containing soluble BMP-2 demonstrated differentiation only at the spheroid periphery. Furthermore, the osteogenic phenotype of MSC spheroids was better retained with BMP-2-laden HA upon the removal of soluble osteogenic cues. These findings represent a promising strategy for simultaneous delivery of osteoconductive and osteoinductive signals for enhancing MSC participation in bone formation.
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Affiliation(s)
- Jacklyn Whitehead
- Department of Biomedical Engineering, University of California, Davis, CA 95616
| | - Alefia Kothambawala
- Department of Biomedical Engineering, University of California, Davis, CA 95616
| | - J Kent Leach
- Department of Biomedical Engineering, University of California, Davis, CA 95616
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Wang Z, Han L, Sun T, Wang W, Li X, Wu B. Preparation and effect of lyophilized platelet-rich fibrin on the osteogenic potential of bone marrow mesenchymal stem cells in vitro and in vivo. Heliyon 2019; 5:e02739. [PMID: 31720476 PMCID: PMC6838904 DOI: 10.1016/j.heliyon.2019.e02739] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/13/2019] [Accepted: 10/23/2019] [Indexed: 01/27/2023] Open
Abstract
Objectives The goal of this study was to prepare lyophilized platelet-rich fibrin (L-PRF) and analyze the combined use of L-PRF and osteogenic bone marrow mesenchymal stem cell (BMSC) sheet fragments for bone tissue engineering via in vivo injection. Methods First, fresh PRF (F-PRF) was lyophilized to prepare L-PRF, the characteristics of which were examined through gross morphological, and histological and microstructural observations. In addition, the kinetics of growth factor release from L-PRF and F-PRF were also determined by enzyme-linked immunosorbent assay (ELISA). Subsequently, after assessing the proliferation and osteogenic differentiation of BMSCs exposed to L-PRF or F-PRF in vitro, we subcutaneously injected BMSC sheet fragments with L-PRF or F-PRF into nude mice and assessed bone formation through microcomputed tomography and histological analyses. Results We observed that L-PRF released growth factors that favored BMSC proliferation and osteogenic differentiation in vitro. The combined use of L-PRF and osteogenic BMSC sheet fragments enabled bone tissue regeneration in vivo, and no significant difference between the F-PRF and L-PRF groups was observed (P = 0.24). Conclusions The results of this study demonstrate that the combined use of L-PRF and osteogenic BMSC sheets may have potential in the fabrication of engineered bone.
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Affiliation(s)
- Zhifa Wang
- School of Stomatology, Southern Medical University, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, PR China.,Department of Stomatology, General Hospital of Southern Theater of PLA, Guangzhou, 510010, China
| | - Leng Han
- Department of Pathology, General Hospital of Southern Theater of PLA, Guangzhou, 510010, China
| | - Tianyu Sun
- School of Stomatology, Southern Medical University, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, PR China
| | - Weijian Wang
- Department of Stomatology, General Hospital of Southern Theater of PLA, Guangzhou, 510010, China
| | - Xiao Li
- Department of Stomatology, General Hospital of Southern Theater of PLA, Guangzhou, 510010, China
| | - Buling Wu
- School of Stomatology, Southern Medical University, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, PR China
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García-Sánchez D, Fernández D, Rodríguez-Rey JC, Pérez-Campo FM. Enhancing survival, engraftment, and osteogenic potential of mesenchymal stem cells. World J Stem Cells 2019; 11:748-763. [PMID: 31692976 PMCID: PMC6828596 DOI: 10.4252/wjsc.v11.i10.748] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 07/15/2019] [Accepted: 07/29/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are promising candidates for bone regeneration therapies due to their plasticity and easiness of sourcing. MSC-based treatments are generally considered a safe procedure, however, the long-term results obtained up to now are far from satisfactory. The main causes of these therapeutic limitations are inefficient homing, engraftment, and osteogenic differentiation. Many studies have proposed modifications to improve MSC engraftment and osteogenic differentiation of the transplanted cells. Several strategies are aimed to improve cell resistance to the hostile microenvironment found in the recipient tissue and increase cell survival after transplantation. These strategies could range from a simple modification of the culture conditions, known as cell-preconditioning, to the genetic modification of the cells to avoid cellular senescence. Many efforts have also been done in order to enhance the osteogenic potential of the transplanted cells and induce bone formation, mainly by the use of bioactive or biomimetic scaffolds, although alternative approaches will also be discussed. This review aims to summarize several of the most recent approaches, providing an up-to-date view of the main developments in MSC-based regenerative techniques.
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Affiliation(s)
- Daniel García-Sánchez
- Department of Molecular Biology, Faculty of Medicine, University of Cantabria, Cantabria 39011, Spain
| | - Darío Fernández
- Laboratorio de Biología Celular y Molecular, Facultad de Odontología, Universidad Nacional del Nordeste, Corrientes W3400, Argentina
| | - José C Rodríguez-Rey
- Department of Molecular Biology, Faculty of Medicine, University of Cantabria, Cantabria 39011, Spain
| | - Flor M Pérez-Campo
- Department of Molecular Biology, Faculty of Medicine, University of Cantabria, Cantabria 39011, Spain.
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Herberg S, McDermott AM, Dang PN, Alt DS, Tang R, Dawahare JH, Varghai D, Shin JY, McMillan A, Dikina AD, He F, Lee YB, Cheng Y, Umemori K, Wong PC, Park H, Boerckel JD, Alsberg E. Combinatorial morphogenetic and mechanical cues to mimic bone development for defect repair. SCIENCE ADVANCES 2019; 5:eaax2476. [PMID: 31489377 PMCID: PMC6713501 DOI: 10.1126/sciadv.aax2476] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 07/19/2019] [Indexed: 05/28/2023]
Abstract
Endochondral ossification during long bone development and natural fracture healing initiates by mesenchymal cell condensation, directed by local morphogen signals and mechanical cues. Here, we aimed to mimic development for regeneration of large bone defects. We hypothesized that engineered human mesenchymal condensations presenting transforming growth factor-β1 (TGF-β1) and/or bone morphogenetic protein-2 (BMP-2) from encapsulated microparticles promotes endochondral defect regeneration contingent on in vivo mechanical cues. Mesenchymal condensations induced bone formation dependent on morphogen presentation, with BMP-2 + TGF-β1 fully restoring mechanical function. Delayed in vivo ambulatory loading significantly enhanced the bone formation rate in the dual morphogen group. In vitro, BMP-2 or BMP-2 + TGF-β1 initiated robust endochondral lineage commitment. In vivo, however, extensive cartilage formation was evident predominantly in the BMP-2 + TGF-β1 group, enhanced by mechanical loading. Together, this study demonstrates a biomimetic template for recapitulating developmental morphogenic and mechanical cues in vivo for tissue engineering.
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Affiliation(s)
- S. Herberg
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - A. M. McDermott
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania
- Philadelphia, PA, USA
| | - P. N. Dang
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - D. S. Alt
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - R. Tang
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | | | - D. Varghai
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - J.-Y. Shin
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - A. McMillan
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - A. D. Dikina
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - F. He
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Y. B. Lee
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Y. Cheng
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - K. Umemori
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - P. C. Wong
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN, USA
| | - H. Park
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - J. D. Boerckel
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania
- Philadelphia, PA, USA
- School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan
| | - E. Alsberg
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
- Department of Orthopaedic Surgery, Case Western Reserve University, Cleveland, OH, USA
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Liu Y, Kuang B, Rothrauff BB, Tuan RS, Lin H. Robust bone regeneration through endochondral ossification of human mesenchymal stem cells within their own extracellular matrix. Biomaterials 2019; 218:119336. [PMID: 31310952 DOI: 10.1016/j.biomaterials.2019.119336] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 06/25/2019] [Accepted: 07/04/2019] [Indexed: 01/23/2023]
Abstract
Mesenchymal stem cells (MSCs) embedded in their secreted extracellular matrix (mECM) constitute an exogenous scaffold-free construct capable of generating different types of tissues. Whether MSC-mECM constructs can recapitulate endochondral ossification (ECO), a developmental process during in vivo skeletogenesis, remains unknown. In this study, MSC-mECM constructs are shown to result in robust bone formation both in vitro and in vivo through the process of endochondral ossification when sequentially exposed to chondrogenic and osteogenic cues. Of interest, a novel trypsin pre-treatment was introduced to change cell morphology, which allowed MSC-mECM constructs to undergo the N-cadherin-mediated developmental condensation process and subsequent chondrogenesis. Furthermore, bone formation by MSC-mECM constructs were significantly enhanced by the ECO protocol, as compared to conventional in vitro culture in osteogenic medium alone. This was designed to promote direct bone formation as seen in intramembranous ossification (IMO). The developmentally informed method reported in this study represents a robust and efficacious approach for stem-cell based bone generation, which is superior to the conventional osteogenic induction procedure.
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Affiliation(s)
- Yuwei Liu
- Department of Orthopaedic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15217, USA
| | - Biao Kuang
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15217, USA; Xiangya Third Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Benjamin B Rothrauff
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15217, USA
| | - Rocky S Tuan
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15217, USA; The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Hang Lin
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15217, USA.
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Wagner DR, Karnik S, Gunderson ZJ, Nielsen JJ, Fennimore A, Promer HJ, Lowery JW, Loghmani MT, Low PS, McKinley TO, Kacena MA, Clauss M, Li J. Dysfunctional stem and progenitor cells impair fracture healing with age. World J Stem Cells 2019; 11:281-296. [PMID: 31293713 PMCID: PMC6600851 DOI: 10.4252/wjsc.v11.i6.281] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/26/2019] [Accepted: 06/13/2019] [Indexed: 02/06/2023] Open
Abstract
Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature; mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics. Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging; a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.
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Affiliation(s)
- Diane R Wagner
- Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Sonali Karnik
- Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Zachary J Gunderson
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Jeffery J Nielsen
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, United States
| | - Alanna Fennimore
- Department of Physical Therapy, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Hunter J Promer
- Division of Biomedical Science, Marian University College of Osteopathic Medicine, Indianapolis, IN 46222, United States
| | - Jonathan W Lowery
- Division of Biomedical Science, Marian University College of Osteopathic Medicine, Indianapolis, IN 46222, United States
| | - M Terry Loghmani
- Department of Physical Therapy, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Philip S Low
- Department of Chemistry, Purdue University, West Lafayette, IN 47907 United States
| | - Todd O McKinley
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Melissa A Kacena
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, United States
| | - Matthias Clauss
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Jiliang Li
- Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
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Sheehy E, Kelly D, O'Brien F. Biomaterial-based endochondral bone regeneration: a shift from traditional tissue engineering paradigms to developmentally inspired strategies. Mater Today Bio 2019; 3:100009. [PMID: 32159148 PMCID: PMC7061547 DOI: 10.1016/j.mtbio.2019.100009] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 05/23/2019] [Accepted: 05/24/2019] [Indexed: 02/06/2023] Open
Abstract
There is an urgent, clinical need for an alternative to the use of autologous grafts for the ever increasing number of bone grafting procedures performed annually. Herein, we describe a developmentally inspired approach to bone tissue engineering, which focuses on leveraging biomaterials as platforms for recapitulating the process of endochondral ossification. To begin, we describe the traditional biomaterial-based approaches to tissue engineering that have been investigated as methods to promote in vivo bone regeneration, including the use of three-dimensional biomimetic scaffolds, the delivery of growth factors and recombinant proteins, and the in vitro engineering of mineralized bone-like tissue. Thereafter, we suggest that some of the hurdles encountered by these traditional tissue engineering approaches may be circumvented by modulating the endochondral route to bone repair and, to that end, we assess various biomaterials that can be used in combination with cells and signaling factors to engineer hypertrophic cartilaginous grafts capable of promoting endochondral bone formation. Finally, we examine the emerging trends in biomaterial-based approaches to endochondral bone regeneration, such as the engineering of anatomically shaped templates for bone and osteochondral tissue engineering, the fabrication of mechanically reinforced constructs using emerging three-dimensional bioprinting techniques, and the generation of gene-activated scaffolds, which may accelerate the field towards its ultimate goal of clinically successful bone organ regeneration.
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Affiliation(s)
- E.J. Sheehy
- Tissue Engineering Research Group (TERG), Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin, Ireland
| | - D.J. Kelly
- Tissue Engineering Research Group (TERG), Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin, Ireland
| | - F.J. O'Brien
- Tissue Engineering Research Group (TERG), Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin, Ireland
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Lu Y, Zhang W, Wang J, Yang G, Yin S, Tang T, Yu C, Jiang X. Recent advances in cell sheet technology for bone and cartilage regeneration: from preparation to application. Int J Oral Sci 2019; 11:17. [PMID: 31110170 PMCID: PMC6527566 DOI: 10.1038/s41368-019-0050-5] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 03/08/2019] [Accepted: 04/10/2019] [Indexed: 12/19/2022] Open
Abstract
Bone defects caused by trauma, tumour resection, infection and congenital deformities, together with articular cartilage defects and cartilage-subchondral bone complex defects caused by trauma and degenerative diseases, remain great challenges for clinicians. Novel strategies utilising cell sheet technology to enhance bone and cartilage regeneration are being developed. The cell sheet technology has shown great clinical potential in regenerative medicine due to its effective preservation of cell-cell connections and extracellular matrix and its scaffold-free nature. This review will first introduce several widely used cell sheet preparation systems, including traditional approaches and recent improvements, as well as their advantages and shortcomings. Recent advances in utilising cell sheet technology to regenerate bone or cartilage defects and bone-cartilage complex defects will be reviewed. The key challenges and future research directions for the application of cell sheet technology in bone and cartilage regeneration will also be discussed.
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Affiliation(s)
- Yuezhi Lu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Engineering Research Center of Advanced Dental Technology and Materials; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Wenjie Zhang
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Engineering Research Center of Advanced Dental Technology and Materials; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Jie Wang
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Engineering Research Center of Advanced Dental Technology and Materials; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Guangzheng Yang
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Engineering Research Center of Advanced Dental Technology and Materials; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Shi Yin
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Engineering Research Center of Advanced Dental Technology and Materials; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Tingting Tang
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chunhua Yu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Engineering Research Center of Advanced Dental Technology and Materials; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.
| | - Xinquan Jiang
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Engineering Research Center of Advanced Dental Technology and Materials; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.
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40
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Orth M, Shenar AK, Scheuer C, Braun BJ, Herath SC, Holstein JH, Histing T, Yu X, Murphy WL, Pohlemann T, Laschke MW, Menger MD. VEGF-loaded mineral-coated microparticles improve bone repair and are associated with increased expression of epo and RUNX-2 in murine non-unions. J Orthop Res 2019; 37:821-831. [PMID: 30835895 DOI: 10.1002/jor.24267] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 02/12/2019] [Indexed: 02/04/2023]
Abstract
A poor vascular supply of the fracture gap is a key factor for the development of atrophic non-unions. Mineral-coated microparticles (MCM) represent a sophisticated carrier system for the delivery of vascular endothelial growth factor (VEGF). Hence, we investigated whether VEGF-loaded MCM improve bone repair in non-unions. For this purpose, we analyzed binding and release kinetics of MCM for VEGF in vitro. Moreover, we applied VEGF-loaded or -unloaded MCM in a murine non-union model in vivo and studied the process of bone healing by means of biomechanical, radiological, histomorphometric, and Western blot techniques. MCM-free non-unions served as controls. The binding efficiency of MCM for VEGF was 46 ± 3% and the release profile revealed an initial minor burst release followed by a sustained release over a 50-day study period, thus, mimicking the physiological expression profile of VEGF during bone healing. In vivo, bone defects treated with VEGF-loaded MCM exhibited a higher bending stiffness, a higher fraction of bone volume/tissue volume and a larger callus area on days 14 and 70 when compared to the other groups. Western blot analyses on day 14 revealed a higher expression of VEGF, erythropoietin (EPO), and runt-related transcription factor 2, but not of EPO-receptor in bone defects treated with VEGF-loaded MCM. These findings demonstrate that the use of MCM for VEGF delivery shows great potential due to the ability to maintain protein stability and functionality in vivo. Moreover, the application of VEGF-loaded MCM represent a promising strategy for the treatment of non-unions. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
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Affiliation(s)
- Marcel Orth
- Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Germany.,Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany
| | - Amira K Shenar
- Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Germany.,Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany
| | - Claudia Scheuer
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany
| | - Benedikt J Braun
- Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Germany
| | - Steven C Herath
- Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Germany
| | - Jörg H Holstein
- Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Germany.,Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany
| | - Tina Histing
- Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Germany.,Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany
| | - Xiaohua Yu
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin
| | - William L Murphy
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin
| | - Tim Pohlemann
- Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Germany
| | - Matthias W Laschke
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany
| | - Michael D Menger
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany
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41
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Shih YV, Varghese S. Tissue engineered bone mimetics to study bone disorders ex vivo: Role of bioinspired materials. Biomaterials 2019; 198:107-121. [PMID: 29903640 PMCID: PMC6281816 DOI: 10.1016/j.biomaterials.2018.06.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 05/25/2018] [Accepted: 06/05/2018] [Indexed: 12/15/2022]
Abstract
Recent advances in materials development and tissue engineering has resulted in a substantial number of bioinspired materials that recapitulate cardinal features of bone extracellular matrix (ECM) such as dynamic inorganic and organic environment(s), hierarchical organization, and topographical features. Bone mimicking materials, as defined by its self-explanatory term, are developed based on the current understandings of the natural bone ECM during development, remodeling, and fracture repair. Compared to conventional plastic cultures, biomaterials that resemble some aspects of the native environment could elicit a more natural molecular and cellular response relevant to the bone tissue. Although current bioinspired materials are mainly developed to assist tissue repair or engineer bone tissues, such materials could nevertheless be applied to model various skeletal diseases in vitro. This review summarizes the use of bioinspired materials for bone tissue engineering, and their potential to model diseases of bone development and remodeling ex vivo. We largely focus on biomaterials, designed to re-create different aspects of the chemical and physical cues of native bone ECM. Employing these bone-inspired materials and tissue engineered bone surrogates to study bone diseases has tremendous potential and will provide a closer portrayal of disease progression and maintenance, both at the cellular and tissue level. We also briefly touch upon the application of patient-derived stem cells and introduce emerging technologies such as organ-on-chip in disease modeling. Faithful recapitulation of disease pathologies will not only offer novel insights into diseases, but also lead to enabling technologies for drug discovery and new approaches for cell-based therapies.
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Affiliation(s)
- Yuru Vernon Shih
- Department of Orthopaedic Surgery, Duke University, Durham, NC 27710, USA.
| | - Shyni Varghese
- Department of Orthopaedic Surgery, Duke University, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA; Department of Materials Science and Engineering, Duke University, Durham, NC 27710, USA.
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Subbiah R, Guldberg RE. Materials Science and Design Principles of Growth Factor Delivery Systems in Tissue Engineering and Regenerative Medicine. Adv Healthc Mater 2019; 8:e1801000. [PMID: 30398700 DOI: 10.1002/adhm.201801000] [Citation(s) in RCA: 119] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 09/13/2018] [Indexed: 01/22/2023]
Abstract
Growth factors (GFs) are signaling molecules that direct cell development by providing biochemical cues for stem cell proliferation, migration, and differentiation. GFs play a key role in tissue regeneration, but one major limitation of GF-based therapies is dosage-related adverse effects. Additionally, the clinical applications and efficacy of GFs are significantly affected by the efficiency of delivery systems and other pharmacokinetic factors. Hence, it is crucial to design delivery systems that provide optimal activity, stability, and tunable delivery for GFs. Understanding the physicochemical properties of the GFs and the biomaterials utilized for the development of biomimetic GF delivery systems is critical for GF-based regeneration. Many different delivery systems have been developed to achieve tunable delivery kinetics for single or multiple GFs. The identification of ideal biomaterials with tunable properties for spatiotemporal delivery of GFs is still challenging. This review characterizes the types, properties, and functions of GFs, the materials science of widely used biomaterials, and various GF loading strategies to comprehensively summarize the current delivery systems for tunable spatiotemporal delivery of GFs aimed for tissue regeneration applications. This review concludes by discussing fundamental design principles for GF delivery vehicles based on the interactive physicochemical properties of the proteins and biomaterials.
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Affiliation(s)
- Ramesh Subbiah
- Parker H. Petit Institute for Bioengineering and Bioscience; George W. Woodruff School of Mechanical Engineering; Georgia Institute of Technology; Atlanta GA 30332 USA
| | - Robert E. Guldberg
- Parker H. Petit Institute for Bioengineering and Bioscience; George W. Woodruff School of Mechanical Engineering; Georgia Institute of Technology; Atlanta GA 30332 USA
- Phil and Penny Knight Campus for Accelerating Scientific Impact; 6231 University of Oregon; Eugene OR 97403 USA
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Critchley S, Cunniffe G, O'Reilly A, Diaz-Payno P, Schipani R, McAlinden A, Withers D, Shin J, Alsberg E, Kelly DJ. Regeneration of Osteochondral Defects Using Developmentally Inspired Cartilaginous Templates. Tissue Eng Part A 2018; 25:159-171. [PMID: 30358516 DOI: 10.1089/ten.tea.2018.0046] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
IMPACT STATEMENT Successfully treating osteochondral defects involves regenerating both the damaged articular cartilage and the underlying subchondral bone, in addition to the complex interface that separates these tissues. In this study, we demonstrate that a cartilage template, engineered using bone marrow-derived mesenchymal stem cells, can enhance the regeneration of such defects and promote the development of a more mechanically functional repair tissue. We also use a computational mechanobiological model to understand how joint-specific environmental factors, specifically oxygen levels and tissue strains, regulate the conversion of the engineered template into cartilage and bone in vivo.
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Affiliation(s)
- Susan Critchley
- 1 Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,2 Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland
| | - Gráinne Cunniffe
- 1 Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,2 Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland
| | - Adam O'Reilly
- 1 Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,2 Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland
| | - Pedro Diaz-Payno
- 1 Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,2 Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland
| | - Rossana Schipani
- 1 Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,2 Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland
| | - Aidan McAlinden
- 3 Section of Veterinary Clinical Studies, School of Veterinary Medicine, University College Dublin, Dublin, Ireland
| | | | - Jungyoun Shin
- 5 Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
| | - Eben Alsberg
- 5 Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio.,6 Department of Orthopaedic Surgery, Case Western Reserve University, Cleveland, Ohio.,7 National Centre for Regenerative Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Daniel J Kelly
- 1 Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,2 Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland.,8 Advanced Materials and Bioengineering Research Centre, Trinity College Dublin and Royal College of Surgeons in Ireland, Dublin, Ireland.,9 Department of Anatomy, Royal College of Surgeons in Ireland, Dublin, Ireland
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Petersen A, Princ A, Korus G, Ellinghaus A, Leemhuis H, Herrera A, Klaumünzer A, Schreivogel S, Woloszyk A, Schmidt-Bleek K, Geissler S, Heschel I, Duda GN. A biomaterial with a channel-like pore architecture induces endochondral healing of bone defects. Nat Commun 2018; 9:4430. [PMID: 30361486 PMCID: PMC6202397 DOI: 10.1038/s41467-018-06504-7] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 08/30/2018] [Indexed: 12/22/2022] Open
Abstract
Biomaterials developed to treat bone defects have classically focused on bone healing via direct, intramembranous ossification. In contrast, most bones in our body develop from a cartilage template via a second pathway called endochondral ossification. The unsolved clinical challenge to regenerate large bone defects has brought endochondral ossification into discussion as an alternative approach for bone healing. However, a biomaterial strategy for the regeneration of large bone defects via endochondral ossification is missing. Here we report on a biomaterial with a channel-like pore architecture to control cell recruitment and tissue patterning in the early phase of healing. In consequence of extracellular matrix alignment, CD146+ progenitor cell accumulation and restrained vascularization, a highly organized endochondral ossification process is induced in rats. Our findings demonstrate that a pure biomaterial approach has the potential to recapitulate a developmental bone growth process for bone healing. This might motivate future strategies for biomaterial-based tissue regeneration.
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Affiliation(s)
- A Petersen
- Julius Wolff Institute, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
- Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
| | - A Princ
- Julius Wolff Institute, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - G Korus
- Julius Wolff Institute, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - A Ellinghaus
- Julius Wolff Institute, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - H Leemhuis
- Matricel GmbH, Kaiserstrasse 100, 52134, Herzogenrath, Germany
| | - A Herrera
- Julius Wolff Institute, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
- Berlin-Brandenburg School for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - A Klaumünzer
- Julius Wolff Institute, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - S Schreivogel
- Julius Wolff Institute, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
- Berlin-Brandenburg School for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - A Woloszyk
- Julius Wolff Institute, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
- Department of Orthopaedic Surgery, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Dr, 78229, San Antonio, TX, USA
| | - K Schmidt-Bleek
- Julius Wolff Institute, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
- Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - S Geissler
- Julius Wolff Institute, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
- Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - I Heschel
- Matricel GmbH, Kaiserstrasse 100, 52134, Herzogenrath, Germany
| | - G N Duda
- Julius Wolff Institute, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
- Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
- Berlin-Brandenburg School for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
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Tatsuhiro F, Seiko T, Yusuke T, Reiko TT, Kazuhito S. Dental Pulp Stem Cell-Derived, Scaffold-Free Constructs for Bone Regeneration. Int J Mol Sci 2018; 19:ijms19071846. [PMID: 29932167 PMCID: PMC6073779 DOI: 10.3390/ijms19071846] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 06/15/2018] [Accepted: 06/19/2018] [Indexed: 12/19/2022] Open
Abstract
In the present study, a scaffold-free tissue construct was developed as an approach for the regeneration of tissue defects, which produced good outcomes. We fabricated a scaffold-free tissue construct from human dental pulp stem cells (hDPSCs construct), and examined the characteristics of the construct. For its fabrication, basal sheets prepared by 4-week hDPSCs culturing were subjected to 1-week three-dimensional culture, with or without osteogenic induction, whereas hDPSC sheets (control) were fabricated by 1-week culturing of basal sheets on monolayer culture. The hDPSC constructs formed a spherical structure and calcified matrix that are absent in the control. The expression levels for bone-related genes in the hDPSC constructs were significantly upregulated compared with those in the control. Moreover, the hDPSC constructs with osteogenic induction had a higher degree of calcified matrix formation, and higher expression levels for bone-related genes, than those for the hDPSC constructs without osteogenic induction. These results suggest that the hDPSC constructs with osteogenic induction are composed of cells and extracellular and calcified matrices, and that they can be a possible scaffold-free material for bone regeneration.
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Affiliation(s)
- Fukushima Tatsuhiro
- Department of Oral Medicine and Stomatology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsrumi-ku, Yokohama 230-8501, Japan.
| | - Tatehara Seiko
- Department of Oral Medicine and Stomatology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsrumi-ku, Yokohama 230-8501, Japan.
| | - Takebe Yusuke
- Department of Oral Medicine and Stomatology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsrumi-ku, Yokohama 230-8501, Japan.
| | - Tokuyama-Toda Reiko
- Department of Oral Medicine and Stomatology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsrumi-ku, Yokohama 230-8501, Japan.
| | - Satomura Kazuhito
- Department of Oral Medicine and Stomatology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsrumi-ku, Yokohama 230-8501, Japan.
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Wong SA, Rivera KO, Miclau T, Alsberg E, Marcucio RS, Bahney CS. Microenvironmental Regulation of Chondrocyte Plasticity in Endochondral Repair-A New Frontier for Developmental Engineering. Front Bioeng Biotechnol 2018; 6:58. [PMID: 29868574 PMCID: PMC5962790 DOI: 10.3389/fbioe.2018.00058] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 04/23/2018] [Indexed: 12/31/2022] Open
Abstract
The majority of fractures heal through the process of endochondral ossification, in which a cartilage intermediate forms between the fractured bone ends and is gradually replaced with bone. Recent studies have provided genetic evidence demonstrating that a significant portion of callus chondrocytes transform into osteoblasts that derive the new bone. This evidence has opened a new field of research aimed at identifying the regulatory mechanisms that govern chondrocyte transformation in the hope of developing improved fracture therapies. In this article, we review known and candidate molecular pathways that may stimulate chondrocyte-to-osteoblast transformation during endochondral fracture repair. We also examine additional extrinsic factors that may play a role in modulating chondrocyte and osteoblast fate during fracture healing such as angiogenesis and mineralization of the extracellular matrix. Taken together the mechanisms reviewed here demonstrate the promising potential of using developmental engineering to design therapeutic approaches that activate endogenous healing pathways to stimulate fracture repair.
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Affiliation(s)
- Sarah A Wong
- Department of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco, San Francisco, CA, United States.,School of Dentistry, University of California, San Francisco, San Francisco, CA, United States
| | - Kevin O Rivera
- Department of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco, San Francisco, CA, United States.,School of Dentistry, University of California, San Francisco, San Francisco, CA, United States
| | - Theodore Miclau
- Department of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco, San Francisco, CA, United States
| | - Eben Alsberg
- Department of Orthopaedic Surgery and Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States
| | - Ralph S Marcucio
- Department of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco, San Francisco, CA, United States.,School of Dentistry, University of California, San Francisco, San Francisco, CA, United States
| | - Chelsea S Bahney
- Department of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco, San Francisco, CA, United States
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Stüdle C, Vallmajó-Martín Q, Haumer A, Guerrero J, Centola M, Mehrkens A, Schaefer DJ, Ehrbar M, Barbero A, Martin I. Spatially confined induction of endochondral ossification by functionalized hydrogels for ectopic engineering of osteochondral tissues. Biomaterials 2018; 171:219-229. [PMID: 29705655 DOI: 10.1016/j.biomaterials.2018.04.025] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 03/13/2018] [Accepted: 04/13/2018] [Indexed: 01/09/2023]
Abstract
Despite the various reported approaches to generate osteochondral composites by combination of different cell types and materials, engineering of templates with the capacity to autonomously and orderly develop into cartilage-bone bi-layered structures remains an open challenge. Here, we hypothesized that the embedding of cells inducible to endochondral ossification (i.e. bone marrow derived mesenchymal stromal cells, BMSCs) and of cells capable of robust and stable chondrogenesis (i.e. nasal chondrocytes, NCs) adjacent to each other in bi-layered hydrogels would develop directly in vivo into osteochondral tissues. Poly(ethylene glycol) (PEG) hydrogels were functionalized with TGFβ3 or BMP-2, enzymatically polymerized encapsulating human BMSCs, combined with a hydrogel layer containing human NCs and ectopically implanted in nude mice without pre-culture. The BMSC-loaded layers reproducibly underwent endochondral ossification and generated ossicles containing bone and marrow. The NC-loaded layers formed cartilage tissues, which (under the influence of BMP-2 but not of TGFβ3 from the neighbouring layer) remained phenotypically stable. The proposed strategy, resulting in orderly connected osteochondral composites, should be further assessed for the repair of osteoarticular defects and will be useful to model developmental processes leading to cartilage-bone interfaces.
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Affiliation(s)
- Chiara Stüdle
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Queralt Vallmajó-Martín
- Department of Obstetrics, University Hospital Zürich, University of Zürich, Zürich, Switzerland; Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Alexander Haumer
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Julien Guerrero
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Matteo Centola
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland; Anika Therapeutics Srl, Padua, Italy
| | - Arne Mehrkens
- Spine Surgery, University Hospital Basel, Basel, Switzerland
| | - Dirk J Schaefer
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland
| | - Martin Ehrbar
- Department of Obstetrics, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Andrea Barbero
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Ivan Martin
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
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48
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McMillan A, Nguyen MK, Gonzalez-Fernandez T, Ge P, Yu X, Murphy WL, Kelly DJ, Alsberg E. Dual non-viral gene delivery from microparticles within 3D high-density stem cell constructs for enhanced bone tissue engineering. Biomaterials 2018; 161:240-255. [PMID: 29421560 PMCID: PMC5826638 DOI: 10.1016/j.biomaterials.2018.01.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 12/24/2017] [Accepted: 01/02/2018] [Indexed: 01/03/2023]
Abstract
High-density mesenchymal stem cell (MSC) aggregates can be guided to form bone-like tissue via endochondral ossification in vitro when culture media is supplemented with proteins, such as growth factors (GFs), to first guide the formation of a cartilage template, followed by culture with hypertrophic factors. Recent reports have recapitulated these results through the controlled spatiotemporal delivery of chondrogenic transforming growth factor-β1 (TGF-β1) and chondrogenic and osteogenic bone morphogenetic protein-2 (BMP-2) from microparticles embedded within human MSC aggregates to avoid diffusion limitations and the lengthy, costly in vitro culture necessary with repeat exogenous supplementation. However, since GFs have limited stability, localized gene delivery is a promising alternative to the use of proteins. Here, mineral-coated hydroxyapatite microparticles (MCM) capable of localized delivery of Lipofectamine-plasmid DNA (pDNA) nanocomplexes encoding for TGF-β1 (pTGF-β1) and BMP-2 (pBMP-2) were incorporated, alone or in combination, within MSC aggregates from three healthy porcine donors to induce sustained production of these transgenes. Three donor populations were investigated in this work due to the noted MSC donor-to-donor variability in differentiation capacity documented in the literature. Delivery of pBMP-2 within Donor 1 aggregates promoted chondrogenesis at week 2, followed by an enhanced osteogenic phenotype at week 4. Donor 2 and 3 aggregates did not promote robust glycosaminoglycan (GAG) production at week 2, but by week 4, Donor 2 aggregates with pTGF-β1/pBMP-2 and Donor 3 aggregates with both unloaded MCM and pBMP-2 enhanced osteogenesis compared to controls. These results demonstrate the ability to promote osteogenesis in stem cell aggregates through controlled, non-viral gene delivery within the cell masses. These findings also indicate the need to screen donor MSC regenerative potential in response to gene transfer prior to clinical application. Taken together, this work demonstrates a promising gene therapy approach to control stem cell fate in biomimetic 3D condensations for treatment of bone defects.
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Affiliation(s)
- Alexandra McMillan
- Department of Pathology Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, USA
| | - Minh Khanh Nguyen
- Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, USA
| | - Tomas Gonzalez-Fernandez
- Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland; Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Ireland; Advanced Materials and Bioengineering Research Centre (AMBERG), Trinity College Dublin and Royal College of Surgeons in Dublin, Ireland; Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Dublin, Ireland
| | - Peilin Ge
- Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, USA
| | - Xiaohua Yu
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA; Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, WI, USA
| | - William L Murphy
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA; Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, WI, USA; Materials Science Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Daniel J Kelly
- Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland; Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Ireland; Advanced Materials and Bioengineering Research Centre (AMBERG), Trinity College Dublin and Royal College of Surgeons in Dublin, Ireland; Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Dublin, Ireland
| | - Eben Alsberg
- Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, USA; Department of Orthopaedic Surgery, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, USA; The National Center for Regenerative Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, USA; School of Dentistry, Kyung Hee University, Seoul, South Korea.
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Abstract
Large bone defects remain a tremendous clinical challenge. There is growing evidence in support of treatment strategies that direct defect repair through an endochondral route, involving a cartilage intermediate. While culture-expanded stem/progenitor cells are being evaluated for this purpose, these cells would compete with endogenous repair cells for limited oxygen and nutrients within ischaemic defects. Alternatively, it may be possible to employ extracellular vesicles (EVs) secreted by culture-expanded cells for overcoming key bottlenecks to endochondral repair, such as defect vascularization, chondrogenesis, and osseous remodelling. While mesenchymal stromal/stem cells are a promising source of therapeutic EVs, other donor cells should also be considered. The efficacy of an EV-based therapeutic will likely depend on the design of companion scaffolds for controlled delivery to specific target cells. Ultimately, the knowledge gained from studies of EVs could one day inform the long-term development of synthetic, engineered nanovesicles. In the meantime, EVs harnessed from in vitro cell culture have near-term promise for use in bone regenerative medicine. This narrative review presents a rationale for using EVs to improve the repair of large bone defects, highlights promising cell sources and likely therapeutic targets for directing repair through an endochondral pathway, and discusses current barriers to clinical translation. Cite this article: E. Ferreira, R. M. Porter. Harnessing extracellular vesicles to direct endochondral repair of large bone defects. Bone Joint Res 2018;7:263-273. DOI: 10.1302/2046-3758.74.BJR-2018-0006.
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Affiliation(s)
- E. Ferreira
- Departments of Internal Medicine and Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - R. M. Porter
- Departments of Internal Medicine and Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
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50
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Herberg S, Varghai D, Cheng Y, Dikina AD, Dang PN, Rolle MW, Alsberg E. High-density human mesenchymal stem cell rings with spatiotemporally-controlled morphogen presentation as building blocks for engineering bone diaphyseal tissue. Nanotheranostics 2018; 2:128-143. [PMID: 29577017 PMCID: PMC5865267 DOI: 10.7150/ntno.23354] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 12/24/2017] [Indexed: 01/23/2023] Open
Abstract
Emerging biomimetic tissue engineering strategies aim to partially recapitulate fundamental events that transpire during embryonic skeletal development; namely, cellular self-organization and targeted morphogenetic pathway activation. Here, we describe self-assembled, scaffold-free human mesenchymal stem cell (hMSC) rings featuring microparticle-mediated presentation of transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2). We tested the hypothesis that spatiotemporally-controlled dual presentation of TGF-β1 and BMP-2 is superior in modulating in vitro endochondral ossification of high-density cellular constructs compared to single morphogen delivery. hMSC rings were engineered by seeding cells with microparticles presenting (1) TGF-β1, (2) BMP-2, or (3) TGF-β1 + BMP-2 in custom agarose wells to facilitate self-assembly within 2 d, followed by horizontal culture on glass tubes for 5 weeks. At day 2, hMSC rings across groups revealed homogenous cellular organization mimetic of early mesenchymal condensation with no evidence of new matrix or mineral deposition. Significant early chondrogenic and osteogenic priming occurred with TGF-β1 + BMP-2 presentation compared to single morphogen-loaded groups. By week 5, TGF-β1-loaded hMSC rings had undergone chondrogenesis, while presentation of BMP-2 alone or in conjunction with TGF-β1 stimulated chondrogenesis, chondrocyte hypertrophy, and osteogenesis indicative of endochondral ossification. Importantly, tissue mineralization was most compelling with TGF-β1 + BMP-2 loading. Lastly, hMSC ring 'building blocks' were shown to efficiently fuse into tubes within 6 d post self-assembly. The resulting tubular tissue units exhibited structural integrity, highlighting the translational potential of this advanced biomimetic technology for potential early implantation in long bone defects.
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Affiliation(s)
- Samuel Herberg
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.,Current address: Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Daniel Varghai
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Yuxuan Cheng
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Anna D Dikina
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Phuong N Dang
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Marsha W Rolle
- Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA, USA
| | - Eben Alsberg
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.,Department of Orthopaedic Surgery, Case Western Reserve University, Cleveland, OH, USA.,National Center for Regenerative Medicine, Division of General Medical Sciences, Case Western Reserve University, Cleveland, OH, USA.,School of Dentistry, Kyung Hee University, Seoul, South Korea
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