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Baek SH, Shim BJ, Won H, Lee S, Lee YK, Park HS, Kim SY. Evaluation of Safety and Efficacy of Cell Therapy Based on Osteoblasts Derived from Umbilical Cord Mesenchymal Stem Cells for Osteonecrosis of the Femoral Head: Study Protocol for a Single-Center, Open-Label, Phase I Clinical Trial. Pharmaceuticals (Basel) 2024; 17:1366. [PMID: 39459006 PMCID: PMC11510171 DOI: 10.3390/ph17101366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 09/24/2024] [Accepted: 09/30/2024] [Indexed: 10/28/2024] Open
Abstract
Although mesenchymal stem cells (MSCs) insertion has gained recent attention as a joint-preserving procedure, no study has conducted direct intralesional implantation of human umbilical cord-derived MSCs (hUCMSCs) in patients with ONFH. This is a protocol for a phase 1 clinical trial designed to assess the safety and exploratory efficacy of human umbilical cord-derived osteoblasts (hUC-Os), osteogenic differentiation-induced cells from hUCMSCs, in patients with early-stage ONFH. Nine patients with Association Research Circulation Osseous (ARCO) stage 1 or 2 will be assigned to a low-dose (1 × 107 hUC-O cells, n = 3), medium-dose (2 × 107 cells, n = 3), and high-dose group (4 × 107 cells, n = 3) in the order of their arrival at the facility, and, depending on the occurrence of dose-limiting toxicity, up to 18 patients can be enrolled by applying the 3 + 3 escalation method. We will perform hUC-O (CF-M801) transplantation combined with core decompression and follow-up for 12 weeks according to the study protocol. Safety will be determined through adverse event assessment, laboratory tests including a panel reactive antibody test, vital sign assessment, physical examination, and electrocardiogram. Efficacy will be explored through the change in pain visual analog scale, Harris hip score, Western Ontario and McMaster Universities Osteoarthritis Index, ARCO stage, and also size and location of necrotic lesion according to Japanese Investigation Committee classification before and after the procedure. Joint preservation is important, particularly in younger, active patients with ONFH. Confirmation of the safety and efficacy of hUC-Os will lead to a further strategy to preserve joints for those suffering from ONFH and improve our current knowledge of cell therapy.
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Affiliation(s)
- Seung-Hoon Baek
- Department of Orthopedic Surgery, Kyungpook National University Hospital, Daegu 41944, Republic of Korea; (S.-H.B.); (H.W.)
- Department of Orthopedic Surgery, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Bum-Jin Shim
- Department of Orthopedic Surgery, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea;
| | - Heejae Won
- Department of Orthopedic Surgery, Kyungpook National University Hospital, Daegu 41944, Republic of Korea; (S.-H.B.); (H.W.)
| | - Sunray Lee
- Cell Engineering For Origin (CEFO) Research Center, Seoul 03150, Republic of Korea; (S.L.); (Y.K.L.)
| | - Yeon Kyung Lee
- Cell Engineering For Origin (CEFO) Research Center, Seoul 03150, Republic of Korea; (S.L.); (Y.K.L.)
| | - Hyun Sook Park
- Cell Engineering For Origin (CEFO) Research Center, Seoul 03150, Republic of Korea; (S.L.); (Y.K.L.)
| | - Shin-Yoon Kim
- Department of Orthopedic Surgery, Kyungpook National University Hospital, Daegu 41944, Republic of Korea; (S.-H.B.); (H.W.)
- Department of Orthopedic Surgery, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
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Moyal AJ, Li AW, Adelstein JM, Moon TJ, Napora JK. Bone marrow aspirate and bone marrow aspirate concentrate: Does the literature support use in long-bone nonunion and provide new insights into mechanism of action? EUROPEAN JOURNAL OF ORTHOPAEDIC SURGERY & TRAUMATOLOGY : ORTHOPEDIE TRAUMATOLOGIE 2024; 34:2871-2880. [PMID: 39060552 PMCID: PMC11377611 DOI: 10.1007/s00590-024-04048-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024]
Abstract
PURPOSE To assess the use of bone marrow aspirate (BM) and bone marrow aspirate concentrate (BMAC) in the treatment of long-bone nonunion and to understand mechanism of action. METHODS A systematic review of PubMed and EBSCOHost was completed to identify studies that investigated the use of BM or BMAC for the diagnosis of delayed union and/or nonunion of long-bone fractures. Studies of isolated bone marrow-mesenchymal stem cells (BM-MSCs) and use in non-long-bone fractures were excluded. Statistical analysis was confounded by heterogeneous fracture fixation methods, treatment history, and scaffold use. RESULTS Our initial search yielded 430 publications, which was screened down to 25 studies. Successful treatment in aseptic nonunion was reported at 79-100% (BM) and 50-100% (BMAC). Septic nonunion rates were slightly better at 73-100% (BM) and 83.3-100% (BMAC). 18/24 studies report union rates > 80%. One study reports successful treatment of septic nonunion with BMAC and no antibiotics. A separate study reported a significant reduction in autograft reinfection rate when combined with BMAC (P = 0.009). Major adverse events include two deep infections at injection site and one case of heterotopic ossification. Most studies note transient mild donor site discomfort and potential injection site discomfort attributed to needle size. CONCLUSION The current literature pertaining to use of BM/BMAC for nonunion is extremely heterogeneous in terms of patient population and concomitant treatment modalities. While results are promising for use of BM/BMAC with other gold standard treatment methodologies, the literature requires additional Level I data to clarify the impact of role BM/BMAC in treating nonunion when used alone and in combination with other modalities. LEVEL OF EVIDENCE Level III.
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Affiliation(s)
- Andrew J Moyal
- University Hospitals Cleveland Medical Center, 11100 Euclid Ave, Cleveland, OH, 44106, USA.
- Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, OH, 44106, USA.
- Department of Orthopedic Surgery, University Hospitals Cleveland Medical Center, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH, 44106, USA.
| | - Austin W Li
- University Hospitals Cleveland Medical Center, 11100 Euclid Ave, Cleveland, OH, 44106, USA
| | - Jeremy M Adelstein
- University Hospitals Cleveland Medical Center, 11100 Euclid Ave, Cleveland, OH, 44106, USA
- Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, OH, 44106, USA
| | - Tyler J Moon
- University Hospitals Cleveland Medical Center, 11100 Euclid Ave, Cleveland, OH, 44106, USA
- Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, OH, 44106, USA
| | - Joshua K Napora
- University Hospitals Cleveland Medical Center, 11100 Euclid Ave, Cleveland, OH, 44106, USA
- Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, OH, 44106, USA
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Maličev E, Jazbec K. An Overview of Mesenchymal Stem Cell Heterogeneity and Concentration. Pharmaceuticals (Basel) 2024; 17:350. [PMID: 38543135 PMCID: PMC10975472 DOI: 10.3390/ph17030350] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/22/2024] [Accepted: 03/05/2024] [Indexed: 01/06/2025] Open
Abstract
Mesenchymal stem cells (MSCs) are of great interest in cell therapies due to the immunomodulatory and other effects they have after autologous or allogeneic transplantation. In most clinical applications, a high number of MSCs is required; therefore, the isolated MSC population must be expanded in the cell culture until the desired number is reached. Analysing freshly isolated MSCs is challenging due to their rareness and heterogeneity, which is noticeable among donors, tissues, and cell subpopulations. Although the phenotype of MSCs in tissue can differ from those of cultured cells, phenotyping and counting are usually performed only after MSC proliferation. As MSC applicability is a developing and growing field, there is a need to implement phenotyping and counting methods for freshly isolated MSCs, especially in new one-step procedures where isolated cells are implanted immediately without cell culturing. Only by analysing harvested cells can we correctly evaluate such studies. This review describes multilevel heterogeneity and concentrations of MSCs and different strategies for phenotype determination and enumeration of freshly isolated MSCs.
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Affiliation(s)
- Elvira Maličev
- Blood Transfusion Centre of Slovenia, Šlajmerjeva 6, 1000 Ljubljana, Slovenia;
- Biotechnical Faculty, University of Ljubljana, Jamnikarjeva ulica 101, 1000 Ljubljana, Slovenia
| | - Katerina Jazbec
- Blood Transfusion Centre of Slovenia, Šlajmerjeva 6, 1000 Ljubljana, Slovenia;
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Salamanna F, Tedesco G, Sartori M, Griffoni C, Spinnato P, Romeo P, Ghermandi R, Fini M, Giavaresi G, Gasbarrini A, Barbanti Brodano G. Safety and efficacy of autologous bone marrow clot as a multifunctional bioscaffold for instrumental posterior lumbar fusion: a 1-year follow-up pilot study. Front Endocrinol (Lausanne) 2024; 14:1245344. [PMID: 38260131 PMCID: PMC10801235 DOI: 10.3389/fendo.2023.1245344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 12/12/2023] [Indexed: 01/24/2024] Open
Abstract
Background Bone marrow aspirate (BMA), when combined with graft substitutes, has long been introduced as a promising alternative to iliac crest bone graft in spinal fusion. However, the use of BMA is limited by the absence of a standardized procedure, a structural texture, and the potential for diffusion away from the implant site. Recently, the potential use of a new formulation of BMA, named BMA clot, has been preclinically described. In this report, we present the results of a prospective pilot clinical study aimed at evaluating the safety and efficacy of autologous vertebral BMA (vBMA) clot as a three-dimensional and multifunctional bioscaffold in instrumented posterior lumbar fusion. Methods Ten consecutive patients with an indication of multilevel (≤5) posterior spinal fusion due to lumbar spine degenerative diseases were included in the study and treated with vBMA. Clinical outcomes were assessed using the Visual Analog Scale (VAS), Oswestry Disability Index (ODI), and EuroQoL-5L (EQ-5L) preoperatively and at 3 months and 12 months after spinal fusion. Bone fusion quality was evaluated at the 12-month follow-up using the Brantigan classification on radiography (XR) imaging. Bone density was measured on computed tomography (CT) scans at 6 and 12 months of follow-up visits at the intervertebral arches and intervertebral joint areas and expressed in Hounsfield unit (HU). Results The results indicate a successful posterolateral fusion rate of approximately 100% (considering levels with C, D, and E grades according to the Brantigan classification) at the 12-month follow-up, along with an increase in bone density from 6 to 12 months of follow-up. An improvement in the quality of life and health status following surgery, as assessed by clinical scores (ODI, VAS, and EQ-5L), was also observed as early as 3 months postsurgery. No adverse events related to the vBMA clot were reported. Conclusion This prospective pilot study demonstrates the effectiveness and safety profile of vBMA clot as an advanced bioscaffold capable of achieving posterior lumbar fusion in the treatment of degenerative spine diseases. This lays the groundwork for a larger randomized clinical study.
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Affiliation(s)
- Francesca Salamanna
- Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Giuseppe Tedesco
- Spine Surgery Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Maria Sartori
- Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | | | - Paolo Spinnato
- Diagnostic and Interventional Radiology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Paolo Romeo
- Diagnostic and Interventional Radiology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | | | - Milena Fini
- Scientific Direction, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Gianluca Giavaresi
- Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
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Jeyaraman M, Verma T, Jeyaraman N, Patro BP, Nallakumarasamy A, Khanna M. Is mandible derived mesenchymal stromal cells superior in proliferation and regeneration to long bone-derived mesenchymal stromal cells? World J Methodol 2023; 13:10-17. [PMID: 37035028 PMCID: PMC10080497 DOI: 10.5662/wjm.v13.i2.10] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/01/2023] [Accepted: 02/10/2023] [Indexed: 03/15/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are cells with the characteristic ability of self-renewal along with the ability to exhibit multilineage differentiation. Bone marrow (BM) is the first tissue in which MSCs were identified and BM-MSCs are most commonly used among various MSCs in clinical settings. MSCs can stimulate and promote osseous regeneration. Due to the difference in the development of long bones and craniofacial bones, the mandibular-derived MSCs (M-MSCs) have distinct differentiation characteristics as compared to that of long bones. Both mandibular and long bone-derived MSCs are positive for MSC-associated markers such as CD-73, -105, and -106, stage-specific embryonic antigen 4 and Octamer-4, and negative for hematopoietic markers such as CD-14, -34, and -45. As the M-MSCs are derived from neural crest cells, they have embryogenic cells which promote bone repair and high osteogenic potential. In vitro and in vivo animal-based studies demonstrate a higher rate of proliferation and high osteogenic potential for M-MSCs as compared to long-bones MSCs, but in vivo studies in human subjects are lacking. The BM-MSCs have their advantages and limitations. M-MSCs may be utilized as an alternative source of MSCs which can be utilized for tissue engineering and promoting the regeneration of bone. M-MSCs may have potential advantages in the repair of craniofacial or orofacial defects. Considering the utility of M-MSCs in the field of orthopaedics, we have discussed various unresolved questions, which need to be explored for their better utility in clinical practice.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600056, Tamil Nadu, India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Department of Regenerative Medicine, Indian Stem Cell Study Group Association, Lucknow 226010, Uttar Pradesh, India
| | - Tushar Verma
- Department of Orthopaedic Rheumatology, Fellow in Indian Orthopaedic Rheumatology Association, Lucknow 226010, Uttar Pradesh, India
| | - Naveen Jeyaraman
- Department of Regenerative Medicine, Indian Stem Cell Study Group Association, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedic Rheumatology, Fellow in Indian Orthopaedic Rheumatology Association, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedics, Rathimed Speciality Hospital, Chennai 600040, Tamil Nadu, India
| | - Bishnu Prasad Patro
- Department of Regenerative Medicine, Indian Stem Cell Study Group Association, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedics, All India Institute of Medical Sciences, Bhubaneswar 751019, Odisha, India
| | - Arulkumar Nallakumarasamy
- Department of Regenerative Medicine, Indian Stem Cell Study Group Association, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedic Rheumatology, Fellow in Indian Orthopaedic Rheumatology Association, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedics, All India Institute of Medical Sciences, Bhubaneswar 751019, Odisha, India
| | - Manish Khanna
- Department of Regenerative Medicine, Indian Stem Cell Study Group Association, Lucknow 226010, Uttar Pradesh, India
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Casanova EA, Rodriguez-Palomo A, Stähli L, Arnke K, Gröninger O, Generali M, Neldner Y, Tiziani S, Dominguez AP, Guizar-Sicairos M, Gao Z, Appel C, Nielsen LC, Georgiadis M, Weber FE, Stark W, Pape HC, Cinelli P, Liebi M. SAXS imaging reveals optimized osseointegration properties of bioengineered oriented 3D-PLGA/aCaP scaffolds in a critical size bone defect model. Biomaterials 2023; 294:121989. [PMID: 36628888 DOI: 10.1016/j.biomaterials.2022.121989] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 12/01/2022] [Accepted: 12/24/2022] [Indexed: 01/03/2023]
Abstract
Healing large bone defects remains challenging in orthopedic surgery and is often associated with poor outcomes and complications. A major issue with bioengineered constructs is achieving a continuous interface between host bone and graft to enhance biological processes and mechanical stability. In this study, we have developed a new bioengineering strategy to produce oriented biocompatible 3D PLGA/aCaP nanocomposites with enhanced osseointegration. Decellularized scaffolds -containing only extracellular matrix- or scaffolds seeded with adipose-derived mesenchymal stromal cells were tested in a mouse model for critical size bone defects. In parallel to micro-CT analysis, SAXS tensor tomography and 2D scanning SAXS were employed to determine the 3D arrangement and nanostructure within the critical-sized bone. Both newly developed scaffold types, seeded with cells or decellularized, showed high osseointegration, higher bone quality, increased alignment of collagen fibers and optimal alignment and size of hydroxyapatite minerals.
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Affiliation(s)
- Elisa A Casanova
- Department of Trauma Surgery, University of Zurich, University Hospital Zurich, Zurich, Switzerland
| | | | - Lisa Stähli
- Department of Trauma Surgery, University of Zurich, University Hospital Zurich, Zurich, Switzerland
| | - Kevin Arnke
- Department of Trauma Surgery, University of Zurich, University Hospital Zurich, Zurich, Switzerland
| | - Olivier Gröninger
- Institute for Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland
| | - Melanie Generali
- Institute for Regenerative Medicine (IREM), Center for Therapy Development and Good Manufacturing Practice, University of Zurich, Zurich, Switzerland
| | - Yvonne Neldner
- Department of Trauma Surgery, University of Zurich, University Hospital Zurich, Zurich, Switzerland
| | - Simon Tiziani
- Department of Trauma Surgery, University of Zurich, University Hospital Zurich, Zurich, Switzerland
| | - Ana Perez Dominguez
- Oral Biotechnology and Bioengineering, Department of Cranio-Maxillofacial and Oral Surgery, Center for Dental Medicine, University of Zurich, Zurich, Switzerland
| | | | - Zirui Gao
- Swiss Light Source, Paul Scherrer Institute, Villigen, Switzerland
| | - Christian Appel
- Swiss Light Source, Paul Scherrer Institute, Villigen, Switzerland
| | - Leonard C Nielsen
- Department of Physics, Chalmers University of Technology, Gothenburg, Sweden
| | - Marios Georgiadis
- Department of Radiology, Stanford School of Medicine, Stanford, CA, USA
| | - Franz E Weber
- Oral Biotechnology and Bioengineering, Department of Cranio-Maxillofacial and Oral Surgery, Center for Dental Medicine, University of Zurich, Zurich, Switzerland
| | - Wendelin Stark
- Institute for Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland
| | - Hans-Christoph Pape
- Department of Trauma Surgery, University of Zurich, University Hospital Zurich, Zurich, Switzerland
| | - Paolo Cinelli
- Department of Trauma Surgery, University of Zurich, University Hospital Zurich, Zurich, Switzerland; Center for Applied Biotechnology and Molecular Medicine (CABMM), University of Zurich, Zurich, Switzerland.
| | - Marianne Liebi
- Department of Physics, Chalmers University of Technology, Gothenburg, Sweden; Centre for X-ray Analytics, Swiss Federal Laboratories for Materials Science and Technology (EMPA), St. Gallen, Switzerland
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Im GI. Regenerative medicine for osteonecrosis of the femoral head : present and future. Bone Joint Res 2023; 12:5-8. [PMID: 36587245 PMCID: PMC9872044 DOI: 10.1302/2046-3758.121.bjr-2022-0057.r1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Cite this article: Bone Joint Res 2023;12(1):5-8.
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Affiliation(s)
- Gun-Il Im
- Research Institute for Convergence Life Science, Dongguk University, Goyang, South Korea, Gun-Il Im. E-mail:
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Dadra A, Rathod PM. Multiple-Choice Questions. INSIGHTS INTO AVASCULAR NECROSIS OF THE FEMORAL HEAD 2023:183-196. [DOI: 10.1007/978-981-99-1346-6_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Day MA, Hancock KJ, Selley RS, Olsen R, Ranawat AS, Nwachukwu BU, Kelly BT, Nawabi DH. Hip Arthroscopy With Bone Marrow Aspirate Injection for Patients With Symptomatic Labral Tears and Early Degenerative Changes Shows Similar Improvement Compared With Patients Undergoing Hip Arthroscopy With Symptomatic Labral Tears Without Arthritis. Arthroscopy 2022; 39:1429-1437. [PMID: 36574821 DOI: 10.1016/j.arthro.2022.12.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/24/2022] [Accepted: 12/01/2022] [Indexed: 12/25/2022]
Abstract
PURPOSE To define the clinical effect of intra-articular injection of iliac crest-derived bone marrow aspirate concentrate (BMAC) at the time of hip arthroscopy in patients with symptomatic labral tears and early radiographic degenerative changes. METHODS A retrospective review of a prospectively collected hip registry database was performed. Patients with symptomatic labral tears and Tönnis grade 1 or 2 degenerative changes who underwent labrum-preserving hip arthroscopy with BMAC injection were included and were matched with patients who underwent hip arthroscopy without BMAC injection. Patient-reported outcomes (PROs) collected preoperatively and up to 2 years postoperatively included the modified Harris Hip Score, Hip Outcome Score-Activities of Daily Living, Hip Outcome Score-Sport, and International Hip Outcome Tool 33 score. Clinical relevance was measured with the minimal clinically important difference, patient acceptable symptom state, and substantial clinical benefit for each outcome score. RESULTS A total of 35 patients underwent labrum-preserving hip arthroscopy with BMAC injection and were matched with 35 control patients. There were no differences in demographic characteristics between the groups (P > .05). The BMAC group consisted of 22 patients (62.9%) with Tönnis grade 1 changes and 13 (37.1%) with Tönnis grade 2 changes, whereas all 35 control patients had Tönnis grade 0 hips. All PROs were significantly improved in both groups at 2 years, with no difference in improvement. The rate of failure requiring conversion to total hip arthroplasty was 14.3% (mean, 1.6 years postoperatively) in the BMAC group and 5.7% (mean, 7 years postoperatively) in the control group (P = .09). The difference in the frequency of patients achieving the minimal clinically important difference, patient acceptable symptom state, and substantial clinical benefit was not statistically significant between cohorts. CONCLUSIONS In a challenging group of patients with symptomatic labral tears and early radiographic degenerative changes, hip arthroscopy with BMAC injection results in statistically and clinically significant improvement in PROs comparable to a group of patients with nonarthritic hips undergoing hip arthroscopy at short-term follow-up. LEVEL OF EVIDENCE Level III, retrospective comparative therapeutic trial.
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Affiliation(s)
- Molly A Day
- Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin, U.S.A.; Sports Medicine Institute, Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, New York, U.S.A..
| | - Kyle J Hancock
- Department of Sports Medicine, Desert Orthopaedic Center, Las Vegas, Nevada, U.S.A.; Sports Medicine Institute, Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, New York, U.S.A
| | - Ryan S Selley
- Sports Medicine Institute, Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, New York, U.S.A
| | - Reena Olsen
- Sports Medicine Institute, Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, New York, U.S.A
| | - Anil S Ranawat
- Sports Medicine Institute, Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, New York, U.S.A
| | - Benedict U Nwachukwu
- Sports Medicine Institute, Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, New York, U.S.A
| | - Bryan T Kelly
- Sports Medicine Institute, Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, New York, U.S.A
| | - Danyal H Nawabi
- Sports Medicine Institute, Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, New York, U.S.A
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Wang YH, Zhao CZ, Wang RY, Du QX, Liu JY, Pan J. The crosstalk between macrophages and bone marrow mesenchymal stem cells in bone healing. Stem Cell Res Ther 2022; 13:511. [PMID: 36333820 PMCID: PMC9636722 DOI: 10.1186/s13287-022-03199-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022] Open
Abstract
Bone injury plagues millions of patients worldwide every year, and it demands a heavy portion of expense from the public medical insurance system. At present, orthopedists think that autologous bone transplantation is the gold standard for treating large-scale bone defects. However, this method has significant limitations, which means that parts of patients cannot obtain a satisfactory prognosis. Therefore, a basic study on new therapeutic methods is urgently needed. The in-depth research on crosstalk between macrophages (Mϕs) and bone marrow mesenchymal stem cells (BMSCs) suggests that there is a close relationship between inflammation and regeneration. The in-depth understanding of the crosstalk between Mϕs and BMSCs is helpful to amplify the efficacy of stem cell-based treatment for bone injury. Only in the suitable inflammatory microenvironment can the damaged tissues containing stem cells obtain satisfactory healing outcomes. The excessive tissue inflammation and lack of stem cells make the transplantation of biomaterials necessary. We can expect that the crosstalk between Mϕs and BMSCs and biomaterials will become the mainstream to explore new methods for bone injury in the future. This review mainly summarizes the research on the crosstalk between Mϕs and BMSCs and also briefly describes the effects of biomaterials and aging on cell transplantation therapy.
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Affiliation(s)
- Yu-Hao Wang
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, #14 Third Section, Renmin Road South, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581Chengdu Advanced Medical Science Center, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 Sichuan Province People’s Republic of China
| | - Cheng-Zhi Zhao
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, #14 Third Section, Renmin Road South, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581Chengdu Advanced Medical Science Center, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 Sichuan Province People’s Republic of China
| | - Ren-Yi Wang
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, #14 Third Section, Renmin Road South, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581Chengdu Advanced Medical Science Center, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 Sichuan Province People’s Republic of China
| | - Qian-Xin Du
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, #14 Third Section, Renmin Road South, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581Chengdu Advanced Medical Science Center, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 Sichuan Province People’s Republic of China
| | - Ji-Yuan Liu
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, #14 Third Section, Renmin Road South, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China
| | - Jian Pan
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, #14 Third Section, Renmin Road South, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581Chengdu Advanced Medical Science Center, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 Sichuan Province People’s Republic of China
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11
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Yang J, Zhang X, Liang W, Chen G, Ma Y, Zhou Y, Fen R, Jiang K. Efficacy of adjuvant treatment for fracture nonunion/delayed union: a network meta-analysis of randomized controlled trials. BMC Musculoskelet Disord 2022; 23:481. [PMID: 35597937 PMCID: PMC9123731 DOI: 10.1186/s12891-022-05407-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 04/18/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Fracture nonunion/delayed union seriously affects physical and mental health and quality of life. The aim of this study was to evaluate the relative efficacy of different adjuvant treatments for nonunion/delayed union by network meta-analysis. METHODS A comprehensive search was performed to identify randomized controlled trials (RCTs) evaluating adjuvant treatment in the management of nonunion/delayed union. A network meta-analysis reporting on healing rate, healing time, and adverse effect (AE) outcomes was conducted to assess and compare different interventions. RESULTS Thirty studies were included in the analysis. For the healing rate outcome, bone marrow aspirate (BMA) + autologous cancellous bone (ACB) was found to be significantly better than ACB alone (odds ratio: 0.12; 95% confidence interval: 0.03, 0.59). In the ranking results, BMA+ platelet-rich plasma (PRP) (96%), BMA + ACB (90%), and BMA alone (82%) showed relative advantages in the healing rate. Low-intensity pulsed ultrasonography (LIUS) intervention significantly shortened the healing time compared with ACB (SMD: -9.26; 95% CI: - 14.64, - 3.87). LIUS (100%), BMA + PRP (74%), and bone morphogenetic proteins (BMPs) (69%) have relative advantages. Compared with the control, electromagnetic field (EMF) (OR: 13.21; 95% CI: 1.58, 110.40) and extracorporeal shock wave (ESWT) (OR: 4.90; 95% CI: 1.38, 17.43) had a higher AE risk. CONCLUSIONS Among the current intervention strategies, BMA in combination with PRP and ACB can improve the healing rate of nonunion/delayed union. LIUS can significantly shorten the healing time. EMF and ESWT may have a high risk of AE. However, large-scale, well-designed studies are still needed to confirm the results. TRIAL REGISTRATION Retrospectively registered.
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Affiliation(s)
- Jun Yang
- Department of Orthopedics and Traumatology, Yuxi Municipal Hospital of TCM, 53 Nie er Rd, Yuxi, Yunnan Province, 653100, People's Republic of China
| | - Xiangmin Zhang
- Department of Orthopedics and Traumatology, Yuxi Municipal Hospital of TCM, 53 Nie er Rd, Yuxi, Yunnan Province, 653100, People's Republic of China
| | - Wangbo Liang
- Department of Orthopedics and Traumatology, Yuxi Municipal Hospital of TCM, 53 Nie er Rd, Yuxi, Yunnan Province, 653100, People's Republic of China.
| | - Guo Chen
- Department of Orthopedics and Traumatology, Yuxi Municipal Hospital of TCM, 53 Nie er Rd, Yuxi, Yunnan Province, 653100, People's Republic of China.
| | - Yanbo Ma
- Department of Orthopedics and Traumatology, Yuxi Municipal Hospital of TCM, 53 Nie er Rd, Yuxi, Yunnan Province, 653100, People's Republic of China
| | - Yonghua Zhou
- Department of Orthopedics and Traumatology, Yuxi Municipal Hospital of TCM, 53 Nie er Rd, Yuxi, Yunnan Province, 653100, People's Republic of China
| | - Rong Fen
- Department of Orthopedics and Traumatology, Yuxi Municipal Hospital of TCM, 53 Nie er Rd, Yuxi, Yunnan Province, 653100, People's Republic of China
| | - Kaichang Jiang
- Department of Orthopedics and Traumatology, Yuxi Municipal Hospital of TCM, 53 Nie er Rd, Yuxi, Yunnan Province, 653100, People's Republic of China
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12
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Hoogervorst P, Campbell JC, Scholz N, Cheng EY. Core Decompression and Bone Marrow Aspiration Concentrate Grafting for Osteonecrosis of the Femoral Head. J Bone Joint Surg Am 2022; 104:54-60. [PMID: 35389906 DOI: 10.2106/jbjs.20.00527] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Core decompression (CD) with bone marrow aspiration concentrate (BMAC) is a technique that may improve outcomes in osteonecrosis of the femoral head (ONFH). The primary aim of this study was to evaluate the radiographic progression free survival (PFS) of CD augmented with BMAC. Secondary aims were to determine the survivorship with conversion (CFS) to total hip arthroplasty (THA) as an endpoint, determine prognostic factors, and characterize the cellular quality of the BMAC. METHODS A retrospective cohort study of 61 femoral heads (40 patients) was performed. Patient demographics, comorbidities, BMI, smoking status, etiology, location and extent of ONFH were recorded. The primary endpoint was radiographic progression of ONFH and secondarily, conversion to THA. Additional aims were to determine predictive factors for progression and report the cellular characteristics of the BMAC. Data obtained were compared to the results of a prior randomized controlled trial comparing CD alone versus CD with polymethylmethacrylate cement (PMMA) augmentation. RESULTS Radiographic PFS of CD with BMAC at 2 and 5 years was 78.3% and 53.3%, respectively. The risk of progression was lower in the CD with BMAC group compared to CD alone (HR0.45, p = 0.03), however this difference no longer remained statistically significant on multivariate analysis. Conversion to total hip arthroplasty free survival (CFS) of CD with BMAC at both 2 and 5 years was 72.1% and 54.6%, respectively with no differences compared to the control groups (CD alone, CD and PMMA). The predictive factors for progression were obesity (BMI ≥ 30) and the extent of the disease as quantified by either percentage involvement, necrotic index or modified necrotic index. CONCLUSIONS No differences in PFS or CFS between CD with BMAC compared to CD alone or CD with PMMA were identified. Independent statistically significant predictors of progression-free survival or conversion to THA are BMI ≥ 30 and the extent of ONFH. Further research with an adequately powered randomized controlled trial is needed. LEVEL OF EVIDENCE 3.
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Affiliation(s)
- Paul Hoogervorst
- Department of Orthopedic Surgery, University of Minnesota, Minneapolis, Minnesota
| | - Joshua C Campbell
- Department of Orthopaedic Surgery, George Washington University, Washington, District of Columbia
| | - Natalie Scholz
- Department of Orthopedic Surgery, University of Minnesota, Minneapolis, Minnesota
| | - Edward Y Cheng
- Department of Orthopedic Surgery, University of Minnesota, Minneapolis, Minnesota
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13
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Salamanna F, Contartese D, Borsari V, Pagani S, Barbanti Brodano G, Griffoni C, Ricci A, Gasbarrini A, Fini M. Two Hits for Bone Regeneration in Aged Patients: Vertebral Bone Marrow Clot as a Biological Scaffold and Powerful Source of Mesenchymal Stem Cells. Front Bioeng Biotechnol 2022; 9:807679. [PMID: 35118056 PMCID: PMC8804319 DOI: 10.3389/fbioe.2021.807679] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/20/2021] [Indexed: 12/26/2022] Open
Abstract
Recently, the use of a new formulation of bone marrow aspirate (BMA), the BMA clot, has been described. This product entails a naturally formed clot from the harvested bone marrow, which retains all the BMA components preserved in a matrix biologically molded by the clot. Even though its beneficial effects were demonstrated by some studies, the impact of aging and aging-associated processes on biological properties and the effect of BMA cell-based therapy are currently unknown. The purpose of our study was to compare selected parameters and properties of clotted BMA and BMA-derived mesenchymal stem cells (MSCs) from younger (<45 years) and older (>65 years) female donors. Clotted BMA growth factors (GFs) expression, MSCs morphology and viability, doubling time, surface marker expression, clonogenic potential, three-lineage differentiation, senescence-associated factors, and Klotho synthesis from younger and older donors were analyzed. Results indicated that donor age does not affect tissue-specific BMA clot regenerative properties such as GFs expression and MSCs morphology, viability, doubling time, surface antigens expression, colony-forming units, osteogenic and adipogenic differentiation, and Klotho and senescence-associated gene expression. Only few differences, i.e., increased platelet-derived growth factor-AB (PDGF-AB) synthesis and MSCs Aggrecan (ACAN) expression, were detected in younger donors in comparison with older ones. However, these differences do not interfere with all the other BMA clot biological properties. These results demonstrated that BMA clot can be applied easily, without any sample processing and avoiding potential contamination risks as well as losing cell viability, proliferation, and differentiation ability, for autologous transplantation in aged patients. The vertebral BMA clot showed two successful hits since it works as a biological scaffold and as a powerful source of mesenchymal stem cells, thus representing a novel and advanced therapeutic alternative for the treatment of orthopedic injuries.
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Affiliation(s)
- Francesca Salamanna
- Complex Structure Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Deyanira Contartese
- Complex Structure Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
- *Correspondence: Deyanira Contartese,
| | - Veronica Borsari
- Complex Structure Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Stefania Pagani
- Complex Structure Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Giovanni Barbanti Brodano
- Department of Oncological and Degenerative Spine Surgery, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Cristiana Griffoni
- Department of Oncological and Degenerative Spine Surgery, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Alessandro Ricci
- Anesthesia-Resuscitation and Intensive Care, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Alessandro Gasbarrini
- Department of Oncological and Degenerative Spine Surgery, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Milena Fini
- Complex Structure Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
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14
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Brozovich A, Sinicrope BJ, Bauza G, Niclot FB, Lintner D, Taraballi F, McCulloch PC. High Variability of Mesenchymal Stem Cells Obtained via Bone Marrow Aspirate Concentrate Compared With Traditional Bone Marrow Aspiration Technique. Orthop J Sports Med 2021; 9:23259671211058459. [PMID: 34901292 PMCID: PMC8655450 DOI: 10.1177/23259671211058459] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 08/24/2021] [Indexed: 12/28/2022] Open
Abstract
Background: Bone marrow aspirate (BMA) is a common source for harvesting mesenchymal stem cells (MSCs), other progenitor cells, and associated cytokines and growth factors to be used in the biologic treatment of various orthopaedic pathologies. The aspirate is commonly centrifuged into a concentrated volume that can be immediately administered to a patient using commercially available kits. However, the handling and efficacy of BMA concentrate (BMAC) are still controversial. Purpose: To characterize BMA versus BMAC for MSC quantity, potency, and cytokine profile. Study Design: Controlled laboratory study. Methods: From 8 participants (age, 17-68 years), 30 mL of bone marrow was aspirated by a single surgeon from either the proximal humerus or distal femur and was separated into 2 equal samples. One sample was kept as BMA, and the other half was centrifuged into BMAC. The 2 samples then underwent flow cytometry for detection of MSCs, cell analysis for colony-forming units (CFUs), and cytokine profiling. A 2-tailed t test was used to detect differences between MSCs, CFUs, and cytokine density concentrations between BMA and BMAC. Results: The average concentration of MSCs in both BMA and BMAC was 0.001%. Average MSC events detected by flow cytometry were significantly higher in BMA versus BMAC (15.1 and 8.1, respectively; P < .045). Expanded MSCs demonstrated similar phenotypes, but CFUs were significantly increased in BMA compared with BMAC (104 vs 68 CFUs, respectively; P < .001). Total protein concentration and cytokine profiling demonstrated great variability between BMA and BMAC and between patients. Most importantly, BMAC failed to concentrate MSCs in 6 of 8 samples. Conclusion: There is great variability in MSC concentration, total protein concentration, and cytokine profile between BMA and BMAC. Clinical Relevance: When studying the clinical efficacy of BMAC, one must also evaluate the sample itself to determine the presence, concentration, and potency of MSCs if this is to be considered a cell-based therapy. Further standard operating procedures need to be investigated to ensure reproducible results and appropriate treatments.
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Affiliation(s)
- Ava Brozovich
- Texas A&M College of Medicine, Bryan, Texas, USA.,Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, Texas, USA.,Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, Texas, USA
| | - Brent J Sinicrope
- Orthopaedic Surgery, King's Daughters' Health, Madison, Indiana, USA
| | - Guillermo Bauza
- Center for NanoHealth, Swansea University Medical School, Swansea, Wales, UK
| | | | - David Lintner
- Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, Texas, USA
| | - Francesca Taraballi
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, Texas, USA.,Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, Texas, USA
| | - Patrick C McCulloch
- Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, Texas, USA
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15
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Reamer-irrigator-aspirate versus bone marrow aspirate concentrate for osteoprogenitor cell retention and osteoinductive protein release on cancellous bone. J Orthop 2021; 27:13-16. [PMID: 34434001 DOI: 10.1016/j.jor.2021.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/08/2021] [Indexed: 11/20/2022] Open
Abstract
Bone defects often require operative intervention with the use of bone graft. Two sources of autologous bone graft include reamer-irrigator-aspirate (RIA) and bone marrow aspirate concentrate (BMC). Osteoprogenitor cells and osteoconductive proteins have been identified in both sources. This study collected samples of these cells and proteins from a canine model and cultured them on human cancellous allograft bone blocks. Findings suggest that BMC may be preferred for indications that allow for delivery via injection, saturation of the patient's tissues, or an implanted scaffold, whereas RIA may be preferred when the biologic augment is delivered as a scaffold or graft.
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16
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Cevolani L, Bianchi G, Costantino E, Staals E, Lucarelli E, Spazzoli B, Frisoni T, Donati DM. Minimally invasive treatment of long bone non-unions with bone marrow concentrate, demineralized bone matrix and platelet-rich fibrin in 38 patients. J Tissue Eng Regen Med 2021; 15:831-840. [PMID: 34318612 DOI: 10.1002/term.3231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/09/2021] [Accepted: 07/22/2021] [Indexed: 11/11/2022]
Abstract
To determine the efficacy of percutaneous injection of autologous bone marrow concentrated (BMC), demineralized bone matrix (DBM), and platelet rich fibrin (PRF) in the treatment of long bone non-unions. From January 2011 to January 2018 patients with non-union of the lower limbs who were on the waiting list for open grafting with established tibial or femoral non-union and minimal deformity were eligible to participate in this study. Patients were treated with a single percutaneous injection of DBM, BMC and PRF. Our study group comprised 38 patients (26 males and 12 females; mean age 39, range 18 to 65). Non-unions were located in the femur (18 cases) and in the tibia (20 cases). Clinical and imaging follow-up ranged from 4 to 60 months (mean 20 months). Bone union occurred in 30 out of 38 patients (79%) in an average of 7 months (range 3 to 12) and all healed patients had full weight bearing after 9 months on average (range 6 to 12) from injection. In 19 cases the osteosynthesis was removed 12 months on average (range 3 to 36) from surgery. One patient developed infection at the non-union site after treatment. Percutaneous injection of DBM, BMC, and PRF is an effective treatment for long-bone non-unions. This technique allows the bone to heal with a minimally invasive approach and with a hospitalization of 2 days. Key elements of bone regeneration consist of a combination of biological and biomechanical therapeutic approach.
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Affiliation(s)
- Luca Cevolani
- Orthopaedic and Traumatologic Clinic Prevalently Oncologic, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Giuseppe Bianchi
- Orthopaedic and Traumatologic Clinic Prevalently Oncologic, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Errani Costantino
- Orthopaedic and Traumatologic Clinic Prevalently Oncologic, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Eric Staals
- Orthopaedic and Traumatologic Clinic Prevalently Oncologic, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Enrico Lucarelli
- Unit of Orthopaedic Pathology and Osteoarticular Tissue Regeneration, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Benedetta Spazzoli
- Orthopaedic and Traumatologic Clinic Prevalently Oncologic, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Tommaso Frisoni
- Orthopaedic and Traumatologic Clinic Prevalently Oncologic, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.,Unit of Orthopaedic Pathology and Osteoarticular Tissue Regeneration, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Davide M Donati
- Orthopaedic and Traumatologic Clinic Prevalently Oncologic, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.,Unit of Orthopaedic Pathology and Osteoarticular Tissue Regeneration, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
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17
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Zhu S, Zhang X, Chen X, Wang Y, Li S, Qian W. Comparison of cell therapy and other novel adjunctive therapies combined with core decompression for the treatment of osteonecrosis of the femoral head : a systematic review and meta-analysis of 20 studies. Bone Joint Res 2021; 10:445-458. [PMID: 34313452 PMCID: PMC8333034 DOI: 10.1302/2046-3758.107.bjr-2020-0418.r1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Aims The value of core decompression (CD) in the treatment of osteonecrosis of the femoral head (ONFH) remains controversial. We conducted a systematic review and meta-analysis to evaluate whether CD combined with other treatments could improve the clinical and radiological outcomes of ONFH patients compared with CD alone. Methods We searched the PubMed, Embase, Web of Science, and Cochrane Library databases until June 2020. All randomized controlled trials (RCTs) and clinical controlled trials (CCTs) comparing CD alone and CD combined with other measures (CD + cell therapy, CD + bone grafting, CD + porous tantalum rod, etc.) for the treatment of ONFH were considered eligible for inclusion. The primary outcomes of interest were Harris Hip Score (HHS), ONFH stage progression, structural failure (collapse) of the femoral head, and conversion to total hip arthroplasty (THA). The pooled data were analyzed using Review Manager 5.3 software. Results A total of 20 studies with 2,123 hips were included (CD alone = 768, CD combined with other treatments = 1,355). The combination of CD with other therapeutic interventions resulted in a higher HHS (mean difference (MD) = 6.46, 95% confidence interval (CI) = 2.10 to 10.83, p = 0.004) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score (MD = −10.92, 95% CI = -21.41 to -4.03, p = 0.040) and a lower visual analogue scale (VAS) score (MD = −0.99, 95% CI = -1.56 to -0.42, p < 0.001) than CD alone. For the rates of disease stage progression, 91 (20%) progressed in the intervention group compared to 146 (36%) in the control group (odds ratio (OR) = 0.32, 95% CI = 0.16 to 0.64, p = 0.001). In addition, the intervention group had a more significant advantage in delaying femoral head progression to the collapsed stage (OR = 0.32, 95% CI = 0.17 to 0.61, p < 0.001) and reducing the odds of conversion to THA (OR = 0.35, 95% CI = 0.23 to 0.55, p < 0.001) compared to the control group. There were no serious adverse events in either group. Subgroup analysis showed that the addition of cell therapy significantly improved clinical and radiological outcomes compared to CD alone, and this approach appeared to be more effective than other therapies, particularly in precollapse (stage I to II) ONFH patients. Conclusion There was marked heterogeneity in the studies. There is a trend towards improved clinical outcomes with the addition of stem cell therapy to CD. Cite this article: Bone Joint Res 2021;10(7):445–458.
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Affiliation(s)
- Shibai Zhu
- Department of Orthopaedics, Beijing Tongren Hospital, Capital Medical University, Beijing, China.,Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaotian Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xi Chen
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yiou Wang
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shanni Li
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenwei Qian
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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18
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Jindal K, Aggarwal S, Kumar P, Rathod P. Core decompression with bone marrow aspirate concentrate in post collapse avascular necrosis of hip: A systematic review and meta-analysis. J Clin Orthop Trauma 2021; 17:78-87. [PMID: 33717975 PMCID: PMC7919970 DOI: 10.1016/j.jcot.2021.02.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/02/2021] [Accepted: 02/10/2021] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Avascular necrosis (AVN) of femoral head is commonly seen in middle age groups and in its advanced stages, it is a common indication for total hip replacements (THRs). These patients invariably require revision surgeries in their lifetime and modalities to delay the first arthroplasty are necessary. Core decompression (CD) with bone marrow aspirate concentrate (BMAC) have proved successful in early stages of AVN, but their role in advanced stages remains unclear. The present review was done to assess the same. RESEARCH QUESTION Is CD and BMAC combination effective in delaying radiographic progression and THRs in post collapse stages of AVN hip? METHODOLOGY A systematic review and meta-analysis was conducted to determine the overall efficacy of CD and BMAC in post collapse stages of AVN hip and to specifically compare primary outcomes like radiographic progression along with need of THR, with CD alone.Three data bases (PubMed, EMBASE and SCOPUS) were searched to identify relevant articles. RESULTS The present review included 12 studies with 3 studies included in the meta-analysis. There were 270 hips across the 12 studies out of which 196 hips were treated with CD + BMAC. PRIMARY OUTCOMES 39.8% cases worsened from stage 3 to stage 4, while the overall incidence of THR in stages 3 and 4 was 38.3%. On comparison with CD alone the combination of CD + BMAC did not show any enhanced efficacy in either delaying progression (Odds ratio of 1.41 (95% CI = 0.55-3.62) or in conversion to THR (Odds Ratio: 0. 92; 95% CI = 0.41-2.06). CONCLUSION CD can be considered in stage 3 of AVN in younger population to delay the need of arthroplasty, before severe head distortion and arthritis sets in, and can be supplemented with bone strut grafts or tantalum rods, for supporting the articular cartilage. BMAC that has shown better results in early AVN, has not shown any additional benefits when compared to CD alone in advanced cases.
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Affiliation(s)
- Karan Jindal
- Department of Orthopaedics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Sameer Aggarwal
- Department of Orthopaedics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Prasoon Kumar
- Department of Orthopaedics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Pratik Rathod
- Department of Orthopaedics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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19
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El-Jawhari JJ, Ganguly P, Jones E, Giannoudis PV. Bone Marrow Multipotent Mesenchymal Stromal Cells as Autologous Therapy for Osteonecrosis: Effects of Age and Underlying Causes. Bioengineering (Basel) 2021; 8:69. [PMID: 34067727 PMCID: PMC8156020 DOI: 10.3390/bioengineering8050069] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 04/29/2021] [Accepted: 05/13/2021] [Indexed: 12/21/2022] Open
Abstract
Bone marrow (BM) is a reliable source of multipotent mesenchymal stromal cells (MSCs), which have been successfully used for treating osteonecrosis. Considering the functional advantages of BM-MSCs as bone and cartilage reparatory cells and supporting angiogenesis, several donor-related factors are also essential to consider when autologous BM-MSCs are used for such regenerative therapies. Aging is one of several factors contributing to the donor-related variability and found to be associated with a reduction of BM-MSC numbers. However, even within the same age group, other factors affecting MSC quantity and function remain incompletely understood. For patients with osteonecrosis, several underlying factors have been linked to the decrease of the proliferation of BM-MSCs as well as the impairment of their differentiation, migration, angiogenesis-support and immunoregulatory functions. This review discusses the quality and quantity of BM-MSCs in relation to the etiological conditions of osteonecrosis such as sickle cell disease, Gaucher disease, alcohol, corticosteroids, Systemic Lupus Erythematosus, diabetes, chronic renal disease and chemotherapy. A clear understanding of the regenerative potential of BM-MSCs is essential to optimize the cellular therapy of osteonecrosis and other bone damage conditions.
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Affiliation(s)
- Jehan J El-Jawhari
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
- Clinical Pathology Department, Mansoura University, Mansoura 35516, Egypt
| | - Payal Ganguly
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK; (P.G.); (E.J.); (P.V.G.)
| | - Elena Jones
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK; (P.G.); (E.J.); (P.V.G.)
| | - Peter V Giannoudis
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK; (P.G.); (E.J.); (P.V.G.)
- Academic Department of Trauma and Orthopedic, School of Medicine, University of Leeds, Leeds LS2 9JT, UK
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Jeyaraman M, Muthu S, Jain R, Khanna M. Autologous bone marrow derived mesenchymal stem cell therapy for osteonecrosis of femoral head: A systematic overview of overlapping meta-analyses. J Clin Orthop Trauma 2021; 13:134-142. [PMID: 33717885 PMCID: PMC7920111 DOI: 10.1016/j.jcot.2020.11.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/17/2020] [Accepted: 11/19/2020] [Indexed: 02/08/2023] Open
Abstract
STUDY DESIGN Systematic Review. OBJECTIVES We performed this systematic overview on the overlapping meta-analyses that analyzed autologous bone marrow-derived mesenchymal stem cell(BM-MSC) therapy along with core decompression(CD) for the management of osteonecrosis of the femoral head(ONFH) and identify which study provides the current best evidence on the topic and generate recommendations for the same. MATERIALS AND METHODS We conducted independent and duplicate electronic database searches in PubMed, Web of Science, Embase, Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effects till September 2020 for meta-analyses that analyzed the efficacy of BM-MSC therapy along with CD for ONFH. Methodological quality assessment was made using Oxford Levels of Evidence, AMSTAR scoring, and AMSTAR 2 grades. We then utilized the Jadad decision algorithm to identify the study with the highest quality to represent the current best evidence to generate the recommendation. RESULTS 6 meta-analyses fulfilling the eligibility criteria were included. The AMSTAR scores of the included studies varied from 4 to 9 (mean:7) and all the included studies had critically low reliability in their summary of results due to their methodological flaws according to AMSTAR 2 grades. The current best evidence showed that utilization of BM-MSC therapy along with CD for ONFH resulted in significant improvement in Harris hip scores at 12 and 24 months along with a significant reduction in the necrotic area of the femoral head and the rate of conversion to total hip arthroplasty(THA) without a significant rise in adverse events due to the procedure. CONCLUSION Based on this systematic overview, we give a Level II recommendation that BM-MSC therapy is more efficacious along with CD in the management of ONFH compared to CD alone. BM-MSC therapy provides better pain relief with significant functional improvement and delaying the collapse of the femoral head thereby preventing further treatment such as THA.
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Affiliation(s)
| | - Sathish Muthu
- Indian Stem Cell Study Group, Lucknow, Uttar Pradesh, India
| | - Rashmi Jain
- Indian Stem Cell Study Group, Lucknow, Uttar Pradesh, India
| | - Manish Khanna
- Indian Stem Cell Study Group, Lucknow, Uttar Pradesh, India
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Blanton CM, Clougherty CO. The Role of Bone Marrow Aspirate in Osseous and Soft Tissue Pathology. Clin Podiatr Med Surg 2021; 38:1-16. [PMID: 33220739 DOI: 10.1016/j.cpm.2020.08.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Bone marrow aspirate (BMA) is an emerging therapy that is gaining popularity for orthoplastic reconstruction. The stem cells collected are multipotent and regenerative in nature. In addition to stem cells, other biological components collected augment the mitogen of local cells, proliferation, and angiogenesis, and inhibit proinflammatory cytokine and bacteria to optimize an environment to heal. The most common site for harvest is the iliac crest. Techniques for harvesting BMA are simple to perform, financially modest, and associated with low morbidity. Additional research is needed to evolve and standardize the technology; however, BMA is proven to be advantageous for tissue repair.
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Affiliation(s)
- Casie M Blanton
- The Reconstruction Institute of The Bellevue Hospital, 102 Commerce Park Drive, Suite D, Bellevue, OH 44811, USA.
| | - Coleman O Clougherty
- The Reconstruction Institute of The Bellevue Hospital, 102 Commerce Park Drive, Suite D, Bellevue, OH 44811, USA
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Migliorini F, Maffulli N, Eschweiler J, Tingart M, Baroncini A. Core decompression isolated or combined with bone marrow-derived cell therapies for femoral head osteonecrosis. Expert Opin Biol Ther 2020; 21:423-430. [PMID: 33297783 DOI: 10.1080/14712598.2021.1862790] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Objectives: The regenerative capabilities of bone marrow-derived cell therapies (BMCTs) have been employed in combination with core decompression (CD) in the management of osteonecrosis of the femoral head to prevent or delay the necessity of total hip arthroplasty (THA).Methods: The authors conducted a meta-analysis to compare the results of level of evidence I trials comparing CD with and without BMCTs.Results: Overall, 579 procedures were analyzed: 265 in the CD group and 263 in the CD + BMCTs group. Comparability concerning age and gender, drill size, etiology, and grade of OFNH was found (P > 0.1). At a mean follow up of 82.29 (24 to 360) months, the VAS scored favourably for the CD + BMCTs group (mean difference: -12.88; P < 0.0001), as well the rate of THA (odd ratio: -0.14; P < 0.0001). Time to failure (P = 0.4) and to THA (P = 0.9) was similar between the two groups, as was the rate of failure (P = 0.3).Conclusion: In patients with femoral head osteonecrosis, core decompression combined with BMCTs demonstrated reduced pain and lower rate of total hip arthroplasty compared to core decompression as an isolated procedure.
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Affiliation(s)
- Filippo Migliorini
- Department of Orthopaedics, University Clinic Aachen, RWTH Aachen University Clinic, Aachen, Germany
| | - Nicola Maffulli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy.,School of Pharmacy and Bioengineering, Keele University School of Medicine, Thornburrow Drive, Stoke on Trent, England.,Barts and the London School of Medicine and Dentistry, Centre for Sports and Exercise Medicine, Mile End Hospital, Queen Mary University of London, London, England
| | - Jörg Eschweiler
- Department of Orthopaedics, University Clinic Aachen, RWTH Aachen University Clinic, Aachen, Germany
| | - Markus Tingart
- Department of Orthopaedics, University Clinic Aachen, RWTH Aachen University Clinic, Aachen, Germany
| | - Alice Baroncini
- Department of Orthopaedics, University Clinic Aachen, RWTH Aachen University Clinic, Aachen, Germany
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Anastasio A, Gergues M, Lebhar MS, Rameshwar P, Fernandez-Moure J. Isolation and characterization of mesenchymal stem cells in orthopaedics and the emergence of compact bone mesenchymal stem cells as a promising surgical adjunct. World J Stem Cells 2020; 12:1341-1353. [PMID: 33312402 PMCID: PMC7705465 DOI: 10.4252/wjsc.v12.i11.1341] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 09/26/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
The potential clinical and economic impact of mesenchymal stem cell (MSC) therapy is immense. MSCs act through multiple pathways: (1) as “trophic” cells, secreting various factors that are immunomodulatory, anti-inflammatory, anti-apoptotic, proangiogenic, proliferative, and chemoattractive; (2) in conjunction with cells native to the tissue they reside in to enhance differentiation of surrounding cells to facilitate tissue regrowth. Researchers have developed methods for the extraction and expansion of MSCs from animal and human tissues. While many sources of MSCs exist, including adipose tissue and iliac crest bone graft, compact bone (CB) MSCs have shown great potential for use in orthopaedic surgery. CB MSCs exert powerful immunomodulatory effects in addition to demonstrating excellent regenerative capacity for use in filling boney defects. CB MSCs have been shown to have enhanced response to hypoxic conditions when compared with other forms of MSCs. More work is needed to continue to characterize the potential applications for CB MSCs in orthopaedic trauma.
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Affiliation(s)
- Albert Anastasio
- Department of Orthopedic Surgery, Duke University Health System, Durham, NC 27710, United States
| | - Marina Gergues
- Department of Medicine, Hematology/Oncology, Rutgers University, New Jersey Medical School, Newark, NJ 07103, United States
| | - Michael S Lebhar
- School of Medicine, Duke University School of Medicine, Durham, NC 27710, United States
| | - Pranela Rameshwar
- Department of Medicine-Hematology/Oncology, Rutgers School of Biomedical Health Science, Newark, NJ 07103, United States
| | - Joseph Fernandez-Moure
- Department of Surgery, Division of Trauma, Acute, and Critical Care Surgery, Duke University School of Medicine, Durham, NC 27710, United States
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Abstract
Multifactorial aetiology defines non-unions, with a biological and a mechanical distortion of the timeline of bone healing. Research on new advances to increase osteogenesis and promote non-union healing is strongly directed towards new forms of cell products. Basic science and research on non-union treatments is needed to compile preclinical data on new treatments. Bone marrow concentration and expanded mesenchymal stromal cells still require extensive clinical research to confirm efficacy in non-union treatment. Solid preclinical studies, precise cell product definition and preparation, and appropriate ethical and regulatory approvals are needed to assess new advanced therapy medicinal products. Cite this article: EFORT Open Rev 2020;5:574-583. DOI: 10.1302/2058-5241.5.190062
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Affiliation(s)
- Enrique Gómez-Barrena
- Servicio de Cirugía Ortopédica y Traumatología, Hospital La Paz-IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain
| | - Norma G Padilla-Eguiluz
- Servicio de Cirugía Ortopédica y Traumatología, Hospital La Paz-IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain
| | - Philippe Rosset
- Service de Chirurgie Orthopédique et Traumatologie, CHU Tours, Université de Tours, Tours, France
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Belk L, Tellisi N, Macdonald H, Erdem A, Ashammakhi N, Pountos I. Safety Considerations in 3D Bioprinting Using Mesenchymal Stromal Cells. Front Bioeng Biotechnol 2020; 8:924. [PMID: 33154961 PMCID: PMC7588840 DOI: 10.3389/fbioe.2020.00924] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 07/17/2020] [Indexed: 12/26/2022] Open
Abstract
Three-dimensional (3D) bioprinting has demonstrated great potential for the fabrication of biomimetic human tissues and complex graft materials. This technology utilizes bioinks composed of cellular elements placed within a biomaterial. Mesenchymal stromal cells (MSCs) are an attractive option for cell selection in 3D bioprinting. MSCs can be isolated from a variety of tissues, can pose vast proliferative capacity and can differentiate to multiple committed cell types. Despite their promising properties, the use of MSCs has been associated with several drawbacks. These concerns are related to the ex vivo manipulation throughout the process of 3D bioprinting. The herein manuscript aims to present the current evidence surrounding these events and propose ways to minimize the risks to the patients following widespread expansion of 3D bioprinting in the medical field.
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Affiliation(s)
- Lucy Belk
- Academic Department of Trauma and Orthopaedics, University of Leeds, Leeds, United Kingdom
- School of Medicine, University of Leeds, Leeds, United Kingdom
| | - Nazzar Tellisi
- Academic Department of Trauma and Orthopaedics, University of Leeds, Leeds, United Kingdom
- School of Medicine, University of Leeds, Leeds, United Kingdom
- Chapel Allerton Hospital, Leeds Teaching Hospitals, Leeds, United Kingdom
| | - Hamish Macdonald
- Gloucester Royal Hospital, Gloucestershire Hospitals NHS Foundation Trust, Gloucester, United Kingdom
| | - Ahmet Erdem
- Center for Minimally Invasive Therapeutics, University of California, Los Angeles, Los Angeles, CA, United States
- Department of Bioengineering, Henry Samueli School of Engineering, University of California, Los Angeles, Los Angeles, CA, United States
- Department of Chemistry, Kocaeli University, Kocaeli, Turkey
- Department of Biomedical Engineering, Kocaeli University, Kocaeli, Turkey
| | - Nureddin Ashammakhi
- Center for Minimally Invasive Therapeutics, University of California, Los Angeles, Los Angeles, CA, United States
- Department of Bioengineering, Henry Samueli School of Engineering, University of California, Los Angeles, Los Angeles, CA, United States
- Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI, United States
| | - Ippokratis Pountos
- Academic Department of Trauma and Orthopaedics, University of Leeds, Leeds, United Kingdom
- School of Medicine, University of Leeds, Leeds, United Kingdom
- Chapel Allerton Hospital, Leeds Teaching Hospitals, Leeds, United Kingdom
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倘 艳, 杨 玉, 李 红, 习 嘉, 李 无, 岳 辰, 王 会, 刘 又. [Effectiveness of percutaneous injection of autologous concentrated bone marrow aspirate combined with platelet-rich plasma in treatment of delayed fracture healing]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2020; 34:1130-1135. [PMID: 32929906 PMCID: PMC8171733 DOI: 10.7507/1002-1892.202002028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 06/11/2020] [Indexed: 11/03/2022]
Abstract
OBJECTIVE To analyze the effectiveness of percutaneous injection of autologous concentrated bone marrow aspirate (cBMA) combined with platelet-rich plasma (PRP) in the treatment of delayed fracture healing. METHODS A prospective, randomized, controlled, single-blind case study was conducted. Between March 2016 and July 2018, 66 patients who met the inclusion and exclusion criteria for delayed fracture healing but had solid internal fixation of the fracture end were randomly divided into control group (31 cases, treated with percutaneous autogenous bone marrow blood injection) and study group (35 cases, treated with percutaneous autogenous cBMA+PRP injection). General data such as gender, age, body mass index, site of delayed fracture healing, length of bone defect at fracture end, and preoperative radiographic union score for tibia (RUST) showed no significant difference between the two groups ( P>0.05). Before injection, Kirschner wire was used in both groups to stimulate the fracture end and cause minor injury. The fracture healing time, treatment cost, and adverse reactions were recorded and compared between the two groups. Visual analogue scale (VAS) score was used to evaluate pain improvement. The tibial RUST score was extended to the tubular bone healing evaluation. RESULTS No infection of bone marrow puncture needle eyes occurred in both groups. In the control group, local swelling was obvious in 5 cases and pain was aggravated at 1 day after operation in 11 cases. In the study group, postoperative swelling and pain were not obvious, but 2 cases presented local swelling and pain. All of them relieved after symptomatic treatment. Patients in both groups were followed up, the follow-up time of the control group was 16-36 months (mean, 21.8 months), and the study group lasted 14-33 months (mean, 23.2 months). The amount of bone marrow blood was significantly lower in the study group than in the control group ( t=4.610, P=0.000). The degree of postoperative pain in the study group was less than that in the control group, and the treatment cost was higher than that in the control group. But the differences between the two groups in VAS score at 1 day after operation and treatment cost were not significant ( P>0.05). Fracture healing was achieved in 19 cases (61.3%) in the control group and 30 cases (85.7%) in the study group. The difference in fracture healing rate between the two groups was significant ( χ 2=5.128, P=0.024). Fracture healing time and RUST score at last follow-up were significantly better in the study group than in the control group ( P<0.05). At last follow-up, RUST scores in both groups were significantly improved when compared with those before operation ( P<0.05). CONCLUSION Autogenous cBMA combined with PRP percutaneous injection can provide high concentration of BMSCs and growth factors, and can improve the fracture healing rate and shorten the fracture healing time better than autogenous bone marrow blood injection.
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Affiliation(s)
- 艳锋 倘
- 河南省洛阳正骨医院(河南省骨科医院)髋部损伤中心(河南洛阳 471002)Hip Injury Center, Luoyang-Orthopedic Traumatological Hospital of Henan Province (Henan Orthopedic Hospital), Luoyang Henan, 471002, P.R.China
| | - 玉霞 杨
- 河南省洛阳正骨医院(河南省骨科医院)髋部损伤中心(河南洛阳 471002)Hip Injury Center, Luoyang-Orthopedic Traumatological Hospital of Henan Province (Henan Orthopedic Hospital), Luoyang Henan, 471002, P.R.China
| | - 红军 李
- 河南省洛阳正骨医院(河南省骨科医院)髋部损伤中心(河南洛阳 471002)Hip Injury Center, Luoyang-Orthopedic Traumatological Hospital of Henan Province (Henan Orthopedic Hospital), Luoyang Henan, 471002, P.R.China
| | - 嘉宁 习
- 河南省洛阳正骨医院(河南省骨科医院)髋部损伤中心(河南洛阳 471002)Hip Injury Center, Luoyang-Orthopedic Traumatological Hospital of Henan Province (Henan Orthopedic Hospital), Luoyang Henan, 471002, P.R.China
| | - 无阴 李
- 河南省洛阳正骨医院(河南省骨科医院)髋部损伤中心(河南洛阳 471002)Hip Injury Center, Luoyang-Orthopedic Traumatological Hospital of Henan Province (Henan Orthopedic Hospital), Luoyang Henan, 471002, P.R.China
| | - 辰 岳
- 河南省洛阳正骨医院(河南省骨科医院)髋部损伤中心(河南洛阳 471002)Hip Injury Center, Luoyang-Orthopedic Traumatological Hospital of Henan Province (Henan Orthopedic Hospital), Luoyang Henan, 471002, P.R.China
| | - 会超 王
- 河南省洛阳正骨医院(河南省骨科医院)髋部损伤中心(河南洛阳 471002)Hip Injury Center, Luoyang-Orthopedic Traumatological Hospital of Henan Province (Henan Orthopedic Hospital), Luoyang Henan, 471002, P.R.China
| | - 又文 刘
- 河南省洛阳正骨医院(河南省骨科医院)髋部损伤中心(河南洛阳 471002)Hip Injury Center, Luoyang-Orthopedic Traumatological Hospital of Henan Province (Henan Orthopedic Hospital), Luoyang Henan, 471002, P.R.China
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Cuthbert RJ, Jones E, Sanjurjo-Rodríguez C, Lotfy A, Ganguly P, Churchman SM, Kastana P, Tan HB, McGonagle D, Papadimitriou E, Giannoudis PV. Regulation of Angiogenesis Discriminates Tissue Resident MSCs from Effective and Defective Osteogenic Environments. J Clin Med 2020; 9:jcm9061628. [PMID: 32481579 PMCID: PMC7355658 DOI: 10.3390/jcm9061628] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 05/20/2020] [Accepted: 05/20/2020] [Indexed: 12/12/2022] Open
Abstract
Background: The biological mechanisms that contribute to atrophic long bone non-union are poorly understood. Multipotential mesenchymal stromal cells (MSCs) are key contributors to bone formation and are recognised as important mediators of blood vessel formation. This study examines the role of MSCs in tissue formation at the site of atrophic non-union. Materials and Methods: Tissue and MSCs from non-union sites (n = 20) and induced periosteal (IP) membrane formed following the Masquelet bone reconstruction technique (n = 15) or bone marrow (n = 8) were compared. MSC content, differentiation, and influence on angiogenesis were measured in vitro. Cell content and vasculature measurements were performed by flow cytometry and histology, and gene expression was measured by quantitative polymerase chain reaction (qPCR). Results: MSCs from non-union sites had comparable differentiation potential to bone marrow MSCs. Compared with induced periosteum, non-union tissue contained similar proportion of colony-forming cells, but a greater proportion of pericytes (p = 0.036), and endothelial cells (p = 0.016) and blood vessels were more numerous (p = 0.001) with smaller luminal diameter (p = 0.046). MSCs showed marked differences in angiogenic transcripts depending on the source, and those from induced periosteum, but not non-union tissue, inhibited early stages of in vitro angiogenesis. Conclusions: In vitro, non-union site derived MSCs have no impairment of differentiation capacity, but they differ from IP-derived MSCs in mediating angiogenesis. Local MSCs may thus be strongly implicated in the formation of the immature vascular network at the non-union site. Attention should be given to their angiogenic support profile when selecting MSCs for regenerative therapy.
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Affiliation(s)
- R. J. Cuthbert
- Leeds Institute of Rheumatic and Musculoskeletal Disease, University of Leeds, Leeds LS16 7PS, UK; (R.J.C.); (E.J.); (C.S.-R.); (P.G.); (S.M.C.); (H.B.T.); (D.M.)
| | - E. Jones
- Leeds Institute of Rheumatic and Musculoskeletal Disease, University of Leeds, Leeds LS16 7PS, UK; (R.J.C.); (E.J.); (C.S.-R.); (P.G.); (S.M.C.); (H.B.T.); (D.M.)
| | - C. Sanjurjo-Rodríguez
- Leeds Institute of Rheumatic and Musculoskeletal Disease, University of Leeds, Leeds LS16 7PS, UK; (R.J.C.); (E.J.); (C.S.-R.); (P.G.); (S.M.C.); (H.B.T.); (D.M.)
- Department of Biomedical Sciences, Medicine and Physiotherapy, University of A Coruña, CIBER-BBN-Institute of Biomedical Research of A Coruña (INIBIC), A Coruña 15001, Spain
| | - A. Lotfy
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni-Suef 62511, Egypt;
| | - P. Ganguly
- Leeds Institute of Rheumatic and Musculoskeletal Disease, University of Leeds, Leeds LS16 7PS, UK; (R.J.C.); (E.J.); (C.S.-R.); (P.G.); (S.M.C.); (H.B.T.); (D.M.)
| | - S. M. Churchman
- Leeds Institute of Rheumatic and Musculoskeletal Disease, University of Leeds, Leeds LS16 7PS, UK; (R.J.C.); (E.J.); (C.S.-R.); (P.G.); (S.M.C.); (H.B.T.); (D.M.)
| | - P. Kastana
- Department of Pharmacy, School of Health Sciences, University of Patras, Patras 265 04, Greece; (P.K.); (E.P.)
| | - H. B. Tan
- Leeds Institute of Rheumatic and Musculoskeletal Disease, University of Leeds, Leeds LS16 7PS, UK; (R.J.C.); (E.J.); (C.S.-R.); (P.G.); (S.M.C.); (H.B.T.); (D.M.)
| | - D. McGonagle
- Leeds Institute of Rheumatic and Musculoskeletal Disease, University of Leeds, Leeds LS16 7PS, UK; (R.J.C.); (E.J.); (C.S.-R.); (P.G.); (S.M.C.); (H.B.T.); (D.M.)
| | - E. Papadimitriou
- Department of Pharmacy, School of Health Sciences, University of Patras, Patras 265 04, Greece; (P.K.); (E.P.)
| | - P. V. Giannoudis
- Leeds Institute of Rheumatic and Musculoskeletal Disease, University of Leeds, Leeds LS16 7PS, UK; (R.J.C.); (E.J.); (C.S.-R.); (P.G.); (S.M.C.); (H.B.T.); (D.M.)
- NIHR Leeds Biomedical Research Center, Chapel Allerton Hospital, Leeds LS7 4SA, UK
- Correspondence: ; Tel.: +44-113-392-2750; Fax: +44-113-392-3290
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Döring M, Kluba T, Cabanillas Stanchi KM, Kahle P, Lenglinger K, Tsiflikas I, Treuner C, Vaegler M, Mezger M, Erbacher A, Schumm M, Lang P, Handgretinger R, Müller I. Longtime Outcome After Intraosseous Application of Autologous Mesenchymal Stromal Cells in Pediatric Patients and Young Adults with Avascular Necrosis After Steroid or Chemotherapy. Stem Cells Dev 2020; 29:811-822. [PMID: 32295491 DOI: 10.1089/scd.2020.0019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Avascular necrosis (AVN) is a severe complication of immunosuppressant therapy or chemotherapy. A beneficial AVN therapy with core decompression (CD) and intraosseous infusion of mesenchymal stromal cells (MSCs) has been described in adult patients, but there are only few data on MSC applications in pediatric and young adult patients (PYAP). Between 2006 and 2015, 14 AVN lesions of 10 PYAP (6 females) with a median age of 16.9 years (range 8.5-25.8 years) received CD and intraosseous application of autologous MSCs. Data of these patients were analyzed regarding efficacy, safety, and feasibility of this procedure as AVN therapy and compared with a control group of 13 AVN lesions of 11 PYAP (5 females) with a median age of 17.9 years (range 13.5-27.5 years) who received CD only. During the follow-up analysis [MSC group: median 3.1 (1.6-5.8) years after CD; CD group: median 2.0 (1.5-8.5) years after CD], relative lesion sizes (as assessed by magnetic resonance imaging) compared with the initial lesion volume, were significantly lower (P < 0.05) in the MSC group (volume reduction to a median of 18.5%) when compared with the CD group (58.0%). One lesion in the MSC group comprised a complete remission. Size progression was not observed in either group. Clinical improvement (pain, mobility) was not significantly different between the two groups. None of the patients experienced treatment-related adverse effects. CD and additional MSC application was regarded safe, effective, feasible, and superior in reducing the lesion size when compared with CD only. Prospective, randomized clinical trials are needed to further evaluate these findings.
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Affiliation(s)
- Michaela Döring
- Department I-General Pediatrics, Hematology and Oncology, University Hospital Tuebingen-Children's Hospital Tuebingen, Tuebingen, Germany
| | - Torsten Kluba
- Department of Orthopedic Surgery, Städtisches Klinikum Dresden, Dresden, Germany
| | - Karin Melanie Cabanillas Stanchi
- Department I-General Pediatrics, Hematology and Oncology, University Hospital Tuebingen-Children's Hospital Tuebingen, Tuebingen, Germany
| | - Peter Kahle
- Department of Orthopedics, University Hospital Tuebingen, Tuebingen, Germany
| | - Katrin Lenglinger
- Department I-General Pediatrics, Hematology and Oncology, University Hospital Tuebingen-Children's Hospital Tuebingen, Tuebingen, Germany
| | - Ilias Tsiflikas
- Department of Diagnostic and Interventional Radiology, University Hospital Tuebingen, Tuebingen, Germany
| | - Claudia Treuner
- Department I-General Pediatrics, Hematology and Oncology, University Hospital Tuebingen-Children's Hospital Tuebingen, Tuebingen, Germany
| | - Martin Vaegler
- Charité - Universitätsmedizin Berlin, Campus Berlin Buch, Experimental and Clinical Research Center, Zellkulturlabor für Klinische Prüfung ZKP, Berlin, Germany
| | - Markus Mezger
- Department I-General Pediatrics, Hematology and Oncology, University Hospital Tuebingen-Children's Hospital Tuebingen, Tuebingen, Germany
| | - Annika Erbacher
- Department I-General Pediatrics, Hematology and Oncology, University Hospital Tuebingen-Children's Hospital Tuebingen, Tuebingen, Germany
| | - Michael Schumm
- Department I-General Pediatrics, Hematology and Oncology, University Hospital Tuebingen-Children's Hospital Tuebingen, Tuebingen, Germany
| | - Peter Lang
- Department I-General Pediatrics, Hematology and Oncology, University Hospital Tuebingen-Children's Hospital Tuebingen, Tuebingen, Germany
| | - Rupert Handgretinger
- Department I-General Pediatrics, Hematology and Oncology, University Hospital Tuebingen-Children's Hospital Tuebingen, Tuebingen, Germany
| | - Ingo Müller
- Department I-General Pediatrics, Hematology and Oncology, University Hospital Tuebingen-Children's Hospital Tuebingen, Tuebingen, Germany
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Petrigliano FA. Editorial Commentary: Bone Marrow Aspirate Concentrate Harvested From the Ilium During Acetabular Labral Repair: Is the Biologic Juice Worth the Squeeze? Arthroscopy 2020; 36:1321-1322. [PMID: 32370894 DOI: 10.1016/j.arthro.2020.02.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 02/15/2020] [Indexed: 02/02/2023]
Abstract
The use of regenerative technologies including mesenchymal stromal cells, also known as connective tissue progenitors (CTPs), has gained tremendous popularity as a primary and adjuvant treatment for many musculoskeletal conditions. The concentration of bone marrow-derived CTPs delivered to the site of injury has been directly correlated to the therapeutic effect in the setting of rotator cuff repair and the healing of long-bone fractures. In addition, there has been some limited in vitro and in vivo evidence to suggest that the delivery of bone marrow-derived CTPs may improve cartilage regeneration. Bone marrow aspirate concentrate harvested from the body of the ilium during hip arthroscopy yields a CTP concentration that is commensurate with other conventional donor sites and appears to be safe. However, the clinical benefit and financial cost associated with the delivery of bone marrow aspirate concentrate to the hip joint at the time of acetabular labral repair remains unclear at best and should be approached with caution.
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Kouroupis D, Ahari AF, Correa D, Shammaa R. Intralesional Injection of Bone Marrow Aspirate Concentrate for the Treatment of Osteonecrosis of the Knee Secondary to Systemic Lupus Erythematosus: A Case Report. Front Bioeng Biotechnol 2020; 8:202. [PMID: 32266233 PMCID: PMC7100546 DOI: 10.3389/fbioe.2020.00202] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 03/02/2020] [Indexed: 01/08/2023] Open
Abstract
Case: An 18-year-old female patient with Systemic Lupus Erythematosus (SLE) and corticosteroid-associated extensive bilateral symptomatic knee Osteonecrosis (ON) (Ficat IV), treated with sequential intralesional injections of autologous bone marrow aspirate concentrate (BMAC) under ultrasound guidance. At 3 months, pain was almost absent (VAS) and KOOS/WOMAC showed significant improvement sustained up to 24 months. At 12 months MRI indicated bone maturation, significantly reduced BM edema and subchondral fluid volume, and no collapse/fragmentation signs. Discussion: The clinical and imaging significant improvement observed in this patient suggests that BMAC intralesional injections effectively restored the compromised bone structure. After larger studies, this technique can become an alternative to decompressing surgery for ON cases.
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Affiliation(s)
- Dimitrios Kouroupis
- Department of Orthopaedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Amir F Ahari
- Canadian Centers for Regenerative Therapy, Toronto, ON, Canada
| | - Diego Correa
- Department of Orthopaedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL, United States.,Diabetes Research Institute & Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Riam Shammaa
- Canadian Centers for Regenerative Therapy, Toronto, ON, Canada.,Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
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A Rationale for the Use of Clotted Vertebral Bone Marrow to Aid Tissue Regeneration Following Spinal Surgery. Sci Rep 2020; 10:4115. [PMID: 32139727 PMCID: PMC7058026 DOI: 10.1038/s41598-020-60934-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 02/19/2020] [Indexed: 12/25/2022] Open
Abstract
Vertebral body bone marrow aspirate (V-BMA), easily accessible simultaneously with the preparation of the site for pedicle screw insertion during spinal procedures, is becoming an increasingly used cell therapy approach in spinal surgery. However, the main drawbacks for V-BMA use are the lack of a standardized procedure and of a structural texture with the possibility of diffusion away from the implant site. The aim of this study was to evaluate, characterize and compare the biological characteristics of MSCs from clotted V-BMA and MSCs from whole and concentrate V-BMAs. MSCs from clotted V-BMA showed the highest cell viability and growth factors expression (TGF-β, VEGF-A, FGF2), the greatest colony forming unit (CFU) potency, cellular homogeneity, ability to differentiate towards the osteogenic (COL1AI, TNFRSF11B, BGLAP) and chondrogenic phenotype (SOX9) and the lowest ability to differentiate toward the adipogenic lineage (ADIPOQ) in comparison to all the other culture conditions. Additionally, results revealed that MSCs, differently isolated, expressed different level of HOX and TALE signatures and that PBX1 and MEIS3 were down-regulated in MSCs from clotted V-BMA in comparison to concentrated one. The study demonstrated for the first time that the cellular source inside the clotted V-BMA showed the best biological properties, representing an alternative and advanced cell therapy approach for patients undergoing spinal surgery.
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Schubert MF, Sidhu R, Getgood AM, Sherman SL. Failures of Realignment Osteotomy. OPER TECHN SPORT MED 2020. [DOI: 10.1016/j.otsm.2019.150714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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33
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Ogawa T, Ochiai N, Hara Y. Bone marrow from the iliac crest versus from the distal radius for revitalizing the necrotic lunate for Kienböck disease. J Hand Surg Eur Vol 2020; 45:299-301. [PMID: 31739734 DOI: 10.1177/1753193419886724] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Takeshi Ogawa
- Department of Orthopaedic Surgery and Sports Medicine, Mito Clinical Education and Training Center, University of Tsukuba Hospital, Mito Kyodo General Hospital, Japan
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Japan
| | - Naoyuki Ochiai
- Department of Orthopaedic Surgery, Kikkoman General Hospital, Japan
| | - Yuki Hara
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Japan
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34
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Wang Q, Li D, Yang Z, Kang P. Femoral Head and Neck Fenestration Through a Direct Anterior Approach Combined With Compacted Autograft for the Treatment of Early Stage Nontraumatic Osteonecrosis of the Femoral Head: A Retrospective Study. J Arthroplasty 2020; 35:652-660. [PMID: 31761674 DOI: 10.1016/j.arth.2019.10.043] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 10/14/2019] [Accepted: 10/23/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND This study aimed to evaluate the effect of femoral head and neck fenestration combined with compacted autograft (light bulb procedure) through a direct anterior approach for early stage nontraumatic osteonecrosis of the femoral head. METHODS We conducted a retrospective cohort study investigating 66 hips undergoing the light bulb procedure through the direct anterior approach (light bulb group) and 59 hips undergoing traditional core decompression (control group). Visual analog scale pain scores and range of hip motion were evaluated before discharge to assess the quality of functional recovery. Follow-up was conducted at 6 weeks, 3 months, 6 months, and annually after surgery until 4 years. The clinical effectiveness was evaluated by Harris hip score and the University of California Los Angeles activity-level score. Patients were followed up with postoperative X-ray and computed tomography. Survival was compared between the 2 groups by radiographic progression and receiving total hip arthroplasty. RESULTS There was no significant difference in quality of functional recovery between the 2 groups. There were no significant differences in clinical outcomes within 1 year after surgery. Patients in the light bulb group had significantly better Harris hip scores and University of California Los Angeles activity-level scores from 2 years after surgery to the end of follow-up. During the 4-year follow-up, significantly fewer patients in light bulb group had radiographic progression (22.7% vs 44.1%) or received total hip arthroplasty (15.2% vs 30.5%). CONCLUSIONS The light bulb procedure through a direct anterior approach offers significantly better results for the treatment of early stage nontraumatic osteonecrosis of the femoral head compared with traditional core decompression.
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Affiliation(s)
- Qiuru Wang
- Department of Orthopaedics Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Donghai Li
- Department of Orthopaedics Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Zhouyuan Yang
- Department of Orthopaedics Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Pengde Kang
- Department of Orthopaedics Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
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35
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Wu ZY, Sun Q, Liu M, Grottkau BE, He ZX, Zou Q, Ye C. Correlation between the efficacy of stem cell therapy for osteonecrosis of the femoral head and cell viability. BMC Musculoskelet Disord 2020; 21:55. [PMID: 31996187 PMCID: PMC6990483 DOI: 10.1186/s12891-020-3064-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 01/14/2020] [Indexed: 02/08/2023] Open
Abstract
Background Osteonecrosis of the femoral head (ONFH) is a common disease that greatly affects the quality of life of patients. Repair of the necrotic area is key to successful treatment. Currently, the combination of stem cell transplantation and decompression is used clinically to promote the repair of necrotic areas based on the characteristics of stem cells. However, a considerable number of patients do not achieve a satisfactory outcome in terms of repair of the femoral head necrotic area, and it is very important to determine the reasons for the poor curative effect. The aim of this study was to investigate the correlation between stem cell viability and the repair efficacy of stem cell therapy combined with core decompression for early-stage ONFH. Methods A total of 30 patients with idiopathic ONFH underwent core decompression combined with autologous stem cell transplantation. The Harris hip score (HHS) and difference in necrosis area before and after surgery were measured. The mean repair ratio was set as the threshold to divide the patients into group A (ratio above the mean) and group B (ratio below the mean). The ultrastructure, proliferative capacity, and multidirectional differentiation ability were compared between the groups. Results At 9 months after surgery, the HHS and magnetic resonance imaging (MRI) findings improved by varying degrees. Based on the mean repair ratio of (62.2 ± 27.0)%, the threshold for dividing the patients into groups A and B was set to 62.2%. Better repair (group A) was associated with more rapid proliferation and a healthier ultrastructure. The cells in group A showed stronger specific staining signifying osteogenic and chondrogenic differentiation; alkaline phosphatase (ALP) activity, an indicator of osteogenic differentiation, was higher in group A than in group B (OD, 2.39 ± 0.44 and 1.85 ± 0.52; p < 0.05). Conclusions The quality of implanted stem cells is closely related to treatment efficacy and determines whether the defective self-repair in the necrotic area can be corrected to enhance repair and thus achieve the desired therapeutic outcome. Trial registration The trial registration number: ChiCTR-ORC-17011698 (retrospectively registered at 2017-06-19).
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Affiliation(s)
- Zhan Yu Wu
- Department of Orthopaedics, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.,Center for Tissue Engineering and Stem Cells, Guizhou Medical University, Guiyang, China
| | - Qi Sun
- Yueyang Traditional Chinese Medicine Hospital, Hunan, China
| | - Ming Liu
- Department of Orthopaedics, West China Hospital of Sichuan University, Chengdu, China
| | - Brian E Grottkau
- Department of Orthopedics, Massachusetts General Hospital, Boston, MA, USA
| | - Zhi Xu He
- Center for Tissue Engineering and Stem Cells, Guizhou Medical University, Guiyang, China.,Key Laboratory of Adult Stem Cell Transformation Research, Chinese Academy of Medical Sciences, Guiyang, 550004, China
| | - Qiang Zou
- Department of Orthopaedics, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.,Center for Tissue Engineering and Stem Cells, Guizhou Medical University, Guiyang, China
| | - Chuan Ye
- Department of Orthopaedics, The Affiliated Hospital of Guizhou Medical University, Guiyang, China. .,Center for Tissue Engineering and Stem Cells, Guizhou Medical University, Guiyang, China. .,Key Laboratory of Adult Stem Cell Transformation Research, Chinese Academy of Medical Sciences, Guiyang, 550004, China. .,China Orthopaedic Regenerative Medicine Group (CORMed), Hangzhou, China.
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36
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Freitas GP, Lopes HB, P Souza AT, F P Oliveira PG, G Almeida AL, Coelho PG, Ferreira FU, Covas DT, Beloti MM, Rosa AL. Effect of cell therapy with osteoblasts differentiated from bone marrow or adipose tissue stromal cells on bone repair. Regen Med 2020; 14:1107-1119. [PMID: 31960753 DOI: 10.2217/rme-2019-0036] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Aim: The aim of this study was to investigate the effect of local injection of osteoblasts differentiated from bone marrow (BM-OB) or adipose tissue (AT-OB) mesenchymal stromal cells on bone tissue formation. Materials & methods: Defects were created in rat calvaria and injected with BM-OB or AT-OB and phosphate-buffered saline without cells were injected as control. Bone formation was evaluated 4 weeks postinjection. Results: Injection of BM-OB or AT-OB resulted in higher bone formation than that obtained with control. The bone tissue induced by cell injections exhibited similar mechanical properties as those of pristine calvarial bone, and its molecular cues suggested the occurrence of a remodeling process. Conclusion: Results of this study demonstrated that cell therapy with osteoblasts induced significant bone formation that exhibited the same quality as that of pre-existent bone.
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Affiliation(s)
- Gileade P Freitas
- Department of Oral & Maxillofacial Surgery & Periodontology, School of Dentistry of Ribeirão Preto, University of São Paulo, SP, Brazil
| | - Helena B Lopes
- Department of Oral & Maxillofacial Surgery & Periodontology, School of Dentistry of Ribeirão Preto, University of São Paulo, SP, Brazil
| | - Alann T P Souza
- Department of Oral & Maxillofacial Surgery & Periodontology, School of Dentistry of Ribeirão Preto, University of São Paulo, SP, Brazil
| | - Paula G F P Oliveira
- Department of Oral & Maxillofacial Surgery & Periodontology, School of Dentistry of Ribeirão Preto, University of São Paulo, SP, Brazil
| | - Adriana L G Almeida
- Department of Oral & Maxillofacial Surgery & Periodontology, School of Dentistry of Ribeirão Preto, University of São Paulo, SP, Brazil
| | - Paulo G Coelho
- Department of Biomaterials, New York University College of Dentistry, NY 10010, USA.,Hansjörg Wyss Department of Plastic Surgery, New York University School of Medicine, NY 10016, USA
| | - Fernanda U Ferreira
- Center for Cell-Based Research, Regional Blood Center of Ribeirão Preto, School of Medicine of Ribeirão Preto, University of São Paulo, SP, Brazil
| | - Dimas T Covas
- Center for Cell-Based Research, Regional Blood Center of Ribeirão Preto, School of Medicine of Ribeirão Preto, University of São Paulo, SP, Brazil.,Department of Clinical Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, SP, Brazil
| | - Marcio M Beloti
- Department of Basic & Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo, SP, Brazil
| | - Adalberto L Rosa
- Department of Oral & Maxillofacial Surgery & Periodontology, School of Dentistry of Ribeirão Preto, University of São Paulo, SP, Brazil
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37
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Li M, Meng Y, Li Y, Long A, Lv H, Yin P, Zhang L, Tang P. Multidirectional percutaneous drilling and autologous bone marrow injection for the treatment of femoral diaphyseal nonunions: a prospective interventional study. Ther Clin Risk Manag 2019; 15:1003-1011. [PMID: 31695392 PMCID: PMC6707371 DOI: 10.2147/tcrm.s209393] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 07/25/2019] [Indexed: 12/28/2022] Open
Abstract
Background To examine the outcomes of multidirectional percutaneous drilling and autologous concentrated bone marrow (BM) transplantation for atrophic femoral diaphyseal nonunion characterized by intact hardware and mechanical stability at the nonunion site. Methods Fourteen patients (22–63 years of age) were admitted to our hospital with atrophic femoral diaphyseal nonunion. All patients were treated with a combination of multidirectional percutaneous drilling and autologous concentrated BM transplantation. Radiographic evaluation was conducted every month after transplantation until bone healing was achieved. Results Bony union was achieved in 13 of the 14 patients (92.9%) after an average of 3.9 months (range: 2.5–6 months). The average radiographic union scale in tibial (RUST) scale score improved significantly from the preoperative period (6.15±1.21) to follow-up (11.23±0.73; P<0.05). The mean follow-up after transplantation was 31.4±9.5 months (range: 18–50 months). At the final follow-up, the quality of function had improved significantly, allowing a return to normal activities. Conclusion Combined multidirectional percutaneous drilling and autologous concentrated BM transplantation is an easy, safe, inexpensive, and efficacious method to treat atrophic femoral diaphyseal nonunion characterized by intact hardware and mechanical stability at the nonunion site. Trial registration number: ISRCTN29808592
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Affiliation(s)
- Ming Li
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing 100853, People's Republic of China
| | - Yutong Meng
- Department of Orthopedics, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, People's Republic of China
| | - Yi Li
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing 100853, People's Republic of China
| | - Anhua Long
- Department of Orthopaedics, Beijing Luhe Hospital, Capital Medical University, Beijing 101100, People's Republic of China
| | - Houchen Lv
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing 100853, People's Republic of China
| | - Pengbin Yin
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing 100853, People's Republic of China
| | - Licheng Zhang
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing 100853, People's Republic of China
| | - Peifu Tang
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing 100853, People's Republic of China
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38
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Freitas GP, Lopes HB, Souza ATP, Oliveira PGFP, Almeida ALG, Souza LEB, Coelho PG, Beloti MM, Rosa AL. Cell Therapy: Effect of Locally Injected Mesenchymal Stromal Cells Derived from Bone Marrow or Adipose Tissue on Bone Regeneration of Rat Calvarial Defects. Sci Rep 2019; 9:13476. [PMID: 31530883 PMCID: PMC6748998 DOI: 10.1038/s41598-019-50067-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 09/05/2019] [Indexed: 02/07/2023] Open
Abstract
Treatment of large bone defects is a challenging clinical situation that may be benefited from cell therapies based on regenerative medicine. This study was conducted to evaluate the effect of local injection of bone marrow-derived mesenchymal stromal cells (BM-MSCs) or adipose tissue-derived MSCs (AT-MSCs) on the regeneration of rat calvarial defects. BM-MSCs and AT-MSCs were characterized based on their expression of specific surface markers; cell viability was evaluated after injection with a 21-G needle. Defects measuring 5 mm that were created in rat calvaria were injected with BM-MSCs, AT-MSCs, or vehicle-phosphate-buffered saline (Control) 2 weeks post-defect creation. Cells were tracked by bioluminescence, and 4 weeks post-injection, the newly formed bone was evaluated by µCT, histology, nanoindentation, and gene expression of bone markers. BM-MSCs and AT-MSCs exhibited the characteristics of MSCs and maintained their viability after passing through the 21-G needle. Injection of both BM-MSCs and AT-MSCs resulted in increased bone formation compared to that in Control and with similar mechanical properties as those of native bone. The expression of genes associated with bone formation was higher in the newly formed bone induced by BM-MSCs, whereas the expression of genes involved in bone resorption was higher in the AT-MSC group. Cell therapy based on local injection of BM-MSCs or AT-MSCs is effective in delivering cells that induced a significant improvement in bone healing. Despite differences observed in molecular cues between BM-MSCs and AT-MSCs, both cells had the ability to induce bone tissue formation at comparable amounts and properties. These results may drive new cell therapy approaches toward complete bone regeneration.
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Affiliation(s)
- Gileade P Freitas
- Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, São Paulo, SP, Brazil
| | - Helena B Lopes
- Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, São Paulo, SP, Brazil
| | - Alann T P Souza
- Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, São Paulo, SP, Brazil
| | - Paula G F P Oliveira
- Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, São Paulo, SP, Brazil
| | - Adriana L G Almeida
- Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, São Paulo, SP, Brazil
| | - Lucas E B Souza
- Hemotherapy Center of Ribeirão Preto, University of São Paulo, São Paulo, SP, Brazil
| | - Paulo G Coelho
- Department of Biomaterials, New York University College of Dentistry, New York, NY, USA.,Hanjorg Wyss Department of Plastic Surgery, New York University School of Medicine, New York, NY, USA
| | - Marcio M Beloti
- Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, São Paulo, SP, Brazil
| | - Adalberto L Rosa
- Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, São Paulo, SP, Brazil.
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39
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Zhou W, Qu M, Lv Y, Zhu J. New Advances in Stem Cell Therapy for Osteonecrosis of the Femoral Head. Curr Stem Cell Res Ther 2019; 14:226-229. [PMID: 30360727 DOI: 10.2174/1574888x13666181025120252] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 09/26/2018] [Accepted: 09/29/2018] [Indexed: 02/07/2023]
Abstract
Osteonecrosis of the femoral head (ONFH) is a common refractory orthopedic disease with multiple etiologies that more frequently occurs in middle-aged and young people. ONFH is the main cause of hip replacement in young patients. Since Professor Hernigou first reported the use of stem cells in the treatment of early stage ONFH, a large number of studies have demonstrated the potential of stem cells in the treatment of adult patients with ONFH. With the rise of interdisciplinary stem cell therapy combined with platelet-rich plasma therapy, gene therapy or other methods have gradually attracted the attention of researchers. This article summarizes the current advances in stem cell therapy for ONFH, as well as the problems and challenges, which may provide reference for further research.
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Affiliation(s)
- Wei Zhou
- Department of Orthopaedics, Chengdu Military General Hospital, Chengdu, Sichuan Province 610036, China
| | - Ming Qu
- Department of Orthopaedics, Fuping Couty Hospital, Fuping, Shaanxi Province, 711700, China
| | - Yajie Lv
- Institute of Orthopaedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 71000, China
| | - Jinyu Zhu
- Institute of Orthopaedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 71000, China.,Department of Orthopaedics, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen, Guangdong Province 518055, China
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40
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Granchi D, Ciapetti G, Gómez-Barrena E, Rojewski M, Rosset P, Layrolle P, Spazzoli B, Donati DM, Baldini N. Biomarkers of bone healing induced by a regenerative approach based on expanded bone marrow-derived mesenchymal stromal cells. Cytotherapy 2019; 21:870-885. [PMID: 31272868 DOI: 10.1016/j.jcyt.2019.06.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/29/2019] [Accepted: 06/09/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND Safety and feasibility of a regenerative strategy based on the use of culture-expanded mesenchymal stromal cells (MSCs) have been investigated in phase 2 trials for the treatment of nonunion and osteonecrosis of the femoral head (ONFH). As part of the clinical study, we aimed to evaluate if bone turnover markers (BTMs) could be useful for predicting the regenerative ability of the cell therapy product. MATERIALS AND METHODS The bone defects of 39 patients (nonunion: n = 26; ONFH: n = 13) were treated with bone marrow-derived MSCs, expanded using a clinical-grade protocol and combined with biphasic calcium phosphate before implantation. Bone formation markers, bone-resorption markers and osteoclast regulatory proteins were measured before treatment (baseline) and after 12 and 24 weeks from surgery. At the same time-points, clinical and radiological controls were performed to evaluate the bone-healing progression. RESULTS We found that C-Propeptide of Type I Procollagen (CICP) and C-terminal telopeptide of type-I collagen (CTX) varied significantly, not only over time, but also according to clinical results. In patients with a good outcome, CICP increased and CTX decreased, and this trend was observed in both nonunion and ONFH. Moreover, collagen biomarkers were able to discriminate healed patients from non-responsive patients with a good diagnostic accuracy. DISCUSSION CICP and CTX could be valuable biomarkers for monitoring and predicting the regenerative ability of cell products used to stimulate the repair of refractory bone diseases. To be translated in a clinical setting, these results are under validation in a currently ongoing phase 3 clinical trial.
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Affiliation(s)
- Donatella Granchi
- SSD Fisiopatologia Ortopedica e Medicina Rigenerativa, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
| | - Gabriela Ciapetti
- SSD Fisiopatologia Ortopedica e Medicina Rigenerativa, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | | | - Markus Rojewski
- Institute for Clinical Transfusion Medicine and Immunogenetic Ulm (IKT Ulm), Ulm, Germany
| | - Philippe Rosset
- Service of Orthopaedic Surgery and Traumatology, CHRU, Tours, France
| | - Pierre Layrolle
- Inserm, UMR 1238, PHY-OS, Bone sarcomas and remodeling of calcified tissues, Faculty of Medicine, University of Nantes, Nantes, France
| | - Benedetta Spazzoli
- Clinica Ortopedica III, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Davide Maria Donati
- Clinica Ortopedica III, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy; Dipartimento di Scienze Biomediche e Neuromotorie, Università degli Studi di Bologna, Bologna, Italy
| | - Nicola Baldini
- SSD Fisiopatologia Ortopedica e Medicina Rigenerativa, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy; Dipartimento di Scienze Biomediche e Neuromotorie, Università degli Studi di Bologna, Bologna, Italy
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41
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Lin H, Sohn J, Shen H, Langhans MT, Tuan RS. Bone marrow mesenchymal stem cells: Aging and tissue engineering applications to enhance bone healing. Biomaterials 2019; 203:96-110. [PMID: 29980291 PMCID: PMC6733253 DOI: 10.1016/j.biomaterials.2018.06.026] [Citation(s) in RCA: 258] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 06/18/2018] [Accepted: 06/19/2018] [Indexed: 12/11/2022]
Abstract
Bone has well documented natural healing capacity that normally is sufficient to repair fractures and other common injuries. However, the properties of bone change throughout life, and aging is accompanied by increased incidence of bone diseases and compromised fracture healing capacity, which necessitate effective therapies capable of enhancing bone regeneration. The therapeutic potential of adult mesenchymal stem cells (MSCs) for bone repair has been long proposed and examined. Actions of MSCs may include direct differentiation to become bone cells, attraction and recruitment of other cells, or creation of a regenerative environment via production of trophic growth factors. With systemic aging, MSCs also undergo functional decline, which has been well investigated in a number of recent studies. In this review, we first describe the changes in MSCs during aging and discuss how these alterations can affect bone regeneration. We next review current research findings on bone tissue engineering, which is considered a promising and viable therapeutic solution for structural and functional restoration of bone. In particular, the importance of MSCs and bioscaffolds is highlighted. Finally, potential approaches for the prevention of MSC aging and the rejuvenation of aged MSC are discussed.
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Affiliation(s)
- Hang Lin
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jihee Sohn
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - He Shen
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Nanobiomedicine, Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences, China
| | - Mark T Langhans
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Rocky S Tuan
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; The Chinese University of Hong Kong, Hong Kong SAR, China.
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42
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Schäfer R, DeBaun MR, Fleck E, Centeno CJ, Kraft D, Leibacher J, Bieback K, Seifried E, Dragoo JL. Quantitation of progenitor cell populations and growth factors after bone marrow aspirate concentration. J Transl Med 2019; 17:115. [PMID: 30961655 PMCID: PMC6454687 DOI: 10.1186/s12967-019-1866-7] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 03/28/2019] [Indexed: 12/15/2022] Open
Abstract
Background The number of Mesenchymal Stem/Stromal Cells (MSCs) in the human bone marrow (BM) is small compared to other cell types. BM aspirate concentration (BMAC) may be used to increase numbers of MSCs, but the composition of MSC subpopulations and growth factors after processing are unknown. The purpose of this study was to assess the enrichment of stem/progenitor cells and growth factors in BM aspirate by two different commercial concentration devices versus standard BM aspiration. Methods 120 mL of BM was aspirated from the iliac crest of 10 male donors. Each sample was processed simultaneously by either Emcyte GenesisCS® (Emcyte) or Harvest SmartPReP2 BMAC (Harvest) devices and compared to untreated BM aspirate. Samples were analyzed with multicolor flow cytometry for cellular viability and expression of stem/progenitor cells markers. Stem/progenitor cell content was verified by quantification of colony forming unit-fibroblasts (CFU-F). Platelet, red blood cell and total nucleated cell (TNC) content were determined using an automated hematology analyzer. Growth factors contents were analyzed with protein quantification assays. Statistical analyses were performed by ANOVA analysis of variance followed by Tukey’s multiple comparison test or Wilcoxon matched-pairs signed rank test with p < 0.05 for significance. Results Cell viability after processing was approximately 90% in all groups. Compared to control, both devices significantly enriched TNCs and platelets, as well as the CD45−CD73+ and CD45−CD73+CD90+ cell populations. Further, Harvest significantly concentrated CD45−CD10+, CD45−CD29+, CD45−CD90+, CD45−CD105+, CD45−CD119+ cells, and CD45dimCD90+CD271+ MSCs, whereas Emcyte significantly enriched CD45dimCD44+CD271+ MSCs. BM concentration also increased the numbers of CFU-F, platelet-derived growth factor, vascular endothelial growth factor, macrophage colony-stimulating factor, interleukin-1b, VCAM-1 and total protein. Neither system concentrated red blood cells, hematopoietic stem cells or bone morphogenetic proteins. Conclusion This data could contribute to the development of BMAC quality control assays as both BMAC systems concentrated platelets, growth factors and non-hematopoietic stem cell subpopulations with distinct phenotypes without loss of cell viability when compared to unprocessed BM. Electronic supplementary material The online version of this article (10.1186/s12967-019-1866-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Richard Schäfer
- Institute for Transfusion Medicine and Immunohematology, German Red Cross Blood Service Baden-Württemberg - Hessen gGmbH, Frankfurt Am Main, Germany
| | - Malcolm R DeBaun
- Department of Orthopedic Surgery, Stanford University School of Medicine, 450 Broadway, Redwood City, CA, 94063, USA
| | - Erika Fleck
- Institute for Transfusion Medicine and Immunohematology, German Red Cross Blood Service Baden-Württemberg - Hessen gGmbH, Frankfurt Am Main, Germany
| | | | - Daniela Kraft
- Institute for Transfusion Medicine and Immunohematology, German Red Cross Blood Service Baden-Württemberg - Hessen gGmbH, Frankfurt Am Main, Germany
| | - Johannes Leibacher
- Institute for Transfusion Medicine and Immunohematology, German Red Cross Blood Service Baden-Württemberg - Hessen gGmbH, Frankfurt Am Main, Germany
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden-Württemberg - Hessen gGmbH, Mannheim, Germany
| | - Erhard Seifried
- Institute for Transfusion Medicine and Immunohematology, German Red Cross Blood Service Baden-Württemberg - Hessen gGmbH, Frankfurt Am Main, Germany
| | - Jason L Dragoo
- Department of Orthopedic Surgery, Stanford University School of Medicine, 450 Broadway, Redwood City, CA, 94063, USA.
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43
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Pajarinen J, Lin T, Gibon E, Kohno Y, Maruyama M, Nathan K, Lu L, Yao Z, Goodman SB. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials 2019; 196:80-89. [PMID: 29329642 PMCID: PMC6028312 DOI: 10.1016/j.biomaterials.2017.12.025] [Citation(s) in RCA: 594] [Impact Index Per Article: 99.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 12/25/2017] [Accepted: 12/31/2017] [Indexed: 12/12/2022]
Abstract
Recent research has brought about a clear understanding that successful fracture healing is based on carefully coordinated cross-talk between inflammatory and bone forming cells. In particular, the key role that macrophages play in the recruitment and regulation of the differentiation of mesenchymal stem cells (MSCs) during bone regeneration has been brought to focus. Indeed, animal studies have comprehensively demonstrated that fractures do not heal without the direct involvement of macrophages. Yet the exact mechanisms by which macrophages contribute to bone regeneration remain to be elucidated. Macrophage-derived paracrine signaling molecules such as Oncostatin M, Prostaglandin E2 (PGE2), and Bone Morphogenetic Protein-2 (BMP2) have been shown to play critical roles; however the relative importance of inflammatory (M1) and tissue regenerative (M2) macrophages in guiding MSC differentiation along the osteogenic pathway remains poorly understood. In this review, we summarize the current understanding of the interaction of macrophages and MSCs during bone regeneration, with the emphasis on the role of macrophages in regulating bone formation. The potential implications of aging to this cellular cross-talk are reviewed. Emerging treatment options to improve facture healing by utilizing or targeting MSC-macrophage crosstalk are also discussed.
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Affiliation(s)
- Jukka Pajarinen
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Tzuhua Lin
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Emmanuel Gibon
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Yusuke Kohno
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Masahiro Maruyama
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Karthik Nathan
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Laura Lu
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Zhenyu Yao
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Stuart B Goodman
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
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Kohno Y, Lin T, Pajarinen J, Romero-Lopez M, Maruyama M, Huang JF, Nathan K, Yao Z, Goodman SB. Osteogenic ability of rat bone marrow concentrate is at least as efficacious as mesenchymal stem cells in vitro. J Biomed Mater Res B Appl Biomater 2019; 107:2500-2506. [PMID: 30779478 DOI: 10.1002/jbm.b.34340] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 11/18/2018] [Accepted: 01/26/2019] [Indexed: 01/01/2023]
Abstract
Cell therapy using bone marrow concentrate (BMC) or purified and expanded mesenchymal stem cells (MSCs) has been shown to have a promising osteogenic capacity. However, few studies have directly compared their relative osteogenic ability. The aim of this study was to compare the osteogenic ability of BMC isolated by density gradient centrifugation with bone marrow-derived MSCs in vitro using the cells of 3-month-old Sprague-Dawley rats. The isolated cells were seeded onto 24-well plates (1 × 105 cells/well) and cultured in control growth media, osteogenic media with dexamethasone, or media without dexamethasone (which simulated the in vivo tissue environment). Alkaline phosphatase activity at week 2, osteocalcin using quantitative real-time polymerase chain reaction at week 4, and Alizarin red staining at week 4 were evaluated. In the osteogenic media with dexamethasone, BMC showed equivalent (osteocalcin) or even greater (Alizarin red staining) osteogenic ability compared to MSCs, suggesting that cross-talk among various cells in the BMC leads to greater osteogenesis. Furthermore, in the osteogenic media without dexamethasone, BMC showed equivalent (osteocalcin) or a trend for greater (Alizarin red staining) bone formation than MSCs alone. Our results suggest that BMC has at least comparable bone regeneration potential to MSCs. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2500-2506, 2019.
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Affiliation(s)
- Yusuke Kohno
- Department of Orthopaedic Surgery, Stanford University, Stanford, California
| | - Tzuhua Lin
- Department of Orthopaedic Surgery, Stanford University, Stanford, California
| | - Jukka Pajarinen
- Department of Orthopaedic Surgery, Stanford University, Stanford, California
| | - Monica Romero-Lopez
- Department of Orthopaedic Surgery, Stanford University, Stanford, California
| | - Masahiro Maruyama
- Department of Orthopaedic Surgery, Stanford University, Stanford, California
| | - Jhih-Fong Huang
- Department of Orthopaedic Surgery, Stanford University, Stanford, California
| | - Karthik Nathan
- Department of Orthopaedic Surgery, Stanford University, Stanford, California
| | - Zhenyu Yao
- Department of Orthopaedic Surgery, Stanford University, Stanford, California
| | - Stuart B Goodman
- Department of Orthopaedic Surgery, Stanford University, Stanford, California.,Department of Bioengineering, Stanford University, Stanford, California
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Osteonecrosis in pediatric cancer survivors: Epidemiology, risk factors, and treatment. Surg Oncol 2019; 28:214-221. [PMID: 30851903 DOI: 10.1016/j.suronc.2019.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 01/25/2019] [Accepted: 02/02/2019] [Indexed: 01/30/2023]
Abstract
Several treatment regimens for childhood malignancies have been associated with the development of osteonecrosis, including radiation therapy, glucocorticoid medications, immunotherapy (including anti-angiogenic agents), and several chemotherapeutic agents. Adolescents older than 10 years are at greatest risk of developing osteonecrosis within 1 year of initiating therapy. Screening with magnetic resonance imaging in this high-risk population may be a useful method for detecting osteonecrosis. Surgery may be required for lesions that have progressed substantially despite nonoperative interventions.
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Fu X, Halim A, Tian B, Luo Q, Song G. MT1-MMP downregulation via the PI3K/Akt signaling pathway is required for the mechanical stretching-inhibited invasion of bone-marrow-derived mesenchymal stem cells. J Cell Physiol 2019; 234:14133-14144. [PMID: 30659604 DOI: 10.1002/jcp.28105] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 12/07/2018] [Indexed: 12/21/2022]
Abstract
Mobilization from the bone marrow and the migration of bone-marrow-derived mesenchymal stem cells (BMSCs) through the peripheral circulation to injured tissue sites are regulated by multiple mechanical and chemical factors. We previously demonstrated that mechanical stretching promotes the migration but inhibits the invasion of BMSCs. However, the involved mechanisms, especially the mechanism of stretching-inhibited BMSC invasion, have not been thoroughly elucidated to date. In this study, we found that mechanical stretching with a 10% amplitude at a 1-Hz frequency for 8 hr significantly reduces BMSC invasion and downregulates the expression of membrane type-1 matrix metalloproteinases (MT1-MMP) at both the messenger RNA and protein levels. The overexpression of MT1-MMP restores mechanical stretching-reduced BMSC invasion. Moreover, phosphatidylinositol 3-kinase (PI3K)-dependent Akt phosphorylation in BMSCs was found to be inactivated by mechanical stretching. Pharmacological inhibitors of PI3K/Akt signaling (LY294002 or A443654) reduced the expression of MT1-MMP and impaired BMSC invasion. In addition, the upregulation of Akt phosphorylation by a pharmacological activator (SC79) increased MT1-MMP expression and suppressed mechanical stretching-reduced BMSC invasion. Taken together, our results suggest that mechanical stretching inhibits BMSC invasion by downregulating MT1-MMP expression by suppressing the PI3K/Akt signaling pathway.
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Affiliation(s)
- Xiaorong Fu
- Department of Bioengineering, College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing, China
| | - Alexander Halim
- Department of Bioengineering, College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing, China
| | - Boren Tian
- Department of Bioengineering, College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing, China
| | - Qing Luo
- Department of Bioengineering, College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing, China
| | - Guanbin Song
- Department of Bioengineering, College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing, China
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Law L, Hunt CL, van Wijnen AJ, Nassr A, Larson AN, Eldrige JS, Mauck WD, Pingree MJ, Yang J, Muir CW, Erwin PJ, Bydon M, Qu W. Office-Based Mesenchymal Stem Cell Therapy for the Treatment of Musculoskeletal Disease: A Systematic Review of Recent Human Studies. PAIN MEDICINE 2018; 20:1570-1583. [DOI: 10.1093/pm/pny256] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Abstract
Background
The use of mesenchymal stem cells (MSCs) in clinical applications for the treatment of musculoskeletal disease is steadily increasing in office-based practice. The so-called “first generation” of MSCs is defined as autologous stem cells that have undergone minimal manipulation and are used for a homologous purpose. Systematic reviews of the clinical trials completed to date of such MSCs enable practitioners to better understand what is currently known about the outcomes and side effects of such treatments.
Study Design
A systematic review of human clinical studies of office-based MSC therapy for the treatment of painful degenerative musculoskeletal conditions.
Methods
A search of the Ovid MEDLINE, EMBASE, and Scopus databases was conducted from 2006 through September 2016. Seven hundred sixty-one records were identified from database searching, and two records from reference review of included papers. Studies with human subjects that evaluated treatment of musculoskeletal disease with minimally manipulated MSCs were included.
Results
Eight studies were included in this review based on selection criteria. A total of 941 patients were included, 841 of whom received cellular products, and no significant adverse events were reported. Symptomatology generally improved, though no differences were seen over controls where present.
Conclusion
Support in the literature is strongest for the use of bone marrow aspirate concentrate (BMAC) injections for the treatment of knee pain, but applications of the use of BMAC and peripheral blood–derived MSCs for the treatment of hip pain, tendon pain, and disc pain have all been reported. Further research is required, with large randomized controlled trials.
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Affiliation(s)
| | | | | | | | | | | | | | - Mathew J Pingree
- Physical Medicine and Rehabilitation
- Anesthesiology, Pain Division
| | - Juan Yang
- Physical Medicine and Rehabilitation
- Anesthesiology, Pain Division
| | | | | | | | - Wenchun Qu
- Physical Medicine and Rehabilitation
- Anesthesiology, Pain Division
- Spine Center; Mayo Clinic, Rochester, Minnesota, USA
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Abstract
Orthobiologics are a group of biological materials and substrates that promote bone, ligament, muscle, and tendon healing. These substances include bone autograft, bone allograft, demineralized bone matrix, bone graft substitutes, bone marrow aspirate concentrate, platelet-rich plasma, bone morphogenetic proteins, platelet-derived growth factor, parathyroid hormone, and vitamin D and calcium. Properties of orthobiologics in bone healing include osteoconduction, osteoinduction, and osteogenesis. This article discusses the important properties of orthobiologics in bone healing, many of the orthobiologics currently available for bone healing, the related literature, their current clinical uses in sports medicine, and systemic factors that inhibit bone healing.
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Affiliation(s)
- Jacob G Calcei
- Department of Sports Medicine and Shoulder, Hospital for Special Surgery, 535 E 70th Street, New York, NY 10021, USA.
| | - Scott A Rodeo
- Department of Sports Medicine and Shoulder, Hospital for Special Surgery, 535 E 70th Street, New York, NY 10021, USA
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Kumagai H, Yoshioka T, Sugaya H, Tomaru Y, Shimizu Y, Yamazaki M, Mishima H. Quantitative assessment of mesenchymal stem cells contained in concentrated autologous bone marrow aspirate transplantation for the treatment of osteonecrosis of the femoral head: predictive factors and differences by etiology. BMC Res Notes 2018; 11:848. [PMID: 30497531 PMCID: PMC6267066 DOI: 10.1186/s13104-018-3949-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 11/23/2018] [Indexed: 11/13/2022] Open
Abstract
Objective We previously established concentrated autologous bone marrow aspirate transplantation as a one-step, lowly invasive, joint-preserving surgical technique for treating osteonecrosis of the femoral head. The objectives of this study were to identify factors that may predict the mesenchymal stem cell (MSC) count in bone marrow aspirate, concentrated using our method, and to clarify etiology related differences in the number of MSCs in concentrated bone marrow aspirate. Results The MSC counts per 106 nucleated cells before concentration in the steroid, alcohol, and trauma groups were 2.31 ± 2.96, 2.58 ± 2.30, and 1.95 ± 1.85, respectively. The MSC counts per 106 nucleated cells after concentration were 3.23 ± 3.41, 3.30 ± 2.83, and 2.56 ± 1.98 cells, respectively. The MSC concentration rates in the steroid, alcohol, and trauma groups were 7.15 ± 5.62, 5.08 ± 1.96, and 8.23 ± 4.82 times, respectively. None of the differences were significant. Multiple regression analysis revealed that MSC count was related to the total bone marrow aspirated, peripheral blood platelet count, and nucleated cell count in the initial aspiration.
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Affiliation(s)
- Hiroshi Kumagai
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Tomokazu Yoshioka
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
| | - Hisashi Sugaya
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yohei Tomaru
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yukiyo Shimizu
- Department of Rehabilitation Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Masashi Yamazaki
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Hajime Mishima
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
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Abstract
In the last few decades, several techniques have been used to optimize tendon, ligament, and musculoskeletal healing. The evidence in favor of these techniques is still not proven, and level I studies are lacking. We performed an analysis of the therapeutic strategies and tissue engineering projects recently published in this field. Here, we try to give an insight into the current status of cell therapies and the latest techniques of bioengineering applied to the field of orthopedic surgery. The future areas for research in the management of musculoskeletal injuries are outlined. There are emerging technologies developing into substantial clinical treatment options that need to be critically evaluated. Mechanical stimulation of the constructs reproduces a more propitious environment for effective healing.
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