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Noh S, Lee SJ, Yoo JJ, Jin YJ, Yun HW, Min BH, Park JY, Park DY. Synovium-Derived Mesenchymal Stem Cell-Based Scaffold-Free Fibrocartilage Engineering for Bone-Tendon Interface Healing in an Anterior Cruciate Ligament Reconstruction Model. Tissue Eng Regen Med 2024; 21:341-351. [PMID: 37856071 PMCID: PMC10825091 DOI: 10.1007/s13770-023-00593-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/21/2023] [Accepted: 08/27/2023] [Indexed: 10/20/2023] Open
Abstract
BACKGROUND Current tendon and ligament reconstruction surgeries rely on scar tissue healing which differs from native bone-to-tendon interface (BTI) tissue. We aimed to engineer Synovium-derived mesenchymal stem cells (Sy-MSCs) based scaffold-free fibrocartilage constructs and investigate in vivo bone-tendon interface (BTI) healing efficacy in a rat anterior cruciate ligament (ACL) reconstruction model. METHODS Sy-MSCs were isolated from knee joint of rats. Scaffold-free sy-MSC constructs were fabricated and cultured in differentiation media including TGF-β-only, CTGF-only, and TGF-β + CTGF. Collagenase treatment on tendon grafts was optimized to improve cell-to-graft integration. The effects of fibrocartilage differentiation and collagenase treatment on BTI integration was assessed by conducting histological staining, cell adhesion assay, and tensile testing. Finally, histological and biomechanical analyses were used to evaluate in vivo efficacy of fibrocartilage construct in a rat ACL reconstruction model. RESULTS Fibrocartilage-like features were observed with in the scaffold-free sy-MSC constructs when applying TGF-β and CTGF concurrently. Fifteen minutes collagenase treatment increased cellular attachment 1.9-fold compared to the Control group without affecting tensile strength. The failure stress was highest in the Col + D + group (22.494 ± 13.74 Kpa) compared to other groups at integration analysis in vitro. The ACL Recon + FC group exhibited a significant 88% increase in estimated stiffness (p = 0.0102) compared to the ACL Recon group at the 4-week postoperative period. CONCLUSION Scaffold-free, fibrocartilage engineering together with tendon collagenase treatment enhanced fibrocartilaginous BTI healing in ACL reconstruction.
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Affiliation(s)
- Sujin Noh
- Department of Biomedical Sciences, Graduate School of Ajou University, 206 World Cup-Ro, Yeongtong-Gu, Suwon, Republic of Korea
| | - Sang Jin Lee
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - James J Yoo
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Yong Jun Jin
- Department of Orthopedic Surgery, School of Medicine, Ajou University, Suwon, Republic of Korea
| | - Hee-Woong Yun
- Cell Therapy Center, Ajou Medical Center, Suwon, Republic of Korea
| | - Byoung-Hyun Min
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Jae-Young Park
- Department of Orthopedics Surgery, CHA University Bundang Medical Center, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, Republic of Korea
| | - Do Young Park
- Department of Biomedical Sciences, Graduate School of Ajou University, 206 World Cup-Ro, Yeongtong-Gu, Suwon, Republic of Korea.
- Department of Orthopedic Surgery, School of Medicine, Ajou University, Suwon, Republic of Korea.
- Cell Therapy Center, Ajou Medical Center, Suwon, Republic of Korea.
- Leading Convergence of Healthcare and Medicine, Institute of Science & Technology (ALCHeMIST), Ajou University, Suwon, Republic of Korea.
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Wang Y, Ren C, Bi F, Li P, Tian K. The hydroxyapatite modified 3D printed poly L-lactic acid porous screw in reconstruction of anterior cruciate ligament of rabbit knee joint: a histological and biomechanical study. BMC Musculoskelet Disord 2023; 24:151. [PMID: 36849968 PMCID: PMC9969685 DOI: 10.1186/s12891-023-06245-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 02/15/2023] [Indexed: 03/01/2023] Open
Abstract
BACKGROUND 3D printing technology has become a research hotspot in the field of scientific research because of its personalized customization, maneuverability and the ability to achieve multiple material fabrications. The focus of this study is to use 3D printing technology to customize personalized poly L-lactic acid (PLLA) porous screws in orthopedic plants and to explore its effect on tendon-bone healing after anterior cruciate ligament (ACL) reconstruction. METHODS Preparation of PLLA porous screws with good orthogonal pore structure by 3D printer. The hydroxyapatite (HA) was adsorbed on porous screws by electrostatic layer-by-layer self-assembly (ELSA) technology, and PLLA-HA porous screws were prepared. The surface and spatial morphology of the modified screws were observed by scanning electron microscopy (SEM). The porosity of porous screw was measured by liquid displacement method. Thirty New Zealand male white rabbits were divided into two groups according to simple randomization. Autologous tendon was used for right ACL reconstruction, and porous screws were inserted into the femoral tunnel to fix the transplanted tendon. PLLA group was fixed with porous screws, PLLA-HA group was fixed with HA modified porous screws. At 6 weeks and 12 weeks after surgery, 5 animals in each group were sacrificed randomly for histological examination. The remaining 5 animals in each group underwent Micro-CT and biomechanical tests. RESULTS The pores of PLLA porous screws prepared by 3D printer were uniformly distributed and connected with each other, which meet the experimental requirements. HA was evenly distributed in the porous screw by ELSA technique. Histology showed that compared with PLLA group, mature bone trabeculae were integrated with grafted tendons in PLLA-HA group. Micro-CT showed that the bone formation index of PLLA-HA group was better than that of PLLA group. The new bone was uniformly distributed in the bone tunnel along the screw channel. Biomechanical experiments showed that the failure load and stiffness of PLLA-HA group were significantly higher than those of PLLA group. CONCLUSIONS The 3D printed PLLA porous screw modified by HA can not only fix the grafted tendons, but also increase the inductivity of bone, promote bone growth in the bone tunnel and promote bone integration at the tendon-bone interface. The PLLA-HA porous screw is likely to be used in clinic in the future.
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Affiliation(s)
- Yafei Wang
- Department of Orthopedic Surgery, the First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe East Road, Zhengzhou, China
| | - Chengzhen Ren
- Department of Orthopedic Surgery, the First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe East Road, Zhengzhou, China
| | - Fanggang Bi
- Department of Orthopedic Surgery, the First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe East Road, Zhengzhou, China
| | - Pengju Li
- Department of Orthopedic Surgery, the Honghui Hospital of Xi'an, No. 76 Nanguo road, Nan Xiaomen, Xi'an, 710054, China
| | - Ke Tian
- Department of Orthopedic Surgery, the First Affiliated Hospital of Zhengzhou University, NO.1 Jianshe East Road, Zhengzhou, China.
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Amini M, Venkatesan JK, Liu W, Leroux A, Nguyen TN, Madry H, Migonney V, Cucchiarini M. Advanced Gene Therapy Strategies for the Repair of ACL Injuries. Int J Mol Sci 2022; 23:ijms232214467. [PMID: 36430947 PMCID: PMC9695211 DOI: 10.3390/ijms232214467] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/07/2022] [Accepted: 11/19/2022] [Indexed: 11/23/2022] Open
Abstract
The anterior cruciate ligament (ACL), the principal ligament for stabilization of the knee, is highly predisposed to injury in the human population. As a result of its poor intrinsic healing capacities, surgical intervention is generally necessary to repair ACL lesions, yet the outcomes are never fully satisfactory in terms of long-lasting, complete, and safe repair. Gene therapy, based on the transfer of therapeutic genetic sequences via a gene vector, is a potent tool to durably and adeptly enhance the processes of ACL repair and has been reported for its workability in various experimental models relevant to ACL injuries in vitro, in situ, and in vivo. As critical hurdles to the effective and safe translation of gene therapy for clinical applications still remain, including physiological barriers and host immune responses, biomaterial-guided gene therapy inspired by drug delivery systems has been further developed to protect and improve the classical procedures of gene transfer in the future treatment of ACL injuries in patients, as critically presented here.
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Affiliation(s)
- Mahnaz Amini
- Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, D-66421 Homburg, Germany
| | - Jagadeesh K. Venkatesan
- Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, D-66421 Homburg, Germany
| | - Wei Liu
- Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, D-66421 Homburg, Germany
| | - Amélie Leroux
- Laboratoire CSPBAT UMR CNRS 7244, Université Sorbonne Paris Nord, Avenue JB Clément, 93430 Villetaneuse, France
| | - Tuan Ngoc Nguyen
- Laboratoire CSPBAT UMR CNRS 7244, Université Sorbonne Paris Nord, Avenue JB Clément, 93430 Villetaneuse, France
| | - Henning Madry
- Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, D-66421 Homburg, Germany
| | - Véronique Migonney
- Laboratoire CSPBAT UMR CNRS 7244, Université Sorbonne Paris Nord, Avenue JB Clément, 93430 Villetaneuse, France
| | - Magali Cucchiarini
- Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, D-66421 Homburg, Germany
- Correspondence: or
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Yu Q, Qiao GH, Wang M, Yu L, Sun Y, Shi H, Ma TL. Stem Cell-Based Therapy for Diabetic Foot Ulcers. Front Cell Dev Biol 2022; 10:812262. [PMID: 35178389 PMCID: PMC8844366 DOI: 10.3389/fcell.2022.812262] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic foot ulcer has become a worldwide clinical medical challenge as traditional treatments are not effective enough to reduce the amputation rate. Therefore, it is of great social significance to deeply study the pathogenesis and biological characteristics of the diabetic foot, explore new treatment strategies and promote their application. Stem cell-based therapy holds tremendous promise in the field of regenerative medicine, and its mechanisms include promoting angiogenesis, ameliorating neuroischemia and inflammation, and promoting collagen deposition. Studying the specific molecular mechanisms of stem cell therapy for diabetic foot has an important role and practical clinical significance in maximizing the repair properties of stem cells. In addition, effective application modalities are also crucial in order to improve the survival and viability of stem cells at the wound site. In this paper, we reviewed the specific molecular mechanisms of stem cell therapy for diabetic foot and the extended applications of stem cells in recent years, with the aim of contributing to the development of stem cell-based therapy in the repair of diabetic foot ulcers.
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Affiliation(s)
- Qian Yu
- Department of Hepatology, Songjiang Hospital Affiliated to Nanjing Medical University, Shanghai, China
| | - Guo-Hong Qiao
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Min Wang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Li Yu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yaoxiang Sun
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Hui Shi
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China.,Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Tie-Liang Ma
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
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Moon SW, Park S, Oh M, Wang JH. Outcomes of human umbilical cord blood-derived mesenchymal stem cells in enhancing tendon-graft healing in anterior cruciate ligament reconstruction: an exploratory study. Knee Surg Relat Res 2021; 33:32. [PMID: 34530924 PMCID: PMC8447562 DOI: 10.1186/s43019-021-00104-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 05/03/2021] [Indexed: 11/30/2022] Open
Abstract
Background The study investigated whether allogeneic human umbilical cord blood-derived MSCs (hUCB-MSCs) could be safely used without treatment-related adverse events, reducing tunnel enlargement, and improve clinical results in human anterior cruciate ligament (ACL) reconstruction. Methods Thirty patients were enrolled consecutively. They were divided into three groups by randomization. In the negative control group, ACL reconstruction surgery without additional treatment was performed. In the experimental group, a hUCB-MSC and hyaluronic acid mixture was applied to the tendon-bone interface of the femoral tunnels during ACL reconstruction surgery. In the positive control group, only hyaluronic acid was applied. Finally, 27 patients were analyzed after the exclusion of three patients. The incidence of treatment-related adverse events, clinical outcomes, including second-look arthroscopic findings, and the amount of tunnel enlargement, were evaluated. Results There were no treatment-related adverse events in the treatment groups. Tunnel enlargement in the experimental group (579.74 ± 389.85 mm3) was not significantly different from those in the negative (641.97 ± 455.84 mm3) and positive control (421.96 ± 274.83 mm3) groups (p = 0.6468). There were no significant differences between the groups in clinical outcomes such as KT-2000 measurement (p = 0.793), pivot shift test (p = 0.9245), International Knee Documentation Committee subjective score (p = 0.9195), Tegner activity level (p = 0.9927), and second-look arthroscopic findings (synovial coverage of the graft, p = 0.7984; condition of the graft, p = 0.8402). Conclusions Allogeneic hUCB-MSCs were used safely for ACL reconstruction without treatment-related adverse event in a 2-year follow-up. However, our study did not suggest any evidence to show clinical advantage such as the prevention of tunnel enlargement postoperatively and a decrease in knee laxity or improvement of clinical outcomes. Trial registration CRIS, Registration Number: KCT0000917. Registered on 12 November 2013; https://cris.nih.go.kr/cris/index.jsp
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Affiliation(s)
- Sang Won Moon
- Department of Orthopaedic Surgery, Inje University Haeundae Paik Hospital, Busan, Korea
| | - Sinhyung Park
- Department of Orthopaedic Surgery, Soonchunhyang University Hospital Bucheon, Gyeonggi-do, Korea
| | - Minkyung Oh
- Clinical Trial Center, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Joon Ho Wang
- Department of Orthopaedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea. .,Department of Health Sciences and Technology and Department of Medical Device Management and Research, SAIHST, Sungkyunkwan University, Seoul, 06351, Korea.
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Prządka P, Buczak K, Frejlich E, Gąsior L, Suliga K, Kiełbowicz Z. The Role of Mesenchymal Stem Cells (MSCs) in Veterinary Medicine and Their Use in Musculoskeletal Disorders. Biomolecules 2021; 11:1141. [PMID: 34439807 PMCID: PMC8391453 DOI: 10.3390/biom11081141] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/27/2021] [Accepted: 07/30/2021] [Indexed: 12/11/2022] Open
Abstract
Regenerative medicine is a dynamically developing field of human and veterinary medicine. The animal model was most commonly used for mesenchymal stem cells (MSCs) treatment in experimental and preclinical studies with a satisfactory therapeutic effect. Year by year, the need for alternative treatments in veterinary medicine is increasing, and other applications for promising MSCs and their biological derivatives are constantly being sought. There is also an increase in demand for other methods of treating disease states, of which the classical treatment methods did not bring the desired results. Cell therapy can be a realistic option for treating human and animal diseases in the near future and therefore additional research is needed to optimize cell origins, numbers, or application methods in order to standardize the treatment process and assess its effects. The aim of the following work was to summarize available knowledge about stem cells in veterinary medicine and their possible application in the treatment of chosen musculoskeletal disorders in dogs and horses.
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Affiliation(s)
- Przemysław Prządka
- Department of Surgery, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Science, Pl. Grunwadzki 51, 50-366 Wroclaw, Poland; (K.B.); (Z.K.)
| | - Krzysztof Buczak
- Department of Surgery, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Science, Pl. Grunwadzki 51, 50-366 Wroclaw, Poland; (K.B.); (Z.K.)
| | - Ewelina Frejlich
- 2nd Department of General Surgery and Surgical Oncology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Ludwika Gąsior
- Vets & Pets Veterinary Clinic, Zakladowa 11N, 50-231 Wroclaw, Poland;
| | - Kamil Suliga
- Student Veterinary Surgical Society “LANCET”, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Science, Pl. Grunwaldzki 51, 50-366 Wroclaw, Poland;
| | - Zdzisław Kiełbowicz
- Department of Surgery, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Science, Pl. Grunwadzki 51, 50-366 Wroclaw, Poland; (K.B.); (Z.K.)
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Yao S, Fu BSC, Yung PSH. Graft healing after anterior cruciate ligament reconstruction (ACLR). ASIA-PACIFIC JOURNAL OF SPORT MEDICINE ARTHROSCOPY REHABILITATION AND TECHNOLOGY 2021; 25:8-15. [PMID: 34094881 PMCID: PMC8134949 DOI: 10.1016/j.asmart.2021.03.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/05/2021] [Accepted: 03/21/2021] [Indexed: 01/11/2023]
Abstract
Anterior cruciate ligament reconstruction (ACLR) is a commonly performed procedure in Orthopaedic sports medicine. With advances in surgical techniques providing better positioning and fixation of the graft, subsequent graft failure to certain extent should be accounted by poor graft healing. Although different biological modulations for enhancement of graft healing have been tried in different clinical and animal studies, complete graft incorporation into bone tunnels and the “ligamentization” of the intra-articular part have not been fully achieved yet. Based on the understanding of graft healing process and its failure mechanism, the purpose of this review is to combine both the known basic science & clinical evidence, to provide a much clearer picture of the obstacle encountered in graft healing, so as to facilitate researchers on subsequent work on the enhancement of ACL graft healing.
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Affiliation(s)
- Shiyi Yao
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong
| | - Bruma Sai-Chuen Fu
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong
| | - Patrick Shu-Hang Yung
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong
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Hexter AT, Sanghani-Kerai A, Heidari N, Kalaskar DM, Boyd A, Pendegrass C, Rodeo SA, Haddad FS, Blunn GW. Mesenchymal stromal cells and platelet-rich plasma promote tendon allograft healing in ovine anterior cruciate ligament reconstruction. Knee Surg Sports Traumatol Arthrosc 2021; 29:3678-3688. [PMID: 33331973 PMCID: PMC8514355 DOI: 10.1007/s00167-020-06392-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/24/2020] [Indexed: 11/30/2022]
Abstract
PURPOSE The effect of bone marrow mesenchymal stromal cells (BMSCs) and platelet-rich plasma (PRP) on tendon allograft maturation in a large animal anterior cruciate ligament (ACL) reconstruction model was reported for the first time. It was hypothesised that compared with non-augmented ACL reconstruction, BMSCs and PRP would enhance graft maturation after 12 weeks and this would be detected using magnetic resonance imaging (MRI). METHODS Fifteen sheep underwent unilateral tendon allograft ACL reconstruction using aperture fixation and were randomised into three groups (n = 5). Group 1 received 10 million allogeneic BMSCs in 2 ml fibrin sealant; Group 2 received 12 ml PRP in a plasma clot injected into the graft and bone tunnels; and Group 3 (control) received no adjunctive treatment. At autopsy at 12 weeks, a graft maturation score was determined by the sum for graft integrity, synovial coverage and vascularisation, graft thickness and apparent tension, and synovial sealing at tunnel apertures. MRI analysis (n = 2 animals per group) of the signal-noise quotient (SNQ) and fibrous interzone (FIZ) was used to evaluate intra-articular graft maturation and tendon-bone healing, respectively. Spearman's rank correlation coefficient (r) of SNQ, autopsy graft maturation score and bone tunnel diameter were analysed. RESULTS The BMSC group (p = 0.01) and PRP group (p = 0.03) had a significantly higher graft maturation score compared with the control group. The BMSC group scored significantly higher for synovial sealing at tunnel apertures (p = 0.03) compared with the control group. The graft maturation score at autopsy significantly correlated with the SNQ (r = - 0.83, p < 0.01). The tunnel diameter of the femoral tunnel at the aperture (r = 0.883, p = 0.03) and mid-portion (r = 0.941, p = 0.02) positively correlated with the SNQ. CONCLUSIONS BMSCs and PRP significantly enhanced graft maturation, which indicates that orthobiologics can accelerate the biologic events in tendon allograft incorporation. Femoral tunnel expansion significantly correlated with inferior maturation of the intra-articular graft. The clinical relevance of this study is that BMSCs and PRP enhance allograft healing in a translational model, and biological modulation of graft healing can be evaluated non-invasively using MRI.
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Affiliation(s)
- Adam T Hexter
- Division of Surgery and Interventional Science, University College London (UCL), London, UK.
- Institute of Orthopaedics and Musculoskeletal Sciences, Division of Surgery and Interventional Science, Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, London, HA7 4LP, UK.
| | - Anita Sanghani-Kerai
- Division of Surgery and Interventional Science, University College London (UCL), London, UK
| | - Nima Heidari
- Royal London Hospital and Orthopaedic Specialists (OS), London, UK
| | - Deepak M Kalaskar
- Division of Surgery and Interventional Science, University College London (UCL), London, UK
| | - Ashleigh Boyd
- Division of Surgery and Interventional Science, University College London (UCL), London, UK
| | - Catherine Pendegrass
- Division of Surgery and Interventional Science, University College London (UCL), London, UK
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Zhang J, Wang RJ, Chen M, Liu XY, Ma K, Xu HY, Deng WS, Ye YC, Li WX, Chen XY, Sun HT. Collagen/heparan sulfate porous scaffolds loaded with neural stem cells improve neurological function in a rat model of traumatic brain injury. Neural Regen Res 2021; 16:1068-1077. [PMID: 33269752 PMCID: PMC8224125 DOI: 10.4103/1673-5374.300458] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
One reason for the poor therapeutic effects of stem cell transplantation in traumatic brain injury is that exogenous neural stem cells cannot effectively migrate to the local injury site, resulting in poor adhesion and proliferation of neural stem cells at the injured area. To enhance the targeted delivery of exogenous stem cells to the injury site, cell therapy combined with neural tissue engineering technology is expected to become a new strategy for treating traumatic brain injury. Collagen/heparan sulfate porous scaffolds, prepared using a freeze-drying method, have stable physical and chemical properties. These scaffolds also have good cell biocompatibility because of their high porosity, which is suitable for the proliferation and migration of neural stem cells. In the present study, collagen/heparan sulfate porous scaffolds loaded with neural stem cells were used to treat a rat model of traumatic brain injury, which was established using the controlled cortical impact method. At 2 months after the implantation of collagen/heparan sulfate porous scaffolds loaded with neural stem cells, there was significantly improved regeneration of neurons, nerve fibers, synapses, and myelin sheaths in the injured brain tissue. Furthermore, brain edema and cell apoptosis were significantly reduced, and rat motor and cognitive functions were markedly recovered. These findings suggest that the novel collagen/heparan sulfate porous scaffold loaded with neural stem cells can improve neurological function in a rat model of traumatic brain injury. This study was approved by the Institutional Ethics Committee of Characteristic Medical Center of Chinese People’s Armed Police Force, China (approval No. 2017-0007.2) on February 10, 2019.
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Affiliation(s)
- Jian Zhang
- Tianjin Key Laboratory of Neurotrauma Repair, Institute of Traumatic Brain Injury and Neuroscience, Characteristic Medical Center of Chinese People's Armed Police Force; Graduate School, Logistics University of People's Armed Police Force, Tianjin, China
| | - Ren-Jie Wang
- Tianjin Key Laboratory of Neurotrauma Repair, Institute of Traumatic Brain Injury and Neuroscience, Characteristic Medical Center of Chinese People's Armed Police Force, Tianjin, China
| | - Miao Chen
- Graduate School, Affiliated Hospital of Traditional Chinese Medicine, Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Xiao-Yin Liu
- Graduate School, Tianjin Medical University, Tianjin, China
| | - Ke Ma
- Tianjin Key Laboratory of Neurotrauma Repair, Institute of Traumatic Brain Injury and Neuroscience, Characteristic Medical Center of Chinese People's Armed Police Force; Graduate School, Logistics University of People's Armed Police Force, Tianjin, China
| | - Hui-You Xu
- Tianjin Key Laboratory of Neurotrauma Repair, Institute of Traumatic Brain Injury and Neuroscience, Characteristic Medical Center of Chinese People's Armed Police Force; Graduate School, Logistics University of People's Armed Police Force, Tianjin, China
| | - Wu-Sheng Deng
- Tianjin Key Laboratory of Neurotrauma Repair, Institute of Traumatic Brain Injury and Neuroscience, Characteristic Medical Center of Chinese People's Armed Police Force, Tianjin, China
| | - Yi-Chao Ye
- Tianjin Key Laboratory of Neurotrauma Repair, Institute of Traumatic Brain Injury and Neuroscience, Characteristic Medical Center of Chinese People's Armed Police Force; Graduate School, Logistics University of People's Armed Police Force, Tianjin, China
| | - Wei-Xin Li
- Graduate School, Logistics University of People's Armed Police Force, Tianjin, China
| | - Xu-Yi Chen
- Tianjin Key Laboratory of Neurotrauma Repair, Institute of Traumatic Brain Injury and Neuroscience, Characteristic Medical Center of Chinese People's Armed Police Force, Tianjin, China
| | - Hong-Tao Sun
- Tianjin Key Laboratory of Neurotrauma Repair, Institute of Traumatic Brain Injury and Neuroscience, Characteristic Medical Center of Chinese People's Armed Police Force, Tianjin, China
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Chen Y, Xu Y, Li M, Shi Q, Chen C. Application of Autogenous Urine-Derived Stem Cell Sheet Enhances Rotator Cuff Healing in a Canine Model. Am J Sports Med 2020; 48:3454-3466. [PMID: 33136424 DOI: 10.1177/0363546520962774] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND A repaired rotator cuff (RC) often heals with interposed scar tissue, making repairs prone to failure. Urine-derived stem cells (USCs), with robust proliferation ability and multilineage differentiation, can be isolated from urine, avoiding invasive and painful surgical procedures for harvesting the cells. These advantages make it a novel cell source for autologous transplantation to enhance RC healing. HYPOTHESIS Implantation of an autogenous USC sheet to the injury site will enhance RC healing. STUDY DESIGN Controlled laboratory study. METHODS USCs isolated from urine were cultured using ascorbic acid and transforming growth factor β3 to form a cell sheet. Sixteen male mature beagles underwent bilateral shoulder surgery. The right shoulder underwent infraspinatus tendon (IT) insertion detachment and repair only, and the other was subjected to IT insertion detachment and repair, followed by autogenous USC sheet implantation. Among the animals, 3 received a Dil (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate)- labeled USC sheet implant in the right shoulder and were sacrificed at postoperative 6 weeks for cell tracking. The other animals were sacrificed at postoperative 12 weeks, and the IT-humerus complexes were harvested for gross observation, micro-computed tomography evaluation and histological analysis (n = 5), and mechanical testing (n = 8). Additionally, 13 unpaired canine cadaveric shoulders were included as native controls. RESULTS Micro-computed tomography analysis showed that the USC sheet group had a significant increase in bone volume/total volume and trabecular thickness at the RC healing site when compared with the control group (P < .05 for all). Histologically, the Dil-labeled USC sheet was still visible at the RC healing site, which suggested that the implanted USCs remained viable at postoperative 6 weeks. Meanwhile, the healing interface in the USC sheet group regenerated significantly more enthesis-like tissue than did that of the control group (P < .05). Additionally, the healing interface in the USC sheet group presented a larger fibrocartilage area, more proteoglycan deposition, and higher collagen birefringence than did that of the control group (P < .05 for all). Biomechanically, the USC sheet group showed significantly higher failure load and stiffness versus the control group (P < .05 for all). CONCLUSION A USC sheet was able to enhance RC healing in a canine model. CLINICAL RELEVANCE The findings of the study showed that USC sheet implantation could serve as a practical application for RC healing.
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Affiliation(s)
- Yang Chen
- Department of Sport Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Yan Xu
- Department of Sport Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Muzhi Li
- Department of Sport Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Qiang Shi
- Department of Sport Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Can Chen
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
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11
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Chen XT, Fang WH, Vangsness CT. Efficacy of Biologics for Ligamentous and Tendon Healing. OPER TECHN SPORT MED 2020. [DOI: 10.1016/j.otsm.2020.150755] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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12
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Hexter AT, Hing KA, Haddad FS, Blunn G. Decellularized porcine xenograft for anterior cruciate ligament reconstruction: A histological study in sheep comparing cross-pin and cortical suspensory femoral fixation. Bone Joint Res 2020; 9:293-301. [PMID: 32728430 PMCID: PMC7376309 DOI: 10.1302/2046-3758.96.bjr-2020-0030.r2] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Aims To evaluate graft healing of decellularized porcine superflexor tendon (pSFT) xenograft in an ovine anterior cruciate ligament (ACL) reconstruction model using two femoral fixation devices. Also, to determine if pSFT allows functional recovery of gait as compared with the preoperative measurements. Methods A total of 12 sheep underwent unilateral single-bundle ACL reconstruction using pSFT. Two femoral fixation devices were investigated: Group 1 (n = 6) used cortical suspensory fixation (Endobutton CL) and Group 2 (n = 6) used cross-pin fixation (Stratis ST). A soft screw was used for tibial fixation. Functional recovery was quantified using force plate analysis at weeks 5, 8, and 11. The sheep were euthanized after 12 weeks and comprehensive histological analysis characterized graft healing at the graft-bone interface and the intra-articular graft (ligamentization). Results The pSFT remodelled into a ligament-like structure and no adverse inflammatory reaction was seen. The ground reaction force in the operated leg of the Endobutton group was higher at 11 weeks (p < 0.05). An indirect insertion was seen at the graft-bone interface characterized by Sharpey-like fibres. Qualitative differences in tendon remodelling were seen between the two groups, with greater crimp-like organization and more aligned collagen fibres seen with Endobutton fixation. One graft rupture occurred in the cross-pin group, which histologically showed low collagen organization. Conclusion Decellularized pSFT xenograft remodels into a ligament-like structure after 12 weeks and regenerates an indirect-type insertion with Sharpey-like fibres. No adverse inflammatory reaction was observed. Cortical suspensory femoral fixation was associated with more enhanced graft remodelling and earlier functional recovery when compared with the stiffer cross-pin fixation.
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Affiliation(s)
- Adam T Hexter
- Institute of Orthopaedics and Musculoskeletal Science, Division of Surgery and Interventional Science, University College London, London, UK; NIHR Academic Clinical Fellow, Royal National Orthopaedic Hospital, London, UK
| | - Karin A Hing
- Institute of Bioengineering and School of Engineering and Materials, Queen Mary University of London, London, UK
| | | | - Gordon Blunn
- School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
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13
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Leong NL, Kator JL, Clemens TL, James A, Enamoto-Iwamoto M, Jiang J. Tendon and Ligament Healing and Current Approaches to Tendon and Ligament Regeneration. J Orthop Res 2020; 38:7-12. [PMID: 31529731 PMCID: PMC7307866 DOI: 10.1002/jor.24475] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Accepted: 09/10/2019] [Indexed: 02/04/2023]
Abstract
Ligament and tendon injuries are common problems in orthopedics. There is a need for treatments that can expedite nonoperative healing or improve the efficacy of surgical repair or reconstruction of ligaments and tendons. Successful biologically-based attempts at repair and reconstruction would require a thorough understanding of normal tendon and ligament healing. The inflammatory, proliferative, and remodeling phases, and the cells involved in tendon and ligament healing will be reviewed. Then, current research efforts focusing on biologically-based treatments of ligament and tendon injuries will be summarized, with a focus on stem cells endogenous to tendons and ligaments. Statement of clinical significance: This paper details mechanisms of ligament and tendon healing, as well as attempts to apply stem cells to ligament and tendon healing. Understanding of these topics could lead to more efficacious therapies to treat ligament and tendon injuries. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:7-12, 2020.
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Affiliation(s)
- Natalie L Leong
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
- Department of Surgery, Baltimore VA Medical Center, Baltimore, Maryland
| | - Jamie L Kator
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
| | - Thomas L Clemens
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
- Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, Maryland
| | - Aaron James
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland
| | - Motomi Enamoto-Iwamoto
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
| | - Jie Jiang
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
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Calejo I, Costa-Almeida R, Reis RL, Gomes ME. Enthesis Tissue Engineering: Biological Requirements Meet at the Interface. TISSUE ENGINEERING PART B-REVIEWS 2019; 25:330-356. [DOI: 10.1089/ten.teb.2018.0383] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Isabel Calejo
- 3B's Research Group, I3Bs—Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Raquel Costa-Almeida
- 3B's Research Group, I3Bs—Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Rui L. Reis
- 3B's Research Group, I3Bs—Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal
- The Discoveries Center for Regenerative and Precision Medicine, Headquarters at University of Minho, Guimarães, Portugal
| | - Manuela E. Gomes
- 3B's Research Group, I3Bs—Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal
- The Discoveries Center for Regenerative and Precision Medicine, Headquarters at University of Minho, Guimarães, Portugal
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Hur CI, Ahn HW, Seon JK, Song EK, Kim GE. Mesenchymal Stem Cells Decrease Tunnel Widening of Anterior Cruciate Ligament Reconstruction in Rabbit Model. Int J Stem Cells 2019; 12:162-169. [PMID: 30595005 PMCID: PMC6457700 DOI: 10.15283/ijsc18022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 03/23/2018] [Accepted: 11/08/2018] [Indexed: 01/04/2023] Open
Abstract
Background and Objectives The study investigated the effect of mesenchymal stem cells (MSCs) or fibrin glue on tunnel widening after anterior cruciate ligament (ACL) reconstruction compared with biologic free control without any biologic agents in the rabbit model. Methods and Results ACL reconstructions were performed in 18 New Zealand white rabbits. All animals were divided into 3 groups according to the following reconstruction conditions and euthanized 12 weeks postoperatively for radiologic and histologic analyses. Thirty-two knees (control group=10; fibrin group=11; MSCs group=11) were finally evaluated. On micro-CT scan, mean femoral tunnel widening on oblique-sagittal image was 0.7±0.4 mm in the control group, 0.22±0.1 mm in the fibrin group and 0.25±0.1 mm in the MSCs group (p=0.001). Fibrin group and MSCs group showed significant differences compared with control group (p=0.002, 0.002). Mean tibial tunnel widening on oblique-sagittal image was 0.76±0.5 mm, 0.27±0.1 mm and 0.29±0.2 mm in the control, fibrin and MSCs group. Fibrin and MSCs group showed significant differences compared with control group (p=0.017, 0.014). Hounsfield Units (HU) were not significantly different between 3 groups (p>0.05). Histological analysis revealed that the architecture of graft in the MSCs group featured hypercellularity and compact collagen deposit. Conclusion ACL reconstruction using MSCs seemed decrease tunnel widening in rabbit model. Further study with large animals is required to confirm efficacy on decreasing tunnel widening.
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Affiliation(s)
- Chang-Ich Hur
- Center for Joint Disease, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Hyeon-Wook Ahn
- Center for Joint Disease, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Jong-Keun Seon
- Center for Joint Disease, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Eun-Kyoo Song
- Center for Joint Disease, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Ga-Eon Kim
- Department of Pathology, Chonnam National University Medical School, Gwangju, Korea
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16
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Setiawan IGNY, Suyasa IK, Astawa P, Dusak IWS, Kawiyana IKS, Aryana IGNW. Recombinant platelet derived growth factor-BB and hyaluronic acid effect in rat osteoarthritis models. J Orthop 2019; 16:230-233. [PMID: 30906129 DOI: 10.1016/j.jor.2019.02.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 02/17/2019] [Indexed: 10/27/2022] Open
Abstract
Osteoarthritis (OA) arises from imbalance of cartilage metabolism between the synthesis and degradation of type II collagen by the chondrocyte. Collagen type II degradation is characterized by increase in the biomarker of C-telopeptide fragment of type II collagen (CTX-II), while the anabolic process of cartilage is characterized by an increase in the biosynthesis of procollagen amino terminal N-propeptide type IIA (PIIANP). Platelet derived growth factor (PDGF) with Hyaluronic Acid (HA) as a potent growth factor can be used to stimulate the higher formation of chondrocyte and PIIANP levels and lower CTX-II levels in mouse knee osteoarthritis model.
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Affiliation(s)
| | - I Ketut Suyasa
- Department of Orthopaedic and Traumatology, Udayana Faculty of Medicine, Indonesia
| | - Putu Astawa
- Department of Orthopaedic and Traumatology, Udayana Faculty of Medicine, Indonesia
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Chen C, Zhang T, Liu F, Qu J, Chen Y, Fan S, Chen H, Sun L, Zhao C, Hu J, Lu H. Effect of Low-Intensity Pulsed Ultrasound After Autologous Adipose-Derived Stromal Cell Transplantation for Bone-Tendon Healing in a Rabbit Model. Am J Sports Med 2019; 47:942-953. [PMID: 30870031 DOI: 10.1177/0363546518820324] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Low-intensity pulsed ultrasound (LIPUS), as a safe biophysiotherapy, can enhance bone-tendon (B-T) healing in vivo and induce osteogenic or chondrogenic differentiation of mesenchymal stromal cells in vitro. This study aimed to determine whether LIPUS can improve the efficacy of transplanted mesenchymal stromal cells on B-T healing. HYPOTHESIS LIPUS can induce lineage-specific differentiation of transplanted adipose-derived stromal cells (ASCs) at the B-T healing site, thus resulting in superior healing quality when compared with LIPUS or ASCs alone. STUDY DESIGN Controlled laboratory study. METHODS A total of 112 mature rabbits with partial patellectomy in the hindlimb were randomly assigned into mock sonication without ASCs (control), ultrasonication without ASCs (LIPUS), mock sonication with ASCs (ASCs), and ultrasonication with ASCs (LIPUS + ASCs). The treatment time of the mock sonication or ultrasonication was 20 minutes per day. Autologous ASCs were transplanted to the healing site by fibrin glue during the operation, and LIPUS was delivered daily starting at postoperative day 3 until euthanasia. The patella-patellar tendon junctions were postoperatively harvested at 8 and 16 weeks for radiological, histological, and mechanical evaluations. Additionally, 9 animals were used for ASC tracking with mCherry protein. RESULTS Radiologically, there was more new bone formation and remodeling in the LIPUS + ASCs group as compared with the other groups. Synchrotron radiation micro-computed tomography showed that the LIPUS + ASCs group significantly increased bone volume fraction, trabecular thickness, and trabecular number at the healing site as compared with the other groups at postoperative 8 weeks ( P < .05 for all). Histologically, immunohistochemical staining confirmed that the transplanted mCherry-ASCs can differentiate into osteoblasts and fibrochondrocytic-like cells. Meanwhile, as compared with the other groups, the LIPUS + ASCs group showed more formation and maturity of the fibrocartilage layer and new bone at postoperative weeks 8 and 16 ( P < .05 for all). Biomechanically, the LIPUS + ASCs group showed significantly higher failure load and stiffness versus the other groups at postoperative weeks 8 and 16 ( P < .05 for all). CONCLUSION Autologous ASC transplantation stimulated with LIPUS can result in superior B-T healing quality when compared with LIPUS or ASCs alone. CLINICAL RELEVANCE This study demonstrates the effectiveness of using ASC transplantation stimulated with LIPUS for B-T healing and provides a foundation for future clinical studies.
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Affiliation(s)
- Can Chen
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Tao Zhang
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Fei Liu
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Jin Qu
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Yang Chen
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Silong Fan
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Huabin Chen
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
| | - Lunquan Sun
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Chunfeng Zhao
- Division of Orthopedic Research and Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Jianzhong Hu
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China.,Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Hongbin Lu
- Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
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Chen C, Liu F, Tang Y, Qu J, Cao Y, Zheng C, Chen Y, Li M, Zhao C, Sun L, Hu J, Lu H. Book-Shaped Acellular Fibrocartilage Scaffold with Cell-loading Capability and Chondrogenic Inducibility for Tissue-Engineered Fibrocartilage and Bone-Tendon Healing. ACS APPLIED MATERIALS & INTERFACES 2019; 11:2891-2907. [PMID: 30620556 DOI: 10.1021/acsami.8b20563] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Functional fibrocartilage regeneration is a bottleneck during bone-tendon healing, and the currently available tissue-engineering strategies for fibrocartilage regeneration are insufficient because of a lack of appropriate scaffold that can load large seeding-cells and induce chondrogenesis of stem cells. The acellular fibrocartilage scaffold (AFS) contains active growth factors as well as tissue-specific epitopes for cell-matrix interactions, which make it a potential scaffold for tissue-engineered fibrocartilage. A limitation to this scaffold is that its low porosity inhibits cells loading and infiltration. Here, inspired by book appearance, we sectioned native fibrocartilage tissue (NFT) into book-shape to improve cells loading and infiltration, and then decellularized with four protocols: (1) 2% SDS for 6-h, (2) 2% SDS for 24-h, (3) 4 SDS for 6-h, (4) 4% SDS for 24-h, followed by nuclease digestion. The optimal protocol was screened with respect to microstructures, DNA residence, native ingredients reservation, and chondrogenic inducibility of the AFS. In vitro studies demonstrated that this screened scaffold is noncytotoxicity and low-immunogenicity, allows adipose-derived stromal cells (ASCs) attachment and proliferation, shows superior chondrogenic inducibility, and stimulates collagen or glycosaminoglycans secretion. The underlying mechanism for this chondrogenic inducibility may be related to hedgehog pathway activating. Additionally, a novel pattern for fabricating tissue-engineered fibrocartilage was developed to enlarge seeding-cells loading, namely, cell-sheets sandwiched by book-shaped scaffold. In-vivo studies indicate that this screened scaffold alone could induce endogenous cells to satisfactorily regenerate fibrocartilage at 16-week, as characterized by fibrocartilaginous extracellular matrix (ECM) deposition and good interface integration. Interleaving this book-shaped AFS with autologous ASCs-sheets significantly enhanced its ability to regenerate fibrocartilage. Cell tracking demonstrated that fibrochondrocytes, osteoblasts, and osteocytes in the healing interface at postoperative 8-week partly originated from the sandwiched ASCs-sheets. On that basis, we propose the use of this book-shaped AFS and cell sheet technique for fabricating tissue-engineered fibrocartilage to improve bone-tendon healing.
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Affiliation(s)
- Can Chen
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Fei Liu
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Yifu Tang
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Jin Qu
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Yong Cao
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Cheng Zheng
- Department of Orthopedics , Hospital of Wuhan Sports University , Wuhan , Hubei , China , 430079
| | - Yang Chen
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Muzhi Li
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Chunfeng Zhao
- Division of Orthopedic Research and Department of Orthopedic Surgery , Mayo Clinic , Rochester , Minnesota 55905 , United States
| | | | - Jianzhong Hu
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
| | - Hongbin Lu
- Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha , Hunan , China , 410008
- Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Center , Changsha , Hunan , China , 410008
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19
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Wang LL, Yin XF, Chu XC, Zhang YB, Gong XN. Platelet-derived growth factor subunit B is required for tendon-bone healing using bone marrow-derived mesenchymal stem cells after rotator cuff repair in rats. J Cell Biochem 2018; 119:8897-8908. [PMID: 30105826 DOI: 10.1002/jcb.27143] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 05/18/2018] [Indexed: 12/26/2022]
Abstract
As a common cause of shoulder pain and disability, rotator cuff injury (RCI) represents a debilitating condition affecting an individual's quality of life. Although surgical repair has been shown to be somewhat effective, many patients may still suffer from reduced shoulder function. The aim of the current study was to identify a more effective mode of RCI treatment by investigating the effect of platelet-derived growth factor subunit B (PDGF-B) on tendon-bone healing after RCI repair by modifying bone marrow-derived mesenchymal stem cells (BMSCs). Surface markers of BMSCs were initially detected by means of flow cytometry, followed by establishment of the rat models and construction of the lentiviral vector. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide (MTT) assay, alizarin red staining, and oil red O staining were used to provide verification that PDGF-B was indeed capable of promoting BMSC viability, osteogenic and adipogenic differentiation capability. Furthermore, biomechanical assessment results indicated that PDGF-B could increase the ultimate load and stiffness of the tendon tissue. Real-time reverse-transcription quantitative polymerase chain reaction and Western blot analysis methods provided evidence suggesting that PDGF-B facilitated the expression of tendon-bone healing-related genes and proteins, while contrasting results were obtained after PDGF-B silencing. Taken together, the key findings of the current study provided evidence suggesting that overexpressed PDGF-B could act to enhance tendon-bone healing after RCI repair, thus highlighting the potential of the functional promotion of PDGF-B as a future RCI therapeutic approach.
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Affiliation(s)
- Lin-Liang Wang
- Department of Joint Surgery, Dongying City People's Hospital, Dongying, China
| | - Xue-Feng Yin
- Department of Joint Surgery, Dongying City People's Hospital, Dongying, China
| | - Xiu-Cheng Chu
- Department of Joint Surgery, Dongying City People's Hospital, Dongying, China
| | - Yong-Bing Zhang
- Department of Joint Surgery, Dongying City People's Hospital, Dongying, China
| | - Xiao-Nan Gong
- Department of Joint Surgery, Dongying City People's Hospital, Dongying, China
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Schneider M, Angele P, Järvinen TA, Docheva D. Rescue plan for Achilles: Therapeutics steering the fate and functions of stem cells in tendon wound healing. Adv Drug Deliv Rev 2018; 129:352-375. [PMID: 29278683 DOI: 10.1016/j.addr.2017.12.016] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Revised: 12/01/2017] [Accepted: 12/22/2017] [Indexed: 02/07/2023]
Abstract
Due to the increasing age of our society and a rise in engagement of young people in extreme and/or competitive sports, both tendinopathies and tendon ruptures present a clinical and financial challenge. Tendon has limited natural healing capacity and often responds poorly to treatments, hence it requires prolonged rehabilitation in most cases. Till today, none of the therapeutic options has provided successful long-term solutions, meaning that repaired tendons do not recover their complete strength and functionality. Our understanding of tendon biology and healing increases only slowly and the development of new treatment options is insufficient. In this review, following discussion on tendon structure, healing and the clinical relevance of tendon injury, we aim to elucidate the role of stem cells in tendon healing and discuss new possibilities to enhance stem cell treatment of injured tendon. To date, studies mainly apply stem cells, often in combination with scaffolds or growth factors, to surgically created tendon defects. Deeper understanding of how stem cells and vasculature in the healing tendon react to growth factors, common drugs used to treat injured tendons and promising cellular boosters could help to develop new and more efficient ways to manage tendon injuries.
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21
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Hexter AT, Thangarajah T, Blunn G, Haddad FS. Biological augmentation of graft healing in anterior cruciate ligament reconstruction: a systematic review. Bone Joint J 2018; 100-B:271-284. [PMID: 29589505 DOI: 10.1302/0301-620x.100b3.bjj-2017-0733.r2] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Aims The success of anterior cruciate ligament reconstruction (ACLR) depends on osseointegration at the graft-tunnel interface and intra-articular ligamentization. Our aim was to conduct a systematic review of clinical and preclinical studies that evaluated biological augmentation of graft healing in ACLR. Materials and Methods In all, 1879 studies were identified across three databases. Following assessment against strict criteria, 112 studies were included (20 clinical studies; 92 animal studies). Results Seven categories of biological interventions were identified: growth factors, biomaterials, stem cells, gene therapy, autologous tissue, biophysical/environmental, and pharmaceuticals. The methodological quality of animal studies was moderate in 97%, but only 10% used clinically relevant outcome measures. The most interventions in clinical trials target the graft-tunnel interface and are applied intraoperatively. Platelet-rich plasma is the most studied intervention, but the clinical outcomes are mixed, and the methodological quality of studies was suboptimal. Other biological therapies investigated in clinical trials include: remnant-augmented ACLR; bone substitutes; calcium phosphate-hybridized grafts; extracorporeal shockwave therapy; and adult autologus non-cultivated stem cells. Conclusion There is extensive preclinical research supporting the use of biological therapies to augment ACLR. Further clinical studies that meet the minimum standards of reporting are required to determine whether emerging biological strategies will provide tangible benefits in patients undergoing ACLR. Cite this article: Bone Joint J 2018;100-B:271-84.
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Affiliation(s)
- A T Hexter
- Institute of Orthopaedics and Musculoskeletal Science, Division of Surgery and Interventional Science, University College London, and Royal National Orthopaedic Hospital Brockley Hill, Stanmore, Middlesex HA7 4LP, UK
| | - T Thangarajah
- Institute of Orthopaedics and Musculoskeletal Science, Division of Surgery and Interventional Science, University College London, and Royal National Orthopaedic Hospital Brockley Hill, Stanmore, Middlesex HA7 4LP, UK
| | - G Blunn
- Institute of Orthopaedics and Musculoskeletal Science, Division of Surgery and Interventional Science, University College London, and Royal National Orthopaedic Hospital Brockley Hill, Stanmore, Middlesex HA7 4LP, UK
| | - F S Haddad
- University College London Hospitals, 235 Euston Road, London, NW1 2BU, UK and NIHR University College London Hospitals Biomedical Research Centre, UK
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Park SH, Choi YJ, Moon SW, Lee BH, Shim JH, Cho DW, Wang JH. Three-Dimensional Bio-Printed Scaffold Sleeves With Mesenchymal Stem Cells for Enhancement of Tendon-to-Bone Healing in Anterior Cruciate Ligament Reconstruction Using Soft-Tissue Tendon Graft. Arthroscopy 2018; 34:166-179. [PMID: 28688825 DOI: 10.1016/j.arthro.2017.04.016] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 04/04/2017] [Accepted: 04/12/2017] [Indexed: 02/02/2023]
Abstract
PURPOSE To investigate the efficacy of the insertion of 3-dimensional (3D) bio-printed scaffold sleeves seeded with mesenchymal stem cells (MSCs) to enhance osteointegration between the tendon and tunnel bone in anterior cruciate ligament (ACL) reconstruction in a rabbit model. METHODS Scaffold sleeves were fabricated by 3D bio-printing. Before ACL reconstruction, MSCs were seeded into the scaffold sleeves. ACL reconstruction with hamstring tendon was performed on both legs of 15 adult rabbits (aged 12 weeks). We implanted 15 bone tunnels with scaffold sleeves with MSCs and implanted another 15 bone tunnels with scaffold sleeves without MSCs before passing the graft. The specimens were harvested at 4, 8, and 12 weeks. H&E staining, immunohistochemical staining of type II collagen, and micro-computed tomography of the tunnel cross-sectional area were evaluated. Histologic assessment was conducted with a histologic scoring system. RESULTS In the histologic assessment, a smooth bone-to-tendon transition through broad fibrocartilage formation was identified in the treatment group, and the interface zone showed abundant type II collagen production on immunohistochemical staining. Bone-tendon healing histologic scores were significantly higher in the treatment group than in the control group at all time points. Micro-computed tomography at 12 weeks showed smaller tibial (control, 9.4 ± 0.9 mm2; treatment, 5.8 ± 2.9 mm2; P = .044) and femoral (control, 9.6 ± 2.9 mm2; treatment, 6.0 ± 1.0 mm2; P = .03) bone-tunnel areas in the treated group than in the control group. CONCLUSIONS The 3D bio-printed scaffold sleeve with MSCs exhibited excellent results in osteointegration enhancement between the tendon and tunnel bone in ACL reconstruction in a rabbit model. CLINICAL RELEVANCE If secure biological healing between the tendon graft and tunnel bone can be induced in the early postoperative period, earlier, more successful rehabilitation may be facilitated. Three-dimensional bio-printed scaffold sleeves with MSCs have the potential to accelerate bone-tendon healing in ACL reconstruction.
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Affiliation(s)
- Sin Hyung Park
- Department of Orthopaedic Surgery, Soonchunhyang University School of Medicine, Bucheon Hospital, Bucheon, Republic of Korea
| | - Yeong-Jin Choi
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Sang Won Moon
- Department of Orthopaedic Surgery, Inje University School of Medicine, Haeundae Paik Hospital, Busan, Republic of Korea
| | - Byung Hoon Lee
- Department of Orthopaedic Surgery, Hallym University School of Medicine, Kangdong Sacred Heart Hospital, Seoul, Republic of Korea
| | - Jin-Hyung Shim
- Department of Mechanical Engineering, Korea Polytechnic University, Siheung, Republic of Korea
| | - Dong-Woo Cho
- Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
| | - Joon Ho Wang
- Department of Orthopaedic Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea.
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Guo R, Gao L, Xu B. Current Evidence of Adult Stem Cells to Enhance Anterior Cruciate Ligament Treatment: A Systematic Review of Animal Trials. Arthroscopy 2018; 34:331-340.e2. [PMID: 28967542 DOI: 10.1016/j.arthro.2017.07.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 07/10/2017] [Accepted: 07/13/2017] [Indexed: 02/02/2023]
Abstract
PURPOSE To systematically review the available preclinical evidence of adult stem cells as a biological augmentation in the treatment of animal anterior cruciate ligament (ACL) injury. STUDY DESIGN Systematic review. METHODS PubMed (MEDLINE) and Embase were searched for the eligible studies. The inclusion criteria were controlled animal trials of adult stem cells used in ACL treatment (repair or reconstruction). Studies of natural ACL healing without intervention, in vitro studies, ex vivo studies, and studies without controls were excluded. Evidence level, methodologic quality, and risk of bias of each included study were identified using previously established tools. RESULTS Thirteen animal studies were included. Six of 7 studies using bone marrow-derived mesenchymal stem (stromal) cells (BMSCs) reported a positive enhancement in histology, biomechanics, and biochemistry within 12 weeks postoperatively. Four studies using ACL-derived vascular stem cells showed a promoting effect in histology, biomechanics, and imaging within 8 weeks postoperatively. Two studies focusing on animal tendon-derived stem cells (TDSCs) and human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) reported promotable effects for the early healing in a small animal ACL model. CONCLUSIONS BMSCs, ACL-derived vascular stem cells, TDSCs, and hUCB-MSCs were shown to enhance the healing of ACL injury during the early phase in small animal models. CLINICAL RELEVANCE Results of clinical trials using adult stem cells in ACL treatment are conflicting, and a systematic review of the current best preclinical evidence is crucial to guide further application.
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Affiliation(s)
- Ruipeng Guo
- Department of Sports Medicine and Arthroscopic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Laboratory for Biomechanics and Biomaterials, Hannover Medical School, Hannover, Germany
| | - Liang Gao
- Center for Experimental Orthopaedics, Saarland University Medical Center, Homburg/Saar, Germany
| | - Bin Xu
- Department of Sports Medicine and Arthroscopic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
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Li G, Hosseini A, Gadikota H, Gill T. A Novel Graft Fixation Technique for Anterior Cruciate Ligament Reconstruction Using Hamstring Tendon Grafts. J Med Device 2017. [DOI: 10.1115/1.4038307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
This study evaluated the biomechanical efficacy of single-tunnel double-bundle anterior cruciate ligament (ACL) reconstruction technique. The graft construct is achieved using a novel fixation device that splits an ACL (SPACL) graft into two bundles, recreating the anteromedial (AM) and posterolateral (PL) bundles for ACL reconstruction. A pullout strength test of the SPACL was performed using a 7-mm bovine digital extensor tendon graft. The capability in restoration of knee kinematics after SPACL reconstruction was investigated using cadaveric human knees on a robotic testing system under an anterior tibial load of 134 N and a simulated quadriceps load of 400 N. The data indicated that the SPACL graft has a pullout strength of 823.7±172.3 N. Under the 134 N anterior tibial load, the anteroposterior joint laxity had increased constraint using the SPACL reconstruction but not significantly (p > 0.05) at all selected flexion angles. Under the 400 N quadriceps load, no significant differences were observed between the anterior tibial translation of intact knee and SPACL conditions at all selected flexion angles, but the SPACL graft induced a significant increase in external tibial rotation compared to the intact knee condition at all selected flexion angles with a maximal external rotation of −3.20 deg ±3.6 deg at 90 deg flexion. These data showed that the SPACL technique is equivalent or superior to existing ACL reconstruction techniques in restoration of knee laxity and kinematics. The new SPACL reconstruction technique could provide a valuable alternation to contemporary ACL reconstruction surgery by more closely recreating native ACL kinematics.
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Affiliation(s)
- Guoan Li
- Orthopaedic Biomechanics Lab, Department of Orthopaedic Surgery, Newton-Wellesley Hospital/Harvard Medical School, Newton, MA 02462 e-mail:
| | - Ali Hosseini
- Orthopaedic Biomechanics Lab, Department of Orthopaedic Surgery, Newton-Wellesley Hospital/Harvard Medical School, Newton, MA 02462
| | - Hemanth Gadikota
- Orthopaedic Biomechanics Lab, Department of Orthopaedic Surgery, Newton-Wellesley Hospital/Harvard Medical School, Newton, MA 02462
| | - Thomas Gill
- Orthopaedic Biomechanics Lab, Department of Orthopaedic Surgery, Newton-Wellesley Hospital/Harvard Medical School, Newton, MA 02462
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25
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Waryasz GR, Marcaccio S, Gil JA, Owens BD, Fadale PD. Anterior Cruciate Ligament Repair and Biologic Innovations. JBJS Rev 2017; 5:e2. [DOI: 10.2106/jbjs.rvw.16.00050] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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26
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Ligament-Derived Stem Cells: Identification, Characterisation, and Therapeutic Application. Stem Cells Int 2017; 2017:1919845. [PMID: 28386284 PMCID: PMC5366203 DOI: 10.1155/2017/1919845] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 02/19/2017] [Indexed: 01/09/2023] Open
Abstract
Ligament is prone to injury and degeneration and has poor healing potential and, with currently ineffective treatment strategies, stem cell therapies may provide an exciting new treatment option. Ligament-derived stem cell (LDSC) populations have been isolated from a number of different ligament types with the majority of studies focussing on periodontal ligament. To date, only a few studies have investigated LDSC populations in other types of ligament, for example, intra-articular ligaments; however, this now appears to be a developing field. This literature review aims to summarise the current information on nondental LDSCs including in vitro characteristics of LDSCs and their therapeutic potential. The stem cell niche has been shown to be vital for stem cell survival and function in a number of different physiological systems; therefore, the LDSC niche may have an impact on LDSC phenotype. The role of the LDSC niche on LDSC viability and function will be discussed as well as the therapeutic potential of LDSC niche modulation.
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27
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Mengsteab PY, Nair LS, Laurencin CT. The past, present and future of ligament regenerative engineering. Regen Med 2016; 11:871-881. [PMID: 27879170 DOI: 10.2217/rme-2016-0125] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Regenerative engineering has been defined as the convergence of Advanced Materials Sciences, Stem Cell Sciences, Physics, Developmental Biology and Clinical Translation for the regeneration of complex tissues and organ systems. Anterior cruciate ligament (ACL) reconstruction necessitates the regeneration of bone, ligament and their interface to achieve superior clinical results. In the past, the ACL has been repaired with the use of autologous and allogeneic grafts, which have their respective drawbacks. Currently, investigations on the use of biodegradable matrices to achieve knee stability and permit tissue regeneration are making promising advancements. In the future, utilizing regenerative biology cues to induce an endogenous regenerative response may aid the enhancement of clinical ACL reconstruction outcomes.
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Affiliation(s)
- Paulos Y Mengsteab
- Institute for Regenerative Engineering, University of Connecticut Health, Farmington, CT 06030, USA.,Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269, USA.,Raymond & Beverly Sackler Center for Biomedical, Biological, Physical & Engineering Sciences, University of Connecticut Health, Farmington, CT 06030, USA.,Department of Orthopaedic Surgery, University of Connecticut Health, Farmington, CT 06030, USA
| | - Lakshmi S Nair
- Institute for Regenerative Engineering, University of Connecticut Health, Farmington, CT 06030, USA.,Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269, USA.,Raymond & Beverly Sackler Center for Biomedical, Biological, Physical & Engineering Sciences, University of Connecticut Health, Farmington, CT 06030, USA.,Department of Orthopaedic Surgery, University of Connecticut Health, Farmington, CT 06030, USA.,Department of Materials Science & Engineering, University of Connecticut, Storrs, CT 06269, USA.,Department of Chemical & Biomolecular Engineering, University of Connecticut, Storrs, CT 06269, USA
| | - Cato T Laurencin
- Institute for Regenerative Engineering, University of Connecticut Health, Farmington, CT 06030, USA.,Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269, USA.,Raymond & Beverly Sackler Center for Biomedical, Biological, Physical & Engineering Sciences, University of Connecticut Health, Farmington, CT 06030, USA.,Department of Orthopaedic Surgery, University of Connecticut Health, Farmington, CT 06030, USA.,Department of Materials Science & Engineering, University of Connecticut, Storrs, CT 06269, USA.,Department of Chemical & Biomolecular Engineering, University of Connecticut, Storrs, CT 06269, USA.,Department of Craniofacial Sciences, School of Dental Medicine, University of Connecticut Health, Farmington, CT 06030, USA
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28
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Teuschl A, Heimel P, Nürnberger S, van Griensven M, Redl H, Nau T. A Novel Silk Fiber-Based Scaffold for Regeneration of the Anterior Cruciate Ligament: Histological Results From a Study in Sheep. Am J Sports Med 2016; 44:1547-57. [PMID: 26957219 DOI: 10.1177/0363546516631954] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Because of ongoing problems with anterior cruciate ligament (ACL) reconstruction, new approaches in the treatment of ACL injuries, particularly strategies based on tissue engineering, have gained increasing research interest. To allow for ACL regeneration, a structured scaffold that provides a mechanical basis, has cells from different sources, and comprises mechanical as well as biological factors is needed. Biological materials, biodegradable polymers, and composite materials are being used and tested as scaffolds. The optimal scaffold for ACL regeneration should be biocompatible and biodegradable to allow tissue ingrowth but also needs to have the right mechanical properties to provide immediate mechanical stability. HYPOTHESES The study hypotheses were that (1) a novel degradable silk fiber-based scaffold with mechanical properties similar to the native ACL will be able to initiate ligament regeneration after ACL resection and reconstruction under in vivo conditions and (2) additional cell seeding of the scaffold with autologous stromal vascular fraction-containing adipose-derived stem cells will increase regenerative activity. STUDY DESIGN Controlled laboratory study. METHODS A total of 33 mountain sheep underwent ACL resection and randomization to 2 experimental groups: (1) ACL reconstruction with a scaffold alone and (2) ACL reconstruction with a cell-seeded scaffold. Histological evaluation of the intra-articular portion of the reconstructed/regenerated ligament was performed after 6 and 12 months. RESULTS After 6 months, connective tissue surrounded the silk scaffold with ingrowth in some areas. The cell-seeded scaffolds had a significant lower silk content compared with the unseeded scaffolds and demonstrated a higher content of newly formed tissue. After 12 months, the density of the silk fibers decreased significantly, and the ingrowth of newly formed tissue increased in both groups. No differences between the 2 groups regarding silk fiber degradation and regenerated tissue were detected at 12 months. CONCLUSION The novel silk fiber-based scaffold was able to stimulate ACL regeneration under in vivo conditions. Additional cell seeding led to increased tissue regeneration and decreased silk fiber content at 6 months, whereas these differences were not present at 12 months. CLINICAL RELEVANCE ACL regeneration using a silk fiber-based scaffold with and without additional cell seeding may provide a new treatment option after joint injuries.
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Affiliation(s)
- Andreas Teuschl
- Department of Biochemical Engineering, University of Applied Sciences Technikum Wien, Vienna, Austria Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Vienna, Austria Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Patrick Heimel
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Vienna, Austria Karl Donath Laboratory for Hard Tissue and Biomaterial Research, Medical University of Vienna, Vienna, Austria
| | - Silvia Nürnberger
- Austrian Cluster for Tissue Regeneration, Vienna, Austria Department of Traumatology, Medical University of Vienna, Vienna, Austria
| | - Martijn van Griensven
- Department of Experimental Trauma Surgery, Technical University of Munich, Munich, Germany
| | - Heinz Redl
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Vienna, Austria Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Thomas Nau
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Vienna, Austria Austrian Cluster for Tissue Regeneration, Vienna, Austria
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29
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Hao ZC, Wang SZ, Zhang XJ, Lu J. Stem cell therapy: a promising biological strategy for tendon-bone healing after anterior cruciate ligament reconstruction. Cell Prolif 2016; 49:154-62. [PMID: 26929145 DOI: 10.1111/cpr.12242] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 12/09/2015] [Indexed: 12/12/2022] Open
Abstract
Tendon-bone healing after anterior cruciate ligament (ACL) reconstruction is a complex process, impacting significantly on patients' prognosis. Natural tendon-bone healing usually results in fibrous scar tissue, which is of inferior quality compared to native attachment. In addition, the early formed fibrous attachment after surgery is often not reliable to support functional rehabilitation, which may lead to graft failure or unsatisfied function of the knee joint. Thus, strategies to promote tendon-bone healing are crucial for prompt and satisfactory functional recovery. Recently, a variety of biological approaches, including active substances, gene transfer, tissue engineering and stem cells, have been proposed and applied to enhance tendon-bone healing. Among these, stem cell therapy has been shown to have promising prospects and draws increasing attention. From commonly investigated bone marrow-derived mesenchymal stem cells (bMSCs) to emerging ACL-derived CD34+ stem cells, multiple stem cell types have been proven to be effective in accelerating tendon-bone healing. This review describes the current understanding of tendon-bone healing and summarizes the current status of related stem cell therapy. Future limitations and perspectives are also discussed.
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Affiliation(s)
- Zi-Chen Hao
- Department of Orthopaedics, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China
| | - Shan-Zheng Wang
- Department of Orthopaedics, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China
| | - Xue-Jun Zhang
- Department of Orthopaedics, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China
| | - Jun Lu
- Department of Orthopaedics, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China.,Surgical Research Center, Medical School of Southeast University, Nanjing, 210009, China
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30
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Jang KM, Lim HC, Jung WY, Moon SW, Wang JH. Efficacy and Safety of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Anterior Cruciate Ligament Reconstruction of a Rabbit Model: New Strategy to Enhance Tendon Graft Healing. Arthroscopy 2015; 31:1530-9. [PMID: 25882182 DOI: 10.1016/j.arthro.2015.02.023] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 02/02/2015] [Accepted: 02/17/2015] [Indexed: 02/08/2023]
Abstract
PURPOSE To investigate whether non-autologous transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) could be integrated safely at the bone-tendon junction without immune rejection and could enhance bone-tendon healing effectively during anterior cruciate ligament (ACL) reconstruction in an animal model. METHODS ACL reconstructions using hamstring tendons were performed in 30 adult rabbits. The bone tunnels were treated with hUCB-MSCs or were untreated. The specimens were harvested at 4, 8, and 12 weeks. We performed a gross examination of the knee joint; a histologic assessment using H&E staining, as well as immunohistochemical staining, for type II collagen; and an evaluation of bone tunnel widening using micro-computed tomography. RESULTS No evidence of immune rejection was detected. Tendon-bone healing through Sharpey-like fibers was noticed around tendon grafts at 12 weeks in the control group. A smooth transition from bone to tendon through broad fibrocartilage formation was identified in the treatment group, and the interface zone showed abundant type II collagen production on immunohistochemical staining. Histologic scores for bone-tendon healing were significantly higher in the treatment group at all time points (P < .001). Micro-computed tomography at 12 weeks showed a significantly smaller tibial (P = .029) and femoral (P = .033) bone tunnel enlargement in the treated group than in the control group. CONCLUSIONS Non-autologous transplantation of hUCB-MSCs was applied in ACL reconstruction without early immune rejection. There was enhanced tendon-bone healing through broad fibrocartilage formation with higher histologic scores and decreased femoral and tibial tunnel widening compared with the control group (79.2% and 80%, respectively, of the control group tunnel area at 12 weeks). CLINICAL RELEVANCE Non-autologous transplantation of hUCB-MSCs has therapeutic potential in promoting tendon-to-bone healing after ACL reconstruction. Further study in the human model is warranted.
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Affiliation(s)
- Ki-Mo Jang
- Department of Orthopaedic Surgery, Anam Hospital, Korea University School of Medicine, Seoul, Republic of Korea
| | - Hong Chul Lim
- Department of Orthopedic Surgery, Guro Hospital, Korea University School of Medicine, Seoul, Republic of Korea
| | - Woon Yong Jung
- Department of Pathology, Guro Hospital, Korea University School of Medicine, Seoul, Republic of Korea
| | - Sang Won Moon
- Department of Orthopaedic Surgery, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Republic of Korea
| | - Joon Ho Wang
- Department of Orthopaedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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31
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Nau T, Teuschl A. Regeneration of the anterior cruciate ligament: Current strategies in tissue engineering. World J Orthop 2015; 6:127-136. [PMID: 25621217 PMCID: PMC4303781 DOI: 10.5312/wjo.v6.i1.127] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 06/19/2014] [Accepted: 07/29/2014] [Indexed: 02/06/2023] Open
Abstract
Recent advancements in the field of musculoskeletal tissue engineering have raised an increasing interest in the regeneration of the anterior cruciate ligament (ACL). It is the aim of this article to review the current research efforts and highlight promising tissue engineering strategies. The four main components of tissue engineering also apply in several ACL regeneration research efforts. Scaffolds from biological materials, biodegradable polymers and composite materials are used. The main cell sources are mesenchymal stem cells and ACL fibroblasts. In addition, growth factors and mechanical stimuli are applied. So far, the regenerated ACL constructs have been tested in a few animal studies and the results are encouraging. The different strategies, from in vitro ACL regeneration in bioreactor systems to bio-enhanced repair and regeneration, are under constant development. We expect considerable progress in the near future that will result in a realistic option for ACL surgery soon.
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The Potentially Positive Role of PRPs in Preventing Femoral Tunnel Widening in ACL Reconstruction Surgery Using Hamstrings: A Clinical Study in 51 Patients. JOURNAL OF SPORTS MEDICINE 2014; 2014:789317. [PMID: 26464895 PMCID: PMC4590903 DOI: 10.1155/2014/789317] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 10/09/2014] [Accepted: 10/17/2014] [Indexed: 01/11/2023]
Abstract
Purpose. In this study, the early and midterm clinical and radiological results of the anterior cruciate ligament (ACL) reconstruction surgery with or without the use of platelet rich plasma (PRP) focusing on the tunnel-widening phenomenon are evaluated. Methods. This is a double blind, prospective randomized study. 51 patients have completed the assigned protocol. Recruited individuals were divided into two groups: a group with and a group without the use of PRPs. Patients were assessed on the basis of MRI scans, which were performed early postoperatively and repeated at least one-year postoperatively. The diameter was measured at the entrance, at the bottom, and at the mid distance of the femoral tunnel. Results. Our study confirmed the existence of tunnel widening as a phenomenon. The morphology of the dilated tunnels was conical in both groups. There was a statistical significant difference in the mid distance of the tunnels between the two groups. This finding may support the role of a biologic response secondary to mechanical triggers. Conclusions. The use of RPRs in ACL reconstruction surgery remains a safe option that could potentially eliminate the biologic triggers of tunnel enlargement. The role of mechanical factors, however, remains important.
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Demange MK, de Almeida AM, Rodeo SA. Updates in biological therapies for knee injuries: tendons. Curr Rev Musculoskelet Med 2014; 7:239-46. [PMID: 24957507 DOI: 10.1007/s12178-014-9230-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Tendons are subjected to tendinopathies caused by inflammation, degeneration, and weakening of the tendon, due to overuse and trauma, which may eventually lead to tendon rupture. Recently, there has been increasing interest in biological approaches to augment tissue healing. Tendon healing occurs through a dynamic process with inflammation, cellular proliferation, and tissue remodeling. In this review article, we discuss the more frequently proposed biological therapies for tendon injuries as platelet-rich plasma, mesenchymal stem cells, extracorporeal shockwave, and scaffolds.
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Affiliation(s)
- Marco Kawamura Demange
- Knee Surgery Division, Hospital das Clínicas, Orthopedic Surgery, Faculty of Medicine, University of São Paulo - Brazil, São Paulo, Brazil,
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34
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Fu SC, Cheuk YC, Yung SH, Rolf CG, Chan KM. Systematic Review of Biological Modulation of Healing in Anterior Cruciate Ligament Reconstruction. Orthop J Sports Med 2014; 2:2325967114526687. [PMID: 26535311 PMCID: PMC4555564 DOI: 10.1177/2325967114526687] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Background: Whether biological modulation is effective to promote healing in anterior cruciate ligament (ACL) reconstruction remains unclear. Purpose: To perform a systematic review of both clinical and experimental evidence of preclinical animal studies on biological modulation to promote healing in ACL reconstruction. Study Design: Systematic review; Level of evidence, 2. Methods: A systematic search was performed using the PubMed, Ovid, and Scopus search engines. Inclusion criteria were clinical and animal studies involving subjects with ACL injury with the use of biological modulation to promote healing outcomes. Methodological quality of clinical studies was evaluated using the Critical Appraisal Skill Programme (CASP) appraisal tool, and animal studies were evaluated by a scoring system based on a published checklist of good animal studies. Results: Ten clinical studies and 50 animal studies were included. Twenty-five included studies were regarded as good quality, with a methodological score ≥5. These studies suggested that transforming growth factor–beta (TGF-β), mesenchymal stem cells, osteogenic factors, and modalities that reduce local inflammation may be beneficial to promote graft healing in ACL reconstruction. Conclusion: This systematic review suggests that biological modulation is able to promote healing on top of surgical treatment for ACL injuries. This treatment strategy chiefly works through promotion of healing at the tunnel-graft interface, but the integrity of the intra-articular midsubstance of the graft would be another target for biological modulation.
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Affiliation(s)
- Sai-Chuen Fu
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. ; Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yau-Chuk Cheuk
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. ; Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Shu-Hang Yung
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. ; Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Christer Gustav Rolf
- Department of Orthopaedic Surgery, Huddinge University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Kai-Ming Chan
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. ; Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
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Lui PPY, Wong OT, Lee YW. Application of tendon-derived stem cell sheet for the promotion of graft healing in anterior cruciate ligament reconstruction. Am J Sports Med 2014; 42:681-9. [PMID: 24451112 DOI: 10.1177/0363546513517539] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Both osteointegration and remodeling of graft midsubstance (collectively called graft healing) are slow processes after anterior cruciate ligament (ACL) reconstruction. Tendon-derived stem cells (TDSCs) form a cell sheet after treatment with connective tissue growth factor (CTGF) and ascorbic acid, which exhibits higher tenogenic and maintains high chondro-osteogenic gene expression of TDSCs. No external scaffold is required for cell delivery. HYPOTHESIS Wrapping the TDSC sheet around the ACL graft would promote early graft healing in a rat model. STUDY DESIGN Controlled laboratory study. METHODS Green fluorescent protein (GFP) rat TDSCs were treated with connective tissue growth factor and ascorbic acid to promote cell sheet formation. Rats undergoing unilateral ACL reconstruction were divided into a control group and a TDSC group. The tendon graft was wrapped with the GFP-TDSC sheet before graft insertion in the TDSC group. At weeks 2, 6, and 12 after reconstruction, the samples were harvested for computed tomography imaging and histologic or biomechanical testing. The fate of the transplanted cell sheet was examined by immunohistochemical staining of GFP. RESULTS There were significantly higher tunnel bone mineral density (BMD) (42.3% increase, P = .047) and bone volume/total volume (BV/TV) (625% increase, P = .009) at the metaphyseal region of the tibial tunnel at week 2 and at the femoral tunnel at week 6 (BMD: 30.8% increase, P = .014; BV/TV: 100% increase, P = .014) in the TDSC group compared with the control group. Only the TDSC group showed a time-dependent increase in tunnel BMD (overall P = .038) and BV/TV (overall P = .015) at the epiphyseal region of the tibial tunnel. Semiquantitative image analysis showed better graft osteointegration and higher intra-articular graft integrity with lower cellularity and vascularity, better cell alignment, and higher collagen birefringence in the TDSC group. The ultimate load at week 2 (52.5% increase, P = .027) and stiffness at week 6 (62% increase, P = .008) were significantly higher in the TDSC group. Cells positive for GFP were observed in all samples in the TDSC group at week 2 but became reduced with time after reconstruction. CONCLUSION The TDSC sheet improved early graft healing after ACL reconstruction in the rat model. CLINICAL RELEVANCE The TDSC sheet could potentially be used for the promotion of graft healing in ACL reconstruction.
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Affiliation(s)
- Pauline Po Yee Lui
- Pauline Po Yee Lui, Headquarters, Hospital Authority, 9/F, Rumsey Street Multi-Storey Carpark Building, 2 Rumsey Street, Sheung Wan, Hong Kong SAR, China.
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Leong NL, Petrigliano FA, McAllister DR. Current tissue engineering strategies in anterior cruciate ligament reconstruction. J Biomed Mater Res A 2013; 102:1614-24. [DOI: 10.1002/jbm.a.34820] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 05/21/2013] [Accepted: 05/22/2013] [Indexed: 12/11/2022]
Affiliation(s)
- Natalie L. Leong
- Department of Orthopaedic Surgery; David Geffen School of Medicine at UCLA; Los Angeles California
| | - Frank A. Petrigliano
- Department of Orthopaedic Surgery; David Geffen School of Medicine at UCLA; Los Angeles California
| | - David R. McAllister
- Department of Orthopaedic Surgery; David Geffen School of Medicine at UCLA; Los Angeles California
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Abstract
Operative reconstruction of a torn anterior cruciate ligament (ACL) has become the most broadly accepted treatment. An important, but underreported, outcome of ACL reconstruction is graft failure, which poses a challenge for the orthopedic surgeon. An understanding of the tendon-bone healing and the intra-articular ligamentization process is crucial for orthopedic surgeons to make appropriate graft choices and to be able to initiate optimal rehabilitation protocols after surgical ACL reconstruction. This article focuses on the current understanding of the tendon-to-bone healing process for both autografts and allografts and discusses strategies to biologically augment healing.
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Affiliation(s)
- Bart Muller
- Department of Orthopaedic Surgery, UPMC Center for Sports Medicine, University of Pittsburgh, PA 15213, USA
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Seto AU, Gatt CJ, Dunn MG. Sterilization of tendon allografts: a method to improve strength and stability after exposure to 50 kGy gamma radiation. Cell Tissue Bank 2012; 14:349-57. [PMID: 22918622 DOI: 10.1007/s10561-012-9336-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Accepted: 07/30/2012] [Indexed: 02/07/2023]
Abstract
Terminal sterilization of tendon allografts with high dose gamma irradiation has deleterious effects on tendon mechanical properties and stability after implantation. Our goal is to minimize these effects with radio protective methods. We previously showed that radio protection via combined crosslinking and free radical scavenging maintained initial mechanical properties of tendon allografts after irradiation at 50 kGy. This study further evaluates the tissue response and simulated mechanical degradation of tendons processed with radio protective treatment, which involves crosslinking in 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide followed by soaking in an ascorbate/riboflavin-5-phosphate solution. Control untreated and treated tendons were irradiated at 50 kGy and implanted in New Zealand White rabbit knees within the joint capsule for four and 8 weeks. Tendons were also exposed to cyclic loading to 20 N at one cycle per 12 s in a collagenase solution for 150 cycles, followed by tension to failure. Control irradiated tendons displayed increased degradation in vivo, and failed prematurely during cyclic processing at an average of 25 cycles. In contrast, radio protected irradiated tendons displayed greater stability following implantation over 8 weeks, and possessed strength at 59 % of native tendons and modulus equivalent to that of native tendons after cyclic loading in collagenase. These results suggest that radio protective treatment improves the strength and the stability of tendon allografts.
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Affiliation(s)
- Aaron U Seto
- University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
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Mifune Y, Matsumoto T, Ota S, Nishimori M, Usas A, Kopf S, Kuroda R, Kurosaka M, Fu FH, Huard J. Therapeutic potential of anterior cruciate ligament-derived stem cells for anterior cruciate ligament reconstruction. Cell Transplant 2012; 21:1651-65. [PMID: 22732227 DOI: 10.3727/096368912x647234] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
We recently reported that the ruptured regions of the human anterior cruciate ligament (ACL) contained vascular-derived stem cells, which showed the potential for high expansion and multilineage differentiation. In this study, we performed experiments to test the hypothesis that ACL-derived CD34(+) cells could contribute to tendon-bone healing. ACL-derived cells were isolated from the rupture site of human ACL by fluorescence-activated cell sorting. Following ACL reconstruction, immunodeficient rats received intracapsular administration of either ACL-derived CD34(+) cells, nonsorted (NS) cells, CD34(+) cells, or phosphate-buffered saline (PBS). We also performed in vitro cell proliferation assays and enzyme-linked immunosorbent assays for vascular endothelial growth factor (VEGF) secretion. We confirmed the recruitment of the transplanted cells into the perigraft site after intracapuslar injection by immunohistochemical staining at week 1. Histological evaluation showed a greater area of collagen fiber formation and more collagen type II expression in the CD34(+) group than the other groups at the week 2 time point. Immunostaining with isolectin B4 and rat osteocalcin demonstrated enhanced angiogenesis and osteogenesis in the CD34(+) group at week 2. Moreover, double immunohistochemical staining for human-specific endothelial cell (EC) and osteoblast (OB) markers at week 2 demonstrated a greater ability of differentiation into ECs and OBs in the CD34(+) group. Microcomputerized tomography showed the greatest healing of perigraft bone at week 4 in the CD34(+) cell group, and the failure load of tensile test at week 8 demonstrated the greatest biomechanical strength in the CD34(+) group. Furthermore, the in vitro studies indicated that the CD34(+) group was superior to the other groups in their cell proliferation and VEGF secretion capacities. We demonstrated that ACL-derived CD34(+) cells contributed to the tendon-bone healing after ACL reconstruction via the enhancement of angiogenesis and osteogenesis, which also contributed to an increase in biomechanical strength.
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Affiliation(s)
- Yutaka Mifune
- Stem Cell Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA 15219, USA
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40
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Hee CK, Dines JS, Solchaga LA, Shah VR, Hollinger JO. Regenerative tendon and ligament healing: opportunities with recombinant human platelet-derived growth factor BB-homodimer. TISSUE ENGINEERING PART B-REVIEWS 2012; 18:225-34. [PMID: 22145770 DOI: 10.1089/ten.teb.2011.0603] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Intrinsic tendon healing in response to injury is a reparative process that often results in formation of scar tissue with functional and mechanical properties inferior to those of the native tendon. Development of therapies that can promote regenerative, rather than reparative, healing hold the promise of improving patient recovery from tendon and ligament injuries by producing tissue that is morphologically and functionally equivalent to the native tissue. One therapeutic approach that has been a frequent topic of investigation in the preclinical literature is the use of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) to augment tendon and ligament repair. The chemotactic, mitogenic, and pro-angiogenic properties of rhPDGF-BB have been shown to result in recruitment and proliferation of tenogenic cells and a commensurate boost in extracellular matrix deposition and organization, improving the morphological and biomechanical properties of healing tendons and ligaments. The outcomes of the preclinical studies reviewed here strongly suggest that rhPDGF-BB will provide a new therapeutic opportunity to improve the treatment of injured tendons and ligaments.
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41
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Eagan MJ, Zuk PA, Zhao KW, Bluth BE, Brinkmann EJ, Wu BM, McAllister DR. The suitability of human adipose-derived stem cells for the engineering of ligament tissue. J Tissue Eng Regen Med 2011; 6:702-9. [PMID: 21953999 DOI: 10.1002/term.474] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2010] [Revised: 05/19/2011] [Accepted: 07/05/2011] [Indexed: 12/24/2022]
Abstract
Rupture of the anterior cruciate ligament (ACL) is the one of the most common sports-related injuries. With its poor healing capacity, surgical reconstruction using either autografts or allografts is currently required to restore function. However, serious complications are associated with graft reconstructions and the number of such reconstructions has steadily risen over the years, necessitating the search for an alternative approach to ACL repair. Such an approach may likely be tissue engineering. Recent engineering approaches using ligament-derived fibroblasts have been promising, but the slow growth rate of such fibroblasts in vitro may limit their practical application. More promising results are being achieved using bone marrow mesenchymal stem cells (MSCs). The adipose-derived stem cell (ASC) is often proposed as an alternative choice to the MSC and, as such, may be a suitable stem cell for ligament engineering. However, the use of ASCs in ligament engineering still remains relatively unexplored. Therefore, in this study, the potential use of human ASCs in ligament tissue engineering was initially explored by examining their ability to express several ligament markers under growth factor treatment. ASC populations treated for up to 4 weeks with TGFβ1 or IGF1 did not show any significant and consistent upregulation in the expression of collagen types 1 and 3, tenascin C and scleraxis. While treatment with EGF or bFGF resulted in increased tenascin C expression, increased expression of collagens 1 and 3 were never observed. Therefore, simple in vitro treatment of human ASC populations with growth factors may not stimulate their ligament differentiative potential.
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Affiliation(s)
- Michael J Eagan
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Center for Health Sciences, Los Angeles, CA, USA
| | - Patricia A Zuk
- Division of Plastic Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Center for Health Sciences, Los Angeles, CA, USA
| | - Ke-Wei Zhao
- VA Greater Los Angeles Healthcare System, West Los Angeles Healthcare Center, Orthopedic Tissue Engineering Laboratory Los Angeles, CA, USA
| | - Benjamin E Bluth
- Division of Plastic Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Center for Health Sciences, Los Angeles, CA, USA
| | - Elyse J Brinkmann
- Department of Biomedical Engineering, Henry Samueli School of Engineering and Applied Science, University of California at Los Angeles, CA, USA
| | - Benjamin M Wu
- Department of Biomedical Engineering, Henry Samueli School of Engineering and Applied Science, University of California at Los Angeles, CA, USA
| | - David R McAllister
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Center for Health Sciences, Los Angeles, CA, USA.,VA Greater Los Angeles Healthcare System, West Los Angeles Healthcare Center, Orthopedic Tissue Engineering Laboratory Los Angeles, CA, USA
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Myers TJ, Granero-Molto F, Longobardi L, Li T, Yan Y, Spagnoli A. Mesenchymal stem cells at the intersection of cell and gene therapy. Expert Opin Biol Ther 2011; 10:1663-79. [PMID: 21058931 DOI: 10.1517/14712598.2010.531257] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
IMPORTANCE OF THE FIELD Mesenchymal stem cells have the ability to differentiate into osteoblasts, chondrocytes and adipocytes. Along with differentiation, MSCs can modulate inflammation, home to damaged tissues and secrete bioactive molecules. These properties can be enhanced through genetic-modification that would combine the best of both cell and gene therapy fields to treat monogenic and multigenic diseases. AREAS COVERED IN THIS REVIEW Findings demonstrating the immunomodulation, homing and paracrine activities of MSCs followed by a summary of the current research utilizing MSCs as a vector for gene therapy, focusing on skeletal disorders, but also cardiovascular disease, ischemic damage and cancer. WHAT THE READER WILL GAIN MSCs are a possible therapy for many diseases, especially those related to the musculoskeletal system, as a standalone treatment, or in combination with factors that enhance the abilities of these cells to migrate, survive or promote healing through anti-inflammatory and immunomodulatory effects, differentiation, angiogenesis or delivery of cytolytic or anabolic agents. TAKE HOME MESSAGE Genetically-modified MSCs are a promising area of research that would be improved by focusing on the biology of MSCs that could lead to identification of the natural and engrafting MSC-niche and a consensus on how to isolate and expand MSCs for therapeutic purposes.
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Affiliation(s)
- Timothy J Myers
- University of North Carolina at Chapel Hill, Department of Pediatrics, Chapel Hill, NC 27599-7239, USA
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43
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Wei X, Mao Z, Hou Y, Lin L, Xue T, Chen L, Wang H, Yu C. Local administration of TGFβ-1/VEGF165 gene-transduced bone mesenchymal stem cells for Achilles allograft replacement of the anterior cruciate ligament in rabbits. Biochem Biophys Res Commun 2011; 406:204-10. [PMID: 21303664 DOI: 10.1016/j.bbrc.2011.02.015] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Accepted: 02/02/2011] [Indexed: 12/13/2022]
Abstract
Graft remodeling following anterior cruciate ligament (ACL) reconstruction requires a long period of recovery before it is capable of withstanding physiological loads. Graft revascularization is extremely important in the remodeling process. In ACL reconstruction, the local administration of vascular endothelial growth factor (VEGF) significantly increased revascularization of the graft, but did not significantly affect the mechanical properties of the graft after implantation (Ju et al., 2006; Yoshikawa, et al., 2006). Our previous studies showed that transforming growth factor-β1 (TGFβ1) could promote improvements in mechanical strength in Achilles tendon regeneration, by regulating collagen type I and type III synthesis, cross-link formation, and matrix-remodeling (Hou et al., 2009). The current study aims to investigate whether the co-expression of TGFβ1/VEGF(165) could beneficially affect the remodeling of ACL grafts. Bone marrow-derived mesenchymal stem cells (BMSCs), transfected with an adenoviral vector encoding TGFβ1, VEGF(165) or TGFβ1/VEGF(165), were surgically implanted into experimental ACL grafts, with non-transfected cells as a control. HE and toluidine blue staining, vascular number, and biomechanical features were analyzed at 3, 6, 12, and 24 weeks after surgery. The results suggest that TGFβ1 expression, in the TGFβ1/VEGF(165)-transfected BMSCs, could accelerate the remodeling of the reconstructed ligament. The cross-talk between TGFβ1 and VEGF(165) has positive consequences, as TGFβ1/VEGF(165)-transfected BMSCs significantly promoted angiogenesis of the reconstructed ligament at 3, 6, 12 weeks, with the best mechanical properties being achieved at 24 weeks. Furthermore, co-expression of these genes is more powerful and efficient than single gene therapy.
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Affiliation(s)
- Xuelei Wei
- Department of Orthopaedic Surgery, Tianjin Hospital, 406 South Jiefang Road, Tianjin, China
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44
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Cheng MT, Liu CL, Chen TH, Lee OK. Comparison of potentials between stem cells isolated from human anterior cruciate ligament and bone marrow for ligament tissue engineering. Tissue Eng Part A 2010; 16:2237-53. [PMID: 20163211 DOI: 10.1089/ten.tea.2009.0664] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
We have previously isolated and identified stem cells from human anterior cruciate ligament (ACL). The purpose of this study was to evaluate the differences in proliferation, differentiation, and extracellular matrix (ECM) formation abilities between bone marrow stem cells (BMSCs) and ACL-derived stem cells (LSCs) from the same donors when cultured with different growth factors, including basic fibroblast growth factor (bFGF), epidermal growth factor, and transforming growth factor-beta 1 (TGF-beta1). Ligament tissues and bone marrow aspirate were obtained from patients undergoing total knee arthroplasty and ACL reconstruction surgeries. Proliferation, colony formation, and population doubling capacity as well as multilineage differentiation potentials of LSCs and BMSCs were compared. Gene expression and ECM production for ligament engineering were also evaluated. It was found that BMSCs possessed better osteogenic differentiation potential than LSCs, while similar adipogenic and chondrogenic differentiation abilities were observed. Proliferation rates of both LSCs and BMSCs were enhanced by bFGF and TGF-beta1. TGF-beta1 treatment significantly increased the expression of type I collagen, type III collagen, fibronectin, and alpha-smooth muscle actin in LSCs, but TGF-beta1 only upregulated type I collagen and tenascin-c in BMSCs. Protein quantification further confirmed the results of differential gene expression and suggested that LSCs and BMSCs increase ECM production upon TGF-beta1 treatment. In summary, in comparison with BMSCs, LSCs proliferate faster and maintain an undifferentiated state with bFGF treatment, whereas under TGF-beta1 treatment, LSCs upregulate major tendinous gene expression and produce a robust amount of ligament ECM protein, making LSCs a potential cell source in future applications of ACL tissue engineering.
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Affiliation(s)
- Ming-Te Cheng
- Department of Surgery, National Yang-Ming University, Taipei, Taiwan
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45
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Tovar N, Bourke S, Jaffe M, Murthy NS, Kohn J, Gatt C, Dunn MG. A comparison of degradable synthetic polymer fibers for anterior cruciate ligament reconstruction. J Biomed Mater Res A 2010; 93:738-47. [PMID: 19623532 DOI: 10.1002/jbm.a.32567] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
We compared mechanical properties, degradation rates, and cellular compatibilities of two synthetic polymer fibers potentially useful as ACL reconstruction scaffolds: poly(desaminotyrosyl-tyrosine dodecyl dodecanedioate)(12,10), p(DTD DD) and poly(L-lactic acid), PLLA. The yield stress of ethylene oxide (ETO) sterilized wet fibers was 150 +/- 22 MPa and 87 +/- 12 MPa for p(DTD DD) and PLLA, respectively, with moduli of 1.7 +/- 0.1 MPa and 4.4 +/- 0.43 MPa. Strength and molecular weight retention were determined after incubation under physiological conditions at varying times. After 64 weeks strength decreased to 20 and 37% of the initial sterile fiber values and MW decreased to 41% and 36% of the initial values for p(DTD DD) and PLLA, respectively. ETO sterilization had no significant effect on mechanical properties. Differences in mechanical behavior may be due to the semicrystalline nature of PLLA and the small degree of crystallinity induced by mesogenic ordering in p(DTD DD) suggested by DSC analysis. Fibroblast growth was similar on 50-fiber scaffolds of both polymers through 16 days in vitro. These data suggest that p(DTD DD) fibers, with higher strength, lower stiffness, favorable degradation rate and cellular compatibility, may be a superior alternative to PLLA fibers for development of ACL reconstruction scaffolds.
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Affiliation(s)
- Nick Tovar
- Orthopaedic Research Laboratory, UMDNJ-RWJMS, New Brunswick, New Jersey, USA.
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46
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Evans CH, Ghivizzani SC, Robbins PD. Progress and Prospects: genetic treatments for disorders of bones and joints. Gene Ther 2009; 16:944-52. [DOI: 10.1038/gt.2009.73] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Nikolaou VS, Efstathopoulos N, Sourlas I, Pilichou A, Papachristou G. Anatomic double-bundle versus single-bundle ACL reconstruction: a comparative biomechanical study in rabbits. Knee Surg Sports Traumatol Arthrosc 2009; 17:895-906. [PMID: 19290508 DOI: 10.1007/s00167-009-0754-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2008] [Accepted: 02/06/2009] [Indexed: 01/29/2023]
Abstract
Thirty New Zealand white rabbits underwent anterior cruciate ligament (ACL) reconstruction in their right knees; 15 animals underwent a double-bundle anatomic ACL reconstruction using the medial third of the patellar tendon and the semitendinosus tendon. Additionally, 15 animals underwent ACL reconstruction, using a single-bundle semitendinosus tendon autograft. The knees of both groups were evaluated with a device similar to the KT1000 arthrometer onto which a dial indicator was attached (Mitutoyo dial indicator 2050) in 30 degrees and 90 degrees of flexion, preoperatively, after ACL resection and 3 months postoperatively. Statistical analysis of the results revealed that for 90 degrees of knee flexion, the mean estimated anterior shift for the double-bundle technique was 1.92 mm lesser than that of the single-bundle technique (P = 0.006). For 30 degrees of knee flexion, the mean anterior shift was again lesser than that of the single-bundle technique by 0.66 mm, but this difference was not statistically significant. The described double-bundle ACL reconstruction technique resulted in a more stable knee as far as the anterior tibial shift was concerned as compared to a single-bundle ACL reconstruction. This animal model may be potentially useful in the future for the study of other parameters influencing the outcome of the double-bundle ACL reconstruction.
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Affiliation(s)
- Vassilios S Nikolaou
- 2nd Academic Department of Trauma and Orthopaedics, School of Medicine, Athens University, Megalou Alexandrou 54, 15124 Maroussi, Athens, Greece.
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48
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Evans CH, Ghivizzani SC, Robbins PD. Orthopedic gene therapy in 2008. Mol Ther 2009; 17:231-44. [PMID: 19066598 PMCID: PMC2835052 DOI: 10.1038/mt.2008.265] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2008] [Accepted: 10/26/2008] [Indexed: 02/07/2023] Open
Abstract
Orthopedic disorders, although rarely fatal, are the leading cause of morbidity and impose a huge socioeconomic burden. Their prevalence will increase dramatically as populations age and gain weight. Many orthopedic conditions are difficult to treat by conventional means; however, they are good candidates for gene therapy. Clinical trials have already been initiated for arthritis and the aseptic loosening of prosthetic joints, and the development of bone-healing applications is at an advanced, preclinical stage. Other potential uses include the treatment of Mendelian diseases and orthopedic tumors, as well as the repair and regeneration of cartilage, ligaments, and tendons. Many of these goals should be achievable with existing technologies. The main barriers to clinical application are funding and regulatory issues, which in turn reflect major safety concerns and the opinion, in some quarters, that gene therapy should not be applied to nonlethal, nongenetic diseases. For some indications, advances in nongenetic treatments have also diminished enthusiasm. Nevertheless, the preclinical and early clinical data are impressive and provide considerable optimism that gene therapy will provide straightforward, effective solutions to the clinical management of several common debilitating disorders that are otherwise difficult and expensive to treat.
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Affiliation(s)
- Christopher H Evans
- Center for Molecular Orthopaedics, Harvard Medical School, Boston, Massachusetts, USA.
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49
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Tapp H, Hanley EN, Patt JC, Gruber HE. Adipose-derived stem cells: characterization and current application in orthopaedic tissue repair. Exp Biol Med (Maywood) 2009; 234:1-9. [PMID: 19109553 DOI: 10.3181/0805-mr-170] [Citation(s) in RCA: 146] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
Orthopaedic tissues, such as bone, cartilage, intervertebral disc and tendon, contain cells that are difficult to culture and stimulate in vitro for repair of damaged tissue. Stem cells have the ability to self-renew and differentiate into many tissue types. Recent progress in stem cell research has led to an enthusiastic effort to utilize stem cells for orthopaedic tissue regeneration. Due to ease of harvest and abundance, adipose-derived mesenchymal cells (ASC) are an attractive, readily available adult stem cell that has become increasingly popular for use in many stem cell applications. Recent progress has been made in characterizing ASC and looking mechanistically at gene expression and cellular pathways involved in differentiation. This review focuses on (i) the characterization of ASC through expression of appropriate surface markers; (ii) modulation of in vitro differentiation of ASC through different scaffolds, growth factors, and media; and (iii) the use of ASC in orthopaedic tissue repair. Strategies for repair involve the use of differentiated or undifferentiated, fresh or passaged ASC, in conjunction with appropriate choice of media, growth factors and scaffolds. Recent in vivo studies utilizing ASC are discussed giving results on defect repair and potential for clinical orthopaedic tissue regeneration.
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Affiliation(s)
- Hazel Tapp
- Department of Family Medicine, Carolinas Medical Center, Charlotte, NC 28232, USA.
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50
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Arthur A, Zannettino A, Gronthos S. The therapeutic applications of multipotential mesenchymal/stromal stem cells in skeletal tissue repair. J Cell Physiol 2008; 218:237-45. [PMID: 18792913 DOI: 10.1002/jcp.21592] [Citation(s) in RCA: 243] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Four decades after the first isolation and characterization of clonogenic bone marrow stromal cells or mesenchymal stem cells (MSC) in the laboratory of Dr. Alexander Friedenstien, the therapeutic application of their progeny following ex vivo expansion are only now starting to be realized in the clinic. The multipotency, paracrine effects, and immune-modulatory properties of MSC present them as an ideal stem cell candidate for tissue engineering and regenerative medicine. In recent years it has come to light that MSC encompass plasticity that extends beyond the conventional bone, adipose, cartilage, and other skeletal structures, and has expanded to the differentiation of liver, kidney, muscle, skin, neural, and cardiac cell lineages. This review will specifically focus on the skeletal regenerative capacity of bone marrow derived MSC alone or in combination with growth factors, biocompatible scaffolds, and following genetic modification.
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Affiliation(s)
- Agnieszka Arthur
- Mesenchymal Stem Cell Group, Division of Haematology, Institute of Medical and Veterinary Science, Hanson Institute/University of Adelaide, Adelaide, South Australia, Australia
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