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Yamaguchi J, Homan K, Onodera T, Matsuoka M, Arakawa S, Ueda N, Sawada S, Kawate N, Nonoyama T, Katsuyama Y, Nagahama K, Saito M, Iwasaki N. Tendon Tissue Regeneration With Cell Orientation Using an Injectable Alginate-Cell Cross-linked Gel. Am J Sports Med 2025; 53:1336-1346. [PMID: 40123102 DOI: 10.1177/03635465251325498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
BACKGROUND Tendons have a limited blood supply and form inferior scar tissue during repair, which increases the risk of reruptures, causes complications, and limits regenerative capacity. Current methods to repair injured tendon tissue use solid scaffolds, which carry the risk of contamination (infections) and require open surgery for transplantation. HYPOTHESIS Alginate-cell cross-linked gels, which can be applied by a percutaneous injection and transmit mechanical stress to cells via direct cell interaction, could induce tendon tissue regeneration. STUDY DESIGN Controlled laboratory study. METHODS A cross-linked gel was prepared to suspend azide-modified mesenchymal stromal cells (MSCs) in a dibenzocyclooctyne-modified branched alginic acid solution. The cross-linked gel was cultured in a bioreactor. In vivo, the Achilles tendon defects of 104 Lewis rats were injected with saline (control group), alginate gel alone (alginate group), alginate gel with MSCs (MSC group), and cross-linked gel (cross-link group). At 2 and 4 weeks postoperatively, histological and biochemical evaluations were performed. The biomechanical properties of repaired tissue were assessed at 4 weeks. RESULTS In the bioreactor culture, the cell orientation in the cross-linked gel was parallel to the direction of tension. Histological analysis of the cross-link group showed significantly more repaired tendon tissue and improved collagen fiber orientation compared with the alginate group or MSC group. The biomechanical properties of the cross-link group included higher stiffness. CONCLUSION The cross-linked gel was injectable at the injury site and was able to induce tissue regeneration with cell-oriented adaptability to the mechanical environment of tissue defects. CLINICAL RELEVANCE Intercellular cross-linking technology holds the potential for clinical application as a minimally invasive therapeutic approach that can contribute to the qualitative improvement of tendon tissue regeneration.
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Affiliation(s)
- Jun Yamaguchi
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Kentaro Homan
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Tomohiro Onodera
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Masatake Matsuoka
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Shoutaro Arakawa
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Natsumi Ueda
- Department of Nanobiochemistry, Frontiers of Innovative Research in Science and Technology, Konan University, Kobe, Japan
| | | | - Nana Kawate
- Department of Nanobiochemistry, Frontiers of Innovative Research in Science and Technology, Konan University, Kobe, Japan
| | - Takayuki Nonoyama
- Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
| | | | - Koji Nagahama
- Department of Nanobiochemistry, Frontiers of Innovative Research in Science and Technology, Konan University, Kobe, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Norimasa Iwasaki
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Gao H, Sun L, Yu C, Huang M, Feng S, Sheng D, Tim Yun Ong M, Sai Chuen Bruma F, Yang X, Hao Y, Rolf C, Chen S, Li Y, Chen J. Anterior Cruciate Ligament Repair Augmented With a Polyethylene Terephthalate Band Supports Biomechanical Stability During the Early Healing Phase in a Rabbit Model. Am J Sports Med 2025; 53:1347-1358. [PMID: 40119494 DOI: 10.1177/03635465251325407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/24/2025]
Abstract
BACKGROUND Augmented repair is an alternative strategy for the treatment of acute ligament and tendon injuries that imparts time-zero biomechanical strength to allow early loading, thereby protecting the repaired structures during the early healing process. PURPOSE To investigate the biomechanical properties and biological healing process after suture repair of acute anterior cruciate ligament (ACL) tears with polyethylene terephthalate (PET) augmentation and compare the findings with those obtained without PET augmentation. STUDY DESIGN Controlled laboratory study. METHODS A total of 48 rabbits were assigned to 3 groups: a PET-augmented group, a nonaugmented suture repair group, and a natural (control) group. All 3 groups were evaluated at 4, 12, and 16 weeks after surgery. Biomechanical performance was assessed using tensile strength testing, and ACL healing and maturation were assessed using histological assessments. RESULTS The PET-augmented group showed less anterior knee laxity at 30° of knee flexion and superior structural continuity compared with the suture group. ACL repair with PET augmentation yielded recovery of the maximum tensile load as early as 4 weeks compared with that of the natural group (110.5 ± 6.5 vs 129.0 ± 8.6 N, respectively; P = .29) and a gradual improvement in linear stiffness from 4 weeks (58.4 ± 3.9 N/mm) to 16 weeks (83.1 ± 5.1 N/mm; P = .04), approaching that of the natural group (106.7 ± 5.8 N/mm). Furthermore, histological analyses revealed that in the PET-augmented group, the ACL healed back to the proximal insertion as early as 4 weeks with angiogenesis and collagen regeneration, and the increased ligament maturity score indicated a gradual healing process from 4 to 16 weeks. CONCLUSION Compared with nonaugmented repair, repair augmented with a PET band enhanced early ACL stability and supported healing of ACL tears in a rabbit model. CLINICAL RELEVANCE The biomechanical and histological findings support subsequent clinical investigations using PET augmentation in patients with acute ACL tears.
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Affiliation(s)
- Han Gao
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Luyi Sun
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Chengxuan Yu
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Mingru Huang
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Sijia Feng
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Dandan Sheng
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Michael Tim Yun Ong
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Fu Sai Chuen Bruma
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | | | | | - Christer Rolf
- Division of Orthopedics and Biotechnology, Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden
| | - Shiyi Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Yunxia Li
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Jun Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
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Dong Y, Li J, Jiang Q, He S, Wang B, Yi Q, Cheng X, Gao X, Bai Y. Structure, ingredient, and function-based biomimetic scaffolds for accelerated healing of tendon-bone interface. J Orthop Translat 2024; 48:70-88. [PMID: 39185339 PMCID: PMC11342074 DOI: 10.1016/j.jot.2024.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 06/11/2024] [Accepted: 07/16/2024] [Indexed: 08/27/2024] Open
Abstract
Background Tendon-bone interface (TBI) repair is slow and challenging owing to its hierarchical structure, gradient composition, and complex function. In this work, enlightened by the natural characteristics of TBI microstructure and the demands of TBI regeneration, a structure, composition, and function-based scaffold was fabricated. Methods: The biomimetic scaffold was designed based on the "tissue-inducing biomaterials" theory: (1) a porous scaffold was created with poly-lactic-co-glycolic-acid, nano-hydroxyapatite and loaded with BMP2-gelatinmp to simulate the bone (BP); (2) a hydrogel was produced from sodium alginate, type I collagen, and loaded with TGF-β3 to simulate the cartilage (CP); (3) the L-poly-lactic-acid fibers were oriented to simulate the tendon (TP). The morphology of tri-layered constructs, gelation kinetics, degradation rate, release kinetics and mechanical strength of the scaffold were characterized. Then, bone marrow mesenchymal stem cells (MSCs) and tenocytes (TT-D6) were cultured on the scaffold to evaluate its gradient differentiation inductivity. A rat Achilles tendon defect model was established, and BMSCs seeded on scaffolds were implanted into the lesionsite. The tendon-bone lesionsite of calcaneus at 4w and 8w post-operation were obtained for gross observation, radiological evaluation, biomechanical and histological assessment. Results The hierarchical microstructures not only endowed the scaffold with gradual composition and mechanical properties for matching the regional biophysical characteristics of TBI but also exhibited gradient differentiation inductivity through providing regional microenvironment for cells. Moreover, the scaffold seeded with cells could effectively accelerate healing in rat Achilles tendon defects, attributable to its enhanced differentiation performance. Conclusion The hierarchical scaffolds simulating the structural, compositional, and cellular heterogeneity of natural TBI tissue performed therapeutic effects on promoting regeneration of TBI and enhancing the healing quality of Achilles tendon. The translational potential of this article The novel scaffold showed the great efficacy on tendon to bone healing by offering a structural and compositional microenvironment. The results meant that the hierarchical scaffold with BMSCs may have a great potential for clinical application.
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Affiliation(s)
- YuHan Dong
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
| | - JiangFeng Li
- Institute of Burn Research, Southwest Hospital & State Key Lab of Trauma, Burn and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Qiang Jiang
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
| | - SiRong He
- School of Basic Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Bin Wang
- Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China
| | - QiYing Yi
- Laboratory Animal Center, Chongqing Medical University, Chongqing, 400016, China
| | - XiTing Cheng
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
| | - Xiang Gao
- College of Stomatology, Chongqing Medical University, Chongqing, 400016, China
| | - Yan Bai
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
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Ali J, Pulatkan A, Kara D, Tezgel O, Misir A, Ucan V, Bozdag E, Yildirim AN, Yildiz F, Tuncay I, Kapicioglu M, Bilsel K. Fibroblast Growth Factor Soaked Collagen Membrane Shows No Biomechanical or Histological Advantages in the Treatment of Chronic Rotator Cuff Tears in a Rabbit Model. Arthroscopy 2024; 40:683-691. [PMID: 37394152 DOI: 10.1016/j.arthro.2023.06.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/04/2023] [Accepted: 06/16/2023] [Indexed: 07/04/2023]
Abstract
PURPOSE To investigate the histological and biomechanical effects of a fibroblast growth factor (FGF-2)-soaked collagen membrane used to treat a full-thickness chronic rotator cuff (RC) rupture in a rabbit model. METHODS Forty-eight shoulders from 24 rabbits were used. At the beginning of the procedure, 8 rabbits were killed to assess the control group (Group IT) with intact tendons. To establish a chronic RC tear model, a full-thickness subscapularis tear was created on both shoulders of the remaining 16 rabbits and left for 3 months. The transosseous mattress suture technique was used to repair tears in the left shoulder (Group R). The tears in the right shoulder (Group CM) were treated using the same approach, with an FGF-soaked collagen membrane inserted and sutured over the repair site. Three months after the procedure, all rabbits were killed. Biomechanical testing was performed on the tendons to determine failure load, linear stiffness, elongation intervals, and displacement. Histologically, the modified Watkins score was used to evaluate tendon-bone healing. RESULTS There was no significant difference among the three groups in terms of failure load, displacement, linear stiffness, and elongation (P > .05). The total modified Watkins score was not affected by applying the FGF-soaked collagen membrane to the repair site (P > .05). Fibrocytes, parallel cells, large-diameter fibers, and the total modified Watkins score were significantly lower in both repair groups when compared to the intact tendon group (P < .05). CONCLUSIONS In addition to tendon repair, FGF-2 soaked collagen membrane -application at the repair site provides neither biomechanical nor histological advantages in the treatment of chronic RC tears. CLINICAL RELEVANCE FGF-soaked collagen membrane augmentation provides no impact on the chronic RC tear healing tissue. The need to investigate alternative methods that may have a positive effect on healing in chronic RC repairs continues.
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Affiliation(s)
- Jotyar Ali
- Department of Orthopedics and Traumatology, Yeni Yuzyil University School of Medicine, Zeytinburnu, Istanbul, Turkey
| | - Anil Pulatkan
- Department of Orthopedics and Traumatology, Bezmialem Vakif University School of Medicine, Fatih, Istanbul, Turkey.
| | - Deniz Kara
- Department of Orthopedics and Traumatology, Bezmialem Vakif University School of Medicine, Fatih, Istanbul, Turkey
| | - Okan Tezgel
- Department of Orthopedics and Traumatology, Bezmialem Vakif University School of Medicine, Fatih, Istanbul, Turkey
| | | | - Vahdet Ucan
- Department of Orthopedics and Traumatology, Bezmialem Vakif University School of Medicine, Fatih, Istanbul, Turkey
| | - Ergun Bozdag
- Biomechanics Laboratory, Department of Mechanical Engineering, Istanbul Technical University, Taksim, Istanbul, Turkey
| | - Ayse Nur Yildirim
- Department of Pathology, Medeniyet University Goztepe Research and Training Hospital), Istanbul, Turkey
| | - Fatih Yildiz
- Department of Orthopedics and Traumatology, Bezmialem Vakif University School of Medicine, Fatih, Istanbul, Turkey
| | - Ibrahim Tuncay
- Department of Orthopedics and Traumatology, Bezmialem Vakif University School of Medicine, Fatih, Istanbul, Turkey
| | - Mehmet Kapicioglu
- Department of Orthopedics and Traumatology, Bezmialem Vakif University School of Medicine, Fatih, Istanbul, Turkey
| | - Kerem Bilsel
- Department of Orthopedics and Traumatology, Bezmialem Vakif University School of Medicine, Fatih, Istanbul, Turkey
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Pinto I, Kostretzis L, Katakalos K, Kazakos G, Cheva A, Chatzisotiriou A, Papadopoulos P, Ditsios K. Repair of chronic and large rotator cuff tears using extra-synovial autografts: An experimental study in rabbits. J Exp Orthop 2024; 11:e12010. [PMID: 38455456 PMCID: PMC10900185 DOI: 10.1002/jeo2.12010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 01/31/2024] [Indexed: 03/09/2024] Open
Abstract
Purpose To investigate whether and how extra-synovial autografts can enhance the reconstruction of chronic and large rotator cuff tears in a rabbit subscapularis model. Methods Twenty rabbits were used to create a large subscapularis tear bilaterally. Six weeks later, the right shoulder of each rabbit was operated to repair the tear with an extra-synovial autograft, whereas the left shoulder did not undergo any surgery. At 6 and 12 weeks after the second procedure, the specimens underwent biomechanical and histological evaluation. Six more rabbits were used only as a normal reference. Results Biomechanical evaluation demonstrated that the ultimate load to failure of the Graft group (184.1 ± 35.7 N) was significantly higher (p = 0.04) than that of the Defect group (144.5 ± 32.2 N) at 12 weeks after repair, rising to 76% of the normal subscapularis tendon tensile strength. Histological analysis revealed an enhanced healing environment with neoangiogenesis and decreased inflammatory response at the repair site. Moreover, the tendon maturing score of the Graft group increased substantially from 6 (15.8 ± 0.9) to 12 (23.1 ± 0.6) weeks after repair (p = 0.01). Conclusion In vivo data support the efficacy of extra-synovial autograft interposition in repairing chronic and large rotator cuff tears in a rabbit subscapularis model. The autografts were capable of enhancing the biomechanical properties of the repaired tendons, as evidenced by increased tensile strength, and forming new connective tissue simulating a fibrocartilage zone, as revealed by histological evaluation. Level of Evidence N/A.
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Affiliation(s)
- Iosafat Pinto
- 2nd Orthopaedic Department, Aristotle University of ThessalonikiGeneral Hospital of Thessaloniki “G.Gennimatas”ThessalonikiGreece
| | - Lazaros Kostretzis
- 2nd Orthopaedic Department, Aristotle University of ThessalonikiGeneral Hospital of Thessaloniki “G.Gennimatas”ThessalonikiGreece
| | - Konstantinos Katakalos
- Laboratory for Strength of Materials and Structures, Civil Engineering DepartmentAristotle University of ThessalonikiThessalonikiGreece
| | - George Kazakos
- School of Veterinary MedicineAristotle University of ThessalonikiThessalonikiGreece
| | - Angeliki Cheva
- Pathology Department, School of MedicineAristotle University of ThessalonikiThessalonikiGreece
| | | | - Pericles Papadopoulos
- 2nd Orthopaedic Department, Aristotle University of ThessalonikiGeneral Hospital of Thessaloniki “G.Gennimatas”ThessalonikiGreece
| | - Konstantinos Ditsios
- 2nd Orthopaedic Department, Aristotle University of ThessalonikiGeneral Hospital of Thessaloniki “G.Gennimatas”ThessalonikiGreece
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Yoo BW, Kong YT, Chae SW, Kim KN, Song B, Kim J. Comparison of the Characteristics of Three Acellular Dermal Matrices Subjected to Distinct Processing Methods Using Five Types of Histochemical Staining. Aesthetic Plast Surg 2023:10.1007/s00266-023-03318-x. [PMID: 37130991 DOI: 10.1007/s00266-023-03318-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 03/04/2023] [Indexed: 05/04/2023]
Abstract
BACKGROUND Acellular dermal matrix (ADM) is treated using various devitalization and aseptic processing methods. The processing effects on ADM were evaluated by histochemical tests. METHODS From January 2014 to December 2016, 18 patients [average age, 43.0 (range, 30-54) years] who underwent breast reconstruction with an ADM and tissue expander were prospectively enrolled. During the permanent implant replacement, a biopsy of the ADM was performed. We used three different human-derived products, namely, Alloderm®, Allomend®, and Megaderm®. Hematoxylin and eosin, CD68, CD3, CD31, and smooth muscle actin were used to evaluate the collagen structure, inflammation, angiogenesis, and myofibroblast infiltration. Each ADM was semi-quantitatively analyzed. RESULTS Significant differences in collagen degradation, acute inflammation, and myofibroblast infiltration were observed among the ADMs. Collagen degeneration (p<0.001) and myofibroblast infiltration (smooth muscle actin-positive, p=0.018; CD31-negative, p=0.765) were the most severe in Megaderm®. Acute inflammation, represented by CD68, was most severe in Alloderm® (p=0.024). Both radiation and freeze-drying treatment physically damaged the collagen structure. Collagen degeneration was most severe in Megaderm®, followed by Allomend® and Alloderm®. Since Alloderm® is treated using chemicals, an assessment of the chemical irritation is warranted. CONCLUSIONS The biopsy results were inconclusive. Therefore, to better interpret processing, more large-scale, serial, histochemical studies of each ADM are needed. LEVEL OF EVIDENCE IV This journal requires that authors 38 assign a level of evidence to each article. For a full 39 description of these Evidence-Based Medicine ratings, 40 please refer to the Table of Contents or the online 41 Instructions to Authors www.springer.com/00266 .
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Affiliation(s)
- Byung Woo Yoo
- Department of Plastic and Reconstructive Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yu Taek Kong
- Department of Plastic and Reconstructive Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seoung Wan Chae
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kyu Nam Kim
- Department of Plastic and Reconstructive Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Boram Song
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Junekyu Kim
- Department of Plastic and Reconstructive Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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Zhong Y, Jin W, Gao H, Sun L, Wang P, Zhang J, Ong MTY, Sai Chuen Bruma F, Chen S, Chen J. A Knitted PET Patch Enhances the Maturation of Regenerated Tendons in Bridging Reconstruction of Massive Rotator Cuff Tears in a Rabbit Model. Am J Sports Med 2023; 51:901-911. [PMID: 36802867 DOI: 10.1177/03635465231152186] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
Abstract
BACKGROUND Although nondegradable synthetic grafts for bridging reconstruction of massive rotator cuff tears (MRCTs) have shown satisfactory clinical outcomes, their function and details on graft-tendon healing and enthesis regeneration have not been fully studied. HYPOTHESIS The knitted polyethylene terephthalate (PET) patch as a nondegradable synthetic graft could provide sustained mechanical support, facilitating enthesis and tendon regeneration in the treatment of MRCTs. STUDY DESIGN Controlled laboratory study. METHODS A knitted PET patch was fabricated for bridging reconstruction (PET group) in a New Zealand White rabbit model of MRCTs (negative control group), and an autologous Achilles tendon was used as a control (autograft group). The animals were sacrificed, and tissue samples were harvested for gross observation as well as histological and biomechanical analyses at 4, 8, and 12 weeks postoperatively. RESULTS Histological analysis showed no significant difference in the graft-bone interface score between the PET and autograft groups at 4, 8, and 12 weeks postoperatively. Interestingly, in the PET group, Sharpey-like fibers were observed at 8 weeks, while fibrocartilage formation and the ingrowth of chondrocytes were recognized at 12 weeks. Meanwhile, the tendon maturing score was significantly higher in the PET group than in the autograft group (19.7 ± 1.5 vs 15.3 ± 1.2, respectively; P = .008) at 12 weeks, with parallel-oriented collagen fibers around the knitted PET patch. Moreover, the ultimate failure load of the PET group was similar to that of a healthy rabbit tendon at 8 weeks (125.6 ± 13.6 vs 130.8 ± 28.6 N, respectively; P > .05) and no different from that of the autograft group at 4, 8, and 12 weeks. CONCLUSION The knitted PET patch could not only immediately reconstruct the mechanical support for the torn tendon postoperatively in the rabbit model of MRCTs but also enhanced maturation of the regenerated tendon by fibrocartilage formation and improved the organization of collagen fibers. Herein, the knitted PET patch could be a promising candidate graft adopted in bridging reconstruction of MRCTs. CLINICAL RELEVANCE A nondegradable knitted PET patch can safely bridge MRCTs with satisfactory mechanical strength and the promotion of tissue regeneration.
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Affiliation(s)
- Yuting Zhong
- Institute of Sports Medicine of Fudan University, Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Wenhe Jin
- Institute of Sports Medicine of Fudan University, Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Han Gao
- Institute of Sports Medicine of Fudan University, Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Luyi Sun
- Institute of Sports Medicine of Fudan University, Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Peng Wang
- Institute of Sports Medicine of Fudan University, Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Jian Zhang
- Institute of Sports Medicine of Fudan University, Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Michael Tim Yun Ong
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Fu Sai Chuen Bruma
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Shiyi Chen
- Institute of Sports Medicine of Fudan University, Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Jun Chen
- Institute of Sports Medicine of Fudan University, Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
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Jenner F, Wagner A, Gerner I, Ludewig E, Trujanovic R, Rohde E, von Rechenberg B, Gimona M, Traweger A. Evaluation of the Potential of Umbilical Cord Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles to Improve Rotator Cuff Healing: A Pilot Ovine Study. Am J Sports Med 2023; 51:331-342. [PMID: 36645050 DOI: 10.1177/03635465221145958] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND Despite significant advancements in surgical techniques to repair rotator cuff (RC) injuries, failure rates remain high and novel approaches to adequately overcome the natural biological limits of tendon and enthesis regeneration of the RC are required. Small extracellular vesicles (sEVs) derived from the secretome of human multipotent mesenchymal stromal cells (MSCs) have been demonstrated to modulate inflammation and reduce fibrotic adhesions, and therefore their local application could improve outcomes after RC repair. PURPOSE In this pilot study, we evaluated the efficacy of clinical-grade human umbilical cord (hUC) MSC-derived sEVs (hUC-MSC-sEVs) loaded onto a type 1 collagen scaffold in an ovine model of acute infraspinatus tendon injury to improve RC healing. STUDY DESIGN Controlled laboratory study. METHODS sEVs were enriched from hUC-MSC culture media and were characterized by surface marker profiling. The immunomodulatory capacity was evaluated in vitro by T-cell proliferation assays, and particle count was determined by nanoparticle tracking analysis. Twelve skeletally mature sheep were subjected to partial infraspinatus tenotomy and enthesis debridement. The defects of 6 animals were treated with 2 × 1010 hUC-MSC-sEVs loaded onto a type 1 collagen sponge, whereas 6 animals received only a collagen sponge, serving as controls. Six weeks postoperatively, the healing of the infraspinatus tendon and the enthesis was evaluated by magnetic resonance imaging (MRI) and hard tissue histology. RESULTS CD3/CD28-stimulated T-cell proliferation was significantly inhibited by hUC-MSC-sEVs (P = .015) that displayed the typical surface marker profile, including the presence of the MSC marker proteins CD44 and melanoma-associated chondroitin sulfate proteoglycan. The local application of hUC-MSC-sEVs did not result in any marked systemic adverse events. Histologically, significantly improved Watkins scores (P = .031) indicated improved tendon and tendon-to-bone insertion repair after sEV treatment and lower postcontrast signal of the tendon and adjacent structures on MRI suggested less residual inflammation at the defect area. Furthermore, the formation of osteophytes at the injury site was significantly attenuated (P = .037). CONCLUSION A local, single-dose application of hUC-MSC-sEVs promoted tendon and enthesis healing in an ovine model of acute RC injury. CLINICAL RELEVANCE Surgical repair of RC tears generally results in a clinical benefit for the patient; however, considerable rerupture rates have been reported. sEVs have potential as a cell-free biotherapeutic to improve healing outcomes after RC injury.
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Affiliation(s)
- Florien Jenner
- VETERM, Equine Surgery Unit, Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Andrea Wagner
- Institute of Tendon and Bone Regeneration, Spinal Cord Injury and Tissue Regeneration Centre Salzburg, Paracelsus Medical University, Salzburg, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Iris Gerner
- VETERM, Equine Surgery Unit, Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Eberhard Ludewig
- Diagnostic Imaging Unit, Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Robert Trujanovic
- Clinical Unit of Anaesthesiology and Perioperative Intensive Care, Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Eva Rohde
- Department of Transfusion Medicine, Salzburger Landeskliniken GesmbH, Paracelsus Medical University, Salzburg, Austria.,GMP Unit, Spinal Cord Injury and Tissue Regeneration Centre Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Brigitte von Rechenberg
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.,Center for Applied Biotechnology and Molecular Medicine (CABMM), University of Zurich, Zurich, Switzerland
| | - Mario Gimona
- GMP Unit, Spinal Cord Injury and Tissue Regeneration Centre Salzburg, Paracelsus Medical University, Salzburg, Austria.,Research Program "Nanovesicular Therapies," Paracelsus Medical University, Salzburg, Austria
| | - Andreas Traweger
- Institute of Tendon and Bone Regeneration, Spinal Cord Injury and Tissue Regeneration Centre Salzburg, Paracelsus Medical University, Salzburg, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
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9
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Song L, Luo X, Tsauo C, Shi B, Liu R, Li C. Histologic characterization of orbicularis oris muscle with a new acellular dermal matrix grafts in a rabbit model. J Tissue Eng Regen Med 2022; 16:707-717. [PMID: 35524474 DOI: 10.1002/term.3310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 11/07/2022]
Abstract
Muscular dysplasia is the key factor in influencing surgical outcomes in patients with cleft lip/palate. In this research, we attempted to evaluate a new acellular dermal matrix (ADM) as a substitute for reconstruction of the orbicularis oris muscle with growth factors such as Insulin-Like Growth Factor I (IGF-I), vascular endothelial growth factor (VEGF) in a rabbit model. 30 male New Zealand Rabbits (2-3 m, 1700-2000 g) were divided into four groups as follows; a group in which the orbicularis oris muscle of the upper lip was implanted with ADM, a group in which the orbicularis oris muscle of the upper lip was implanted with ADM + IGF-I + VEGF, a group in which the upper lip was operated without implantation of an ADM scaffold, and a normal upper lip for comparison. Macroscopic observation, histological evaluation, and immunohistochemistry were employed to evaluate levels of the muscle regeneration, vascularization, and inflammation at 1, 2, 4, 6, and 12 weeks after the operation. All wounds healed well without infection, immune rejection and so on. Histological evaluation showed that ADM was totally degraded and replaced by connective tissue. The area in which the ADM scaffold was coated with growth factors show a significant increase in the formation of new myofibers after injury, and the vascularization improved compared to the control group and the normal group. In regard to the degrees of inflammation, there were no notable differences among the groups. In conclusion, Our study indicated that ADM grafts combined with IGF-I and VEGF have potential advantages in alleviating muscular dysplasia in cleft lip treatment.
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Affiliation(s)
- Lei Song
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cleft Lip and Palate Surgery, West China School of Stomatology, Sichuan University, Chengdu, China.,Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiao Luo
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cleft Lip and Palate Surgery, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Chialing Tsauo
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cleft Lip and Palate Surgery, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Bing Shi
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cleft Lip and Palate Surgery, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Renkai Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cleft Lip and Palate Surgery, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Chenghao Li
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cleft Lip and Palate Surgery, West China School of Stomatology, Sichuan University, Chengdu, China
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10
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Yang J, Kang Y, Zhao W, Jiang J, Jiang Y, Zhao B, Jiao M, Yuan B, Zhao J, Ma B. Evaluation of patches for rotator cuff repair: A systematic review and meta-analysis based on animal studies. Bioact Mater 2022; 10:474-491. [PMID: 34901561 PMCID: PMC8633530 DOI: 10.1016/j.bioactmat.2021.08.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/12/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023] Open
Abstract
Based on the published animal studies, we systematically evaluated the outcomes of various materials for rotator cuff repair in animal models and the potentials of their clinical translation. 74 animal studies were finally included, of which naturally derived biomaterials were applied the most widely (50.0%), rats were the most commonly used animal model (47.0%), and autologous tissue demonstrated the best outcomes in all animal models. The biomechanical properties of naturally derived biomaterials (maximum failure load: WMD 18.68 [95%CI 7.71-29.66]; P = 0.001, and stiffness: WMD 1.30 [95%CI 0.01-2.60]; P = 0.048) was statistically significant in the rabbit model. The rabbit model showed better outcomes even though the injury was severer compared with the rat model.
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Affiliation(s)
- Jinwei Yang
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
- Reproductive Medicine Center, Gansu Provincial Maternity and Child-Care Hospital, Lanzhou, 730050, China
| | - Yuhao Kang
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Wanlu Zhao
- College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China
- National Engineering Research Center for Biomaterials, Chengdu, 610064, China
| | - Jia Jiang
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Yanbiao Jiang
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Bing Zhao
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Mingyue Jiao
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Bo Yuan
- College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China
- National Engineering Research Center for Biomaterials, Chengdu, 610064, China
| | - Jinzhong Zhao
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Bin Ma
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
- Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, 730000, China
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11
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Prabhath A, Vernekar VN, Esdaille CJ, Eisenberg E, Lebaschi A, Badon M, Seyedsalehi A, Dzidotor G, Tang X, Dyment N, Thomopoulos S, Kumbar SG, Deymier A, Weber E, Laurencin CT. Pegylated insulin-like growth factor-1 biotherapeutic delivery promotes rotator cuff regeneration in a rat model. J Biomed Mater Res A 2022; 110:1356-1371. [PMID: 35253991 DOI: 10.1002/jbm.a.37378] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/17/2022] [Accepted: 02/25/2022] [Indexed: 12/27/2022]
Abstract
Tears in the rotator cuff are challenging to repair because of the complex, hypocellular, hypovascular, and movement-active nature of the tendon and its enthesis. Insulin-like Growth Factor-1 (IGF-1) is a promising therapeutic for this repair. However, its unstable nature, short half-life, and ability to disrupt homeostasis has limited its clinical translation. Pegylation has been shown to improve the stability and sustain IGF-1 levels in the systemic circulation without disrupting homeostasis. To provide localized delivery of IGF-1 in the repaired tendons, we encapsulated pegylated IGF-1 mimic and its controls (unpegylated IGF-1 mimic and recombinant human IGF-1) in polycaprolactone-based matrices and evaluated them in a pre-clinical rodent model of rotator cuff repair. Pegylated-IGF-1 mimic delivery reestablished the characteristic tendon-to-bone enthesis structure and improved tendon tensile properties within 8 weeks of repair compared to controls, signifying the importance of pegylation in this complex tissue regeneration. These results demonstrate a simple and scalable biologic delivery technology alternative to tissue-derived grafts for soft tissue repair.
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Affiliation(s)
- Anupama Prabhath
- Connecticut Convergence Institute for Translation in Regenerative Engineering, Farmington, Connecticut, USA.,Department of Orthopaedic Surgery, UConn Health, Farmington, Connecticut, USA.,Department of Biomedical Engineering, UConn Health, Farmington, Connecticut, USA
| | - Varadraj N Vernekar
- Connecticut Convergence Institute for Translation in Regenerative Engineering, Farmington, Connecticut, USA.,Department of Orthopaedic Surgery, UConn Health, Farmington, Connecticut, USA
| | - Caldon J Esdaille
- Connecticut Convergence Institute for Translation in Regenerative Engineering, Farmington, Connecticut, USA
| | - Ellen Eisenberg
- Department of Pathology and Laboratory Medicine, UConn Health, Farmington, Connecticut, USA
| | - Amir Lebaschi
- Department of Orthopaedic Surgery, UConn Health, Farmington, Connecticut, USA
| | - Mary Badon
- Connecticut Convergence Institute for Translation in Regenerative Engineering, Farmington, Connecticut, USA
| | - Amir Seyedsalehi
- Connecticut Convergence Institute for Translation in Regenerative Engineering, Farmington, Connecticut, USA.,Department of Orthopaedic Surgery, UConn Health, Farmington, Connecticut, USA.,Department of Biomedical Engineering, UConn Health, Farmington, Connecticut, USA
| | - Godwin Dzidotor
- Connecticut Convergence Institute for Translation in Regenerative Engineering, Farmington, Connecticut, USA.,Department of Orthopaedic Surgery, UConn Health, Farmington, Connecticut, USA.,Department of Chemical Engineering, University of Connecticut, Storrs, Connecticut, USA
| | - Xiaoyan Tang
- Connecticut Convergence Institute for Translation in Regenerative Engineering, Farmington, Connecticut, USA.,Department of Orthopaedic Surgery, UConn Health, Farmington, Connecticut, USA.,Department of Material Science and Engineering, University of Connecticut, Storrs, Connecticut, USA
| | - Nathaniel Dyment
- McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Stavros Thomopoulos
- Department of Orthopedic Surgery, Columbia University, New York, New York, USA.,Department of Biomedical Engineering, Columbia University, New York, New York, USA
| | - Sangamesh G Kumbar
- Department of Orthopaedic Surgery, UConn Health, Farmington, Connecticut, USA.,Department of Biomedical Engineering, UConn Health, Farmington, Connecticut, USA.,Department of Material Science and Engineering, University of Connecticut, Storrs, Connecticut, USA
| | - Alix Deymier
- Department of Biomedical Engineering, UConn Health, Farmington, Connecticut, USA
| | - Eckhard Weber
- Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland
| | - Cato T Laurencin
- Connecticut Convergence Institute for Translation in Regenerative Engineering, Farmington, Connecticut, USA.,Department of Orthopaedic Surgery, UConn Health, Farmington, Connecticut, USA.,Department of Biomedical Engineering, UConn Health, Farmington, Connecticut, USA.,Department of Chemical Engineering, University of Connecticut, Storrs, Connecticut, USA.,Department of Material Science and Engineering, University of Connecticut, Storrs, Connecticut, USA
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12
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Xu J, Li Y, Ye Z, Wu C, Han K, Zheng T, Jiang J, Yan X, Su W, Zhao J. Biceps Augmentation Outperforms Tear Completion Repair or In Situ Repair for Bursal-Sided Partial-Thickness Rotator Cuff Tears in a Rabbit Model. Am J Sports Med 2022; 50:195-207. [PMID: 34779674 DOI: 10.1177/03635465211053334] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [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 There is an ongoing debate on the treatment of bursal-sided partial-thickness rotator cuff tears (PTRCTs), including ideal repair techniques. Augmentation using a collagen patch has been introduced as a new surgical approach to treat PTRCTs, while the effect of autogenous biceps augmentation (BA) has not been investigated. PURPOSE To analyze the effects of BA on bursal-sided PTRCTs and compare its histological and biomechanical results with those of tear completion followed by repair and in situ repair (ISR). STUDY DESIGN Controlled laboratory study. METHODS Unilateral chronic PTRCTs were created in 96 mature New Zealand White rabbits, which were randomly divided into 4 groups: no repair, tear completion repair (TCR), ISR, and BA. A new bicipital groove was fabricated in BA for the biceps tendon that was transferred to augment the bursal-sided PTRCT repair. In each group, we sacrificed 6 rabbits for biomechanical testing of the whole tendon-to-bone complex (WTBC) and 6 for histological evaluation of bursal- and articular-sided layers at 6 and 12 weeks postoperatively. Healing responses between the biceps and new bicipital groove in the BA group were determined using histological analysis, and final groove morphologies were evaluated using micro-computed tomography. RESULTS The remaining tendon and enthesis in bursal-sided PTRCTs progressively degenerated over time. WTBCs of ISR exhibited a larger failure load than those of TCR, although better healing properties in the bursal-sided repaired site were achieved using TCR based on histological scores and superior articular-sided histological scores were observed using ISR. However, WTBCs of BA displayed the best biomechanical results and superior histological scores for bursal- and articular-sided regions. The new bicipital groove in BA remodeled over time and formed similar morphologies to a native groove, which provided a mature bone bed for transferred biceps tendon healing to augment bursal-sided PTRCTs. CONCLUSION BA achieved better biomechanical and histological results for repairing bursal-sided PTRCTs as compared with TCR and ISR. When compared with that of TCR, the WTBC of ISR exhibited a higher failure load, showing histological superiority in the articular-sided repair and inferiority in the bursal-sided repair. CLINICAL RELEVANCE BA may be an approach to improve bursal-sided PTRCT repair in humans, which warrants further clinical investigation.
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Affiliation(s)
- Junjie Xu
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yufeng Li
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zipeng Ye
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Chenliang Wu
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Kang Han
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Ting Zheng
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jia Jiang
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xiaoyu Yan
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wei Su
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jinzhong Zhao
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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13
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Liu C, Jiang S, Wu Y, Liu L, Su S, Liang T, He R, Guo Z, Zhang Y, Lin Z, Niu W, Zhu L, Xu T, Wang K. The Regenerative Role of Gelatin in PLLA Electrospun Membranes for the Treatment of Chronic Massive Rotator Cuff Injuries. Macromol Biosci 2021; 22:e2100281. [PMID: 34708919 DOI: 10.1002/mabi.202100281] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/25/2021] [Indexed: 11/08/2022]
Abstract
Failing to regenerate native tendon tissue in chronic massive rotator cuff tears (CMRCTs) results in high retear rates after surgery. Gelatin is a hydrolyzed form of collagen which is bioactive and biocompatible. This study intends to investigate the suitability of integrating gelatin to poly (l-lactic acid) (PLLA) fibrous membranes for promoting the healing of CMRCTs. PLLA/Gelatin electrospun membranes (PGEM) are fabricated using electrospinning technology. The fourier transform infrared, static contact angles are tested sequentially. Cytocompatibility is evaluated with rat tendon fibroblasts and human umbilical endothelial cells (HUEVCs) lines. CMRCTs rat models are established and assigned into three groups (the sham group, the repaired group, and the augmentation group) to perform histomorphological and biomechanical evaluations. Gelatin is successfully integrated into PLLA fibrous membranes by the electrospinning technique. In vitro studies indicate that PGEM shows a great cytocompatibility for rat tendon fibroblasts and HUEVCs. In vivo studies find that applications of PGEM significantly promote well-aligned collagen I fibers formation and enhance biomechanical properties of the repaired tendon in CMRCTs rat models. In summary, gelatin promotes tendon fibroblasts and HUEVCs adhesion, migration, and proliferation on the PLLA fibrous membranes, and PGEM may provide a great prospect for clinical application.
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Affiliation(s)
- Chang Liu
- Department of Joint and Trauma Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,East China Institute of Digital Medical Engineering, Shangrao, 334000, China
| | - Shihai Jiang
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, 04103, Germany
| | - Yu Wu
- Department of Plastic and Aesthetic Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,East China Institute of Digital Medical Engineering, Shangrao, 334000, China
| | - Libiao Liu
- East China Institute of Digital Medical Engineering, Shangrao, 334000, China.,Biomanufacturing and Rapid Forming Technology Key Laboratory of Beijing, Department of Mechanical Engineering, Key Laboratory for Advanced Materials Processing Technology, Ministry of Education, Department of Mechanical Engineering, Tsinghua University, Beijing, 100084, China
| | - Shouwen Su
- Department of Joint and Trauma Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Tangzhao Liang
- Department of Joint and Trauma Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Ronghan He
- Department of Joint and Trauma Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Zeyue Guo
- East China Institute of Digital Medical Engineering, Shangrao, 334000, China
| | - Yuanyuan Zhang
- Department of Obstetrics and Gynaecology, Maternal and Child Health Care Hospital of Jiaozuo, Jiaozuo, 454000, China
| | - Zhidong Lin
- East China Institute of Digital Medical Engineering, Shangrao, 334000, China.,Department of Orthopedics, The Second Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Wei Niu
- Department of Orthopedics, The Second Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Lei Zhu
- Department of Plastic and Aesthetic Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Tao Xu
- Biomanufacturing and Rapid Forming Technology Key Laboratory of Beijing, Department of Mechanical Engineering, Key Laboratory for Advanced Materials Processing Technology, Ministry of Education, Department of Mechanical Engineering, Tsinghua University, Beijing, 100084, China.,Department of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, 518055, China
| | - Kun Wang
- Department of Joint and Trauma Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
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14
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Wang D, Zhang X, Huang S, Liu Y, Fu BSC, Mak KKL, Blocki AM, Yung PSH, Tuan RS, Ker DFE. Engineering multi-tissue units for regenerative Medicine: Bone-tendon-muscle units of the rotator cuff. Biomaterials 2021; 272:120789. [PMID: 33845368 DOI: 10.1016/j.biomaterials.2021.120789] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 12/13/2022]
Abstract
Our body systems are comprised of numerous multi-tissue units. For the musculoskeletal system, one of the predominant functional units is comprised of bone, tendon/ligament, and muscle tissues working in tandem to facilitate locomotion. To successfully treat musculoskeletal injuries and diseases, critical consideration and thoughtful integration of clinical, biological, and engineering aspects are necessary to achieve translational bench-to-bedside research. In particular, identifying ideal biomaterial design specifications, understanding prior and recent tissue engineering advances, and judicious application of biomaterial and fabrication technologies will be crucial for addressing current clinical challenges in engineering multi-tissue units. Using rotator cuff tears as an example, insights relevant for engineering a bone-tendon-muscle multi-tissue unit are presented. This review highlights the tissue engineering strategies for musculoskeletal repair and regeneration with implications for other bone-tendon-muscle units, their derivatives, and analogous non-musculoskeletal tissue structures.
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Affiliation(s)
- Dan Wang
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR; Ministry of Education Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR; Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR
| | - Xu Zhang
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR
| | - Shuting Huang
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR
| | - Yang Liu
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR
| | - Bruma Sai-Chuen Fu
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR
| | | | - Anna Maria Blocki
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR; Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR
| | - Patrick Shu-Hang Yung
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR
| | - Rocky S Tuan
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR
| | - Dai Fei Elmer Ker
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR; Ministry of Education Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR; Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR.
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15
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Lim TK, Dorthé E, Williams A, D'Lima DD. Nanofiber Scaffolds by Electrospinning for Rotator Cuff Tissue Engineering. Chonnam Med J 2021; 57:13-26. [PMID: 33537215 PMCID: PMC7840345 DOI: 10.4068/cmj.2021.57.1.13] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 12/21/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022] Open
Abstract
Rotator cuff tears continue to be at risk of retear or failure to heal after surgical repair, despite the use of various surgical techniques, which stimulate development of novel scaffolding strategies. They should be able to address the known causes of failure after the conventional rotator cuff repair: (1) failure to reproduce the normal tendon healing process, (2) resultant failure to reproduce four zones of the enthesis, and (3) failure to attain sufficient mechanical strength after repair. Nanofiber scaffolds are suited for this application because they can be engineered to mimic the ultrastructure and properties of the native rotator cuff tendon. Among various methods for tissue-engineered nanofibers, electrospinning has recently been highlighted in the rotator cuff field. Electrospinning can create fibrous and porous structures that resemble natural tendon's extracellular matrix. Other advantages include the ability to create relatively large surface-to-volume ratios, the ability to control fiber size from the micro to the nano scale, and the flexibility of material choices. In this review, we will discuss the anatomical and mechanical features of the rotator cuff tendon, their potential impacts on improper healing after repair, and the current knowledge of the use of electrospinning for rotator cuff tissue engineering.
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Affiliation(s)
- Tae Kang Lim
- Department of Orthopaedic Surgery, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea.,Shiley Center for Orthopedic Research & Education at Scripps Clinic, CA, USA.,Department of Molecular Medicine, Scripps Research, La Jolla, CA, USA
| | - Erik Dorthé
- Shiley Center for Orthopedic Research & Education at Scripps Clinic, CA, USA.,Department of Molecular Medicine, Scripps Research, La Jolla, CA, USA
| | - Austin Williams
- Shiley Center for Orthopedic Research & Education at Scripps Clinic, CA, USA.,Department of Molecular Medicine, Scripps Research, La Jolla, CA, USA
| | - Darryl D D'Lima
- Shiley Center for Orthopedic Research & Education at Scripps Clinic, CA, USA.,Department of Molecular Medicine, Scripps Research, La Jolla, CA, USA
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16
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Regeneration of the rotator cuff tendon-to-bone interface using umbilical cord-derived mesenchymal stem cells and gradient extracellular matrix scaffolds from adipose tissue in a rat model. Acta Biomater 2020; 114:104-116. [PMID: 32682057 DOI: 10.1016/j.actbio.2020.07.020] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 07/07/2020] [Accepted: 07/09/2020] [Indexed: 12/17/2022]
Abstract
Regeneration of the gradient structure of the tendon-to-bone interface (TBI) is a crucial goal after rotator cuff repair. The purpose of this study was to investigate the efficacy of a biomimetic hydroxyapatite-gradient scaffold (HA-G scaffold) isolated from adipose tissue (AD) with umbilical cord derived mesenchymal stem cells (UC MSCs) on the regeneration of the structure of the TBI by analyzing the histological and biomechanical changes in a rat repair model. As a result, the HA-G scaffold had progressively increased numbers of hydroxyapatite (HA) particles from the tendon to the bone phase. After seeding UC MSCs to the scaffold, specific matrices, such as collagen, glycoaminoglycan, and calcium, were synthesized with respect to the HA density. In a rat repair model, compared to the repair group, the UC MSCs seeded HA-G scaffold group had improved collagen organization and cartilage formation by 52% at 8 weeks and 262.96% at 4 weeks respectively. Moreover, ultimate failure load also increased by 30.71% at 4 weeks in the UC MSCs seeded HA-G scaffold group compared to the repair group. Especially, the improved values were comparable to values in normal tissue. This study demonstrated that HA-G scaffold isolated from AD induced UC MSCs to form tendon, cartilage and bone matrices similar to the TBI structure according to the HA density. Furthermore, UC MSC-seeded HA-G scaffold regenerated the TBI of the rotator cuff in a rat repair model in terms of histological and biomechanical properties similar to the normal TBI. Statement of Significance We found specific extracellular matrix (ECM) formation in the biomimetic-hydroxyapatite-gradient-scaffold (HA-G-scaffold) in vitro as well as improved histological and biomechanical results of repaired rotator cuff after the scaffold implantation in a rat model. This study has four strengths; An ECM scaffold derived from human adipose tissue; only one-layer used for a gradient scaffold not a multilayer used to mimic the unique structure of the gradient tendon-to-bone-interface (TBI) of the rotator cuff; UC-MSCs as a new cell source for TBI regeneration; and the UC-MSCs synthesized specific matrices with respect to the HA density without any other stimuli. This study suggested that the UC-MSC seeded HA-G-scaffold could be used as a promising strategy for the regeneration of rotator cuff tears.
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17
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Cong S, Sun Y, Lin J, Liu S, Chen J. A Synthetic Graft With Multilayered Co-Electrospinning Nanoscaffolds for Bridging Massive Rotator Cuff Tear in a Rat Model. Am J Sports Med 2020; 48:1826-1836. [PMID: 32453629 DOI: 10.1177/0363546520917684] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Graft bridging is used in massive rotator cuff tear (MRCT); however, the integration of graft-tendon and graft-bone is still a challenge. HYPOTHESIS A co-electrospinning nanoscaffold of polycaprolactone (PCL) with an "enthesis-mimicking" (EM) structure could bridge MRCT, facilitate tendon regeneration, and improve graft-bone healing. STUDY DESIGN Controlled laboratory study. METHODS First, we analyzed the cytocompatibility of the electrospinning nanoscaffolds, including aligned PCL (aPCL), nonaligned PCL (nPCL), aPCL-collagen I, nPCL-collagen II, and nPCL-nanohydroxyapatite (nHA). Second, for the EM condition, nPCL-collagen II and nPCL-nHA were electrospun layer by layer at one end of the aPCL-collagen I; for the control condition, the nPCL was electrospun on the aPCL. In 40 mature male rats, resection of both the supraspinatus and infraspinatus tendons was performed to create MRCT, and the animals were divided randomly into EM and control groups. In both groups, one end of the layered structure was fixed on the footprint of the rotator cuff, whereas the other end of the layered structure was sutured with the tendon stump. The animals were euthanized for harvesting of tissues for histologic and biomechanical analysis at 4 weeks or 8 weeks postoperatively. RESULTS All scaffolds showed good cytocompatibility in vitro. The graft-tendon tissue in the EM group had more regularly arranged cells, denser tissue, a significantly higher tendon maturing score, and more birefringence compared with the control group at 8 weeks after operation. Newly formed fibrocartilage could be observed at the graft-bone interface in both groups by 8 weeks, but the EM group had a higher graft-bone healing score and significantly more newly formed fibrocartilage than the control group. An enthesis-like structure with transitional layers was observed in the EM group at 8 weeks. Biomechanically, the values for maximum failure load and stiffness of the tendon-graft-bone complex were significantly higher in the EM group than in the control group at 8 weeks. CONCLUSION The co-electrospinning nanoscaffold of aPCL-collagen I could be used as a bridging graft to improve early graft-tendon healing for MRCT in a rat model and enhance early enthesis reconstruction in combination with a multilayered structure of nPCL-collagen II and nPCL-nHA. CLINICAL RELEVANCE We constructed a graft to bridge MRCT, enhance graft-tendon healing and graft-bone healing, and reconstruct the enthesis structure.
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Affiliation(s)
- Shuang Cong
- Department of Sports Medicine, Huashan Hospital, Shanghai, China
| | - Yaying Sun
- Department of Sports Medicine, Huashan Hospital, Shanghai, China
| | - Jinrong Lin
- Department of Sports Medicine, Huashan Hospital, Shanghai, China
| | - Shaohua Liu
- Department of Sports Medicine, Huashan Hospital, Shanghai, China
| | - Jiwu Chen
- Department of Sports Medicine, Huashan Hospital, Shanghai, China
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18
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Altintas B, Scibetta AC, Storaci HW, Lacheta L, Anderson NL, Millett PJ. Biomechanical and Histopathological Analysis of a Retrieved Dermal Allograft After Superior Capsule Reconstruction: A Case Report. Arthroscopy 2019; 35:2959-2965. [PMID: 31604518 DOI: 10.1016/j.arthro.2019.07.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 07/02/2019] [Accepted: 07/03/2019] [Indexed: 02/02/2023]
Abstract
The purpose of this study was to evaluate biomechanical and histopathological results of a retrieved acellular human dermal allograft (AHDA) after superior capsule reconstruction (SCR). A 67-year-old man with pseudoparalysis was treated with SCR for an irreparable posterosuperior rotator cuff tear. The patient failed clinically 4.5 months postoperatively and elected to undergo reverse total shoulder arthroplasty (RTSA). At the time of RTSA, the AHDA was harvested. Biomechanical and histopathologic analyses were performed and compared to native grafts. Failure loads for the explanted graft and native grafts 1 and 2 were 158, 790, and 749 N, respectively. The stiffness values were 20.2, 73, and 100.5 N/mm. The displacement at failure for each graft was 10.1, 27.9, and 17.0 mm. Hematoxylin and eosin and Masson's trichrome staining revealed the presence of cells in all portions of the AHDA. The medial portion presented extensive cellular infiltration, the middle portion moderate, and the lateral portion the least infiltration. Although the only identifiable cells in the lateral portions were found in pockets on the interior of the graft, cells were mainly localized on the exterior. Postoperative cell incorporation could be found in acellular dermal allograft after SCR. However, biomechanical properties in the early postoperative phase were inferior compared with unimplanted allografts.
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Affiliation(s)
- Burak Altintas
- Steadman Philippon Research Institute, Vail, Colorado; Steadman Clinic, Vail, Colorado; Department of Orthopaedic Surgery, University of Kentucky School of Medicine, Lexington, Kentucky, U.S.A
| | | | | | - Lucca Lacheta
- Steadman Philippon Research Institute, Vail, Colorado; Steadman Clinic, Vail, Colorado
| | | | - Peter J Millett
- Steadman Philippon Research Institute, Vail, Colorado; Steadman Clinic, Vail, Colorado.
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19
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Baldwin M, Snelling S, Dakin S, Carr A. Augmenting endogenous repair of soft tissues with nanofibre scaffolds. J R Soc Interface 2019; 15:rsif.2018.0019. [PMID: 29695606 DOI: 10.1098/rsif.2018.0019] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 04/04/2018] [Indexed: 12/21/2022] Open
Abstract
As our ability to engineer nanoscale materials has developed we can now influence endogenous cellular processes with increasing precision. Consequently, the use of biomaterials to induce and guide the repair and regeneration of tissues is a rapidly developing area. This review focuses on soft tissue engineering, it will discuss the types of biomaterial scaffolds available before exploring physical, chemical and biological modifications to synthetic scaffolds. We will consider how these properties, in combination, can provide a precise design process, with the potential to meet the requirements of the injured and diseased soft tissue niche. Finally, we frame our discussions within clinical trial design and the regulatory framework, the consideration of which is fundamental to the successful translation of new biomaterials.
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Affiliation(s)
- Mathew Baldwin
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Sarah Snelling
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Stephanie Dakin
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Andrew Carr
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
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20
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Nakanishi Y, Okada T, Takeuchi N, Kozono N, Senju T, Nakayama K, Nakashima Y. Histological evaluation of tendon formation using a scaffold-free three-dimensional-bioprinted construct of human dermal fibroblasts under in vitro static tensile culture. Regen Ther 2019; 11:47-55. [PMID: 31193148 PMCID: PMC6517794 DOI: 10.1016/j.reth.2019.02.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 01/11/2019] [Accepted: 02/03/2019] [Indexed: 10/26/2022] Open
Abstract
Introduction Tendon tissue engineering requires scaffold-free techniques for safe and long-term clinical applications and to explore alternative cell sources to tenocytes. Therefore, we histologically assessed tendon formation in a scaffold-free Bio-three-dimensional (3D) construct developed from normal human dermal fibroblasts (NHDFs) using our Bio-3D printer system under tensile culture in vitro. Methods Scaffold-free ring-like tissues were constructed from 120 multicellular spheroids comprising NHDFs using a bio-3D printer. Ring-like tissues were cultured in vitro under static tensile-loading with or without in-house tensile devices (tension-loaded and tension-free groups), with increases in tensile strength applied weekly to the tensile-loaded group. After a 4 or 8-week culture on the device, we evaluated histological findings according to tendon-maturing score and immunohistological findings of the middle portion of the tissues for both groups (n = 4, respectively). Results Histology of the tension-loaded group revealed longitudinally aligned collagen fibers with increased collagen deposition and spindle-shaped cells with prolonged culture. By contrast, the tension-free group showed no organized cell arrangement or collagen fiber structure. Additionally, the tension-loaded group showed a significantly improved tendon-maturing score as compared with that for the tension-free group at week 8. Moreover, immunohistochemistry revealed tenascin C distribution with a parallel arrangement in the tensile-loading direction at week 8 in the tension-loaded group, which exhibited stronger scleraxis-staining intensity than that observed in the tension-free group at weeks 4 and 8. Conclusions The NHDF-generated scaffold-free Bio-3D construct underwent remodeling and formed tendon-like structures under tensile culture in vitro.
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Affiliation(s)
- Yoshitaka Nakanishi
- Department of Orthopaedic Surgery, School of Medicine, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Takamitsu Okada
- Department of Orthopaedic Surgery, School of Medicine, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Naohide Takeuchi
- Department of Orthopaedic Surgery, School of Medicine, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Naoya Kozono
- Department of Orthopaedic Surgery, School of Medicine, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Takahiro Senju
- Department of Orthopaedic Surgery, School of Medicine, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Koichi Nakayama
- Department of Regenerative Medicine and Biomedical Engineering, Faculty of Medicine, Saga University, Honjyo 1-chome, Honjyo-cho, Saga, 840-8502, Japan
| | - Yasuharu Nakashima
- Department of Orthopaedic Surgery, School of Medicine, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka-shi, Fukuoka, 812-8582, Japan
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21
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Lei X, Yang Y, Shan G, Pan Y, Cheng B. Preparation of ADM/PRP freeze-dried dressing and effect of mice full-thickness skin defect model. Biomed Mater 2019; 14:035004. [DOI: 10.1088/1748-605x/ab0060] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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22
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Use of stem cells and growth factors in rotator cuff tendon repair. EUROPEAN JOURNAL OF ORTHOPAEDIC SURGERY AND TRAUMATOLOGY 2019; 29:747-757. [PMID: 30627922 DOI: 10.1007/s00590-019-02366-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 01/03/2019] [Indexed: 12/13/2022]
Abstract
The management of rotator cuff tears continues to prove challenging for orthopaedic surgeons. Such tears affect most age groups and can lead to significant morbidity in patients. The aetiology of these tears is likely to be multifactorial; however, an understanding of the mechanisms involved is still under review. Despite advancements in surgical operative techniques and the materials used, post-operative recurrence rates after surgical repair remain high. A growing area of research surrounds biological adjuncts used to improve the healing potential of the repaired tissues. This review of recent publications focuses on the strengths and limitations of using stem cells and growth factors in rotator cuff repair.
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23
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Bianco ST, Moser HL, Galatz LM, Huang AH. Biologics and stem cell-based therapies for rotator cuff repair. Ann N Y Acad Sci 2018; 1442:35-47. [PMID: 30008172 DOI: 10.1111/nyas.13918] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 06/01/2018] [Accepted: 06/11/2018] [Indexed: 12/20/2022]
Abstract
The rotator cuff is composed of several distinct muscles and tendons that function in concert to coordinate shoulder motion. Injuries to these tendons frequently result in permanent dysfunction and persistent pain. Despite considerable advances in operation techniques, surgical repair alone still does not fully restore rotator cuff function. This review focuses on recent research in the use of biologics and stem cell-based therapies to augment repair, highlighting promising avenues for future work and remaining challenges. While a number of animal models are used for rotator cuff studies, the anatomy of the rotator cuff varies dramatically between species. Since the rodent rotator cuff shares the most anatomical features with the human, this review will focus primarily on rodent models to enable consistent interpretation of outcome measures.
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Affiliation(s)
- Spencer T Bianco
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Helen L Moser
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York.,Shoulder, Elbow and Orthopaedic Sports Medicine, Department of Orthopaedic Surgery and Traumatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Leesa M Galatz
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Alice H Huang
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
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24
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Mistry J, Henn RF, Etcheson JI, Gwam CU, George NE, Delanois RE. Biologic Therapies as Adjunctive Treatments in Rotator Cuff Repair. JBJS Rev 2018; 6:e1. [PMID: 29979232 DOI: 10.2106/jbjs.rvw.17.00149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Jaydev Mistry
- Rubin Institute for Advanced Orthopedics, Center for Joint Preservation and Replacement, Sinai Hospital of Baltimore, Baltimore, Maryland
| | - R Frank Henn
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland
| | - Jennifer I Etcheson
- Rubin Institute for Advanced Orthopedics, Center for Joint Preservation and Replacement, Sinai Hospital of Baltimore, Baltimore, Maryland
| | - Chukwuweike U Gwam
- Rubin Institute for Advanced Orthopedics, Center for Joint Preservation and Replacement, Sinai Hospital of Baltimore, Baltimore, Maryland
| | - Nicole E George
- Rubin Institute for Advanced Orthopedics, Center for Joint Preservation and Replacement, Sinai Hospital of Baltimore, Baltimore, Maryland
| | - Ronald E Delanois
- Rubin Institute for Advanced Orthopedics, Center for Joint Preservation and Replacement, Sinai Hospital of Baltimore, Baltimore, Maryland
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25
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Bedeir YH, Jimenez AE, Grawe BM. Recurrent tears of the rotator cuff: Effect of repair technique and management options. Orthop Rev (Pavia) 2018; 10:7593. [PMID: 30057724 PMCID: PMC6042049 DOI: 10.4081/or.2018.7593] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 04/13/2018] [Indexed: 12/13/2022] Open
Abstract
Retears of the rotator cuff, following operative repair, is not an uncommon event. Various factors have been shown to influence recurrence including the technique of repair. Multiple techniques have been performed with varying results and complications. The repair technique significantly affects the rate and pattern of retears. Although risk of retears with double row and suture bridge techniques is relatively low, medial cuff failure is a potential complication which poses significant challenges when revision repair is undertaken. Modifications in surgical techniques in, both, double row and suture bridge repairs can help decrease the risk of medial cuff failure. Thorough analysis of retear rates and patterns reported, and their relation with the repair technique, provides new insights about the pathogenesis of rotator cuff retears, their future prevention and appropriate management.
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Affiliation(s)
- Yehia H Bedeir
- Department of Orthopedic Surgery, University of Cincinnati Medical Center, OH, USA.,Department of Orthopedic Surgery, University of Alexandria Medical School, Egypt
| | - Andrew E Jimenez
- Department of Orthopedic Surgery, University of Cincinnati Medical Center, OH, USA
| | - Brian M Grawe
- Department of Orthopedic Surgery, University of Cincinnati Medical Center, OH, USA
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26
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Ide J, Tokunaga T. Rotator cuff tendon-to-bone healing at 12 months after patch grafting of acellular dermal matrix in an animal model. J Orthop Sci 2018; 23:207-212. [PMID: 29277362 DOI: 10.1016/j.jos.2017.11.018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 11/13/2017] [Accepted: 12/05/2017] [Indexed: 02/09/2023]
Abstract
There is no report to investigate the histology and biomechanical strength of remodeled tendon-to-bone junction more than 6 months after patch grafting with acellular dermal matrix (ADM) on rotator cuff defect. We investigated those 12 months after surgery and hypothesized that a new native enthesis is not regenerated and the biomechanical strength is inferior to normal control. Adult male Sprague-Dawley rats underwent ADM patch grafting for the rotator cuff defect. Quantitative histological analysis, immunohistochemical analysis for collagen type I and III, and biomechanical testing were performed 12 months after surgery. The controls were unoperated age-matched rats. In the grafted rats, the collagen arrangement was more irregular and the fibrocartilage layer was smaller at the tendon-bone interface than in the controls although dense collagen fibers in the remodeled tendon were observed; the number of chondrocytes, the percentage of chondrocytes aligned in rows, and the area of the fibrocartilage layer were significantly smaller than in the control group (p = 0.0252, 0.0039, and 0.0252, respectively). Grafted specimens showed significantly lower collagen organization in the midsubstance and tendon-bone interface than the controls (p = 0.0252 and 0.0374, respectively). Immunohistochemical analysis demonstrated that the remodeled tendon fibers were stained more strongly for type III than type I. At 12 months postoperatively, the ultimate load to failure was significantly lower in the graft group than normal control (p = 0.0026); that was 47.8% of normal controls. 12 months after rotator cuff patch grafting with ADM, the formation of a new enthesis grossly resembled the native structure but there was poor cellular organization and the biomechanical strength of remodeled tendon-to-bone was only 48% of normal controls. Advances in tissue engineering and postoperative rehabilitation are needed to promote the healing process after rotator cuff patch grafting.
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Affiliation(s)
- Junji Ide
- Department of Advanced Joint Reconstructive Surgery, Kumamoto University Hospital, Kumamoto University, Kumamoto, Japan.
| | - Takuya Tokunaga
- Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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27
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Charles MD, Christian DR, Cole BJ. The Role of Biologic Therapy in Rotator Cuff Tears and Repairs. Curr Rev Musculoskelet Med 2018; 11:150-161. [PMID: 29411322 DOI: 10.1007/s12178-018-9469-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE OF REVIEW The purpose of this review was to establish the foundation of the major biologic adjuvants to rotator cuff repairs and review recent scientific findings. RECENT FINDINGS Platelet-rich plasma (PRP) overall has no significant impact on functional outcomes and repair integrity, but may be more advantageous in small to medium tears. Further studies should focus on leukocyte-rich versus poor preparations and the use of PRP in patients that are high risk for repair failure. Biologic and synthetic patches or augments provide mechanical stability for large and massive rotator cuff tears and decrease re-tear rates. Mesenchymal stem cells have demonstrated improved healing rates without an impact on outcomes. Cytokines and growth factors show promise in animal models, but require human trials to further evaluate. In massive or revision repairs, allograft or synthetic patch augmentation should be considered. Platelet-rich plasma may have benefit in smaller tears. Further studies are needed to evaluate the value of mesenchymal stem cells and various cytologic chemical signals.
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Affiliation(s)
- Michael D Charles
- Department of Orthopaedics, Rush University Medical Center, Chicago, IL, USA
| | - David R Christian
- Department of Orthopaedics, Rush University Medical Center, Chicago, IL, USA
| | - Brian J Cole
- Department of Orthopaedics, Rush University Medical Center, Chicago, IL, USA. .,, Chicago, USA.
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28
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Narayanan G, Nair LS, Laurencin CT. Regenerative Engineering of the Rotator Cuff of the Shoulder. ACS Biomater Sci Eng 2018; 4:751-786. [PMID: 33418763 DOI: 10.1021/acsbiomaterials.7b00631] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Rotator cuff tears often heal poorly, leading to re-tears after repair. This is in part attributed to the low proliferative ability of the resident cells (tendon fibroblasts and tendon-stem cells) upon injury to the rotator cuff tissue and the low vascularity of the tendon insertion. In addition, surgical outcomes of current techniques used in clinical settings are often suboptimal, leading to the formation of neo-tissue with poor biomechanics and structural characteristics, which results in re-tears. This has prompted interest in a new approach, which we term as "Regenerative Engineering", for regenerating rotator cuff tendons. In the Regenerative Engineering paradigm, roles played by stem cells, scaffolds, growth factors/small molecules, the use of local physical forces, and morphogenesis interplayed with clinical surgery techniques may synchronously act, leading to synergistic effects and resulting in successful tissue regeneration. In this regard, various cell sources such as tendon fibroblasts and adult tissue-derived stem cells have been isolated, characterized, and investigated for regenerating rotator cuff tendons. Likewise, numerous scaffolds with varying architecture, geometry, and mechanical characteristics of biologic and synthetic origin have been developed. Furthermore, these scaffolds have been also fabricated with biochemical cues (growth factors and small molecules), facilitating tissue regeneration. In this Review, various strategies to regenerate rotator cuff tendons using stem cells, advanced materials, and factors in the setting of physical forces under the Regenerative Engineering paradigm are described.
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Affiliation(s)
- Ganesh Narayanan
- Institute for Regenerative Engineering, University of Connecticut Health Center, Farmington, Connecticut 06030, United States.,Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, Farmington, Connecticut 06030, United States.,Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, Connecticut 06030, United States
| | - Lakshmi S Nair
- Institute for Regenerative Engineering, University of Connecticut Health Center, Farmington, Connecticut 06030, United States.,Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, Farmington, Connecticut 06030, United States.,Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, Connecticut 06030, United States.,Department of Biomedical Engineering, University of Connecticut, Storrs, Connecticut 06269, United States.,Department of Materials Science and Engineering, University of Connecticut, Storrs, Connecticut 06269, United States
| | - Cato T Laurencin
- Institute for Regenerative Engineering, University of Connecticut Health Center, Farmington, Connecticut 06030, United States.,Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, Farmington, Connecticut 06030, United States.,Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, Connecticut 06030, United States.,Department of Reconstructive Sciences, University of Connecticut Health Center, Farmington, Connecticut 06030, United States.,Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, Connecticut 06269, United States.,Department of Biomedical Engineering, University of Connecticut, Storrs, Connecticut 06269, United States.,Department of Materials Science and Engineering, University of Connecticut, Storrs, Connecticut 06269, United States.,Connecticut Institute for Clinical and Translational Science, University of Connecticut Health Center, Farmington, Connecticut 06030, United States
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29
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Sevivas N, Teixeira FG, Portugal R, Direito-Santos B, Espregueira-Mendes J, Oliveira FJ, Silva RF, Sousa N, Sow WT, Nguyen LTH, Ng KW, Salgado AJ. Mesenchymal Stem Cell Secretome Improves Tendon Cell Viability In Vitro and Tendon-Bone Healing In Vivo When a Tissue Engineering Strategy Is Used in a Rat Model of Chronic Massive Rotator Cuff Tear. Am J Sports Med 2018; 46:449-459. [PMID: 29053925 DOI: 10.1177/0363546517735850] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Massive rotator cuff tears (MRCTs) represent a major clinical concern, especially when degeneration and chronicity are involved, which highly compromise healing capacity. PURPOSE To study the effect of the secretome of mesenchymal stem cells (MSCs) on tendon cells (TCs) followed by the combination of these activated TCs with an electrospun keratin-based scaffold to develop a tissue engineering strategy to improve tendon-bone interface (TBi) healing in a chronic MRCT rat model. STUDY DESIGN Controlled laboratory study. METHODS Human TCs (hTCs) cultured with the human MSCs (hMSCs) secretome (as conditioned media [CM]) were combined with keratin electrospun scaffolds and further implanted in a chronic MRCT rat model. Wistar-Han rats (N = 15) were randomly assigned to 1 of 3 groups: untreated lesion (MRCT group, n = 5), lesion treated with a scaffold only (scaffold-only group, n = 5), and lesion treated with a scaffold seeded with hTCs preconditioned with hMSCs-CM (STC_hMSC_CM group, n = 5). After sacrifice, 16 weeks after surgery, the rotator cuff TBi was harvested for histological analysis and biomechanical testing. RESULTS The hMSCs secretome increased hTCs viability and density in vitro. In vivo, a significant improvement of the tendon maturing score was observed in the STC_hMSC_CM group (mean ± standard error of the mean, 15.6 ± 1.08) compared with the MRCT group (11.0 ± 1.38; P < .05). Biomechanical tests revealed a significant increase in the total elongation to rupture (STC_hMSC_CM, 11.99 ± 3.30 mm; scaffold-only, 9.89 ± 3.47 mm; MRCT, 5.86 ± 3.16 mm; P < .05) as well as a lower stiffness (STC_hMSC_CM, 6.25 ± 1.74 N/mm; scaffold-only, 6.72 ± 1.28 N/mm; MRCT, 11.54 ± 2.99 N/mm; P < .01). CONCLUSION The results demonstrated that hMSCs-CM increased hTCs viability and density in vitro. Clear benefits also were observed when these primed cells were integrated into a tissue engineering strategy with an electrospun keratin scaffold, as evidenced by improved histological and biomechanical properties for the STC_hMSC_CM group compared with the MRCT group. CLINICAL RELEVANCE This work supports further investigation into the use of MSC secretome for priming TCs toward a more differentiated phenotype, and it promotes the tissue engineering strategy as a promising modality to help improve treatment outcomes for chronic MRCTs.
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Affiliation(s)
- Nuno Sevivas
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.,Orthopaedics Department, Hospital de Braga and Hospital Privado de Braga, Braga, Portugal.,Clínica Espregueira-Mendes, FIFA Medical Centre of Excellence, Estádio do Dragão, Porto, Portugal
| | - Fábio Gabriel Teixeira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | | | - Bruno Direito-Santos
- Orthopaedics Department, Hospital de Braga and Hospital Privado de Braga, Braga, Portugal
| | - João Espregueira-Mendes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.,Clínica Espregueira-Mendes, FIFA Medical Centre of Excellence, Estádio do Dragão, Porto, Portugal.,3B's Research Group, Biomaterials, Biodegradables and Biomimetics, Department of Polymer Engineering, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
| | - Filipe J Oliveira
- CICECO, Department of Materials and Ceramic Engineering, University of Aveiro, Campus Universitário de Santiago, Aveiro, Portugal
| | - Rui F Silva
- CICECO, Department of Materials and Ceramic Engineering, University of Aveiro, Campus Universitário de Santiago, Aveiro, Portugal
| | - Nuno Sousa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Wan Ting Sow
- School of Materials Science and Engineering, Nanyang Technological University, Singapore
| | - Luong T H Nguyen
- School of Materials Science and Engineering, Nanyang Technological University, Singapore
| | - Kee Woei Ng
- School of Materials Science and Engineering, Nanyang Technological University, Singapore
| | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
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Tokunaga T, Karasugi T, Arimura H, Yonemitsu R, Sakamoto H, Ide J, Mizuta H. Enhancement of rotator cuff tendon-bone healing with fibroblast growth factor 2 impregnated in gelatin hydrogel sheets in a rabbit model. J Shoulder Elbow Surg 2017; 26:1708-1717. [PMID: 28506489 DOI: 10.1016/j.jse.2017.03.020] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 03/09/2017] [Accepted: 03/13/2017] [Indexed: 02/01/2023]
Abstract
BACKGROUND Application of fibroblast growth factor 2 (FGF-2) may improve the healing response after rotator cuff (RC) surgical repair. This study aimed to determine whether FGF-2-impregnated gelatin hydrogel sheet (GHS) incorporation into the bony trough on the greater tuberosity facilitates healing after RC surgical repair in rabbits. METHODS We assigned 120 adult male Japanese white rabbits treated with unilateral surgery for supraspinatus tendon repair into the following groups: suture-only group (suture); suture and GHS with phosphate-buffered saline (carrier); suture and GHS with 3 µg of FGF-2 (F3); and suture and GHS with 30 µg of FGF-2 (F30). The effect of FGF-2 was assessed using histologic, biomechanical, and microcomputed tomography evaluations at 2, 6, and 12 weeks. RESULTS At 12 weeks, loose fibrovascular tissues emerged at the repair site in the suture and carrier groups and dense tendon-like tissues in the F3 and F30 groups, which demonstrated significantly higher ultimate load-to-failure and stress-to-failure at 12 weeks than that in the suture and carrier groups. Microcomputed tomography imaging showed ectopic calcification formation in some specimens from each group. Appearances or frequencies were similar among groups. The histologic and biomechanical effects of FGF-2 on RC healing were obvious at ≥6 weeks postoperatively. CONCLUSION FGF-2-impregnated GHS incorporation into the bony trough on the greater tuberosity before RC surgical repair is feasible and results in histologic and biomechanical improvements during RC healing in rabbits. No detrimental effect on ectopic calcification was observed.
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Affiliation(s)
- Takuya Tokunaga
- Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
| | - Tatsuki Karasugi
- Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hitoshi Arimura
- Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Ryuji Yonemitsu
- Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hidetoshi Sakamoto
- Department of Mechanical System Engineering, Doshisha University, Kyoto, Japan
| | - Junji Ide
- Department of Advanced Joint Reconstructive Surgery, Kumamoto University Hospital, Kumamoto, Japan
| | - Hiroshi Mizuta
- Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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Engineered stem cell niche matrices for rotator cuff tendon regenerative engineering. PLoS One 2017; 12:e0174789. [PMID: 28369135 PMCID: PMC5378368 DOI: 10.1371/journal.pone.0174789] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 03/15/2017] [Indexed: 12/29/2022] Open
Abstract
Rotator cuff (RC) tears represent a large proportion of musculoskeletal injuries attended to at the clinic and thereby make RC repair surgeries one of the most widely performed musculoskeletal procedures. Despite the high incidence rate of RC tears, operative treatments have provided minimal functional gains and suffer from high re-tear rates. The hypocellular nature of tendon tissue poses a limited capacity for regeneration. In recent years, great strides have been made in the area of tendonogenesis and differentiation towards tendon cells due to a greater understanding of the tendon stem cell niche, development of advanced materials, improved scaffold fabrication techniques, and delineation of the phenotype development process. Though in vitro models for tendonogenesis have shown promising results, in vivo models have been less successful. The present work investigates structured matrices mimicking the tendon microenvironment as cell delivery vehicles in a rat RC tear model. RC injuries augmented with a matrix delivering rat mesenchymal stem cells (rMSCs) showed enhanced regeneration over suture repair alone or repair with augmentation, at 6 and 12-weeks post-surgery. The local delivery of rMSCs led to increased mechanical properties and improved tissue morphology. We hypothesize that the mesenchymal stem cells function to modulate the local immune and bioactivity environment through autocrine/paracrine and/or cell homing mechanisms. This study provides evidence for improved tendon healing with biomimetic matrices and delivered MSCs with the potential for translation to larger, clinical animal models. The enhanced regenerative healing response with stem cell delivering biomimetic matrices may represent a new treatment paradigm for massive RC tendon tears.
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Liu Y, Suen CW, Zhang JF, Li G. Current concepts on tenogenic differentiation and clinical applications. J Orthop Translat 2017; 9:28-42. [PMID: 29662797 PMCID: PMC5822963 DOI: 10.1016/j.jot.2017.02.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 02/21/2017] [Accepted: 02/23/2017] [Indexed: 12/16/2022] Open
Abstract
Tendon is a tissue that transmits force from muscle to bone. Chronic or acute tendon injuries are very common, and are always accompanied by pain and a limited range of motion in patients. In clinical settings, management of tendon injuries still remains a big challenge. Cell therapies, such as the application of stem cells for tenogenic differentiation, were suggested to be an ideal strategy for clinical translation. However, there is still a lack of specific methods for tenogenic differentiation due to the limited understanding of tendon biology currently. This review focuses on the summary of current published strategies for tenogenic differentiation, such as the application of growth factors, mechanical stimulation, biomaterials, coculture, or induced pluripotent stem cells. Current clinical applications of stem cells for treatment of tendon injuries and their limitations have also been discussed in this review.
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Affiliation(s)
- Yang Liu
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Chun-Wai Suen
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Jin-fang Zhang
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Gang Li
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
- Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
- Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, China
- Corresponding author. Department of Orthopaedics and Traumatology and Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong, China.Department of Orthopaedics and Traumatology and Li Ka Shing Institute of Health SciencesPrince of Wales HospitalThe Chinese University of Hong Kong30-32 Ngan Shing StreetShatinNew TerritoriesHong Kong, China
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Giotis D, Aryaei A, Vasilakakos T, Paschos NK. Effectiveness of Biologic Factors in Shoulder Disorders. Open Orthop J 2017; 11:163-182. [PMID: 28400884 PMCID: PMC5366381 DOI: 10.2174/1874325001711010163] [Citation(s) in RCA: 6] [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: 01/01/2016] [Revised: 04/20/2016] [Accepted: 04/20/2016] [Indexed: 12/17/2022] Open
Abstract
Background: Shoulder pathology can cause significant pain, discomfort, and loss of function that all interfere with activities of daily living and may lead to poor quality of life. Primary osteoarthritis and rotator cuff diseases with its sequalae are the main culprits. Management of shoulder disorders using biological factors gained an increasing interest over the last years. This interest reveals the need of effective treatments for shoulder degenerative disorders, and highlights the importance of a comprehensive and detailed understanding of the rapidly increasing knowledge in the field. Methods: This study will describe most of the available biology-based strategies that have been recently developed, focusing on their effectiveness in animal and clinical studies. Results: Data from in vitro work will also be briefly presented; in order to further elucidate newly acquired knowledge regarding mechanisms of tissue degeneration and repair that would probably drive translational work in the next decade. The role of platelet rich-plasma, growth factors, stem cells and other alternative treatments will be described in an evidence-based approach, in an attempt to provide guidelines for their clinical application. Finally, certain challenges that biologic treatments face today will be described as an initiative for future strategies. Conclusion: The application of different growth factors and mesenchymal stem cells appears as promising approaches for enhancing biologic repair. However, data from clinical studies are still limited, and future studies need to improve understanding of the repair process in cellular and molecular level and evaluate the effectiveness of biologic factors in the management of shoulder disorders.
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Affiliation(s)
- Dimitrios Giotis
- Department of Trauma & Orthopaedic Surgery, University of Ioannina, Ioannina, Greece
| | - Ashkan Aryaei
- Department of Biomedical Engineering, University of California, Davis, USA
| | - Theofanis Vasilakakos
- Department of Trauma & Orthopaedic Surgery, University of Ioannina, Ioannina, Greece
| | - Nikolaos K Paschos
- Department of Trauma & Orthopaedic Surgery, University of Ioannina, Ioannina, Greece; Department of Biomedical Engineering, University of California, Davis, USA
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Farnebo S, Farnebo L, Kim M, Woon C, Pham H, Chang J. Optimized Repopulation of Tendon Hydrogel: Synergistic Effects of Growth Factor Combinations and Adipose-Derived Stem Cells. Hand (N Y) 2017; 12:68-77. [PMID: 28082847 PMCID: PMC5207276 DOI: 10.1177/1558944715628005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Background: Tendon-derived extracellular matrix (ECM) hydrogel has been shown to augment tendon healing in vivo. We hypothesized that reseeding of the gel with adipose-derived stem cells (ASCs) could further assist repopulation of the gel and that combinations of growth factors (GFs) would improve the survival of these cells after reseeding. Methods: A tendon-specific ECM solution was supplemented with varying concentrations of basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), and platelet-derived growth factor-BB (PDGF-BB). Gels were then seeded with ASCs transfected with a green fluorescent protein/luciferin construct. Cell proliferation was determined using the MTT assay and histology, and GF and ASC augmented gels were injected into the back of Sprague Dawley rats. Bioluminescence of seeded gels was continuously followed after reseeding, and cell counts were performed after the gels were explanted at 14 days. Results: Synergistic effects of the GFs were seen, and an optimal combination was determined to be 10 ng/mL bFGF, 100 ng/mL IGF-1, and 100 ng/mL PDGF-BB (2.8-fold increase; P < .05). In vivo bioluminescence showed an improved initial survival of cells in gels supplemented with the optimal concentration of GF compared with the control group (10.6-fold increase at 8 days; P < .05). Cell counts of explants showed a dramatic endogenous repopulation of gels supplemented by GF + ASCs compared with both gels with GF but no ASCs (7.6-fold increase) and gels with ASCs but no GF (1.6-fold increase). Conclusion: Synergistic effects of GFs can be used to improve cellular proliferation of ASCs seeded to a tendon ECM gel. Reseeding with ASCs stimulates endogenous repopulation of the gel in vivo and may be used to further augment tendon healing.
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Affiliation(s)
- Simon Farnebo
- VA Palo Alto Health Care System, Livermore, CA, USA,Linköping University, Sweden,Simon Farnebo, Division of Plastic Surgery, Stanford University Medical Center, 770 Welch Road, Suite 400, Stanford, CA 94305, USA.
| | | | - Maxwell Kim
- VA Palo Alto Health Care System, Livermore, CA, USA,Stanford University, CA, USA
| | - Colin Woon
- VA Palo Alto Health Care System, Livermore, CA, USA,Stanford University, CA, USA
| | - Hung Pham
- VA Palo Alto Health Care System, Livermore, CA, USA,Stanford University, CA, USA
| | - James Chang
- VA Palo Alto Health Care System, Livermore, CA, USA,Stanford University, CA, USA
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36
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Biologic and Tissue Engineering Strategies for Tendon Repair. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2016. [DOI: 10.1007/s40883-016-0019-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Greenspoon JA, Moulton SG, Millett PJ, Petri M. The Role of Platelet Rich Plasma (PRP) and Other Biologics for Rotator Cuff Repair. Open Orthop J 2016; 10:309-314. [PMID: 27708732 PMCID: PMC5039951 DOI: 10.2174/1874325001610010309] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Revised: 08/07/2015] [Accepted: 02/01/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Surgical treatment of rotator cuff tears has consistently demonstrated good clinical and functional outcomes. However, in some cases, the rotator cuff fails to heal. While improvements in rotator cuff constructs and biomechanics have been made, the role of biologics to aid healing is currently being investigated. METHODS A selective literature search was performed and personal surgical experiences are reported. RESULTS Biologic augmentation of rotator cuff repairs can for example be performed wtableith platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs). Clinical results on PRP application have been controversial. Application of MSCs has shown promise in animal studies, but clinical data on its effectiveness is presently lacking. The role of Matrix Metalloproteinase (MMP) inhibitors is another interesting field for potential targeted drug therapy after rotator cuff repair. CONCLUSIONS Large randomized clinical studies need to confirm the benefit of these approaches, in order to eventually lower retear rates and improve clinical outcomes after rotator cuff repair.
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Affiliation(s)
- Joshua A. Greenspoon
- Steadman Philippon Research Institute, 181 West Meadow Drive, Suite 1000 Vail, CO, 81657, USA
| | - Samuel G. Moulton
- Steadman Philippon Research Institute, 181 West Meadow Drive, Suite 1000 Vail, CO, 81657, USA
| | - Peter J. Millett
- Steadman Philippon Research Institute, 181 West Meadow Drive, Suite 1000 Vail, CO, 81657, USA
- The Steadman Clinic, 181 West Meadow Drive Vail, CO, 81657, USA
| | - Maximilian Petri
- Steadman Philippon Research Institute, 181 West Meadow Drive, Suite 1000 Vail, CO, 81657, USA
- The Steadman Clinic, 181 West Meadow Drive Vail, CO, 81657, USA
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Murray IR, LaPrade RF, Musahl V, Geeslin AG, Zlotnicki JP, Mann BJ, Petrigliano FA. Biologic Treatments for Sports Injuries II Think Tank-Current Concepts, Future Research, and Barriers to Advancement, Part 2: Rotator Cuff. Orthop J Sports Med 2016; 4:2325967116636586. [PMID: 27099865 PMCID: PMC4820026 DOI: 10.1177/2325967116636586] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Rotator cuff tears are common and result in considerable morbidity. Tears within the tendon substance or at its insertion into the humeral head represent a considerable clinical challenge because of the hostile local environment that precludes healing. Tears often progress without intervention, and current surgical treatments are inadequate. Although surgical implants, instrumentation, and techniques have improved, healing rates have not improved, and a high failure rate remains for large and massive rotator cuff tears. The use of biologic adjuvants that contribute to a regenerative microenvironment have great potential for improving healing rates and function after surgery. This article presents a review of current and emerging biologic approaches to augment rotator cuff tendon and muscle regeneration focusing on the scientific rationale, preclinical, and clinical evidence for efficacy, areas for future research, and current barriers to advancement and implementation.
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Affiliation(s)
| | | | - Volker Musahl
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Andrew G Geeslin
- Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA
| | - Jason P Zlotnicki
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Barton J Mann
- Author deceased.; American Orthopaedic Society for Sports Medicine, Rosemont, Illinois, USA
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Müller SA, Todorov A, Heisterbach PE, Martin I, Majewski M. Tendon healing: an overview of physiology, biology, and pathology of tendon healing and systematic review of state of the art in tendon bioengineering. Knee Surg Sports Traumatol Arthrosc 2015; 23:2097-105. [PMID: 24057354 DOI: 10.1007/s00167-013-2680-z] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2013] [Accepted: 09/07/2013] [Indexed: 12/18/2022]
Abstract
PURPOSE Tendon injuries vary from acute rupture to chronic tendinopathy. For an optimal treatment of either condition, a profound knowledge is essential. Therefore, this article shall give an overview of physiology, biology, and pathology of tendon healing and state of the art in tendon bioengineering. METHODS For a preferably comprehensive survey, the current literature listed in PubMed and published in English peer-reviewed journals (March 2013) was systematically reviewed for tendon healing and tendon bioengineering including cytokine modulation, autologous sources of growth factors, biomaterials, gene therapy, and cell-based therapy. No differentiation was made between clinical and preclinical in vitro investigations. RESULTS Tendon healing happens in certain stadiums of inflammation, formation, and remodelling. An additional process of "collagen recycling" close to the healing site has been described recently. With increasing comprehension of physiology and pathology of tendon healing, several promising approaches in tendon bioengineering using growth factors, biomaterials, gene therapy, or cell-based therapy are described. However, only some of these are already used routinely in clinics. CONCLUSION Strong and resistant tendons are crucial for a healthy musculoskeletal system. The new approaches in tendon bioengineering are promising to aid physiological tendon healing and thus resulting in a stronger and more resistant tendon after injury. The growing knowledge in this field will need to be further taken into clinical studies so that especially those patients with prolonged courses, revision surgery, or chronic tendinopathy and high-demanding patients, i.e., professional athletes would benefit. LEVEL OF EVIDENCE II.
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Affiliation(s)
- Sebastian A Müller
- Department of Orthopedic Surgery, University Hospital Basel, Spitalstrasse 21, 4031, Basel, Switzerland,
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40
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Ross D, Maerz T, Kurdziel M, Hein J, Doshi S, Bedi A, Anderson K, Baker K. The effect of granulocyte-colony stimulating factor on rotator cuff healing after injury and repair. Clin Orthop Relat Res 2015; 473:1655-64. [PMID: 25733010 PMCID: PMC4385377 DOI: 10.1007/s11999-015-4218-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND The failure rate of tendon-bone healing after repair of rotator cuff tears remains high. A variety of biologic- and cell-based therapies aimed at improving rotator cuff healing have been investigated, and stem cell-based techniques have become increasingly more common. However, most studies have focused on the implantation of exogenous cells, which introduces higher risk and cost. We aimed to improve rotator cuff healing by inducing endogenous stem cell mobilization with systemic administration of granulocyte-colony stimulating factor (G-CSF). QUESTIONS/PURPOSES We asked: (1) Does G-CSF administration increase local cellularity after acute rotator cuff repair? (2) Is there histologic evidence that G-CSF improved organization at the healing enthesis? (3) Does G-CSF administration improve biomechanical properties of the healing supraspinatus tendon-bone complex? (4) Are there micro-MRI-based observations indicating G-CSF-augmented tendon-bone healing? METHODS After creation of full-thickness supraspinatus tendon defects with immediate repair, 52 rats were randomized to control or G-CSF-treated groups. G-CSF was administered for 5 days after repair and rats were euthanized at 12 or 19 postoperative days. Shoulders were subjected to micro-MR imaging, stress relaxation, and load-to-failure as well as blinded histologic and histomorphometric analyses. RESULTS G-CSF-treated animals had significantly higher cellularity composite scores at 12 and 19 days compared with both control (12 days: 7.40 ± 1.14 [confidence interval {CI}, 5.98-8.81] versus 4.50 ± 0.57 [CI, 3.58-5.41], p = 0.038; 19 days: 8.00 ± 1.00 [CI, 6.75-9.24] versus 5.40 ± 0.89 [CI, 4.28-6.51], p = 0.023) and normal animals (12 days: p = 0.029; 19 days: p = 0.019). There was no significant difference between G-CSF-treated animals or control animals in ultimate stress (MPa) and strain, modulus (MPa), or yield stress (MPa) and strain at either 12 days (p = 1.000, p = 0.104, p = 1.000, p = 0.909, and p = 0.483, respectively) or 19 days (p = 0.999, p = 0.964, p = 1.000, p = 0.988, and p = 0.904, respectively). There was no difference in MRI score between G-CSF and control animals at either 12 days (2.7 ± 1.8 [CI, 1.08-4.24] versus 2.3 ± 1.8 [CI, 0.49-4.17], p = 0.623) or 19 days (2.5 ± 1.4 [CI, 1.05-3.94] versus 2.3 ± 1.5 [CI, 0.75-3.91], p = 0.737). G-CSF-treated animals exhibited significantly lower relative bone volume compared with normal animals in the entire humeral head (24.89 ± 3.80 [CI, 20.17-29.60) versus 32.50 ± 2.38 [CI, 29.99-35.01], p = 0.009) and at the supraspinatus insertion (25.67 ± 5.33 [CI, 19.04-32.29] versus 33.36 ± 1.69 [CI, 31.58-35.14], p = 0.027) at 12 days. Further analysis did not reveal any additional significant relationships with respect to regional bone volume or trabecular thickness between groups and time points (p > 0.05). CLINICAL RELEVANCE Postoperative stem cell mobilization agents may be an effective way to enhance rotator cuff repair. Future studies regarding the kinetics of mobilization, the homing capacity of mobilized cells to injured tissues, and the ability of homing cells to participate in regenerative pathways are necessary.
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Affiliation(s)
- David Ross
- />Department of Orthopaedic Surgery, Beaumont Health System, Royal Oak, MI USA
| | - Tristan Maerz
- />Orthopaedic Research Laboratories, Beaumont Health System, 3811 W 13 Mile Road, Royal Oak, MI 48073 USA
| | - Michael Kurdziel
- />Orthopaedic Research Laboratories, Beaumont Health System, 3811 W 13 Mile Road, Royal Oak, MI 48073 USA
| | - Joel Hein
- />Department of Orthopaedic Surgery, Beaumont Health System, Royal Oak, MI USA
| | - Shashin Doshi
- />Department of Diagnostic Radiology, Beaumont Health System, Royal Oak, MI USA
| | - Asheesh Bedi
- />Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, MI USA
| | - Kyle Anderson
- />Department of Orthopaedic Surgery, Beaumont Health System, Royal Oak, MI USA
| | - Kevin Baker
- />Orthopaedic Research Laboratories, Beaumont Health System, 3811 W 13 Mile Road, Royal Oak, MI 48073 USA
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Abstract
Tendon injuries are common and present a clinical challenge to orthopedic surgery mainly because these injuries often respond poorly to treatment and require prolonged rehabilitation. Therapeutic options used to repair ruptured tendons have consisted of suture, autografts, allografts, and synthetic prostheses. To date, none of these alternatives has provided a successful long-term solution, and often the restored tendons do not recover their complete strength and functionality. Unfortunately, our understanding of tendon biology lags far behind that of other musculoskeletal tissues, thus impeding the development of new treatment options for tendon conditions. Hence, in this review, after introducing the clinical significance of tendon diseases and the present understanding of tendon biology, we describe and critically assess the current strategies for enhancing tendon repair by biological means. These consist mainly of applying growth factors, stem cells, natural biomaterials and genes, alone or in combination, to the site of tendon damage. A deeper understanding of how tendon tissue and cells operate, combined with practical applications of modern molecular and cellular tools could provide the long awaited breakthrough in designing effective tendon-specific therapeutics and overall improvement of tendon disease management.
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Kim MC, Kim MS. Characteristics of Animal Shoulder Models for Rotator Cuff Experiments. Clin Shoulder Elb 2015. [DOI: 10.5397/cise.2015.18.1.52] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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Abtahi AM, Granger EK, Tashjian RZ. Factors affecting healing after arthroscopic rotator cuff repair. World J Orthop 2015; 6:211-220. [PMID: 25793161 PMCID: PMC4363803 DOI: 10.5312/wjo.v6.i2.211] [Citation(s) in RCA: 142] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Revised: 08/06/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023] Open
Abstract
Rotator cuff repair has been shown to have good long-term results. Unfortunately, a significant proportion of repairs still fail to heal. Many factors, both patient and surgeon related, can influence healing after repair. Older age, larger tear size, worse muscle quality, greater muscle-tendon unit retraction, smoking, osteoporosis, diabetes and hypercholesterolemia have all shown to negatively influence tendon healing. Surgeon related factors that can influence healing include repair construct-single vs double row, rehabilitation, and biologics including platelet rich plasma and mesenchymal stem cells. Double-row repairs are biomechanically stronger and have better healing rates compared with single-row repairs although clinical outcomes are equivalent between both constructs. Slower, less aggressive rehabilitation programs have demonstrated improved healing with no negative effect on final range of motion and are therefore recommended after repair of most full thickness tears. Additionally no definitive evidence supports the use of platelet rich plasma or mesenchymal stem cells regarding improvement of healing rates and clinical outcomes. Further research is needed to identify effective biologically directed augmentations that will improve healing rates and clinical outcomes after rotator cuff repair.
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Warth RJ, Dornan GJ, James EW, Horan MP, Millett PJ. Clinical and structural outcomes after arthroscopic repair of full-thickness rotator cuff tears with and without platelet-rich product supplementation: a meta-analysis and meta-regression. Arthroscopy 2015; 31:306-20. [PMID: 25450417 DOI: 10.1016/j.arthro.2014.09.007] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 09/08/2014] [Accepted: 09/09/2014] [Indexed: 02/02/2023]
Abstract
PURPOSE The purpose of this study was to perform a systematic review, meta-analysis, and meta-regression of all Level I and Level II studies comparing the clinical or structural outcomes, or both, after rotator cuff repair with and without platelet-rich product (PRP) supplementation. METHODS A literature search of the PubMed and EMBASE databases was performed to identify all Level I or II studies comparing the clinical or structural outcomes, or both, after arthroscopic repair of full-thickness rotator cuff tears with (PRP+ group) and without (PRP- group) PRP supplementation. Data included outcome scores (American Shoulder and Elbow Surgeons [ASES], University of California Los Angeles [UCLA], Constant, Simple Shoulder Test [SST] and visual analog scale [VAS] scores) and retears diagnosed with imaging studies. Meta-analyses compared preoperative, postoperative, and gain in outcome scores and relative risk ratios for retears. Meta-regression compared the effect of PRP treatment on outcome scores and retear rates according to 6 covariates. Minimum effect sizes that were detectable with 80% power were also calculated for each study. RESULTS Eleven studies were included in this review and a maximum of 8 studies were used for meta-analyses according to data availability. There were no statistically significant differences between the PRP+ and PRP- groups for overall outcome scores or retear rates (P > .05). Overall gain in the Constant score was decreased when liquid PRP was injected over the tendon surface compared with PRP application at the tendon-bone interface (-6.88 points v +0.78 points, respectively; P = .046); however, this difference did not reach the previously reported minimum clinically important difference (MCID) for Constant scores. When the initial tear size was greater than 3 cm in anterior-posterior length, the PRP+ group exhibited decreased retear rates after double-row repairs when compared with the PRP- group (25.9% v 57.1%, respectively; P = .046). Sensitivity power analyses revealed that most included studies were only powered to detect large differences in outcome scores between groups. CONCLUSIONS There were no statistically significant differences in overall gain in outcome scores or retear rates between treatment groups. Gain in Constant scores was significantly increased when PRPs were applied at the tendon-bone interface when compared with application over the top of the repaired tendon. Retear rates were significantly decreased when PRPs were used for the treatment of tears greater than 3 cm in anterior-posterior length using a double-row technique. Most of the included studies were only powered to detect large differences in outcome scores between treatment groups. In addition, an increased risk for selection, performance, and attrition biases was found. LEVEL OF EVIDENCE Level II, meta-analysis of Level I and Level II studies.
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Affiliation(s)
- Ryan J Warth
- Steadman Philippon Research Institute, Vail, Colorado, U.S.A
| | - Grant J Dornan
- Steadman Philippon Research Institute, Vail, Colorado, U.S.A
| | - Evan W James
- Steadman Philippon Research Institute, Vail, Colorado, U.S.A
| | - Marilee P Horan
- Steadman Philippon Research Institute, Vail, Colorado, U.S.A
| | - Peter J Millett
- Steadman Philippon Research Institute, Vail, Colorado, U.S.A.; The Steadman Clinic, Vail, Colorado, U.S.A..
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Zhao S, Xie X, Pan G, Shen P, Zhao J, Cui W. Healing improvement after rotator cuff repair using gelatin-grafted poly(L-lactide) electrospun fibrous membranes. J Surg Res 2014; 193:33-42. [PMID: 25241723 DOI: 10.1016/j.jss.2014.08.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 08/05/2014] [Accepted: 08/13/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND Rotator cuff tears (RCTs) are a common cause of shoulder pain and disability in middle and older age. Despite improvements in the understanding of this disease process and advances in surgical treatment, rotator cuff (RC) repair failure rates remain high. Insufficient healing capacity is likely the main factor for failure of reconstruction. MATERIALS AND METHODS We fabricated implantable biodegradable gelatin-grafted poly(L-lactide) (PLLA) fibrous membranes using electrospinning technology and evaluated them using in vitro cell proliferation assays. Then, we established chronic rat RCT models and randomly assigned rats into one of three groups. In group 1 (n = 48), the detached supraspinatus tendon was repaired to its anatomic footprint (transosseous repair). In groups 2 and 3, the rats underwent transosseous repair and were implanted with either pure PLLA membranes (n = 48) or gelatin-PLLA membranes (n = 48) to augment the repairs. The animals were killed at 2, 4, and 8 wk postoperatively, which was followed by histomorphometric and biomechanical evaluation. RESULTS Histologic observations revealed that gelatin-PLLA membranes have excellent biocompatibility and biodegradability. At 2, 4, and 8 wk postoperatively, the gelatin-PLLA membranes significantly increased the area of glycosaminoglycan staining at the tendon-bone interface compared with the control group (P < 0.05) and significantly improved collagen organization, as measured by birefringence under polarized light at the healing enthesis compared with the control and PLLA groups (P < 0.05). Biomechanical testing revealed that the gelatin-PLLA group had a greater ultimate load to failure and stiffness than the control group at 4 and 8 wk (P < 0.05). The gelatin-PLLA membranes had the highest stress of the healing enthesis. CONCLUSIONS Local application of gelatin-PLLA fibrous membranes to the healing tendon-bone interface after RC repair in a rat chronic RCT model was found to strengthen the healing enthesis, increase the area of fibrocartilage, and improve collagen organization compared with repair alone. Augmentation with gelatin-grafted PLLA may enhance healing after RC repair and might eventually lead to improvement of clinical surgical outcomes.
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Affiliation(s)
- Song Zhao
- Department of Orthopaedics, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, P. R. China
| | - Xiaoxing Xie
- Department of Orthopedics, Changzheng Hospital, Second Military Medical University of China, Shanghai, P. R. China
| | - Guoqing Pan
- Orthopedic Institute, Soochow University, Suzhou, Jiangsu, P.R. China; Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China
| | - Peng Shen
- Department of Arthroscopic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Jinzhong Zhao
- Department of Arthroscopic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
| | - Wenguo Cui
- Orthopedic Institute, Soochow University, Suzhou, Jiangsu, P.R. China; Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.
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Regenerative medicine in rotator cuff injuries. BIOMED RESEARCH INTERNATIONAL 2014; 2014:129515. [PMID: 25184132 PMCID: PMC4145545 DOI: 10.1155/2014/129515] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 07/23/2014] [Accepted: 07/27/2014] [Indexed: 02/07/2023]
Abstract
Rotator cuff injuries are a common source of shoulder pathology and result in an important decrease in quality of patient life. Given the frequency of these injuries, as well as the relatively poor result of surgical intervention, it is not surprising that new and innovative strategies like tissue engineering have become more appealing. Tissue-engineering strategies involve the use of cells and/or bioactive factors to promote tendon regeneration via natural processes. The ability of numerous growth factors to affect tendon healing has been extensively analyzed in vitro and in animal models, showing promising results. Platelet-rich plasma (PRP) is a whole blood fraction which contains several growth factors. Controlled clinical studies using different autologous PRP formulations have provided controversial results. However, favourable structural healing rates have been observed for surgical repair of small and medium rotator cuff tears. Cell-based approaches have also been suggested to enhance tendon healing. Bone marrow is a well known source of mesenchymal stem cells (MSCs). Recently, ex vivo human studies have isolated and cultured distinct populations of MSCs from rotator cuff tendons, long head of the biceps tendon, subacromial bursa, and glenohumeral synovia. Stem cells therapies represent a novel frontier in the management of rotator cuff disease that required further basic and clinical research.
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Uezono K, Ide J, Tokunaga T, Arimura H, Sakamoto H, Nakanishi Y, Mizuta H. Effect of Postoperative Passive Motion on Rotator Cuff Reconstruction With Acellular Dermal Matrix Grafts in a Rat Model. Am J Sports Med 2014; 42:1930-8. [PMID: 24812197 DOI: 10.1177/0363546514532338] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Although postoperative rehabilitation is critical for rotator cuff tendon-to-bone healing and shoulder function recovery, no standardized protocol has been established. HYPOTHESIS Postoperative immediate passive motion is detrimental to tendon-to-bone remodeling and tendon maturation after rotator cuff acellular dermal matrix (ADM) grafting, although postoperative delayed passive motion does no harm. STUDY DESIGN Controlled laboratory study. METHODS Male Sprague-Dawley rats underwent rotator cuff reconstruction with ADM grafts. Their shoulders were immobilized for 2 weeks thereafter. The rats were assigned to 3 different rehabilitation protocols: (1) immobilization without passive motion (nonpassive motion [N-PM], controls), (2) immobilization with immediate passive motion (I-PM), and (3) immobilization with delayed passive motion (D-PM). Specimens obtained 2, 6, and 12 weeks postoperatively were analyzed histologically, and semiquantitative histomorphological measurements of collagen organization, vascularity, and cellularity were obtained; the area of interest was divided into 2 zones, the midsubstance of the graft and the graft-bone interface. Another set of samples taken at 12 weeks was subjected to biomechanical analysis. RESULTS At 2 weeks, there was no significant difference among the groups in terms of semiquantitative histomorphological measurements of collagen organization, vascularity, and cellularity. At 6 weeks, collagen organization at the insertion site was significantly poorer in I-PM than in N-PM and D-PM rats (P = .0095). At 12 weeks, collagen organization at the insertion site and midsubstance of ADM grafts was also significantly poorer in I-PM rats (P = .0125 and P = .0018, respectively), and ultimate load-to-failure was lower in this group (P = .0043). CONCLUSION While postoperative immediate passive motion was detrimental to remodeled tendon-to-bone healing and to the tendon maturation of ADM grafts placed in the rotator cuff tendon defects, delayed passive motion did no harm. CLINICAL RELEVANCE For patients with 6-week immobilization after rotator cuff reconstruction, we recommend that early passive motion be started no sooner than 3 weeks after surgery. Immediate early passive motion should be avoided.
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Affiliation(s)
- Keiji Uezono
- Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Junji Ide
- Department of Advanced Joint Reconstructive Surgery, Kumamoto University Hospital, Kumamoto University, Kumamoto, Japan
| | - Takuya Tokunaga
- Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hitoshi Arimura
- Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hidetoshi Sakamoto
- Department of Mechanical System Engineering, Graduate School of Science and Technology, Kumamoto University, Kumamoto, Japan
| | - Yoshitaka Nakanishi
- Department of Mechanical System Engineering, Graduate School of Science and Technology, Kumamoto University, Kumamoto, Japan
| | - Hiroshi Mizuta
- Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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Zhao S, Peng L, Xie G, Li D, Zhao J, Ning C. Effect of the Interposition of Calcium Phosphate Materials on Tendon-Bone Healing During Repair of Chronic Rotator Cuff Tear. Am J Sports Med 2014; 42:1920-9. [PMID: 24853168 DOI: 10.1177/0363546514532781] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND The current nature of tendon-bone healing after rotator cuff (RC) repair is still the formation of granulation tissue at the tendon-bone interface rather than the formation of fibrocartilage, which is the crucial structure in native tendon insertion and can be observed after knee ligament reconstruction. The interposition of calcium phosphate materials has been found to be able to enhance tendon-bone healing in knee ligament reconstruction. However, whether the interposition of these kinds of materials can enhance tendon-bone healing or even change the current nature of tendon-bone healing after RC repair still needs to be explored. HYPOTHESIS The interposition of calcium phosphate materials during RC repair would enhance tendon-bone healing or change its current nature of granulation tissue formation into a more favorable process. STUDY DESIGN Controlled laboratory study. METHODS A total of 144 male Sprague-Dawley rats underwent unilateral detachment of the supraspinatus tendon, followed by delayed repair after 3 weeks. The animals were allocated into 1 of 3 groups: (1) repair alone, (2) repair with Ca5(PO4)2SiO4 (CPS) bioceramic interposition, or (3) repair with hydroxyapatite (HA) bioceramic interposition at the tendon-bone interface. Animals were sacrificed at 2, 4, or 8 weeks postoperatively, and microcomputed tomography (micro-CT) was used to quantify the new bone formation at the repair site. New fibrocartilage formation and collagen organization at the tendon-bone interface was evaluated by histomorphometric analysis. Biomechanical testing of the supraspinatus tendon-bone complex was performed. Statistical analysis was performed using 1-way analysis of variance. Significance was set at P < .05. RESULTS The micro-CT analysis demonstrated remarkable osteogenic activity and osteoconductivity to promote new bone formation and ingrowth of CPS and HA bioceramic, with CPS bioceramic showing better results than HA. Histological observations indicated that CPS bioceramic had excellent biocompatibility and biodegradability. At early time points after the RC repair, CPS bioceramic significantly increased the area of fibrocartilage at the tendon-bone interface compared with the control and HA groups. Moreover, CPS and HA bioceramics had significantly improved collagen organization. Biomechanical tests indicated that the CPS and HA groups have greater ultimate load to failure and stiffness than the control group at 4 and 8 weeks, and the CPS specimens exhibited the maximum ultimate load to failure, stiffness, and stress of the healing enthesis. CONCLUSION Both CPS and HA bioceramics aid in cell attachment and proliferation and accelerate new bone formation, and CPS bioceramic has a more prominent effect on tendon-to-bone healing. CLINICAL RELEVANCE Local application of CPS and HA bioceramic at the tendon-bone interface shows promise in improving healing after rotator cuff tear repair.
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Affiliation(s)
- Song Zhao
- Department of Arthroscopic Surgery, Shanghai Jiao Tong University-Affiliated Sixth People's Hospital, Shanghai, P.R. China
| | - Lingjie Peng
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, P.R. China
| | - Guoming Xie
- Department of Arthroscopic Surgery, Shanghai Jiao Tong University-Affiliated Sixth People's Hospital, Shanghai, P.R. China
| | - Dingfeng Li
- Department of Arthroscopic Surgery, Shanghai Jiao Tong University-Affiliated Sixth People's Hospital, Shanghai, P.R. China
| | - Jinzhong Zhao
- Department of Arthroscopic Surgery, Shanghai Jiao Tong University-Affiliated Sixth People's Hospital, Shanghai, P.R. China
| | - Congqin Ning
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, P.R. China
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Zhao S, Zhao J, Dong S, Huangfu X, Li B, Yang H, Zhao J, Cui W. Biological augmentation of rotator cuff repair using bFGF-loaded electrospun poly(lactide-co-glycolide) fibrous membranes. Int J Nanomedicine 2014; 9:2373-85. [PMID: 24868155 PMCID: PMC4027937 DOI: 10.2147/ijn.s59536] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Clinically, rotator cuff tear (RCT) is among the most common shoulder pathologies. Despite significant advances in surgical techniques, the re-tear rate after rotator cuff (RC) repair remains high. Insufficient healing capacity is likely the main factor for reconstruction failure. This study reports on a basic fibroblast growth factor (bFGF)-loaded electrospun poly(lactide-co-glycolide) (PLGA) fibrous membrane for repairing RCT. Implantable biodegradable bFGF-PLGA fibrous membranes were successfully fabricated using emulsion electrospinning technology and then characterized and evaluated with in vitro and in vivo cell proliferation assays and repairs of rat chronic RCTs. Emulsion electrospinning fabricated ultrafine fibers with a core-sheath structure which secured the bioactivity of bFGF in a sustained manner for 3 weeks. Histological observations showed that electrospun fibrous membranes have excellent biocompatibility and biodegradability. At 2, 4, and 8 weeks after in vivo RCT repair surgery, electrospun fibrous membranes significantly increased the area of glycosaminoglycan staining at the tendon-bone interface compared with the control group, and bFGF-PLGA significantly improved collagen organization, as measured by birefringence under polarized light at the healing enthesis compared with the control and PLGA groups. Biomechanical testing showed that the electrospun fibrous membrane groups had a greater ultimate load-to-failure and stiffness than the control group at 4 and 8 weeks. The bFGF-PLGA membranes had the highest ultimate load-to-failure, stiffness, and stress of the healing enthesis, and their superiority compared to PLGA alone was significant. These results demonstrated that electrospun fibrous membranes aid in cell attachment and proliferation, as well as accelerating tendon-bone remodeling, and bFGF-loaded PLGA fibrous membranes have a more pronounced effect on tendon-bone healing. Therefore, augmentation using bFGF-PLGA electrospun fibrous membranes is a promising treatment for RCT.
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Affiliation(s)
- Song Zhao
- Department of Arthroscopic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
| | - Jingwen Zhao
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People's Republic of China
| | - Shikui Dong
- Department of Arthroscopic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
| | - Xiaoqiao Huangfu
- Department of Arthroscopic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
| | - Bin Li
- Orthopedic Institute, Soochow University, Suzhou, Jiangsu, People's Republic of China ; Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People's Republic of China
| | - Huilin Yang
- Orthopedic Institute, Soochow University, Suzhou, Jiangsu, People's Republic of China ; Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People's Republic of China
| | - Jinzhong Zhao
- Department of Arthroscopic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
| | - Wenguo Cui
- Orthopedic Institute, Soochow University, Suzhou, Jiangsu, People's Republic of China ; Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People's Republic of China
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Evidence of genetic variations associated with rotator cuff disease. J Shoulder Elbow Surg 2014; 23:227-35. [PMID: 24129055 DOI: 10.1016/j.jse.2013.07.053] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 07/23/2013] [Accepted: 07/28/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND Rotator cuff disease (RCD) is a complex process influenced by a multitude of factors, and a number of gene pathways are altered in rotator cuff tears. Polymorphisms in these genes can lead to an extended tendon degeneration process, which explains why subsets of patients are more susceptible to RCD. MATERIALS AND METHODS Twenty-three single-nucleotide polymorphisms within 6 genes involved in repair and degenerative processes (DEFB1, DENND2C, ESRRB, FGF3, FGF10, and FGFR1) were investigated in 410 patients, 203 with a diagnosis of RCD and 207 presenting with absence of RCD. Exclusion criteria were patients older than 60 years and younger than 45 years with a history of trauma, rheumatoid arthritis, autoimmune syndrome, pregnancy, and use of corticosteroids. Genomic DNA was obtained from saliva samples. Genetic markers were genotyped with TaqMan real-time polymerase chain reaction. The χ(2) test compared genotypes and haplotype differences between groups. Multivariate logistic regression analyzed the significance of many covariates and the incidence of RCD. RESULTS Statistical analysis revealed female sex (P = .001; odds ratio, 2.07 [1.30-3.30]) and being white (P = .002; odds ratio, 1.88 [1.21-2.90]) to be risk factors for RCD development. A significant association of haplotypes CCTTCCAG in ESRRB (P = .05), CGACG in FGF3 (P = .01), CC in DEFB1 (P = .03), and FGFR1 rs13317 (P = .02) with RCD could be observed. Also, association between FGF10 rs11750845 (P = .03) and rs1011814 (P = .01) was observed after adjustment by ethnic group and sex. CONCLUSIONS Our work clearly supports the role of DEFB1, ESRRB, FGF3, FGF10, and FGFR1 genes in RCD. Identification of these variants can clarify causal pathways and provide a clue for therapeutic targets.
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