|
1
|
Papalia GF, Franceschetti E, Giurazza G, Parisi FR, Gregori P, Zampogna B, Longo UG, Papalia R. MicroRNA expression changes in the development of rotator cuff tendon injuries. JSES REVIEWS, REPORTS, AND TECHNIQUES 2023; 3:343-349. [PMID: 37588508 PMCID: PMC10426526 DOI: 10.1016/j.xrrt.2023.03.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/18/2023]
Abstract
Traumatic or degenerative rotator cuff (RC) tendon injuries are a leading cause of persistent shoulder pain and reduction of mobility with associated disability and dysfunction, which require each year more than 250,000 surgical repairs in the United States. MicroRNAs (miRNAs) are small noncoding RNAs, that in the posttranscriptional phase lead to the development and function of tissues. The aim of this review was to identify miRNA expression changes in patients with RC pathologies and to determine their relevance as a potential novel diagnostic and potentially therapeutic tool for RC disorders. Various miRNAs seemed to be key regulators in the muscle architecture, determining several modifications in muscle atrophy, skeletal muscle mechanical adaptation, lipid accumulation, and fibrosis in the presence of RC tears. The search was executed using PubMed, Medline, Scopus, and Cochrane Central. We included studies written in English that evaluated the role of miRNA in diagnosis, physiopathology, and potential therapeutic application of RC tendon injuries. We included 11 studies in this review. Many miRNAs emerged as key regulators in the pathogenesis of RC tears, inflammation, and muscle fatty degeneration. In fact, they are involved in the regulation of myogenesis, inflammatory cytokines, metalloproteases expression, muscle adaptation, adipogenesis, fibrogenic factors, and extracellular matrix synthesis. The gene expression may be altered in the pathological processes of tendon lesions. Therefore, the knowledge of all the gene mechanisms underlying RC tendinopathy should be achieved with future diagnostic and clinical studies.
Collapse
Affiliation(s)
- Giuseppe Francesco Papalia
- Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| | - Edoardo Franceschetti
- Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| | - Giancarlo Giurazza
- Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| | - Francesco Rosario Parisi
- Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| | - Pietro Gregori
- Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| | - Biagio Zampogna
- Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| | - Umile Giuseppe Longo
- Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| | - Rocco Papalia
- Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| |
Collapse
|
|
2
|
Tindell RK, Busselle LP, Holloway JL. Magnetic fields enable precise spatial control over electrospun fiber alignment for fabricating complex gradient materials. J Biomed Mater Res A 2023; 111:778-789. [PMID: 36594559 DOI: 10.1002/jbm.a.37492] [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: 10/01/2022] [Revised: 12/14/2022] [Accepted: 12/16/2022] [Indexed: 01/04/2023]
Abstract
Musculoskeletal interfacial tissues consist of complex gradients in structure, cell phenotype, and biochemical signaling that are important for function. Designing tissue engineering strategies to mimic these types of gradients is an ongoing challenge. In particular, new fabrication techniques that enable precise spatial control over fiber alignment are needed to better mimic the structural gradients present in interfacial tissues, such as the tendon-bone interface. Here, we report a modular approach to spatially controlling fiber alignment using magnetically-assisted electrospinning. Electrospun fibers were highly aligned in the presence of a magnetic field and smoothly transitioned to randomly aligned fibers away from the magnetic field. Importantly, magnetically-assisted electrospinning allows for spatial control over fiber alignment at sub-millimeter resolution along the length of the fibrous scaffold similar to the native structural gradient present in many interfacial tissues. The versatility of this approach was further demonstrated using multiple electrospinning polymers and different magnet configurations to fabricate complex fiber alignment gradients. As expected, cells seeded onto gradient fibrous scaffolds were elongated and aligned on the aligned fibers and did not show a preferential alignment on the randomly aligned fibers. Overall, this fabrication approach represents an important step forward in creating gradient fibrous materials, where such materials are promising as tissue-engineered scaffolds for regenerating functional musculoskeletal interfacial tissues.
Collapse
Affiliation(s)
- Raymond Kevin Tindell
- Chemical Engineering, School of Engineering of Matter, Transport and Energy, Arizona State University, Tempe, Arizona, USA
| | - Lincoln P Busselle
- Chemical Engineering, School of Engineering of Matter, Transport and Energy, Arizona State University, Tempe, Arizona, USA
| | - Julianne L Holloway
- Chemical Engineering, School of Engineering of Matter, Transport and Energy, Arizona State University, Tempe, Arizona, USA
| |
Collapse
|
|
3
|
Makuku R, Werthel JD, Zanjani LO, Nabian MH, Tantuoyir MM. New frontiers of tendon augmentation technology in tissue engineering and regenerative medicine: a concise literature review. J Int Med Res 2022; 50:3000605221117212. [PMID: 35983666 PMCID: PMC9393707 DOI: 10.1177/03000605221117212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Tissue banking programs fail to meet the demand for human organs and tissues for
transplantation into patients with congenital defects, injuries, chronic
diseases, and end-stage organ failure. Tendons and ligaments are among the most
frequently ruptured and/or worn-out body tissues owing to their frequent use,
especially in athletes and the elderly population. Surgical repair has remained
the mainstay management approach, regardless of scarring and adhesion formation
during healing, which then compromises the gliding motion of the joint and
reduces the quality of life for patients. Tissue engineering and regenerative
medicine approaches, such as tendon augmentation, are promising as they may
provide superior outcomes by inducing host-tissue ingrowth and tendon
regeneration during degradation, thereby decreasing failure rates and morbidity.
However, to date, tendon tissue engineering and regeneration research has been
limited and lacks the much-needed human clinical evidence to translate most
laboratory augmentation approaches to therapeutics. This narrative review
summarizes the current treatment options for various tendon pathologies, future
of tendon augmentation, cell therapy, gene therapy, 3D/4D bioprinting,
scaffolding, and cell signals.
Collapse
Affiliation(s)
- Rangarirai Makuku
- Center for Orthopedic Trans-Disciplinary Applied Research (COTAR), School of Medicine, 48439Tehran University of Medical Sciences, Tehran, Iran.,Department of Orthopedic Surgery, Hospital Ambroise Pare, Boulogne-Billancourt, France
| | - Jean-David Werthel
- Department of Orthopedic and Trauma Surgery, Shariati Hospital, 48439Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Oryadi Zanjani
- Center for Orthopedic Trans-Disciplinary Applied Research (COTAR), School of Medicine, 48439Tehran University of Medical Sciences, Tehran, Iran.,Department of Orthopedic Surgery, Hospital Ambroise Pare, Boulogne-Billancourt, France
| | - Mohammad Hossein Nabian
- Center for Orthopedic Trans-Disciplinary Applied Research (COTAR), School of Medicine, 48439Tehran University of Medical Sciences, Tehran, Iran.,Department of Orthopedic Surgery, Hospital Ambroise Pare, Boulogne-Billancourt, France
| | - Marcarious M Tantuoyir
- Center for Orthopedic Trans-Disciplinary Applied Research (COTAR), School of Medicine, 48439Tehran University of Medical Sciences, Tehran, Iran.,Department of Orthopedic Surgery, Hospital Ambroise Pare, Boulogne-Billancourt, France.,Biomedical Engineering Unit, University of Ghana Medical Centre, Accra, Ghana
| |
Collapse
|
|
4
|
Zhu M, Lin Tay M, Lim KS, Bolam SM, Tuari D, Callon K, Dray M, Cornish J, Woodfield TBF, Munro JT, Coleman B, Musson DS. Novel Growth Factor Combination for Improving Rotator Cuff Repair: A Rat In Vivo Study. Am J Sports Med 2022; 50:1044-1053. [PMID: 35188803 DOI: 10.1177/03635465211072557] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND The lack of healing at the repaired tendon-bone interface is an important cause of failure after rotator cuff repair. While augmentation with growth factors (GFs) has demonstrated promise, the ideal combination must target all 3 tissue types at the tendon-bone interface. HYPOTHESIS The GF combination of transforming growth factor beta 1, Insulin-like growth factor 1, and parathyroid hormone will promote tenocyte proliferation and differentiation and improve the biomechanical and histological quality of the repaired tendon-bone interface. STUDY DESIGN Controlled laboratory study. METHODS In vitro, human tenocytes were cultured in the presence of the GF combination for 72 hours, and cell growth assays and the expression of genes specific to tendon, cartilage, and bone were analyzed. In vivo, adult rats (N = 46) underwent detachment and repair of the left supraspinatus tendon. A PVA-tyramine gel was used to deliver the GF combination to the tendon-bone interface. Histological, biomechanical, and RNA microarray analysis was performed at 6 and 12 weeks after surgery. Immunohistochemistry for type II and X collagen was performed at 12 weeks. RESULTS When treated with the GF combination in vitro, human tenocytes proliferated 1.5 times more than control (P = .04). The expression of scleraxis increased 65-fold (P = .013). The expression of Sox-9 (P = .011), type I collagen (P = .021), fibromodulin (P = .0075), and biglycan (P = .010) was also significantly increased, while the expression of PPARγ was decreased (P = .007). At 6 and 12 weeks postoperatively, the quality of healing on histology was significantly higher in the GF group, with the formation of a more mature tendon-bone interface, as confirmed by immunohistochemistry for type II and X collagen. The GF group achieved a load at failure and Young modulus >1.5 times higher at both time points. Microarrays at 6 weeks demonstrated upregulation of genes involved in leukocyte aggregation (S100A8, S100A9) and tissue mineralization (Bglap, serglycin, Fam20c). CONCLUSION The GF combination promoted protendon and cartilage responses in human tenocytes in vitro; it also improved the histological appearance and mechanical properties of the repair in vivo. Microarrays of the tendon-bone interface identified inflammatory and mineralization pathways affected by the GF combination, providing novel therapeutic targets for further research. CLINICAL RELEVANCE The use of this GF combination is translatable to patients and may improve healing after rotator cuff repair.
Collapse
Affiliation(s)
- Mark Zhu
- Bone and Joint Laboratory, School of Medicine, University of Auckland, Auckland, New Zealand
| | - Mei Lin Tay
- Bone and Joint Laboratory, School of Medicine, University of Auckland, Auckland, New Zealand
| | - Khoon S Lim
- Department of Orthopaedic Surgery and Musculoskeletal Medicine, University of Otago, Christchurch, New Zealand
| | - Scott M Bolam
- Bone and Joint Laboratory, School of Medicine, University of Auckland, Auckland, New Zealand
| | - Donna Tuari
- Bone and Joint Laboratory, School of Medicine, University of Auckland, Auckland, New Zealand
| | - Karen Callon
- Bone and Joint Laboratory, School of Medicine, University of Auckland, Auckland, New Zealand
| | - Michael Dray
- Department of Pathology, Waikato Hospital, Hamilton, New Zealand
| | - Jillian Cornish
- Bone and Joint Laboratory, School of Medicine, University of Auckland, Auckland, New Zealand
| | - Tim B F Woodfield
- Department of Orthopaedic Surgery and Musculoskeletal Medicine, University of Otago, Christchurch, New Zealand
| | - Jacob T Munro
- Bone and Joint Laboratory, School of Medicine, University of Auckland, Auckland, New Zealand.,Department of Orthopaedic Surgery, Auckland City Hospital, Auckland, New Zealand
| | - Brendan Coleman
- Department of Orthopaedic Surgery, Counties Manukau Health, Auckland, New Zealand
| | - David S Musson
- Bone and Joint Laboratory, School of Medicine, University of Auckland, Auckland, New Zealand
| |
Collapse
|
|
5
|
Figueiredo EA, Loyola LC, Belangero PS, Campos Ribeiro-Dos-Santos ÂK, Emanuel Batista Santos S, Cohen C, Wajnsztejn A, Martins de Oliveira A, Smith MC, Pochini ADC, Andreoli CV, Ejnisman B, Cohen M, Leal MF. Rotator Cuff Tear Susceptibility Is Associated With Variants in Genes Involved in Tendon Extracellular Matrix Homeostasis. J Orthop Res 2020; 38:192-201. [PMID: 31444797 DOI: 10.1002/jor.24455] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 08/13/2019] [Indexed: 02/04/2023]
Abstract
Rotator cuff tears (RCT) is a multifactorial disease with genetic factors contributing for the disease etiology. We hypothesized that genetic variants in genes involved in extracellular matrix (ECM) homeostasis may alter susceptibility to RCT. We evaluated 20 polymorphisms of genes involved in ECM homeostasis in 211 cases of full-thickness tears of the supraspinatus (Nfemales = 130; Nmales = 81) and 567 age-matched controls (Nfemales = 317; Nmales = 250). Multivariate logistic regressions were carried out with age, gender, genetic ancestry (based on the analysis of 61 biallelic short insertion/deletion polymorphisms), and common co-morbidities (diabetes, dyslipidemia, and smoking habits) as covariates. We observed that carriers of the rare allele of both studied variants of TGFB1, as well as their G/A (rs1800470/rs1800469) haplotype, were less susceptible to RCT (p < 0.05). In contrast, carriers of the G allele of MMP9 rs17576 (p = 0.014) or G/G haplotype (rs17576/rs17577; p < 0.001) had an increased risk for tendon tears. The presence of the T allele of MMP2 rs2285053 (p = 0.033), the T allele of MMP3 rs679620 (p = 0.024), and the TT-genotype of TIMP2 rs2277698 (p = 0.01) was associated with susceptibility to tears, especially in females. In males, the A allele of COL5A1 rs3196378 (p = 0.032) and the G allele of TGFBR1 rs1590 (p = 0.039) were independent risk factors for RCT. The C/T COL5A1 (rs3196378/rs11103544) haplotype was associated with a reduced risk of tears in males (p = 0.03). In conclusion, we identified the genetic variants associated with RCT susceptibility, thereby reinforcing the role of genes involved in the structure and homeostasis of the ECM of tendons in disease development. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:192-201, 2020.
Collapse
Affiliation(s)
- Eduardo A Figueiredo
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, 04038-032, São Paulo, Brazil
| | - Leonor Casilla Loyola
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, 04038-032, São Paulo, Brazil.,Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, 04023-001, São Paulo, Brazil
| | - Paulo S Belangero
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, 04038-032, São Paulo, Brazil
| | | | - Sidney Emanuel Batista Santos
- Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Pará, Brazil
| | - Carina Cohen
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, 04038-032, São Paulo, Brazil
| | - Andre Wajnsztejn
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, 04038-032, São Paulo, Brazil
| | - Adrielle Martins de Oliveira
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, 04038-032, São Paulo, Brazil.,Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, 04023-001, São Paulo, Brazil
| | - Marília C Smith
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, 04023-001, São Paulo, Brazil
| | - Alberto de Castro Pochini
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, 04038-032, São Paulo, Brazil
| | - Carlos V Andreoli
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, 04038-032, São Paulo, Brazil
| | - Benno Ejnisman
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, 04038-032, São Paulo, Brazil
| | - Moises Cohen
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, 04038-032, São Paulo, Brazil
| | - Mariana F Leal
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, 04038-032, São Paulo, Brazil.,Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, 04023-001, São Paulo, Brazil
| |
Collapse
|
|
6
|
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.
Collapse
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
| |
Collapse
|
|
7
|
Wragg NM, Mosqueira D, Blokpeol-Ferreras L, Capel A, Player DJ, Martin NRW, Liu Y, Lewis MP. Development of a 3D Tissue-Engineered Skeletal Muscle and Bone Co-culture System. Biotechnol J 2019; 15:e1900106. [PMID: 31468704 DOI: 10.1002/biot.201900106] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 07/05/2019] [Indexed: 12/26/2022]
Abstract
In vitro 3D tissue-engineered (TE) structures have been shown to better represent in vivo tissue morphology and biochemical pathways than monolayer culture, and are less ethically questionable than animal models. However, to create systems with even greater relevance, multiple integrated tissue systems should be recreated in vitro. In the present study, the effects and conditions most suitable for the co-culture of TE skeletal muscle and bone are investigated. High-glucose Dulbecco's modified Eagle medium (HG-DMEM) supplemented with 20% fetal bovine serum followed by HG-DMEM with 2% horse serum is found to enable proliferation of both C2C12 muscle precursor cells and TE85 human osteosarcoma cells, fusion of C2C12s into myotubes, as well as an upregulation of RUNX2/CBFa1 in TE85s. Myotube formation is also evident within indirect contact monolayer cultures. Finally, in 3D co-cultures, TE85 collagen/hydroxyapatite constructs have significantly greater expression of RUNX2/CBFa1 and osteocalcin/BGLAP in the presence of collagen-based C2C12 skeletal muscle constructs; however, fusion within these constructs appears reduced. This work demonstrates the first report of the simultaneous co-culture and differentiation of 3D TE skeletal muscle and bone, and represents a significant step toward a full in vitro 3D musculoskeletal junction model.
Collapse
Affiliation(s)
- Nicholas M Wragg
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Loughborough, UK
| | - Diogo Mosqueira
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Lia Blokpeol-Ferreras
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Andrew Capel
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Darren J Player
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,Institute of Orthopaedics and Musculoskeletal Sciences, RNOH University College London, Stanmore, UK
| | - Neil R W Martin
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Yang Liu
- Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Loughborough, UK
| | - Mark P Lewis
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| |
Collapse
|
|
8
|
Cancienne JM, Brockmeier SF, Kew ME, Werner BC. Perioperative Serum 25-Hydroxyvitamin D Levels Affect Revision Surgery Rates After Arthroscopic Rotator Cuff Repair. Arthroscopy 2019; 35:763-769. [PMID: 30704888 DOI: 10.1016/j.arthro.2018.09.032] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 09/05/2018] [Accepted: 09/29/2018] [Indexed: 02/02/2023]
Abstract
PURPOSE To examine any association between perioperative serum 25-hydroxyvitamin D levels and failure of arthroscopic rotator cuff repair (RCR) requiring revision surgery. METHODS Using a private-payer national insurance database, patients who underwent arthroscopic RCR with perioperative serum 25-hydroxyvitamin D levels recorded were included. Patients were stratified into groups of (1) serum 25-hydroxyvitamin D deficiency (<20 ng/mL), (2) insufficiency (20-30 ng/mL), or (3) sufficient (>30-<150 ng/mL). The primary outcome measure was ipsilateral revision rotator cuff surgery, including revision repair, debridement, or reverse shoulder arthroplasty. A multivariable logistic regression analysis was used to control for patient demographics and comorbidities during comparisons. RESULTS A total of 982 patients were included in the study. The rate of revision rotator cuff surgery was significantly higher in patients in the serum 25-hydroxyvitamin D-deficient group (5.88%) compared with the serum 25-hydroxyvitamin D-sufficient control group (3.7%) (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.6-5.8; P = .007). Patients with serum 25-hydroxyvitamin D deficiency (5.88%) also had a significantly higher incidence of revision surgery compared with patients with serum 25-hydroxyvitamin D insufficiency (OR, 2.4; 95% CI, 1.5-3.9; P = .011). There was no significant difference in the incidence of revision surgery in the serum 25-hydroxyvitamin D-insufficient group (4.97%) compared with the serum 25-hydroxyvitamin D-sufficient control group (3.7%) (OR, 1.4; 95% CI, 0.8-2.3; P = .250). The absolute risk reduction of revision surgery for 25-hydroxyvitamin D-deficient patients compared with controls was 2.2%, corresponding to a number needed to treat to avoid 1 revision surgery of 46 patients, relative risk reduction = 0.59. CONCLUSIONS Although the present study found a significant statistical association between serum 25-hydroxyvitamin D deficiency and insufficiency and the rate of revision rotator cuff surgery after primary arthroscopic RCR, the absolute differences of these revision rates are minimal and are accompanied with overlapping confidence intervals limiting the clinical significance of these findings. LEVEL OF EVIDENCE Level III, retrospective cohort study.
Collapse
Affiliation(s)
- Jourdan M Cancienne
- Department of Orthopaedic Surgery, University of Virginia Health System, Charlottesville, Virginia, U.S.A
| | - Stephen F Brockmeier
- Department of Orthopaedic Surgery, University of Virginia Health System, Charlottesville, Virginia, U.S.A
| | - Michelle E Kew
- Department of Orthopaedic Surgery, University of Virginia Health System, Charlottesville, Virginia, U.S.A
| | - Brian C Werner
- Department of Orthopaedic Surgery, University of Virginia Health System, Charlottesville, Virginia, U.S.A..
| |
Collapse
|
|
9
|
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
| |
Collapse
|
|
10
|
Abstract
PURPOSE OF REVIEW To outline the radiographic and clinical outcomes after a rotator cuff surgery in order to set the expectations with the patient before the surgery to obtain a better outcome, taking into account the factors that can affect the outcome and the technique used for the repair. RECENT FINDINGS The majority of surgeons use arthroscopic repair. The double-row repair has better biomechanical strength, footprint coverage, and radiographic healing rates. The principal factors that can affect the outcome of the surgery are the tendon quality, tear size and retraction, fatty infiltration, chronicity of the tear, and concomitant pathologies. Arthroscopic rotator cuff repair can decrease pain and increase function allowing patients to improve their quality of life; 90% of patients are happy 6 months after the surgery and maintain stability during 5 years. Greater preoperative expectations would show better outcomes and patient satisfaction after the surgery.
Collapse
Affiliation(s)
- Alejandro Novoa-Boldo
- Sports Medicine and Shoulder Service, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021 USA
| | - Lawrence V. Gulotta
- Sports Medicine and Shoulder Service, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021 USA
| |
Collapse
|
|
11
|
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.
Collapse
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
| |
Collapse
|
|
12
|
Growth factor delivery strategies for rotator cuff repair and regeneration. Int J Pharm 2018; 544:358-371. [PMID: 29317260 DOI: 10.1016/j.ijpharm.2018.01.006] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 12/21/2017] [Accepted: 01/01/2018] [Indexed: 12/21/2022]
Abstract
The high incidence of degenerative tears and prevalence of retears (20-95%) after surgical repair makes rotator cuff injuries a significant health problem. This high retear rate is attributed to the failure of the repaired tissue to regenerate the native tendon-to-bone insertion (enthesis). Biological augmentation of surgical repair such as autografts, allografts, and xenografts are confounded by donor site morbidity, immunogenicity, and disease transmission, respectively. In contrast, these risks may be alleviated via growth factor therapy, which can actively influence the healing environment to promote functional repair. Several challenges have to be overcome before growth factor delivery can translate into clinical practice such as the selection of optimal growth factor(s) or combination, identification of the most efficient stage and duration of delivery, and the design considerations for the delivery device. Emerging insight into the injury-repair microenvironment and our understanding of growth factor mechanisms in healing are informing the design of advanced delivery scaffolds to effectively treat rotator cuff tears. Here, we review potential growth factor candidates, design parameters and material selection for growth factor delivery, innovative and dynamic delivery scaffolds, and novel therapeutic targets from tendon and developmental biology for the structural and functional healing of rotator cuff repair.
Collapse
|
|
13
|
Qian Y, Han Q, Chen W, Song J, Zhao X, Ouyang Y, Yuan W, Fan C. Platelet-Rich Plasma Derived Growth Factors Contribute to Stem Cell Differentiation in Musculoskeletal Regeneration. Front Chem 2017; 5:89. [PMID: 29164105 PMCID: PMC5671651 DOI: 10.3389/fchem.2017.00089] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Accepted: 10/16/2017] [Indexed: 12/24/2022] Open
Abstract
Stem cell treatment and platelet-rich plasma (PRP) therapy are two significant issues in regenerative medicine. Stem cells such as bone marrow mesenchymal stem cells, adipose-derived stem cells and periodontal ligament stem cells can be successfully applied in the field of tissue regeneration. PRP, a natural product isolated from whole blood, can secrete multiple growth factors (GFs) for regulating physiological activities. These GFs can stimulate proliferation and differentiation of different stem cells in injury models. Therefore, combination of both agents receives wide expectations in regenerative medicine, especially in bone, cartilage and tendon repair. In this review, we thoroughly discussed the interaction and underlying mechanisms of PRP derived GFs with stem cells, and assessed their functions in cell differentiation for musculoskeletal regeneration.
Collapse
Affiliation(s)
- Yun Qian
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine and Health, Shanghai, China
| | - Qixin Han
- Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Chen
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine and Health, Shanghai, China
| | - Jialin Song
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine and Health, Shanghai, China
| | - Xiaotian Zhao
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Yuanming Ouyang
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine and Health, Shanghai, China
| | - Weien Yuan
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Cunyi Fan
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| |
Collapse
|
|
14
|
Leal MF, Caires dos Santos L, Martins de Oliveira A, Santoro Belangero P, Antônio Figueiredo E, Cohen C, de Seixas Alves F, Hiromi Yanaguizawa W, Vicente Andreoli C, de Castro Pochini A, Ejnisman B, Cardoso Smith M, de Seixas Alves MT, Cohen M. Epigenetic regulation of metalloproteinases and their inhibitors in rotator cuff tears. PLoS One 2017; 12:e0184141. [PMID: 28902861 PMCID: PMC5597200 DOI: 10.1371/journal.pone.0184141] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 08/18/2017] [Indexed: 01/10/2023] Open
Abstract
Rotator cuff tear is a common orthopedic condition. Metalloproteinases (MMP) and their inhibitors (TIMP) seem to play a role in the development of joint injuries and in the failure of tissue healing. However, the mechanisms of regulation of gene expression in tendons are still unknown. Epigenetic mechanisms, such as DNA methylation and microRNAs regulation, are involved in the dynamic control of gene expression. Here, the mRNA expression and DNA methylation status of MMPs (MMP1, MMP2, MMP3, MMP9, MMP13, and MMP14) and TIMPs (TIMP1-3) and the expression of miR-29 family members in ruptured supraspinatus tendons were compared with non-injured tendons of individuals without this lesion. Additionally, the gene expression and methylation status at the edge of the ruptured tendon were compared with macroscopically non-injured rotator cuff tendon samples from the anterior and posterior regions of patients with tendon tears. Moreover, the possible associations between the molecular alterations and the clinical and histologic characteristics were investigated. Dysregulated expression and DNA methylation of MMP and TIMP genes were found across the rotator cuff tendon samples of patients with supraspinatus tears. These alterations were influenced at least in part by age at surgery, sex, smoking habit, tear size, and duration of symptoms. Alterations in the studied MMP and TIMP genes may contribute to the presence of microcysts, fissures, necrosis, and neovascularization in tendons and may thus be involved in the tendon healing process. In conclusion, MMPs and their inhibitors are regulated by epigenetic modifications and may play a role in rotator cuff tears.
Collapse
Affiliation(s)
- Mariana Ferreira Leal
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- * E-mail:
| | - Leonardo Caires dos Santos
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Adrielle Martins de Oliveira
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Paulo Santoro Belangero
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | | | - Carina Cohen
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Felipe de Seixas Alves
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Departamento de Patologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Wânia Hiromi Yanaguizawa
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Departamento de Patologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Carlos Vicente Andreoli
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | | | - Benno Ejnisman
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Marília Cardoso Smith
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | | | - Moises Cohen
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| |
Collapse
|
|
15
|
Lipner J, Boyle JJ, Xia Y, Birman V, Genin GM, Thomopoulos S. Toughening of fibrous scaffolds by mobile mineral deposits. Acta Biomater 2017; 58:492-501. [PMID: 28532898 DOI: 10.1016/j.actbio.2017.05.033] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 05/10/2017] [Accepted: 05/15/2017] [Indexed: 10/19/2022]
Abstract
Partially mineralized fibrous tissue situated between tendon and bone is believed to be tougher than either tendon or bone, possibly serving as a compliant, energy absorptive, protective barrier between the two. This tissue does not reform following surgical repair (e.g., rotator cuff tendon-to-bone re-attachment) and might be a factor in the poor outcomes following such surgeries. Towards our long-term goal of tissue engineered solutions to functional tendon-to-bone re-attachment, we tested the hypotheses that partially mineralized fibrous matrices can derive toughness from mobility of mineral along their fibers, and that in such cases toughness is maximized at levels of mineralization sufficiently low to allow substantial mobility. Nanofibrous electrospun poly(lactic-co-glycolic acid) (PLGA) scaffolds mineralized for prescribed times were fabricated as model systems to test these hypotheses. Tensile tests performed at varying angles relative to the dominant fiber direction confirmed that mineral cross-linked PLGA nanofibers without adhering to them. Peel tests revealed that fracture toughness increased with mineralization time up to a peak value, then subsequently decreased with increasing mineralization time back to the baseline toughness of unmineralized scaffolds. These experimental results were predicted by a theoretical model combining mineral growth kinetics with fracture energetics, suggesting that toughness increased with mineralization time until mineral mobility was attenuated by steric hindrance, then returned to baseline levels following the rigid percolation threshold. Results supported our hypotheses, and motivate further study of the roles of mobile mineral particles in toughening the tendon-to-bone attachment. STATEMENT OF SIGNIFICANCE Effective surgical repair of interfaces between tendon and bone remains an unmet clinical need, in part due to a lack of understanding of how toughness is achieved in the healthy tissue. Using combined synthesis, experiment, and modeling approaches, the current work supported the hypothesis that toughening of a fibrous scaffold arises from brittle mineral particles that crosslink the fibers, but only if the particles are free to slide relative to the fibers. In the case of the tendon-to-bone interface, this suggests that partially mineralized tissue between tendon and bone, with mobile mineral but relatively low stiffness, may serve as a compliant, energy-absorbing barrier that guards against injury. These results suggest an opportunity for fabrication of tough and strong fibrous scaffolds for tissue engineering applications.
Collapse
|
|
16
|
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.
Collapse
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
| |
Collapse
|
|
17
|
Dyrna F, Herbst E, Hoberman A, Imhoff AB, Schmitt A. Stem cell procedures in arthroscopic surgery. Eur J Med Res 2016; 21:29. [PMID: 27411303 PMCID: PMC4944463 DOI: 10.1186/s40001-016-0224-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 07/05/2016] [Indexed: 12/13/2022] Open
Abstract
The stem cell as the building block necessary for tissue reparation and homeostasis plays a major role in regenerative medicine. Their unique property of being pluripotent, able to control immune process and even secrete a whole army of anabolic mediators, draws interest. While new arthroscopic procedures and techniques involving stem cells have been established over the last decade with improved outcomes, failures and dissatisfaction still occur. Therefore, there is increasing interest in ways to improve the healing response. MSCs are particularly promising for this task given their regenerative potential. While methods of isolating those cells are no longer poses a challenge, the best way of application is not clear. Several experiments in the realm of basic science and animal models have recently been published, addressing this issue, yet the application in clinical practice has lagged. This review provides an overview addressing the current standing of MSCs in the field of arthroscopic surgery.
Collapse
Affiliation(s)
- Felix Dyrna
- Department of Sports Orthopedics Klinikum rechts der Isar, Technical University, Ismaninger Str. 22, 81675, Munich, Germany
| | - Elmar Herbst
- Department of Sports Orthopedics Klinikum rechts der Isar, Technical University, Ismaninger Str. 22, 81675, Munich, Germany
| | - Alexander Hoberman
- Department of Orthopaedic Surgery, University of Connecticut, Farmington, CT, USA
| | - Andreas B Imhoff
- Department of Sports Orthopedics Klinikum rechts der Isar, Technical University, Ismaninger Str. 22, 81675, Munich, Germany
| | - Andreas Schmitt
- Department of Sports Orthopedics Klinikum rechts der Isar, Technical University, Ismaninger Str. 22, 81675, Munich, Germany.
| |
Collapse
|
|
18
|
Abstract
Rotator cuff tears continue to be at significant risk for re-tear or for failure to heal after surgical repair despite the use of a variety of surgical techniques and augmentation devices. Therefore, there is a need for functionalized scaffold strategies to provide sustained mechanical augmentation during the critical first 12-weeks following repair, and to enhance the healing potential of the repaired tendon and tendon-bone interface. Tissue engineered approaches that combine the use of scaffolds, cells, and bioactive molecules towards promising new solutions for rotator cuff repair are reviewed. The ideal scaffold should have adequate initial mechanical properties, be slowly degrading or non-degradable, have non-toxic degradation products, enhance cell growth, infiltration and differentiation, promote regeneration of the tendon-bone interface, be biocompatible and have excellent suture retention and handling properties. Scaffolds that closely match the inhomogeneity and non-linearity of the native rotator cuff may significantly advance the field. While substantial pre-clinical work remains to be done, continued progress in overcoming current tissue engineering challenges should allow for successful clinical translation.
Collapse
|
|
19
|
Weber SC. Platelet-rich Plasma in the Management of Arthroscopic Rotator Cuff Repair: Update 2016. Tech Orthop 2016. [DOI: 10.1097/bto.0000000000000178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
20
|
Abstract
The addition of specific proteins or growth factors onto sutures would provide a direct application of exogenous factors to promote tissue repair. The higher levels of growth factors and cytokines may optimize the healing environment and promote tissue recovery. Despite this proposed benefit, the current orthopedic literature on the use of coated sutures is limited. Although several of the published studies investigating healing improvement by coated sutures have shown promising results, these data are only based on in vitro or small animal experiments. Recent meta-analyses have reported positive effects of triclosan-coated antimicrobial sutures in regards to reduction of surgical site complications. However, biologically coated sutures are not yet widely accepted due to several unanswered questions (concentration, release kinematics, tissue reactions, etc.) in addition to the high costs of such products. Further studies are needed to demonstrate the efficacy of coated sutures in orthopedic surgery.
Collapse
|
|
21
|
Valencia Mora M, Ruiz Ibán MA, Díaz Heredia J, Barco Laakso R, Cuéllar R, García Arranz M. Stem cell therapy in the management of shoulder rotator cuff disorders. World J Stem Cells 2015; 7:691-9. [PMID: 26029341 PMCID: PMC4444610 DOI: 10.4252/wjsc.v7.i4.691] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Revised: 01/26/2015] [Accepted: 02/04/2015] [Indexed: 02/07/2023] Open
Abstract
Rotator cuff tears are frequent shoulder problems that are usually dealt with surgical repair. Despite improved surgical techniques, the tendon-to-bone healing rate is unsatisfactory due to difficulties in restoring the delicate transitional tissue between bone and tendon. It is essential to understand the molecular mechanisms that determine this failure. The study of the molecular environment during embryogenesis and during normal healing after injury is key in devising strategies to get a successful repair. Mesenchymal stem cells (MSC) can differentiate into different mesodermal tissues and have a strong paracrine, anti-inflammatory, immunoregulatory and angiogenic potential. Stem cell therapy is thus a potentially effective therapy to enhance rotator cuff healing. Promising results have been reported with the use of autologous MSC of different origins in animal studies: they have shown to have better healing properties, increasing the amount of fibrocartilage formation and improving the orientation of fibrocartilage fibers with less immunologic response and reduced lymphocyte infiltration. All these changes lead to an increase in biomechanical strength. However, animal research is still inconclusive and more experimental studies are needed before human application. Future directions include expanded stem cell therapy in combination with growth factors or different scaffolds as well as new stem cell types and gene therapy.
Collapse
Affiliation(s)
- Maria Valencia Mora
- Maria Valencia Mora, Miguel A Ruiz Ibán, Jorge Díaz Heredia, Unidad de Hombro y Codo, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Miguel A Ruiz Ibán
- Maria Valencia Mora, Miguel A Ruiz Ibán, Jorge Díaz Heredia, Unidad de Hombro y Codo, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Jorge Díaz Heredia
- Maria Valencia Mora, Miguel A Ruiz Ibán, Jorge Díaz Heredia, Unidad de Hombro y Codo, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Raul Barco Laakso
- Maria Valencia Mora, Miguel A Ruiz Ibán, Jorge Díaz Heredia, Unidad de Hombro y Codo, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Ricardo Cuéllar
- Maria Valencia Mora, Miguel A Ruiz Ibán, Jorge Díaz Heredia, Unidad de Hombro y Codo, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Mariano García Arranz
- Maria Valencia Mora, Miguel A Ruiz Ibán, Jorge Díaz Heredia, Unidad de Hombro y Codo, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| |
Collapse
|
|
22
|
Leal MF, Belangero PS, Figueiredo EA, Cohen C, Loyola LC, Andreoli CV, Smith MC, de Castro Pochini A, Ejnisman B, Cohen M. Identification of suitable reference genes for gene expression studies in tendons from patients with rotator cuff tear. PLoS One 2015; 10:e0118821. [PMID: 25768100 PMCID: PMC4358921 DOI: 10.1371/journal.pone.0118821] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Accepted: 01/09/2015] [Indexed: 01/17/2023] Open
Abstract
Rotator cuff tear is one of the most common causes of shoulder dysfunction. Gene expression analysis may be a useful tool for understanding tendon tears and the failure of cuff healing, and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) has become an effective method for such studies. However, this technique requires the use of suitable reference genes for data normalization. Here, we evaluate the suitability of six reference genes (18S, ACTB, B2M, GAPDH, HPRT1 and TBP) using samples from the rotator cuff tendons of 28 individuals with tendon tears (3 tendons regions) and 8 controls (2 tendon regions); for the tear patients, we evaluated ruptured and non-ruptured tendon samples. The stability of the candidate reference genes was determined using the NormFinder, geNorm, BestKeeper and DataAssist software packages. Overall, HPRT1 was the best single reference gene, and HPRT1+TBP composed the best pair and HPRT1+TBP+ACTB composed the best trio of reference genes from the analysis of different groups, including the simultaneous analysis of all tissue samples. To identify the optimal combination of reference genes, we evaluated the expression of COL1A1 and COL3A1, and no obvious differences were observed when using 2, 3 or 4 reference genes for most of the analyses. However, COL3A1 expression differed between ruptured and non-ruptured (posterior superior region) tendons of patients only when normalized by HPRT1+TBP+B2M and HPRT1+TBP. On the other hand, the comparison between these two groups using the best trio of reference genes (HPRT1+TBP+ACTB) and 4 reference genes did not revealed a significant difference in COL3A1 expression. Consequently, the use of suitable reference genes for a reliable gene expression evaluation by RT-qPCR should consider the type of tendon samples investigated. HPRT1+TBP+ACTB seems to be the best combination of reference genes for the analysis of involving different tendon samples of individuals with rotator cuff tears.
Collapse
Affiliation(s)
- Mariana Ferreira Leal
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- * E-mail:
| | - Paulo Santoro Belangero
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | | | - Carina Cohen
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Leonor Casilla Loyola
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Carlos Vicente Andreoli
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Marília Cardoso Smith
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | | | - Benno Ejnisman
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Moises Cohen
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| |
Collapse
|
|
23
|
Reduced levels of mesenchymal stem cells at the tendon-bone interface tuberosity in patients with symptomatic rotator cuff tear. INTERNATIONAL ORTHOPAEDICS 2015. [PMID: 25757411 DOI: 10.1007/s00264- 015-2724-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE While the use of bone marrow concentrate (BMC) has been described in the treatment of rotator cuff tears, the impact of a rotator cuff injury on the mesenchymal stem cells (MSCs) content present in the human shoulder has not been determined, especially with regard to changes in the levels of MSCs at the tendon-bone interface. With the hypothesis that there was a decreased level of MSCs at the tendon-bone interface tuberosity in patients with rotator cuff tear, we assessed the level of MSCs in the tuberosity of the shoulder of patients undergoing a rotator cuff repair. METHODS We analysed the data of 125 patients with symptomatic rotator cuff tears and of 75 control patients without rotator cuff injury. We recorded the following data: size of tear, number of torn tendons, aetiology of the tear, lag time between onset of shoulder symptoms/injury and repair, and also fatty infiltration of muscles. Mesenchymal stem cell content at the tendon-bone interface tuberosity was evaluated by bone marrow aspiration collected in the humeral tuberosities of patients at the beginning of surgery. RESULTS A significant reduction in MSC content (from moderate, 30-50 %, to severe >70 %) at the tendon-bone interface tuberosity relative to the MSC content of the control was observed in all rotator cuff repair study patients. Severity of the decrease was statistically correlated to a number of factors, including the delay between onset of symptoms and surgery, number of involved tendons, fatty infiltration stage and increasing patient age. CONCLUSION This study demonstrates that the level of MSCs present in the greater tuberosity of patients with a rotator cuff tear decreases as a function of a number of clinical factors, including lag time from tear onset to treatment, tear size, number of tears and stage of fatty infiltration, among others. This information may help the practices in using biologic augmentation of a rotator cuff repair.
Collapse
|
|
24
|
Hernigou P, Merouse G, Duffiet P, Chevalier N, Rouard H. Reduced levels of mesenchymal stem cells at the tendon-bone interface tuberosity in patients with symptomatic rotator cuff tear. INTERNATIONAL ORTHOPAEDICS 2015; 39:1219-25. [PMID: 25757411 DOI: 10.1007/s00264-015-2724-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 02/24/2015] [Indexed: 12/21/2022]
Abstract
PURPOSE While the use of bone marrow concentrate (BMC) has been described in the treatment of rotator cuff tears, the impact of a rotator cuff injury on the mesenchymal stem cells (MSCs) content present in the human shoulder has not been determined, especially with regard to changes in the levels of MSCs at the tendon-bone interface. With the hypothesis that there was a decreased level of MSCs at the tendon-bone interface tuberosity in patients with rotator cuff tear, we assessed the level of MSCs in the tuberosity of the shoulder of patients undergoing a rotator cuff repair. METHODS We analysed the data of 125 patients with symptomatic rotator cuff tears and of 75 control patients without rotator cuff injury. We recorded the following data: size of tear, number of torn tendons, aetiology of the tear, lag time between onset of shoulder symptoms/injury and repair, and also fatty infiltration of muscles. Mesenchymal stem cell content at the tendon-bone interface tuberosity was evaluated by bone marrow aspiration collected in the humeral tuberosities of patients at the beginning of surgery. RESULTS A significant reduction in MSC content (from moderate, 30-50 %, to severe >70 %) at the tendon-bone interface tuberosity relative to the MSC content of the control was observed in all rotator cuff repair study patients. Severity of the decrease was statistically correlated to a number of factors, including the delay between onset of symptoms and surgery, number of involved tendons, fatty infiltration stage and increasing patient age. CONCLUSION This study demonstrates that the level of MSCs present in the greater tuberosity of patients with a rotator cuff tear decreases as a function of a number of clinical factors, including lag time from tear onset to treatment, tear size, number of tears and stage of fatty infiltration, among others. This information may help the practices in using biologic augmentation of a rotator cuff repair.
Collapse
|
|
25
|
Valencia Mora M, Antuña Antuña S, García Arranz M, Carrascal MT, Barco R. Application of adipose tissue-derived stem cells in a rat rotator cuff repair model. Injury 2014; 45 Suppl 4:S22-7. [PMID: 25384471 DOI: 10.1016/s0020-1383(14)70006-3] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Healing tissue of the rotator cuff does not regenerate the native enthesis; fibrovascular scar tissue is formed instead and this has less favourable biomechanical properties. The purpose of this study was to determine if the application of adipose tissue-derived stem cells (ASCs) could improve biomechanical and histological properties of the repair. MATERIAL AND METHODS Fifty Sprague-Dawley rats underwent detachment and repair of the supraspinatus tendon, 32 for the biomechanical study and 18 for the histological examination. Animals were randomised in two groups to receive either a collagen carrier alone (untreated group) or the carrier plus 2×10(6) ASCs (ASCs group). A control group (suture only) was also included for the histological examination. The animals were sacrificed at 2 and 4 weeks for the biomechanical study and at 24 hours, and 1 and 4 weeks for the histological study. Maximum load failure energy, elastic energy, mechanical deformation, stiffness and absorbed energy were measured. Immunofluorescence testing was conducted to show the presence of ASCs in the repair area. RESULTS There were no differences between the untreated group and the ASCs group in any of the biomechanical variables at the 2- and 4-week time points. The mechanical deformation before failure was higher for the ASCs group compared with the untreated group at 2 weeks and 4 weeks (p=0.09), as was the absorbed energy (p=0.06). Differences in maximum load to failure between 2 and 4 weeks were significant for the untreated group (p=0.04) but not for the ASCs group (p=0.17). Histological examination showed less acute inflammation with diminished presence of oedema and neutrophils in the ASCs group. There were no differences in the orientation of collagen fibres between groups at either time point. In the ASCs group, collagen was present only at the last time point. CONCLUSION The application of ASCs in a rat rotator cuff repair model did not improve the biomechanical properties of the tendon-to-bone healing. However, the ASCs group showed less inflammation, which may lead to a more elastic repair and less scarred healing.
Collapse
Affiliation(s)
| | | | | | - Maria Teresa Carrascal
- Departamento de Biomecánica; Escuela Técnica Superior de Ingeniería Industrial UNED, Madrid, Spain
| | - Raúl Barco
- Hospital Universitario La Paz, Madrid, Spain.
| |
Collapse
|
|
26
|
Ghorayeb SR, Levin A, Ast M, Schwartz JA, Grande DA. Sonographic evaluation of knee cartilage defects implanted with preconditioned scaffolds. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2014; 33:1241-1253. [PMID: 24958411 DOI: 10.7863/ultra.33.7.1241] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
OBJECTIVES The purpose of this study was to develop a novel method for creating an acellular bioactive scaffold, to prove its efficacy in vivo and in vitro for the augmentation of biological repair, and to confirm that sonographic microscopy is a viable modality for monitoring the healing process of osteochondral defects implanted with preconditioned bioactive scaffolds. METHODS Rabbit marrow stromal cells were retrovirally transduced with either bone morphogenetic protein 7 (BMP-7) or insulinlike growth factor 1 (IGF-1) genes, cultured for 9 weeks in nonwoven poly-L-lactic acid scaffolds, and then frozen and lyophilized. The knees were evaluated at 3, 6, and 12 weeks after surgery using 20-MHz ultrasound and then prepared for routine histologic analysis. B-scans of the extracellular matrix defects were compared to histologic results. RESULTS Control defects showed a void or a mixture of fibrocartilage tissue. Both types of scaffolds resulted in a higher percentage (both P< .001) of primarily hyaline cartilage tissue with intact articular surfaces. The osteochondral defects were clearly observed in each sonographic signature. There were no differences between images of scaffolds treated with IGF-1 or BMP-7. Extracellular matrix regrowth was found to closely parallel (R(2) = 0.968; P < .003) the histologic images. A 3-mm defect depth and a 2.5-mm scaffold thickness were measured on the sonograms, comparing well to actual dimensions. CONCLUSIONS There was a gradual increase in healing bordering the defects for the 3-, 6-, and 12-week samples. Also, we have shown that sonography can aid in monitoring implantation of preconditioned scaffolds in osteochondral defects and thus assessing the healing process and cartilage/bone quality.
Collapse
Affiliation(s)
- Sleiman R Ghorayeb
- School of Engineering and Applied Sciences, Ultrasound Research Laboratory, Hofstra University, Hempstead, New York USA (S.R.G.); Department of Orthopedic Surgery, North Shore-LIJ Health System, Great Neck, New York USA (A.L., M.A.); and Orthopedics Research Laboratory, Feinstein Institute for Medical Research, North Shore Hospital, Manhasset, New York USA (S.R.G., J.A.S., D.A.G.).
| | - Adam Levin
- School of Engineering and Applied Sciences, Ultrasound Research Laboratory, Hofstra University, Hempstead, New York USA (S.R.G.); Department of Orthopedic Surgery, North Shore-LIJ Health System, Great Neck, New York USA (A.L., M.A.); and Orthopedics Research Laboratory, Feinstein Institute for Medical Research, North Shore Hospital, Manhasset, New York USA (S.R.G., J.A.S., D.A.G.)
| | - Michael Ast
- School of Engineering and Applied Sciences, Ultrasound Research Laboratory, Hofstra University, Hempstead, New York USA (S.R.G.); Department of Orthopedic Surgery, North Shore-LIJ Health System, Great Neck, New York USA (A.L., M.A.); and Orthopedics Research Laboratory, Feinstein Institute for Medical Research, North Shore Hospital, Manhasset, New York USA (S.R.G., J.A.S., D.A.G.)
| | - John A Schwartz
- School of Engineering and Applied Sciences, Ultrasound Research Laboratory, Hofstra University, Hempstead, New York USA (S.R.G.); Department of Orthopedic Surgery, North Shore-LIJ Health System, Great Neck, New York USA (A.L., M.A.); and Orthopedics Research Laboratory, Feinstein Institute for Medical Research, North Shore Hospital, Manhasset, New York USA (S.R.G., J.A.S., D.A.G.)
| | - Daniel A Grande
- School of Engineering and Applied Sciences, Ultrasound Research Laboratory, Hofstra University, Hempstead, New York USA (S.R.G.); Department of Orthopedic Surgery, North Shore-LIJ Health System, Great Neck, New York USA (A.L., M.A.); and Orthopedics Research Laboratory, Feinstein Institute for Medical Research, North Shore Hospital, Manhasset, New York USA (S.R.G., J.A.S., D.A.G.)
| |
Collapse
|
|
27
|
Angeline ME, Ma R, Pascual-Garrido C, Voigt C, Deng XH, Warren RF, Rodeo SA. Effect of diet-induced vitamin D deficiency on rotator cuff healing in a rat model. Am J Sports Med 2014; 42:27-34. [PMID: 24131579 DOI: 10.1177/0363546513505421] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [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 Few studies have considered hormonal influences, particularly vitamin D, on healing. HYPOTHESIS Vitamin D deficiency would have a negative effect on the structure of the healing tendon-bone interface in a rat model and would result in decreased tendon attachment strength. STUDY DESIGN Controlled laboratory study. METHODS Vitamin D deficiency was induced in 28 male Sprague-Dawley rats using a specialized vitamin D-deficient diet and ultraviolet light restriction. Serum levels of vitamin D were measured after 6 weeks. These vitamin D-deficient animals (experimental group) plus 32 rats with normal vitamin D levels (controls) underwent unilateral detachment of the right supraspinatus tendon from the greater tuberosity of the humerus, followed by immediate repair using bone tunnel suture fixation. The animals were sacrificed at 2- and 4-week intervals after surgery for biomechanical analysis. A paired t test was used to compare serum vitamin D levels at day 0 and at 6 weeks. A nonparametric Mann-Whitney U test was used to compare load-to-failure and stiffness values between the experimental group and controls. Bone density and new bone formation at the tendon insertion site on the greater tuberosity were assessed with micro-computed tomography (CT). The organization of collagen tissue, new bone formation, vascularity at the tendon-bone interface, fibrocartilage at the tendon-bone interface, and collagen fiber continuity between the tendon and bone tissue were evaluated with safranin O and picrosirius red staining. RESULTS Blood draws confirmed vitamin D deficiency at 6 weeks compared with time zero/baseline for rats in the experimental group (10.9 ng/mL vs 6.5 ng/mL, respectively; P < .001). Biomechanical testing demonstrated a significant decrease in load to failure in the experimental group compared with controls at 2 weeks (5.8 ± 2.0 N vs 10.5 ± 4.4 N, respectively; P < .006). There was no difference in stiffness at 2 weeks between the control and experimental groups. At 4 weeks, there was no significant difference in load to failure or stiffness between the control and experimental groups. Histological analysis showed less bone formation and less collagen fiber organization in the vitamin D-deficient specimens at 4 weeks as compared with controls. Micro-CT analysis showed no significant difference between groups for total mineral density and bone volume fraction of cortical, whole, or trabecular bone at 4 weeks. CONCLUSION The biomechanical and histological data from this study suggest that low vitamin D levels may negatively affect early healing at the rotator cuff repair site. CLINICAL RELEVANCE It is estimated that 1 billion people worldwide are vitamin D deficient. In the deficient state, acutely injured rotator cuffs may have a reduced ability for tendon healing. Further studies are needed to determine the exact mechanism by which vitamin D affects tendon healing and whether vitamin D supplementation can improve rotator cuff tendon healing and reduce the incidence of retears.
Collapse
Affiliation(s)
- Michael E Angeline
- Scott A. Rodeo, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021.
| | | | | | | | | | | | | |
Collapse
|
|
28
|
Gartsman GM, Drake G, Edwards TB, Elkousy HA, Hammerman SM, O'Connor DP, Press CM. Ultrasound evaluation of arthroscopic full-thickness supraspinatus rotator cuff repair: single-row versus double-row suture bridge (transosseous equivalent) fixation. Results of a prospective, randomized study. J Shoulder Elbow Surg 2013; 22:1480-7. [PMID: 24012360 DOI: 10.1016/j.jse.2013.06.020] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Revised: 06/13/2013] [Accepted: 06/16/2013] [Indexed: 02/01/2023]
Abstract
BACKGROUND The purpose of this study was to compare the structural outcomes of a single-row rotator cuff repair and double-row suture bridge fixation after arthroscopic repair of a full-thickness supraspinatus rotator cuff tear. MATERIAL AND METHODS We evaluated with diagnostic ultrasound a consecutive series of ninety shoulders in ninety patients with full-thickness supraspinatus tears at an average of 10 months (range, 6-12) after operation. A single surgeon at a single hospital performed the repairs. Inclusion criteria were full-thickness supraspinatus tears less than 25 mm in their anterior to posterior dimension. Exclusion criteria were prior operations on the shoulder, partial thickness tears, subscapularis tears, infraspinatus tears, combined supraspinatus and infraspinatus repairs and irreparable supraspinatus tears. Forty-three shoulders were repaired with single-row technique and 47 shoulders with double-row suture bridge technique. Postoperative rehabilitation was identical for both groups. Ultrasound criteria for healed repair included visualization of a tendon with normal thickness and length, and a negative compression test. RESULTS Eighty-three patients were available for ultrasound examination (40 single-row and 43 suture-bridge). Thirty of 40 patients (75%) with single-row repair demonstrated a healed rotator cuff repair compared to 40/43 (93%) patients with suture-bridge repair (P = .024). CONCLUSION Arthroscopic double-row suture bridge repair (transosseous equivalent) of an isolated supraspinatus rotator cuff tear resulted in a significantly higher tendon healing rate (as determined by ultrasound examination) when compared to arthroscopic single-row repair.
Collapse
Affiliation(s)
- Gary M Gartsman
- Fondren Orthopedic Group, Texas Orthopedic Hospital, Houston, TX, USA
| | | | | | | | | | | | | |
Collapse
|
|
29
|
Weber SC, Kauffman JI, Parise C, Weber SJ, Katz SD. Platelet-rich fibrin matrix in the management of arthroscopic repair of the rotator cuff: a prospective, randomized, double-blinded study. Am J Sports Med 2013. [PMID: 23204506 DOI: 10.1177/0363546512467621] [Citation(s) in RCA: 125] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Arthroscopic rotator cuff repair has a high rate of patient satisfaction. However, multiple studies have shown significant rates of anatomic failure. Biological augmentation would seem to be a reasonable technique to improve clinical outcomes and healing rates. PURPOSE To represent a prospective, double-blinded, randomized study to assess the use of platelet-rich fibrin matrix (PRFM) in rotator cuff surgery. STUDY DESIGN Randomized controlled trial; level of evidence, 1. METHODS Prestudy power analysis demonstrated that a sample size of 30 patients in each group (PRFM vs control) would allow recognition of a 20% difference in perioperative pain scores. Sixty consecutive patients were randomized to either receive a commercially available PRFM product or not. Preoperative and postoperative range of motion (ROM), University of California-Los Angeles (UCLA), and simple shoulder test (SST) scores were recorded. Surgery was performed using an arthroscopic single-row technique. Visual analog scale (VAS) pain scores were obtained upon arrival to the recovery room and 1 hour postoperatively, and narcotic consumption was recorded and converted to standard narcotic equivalents. The SST and ROM measurements were taken at 3, 6, 9, and 12 weeks postoperatively, and final (1 year) American shoulder and elbow surgeons (ASES) shoulder and UCLA shoulder scores were assessed. RESULTS There were no complications. Randomization created comparable groups except that the PRFM group was younger than the control group (mean ± SD, 59.67 ± 8.16 y vs 64.50 ± 8.59 y, respectively; P < .05). Mean surgery time was longer for the PRFM group than for the control group (83.28 ± 17.13 min vs 73.28 ± 17.18 min, respectively; P < .02). There was no significant difference in VAS scores or narcotic use between groups and no statistically significant differences in recovery of motion, SST, or ASES scores. Mean ASES scores were 82.48 ± 8.77 (PRFM group) and 82.52 ± 12.45 (controls) (F(1,56) = 0.00, P > .98). Mean UCLA shoulder scores were 27.94 ± 4.98 for the PRFM group versus 29.59 ± 1.68 for the controls (P < .046). Structural results correlated with age and size of the tear and did not differ between the groups. CONCLUSION Platelet-rich fibrin matrix was not shown to significantly improve perioperative morbidity, clinical outcomes, or structural integrity. While longer term follow-up or different platelet-rich plasma formulations may show differences, early follow-up does not show significant improvement in perioperative morbidity, structural integrity, or clinical outcome.
Collapse
Affiliation(s)
- Stephen C Weber
- Sacramento Knee and Sports Medicine, 2801 K Street, Suite 310, Sacramento, CA 95816, USA.
| | | | | | | | | |
Collapse
|
|
30
|
Abstract
The rotator cuff enthesis is not reestablished after a rotator cuff repair. Instead, a scar-mediated healing response occurs at the tendon-bone interface, which is notably weaker than the native enthesis and thus more prone to failure. Biological augmentation through growth factors, AASs, biomimetic scaffolds, or siRNA therapy has the potential to enhance the healing response. The ultimate key, however, is in determining which of these enables a more regenerative healing response of the native tissue rather than enhanced production of scar tissue. In addition, the optimal combination of factors, dosing, and delivery methods remains to be clearly elucidated. Biological augmentation and tissue engineering for tendon healing remains promising, but much work still needs to be done.
Collapse
|
|
31
|
Schaer M, Schober M, Berger S, Boileau P, Zumstein MA. Biologically based strategies to augment rotator cuff tears. INTERNATIONAL JOURNAL OF SHOULDER SURGERY 2012; 6:51-60. [PMID: 22787334 PMCID: PMC3391785 DOI: 10.4103/0973-6042.96995] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Lesions of the rotator cuff (RC) are among the most frequent tendon injuries. In spite of the developments in both open and arthroscopic surgery, RC repair still very often fails. In order to reduce the failure rate after surgery, several experimental in vitro and in vivo therapy methods have been developed for biological improvement of the reinsertion. This article provides an overview of the current evidence for augmentation of RC reconstruction with growth factors. Furthermore, potential future therapeutic approaches are discussed. We performed a comprehensive search of the PubMed database using various combinations of the keywords “tendon,” “rotator cuff,” “augmentation,” “growth factor,” “platelet-rich fibrin,” and “platelet-rich plasma” for publications up to 2011. Given the linguistic capabilities of the research team, we considered publications in English, German, French, and Spanish. We excluded literature reviews, case reports, and letters to the editor.
Collapse
Affiliation(s)
- M Schaer
- Department of Orthopaedic Surgery and Traumatology, Inselspital, Bern, Switzerland
| | | | | | | | | |
Collapse
|
|
32
|
Leek BT, Tasto JP, Tibor LM, Healey RM, Freemont A, Linn MS, Chase DE, Amiel D. Augmentation of tendon healing with butyric acid-impregnated sutures: biomechanical evaluation in a rabbit model. Am J Sports Med 2012; 40:1762-71. [PMID: 22729622 DOI: 10.1177/0363546512450691] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Butyric acid (BA) has been shown to be angiogenic and to enhance transcriptional activity in tissue. These properties of BA have the potential to augment biological healing of a repaired tendon. PURPOSE To evaluate this possibility both biomechanically and histologically in an animal tendon repair model. STUDY DESIGN Controlled laboratory study. METHODS A rabbit Achilles tendon healing model was used to evaluate the biomechanical strength and histological properties at 6 and 12 weeks after repair. Unilateral tendon defects were created in the middle bundle of the Achilles tendon of each rabbit, which were repaired equivalently with either Ultrabraid BA-impregnated sutures or control Ultrabraid sutures. RESULTS After 6 weeks, BA-impregnated suture repairs had a significantly increased (P < .0001) Young's modulus and ultimate tensile strength relative to the control suture repairs. At 12 weeks, no statistical difference was observed between these measures. The histological data at 6 weeks demonstrated significantly increased (P < .005) vessel density within 0.25 mm of the repair suture in the BA-impregnated group. There was also an associated 42% increase in the local number of myofibroblasts in the BA samples relative to the controls at this time. By 12 weeks, these differences were not observed. CONCLUSION Tendons repaired with BA-impregnated sutures demonstrated improved biomechanical properties at 6 weeks relative to control sutures, suggesting a neoangiogenic mechanism of enhanced healing through an increased myofibroblast presence. CLINICAL RELEVANCE These findings demonstrate that a relatively simple alteration of suture material may augment early tendon healing to create a stronger repair construct during this time.
Collapse
Affiliation(s)
- Bryan T Leek
- San Diego Sports Medicine and Orthopaedic Center, San Diego, California, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Hee CK, Dines JS, Solchaga LA, Shah VR, Hollinger JO. Regenerative tendon and ligament healing: opportunities with recombinant human platelet-derived growth factor BB-homodimer. TISSUE ENGINEERING PART B-REVIEWS 2012; 18:225-34. [PMID: 22145770 DOI: 10.1089/ten.teb.2011.0603] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Intrinsic tendon healing in response to injury is a reparative process that often results in formation of scar tissue with functional and mechanical properties inferior to those of the native tendon. Development of therapies that can promote regenerative, rather than reparative, healing hold the promise of improving patient recovery from tendon and ligament injuries by producing tissue that is morphologically and functionally equivalent to the native tissue. One therapeutic approach that has been a frequent topic of investigation in the preclinical literature is the use of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) to augment tendon and ligament repair. The chemotactic, mitogenic, and pro-angiogenic properties of rhPDGF-BB have been shown to result in recruitment and proliferation of tenogenic cells and a commensurate boost in extracellular matrix deposition and organization, improving the morphological and biomechanical properties of healing tendons and ligaments. The outcomes of the preclinical studies reviewed here strongly suggest that rhPDGF-BB will provide a new therapeutic opportunity to improve the treatment of injured tendons and ligaments.
Collapse
|
|
34
|
Nixon AJ, Watts AE, Schnabel LV. Cell- and gene-based approaches to tendon regeneration. J Shoulder Elbow Surg 2012; 21:278-94. [PMID: 22244071 DOI: 10.1016/j.jse.2011.11.015] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Revised: 11/14/2011] [Accepted: 11/15/2011] [Indexed: 02/06/2023]
Abstract
Repair of rotator cuff tears in experimental models has been significantly improved by the use of enhanced biologic approaches, including platelet-rich plasma, bone marrow aspirate, growth factor supplements, and cell- and gene-modified cell therapy. Despite added complexity, cell-based therapies form an important part of enhanced repair, and combinations of carrier vehicles, growth factors, and implanted cells provide the best opportunity for robust repair. Bone marrow-derived mesenchymal stem cells provide a stimulus for repair in flexor tendons, but application in rotator cuff repair has not shown universally positive results. The use of scaffolds such as platelet-rich plasma, fibrin, and synthetic vehicles and the use of gene priming for stem cell differentiation and local anabolic and anti-inflammatory impact have both provided essential components for enhanced tendon and tendon-to-bone repair in rotator cuff disruption. Application of these research techniques in human rotator cuff injury has generally been limited to autologous platelet-rich plasma, bone marrow concentrate, or bone marrow aspirates combined with scaffold materials. Cultured mesenchymal progenitor therapy and gene-enhanced function have not yet reached clinical trials in humans. Research in several animal species indicates that the concept of gene-primed stem cells, particularly embryonic stem cells, combined with effective culture conditions, transduction with long-term integrating vectors carrying anabolic growth factors, and development of cells conditioned by use of RNA interference gene therapy to resist matrix metalloproteinase degradation, may constitute potential advances in rotator cuff repair. This review summarizes cell- and gene-enhanced cell research for tendon repair and provides future directions for rotator cuff repair using biologic composites.
Collapse
Affiliation(s)
- Alan J Nixon
- Comparative Orthopaedics Laboratory, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
| | | | | |
Collapse
|
|
35
|
Malavolta EA, Gracitelli MEC, Sunada EE, Benegas E, de Santis Prada F, Neto RB, Rodrigues MB, Neto AAF, de Camargo OP. PLATELET-RICH PLASMA IN ARTHROSCOPIC REPAIRS OF COMPLETE TEARS OF THE ROTATOR CUFF. Rev Bras Ortop 2012; 47:741-7. [PMID: 27047894 PMCID: PMC4799491 DOI: 10.1016/s2255-4971(15)30032-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Accepted: 02/07/2012] [Indexed: 01/01/2023] Open
Abstract
Objective: To evaluate shoulder functional results and the retear rate of arthroscopic repair of the rotator cuff augmented with platelet-rich plasma (PRP).Methods: Prospective case series with single-row arthroscopic repair of the rotator cuff augmented with PRP. Only cases of isolated supraspinatus tears with retraction of less than 3 cm were included in this series. The PRP used was obtained by apheresis. It was applied on liquid consistency in its activated form, with the addition of autologous thrombin. Patients were evaluated after 12 months of the surgical procedure. The Constant-Murley, UCLA and VAS scales were used, and the retear rate was assessed using magnetic resonance imaging (MRI). Results: Fourteen patients were evaluated (14 shoulders). The mean Constant-Murley score was 45.64 ± 12.29 before the operation and evolved to 80.78 ± 13.22 after the operation (p < 0.001). The UCLA score increased from 13.78 ± 5.66 to 31.43 ± 3.9 (p < 0.001). The patients’ pain level decreased from a median of 7.5 (p25% = 6, p75% = 8) to 0.5 (p25% = 0, p75% = 3) (p = 0.0013) according to the VAS score. None of the patients presented complete retear. Three patients (21.4%) showed partial retear, without transfixation. Only one patient developed complications (adhesive capsulitis). Conclusion: Patients submitted to arthroscopic rotator cuff repair augmented with PRP showed significant functional improvement and none of them had complete retearing.
Collapse
Affiliation(s)
- Eduardo Angeli Malavolta
- Assistant Physician, Shoulder and Elbow Group and Trauma Group, Institute of Orthopedics and Traumatology, USP School of Medicine, São Paulo, SP, Brazil
| | - Mauro Emilio Conforto Gracitelli
- Assistant Physician, Shoulder and Elbow Group and Trauma Group, Institute of Orthopedics and Traumatology, USP School of Medicine, São Paulo, SP, Brazil
| | - Edwin Eiji Sunada
- Collaborating Orthopedist, Shoulder and Elbow Group, Institute of Orthopedics and Traumatology, USP School of Medicine, São Paulo, SP, Brazil
| | - Eduardo Benegas
- Doctor's degree in Medicine; Assistant Physician, Shoulder and Elbow Group, Institute of Orthopedics and Traumatology, USP School of Medicine, São Paulo, SP, Brazil
| | - Flavia de Santis Prada
- Doctor's degree in Medicine; Assistant Physician, Shoulder and Elbow Group, Institute of Orthopedics and Traumatology, USP School of Medicine, São Paulo, SP, Brazil
| | - Raul Bolliger Neto
- Doctor's degree in Medicine; Assistant Physician, Shoulder and Elbow Group, Institute of Orthopedics and Traumatology, USP School of Medicine, São Paulo, SP, Brazil
| | - Marcelo Bordalo Rodrigues
- Chief Physician, Department of Radiology, Institute of Orthopedics and Traumatology, USP School of Medicine, São Paulo, SP, Brazil
| | - Arnaldo Amado Ferreira Neto
- Doctor's degree in Medicine; Head, Shoulder and Elbow Group, Institute of Orthopedics and Traumatology, USP School of Medicine, São Paulo, SP, Brazil
| | - Olavo Pires de Camargo
- Full Professor, Department of Orthopedics and Traumatology, USP School of Medicine, São Paulo, SP, Brazil
| |
Collapse
|
|
36
|
Gulotta LV, Rodeo SA. Emerging ideas: Evaluation of stem cells genetically modified with scleraxis to improve rotator cuff healing. Clin Orthop Relat Res 2011; 469:2977-80. [PMID: 21132407 PMCID: PMC3171546 DOI: 10.1007/s11999-010-1727-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2010] [Accepted: 11/22/2010] [Indexed: 01/31/2023]
Abstract
BACKGROUND Rotator cuffs heal with an interposed layer of scar tissue that makes repairs prone to failure. Cell-based biologic therapies have the potential to augment this healing process. Scleraxis (Scx) is a transcription factor that is involved in tendon development during embryogenesis, and may help drive stem cells toward tenocyte differentiation in adults. QUESTIONS/HYPOTHESIS: (1) Overexpression of Scx with adenoviral-mediated gene transfer in stem cells will drive pluripotent stem cells toward tenoblastogenic lineages in vitro; (2) the application of these genetically modified cells will result in improved histologic and biomechanical healing of rotator cuff repairs. METHOD OF STUDY For the first hypothesis, we will determine whether stem cells derived from various sources can differentiate into tenocytes when genetically modified with Scx in vitro. We will assess morphologic features of cells with light microscopy, and gene expression analyses to confirm phenotypes consistent with tenocyte differentiation. For the second hypothesis, we will determine whether these genetically modified cells augment rotator cuff repairs in a rat model based on histology and biomechanical outcomes. SIGNIFICANCE Development of this technology may substantially advance our ability to repair large to massive rotator cuff tears while limiting the rates of anatomic failure.
Collapse
Affiliation(s)
- Lawrence V. Gulotta
- Sports Medicine/Shoulder Service, Hospital for Special Surgery, New York, NY USA ,Hospital for Special Surgery, 535 E 70th Street, New York, NY 10021 USA
| | - Scott A. Rodeo
- Sports Medicine/Shoulder Service, Hospital for Special Surgery, New York, NY USA
| |
Collapse
|
|
37
|
Hee CK, Dines JS, Dines DM, Roden CM, Wisner-Lynch LA, Turner AS, McGilvray KC, Lyons AS, Puttlitz CM, Santoni BG. Augmentation of a rotator cuff suture repair using rhPDGF-BB and a type I bovine collagen matrix in an ovine model. Am J Sports Med 2011; 39:1630-9. [PMID: 21555508 DOI: 10.1177/0363546511404942] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Rotator cuff tears are a common source of shoulder pain. High rates (20%-94%) of structural failure of the repair have been attributed to multiple factors, including poor repair tissue quality and tendon-to-bone integration. Biologic augmentation using growth factors has potential to promote tendon-to-bone integration, improving the function and long-term success of the repair. One such growth factor is platelet-derived growth factor-BB (PDGF-BB), which has been shown to improve healing in tendon and bone repair models. HYPOTHESIS Recombinant human PDGF-BB (rhPDGF-BB) combined with a highly porous type I bovine collagen matrix will improve the biomechanical function and morphologic appearance of the repair in a dose-dependent manner, relative to a suture-only control, after 12 weeks in an acute ovine model of rotator cuff repair. STUDY DESIGN Controlled laboratory study. METHODS An interpositional graft consisting of rhPDGF-BB and a type I collagen matrix was implanted in an ovine model of rotator cuff repair. Biomechanical and histologic analyses were performed to determine the functional and anatomic characteristics of the repair after 12 weeks. RESULTS A significant increase in the ultimate load to failure was observed in repairs treated with 75 µg (1490.5 ± 224.5 N, P = .029) or 150 µg (1486.6 ± 229.0 N, P = .029) of rhPDGF-BB, relative to suture-only controls (910.4 ± 156.1 N) and the 500-µg rhPDGF-BB group (677.8 ± 105.9 N). The 75-µg and 150-µg rhPDGF-BB groups also exhibited increased tendon-to-bone interdigitation histologically. No differences in inflammation or cellularity were observed among treatments. CONCLUSION This study demonstrated that an interpositional graft consisting of rhPDGF-BB (75 or 150 µg) and a type I collagen matrix was able to improve the biomechanical strength and anatomic appearance in an ovine model of rotator cuff repair compared to a suture-only control and the 500-µg rhPDGF-BB group. CLINICAL RELEVANCE Recombinant human PDGF-BB combined with a type I collagen matrix has potential to be used to augment surgical repair of rotator cuff tears, thereby improving clinical success.
Collapse
Affiliation(s)
- Christopher K Hee
- Sports Medicine, BioMimetic Therapeutics, Franklin, Tennessee 37067, USA.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Caliari SR, Harley BA. The effect of anisotropic collagen-GAG scaffolds and growth factor supplementation on tendon cell recruitment, alignment, and metabolic activity. Biomaterials 2011; 32:5330-40. [PMID: 21550653 PMCID: PMC3947515 DOI: 10.1016/j.biomaterials.2011.04.021] [Citation(s) in RCA: 168] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Accepted: 04/05/2011] [Indexed: 02/04/2023]
Abstract
Current surgical and tissue engineering approaches for treating tendon injuries have shown limited success, suggesting the need for new biomaterial strategies. Here we describe the development of an anisotropic collagen-glycosaminoglycan (CG) scaffold and use of growth factor supplementation strategies to create a 3D platform for tendon tissue engineering. We fabricated cylindrical CG scaffolds with aligned tracks of ellipsoidal pores that mimic the native physiology of tendon by incorporating a directional solidification step into a conventional lyophilization strategy. By modifying the freezing temperature, we created a homologous series of aligned CG scaffolds with constant relative density and degree of anisotropy but a range of pore sizes (55-243 μm). Equine tendon cells showed greater levels of attachment, metabolic activity, and alignment as well as less cell-mediated scaffold contraction, when cultured in anisotropic scaffolds compared to an isotropic CG scaffold control. The anisotropic CG scaffolds also provided critical contact guidance cues for cell alignment. While tendon cells were randomly oriented in the isotropic control scaffold and the transverse (unaligned) plane of the anisotropic scaffolds, significant cell alignment was observed in the direction of the contact guidance cues in the longitudinal plane of the anisotropic scaffolds. Scaffold pore size was found to significantly influence tendon cell viability, proliferation, penetration into the scaffold, and metabolic activity in a manner predicted by cellular solids arguments. Finally, the addition of the growth factors PDGF-BB and IGF-1 to aligned CG scaffolds was found to enhance tendon cell motility, viability, and metabolic activity in dose-dependent manners. This work suggests a composite strategy for developing bioactive, 3D material systems for tendon tissue engineering.
Collapse
Affiliation(s)
- Steven R. Caliari
- Dept. Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Brendan A.C. Harley
- Dept. Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Institute for Genomic Biology University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| |
Collapse
|
|
39
|
Liu X, Manzano G, Kim HT, Feeley BT. A rat model of massive rotator cuff tears. J Orthop Res 2011; 29:588-95. [PMID: 20949443 DOI: 10.1002/jor.21266] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2010] [Accepted: 08/23/2010] [Indexed: 02/04/2023]
Abstract
Rotator cuff tears (RCTs) are the most common tendon injury seen in orthopedic patients. Massive RCT does not heal spontaneously and results in poor clinical outcomes. Muscle atrophy and fatty infiltration in rotator cuff muscles are major complications of chronic massive RCT and are thought to be the key factors responsible for the failure of attempted massive RCT repair. However, the pathophysiology of rotator cuff muscle atrophy and fat infiltration remains largely unknown, and no small animal model has been shown to reproduce the histologic and molecular changes seen in massive RCT. In this article, we report a novel rat massive RCT model, in which significant and consistent muscle atrophy and fat infiltration were observed in the rotator cuff muscles after rotator cuff tendon transection and denervation. The supraspinatus and infraspinatus muscle lost 25.4% and 28.9% of their wet weight 2 weeks after complete tendon transection, respectively. Six weeks after surgery, the average wet weight of supraspinatus and infraspinatus muscles decreased 13.2% and 28.3%, respectively. Significant fat infiltration was only observed in infraspinatus 6 weeks after tendon transection.
Collapse
Affiliation(s)
- Xuhui Liu
- Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA
| | | | | | | |
Collapse
|
|
40
|
Longo UG, Lamberti A, Maffulli N, Denaro V. Tissue engineered biological augmentation for tendon healing: a systematic review. Br Med Bull 2011; 98:31-59. [PMID: 20851817 DOI: 10.1093/bmb/ldq030] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Tendon injuries give rise to significant morbidity. In the last few decades, several techniques have been increasingly used to optimize tendon healing. SOURCES OF DATA We performed a comprehensive search of PubMed, Medline, Cochrane, CINAHL and Embase databases using various combinations of the commercial names of each scaffold and the keywords 'tendon', 'rotator cuff', 'supraspinatus tendon', 'Achilles tendon', 'growth factors', 'cytokines', 'gene therapy', 'tissue engineering', 'mesenchymal' and 'stem cells' over the years 1966-2009. All articles relevant to the subject were retrieved, and their bibliographies were hand searched for further references in the context to tissue-engineered biological augmentation for tendon healing. AREAS OF AGREEMENT Several new techniques are available for tissue-engineered biological augmentation for tendon healing, growth factors, gene therapy and mesenchimal stem cells. AREAS OF CONTROVERSY Data are lacking to allow definitive conclusions on the use of these techniques for routine management of tendon ailments. GROWING POINTS The emerging field of tissue engineering holds the promise to use new techniques for tendon augmentation and repair. Preliminary studies support the idea that these techniques can provide an alternative for tendon augmentation with great therapeutic potential. AREAS TIMELY FOR DEVELOPING RESEARCH The optimization strategies discussed in this article are currently at an early stage of development. Although these emerging technologies may develop into substantial clinical treatment options, their full impact needs to be critically evaluated in a scientific fashion.
Collapse
Affiliation(s)
- Umile Giuseppe Longo
- Department of Orthopaedic and Trauma Surgery, Campus Biomedico University, Trigoria, Rome, Italy
| | | | | | | |
Collapse
|
|
41
|
Uggen C, Dines J, McGarry M, Grande D, Lee T, Limpisvasti O. The effect of recombinant human platelet-derived growth factor BB-coated sutures on rotator cuff healing in a sheep model. Arthroscopy 2010; 26:1456-62. [PMID: 20729027 DOI: 10.1016/j.arthro.2010.02.025] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2009] [Revised: 02/15/2010] [Accepted: 02/16/2010] [Indexed: 02/02/2023]
Abstract
PURPOSE The purpose of this study was to determine whether suture could be coated with recombinant human platelet-derived growth factor BB (rhPDGF-BB) and whether the coated suture would improve histologic scores and biomechanical strength of sheep rotator cuff repairs. METHODS FiberWire sutures (Arthrex, Naples, FL) were dip coated in a collagen-rhPDGF-BB solution. Coating was confirmed by use of enzyme-linked immunosorbent assay. Rotator cuff tears were created in 18 sheep. The tendons were wrapped in Gortex (Gore Medical, Flagstaff, AZ) and allowed to scar for 2 weeks. Tendons were then repaired to bone by use of standard anchors loaded with either rhPDGF-BB-coated sutures or uncoated sutures. Gross examination, histologic analysis, and biomechanical testing were performed 6 weeks after repair. RESULTS Enzyme-linked immunosorbent assay confirmed successful loading of the growth factor onto the sutures. Gross examination showed well-healed tendon-to-bone interfaces in both rhPDGF-BB-augmented repairs and controls. Histologic analysis using a semiquantitative rating scale showed improved tendon-to-bone healing in the rhPDGF-BB-augmented repairs. There was no significant difference in the ultimate load to failure of rhPDGF-BB-augmented rotator cuff repairs compared with standard suture repairs at 6 weeks after repair. CONCLUSIONS We were able to coat No. 2 FiberWire with rhPDGF-BB. At short-term follow-up, rhPDGF-BB-coated sutures enhanced histologic scores of sheep rotator cuff repairs; however, ultimate load to failure was equivalent to standard suture repairs. CLINICAL RELEVANCE rhPDGF-BB-coated sutures seem to produce a more histologically normal tendon insertion.
Collapse
|
|
42
|
Cheung EV, Silverio L, Yao J. Delivered growth factor therapy to improve healing after rotator cuff repair. STEM CELLS AND CLONING-ADVANCES AND APPLICATIONS 2010; 3:135-44. [PMID: 24198519 PMCID: PMC3781738 DOI: 10.2147/sccaa.s7359] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Background Degenerative rotator cuff tears are a significant cause of shoulder pain in the aging population. Rotator cuff repair surgery may be more successful when growth factors are delivered to the repair site. This study was designed to determine the cellular processes involved in normal bone-to-tendon healing and the current approaches used for biologic augmentation of rotator cuff repair. Methods This review focuses on animal studies of rotator cuff repair and early human trials. Results Regular bone-to-tendon healing forms a fibrous junction between tendon and bone that is markedly different from the original bone-to-tendon junction. Tendon augmentation with cellular components serves as scaffolding for endogenous fibroblastic cells and a possible source of growth factors and fibroblastic cells. Extracellular matrices provide a scaffold for incoming fibroblastic cells. However, research in extracellular matrices is not conclusive due to intermanufacturer variation and the lack of human subject research. Growth factors and platelet-rich plasma are established in other fields of research and show promise, but have not yet been rigorously tested in rotator cuff repair augmentation. Conclusions Rotator cuff repair can benefit from biologic augmentation. However, research in this field is still young and has not yet demonstrated that the benefits in healing rates are significant enough to merit regular clinical use. Randomized controlled trials will elucidate the use of biologic augmentation in rotator cuff repairs.
Collapse
Affiliation(s)
- Emilie V Cheung
- Department of Orthopedic Surgery, Stanford University, Redwood City, CA, USA
| | | | | |
Collapse
|
|
43
|
Rosenbaum AJ, Wicker JF, Dines JS, Bonasser L, Razzano P, Dines DM, Grande DA. Histologic stages of healing correlate with restoration of tensile strength in a model of experimental tendon repair. HSS J 2010; 6:164-70. [PMID: 21886531 PMCID: PMC2926361 DOI: 10.1007/s11420-009-9152-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2009] [Accepted: 12/09/2009] [Indexed: 02/07/2023]
Abstract
Much current research is focused on biologic enhancement of the tendon repair process. To evaluate the different methods, which include a variety of gene therapy and tissue engineering techniques, histological and biomechanical testing is often employed. Both modalities offer information on the progress and quality of repair; however, they have been historically considered as two separate entities. Histological evaluation is a less costly undertaking; however, there is no validated scoring scale to compare the results of different studies or even the results within a given study. Biomechanical testing can provide validated outcome measures; however, it is associated with increased cost and is more labor intensive. We hypothesized that a properly developed, objective histological scoring system would provide a validated outcome measure to compare histological results and correlate with biomechanics. In an Achilles tendon model, we have developed a histological scoring scale to assess tendon repair. The system grades collagen orientation, angiogenesis, and cartilage induction. In this study, histology scores were plotted against biomechanical testing results of healing tendons which indicated that a strong linear correlation exists between the histological properties of repaired tendons and their biomechanical characteristics. Concordantly, this study provides a pragmatic and financially feasible means of evaluating repair while accounting for both the histology and biomechanical properties observed in surgically repaired, healing tendon.
Collapse
Affiliation(s)
- Andrew J. Rosenbaum
- Feinstein Institute for Medical Research, North Shore-LIJHS, Manhasset, NY USA ,Robert Wood Johnson Medical School, 401 Haddon Avenue, Suite 154, Camden, NJ 08103 USA
| | - Jordan F. Wicker
- Feinstein Institute for Medical Research, North Shore-LIJHS, Manhasset, NY USA
| | | | - Lawrence Bonasser
- Department of Mechanical Engineering, Cornell University, Ithaca, NY USA
| | - Pasquale Razzano
- Feinstein Institute for Medical Research, North Shore-LIJHS, Manhasset, NY USA
| | | | - Daniel A. Grande
- Feinstein Institute for Medical Research, North Shore-LIJHS, Manhasset, NY USA
| |
Collapse
|
|
44
|
Exuberant synovitis after subacromial decompression and platelet rich growth factor (PRGF) injection. J Shoulder Elbow Surg 2010; 19:e6-9. [PMID: 20452249 DOI: 10.1016/j.jse.2010.01.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2009] [Revised: 01/15/2010] [Accepted: 01/17/2010] [Indexed: 02/01/2023]
|
|
45
|
Cheung EV, Silverio L, Sperling JW. Strategies in biologic augmentation of rotator cuff repair: a review. Clin Orthop Relat Res 2010; 468:1476-84. [PMID: 20352390 PMCID: PMC2865611 DOI: 10.1007/s11999-010-1323-7] [Citation(s) in RCA: 114] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Degenerative rotator cuff tears are increasing with the aging population, and healing is not uniform after surgery. Rotator cuffs may show improved healing when biologic factors are added during surgery. QUESTIONS/PURPOSES We asked: (1) What cellular processes are involved in normal bone-to-tendon healing? (2) What approaches are being developed in tendon augmentation? (3) What approaches are being developed with the addition of growth factors? METHODS We reviewed research in relating to biologic augmentation and cellular processes involved in rotator cuff repair, focusing on animal models of rotator cuff repair and nonrandomized human trials. RESULTS Regular bone-to-tendon healing forms a fibrous junction between tendon and bone that is distinct from the original bone-to-tendon junction. Tendon augmentation with cellular components serves as scaffolding for fibroblastic cells and a possible source of growth factors and fibroblastic cells. Extracellular matrices provide a scaffold for incoming fibroblastic cells, although current research does not conclusively confirm which if any of these scaffolds enhance repair owing in part to intermanufacturer variations and the limited human research. Growth factors and platelet-rich-plasma are established in other fields of research and may enhance repair but have not been rigorously tested. CONCLUSIONS There is potential application of biologic augmentation to improve healing after rotator cuff repair. However, research in this field is still inconclusive and has not been sufficiently demonstrated to merit regular clinical use. Future human trials can elucidate the use of biologic augmentation in rotator cuff repairs.
Collapse
Affiliation(s)
- Emilie V. Cheung
- Department of Orthopedic Surgery, Stanford University, 450 Broadway Street, MC 6342, Redwood City, CA 94063 USA
| | - Luz Silverio
- Department of Orthopedic Surgery, Stanford University, 450 Broadway Street, MC 6342, Redwood City, CA 94063 USA
| | - John W. Sperling
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN USA
| |
Collapse
|
|
46
|
Transient decreases in forelimb gait and ground reaction forces following rotator cuff injury and repair in a rat model. J Biomech 2010; 43:778-82. [PMID: 19931082 DOI: 10.1016/j.jbiomech.2009.10.031] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2009] [Revised: 10/07/2009] [Accepted: 10/14/2009] [Indexed: 12/22/2022]
Abstract
Due to inadequate healing, surgical repairs of torn rotator cuff tendons often fail, limiting the recovery of upper extremity function. The rat is frequently used to study rotator cuff healing; however, there are few systems capable of quantifying forelimb function necessary to interpret the clinical significance of tissue level healing. We constructed a device to capture images, ground reaction forces and torques, as animals ambulated in a confined walkway, and used it to evaluate forelimb function in uninjured control and surgically injured/repaired animals. Ambulatory data were recorded before (D-1), and 3, 7, 14, 28 and 56 days after surgery. Speed as well as step width and length were determined by analyzing ventral images, and ground reaction forces were normalized to body weight. Speed averaged 22+/-6 cm/s and was not affected by repair or time. Step width and length of uninjured animals compared well to values measured with our previous system. Forelimbs were used primarily for braking (-1.6+/-1.5% vs +2.5+/-0.6%), bore less weight than hind limbs (49+/-5% vs 58+/-4%), and showed no differences between sides (49+/-5% vs 46+/-5%) for uninjured control animals. Step length and ground reaction forces of the repaired animals were significantly less than control initially (days 3, 7 and 14 post-surgery), but not by day 28. Our new device provided uninjured ambulatory data consistent with our previous system and available literature, and measured reductions in forelimb function consistent with the deficit expected by our surgical model.
Collapse
|
|
47
|
Abstract
Different options are reviewed in the field of musculoskeletal tissue reconstruction, from the addition of biological actors (cells, growth factors, biological or artificial scaffolds) to the application of gene therapy or tissue engineering. Growth factors can enable innovative solutions to treat such disease if we can extrapolate to soft tissue the promising results obtained in bone reconstruction with bone morphogenetic proteins. However, as in bone reconstruction, soft-tissue regeneration will depend on the drug delivery carrier, the scaffold for the newly formed tissue, the dose of growth factor and the animal model, which must all be explored before extrapolation to clinical problems.
Collapse
Affiliation(s)
- L Obert
- Orthopaedic, Traumatology, Plastic and Hand Surgery Unit, University of Franche Comté, CHU Jean Minjoz, Besancon, France.
| | | | | | | |
Collapse
|
|
48
|
|
|
49
|
Rotini R, Fini M, Giavaresi G, Marinelli A, Guerra E, Antonioli D, Castagna A, Giardino R. New perspectives in rotator cuff tendon regeneration: review of tissue engineered therapies. ACTA ACUST UNITED AC 2008; 91:87-92. [PMID: 18320380 DOI: 10.1007/s12306-007-0015-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2007] [Accepted: 09/25/2007] [Indexed: 11/27/2022]
Abstract
Tissue engineering may play a major role in the treatment of rotator cuff tendon lesions through replacement of an injured tendon segment. Tendons have very poor spontaneous regenerative capabilities, and despite intensive remodelling, complete regeneration is never achieved and the strength of tendon and ligaments remains as much as 30% lower than normal even months or years following an acute injury. Tendons seem to be the least complex of the connective tissues with respect to their composition and architecture and this leads to the expectation that they would be more amenable to tissue engineered approaches than other tissues. An accurate literature revision was done in order to know the state of the art of tissue engineering therapies in the field of rotator cuff regeneration. The following techniques of tissue engineering were considered: local injection of stem cells or growth factors, gene transfer, in situ tissue engineering and in vitro production of bioengineered tendons to be further transplanted in the lesion site. So far, few experimental or clinical studies have been done on tendon tissue engineering compared to the extensive work on other tissues of orthopaedic interest, such as bone and cartilage. The existing studies are related to the following tissue engineering methodologies: gene transfer, in situ tissue engineering and in vitro production of bioengineered tendons. In our opinion the previously described literature revision showed the necessity for future studies in this area also because of recent advances in biological and bioactive scaffolds.
Collapse
Affiliation(s)
- Roberto Rotini
- Division of Orthopedic Surgery (Section B), Istituti Ortopedici Rizzoli, Bologna, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Tsiridis E, Velonis S, Limb D, Giannoudis PV. Tissue engineering approaches to rotator cuff tendon deficiency. Connect Tissue Res 2008; 49:455-63. [PMID: 19085246 DOI: 10.1080/03008200802325383] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Tissue engineering is an emerging scientific approach that may offer alternative pathways for managing tissue degeneration. The use of cellular and acellular matrix in combination with cells and/or growth factors is one approach currently being explored in the management of rotator cuff disease. Interestingly, the integration of gene therapy with this technique introduces a new dimension to treatment options. The scope of this article is to present an overview of the current tissue engineering in vivo methods being clinically investigated in rotator cuff disease.
Collapse
Affiliation(s)
- Eleftherios Tsiridis
- Academic Department of Trauma and Orthopaedic Surgery, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, School of Medicine, Leeds University, Leeds, United Kingdom.
| | | | | | | |
Collapse
|