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Pinheiro VH, Laughlin M, Borque KA, Ngo D, Kent MR, Jones M, Neves N, Fonseca F, Williams A. Career Length After Surgically Treated ACL Plus Collateral Ligament Injury in Elite Athletes. Am J Sports Med 2024; 52:2472-2481. [PMID: 39097768 DOI: 10.1177/03635465241262440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/05/2024]
Abstract
BACKGROUND Limited data are available regarding career length and competition level after combined anterior cruciate ligament (ACL) and medial- or lateral-sided surgeries in elite athletes. PURPOSE To evaluate career length after surgical treatment of combined ACL plus medial collateral ligament (MCL) and ACL plus posterolateral corner (PLC) injuries in elite athletes and, in a subgroup analysis of male professional soccer players, to compare career length and competition level after combined ACL+MCL or ACL+PLC surgeries with a cohort who underwent isolated ACL reconstruction (ACLR). STUDY DESIGN Cohort study; Level of evidence, 3. METHODS A consecutive cohort of elite athletes undergoing combined ACL+MCL and ACL+PLC surgery was analyzed between February 2001 and October 2019. A subgroup of male elite soccer players from this population was compared with a previously identified cohort having had isolated primary ACLR without other ligament surgery. A minimum 2-year follow-up was required. Outcome measures were career length and competition level. RESULTS A total of 98 elite athletes met the inclusion criteria, comprising 50 ACL+PLC and 48 ACL+MCL surgeries. The mean career length after surgical treatment of combined ACL+MCL and ACL+PLC injuries was 4.5 years. Return-to-play (RTP) time was significantly longer for ACL+PLC injuries (12.8 months; P = .019) than for ACL+MCL injuries (10.9 months). In the subgroup analysis of soccer players, a significantly lower number of players with combined ACL+PLC surgery were able to RTP (88%; P = .003) compared with 100% for ACL+MCL surgery and 97% for isolated ACLR, as well as requiring an almost 3 months longer RTP timeline (12.9 months; P = .002) when compared with the isolated ACL (10.2 months) and combined ACL+MCL (10.0 months) groups. However, career length and competition level were not significantly different between groups. CONCLUSION Among elite athletes, the mean career length after surgical treatment of combined ACL+MCL and ACL+PLC injuries was 4.5 years. Professional soccer players with combined ACL+PLC surgery returned at a lower rate and required a longer RTP time when compared with the players with isolated ACL or combined ACL+MCL injuries. However, those who did RTP had the same career longevity and competition level.
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Affiliation(s)
| | - Mitzi Laughlin
- Houston Methodist Orthopedics and Sports Medicine, Houston, Texas, USA
| | - Kyle A Borque
- Houston Methodist Orthopedics and Sports Medicine, Houston, Texas, USA
| | - Dylan Ngo
- Houston Methodist Orthopedics and Sports Medicine, Houston, Texas, USA
| | - Madison R Kent
- Houston Methodist Orthopedics and Sports Medicine, Houston, Texas, USA
| | - Mary Jones
- Fortius Clinic, London, UK
- FIFA Medical Centre of Excellence, London, UK
| | - Nuno Neves
- Orthopaedic Department, Hospital CUF Porto, Porto, Portugal
- Faculty of Medicine, University of Porto, Portugal
| | | | - Andy Williams
- Fortius Clinic, London, UK
- FIFA Medical Centre of Excellence, London, UK
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Shultz CL, Poehlein E, Morriss NJ, Green CL, Hu J, Lander S, Amoo-Achampong K, Lau BC. Nonoperative Management, Repair, or Reconstruction of the Medial Collateral Ligament in Combined Anterior Cruciate and Medial Collateral Ligament Injuries-Which Is Best? A Systematic Review and Meta-analysis. Am J Sports Med 2024; 52:522-534. [PMID: 36960920 DOI: 10.1177/03635465231153157] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/25/2023]
Abstract
BACKGROUND Combined injury of the anterior cruciate ligament (ACL) and the medial collateral ligament (MCL) is a common injury pattern and accounts for 20% of all ligamentous knee injuries. Despite advancements in surgical technique, there is no up-to-date consensus regarding the superiority of nonoperative versus operative management in higher-grade MCL tears of combined ACL-MCL injuries. PURPOSE To interpret recent literature on treatment options and to provide an updated evidence-based approach for management of combined ACL-MCL knee injuries. STUDY DESIGN Systematic review and meta-analysis; Level of evidence, 4. METHODS We performed a systematic review on outcomes following treatment of concomitant ACL and MCL injuries. A computerized search was conducted in PubMed, Embase.com, and Scopus.com. Authors independently assessed eligible studies and screened titles and abstracts. Articles reporting on patients with concomitant ACL and MCL injuries with or without concomitant procedures were included. Data regarding study design, sample size, patient age and sex, length of follow-up, timing of surgery, indications, surgical methods, concomitant procedures, outcomes, and complications were recorded. Patient-reported outcomes (PROs) and functional outcomes, including Knee injury and Osteoarthritis Outcome Score, International Knee Documentation Committee scores, Lysholm and Tegner scores, and range of motion, were estimated via meta-analysis and compared statistically by surgical approach. RESULTS In total, 18 studies were included in the systematic review with level 1 to level 4 evidence, with a total of 1,534 cases, were included in the systematic review. Of these, 16 studies with sufficient statistical reporting including 997 cases with sufficient follow-up were included in meta-analysis. Three different approaches to combined ACL-MCL injuries were identified: ACL reconstruction with (1) nonoperative MCL, (2) MCL repair, and (3) MCL reconstruction. There was no statistical difference between nonoperative versus surgically managed MCL injuries for PROs, range of motion at final follow up, or quadriceps strength. CONCLUSION Reconstruction of combined injury in a delayed fashion facilitates return of range of motion and may allow time for low-grade MCL tears to heal. If residual valgus or anteromedial rotatory laxity remains after a period of rehabilitation, then concomitant surgical management of ACL and MCL injuries is warranted. Avulsion MCL injuries and Stener-type lesions may benefit from early repair techniques.
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Affiliation(s)
- Christopher L Shultz
- Department of Orthopaedic Surgery, University of New Mexico Hospital, Albuquerque, New Mexico, USA
| | - Emily Poehlein
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Duke University School of Medicine, Durham, North Carolina, USA
| | - Nicholas J Morriss
- Duke University Medical Center, Duke University School of Medicine, Durham, North Carolina, USA
| | - Cynthia L Green
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Duke University School of Medicine, Durham, North Carolina, USA
| | - Jessica Hu
- Department of Orthopaedic Surgery, Duke University Medical Center, Duke University School of Medicine, Durham, North Carolina, USA
| | - Sarah Lander
- Department of Orthopaedic Surgery, Duke University Medical Center, Duke University School of Medicine, Durham, North Carolina, USA
| | - Kelms Amoo-Achampong
- Department of Orthopaedic Surgery, Duke University Medical Center, Duke University School of Medicine, Durham, North Carolina, USA
| | - Brian C Lau
- Department of Orthopaedic Surgery, Duke University Medical Center, Duke University School of Medicine, Durham, North Carolina, USA
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Kano T, Minegish Y, Terada H, Takasu C, Kojima T, Oka Y, Kawabata S, Shimada N, Morishita Y, Murata K, Kanemura N. The infrapatellar fat pad contributes to spontaneous healing after complete anterior cruciate ligament injury. Exp Biol Med (Maywood) 2023; 248:1895-1904. [PMID: 38149772 PMCID: PMC10792419 DOI: 10.1177/15353702231215921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 10/12/2023] [Indexed: 12/28/2023] Open
Abstract
Anterior cruciate ligament (ACL) injuries have a very low healing capacity but have recently been shown to heal spontaneously with conservative treatment. This study examined the mechanism of spontaneous ACL healing by focusing on the intra-articular tissues of the knee joint. Skeletally mature Wistar rats (n = 70) were randomly assigned to two groups: the controlled abnormal movement (CAM) and anterior cruciate ligament transection (ACLT) groups. The ACL was completely transected at the mid-portion in both groups. Only the CAM group underwent extra-articular braking to control for abnormal tibial translation. The animals were allowed full cage activity until sacrifice for histological, and molecular biology analyses. The results showed that the behavior of the stump after ACL injury differed between models 12 h after injury. The femoral stump in the ACLT group retreated posteriorly and upwardly. Macrophage polarity analysis revealed that the stump immune response in the CAM group was more activated than that in the ACLT group 6 h after injury. Microarray analysis of the ACL parenchyma and infrapatellar fat pads suggested the involvement of nuclear factor kappa B (NF-κB) signaling. Real-time polymerase chain reaction (PCR) analysis showed that NF-κB gene expression in the infrapatellar fat pad was significantly increased in the CAM group than in the ACLT group. However, there was no difference in the gene expression levels in the ACL parenchyma between models. In conclusion, the healing response of the ACL was activated within 12 h of injury, resulting in differences in the healing response between the models. It has been suggested that infrapatellar fat pads are involved in the healing process and that angiogenesis and antiapoptotic effects through NF-κB signaling may contribute to this mechanism.
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Affiliation(s)
- Takuma Kano
- Department of Health and Social Services, Graduate School of Saitama Prefectural University, Saitama 343-8540, Japan
- Soka Orthopedic Internal Medicine, Saitama 340-0016, Japan
- Yatsuka Orthopedic Internal Medicine, Saitama 340-0028, Japan
| | - Yuki Minegish
- Department of Health and Social Services, Graduate School of Saitama Prefectural University, Saitama 343-8540, Japan
- Department of Rehabilitation, Faculty of Health Sciences, Nihon Institute of Medical Science, Saitama 350-0435, Japan
| | - Hidenobu Terada
- Department of Health and Social Services, Graduate School of Saitama Prefectural University, Saitama 343-8540, Japan
- Yatsuka Orthopedic Internal Medicine, Saitama 340-0028, Japan
| | - Chiharu Takasu
- Department of Health and Social Services, Graduate School of Saitama Prefectural University, Saitama 343-8540, Japan
- Yatsuka Orthopedic Internal Medicine, Saitama 340-0028, Japan
| | - Takuma Kojima
- Department of Health and Social Services, Graduate School of Saitama Prefectural University, Saitama 343-8540, Japan
- Soka Orthopedic Internal Medicine, Saitama 340-0016, Japan
| | - Yuichiro Oka
- Faculty of Health Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Sora Kawabata
- Department of Health and Social Services, Graduate School of Saitama Prefectural University, Saitama 343-8540, Japan
| | - Naoki Shimada
- Department of Health and Social Services, Graduate School of Saitama Prefectural University, Saitama 343-8540, Japan
| | | | - Kenji Murata
- Saitama Prefectural University, Saitama 343-8540, Japan
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Ishibashi K, Ikegami K, Shimbo T, Sasaki E, Kitayama T, Nakamura Y, Tsushima T, Ishibashi Y, Tamai K. Single-cell transcriptome analysis reveals cellular heterogeneity in mouse intra- and extra articular ligaments. Commun Biol 2022; 5:1233. [PMID: 36371589 PMCID: PMC9653455 DOI: 10.1038/s42003-022-04196-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 10/31/2022] [Indexed: 11/13/2022] Open
Abstract
Ligaments are collagenous connective tissues that connect bones. Injury of knee ligaments, namely anterior cruciate ligament (ACL) and medial collateral ligament (MCL), is common in athletes. Both ligaments have important functions, but distinct regeneration capacities. The capacity for recovery after injury also diminishes with age. However, cellular heterogeneity in the ligaments remains unclear. Here, we profiled the transcriptional signatures of ACL and MCL cells in mice using single-cell RNA sequencing. These ligaments comprise three fibroblast types expressing Col22a1, Col12a1, or Col14a1, but have distinct localizations in the tissue. We found substantial heterogeneity in Col12a1- and Col14a1-positive cells between ACL and MCL. Gene Ontology analysis revealed that angiogenesis- and collagen regulation-related genes were specifically enriched in MCL cells. Furthermore, we identified age-related changes in cell composition and gene expression in the ligaments. This study delineates cellular heterogeneity in ligaments, serving as a foundation for identifying potential therapeutic targets for ligament injuries. Cell heterogeneity in the mouse anterior cruciate ligament (ACL) and medial collateral ligament (MCL) is demonstrated using single-cell analysis with three types of fibroblasts identified, expressing Col14a1, Col12a1, or Col22a1.
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TGF-β1 and Mechanical-Stretch Induction of Lysyl-Oxidase and Matrix-Metalloproteinase Expression in Synovial Fibroblasts Requires NF-κB Pathways. Processes (Basel) 2022. [DOI: 10.3390/pr10081574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The imbalance in the expression of matrix metalloproteinases (MMPs) and lysyl oxidases (LOXs) in synovial fibroblasts (SFs) caused by mechanical injury and inflammatory response prevents injured anterior cruciate ligaments (ACLs) from self-healing. However, research on the effect of growth factors on SFs on regulating the microenvironment is limited. In this study, mechanical injury and exogenous transform growth factor-β1 (TGF-β1) were employed to mimic a joint-cavity microenvironment with ACL trauma. The function of the NF-κB transcription factor was further studied. The study found that the gene expression of LOXs (except LOXL-1), MMP-1, -2, and -3 in SFs was promoted by the combination of injurious mechanical stretching and TGF-β1 and that the upregulation of MMPs was higher than that of LOXs. In addition, MMP-2 activity induced by the combination of injurious stretch and TGF-β1 was inhibited by NF-κB inhibitors such as Bay11-7082 and Bay11-7085. The findings concluded that the synovium was an important regulator of the knee joint-cavity microenvironment after ACL injury and that the NF-κB pathway mediated the regulation of MMP-2 in SFs via mechanical factors and TGF-β1.
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Kharaz YA, Birch H, Chester A, Alchorne E, Simpson D, Clegg P, Comerford E. The effect of exercise on the protein profile of rat knee joint intra- and extra-articular ligaments. Scand J Med Sci Sports 2021; 31:2033-2043. [PMID: 34271594 DOI: 10.1111/sms.14023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 07/15/2021] [Indexed: 01/13/2023]
Abstract
Injuries to the intra-articular anterior cruciate ligament (ACL) and the extra-articular medial collateral ligament (MCL) result in significant knee joint instability, pain, and immobility. Moderate endurance-type exercise can increase ligament strength but little is known on the effect of short-term regular bouts of high-intensity exercise on the extracellular matrix (ECM) structure of knee ligaments. Therefore, this study aimed to identify the effect of short-term regular bouts high exercise on the proteome of the rat ACL and MCL using mass spectrometry. Sprague-Dawley male rats (n = 6) were split into control and exercise groups, and subjected to high-intensity training for four 4 weeks followed by proteomic analyses of the ACL and MCL. Knee joint health status was assessed using OARSI and a validated histological scoring system. Histopathological analyses demonstrated no significant changes in either in cruciate, collateral ligaments, or cartilage between the control and exercised knee joints. However, significant proteins were found to be more abundant in the exercised ACL compared to ACL control group but not between the exercised MCL and control MCL groups. The significant abundant proteins in ACL exercise groups were mostly cytoskeletal, ribosomal and enzymes with several abundant matrisomal proteins such as collagen proteins and proteoglycans being found in this group. In conclusion, our results indicate that short-term regular bouts of high-intensity exercise have an impact on the intra-articular ACL but not extra-articular MCL ECM protein expression.
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Affiliation(s)
- Yalda A Kharaz
- Department of Musculoskeletal and Ageing Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Helen Birch
- Department of Orthopaedics and Musculoskeletal Science, University College London, London, UK
| | | | | | - Deborah Simpson
- Centre for Proteome Research, Institute of Integrative Biology, University of Liverpool, Liverpool, UK
| | - Peter Clegg
- Department of Musculoskeletal and Ageing Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.,School of Veterinary Science, Leahurst Campus, Neston, UK
| | - Eithne Comerford
- Department of Musculoskeletal and Ageing Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.,School of Veterinary Science, Leahurst Campus, Neston, UK
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Biological Augmentation of ACL Repair and Reconstruction: Current Status and Future Perspective. Sports Med Arthrosc Rev 2020; 28:49-55. [PMID: 32345926 DOI: 10.1097/jsa.0000000000000266] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Historically, anterior cruciate ligament (ACL) suture repair mostly resulted in failure because of intra-articular hypovascularity and poor intrinsic healing capacity of ACL. ACL reconstruction was therefore deemed the gold standard with a high success rate because of more evolved surgical technique. There are, however, clinical and subclinical disadvantages of reconstruction; low rate in full recovery to sports, donor harvest morbidity, tunnel enlargement, and incomplete microscopic healing of the graft. Recent experimental and clinical studies on biological augmentation of mesenchymal stem cells, platelet-rich plasma, or the other biologic agents with scaffold suggested potential feasibility of positive effects by such bio-therapies for both ACL repair and reconstruction. Biological augmentation of ACL surgery is still in the exploratory stages and more evidence from preclinical and clinical studies is required for implementation in clinical practice.
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8
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Hovey S, Wang H, Judge LW, Avedesian JM, Dickin DC. The effect of landing type on kinematics and kinetics during single-leg landings. Sports Biomech 2019; 20:543-559. [PMID: 30882276 DOI: 10.1080/14763141.2019.1582690] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Landing research attempts to simulate sport activities; however, movements performed pre- or post-landing may alter landing mechanics and injury risk. Therefore, this study compared lower extremity biomechanics of single-leg drop landings, drop jump (DJ) and countermovement jump (CMJ) landings as well as sex-related differences. A total of 25 recreational athletes (11 females) performed landings from 80% maximum jump height with impact forces, kinematics and joint moments measured during each landing. Altered kinematic and kinetic variables were revealed when a jump was performed pre- or post-landing. CMJ landings were generally performed with a more extended lower extremity at ground contact, less hip and knee motion in the frontal and transverse planes and larger joint moments compared to other landings (p < 0.01). The DJ landings demonstrated greater joint flexion and large frontal and transverse plane motion, paired with decreased impact forces and joint moments (p < 0.05). Across all landings, males displayed larger impact forces and joint moments (p < 0.01), and females demonstrated frontal plane kinematics associated with increased injury risk (p < 0.05). These findings suggest that activities surrounding the landing directly impact landing mechanics and overall risk. Therefore, matching landing type to sport-specific activities increases the efficacy of assessing injury risk during training or rehabilitation programmes.
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Affiliation(s)
- Sarah Hovey
- College of Health, Biomechanics Laboratory, Ball State University, Muncie, IN, USA.,School of Kinesiology, Ball State University, Muncie, IN, USA
| | - Henry Wang
- College of Health, Biomechanics Laboratory, Ball State University, Muncie, IN, USA.,School of Kinesiology, Ball State University, Muncie, IN, USA
| | | | - Jason M Avedesian
- College of Health, Biomechanics Laboratory, Ball State University, Muncie, IN, USA.,School of Kinesiology, Ball State University, Muncie, IN, USA
| | - D Clark Dickin
- College of Health, Biomechanics Laboratory, Ball State University, Muncie, IN, USA.,School of Kinesiology, Ball State University, Muncie, IN, USA
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Gobbi A, Whyte GP. Long-term Outcomes of Primary Repair of the Anterior Cruciate Ligament Combined With Biologic Healing Augmentation to Treat Incomplete Tears. Am J Sports Med 2018; 46:3368-3377. [PMID: 30398894 DOI: 10.1177/0363546518805740] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Surgical treatment to repair partial anterior cruciate ligament (ACL) injury without reconstruction has demonstrated inconsistent clinical success. PURPOSE To examine the long-term clinical outcomes of primary ACL repair combined with biologic healing augmentation in patients with symptomatic partial ACL tears. STUDY DESIGN Case series; Level of evidence, 4. METHODS 50 patients (mean age, 29.5 years) with a partial ACL tear and symptomatic knee instability were treated with primary ligament repair in conjunction with marrow stimulation and followed prospectively for a mean duration of 10.2 years (range, 5.3-14.3 years). Comparative analysis of preinjury, preoperative, and postoperative scores using patient-reported assessment instruments was performed to examine clinical outcomes. Correlation of final outcome scores with patient age, type of ACL tear, side-to-side difference in ligamentous laxity, and body mass index (BMI) was performed through use of Spearman rank analysis. RESULTS 44 patients were available for assessment at final follow-up. The median Tegner Activity Scale score of 7 at final follow-up was the same as the preinjury median score of 7 ( P = .128). The mean Marx Activity Scale, International Knee Documentation Committee (IKDC) Subjective, and Lysholm Knee Questionnaire scores were 10.8, 90.4, and 96.2, respectively, at final follow-up. Mean final Knee injury and Osteoarthritis Outcome Score (KOOS) subset assessments of Pain, Symptoms, Activities of Daily Living, Sports, and Quality of Life were 98.6, 97.5, 99.7, 94.3, and 95.6, respectively. Secondary ACL insufficiency occurred in 27% of patients. Clinical outcome scores were similar for all scoring instruments between patients treated for an associated diagnosis of meniscal or articular cartilage injury. No significant correlations of age, BMI, ACL tear type, or laxity and final IKDC Subjective, Lysholm, or KOOS scores were found. Analysis revealed a negative correlation of patient age and Tegner score at preinjury ( rs = -0.333, P = .022) and at final follow-up ( rs = -0.376, P = .013). The mean side-to-side difference in ligamentous laxity of 3.4 mm at short-term follow-up in those patients who developed secondary ACL insufficiency over the duration of follow-up was significantly greater than the mean of 0.9 mm in those who did not ( P = .010). CONCLUSION Primary ACL repair combined with biologic healing augmentation to treat select cases of knee instability secondary to incomplete ACL rupture demonstrated good to excellent long-term outcomes in this cohort for those patients who did not experience secondary ACL insufficiency, with high rates of restoration of knee stability and return to preinjury athletic activities. The rate of secondary treatment for recurrent ACL insufficiency over the course of long-term follow-up was greater than would be expected for primary ACL reconstruction. Greater side-to-side differences in objective findings of ligamentous laxity were identified at shorter term follow-up in the patients who later went on to experience symptomatic secondary ACL insufficiency, compared with those who maintained stability long term.
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Affiliation(s)
- Alberto Gobbi
- Orthopaedic Arthroscopic Surgery International (OASI) Bioresearch Foundation, Milan, Italy
| | - Graeme P Whyte
- Orthopaedic Arthroscopic Surgery International (OASI) Bioresearch Foundation, Milan, Italy.,Cornell University, Weill Medical College, New York, NY, USA.,New York Presbyterian Hospital/Queens, Queens, New York, NY, USA
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10
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Wang C, Xu C, Chen R, Yang L, Sung KP. Different expression profiles of the lysyl oxidases and matrix metalloproteinases in human ACL fibroblasts after co-culture with synovial cells. Connect Tissue Res 2018; 59:369-380. [PMID: 29431515 DOI: 10.1080/03008207.2017.1401615] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Purposes The anterior cruciate ligament (ACL) has poor functional healing response. The synovial tissue surrounding ACL ligament might be a major regulator of the microenvironment in the joint cavity after ACL injury, thus affecting the repair process. Using transwell co-culture, this study explored the direct influence of human synovial cells (HSCs) on ACL fibroblasts (ACLfs) by characterizing the differential expression of the lysyl oxidase family (LOXs) and matrix metalloproteinases (MMP-1, -2, -3), which facilitate extracellular matrix (ECM) repair and degradation, respectively. Methods The mRNA expression levels of LOXs and MMP-1, -2, -3 were analyzed by semi-quantitative PCR and quantitative real-time PCR. The protein expression levels of LOXs and MMP-1, -2, -3 were detected by western blot. Results We found that co-culture resulted in an increase in the mRNAs of LOXs in normal ACLfs and differentially regulated the expression of MMPs. Then we applied 12% mechanical stretch on ACLfs to induce injury and found the mRNA expression levels of LOXs in injured ACLfs were decreased in the co-culture group relative to the mono-culture group. Conversely, the mRNA expression levels of MMPs in injured ACLfs were promoted in the co-culture group compared with the mono-culture group. At translational level, we found that LOXs were lower while MMPs were highly expressed in the co-culture group compared to the mono-culture group. Conclusions The co-culture of ACLfs and HSCs, which mimicked the cell-to-cell contact in a micro-environment, could contribute to protein modulators for wound healing, inferring the potential reason for the poor self-healing of injured ACL.
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Affiliation(s)
- Chunli Wang
- a "111" project Laboratory of Biomechanics and Tissue Repair, Bioengineering College , Chongqing University , Chongqing , China
| | - Chunming Xu
- a "111" project Laboratory of Biomechanics and Tissue Repair, Bioengineering College , Chongqing University , Chongqing , China
| | - Rongfu Chen
- b Department of Orthopedics , People's hospital of changshou Chongqing , Chongqing , China
| | - Li Yang
- a "111" project Laboratory of Biomechanics and Tissue Repair, Bioengineering College , Chongqing University , Chongqing , China
| | - Kl Paul Sung
- a "111" project Laboratory of Biomechanics and Tissue Repair, Bioengineering College , Chongqing University , Chongqing , China.,c Departments of Bioengineering and Orthopedics , University of California , San Diego , California , USA
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11
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A Review on Biomechanics of Anterior Cruciate Ligament and Materials for Reconstruction. Appl Bionics Biomech 2018; 2018:4657824. [PMID: 29861784 PMCID: PMC5971278 DOI: 10.1155/2018/4657824] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 04/10/2018] [Indexed: 01/25/2023] Open
Abstract
The anterior cruciate ligament is one of the six ligaments in the human knee joint that provides stability during articulations. It is relatively prone to acute and chronic injuries as compared to other ligaments. Repair and self-healing of an injured anterior cruciate ligament are time-consuming processes. For personnel resuming an active sports life, surgical repair or replacement is essential. Untreated anterior cruciate ligament tear results frequently in osteoarthritis. Therefore, understanding of the biomechanics of injury and properties of the native ligament is crucial. An abridged summary of the prominent literature with a focus on key topics on kinematics and kinetics of the knee joint and various loads acting on the anterior cruciate ligament as a function of flexion angle is presented here with an emphasis on the gaps. Briefly, we also review mechanical characterization composition and anatomy of the anterior cruciate ligament as well as graft materials used for replacement/reconstruction surgeries. The key conclusions of this review are as follows: (a) the highest shear forces on the anterior cruciate ligament occur during hyperextension/low flexion angles of the knee joint; (b) the characterization of the anterior cruciate ligament at variable strain rates is critical to model a viscoelastic behavior; however, studies on human anterior cruciate ligament on variable strain rates are yet to be reported; (c) a significant disparity on maximum stress/strain pattern of the anterior cruciate ligament was observed in the earlier works; (d) nearly all synthetic grafts have been recalled from the market; and (e) bridge-enhanced repair developed by Murray is a promising technique for anterior cruciate ligament reconstruction, currently in clinical trials. It is important to note that full extension of the knee is not feasible in the case of most animals and hence the loading pattern of human ACL is different from animal models. Many of the published reviews on the ACL focus largely on animal ACL than human ACL. Further, this review article summarizes the issues with autografts and synthetic grafts used so far. Autografts (patellar tendon and hamstring tendon) remains the gold standard as nearly all synthetic grafts introduced for clinical use have been withdrawn from the market. The mechanical strength during the ligamentization of autografts is also highlighted in this work.
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Bakshi NK, Khan M, Lee S, Finney FT, Stotts J, Sikka RS, Bedi A. Return to Play After Multiligament Knee Injuries in National Football League Athletes. Sports Health 2018; 10:495-499. [PMID: 29638200 PMCID: PMC6204640 DOI: 10.1177/1941738118768812] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Background: Return to play (RTP) of National Football League (NFL) athletes after isolated anterior cruciate ligament (ACL) tears has been reported. However, no studies have reported on RTP of NFL athletes after multiligament knee injuries. Hypotheses: NFL athletes with multiligament knee injuries have lower RTP rates and longer recoveries than athletes with isolated ACL tears. Second, athletes with ACL and medial collateral ligament (MCL) injuries will have higher RTP rates and shorter time to RTP than athletes with an ACL tear and posterolateral corner involvement. Study Design: Retrospective cohort study. Level of Evidence: Level 4. Methods: Publicly available NFL injury data were reviewed for all multiligament knee injuries incurred between 2000 and 2016 with RTP information. Athletes were excluded if RTP was limited for reasons unrelated to the injury. Extracted data included type of injury, RTP, time to RTP (days), number and percentage of games played, and performance. Results: A total of 50 NFL athletes with multiligament knee injuries met inclusion and exclusion criteria. The overall RTP rate was 64.0%. Athletes with ACL/MCL tears had an RTP rate of 70.8%, whereas athletes with ACL and posterior collateral ligament/lateral collateral ligament (PCL/LCL) tears had an RTP rate of 55.6% (P = 0.26). Mean time to RTP for all 50 athletes was 388.71 ± 198.52 days. The mean time to RTP for athletes with ACL/MCL injuries was 305.1 ± 58.9 days, compared with 459.2 ± 245.1 days (P = 0.004) and 609.3 ± 183.1 days (P < 0.0001) for those with combined ACL and PCL/LCL injuries and frank knee dislocations, respectively. Athletes with ACL/MCL injuries were more likely to return to prior performance level (43.5%) than those with ACL and PCL/LCL injuries (18.5%) (P < 0.001). Conclusion: The RTP rate for athletes with multiligament knee injuries is significantly less than the RTP rate for athletes with isolated ACL tears. In addition, athletes with ACL and MCL tears have a higher RTP rate, a significantly shorter time to RTP, and a greater likelihood of returning to prior performance than athletes with ACL and PCL/LCL tears. Clinical Relevance: Multiligament knee injuries significantly affect the ability of a football player to return to sport. ACL and MCL tears are associated with better RTP prognosis compared with ACL and PCL/LCL tears.
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Affiliation(s)
- Neil K. Bakshi
- Neil K. Bakshi, MD, University of Michigan, Department of Orthopaedic Surgery, 24 Frank Lloyd Wright Drive, Lobby A, Ann Arbor, MI 48106 ()
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Scaglione S, Zerega B, Badano R, Benatti U, Fato M, Quarto R. A Three-Dimensional Traction/Torsion Bioreactor System for Tissue Engineering. Int J Artif Organs 2018. [DOI: 10.1177/039139881003300604] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Purpose The aim of this study was to design, develop and validate a simple, compact bioreactor system for tissue engineering. The resulting bioreactor was designed to achieve ease-of-use and low costs for automated cell-culturing procedures onto three-dimensional scaffolds under controlled torsion/traction regimes. Methods Highly porous poly-caprolactone-based scaffolds were used as substrates colonized by fibroblast cells (3T3 cell line). Constructs were placed within the cylindrical culture chamber, clumped at the ends and exposed to controlled sequences of torsional stimuli (forward/back-forward sequential cycles of 100° from neutral position at a rate of 600°/min) through a stepper-motor; working settings were defined via PC by an easy user-interface. Cell adhesion, morphology, cytoskeletal fiber orientation and gene expression of extracellular matrix proteins (collagen type I, tenascin C, collagen type III) were evaluated after three days of torsional stimulation in the bioreactor system. Results and Conclusions The 3D bioreactor system was validated in terms of sterility, experimental reproducibility and flexibility. Cells adhered well onto the polymeric scaffolds. Collagen type I, tenascin C and collagen type III gene expression were significantly up-regulated when cells were cultured under torsion in the bioreactor for three days. In conclusion, we have developed a simple, efficient and versatile 3D cell-culture system to engineer ligament grafts. This system can be used either as a model to investigate mechanisms of tissue development or as a graft manufacturing system for possible clinical use in the field of regenerative medicine.
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Affiliation(s)
- Silvia Scaglione
- Advanced Biotechnology Center (CBA), Genoa - Italy
- Department of Computer Science, Systems and Telematics (DIST), University of Genoa, Genoa - Italy
| | | | - Roberto Badano
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa - Italy
| | - Umberto Benatti
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa - Italy
| | - Marco Fato
- Department of Computer Science, Systems and Telematics (DIST), University of Genoa, Genoa - Italy
| | - Rodolfo Quarto
- Advanced Biotechnology Center (CBA), Genoa - Italy
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa - Italy
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Zhang Y, Jiang J, Xie J, Xu C, Wang C, Yin L, Yang L, Sung KLP. Combined effects of tumor necrosis factor-α and interleukin-1β on lysyl oxidase and matrix metalloproteinase expression in human knee synovial fibroblasts in vitro. Exp Ther Med 2017; 14:5258-5266. [PMID: 29285051 PMCID: PMC5740568 DOI: 10.3892/etm.2017.5264] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Accepted: 01/13/2017] [Indexed: 12/23/2022] Open
Abstract
Previous studies have demonstrated that inflammatory cytokines are associated with matrix metalloproteinases (MMPs) and/or lysyl oxidases (LOXs) produced by anterior cruciate ligament (ACL) fibroblasts, which may contribute to the poor healing ability of the ACL. To evaluate whether the synovium also participates in ACL healing, the inflammatory microenvironment of the knee joint cavity was mimicked following ACL injury, and the combined effects of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) on the expression of MMPs and LOXs in synovial fibroblasts were studied. Cell viability was evaluated using trypan blue staining in the presence of TNF-α and IL-1β, and the expression of LOXs and MMPs was measured by reverse transcription-quantitative polymerase chain reaction. MMP-2 activity was also measured by zymography. The results indicated that the combined effects of TNF-α and IL-1β inhibited LOX expression, while promoting MMP-1, −2 and −3 expression and MMP-2 activity in synovial fibroblasts. These changes may impede healing by altering the balance between the degradative and biosynthetic arms of the ligament tissue remodeling process. Collectively, the present results suggest that the poor healing ability of cruciate ligaments may be due to the sensitivity of the synovium to inflammatory factors. Therefore, the synovium potentially serves a key regulatory role in the joint cavity microenvironment and in the healing process of the ACL, and thus should be considered as a therapeutic target to aid in the treatment of patients with ACL trauma.
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Affiliation(s)
- Yanjun Zhang
- Department of Life Science, Hunan University of Science and Technology, Xiangtan, Hunan 411201, P.R. China.,Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, P.R. China
| | - Jiahuan Jiang
- Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, P.R. China
| | - Jing Xie
- Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, P.R. China
| | - Chunming Xu
- Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, P.R. China
| | - Chunli Wang
- Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, P.R. China
| | - Lin Yin
- Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, P.R. China
| | - Li Yang
- Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, P.R. China
| | - Kuo-Li Paul Sung
- Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, P.R. China.,Departments of Bioengineering and Orthopedics, University of California, San Diego, California 92093-0412, USA
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Ligament-Derived Stem Cells: Identification, Characterisation, and Therapeutic Application. Stem Cells Int 2017; 2017:1919845. [PMID: 28386284 PMCID: PMC5366203 DOI: 10.1155/2017/1919845] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 02/19/2017] [Indexed: 01/09/2023] Open
Abstract
Ligament is prone to injury and degeneration and has poor healing potential and, with currently ineffective treatment strategies, stem cell therapies may provide an exciting new treatment option. Ligament-derived stem cell (LDSC) populations have been isolated from a number of different ligament types with the majority of studies focussing on periodontal ligament. To date, only a few studies have investigated LDSC populations in other types of ligament, for example, intra-articular ligaments; however, this now appears to be a developing field. This literature review aims to summarise the current information on nondental LDSCs including in vitro characteristics of LDSCs and their therapeutic potential. The stem cell niche has been shown to be vital for stem cell survival and function in a number of different physiological systems; therefore, the LDSC niche may have an impact on LDSC phenotype. The role of the LDSC niche on LDSC viability and function will be discussed as well as the therapeutic potential of LDSC niche modulation.
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Abstract
This review describes the normal healing process for bone, ligaments, and tendons, including primary and secondary healing as well as bone-to-bone fusion. It depicts the important mediators and cell types involved in the inflammatory, reparative, and remodeling stages of each healing process. It also describes the main challenges for clinicians when trying to repair bone, ligaments, and tendons with a specific emphasis on Charcot neuropathy, fifth metatarsal fractures, arthrodesis, and tendon sheath and adhesions. Current treatment options and research areas are also reviewed.
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Affiliation(s)
- Jessica A Cottrell
- Department of Biological Sciences, Seton Hall University, 400 South Orange Avenue, South Orange, NJ 07101, USA.
| | - Jessica Cardenas Turner
- Department of Biomedical Engineering, New Jersey Institute of Technology, 323 Martin Luther King Boulevard, Newark, NJ 07102, USA
| | - Treena Livingston Arinzeh
- Department of Biomedical Engineering, New Jersey Institute of Technology, 323 Martin Luther King Boulevard, Newark, NJ 07102, USA
| | - J Patrick O'Connor
- Department of Orthopaedics, Rutgers-New Jersey Medical School, Medical Sciences Building, Room E-659, 185 South Orange Avenue, Newark, NJ 07103, USA
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17
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Ateschrang A, Döbele S, Freude T, Stöckle U, Schröter S, Kraus TM. Acute MCL and ACL injuries: first results of minimal-invasive MCL ligament bracing with combined ACL single-bundle reconstruction. Arch Orthop Trauma Surg 2016; 136:1265-1272. [PMID: 27435334 DOI: 10.1007/s00402-016-2497-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Indexed: 01/13/2023]
Abstract
BACKGROUND There is an on-going discussion whether to operatively treat combined grade II and III lesions of the medial collateral ligament (MCL) with anterior cruciate ligament (ACL) in the acute phase rather than conservative treatment of the MCL lesion with a delayed unitary ACL replacement. Another issue is the question how to technically address these MCL lesions. The aim of this study was, therefore, to analyze the results of simultaneous ACL replacement (hamstrings) in a single-bundle technique with a simultaneous MCL ligament bracing procedure. METHODS In this prospective non-randomized trial,, 16 patients were included with grade II and III lesions of the MCL. Surgical treatment was performed within 14 days (mean 10.4 days, SD ±2.3 days) by one single expert orthopedic surgeon using the semitendinosus tendon and Rigidfix® system for femoral and tibial fixation and 3.5 mm screws with one 1.3 mm PDS Cord for minimal-invasive MCL ligament bracing with screw fixation. Knee stability was measured with the Rolimeter® and KT-1000®. MCL stability was assessed in clinically and radiographically with valgus stress projections. RESULTS The mean patient age was 36.4 with six female and ten male patients. There were no surgical complications such as infections or healing disturbances. Mean operation time was 64 ± 6 min. The arthrofibrosis rate was 0 %. Medial knee stability was normal in full extension for all cases with no intra-individual side-to-side difference. Radiological assessed MCL stability revealed Δ values with a mean of 1.1 ± 1.3 mm compared to the contra-lateral side. The Lachman Test revealed a side-to-side difference of 1.6 mm with the KT-1000® and 2.6 ± 0.9 mm when measured with the Rolimeter®. Subjective clinical assessment revealed good results with a mean Lysholm Score of 89.1 points. CONCLUSION Acute ACL replacement and MCL ligament bracing with this novel technique revealed in this study good clinical results and objective restored knee stability without cases of knee stiffness or arthrofibrosis. The remarkable shortcoming is the small cohort number making further studies necessary.
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Affiliation(s)
- A Ateschrang
- BG Trauma Center Tübingen, Eberhard Karls University, Schnarrenbergstr. 95, 72076, Tübingen, Germany
| | - S Döbele
- BG Trauma Center Tübingen, Eberhard Karls University, Schnarrenbergstr. 95, 72076, Tübingen, Germany
| | - T Freude
- BG Trauma Center Tübingen, Eberhard Karls University, Schnarrenbergstr. 95, 72076, Tübingen, Germany
| | - U Stöckle
- BG Trauma Center Tübingen, Eberhard Karls University, Schnarrenbergstr. 95, 72076, Tübingen, Germany
| | - S Schröter
- BG Trauma Center Tübingen, Eberhard Karls University, Schnarrenbergstr. 95, 72076, Tübingen, Germany
| | - T M Kraus
- BG Trauma Center Tübingen, Eberhard Karls University, Schnarrenbergstr. 95, 72076, Tübingen, Germany.
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Liang R, Yang G, Kim KE, D'Amore A, Pickering AN, Zhang C, Woo SLY. Positive effects of an extracellular matrix hydrogel on rat anterior cruciate ligament fibroblast proliferation and collagen mRNA expression. J Orthop Translat 2015; 3:114-122. [PMID: 30035048 PMCID: PMC5982358 DOI: 10.1016/j.jot.2015.05.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 05/01/2015] [Accepted: 05/28/2015] [Indexed: 12/21/2022] Open
Abstract
Background/Objective We have previously shown that an extracellular matrix (ECM) bioscaffold derived from porcine small intestine submucosa (SIS) enhanced the healing of a gap injury of the medial collateral ligament as well as the central third defect of the patellar tendon. With the addition of a hydrogel form of SIS, we found that a transected goat anterior cruciate ligament (ACL) could also be healed. The result begs the research question of whether SIS hydrogel has positive effects on ACL fibroblasts (ACLFs) and thus facilitates ACL healing. Methods In the study, ECM-SIS hydrogel was fabricated from the digestion of decellularised and sterilised sheets of SIS derived from αGal-deficient (GalSafe) pigs. As a comparison, a pure collagen hydrogel was also fabricated from commercial collagen type I solution. The morphometrics of hydrogels was assessed with scanning electron microscopy. The ECM-SIS and collagen hydrogels had similar fibre diameters (0.105 ± 0.010 μm vs. 0.114 ± 0.004 μm), fibre orientation (0.51 ± 0.02 vs. 0.52 ± 0.02), and pore size (0.092 ± 0.012 μm vs. 0.087 ± 0.008 μm). The preservation of bioactive properties of SIS hydrogel was assessed by detecting bioactive molecules sensitive to processing and enzyme digestion, such as growth factors fibroblast growth factor-2 (FGF-2) and transforming growth factor-beta 1 (TGF-β1), with enzyme-linked immunosorbent assay. ACLFs were isolated and expanded in culture from explants of rat ACLs (n = 3). The cells were then seeded on the hydrogels and cultured with 0%, 1%, and 10% foetal bovine serum (FBS) for 3 days and 7 days. Cell attachment was observed using a light microscope and scanning electron microscopy, whereas cell proliferation and matrix production (collagen types I and III) were examined with bromodeoxyuridine assays and reverse transcription-polymerase chain reaction, respectively. Results The results showed that FGF-2 and TGF-β1 in the SIS hydrogel were preserved by 50% (65.9 ± 26.1 ng/g dry SIS) and 90% (4.4 ± 0.6 ng/g dry SIS) relative to their contents in ECM-SIS sheets, respectively. At Day 3 of culture, ACLFs on the SIS hydrogel were found to proliferate 39%, 31%, and 22% more than those on the pure collagen hydrogel at 0%, 1%, and 10% FBS, respectively (p < 0.05). Collagen type I mRNA expression was increased by 150%, 207%, and 100%, respectively, compared to collagen hydrogel (p < 0.05), whereas collagen type III mRNA expression was increased by 123% and 132% at 0% and 1% FBS, respectively (all p < 0.05) but not at 10% FBS. By Day 7, collagen type I mRNA expression was still elevated by 137% and 100% compared to collagen hydrogel at 1% and 10% FBS, respectively (p < 0.05). Yet, collagen type III mRNA levels were not significantly different between the two groups at any FBS concentrations. Conclusion Our data showed that the ECM-SIS hydrogel not only supported the growth of ACLFs, but also promoted their proliferation and matrix production relative to a pure collagen hydrogel. As such, ECM-SIS hydrogel has potential therapeutic value to facilitate ACL healing at the early stage after injury.
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Affiliation(s)
| | | | | | | | | | | | - Savio L-Y. Woo
- Corresponding author. Musculoskeletal Research Center, Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, 405 Center for Bioengineering, 300 Technology Drive, Pittsburgh, PA 15219, USA.
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Kato S, Saito M, Funasaki H, Marumo K. Distinctive collagen maturation process in fibroblasts derived from rabbit anterior cruciate ligament, medial collateral ligament, and patellar tendon in vitro. Knee Surg Sports Traumatol Arthrosc 2015; 23:1384-1392. [PMID: 24221246 PMCID: PMC4555208 DOI: 10.1007/s00167-013-2773-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Accepted: 10/31/2013] [Indexed: 01/08/2023]
Abstract
PURPOSE Differences in the tissue-specific collagen maturation process between tendon and ligament are still unknown. Collagen cross-link formation is crucial for the collagen maturation process. The aim of this study is to examine collagen maturation processes of anterior cruciate ligament (ACL), medial collateral ligament (MCL), and patellar tendon (PT) in vitro, in order to determine the optimal cell source for tissue engineering of ligament. METHODS Cells derived from the ACL, MCL, and PT of New Zealand white rabbits were isolated. Each cell type was cultured for up to 4 weeks after reaching confluence. Cell-matrix layers were evaluated and compared for their morphology, collagen cross-links, and gene expression levels of lysine hydroxylase 1 and 2, lysyl oxidase (LOX), tenomodulin, collagen1A1 (Col1A1), and collagen3A1 (Col3A1). RESULTS Transmission electron microscopy photomicrographs verified that collagen fibrils were secreted from all three types of fibroblasts. A higher ratio of dihydroxylysinonorleucine/hydroxylysinonorleucine was evident in the ligament compared to the tendon, which was consistent with lysine hydroxylase 2/lysine hydroxylase 1 gene expression. The gene expression of LOX, which regulates the total amount of enzymatic cross-linking, and the gene expression levels of Col1A1 and Col3A1 were higher in the ACL matrix than in the MCL and PT matrices. CONCLUSION ACL, MCL, and PT cells have distinct collagen maturation processes at the cellular level. In addition, the collagen maturation of ACL cells is not necessarily inferior to that of MCL and PT cells in that all three cell types have a good ability to synthesize collagen and induce collagen maturation. This bioactivity of ACL cells in terms of ligament-specific mature collagen induction can be applied to tissue-engineered ACL reconstruction or remnant preserving procedure with ACL reconstruction.
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Affiliation(s)
- Soki Kato
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Hiroki Funasaki
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Keishi Marumo
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan
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Smith J, Hackel JG, Khan U, Pawlina W, Sellon JL. Sonographically Guided Anterior Cruciate Ligament Injection: Technique and Validation. PM R 2015; 7:736-745. [PMID: 25637471 DOI: 10.1016/j.pmrj.2015.01.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 01/20/2015] [Accepted: 01/22/2015] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To describe and validate a practical technique for sonographically guided anterior cruciate ligament (ACL) injections. DESIGN Prospective, cadaveric laboratory investigation. SETTING Procedural skills laboratory in a tertiary medical center. SUBJECTS Ten unembalmed, cadaveric mid-thigh-knee-ankle foot specimens (5 left knees and 5 right knees; 5 male and 5 female) from 10 donors aged 76 to 93 years (mean 85.6 years) with body mass indices of 17.6 to 42.2 kg/m(2) (mean 28.8 kg/m(2)). METHODS A single, experienced operator used a 22-gauge, 63.5-mm stainless steel needle and a 12-3-MHz linear transducer to inject 1.5 mL of diluted colored latex into the ACLs of 10 unembalmed cadaveric specimens via an in-plane, caudad-to-cephalad approach, long axis to the ACL. At a minimum of 24 hours postinjection, specimens were dissected, and the presence and distribution of latex within the ACL assessed by a study co-investigator. MAIN OUTCOME Presence and distribution of latex within the ACL. RESULTS All 10 injections accurately delivered latex into the proximal (femoral), midsubstance, and distal (tibial) portions of the ACL. No specimens exhibited evidence of needle injury or latex infiltration with respect to the menisci, hyaline cartilage, or posterior cruciate ligament. CONCLUSIONS Sonographically guided intra-ligamentous ACL injections are technically feasible and can be performed with a high degree of accuracy. Sonographically guided ACL injections could be considered for research and clinical purposes to directly deliver injectable agents into the healing ACL postinjury or postreconstruction.
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Affiliation(s)
- Jay Smith
- Department of Physical Medicine & Rehabilitation, Mayo Clinic, W14, Mayo Building, 200 1st St, SW, Rochester, MN 55905; and Departments of Radiology and Anatomy, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN
| | | | - Umar Khan
- Regenerative Orthopedic and Sports Medicine Institute, Bowling Green, KY
| | - Wojciech Pawlina
- Department of Anatomy, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN
| | - Jacob L Sellon
- Department of Physical Medicine & Rehabilitation, Mayo Clinic Sports Medicine Center, Mayo Clinic, Rochester, MN
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Nau T, Teuschl A. Regeneration of the anterior cruciate ligament: Current strategies in tissue engineering. World J Orthop 2015; 6:127-136. [PMID: 25621217 PMCID: PMC4303781 DOI: 10.5312/wjo.v6.i1.127] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 06/19/2014] [Accepted: 07/29/2014] [Indexed: 02/06/2023] Open
Abstract
Recent advancements in the field of musculoskeletal tissue engineering have raised an increasing interest in the regeneration of the anterior cruciate ligament (ACL). It is the aim of this article to review the current research efforts and highlight promising tissue engineering strategies. The four main components of tissue engineering also apply in several ACL regeneration research efforts. Scaffolds from biological materials, biodegradable polymers and composite materials are used. The main cell sources are mesenchymal stem cells and ACL fibroblasts. In addition, growth factors and mechanical stimuli are applied. So far, the regenerated ACL constructs have been tested in a few animal studies and the results are encouraging. The different strategies, from in vitro ACL regeneration in bioreactor systems to bio-enhanced repair and regeneration, are under constant development. We expect considerable progress in the near future that will result in a realistic option for ACL surgery soon.
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Zhang Y, Huang W, Jiang J, Xie J, Xu C, Wang C, Yin L, Yang L, Zhou K, Chen P, Sung KP. Influence of TNF-α and biomechanical stress on matrix metalloproteinases and lysyl oxidases expressions in human knee synovial fibroblasts. Knee Surg Sports Traumatol Arthrosc 2014; 22:1997-2006. [PMID: 23377799 DOI: 10.1007/s00167-013-2425-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 01/21/2013] [Indexed: 01/10/2023]
Abstract
PURPOSE It was reported that not only ACL but also the synovium may be the major regulator of matrix metalloproteinases (MMPs) in synovial fluids after ACL injury. In order to further confirm whether synovium is capable of regulating the microenvironment in the process of ACL injury, the complicated microenvironment of joint cavity after ACL injury was mimicked and the combined effects of mechanical injury and inflammatory factor [tumour necrosis factor-α (TNF-α)] on expressions of lysyl oxidases (LOXs) and MMPs in synovial fibroblasts derived from normal human synovium were studied. METHODS Human normal knee joint synovial fibroblasts were stimulated for 1-6 h with mechanical stretch and inflammatory factor (TNF-α). Total RNA was harvested, reverse transcribed and assessed by real-time polymerase chain reaction for the expression of LOXs and MMP-1, 2, 3 messenger RNAs. MMP-2 activity was assayed from the collected culture media samples using zymography. RESULTS Compared to control group, our results showed that 6% physiological stretch increased MMP-2 and LOXs (except LOXL-3), decreased MMP-1 and MMP-3; injurious stretch (12%) decreased LOXs (except LOXL-2)and increased MMP-1, 2 and 3; the combination of injurious stretch and TNF-α decreased LOXs and increased MMP-1, 2 and 3 in synovial fibroblasts in a synergistical manner. CONCLUSION This study demonstrated that combination of mechanical injury and inflammatory factors up-regulated the expressions of MMPs and down-regulated the expressions of LOXs in synovial fibroblasts, eventually alter the balance of tissue healing. Thus, synovium may be involved in regulating the microenvironment of joint cavity. Based on the mechanism, early interventions to inhibit the production of MMPs or promote the production of LOXs in the synovial fibroblasts should be performed to facilitate the healing of tissue.
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Affiliation(s)
- Yanjun Zhang
- "111" Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing, 400044, China
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Teuschl AH, Neutsch L, Monforte X, Rünzler D, van Griensven M, Gabor F, Redl H. Enhanced cell adhesion on silk fibroin via lectin surface modification. Acta Biomater 2014; 10:2506-17. [PMID: 24530561 DOI: 10.1016/j.actbio.2014.02.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Revised: 01/25/2014] [Accepted: 02/04/2014] [Indexed: 01/13/2023]
Abstract
Various tissue engineering (TE) approaches are based on silk fibroin (SF) as scaffold material because of its superior mechanical and biological properties compared to other materials. The translation of one-step TE approaches to clinical application has generally failed so far due to the requirement of a prolonged cell seeding step before implantation. Here, we propose that the plant lectin WGA (wheat germ agglutinin), covalently bound to SF, will mediate cell adhesion in a time frame acceptable to be part of a one-step surgical intervention. After the establishment of a modification protocol utilizing carbodiimide chemistry, we examined the attachment of cells, with a special focus on adipose-derived stromal cells (ASC), on WGA-SF compared to pure native SF. After a limited time frame of 20min the attachment of ASCs to WGA-SF showed an increase of about 17-fold, as compared to pure native SF. The lectin-mediated cell adhesion further showed an enhanced resistance to trypsin (as a protease model) and to applied fluid shear stress (mechanical stability). Moreover, we could demonstrate that the adhesion of ASCs on the WGA-SF does not negatively influence proliferation or differentiation potential into the osteogenic lineage. To test for in vitro immune response, the proliferation of peripheral blood mononuclear cells in contact with the WGA-SF was determined, showing no alterations compared to plain SF. All these findings suggest that the WGA modification of SF offers important benefits for translation of SF scaffolds into clinical applications.
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Affiliation(s)
- Andreas H Teuschl
- University of Applied Sciences Technikum Wien, Department of Biochemical Engineering, Höchstädtplatz 5, 1200 Vienna, Austria; The Austrian Cluster for Tissue Regeneration, Vienna, Austria.
| | - Lukas Neutsch
- Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Vienna 1090, Althanstraße 14, Austria
| | - Xavier Monforte
- University of Applied Sciences Technikum Wien, Department of Biochemical Engineering, Höchstädtplatz 5, 1200 Vienna, Austria; The Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Dominik Rünzler
- University of Applied Sciences Technikum Wien, Department of Biochemical Engineering, Höchstädtplatz 5, 1200 Vienna, Austria; The Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Martijn van Griensven
- The Austrian Cluster for Tissue Regeneration, Vienna, Austria; Ludwig Boltzmann Institute for Experimental and Clinical Traumatology/AUVA Research Center, Vienna 1200, Donaueschingenstraße 13, Austria
| | - Franz Gabor
- Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Vienna 1090, Althanstraße 14, Austria
| | - Heinz Redl
- The Austrian Cluster for Tissue Regeneration, Vienna, Austria; Ludwig Boltzmann Institute for Experimental and Clinical Traumatology/AUVA Research Center, Vienna 1200, Donaueschingenstraße 13, Austria
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Figueroa D, Espinosa M, Calvo R, Scheu M, Vaisman A, Gallegos M, Conget P. Anterior cruciate ligament regeneration using mesenchymal stem cells and collagen type I scaffold in a rabbit model. Knee Surg Sports Traumatol Arthrosc 2014; 22:1196-202. [PMID: 23474696 DOI: 10.1007/s00167-013-2471-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Accepted: 02/28/2013] [Indexed: 01/13/2023]
Abstract
PURPOSE The objective of this study was to determine whether using mesenchymal stem cells (MSC) seeded in a collagen type I scaffold would be sufficient to regenerate the torn anterior cruciate ligament (ACL). METHODS Anterior cruciate ligament transection was performed on both knees in 10 New Zealand rabbits and then repaired with as follows: suture alone (suture-treated group, n = 6), suture associated with collagen type I scaffold (collagen type I scaffold-treated group, n = 8) or suture associated with autologous MSC seeded on collagen type I scaffold (MSC/collagen type I scaffold-treated group, n = 6). At 12-week post-intervention, the animals were killed and the ACLs were characterised macroscopically and histologically. Data of the 3 groups were against normal ACL (normal group, n = 10). RESULTS Macroscopic observation found that in MSC/collagen type I scaffold group, 33% of specimens showed a complete ACL regeneration, with a tissue similar to the normal ACL. Regeneration was not observed in the group treated with suture alone or associated with collagen type I scaffold without cells. In the latter, only a reparative attempt at the ends was observed. Histological analysis of the regenerated ACL showed a tissue with organised collagen and peripheric vessels. CONCLUSIONS These results provide evidence that the use of MSC seeded in a collagen type I scaffold in the treatment of ACL injuries is associated with an enhancement of ligament regeneration. This MSC-based technique is a potentially attractive tool for improving the treatment of ACL ruptures.
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Affiliation(s)
- David Figueroa
- Orthopedic Surgery Department, Clínica Alemana de Santiago, Avda Vitacura 5951, Santiago, Chile,
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25
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Teuschl AH, van Griensven M, Redl H. Sericin removal from raw Bombyx mori silk scaffolds of high hierarchical order. Tissue Eng Part C Methods 2014; 20:431-9. [PMID: 24066942 DOI: 10.1089/ten.tec.2013.0278] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Silk fibroin has previously been described as a promising candidate for ligament tissue engineering (TE) approaches. For biocompatibility reasons, silkworm silk requires removal of sericin, which can elicit adverse immune responses in the human body. One disadvantage of the required degumming process is the alteration of the silk fiber structural properties, which can hinder textile engineering of high order hierarchical structures. Therefore, the aim of this study was to find a way to remove sericin from a compact and highly ordered raw silk fiber matrix. The wire rope design of the test model scaffold comprises several levels of geometric hierarchy. Commonly used degumming solutions fail in removing sericin in this wire rope design. Weight loss measurements, picric acid and carmine staining as well as scanning electron microscopy demonstrated that the removal of sericin from the model scaffold of a wire rope design can be achieved through a borate buffer-based system. Furthermore, the borate buffer degummed silks were shown to be nontoxic and did not alter cell proliferation behavior. The possibility to remove sericin after the textile engineering process has taken place eases the production of highly ordered scaffold structures and may expand the use of silk as scaffold material in further TE and regenerative medicine applications.
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Affiliation(s)
- Andreas Herbert Teuschl
- 1 Department of Biochemical Engineering, University of Applied Sciences Technikum Wien , Wien, Austria
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26
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Abstract
Injury to the anterior cruciate ligament (ACL) is one of the most devastating and frequent injuries of the knee. Surgical reconstruction is the current standard of care for treatment of ACL injuries in active patients. The widespread adoption of ACL reconstruction over primary repair was based on early perception of the limited healing capacity of the ACL. Although the majority of ACL reconstruction surgeries successfully restore gross joint stability, post-traumatic osteoarthritis is commonplace following these injuries, even with ACL reconstruction. The development of new techniques to limit the long-term clinical sequelae associated with ACL reconstruction has been the main focus of research over the past decades. The improved knowledge of healing, along with recent advances in tissue engineering and regenerative medicine, has resulted in the discovery of novel biologically augmented ACL-repair techniques that have satisfactory outcomes in preclinical studies. This instructional review provides a summary of the latest advances made in ACL repair. Cite this article: Bone Joint Res 2014;3:20-31.
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Affiliation(s)
- A M Kiapour
- Boston Children's Hospital, Harvard MedicalSchool, Sports Medicine Research Laboratory, Departmentof Orthopaedic Surgery, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
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27
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Nguyen DT, Ramwadhdoebe TH, van der Hart CP, Blankevoort L, Tak PP, van Dijk CN. Intrinsic healing response of the human anterior cruciate ligament: an histological study of reattached ACL remnants. J Orthop Res 2014; 32:296-301. [PMID: 24600702 DOI: 10.1002/jor.22511] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
A reattachment of the tibial remnant of the torn anterior cruciate ligament (ACL) to the posterior cruciate ligament is sometimes observed during surgery and apparently implies that the human ACL does have a healing response. The aim of this study was to investigate whether this reattachment tissue has similar histological characteristics of a healing response as the medial collateral ligament (MCL), which can heal spontaneously. Standard histology and immunostaining of α-smooth muscle actin and collagen type 3 was performed. The results shows that the reattached tissue has typical characteristics of a healing response: there attached ACL remnant could not be released by forceful traction; microscopy showed that the collagen fibers of the reattached tissue were disorganized with no preferred direction; increased neovascularization; the presence of lipid vacuoles; the mean number of cells within the biopsy tissue was 631±269 cells per mm2; and 68±20% was expressing α-SMA; semi-quantitative analysis of collagen type 3 expression showed that collagen type 3 had an high expression with an average score of 3. In conclusion, this study shows that the human proximal 1/3 ACL has an intrinsic healing response with typical histological characteristics similar to the MCL.
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Affiliation(s)
- Duy Tan Nguyen
- Department of Orthopedic Surgery, Orthopaedic Research Center Amsterdam; Academic Medical Center, University of Amsterdam; 1100 DD Amsterdam The Netherlands
| | - Tamara H. Ramwadhdoebe
- Division of Clinical Immunology and Rheumatology; Academic Medical Center, University of Amsterdam; Amsterdam The Netherlands
| | | | - Leendert Blankevoort
- Department of Orthopedic Surgery, Orthopaedic Research Center Amsterdam; Academic Medical Center, University of Amsterdam; 1100 DD Amsterdam The Netherlands
| | - Paul Peter Tak
- Division of Clinical Immunology and Rheumatology; Academic Medical Center, University of Amsterdam; Amsterdam The Netherlands
| | - Cornelis Niek van Dijk
- Department of Orthopedic Surgery, Orthopaedic Research Center Amsterdam; Academic Medical Center, University of Amsterdam; 1100 DD Amsterdam The Netherlands
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Abstract
Cells, scaffold, and growth factors are crucially important in regenerative medicine and tissue engineering. Progress in science and technology has enabled development of these three factors, with basic research being applied clinically. In the past decade, we have investigated tissue regeneration in animal models of musculoskeletal disorders by using cells, scaffold, and delivery systems which has been relatively easy to apply and develop in clinical settings. Moreover, microRNA (miRNA), which are important in biological processes and in the pathogenesis of human diseases, have been used in research on regenerative medicine. For the cell source, we focused on mesenchymal stem cells (MSC) and CD34(+) and CD133(+) cells as endothelial progenitor cells for regeneration of musculoskeletal organs. These cells are accessible and safe. For less invasive and more effective therapy, we developed a novel cell-delivery system using magnetic force to accumulate cells at a desired site. Furthermore, administration of synthetic miRNA could enhance tissue regeneration. In our studies, use of these cells combined with a cell-delivery system, miRNA, scaffold, and cytokines has led to effective regeneration of musculoskeletal tissues including cartilage, bone, ligaments, muscle, peripheral nerves, and spinal cord. The current and future objective is more effective and less invasive cell-based therapy with spatial control of transplanted cells by use of an external magnetic force. Analysis of efficiency, safety, and the mechanism of tissue regeneration by cells, scaffold, and miRNA will lead to more promising regenerative medicine, involving the development of a new generation of therapy. This review will focus on our regenerative medicine research, which focuses on clinical application of cells, scaffold, and miRNA.
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29
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Yuan T, Zhang CQ, Wang JHC. Augmenting tendon and ligament repair with platelet-rich plasma (PRP). Muscles Ligaments Tendons J 2013. [PMID: 24367773 DOI: 10.11138/mltj/2013.3.3.139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Tendon and ligament injuries (TLI) commonly occur in athletes and non-athletes alike, and remarkably debilitate patients' athletic and personal abilities. Current clinical treatments, such as reconstruction surgeries, do not adequately heal these injuries and often result in the formation of scar tissue that is prone to re-injury. Platelet-rich plasma (PRP) is a widely used alternative option that is also safe because of its autologous nature. PRP contains a number of growth factors that are responsible for its potential to heal TLIs effectively. In this review, we provide a comprehensive report on PRP. While basic science studies in general indicate the potential of PRP to treat TLIs effectively, a review of existing literature on the clinical use of PRP for the treatment of TLIs indicates a lack of consensus due to varied treatment outcomes. This suggests that current PRP treatment protocols for TLIs may not be optimal, and that not all TLIs may be effectively treated with PRP. Certainly, additional basic science studies are needed to develop optimal treatment protocols and determine those TLI conditions that can be treated effectively.
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Affiliation(s)
- Ting Yuan
- Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, USA ; Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai, China
| | - Chang-Qing Zhang
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai, China
| | - James H-C Wang
- Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, USA
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30
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Nguyen DT, Geel J, Schulze M, Raschke MJ, Woo SLY, van Dijk CN, Blankevoort L. Healing of the goat anterior cruciate ligament after a new suture repair technique and bioscaffold treatment. Tissue Eng Part A 2013; 19:2292-9. [PMID: 23725556 DOI: 10.1089/ten.tea.2012.0535] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Primary suture repair of the anterior cruciate ligament (ACL) has been used clinically in an attempt to heal the ruptured ACL. The results, however, were not satisfactory, which in retrospect can be attributed to the used suturing technique and the suboptimal healing conditions. These constraining conditions can be improved by introducing a new suturing technique and by using small intestinal submucosa (SIS) as a bioscaffold. It is hypothesized that the suturing technique keep the torn ends together and that SIS enhance and promote the healing of the ACL. The goat was used as the study model. In the Suture group, the left ACL was transected and suture repaired with a new locking suture repair technique (n=5) allowing approximation and fixation under tension. The Suture-SIS group underwent the same procedure with the addition of SIS (n=5). The right ACL served as control. After 12 weeks of healing, anterior-posterior translation and in situ force of the healing ACL were measured, followed by the measurement of the cross-sectional area and structural stiffness. Routine histology was performed on tissue samples. Gross morphology showed that the healing ACL was continuous with collagenous tissue in both groups. The cross-sectional area of the Suture and the Suture-SIS group was 35% and 50% of the intact control, respectively. The anterior-posterior translations at different flexion angles were statistically not different between the Suture group and the Suture-SIS group. Only the in situ force at 30° in the Suture-SIS group was higher than in the Suture group. Tensile tests showed that the stiffness for the Suture group was not different from the Suture-SIS group (31.1±8.1 N/mm vs. 41.9±18.0 N/mm [p>0.05]). Histology showed longitudinally aligned collagen fibers from origo to insertion. More fibroblasts were present in the healing tissue than in the control intact tissue. The study demonstrated the proof of concept of ACL repair in a goat model with a new suture technique and SIS. The mechanical outcome is not worse than previously reported for ACL reconstruction. In conclusion, the approach of using a new suture technique, with or without a bioscaffold to heal the ACL is promising.
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Affiliation(s)
- D Tan Nguyen
- Department of Orthopedic Surgery, Orthopaedic Research Center Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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31
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Canseco JA, Kojima K, Penvose AR, Ross JD, Obokata H, Gomoll AH, Vacanti CA. Effect on ligament marker expression by direct-contact co-culture of mesenchymal stem cells and anterior cruciate ligament cells. Tissue Eng Part A 2012; 18:2549-58. [PMID: 22780864 DOI: 10.1089/ten.tea.2012.0030] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Ligament and tendon repair is an important topic in orthopedic tissue engineering; however, the cell source for tissue regeneration has been a controversial issue. Until now, scientists have been split between the use of primary ligament fibroblasts or marrow-derived mesenchymal stem cells (MSCs). The objective of this study was to show that a co-culture of anterior cruciate ligament (ACL) cells and MSCs has a beneficial effect on ligament regeneration that is not observed when utilizing either cell source independently. Autologous ACL cells (ACLcs) and MSCs were isolated from Yorkshire pigs, expanded in vitro, and cultured in multiwell plates in varying %ACLcs/%MSCs ratios (100/0, 75/25, 50/50, 25/75, and 0/100) for 2 and 4 weeks. Quantitative mRNA expression analysis and immunofluorescent staining for ligament markers Collagen type I (Collagen-I), Collagen type III (Collagen-III), and Tenascin-C were performed. We show that Collagen-I and Tenascin-C expression is significantly enhanced over time in 50/50 co-cultures of ACLcs and MSCs (p≤0.03), but not in other groups. In addition, Collagen-III expression was significantly greater in MSC-only cultures (p≤0.03), but the Collagen-I-to-Collagen-III ratio in 50% co-culture was closest to native ligament levels. Finally, Tenascin-C expression at 4 weeks was significantly higher (p≤0.02) in ACLcs and 50% co-culture groups compared to all others. Immunofluorescent staining results support our mRNA expression data. Overall, 50/50 co-cultures had the highest Collagen-I and Tenascin-C expression, and the highest Collagen-I-to-Collagen-III ratio. Thus, we conclude that using a 50% co-culture of ACLcs and MSCs, instead of either cell population alone, may better maintain or even enhance ligament marker expression and improve healing.
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Affiliation(s)
- Jose A Canseco
- Department of Anesthesiology, Laboratory for Tissue Engineering and Regenerative Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA
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32
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Xie J, Wang C, Yin L, Xu C, Zhang Y, Sung KLP. Interleukin-1 beta influences on lysyl oxidases and matrix metalloproteinases profile of injured anterior cruciate ligament and medial collateral ligament fibroblasts. INTERNATIONAL ORTHOPAEDICS 2012; 37:495-505. [PMID: 22588690 DOI: 10.1007/s00264-012-1549-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Accepted: 04/06/2012] [Indexed: 01/05/2023]
Abstract
PURPOSE The anterior cruciate ligament (ACL) is known to have a poor healing ability, especially in comparison with the medial collateral ligament (MCL) which can heal relatively well. Interleukin-1beta (IL-1β) is considered to be an important chemical mediator in the acute inflammatory phase of ligament injury. The role of IL-1β-induced expressions of lysyl oxidases (LOXs) and matrix metalloproteinases (MMPs), which respectively facilitate extracellular matrix (ECM) repair and degradation, is poorly understood. In this study, we aim to determine the intrinsic differences between ACL and MCL by characterising the differential expressions of LOXs and MMPs in response to IL-1β in the injury process. METHODS Semi-quantitative polymerase chain reaction (PCR), quantitative real-time PCR, Western blot, and zymography were performed. RESULTS We detected high expressions of IL-1β-induced LOXs in normal ACL and MCL. Then, we found IL-1β induced injured MCL to express more LOXs than injured ACL (up to 2.85-fold in LOX, 2.58-fold in LOXL-1, 1.89-fold in LOXL-2, 2.46-fold in LOXL-3 and 2.18-fold in LOXL-4). Meanwhile, we found IL-1β induced injured ACL to express more MMPs than injured MCL (up to 1.72-fold in MMP-1, 1.95-fold in MMP-2, 2.05-fold in MMP-3 and 2.3-fold in MMP-12). The further protein results coincided with gene expressions above. CONCLUSIONS Lower expressions of LOXs and higher expressions of MMPs might help to explain the poor healing ability of ACL.
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Affiliation(s)
- Jing Xie
- 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing, 400044, People's Republic of China.
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33
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Abstract
BACKGROUND We developed the rectangular tunnel ACL reconstruction (RT ACLR) using a 10-mm wide bone-patellar tendon-bone (BTB) graft through rectangular tunnels with a rectangular aperture to reduce tunnel size: the cross-sectional area of the tunnels of 50 mm(2) (5 × 10 mm) in RT ACLR is less than that of 79 mm(2) in a conventional 10-mm round tunnel technique presuming the technique would be more suitable in revision ACLR with previous improperly placed tunnels. DESCRIPTION OF TECHNIQUE Two contiguous 5-mm tunnels inside the anatomic ACL femoral and tibial attachment areas along their long axes, and they are expanded with a 5 × 10-mm dilator into parallelepiped ones. PATIENTS AND METHODS We indicated and intended to perform the RT ACLR procedure in 31 patients requiring revision between 2004 and 2008. Eighteen of the 31 patients treated with the procedure were followed a minimum of 24 months (mean, 38 months; range, 24 to 73 months). We evaluated ROM, obtained IKDC scores, and determined stability with KT-1000. RESULTS The procedure could be applied in 30 of the 31 cases. One of the 18 reruptured the graft at 28 months. Of the remaining 17 patients with followup of 24 months or longer, 15 had full ROM, while the remaining two lost 5° of flexion; 11 were classified as normal and six were nearly normal according to the IKDC evaluation. Stability measured with KT-1000 was 1.0 ± 1.5 mm. CONCLUSION The RT ACLR technique provided acceptable results after one-stage revision ACLR. LEVEL OF EVIDENCE Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
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Surgical management of grade 3 medial knee injuries combined with cruciate ligament injuries. Knee Surg Sports Traumatol Arthrosc 2012; 20:88-94. [PMID: 21556825 DOI: 10.1007/s00167-011-1541-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2010] [Accepted: 05/02/2011] [Indexed: 02/07/2023]
Abstract
PURPOSE Although various surgical procedures have attempted to restore valgus stability in medial knee injuries, so far none has achieved satisfactory results. The purpose of this study was to assess clinical outcome for patients with grade 3 valgus instability who were treated according to our surgical management strategy. METHODS Eighteen patients with both acute and chronic grade 3 medial knee injuries, all of which had combined cruciate ligament injuries, were treated with a proximal advancement of both the superficial medial collateral ligament (MCL) and posterior oblique ligament together with underlying deep MCL and joint capsule, in conjunction with cruciate ligament reconstructions in chronic phase. Augmentation with doubled semitendinosus tendon was added in 7 patients whose medial knee stability had been considered to be insufficient with only the proximal advancement procedure. They were evaluated preoperatively and at final follow-up. RESULTS Manual valgus laxities at 0° and 30°, as well as side-to-side difference in medial joint opening in stress radiograph, were significantly improved at final follow-up. The Lysholm knee scale was also significantly improved. Median values of the subjective evaluations of the patients' satisfaction, stability and sports performance level measured with visual analogue scale at final follow-up were 82 (60-100), 94 (71-100) and 88 (60-100), respectively. CONCLUSIONS Clinical outcomes of our surgical management strategy were reasonable in terms of restoring medial knee stability. This treatment protocol can help determine the surgical management of grade 3 medial knee injuries combined with cruciate ligament injuries. LEVEL OF EVIDENCE Retrospective case series, Level IV.
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35
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Eagan MJ, Zuk PA, Zhao KW, Bluth BE, Brinkmann EJ, Wu BM, McAllister DR. The suitability of human adipose-derived stem cells for the engineering of ligament tissue. J Tissue Eng Regen Med 2011; 6:702-9. [PMID: 21953999 DOI: 10.1002/term.474] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2010] [Revised: 05/19/2011] [Accepted: 07/05/2011] [Indexed: 12/24/2022]
Abstract
Rupture of the anterior cruciate ligament (ACL) is the one of the most common sports-related injuries. With its poor healing capacity, surgical reconstruction using either autografts or allografts is currently required to restore function. However, serious complications are associated with graft reconstructions and the number of such reconstructions has steadily risen over the years, necessitating the search for an alternative approach to ACL repair. Such an approach may likely be tissue engineering. Recent engineering approaches using ligament-derived fibroblasts have been promising, but the slow growth rate of such fibroblasts in vitro may limit their practical application. More promising results are being achieved using bone marrow mesenchymal stem cells (MSCs). The adipose-derived stem cell (ASC) is often proposed as an alternative choice to the MSC and, as such, may be a suitable stem cell for ligament engineering. However, the use of ASCs in ligament engineering still remains relatively unexplored. Therefore, in this study, the potential use of human ASCs in ligament tissue engineering was initially explored by examining their ability to express several ligament markers under growth factor treatment. ASC populations treated for up to 4 weeks with TGFβ1 or IGF1 did not show any significant and consistent upregulation in the expression of collagen types 1 and 3, tenascin C and scleraxis. While treatment with EGF or bFGF resulted in increased tenascin C expression, increased expression of collagens 1 and 3 were never observed. Therefore, simple in vitro treatment of human ASC populations with growth factors may not stimulate their ligament differentiative potential.
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Affiliation(s)
- Michael J Eagan
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Center for Health Sciences, Los Angeles, CA, USA
| | - Patricia A Zuk
- Division of Plastic Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Center for Health Sciences, Los Angeles, CA, USA
| | - Ke-Wei Zhao
- VA Greater Los Angeles Healthcare System, West Los Angeles Healthcare Center, Orthopedic Tissue Engineering Laboratory Los Angeles, CA, USA
| | - Benjamin E Bluth
- Division of Plastic Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Center for Health Sciences, Los Angeles, CA, USA
| | - Elyse J Brinkmann
- Department of Biomedical Engineering, Henry Samueli School of Engineering and Applied Science, University of California at Los Angeles, CA, USA
| | - Benjamin M Wu
- Department of Biomedical Engineering, Henry Samueli School of Engineering and Applied Science, University of California at Los Angeles, CA, USA
| | - David R McAllister
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Center for Health Sciences, Los Angeles, CA, USA.,VA Greater Los Angeles Healthcare System, West Los Angeles Healthcare Center, Orthopedic Tissue Engineering Laboratory Los Angeles, CA, USA
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Menetrey J, Laumonier T, Garavaglia G, Hoffmeyer P, Fritschy D, Gabbiani G, Bochaton-Piallat ML. α-Smooth muscle actin and TGF-β receptor I expression in the healing rabbit medial collateral and anterior cruciate ligaments. Injury 2011; 42:735-41. [PMID: 20800229 DOI: 10.1016/j.injury.2010.07.246] [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: 04/06/2010] [Revised: 06/08/2010] [Accepted: 07/12/2010] [Indexed: 02/02/2023]
Abstract
The aim of our study was to advance the knowledge about the biological differences in the healing of the anterior cruciate ligament (ACL) versus the medial collateral ligament (MCL). We quantified α-smooth muscle actin (α-SMA) expression and TGF-β receptor I (TGF-βRI) expression in experimentally injured rabbit ligaments (from day 3 to 12 weeks post-injury). Myofibroblasts (α-SMA positive cells) were identified as early as the third day post-injury in MCL and their density increased steadily up to day 21. Myofibroblasts were also detected in injured ACL but their density remained very low at all time points. The percentage of positive TGF-βRI area significantly increased in both injured ligaments compared to controls, with a peak expression at day 21; however, it remained constantly lower in ACL compared to MCL. A significant correlation was found between the percentage of TGF-βRI positive cells and the percentage of α-SMA expression only in injured MCL. These results provide evidence that myofibroblasts are important players in MCL remodelling after injury. The combined presence of myofibroblasts and TGF-βRI in the first 3 weeks post-MCL injury may partially explain the difference in the MCL and ACL healing process.
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Affiliation(s)
- Jacques Menetrey
- Orthopaedic Surgery Service, Geneva University Hospitals & Faculty of Medicine, University of Geneva, 4 Rue Gabrielle Perret-Gentil, Geneva 14, Switzerland.
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Zhang J, Pan T, Im HJ, Fu FH, Wang JHC. Differential properties of human ACL and MCL stem cells may be responsible for their differential healing capacity. BMC Med 2011; 9:68. [PMID: 21635735 PMCID: PMC3126732 DOI: 10.1186/1741-7015-9-68] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2011] [Accepted: 06/02/2011] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The human anterior cruciate ligament (hACL) and medial collateral ligament (hMCL) of the knee joint are frequently injured, especially in athletic settings. It has been known that, while injuries to the MCL typically heal with conservative treatment, ACL injuries usually do not heal. As adult stem cells repair injured tissues through proliferation and differentiation, we hypothesized that the hACL and hMCL contain stem cells exhibiting unique properties that could be responsible for the differential healing capacity of the two ligaments. METHODS To test the above hypothesis, we derived ligament stem cells from normal hACL and hMCL samples from the same adult donors using tissue culture techniques and characterized their properties using immunocytochemistry, RT-PCR, and flow cytometry. RESULTS We found that both hACL stem cells (hACL-SCs) and hMCL stem cells (hMCL-SCs) formed colonies in culture and expressed stem cell markers nucleostemin and stage-specific embryonic antigen-4 (SSEA-4). Moreover, both hACL-SCs and hMCL-SCs expressed CD surface markers for mesenchymal stem cells, including CD44 and CD90, but not those markers for vascular cells, CD31, CD34, CD45, and CD146. However, hACL-SCs differed from hMCL-SCs in that the size and number of hACL-SC colonies in culture were much smaller and grew more slowly than hMCL-SC colonies. Moreover, fewer hACL-SCs in cell colonies expressed stem cell markers STRO-1 and octamer-binding transcription factor-4 (Oct-4) than hMCL-SCs. Finally, hACL-SCs had less multi-differentiation potential than hMCL-SCs, evidenced by differing extents of adipogenesis, chondrogenesis, and osteogenesis in the respective induction media. CONCLUSIONS This study shows for the first time that hACL-SCs are intrinsically different from hMCL-SCs. We suggest that the differences in their properties contribute to the known disparity in healing capabilities between the two ligaments.
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Affiliation(s)
- Jianying Zhang
- MechanoBiology Laboratory, Department of Orthopedic Surgery, University of Pittsburgh, PA 15213, USA
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Irie T, Majima T, Sawaguchi N, Funakoshi T, Nishimura SI, Minami A. Biomechanical and histologic evaluation of tissue engineered ligaments using chitosan and hyaluronan hybrid polymer fibers: A rabbit medial collateral ligament reconstruction model. J Biomed Mater Res A 2011; 97:111-7. [DOI: 10.1002/jbm.a.32938] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2008] [Revised: 12/21/2009] [Accepted: 07/19/2010] [Indexed: 01/13/2023]
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Cheng MT, Liu CL, Chen TH, Lee OK. Comparison of potentials between stem cells isolated from human anterior cruciate ligament and bone marrow for ligament tissue engineering. Tissue Eng Part A 2010; 16:2237-53. [PMID: 20163211 DOI: 10.1089/ten.tea.2009.0664] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
We have previously isolated and identified stem cells from human anterior cruciate ligament (ACL). The purpose of this study was to evaluate the differences in proliferation, differentiation, and extracellular matrix (ECM) formation abilities between bone marrow stem cells (BMSCs) and ACL-derived stem cells (LSCs) from the same donors when cultured with different growth factors, including basic fibroblast growth factor (bFGF), epidermal growth factor, and transforming growth factor-beta 1 (TGF-beta1). Ligament tissues and bone marrow aspirate were obtained from patients undergoing total knee arthroplasty and ACL reconstruction surgeries. Proliferation, colony formation, and population doubling capacity as well as multilineage differentiation potentials of LSCs and BMSCs were compared. Gene expression and ECM production for ligament engineering were also evaluated. It was found that BMSCs possessed better osteogenic differentiation potential than LSCs, while similar adipogenic and chondrogenic differentiation abilities were observed. Proliferation rates of both LSCs and BMSCs were enhanced by bFGF and TGF-beta1. TGF-beta1 treatment significantly increased the expression of type I collagen, type III collagen, fibronectin, and alpha-smooth muscle actin in LSCs, but TGF-beta1 only upregulated type I collagen and tenascin-c in BMSCs. Protein quantification further confirmed the results of differential gene expression and suggested that LSCs and BMSCs increase ECM production upon TGF-beta1 treatment. In summary, in comparison with BMSCs, LSCs proliferate faster and maintain an undifferentiated state with bFGF treatment, whereas under TGF-beta1 treatment, LSCs upregulate major tendinous gene expression and produce a robust amount of ligament ECM protein, making LSCs a potential cell source in future applications of ACL tissue engineering.
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Affiliation(s)
- Ming-Te Cheng
- Department of Surgery, National Yang-Ming University, Taipei, Taiwan
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Funakoshi T, Spector M. Chondrogenic differentiation and lubricin expression of caprine infraspinatus tendon cells. J Orthop Res 2010; 28:716-25. [PMID: 20058273 DOI: 10.1002/jor.21053] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Reparative strategies for the treatment of injuries to tendons, including those of the rotator cuff of the shoulder, need to address the formation of the cartilage which serves as the attachment apparatus to bone and which forms at regions undergoing compressive loading. Moreover, recent work indicates that cells employed for rotator cuff repair may need to synthesize a lubricating glycoprotein, lubricin, which has recently been found to play a role in tendon tribology. The objective of the present study was to investigate the chondrogenic differentiation and lubricin expression of caprine infraspinatus tendon cells in monolayer and three-dimensional culture, and to compare the behavior with bone marrow-derived mesenchymal stem cells (MSCs). The results demonstrated that while tendon cells in various media, including chondrogenic medium, expressed lubricin, virtually none of the MSCs synthesized this important lubricating molecule. Also of interest was that the cartilage formation capacity of the tendon cells grown in pellet culture in chondrogenic medium was comparable with MSCs. These data inform the use of tendon cells for rotator cuff repair, including for fibrocartilaginous zones.
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Affiliation(s)
- Tadanao Funakoshi
- Tissue Engineering, VA Boston Healthcare System, Boston, Massachusetts 02130, USA
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Hsu SL, Liang R, Woo SL. Functional tissue engineering of ligament healing. BMC Sports Sci Med Rehabil 2010; 2:12. [PMID: 20492676 PMCID: PMC2879239 DOI: 10.1186/1758-2555-2-12] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2010] [Accepted: 05/21/2010] [Indexed: 12/18/2022]
Abstract
Ligaments and tendons are dense connective tissues that are important in transmitting forces and facilitate joint articulation in the musculoskeletal system. Their injury frequency is high especially for those that are functional important, like the anterior cruciate ligament (ACL) and medial collateral ligament (MCL) of the knee as well as the glenohumeral ligaments and the rotator cuff tendons of the shoulder. Because the healing responses are different in these ligaments and tendons after injury, the consequences and treatments are tissue- and site-specific. In this review, we will elaborate on the injuries of the knee ligaments as well as using functional tissue engineering (FTE) approaches to improve their healing. Specifically, the ACL of knee has limited capability to heal, and results of non-surgical management of its midsubstance rupture have been poor. Consequently, surgical reconstruction of the ACL is regularly performed to gain knee stability. However, the long-term results are not satisfactory besides the numerous complications accompanied with the surgeries. With the rapid development of FTE, there is a renewed interest in revisiting ACL healing. Approaches such as using growth factors, stem cells and scaffolds have been widely investigated. In this article, the biology of normal and healing ligaments is first reviewed, followed by a discussion on the issues related to the treatment of ACL injuries. Afterwards, current promising FTE methods are presented for the treatment of ligament injuries, including the use of growth factors, gene delivery, and cell therapy with a particular emphasis on the use of ECM bioscaffolds. The challenging areas are listed in the future direction that suggests where collection of energy could be placed in order to restore the injured ligaments and tendons structurally and functionally.
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Affiliation(s)
- Shan-Ling Hsu
- Musculoskeletal Research Center, Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Orthopaedic Surgery, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Rui Liang
- Musculoskeletal Research Center, Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA
| | - Savio Ly Woo
- Musculoskeletal Research Center, Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA
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Rehabilitation following a minimally invasive procedure for the repair of a combined anterior cruciate and posterior cruciate ligament partial rupture in a 15-year-old athlete. J Orthop Sports Phys Ther 2010; 40:297-309. [PMID: 20842771 DOI: 10.2519/jospt.2010.3162] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
STUDY DESIGN Case report. BACKGROUND The healing response procedure is a minimally invasive arthroscopic surgical technique used to stimulate healing in the treatment of partial cruciate ligament tears. The purpose of this report is to provide information on the surgical procedure, the postoperative rehabilitation, and the overall functional results in a patient who underwent such a procedure. CASE DESCRIPTION A 15-year-old male, who sustained a partial tear of both the anterior cruciate and posterior cruciate ligament while playing football, underwent arthroscopic surgical management utilizing a healing response technique. Precautions concerning range of motion and resisted activities were followed postoperatively to protect the healing cruciate ligaments. The postoperative protocol consisted of 3 phases, culminating in return-to-sport training. Treatment incorporated cardiovascular, proprioceptive, strength, power, plyometric, and sport-specific activities. Treatment was progressed based on specific criteria emphasizing proper movement patterns and eccentric control during functional activities. OUTCOMES The patient attended 31 physical therapy sessions over 17 weeks. Strength improved from 3/5 to 5/5, knee range of motion returned to normal, Lower Extremity Functional Scale scores improved from 21/80 to 80/80, and successful outcomes on functional return-to-sport testing allowed the patient to return to competitive athletics. DISCUSSION Primary repair of cruciate ligament tears has yielded poor results, and partial cruciate ligament tears may not require complete surgical reconstruction. The healing response technique offers a possible solution for the treatment of partial cruciate ligament tears. A criterion-based postoperative protocol was derived based on current evidence regarding rehabilitation following cruciate ligament reconstruction and evidence regarding lower extremity rehabilitation principles and injury prevention. LEVEL OF EVIDENCE Therapy, level 4.
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Nayak BP, Goh JCH, Toh SL, Satpathy GR. In vitro study of stem cell communication via gap junctions for fibrocartilage regeneration at entheses. Regen Med 2010; 5:221-9. [PMID: 20210582 DOI: 10.2217/rme.09.86] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Entheses are fibrocartilaginous organs that bridge ligament with bone at their interface and add significant insertional strength. To replace a severely damaged ligament, a tissue-engineered graft preinstalled with interfacial fibrocartilage, which is being regenerated from stem cells, appears to be more promising than ligament-alone graft. Such a concept can be realized by a biomimetic approach of establishing a dynamic communication of stem cells with bone cells and/or ligament fibroblasts in vitro. AIM The current study has two objectives. The first objective is to demonstrate functional coculture of bone marrow-derived stem cells (BMSCs) with mature bone cells/ligament fibroblasts as evidenced by gap-junctional communication in vitro. The second objective is to investigate the role of BMSCs in the regeneration of fibrocartilage within the coculture. MATERIALS & METHODS Rabbit bone/ligament fibroblasts were dual-stained with DiI-Red and calcein (gap-junction permeable dye), and cocultured with unlabeled BMSCs at fixed ratio (1:10). The functional gap junction was demonstrated by the transfer of calcein from donor to recipient cells that was confirmed and quantified by flow cytometry. Type 2 collagen (cartilage extracellular matrix-specific protein) expressed by the mixed cell lines in the cocultures were estimated by real-time reverse transcription PCR and compared with that of the ligament-bone coculture (control). RESULTS Significant transfer of calcein into BMSCs was observed and flow cytometry analyses showed a gradual increase in the percentage of BMSCs acquiring calcein with time. Cocultures that included BMSCs expressed significantly more type 2 collagen compared with the control. CONCLUSION The current study, for the first time, reported the expression of gap-junctional communication of BMSCs with two adherent cell lines of musculoskeletal system in vitro and also confirmed that incorporation of stem cells augments fibrocartilage regeneration. The results open up a path to envisage a composite graft preinstalled with enthesial fibrocartilage using a stem cell-based coculture system.
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Affiliation(s)
- Bibhukalyan Prasad Nayak
- Department of Biotechnology & Medical Engineering, National Institute of Technology, Rourkela, India.
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Date H, Furumatsu T, Sakoma Y, Yoshida A, Hayashi Y, Abe N, Ozaki T. GDF-5/7 and bFGF activate integrin alpha2-mediated cellular migration in rabbit ligament fibroblasts. J Orthop Res 2010; 28:225-31. [PMID: 19725104 DOI: 10.1002/jor.20981] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Cellular activities responding to growth factors are important in ligament healing. The anterior cruciate ligament (ACL) has poor healing potential compared to the medial collateral ligament (MCL). To assess the differences, we investigated the proliferation, migration, adhesion, and matrix synthesis responding to growth factors in rabbit ACL and MCL fibroblasts. ACL cell proliferation to basic fibroblast growth factor (bFGF), bone morphogenetic protein-2, growth and differentiation factor (GDF)-5, and GDF-7 treatment was similar to that of MCL cells. GDF-5 enhanced Col1a1 expression in ACL and MCL fibroblasts up to 4.7- and 17-fold levels of control, respectively. MCL fibroblasts showed stronger migration activities in response to bFGF and GDF-5 than ACL cells. GDF-5/7 and bFGF also changed the stress fiber formation and cellular adhesion by modulating the distribution of integrin alpha2. Functional blocking analyses using anti-integrin alpha2 antibodies revealed that cellular migration responding to growth factors depended on the integrin alpha2-mediated adhesion on type I collagen. The expression of integrin alpha2 was also increased by growth factors in both cells. Our results demonstrate that GDF-5/7 and bFGF stimulate cellular migration by modulating integrin alpha2 expression and integrin alpha2-dependent adhesion, especially in MCL fibroblasts. These findings suggest that the different healing potential between ACL and MCL may be caused by different cellular behavior in the integrin alpha2-mediated cellular migration in response to growth factors.
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Affiliation(s)
- Hirokazu Date
- Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Kitaku, Okayama 700-8558, Japan
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Attia E, Brown H, Henshaw R, George S, Hannafin JA. Patterns of gene expression in a rabbit partial anterior cruciate ligament transection model: the potential role of mechanical forces. Am J Sports Med 2010; 38:348-56. [PMID: 19966107 DOI: 10.1177/0363546509348052] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND The inconsistency in healing after anterior cruciate ligament (ACL) repair has been attributed to ACL fibroblast cellular metabolism, lack of a sufficient vascular supply, and the inability to form a scar or scaffold after ligament rupture because of the uniqueness of the intra-articular environment. Hypotheses (1) Stress deprivation in the surgically transected ACL will increase matrix metalloproteinase (MMP) and alpha smooth muscle actin (alpha-SMA) expression. (2) Stress deprivation will decrease collagen expression. (3) The transected anteromedial bundle of the ACL will demonstrate a pattern of gene expression similar to the completely transected ACL, while gene expression profiles in the intact posterolateral bundle will be similar to the sham-operated controls. STUDY DESIGN Controlled laboratory study. METHODS Thirty-six New Zealand White rabbits underwent a partial ACL surgical transection separating the anteromedial (AM) and posterolateral (PL) bundles and transecting the AM bundle. Contralateral ACLs were either sham operated or completely transected. Ligament tissue was harvested at 1, 2, or 6 weeks after surgery, and real-time PCR was performed using primers for collagen I, collagen III, alpha-SMA, MMP-1, and MMP-13. RESULTS At 1 week, a 28- and 29-fold increase in MMP-13 expression was seen in the complete transection and the transected AM bundle specimens when compared with sham-operated controls (P = .049, P = .018), respectively. There was no significant difference in MMP-13 between the sham controls and the intact PL bundle specimens. A 22- and 23-fold increase in alpha-SMA was seen (P = .03, P = .009) in the complete transection and transected AM bundle specimens, respectively, while no difference was seen between the intact PL bundle and controls. No significant differences were seen in collagen I (Col I) or collagen III (Col III) gene expression at 1 week. At 6 weeks, Col I expression increased 5-fold in complete transection samples (P = 3.9 x 10(-6)), 3-fold in transected AM samples (P = 3.3 x 10(-6)), and 2-fold in the intact PL bundle samples as compared with controls. alpha-SMA was increased 7.5-fold and 5-fold in complete transection and transected AM samples, respectively (P = .004, P = 2.2 x 10(-6)), while no significant change was seen in the intact PL bundle samples compared with controls. Complete transection specimens showed a 3-fold increase in MMP-1 expression. Col III increased 5.4-, 2.6-, and 2.4-fold in the complete transection, transected AM, and intact PL groups, respectively (P = .003, P = .004, P = .04). CONCLUSION Partial or complete surgical transection of the rabbit ACL with resultant loss of mechanical stimuli results in an increase in MMP-13 and alpha-SMA expression at the early time point (1 week) and an increase in alpha-SMA, Col I, and Col III expression at the later time point (6 weeks). These data provide support for the hypothesis that there is a time-dependent alteration of anabolic and catabolic matrix gene expression after injury/loss of ligament integrity. Clinical Relevance Identification of pathways that respond to mechanical stress in the intact ACL and after surgical transection may permit development of novel therapies to alter healing of the partial ACL injury or to assist in the development of biomechanical active ''smart'' scaffolds for tissue-engineered ligament replacements.
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Affiliation(s)
- Erik Attia
- Laboratory for Soft Tissue Research, Tissue Engineering Repair and Regeneration Program, Hospital for Special Surgery, New York, New York 10021, USA.
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Furumatsu T, Hachioji M, Saiga K, Takata N, Yokoyama Y, Ozaki T. Anterior cruciate ligament-derived cells have high chondrogenic potential. Biochem Biophys Res Commun 2009; 391:1142-7. [PMID: 20006576 DOI: 10.1016/j.bbrc.2009.12.044] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2009] [Accepted: 12/10/2009] [Indexed: 12/25/2022]
Abstract
Anterior cruciate ligament (ACL)-derived cells have a character different from medial collateral ligament (MCL)-derived cells. However, the critical difference between ACL and MCL is still unclear in their healing potential and cellular response. The objective of this study was to investigate the mesenchymal differentiation property of each ligament-derived cell. Both ligament-derived cells differentiated into adipogenic, osteogenic, and chondrogenic lineages. In chondrogenesis, ACL-derived cells had the higher chondrogenic property than MCL-derived cells. The chondrogenic marker genes, Sox9 and alpha1(II) collagen (Col2a1), were induced faster in ACL-derived pellets than in MCL-derived pellets. Sox9 expression preceded the increase of Col2a1 in both pellet-cultured cells. However, the expression level of Sox9 and a ligament/tendon transcription factor Scleraxis did not parallel the increase of Col2a1 expression along with chondrogenic induction. The present study demonstrates that the balance between Sox9 and Scleraxis have an important role in the chondrogenic differentiation of ligament-derived cells.
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Affiliation(s)
- Takayuki Furumatsu
- Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikatacho, Kitaku, Okayama 700-8558, Japan.
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Cheng MT, Yang HW, Chen TH, Lee OKS. Modulation of Proliferation and Differentiation of Human Anterior Cruciate Ligament–Derived Stem Cells by Different Growth Factors. Tissue Eng Part A 2009; 15:3979-89. [DOI: 10.1089/ten.tea.2009.0172] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Affiliation(s)
- Ming-Te Cheng
- Department of Surgery, National Yang-Ming University, Taipei, Taiwan
- Taipei City Hospital, Taipei, Taiwan
- Taoyuan General Hospital, Taoyuan, Taiwan
| | - Hui-Wen Yang
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Tain-Hsiung Chen
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Oscar Kuang-Sheng Lee
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
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Tapper JE, Funakoshi Y, Hariu M, Marchuk L, Thornton GM, Ronsky JL, Zernicke R, Shrive NG, Frank CB. ACL/MCL transection affects knee ligament insertion distance of healing and intact ligaments during gait in the Ovine model. J Biomech 2009; 42:1825-33. [PMID: 19643414 DOI: 10.1016/j.jbiomech.2009.05.034] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2008] [Revised: 05/22/2009] [Accepted: 05/23/2009] [Indexed: 01/13/2023]
Abstract
The objective of this study was to assess the impact of combined transection of the anterior cruciate and medial collateral ligaments on the intact and healing ligaments in the ovine stifle joint. In vivo 3D stifle joint kinematics were measured in eight sheep during treadmill walking (accuracy: 0.4+/-0.4mm, 0.4+/-0.4 degrees ). Kinematics were measured with the joint intact and at 2, 4, 8, 12, 16 and 20 weeks after either surgical ligament transection (n=5) or sham surgery without transection (n=3). After sacrifice at 20 weeks, the 3D subject-specific bone and ligament geometry were digitized, and the 3D distances between insertions (DBI) of ligaments during the dynamic in vivo motion were calculated. Anterior cruciate ligament/medial collateral ligament (ACL/MCL) transection resulted in changes in the DBI of not only the transected ACL, but also the intact lateral collateral ligament (LCL) and posterior cruciate ligament (PCL), while the DBI of the transected MCL was not significantly changed. Increases in the maximal ACL DBI (2 week: +4.2mm, 20 week: +5.7mm) caused increases in the range of ACL DBI (2 week: 3.6mm, 20 week: +3.8mm) and the ACL apparent strain (2 week: +18.9%, 20 week: +24.0%). Decreases in the minimal PCL DBI (2 week: -3.2mm, 20 week: -4.3mm) resulted in increases in the range of PCL DBI (2 week: +2.7mm, 20 week: +3.2mm). Decreases in the maximal LCL DBI (2 week: -1.0mm, 20 week: -2.0mm) caused decreased LCL apparent strain (2 week: -3.4%, 20 week: -6.9%). Changes in the mechanical environment of these ligaments may play a significant role in the biological changes observed in these ligaments.
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Affiliation(s)
- Janet E Tapper
- Department of Mechanical and Manufacturing Engineering, University of Calgary, Calgary, Alberta, Canada.
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Huang TF, Chen YT, Yang TH, Chen LL, Chiou SH, Tsai TH, Tsai CC, Chen MH, Ma HL, Hung SC. Isolation and characterization of mesenchymal stromal cells from human anterior cruciate ligament. Cytotherapy 2009; 10:806-14. [PMID: 19023768 DOI: 10.1080/14653240802474323] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND The anterior cruciate ligament (ACL) is one of the most commonly injured ligaments of the knee. Because the torn ACL is always discarded during ACL reconstruction, it may be a potential source for isolating mesenchymal stromal cells (MSC). METHODS To characterize MSC from human ACL, cells were enzymatically released from the ACL of adult human donors and seeded in plastic dishes with serial passages at confluence. At different passages, ACL-derived cells were subjected to in vitro assays to investigate their multilineage potential. Upon treatment, the phenotypes of the cell cultures were analyzed by histo- and immunohistochemistry and semi-quantitative reverse transcription-polymerase chain reaction for the expression of lineage-specific genes. RESULTS Six independent cell lines from individual donors showed diversity in multilineage potential. Interestingly, five of the six lines displayed adipogenic potential, four had osteogenic and adipogenic potential, and only one cell line was tripotent. Both bone marrow (BM)- and ACL-derived MSC expressed marker genes for ligament fibroblasts, whereas the mRNA levels of collagen I and III were more abundant in ACL-derived MSC. DISCUSSION Our study demonstrates that human MSC can be isolated from ACL with diversity in the potential to form bone, fat and cartilage and an increase as compared to BM MSC, in the potential to form ligament fibroblasts.
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Affiliation(s)
- T-F Huang
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
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Woo SLY, Liang R, Fisher MB. Future of Orthopaedic Sports Medicine and Soft Tissue Healing: The Important Role of Engineering. Cell Mol Bioeng 2009. [DOI: 10.1007/s12195-009-0065-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
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