|
1
|
Wang C, Li H, Li F, Yang Y, Xu Z, Gao T, Li R, Zhang R, Mu Y, Guo Z, Guo Q, Liu S. The mitochondrial protectant SS31 optimized decellularized Wharton's jelly scaffold improves allogeneic chondrocyte implantation-mediated articular cartilage repair. J Orthop Translat 2025; 52:126-137. [PMID: 40291636 PMCID: PMC12032180 DOI: 10.1016/j.jot.2025.03.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 03/24/2025] [Accepted: 03/31/2025] [Indexed: 04/30/2025] Open
Abstract
Background The process of allogeneic chondrocyte implantation entails obtaining donor chondrocytes, culturing them in a medium enriched with growth factors, and then introducing them-either individually or in conjunction with biocompatible scaffolds-into areas of cartilage damage. While promising, this approach is hindered by mitochondrial dysfunction in the implanted chondrocytes. Methods This research introduced an innovative approach by creating a new type of scaffold derived from Decellularized Umbilical Cord Wharton's Jelly (DUCWJ) extracted from human umbilical cords. The scaffold was manufactured using procedures involving decellularization and lyophilization. The resulting scaffold demonstrated superior characteristics, including high porosity, hydrophilic properties, and excellent biocompatibility. To enhance its function, SS31 peptides, known for their mitochondrial-protective properties, were chemically bonded to the scaffold surface, creating an SS31@DUCWJ system. This system aims to protect chondrocytes and regulate the mitochondrial respiratory chain (MRC), thereby improving cartilage repair mediated by allogeneic chondrocyte implantation. Results In vitro studies have shown that SS31 effectively attenuates metabolic dysfunction, extracellular matrix degradation, oxidative stress, inflammation, and mitochondrial damage induced by serial cell passages. Complementary in vivo experiments showed that the SS31@DUCWJ scaffold promoted regeneration of healthy articular cartilage in femoral condylar defects in rabbits. Conclusions This SS31-modified porous decellularized scaffold represents an innovative biomaterial with anti-inflammatory properties and targeted mitochondrial regulation. It offers a promising new approach for treating articular cartilage injuries. The translational potential of this article Our study was the first to successfully load the mitochondrial protectant SS31 onto a DUCWJ hydrogel scaffold for localized drug delivery. This method is highly efficacious in repairing cartilage defects and offers a promising new avenue for the treatment of such conditions.
Collapse
Affiliation(s)
- Chao Wang
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Hao Li
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Fakai Li
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Yongkang Yang
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Ziheng Xu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Tianze Gao
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Runmeng Li
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Ruiyang Zhang
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Yuhao Mu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Zheng Guo
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Quanyi Guo
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Shuyun Liu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| |
Collapse
|
|
2
|
Niemeyer P, Hanus M, Belickas J, László T, Gudas R, Fiodorovas M, Cebatorius A, Pastucha M, Izadpanah K, Prokeš J, Sisák K, Mohyla M, Farkas C, Kessler O, Kybal S, Spiro R, Trattnig S, Köhler A, Kirner A, Gaissmaier C. Treatment of Large Cartilage Defects in the Knee by Hydrogel-Based Autologous Chondrocyte Implantation: A 5-Year Follow-Up of a Prospective, Multicenter, Single-Arm Phase III Trial. Cartilage 2025:19476035251334737. [PMID: 40289921 PMCID: PMC12037527 DOI: 10.1177/19476035251334737] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/20/2025] [Accepted: 03/29/2025] [Indexed: 04/30/2025] Open
Abstract
ObjectiveTo evaluate efficacy and safety at 5 years after treatment with hydrogel-based autologous chondrocyte implantation (ACI) for large cartilage defects in the knee.DesignProspective, multicenter, single-arm, Phase III clinical trial. ACI was performed in 100 patients with focal full-thickness cartilage defects ranging from 4 to 12 cm2 in size. The primary outcome measure was the responder rate (defined as improvement by ≥10 points) at 2 years using the Knee Injury and Osteoarthritis Outcome Score (KOOS).ResultsThe preoperative overall KOOS was 39.8 points and continuously increased to 84.7 points at 5 years (mean increase 44.1 points, 95% CI = 40.4-47.9, P < 0.0001). The primary study endpoint (i.e., a KOOS responder rate of >40%) was descriptively met at each assessment timepoint from 3 months to 5 years (Month 3: 75.5%, 95% CI = 65.6-83.8; Year 2: 93.0%, 95% CI = 86.1-97.1, Year 5: 92.8%, 95% CI = 85.7-97.0). International Knee Documentation Committee (IKDC) subjective and objective scores and quality of life assessments (EQ-5D-5L) supported the results seen for the KOOS. The overall treatment failure rate at 5 years was 1%. All treatment-related adverse events were of mild or moderate intensity and mostly occurred within the first year after treatment.ConclusionsHydrogel-based ACI has been shown to be a safe and effective treatment option for patients with large knee cartilage defects with sustained efficacy up to 5 years as demonstrated by consistent and clinically relevant improvements in all investigated efficacy variables. No remarkable adverse events or safety issues were noted.
Collapse
Affiliation(s)
| | - M. Hanus
- Department of Orthopaedics and Traumatology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Praha, Czech Republic
| | - J. Belickas
- Lithuanian University of Health Sciences, Ortopedijos Technika, Kaunas, Lithuania
| | - T. László
- Clinic of Traumatology, Jász-Nagykun-Szolnok County Hetényi Géza Hospital, Szolnok, Hungary
| | - R. Gudas
- Hospital of Lithuanian University of Health Sciences, Kaunas Clinics, Kaunas, Lithuania
| | | | | | - M. Pastucha
- Department of Orthopaedics, Hospital Hořovice, Hořovice, Czech Republic
| | - K. Izadpanah
- Department of Orthopaedics and Trauma Surgery, Medical Center, Faculty of Medicine, Albert Ludwigs University of Freiburg, Freiburg, Germany
| | - J. Prokeš
- Clinic of Traumatology, Faculty of Medicine, Masaryk University Brno and Úrazová Nemocnice, Brno, Czech Republic
| | - K. Sisák
- Department of Traumatology and Orthopaedics, University of Szeged, Szeged, Hungary
| | - M. Mohyla
- Department of Orthopaedics, University Hospital Ostrava, Ostrava-Poruba, Czech Republic
| | - C. Farkas
- Department of Orthopaedics, Szabolcs-Szatmár-Bereg County Hospitals, University Teaching Hospital, Nyíregyháza, Hungary
| | - O. Kessler
- Centrum for Orthopaedics & Sports, Zürich, Switzerland
| | - S. Kybal
- Orthopaedic Department, Hospital Benešov, Benešov, Czech Republic
| | - R. Spiro
- Octane Biotherapeutics, Inc., Breinigsville, PA, USA
| | - S. Trattnig
- High Field MR Center, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - A. Köhler
- TETEC–Tissue Engineering Technologies AG, Reutlingen, Germany
| | - A. Kirner
- TETEC–Tissue Engineering Technologies AG, Reutlingen, Germany
| | - C. Gaissmaier
- TETEC–Tissue Engineering Technologies AG, Reutlingen, Germany
| |
Collapse
|
|
3
|
Weldon KC, Longaker MT, Ambrosi TH. Harnessing the diversity and potential of endogenous skeletal stem cells for musculoskeletal tissue regeneration. Stem Cells 2025; 43:sxaf006. [PMID: 39945760 PMCID: PMC11892563 DOI: 10.1093/stmcls/sxaf006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 01/21/2025] [Indexed: 03/11/2025]
Abstract
In our aging society, the degeneration of the musculoskeletal system and adjacent tissues is a growing orthopedic concern. As bones age, they become more fragile, increasing the risk of fractures and injuries. Furthermore, tissues like cartilage accumulate damage, leading to widespread joint issues. Compounding this, the regenerative capacity of these tissues declines with age, exacerbating the consequences of fractures and cartilage deterioration. With rising demand for fracture and cartilage repair, bone-derived stem cells have attracted significant research interest. However, the therapeutic use of stem cells has produced inconsistent results, largely due to ongoing debates and uncertainties regarding the precise identity of the stem cells responsible for musculoskeletal growth, maintenance and repair. This review focuses on the potential to leverage endogenous skeletal stem cells (SSCs)-a well-defined population of stem cells with specific markers, reliable isolation techniques, and functional properties-in bone repair and cartilage regeneration. Understanding SSC behavior in response to injury, including their activation to a functional state, could provide insights into improving treatment outcomes. Techniques like microfracture surgery, which aim to stimulate SSC activity for cartilage repair, are of particular interest. Here, we explore the latest advances in how such interventions may modulate SSC function to enhance bone healing and cartilage regeneration.
Collapse
Affiliation(s)
- Kelly C Weldon
- Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA 95817, United States
- School of Medicine, University of California, Sacramento, CA 95817, United States
| | - Michael T Longaker
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, United States
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Thomas H Ambrosi
- Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA 95817, United States
| |
Collapse
|
|
4
|
Gudas R, Staškūnas M, Mačiulaitis J, Gudaitė E, Aleknaite-Dambrauskiene I. Arthroscopic Implantation of a Cell-Free Bilayer Scaffold for the Treatment of Knee Chondral Lesions: A 2-Year Prospective Study. Cartilage 2025; 16:5-16. [PMID: 38501456 PMCID: PMC11569651 DOI: 10.1177/19476035241232061] [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] [Received: 10/26/2023] [Revised: 01/18/2024] [Accepted: 01/26/2024] [Indexed: 03/20/2024] Open
Abstract
OBJECTIVE The main objective of this study is to assess the safety and clinical efficacy of a cell-free bilayer scaffold (MaioRegen Chondro+ by Fin-Ceramica) in patients affected by chondral knee lesions of different origin and localization. DESIGN Thirty-one patients with focal chondral lesions of the knee were arthroscopically treated with MaioRegen Chondro+. All patients were prospectively evaluated for a minimum of 2 years using the International Knee Documentation Committee (IKDC) Questionnaire and the Tegner Activity Scale. Cartilage repair was assessed based on the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) 2.0 score at 12 months. Follow-up at 36 months was available for 25 out of 31 patients. RESULTS From baseline to 6-, 12-, and 24-month follow-up, IKDC score significantly improved by 19.5 ± 7.27 (95% confidence interval [CI]: 16.9-22.2, P < 0.001), 30.8 ± 7.63 (95% CI: 28.0-33.6, P < 0.001), and 36.2 ± 8.00 points (95% CI: 33.3-39.2, P < 0.001), respectively. Tegner scores documented a substantial clinical improvement as early as 12 months after surgery (change of -0.6 ± 0.62; 95% CI: -0.8 to -0.4, P < 0.001), reaching the preinjury values. There was a statistically significant increase in the MOCART scores (P < 0.001). Comparable results were observed regardless of preintervention demographic characteristics, lesion site or etiology, or the number of treated sites. Notably, the significant clinical benefit was maintained in a subset of patients who reached 3-year follow-up. No adverse events were reported in the entire analyzed population. CONCLUSION MaioRegen Chondro+ is a safe and effective device for the treatment of knee chondral lesions, enabling a significant clinical improvement for at least 2 years.
Collapse
Affiliation(s)
- Rimtautas Gudas
- Department of Orthopedics and Traumatology, Hospital of Lithuanian University of Health Sciences, Kaunas Clinics, Kaunas, Lithuania
| | - Mantas Staškūnas
- Department of Orthopedics and Traumatology, Hospital of Lithuanian University of Health Sciences, Kaunas Clinics, Kaunas, Lithuania
| | - Justinas Mačiulaitis
- Advanced Cell Therapy Unit, Physiology and Pharmacology Department, Lithuanian University of Health Sciences, Kaunas, Lithuania
- Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Emilė Gudaitė
- Lithuanian University of Health Sciences, Kaunas, Lithuania
| | | |
Collapse
|
|
5
|
Hayashi K, Tokumaru T, Shibahara K, Taleb Alashkar AN, Zhang C, Kishida R, Nakashima Y, Ishikawa K. Wood-Derived Hydrogels for Osteochondral Defect Repair. ACS NANO 2025; 19:520-534. [PMID: 39730305 PMCID: PMC11752520 DOI: 10.1021/acsnano.4c10430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 11/07/2024] [Accepted: 11/20/2024] [Indexed: 12/29/2024]
Abstract
Repairing cartilage tissue is a serious global challenge. Herein, we focus on wood skeletal structures that are highly porous for cell penetration yet have load-bearing strength, and aim to synthesize wood-derived hydrogels with the ability to regenerate cartilage tissues. The hydrogels were synthesized by wood delignification and the subsequent intercalation of citric acid (CA), which is involved in tricarboxylic acid cycles and essential for energy production, and N-acetylglucosamine (NAG), which is a cartilage glycosaminoglycan, among cellulose microfibrils. CA and NAG intercalation increased the amorphous region of the cellulose microfibrils and endowed them with flexibility while maintaining the skeletal structure of the wood. Consequently, the CA-NAG-treated wood hydrogels became twistable and bendable, and the acquired stiffness, compressive strength, water content, and cushioning characteristics were similar to those of the cartilage. In rabbit femur cartilage defects, CA-NAG-treated wood hydrogels induced the differentiation of surrounding cells into chondrocytes. Consequently, the CA-NAG-treated wood hydrogels repaired cartilage defects, whereas the collagen scaffolds, delignified wood materials, and CA-treated wood hydrogels did not. The CA-NAG-treated wood hydrogels exhibit superior structural and mechanical characteristics over conventional cellulose-fiber-containing scaffolds. Furthermore, the CA-NAG-treated wood hydrogels can effectively repair cartilage on their own, whereas conventional natural and synthetic polymeric materials need to be combined with cells and growth factors to achieve a sufficient therapeutic effect. Therefore, the CA-NAG-treated wood hydrogels successfully address the limitations of current therapies that either fail to repair articular cartilage or sacrifice healthy cartilage. To our knowledge, this is the pioneer study on the utilization of thinned wood for tissue engineering, which will contribute to solving both global health and environmental problems and to creating a sustainable society.
Collapse
Affiliation(s)
- Koichiro Hayashi
- Department
of Biomaterials, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812−8582, Japan
| | - Tatsuya Tokumaru
- Department
of Biomaterials, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812−8582, Japan
- Department
of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812−8582, Japan
| | - Keigo Shibahara
- Department
of Biomaterials, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812−8582, Japan
- Department
of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812−8582, Japan
| | - Ahmad Nazir Taleb Alashkar
- Department
of Biomaterials, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812−8582, Japan
| | - Cheng Zhang
- Department
of Biomaterials, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812−8582, Japan
| | - Ryo Kishida
- Department
of Biomaterials, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812−8582, Japan
| | - Yasuharu Nakashima
- Department
of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812−8582, Japan
| | - Kunio Ishikawa
- Department
of Biomaterials, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812−8582, Japan
| |
Collapse
|
|
6
|
Oliveira JP, Mendes JC, Fonseca F. Fresh osteochondral allograft transplantation of the medial femoral condyle in an elite football player. BMJ Case Rep 2024; 17:e262374. [PMID: 39694644 DOI: 10.1136/bcr-2024-262374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2024] Open
Abstract
We present an elite footballer in his 20s with a large and symptomatic osteochondral lesion of the weight-bearing area of the medial femoral condyle, who was proposed for a single plug fresh osteochondral allograft transplantation. The lesion was due to repetitive micro traumas and had become highly symptomatic being responsible for making the football practice at a professional level almost impossible, reaching a point that keeping an elite sports career was compromised. Six months after surgery, the athlete returned to sports and, at a 3-year follow-up, still participated in elite high-level football, with a Tegner Activity Scale 10/10, IKDC 93.1, KOOS 97 and Lysholm Scoring 100.
Collapse
Affiliation(s)
- João Pedro Oliveira
- University of Coimbra Faculty of Medicine, Coimbra, Coimbra, Portugal
- Orthopaedic Department, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal
| | - João Castro Mendes
- Orthopaedic Department, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal
| | - Fernando Fonseca
- University of Coimbra Faculty of Medicine, Coimbra, Coimbra, Portugal
- Orthopaedic Department, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal
| |
Collapse
|
|
7
|
Liu Y, Li S, Zhu J, Fan L, Wang L. Rapid preparation of injectable dual-network hydrogels for biomedical applications using UV-triggered sulfhydryl click reactions. Colloids Surf B Biointerfaces 2024; 244:114180. [PMID: 39217728 DOI: 10.1016/j.colsurfb.2024.114180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 08/21/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
The use of hydrogels to mimic natural cartilage implantation can effectively solve the current problems of insufficient cartilage donors and low rate of injury healing. In particular, injectable hydrogels are less invasive in clinical applications and better able to fill uneven injury surfaces. Here, we prepared NorCS and CS-SH by modifying chitosan with 5-norbornene-2-carboxylic acid and N-Acetyl-L-cysteine, respectively. Dual-network hydrogels were prepared by using UV-triggered thiol-ene click reaction between NorCS and CS-SH and the metal coordination between SA and Ca2+. The prepared hydrogels can be cross-linked quickly and exhibit excellent degradability, self-healing and injectable properties. At the same time, the hydrogel also showed good cytocompatibility and could significantly restore the motor function of mice. This study provides an effective strategy for preparing injectable hydrogels capable of rapid cross-linking.
Collapse
Affiliation(s)
- Yanhao Liu
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, PR China
| | - Shubin Li
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, PR China
| | - Jiang Zhu
- Department of Orthopedics, The First Affifiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin 150001, PR China
| | - Lili Fan
- State Key Laboratory of Black Soils Conservation and Utilization, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun 130102, PR China
| | - Lu Wang
- State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin 150090, PR China.
| |
Collapse
|
|
8
|
Birkenes T, Furnes O, Laastad Lygre SH, Solheim E, Aaroen A, Knutsen G, Drogset JO, Heir S, Engebretsen L, Loken S, Visnes H. Long-Term Outcomes of Arthroscopically Verified Focal Cartilage Lesions in the Knee: A 19-Year Multicenter Follow-up with Patient-Reported Outcomes. J Bone Joint Surg Am 2024; 106:1991-2000. [PMID: 39283959 PMCID: PMC11548812 DOI: 10.2106/jbjs.23.00568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2024]
Abstract
BACKGROUND Focal cartilage lesions (FCLs) are frequently found during knee arthroscopies and may impair quality of life (QoL) significantly. Several treatment options with good short-term results are available, but the natural history without any treatment is largely unknown. The aim of this study was to evaluate patient-reported outcome measures (PROMs), the need for subsequent cartilage surgery, and the risk of treatment failure 20 years after diagnosis of an FCL in the knee. METHODS Patients undergoing any knee arthroscopy for an FCL between 1999 and 2012 in 6 major Norwegian hospitals were identified. Inclusion criteria were an arthroscopically classified FCL in the knee, patient age of ≥18 years at surgery, and any preoperative PROM. Exclusion criteria were lesions representing knee osteoarthritis or "kissing lesions" at surgery. Demographic data, later knee surgery, and PROMs were collected by questionnaire. Regression models were used to adjust for and evaluate the factors impacting the long-term PROMs and risk factors for treatment failure (defined as knee arthroplasty, osteotomy, or a Knee injury and Osteoarthritis Outcome Score-Quality of Life [KOOS QoL] subscore of <50). RESULTS Of the 553 eligible patients, 322 evaluated patients (328 knees) were included and analyzed. The mean follow-up was 19.1 years, and the mean age at index FCL surgery was 36.8 years (95% confidence interval [CI], 35.6 to 38.0 years). The patients without knee arthroplasty or osteotomy had significantly better mean PROMs (pain, Lysholm, and KOOS) at the time of final follow-up than preoperatively. At the time of follow-up, 17.7% of the knees had undergone subsequent cartilage surgery. Nearly 50% of the patients had treatment failure, and the main risk factors were a body mass index of ≥25 kg/m 2 (odds ratio [OR] for overweight patients, 2.0 [95% CI, 1.1 to 3.6]), >1 FCL (OR, 1.9 [CI, 1.1 to 3.3]), a full-thickness lesion (OR, 2.5 [95% CI, 1.3 to 5.0]), and a lower level of education (OR, 1.8 [95% Cl, 1.1 to 2.8]). Autologous chondrocyte implantation (ACI) was associated with significantly higher KOOS QoL, by 17.5 (95% CI, 3.2 to 31.7) points, and a lower risk of treatment failure compared with no cartilage treatment, microfracture, or mosaicplasty. CONCLUSIONS After a mean follow-up of 19 years, patients with an FCL who did not require a subsequent knee arthroplasty had significantly higher PROM scores than preoperatively. Nonsurgical treatment of FCLs had results equal to those of the surgical FCL treatments except for ACI, which was associated with a better KOOS and lower risk of treatment failure. Full-thickness lesions, >1 FCL, a lower level of education, and a greater BMI were the main risk factors associated with poorer results. LEVEL OF EVIDENCE Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.
Collapse
Affiliation(s)
- Thomas Birkenes
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
- Sports Traumatology and Arthroscopy Research Group, Bergen, Norway
| | - Ove Furnes
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
- Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
| | - Stein Haakon Laastad Lygre
- Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
- Department of Occupational Medicine, Haukeland University Hospital, Bergen, Norway
| | - Eirik Solheim
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Asbjorn Aaroen
- University of Oslo, Oslo, Norway
- Akershus University Hospital, Lorenskog, Norway
- Oslo Sports Trauma Research Center, Oslo, Norway
| | | | - Jon Olav Drogset
- Trondheim University Hospital, Trondheim, Norway
- Norwegian University of Science and Technology, Trondheim, Norway
- Norwegian Knee Ligament Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
| | - Stig Heir
- Martina Hansen Hospital, Bæerum, Norway
| | - Lars Engebretsen
- University of Oslo, Oslo, Norway
- Oslo Sports Trauma Research Center, Oslo, Norway
- Oslo University Hospital, Oslo, Norway
| | | | - Haavard Visnes
- Oslo Sports Trauma Research Center, Oslo, Norway
- Norwegian Knee Ligament Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
- Hospital of Southern Norway, Kristiansand, Norway
| |
Collapse
|
|
9
|
Mason TW, Gwilt MS, Glover MA, Villa RS, van der List JP, Trasolini NA, Waterman BR. Rates and predictors of reimplantation of matrix-induced autologous chondrocyte implantation following first stage cartilage harvest: A cohort study. Knee 2024; 48:257-264. [PMID: 38788308 DOI: 10.1016/j.knee.2024.04.006] [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] [Received: 01/04/2024] [Revised: 02/21/2024] [Accepted: 04/29/2024] [Indexed: 05/26/2024]
Abstract
PURPOSE To assess the reimplantation rate and predictors of patients requiring second-staged matrix-induced autologous chondrocyte implantation (MACI) reimplantation after initial first stage cartilage biopsy. METHODS A retrospective review was performed from 2018 to 2022 among patients who underwent only phase I MACI biopsy procedure (biopsy group) or both phase I with transition to phase II implantation of chondrocytes (implantation group) at a single tertiary center. Demographic, qualitative, and quantitative measurements were recorded, and univariate and multivariate regression analysis was performed to assess predictors of ultimately requiring second stage MACI implantation. RESULTS A total of 71 patients (51% female, age 27.7 ± 10.6 years (range 12-50)) were included in this study. Eventually, 25 of 71 patients (35.2%) experienced persistence of symptoms after initial MACI biopsy and other concomitant procedures, requiring second-stage implantation. Univariate analysis showed the implantation group compared to the biopsy group had a greater lesion size (5.2 cm2 ± 3.3 vs. 3.3 cm2 ± 1.4, p = 0.024), a higher proportion patients ≥ 26 years of age (76% vs. 43%, p = 0.009), a medial femoral condyle lesion more commonly (33% vs 11%, p = 0.005), were more often female (72% vs. 39%, p = 0.008), and had less often soft tissue repair at time of biopsy (32% vs. 61%, p = 0.020). Backward multivariate logistic regression analysis revealed that size of the lesion (OR 1.43, p = 0.031) and age ≥ 26 years old at time of biopsy (OR 3.55, p = 0.042) were independent predictors of not responding to initial surgery and requiring implantation surgery. CONCLUSION This study found that 35% of patients undergoing MACI phase I biopsy harvest eventually required autologous implantation. Independent risk factors for progressing to implantation after failed initial surgery were larger defect size and older age. LEVEL OF EVIDENCE III, Cohort Study.
Collapse
Affiliation(s)
- Thomas W Mason
- Wake Forest University School of Medicine, Winston-Salem, NC, United States of America.
| | - Matthew S Gwilt
- Wake Forest University School of Medicine, Winston-Salem, NC, United States of America
| | - Mark A Glover
- Wake Forest University School of Medicine, Winston-Salem, NC, United States of America
| | - Richard S Villa
- Wake Forest University School of Medicine, Winston-Salem, NC, United States of America
| | - Jelle P van der List
- Atrium Health Wake Forest Baptist, Department of Orthopaedic Surgery and Rehabilitation, Winston-Salem, NC, United States of America
| | - Nicholas A Trasolini
- Wake Forest University School of Medicine, Winston-Salem, NC, United States of America; Atrium Health Wake Forest Baptist, Department of Orthopaedic Surgery and Rehabilitation, Winston-Salem, NC, United States of America
| | - Brian R Waterman
- Wake Forest University School of Medicine, Winston-Salem, NC, United States of America; Atrium Health Wake Forest Baptist, Department of Orthopaedic Surgery and Rehabilitation, Winston-Salem, NC, United States of America
| |
Collapse
|
|
10
|
Epanomeritakis IE, Khan WS. Adipose-derived regenerative therapies for the treatment of knee osteoarthritis. World J Stem Cells 2024; 16:324-333. [PMID: 38690511 PMCID: PMC11056639 DOI: 10.4252/wjsc.v16.i4.324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 02/15/2024] [Accepted: 03/01/2024] [Indexed: 04/25/2024] Open
Abstract
Knee osteoarthritis is a degenerative condition with a significant disease burden and no disease-modifying therapy. Definitive treatment ultimately requires joint replacement. Therapies capable of regenerating cartilage could significantly reduce financial and clinical costs. The regenerative potential of mesenchymal stromal cells (MSCs) has been extensively studied in the context of knee osteoarthritis. This has yielded promising results in human studies, and is likely a product of immunomodulatory and chondroprotective biomolecules produced by MSCs in response to inflammation. Adipose-derived MSCs (ASCs) are becoming increasingly popular owing to their relative ease of isolation and high proliferative capacity. Stromal vascular fraction (SVF) and micro-fragmented adipose tissue (MFAT) are produced by the enzymatic and mechanical disruption of adipose tissue, respectively. This avoids expansion of isolated ASCs ex vivo and their composition of heterogeneous cell populations, including immune cells, may potentiate the reparative function of ASCs. In this editorial, we comment on a multicenter randomized trial regarding the efficacy of MFAT in treating knee osteoarthritis. We discuss the study's findings in the context of emerging evidence regarding adipose-derived regenerative therapies. An underlying mechanism of action of ASCs is proposed while drawing important distinctions between the properties of isolated ASCs, SVF, and MFAT.
Collapse
Affiliation(s)
- Ilias E Epanomeritakis
- Division of Trauma and Orthopaedic Surgery, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Wasim S Khan
- Division of Trauma and Orthopaedic Surgery, Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
| |
Collapse
|
|
11
|
Muthu S, Viswanathan VK, Sakthivel M, Thabrez M. Does progress in microfracture techniques necessarily translate into clinical effectiveness? World J Orthop 2024; 15:266-284. [PMID: 38596189 PMCID: PMC10999967 DOI: 10.5312/wjo.v15.i3.266] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 12/21/2023] [Accepted: 01/23/2024] [Indexed: 03/15/2024] Open
Abstract
BACKGROUND Multitudinous advancements have been made to the traditional microfracture (MFx) technique, which have involved delivery of various acellular 2nd generation MFx and cellular MFx-III components to the area of cartilage defect. The relative benefits and pitfalls of these diverse modifications of MFx technique are still not widely understood. AIM To comparatively analyze the functional, radiological, and histological outcomes, and complications of various generations of MFx available for the treatment of cartilage defects. METHODS A systematic review was performed using PubMed, EMBASE, Web of Science, Cochrane, and Scopus. Patients of any age and sex with cartilage defects undergoing any form of MFx were considered for analysis. We included only randomized controlled trials (RCTs) reporting functional, radiological, histological outcomes or complications of various generations of MFx for the management of cartilage defects. Network meta-analysis (NMA) was conducted in Stata and Cochrane's Confidence in NMA approach was utilized for appraisal of evidence. RESULTS Forty-four RCTs were included in the analysis with patients of mean age of 39.40 (± 9.46) years. Upon comparing the results of the other generations with MFX-I as a constant comparator, we noted a trend towards better pain control and functional outcome (KOOS, IKDC, and Cincinnati scores) at the end of 1-, 2-, and 5-year time points with MFx-III, although the differences were not statistically significant (P > 0.05). We also noted statistically significant Magnetic resonance observation of cartilage repair tissue score in the higher generations of microfracture (weighted mean difference: 17.44, 95% confidence interval: 0.72, 34.16, P = 0.025; without significant heterogeneity) at 1 year. However, the difference was not maintained at 2 years. There was a trend towards better defect filling on MRI with the second and third generation MFx, although the difference was not statistically significant (P > 0.05). CONCLUSION The higher generations of traditional MFx technique utilizing acellular and cellular components to augment its potential in the management of cartilage defects has shown only marginal improvement in the clinical and radiological outcomes.
Collapse
Affiliation(s)
- Sathish Muthu
- Department of Orthopaedics, Orthopaedic Research Group, Coimbatore 641045, Tamil Nadu, India
- Department of Biotechnology, Karpagam Academy of Higher Education, Coimbatore 641021, Tamil Nadu, India
- Department of Orthopaedics, Government Medical College, Karur 639004, Tamil Nadu, India
| | | | - Manoharan Sakthivel
- Department of Orthopaedics, Government Medical College, Karur 639004, Tamil Nadu, India
| | - Mohammed Thabrez
- Department of Medical Oncology, Aster Medcity Hospital, Kochi 682034, India
| |
Collapse
|
|
12
|
Shan BH, Wu FG. Hydrogel-Based Growth Factor Delivery Platforms: Strategies and Recent Advances. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2210707. [PMID: 37009859 DOI: 10.1002/adma.202210707] [Citation(s) in RCA: 119] [Impact Index Per Article: 119.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 03/25/2023] [Indexed: 06/19/2023]
Abstract
Growth factors play a crucial role in regulating a broad variety of biological processes and are regarded as powerful therapeutic agents in tissue engineering and regenerative medicine in the past decades. However, their application is limited by their short half-lives and potential side effects in physiological environments. Hydrogels are identified as having the promising potential to prolong the half-lives of growth factors and mitigate their adverse effects by restricting them within the matrix to reduce their rapid proteolysis, burst release, and unwanted diffusion. This review discusses recent progress in the development of growth factor-containing hydrogels for various biomedical applications, including wound healing, brain tissue repair, cartilage and bone regeneration, and spinal cord injury repair. In addition, the review introduces strategies for optimizing growth factor release including affinity-based delivery, carrier-assisted delivery, stimuli-responsive delivery, spatial structure-based delivery, and cellular system-based delivery. Finally, the review presents current limitations and future research directions for growth factor-delivering hydrogels.
Collapse
Affiliation(s)
- Bai-Hui Shan
- State Key Laboratory of Digital Medical Engineering Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, 2 Sipailou Road, Nanjing, 210096, P. R. China
| | - Fu-Gen Wu
- State Key Laboratory of Digital Medical Engineering Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, 2 Sipailou Road, Nanjing, 210096, P. R. China
| |
Collapse
|
|
13
|
Jonidi Shariatzadeh F, Solouk A, Mirzadeh H, Bonakdar S, Sadeghi D, Khoulenjani SB. Cellulose nanocrystals-reinforced dual crosslinked double network GelMA/hyaluronic acid injectable nanocomposite cryogels with improved mechanical properties for cartilage tissue regeneration. J Biomed Mater Res B Appl Biomater 2024; 112:e35346. [PMID: 38359175 DOI: 10.1002/jbm.b.35346] [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: 05/09/2023] [Revised: 09/04/2023] [Accepted: 10/14/2023] [Indexed: 02/17/2024]
Abstract
Improvement of mechanical properties of injectable tissue engineering scaffolds is a current challenge. The objective of the current study is to produce a highly porous injectable scaffold with improved mechanical properties. For this aim, cellulose nanocrystals-reinforced dual crosslinked porous nanocomposite cryogels were prepared using chemically crosslinked methacrylated gelatin (GelMA) and ionically crosslinked hyaluronic acid (HA) through the cryogelation process. The resulting nanocomposites showed highly porous structures with interconnected porosity (>90%) and mean pore size in the range of 130-296 μm. The prepared nanocomposite containing 3%w/v of GelMA, 20 w/w% of HA, and 1%w/v of CNC showed the highest Young's modulus (10 kPa) and excellent reversibility after 90% compression and could regain its initial shape after injection by a 16-gauge needle in the aqueous media. The in vitro results demonstrated acceptable viability (>90%) and migration of the human chondrocyte cell line (C28/I2), and chondrogenic differentiation of human adipose stem cells. A two-month in vivo assay on a rabbit's ear model confirmed that the regeneration potential of the prepared cryogel is comparable to the natural autologous cartilage graft, suggesting it is a promising alternative for autografts in the treatment of cartilage defects.
Collapse
Affiliation(s)
| | - Atefeh Solouk
- Biomedical Engineering Department, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | - Hamid Mirzadeh
- Biomedical Engineering Department, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
- Polymer and Color Engineering Department, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | - Shahin Bonakdar
- National Cell Bank Department, Pasteur Institute of Iran, Tehran, Iran
| | - Davoud Sadeghi
- Biomedical Engineering Department, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | - Shadab Bagheri Khoulenjani
- Polymer and Color Engineering Department, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| |
Collapse
|
|
14
|
Birkenes T, Furnes O, Lygre SHL, Solheim E, Årøen A, Knutsen G, Drogset JO, Heir S, Engebretsen L, Løken S, Visnes H. Previous cartilage surgery is associated with inferior patient-reported outcomes after knee arthroplasty. Knee Surg Sports Traumatol Arthrosc 2024; 32:361-370. [PMID: 38294966 DOI: 10.1002/ksa.12050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/19/2023] [Accepted: 12/24/2023] [Indexed: 02/02/2024]
Abstract
PURPOSE The hypothesis of the present study assumed that a history of focal cartilage lesions would not affect Knee Injury and Osteoarthritis Outcome scores (KOOSs) following knee arthroplasty compared to a matched national cohort of knee arthroplasty patients. METHODS Fifty-eight knee arthroplasty patients with previous surgery for focal cartilage lesions (cartilage cohort) were compared to a matched cohort of 116 knee arthroplasty patients from the Norwegian Arthroplasty Register (control group). Age, sex, primary or revision arthroplasty, type of arthroplasty (total, unicondylar or patellofemoral), year of arthroplasty surgery and arthroplasty brand were used as matching criteria. Demographic data and KOOS were obtained through questionnaires. Regression models were employed to adjust for confounding factors. RESULTS Mean follow-up post knee arthroplasty surgery was 7.6 years (range 1.2-20.3) in the cartilage cohort and 8.1 (range 1.0-20.9) in the control group. The responding patients were at the time of surgery 54.3 versus 59.0 years in the cartilage and control group, respectively. At follow-up the control group demonstrated higher adjusted Knee Injury and Osteoarthritis Outcome subscores than the previous focal cartilage patients with a mean adjusted difference (95% confidence interval in parentheses): Symptoms 8.4 (0.3, 16.4), Pain 11.8 (2.2, 21.4), Activities of daily living (ADL) 9.3 (-1.2, 18.6), Sport and recreation 8.9 (-1.6, 19.4) and Quality of Life (QoL) 10.6 (0.2, 21.1). The control group also demonstrated higher odds of reaching the patient-acceptable symptom state threshold for the Knee Injury and Osteoarthritis Outcome subscores with odds ratio: Symptoms 2.7 (1.2, 6.4), Pain 3.0 (1.3, 7.0), ADL 2.1 (0.9, 4.6) and QoL 2.4 (1.0, 5.5). CONCLUSION Previous cartilage surgery was associated with inferior patient-reported outcomes after knee arthroplasty. These patients also exhibited significantly lower odds of reaching the patient-acceptable symptom state threshold for the Knee Injury and Osteoarthritis Outcome subscores. LEVEL OF EVIDENCE Level III.
Collapse
Affiliation(s)
- Thomas Birkenes
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
- Sports Traumatology and Arthroscopy Research Group, Bergen, Norway
| | - Ove Furnes
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
- Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
| | - Stein Håkon Låstad Lygre
- Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
- Department of Occupational Medicine, Haukeland University Hospital, Bergen, Norway
| | - Eirik Solheim
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Asbjørn Årøen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Akershus University Hospital, Lorenskog, Norway
- Oslo Sports Trauma Research Center, Oslo, Norway
| | | | - Jon Olav Drogset
- Trondheim University Hospital, Trondheim, Norway
- Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway
- Norwegian Knee Ligament Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
| | - Stig Heir
- Martina Hansen Hospital, Baerum, Norway
| | - Lars Engebretsen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Oslo Sports Trauma Research Center, Oslo, Norway
- Oslo University Hospital, Oslo, Norway
| | | | - Håvard Visnes
- Oslo Sports Trauma Research Center, Oslo, Norway
- Norwegian Knee Ligament Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
- Hospital of Southern Norway, Kristiansand, Norway
| |
Collapse
|
|
15
|
Peláez-Gorrea P, Damiá-Giménez E, Rubio-Zaragoza M, Cuervo-Serrato B, Hernández-Guerra ÁM, Miguel-Pastor L, Del Romero-Martínez A, Sopena-Juncosa J, Torres-Torrillas M, Santana A, Cugat-Bertomeu R, Vilar-Guereño JM, Carrillo-Poveda JM. The autologous chondral platelet-rich plasma matrix implantation. A new therapy in cartilage repair and regeneration: macroscopic and biomechanical study in an experimental sheep model. Front Vet Sci 2023; 10:1223825. [PMID: 38146499 PMCID: PMC10749322 DOI: 10.3389/fvets.2023.1223825] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 11/17/2023] [Indexed: 12/27/2023] Open
Abstract
Introduction Articular cartilage injuries are a severe problem, and the treatments for these injuries are complex. The present study investigates a treatment for full-thickness cartilage defects called Autologous Chondral Platelet Rich Plasma Matrix Implantation (PACI) in a sheep model. Methods Chondral defects 8 mm in diameter were surgically induced in the medial femoral condyles of both stifles in eight healthy sheep. Right stifles were treated with PACI and an intraarticular injection with a plasma rich in growth factors (PRGF) solution [treatment group (TRT)], while an intraarticular injection of Ringer's lactate solution was administered in left stifles [Control group (CT)]. The limbs' function was objectively assessed with a force platform to obtain the symmetry index, comparing both groups. After 9 and 18 months, the lesions were macroscopically evaluated using the International Cartilage Repair Society and Goebel scales. Results Regarding the symmetry index, the TRT group obtained results similar to those of healthy limbs at 9 and 18 months after treatment. Regarding the macroscopic assessment, the values obtained by the TRT group were very close to those of normal cartilage and superior to those obtained by the CT group at 9 months. Conclusion This new bioregenerative treatment modality can regenerate hyaline articular cartilage. High functional outcomes have been reported, together with a good quality repair tissue in sheep. Therefore, PACI treatment might be a good therapeutic option for full-thickness chondral lesions.
Collapse
Affiliation(s)
- Pau Peláez-Gorrea
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
- García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
| | - Elena Damiá-Giménez
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
- García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
| | - Mónica Rubio-Zaragoza
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
- García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
| | - Belén Cuervo-Serrato
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
- García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
| | - Ángel María Hernández-Guerra
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
- García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
| | - Laura Miguel-Pastor
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
- García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
| | - Ayla Del Romero-Martínez
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
- García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
| | - Joaquín Sopena-Juncosa
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
- García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
| | - Marta Torres-Torrillas
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
- García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
| | - Angelo Santana
- Departament of Mathematics, Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
| | - Ramón Cugat-Bertomeu
- García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
| | - José Manuel Vilar-Guereño
- García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
- Department of Animal Pathology, Instituto Universitario de Investigaciones Biomédicas y Sanitarias, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Jose Maria Carrillo-Poveda
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
- García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU-Cardenal Herrera University, CEU Universities, Valencia, Spain
| |
Collapse
|
|
16
|
Omoumi P, Mourad C, Ledoux JB, Hilbert T. Morphological assessment of cartilage and osteoarthritis in clinical practice and research: Intermediate-weighted fat-suppressed sequences and beyond. Skeletal Radiol 2023; 52:2185-2198. [PMID: 37154871 PMCID: PMC10509097 DOI: 10.1007/s00256-023-04343-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 03/28/2023] [Accepted: 04/10/2023] [Indexed: 05/10/2023]
Abstract
Magnetic resonance imaging (MRI) is widely regarded as the primary modality for the morphological assessment of cartilage and all other joint tissues involved in osteoarthritis. 2D fast spin echo fat-suppressed intermediate-weighted (FSE FS IW) sequences with a TE between 30 and 40ms have stood the test of time and are considered the cornerstone of MRI protocols for clinical practice and trials. These sequences offer a good balance between sensitivity and specificity and provide appropriate contrast and signal within the cartilage as well as between cartilage, articular fluid, and subchondral bone. Additionally, FS IW sequences enable the evaluation of menisci, ligaments, synovitis/effusion, and bone marrow edema-like signal changes. This review article provides a rationale for the use of FSE FS IW sequences in the morphological assessment of cartilage and osteoarthritis, along with a brief overview of other clinically available sequences for this indication. Additionally, the article highlights ongoing research efforts aimed at improving FSE FS IW sequences through 3D acquisitions with enhanced resolution, shortened examination times, and exploring the potential benefits of different magnetic field strengths. While most of the literature on cartilage imaging focuses on the knee, the concepts presented here are applicable to all joints. KEY POINTS: 1. MRI is currently considered the modality of reference for a "whole-joint" morphological assessment of osteoarthritis. 2. Fat-suppressed intermediate-weighted sequences remain the keystone of MRI protocols for the assessment of cartilage morphology, as well as other structures involved in osteoarthritis. 3. Trends for further development in the field of cartilage and joint imaging include 3D FSE imaging, faster acquisition including AI-based acceleration, and synthetic imaging providing multi-contrast sequences.
Collapse
Affiliation(s)
- Patrick Omoumi
- Department of Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
| | - Charbel Mourad
- Department of Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Department of Diagnostic and Interventional Radiology, Hôpital Libanais Geitaoui CHU, Achrafieh, Beyrouth, Lebanon
| | - Jean-Baptiste Ledoux
- Department of Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Tom Hilbert
- Department of Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Advanced Clinical Imaging Technology, Siemens Healthineers International AG, Lausanne, Switzerland
- LTS5, École Polytechnique FÉdÉrale de Lausanne (EPFL), Lausanne, Switzerland
| |
Collapse
|
|
17
|
Niemeyer P, Angele P, Spiro RC, Kirner A, Gaissmaier C. Comparison of Hydrogel-Based Autologous Chondrocyte Implantation Versus Microfracture: A Propensity Score Matched-Pair Analysis. Orthop J Sports Med 2023; 11:23259671231193325. [PMID: 37655236 PMCID: PMC10467419 DOI: 10.1177/23259671231193325] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 05/04/2023] [Indexed: 09/02/2023] Open
Abstract
Background Few studies exist for large defects comparing matrix-associated autologous chondrocyte implantation (M-ACI) with other cartilage repair methods due to the limited availability of suitable comparator treatments. Purpose To compare the clinical efficacy of a novel hydrogel-based M-ACI method (NOVOCART Inject plus) versus microfracture (MFx) in patients with knee cartilage defects. Study Design Cohort study; Level of evidence, 3. Methods Propensity score matched-pair analysis was used to compare the 24-month outcomes between the M-ACI treatment group from a previous single-arm phase 3 study and the MFx control group from another phase 3 study. Patients were matched based on preoperative Knee injury and Osteoarthritis Outcomes Score (KOOS), symptom duration, previous knee surgeries, age, and sex, resulting in 144 patients in the matched-pair set (72 patients per group). The primary endpoint was the change in least-squares means (ΔLSmeans) for the KOOS from baseline to the 24-month assessment. Results Defect sizes in the M-ACI group were significantly larger than in the MFx group (6.4 versus 3.7 cm2). Other differences included defect location (no patellar or tibial defects in the MFx group), number of defects (33.3% with 2 defects in the M-ACI group versus 9.7% in the MFx group), and defect cause (more patients with degenerative lesions in the M-ACI group). The M-ACI group had higher posttreatment KOOS (M-ACI versus MFX: 81.8 ± 16.8 versus 73.0 ± 20.6 points) and KOOS ΔLSmeans from baseline to 24 months posttreatment (M-ACI versus MFX: 36.9 versus 26.9 points). Treatment contrasts in KOOS ΔLSmeans from baseline indicated statistical significance in favor of M-ACI from 3 to 24 months posttreatment (P = .0026). Significant and clinically meaningful differences in favor of M-ACI at 24 months were also found regarding International Knee Documentation Committee (IKDC) score ΔLSmeans from baseline (37.8 versus 30.4 points; P = .0334), KOOS responder rates at 24 months (≥10-point improvement from baseline; 94.4% versus 65.3%; P < .0001), IKDC responder rates at 24 months (>20.5-point improvement from baseline; 83.3% versus 61.1%, P = .0126) and MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) score in a subgroup of patients (LS means, 86.9 versus 69.1; P = .0096). Conclusion In this exploratory analysis, M-ACI using an in situ crosslinked hydrogel demonstrated superior clinical and structural (MOCART) 24-month outcomes compared with MFx in patients with knee cartilage defects.
Collapse
Affiliation(s)
- Philipp Niemeyer
- OCM Orthopädische Chirurgie München, Munich, Germany
- Department of Orthopedics and Trauma Surgery, University Medical Center Freiburg, Albert Ludwig University of Freiburg, Freiburg, Germany
| | - Peter Angele
- Sporthopaedicum Regensburg, Regensburg, Germany
- Department of Trauma Surgery, University Medical Centre Regensburg, Germany
| | | | | | | |
Collapse
|
|
18
|
Anitua E, Prado R, Guadilla J, Alkhraisat MH, Laiz P, Padilla S, García-Balletbó M, Cugat R. The Dual-Responsive Interaction of Particulated Hyaline Cartilage and Plasma Rich in Growth Factors (PRGF) in the Repair of Cartilage Defects: An In Vitro Study. Int J Mol Sci 2023; 24:11581. [PMID: 37511339 PMCID: PMC10380225 DOI: 10.3390/ijms241411581] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/10/2023] [Accepted: 07/15/2023] [Indexed: 07/30/2023] Open
Abstract
The treatment of chondral and osteochondral defects is challenging. These types of lesions are painful and progress to osteoarthritis over time. Tissue engineering offers tools to address this unmet medical need. The use of an autologous cartilage construct consisting of hyaline cartilage chips embedded in plasma rich in growth factors (PRGF) has been proposed as a therapeutic alternative. The purpose of this study was to dig into the potential mechanisms behind the in vitro remodelling process that might explain the clinical success of this technique and facilitate its optimisation. Chondrocyte viability and cellular behaviour over eight weeks of in vitro culture, type II collagen synthesis, the dual delivery of growth factors by hyaline cartilage and PRGF matrix, and the ultrastructure of the construct and its remodelling were characterised. The main finding of this research is that the cartilage fragments embedded in the three-dimensional PRGF scaffold contain viable chondrocytes that are able to migrate into the fibrin network, proliferate and synthesise extracellular matrix after the second week of in vitro culture. The characterization of this three-dimensional matrix is key to unravelling the molecular kinetics responsible for its efficacy.
Collapse
Affiliation(s)
- Eduardo Anitua
- Eduardo Anitua Foundation for Biomedical Research, 01007 Vitoria, Spain
- Regenerative Medicine Laboratory, BTI-Biotechnology Institute IMASD, 01007 Vitoria, Spain
- University Institute for Regenerative Medicine & Oral Implantology-UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria, Spain
| | - Roberto Prado
- Eduardo Anitua Foundation for Biomedical Research, 01007 Vitoria, Spain
- Regenerative Medicine Laboratory, BTI-Biotechnology Institute IMASD, 01007 Vitoria, Spain
- University Institute for Regenerative Medicine & Oral Implantology-UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria, Spain
| | - Jorge Guadilla
- Osakidetza Basque Health Service, Araba University Hospital, 01009 Vitoria, Spain
- Arthroscopic Surgery Unit, Hospital Vithas Vitoria, 01008 Vitoria, Spain
- Department of Surgery and Radiology and Physical Medicine, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 01006 Vitoria, Spain
| | - Mohammad H Alkhraisat
- Eduardo Anitua Foundation for Biomedical Research, 01007 Vitoria, Spain
- Regenerative Medicine Laboratory, BTI-Biotechnology Institute IMASD, 01007 Vitoria, Spain
- University Institute for Regenerative Medicine & Oral Implantology-UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria, Spain
| | - Patricia Laiz
- Fundación García Cugat para Investigación Biomédica, 08023 Barcelona, Spain
- Instituto Cugat, Hospital Quirónsalud, 08023 Barcelona, Spain
| | - Sabino Padilla
- Eduardo Anitua Foundation for Biomedical Research, 01007 Vitoria, Spain
- Regenerative Medicine Laboratory, BTI-Biotechnology Institute IMASD, 01007 Vitoria, Spain
- University Institute for Regenerative Medicine & Oral Implantology-UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria, Spain
| | - Montserrat García-Balletbó
- Fundación García Cugat para Investigación Biomédica, 08023 Barcelona, Spain
- Instituto Cugat, Hospital Quirónsalud, 08023 Barcelona, Spain
| | - Ramón Cugat
- Fundación García Cugat para Investigación Biomédica, 08023 Barcelona, Spain
- Instituto Cugat, Hospital Quirónsalud, 08023 Barcelona, Spain
- Mutualidad de Futbolistas Españoles, Delegación Catalana, 08010 Barcelona, Spain
| |
Collapse
|
|
19
|
Seewoonarain S, Ganesh D, Perera E, Popat R, Jones J, Sugand K, Gupte C. Scaffold-associated procedures are superior to microfracture in managing focal cartilage defects in the knee: A systematic review & meta-analysis. Knee 2023; 42:320-338. [PMID: 37148615 DOI: 10.1016/j.knee.2023.04.001] [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] [Received: 07/23/2022] [Revised: 01/10/2023] [Accepted: 04/02/2023] [Indexed: 05/08/2023]
Abstract
BACKGROUND Debate continues as to whether surgical treatment with chondral-regeneration devices is superior to microfracture for focal articular cartilage defects in the knee. PURPOSE To evaluate the superiority of scaffold-associated chondral-regeneration procedures over microfracture by assessing: (1) Patient-reported outcomes; (2) Intervention failure; (3) Histological quality of cartilage repair. STUDY DESIGN A three-concept keyword search strategy was designed, in accordance with PRISMA guidelines: (i) knee (ii) microfracture (iii) scaffold. Four databases (Ovid Medline, Embase, CINAHL and Scopus) were searched for comparative clinical trials (Level I-III evidence). Critical appraisal used two Cochrane tools: the Risk of Bias tool (RoB2) for randomized control trials and the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I). Study heterogeneity permitted qualitative analysis with the exception of three patient-reported scores, for which a meta-analysis was performed. RESULTS Twenty-one studies were identified (1699 patients, age range 18-66 years): ten randomized control trials and eleven non-randomized study interventions. Meta-analyses of the International Knee Documentation Committee (IKDC), Knee Injury And Osteoarthritis Outcome Score (KOOS) for pain and activities of daily living, and Lysholm score demonstrated statistically significant improvement in outcomes for scaffold procedures compared to microfracture at two years. No statistical difference was seen at five years. CONCLUSION Despite the limitations of study heterogeneity, scaffold-associated procedures appear to be superior to MF in terms of patient-reported outcomes at two years though similar at five years. Future evaluation would benefit from studies using validated clinical scoring systems, reporting failure, adverse events and long-term clinical follow up to determine technique safety and superiority.
Collapse
Affiliation(s)
- Sheena Seewoonarain
- MsK Lab, Dept of Medicine and Surgery, Sir Michael Uren Hub, Imperial College, London W12 0BZ, United Kingdom
| | - Divolka Ganesh
- MsK Lab, Dept of Medicine and Surgery, Sir Michael Uren Hub, Imperial College, London W12 0BZ, United Kingdom.
| | - Edward Perera
- MsK Lab, Dept of Medicine and Surgery, Sir Michael Uren Hub, Imperial College, London W12 0BZ, United Kingdom.
| | - Ravi Popat
- MsK Lab, Dept of Medicine and Surgery, Sir Michael Uren Hub, Imperial College, London W12 0BZ, United Kingdom.
| | - Julian Jones
- MsK Lab, Dept of Medicine and Surgery, Sir Michael Uren Hub, Imperial College, London W12 0BZ, United Kingdom.
| | - Kapil Sugand
- MsK Lab, Dept of Medicine and Surgery, Sir Michael Uren Hub, Imperial College, London W12 0BZ, United Kingdom.
| | - Chinmay Gupte
- MsK Lab, Dept of Medicine and Surgery, Sir Michael Uren Hub, Imperial College, London W12 0BZ, United Kingdom.
| |
Collapse
|
|
20
|
Sahin N, Yesil H. Regenerative methods in osteoarthritis. Best Pract Res Clin Rheumatol 2023; 37:101824. [PMID: 37244803 DOI: 10.1016/j.berh.2023.101824] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 04/21/2023] [Indexed: 05/29/2023]
Abstract
Osteoarthritis (OA) is the most common type of arthritis that can affect all joint structures. The primary goals of osteoarthritis treatment are to alleviate pain, reduce functional limitations, and improve quality of life. Despite its high prevalence, treatment options for osteoarthritis are limited, with most therapeutic approaches focusing on symptom management. Tissue engineering and regenerative strategies based on biomaterials, cells, and other bioactive molecules have emerged as viable options for osteoarthritis cartilage repair. Platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs) are the most commonly used regenerative therapies today to protect, restore, or increase the function of damaged tissues. Despite promising results, there is conflicting evidence regarding the efficacy of regenerative therapies, and their efficacy remains unknown. The data suggest that more research and standardization are required for the use of these therapies in osteoarthritis. This article provides an overview of the application of MSCs and PRP applications.
Collapse
Affiliation(s)
- Nilay Sahin
- Balikesir University, Faculty of Medicine, Physical Medicine and Rehabilitation Department, Balıkesir, Turkey.
| | - Hilal Yesil
- Afyonkarahisar Health Sciences University, Faculty of Medicine, Physical Medicine and Rehabilitation Department, Afyon, Turkey.
| |
Collapse
|
|
21
|
Birkenes T, Furnes O, Laastad Lygre SH, Solheim E, Aaroen A, Knutsen G, Drogset JO, Heir S, Engebretsen L, Loken S, Visnes H. The Long-Term Risk of Knee Arthroplasty in Patients with Arthroscopically Verified Focal Cartilage Lesions: A Linkage Study with the Norwegian Arthroplasty Register, 1999 to 2020. J Bone Joint Surg Am 2023:00004623-990000000-00790. [PMID: 37104554 DOI: 10.2106/jbjs.22.01174] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Abstract
BACKGROUND Focal cartilage lesions are common in the knee. The risk of later ipsilateral knee arthroplasty remains unknown. The purposes of the present study were to evaluate the long-term cumulative risk of knee arthroplasty after arthroscopic identification of focal cartilage lesions in the knee, to investigate the risk factors for subsequent knee arthroplasty, and to estimate the subsequent cumulative risk of knee arthroplasty compared with that in the general population. METHODS Patients who had undergone surgical treatment of focal cartilage lesions at 6 major Norwegian hospitals between 1999 and 2012 were identified. The inclusion criteria were an arthroscopically classified focal cartilage lesion in the knee, an age of ≥18 years at the time of surgery, and available preoperative patient-reported outcomes (PROMs). The exclusion criteria were osteoarthritis or "kissing lesions" at the time of surgery. Demographic data, later knee surgery, and PROMs were collected with use of a questionnaire. A Cox regression model was used to adjust for and investigate the impact of risk factors, and Kaplan-Meier analysis was performed to estimate cumulative risk. The risk of knee arthroplasty in the present cohort was compared with that in the age-matched general Norwegian population. RESULTS Of the 516 patients who were eligible, 322 patients (328 knees) consented to participate. The mean age at the time of the index procedure was 36.8 years, and the mean duration of follow-up was 19.8 years. The 20-year cumulative risk of knee arthroplasty in the cartilage cohort was 19.1% (95% CI, 14.6% to 23.6%). Variables that had an impact on the risk of knee arthroplasty included an ICRS grade of 3 to 4 (hazard ratio [HR], 3.1; 95% CI, 1.1 to 8.7), an age of ≥40 years at time of cartilage surgery (HR, 3.7; 95% CI, 1.8 to 7.7), a BMI of 25 to 29 kg/m2 (HR, 3.9; 95% CI, 1.7 to 9.0), a BMI of ≥30 kg/m2 (HR, 5.9; 95% CI, 2.4 to 14.3) at the time of follow-up, autologous chondrocyte implantation (ACI) at the time of the index procedure (HR, 3.4; 95% CI, 1.0 to 11.4), >1 focal cartilage lesion (HR, 2.1; 95% CI, 1.1 to 3.7), and a high preoperative visual analog scale (VAS) score for pain at the time of the index procedure (HR, 1.1; 95% CI, 1.0 to 1.1). The risk ratio of later knee arthroplasty in the cartilage cohort as compared with the age-matched general Norwegian population was 415.7 (95% CI, 168.8 to 1,023.5) in the 30 to 39-year age group. CONCLUSIONS In the present study, we found that the 20-year cumulative risk of knee arthroplasty after a focal cartilage lesion in the knee was 19%. Deep lesions, higher age at the time of cartilage surgery, high BMI at the time of follow-up, ACI, and >1 cartilage lesion were associated with a higher risk of knee arthroplasty. LEVEL OF EVIDENCE Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Collapse
Affiliation(s)
- Thomas Birkenes
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
- Sports Traumatology and Arthroscopy Research Group, Bergen, Norway
| | - Ove Furnes
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
- Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
| | - Stein Haakon Laastad Lygre
- Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
- Department of Occupational Medicine, Haukeland University Hospital, Bergen, Norway
| | - Eirik Solheim
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Asbjorn Aaroen
- University of Oslo, Oslo, Norway
- Akershus University Hospital, Lorenskog, Norway
- Oslo Sports Trauma Research Center, Oslo, Norway
| | | | - Jon Olav Drogset
- Trondheim University Hospital, Trondheim, Norway
- Norwegian University of Science and Technology, Trondheim, Norway
- Norwegian Knee Ligament Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
| | - Stig Heir
- Martina Hansen Hospital, Baerum, Norway
| | - Lars Engebretsen
- University of Oslo, Oslo, Norway
- Oslo Sports Trauma Research Center, Oslo, Norway
- Oslo University Hospital, Oslo, Norway
| | | | - Haavard Visnes
- Oslo Sports Trauma Research Center, Oslo, Norway
- Norwegian Knee Ligament Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
- Hospital of Southern Norway, Kristiansand, Norway
| |
Collapse
|
|
22
|
Vaiciuleviciute R, Uzieliene I, Bernotas P, Novickij V, Alaburda A, Bernotiene E. Electrical Stimulation in Cartilage Tissue Engineering. Bioengineering (Basel) 2023; 10:bioengineering10040454. [PMID: 37106641 PMCID: PMC10135934 DOI: 10.3390/bioengineering10040454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 03/31/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Electrical stimulation (ES) has been frequently used in different biomedical applications both in vitro and in vivo. Numerous studies have demonstrated positive effects of ES on cellular functions, including metabolism, proliferation, and differentiation. The application of ES to cartilage tissue for increasing extracellular matrix formation is of interest, as cartilage is not able to restore its lesions owing to its avascular nature and lack of cells. Various ES approaches have been used to stimulate chondrogenic differentiation in chondrocytes and stem cells; however, there is a huge gap in systematizing ES protocols used for chondrogenic differentiation of cells. This review focuses on the application of ES for chondrocyte and mesenchymal stem cell chondrogenesis for cartilage tissue regeneration. The effects of different types of ES on cellular functions and chondrogenic differentiation are reviewed, systematically providing ES protocols and their advantageous effects. Moreover, cartilage 3D modeling using cells in scaffolds/hydrogels under ES are observed, and recommendations on reporting about the use of ES in different studies are provided to ensure adequate consolidation of knowledge in the area of ES. This review brings novel insights into the further application of ES in in vitro studies, which are promising for further cartilage repair techniques.
Collapse
Affiliation(s)
- Raminta Vaiciuleviciute
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Santariskiu g. 5, 08410 Vilnius, Lithuania
| | - Ilona Uzieliene
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Santariskiu g. 5, 08410 Vilnius, Lithuania
| | - Paulius Bernotas
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Santariskiu g. 5, 08410 Vilnius, Lithuania
| | - Vitalij Novickij
- Department of Immunology, State Research Institute Centre for Innovative Medicine, Santariškių g. 5, 08410 Vilnius, Lithuania
- Faculty of Electronics, High Magnetic Field Institute, Vilnius Gediminas Technical University, Plytines g. 27, 10105 Vilnius, Lithuania
| | - Aidas Alaburda
- Life Sciences Center, Institute of Biosciences, Vilnius University, Sauletekio al. 7, 10257 Vilnius, Lithuania
| | - Eiva Bernotiene
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Santariskiu g. 5, 08410 Vilnius, Lithuania
- VilniusTech, Faculty of Fundamental Sciences, Sauletekio al. 11, 10223 Vilnius, Lithuania
| |
Collapse
|
|
23
|
Oliveira AS, Silva JC, Loureiro MV, Marques AC, Kotov NA, Colaço R, Serro AP. Super-Strong Hydrogel Composites Reinforced with PBO Nanofibers for Cartilage Replacement. Macromol Biosci 2023; 23:e2200240. [PMID: 36443994 DOI: 10.1002/mabi.202200240] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 10/28/2022] [Indexed: 11/30/2022]
Abstract
Cartilage replacement materials exhibiting a set of demanding properties such as high water content, high mechanical stiffness, low friction, and excellent biocompatibility are quite difficult to achieve. Here, poly(p-phenylene-2,6-benzobisoxazole) (PBO) nanofibers are combined with polyvinyl alcohol (PVA) to form a super-strong structure with a performance that surpasses the vast majority of previously existing hydrogels. PVA-PBO composites with water contents in the 59-76% range exhibit tensile and compressive moduli reaching 20.3 and 4.5 MPa, respectively, and a coefficient of friction below 0.08. Further, they are biocompatible and support the viability of chondrocytes for 1 week, with significant improvements in cell adhesion, proliferation, and differentiation compared to PVA. The new composites can be safely sterilized by steam heat or gamma radiation without compromising their integrity and overall performance. In addition, they show potential to be used as local delivery platforms for anti-inflammatory drugs. These attractive features make PVA-PBO composites highly competitive engineered materials with remarkable potential for use in the design of load-bearing tissues. Complementary work has also revealed that these composites will be interesting alternatives in other industrial fields where high thermal and mechanical resistance are essential requirements, or which can take advantage of the pH responsiveness functionality.
Collapse
Affiliation(s)
- Andreia S Oliveira
- Centro de Química Estrutural, Institute of Molecular Sciences, and Department of Chemical Engineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, Lisbon, 1049-001, Portugal.,Centro de Investigação Interdisciplinar Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, Caparica, 2829-511, Portugal.,Instituto de Engenharia Mecânica and Department of Mechanical Engineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, Lisbon, 1049-001, Portugal
| | - João C Silva
- Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, Lisbon, 1049-001, Portugal.,Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, Lisbon, 1049-001, Portugal.,Centre for Rapid and Sustainable Product Development, Politécnico de Leiria, Rua de Portugal-Zona Industrial, Marinha Grande, 2430-028, Portugal
| | - Mónica V Loureiro
- Centro de Recursos Naturais e Ambiente, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, Lisbon, 1049-001, Portugal
| | - Ana C Marques
- Centro de Recursos Naturais e Ambiente, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, Lisbon, 1049-001, Portugal
| | - Nicholas A Kotov
- Biointerfaces Institute, Department of Chemical Engineering, and Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Rogério Colaço
- Instituto de Engenharia Mecânica and Department of Mechanical Engineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, Lisbon, 1049-001, Portugal
| | - Ana P Serro
- Centro de Química Estrutural, Institute of Molecular Sciences, and Department of Chemical Engineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, Lisbon, 1049-001, Portugal.,Centro de Investigação Interdisciplinar Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, Caparica, 2829-511, Portugal
| |
Collapse
|
|
24
|
Angele P, Zellner J, Schröter S, Flechtenmacher J, Fritz J, Niemeyer P. Biological Reconstruction of Localized Full-Thickness Cartilage Defects of the Knee: A Systematic Review of Level 1 Studies with a Minimum Follow-Up of 5 Years. Cartilage 2022; 13:5-18. [PMID: 36250517 PMCID: PMC9924981 DOI: 10.1177/19476035221129571] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
OBJECTIVE The objective of this study was to evaluate the best available mid- to long-term evidence of surgical procedures for the treatment of localized full-thickness cartilage defects of the knee. DESIGN Systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of Level 1 randomized clinical trials (RCTs), meta-analyses of RCTs and systematic reviews with a minimum follow-up of 5 years. Data extracted included patient demographics, defect characteristics, clinical and radiological outcomes, as well as treatment failures. RESULTS Six RCTs and 3 Level 1 systematic reviews were included. Two RCTs compared microfracture (MFx) to periosteum-covered autologous chondrocyte implantation (ACI-P), 1 to matrix-associated ACI (M-ACI) and 2 to osteochondral autograft transplantation (OAT). One study compared OAT to collagen membrane covered ACI (ACI-C). The 3 Level 1 systematic reviews/meta-analyses assessed the outcome of MFx, OAT, and various ACI methods in RCTs. OAT showed significantly better outcomes compared with MFx. In the 2 RCTs comparing ACI-P and MFx, no significant differences in clinical outcomes were seen, whereas significantly better outcomes were reported for M-ACI versus MFx in 1 study including patients with larger defects (5 cm2), and for ACI-C versus OAT in terms of Cincinnati Score. Higher failure rates were reported for MFx compared with OAT and for OAT compared with ACI-C, while no significant differences in failure rates were observed for ACI-P compared to MFx. CONCLUSION Restorative cartilage procedures (ACI-C or M-ACI and OAT) are associated with better long-term clinical outcomes including lower complication and failure rates when compared with reparative techniques (MFx). Among the restorative procedures, OAT seems to be inferior to ACI especially in larger defects after longer follow-up periods. LEVEL OF EVIDENCE Level I: Systematic review of Level I studies.
Collapse
Affiliation(s)
- Peter Angele
- Sporthopaedicum Regensburg, Regensburg,
Germany,Klinik für Unfall- und
Wiederherstellungschirurgie, Universitätsklinikum Regensburg, Regensburg,
Germany,Peter Angele, Sporthopaedicum Regensburg,
Hildegard-von-Bingen-Strasse 1, 93053 Regensburg, Germany.
| | | | - Steffen Schröter
- Abteilung für Unfall- und
Wiederherstellungschirurgie, Jung-Stilling Krankenhaus, Diakonie Klinikum GmbH,
Siegen, Germany
| | | | - Jürgen Fritz
- Orthopädisch Chirurgisches Centrum,
Tübingen, Germany
| | - Philipp Niemeyer
- OCM—Orthopädische Chirurgie München,
München, Germany,Klinik für Orthopädie und
Traumatologie, Universitätsklinikum Freiburg, Freiburg, Germany
| |
Collapse
|
|
25
|
Chen Q, Zhang X, Chen K, Feng C, Wang D, Qi J, Li X, Zhao X, Chai Z, Zhang D. Bilayer Hydrogels with Low Friction and High Load-Bearing Capacity by Mimicking the Oriented Hierarchical Structure of Cartilage. ACS APPLIED MATERIALS & INTERFACES 2022; 14:52347-52358. [PMID: 36349936 DOI: 10.1021/acsami.2c13641] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Natural articular cartilages exhibit extraordinary lubricating properties and excellent load-bearing capacity based on their penetrated surface lubricated biomacromolecules and gradient-oriented hierarchical structure. Hydrogels are considered as the most promising cartilage replacement materials due to their excellent flexibility, good biocompatibility, and low friction coefficient. However, the construction of high-strength, low-friction hydrogels to mimic cartilage is still a great challenge. Here, inspired by the structure and functions of natural articular cartilage, anisotropic hydrogels with horizontal and vertical orientation structure were constructed layer by layer and bonded with each other, successfully developing a bilayer oriented heterogeneous hydrogel with a high load-bearing capacity, low friction, and excellent fatigue resistance. The bilayer hydrogel exhibited a high compressive strength of 5.21 ± 0.45 MPa and a compressive modulus of 4.06 ± 0.31 MPa due to the enhancement mechanism of the anisotropic structure within the bottom anisotropic hydrogel. Moreover, based on the synergistic effect of the high load-bearing capacity of the bottom layer and the lubrication of the surface layer, the bilayer hydrogel possesses excellent biotribological properties in hard/soft (0.032) and soft/soft (0.028) contact, which is close to that of natural cartilage. It is worth noting that the bilayer oriented heterogeneous hydrogel is able to withstand repeated loading without fatigue crack. Therefore, this work could open up a new avenue for constructing cartilage-like materials with both high strength and low friction.
Collapse
Affiliation(s)
- Qin Chen
- School of Chemical Engineering and Technology, School of Materials Science and Physics, School of Mechatronic Engineering, China University of Mining and Technology, Xuzhou221116, China
| | - Xinyue Zhang
- School of Chemical Engineering and Technology, School of Materials Science and Physics, School of Mechatronic Engineering, China University of Mining and Technology, Xuzhou221116, China
| | - Kai Chen
- School of Chemical Engineering and Technology, School of Materials Science and Physics, School of Mechatronic Engineering, China University of Mining and Technology, Xuzhou221116, China
- State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou730000, China
- State Key Laboratory of Tribology in Advanced Equipment, Tsinghua University, Beijing100084, China
| | - Cunao Feng
- School of Chemical Engineering and Technology, School of Materials Science and Physics, School of Mechatronic Engineering, China University of Mining and Technology, Xuzhou221116, China
| | - Dagang Wang
- School of Chemical Engineering and Technology, School of Materials Science and Physics, School of Mechatronic Engineering, China University of Mining and Technology, Xuzhou221116, China
| | - Jianwei Qi
- School of Chemical Engineering and Technology, School of Materials Science and Physics, School of Mechatronic Engineering, China University of Mining and Technology, Xuzhou221116, China
| | - Xiaowei Li
- School of Chemical Engineering and Technology, School of Materials Science and Physics, School of Mechatronic Engineering, China University of Mining and Technology, Xuzhou221116, China
| | - Xiaoduo Zhao
- State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou730000, China
| | - Zhimin Chai
- State Key Laboratory of Tribology in Advanced Equipment, Tsinghua University, Beijing100084, China
| | - Dekun Zhang
- School of Chemical Engineering and Technology, School of Materials Science and Physics, School of Mechatronic Engineering, China University of Mining and Technology, Xuzhou221116, China
| |
Collapse
|
|
26
|
Yanke AB, Hevesi M, Dandu N, Trasolini NA, Darwish RY, Zavras AG, Cole BJ. After Chondroplasty, Patient Election to Proceed With Cartilage Transplantation Is Closely and Additively Associated With Preoperative AMADEUS (Area Measurement And DEpth Underlying Structure) Grade, Condylar Involvement, Knee Injury and Osteoarthritis Outcome Score Pain Score, and Veterans Rand 12-Item Health Survey Physical Score. Arthrosc Sports Med Rehabil 2022; 4:e1903-e1912. [PMID: 36579045 PMCID: PMC9791869 DOI: 10.1016/j.asmr.2022.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 12/31/2022] Open
Abstract
Purpose To identify risk factors for patient election to proceed with cartilage transplant after staging chondroplasty. Methods This study retrospective reviewed patients prospectively enrolled at the time of staging chondroplasty, with early election defined as patient decision to proceed to cartilage transplantation within 6 months of chondroplasty. Cox proportional hazards analysis was used to determine univariate predictors of conversion, and a predictive calculator, the Cartilage Early Return for Transplant score, was formulated using stepwise regression employing the Akaike information criterion. Receiver operator curves and the area under the curve were used to evaluate the predictive ability of the final model on the studied patient population. Results Sixty-five knees (63 patients) were evaluated, with an overall transplant election rate of 27.7% within 6 months after chondroplasty. Based on multivariate results, the final Akaike information criterion-driven Cartilage Early Return for Transplant score employed preoperative Knee Injury and Osteoarthritis Outcome Score Pain Score, Veterans Rand 12-Item Health Survey Physical Score, condylar involvement, and AMADEUS (Area Measurement And DEpth Underlying Structure) score to generate a 0- to 7-point risk-stratification system with a 3% early election to proceed to transplant risk in the 0- to 2-point score group, 33% risk in the 3- to 4-point group, and 79% risk in the 5+-point group (P < .01) and an overall AUC of 0.906 (P < .01). Conclusions Risk of early patient election to pursue cartilage transplantation after chondroplasty is closely and additively associated with preoperative AMADEUS grade, condylar involvement, Knee Injury and Osteoarthritis Outcome Score Pain Score, and Veterans Rand 12-Item Health Survey Physical Score. Clinical Relevance Understanding risk factors for conversion to cartilage transplantation may improve preoperative planning and counseling prior to staging chondroplasty.
Collapse
Affiliation(s)
- Adam B. Yanke
- Address correspondence to Adam B. Yanke, M.D., Ph.D., 1611 W. Harrison St., St 300, Chicago, IL 60612.
| | | | | | | | | | | | | |
Collapse
|
|
27
|
Thampi P, Samulski RJ, Grieger JC, Phillips JN, McIlwraith CW, Goodrich LR. Gene therapy approaches for equine osteoarthritis. Front Vet Sci 2022; 9:962898. [PMID: 36246316 PMCID: PMC9558289 DOI: 10.3389/fvets.2022.962898] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 08/08/2022] [Indexed: 01/24/2023] Open
Abstract
With an intrinsically low ability for self-repair, articular cartilage injuries often progress to cartilage loss and joint degeneration resulting in osteoarthritis (OA). Osteoarthritis and the associated articular cartilage changes can be debilitating, resulting in lameness and functional disability both in human and equine patients. While articular cartilage damage plays a central role in the pathogenesis of OA, the contribution of other joint tissues to the pathogenesis of OA has increasingly been recognized thus prompting a whole organ approach for therapeutic strategies. Gene therapy methods have generated significant interest in OA therapy in recent years. These utilize viral or non-viral vectors to deliver therapeutic molecules directly into the joint space with the goal of reprogramming the cells' machinery to secrete high levels of the target protein at the site of injection. Several viral vector-based approaches have demonstrated successful gene transfer with persistent therapeutic levels of transgene expression in the equine joint. As an experimental model, horses represent the pathology of human OA more accurately compared to other animal models. The anatomical and biomechanical similarities between equine and human joints also allow for the use of similar imaging and diagnostic methods as used in humans. In addition, horses experience naturally occurring OA and undergo similar therapies as human patients and, therefore, are a clinically relevant patient population. Thus, further studies utilizing this equine model would not only help advance the field of human OA therapy but also benefit the clinical equine patients with naturally occurring joint disease. In this review, we discuss the advancements in gene therapeutic approaches for the treatment of OA with the horse as a relevant patient population as well as an effective and commonly utilized species as a translational model.
Collapse
Affiliation(s)
- Parvathy Thampi
- Orthopaedic Research Center, C. Wayne McIlwraith Translational Research Institute, College of Veterinary Medicine, Colorado State University, Fort Collins, CO, United States
| | - R. Jude Samulski
- Gene Therapy Center, University of North Carolina, Chapel Hill, NC, United States
| | - Joshua C. Grieger
- Gene Therapy Center, University of North Carolina, Chapel Hill, NC, United States
| | - Jennifer N. Phillips
- Orthopaedic Research Center, C. Wayne McIlwraith Translational Research Institute, College of Veterinary Medicine, Colorado State University, Fort Collins, CO, United States
| | - C. Wayne McIlwraith
- Orthopaedic Research Center, C. Wayne McIlwraith Translational Research Institute, College of Veterinary Medicine, Colorado State University, Fort Collins, CO, United States
| | - Laurie R. Goodrich
- Orthopaedic Research Center, C. Wayne McIlwraith Translational Research Institute, College of Veterinary Medicine, Colorado State University, Fort Collins, CO, United States,*Correspondence: Laurie R. Goodrich
| |
Collapse
|
|
28
|
Zhu Y, Sun Y, Rui B, Lin J, Shen J, Xiao H, Liu X, Chai Y, Xu J, Yang Y. A Photoannealed Granular Hydrogel Facilitating Hyaline Cartilage Regeneration via Improving Chondrogenic Phenotype. ACS APPLIED MATERIALS & INTERFACES 2022; 14:40674-40687. [PMID: 36052731 DOI: 10.1021/acsami.2c11956] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Hydrogel-based chondrocyte implantation presents a promising tissue engineering strategy for cartilage repair. However, the widely used elastic hydrogels usually restrict cell volume expansion and induce the dedifferentiation of encapsulated chondrocytes. To address this limitation, a photoannealed granular hydrogel (GH) composed of hyaluronic acid, polyethylene glycol, and gelatin was formulated for cartilage regeneration in this study. The unannealed GH prepared by Diels-Alder cross-linked microgels could be mixed with chondrocytes and delivered to cartilage defects by injection, after which light was introduced to anneal the scaffold, leading to the formation of a stable and microporous chondrocyte deploying scaffold. The in vitro studies showed that GH could promote the volume expansion and morphology recovery of chondrocytes and significantly improve their chondrogenic phenotype compared to the nongranular hydrogel (nGH) with similar compositions. Further in vivo studies of subcutaneous culture and the rat full-thickness cartilage defect model proved that chondrocyte loaded GH could significantly stimulate hyaline cartilage matrix deposition and connection, therefore facilitating hyaline-like cartilage regeneration. Finally, the mechanistic study revealed that GH might improve chondrogenic phenotype via activating the AMP-activated protein kinase/glycolysis axis. This study proves the great feasibility of GHs as in situ chondrocyte deploying scaffolds for cartilage regeneration and brings new insights in designing hydrogel scaffold for cartilage tissue engineering.
Collapse
Affiliation(s)
- Yu Zhu
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, China
- Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, China
| | - Yi Sun
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, China
| | - Biyu Rui
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, China
| | - Junqing Lin
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, China
| | - Junjie Shen
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, China
| | - Huimin Xiao
- Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, China
| | - Xuanzhe Liu
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, China
| | - Yimin Chai
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, China
- Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, China
| | - Jia Xu
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, China
- Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, China
| | - Yunlong Yang
- Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai 200233, China
| |
Collapse
|
|
29
|
Photo-Crosslinkable Hydrogels for 3D Bioprinting in the Repair of Osteochondral Defects: A Review of Present Applications and Future Perspectives. MICROMACHINES 2022; 13:mi13071038. [PMID: 35888855 PMCID: PMC9318225 DOI: 10.3390/mi13071038] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/08/2022] [Accepted: 06/22/2022] [Indexed: 11/23/2022]
Abstract
An osteochondral defect is a common and frequent disease in orthopedics and treatment effects are not good, which can be harmful to patients. Hydrogels have been applied in the repair of cartilage defects. Many studies have reported that hydrogels can effectively repair osteochondral defects through loaded cells or non-loaded cells. As a new type of hydrogel, photo-crosslinked hydrogel has been widely applied in more and more fields. Meanwhile, 3D bioprinting serves as an attractive platform to fabricate customized tissue-engineered substitutes from biomaterials and cells for the repair or replacement of injured tissues and organs. Although photo-crosslinkable hydrogel-based 3D bioprinting has some advantages for repairing bone cartilage defects, it also has some disadvantages. Our aim of this paper is to review the current status and prospect of photo-crosslinkable hydrogel-based 3D bioprinting for repairing osteochondral defects.
Collapse
|
|
30
|
Migliorini F, Eschweiler J, Goetze C, Pastor T, Giorgino R, Hildebrand F, Maffulli N. Cell therapies for chondral defects of the talus: a systematic review. J Orthop Surg Res 2022; 17:308. [PMID: 35690865 PMCID: PMC9188715 DOI: 10.1186/s13018-022-03203-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/31/2022] [Indexed: 12/12/2022] Open
Abstract
Background This systematic review investigated the efficacy and safety of surgical procedures augmented with cell therapies for chondral defects of the talus. Methods The present systematic review was conducted according to the 2020 PRISMA guidelines. PubMed, Google scholar, Embase, and Scopus databases were accessed in March 2022. All the clinical trials investigating surgical procedures for talar chondral defects augmented with cell therapies were accessed. The outcomes of interest were to investigate whether surgical procedures augmented with cell therapies promoted improvement in patients reported outcomes measures (PROMs) with a tolerable rate of complications. Results Data from 477 procedures were retrieved. At a mean follow-up of 34.8 ± 9.7 months, the Visual Analogic Scale (VAS) improved of 4.4/10 (P = 0.002) and the American Orthopaedic Foot and Ankle Score (AOFAS) of 31.1/100 (P = 0.0001) points. No improvement was found in Tegner score (P = 0.4). Few articles reported data on complications. At last follow-up, the rate of reoperation and failure were 0.06% and 0.03%, respectively. No graft delamination or hypertrophy was observed. Conclusion The current evidence suggests that cell therapies may be effective and safe to enhance surgical procedures for chondral defects of the talus. These results should be considered within the limitations of the present study. The current literature should be enriched with randomized controlled clinical trials with larger population size and longer follow-up.
Collapse
Affiliation(s)
- Filippo Migliorini
- Department of Orthopaedic, Trauma, and Reconstructive Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany.
| | - Jörg Eschweiler
- Department of Orthopaedic, Trauma, and Reconstructive Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Christian Goetze
- Department of Orthopaedic Surgery, Auguste-Viktoria Clinic, Ruhr University Bochum, 32545, Bad Oeynhausen, Germany
| | - Torsten Pastor
- Department of Orthopaedic and Trauma Surgery, Cantonal Hospital, 6000, Lucerne, Switzerland
| | - Riccardo Giorgino
- IRCCS Istituto Ortopedico Galeazzi, University of Milan, 20161, Milan, Italy
| | - Frank Hildebrand
- Department of Orthopaedic, Trauma, and Reconstructive Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Nicola Maffulli
- Department of Medicine, Surgery and Dentistry, University of Salerno, 84081, Baronissi, Italy.,Faculty of Medicine, School of Pharmacy and Bioengineering, Keele University, ST4 7QB, Stoke on Trent, England.,Barts and the London School of Medicine and Dentistry, Centre for Sports and Exercise Medicine, Mile End Hospital, Queen Mary University of London, E1 4DG, London, England
| |
Collapse
|
|
31
|
Hao M, Wang Y, Li L, Liu Y, Bai Y, Zhou W, Lu Q, Sun F, Li L, Feng S, Wei W, Zhang T. Tough Engineering Hydrogels Based on Swelling-Freeze-Thaw Method for Artificial Cartilage. ACS APPLIED MATERIALS & INTERFACES 2022; 14:25093-25103. [PMID: 35606333 DOI: 10.1021/acsami.2c02990] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Articular cartilage, which exhibits toughness and ultralow friction even under high squeezing pressures, plays an important role in the daily movement of joints. However, joint soft tissue lesions or injuries caused by diseases, trauma, or human functional decline are inevitable. Poly(vinyl alcohol) (PVA) hydrogels, which have a water content and compressive strength similar to those of many tissues and organs, have the potential to replace tough connective tissues, including cartilage. However, currently, PVA hydrogels are not suitable for complex dynamic environments and lack rebound resilience, especially under long-term or multicycle mechanical loads. Inspired by biological tissues that exhibit increased mechanical strength after swelling, we report a tough engineered hydrogel (TEHy) fabricated by swelling and freeze-thaw methods with a high compressive strength (31 MPa), high toughness (1.17 MJ m-3), a low friction coefficient (0.01), and a low energy loss factor (0.22). Notably, the TEHy remained remarkably resilient after 100 000 cycles of contact extrusion and remains intact after being compressed by an automobile with a weight of approximately 1600 kg. The TEHy also exhibited excellent water swelling resistance (volume and weight changes less than 5%). Moreover, skeletal muscle cells were able to readily attach and proliferate on the surface of TEHy-6, suggesting its outstanding biocompatibility. Overall, this swelling and freeze-thaw strategy solves the antifatigue and stability problems of PVA hydrogels under large static loads (>10 000 N) and provides an avenue to fabricate engineering hydrogels with strong antifatigue and antiswelling properties and ultralow friction for potential use as biomaterials in tissue engineering.
Collapse
Affiliation(s)
- Mingming Hao
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. China
- i-Lab, Key Laboratory of Multifunctional Nanomaterials and Smart Systems, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences (CAS), 398 Ruoshui Road, Suzhou 215123, P. R. China
| | - Yongfeng Wang
- i-Lab, Key Laboratory of Multifunctional Nanomaterials and Smart Systems, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences (CAS), 398 Ruoshui Road, Suzhou 215123, P. R. China
| | - Lianhui Li
- i-Lab, Key Laboratory of Multifunctional Nanomaterials and Smart Systems, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences (CAS), 398 Ruoshui Road, Suzhou 215123, P. R. China
| | - Yinhang Liu
- i-Lab, Key Laboratory of Multifunctional Nanomaterials and Smart Systems, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences (CAS), 398 Ruoshui Road, Suzhou 215123, P. R. China
| | - Yuanyuan Bai
- i-Lab, Key Laboratory of Multifunctional Nanomaterials and Smart Systems, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences (CAS), 398 Ruoshui Road, Suzhou 215123, P. R. China
| | - Weifan Zhou
- i-Lab, Key Laboratory of Multifunctional Nanomaterials and Smart Systems, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences (CAS), 398 Ruoshui Road, Suzhou 215123, P. R. China
| | - Qifeng Lu
- School of Chips, XJTLU Entrepreneur College (Taicang), Xi'an Jiaotong-Liverpool University, 111 Ren'ai Road, Suzhou, Jiangsu 215123, P. R. China
| | - Fuqin Sun
- i-Lab, Key Laboratory of Multifunctional Nanomaterials and Smart Systems, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences (CAS), 398 Ruoshui Road, Suzhou 215123, P. R. China
| | - Lili Li
- i-Lab, Key Laboratory of Multifunctional Nanomaterials and Smart Systems, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences (CAS), 398 Ruoshui Road, Suzhou 215123, P. R. China
| | - Simin Feng
- i-Lab, Key Laboratory of Multifunctional Nanomaterials and Smart Systems, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences (CAS), 398 Ruoshui Road, Suzhou 215123, P. R. China
| | - Wei Wei
- Jiangsu Key Laboratory of Neuropsychiatric Diseases Research and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215123, P. R. China
| | - Ting Zhang
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. China
- i-Lab, Key Laboratory of Multifunctional Nanomaterials and Smart Systems, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences (CAS), 398 Ruoshui Road, Suzhou 215123, P. R. China
- Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, P. R. China
| |
Collapse
|
|
32
|
Matthews JR, Brutico J, Heard J, Chauhan K, Tucker B, Freedman KB. Comparison of clinical outcomes following osteochondral allograft transplantation for osteochondral versus chondral defects in the knee. Knee Surg Relat Res 2022; 34:23. [PMID: 35509057 PMCID: PMC9066852 DOI: 10.1186/s43019-022-00149-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 04/03/2022] [Indexed: 11/10/2022] Open
Abstract
Purpose Osteochondral allograft (OCA) transplantation is a restorative technique for addressing articular cartilage defects by transferring mature viable chondrocytes with subchondral bone into size-matched lesions. The purpose of this study was to compare differences in clinical and functional outcomes in patients treated with OCA for osteochondral defects compared with isolated chondral pathology.
Methods A retrospective review identified patients who underwent OCA transplantation and grouped them into osteochondral or isolated chondral pathology. Demographic data, surgical history, lesion characteristics, complications, and rate of subsequent surgery were reviewed. The review included 86 patients (24 osteochondral, 62 chondral) with a mean follow-up of 5.4 ± 1.4 years. Outcome measures included the Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS, JR.), International Knee Documentation Committee (IKDC), and Short Form Health Survey (SF-12) physical scores. Failure was defined to include revision OCA, graft removal, conversion to ACI, or conversion to arthroplasty.
Results The average age at surgery was 32.3 and 37.3 years for the osteochondral and chondral groups, respectively (P = 0.056). The medial femoral condyle was the most common defect location in both groups. P < 0.05 was considered statistically significant. Patients with osteochondral pathology had significantly greater KOOS JR., IKDC, and SF-12 scores (P < 0.05), and fewer failures were reported in the osteochondral group (8.3% versus 32.3%, P = 0.045). When controlling for age, sex, laterality, BMI, and presence of a concomitant procedure, patients with osteochondral pathology were found to have better KOOS and IKDC scores, but there was no difference in SF12 scores or rates of failure between groups.
Conclusion The findings of this study indicate that patients undergoing OCA for osteochondral defects may have greater functional outcomes and similar failure rates compared with OCA transplantation for isolated chondral pathology.
Collapse
Affiliation(s)
- John Reza Matthews
- Department of Orthopedic Surgery, Thomas Jefferson Rothman Institute Sports Fellow, 925 Chestnut St., Philadelphia, PA, 19107, USA.
| | - Joseph Brutico
- Department of Orthopedic Surgery, Rothman Institute Research Fellow, Philadelphia, USA
| | - Jeremy Heard
- Internal Medicine Resident, Thomas Jefferson University, Philadelphia, USA
| | - Kashyap Chauhan
- Internal Medicine Resident, Thomas Jefferson University, Philadelphia, USA
| | - Bradford Tucker
- Cartilage Restoration Center, Orthopaedic Surgery, Thomas Jefferson Rothman Institute, Philadelphia, USA
| | - Kevin Blake Freedman
- Cartilage Restoration Center, Orthopaedic Surgery, Thomas Jefferson Rothman Institute, Philadelphia, USA
| |
Collapse
|
|
33
|
Epanomeritakis IE, Lee E, Lu V, Khan W. The Use of Autologous Chondrocyte and Mesenchymal Stem Cell Implants for the Treatment of Focal Chondral Defects in Human Knee Joints-A Systematic Review and Meta-Analysis. Int J Mol Sci 2022; 23:ijms23074065. [PMID: 35409424 PMCID: PMC8999850 DOI: 10.3390/ijms23074065] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/02/2022] [Accepted: 04/03/2022] [Indexed: 12/16/2022] Open
Abstract
Focal chondral defects of the knee occur commonly in the young, active population due to trauma. Damage can insidiously spread and lead to osteoarthritis with significant functional and socioeconomic consequences. Implants consisting of autologous chondrocytes or mesenchymal stem cells (MSC) seeded onto scaffolds have been suggested as promising therapies to restore these defects. However, the degree of integration between the implant and native cartilage still requires optimization. A PRISMA systematic review and meta-analysis was conducted using five databases (PubMed, MEDLINE, EMBASE, Web of Science, CINAHL) to identify studies that used autologous chondrocyte implants (ACI) or MSC implant therapies to repair chondral defects of the tibiofemoral joint. Data on the integration of the implant-cartilage interface, as well as outcomes of clinical scoring systems, were extracted. Most eligible studies investigated the use of ACI only. Our meta-analysis showed that, across a total of 200 patients, 64% (95% CI (51%, 75%)) achieved complete integration with native cartilage. In addition, a pooled improvement in the mean MOCART integration score was observed during post-operative follow-up (standardized mean difference: 1.16; 95% CI (0.07, 2.24), p = 0.04). All studies showed an improvement in the clinical scores. The use of a collagen-based scaffold was associated with better integration and clinical outcomes. This review demonstrated that cell-seeded scaffolds can achieve good quality integration in most patients, which improves over time and is associated with clinical improvements. A greater number of studies comparing these techniques to traditional cartilage repair methods, with more inclusion of MSC-seeded scaffolds, should allow for a standardized approach to cartilage regeneration to develop.
Collapse
Affiliation(s)
| | - Ernest Lee
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK; (I.E.E.); (E.L.); (V.L.)
| | - Victor Lu
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK; (I.E.E.); (E.L.); (V.L.)
| | - Wasim Khan
- Department of Trauma and Orthopaedic Surgery, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK
- Correspondence: ; Tel.: +44-(0)-7791-025554
| |
Collapse
|
|
34
|
Niemeyer P, Hanus M, Belickas J, László T, Gudas R, Fiodorovas M, Cebatorius A, Pastucha M, Hoza P, Magos K, Izadpanah K, Paša L, Vásárhelyi G, Sisák K, Mohyla M, Farkas C, Kessler O, Kybal S, Spiro R, Köhler A, Kirner A, Trattnig S, Gaissmaier C. Treatment of Large Cartilage Defects in the Knee by Hydrogel-Based Autologous Chondrocyte Implantation: Two-Year Results of a Prospective, Multicenter, Single-Arm Phase III Trial. Cartilage 2022; 13:19476035221085146. [PMID: 35354310 PMCID: PMC9137299 DOI: 10.1177/19476035221085146] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVE To evaluate the clinical outcome of a hydrogel-based autologous chondrocyte implantation (ACI) for large articular cartilage defects in the knee joint. DESIGN Prospective, multicenter, single-arm, phase III clinical trial. ACI was performed in 100 patients with focal full-thickness cartilage defects ranging from 4 to 12 cm2 in size. The primary outcome measure was the responder rate at 2 years using the Knee Injury and Osteoarthritis Outcome Score (KOOS). RESULTS Two years after ACI treatment, 93% of patients were KOOS responders having improved by ≥10 points compared with their pre-operative level. The primary endpoint of the study was met and demonstrated that the KOOS response rate is markedly greater than 40% with a lower 95% CI (confidence interval) of 86.1, more than twice the pre-specified no-effect level. KOOS improvement (least squares mean) was 42.0 ± 1.8 points (95% CI between 38.4 and 45.7). Mean changes from baseline were significant in the overall KOOS and in all 5 KOOS subscores from Month 3 (first measurement) to Month 24 (inclusive) (P < 0.0001). The mean MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) score after 24 months reached 80.0 points (95% CI: 70.0-90.0 points) and 92.1 points in lesions ≤ 5 cm2. CONCLUSIONS Overall, hydrogel-based ACI proved to be a valuable treatment option for patients with large cartilage defects in the knee as demonstrated by early, statistically significant, and clinically meaningful improvement up to 2 years follow-up. Parallel to the clinical improvements, MRI analyses suggested increasing maturation, re-organization, and integration of the repair tissue. TRIAL REGISTRATION NCT03319797; EudraCT No.: 2016-002817-22.
Collapse
Affiliation(s)
| | - M. Hanus
- Department of Orthopaedics and Traumatology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
| | - J. Belickas
- Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - T. László
- Clinic of Traumatology, Jász-Nagykun-Szolnok County Hetényi Géza Hospital, Szolnok, Hungary
| | - R. Gudas
- Hospital of Lithuanian University of Health Sciences Kaunas Clinics, Kaunas, Lithuania
| | | | | | - M. Pastucha
- Department of Orthopaedics, Hořovice Hospital, Hořovice, Czech Republic
| | - P. Hoza
- Department of Orthopaedics, Pardubice Hospital, Pardubice, Czech Republic
| | - K. Magos
- Kastélypark Clinic, Tata, Hungary
| | - K. Izadpanah
- Department of Orthopedics and Trauma Surgery, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - L. Paša
- Clinic of Traumatology, Faculty of Medicine, Masaryk Univerzity Brno and Úrazová Nemocnice, Brno, Czech Republic
| | - G. Vásárhelyi
- Department of Orthopaedics and Traumatology, Uzsoki Hospital, Budapest, Hungary
| | - K. Sisák
- Department of Orthopaedics, University of Szeged, Szeged, Hungary
| | - M. Mohyla
- Department of Orthopaedics, University Hospital in Ostrava, Ostrava-Poruba, Czech Republic
| | - C. Farkas
- Department of Orthopaedics, Szabolcs-Szatmár-Bereg County Hospitals, University Teaching Hospital, Nyíregyháza, Hungary
| | - O. Kessler
- Center for Orthopedics & Sports, Zürich, Switzerland
| | - S. Kybal
- Orthopaedics Department of Hospital Benešov, Benešov, Czech Republic
| | - R. Spiro
- Aesculap Biologics, LLC, Breinigsville, PA, USA
| | - A. Köhler
- TETEC—Tissue Engineering Technologies AG, Reutlingen, Germany
| | - A. Kirner
- TETEC—Tissue Engineering Technologies AG, Reutlingen, Germany
| | - S. Trattnig
- The High Field MR Centre, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - C. Gaissmaier
- TETEC—Tissue Engineering Technologies AG, Reutlingen, Germany,Christoph Gaissmaier, TETEC—Tissue Engineering Technologies AG, Aspenhaustr. 18, 72770 Reutlingen, Germany.
| |
Collapse
|
|
35
|
Jin Y, Liu Q, Chen P, Zhao S, Jiang W, Wang F, Li P, Zhang Y, Lu W, Zhong TP, Ma X, Wang X, Gartland A, Wang N, Shah KM, Zhang H, Cao X, Yang L, Liu M, Luo J. A novel prostaglandin E receptor 4 (EP4) small molecule antagonist induces articular cartilage regeneration. Cell Discov 2022; 8:24. [PMID: 35256606 PMCID: PMC8901748 DOI: 10.1038/s41421-022-00382-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 01/28/2022] [Indexed: 01/15/2023] Open
Abstract
Articular cartilage repair and regeneration is an unmet clinical need because of the poor self-regeneration capacity of the tissue. In this study, we found that the expression of prostaglandin E receptor 4 (PTGER4 or EP4) was largely increased in the injured articular cartilage in both humans and mice. In microfracture (MF) surgery-induced cartilage defect (CD) and destabilization of the medial meniscus (DMM) surgery-induced CD mouse models, cartilage-specific deletion of EP4 remarkably promoted tissue regeneration by enhancing chondrogenesis and cartilage anabolism, and suppressing cartilage catabolism and hypertrophy. Importantly, knocking out EP4 in cartilage enhanced stable mature articular cartilage formation instead of fibrocartilage, and reduced joint pain. In addition, we identified a novel selective EP4 antagonist HL-43 for promoting chondrocyte differentiation and anabolism with low toxicity and desirable bioavailability. HL-43 enhanced cartilage anabolism, suppressed catabolism, prevented fibrocartilage formation, and reduced joint pain in multiple pre-clinical animal models including the MF surgery-induced CD rat model, the DMM surgery-induced CD mouse model, and an aging-induced CD mouse model. Furthermore, HL-43 promoted chondrocyte differentiation and extracellular matrix (ECM) generation, and inhibited matrix degradation in human articular cartilage explants. At the molecular level, we found that HL-43/EP4 regulated cartilage anabolism through the cAMP/PKA/CREB/Sox9 signaling. Together, our findings demonstrate that EP4 can act as a promising therapeutic target for cartilage regeneration and the novel EP4 antagonist HL-43 has the clinical potential to be used for cartilage repair and regeneration.
Collapse
Affiliation(s)
- Yunyun Jin
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Qianqian Liu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Peng Chen
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Siyuan Zhao
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Wenhao Jiang
- Yangzhi Rehabilitation Hospital (Sunshine Rehabilitation Centre), Tongji University School of Medicine, Shanghai, China
| | - Fanhua Wang
- Yangzhi Rehabilitation Hospital (Sunshine Rehabilitation Centre), Tongji University School of Medicine, Shanghai, China
| | - Peng Li
- Orthopedic Institute, Soochow University, Suzhou, Jiangsu, China
| | - Yuanjin Zhang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Weiqiang Lu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Tao P Zhong
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Xinran Ma
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Xin Wang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Alison Gartland
- Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK
| | - Ning Wang
- Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK
| | - Karan Mehul Shah
- Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK
| | - Hankun Zhang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Xu Cao
- Departments of Orthopaedic Surgery and Biomedical Engineering and Institute of Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lei Yang
- Orthopedic Institute, Soochow University, Suzhou, Jiangsu, China.,Center for Health Science and Engineering, School of Materials Science and Engineering, Hebei University of Technology, Tianjin, China
| | - Mingyao Liu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Jian Luo
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. .,Yangzhi Rehabilitation Hospital (Sunshine Rehabilitation Centre), Tongji University School of Medicine, Shanghai, China.
| |
Collapse
|
|
36
|
Aprile P, Whelan IT, Sathy BN, Carroll SF, Kelly DJ. Soft Hydrogel Environments that Facilitate Cell Spreading and Aggregation Preferentially Support Chondrogenesis of Adult Stem Cells. Macromol Biosci 2022; 22:e2100365. [PMID: 35171524 DOI: 10.1002/mabi.202100365] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 01/14/2022] [Indexed: 11/10/2022]
Abstract
Mesenchymal stem/stromal cells (MSCs) represent a promising cell type for treating damaged and diseased synovial joints. The therapeutic potential of MSCs will be facilitated by the engineering of biomaterial environments capable of directing their fate. Here we explored the interplay between matrix elasticity and cell morphology in regulating the chondrogenic differentiation of MSCs when seeded onto or encapsulated within hydrogels made of interpenetrating networks (IPN) of alginate and collagen type I. This IPN system enabled the independent control of substrate stiffness (in 2D and in 3D) and cell morphology (3D only). In a 2D culture environment, the expression of chondrogenic markers SOX9, ACAN and COL2 increased on a soft substrate, which correlated with increased SMAD2/3 nuclear localization, enhanced MSCs condensation and the formation of larger cellular aggregates. The encapsulation of spread MSCs within a soft IPN dramatically increased the expression of cartilage-specific genes, which was linked to higher levels of cellular condensation and nuclear SMAD2/3 localization. Surprisingly, cells forced to adopt a more rounded morphology within the same soft IPNs expressed higher levels of the osteogenic markers RUNX2 and COL1. The insight provided by this study suggests that a mechanobiology informed approach to biomaterial development will be integral to the development of successful cartilage tissue engineering strategies. This article is protected by copyright. All rights reserved.
Collapse
Affiliation(s)
- Paola Aprile
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,Department of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland
| | - Ian T Whelan
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,Department of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland.,CÚRAM Center for Research in Medical Devices, National University of Ireland, Galway, Ireland
| | - Binulal N Sathy
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,Department of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland.,Centre for Nanoscience and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, India
| | - Simon F Carroll
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,Department of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland
| | - Daniel J Kelly
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,Department of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland.,CÚRAM Center for Research in Medical Devices, National University of Ireland, Galway, Ireland.,The Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.,Advanced Materials and Bioengineering Research (AMBER) Centre, Trinity College Dublin, Ireland
| |
Collapse
|
|
37
|
Matthews JR, Brutico JM, Abraham DT, Heard JC, Tucker BS, Tjoumakaris FP, Freedman KB. Differences in Clinical and Functional Outcomes Between Osteochondral Allograft Transplantation and Autologous Chondrocyte Implantation for the Treatment of Focal Articular Cartilage Defects. Orthop J Sports Med 2022; 10:23259671211058425. [PMID: 35155699 PMCID: PMC8832612 DOI: 10.1177/23259671211058425] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 08/24/2021] [Indexed: 11/17/2022] Open
Abstract
Background: Articular cartilage pathology can result from a spectrum of origins, including trauma, osteochondritis dissecans, avascular necrosis, or degenerative joint disease. Purpose: To compare the differences in clinical and patient-reported outcomes after autologous chondrocyte implantation (ACI) versus osteochondral allograft transplantation (OCA) in patients with focal articular cartilage defects without underlying bone loss. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective review identified patients who underwent ACI or OCA between 2008 and 2016 for isolated grades 3 and 4 articular cartilage defects without underlying bone loss. Outcome measures included the Knee injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS JR), International Knee Documentation Committee (IKDC) evaluation, and 12-Item Short Form Health Survey–Physical Component (SF-12-P) scores. Defect location, size, complications, and rate of subsequent surgery were determined. Results: Overall, 148 patients were included: 82 (55%) underwent ACI and 66 (45%) underwent OCA. The mean age at the time of surgery was 31.2 years within the ACI cohort and 37.7 years within the OCA cohort (P < .001); the mean follow-up for both cohorts was 6.7 years (P = .902). Within the ACI group, 28 (34%) patients had multifocal defects, 21 (26%) had defects confined to the femoral condyles, and 33 (40%) had defects in the patellofemoral region. Within the OCA group, 23 (35%) patients had multifocal defects, 30 (46%) had confined femoral condyle lesions, and 13 (20%) had patellofemoral defects. When comparing by lesion location, there were no significant differences in KOOS JR, and IKDC scores between the ACI and OCA cohorts (P < .05). There was, however, a significant difference for SF-12-P scores for FDD trochlear lesions. In both cohorts, traumatic patellofemoral pathology demonstrated lower patient-reported outcomes and higher failure rates than degenerative lesions. The overall rate of failure, defined as graft failure with revision surgery and/or conversion to arthroplasty, was significantly greater in the OCA group (21% vs 4%; P = .002). Conclusion: Study results indicated that ACI provides similar outcomes to OCA with or without concomitant procedures for the treatment of symptomatic articular cartilage defects in all lesion locations and may have a lower revision rate for multifocal and condylar lesions.
Collapse
Affiliation(s)
- John R. Matthews
- Thomas Jefferson Rothman Orthopedic Institute, Philadelphia, Pennsylvania, USA
| | - Joseph M. Brutico
- Thomas Jefferson Rothman Orthopedic Institute, Philadelphia, Pennsylvania, USA
| | | | - Jeremy C. Heard
- Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Bradford S. Tucker
- Thomas Jefferson Rothman Orthopedic Institute, Philadelphia, Pennsylvania, USA
| | | | - Kevin B. Freedman
- Thomas Jefferson Rothman Orthopedic Institute, Philadelphia, Pennsylvania, USA
| |
Collapse
|
|
38
|
Hoburg A, Niemeyer P, Laute V, Zinser W, John T, Becher C, Izadpanah K, Diehl P, Kolombe T, Fay J, Siebold R, Fickert S. Safety and Efficacy of Matrix-Associated Autologous Chondrocyte Implantation With Spheroids for Patellofemoral or Tibiofemoral Defects: A 5-Year Follow-up of a Phase 2, Dose-Confirmation Trial. Orthop J Sports Med 2022; 10:23259671211053380. [PMID: 35071653 PMCID: PMC8777354 DOI: 10.1177/23259671211053380] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 07/14/2021] [Indexed: 11/15/2022] Open
Abstract
Background: Matrix-associated autologous chondrocyte implantation (ACI) is a
well-established treatment for cartilage defects. High-level evidence at
midterm follow-up is limited, especially for ACI using spheroids (spherical
aggregates of ex vivo expanded human autologous chondrocytes and
self-synthesized extracellular matrix). Purpose: To assess the safety and efficacy of 3-dimensional matrix-associated ACI
using spheroids to treat medium to large cartilage defects on different
locations in the knee joint (patella, trochlea, and femoral condyle) at
5-year follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 75 patients aged 18 to 50 years with medium to large (4-10
cm2), isolated, single cartilage defects, International
Cartilage Repair Society grade 3 or 4, were randomized on a single-blind
basis to treatment with ACI at 1 of 3 dose levels: 3 to 7, 10 to 30, or 40
to 70 spheroids/cm2 of defect size. Outcomes were assessed via
changes from baseline Knee injury and Osteoarthritis Outcome Score (KOOS),
International Knee Documentation Committee score, and modified Lysholm
assessments at 1- and 5-year follow-up. Structural repair was evaluated
using MOCART (magnetic resonance observation of cartilage repair tissue)
score. Treatment-related adverse events were assessed up to 5 years for all
patients. The overall KOOS at 12 months was assessed for superiority versus
baseline in a 1-sample, 2-sided t test. Results: A total of 73 patients were treated: 24 in the low-dose group, 25 in the
medium-dose group, and 24 in the high-dose group. The overall KOOS improved
from 57.0 ± 15.2 at baseline to 73.4 ± 17.3 at 1-year follow-up
(P < .0001) and 76.9 ± 19.3 at 5-year follow-up
(P < .0001), independent of the applied dose. The
different defect locations (patella, trochlea, and weightbearing part of the
femoral condyles; P = .2216) and defect sizes
(P = .8706) showed comparable clinical improvement. No
differences between the various doses were observed. The overall treatment
failure rate until 5 years was 4%. Most treatment-related adverse events
occurred within the first 12 months after implantation, with the most
frequent adverse reactions being joint effusion (n = 71), arthralgia (n =
14), and joint swelling (n = 9). Conclusion: ACI using spheroids was safe and effective for defect sizes up to 10
cm2 and showed maintenance of efficacy up to 5 years for all
3 doses that were investigated. Registration: NCT01225575 (ClinicalTrials.gov identifier); 2009-016816-20 (EudraCT
number).
Collapse
Affiliation(s)
| | - Philipp Niemeyer
- Department of Orthopedic Surgery and Traumatology, Freiburg University Hospital, Germany and OCM Clinic, Munich, Germany
| | | | - Wolfgang Zinser
- Department of Orthopedic Surgery and Traumatology, St. Vinzenz Hospital, Dinslaken, Germany
| | - Thilo John
- Clinic for Traumatology and Orthopedic Surgery, DRK Hospital Westend, Berlin, Germany
| | - Christoph Becher
- Department of Orthopaedic Surgery, Hannover Medical School, Diakovere Annastift, Hannover, Germany
| | - Kaywan Izadpanah
- Department of Orthopedic and Trauma Surgery, Freiburg University Hospital, Freiburg, Germany
| | - Peter Diehl
- Department of Orthopedic Surgery and Traumatology, Orthopedic Center Munich East, Munich, Germany
| | - Thomas Kolombe
- Traumatology and Reconstructive Surgery, DRK Hospital, Luckenwalde, Germany
| | - Jakob Fay
- Department of Traumatology and Arthroscopic Surgery, Lubinus Clinicum, Kiel, Germany
| | - Rainer Siebold
- Center for Hip, Knee and Foot Surgery, ATOS Clinic, Heidelberg, Germany
| | - Stefan Fickert
- Sporthopaedicum, Straubing, Germany
- Department of Orthopedic Surgery and Traumatology, Mannheim University Hospital, Mannheim, Germany
| |
Collapse
|
|
39
|
van der Stok J, van Buul GM, Stanclik J, Queally JM, O'Donnell T. Focal articular surface replacement as primary treatment for focal chondral defects of the femoral condyles: A series of 157 cases. Knee 2022; 34:108-117. [PMID: 34890923 DOI: 10.1016/j.knee.2021.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 09/27/2021] [Accepted: 11/05/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Focal chondral defects (FCDs) of the femoral condyle are common. Treatment has heretofore primarily consisted of non-surgical and biological treatments. Focal articular surface replacement (FASR) is an emerging technique utilizing small implants to essentially fill the FCD. Here we report functional outcome and re-operation rates following FASR as a primary treatment for FCDs of the femoral condyles. METHODS Retrospective analysis of a prospectively collected database including 327 FASR procedures was performed to identify patients who underwent FASR of the femoral condyle with a modular cementless metallic implant (HemiCAPTM) as a primary procedure. Knee Injury and Osteoarthritis Outcome Score (KOOS), Oxford Knee Score (OKS), SF-36 Health Status Survey (SF-36) and Visual Analog Scale (VAS) were collected before and 6 weeks, 6 months, and 4 years after surgery. Implant revision and re-operation rate were recorded. RESULTS 157 patients were included with a mean follow-up of 9.4 ± 1.3 years (range 7.0 to 11.4 years). The average age was 40.2 ± 5.3 years, 85% involved the medial condyle, and the average defect size was 3.6 ± 0.5 cm2. Primary FASR resulted in functional improvement on the KOOS (+52%), OKS (+69%) and SF-36 (+50%) scores and a reduction in VAS scores (-70%) at 4-year follow-up. Revision rate was 0.64% and the re-operation rate was 11%. CONCLUSION This retrospective case-series supports primary FASR with HemiCAPTM implants as an alternative to biological procedures to treat medium-sized FCDs (2.5-4 cm2) of the femoral condyle, although long-term follow-up is necessary to determine if the clinical outcome and low revision rate can be maintained.
Collapse
Affiliation(s)
- Johan van der Stok
- The Centre for Orthopaedics, Beacon Hospital, Bracken Road, Sandyford, Dublin D18 AK67, Ireland.
| | - Gerben M van Buul
- The Centre for Orthopaedics, Beacon Hospital, Bracken Road, Sandyford, Dublin D18 AK67, Ireland; Zuyderland Medical Center, Henri Dunantstraat 5, 6419PC Heerlen, the Netherlands
| | - Jaroslaw Stanclik
- The Centre for Orthopaedics, Beacon Hospital, Bracken Road, Sandyford, Dublin D18 AK67, Ireland
| | - Joseph M Queally
- The Centre for Orthopaedics, Beacon Hospital, Bracken Road, Sandyford, Dublin D18 AK67, Ireland
| | - Turlough O'Donnell
- The Centre for Orthopaedics, Beacon Hospital, Bracken Road, Sandyford, Dublin D18 AK67, Ireland; University College Dublin School of Medicine, Health Sciences Centre, Belfield, Donnybrook, Dublin D04 C7X2, Ireland
| |
Collapse
|
|
40
|
Tang Z, Lu Y, Zhang S, Wang J, Wang Q, Xiao Y, Zhang X. Chondrocyte secretome enriched microparticles encapsulated with the chondrocyte membrane to facilitate the chondrogenesis of BMSCs and reduce hypertrophy. J Mater Chem B 2021; 9:9989-10002. [PMID: 34874033 DOI: 10.1039/d1tb02319e] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Co-culture of chondrocytes and mesenchymal stem cells (MSCs) represents an effective way to stimulate the chondrogenesis of MSCs and reduce hypertrophy, but the limited donor site supply and the requirement of two-stage operations are among the major barriers of using autologous chondrocytes in clinical settings. With recent evidence indicating that the chondrogenic effects of the above co-culture mainly lied on the paracrine secretion, and that cell membranes also played crucial roles during the chondrocyte-MSC interaction, we fabricated a multifunctional design of "artificial chondrocytes", which consist of chondrocyte secretome enriched PLGA microparticles with the encapsulation of chondrocytes' membrane fragments. The artificial chondrocytes had shown a similar diameter and surface electrical charge to natural chondrocytes, with the preserved key chondrocyte membrane surface proteins and sustainedly released chondrogenic cytokines from the chondrocyte secretome to extend their effects in vivo. Consequently, the co-culture studies of artificial chondrocytes and bone marrow MSCs had shown the beneficial effects from both chondrocyte secretome and membrane fragments, which also synergistically facilitated the cell proliferation, chondrogenic gene expression, cartilaginous matrix production, and reduced phenotypic hypertrophy in vitro and in vivo. Together, this study has successfully developed the proof-of-concept design of "artificial chondrocytes", which could potentially conquer many major barriers of using natural chondrocytes and provided a novel synthetic-cell approach to current therapeutical strategies towards the functional regeneration of articular cartilage.
Collapse
Affiliation(s)
- Zizhao Tang
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan, 610065, China. .,College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan, 610065, China
| | - Yan Lu
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan, 610065, China. .,College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan, 610065, China
| | - Shixin Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan, 610065, China. .,College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan, 610065, China
| | - Jing Wang
- College of Materials and Chemistry & Chemical Engineering, Chengdu University of Technology, Chengdu, Sichuan, 610059, China
| | - Qiguang Wang
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan, 610065, China. .,College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan, 610065, China
| | - Yumei Xiao
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan, 610065, China. .,College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan, 610065, China
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan, 610065, China. .,College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan, 610065, China
| |
Collapse
|
|
41
|
Hoburg A, Niemeyer P, Laute V, Zinser W, Becher C, Kolombe T, Fay J, Pietsch S, Kuźma T, Widuchowski W, Fickert S. Matrix-Associated Autologous Chondrocyte Implantation with Spheroid Technology Is Superior to Arthroscopic Microfracture at 36 Months Regarding Activities of Daily Living and Sporting Activities after Treatment. Cartilage 2021; 13:437S-448S. [PMID: 31893951 PMCID: PMC8808956 DOI: 10.1177/1947603519897290] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Matrix-associated autologous chondrocyte implantation (ACI) and microfracture (MF) are well-established treatments for cartilage defects of the knee. However, high-level evidence comparing microfracture and spheroid technology ACI is limited. DESIGN Prospective, phase III clinical trial with patients randomized to ACI (N = 52) or MF (N = 50). Level of evidence: 1, randomized controlled trial. Both procedures followed standard protocols. For ACI 10 to 70 spheroids/cm2 were administered. Primary outcome measure was the Knee Injury and Osteoarthritis Outcome Score (KOOS). This report presents results for 36 months after treatment. RESULTS Both ACI and MF showed significant improvement over the entire 3-year observation period. For the overall KOOS, noninferiority of ACI (the intended primary goal of the study) was formally confirmed; additionally, for the subscores "Activities of Daily Living" and "Sport and Recreation," superiority of ACI over MF was shown at descriptive level. Occurrence of adverse events were not different between both treatments (ACI 77%; MF 74%). Four patients in the MF group required reoperation which was defined as treatment failure. No treatment failure was reported for the ACI group. CONCLUSIONS Patients treated with matrix-associated ACI with spheroid technology showed substantial improvement in various clinical outcomes after 36 months. The advantages of ACI compared with microfracture was underlined by demonstrating noninferiority, in overall KOOS and superiority in the KOOS subscores "Activities of Daily Living" and "Sport and Recreation." In the present study, subgroups comparing different age groups and defect sizes showed comparable clinical outcomes.
Collapse
Affiliation(s)
- Arnd Hoburg
- Joint and Spine Centre Steglitz, Berlin,
Germany,Arnd Hoburg, Joint and Spine Centre
Steglitz, Kieler Straße 1, Berlin, 12163, Germany.
| | - Philipp Niemeyer
- Department of Orthopedic Surgery and
Traumatology, University Hospital, Freiburg, Germany,OCM Clinic, Munich, Germany
| | - Volker Laute
- Joint and Spine Centre Steglitz, Berlin,
Germany
| | - Wolfgang Zinser
- Department of Orthopedic Surgery and
Traumatology, St. Vinzenz-Hospital, Dinslaken, Germany
| | - Christoph Becher
- Department of Orthopedic Surgery,
Medical University Annastift, Hannover, Germany
| | - Thomas Kolombe
- Traumatology and Reconstructive Surgery,
DRK Hospital, Luckenwalde, Germany
| | - Jakob Fay
- Department of Traumatology and
Arthroscopic Surgery, Lubinus Clinicum, Kiel, Germany
| | - Stefan Pietsch
- Department of Orthopedic Surgery and
Traumatology, Rudolf Elle Hospital, Eisenberg, Germany
| | - Tomasz Kuźma
- Department of Orthopedic Surgery and
Traumatology, Center of Sports Medicine, Orthopedic Clinic, Warsaw, Poland
| | | | - Stefan Fickert
- Sporthopaedicum Straubing, Straubing,
Germany,Department of Orthopedic Surgery and
Traumatology, Medical Faculty Mannheim, University Medical Centre Mannheim,
University of Heidelberg, Mannheim, Germany
| |
Collapse
|
|
42
|
Juras V, Szomolanyi P, Janáčová V, Kirner A, Angele P, Trattnig S. Differentiation of Cartilage Repair Techniques Using Texture Analysis from T 2 Maps. Cartilage 2021; 13:718S-728S. [PMID: 34269072 PMCID: PMC8808785 DOI: 10.1177/19476035211029698] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/07/2021] [Accepted: 06/07/2021] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE The aim of this study was to investigate texture features from T2 maps as a marker for distinguishing the maturation of repair tissue after 2 different cartilage repair procedures. DESIGN Seventy-nine patients, after either microfracture (MFX) or matrix-associated chondrocyte transplantation (MACT), were examined on a 3-T magnetic resonance (MR) scanner with morphological and quantitative (T2 mapping) MR sequences 2 years after surgery. Twenty-one texture features from a gray-level co-occurrence matrix (GLCM) were extracted. The texture feature difference between 2 repair types was assessed individually for the femoral condyle and trochlea/anterior condyle using linear regression models. The stability and reproducibility of texture features for focal cartilage were calculated using intra-observer variability and area under curve from receiver operating characteristics. RESULTS There was no statistical significance found between MFX and MACT for T2 values (P = 0.96). There was, however, found a statistical significance between MFX and MACT in femoral condyle in GLCM features autocorrelation (P < 0.001), sum of squares (P = 0.023), sum average (P = 0.005), sum variance (P = 0.0048), and sum entropy (P = 0.05); and in anterior condyle/trochlea homogeneity (P = 0.02) and dissimilarity (P < 0.001). CONCLUSION Texture analysis using GLCM provides a useful extension to T2 mapping for the characterization of cartilage repair tissue by increasing its sensitivity to tissue structure. Some texture features were able to distinguish between repair tissue after different cartilage repair procedures, as repair tissue texture (and hence, probably collagen organization) 24 months after MACT more closely resembled healthy cartilage than did MFX repair tissue.
Collapse
Affiliation(s)
- Vladimir Juras
- High-Field MR Centre, Department of
Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna,
Austria
| | - Pavol Szomolanyi
- High-Field MR Centre, Department of
Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna,
Austria
- Institute of Measurement Science,
Slovak Academy of Sciences, Bratislava, Slovakia
| | - Veronika Janáčová
- High-Field MR Centre, Department of
Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna,
Austria
| | | | | | - Siegfried Trattnig
- High-Field MR Centre, Department of
Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna,
Austria
- CD laboratory for Clinical Molecular MR
imaging, Vienna, Austria
- Austrian Cluster for Tissue
Regeneration, Vienna, Austria
- Institute for Clinical Molecular MRI in
the Musculoskeletal System, Karl Landsteiner Society, Vienna, Austria
| |
Collapse
|
|
43
|
Galarraga JH, Locke RC, Witherel CE, Stoeckl BD, Castilho M, Mauck RL, Malda J, Levato R, Burdick JA. Fabrication of MSC-laden composites of hyaluronic acid hydrogels reinforced with MEW scaffolds for cartilage repair. Biofabrication 2021; 14. [PMID: 34788748 DOI: 10.1088/1758-5090/ac3acb] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 11/17/2021] [Indexed: 01/04/2023]
Abstract
Hydrogels are of interest in cartilage tissue engineering due to their ability to support the encapsulation and chondrogenesis of mesenchymal stromal cells (MSCs). However, features such as hydrogel crosslink density, which can influence nutrient transport, nascent matrix distribution, and the stability of constructs during and after implantation must be considered in hydrogel design. Here, we first demonstrate that more loosely crosslinked (i.e. softer, ∼2 kPa) norbornene-modified hyaluronic acid (NorHA) hydrogels support enhanced cartilage formation and maturation when compared to more densely crosslinked (i.e. stiffer, ∼6-60 kPa) hydrogels, with a >100-fold increase in compressive modulus after 56 d of culture. While soft NorHA hydrogels mature into neocartilage suitable for the repair of articular cartilage, their initial moduli are too low for handling and they do not exhibit the requisite stability needed to withstand the loading environments of articulating joints. To address this, we reinforced NorHA hydrogels with polycaprolactone (PCL) microfibers produced via melt-electrowriting (MEW). Importantly, composites fabricated with MEW meshes of 400µm spacing increased the moduli of soft NorHA hydrogels by ∼50-fold while preserving the chondrogenic potential of the hydrogels. There were minimal differences in chondrogenic gene expression and biochemical content (e.g. DNA, GAG, collagen) between hydrogels alone and composites, whereas the composites increased in compressive modulus to ∼350 kPa after 56 d of culture. Lastly, integration of composites with native tissue was assessedex vivo; MSC-laden composites implanted after 28 d of pre-culture exhibited increased integration strengths and contact areas compared to acellular composites. This approach has great potential towards the design of cell-laden implants that possess both initial mechanical integrity and the ability to support neocartilage formation and integration for cartilage repair.
Collapse
Affiliation(s)
- Jonathan H Galarraga
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Ryan C Locke
- Translational Musculoskeletal Research Center, Philadelphia VA Medical Center, Philadelphia, PA, United States of America.,Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Claire E Witherel
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Brendan D Stoeckl
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States of America.,Translational Musculoskeletal Research Center, Philadelphia VA Medical Center, Philadelphia, PA, United States of America.,Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Miguel Castilho
- Department of Orthopaedics, University Medical Center-Utrecht, Utrecht, The Netherlands.,Department of Biomedical Engineering, Technical University of Eindhoven, Eindhoven, The Netherlands
| | - Robert L Mauck
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States of America.,Translational Musculoskeletal Research Center, Philadelphia VA Medical Center, Philadelphia, PA, United States of America.,Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Jos Malda
- Department of Orthopaedics, University Medical Center-Utrecht, Utrecht, The Netherlands.,Department of Clinical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Riccardo Levato
- Department of Orthopaedics, University Medical Center-Utrecht, Utrecht, The Netherlands.,Department of Clinical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Jason A Burdick
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States of America
| |
Collapse
|
|
44
|
Calvo R, Figueroa D, Figueroa F, Bravo J, Contreras M, Zilleruelo N. Treatment of Patellofemoral Chondral Lesions Using Microfractures Associated with a Chitosan Scaffold: Mid-Term Clinical and Radiological Results. Cartilage 2021; 13:1258S-1264S. [PMID: 33906468 PMCID: PMC8808950 DOI: 10.1177/19476035211011506] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE To assess the clinical and radiological results of patellofemoral osteochondral lesions treated with microfractures associated with a chitosan scaffold. DESIGN A retrospective observational analytical study was performed. Fifteen patients with full-thickness patellofemoral osteochondral lesions were included. Quantity and quality of the reparation cartilage was assessed with the MOCART 2.0 score on a postoperative magnetic resonance imaging (MRI), and clinical outcomes were evaluated with pre- and postoperative Kujala score tests. Shapiro-Wilk test for normality was applied as well as Wilcoxon's signed rank test and Kruskal-Wallis H test for clinical scores within subjects and patella versus trochlea subgroups comparisons. Analysis of variance test was used for imaging subgroups comparison, with P < 0.05 defined as statistical significance. RESULTS Mean follow-up was 33.36 months (range 24-60 months). Postoperative Kujala scores improved an average of 19 points compared with the preoperative state (SE = 17.6; P < 0.001). No statistical difference was found through the clinical location assessment (P = 0.756), as well as the cartilage imaging assessment (P = 0.756). The mean MOCART 2.0 scale was 67.67 (range 50-85). CONCLUSIONS Treating full-thickness patellofemoral osteochondral lesions with microfractures associated with a chitosan scaffold proved to be effective regarding defect filling and symptomatic improvement.
Collapse
Affiliation(s)
- Rafael Calvo
- Clinica Alemana–Universidad del
Desarrollo, Santiago, Chile
| | - David Figueroa
- Clinica Alemana–Universidad del
Desarrollo, Santiago, Chile
| | - Francisco Figueroa
- Clinica Alemana–Universidad del
Desarrollo, Santiago, Chile,Hospital Sotero del Rio, Santiago,
Chile,Francisco Figueroa, Clinica
Alemana–Universidad del Desarrollo, Vitacura 5951, Santiago, 22222222, Chile.
| | - Jose Bravo
- Clinica Alemana–Universidad del
Desarrollo, Santiago, Chile
| | | | | |
Collapse
|
|
45
|
Karpinski K, Häner M, Bierke S, Petersen W. Matrix-induced chondrogenesis is a valid and safe cartilage repair option for small- to medium-sized cartilage defects of the knee: a systematic review. Knee Surg Sports Traumatol Arthrosc 2021; 29:4213-4222. [PMID: 33743030 DOI: 10.1007/s00167-021-06513-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 02/19/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE The purpose of this study was to perform a systematic review of randomized controlled trials comparing the results of matrix-induced chondrogenesis with other therapies for local chondral lesions of the knee. METHODS A systematic search for randomized controlled trials (RCT) about matrix-induced chondrogenesis for focal chondral lesions in the knee was performed according to the PRISMA guidelines. Data source was PubMed central, EMBASE and Google scholar. RESULTS Five articles could be included, whereas two originated from the same study group. Three studies compared matrix-induced chondrogenesis to microfracture (MFx) only. One trial compared AMIC® to collagen-covered autologous chondrocyte implantation (ACI-C). One study assessed the improvements given by the combination of AMIC® with bone marrow aspirate concentrate (BMAC). In three studies, clinical improvements compared to baseline were seen at 2-year postoperation, irrespective of the technique used. After 5 years, one trial showed better results for the AMIC® group compared to MFx, including MRI defect filling. One study showed also good results after AMIC® with faster recovery for patients with AMIC® + BMAC 12 months postoperatively. CONCLUSION Results of RCTs comparing matrix-induced chondrogenesis with other treatment options showed that matrix-induced chondrogenesis is a valid and safe cartilage repair option for small- to medium-sized cartilage defects of the knee. This one-stage surgical technique presents a good alternative for patients. LEVEL OF EVIDENCE I.
Collapse
Affiliation(s)
- Katrin Karpinski
- Martin Luther Krankenhaus, Caspar Theyß Str. 27-31, 14193, Berlin, Germany.
| | - Martin Häner
- Martin Luther Krankenhaus, Caspar Theyß Str. 27-31, 14193, Berlin, Germany
| | - Sebastian Bierke
- Martin Luther Krankenhaus, Caspar Theyß Str. 27-31, 14193, Berlin, Germany
| | - Wolf Petersen
- Martin Luther Krankenhaus, Caspar Theyß Str. 27-31, 14193, Berlin, Germany
| |
Collapse
|
|
46
|
Stem cells and regenerative medicine in sport science. Emerg Top Life Sci 2021; 5:563-573. [PMID: 34448473 PMCID: PMC8589434 DOI: 10.1042/etls20210014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 07/29/2021] [Accepted: 08/09/2021] [Indexed: 12/13/2022]
Abstract
The estimated cost of acute injuries in college-level sport in the USA is ∼1.5 billion dollars per year, without taking into account the cost of follow up rehabilitation. In addition to this huge financial burden, without appropriate diagnosis and relevant interventions, sport injuries may be career-ending for some athletes. With a growing number of females participating in contact based and pivoting sports, middle aged individuals returning to sport and natural injuries of ageing all increasing, such costs and negative implications for quality of life will expand. For those injuries, which cannot be predicted and prevented, there is a real need, to optimise repair, recovery and function, post-injury in the sporting and clinical worlds. The 21st century has seen a rapid growth in the arena of regenerative medicine for sporting injuries, in a bid to progress recovery and to facilitate return to sport. Such interventions harness knowledge relating to stem cells as a potential for injury repair. While the field is rapidly growing, consideration beyond the stem cells, to the factors they secrete, should be considered in the development of effective, affordable treatments.
Collapse
|
|
47
|
Garcia-Ruiz A, Sánchez-Domínguez CN, Moncada-Saucedo NK, Pérez-Silos V, Lara-Arias J, Marino-Martínez IA, Camacho-Morales A, Romero-Diaz VJ, Peña-Martinez V, Ramos-Payán R, Castro-Govea Y, Tuan RS, Lin H, Fuentes-Mera L, Rivas-Estilla AM. Sequential growth factor exposure of human Ad-MSCs improves chondrogenic differentiation in an osteochondral biphasic implant. Exp Ther Med 2021; 22:1282. [PMID: 34630637 PMCID: PMC8461520 DOI: 10.3892/etm.2021.10717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 07/28/2021] [Indexed: 11/17/2022] Open
Abstract
Joint cartilage damage affects 10-12% of the world's population. Medical treatments improve the short-term quality of life of affected individuals but lack a long-term effect due to injury progression into fibrocartilage. The use of mesenchymal stem cells (MSCs) is one of the most promising strategies for tissue regeneration due to their ability to be isolated, expanded and differentiated into metabolically active chondrocytes to achieve long-term restoration. For this purpose, human adipose-derived MSCs (Ad-MSCs) were isolated from lipectomy and grown in xeno-free conditions. To establish the best differentiation potential towards a stable chondrocyte phenotype, isolated Ad-MSCs were sequentially exposed to five differentiation schemes of growth factors in previously designed three-dimensional biphasic scaffolds with incorporation of a decellularized cartilage matrix as a bioactive ingredient, silk fibroin and bone matrix, to generate a system capable of being loaded with pre-differentiated Ad-MSCs, to be used as a clinical implant in cartilage lesions for tissue regeneration. Chondrogenic and osteogenic markers were analyzed by reverse transcription-quantitative PCR and cartilage matrix generation by histology techniques at different time points over 40 days. All groups had an increased expression of chondrogenic markers; however, the use of fibroblast growth factor 2 (10 ng/ml) followed by a combination of insulin-like growth factor 1 (100 ng/ml)/TGFβ1 (10 ng/ml) and a final step of exposure to TGFβ1 alone (10 ng/ml) resulted in the most optimal chondrogenic signature towards chondrocyte differentiation and the lowest levels of osteogenic expression, while maintaining stable collagen matrix deposition until day 33. This encourages their possible use in osteochondral lesions, with appropriate properties for use in clinical patients.
Collapse
Affiliation(s)
- Alejandro Garcia-Ruiz
- Biochemistry and Molecular Medicine Department, Faculty of Medicine and University Hospital 'Dr José E. González', Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Celia N Sánchez-Domínguez
- Biochemistry and Molecular Medicine Department, Faculty of Medicine and University Hospital 'Dr José E. González', Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Nidia K Moncada-Saucedo
- Biochemistry and Molecular Medicine Department, Faculty of Medicine and University Hospital 'Dr José E. González', Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Vanessa Pérez-Silos
- Biochemistry and Molecular Medicine Department, Faculty of Medicine and University Hospital 'Dr José E. González', Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Jorge Lara-Arias
- Orthopedics and Traumatology Service, Faculty of Medicine and University Hospital 'Dr José E. González', Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Iván A Marino-Martínez
- Pathology Department, Faculty of Medicine and University Hospital 'Dr José E. González', Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico.,Experimental Therapies Unit, Center for Research and Development in Health Sciences, Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Alberto Camacho-Morales
- Biochemistry and Molecular Medicine Department, Faculty of Medicine and University Hospital 'Dr José E. González', Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico.,Neurometabolism Unit, Center for Research and Development in Health Sciences, Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Víktor J Romero-Diaz
- Histology Department, Faculty of Medicine and University Hospital 'Dr José E. González', Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Víctor Peña-Martinez
- Orthopedics and Traumatology Service, Faculty of Medicine and University Hospital 'Dr José E. González', Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Rosalío Ramos-Payán
- Microbiology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Sinaloa, Culiacan, Sinaloa 80040, Mexico
| | - Yanko Castro-Govea
- Plastic Surgery Department, Faculty of Medicine and University Hospital 'Dr José E. González', Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Rocky S Tuan
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.,McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Hang Lin
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Lizeth Fuentes-Mera
- Biochemistry and Molecular Medicine Department, Faculty of Medicine and University Hospital 'Dr José E. González', Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Ana María Rivas-Estilla
- Biochemistry and Molecular Medicine Department, Faculty of Medicine and University Hospital 'Dr José E. González', Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| |
Collapse
|
|
48
|
Camacho P, Behre A, Fainor M, Seims KB, Chow LW. Spatial organization of biochemical cues in 3D-printed scaffolds to guide osteochondral tissue engineering. Biomater Sci 2021; 9:6813-6829. [PMID: 34473149 DOI: 10.1039/d1bm00859e] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Functional repair of osteochondral (OC) tissue remains challenging because the transition from bone to cartilage presents gradients in biochemical and physical properties necessary for joint function. Osteochondral regeneration requires strategies that restore the spatial composition and organization found in the native tissue. Several biomaterial approaches have been developed to guide chondrogenic and osteogenic differentiation of human mesenchymal stem cells (hMSCs). These strategies can be combined with 3D printing, which has emerged as a useful tool to produce tunable, continuous scaffolds functionalized with bioactive cues. However, functionalization often includes one or more post-fabrication processing steps, which can lead to unwanted side effects and often produce biomaterials with homogeneously distributed chemistries. To address these challenges, surface functionalization can be achieved in a single step by solvent-cast 3D printing peptide-functionalized polymers. Peptide-poly(caprolactone) (PCL) conjugates were synthesized bearing hyaluronic acid (HA)-binding (HAbind-PCL) or mineralizing (E3-PCL) peptides, which have been shown to promote hMSC chondrogenesis or osteogenesis, respectively. This 3D printing strategy enables unprecedented control of surface peptide presentation and spatial organization within a continuous construct. Scaffolds presenting both cartilage-promoting and bone-promoting peptides had a synergistic effect that enhanced hMSC chondrogenic and osteogenic differentiation in the absence of differentiation factors compared to scaffolds without peptides or only one peptide. Furthermore, multi-peptide organization significantly influenced hMSC response. Scaffolds presenting HAbind and E3 peptides in discrete opposing zones promoted hMSC osteogenic behavior. In contrast, presenting both peptides homogeneously throughout the scaffolds drove hMSC differentiation towards a mixed population of articular and hypertrophic chondrocytes. These significant results indicated that hMSC behavior was driven by dual-peptide presentation and organization. The downstream potential of this platform is the ability to fabricate biomaterials with spatially controlled biochemical cues to guide functional tissue regeneration without the need for differentiation factors.
Collapse
Affiliation(s)
- Paula Camacho
- Department of Bioengineering, Lehigh University, Bethlehem, PA, USA
| | - Anne Behre
- Department of Bioengineering, Lehigh University, Bethlehem, PA, USA
| | - Matthew Fainor
- Integrated Degree in Engineering, Arts, and Sciences Program, Lehigh University, Bethlehem, PA, USA
| | - Kelly B Seims
- Department of Materials Science and Engineering, Lehigh University, Bethlehem, PA, USA.
| | - Lesley W Chow
- Department of Bioengineering, Lehigh University, Bethlehem, PA, USA.,Department of Materials Science and Engineering, Lehigh University, Bethlehem, PA, USA.
| |
Collapse
|
|
49
|
Arthroscopic Subchondral Drilling Followed by Injection of Peripheral Blood Stem Cells and Hyaluronic Acid Showed Improved Outcome Compared to Hyaluronic Acid and Physiotherapy for Massive Knee Chondral Defects: A Randomized Controlled Trial. Arthroscopy 2021; 37:2502-2517. [PMID: 34265388 DOI: 10.1016/j.arthro.2021.01.067] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 01/18/2021] [Accepted: 01/25/2021] [Indexed: 02/02/2023]
Abstract
PURPOSE The purpose of this study was to evaluate the safety and efficacy of intra-articular injections of autologous peripheral blood stem cells (PBSCs) plus hyaluronic acid (HA) after arthroscopic subchondral drilling into massive chondral defects of the knee joint and to determine whether PBSC therapy can improve functional outcome and reduce pain of the knee joint better than HA plus physiotherapy. METHODS This is a dual-center randomized controlled trial (RCT). Sixty-nine patients aged 18 to 55 years with International Cartilage Repair Society grade 3 and 4 chondral lesions (size ≥3 cm2) of the knee joint were randomized equally into (1) a control group receiving intra-articular injections of HA plus physiotherapy and (2) an intervention group receiving arthroscopic subchondral drilling into chondral defects and postoperative intra-articular injections of PBSCs plus HA. The coprimary efficacy endpoints were subjective International Knee Documentation Committee (IKDC) and Knee Injury and Osteoarthritis Outcome Score (KOOS)-pain subdomain measured at month 24. The secondary efficacy endpoints included all other KOOS subdomains, Numeric Rating Scale (NRS), and Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores. RESULTS At 24 months, the mean IKDC scores for the control and intervention groups were 48.1 and 65.6, respectively (P < .0001). The mean for KOOS-pain subdomain scores were 59.0 (control) and 86.0 (intervention) with P < .0001. All other KOOS subdomain, NRS, and MOCART scores were statistically significant (P < .0001) at month 24. Moreover, for the intervention group, 70.8% of patients had IKDC and KOOS-pain subdomain scores exceeding the minimal clinically important difference values, indicating clinical significance. There were no notable adverse events that were unexpected and related to the study drug or procedures. CONCLUSIONS Arthroscopic marrow stimulation with subchondral drilling into massive chondral defects of the knee joint followed by postoperative intra-articular injections of autologous PBSCs plus HA is safe and showed a significant improvement of clinical and radiologic scores compared with HA plus physiotherapy. LEVEL OF EVIDENCE Level I, RCT.
Collapse
|
|
50
|
Crispim JF, Ito K. De novo neo-hyaline-cartilage from bovine organoids in viscoelastic hydrogels. Acta Biomater 2021; 128:236-249. [PMID: 33894352 DOI: 10.1016/j.actbio.2021.04.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/31/2021] [Accepted: 04/01/2021] [Indexed: 12/22/2022]
Abstract
Regenerative therapies for articular cartilage are currently clinically available. However, they are associated with several drawbacks that require resolution. Optimizing chondrocyte expansion and their assembly, can reduce the time and costs of these therapies and more importantly increase their clinical success. In this study, cartilage organoids were quickly mass produced from bovine chondrocytes with a new suspension expansion protocol. This new approach led to massive cell proliferation, high viability and the self-assembly of organoids. These organoids were composed of collagen type II, type VI, glycosaminoglycans, with Sox9 positive cells, embedded in a pericellular and interterritorial matrix similarly to hyaline cartilage. With the goal of producing large scale tissues, we then encapsulated these organoids into alginate hydrogels with different viscoelastic properties. Elastic hydrogels constrained the growth and fusion of the organoids inhibiting the formation of a tissue. In contrast, viscoelastic hydrogels allowed the growth and fusion of the organoids into a homogenous tissue that was rich in collagen type II and glycosaminoglycans. The encapsulation of organoids to produce in vitro neocartilage also proved to be superior to the conventional method of encapsulating 2D expanded chondrocytes. This study describes a multimodal approach that involves chondrocyte expansion, organoid formation and their assembly into neohyaline-cartilage which proved to be superior to the current standard approaches used in cartilage tissue engineering. STATEMENT OF SIGNIFICANCE: In this manuscript, we describe a new and simple methodology to quickly mass produce self-assembling cartilage organoids. Due to their matrix content and structure similarities with native cartilage, these organoids on their own have the potential to revolutionize cartilage research and the manner in which we study signaling pathways, disease progression, tissue engineering, drug development, etc. Furthermore, these organoids and their fast mass production were combined with a key relatively ignored hydrogel characteristic, viscoelasticity, to demonstrate their fusion into a neo-tissue. This has the potential to open the door for large scale cartilage regeneration such as for entire joint surfaces.
Collapse
Affiliation(s)
- João F Crispim
- Orthopaedic Biomechanics group, Regenerative Engineering & Materials cluster, Dept. of Biomedical Engineering and the Institute for Complex Molecular Systems, Eindhoven University of Technology, The Netherlands.
| | - Keita Ito
- Orthopaedic Biomechanics group, Regenerative Engineering & Materials cluster, Dept. of Biomedical Engineering and the Institute for Complex Molecular Systems, Eindhoven University of Technology, The Netherlands.
| |
Collapse
|