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Cartilage Repair and Restorative Procedures

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Orthopedics".

Deadline for manuscript submissions: closed (20 September 2019) | Viewed by 43931

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Dr. Giuseppe Filardo

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Applied and Translational Research Center, Rizzoli Orthopaedic Institute, Via Di Barbiano 1/10, 40136 Bologna, Italy
Interests: cartilage; osteochondral; knee; scaffold; injectives

Dr. Laura de Girolamo

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Orthopaedic Biotechnology Laboratory, IRCCS Galeazzi Orthopaedic Institute, Via R. Galeazzi 4, 20161 Milan, Italy
Interests: regenerative medicine; mesenchymal stem cells; cartilage; tendon

Special Issue Information

Dear Colleagues,

Articular chondral lesions are a common cause of disability, often associated with pain, a reduction of joint mobility, and a loss of function, and may predispose patients to osteoarthritis, which entails a huge social impact. It is well known that articular cartilage has a very limited capacity for self-repair, because of the intrinsic biological features of this tissue; this makes cartilage lesions still a major challenge for orthopaedic surgeons and researchers. Although the last decades have brought several improvements in this field, such as the understanding of the subchondral involvement in many of these lesions, the extension of treatment indications not only to focal traumatic cases, and the documentation of the outcome of both traditional treatments and more ambitious regenerative strategies, the clinical results are still only partially satisfactory. In this light, there is a need to develop more effective treatment options, to be translated and tested in the clinical practice, as well to understand the best indications for such treatments in the light of their results over time. We, therefore, welcome the submission of studies focusing on “Cartilage Repair and Restorative Procedures”, from preclinical and early experiences of new treatments, to the definition of potential limitations, up to a long-term follow-up of both traditional and new approaches, as well as studies aimed at identifying the responders and factors that might help to improve the management of patients affected by cartilage lesions.

Dr. Giuseppe Filardo
Dr. Laura de Girolamo
Guest Editors

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Keywords

Cartilage
Regenerative medicine
Osteochondral
Scaffold
Injective treatments

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Published Papers (11 papers)

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Research

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12 pages, 1232 KiB

Open AccessArticle

Evaluation of Patellar Contact Pressure Changes after Static versus Dynamic Medial Patellofemoral Ligament Reconstructions Using a Finite Element Model

by Vicente Sanchis-Alfonso, Gerard Ginovart, Diego Alastruey-López, Erik Montesinos-Berry, Joan Carles Monllau, Angel Alberich-Bayarri and María Angeles Pérez

J. Clin. Med. 2019, 8(12), 2093; https://doi.org/10.3390/jcm8122093 - 1 Dec 2019

Cited by 15 | Viewed by 4011

Abstract

Objectives: To evaluate the effect of various medial patellofemoral ligament (MPFL) fixation techniques on patellar pressure compared with the native knee. Methods: A finite element model of the patellofemoral joint consisting of approximately 30,700 nodes and 22,200 elements was created from computed tomography scans of 24 knees with chronic lateral patellar instability. Patellar contact pressures and maximum MPFL graft stress at five positions of flexion (0°, 30°, 60°, 90°, and 120°) were analyzed in three types of MPFL reconstruction (MPFLr): (1) static/anatomic, (2) dynamic, using the adductor magnus tendon (AMT) as the femoral fixation, and (3) dynamic, using the quadriceps tendon as the attachment (medial quadriceps tendon-femoral ligament (MQTFL) reconstruction). Results: In the static/anatomic technique, the patellar contact pressures at 0° and 30° were greater than in the native knee. As in a native knee, the contact pressures at 60°, 90°, and 120° were very low. The maximum MPFL graft stress at 0° and 30° was greater than in a native knee. However, the MPFL graft was loose at 60°, 90°, and 120°, meaning it had no tension. In the dynamic MPFLr using the AMT as a pulley, the patellar contact pressures were like those of a native knee throughout the entire range of motion. However, the maximum stress of the MPFL graft at 0° was less than that of a native ligament. Yet, the maximum MPFL graft stress was greater at 30° than in a native ligament. After 30° of flexion, the MPFL graft loosened, similarly to a native knee. In the dynamic MQTFL reconstruction, the maximum patellar contact pressure was slightly greater than in a normal knee. The maximum stress of the MPFL graft was much greater at 0° and 30° than that of a native MPFL. After 30° of flexion, the MQPFL graft loosened just as in the native knee. Conclusions: The patellar contact pressures after the dynamic MPFLr were like those of the native knee, whereas a static reconstruction resulted in greater pressures, potentially increasing the risk of patellofemoral osteoarthritis in the long term. Therefore, the dynamic MPFLr might be a safer option than a static reconstruction from a biomechanical perspective. Full article

(This article belongs to the Special Issue Cartilage Repair and Restorative Procedures)

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9 pages, 460 KiB

Open AccessArticle

Cell-Free Osteochondral Scaffold for the Treatment of Focal Articular Cartilage Defects in Early Knee OA: 5 Years’ Follow-Up Results

by Andrea Sessa, Luca Andriolo, Alessandro Di Martino, Iacopo Romandini, Roberto De Filippis, Stefano Zaffagnini and Giuseppe Filardo

J. Clin. Med. 2019, 8(11), 1978; https://doi.org/10.3390/jcm8111978 - 14 Nov 2019

Cited by 15 | Viewed by 2332

Abstract

The purpose of this study was to investigate the clinical results at five years’ follow-up of a tri-layered nanostructured biomimetic osteochondral scaffold used for focal articular cartilage defects in patients meeting the criteria of early osteoarthritis (EOA). The study population comprised 22 patients (mean age: 39 years), prospectively assessed before surgery, at 24 and 60 months’ follow-up. Inclusion criteria were: at least two episodes of knee pain for more than 10 days in the last year, Kellgren-Lawrence OA grade 0, I or II and arthroscopic or MRI findings according to the European Society of Sports Traumatology, Knee Surgery & Arthroscopy (ESSKA) criteria. Clinical results demonstrated significant improvement in International Knee Documentation Committee (IKDC) subjective and objective scores and in Tegner score, although activity level never reached the pre-injury level. The complication rate of this study was 8.3%. Two patients underwent re-operation (8.3%), while a comprehensive definition of failure (including both surgical and clinical criteria) identified four failed patients (16.6%) at this mid-term follow-up evaluation. The use of a free-cell osteochondral scaffold represented a safe and valid alternative for the treatment of focal articular cartilage defects in the setting of an EOA, and was able to permit a significant clinical improvement and stable outcome with low complication and failure rates. Full article

(This article belongs to the Special Issue Cartilage Repair and Restorative Procedures)

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11 pages, 1640 KiB

Open AccessArticle

Osteoarthritis Severely Decreases the Elasticity and Hardness of Knee Joint Cartilage: A Nanoindentation Study

by Adam Aron Mieloch, Magdalena Richter, Tomasz Trzeciak, Michael Giersig and Jakub Dalibor Rybka

J. Clin. Med. 2019, 8(11), 1865; https://doi.org/10.3390/jcm8111865 - 3 Nov 2019

Cited by 27 | Viewed by 3429

Abstract

The nanoindentation method was applied to determine the elastic modulus and hardness of knee articular cartilage. Cartilage samples from both high weight bearing (HWB) and low weight bearing (LWB) femoral condyles were collected from patients diagnosed with osteoarthritis (OA). The mean elastic modulus of HWB cartilage was 4.46 ± 4.44 MPa in comparison to that of the LWB region (9.81 ± 8.88 MPa, p < 0.001). Similarly, the hardness was significantly lower in HWB tissue (0.317 ± 0.397 MPa) than in LWB cartilage (0.455 ± 0.434 MPa, p < 0.001). When adjusted to patients’ ages, the mean elastic modulus and hardness were both significantly lower in the age group over 70 years (p < 0.001). A statistically significant difference in mechanical parameters was also found in grade 3 and 4 OA. This study provides an insight into the nanomechanical properties of the knee articular cartilage and provides a starting point for personalized cartilage grafts that are compatible with the mechanical properties of the native tissue. Full article

(This article belongs to the Special Issue Cartilage Repair and Restorative Procedures)

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16 pages, 2598 KiB

Open AccessArticle

Re-Differentiation Capacity of Human Chondrocytes in Vitro Following Electrical Stimulation with Capacitively Coupled Fields

by Simone Krueger, Sophie Achilles, Julius Zimmermann, Thomas Tischer, Rainer Bader and Anika Jonitz-Heincke

J. Clin. Med. 2019, 8(11), 1771; https://doi.org/10.3390/jcm8111771 - 24 Oct 2019

Cited by 27 | Viewed by 3839

Abstract

Treatment of cartilage lesions remains a clinical challenge. Therefore, biophysical stimuli like electric fields seem to be a promising tool for chondrocytic differentiation and treatment of cartilage lesions. In this in vitro study, we evaluated the effects of low intensity capacitively coupled electric fields with an alternating voltage of 100 mV_RMS (corresponds to 5.2 × 10⁻⁵ mV/cm) or 1 V_RMS (corresponds to 5.2 × 10⁻⁴ mV/cm) with 1 kHz, on human chondrocytes derived from osteoarthritic (OA) and non-degenerative hyaline cartilage. A reduction of metabolic activity after electrical stimulation was more pronounced in non-degenerative cells. In contrast, DNA contents in OA cells were significantly decreased after electrical stimulation. A difference between 100 mV_RMS and 1 V_RMS was not detected. However, a voltage-dependent influence on gene and protein expression was observed. Both cell types showed increased synthesis rates of collagen (Col) II, glycosaminoglycans (GAG), and Col I protein following stimulation with 100 mV_RMS, whereas this increase was clearly higher in OA cells. Our results demonstrated the sensitization of chondrocytes by alternating electric fields, especially at 100 mV_RMS, which has an impact on chondrocytic differentiation capacity. However, analysis of further electrical stimulation parameters should be done to induce optimal hyaline characteristics of ex vivo expanded human chondrocytes. Full article

(This article belongs to the Special Issue Cartilage Repair and Restorative Procedures)

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15 pages, 5478 KiB

Open AccessArticle

Effects of rAAV-Mediated sox9 Overexpression on the Biological Activities of Human Osteoarthritic Articular Chondrocytes in Their Intrinsic Three-Dimensional Environment

by Oliver Daniels, Janina Frisch, Jagadeesh K. Venkatesan, Ana Rey-Rico, Gertrud Schmitt and Magali Cucchiarini

J. Clin. Med. 2019, 8(10), 1637; https://doi.org/10.3390/jcm8101637 - 7 Oct 2019

Cited by 7 | Viewed by 2607

Abstract

Gene therapy for osteoarthritis offers powerful, long-lasting tools that are well adapted to treat such a slow, progressive disorder, especially those therapies based on the clinically adapted recombinant adeno-associated viral (rAAV) vectors. Here, we examined the ability of an rAAV construct carrying a therapeutic sequence for the cartilage-specific SOX9 transcription factor to modulate the phenotype of human osteoarthritic articular chondrocytes compared with normal chondrocytes in a three-dimensional environment where the cells are embedded in their extracellular matrix. Successful sox9 overexpression via rAAV was noted for at least 21 days, leading to the significant production of major matrix components (proteoglycans, type-II collagen) without affecting the proliferation of the cells, while the cells contained premature hypertrophic processes relative to control conditions (reporter rAAV-lacZ application, absence of vector treatment). These findings show the value of using rAAV to adjust the osteoarthritic phenotype when the chondrocytes are confined in their inherently altered environment and the possibility of impacting key cellular processes via gene therapy to remodel human osteoarthritic cartilage lesions. Full article

(This article belongs to the Special Issue Cartilage Repair and Restorative Procedures)

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14 pages, 3495 KiB

Open AccessArticle

Remodeling of Human Osteochondral Defects via rAAV-Mediated Co-Overexpression of TGF-β and IGF-I from Implanted Human Bone Marrow-Derived Mesenchymal Stromal Cells

by Stephanie Morscheid, Jagadeesh Kumar Venkatesan, Ana Rey-Rico, Gertrud Schmitt and Magali Cucchiarini

J. Clin. Med. 2019, 8(9), 1326; https://doi.org/10.3390/jcm8091326 - 28 Aug 2019

Cited by 6 | Viewed by 2479

Abstract

The application of chondrogenic gene sequences to human bone marrow-derived mesenchymal stromal cells (hMSCs) is an attractive strategy to activate the reparative activities of these cells as a means to enhance the processes of cartilage repair using indirect cell transplantation procedures that may improve the repopulation of cartilage lesions. In the present study, we examined the feasibility of co-delivering the highly competent transforming growth factor beta (TGF-β) with the insulin-like growth factor I (IGF-I) in hMSCs via recombinant adeno-associated virus (rAAV) vector-mediated gene transfer prior to implantation in a human model of osteochondral defect (OCD) ex vivo that provides a microenvironment similar to that of focal cartilage lesions. The successful co-overexpression of rAAV TGF-β/IGF-I in implanted hMSCs promoted the durable remodeling of tissue injury in human OCDs over a prolonged period of time (21 days) relative to individual gene transfer and the control (reporter lacZ gene) treatment, with enhanced levels of cell proliferation and matrix deposition (proteoglycans, type-II collagen) both in the lesions and at a distance, while hypertrophic, osteogenic, and catabolic processes could be advantageously delayed. These findings demonstrate the value of indirect, progenitor cell-based combined rAAV gene therapy to treat human focal cartilage defects in a natural environment as a basis for future clinical applications. Full article

(This article belongs to the Special Issue Cartilage Repair and Restorative Procedures)

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13 pages, 2377 KiB

Open AccessArticle

Intra-Articular Injection of Hydrolyzed Collagen to Treat Symptoms of Knee Osteoarthritis. A Functional In Vitro Investigation and a Pilot Retrospective Clinical Study

by Paola De Luca, Alessandra Colombini, Giulia Carimati, Michelangelo Beggio, Laura de Girolamo and Piero Volpi

J. Clin. Med. 2019, 8(7), 975; https://doi.org/10.3390/jcm8070975 - 4 Jul 2019

Cited by 22 | Viewed by 5096

Abstract

Among all joints affected, knee osteoarthritis has a prevalence of about 10% in men and 13% in women over 60 years old. Knee osteoarthritis has high economic and social costs and may have a devastating impact on patient quality of life. Treatment of symptomatic knee Osteoarthritis may involve oral or topical administration of non-steroidal anti-inflammatory drugs or intra-articular injection of corticosteroids. Recently, a novel injectable collagen formulation (ChondroGrid) consisting of bovine hydrolyzed <3 kDa type I collagen has been developed and is currently available on the market as an injectable medical device. The primary objective of this study was to investigate the in vitro and in vivo effects of ChondroGrid in treating knee osteoarthritis symptoms to assess its safety and performance. Viability and proliferation of ChondroGrid-exposed human chondrocytes derived from five donors were assessed through the Alamar Blue/CyQuant assays. Their expression of MMP1/MMP3 and TIMP1/TIMP3 was then assessed through RT-PCR and that of TGFβ1, IGF-I, and VEGF using ELISA assays. Shape and ECM deposition were assessed using the Bern score after a 28-day ChondroGrid exposure, and collagen deposition was assessed using immunostaining. Records of 20 patients affected by Kellgren Lawrence grade 1 to 4 knee osteoarthritis who received three 4 mg/2 mL ChondroGrid injections 2 weeks apart were then retrospectively assessed to compare VAS, Lequesne, and WOMAC scores collected before and 15, 45, and 225 days after the first injection. ChondroGrid had no effects on the markers under consideration, but induced type-II and inhibited type-I collagen deposition; the Bern score was higher when cells were cultured with ChondroGrid. Patients experienced a 44% Lequesne score and a 55% VAS at moving score reduction. All other scores decreased >70%. ChondroGrid may prompt chondrocytes to produce hyaline cartilage, prevent fibrous tissue formation, and be a safe and effective adjuvant to treat symptomatic knee osteoarthritis. Full article

(This article belongs to the Special Issue Cartilage Repair and Restorative Procedures)

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15 pages, 36789 KiB

Open AccessArticle

Human Diseased Articular Cartilage Contains a Mesenchymal Stem Cell-Like Population of Chondroprogenitors with Strong Immunomodulatory Responses

by Paola De Luca, Dimitrios Kouroupis, Marco Viganò, Carlotta Perucca-Orfei, Lee Kaplan, Luigi Zagra, Laura de Girolamo, Diego Correa and Alessandra Colombini

J. Clin. Med. 2019, 8(4), 423; https://doi.org/10.3390/jcm8040423 - 28 Mar 2019

Cited by 48 | Viewed by 3866

Abstract

Background: osteoarthritic human articular cartilage (AC)-derived cartilage cells (CCs) with same-donor bone marrow (BMSCs) and adipose tissue (ASCs)-derived mesenchymal stem cells were compared, in terms of stemness features, and secretory and immunomodulatory responses to inflammation. Methods: proteoglycan 4 (PRG4) presence was evaluated in AC and CCs. MSCs and CCs (n = 8) were cultured (P1 to P4) and characterized for clonogenicity, nanog homeobox (NANOG), and POU class 5 homeobox 1 (POU5F1) expression, immunotypification, and tri-lineage differentiation. Their basal and interleukin-1β (IL-1β)-stimulated expression of matrix metalloproteases (MMPs), tissue inhibitors (TIMPs), release of growth factors, and cytokines were analyzed, along with the immunomodulatory ability of CCs. Results: PRG4 was mainly expressed in the intact AC surface, whereas shifted to the intermediate zone in damaged cartilage and increased its expression in CCs upon culture. All cells exhibited a similar phenotype and stemness maintenance over passages. CCs showed highest chondrogenic ability, no adipogenic potential, a superior basal secretion of growth factors and cytokines, the latter further increased after inflammatory stimulation, and an immunomodulatory behavior. All stimulated cells shared an increased MMP expression without a corresponding TIMP production. Conclusion: based on the observed features, CCs obtained from pathological joints may constitute a potential tissue-specific therapeutic target or agent to improve damaged cartilage healing, especially damage caused by inflammatory/immune mediated conditions. Full article

(This article belongs to the Special Issue Cartilage Repair and Restorative Procedures)

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15 pages, 3146 KiB

Open AccessArticle

Autologous Matrix-Induced Chondrogenesis (AMIC) and AMIC Enhanced by Autologous Concentrated Bone Marrow Aspirate (BMAC) Allow for Stable Clinical and Functional Improvements at up to 9 Years Follow-Up: Results from a Randomized Controlled Study

by Laura de Girolamo, Herbert Schönhuber, Marco Viganò, Corrado Bait, Alessandro Quaglia, Gabriele Thiebat and Piero Volpi

J. Clin. Med. 2019, 8(3), 392; https://doi.org/10.3390/jcm8030392 - 21 Mar 2019

Cited by 48 | Viewed by 4953

Abstract

The aims of the study were to evaluate long-term outcomes after autologous matrix-induced chondrogenesis (AMIC) in the treatment of focal chondral lesions and to assess the possible improvements given by the combination of this technique with bone marrow aspirate concentrate (BMAC). Twenty-four patients (age range 18–55 years) affected by focal knee chondral lesions were treated with standard AMIC or AMIC enhanced by BMAC (AMIC+). Pain (Visual Analogue Scale (VAS)) and functional scores (Lysholm, International Knee Documentation Committee (IKDC), Tegner, Knee injury and Osteoarthritis Outcome Score (KOOS)) were collected pre-operatively and then at 6, 12, 24, 60, and 100 months after treatment. Magnetic resonance imaging (MRI) evaluation was performed pre-operatively and at 6, 12, and 24 months follow-ups. Patients treated with AMIC+ showed higher Lysholm scores (p = 0.015) and lower VAS (p = 0.011) in comparison with patients in the standard AMIC group at the 12 months follow-up. Both treatments allowed for functional and pain improvements with respect to pre-operative levels lasting up to 100 months. MRI revealed consistent cartilage repair at 24 months in both groups. This study shows that AMIC and AMIC+ are effective treatments for focal chondral lesions with beneficial effect lasting up to 9 years. AMIC+ allows for faster recovery from injury, and is thus more indicated for patients requiring a prompt return to activity. Level of evidence: II, randomized controlled trial in an explorative cohort. Full article

(This article belongs to the Special Issue Cartilage Repair and Restorative Procedures)

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Review

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16 pages, 1029 KiB

Open AccessReview

Secretome and Extracellular Vesicles as New Biological Therapies for Knee Osteoarthritis: A Systematic Review

by Daniele D’Arrigo, Alice Roffi, Magali Cucchiarini, Matteo Moretti, Christian Candrian and Giuseppe Filardo

J. Clin. Med. 2019, 8(11), 1867; https://doi.org/10.3390/jcm8111867 - 4 Nov 2019

Cited by 66 | Viewed by 6649

Abstract

Secretome and extracellular vesicles (EVs) are considered a promising option to exploit mesenchymal stem cells’ (MSCs) properties to address knee osteoarthritis (OA). The aim of this systematic review was to analyze both the in vitro and in vivo literature, in order to understand the potential of secretome and EVs as a minimally invasive injective biological approach. A systematic review of the literature was performed on PubMed, Embase, and Web of Science databases up to 31 August 2019. Twenty studies were analyzed; nine in vitro, nine in vitro and in vivo, and two in vivo. The analysis showed an increasing interest in this emerging field, with overall positive findings. Promising in vitro results were documented in terms of enhanced cell proliferation, reduction of inflammation, and down-regulation of catabolic pathways while promoting anabolic processes. The positive in vitro findings were confirmed in vivo, with studies showing positive effects on cartilage, subchondral bone, and synovial tissues in both OA and osteochondral models. However, several aspects remain to be clarified, such as the different effects induced by EVs and secretome, which is the most suitable cell source and production protocol, and the identification of patients who may benefit more from this new biological approach for knee OA treatment. Full article

(This article belongs to the Special Issue Cartilage Repair and Restorative Procedures)

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14 pages, 598 KiB

Open AccessReview

MaioRegen Osteochondral Substitute for the Treatment of Knee Defects: A Systematic Review of the Literature

by Riccardo D’Ambrosi, Federico Valli, Paola De Luca, Nicola Ursino and Federico Giuseppe Usuelli

J. Clin. Med. 2019, 8(6), 783; https://doi.org/10.3390/jcm8060783 - 1 Jun 2019

Cited by 41 | Viewed by 4115

Abstract

Background: This study aims to investigate the clinical and radiological efficacy of three-dimensional acellular scaffolds (MaioRegen) in restoring osteochondral knee defects. Methods: MEDLINE, Scopus, CINAHL, Embase, and Cochrane Databases were searched for articles in which patients were treated with MaioRegen for osteochondral knee defects. Results: A total of 471 patients were included in the study (mean age 34.07 ± 5.28 years). The treatment involved 500 lesions divided as follows: 202 (40.4%) medial femoral condyles, 107 (21.4%) lateral femoral condyles, 28 (5.6%) tibial plateaus, 46 (9.2%) trochleas, 74 (14.8%) patellas, and 43 (8.6%) unspecified femoral condyles. Mean lesion size was 3.6 ± 0.85 cm². Only four studies reported a follow-up longer than 24 months. Significant clinical improvement has been reported in almost all studies with further improvement up to 5 years after surgery. A total of 59 complications were reported of which 52 (11.1%) experienced minor complications and 7 (1.48%) major complications. A total of 16 (3.39%) failures were reported. Conclusion: This systematic review describes the current available evidence for the treatment of osteochondral knee defects with MaioRegen Osteochondral substitute reporting promising satisfactory and reliable results at mid-term follow-up. A low rate of complications and failure was reported, confirming the safety of this scaffold. Considering the low level of evidence of the study included in the review, this data does not support the superiority of the Maioregen in terms of clinical improvement at follow-up compared to conservative treatment or other cartilage techniques. Full article

(This article belongs to the Special Issue Cartilage Repair and Restorative Procedures)

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