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Extended Abstract (for invited Faculty only) Chondrocytes

0.1 - Introduction: 21st Century Cartilage Regeneration in Germany

Presentation Topic
Chondrocytes
Date
12.04.2022
Lecture Time
10:00 - 10:15
Room
Potsdam 3
Session Type
Plenary Session

Abstract

Introduction

For 30 years several regenerative cartilage treatment procedures are in clinical use in Germany. Not all of them are available in other countries inside and outside Europe.

Content

According to guidelines from the working group “Clinical Tissue Regeneration” of the German Society of Orthopaedics and Trauma (DGOU) the selection of a distinct regenerative cartilage treatment procedure is dependent on cartilage defect size, the involvement of the subchondral plate and the underlying subchondral bone. Of course, further patient-specific parameters, like BMI, sport / work activities and patient expectations will further help to choose the most suitable regenerative cartilage treatment procedure for an individual patient. Also the necessity of treating the comorbidities (Leg axis deviation, instability, meniscus tear) has to be included in the treatment plan of the patients.

Microfracture is still the most frequently used technique for cartilage repair, also in Germany. In order to be successful with microfracture, one should use it only in small defects (<2cm2) or combine it with cell free biomaterials.

The indication of Osteochondral transplantation (OCT) has narrowed over the years. It is indicated for small, mainly osteochondral defects, which allow sufficient treatment with one or two osteochondral plugs. For larger defects, the donor-side morbidity is of concern.

Autologous chondrocyte implantation (ACI) is an established and well-accepted procedure for the treatment of localised full-thickness cartilage defects of the knee. This technique is available and widely used in Germany. Due to regulatory burdens in terms of harvest and culture of chondrocytes, the organizational effort of this technique is high. Therefore, this technique is mainly performed in center with specialization to cartilage treatment. In Germany, 3 different chondrocyte-based transplantation techniques are available (Novocart 3D (Aesculap, TETEC), Novocart inject (Aesculap, TETEC), Spherox (Codon). According to the German cartilage registry, which include over 10.000 patients, treated with regenerative cartilage procedures, the outcome of the 3 techniques is significant but comparable with each other. Based on best available scientific evidence, an indication for ACI is given for symptomatic cartilage defects, not only for traumatic but also for early-OA cartilage defects, starting from defect sizes of more than 2 cm2, while advanced degenerative joint disease needs to be considered as the most important contraindication.

Due to the limited access to osteochondral allografts, special sandwich techniques were developed in Germany to address bone and cartilage defects in huge osteochondral defects. The talk will describe recent developed techniques and show outcome results.

Unfortunately, recent advances in stem cell technology could not be translated in the clinic due to regulatory burdens in Germany. The use of these techniques in clinical trials would be of interest.

A newly developed cartilage repair procedure, minced cartilage technique, is used in Germany. The advantage is an one-step cartilage repair procedure without the regulatory burdens of the ACI technique. First results are promising, however, prospective outcome results are not available.

The rehabilitation after regenerative cartilage repair procedures is long. After ACI a return to sport is possible approximately after 1 year. Return to sport tests are used in Germany in order to analyze the neuromuscular ability for pivoting sports after 1year. The talk will show the need for these return to sport tests to avoid further reinjuries after rehabilitation.

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Extended Abstract (for invited Faculty only) Cartilage and Meniscus

0.2 - Matrix-Induced Autologous Cartilage Repair (MACR) – An Update

Presentation Topic
Cartilage and Meniscus
Date
12.04.2022
Lecture Time
10:15 - 10:30
Room
Potsdam 3
Session Type
Plenary Session
Disclosure
Gille J: Grant Research Support, Geistlich Biomaterials

Abstract

Introduction

Articular cartilage lesions are a common pathology of the knee joint even in young patients resulting in pain and function loss. ith time). Given the limitations of MFx, efforts have focused on modifications and augmentation techniques for improving the quality of the repair tissue. Autologous, matrix-induced chondrogenesis (AMIC) is an enhanced MFx technique by covering the microfractured lesion site with a collagen I/III membrane in the knee (ChondroGide®, Geistlich Pharma AG).

Content

In basic science, Kramer et al. showed in an in-vitro work that a membrane consisting of collagen can retain cartilage building cells, like, e.g., mesenchymal stem cells from bone marrow after microfracturing [1]. Dickhut et al. [2] demonstrated in another in-vitro study that a biphasic carrier made of collagen type I/III supports chondrogenesis of MSCs and further that in comparison to collagen-free-membrane the form stability of the repair tissue was enhanced.

In vivo, 1 long-term study in sheep showed that AMIC significantly enhanced the cartilaginous repair tissue volume (eg, defect fill) compared with microfracture alone [3].

Intial clincal studies that have investigated short-term and medium-term follow-up cohorts suggest that AMIC in cartilage repair is a safe and effective treatment option that improves patient outcome measures and pain [4, 5]. To assess extended effectiveness and reliability of the AMIC procedure as well as the durability of the repaired cartilage, long-term follow up is essential. Two studies provide longer term data following an AMIC procedure, in which significant clinical and functional improvement was maintained over the 7-year follow-up [6, 7]. The AMIC procedure can be either performed with an open surgical approach or arthroscopically [8].

Steinwachs et al. summarize the results of 12 studies including 375 patients in a recent meta-analysis. The authors conclude that the AMIC procedure significantly improved the clinical status and functional scoring versus preoperative values [9].

References

[1] Kramer J, Böhrnsen F, Lindner U, Behrens P, Schlenke P, Rohwedel J. In vivo matrix-guided human mesenchymal stem cells. Cell Mol Life Sci 2006; 63: 616-626 [PMID: 16482398 DOI: 10.1007/s00018-005-5527-z]

[2] Dickhut A, Gottwald E, Steck E, Heisel C, Richter W. Chondrogenesis of mesenchymal stem cells in gel-like biomaterials in vitro and in vivo. Front Biosci 2008; 13: 4517-4528 [PMID: 18508526 DOI: 10.2741/3020]

[3] Gille J, Kunow J, Boisch L, Behrens P, Bos I, Hoffmann C, Köller W, Russlies M, Kurz B. Cell-Laden and Cell-Free Matrix-Induced Chondrogenesis versus Microfracture for the Treatment of Articular Cartilage Defects: A Histological and Biomechanical Study in Sheep. Cartilage 2010; 1: 29-42 [DOI: 10.1177/1947603509358721]

[4] Gille J, Behrens P, Volpi P, et al. Outcome of Autologous Matrix Induced Chondrogenesis (AMIC) in cartilage knee surgery: data of the AMIC Registry. Arch Orthop Trauma Surg. 2013;133(1):87-93.

[5] Gille J, Schuseil E, Wimmer J, et al. Mid-term results of Autologous Matrix-Induced Chondrogenesis for treatment of focal cartilage defects in the knee. Knee Surg Sports Traumatol Arthrosc. 2010;18(11):1456-1464.

[6] Schiavone Panni A, Del Regno C, Mazzitelli G, et al. Good clinical results with autologous matrix-induced chondrogenesis (AMIC) technique in large knee chondral defects. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA. 2018;26(4):1130-1136.

[7] Gille J, Reiss E, Freitag M et al. AMIC for treatment of focal cartilage defects in the knee. Orthopaedic Journal of Sports Medicine. 2021; 66, 9(2) 2325967120981872

[8] Schagemann J, Behrens P, Paech A, et al. Mid-term outcome of arthroscopic AMIC for the treatment of articular cartilage defects in the knee joint is equivalent to mini-open procedures. Arch Orthop Trauma Surg. 2018;138(6):819-825.

[9] Steinwachs MR, Gille J, Volz M, et al. Systematic Review and Meta-Analysis of the Clinical Evidence on the Use of Autologous Matrix-Induced Chondrogenesis in the Knee. Cartilage. 2019:1947603519870846.

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Extended Abstract (for invited Faculty only) Microfracture/Bone Marrow Stimulation

0.3 - Is it About Time to Abandon Microfracture?

Presentation Topic
Microfracture/Bone Marrow Stimulation
Date
12.04.2022
Lecture Time
10:30 - 10:45
Room
Potsdam 3
Session Type
Plenary Session

Abstract

Content

Hyaline articular cartilage is critical for the normal functioning of the knee joint. Untreated focal cartilage defects have the potential to rapidly progress to diffuse osteoarthritis. Over the last several decades, a variety of interventions aiming at preserving articular cartilage and preventing osteoarthritis have been investigated. There have been numerous clinical studies that support the use of marrow-stimulation techniques.

Reparative cartilage procedures, such as microfracture, penetrate the subchondral bone plate in effort to fill focal cartilage defects with marrow elements and stimulate fibrocartilaginous repair.

Although microfracture is still a popular iteration of marrow stimulation, many leaders in the field question the technique’s sustainability (1,2). Unquestionably, the early clinical outcomes of microfracture have been proven positive; however, a loss of benefit has been described after ~2 years raising concerns of the technique’s validity (3). Complications are not uncommon, such as early OA reported in 40–50% of cases (4,5) and bone overgrowth which is visualized on MRI in 63% of cases at 2 years. Whilst over- growth is rarely symptomatic, with no significant difference in KOOS scores between those radiographically diagnosed with or without overgrowth, it does predict a significantly higher failure rate (25% vs. 3%) (6). Risk factors for poorer outcomes include long-standing symptoms, poor baseline Lysholm score, concurrent mild degenerative changes or partial meniscectomy (7). Long-term outcomes have been negatively correlated with increased age, larger defects ( > 2.5 cm2), and increased BMI (BMI > 30 kg/m2) (8). Furthermore, several authors have reported suboptimal outcomes in highly active and athletic patients (9). Microfracture when applied in young patients with smaller lesions can offer good clinical results at short- and long-term follow-up; lesion size is more important prognostic factor of outcome than age. Deterioration of the clinical outcome should be expected after 2 and 5 years post-treatment and degenerative changes are present at long-term follow-up corroborated by several authors.

Conclusion: Isolated microfracture is a non anatomical treatment compromising intact anatomical structures leading to avoidable complications and therefore should be abandoned instead of superior alternative therapies which furthermore have proven to be more cost effective in the long run.

References

1)Case JM, Scopp JM. Treatment of articular cartilage defects of the knee with microfracture and enhanced microfracture techniques. Sports Med Arthrosc Rev. 2016;24:63–68.

2) Steinwachs MR, Guggi T, Kreuz PC. Marrow stimulation techniques. Injury. 2008;39(suppl 1):S26–S31.

3)Gudas R, Gudaite A, Pocius A, et al. Ten-year follow-up of a prospective, randomized clinical study of mosaic osteochondral autologous transplantation versus microfracture for the treatment of osteochondral defects in the knee joint of athletes. Am J Sports Med. 2012;40:2499–2508.

4)Knutsen G, Drogset JO, Engebretsen L, Grontvedt T, Ludvigsen TC, Loken S, et al. A randomized multicenter trial comparing au- tologous chondrocyte implantation with microfracture: long-term follow-up at 14 to 15 years. J Bone Joint Surg Am. 2016;98: 1332–9.

5)Ulstein S, Aroen A, Rotterud JH, Loken S, Engebretsen L, Heir S. Microfracture technique versus osteochondral autologous trans- plantation mosaicplasty in patients with articular chondral lesions of the knee: a prospective randomized trial with long-term follow- up. Knee Surg Sports Traumatol Arthrosc. 2014;22:1207–15.

6)Mithoefer K, Venugopal V, Manaqibwala M. Incidence, degree, and clinical effect of subchondral bone overgrowth after microfracture in the knee. Am J Sports Med. 2016;44:2057–63.

7)Solheim E, Hegna J, Inderhaug E, Oyen J, Harlem T, Strand T. Results at 10–14 years after microfracture treatment of articular cartilage defects in the knee. Knee Surg Sports Traumatol Arthrosc. 2016;24:1587–93.

8)Mithoefer K, McAdams T, Williams RJ, et al. Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis. Am J Sports Med. 2009;37:2053–2063.

9)Harris JD, Walton DM, Erickson BJ, et al. Return to sport and performance after microfracture in the knees of National Basketball Association Players. Orthop J Sports Med. 2013;1: 2325967113512759.

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Extended Abstract (for invited Faculty only) Please select your topic

0.4 - Arthroscopic Matrix-Assisted Chondrocyte Transplantation (MACT) – State of the Art?

Presentation Topic
Please select your topic
Date
12.04.2022
Lecture Time
10:45 - 11:00
Room
Potsdam 3
Session Type
Plenary Session
Extended Abstract (for invited Faculty only) Please select your topic

0.5 - Minced Cartilage – A Promising New Technique

Presentation Topic
Please select your topic
Date
12.04.2022
Lecture Time
11:00 - 11:15
Room
Potsdam 3
Session Type
Plenary Session
Extended Abstract (for invited Faculty only) Rehabilitation and Sport

0.6 - Rehabilitation After Cartilage Procedures – Do We Need Special Concepts?

Presentation Topic
Rehabilitation and Sport
Date
12.04.2022
Lecture Time
11:15 - 11:30
Room
Potsdam 3
Session Type
Plenary Session

Abstract

Introduction

The rehabilitation of cartilage-regenerative interventions, especially after autologous chondrocyte transplantation, is a scientifically well-studied field. There are several randomized, controlled studies with a follow-up of up to 10 years that surveyed various follow-up treatment schemes [2–5, 15].

Content

The extent of postoperative weightbearing of the treated leg plays an important role in early rehabilitation after cartilage intervention. Especially in that point the rehabilitation differs significantly from other sport-orthopedic interventions such as anterior cruciate ligament reconstructions (ACLR) or meniscus surgery. Already in a review from 2006 it became apparent that the point in time at which full weight-bearing was permitted varied greatly between the different centers; for patellofemoral interventions between 6 hours and 12 weeks [9]. Because the patella does not articulate with the trochlea in full extension up to about 20° flexion, or only to an extent, in 2003 the "Oscell protocol" stipulated direct postoperative full weight bearing with a permitted range of motion (ROM) of 0/0/30 recommended [1]. This recommendation was also made in a consensus of US orthopedists in 2020 [8]. A scientific investigation in the sense of a controlled study or a specific clinical and/or radiological trials of this early full weight-bearing has not yet taken place. Wondrasch and Ebert examined the radiological and functional outcome of earlier full weightbearing (after up to 6 weeks) in multiple studies with a follow-up of up to 10 years and showed that a scheme with increasing weight-bearing with return to full weight-bearing after 6 weeks is safe. In all those randomized controlled trials, patients were prescribed a range of motion (ROM) controlled orthosis as well as CPM (Continuous Passive Motion). The flexion for the CPM was limited to 30°-40° and the use was recommended for 1-3 hours a day [1, 3, 8, 12, 15]. The use of passive motor movement can be found in many study protocols and aftercare recommendations from various societies and centers after cartilage regenerative interventions even though there are no randomized controlled studies on their use after cartilage regenerative therapies. Individual studies have demonstrated an advantage both subjectively and histologically [13].

One subject which is implemented in many rehabilitation protocols, but was never studied individually is the need and duration of postoperative immobilization or bed rest.

Throughout the whole rehabilitation process the integrity and safety of the “new” cartilage plays the most important role and influence not only early rehabilitation. That is also the reason why it is reasonable to refer cartilage patient to physiotherapeutic facilities that are familiar with the aftercare, so that the right amount of training is applied. In comparison to ACLR return to low- and high-impact sports are recommended at later timepoints for patients who underwent cartilage repair. Study protocols and recommendations from different cartilage societies show similar timeframes for return to different sport intensities: very-low-impact (ergometer, walking, exercises in closed-chain) after 7 weeks, rowing ergometer, cross-trainer, and open-chain exercises after 12 weeks, jogging (starting on a treadmill) after 6 months and return to high-impact-sports after 1 year [2, 6, 7, 10, 14]. Whereas the late rehabilitation is not as well studied scientifically as the early rehabilitation, such that there are no controlled trials on that topic. One study of Niethammer at al. from 2014 showed within a group of 44 patients, that the ones returning to high-impact sports after 12 months or more, showed significantly better results after two years [11].

In summary: we definitely need special concepts for patients undergoing cartilage repair. Many aspects of the rehabilitation are scientifically well studied, but many open questions remain, such as postoperative bed rest, very early full weight-bearing after cartilage repair in the patellofemoral compartment, and timepoints in return to low- and high-impact sports as well as patient-and therapeutic-individual cofounders.

References

1. Bailey A, Goodstone N, Roberts S et al (2003) Rehabilitation after oswestry autologous-chondrocyte implantation: The Oscell protocol. Journal of Sport Rehabilitation 12:104–118. https://doi.org/10.1123/jsr.12.2.104

2. Ebert JR, Edwards PK, Fallon M et al (2017) Two-Year Outcomes of a Randomized Trial Investigating a 6-Week Return to Full Weightbearing after Matrix-Induced Autologous Chondrocyte Implantation. American Journal of Sports Medicine 45:838–848. https://doi.org/10.1177/0363546516673837

3. Ebert JR, Fallon M, Ackland TR et al (2020) Minimum 10-Year Clinical and Radiological Outcomes of a Randomized Controlled Trial Evaluating 2 Different Approaches to Full Weightbearing After Matrix-Induced Autologous Chondrocyte Implantation. American Journal of Sports Medicine 48:133–142. https://doi.org/10.1177/0363546519886548

4. Ebert JR, Fallon M, Wood DJ, Janes GC (2021) An accelerated 6-week return to full weight bearing after matrix-induced autologous chondrocyte implantation results in good clinical outcomes to 5 years post-surgery. Knee Surgery, Sports Traumatology, Arthroscopy. https://doi.org/10.1007/s00167-020-06422-6

5. Ebert JR, Fallon M, Zheng MH et al (2012) A randomized trial comparing accelerated and traditional approaches to postoperative weightbearing rehabilitation after matrix-induced autologous chondrocyte implantation: Findings at 5 years. American Journal of Sports Medicine 40:1527–1537. https://doi.org/10.1177/0363546512445167

6. Edwards PK, Ackland T, Ebert JR (2014) Clinical rehabilitation guidelines for matrix-induced autologous chondrocyte implantation on the tibiofemoral joint. Journal of Orthopaedic and Sports Physical Therapy 44:102–119. https://doi.org/10.2519/jospt.2014.5055

7. Edwards PK, Ackland TR, Ebert JR (2013) Accelerated weightbearing rehabilitation after matrix-induced autologous chondrocyte implantation in the tibiofemoral joint: Early clinical and radiological outcomes. American Journal of Sports Medicine 41:2314–2324. https://doi.org/10.1177/0363546513495637

8. Flanigan DC, Sherman SL, Chilelli B et al (2020) Consensus on Rehabilitation Guidelines among Orthopedic Surgeons in the United States following Use of Third-Generation Articular Cartilage Repair (MACI) for Treatment of Knee Cartilage Lesions. Cartilage. https://doi.org/10.1177/1947603520968876

9. Hambly K, Bobic V, Wondrasch B et al (2006) Autologous chondrocyte implantation postoperative care and rehabilitation: Science and practice. American Journal of Sports Medicine 34:1020–1038. https://doi.org/10.1177/0363546505281918

10. Hirschmüller A, Baur H, Braun S et al (2011) Rehabilitation after autologous chondrocyte implantation for isolated cartilage defects of the knee. American Journal of Sports Medicine 39:2686–2696. https://doi.org/10.1177/0363546511404204

11. Niethammer TR, Müller PE, Safi E et al (2014) Early resumption of physical activities leads to inferior clinical outcomes after matrix-based autologous chondrocyte implantation in the knee. Knee Surgery, Sports Traumatology, Arthroscopy 22:1345–1352. https://doi.org/10.1007/s00167-013-2583-z

12. Pietschmann MF, Horng A, Glaser C et al (2014) Post-treatment rehabilitation after autologous chondrocyte implantation: State of the art and recommendations of the clinical tissue regeneration study group of the German Society for Accident Surgery and the German Society for Orthopedics and Orthopedic. Unfallchirurg 117:235–241. https://doi.org/10.1007/s00113-012-2293-x

13. Rogan S, Taeymans J, Hirschmüller A et al (2013) Wirkung von passiven Motorbewegungsschienen nach knorpelregenerativen Eingriffen - eine systematische Literaturübersicht. Zeitschrift fur Orthopadie und Unfallchirurgie 151:468–474. https://doi.org/10.1055/s-0033-1350707

14. Villa S della, Kon E, Filardo G et al (2010) Does intensive rehabilitation permit early return to sport without compromising the clinical outcome after arthroscopic autologous chondrocyte implantation in highly competitive athletes? American Journal of Sports Medicine 38:68–77. https://doi.org/10.1177/0363546509348490

15. Wondrasch B, Zak L, Welsch GH, Marlovits S (2009) Effect of Accelerated Weightbearing after Matrix-Associated Autologous Chondrocyte Implantation on the Femoral Condyle on Radiographic and Clinical Outcome after 2 Years: A Prospective, Randomized Controlled Pilot Study. American Journal of Sports Medicine 37:88S-96S. https://doi.org/10.1177/0363546509351272

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Extended Abstract (for invited Faculty only) Please select your topic

1.1.1 - Cartilage Repair - The Clinical Perspective

Presentation Topic
Please select your topic
Date
12.04.2022
Lecture Time
12:00 - 12:15
Room
Potsdam 1
Session Type
Special Session
Extended Abstract (for invited Faculty only) Please select your topic

1.1.2 - Cartilage Repair - The Register Perspective

Presentation Topic
Please select your topic
Date
12.04.2022
Lecture Time
12:15 - 12:30
Room
Potsdam 1
Session Type
Special Session
Extended Abstract (for invited Faculty only) Microfracture/Bone Marrow Stimulation

1.1.3 - Cartilage Repair - The Translational Perspective

Presentation Topic
Microfracture/Bone Marrow Stimulation
Date
12.04.2022
Lecture Time
12:30 - 12:45
Room
Potsdam 1
Session Type
Special Session

Abstract

Introduction

Cartilage defects represent common, acquired intra-articular pre-osteoarthritic deformities that disturb as the structural integrity of the osteochondral unit.

Content

It is important to distinguish the well-defined focal non-OA defects such as occurring after trauma from the ill-defined large OA defects. Cartilage regeneration is defined as the identical reduplication of the original hyaline articular cartilage structure, while repair results in a disorganized, non-stratified fibrocartilage. Chondral defects are restricted to the articular cartilage. Based on their depth, they are classified as partial- or full-thickness chondral defects. Osteochondral defects extend into the subchondral bone, disrupting its entire functional unit. Spontaneously, chondral defects are only sparsely repopulated by cells from the synovium while mesenchymal stromal cells (MSCs) originating from the bone marrow induce an (insufficient) repair of osteochondral defects, a paradigm exploited in marrow-stimulating techniques. The reason for treating a symptomatic focal cartilage defect is twofold. First, it is to provide for a repair tissue that fills the defect. Second, the repair tissue restores local joint congruity and stabilizes the adjacent cartilage by integrating with it, restoring load distribution and thereby possibly preventing perifocal OA progression. Although the natural history of an untreated cartilage defect is difficult to predict, lesion size may increase, both in symptomatic or asymptomatic patients and induce OA. In general, symptomatic focal articular cartilage defects extending to more than 50% of cartilage depth are treated. A chondral defect may primarily be treated with a chondral repair technique, leaving the underlying subchondral bone untouched. Small chondral defects can be treated with marrow stimulation techniques, small osteochondral defects with a single osteochondral auto- or allograft. Large chondral defects are ideally managed with autologous chondrocyte implantation. Large osteochondral defects can be treated by combining ACI with autologous cancellous bone grafting, using multiple osteochondral autografts or a large single osteochondral allograft. Surgical refixation of a detached (osteo)chondral fragment, if possible, is highly desirable as it regenerates the original joint congruence.

This talk will outline translational aspects of cartilage repair with a focus on the osteochondral unit. Problems of subchondral bone repair, among which upward migration of the subchondral bone plate, formation of intralesional osteophytes, development of subchondral bone cysts and changes of subchondral bone microarchitecture will be covered. Moreover, effects of instrument morphology on osteochondral repair upon marrow stimulation based on investigations in large animal models of cartilage defects will be outlined. Precise topographical investigations on the development of knee osteoarthritis affected by axial alignment caused by meniscal defects will be elaborated on. Finally, biomaterial based gene therapy approaches for cartilage defects will be covered.

References

Hunziker EB, Lippuner K, Keel MJ, Shintani N. An educational review of cartilage repair: precepts & practice--myths & misconceptions--progress & prospects. Osteoarthritis Cartilage 2015; 23: 334-350

Sanders TL, Pareek A, Obey MR, Johnson NR, Carey JL, Stuart MJ, et al. High Rate of Osteoarthritis After Osteochondritis Dissecans Fragment Excision Compared With Surgical Restoration at a Mean 16-Year Follow-up. Am J Sports Med 2017; 45: 1799-1805.

Madry H, Hunziker EB. 'Actum ne agas'. Osteoarthritis Cartilage 2021; 29: 300-303.

Orth P, Cucchiarini M, Kohn D, Madry H. Alterations of the subchondral bone in osteochondral repair--translational data and clinical evidence. Eur Cell Mater 2013; 25: 299-316; discussion 314-296.

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Extended Abstract (for invited Faculty only) Cartilage /Cell Transplantation

1.1.4 - Cartilage Repair - The Research Perspective

Presentation Topic
Cartilage /Cell Transplantation
Date
12.04.2022
Lecture Time
12:45 - 13:00
Room
Potsdam 1
Session Type
Special Session

Abstract

Introduction

Introduction

Focal chondral or osteochondral lesions can be painful and disabling because they have insufficient intrinsic repair potential, and constitute one of the major extrinsic risk factors for osteoarthritis (OA). Articular cartilage lesions greater than 5 mm2 do not heal spontaneously and if left untreated they lead, after a long asymptomatic interval, to full clinical OA. The major challenges in regenerative medicine for cartilage repair are restoration of a biomechanically competent extracellular matrix (ECM) and intimate integration of this newly synthesized matrix within the resident tissue. To address this specific challenge, autologous chondrocyte implantation (ACI) was developed and has paved the way for novel cell-based therapy and biomaterial-assisted cartilage engineering. However, long-term quality of the regenerated ECM is often compromised, in particular when proceeded to OA. Fragile neocartilage constructs produced by implanted or injected mesenchymal stem cells (MSCs) or chondrocytes may undergo rapid degradation when situated in inflamed or diseased joints. Therefore the underlying pathology must be brought effectively under control, because otherwise any cell-based or otherwise regenerative treatment strategy of OA is unlikely to be successful long-term. This knowledge implies that cartilage repair lacks a one-for-all therapy and research for long-term regeneration options is ongoing yet (Grässel & Lorenz, 2014).

Content

Content

In my talk, I would like to present the advantages of cell-free versus cell-based repair strategies in cartilage pathology from the research perspective focussing on mesenchymal stem cells (MSC) or adipose derived stem cells (ASC) and their secretome. In the past years, the musculoskeletal research field has seen an increased interest in the MSC secretome and, in particular in extracellular vesicles (EVs), due to their prognostic and therapeutic potential. EV secretion has been shown for virtually any cell type. EVs carry proteins, lipids and nucleic acids and thus are critically involved in cell-to-cell communication. EVs participate in autocrine, paracrine and systemic signalling processes and have accordingly been detected in most body fluids. There is increasing evidence for a critical role of EVs in both progression of musculoskeletal diseases as well as tissue regeneration. Therapeutic application of MSC-EVs revealed overall positive effects in various situations of musculoskeletal trauma, including repair of chondral and osteochondral lesions. EV therapy after joint trauma and concurrent cartilage injury, the main risk factor for the development of post-traumatic osteoarthritis (PTOA), can be therefore of critical importance to avoid pathogenesis of OA. There is increasing consent that MSC/ASC-EVs could protect cartilage and bone from degradation during OA pathogenesis by increasing the expression of chondrogenic markers. In that line, our group and others demonstrated that pre-treatment of MSCs with different factors, as TGFß or anti-inflammatory compounds as curcumin among others, can improve the effectiveness of EVs in cartilage regeneration. Influencing the composition of EV cargo through ex vivo pre-treatment and/or pre-activation of MSCs/ASCs with different factors thus constitute another interesting therapeutic approach to maximize pro-regenerative potential of EVs. Overall, stem cell secretomes and EVs applied intra-articularly for the treatment of cartilage pathology in knee OA had pleiotropic and mostly positive effects. Pre-clinical in vivo studies in rat, mouse and rabbit OA models resulted in positive effects on the joints and supported the effectiveness of EV intra-articular injections as a minimally invasive therapy (Grässel & Muschter, 2020).

Taken together, intra-articular EV injection might be a promising approach to prevent the development of PTOA and to improve structural damage of joint tissues in chronic OA. Moreover, EVs might enable hyaline cartilage restoration without fibrous tissue formation; thus, facilitating one of the most challenging issues in cartilage regeneration, which was not achieved so far using cell-based therapies. Considering the poor intrinsic regenerative capacity of adult human articular cartilage, it might be reasonable to apply EVs directly after a traumatic incidence to achieve an early harm reduction and reduce the risk of irreversible cartilage damage and structural tissue alteration.

However, many details of the EV biology is to be revealed yet and the biggest hurdle in EV research so far are inconsistent preparation and characterization methods. In addition, it is not fully understood how the parental cell produces EVs and incorporates the potential therapeutic effective molecules into the EVs. A detailed understanding of how the recipient cell internalizes EVs is critical to increase therapeutic effects of EVs and to develop highly efficient EVs for drug delivery and even gene therapy. This will be a requirement for the translation of EV-based procedures to clinical application.

Nevertheless, there is a big need for new therapeutic strategies in musculoskeletal diseases as incidences are increasing with an ever-growing aging population and cell-based therapies have shown limited success so far. In this light, EV-based therapies, which can circumvent many of the disadvantages related to cell therapies have a tremendous potential. EV-based therapies may also benefit from EV-engineering approaches that aim at modulating either the cargo or the targeting of EVs in order to improve their therapeutic efficiency. This includes the use of EVs as drug delivery vehicle and particularly for the delivery of lipophilic small molecules. EVs can overcome also problems arising from low solubility or bioavailability of molecules, as we and others could demonstrate for the anti-inflammatory agent curcumin. However, in common for all those features of EVs is that we still lack the full insight in underlying mechanisms and functional active components, which are responsible for the observed effects of EVs (Herrmann et al., 2021).

References

Grässel S. & Lorenz J.: Tissue-Engineering Strategies to Repair Chondral and Osteochondral Tissue in Osteoarthritis: Use of Mesenchymal Stem Cells. 2014, Curr. Rheumatol. Rep., Review, Doi: 10.1007/s11926-014-0452-5

Grässel S. & Muschter D.: Recent advances in the treatment of osteoarthritis. 2020, F1000Research, Review, Doi: 10.12688/f1000research.22115.1

Herrmann M., Diederichs S., Melnik S., Riegger J., Trivanovic D., Li S., Jenei-Lanzl Z., Brenner RE., Huber-Lang M., Zaucke F., Schildberg FA., Grässel S.: Extracellular vesicles in musculoskeletal pathologies and regeneration. 2021, Frontiers in Bioengineering & Biotechnology, Review, Doi: 10.3389/fbioe.2020.624096

Acknowledgments

This work was supported by a grant from the DFG (GR1301/19-1/2) and a grant from the DGOOC for establishing a German stem cell net work.

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Extended Abstract (for invited Faculty only) Osteoarthritis

1.2.1 - Role of Exosomal Connexin43 in Chondrocyte Senescence and OA Progression

Presentation Topic
Osteoarthritis
Date
12.04.2022
Lecture Time
12:00 - 12:15
Room
Potsdam 3
Session Type
Special Session

Abstract

Introduction

Role of exosomal connexin43 in chondrocyte senescence and OA progression

The accumulation of senescent cells is a key characteristic of aging, leading to the progression of age-related pathologies such as osteoarthritis (OA). Previous data from our laboratory has demonstrated that high levels of the transmembrane protein connexin43 (Cx43) are associated with a senescent phenotype in chondrocytes from osteoarthritic cartilage. OA has been reclassified as a musculoskeletal disease characterized by the breakdown of the articular cartilage affecting the whole joint, subchondral bone, synovium, ligaments, tendons and muscles. However, the mechanisms that contribute to the spread of pathogenic factors throughout the joint tissues are still unknown. Here, we show for the first time that small extracellular vesicles (sEVs) released by human OA-derived chondrocytes contain high levels of Cx43 and are able to induce a senescent phenotype in targeted chondrocytes, synovial and bone cells contributing to the formation of an inflammatory and degenerative joint environment by the secretion of senescence-associated secretory associated phenotype (SASP) molecules, including IL-1ß and IL-6 and MMPs. The enrichment of Cx43 changes the protein profile and activity of the secreted sEVs. Our results indicate a dual role for sEVs containing Cx43 inducing senescence and activating cellular plasticity in target cells mediated by NF-kß and the extracellular signal-regulated kinase 1/2 (ERK1/2), inducing epithelial-to-mesenchymal transition (EMT) signalling program and contributing to the loss of the fully differentiated phenotype. Our results demonstrated that Cx43-sEVs released by OA-derived chondrocytes spread senescence, inflammation and reprogramming factors involved in wound healing failure to neighboring tissues, contributing to the progression of the disease among cartilage, synovium, and bone and probably from one joint to another. These results highlight the importance for futures studies to consider sEVs positive for Cx43 as a new biomarker of disease progression and new target to treat OA.

Content

Role of exosomal connexin43 in chondrocyte senescence and OA progression

The accumulation of senescent cells is a key characteristic of aging, leading to the progression of age-related pathologies such as osteoarthritis (OA). Previous data from our laboratory has demonstrated that high levels of the transmembrane protein connexin43 (Cx43) are associated with a senescent phenotype in chondrocytes from osteoarthritic cartilage. OA has been reclassified as a musculoskeletal disease characterized by the breakdown of the articular cartilage affecting the whole joint, subchondral bone, synovium, ligaments, tendons and muscles. However, the mechanisms that contribute to the spread of pathogenic factors throughout the joint tissues are still unknown. Here, we show for the first time that small extracellular vesicles (sEVs) released by human OA-derived chondrocytes contain high levels of Cx43 and are able to induce a senescent phenotype in targeted chondrocytes, synovial and bone cells contributing to the formation of an inflammatory and degenerative joint environment by the secretion of senescence-associated secretory associated phenotype (SASP) molecules, including IL-1ß and IL-6 and MMPs. The enrichment of Cx43 changes the protein profile and activity of the secreted sEVs. Our results indicate a dual role for sEVs containing Cx43 inducing senescence and activating cellular plasticity in target cells mediated by NF-kß and the extracellular signal-regulated kinase 1/2 (ERK1/2), inducing epithelial-to-mesenchymal transition (EMT) signalling program and contributing to the loss of the fully differentiated phenotype. Our results demonstrated that Cx43-sEVs released by OA-derived chondrocytes spread senescence, inflammation and reprogramming factors involved in wound healing failure to neighboring tissues, contributing to the progression of the disease among cartilage, synovium, and bone and probably from one joint to another. These results highlight the importance for futures studies to consider sEVs positive for Cx43 as a new biomarker of disease progression and new target to treat OA.

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Extended Abstract (for invited Faculty only) Please select your topic

1.2.2 - The Role of Extracellular Vesicles in Cellular Senescence in Synovial Joints; Disease and Regeneration (Pre-Recorded)

Presentation Topic
Please select your topic
Date
12.04.2022
Lecture Time
12:15 - 12:30
Room
Potsdam 3
Session Type
Special Session