Physicians
Whenever one thing ends, another begins – That´s our opportunity
The incidence of damage caused to knee and ankle joints, by accidents, sporting injuries and strains, has increased continuously in recent years. The fact that defective cartilage cannot regenerate itself, in adults in particular, represents a major problem in this respect, meaning that operative reconstructive intervention is often called for to delay and avoid arthrosis or the implantation of artificial joints. In Germany alone, the number of people suffering from arthrosis is estimated to be several million. Worldwide, too, the number of implants of artificial knee joints is rising constantly. One key reason for this is non- or insufficiently treated cartilage damage lead to further arthrosis of the knee joint.
First presented in 1994, autologous cartilage cell transplanting – or ACT – is the first procedure through which full-layer defects in joint cartilage can be permanently re-covered with hyaline-like cartilage, using the body’s own cells.
Existing methods for treating cartilage defects:
Refixation
Detached fragments of bone cartilage are re-fixed in fresh injuries.
Tissue-response procedure (microfracturing)
With smaller defects, the cartilage is reconstructed following microfracturing of the bone lamella using precursor cells from the spinal cord. In most cases, however, this results in a biomechanically inferior scar tissue, often referred to as “fibrous cartilage”. In larger defects in particular, this regenerated tissue fails relatively quickly, and clinical results tend to be disappointing. On smaller defects and in younger patients, on the other hand, this method can be used successfully in many cases.
Osteocondral transplantation (OCT)
Unlike these methods, ACT delivers extremely good results on larger traumatic defects of up to 14 cm2. The use of NOVOCART®3D allows for gentle reconstruction in a short OP time with overwhelmingly positive clinical results.
ACT cannot yet be used to treat generalized arthroses. Intensive work is currently being conducted in research, however, to enable even such degenerative joint diseases to be therapeutically treated using tissue-engineered products.
With NOVOCART®3D, the foundation stones for this have already been laid.
However, ACT remains a complex procedure, not least due to the complicated process of cell cultivation. To ensure successful application of NOVOCART® products, we train the treating physician extensively in theory and practice and provide assistance in the correct indication and cartilage extraction, through the use of a specially developed set of instruments, as well as support in transplantation and follow-up treatment.
Why ACT?
The biological function of cartilage transplantation
The limited ability hyaline joint cartilage has to heal itself has long been known and is essentially due to its extraordinary structure and anatomy. As it has no direct nerve or vascular supply, it receives its nutrition predominantly via lengthy stretches of diffusion from the synovia in the joint interior.
The highly specialized chondrocytes are largely "interred" in the compact extracellular matrix of the cartilage and are therefore immobilized. In addition, the cell impoverished joint cartilage has no direct access to the tissue-specific regenerative cell populations after the closure of the growth plates. Because of this, following damage to the cartilage there is generally an absence of immigration and cultivation processes through specialized progenitor cells. The absence of this important and early part of an intrinsic regeneration response leads in turn, depending on the nature and extent of the damage, to a complete lack of replenishment of the defect or the formation of an inferior biomechanical replacement tissue.
The key biological task of autologous cartilage cell transplantation and procedures developed from it, is to compensate for these lacking steps in intrinsic healing to induce healing of the cartilage damage to the fullest degree possible. Transplanted cells must therefore be capable of colonizing the existing defect in a robust state, in order to subsequently build it up again with biomechanically superior basic cartilage substance through the synthesis and secretion of cartilage specific matrix proteins.
Clinical results
Every therapy thrives on success – Reported success rates of up to 90% with ACT
The first clinical experience with ACT (autologous chondrocyte transplantation) was reported on in 1994 by Brittberg et al. The primary success rate then stood at over 75% with clinically good and very good outcomes. The new formation of "hyaline-like" articular cartilage was histologically proven. These results were confirmed later by many other authors. The term "hyaline-like" was chosen because following the ACT a zonal structure formation, such as the one which exists in healthy hyaline cartilage had not yet been observed, although the biochemical constitution and the biomechanical weight bearing capacity of the newly formed cartilage basic structure corresponds closely to that of hyaline cartilage.
Both the results of long-term studies conducted and the results of prospective randomized studies show that ACT is superior to other methods at the latest in cartilage damage with a defect area of over 4 cm2. Consequently, ACT has since been recommended as the primary therapeutic procedure for defects of this size and given indications by the national German specialist associations for trauma surgery (DGU) and for orthopedics (DGOOC).
Initial first clinical trials indicate that even patients with limited degenerative cartilage damage benefit from an ACT. In addition, the use of NOVOCART® 3D allows for simpler, quicker application, principally for defects with unmaintained containment (= incomplete cartilage margin).
A number of authors reported the formation of biomechanically inferior replacement (fibrous) cartilage following an ACT. Reasons discussed for the cause of this have been false determination of indications, variable cell culture conditions and/or the resultant variable transplant quality. According to current knowledge, the cause of treatment failure of ACT could also be intraoperative injuries to the subchondral bone lamella or an insufficient periost covering (with the conventional form of ACT).
Altogether, over a period of over 14 years, clinical trials have now reported success rates of up to 90%. Various studies of ACT show that the success of the procedure is essentially dependent on the abovementioned factors:
Indication, cell quality and correct operative technique
The procedure introduced by TETEC takes these learnings fully into account. An innovative isolation and cultivation process results in excellent cell quality, guaranteed through the regular conducting of quality assurance controls. The biphasic support material developed by our working group especially for human cartilage cells makes transplantation of the cells both safer and more straightforward.
Cell biology
How we turn 2% cell volume into 100% quality
Hyaline articular cartilage is a cell impoverished tissue Its cell volume contributes only around 1 to 3% of the total volume of cartilage. The main components of the cartilage substance – collagen Type-II and aggrecan – are produced by the chondrocyte and are of key importance due to their extraordinary biomechanical properties.
To achieve a high-quality reconstruction outcome, transplanted cartilage cells must therefore be capable of synthesizing these matrix components. If chondrocytes are cultivated in cell culture for the purposes of cell multiplication, they can lose their cartilage specific qualities, depending on the method and duration of cultivation. This process, also known as “dedifferentiation”, is also associated with the ongoing loss of synthesis capability for cartilage-specific matrix proteins. In this state, the dedifferentiated chondrocytes takes on the properties of fibroblast-like cells, which mainly produce collagen Type-I. Type 1 collagen in healthy hyaline cartilage, however, is not a component of cartilage's basic structure and is at most present in greater amounts in articular cartilage which has been changed by arthrosis, or biomechanicallly inferior replacement (fibre) cartilage.
Using the isolation and cultivation procedure developed by TETEC, it is possible to cultivate sufficient cells with cartilage-specific metabolic performance from joint cartilage. The optimized cells cultivated using this procedure also show high metabolic performance for collagen Type-II, aggrecan and cartilage-relevant growth factors such as BMP-2 (bone morphogenic protein-2), without the use of controversial genetic methods. Colagen Type-II and aggrecan are the most important matrix proteins of the hyaline cartilage.
In a comparative study, conducted by a research group independent of TETEC, into the biological properties of various support-based ACT procedures available in Europe, NOVOCART 3D® emerged as the only product to contain largely highly differentiated (i.e. high quality) cartilage cells. Similarly, impressive properties have been demonstrated for the hydrogel used in the manufacture of NOVOCART® Inject and NOVOCART® Disc.
Quality assurance
Building trust through quality and safety
Special instrument set for extraction and transplantation
Working in conjunction with Aesculap AG, we have developed special instruments for extracting biopsies and for the transplantation of autologous chondrocytes. These make the OP procedure both easier and more standardized. The instruments can be provided on a loan basis without additional cost, and serviced and maintained by Aesculap.
Manufacture
From the beginning of the process to the point where they are ready to ship, manufacture of all NOVOCART® products takes place in state-of-the-art, GMP-compliant cleanroom facilities equipped with isolators that meet the requirements of cleanroom class A. All steps in the process are standardized, and are continually checked and documented. By using only tested homologous serum and barring animal-derived ingredients from the culture procedure, we are in a position to practically exclude the possibility of immunological reactions or the transfer of infections of animal origin. We use neither antibiotics nor antimycotics. In addition, we conduct repeated sterility checks.
Production period
The manufacture of NOVOCART® 3D and NOVOCART® Inject takes exactly three weeks from the point at which the biopsy is extracted. With NOVOCART® Disc, the cultivated disc cells are transplanted three months after operative removal of the disc prolapse. The relatively long period between extraction and transplantation must be adhered to in order to ensure that the fibrous ring (annulus fibrosus) surrounding the ring is fully healed.
Quality checks and records
The high quality of the cells and molecular biology of the transplant are checked using state-of-the-art analysis techniques (e.g. quantitative PCR) immediately prior to the return of the product to the user. Detailed log sheets with concluding test reports on the sterility tests, cellular and microbiological analyses are prepared for each transplant. Along with the product, the user receives a concluding test report which, in addition to information as to the sterility tests conducted, contains detailed information about cell vitality and the quantitative expression analyses performed.
The binding “Resolution on quality assurance measures to be applied for autologous chondrocytes in the knee joint”, issued by Germany’s Joint Federal Committee (GBA) in line with section 137c of the country’s Social Act (SGB) is fully taken into account in respect of our products. ACT with NOVOCART3D is this a reimbursable procedure under Germany’s statutory health insurance scheme (GKV).
Our research team has been recognized with the Scientific Award of the Association for Orthopaedic Research (AFOR) for the cellular and microbiological principles of the culture procedure developed by TETEC for retaining the differentiated phenotype of chondrocytes.