In the present study, we showed the benefit and reliability of the use of the autologous gel-polymer-based cartilage tissue engineering graft BioSeed-C for the treatment of full-thickness cartilage defects of the knee. The evaluation of the clinical outcome 2 years after implantation demonstrated that BioSeed-C is well suited for the treatment of patients with posttraumatic and mild degenerative defects as well as for the treatment of focal osteoarthritic defects.
The implantation of first-generation tissue engineering grafts such as ACI has been shown to be suitable for the regeneration of posttraumatic defects [12
]. However, second-generation cartilage tissue engineering grafts using a variety of matrices to support the autologous chondrocytes were recently considered to be technically more attractive. For instance, Bartlett and colleagues reported the use of a collagen-based scaffold seeded with autologous chondrocytes for the treatment of 47 symptomatic chondral defects. After 1 year, the Cincinnati Knee Rating System score increased by 19.6, and 36.4% of the biopsies showed hyaline-like cartilage or a mixed repair tissue with fibrocartilage. Similar outcomes were obtained for defects treated with 'classical' ACI with a porcine-based collagen membrane covering the defects [21
]. In a prospective study, 5 years after transplantation of cell-seeded collagen grafts, 8 of 11 patients rated the function of their knee better than before, and the clinical evaluation showed significant improvement in the Meyers score, the Lysholm-Gillquist score and the International Cartilage Repair Society score [22
]. In a multicenter retrospective cohort study with Hyalograft C, a graft of autologous chondrocytes embedded in a derivative of hyaluronic acid, 91.5% of 141 patients with a follow-up from 2 to 5 years improved according to the IKDC subjective evaluation, and second-look biopsies showed hyaline-like cartilage [19
]. The use of second-generation cartilage grafts based on collagen or hyaluronan matrices is therefore suggested to be as effective as ACI, both clinically and histologically.
Here we introduced the use of a new second-generation cartilage graft based on a biocompatible and bioresorbable two-component gel-polymer scaffold. The BioSeed-C concept of embedding autologous chondrocytes in a gel-like matrix distributed in a porous three-dimensional textile polymer structure goes back to more than 10 years of cartilage tissue engineering research [24
]. Gel-like matrices such as fibrin allow the even distribution of a large number of vital chondrocytes within the graft and promote chondrocyte differentiation as well as the formation of a cartilaginous repair tissue, while the polymer scaffold mediates initial biomechanical stability and allows easy handling of the graft by the surgeon [23
]. The arrangement of chondrocytes in three-dimensional scaffolds permits the arthroscopic implantation of cells, ensures secure fixation of the graft even in posttraumatic or degenerative defects without intact surrounding cartilage, and avoids the loss of cells into the joint cavity even after implantation in defects without an intact surrounding cartilage rim [28
]. Drobnic and colleagues have shown that the transosseous fixation technique provides excellent stability of the polymer-based graft with high endpoint fixation strength and no detachment after continuous passive motion with loading in the initial postoperative period [39
]. Mechanical testing of the scaffold used in this study showed that the graft withstands a maximal tensile load of up to 15 N when fixed transosseously or by chondral suture, whereas gel-like matrices or collagen membranes ruptured on being loaded with up to 10 N [40
]. The capability of such polymer-based grafts to form an adequate cartilaginous repair tissue has been shown preclinically in several animal studies with cryopreserved and non-cryopreserved chondrocytes [41
]. In addition, in a large-animal model system with Haflinger horses, polymer-based cartilage grafts have been shown to develop a cartilaginous repair tissue that is well integrated into the surrounding cartilage and is firmly bonded to the subchondral bone [27
]. The bioresorbable scaffold material is composed of a copolymer of polyglactin (vicryl) and polydioxanone, shows good biocompatibility, and is frequently used clinically as suture material. In a rabbit dural tissue reaction study, the absorbable polyglactin and polydioxanone material guided tissue development with complete resolution of the inflammatory reaction during absorption and without any morphological sequelae [43
]. Additionally, in cartilage regeneration, various in vitro
and animal studies have shown that the scaffold supports cartilaginous tissue development with no signs of necrosis, apoptosis, or abnormal tissue reaction [26
In this case series we demonstrated the benefit and reliability of the gel-polymer-based chondrocyte graft BioSeed-C for the treatment of posttraumatic and degenerative large full-thickness cartilage lesions of the knee. Histological analysis of the biopsies after implantation of BioSeed-C showed good formation of a cartilaginous repair tissue, and significant improvements in the clinical scores used could be ascertained, implying improvements in activities of daily living, ability to work, and in sports. However, despite these encouraging results one must take into account the fact that randomized clinical trials and long follow-up periods may offer more widespread information about the clinical effectiveness of a given cartilage repair approach [13
]. ACI will therefore not be given an unrestricted recommendation for the treatment of full-thickness cartilage lesions of the knee. Nevertheless, patient status at 2 years of follow-up was reported as an important indicator for future outcome [10
], because most of the complications of ACI occur during this period. In addition, major improvements in clinical scores, clinical evaluation, and subjective patient satisfaction were found during this time; for example, patients who did not return to sports within 2 years did not return later. The features identified as an indicator of a worse prognosis, namely multiple surgical procedures, higher age, and large defects, correspond to findings published by others [21
With the gel-polymer-based three-dimensional cartilage grafts, 18% of the patients in this study underwent second-look arthroscopy as a result of grinding, catching, pain, or swelling of the knee. This is consistent with other studies reporting rates of revision surgery between 0% [48
] and 25% [18
]. Instead, 2 of 79 patients treated with BioSeed-C showed a failure of the graft, which represents a lower rate of graft failure than earlier findings, in which rates of failure in ACI with other implants between 5% [9
] to 13% [18
] were described. Repeat operations using the 'classical' ACI procedure as described by Peterson and Brittberg were mainly caused by problems associated with the periosteal flap [9
]. This disadvantage of the original ACI technique could not occur in patients treated with BioSeed-C. Another advantage of the BioSeed technique is the reduced operating time. Furthermore, the procedure is less invasive because there is no need to harvest periosteum from the tibia. The complication rate is lower because there is no possibility of periosteal hypertrophy, which is a common complication of ACI [15
]. Furthermore, the BioSeed-C procedure can be performed arthroscopically, which may be associated with faster recovery after surgery and with cosmetically better results. However, it should be taken into consideration that performing ACI arthroscopically is technically demanding and the use of specially designed instruments is essential.
After 2 years of follow-up, mean scores increased significantly, between 20 and 35% depending on the score analyzed. This indicates a significant decrease in the patient's pain and knee instabilities during activity. Intriguingly, Cincinnati score improvement at 6 months after implantation of BioSeed-C could be observed only in patients with osteoarthritic degenerations. In addition, patients suffering from osteoarthritic degenerations showed an improved Knee injury and Osteoarthritis Outcome Score in pain, symptoms, and quality of life, whereas scores for patients whose cartilage defects resulted from posttraumatic causes increased only in the quality of life section. According to the impact of the degree of osteoarthritic degeneration, patients with osteoarthritis of the knee reported impairment in four subclasses of the SF-36 score. Obviously, tissue regeneration, improvement in clinical scores, and improvement in patient's quality of life are achieved after implantation of polymer-based autologous cartilage grafts even in osteoarthritic conditions.
Currently, ACI is considered not to be indicated for osteoarthritic patients. In spite of this, many young patients suffer from early stages of osteoarthritis or display deformities predisposing to osteoarthritis that are idiopathic or follow trauma. These patients lack good treatment options and are too young for total joint replacement. This is particularly true for those having an active lifestyle that includes sports or demanding recreational activities. Most of the patients of the present study suffered preoperatively from pain or dysfunction of the knee joint. They frequently underwent several failed cartilage repair procedures, and subsequently had to endure massive restrictions of quality of life, ability to work, and sporting activities. Thus, we consider the outcome of this study as a promising result for the treatment of large cartilage lesions of the knee, particularly for this challenging patient cohort with difficult cartilage conditions and in need of a variety of concomitant surgery procedures such as anterior cruciate ligament reconstruction or high tibial osteotomy. Besides, as a first step, it would be a beneficial effort to postpone total joint replacement for a decade. Recently, the effectiveness of second-generation cartilage grafts has been shown for the treatment of osteoarthritic knees. Hollander and colleagues reported the use of a hyaluronan-based second-generation cartilage tissue engineering graft for the treatment of osteoarthritic knees [50
]. Histological and biochemical analyses of second-look biopsies documented the regeneration of cartilage as early as about 1 year after transplantation in 10 of 23 patients and showed that osteoarthritis did not inhibit the regeneration progress.