Restoration of a large osteochondral defect of the knee using a composite of umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel: a case report with a 5-year follow-up
© The Author(s). 2017
Received: 7 November 2016
Accepted: 19 January 2017
Published: 2 February 2017
The treatment of articular cartilage defects is a therapeutic challenge for orthopaedic surgeons. Furthermore, large osteochondral defects needs restoration of the underlying bone for sufficient biomechanical characteristics as well as the overlying cartilage.
A symptomatic large osteochondral defect in the knee joint was restored using a composite of umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) 0.5 x 107/ml and 4% hyaluronic acid (HA) hydrogel. Significant improvements in pain and function of the knee joint were identified by the evaluation at 12 months after surgery. A hyaline-like cartilage completely filled the defect and was congruent with the surrounding normal cartilage as revealed by magnetic resonance imaging (MRI), a second-look arthroscopy and histological assessment. The improved clinical outcomes maintained until 5.5 years. MRI also showed the maintenance of the restored bony and cartilaginous tissues.
This case report suggests that the composite of allogeneic UCB-MSCs and HA hydrogel can be considered a safe and effective treatment option for large osteochondral defects of the knee.
KeywordsKnee Large osteochondral defect Umbilical cord blood Mesenchymal stem cell Hyaluronic acid
The treatment of articular cartilage defects continues to be one of the most challenging clinical problems for orthopaedic surgeons. When isolated chondral or osteochondral defects are left untreated, they do not heal and may progress to symptomatic degeneration of the joint . Therefore, early surgical intervention for symptomatic lesions which are not responding to conservative treatment is often suggested in an effort to restore normal joint congruity and pressure distribution, and to prevent further injury. Therefore, several techniques for cartilage restoration have been developed [2–4]. Microfracture, osteochondral autograft transfer (OAT) and autologous chondrocyte implantation (ACI) are the commonly applied methods, which will be introduced more in detail below regarding the case of this paper.
The treatment of large osteochondral defects involving the cartilage as well as the subchondral bone is more challenging because of two different tissues with different healing potential . Microfracture, a bone marrow stimulating arthroscopic technique, seems to be the most frequently used method to repair small sized articular cartilage defects (<2 cm2) , however, it is generally not recommended for osteochondral defects due to limited potential for restoring the underlying bony tissue . OAT offers the advantage of restoring cartilage tissue as well as subchondral bony tissue. However, limited graft availability and donor site morbidity are major limitations . Furthermore, uneven surface or unstable fixation in multiple grafting for a large defect is also a concern . Large osteochondral defects can sometimes be treated by ACI, however ACI is a two-staged procedure and it is hard to apply the graft in lesions with deep (more than 6 to 8 mm) subchondral defects . ACI is also known to have very limited potential in restoring bony tissues and often requires bone grafts for subchondral bone restoration in cases of large osteochondral defects [11, 12]. Osteochondral allograft is an another possible option, but the limited availability of fresh allograft is a major drawback in clinical practice . Therefore, there still lacks an optimal method to restore the cartilaginous and bony tissue in a large osteochondral defect.
Recently, mesenchymal stem cells (MSCs) have become attractive as one of the potential candidates for cellular therapy, featuring self-renewal, proliferation and differentiation into mesenchymal tissues, including bone, tendon, muscle and cartilage . Moreover, MSCs likely exhibit a capacity of immune-tolerance or immune modulation that may allow allogeneic MSCs transplantation feasible . There are only two reports in the literature on the effect of autologous MSCs for osteochondral defect of the knee [16, 17]. We, however, could not find a report of allogeneic MSCs transplantation for the restoration of osteochondral defect. In addition, it was hardly investigated whether MSCs were effective to treat large osteochondral defect. Umbilical cord blood-derived MSCs (UCB-MSCs) are ease to obtain, are non-invasively collected, and have a good expansible capacity [18, 19]. In addition, some studies suggest immunomodulatory effects [20, 21]. Therefore, UCB-MSCs can be an appropriate source for allogeneic transplantation.
We previously reported that transplanting of UCB-MSCs and hyaluronic acid hydrogel composite resulted in favorable cartilage repair in animal models [22–26]. Moreover, recently, we demonstrated that transplantation a composite of allogeneic UCB-MSCs and HA hydrogel was safe and effective modality for cartilage repair in osteoarthritic knees, which was followed up for more than 7 years without any significant adverse events . In this paper, we report a first case of transplanting a composite of allogeneic UCB-MSCs and HA hydrogel in large osteochondral defect.
We report a case of a successful outcome using the composite of UCB-MSCs 0.5 x 107/ml and 4% HA hydrogel for the treatment of large and deep osteochondral defect of the knee. The clinical results at 1 year and at 5.5 years postoperatively suggest that this method can be a viable option in restoring large and deep osteochondral defects. To our knowledge, this is the first report of a successful treatment of large osteochondral defect of a human joint by application of allogeneic MSCs-based product.
Over the past decade, clinical and basic research has provided the foundation for successful treatment of focal cartilage defects [31, 32]. The main approaches currently used in clinical practice are microfracture, OAT, and ACI. Microfracture and OAT are generally known that they not recommended for large lesions [33, 34]. ACI was the first cell therapy used clinically to treat cartilage defects . ACI has undergone several improvements over time [36, 37]. However, there are still several shortcomings even with the newly developed ACI techniques; the main shortcoming is an age-related chondrocyte de-differentiation during the expansion phase . Chondrocyte is known to dedifferentiate to a fibroblast-like state during cultivation in monolayers. The dedifferentiation represents both morphological changes and alterations in collagen expression patterns, which negatively affects the potential of the implanted cells to restore the cartilage tissue. In addition, ACI requires autologous bone implant for the restoration of the subchondral bone in large osteochondral defects [11, 12].
To overcome the limitation and shortcomings of currently available options, a novel option seems to be required for the treatment of large osteochondral lesion of the knee. In this regard, the use of MSCs can be a potential therapeutic option for the restoration of cartilage as well as bone in the osteochondral defects, considering the MSCs’ capacity of self-renewal, multi-lineage differentiation potential and immunomodulation . Several studies reported that MSCs with scaffold can repair osteochondral defects in animal models [40–43]. We have already experienced successful restoration of osteochondral defects with no immunologic problem after transplantation of human UCB-MSCs in an animal model which was a xenograft model [22–26]. Also, we had seen the safety and efficacy of UCB-MSCs for the restoration of articular cartilage defect in seven osteoarthritic patients in phase 1/2 clinical trial performed at our institution . Therefore, we tried to extend the novel approach to the restoration of subchondral bone as well as the articular cartilage in large osteochondral defect case, and the result was encouraging without any significant adverse events.
To our knowledge, this is the first case report of the transplantation of allogeneic MSCs for the restoration of large osteochondral defects of the human knee. In the literature, there have been only two previous studies which used autologous MSCs or mixed cell concentrate containing MSC for the treatment of osteochondral defect of the human knee [16, 17]. A case report of one patient with a 1-year follow-up presented that the restoration of articular cartilage and subchondral bone for an osteochondral defect was promoted by implantation of autologous bone marrow (BM)-MSCs embedded in calcium hydroxyapatite ceramic with interconnected pores . The technique required two-stage surgery and invasive BM collection. The other study with a 2-year follow-up described the use of BM aspirate concentrate (BMAC), a mixture of heterogeneous cell populations, embedded in hyaluronan based scaffold for osteochondral defects of the knee in 20 patients . Clinical outcomes were improved and MRI showed bone and cartilage growth, nearly complete defect filling and satisfactory integration with surrounding tissue in 80% of patients at 1 year. Histological staining showed the presence of proteoglycan, particularly in the middle and deep zone. Unfortunately, the images of immunohistochemical staining for type 1 and type 2 collagen were not provided. Although this technique was one-stage surgery, it also required invasive BM aspiration for cell collection. In addition, heterogeneous cell populations had been used in this study. The MSCs are known to be present in less than 0.1% of BM aspirate concentrates . Thus it is difficult to determine whether the bone and cartilage repair was by the MSCs or other components, such as platelet derived growth factors, and consistent results could not be expected. Moreover, these two related previous reports lacked longer term follow-up to evaluate whether the restored tissues were maintained and provided reliable and durable clinical outcomes. We believe the results of the case in the current report warrant further investigations on the application of allogeneic MSCs for the restoration of osteochondral defects.
In this case report, the improvements in pain and function at 1-year post-transplantation were maintained for 5.5 years. At the latest clinic visit of 5.5 years postoperatively, she had returned to full activity without any limitation as a nurse in a local hospital. In MRI and second-look arthroscopy at postoperative 1 year, no overgrowth, delamination or fibrous degeneration at the site of newly formed tissue were observed, which is often observed after ACI . In addition, MRI at 5.5 years after surgery showed the maintenance of restored subchondral bone as well as the overlying articular cartilage with excellent peripheral integration. We think that the restoration of subchondral bone which provide a sound biomechanical environment for the restored defect site as well as the restoration of good quality cartilage should have contributed to the observed durable improvement in pain and function. The result of this case suggests that the transplantation of the composite of UCB-MSCs and HA will be an effective therapeutic option for the treatment of large osteochondral defects of the knee.
There was no adverse effect for 5.5 years. No abnormal findings suggesting rejection, foreign body reaction, or differentiation towards other mesenchymal lineage was observed. UCB-MSCs showed low immunogenicity and immunomodulatory activity [46, 47]. Other in vivo studies using UCB-MSCs have shown no immune rejection [22, 23, 25]. One recent study reported that UCB-MSCs transplanted cells disappeared at 4–8 weeks , which may contribute to the safety of transplantation of allogeneic UCB-MSCs in this case.
Some limitations of this study needs to be addressed. First, allogeneic MSCs transplantation might induce an immune reaction. However, the UCB-MSCs show low immunogenicity, and have immunomodulatory activity [47, 49]. In addition, previous in vivo studies using UCB-MSCs have not shown an immune rejection [22–24, 27]. In this study, there was no adverse reaction resulting from the rejection response. Second, the lateral meniscectomy and removal of intra-articular osteochondral loose bodies have also contributed for the improvement of the pain and function of the patient. However, we believe that the improvement could have not been that much as in this case without repair of the large and deep osteochondral defect. Third, meniscal loss (especially at the lateral compartment) has been considered as the contraindication of cell-based cartilage repair. However, we demonstrated that transplantation a composite of allogeneic UCB-MSCs and HA hydrogel was safe and effective modality for cartilage repair in osteoarthritic knees in which meniscal loss was combined, which was maintained more than 7 years without deterioration or significant adverse events . Therefore, we believe that transplantation of the composite of UCB-MSCs and HA hydrogel is an appropriate modality for cartilage repair even though patients have an meniscal problem. Fourth, we could not rule out the effect of HA in the restoration of the osteochondral defect, although the HA hydrogel was used for delivering the MSCS and holding the MSCs in place. However, we learned from the preclinical studies using HA hydrogel with or without UCB-MSCs that the role of HA hydrogel in restoring the articular cartilage defect had been limited and the composite of UCB-MSCs and HA hydrogel showed consistently better results [22, 24]. Fifth, with the result of this case, we cannot tell whether the result of UCB-MSCs transplantation is better than ACI-collagen or matrix-associated ACI . However, considering the fact that the integrity of the subchondral bone is important for a long term integrity of the overlying articular cartilage due to the biomechanical environment issue [51, 52], we believe that the novel option we report here will be more suitable than ACI or its modifications. Finally, this case may need an even longer term outcome.
The results of this study showed that the transplantation of the composite of UCB-MSCs and HA hydrogel can be a viable therapeutic option for the restoration of large osteochondral defects of the human joint. It can be performed through a one-stage arthroscopy assisted surgery with a small arthrotomy. The result of this case report warrants further studies on this novel therapeutic option.
Autologous chondrocyte implantation
Magnetic resonance imaging
Mesenchymal stem cell
Osteochondral autograft transfer
Umbilical cord blood
We thank Tai-Hee Seo BS for her effort in the management of the data.
This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (HI14C3484). The funding sources were not involved in the study design, collection, analysis or interpretation of the data, writing of the manuscript, or in the decision to submit the manuscript for publication.
Availability of data and materials
All data supporting the conclusions of this article are included in this published article. The raw data can be requested from the corresponding author.
YBP wrote the manuscript and performed data collection and data interpretation. CWH designed and performed the study, and wrote the manuscript. CHL performed literature search, data collection, made figures, and helped to write the manuscript. YGP performed literature search, data interpretation, and helped to write the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
A written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from patient included in the study.
The study was approved by the institutional review board at investigational hospital (SMC IRB No.2008-09-053).
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