We surveyed the website ClinicalTrials.gov and selected 203 studies on regenerative cartilage repair. Using the retrieved data, we then analyzed the translational trends described in these studies. First, we classified the entire list of studies by the cell source organ used. The results are shown in Fig. 1a. The major organs used were as follows: bone marrow (31%), cartilage (28%), adipose tissue (25%), and umbilical cord (12%).

Fig. 1 Analysis of projects in ClinicalTrials.gov according to the cell source organ used for cell therapy and cartilage repair. “Others” include studies that are using multiple cell sources for combination or comparison. a Percentage of each cell source relative to the total number of studies. b Comparison of number of clinical trials on cartilage repair according to countries of origin. Each color-coded part of the bar depicts the corresponding cell-source organ by country. The top 12 countries are shown in this graph. c Each study was color-coded by the corresponding cell source organ and displayed from the start year to the (planned) completion year, sorted by start year in chronological order. Shaded column: current year (2018) to 2025. Since 2018, a trial bar displays if the trial is registered. Please note that we could not show if the trial continued or was halted prematurely. Red-dashed column: 2014–15. Vertical-striped bar indicates “suspended,” “terminated,” or “withdrawn” study Full size image

Figure 1b shows the analyzed results by country. The United States, which manages ClinicalTrials.gov, had 79 studies, ranking at the top. In second place was Korea, followed by China, Germany, France, Iran, and Spain. In the same graph, each color-coded bar depicts the corresponding source of cells by country. The US studies used mainly cartilage, bone marrow, and adipose tissues at a rate of approximately 1:1:1 as the cell source. This rate varied among the listed countries. For example, Korea and Germany used mainly cartilage, while Iran, Spain, and Australia used bone marrow only.

To analyze the clinical research trends described in these projects chronologically, we arranged all studies by order of the corresponding start year, plotted them from the start year to the completion year, and color-coded them according to the organs of cell origin (Fig. 1c). This analysis showed that cartilage was used as a source of cells from the beginning of 1995 to the present, but the rate of use decreased from an average of 45% (2006–2012) to 10–15% (after 2013). On the other hand, bone marrow has been used since 2009, followed by adipose tissue since 2012. The total number of studies using umbilical cord is small, but this source of cells has been implemented since 2009. The above trends have continued to date. Interestingly, a clinical trend of cell-derived tissues shifting from cartilage and bone marrow to adipose tissue has been observed since 2014–2015. Collectively, these findings indicate that the clinical application of cartilage repair began in the mid-1990s with the use of cartilage tissue as the cell source, and bone marrow has also been studied since the mid-2000s, but in the mid-2010s, both were replaced mainly with adipose tissue.

In the next step, the origin (autologous or allogeneic) of each cell source was analyzed (Fig. 2a). Studies that used cells of allogeneic origin comprised approximately one-third of the entire database. Overall, no specific chronological trend was observed for either origin (Fig. 2b).

Fig. 2 Analysis of origin of cells (autologous or allogeneic) used for cell therapy and cartilage repair in clinical trials registered in ClinicalTrials.gov. a Percentage of each origin of cells relative to the total number of studies. b Each study is color-coded by corresponding origin of cells and displayed from the start year to the (planned) completion year, sorted by start year in chronological order. Shaded column: current year (2018) to 2025. Since 2018, a trial bar displays if the trial is registered. Please note that we could not show if the trial continued or was halted prematurely. Vertical-striped bar indicates “suspended,” “terminated,” or “withdrawn” study Full size image

Table 1 provides a detailed list of the cell therapy products designed for cartilage repair that are approved by the regulatory authorities of various countries and are currently available in the market. Briefly, Carticel®2 was a first-generation autologous chondrocyte implantation (ACI) product, which required open arthrotomy implantation of in vitro-cultured autologous chondrocytes beneath an autologous periosteal cover. ChondroCelect®8 was also a first-generation ACI product utilizing a proprietary genetic marker profile score that optimizes the likelihood of a hyaline phenotype and its associated biological, cartilage-forming capability. MACI®3,4,8,9 is a type I/III collagen membrane seeded with expanded autologous chondrocytes. Spherox (chondrosphere®16) consists of small spheroids of neocartilage composed of expanded autologous chondrocytes and their associated matrix. Chondron™5 is an autologous chondrocyte-pre-seeded fibrin three-dimensional matrix gel. CARTISTEM®617 is a composite of allogeneic umbilical blood mesenchymal stem cells (MSCs) and hyaluronic acid hydrogel. Invossa™18 (TissueGene-C) is a gene therapy implant that includes modified transforming growth factor-β (TGF-β)-expressing allogeneic chondrocytes.19 JACC is cultured autologous chondrocytes embedded in atelocollagen gel.7 Although MACI® was initially approved by European Medicines Agency (EMA), it was suspended in the European Union (EU) in 2014 because of a manufacturing site closure in Europe.20 Furthermore, ChondroCelect® was withdrawn from the market in 2016 because of a reimbursement problem in the EU.21 Carticel® was phased out because of the new approval of MACI® in the United States.22 On the other hand, two new products, Spherox16 and Invossa™18 were recently approved in the EU and Korea, respectively. Both are derived from cartilage as the cell sources. As shown in Table 1, most of the globally marketed products for cartilage repair (with the exception of CARTISTEM®6) are derived from cartilage. Unfortunately, the available data on the registered studies in ClinicalTrials.gov do not allow for direct estimation of the market share of each type of product.

Table 1 List of cell therapy products used in cartilage repair area available on the world market Full size table

The origin of the cell source (autologous or allogeneic) and the clinical stage were analyzed chronologically to determine progress in testing new products derived from each of the four main cell sources (bone marrow, cartilage, adipose tissue, and umbilical cord). Although not shown in Fig. 3a because of the lack of description of the phase of trial, the earliest cartilage cell therapy trials in ClinicalTrials.gov started in 1995 (Fig. 1c). As shown, cartilage has been examined as a material for cell therapy for cartilage repair for a long time. The start of phase III clinical trials on a newly developed product reflects positive results in phase II studies with regard to its effectiveness. Interestingly, a large proportion (15%) of phase III clinical trials for cartilage repair registered in the ClinicalTrials.gov database was included in this group, most of which used autologous cells (12/15). Therefore, our findings indicate that several earlier clinical studies using autologous cartilage as the cell source have shown encouraging results to warrant phase III clinical trials for cartilage repair. On the other hand, allogeneic cartilage cells were used in 11 studies. Only 4 of these were registered as phase III, but all of them were studies on TissueGene-C (NCT02072070, NCT03203330, NCT03291470, and NCT03383471). TissueGene-C was approved by the Korean authorities in July 2017 and marketed as Invossa™ (Table 1).

Fig. 3 Chronological display (sorted by start year) of cartilage repair trials in which a cartilage, b bone marrow, c adipose tissue, or d umbilical cord7 was used as the cell source. Each study was plotted from start year to completion year as a color-coded bar showing the origin of the cell source (autologous or allogeneic) and the corresponding clinical stage, as shown in examples in the frame below d. For convenience, trackable products with multiple trials were linked with colored lines and arrows as follows; a blue: Chondron, green: NeoCart, yellow: TissueGene-C, black: Chondrosphere, and purple: Novocart; b blue: NeoFuse and yellow: Chondrogen; c blue: JointStem and yellow: StroMed; d black: CARTISTEM. e Chronological display (sorted by start year) of the clinical trials of each generation of ACI products. Each study was plotted from the start to the completion year as a color-coded bar, which indicates the generation of ACI and corresponding clinical phases, as shown in examples in the frame below e. We could not find any phase I and II studies corresponding to the first ACI in ClinicalTrials.gov. Shaded column: current year (2018) to 2025. Since 2018, a trial bar displays if the trial is registered. Please note that we could not show if the trial continued or was halted prematurely. Vertical-striped bar indicates “suspended,” “terminated,” or “withdrawn” study Full size image

Six of the phase III clinical trials using autologous cartilage cells are currently being conducted in 2018. They are examining three products (NeoCart8 (NCT01066702), chondrosphere® (NCT01222559), and Novocart 3D8 (including 3D plus, and Inject plus) (NCT01656902, NCT01957722, NCT03219307, NCT03319797, and NCT03383471)), all of which are classified as ACI. Among them, Chondrosphere® and Novocart 3D are cell therapies that have already been used clinically under the hospital exemption (HE) scheme in Germany. The HE is a European-specific scheme that grants approval for use of medical products on an experimental basis in specific hospitals, even though the effectiveness of such products remains to be confirmed.23 Chondrosphere® was also approved by EMA in July 2017 and marketed as Spherox (Table 1).

Since Wakitani et al.24 reported the first case of treatment of cartilage defects with autologous MSCs in 2004, bone marrow has often been used as a source of MSCs. Figure 3b shows the results of studies to repair cartilage defect using bone marrow as the cell source. The earliest study was conducted in 2006. Research employing bone marrow as the source for chondrocytes became active around 2009. Two phase II/III trials (NCT00891501 and NCT01873625) were conducted in the early years (2006 and 2009, respectively), although no information is available regarding their approval. Interestingly, no phase III trials were conducted for several years after the above two studies. One phase III trial using an autologous cell source in 2015 was found, but this study (NCT02848027) was not relevant to our analysis because it was for a 361 HCT/P product, which does not require the approval of the US Food and Drug Administration (FDA).25

Although many studies using allogeneic cell sources were also examined in the initial stages, no phase III studies were registered in the database until 2014. While degenerative disc disease (DDD) is not an articular cartilage disease, one phase III clinical trial using rexlemestrocel-L (NeoFuse™)26 for DDD in the United States and Australia (NCT02412735) was registered in 2015. In summary, there are no approved cartilage repair products based on clinical trials that used bone marrow-derived cells registered in ClinicalTrials.gov, and the rate of progression to phase III is low (3.2%). Among these studies, there is only one allogeneic product for DDD that is currently under development in a phase III clinical trial.

Adipose tissue has also been used as a source for MSCs. Figure 3c shows the analysis of the projects that used adipose tissue as the cell source. The earliest study was conducted in 2008, but such studies became more common after 2012. There is only one phase III trial among these studies (NCT03467919). Although this study used MSCs extracted from adipose tissue, any earlier corresponding trials were not found in ClinicalTrials.gov. On the other hand, the use of allogeneic cell sources was low (3.9%). Aggressive use of adipose tissue as the cell source for cartilage repair began around 2012 and has been actively studied, but other phase III trials were not found.

The results of the analysis of studies using cells originating from the umbilical cord are shown in Fig. 3d. The data shown in this figure also include studies using cells from Wharton’s jelly, placenta, and amniotic membrane/fluid. All registered studies were conducted after 2008 and included two phase III trials in the early years for CARTISTEM® (NCT01041001 and NCT01626677). A phase II/III trial using amniotic fluid started last year, although we could not find any earlier corresponding trials in ClinicalTrials.gov. All other studies using cell sources classified in this category remain in phase II or earlier phases to date.

We also focused on studies on ACIs that were translationally successful among all clinical trials. Figure 3e includes information on ACI studies that were analyzed for clinical development trends in chronological order. The ACI studies were classified into three generations based on the method described by Harris et al.8 Studies on the first-generation ACI were completed by 2010, while the second-generation ACI has been actively studied since 2006 to the present. Furthermore, the third generation was also studied at almost the same time as the second generation. Interestingly, the proportion of phase III trials relative to all trials for each generation was high, suggesting successful development of the technology. Thus, our analysis suggests that the major current trend in clinical development is the second- and third-generation ACI, while the first-generation ACI is superseded technology.

Next, we analyzed the time required for clinical development in this field. For this purpose, we analyzed all products (including candidates) that were used in phase I to phase III and that could be traced by product name or development code. Specifically, we analyzed the time required for a series of studies from phase I to phase III trials. Only two products/three research projects that covered phases I–III were identified in the ClinicalTrials.gov database (Table 2). Among the three projects that were entirely trackable (from the start of phase I to the completion of phase III) in ClinicalTrials.gov, only one project completed in practice was for TissueGene-C in Korea, and the time required to complete this entire project was 103 months. Since the remaining two projects were incomplete at this time (June 2018), it is necessary to be aware that these are projected periods. With regard to the clinical trial on the use of NeoFuse™ for DDD, the estimated time for the completion of phase I–phase III is 150 months.

Table 2 List of clinical research series of product candidates that included phases I–III Full size table

Alternatively, to examine whether there is any tendency in the period required for each trial depending on the combination of cell source and origin, we extracted all the completed trials in practice and classified them according to their cell source and origin, and calculated the actual period taken to complete each study. Studies using autologous cartilage cells reached completion at a median of 74 months, while those using allogeneic cartilage cells were completed within a median of about 26 months, and the difference between these two types was significant. On the other hand, the use of allogeneic bone marrow cells and adipose tissue cells was associated with slightly longer times (median 46 and 36 months, respectively) than those using corresponding autologous cells (median 34 and 32 months), although the difference in these times was not significant. Interestingly, compared to the use of autologous chondrocytes, both the use of autologous bone marrow and autologous adipose tissue was significantly shorter, with a median of 34 and 32 months, respectively.

Finally, to examine the time required for each phase in more detail, the completed studies registered as phase I, phase II, or phase III were extracted, and we analyzed them by the time required for individual studies using the completion year, instead of the start year. Figure 4b shows the median time required for completion of individual studies completed by 2017 by each phase as boxplots. In the entire period, the phase I trials were completed in a median of 24 months, the phase II trials in a median of 36 months, and the phase III trials in a median of 41 months. Moreover, significant differences were observed in the required times between the phase I and phase III studies, and a difference in those between phase I and phase II studies was nearly significant (p = 0.0563). The simple summation of the median time required to complete each phase was 102 months. As few corresponding studies were completed by 2008, the period from 2009 to 2017 was divided into three sections, which are shown in the figure, to reveal the transition every 3 years. Although statistical analysis was impossible because of the small number of samples, it was found that the median duration of phase I studies was 15–31 months, 14–35 months for phase II studies, and 35–61 months for phase III studies.