Can intra-articular injection of freeze-dried platelet-derived factor concentrate regenerate articular cartilage in the knee joint?

Freeze-drying methods not only enable the delivery of growth factors using platelets, but also extend the shelf-life of platelet concentrates. The present study shows the clinical results of treating knee osteoarthritis with freeze-dried platelet-derived factor concentrate (PFC). While it improved pain, activities of daily living, sports and recreational activities, and knee-related quality of life, it did not significantly improve symptoms other than pain, such as restricted range of motion and mechanical symptoms. As such, the treatment effect may be attributed to anti-inflammatory action rather than actual cartilage regeneration.

Introduction

The use of regenerative therapies for degenerative orthopedic conditions such as osteoarthritis is increasing. As surgical treatment options such as autologous chondrocyte implantation are now widely used [1], [2], so are clinical procedures such as the use of mesenchymal stem cells [3], platelet-rich plasma (PRP) [4], and platelet-derived factor concentrate (PFC) [5]. Although intra-articular PRP injection has already been shown to be effective in treating knee osteoarthritis (OA) [6], [7], [8], the present study is the first to use freeze-dried PFC and describe the clinical results.

Methods

In this retrospective case series, we evaluated 11 patients (5 males and 6 females) with knee OA who were given intra-articular PFC injections. The average age was 71.2 ± 16.6 years (range, 30–90). The Kellgren and Lawrence (KL) system was used to radiographically grade knee OA severity. Three patients had beginning OA changes (KL grade 1); 4 had mild changes (KL grade 2); 2 had moderate changes (KL grade 3); and 2 had severe changes (KL grade 4).

The process of preparing freeze-dried PFC begins with the extraction of 49 ml of autologous blood from each patient. Sterility testing was performed on a 9 ml portion of the blood sample. Platelet-rich plasma was prepared from the remaining 40 ml by centrifugation. PFC was then prepared according to a method described by Araki et al. [9], and was subsequently freeze-dried and powdered. The resulting product could be preserved for 6 months at room temperature. In order to create a solution for injection into the knee joint, the freeze-dried PFC was dissolved in 6 ml of physiological saline.

Since the freeze-dried PFC was decellularized, approval from the MHLW was not required to use it at our clinic. As the patients in this study were seen in a private clinic, institutional review board approval was not sought. However, informed consent was obtained from each patient in this study.

Assessment was conducted before the procedure, as well as 1, 3, and 6 months after the procedure, using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and each of its 5 subscales: pain, other symptoms, activities of daily living (ADL), function in sport and recreation (Sport/Rec), and knee-related quality of life (QOL). One way analysis of variance was used for statistical analysis. Statistical significance was assumed when p-value was less than 0.05.

Results

General improvement was noted with respect to the KOOS. Total KOOS was significantly improved from pre-injection and 1, 3, and 6 months after injection (p = 0.013, 0.048, and 0.006, respectively), from 1 to 6 months (p = 0.037), and from 3 to 6 months (p = 0.039). KOOS pain was significantly improved from pre-injection to 1 and 6 months (p = 0.006 and 0.009, respectively). KOOS ADL was significantly improved from pre-injection to 1, 3, and 6 months (p = 0.015, 0.036, and 0.004, respectively). KOOS Sport/Rec was significantly improved from pre-injection to 6 months (p = 0.038). KOOS QOL was significantly improved from pre-injection, 1 and 3 months to6 months (p = 0.005, 0.016, and 0.044, respectively). However, no significant improvement was noted in “other symptoms” (Fig. 1). There were no adverse events throughout the follow-up period in all patients.

Fig. 1

Assessment of intra-articular platelet-rich plasma injection for patients with knee osteoarthritis (n = 11) using the Knee Injury and Osteoarthritis Outcome Score.

Discussion

There are few clinical reports on intra-articular injection of freeze-dried PFC. Freeze drying has been shown to be the most suitable technique for preserving PRP bioactivity because both platelet counts and growth factor levels are preserved [10]. However, it is still unclear that freeze-dried PRF can preserve its bioactivity. The present study showed that the use of freeze-dried PFC brought about no significant improvement in “other symptoms” in the KOOS, indicating that the procedure may be ineffective for patients with mechanical symptoms due to meniscal tears or articular cartilage defects. Therefore, the general improvement in scores on the other subscales may be due to the anti-inflammatory effect of the product [11] rather than its regenerative potential. The perceived improvement was caused by the relief of the symptoms and not by treatment of the actual cause of the symptoms. As an analogy, the effect may be similar to experiencing temporary relief by taking antipyretics for fever instead of antibiotics to treat the underlying cause of the fever.

Consequently, it remains difficult to justify the high cost of PRP or PFC injection since they only treat the symptoms of OA, and not the underlying disease itself. In Japan, as in most other countries, these injections are not covered by the national health insurance. Thus, the cost to patients would be at least JPY 10,000, depending on the treating center. Most government and insurance companies believe that while the potential benefit of treatment is acknowledged, more outcomes should be collected to investigate its effectiveness [12]. Moreover, the literature contains conflicting evidence regarding the effectiveness of PRP injection compared to options such as hyaluronic acid [13], [14], [15], [16]. Patients may end up seeking affordable alternatives such as steroids, which cause cartilage degeneration and volume loss with long-term use, if the high cost of PRP injection continues to make it less accessible [17].

This study has certain limitations. First, only a limited sample size of 11 patients was used for the study. A larger sample size may increase the power of the hypothesis and may also demonstrate a correlation between OA severity grade and treatment results. Second, the study utilized subjective outcome measures in the form of the KOOS and its subscores. Future studies should use objective outcome measures, such as magnetic resonance imaging and second-look arthroscopy, to identify correlations with subjective outcome assessments.

Conclusion

Intra-articular injection of freeze-dried PFC for knee OA was effective in improving pain, ADLs, sports and recreational activities, and knee-related QOL. However, it was not effective in improving restricted range of motion and mechanical symptoms.

Conflicts of interest

All the authors declare that they do not have any conflicts of interest concerning this article.