Shocking Results of Platelet-Rich Plasma Administration Concurrent With Autologous Chondrocyte Implantation Negatively Impacting Cartilage Repair: Response

We appreciate the thoughtful feedback and questions raised regarding our article titled “Effect of Platelet-Rich Plasma on Autologous Chondrocyte Implantation for Chondral Defects: Results Using an In Vivo Rabbit Model.” ⁵ The insights provided have stimulated a valuable discussion and allowed us to reflect further on our methodology and findings. Below, we address the key points raised by the authors of the letter to the editor.

Impact of Platelet-Rich Plasma's (PRP’s) Negative Effects on Autologous Chondrocyte Implantation (ACI)

The finding that PRP may exert negative effects on ACI outcomes has had a profound impact on our understanding of its role in cartilage repair. This result aligns with the growing body of evidence suggesting that PRP's primary clinical benefit lies in its anti-inflammatory properties rather than direct cartilage regeneration. ¹ However, we emphasize that the primary objective of our study was to investigate whether PRP could enhance cartilage repair following ACI (ie, to maximize the therapeutic efficacy of current ACI treatment). We focused on cartilage regeneration as the primary outcome measure.

Techniques and Consistency With Previous Studies

Regarding the use of nonabsorbable nylon sutures for collagen membrane fixation and the creation of cartilage defects, we adopted protocols consistently utilized in our extensive series of experiments involving the development of 3-dimensional autologous cultured cartilage sheets (JACC; Japan Tissue Engineering). These techniques have demonstrated the effectiveness of JACC in both animal models^5,6 and clinical settings,^2-4,7 ensuring reproducibility and reliability in our methodology.

Responses to Specific Comments

Foreign Body and Thickness Effects of Nylon Sutures

We agree with Dr Qingyu Xu's comments regarding this concern. Based on the studies by Katsube et al ⁶ and supporting clinical literature,^2-4,7 we believe that the influence of suture material and thickness on transplanted cells’ proliferation, as well as on subchondral bone and surrounding tissue repair, is minimal. However, we acknowledge that some practitioners worldwide prefer absorbable sutures due to concerns about potential effects. Future comparative studies are warranted to clarify the extent of these influences.

Impact of Defect Diameter and Depth

To evaluate ACI's efficacy, we adopted a defect model with a 5-mm diameter and a 3-mm depth in the femoral trochlea of Japanese White rabbits, as described in our previous work. ⁵ This osteochondral defect model does not heal spontaneously, allowing us to investigate PRP's influence on subchondral bone and cartilage repair in a controlled manner. We observed that PRP significantly affected subchondral bone, supporting its potential role in cartilage repair.

Potential PRP Loss and Volume Consideration

As shown in Figure 1 of our previous study, ⁵ 50 µL of PRP sufficiently filled the cartilage defect area (Figure 1B) and was administered into the collagen membrane and cartilage sheet space in the ACI group (Figure 1D). While we agree that retaining PRP at the transplantation site is critical, we initially considered using gel-type PRP but ultimately decided against it. Instead, we selected PRP prepared using the double-spin method for its clinical applicability and ease of use. The collagen membrane was used in its dry state, serving as a carrier for PRP impregnation, which contributed to its retention. Our goal was to simulate clinical conditions, where PRP administration is performed concurrently with ACI as a single-stage procedure. This study demonstrated the feasibility and efficacy of this approach. Additionally, we have completed another study investigating PRP administration after wound closure, which addresses the potential benefits of postclosure application. These unpublished findings are being prepared for submission.

Timing of PRP Administration

In our study, PRP was administered to the transplantation site simultaneously with the ACI procedure, precisely at the same time, referred to as time 0. Immediate application was hypothesized to promote the engraftment of transplanted cartilage while also potentially contributing to subchondral bone formation. However, we recognize that the timing of PRP administration could critically influence its efficacy. To explore this, we conducted additional experiments (unpublished data) comparing the effects of PRP administered at different time points. Notably, PRP application at 2 weeks post-ACI resulted in increased chondrocyte density and improved cartilage repair outcomes compared to immediate administration. These findings suggest that delayed PRP application might enhance its therapeutic potential. We plan to submit these results to this journal, providing valuable insights for optimizing PRP use in clinical practice.

Conclusion

We are deeply grateful for the opportunity to engage in this academic dialogue and for the recognition of our work's contributions to regenerative medicine. The feedback has provided a valuable opportunity to refine our hypotheses and explore future research directions. We look forward to submitting our additional findings to this journal and continuing to contribute to a deeper understanding of PRP and ACI.

Sincerely,

Yuki Kato, MD, PhDKamogawa, Japan Shinobu Yanada, PhD Hitoshi Morikawa, MScGamagori, Japan