Allogeneic Umbilical Cord Blood-Derived Mesenchymal Stem Cell Implantation Versus Microdrilling combined with High Tibial Osteotomy for Cartilage Regeneration

doi:10.21203/rs.3.rs-3231946/v1

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Allogeneic Umbilical Cord Blood-Derived Mesenchymal Stem Cell Implantation Versus Microdrilling combined with High Tibial Osteotomy for Cartilage Regeneration

https://doi.org/10.21203/rs.3.rs-3231946/v1

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published 09 Feb, 2024

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This study compared cartilage regeneration outcomes in knee osteoarthritis (OA) using allogeneic human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) implantation and microdrilling with high tibial osteotomy (HTO). Fifty-four patients (60 knees) were included: 24 in the hUCB-MSC group and 30 in the microdrilling group. Both groups showed significant improvements in pain and functional scores at 6, 12, and 24 months compared to baseline. At 24 months, hUCB-MSC group had significantly improved scores. Arthroscopic assessment at 12 months revealed better cartilage healing in the hUCB-MSC group. In subgroup analysis, hUCB-MSC showed superior results for anterior lesions. Both treatments demonstrated effectiveness for medial OA. However, hUCB-MSC implantation had better patient-reported outcomes and cartilage regeneration than microdrilling. The study suggests promising approaches for cartilage restoration in large knee defects due to OA.

Biological sciences/Stem cells

Biological sciences/Stem cells/Mesenchymal stem cells

Biological sciences/Stem cells/Regeneration

Health sciences/Diseases/Rheumatic diseases/Osteoarthritis

Osteoarthritis (OA) of the knee is a common source of pain, with potential for the development and progression of osteoarthritis secondary to the limited capacity for cartilage repair ^1–3. Cartilage defects located on the medial femoral condyle (MFC) with varus deformity are one of the major underlying pathologies leading to a significant increase in forces in the medial compartment ^4,5.

Biomechanical studies have demonstrated the potential of high tibial osteotomy (HTO) in terms of the reduction of load in the medial compartment and peak pressure in focal cartilage defects associated with varus deformities ^6–8. HTO alone offers excellent short- and mid-term outcomes; however, these outcomes tend to deteriorate over time ^9–12. To overcome these limitations and to improve articular cartilage regeneration and surgical outcomes, HTO and additional cartilage regenerative procedures are increasingly being combined.

Cartilage regeneration procedures, such as microfracture (MFx), microdrilling, and autologous chondrocyte implantation (ACI) with concomitant HTO, may improve long-term outcomes ^13–16. The MFx technique is applicable for the repair of small- to mid-sized cartilage defects in OA; however, the results are suboptimal, and cartilage tends to deteriorate within a few years ^17–19. Autologous chondrocyte implantation (ACI) is not routinely recommended in older patients because of accelerated cellular senescence and the dedifferentiation of autologous chondrocytes during the culture expansion process ²⁰.

Recently, mesenchymal stem cells (MSCs) with concomitant HTO have been proposed as a potential treatment option for cartilage restoration in older patients ^21,22. MSCs can be obtained from various tissues of the human body such as the bone marrow (BM), synovium, adipose tissue, and umbilical cord ^23–25. Among the variously sourced MSCs, human umbilical cord blood-derived MSCs (hUCB-MSCs) have shown superior cartilage repair without bone formation or degeneration of the repaired cartilage. Furthermore, hUCB-MSCs have a high capacity for expansion, providing sufficient cells for therapeutic applications ^26,27.

This study aimed to compare the clinical and radiographic outcomes, as well as second-look arthroscopic outcomes after combining HTO with hUCB-MSC or microdrilling treatments, and to determine the relationship between articular cartilage regeneration and the defect site. Based on second-look arthroscopy, we hypothesized that HTO with hUCB-MSC implantation would demonstrate better clinical outcomes and superior articular cartilage regeneration than HTO combined with microdrilling.

Demographics

Of the 81 eligible patients (87 knees), 54 patients who met the inclusion criterion were included in this study and divided into two groups according to cartilage procedure. The distribution of patients was as follows: (1) group 1, 24 patients (27 knees) with implantation of allogenic hUCB-MSCs, (2) group 2, 30 patients (33 knees) microdrilling with concomitant HTO (Fig. 1). The mean age of participants was 56.88 years in the hUCB-MSC group and 59.91 years in the microdrilling group; mean body mass index was 26.55 (hUCB-MSC) and 26.60 (microdrilling). The mean lesion size of MFC and TCH was 7.25, 2.17 cm² in the hUCB-MSC group and 6.61, 2.48 cm² in the microdrilling group. Besides the time to hardware removal, the baseline characteristics were similar between the two groups (Table 1). Since the clinical trial was conducted on the hUCB-MSC group, stricter follow-up was possible, and the period until hardware removal was short.

Table 1

Comparison of baseline characteristics
Parameters	hUCB-MSC (n = 27)	Microdrilling (n = 33)	P value
Side (R/L)	13/14	16/17	0.98
Sex (M/F)	7/20	11/22	0.34
Age (yr)	56.88 ± 6.97	59.91 ± 4.56	0.06
Body mass index (kg/m²)	26.55 ± 3.47	26.60 ± 3.68	0.95
Follow-up period (months)	22.07 ± 7.61	18.61 ± 6.18	0.56
Defect size (MFC, cm²)	7.25 ± 2.51	6.61 ± 3.31	0.42
Defect size (TCH, cm²)	2.17 ± 1.31	2.48 ± 1.25	0.58
Time to hardware removal (months)	12.33 ± 0.68	13.00 ± 1.39	0.027

Clinical outcomes

There were no significant differences in the preoperative clinical scores between the two groups. From the preoperative to the final follow-up, significant improvements from baseline regarding VAS pain, WOMAC, and IKDC scores were observed in both the hUCB-MSC and microdrilling groups. At 24 months after surgery, the hUCB-MSC group demonstrated significantly greater levels of improvement than did the microdrilling group on both VAS (15.21 vs 28.57, P = 0.016) and IKDC scores (58.54 vs 50.29, P = 0.038) (Table 2 and Fig. 2).

Table 2

Comparison of baseline characteristics
	hUCB-MSC	Microdrilling	P value
Pre_VAS	48 ± 25.1	52.21 ± 27.46	0.54
Post_6M_VAS	33.91 ± 18.86	36.03 ± 25.18	0.74
Post_12M_VAS	23 ± 14.08	26.52 ± 18.42	0.41
Post_24M_VAS	15.21 ± 13.12	28.57 ± 20.23	0.016
Pre_Lysholm	48.26 ± 16.89	46.03 ± 18.96	0.64
Post_6M_ Lysholm	29.14 ± 20.32	58.17 ± 20.79	0.13
Post_12M_ Lysholm	67.56 ± 13.34	65.48 ± 20.93	0.66
Post_24M_ Lysholm	71.16 ± 20.37	66.93 ± 14.11	0.51
Pre_IKDC	36.65 ± 13.74	35.75 ± 17.12	0.83
Post_6M_ IKDC	63.75 ± 9.30	42.89 ± 14.16	0.083
Post_12M_ IKDC	49.5 ± 11.23	50.86 ± 13.23	0.06
Post_24M_ IKDC	58.54 ± 11.72	50.29 ± 9.46	0.038

Radiologic outcomes and arthroscopic findings

One year after surgery, 85% (51 of 60) of the patients underwent MRI. The hUCB-MSC group showed a higher mean MOCART 2.0 score; however, there was no statistically significant difference between the two groups (53.7 vs 53.04, p = 0.85).

The mean time to hardware removal was 12.7 months after the initial surgery, and second-look arthroscopy was also performed. The second-look arthroscopy findings related to articular cartilage regeneration according to the ICRS CRA grading system are summarized in Table 3. The hUCB-MSC group showed significantly better cartilage regeneration than did the microdrilling group in the ICRS CRA score (9.41 vs 7.94, p = 0.021).

Table 3

Outcome of MRI (MOCART 2.0 Score), second-look arthroscopy (ICRS CRA score)
	hUCB-MSC	Microdrilling	P value
MOCART 2.0 score	53.7 ± 9.07	53.04 ± 14.49	0.85
ICRS CRA score	9.41 ± 1.76	7.94 ± 2.78	0.021

In the subgroup analysis according to the site of cartilage defect, the results of the comparative analysis of the anterior, middle, and posterior sites in both the hUCB-MSC and microdrilling groups are shown in Table 3. In the hUCB-MSC group, the anterior lesion showed a statistically significant increase in the MOCART (P < 0.001) and ICRS CRA (P < 0.001) scores compared to the middle and posterior lesions. In the microdrilling group, the anterior lesion showed a statistically significant increase in the MOCART (p = 0.019) and ICRS CRA (p = 0.034) scores as compared to the posterior lesion. (Tables 4 and 5)

Table 4

Outcome of MRI (MOCART 2.0 Score), second-look arthroscopy (ICRS CRA score)
hUCB-MSC	Ant	Mid	Post	P (Ant-Mid)	P (Mid-Post)	P (Ant-Post)
MOCART 2.0	69.29	53.75	45	0.001	0.098	0.001
ICRS CRA	10.72	7.6	6	0.001	0.213	0.001

Table 5

Outcome of MRI (MOCART 2.0 Score), second-look arthroscopy (ICRS CRA score)
Microdrilling	Ant	Mid	Post	P (Ant-Mid)	P (Mid-Post)	P (Ant-Post)
MOCART 2.0	57.83	51.14	40.56	0.288	0.199	0.019
ICRS CRA	9.54	7.6	5.8	0.06	0.559	0.034

The main aim of this study was to evaluate the effect of hUCB-MSC treatment with HTO by comparing the clinical and radiological outcomes between the two groups. These outcomes improved in both groups regardless of the treatment administered. However, the hUCB-MSC procedure was more effective than microdrilling in terms of clinical results and cartilage regeneration.

A number of previous studies comparing hUCB-MSCs and BMAC reported that the clinical outcomes of these two procedures were similarly improved; however, hUCB-MSCs showed better cartilage regeneration ^28–30. Another study compared microfractures and hUCB-MSCs and reported that clinical outcomes and cartilage regeneration were significantly improved in the hUCB-MSC group ³¹. There was also a report that the clinical and radiologic outcomes were improved in patients who underwent the hUCB-MSC procedure together with HTO ^32–34. Similar to these studies, in the current study, hUCB-MSC performed with HTO yielded superior results compared to microdrilling in terms of clinical outcomes, second-look assessment, and MRI findings.

New findings were discovered in the course of MRI analysis and second-look arthroscopy analysis at 1 year postoperatively. In some patients with large cartilage defects, cartilage regeneration occurred differently depending on the location of the MFC, even within a single patient (Fig. 3). This meant that the results of cartilage regeneration could differ depending on the location of the lesion, and therefore a subgroup analysis was conducted. The results are presented in Tables 4 and 5, respectively. In the hUCB-MSC group, the anterior lesion showed a statistically significant increase in the MOCART and ICRS CRA scores as compared to the middle and posterior lesion. In the microdrilling group, the anterior lesion showed a statistically significant increase in the MOCART and ICRS CRA score as compared to the posterior lesion. The results showed that cartilage regeneration in the anterior lesion was superior to that in the posterior lesion in both groups.

Degenerative meniscal tears occur mainly in the posterior 1/3 of the medial meniscus. In the older adults group, it is reported that approximately 80% of articular cartilage lesions are accompanied by this, indicating that the prevalence increases as age increases and the accompanying articular cartilage lesions also increase ^35,36. In this study, degenerative meniscal tears of the posterior horn of MM were observed in most patients with medial OA, and it was confirmed that they did not function. It can be speculated that the absence of this meniscal function may have affected cartilage regeneration. Further research on cartilage regeneration and meniscal function is warranted. Therefore, in the case of cartilage defects involving the anterior part of the MFC, it can be expected that good cartilage regeneration can be seen when the cartilage procedure is performed. In addition, if these defects are large in size, we can provide guidelines that hUCB-MSCs can be a good surgical option.

This study had some limitations. First, this was a retrospective study, and a small number of patients in both groups participated. Small sample sizes may have had less power to detect significant effects. Therefore, there is a need for well-designed prospective randomized trials with large sample sizes. Second, histological assessments were not performed to evaluate cartilage regeneration. This study is currently in progress and will be evaluated in future studies. Third, there were differences in the indications for allogenic hUCB-MSC implantation and microdrilling. Microdrilling is not generally considered the standard care option for the restoration of large, full-thickness cartilage defects, particularly in older patients. However, we compared the two groups without considering the differences in these indications.

Despite these limitations, the present study had several strengths. To the best of our knowledge, this is the first study to compare the clinical, MRI, and second-look assessment outcomes using hUCB-MSCs or microdrilling for cartilage repair. We also compared the results of site-based cartilage repair regardless of the treatment method. This can aid surgeons in determining how to repair the cartilage based on the location of the lesion in the patient.

In conclusion, both microdrilling and hUCB-MSC implantation combined with HTO are effective treatments for medial OA in terms of radiological and clinical outcomes. However, hUCB-MSC implantation was more effective than microdrilling in terms of patient-reported outcomes and articular cartilage regeneration. The anterior lesion of the medial femoral condyle showed relatively good cartilage regeneration in both groups.

Patients

We retrospectively reviewed the medical records of patients who underwent implantation of allogenic hUCB-MSCs or microdrilling with concomitant HTO for the treatment of medial compartmental OA at one hospital between April 2019 and May 2021 after obtaining approval from the Institutional Review Board and Ethics Committee of our institution (Gangnam Severance Hospital, Institutional Review Board). All methods were performed in accordance with relavant guidelines and regulations. This study received exemption from informed consent by the Institutional Review Board and Ethics Committee of our institution (Gangnam Severance Hospital, Institutional Review Board). We included patients who underwent plate removal and second-look arthroscopy to check cartilage regeneration after complete bony union at least at the 1-year follow-up and had a full-thickness cartilage defect in the medial femoral condyle (MFC) (ICRS grade 3) with varus deformity.

We excluded patients with grade IV OA of the medial compartment (identified by radiological assessment according to the Kellgren and Lawrence system)³⁷, knee range of motion < 100° with flexion contracture > 15, additional surgical procedures of the same knee, knee ligament injuries, metabolic arthritis, joint infections, articular cartilage lesions in the lateral compartment, or a follow-up duration of less than 1 year.

Cell Preparation

Allogeneic UCB-MSCs were produced at a cell manufacturing facility operated by MEDIPOST Co. Ltd. in full compliance with the Good Manufacturing Practice requirements of the MFDS, as well as with donor screening, cell isolation and expansion, and quality control measures. The therapeutic use of the Cartistem for cartilage repair was reviewed and approved by the Korea Food and Drug Administration in January 2012. Commercially available hUCB-MSCs (Cartistem®, Medipost Inc., a composite of hUCB-MSCs 0.5 x 107/ml and freeze-drying sodium hyaluronate [HA]) were mixed to a gel-type consistency according to the manufacturer’s instructions prior to the application during surgery ³⁸.

Surgical techniques and postoperative management

All procedures were performed under general or spinal anesthesia. Diagnostic arthroscopy was performed before the osteotomy procedure and the status of the articular cartilage was evaluated thoroughly. After a complete inspection of the joints and assessment of the cartilage defects, biplane medial open-wedge HTO was performed in the same manner as in the previous study ³⁹.

In the microdrilling group, the chondral defect lesion was debrided and prepared using gouges and curettes prior to the HTO procedure. Multiple drill holes (1.5 x 14 mm [diameter × depth]; approximately 1–2 mm apart) were then made in the subchondral bone. In the hUCB-MSCs group, a mini-arthrotomy through an incision of approximately 3–4 cm in length was made through the anteromedial portal after the HTO procedure. After preparing the chondral lesion, multiple drill holes of two different sizes (4 × 7 mm, 2 × 7 mm [diameter × depth], approximately 2 mm apart) were made in the subchondral bone for the insertion of the UCB-MSC-HA composite. After preparing the lesion, the hUCB-MSC and HA mixture was slowly implanted into the prepared lesions to avoid any defects. The wound was closed, and a long leg splint was applied.

After the procedure, the knee was immobilized using an extension knee splint for 2 weeks. Continuous passive range of motion exercise was recommended from 2 weeks after surgery, and weight-bearing was restricted for 10 weeks. Toe-touch weight-bearing was allowed for 4 weeks, following which partial weight-bearing was allowed for 6 weeks.

Clinical evaluation

To assess pain and function of the knees, we used the visual analog scale (VAS), International Knee Documentation Committee (IKDC) subjective score, and Lysholm Knee Scoring Scale preoperatively as well as at 6 months and 1, 2, and 3 years after surgery. ^40,41

Magnetic Resonance Imaging evaluation

The quality of cartilage repair tissue, which was the primary efficacy endpoint, was evaluated via magnetic resonance imaging (MRI) using a 3-T scanner preoperatively and at 1 year postoperatively. MRI images were analyzed using the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) 2.0 Knee Score. Although MRI is unable to accurately determine the status of cartilage repair ⁴², the MOCART 2.0 score (0 = worst cartilage status, 100 = best articular cartilage status) was highly correlated with clinical outcome ^43,44. To avoid bias, two orthopedic surgeons specialized in knee surgery and one radiologist trained in musculoskeletal radiology evaluated the MR images acquired from all participants in a blinded manner. Each of the scores for the variables of the MOCART score reported by the two orthopedic surgeons and radiologist were recorded separately, and the total MOCART score was calculated from the mean of the three scores.

Arthroscopic evaluation

Second-look arthroscopy was performed one year after the initial HTO surgery in patients who underwent surgical treatment for hardware removal. During the second-look procedure, the repaired cartilage was inspected and evaluated using the International Cartilage Repair Society (ICRS) grading system and the ICRS cartilage repair assessment (CRA) scoring system (score 0–12), including the degree of defect fill, the degree of graft integration to the adjacent normal articular surface, and the gross appearance of the graft surface.^45,46

Subgroup analyses according to the defect site

The MOCART and ICRS CRA scores were used to evaluate the defect site according to the following criteria: The distal medial femoral condyle is divided into four sub-regions: trochlea, anterior, middle, and posterior femur.

Method of dividing subregions (Fig. 4)

To divide the trochlea and anterior regions, on the sagittal image, a line was drawn tangentially to the anterior horn of the meniscus (at the margin of the tibial plateau) until it intersected the femoral surface. The division between the anterior and middle femur is a line constructed vertically at half of the entire tibia, and the division between the middle and posterior femur is a line constructed tangentially to the posterior horn of the meniscus. The superior border of the femur was the physeal line.

Statistical Analysis

Differences in normally distributed variables, such as the clinical outcome, MOCART 2.0, and ICRS CRA between hUCB-MSC implantation and microdrilling, were analyzed using paired and independent t-tests. The Wilcoxon signed-rank test and Mann–Whitney U test were used to analyze differences when normality was absent. A repeated-measures ANOVA test was performed to evaluate the subgroup analysis (the relationship between articular cartilage regeneration and defect site). The level of significance was set at P < 0.05. All statistical analyses were performed using the IBM SPSS Statistics for Windows software (version 26.0; IBM, Armonk, New York, USA).

Institutional review board (IRB): This study was approved by the institutional review board of our institution (2022-1107-001).

Data Availability Statement

The datasets generated and analyzed in the current study are not publicly available to protect the patients’ personal information but are available from the corresponding author on reasonable request.

Author contributions

The concept of the study was generated, and project was coordinated by S-H. K. S-H. J. and B-J. N. drafted the manuscript, together with C-H. C, M. J., K. C. The acquisition of data and analysis was done by S.H. Jung, B-J. N. Y.J. and J. Park. S. K., specialized in musculoskeletal radiology, participated in the acquisition and analysis of the radiologic data. S.H Jung and S.H. Kim revised the ﬁnal draft critically for important intellectual content and approved the version to be submitted.

Additional Information

Competing interests:The authors declare no competing interests.

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No competing interests reported.

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Reviews received at journal
17 Oct, 2023
Reviews received at journal
11 Oct, 2023
Reviewers agreed at journal
06 Oct, 2023
Reviewers agreed at journal
25 Sep, 2023
Reviewers invited by journal
04 Sep, 2023
Editor assigned by journal
04 Sep, 2023
Editor invited by journal
16 Aug, 2023
Submission checks completed at journal
16 Aug, 2023
First submitted to journal
03 Aug, 2023

You are reading this latest preprint version

Allogeneic Umbilical Cord Blood-Derived Mesenchymal Stem Cell Implantation Versus Microdrilling combined with High Tibial Osteotomy for Cartilage Regeneration

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Results

Demographics

Clinical outcomes

Radiologic outcomes and arthroscopic findings

Discussion

Methods

Patients

Cell Preparation

Surgical techniques and postoperative management

Clinical evaluation

Magnetic Resonance Imaging evaluation

Arthroscopic evaluation

Subgroup analyses according to the defect site

Method of dividing subregions (Fig. 4)

Statistical Analysis

Declarations

Data Availability Statement

References

Additional Declarations

Status:

Journal Publication

Version 1