Autologous Chondrocyte Implantation Combined with High Tibial Osteotomy for Spontaneous Osteonecrosis of the Knee with a Relatively Large Cartilage Lesion in Elderly Patients

Abstract

Objective

This study aimed to evaluate clinical outcomes and cartilage repair following autologous chondrocyte implantation (ACI) combined with high tibial osteotomy (HTO) in elderly patients with spontaneous osteonecrosis of the knee (SONK) presenting with large cartilage defects.

Design

Eleven knees of 11 patients with SONK (lesion size ≥4 cm²) aged 60 years or older underwent ACI and concomitant opening-wedge HTO. Patients were followed for at least 1 year. Clinical outcomes were assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS). Cartilage repair was evaluated arthroscopically using the International Cartilage Repair Society (ICRS) grade and histologically using the ICRS II score at second-look arthroscopy.

Results

The overall KOOS improved significantly from a preoperative value of 38.4 ± 8.5 to a 1-year postoperative value of 77.8 ± 10.9 (P < 0.01). Arthroscopy showed cartilage repair to normal or nearly normal in 91% of cases. The mean histological ICRS II score was 67.5 ± 16.2. No postoperative complications or need for additional surgical interventions was observed.

Conclusions

ACI combined with HTO provides good clinical and histological outcomes in elderly patients with SONK and large cartilage defects. This approach represents an effective joint-preserving treatment option, even in patients aged 60 years or older.

Keywords

autologous chondrocyte implantation elderly patients high tibial osteotomy large cartilage defect spontaneous osteonecrosis of the knee

Introduction

Spontaneous osteonecrosis of the knee (SONK) is primarily observed in elderly patients without risk of secondary osteonecrosis. It has recently been reconsidered to represent the advanced spectrum of subchondral insufficiency fractures of the knee.^1,2 SONK typically presents as a localized lesion, notably involving the superficial subchondral area of the medial femoral condyle (MFC), and the lesions are generally smaller than those observed in secondary osteonecrosis. This condition can progress rapidly to end-stage osteoarthritis, often requiring surgical treatment.

Various surgical options are available for SONK, including arthroscopic debridement, bone marrow stimulation (BMS) with drilling or microfracture, core decompression, high tibial osteotomy (HTO), osteochondral autograft transplantation (OAT), and more extensive procedures such as total knee arthroplasty.^3
-5 The selection of a surgical approach depends on the lesions’ characteristics, which are typically localized to MFC but are mostly accompanied by varus knee deformity in advanced cases. Of these surgical options, HTO is an established procedure to correct varus malalignment in patients with SONK.^6,7 Furthermore, combining OAT with HTO has been shown to effectively restore cartilage in SONK cases with extensive lesions, leading to good clinical outcomes.⁸

Autologous chondrocyte implantation (ACI) is an established surgical option for treating full-thickness cartilage defects of the knee joint. ACI is particularly effective for repairing large cartilage defects (e.g., >4 cm²), producing repair tissue that closely approximates hyaline cartilage.⁹ Use of ACI as an alternative to OAT has recently increased due to less donor site morbidity.¹⁰ ACI is more commonly performed in younger patients, and good clinical outcomes have been reported when combined with realignment procedures such as HTO.¹¹ However, the efficacy of ACI in combination with HTO for elderly patients with SONK remains unclear.

The aim of this study was to evaluate the clinical outcomes and cartilage repair after ACI with concomitant HTO in elderly patients with a large SONK lesion. It was hypothesized that ACI and concomitant HTO provide good cartilage repair and improve clinical outcomes in patients 60 years of age and older.

Materials and Methods

Patients

A total of 11 knees of 11 consecutive patients with SONK who underwent ACI and concomitant opening-wedge HTO between 2015 and 2023 were prospectively investigated. All patients were followed-up postoperatively for at least 1 year and underwent biopsy of regenerated articular cartilage during second-look arthroscopy. The inclusion criterion was painful SONK with a history of minor trauma in a lesion ≥4 cm² in area localized to the MFC (lesions <4 cm² were not treated with ACI). The exclusion criteria were patients with severe varus deformity with mechanical varus alignment greater than 10° on a weightbearing radiograph, flexion contracture greater than 15°, or a history of inflammatory arthritis, joint infection, or corticosteroid intake. The study protocol and publication were approved by the institutional review board. Written, informed consent was obtained from all individual participants included in this study.

Surgical Procedure and Postoperative Management

ACI was performed in 2-stage procedures. First, cartilage tissue (~0.4 g) was arthroscopically harvested from non-weightbearing areas of the knee. The cartilage tissue was delivered to the facility (Japan Tissue Engineering Co., Ltd., Aichi, Japan). Cartilage tissue was subjected to enzymatic digestion, and chondrocytes were isolated and embedded in an atelocollagen gel. The tissue-engineered cartilage (JACC) was cultured in a 3-dimensional environment for 4 weeks. The manufacturer ensured sterility and cell viability through rigorous standard operating procedures prior to shipping the tissue-engineered cartilage to the hospital for implantation.¹² Second, ACI and opening-wedge HTO were performed on the same day. The lesion of the MFC was exposed through subvastus arthrotomy, and debridement of damaged cartilage was performed. JACC was placed on the defect and covered with a patch of periosteum or a collagen membrane (Chondro-Gide, Geistlich Pharma AG, Wolhusen, Switzerland) using suture anchors and nylon sutures. Opening-wedge HTO was performed using rigid plate fixation through an anteromedial approach under fluoroscopic guidance.⁷ The amount of angular correction was planned preoperatively, aiming to achieve tibiofemoral mechanical valgus of 5° on a 1-leg standing radiograph postoperatively. The osteotomy was started 35 mm below the medial articular surface of the tibia. An oblique osteotomy was performed from the medial cortex to the upper third of the proximal tibiofibular joint using a biplanar technique, leaving the tibial tuberosity intact. The osteotomized gap was gradually opened and filled with 2 wedged blocks of beta-tricalcium phosphate with 60% porosity (Osferion, Olympus Terumo Biomaterials. Corp., Tokyo, Japan) and fixed with TomoFix (DePuy Synthes, Zuchwil, Switzerland). No meniscal procedures, such as repair or partial meniscectomy, were performed in any of the cases.

Patients started range-of-motion exercise 1 week after surgery. A non-weightbearing regimen was prescribed for 3 weeks, followed by partial weightbearing exercise. Full weightbearing exercise was permitted 6 weeks postoperatively.

Assessment of Clinical and Radiographic Outcomes

Clinical evaluation was carried out using the Knee Injury and Osteoarthritis Outcome Score (KOOS). For radiographic assessment, full-length anteroposterior radiographs of the lower limb were taken in the standing position, and limb alignment was expressed as the hip-knee-ankle (HKA) angle, measuring the angle between the mechanical axes of the femur and tibia, with negative values for varus and positive values for valgus. The outcomes were assessed between preoperative and postoperative 1 year.

Arthroscopic Assessment of Articular Cartilage Repair

Second-look arthroscopy was performed in all patients at the time of plate removal, and images of the MFC were recorded. Cartilage repair was evaluated by 2 independent observers according to the International Cartilage Repair Society (ICRS) repair grade. In cases of disagreement about the grading, a final decision was reached through consensus between the observers.

Histological Assessment of Articular Cartilage Repair

At the time of second-look arthroscopy, a core biopsy sample including both cartilaginous tissue and subchondral bone was obtained arthroscopically from the center of the repair tissue, perpendicular to the articular surface, using a 2.0-mm diameter bone biopsy needle. The specimens were fixed in 4% formaldehyde, decalcified, dehydrated, and then embedded in paraffin. Sections were made through the longitudinal axis of the specimens and stained with safranin O. Histological assessment was carried out by 2 independent observers using the ICRS II scoring system,¹³ and the mean of 2 values was used as the final score.

Statistical Analysis

Statistical analysis was carried out using BellCurve for Excel version 4.08 (Social Survey Research Information Co., Ltd., Tokyo, Japan). Since histograms of the data indicated that the variables had non-normal distributions, nonparametric statistical methods were used to analyze the data. The Wilcoxon signed-rank test was used to test for significant differences in within-participant changes of continuous variables. Pearson’s chi-squared test was used to test for significant differences in the distributions of categorical variables. An adjusted P-value < 0.05 was considered significant. A post hoc power analysis for the paired pre-to-post change in the KOOS overall score was conducted (2-tailed α = 0.05), calculating Cohen’s dz from the observed mean difference and the SD of paired differences; because the pre–post correlation (r) was not recorded, sensitivity analyses were performed assuming r = 0.3, 0.5, and 0.7.

Results

Characteristics of Patients and Implanted Tissue-Engineered Cartilage

Of the 11 patients included, 8 were female and 3 were male, with a mean age of 68.9 years (range = 60–77). The mean body mass index was 24.9 kg/m² (range = 21.1–31.4). The average lesion size was 4.8 cm² (range = 4.0–5.3). Second-look arthroscopy was performed at a mean of 13.7 months postoperatively (range, 12–16).

The tissue-engineered cartilage cultured for 4 weeks contained 3.8 ± 1.7 × 10⁶ viable cells with 249.6 ± 134.1 µg of glycosaminoglycan content per implantation. All tissue-engineered cartilage constructs met the regulatory criteria for manufacturing, including sterility and cell viability, and were successfully implanted into patients.

Postoperative Course and Complications

All patients completed the planned rehabilitation protocol and achieved the ability to walk unaided within 2 to 3 months. No cases had complications including neurovascular injury, wound-healing problems, infection, venous thromboembolism, fracture, and delayed union at the osteotomy site. There were no cases that required additional surgical treatment until plate removal.

Clinical and Radiographic Outcomes

The mean overall KOOS improved from a preoperative value of 38.4 ± 8.5 to a postoperative value of 77.8 ± 10.9 at 1 year (P < 0.01). The mean KOOS subscales of Symptoms, Pain, Activity of Daily Living (ADL), Sport and Recreational Activities (Sport/rec), and knee-related Quality of Life (QOL) improved from preoperative values of 43.2 ± 12.8, 38.9 ± 9.7, 43.3 ± 8.1, 22.7 ± 14.0, and 27.8 ± 10.6 to postoperative values of 78.9 ± 11.6, 81.6 ± 11.3, 83.3 ± 11.1, 59.6 ± 14.6, and 67.0 ± 13.1 at 1 year, respectively (all P < 0.01). The observed KOOS improvement yielded large paired effect sizes (Cohen’s dz = 3.39–5.03 across r = 0.3–0.7), corresponding to an achieved statistical power ≈1.00 (2-tailed α = 0.05). The mean HKA angle increased significantly, from −6.0 ± 2.2° preoperatively to 4.5 ± 2.0° at 1 year after surgery (P < 0.01).

Arthroscopic Outcomes

Preoperative first-look arthroscopy revealed that all cartilage lesions were classified as ICRS grade 4, indicating full-thickness cartilage loss with exposure of the subchondral bone. Second-look arthroscopy showed that the cartilage defect was covered with white cartilaginous tissue, with neither hypertrophy nor ossification in all cases. Cartilage status according to the ICRS overall repair grade classification is summarized in Table 1 . Cartilage repair with normal or nearly normal status was achieved in 10 cases (90.9%).

Table 1.

Cartilage Repair Assessment by Second-Look Arthroscopy.

ICRS Grade	1: normal	3 (27%)
	2: nearly normal	7 (64%)
	3: abnormal	1 (9%)
	4: severely abnormal	0 (0%)

ICRS = International Cartilage Repair Society.

Histological Outcomes

Histological assessment according to the ICRS II score is summarized in Table 2 . The mean overall assessment of the repaired tissue was 67.5 ± 16.2. A representative case with histological findings is shown in Figure 1 . The mid-to-deep zone of regenerated cartilage was strongly stained with safranin O. Many round or oval cells were observed, scattered in a disorderly manner throughout the repaired tissue. Regenerated tissue was almost completely integrated into subchondral bone.

Table 2.

Histological Assessment.

ICRS II histological parameter	Score
Tissue morphology	47.0 ± 25.3
Matrix staining	65.5 ± 18.8
Cell morphology	61.0 ± 24.0
Chondrocyte clustering	77.5 ± 18.7
Surface architecture	79.5 ± 21.3
Basal integration	95.0 ± 8.8
Formation of a tidemark	53.5 ± 25.7
Subchondral bone abnormalities/marrow fibrosis	81.5 ± 14.3
Inflammation	96.0 ± 5.7
Abnormal calcification/ossification	100.0 ± 0
Vascularization	93.0 ± 6.7
Surface/superficial assessment	65.0 ± 22.5
Mid/deep zone assessment	72.0 ± 15.7
Overall assessment	67.5 ± 16.2

ICRS = International Cartilage Repair Society.

The values are reported as mean ± standard deviation.

Figure 1.

A 77-year-old woman with spontaneous osteonecrosis of the knee who was treated with autologous chondrocyte implantation and opening-wedge high tibial osteotomy. (A) Preoperative radiograph of the knee. (B) Postoperative radiograph of the knee. (C) Tissue-engineered cartilage (JACC). (D) Cartilage defect of the medial femoral condyle. JACC is placed on the cartilage defect (E) and is covered with a collagen membrane (F). (G) Arthroscopic image at postoperative 12 months showing full coverage with white cartilaginous tissue over the surface of the medial femoral condyle (ICRS total score 11, grade 2). (H) Whole histological image of a biopsy sample from the medial femoral condyle at second-look arthroscopy. (I-K) Photomicrographs of regenerative cartilage tissue with safranin O staining in the surface layer (I), middle layer (J), and deep layer (K). Scale bars = 50 μm.

Discussion

This study was intended to clarify the impact on the outcomes among elderly patients of opening-wedge HTO and ACI for SONK with a relatively large cartilage lesion. The results of the present series support the initial hypothesis that ACI and concomitant HTO provide good cartilage repair and improve clinical outcomes in patients aged 60 years and older.

SONK often results in large, full-thickness cartilage defects, whose repair is particularly challenging. Of the various surgical options, OAT provides immediate structural support and delivers native hyaline cartilage, making it a more reliable option for SONK cases with extensive subchondral bone damage.^4,14 A previous study reported that BMS combined with HTO failed to repair necrotic lesions larger than 4 cm², whereas OAT was successful regardless of lesion size.¹⁴ Despite this, ACI is often preferred over OAT due to its ability to avoid donor site morbidity, its suitability for larger defects, and the quality of the repaired cartilage. Importantly, the present study demonstrated good cartilage repair outcomes with ACI even in patients with relatively large necrotic lesions, suggesting its potential efficacy in challenging SONK cases.

OAT requires harvesting healthy cartilage from a non-weightbearing area, typically the MFC or trochlea, which creates a new defect at the donor site,¹⁰ whereas ACI uses cultured chondrocytes for transplantation, eliminating the need for a large amount of donor site harvesting and preventing additional cartilage damage. Furthermore, OAT involves the placement of multiple cylindrical osteochondral plugs in a mosaic-like pattern, which can result in differences in plug height and gaps between grafts, potentially compromising the smoothness of the articular surface.^15,16 In contrast, ACI allows for uniform distribution of chondrocytes over a broader area and leads to smoother articular surface formation with hyaline-like cartilage, which makes it more suitable for larger chondral defects (typically up to 10 cm²).^9,17,18

In addition to ACI and OAT, several other cartilage repair or biologic augmentation strategies have been investigated in elderly patients. Matrix-induced ACI has shown promising outcomes with less invasive surgical techniques and improved cell distribution, although evidence in older cohorts remains limited.¹⁹ Biologic adjuncts such as bone marrow aspirate concentrate (BMAC) and platelet-rich plasma (PRP) have also been evaluated, primarily for their potential to enhance the biological environment for repair rather than to provide structural restoration. Recent reviews have highlighted that while BMAC and PRP may offer symptomatic relief and possibly support tissue repair in degenerative settings, the heterogeneity of study designs and short-term follow-up periods limit definitive conclusions.²⁰ Nevertheless, these emerging approaches suggest that biologic augmentation could be considered as an adjunct in carefully selected elderly patients, particularly when conventional repair options are less feasible. However, long-term randomized controlled trials are still required to clarify their durability and comparative efficacy.²¹

The success of ACI may depend on the concomitant realignment procedure. Knee osteotomy is often performed alongside cartilage repair procedures, but the key question is whether realignment knee osteotomy is necessary for cartilage repair or whether cartilage repair is necessary for realignment knee osteotomy. A study comparing isolated ACI and ACI with concomitant HTO in patients with cartilage defects of the MFC and mild varus deformity (1–5°) found that failure rates, defined as the need for revision surgery, were significantly higher in isolated ACI than in ACI combined with HTO.²² This suggests that, even in cases of mild varus deformity, concomitant knee osteotomy is recommended to enhance ACI outcomes. Another study examining reoperation rates after ACI and OAT, both with and without osteotomy, demonstrated that concomitant osteotomy significantly reduced the risk of reoperation for both cartilage repair procedures.²³ These findings suggest that realignment knee osteotomy plays a role in preserving the implanted cartilage tissue by optimizing the mechanical environment. Although HTO may be the dominant factor in cartilage regeneration, cartilage repair procedures such as ACI and OAT remain essential for large chondral defects that cannot be addressed by osteotomy alone.^8,11,14 Further comparative studies of ACI and OAT in combination with HTO are needed to establish optimal treatment algorithms.

Age has been traditionally considered a limiting factor for ACI, primarily due to the reduced regenerative capacity of chondrocytes. One explanation is that aged chondrocytes exhibit diminished proliferation and extracellular matrix production,^24
-26 and osteoarthritic changes in both transplanted and residual chondrocytes may compromise the quality of cartilage repair in older individuals. In clinical practice, age remains a controversial factor in eligibility for ACI. Whereas ACI is generally recommended for younger patients,²⁷ several studies have reported comparable outcomes in patients older than 40–50 years.^19,28,29 However, the clinical efficacy of ACI in patients over 60 years of age remains largely unexplored. In the present study, despite all patients being over 60 years of age, they showed good cartilage repair and good short-term clinical outcomes. Notably, the chondrocytes harvested from these elderly patients successfully met the regulatory criteria for manufacturing, suggesting that autologous chondrocyte processing is feasible even in advanced age. Furthermore, histological assessment of the repaired tissue in this study showed an ICRS II overall score of 67.5 ± 16.2, which is comparable to previously reported outcomes (70.4 ± 20.8) using the same atelocollagen-associated ACI procedure in a younger population.³⁰ Although this value can be regarded as modest in absolute terms, an ICRS II score in this range typically indicates the presence of hyaline-like cartilage with partial structural or cellular irregularities compared to native cartilage. Previous studies have shown that such repair tissue, while not perfectly restored, can still provide substantial pain relief and functional improvement.^30,31 In the context of elderly patients with SONK, achieving histological quality comparable to that of younger cohorts supports the biological potential of ACI even in a less favorable degenerative environment. However, whether this level of repair tissue quality is sufficient to maintain function and delay osteoarthritis progression in the long term remains to be determined. Given these results, age alone should not be a strict exclusion criterion for ACI, although further long-term studies are needed to validate its efficacy in older patients.

This study has several limitations. First, the follow-up period was relatively short, limiting the ability to evaluate the long-term durability of the repaired cartilage or the risk of progression to osteoarthritis and subsequent arthroplasty in elderly patients. Continued follow-up of this cohort is underway, and inclusion of similar cases into multicenter registries is under consideration to provide more robust mid- to long-term evidence. Second, the sample size was small, which may have affected statistical power and generalizability. Although a post hoc power analysis for the KOOS overall score demonstrated large effect sizes with achieved power close to 1.00 for the observed within-cohort improvements, the small sample size inevitably limits external validity. Third, although this study focused on ACI, other cartilage repair techniques such as OAT and cell-based therapies (e.g., mesenchymal stem cells) should be compared to determine the most effective approach for elderly patients. Fourth, the effects of HTO versus cartilage repair procedures alone remain unclear, and further prospective trials are needed to delineate their respective contributions to clinical outcomes. Fourth, no comparison group (e.g., HTO alone or ACI alone) was included, making it difficult to determine the additive contribution of each procedure. Given the rarity of elderly patients with SONK and large cartilage defects who are suitable candidates for ACI, it was not feasible to recruit a sufficiently powered control group within a reasonable timeframe. Finally, the issue of cost-effectiveness remains unresolved, as ACI is a resource-intensive procedure, and further studies comparing its economic impact with other treatment options are warranted.

Conclusions

The present study demonstrated that HTO and ACI for relatively large cartilage lesions were effective in patients 60 years of age and older at short-term follow-up. The findings suggest that ACI with concomitant HTO may represent a viable joint-preserving option for elderly patients with SONK, although further long-term and comparative studies are warranted to confirm its efficacy.

Footnotes

ORCID iD

Ken Kumagai

Ethical Considerations

Ethical approval for this study was obtained from the institutional review board at Yokohama City University (#B160204001).

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability

The data that support the findings of this study are available from the corresponding author, K.K., upon reasonable request.

Consent to Participate

Written informed consent was obtained from all subjects before the study.

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