Report on Evolving Indications, Techniques, and Outcome of Novel and Innovative Surgical procedure – Agili C®

Abstract

Background

Purpose of review

Agili-C® (CartiHeal, Smith & Nephew) is an off-the-shelf aragonite-based (inorganic calcium carbonate) scaffold approved for clinical use in 2022 to treat chondral and osteochondral lesions eventually also in the context of mild to moderate knee osteoarthritis (Kellgren-Lawrence 0–3). The successful preclinical studies justified the subsequent clinical trials which reported both clinical and radiological significant improvements over time as well as superiority over standard surgical techniques for cartilage lesions treatment (i.e. microfractures/debridement). The aim of the present review is to summarize the available preclinical and clinical evidence and to report the current indications, surgical techniques and outcomes of this novel and innovative osteochondral scaffold.

Recent findings

A total of six clinical reports, four single cohorts studies and a recent double arm randomized control trial followed by an analysis differentiating between femoral and trochlear lesions, have been published on Agili-C® safety and efficacy. Supported with an excellent safety profile, Agili-C® provided statistically significant clinical benefits at short and medium-term follow up in patients affected by knee joint surface lesions also when presenting in the context of mild to moderate knee osteoarthritis (Kellgren-Lawrence 0–3).

Summary

Agili-C® (CartiHeal, Smith & Nephew) is an innovative aragonite-based osteochondral scaffold. It is an CE-marked and FDA approved off-the-shelf, cell-free, and cost-effective implant designed to treat knee joint surface lesions in the form of chondral and osteochondral defects. Its indications, supported by consistent clinical evidence, are single or multiple knee joint surface lesions (ICRS grade III or IV), with a total treatable area of 1-7cm², without severe knee OA (Kellgren-Lawrence grade 0–3).

Introduction

Articular cartilage defects of the knee have always been a significant challenge for surgeons due to their limited spontaneous healing potential and propensity to worsen over time [1]. Mature cartilage is, by definition, avascular and has a slow cellular turnover [2]. The relationship between these lesions and the underlying bone further complicates things, creating a multifaceted problem that demands precise intervention to relieve pain and restore joint function [3]. Moreover, the long-run problem of these lesions being left untreated, goes beyond symptomatic and functional impairment, resulting in a slow but steadily progressing knee osteoarthritis (OA) [4].

Given the burden of the disease, several techniques have been developed over the years to address articular cartilage defects [5]. Microfracture are often considered the first line of treatment, despite the lack of long-term benefit and high rates of osteoarthritic progression [6, 7]. Chondral regenerative techniques such as autologous chondrocyte implantation are a valid option with satisfactory clinical outcomes, despite burdened by high-costs, regulatory limits and the need of a two-step’s procedure, with a long postoperative care. More importantly, though, they did not provide an optimal solution for osteochondral lesions since not addressing the complexity of the cartilage-bone interface and the impossibility to target the subchondral bone [8]. On the other hand, the subchondral unit can be targeted with effective treatment such as osteochondral autograft transfers (OATs) or osteochondral allograft (OCAs) [6, 9–11]. Nonetheless, the first are linked with frequent donor site morbidity, conversely the use of the OCAs can be impeded by regulatory issues, availability limitations and excessive costs. This is why, with the advent of tissue bioengineering, we have witnessed a shift towards the development of innovative off-the-shelf cell-free treatment strategies that target the entire ‘osteochondral unit’ as a whole while overcoming the aforementioned limitations of OATs and OCAs [12]. Recognizing the integral role of the subchondral bone in lesion pathogenesis, researchers have focused on devising scaffolds that facilitate regeneration across both cartilage and bone regions [13]. This approach aims to restore the osteochondral unit, offering a more comprehensive solution to joint surface defects aiming at more durable results and improved clinical outcomes [14]. On top of this, scaffolds are easy to handle, are not associated with donor site morbidity, and do not depend on the viability of grafts but consist of an off-the-shelf solution. Moreover, they can be used in one-step procedures, avoiding issues related to cell manipulation and culture as well as regulatory issues, while reducing costs [15].

Among these innovative therapies, one has gained particular attention. Agili-C® (CartiHeal, Smith & Nephew) is a novel aragonite-based (inorganic calcium carbonate) osteochondral scaffold approved for clinical use from FDA in 2022 and CE-marked. It is a porous, biocompatible, and biodegradable bi-phasic scaffold, consisting of interconnected natural inorganic calcium carbonate (aragonite) derived from purified, inorganic, coral exoskeleton [16, 17]. The theoretical potentials of this breakthrough engineered material have been supported by in vitro and pre-clinical studies [14, 16] and recently, by clinical results [18–23]. The aim of the present review is to summarize the available evidence on the Agili-C™ scaffold, underlying the scientific rationale along with the current indications, techniques, and clinical outcomes.

Agili-C® (CartiHeal, Smith & Nephew) Microstructure and the Bioengineering idea behind it

The optimal osteochondral scaffold should support bone repair in the subchondral area while facilitating the migration of mesenchymal stem cells from bone marrow into the superficial cartilaginous layers. It should also enable cartilage repair at the articular surface and promote the integration of the neocartilage with the surrounding cartilage while undergoing reabsorption.

Coral exoskeletons (aragonite) structurally resemble human bone, sharing similar 3D design and internal composition (mainly consisting in calcium carbonate). Coral exoskeletons have been seen to have osteoconductive and osteogenetic properties and, with time, are fully reabsorbed and replaced by autologous tissue representing an interesting solution when trying to produce the ideal osteochondral scaffold [16, 24].

The Agili-C® implant (CartiHeal, Smith & Nephew) is a novel, innovative product consisting in a porous, interconnected, natural, inorganic calcium carbonate device derived from a purified, inorganic coral exoskeleton. This material provides a 3-dimensional design combining optimal mechanical properties to the high interconnected macroporosity required for vascular tissue ingrowth inside the device. Agili-C® is biocompatible, fully resorbable, and is bi-phasic, meaning that it has a two-part structure (Fig. 1): the lower segment, being inserted deeply in contact with the subchondral bone, is made of inorganic aragonite and has large pores (100–200 μm) that allow new blood vessels to grow into it colonizing the implant. Osteoclasts and osteoblasts degrade and reconstitute this part into new subchondral bone resulting in a biocompatible and resorbable implant [25].

Fig. 1.

Micrograph of the Agili-C™ (CartiHeal, Smith & Nephew) scaffold. (A) Interconnected natural inorganic calcium carbonate (aragonite) derived from purified, inorganic, coral exoskeleton. (B) and (C) are close-ups of the bone phase that reveal its porous microstructure

The upper segment, the chondral phase facing the joint environment, is mechanically processed to create a grid of small micro-drilled channels (2 mm deep). This configuration facilitates adhesion, differentiation, and proliferation of bone marrow and synovial mesenchymal stem cells to chondrocytes, thereby fostering articular cartilage formation. Finally, the implant design is now tapered and angled at 2° to improve press-fit implantation and enhance patient outcomes providing a stable implantation through time [19]. Before the clinical application, an extensive purification process is performed to treat and remove trapped particles, debris and organic remnants, and the implants are sterilized by 25 kGy gamma radiation. The surgical implantation consists in a simple and quick open procedure described in the following paragraphs.

Extensive research has been conducted to develop the current implant. Kon et al. initially showed how mechanical modification with drilled channels and biological augmentation with HA were able to enhance the scaffold’s regenerative potential [16]. In this initial animal study, a total of 28 osteochondral lesions were performed on goat animal models. Implants were placed in two locations: the medial femoral condyle (MFC) and the lateral femoral condyle (LFC). In each site, a single device was inserted into the central part of the condyle in a weight-bearing area. Animals were randomized into four groups to compare the outcomes of untreated control animals to the ones of goats treated with implants with drilled channels in the cartilage phase, with drilled channels in the bone phase or unmodified implants. Furthermore, 50% of the implants within each treatment group had hyaluronic acid (HA) impregnated in the upper cartilage section of the implant. After 6 months the animals were sacrificed, and the knee joints underwent histopathological evaluations that demonstrated how implants impregnated with HA outperformed all other solutions in all evaluation methods and those implants were found to be replaced by newly formed hyaline cartilage and subchondral bone. The repair tissue found colonizing the implants had a smooth contour, integrated well with adjacent cartilage, and showed typical characteristics of hyaline cartilage: high levels of proteoglycans and collagen type II and absence of collagen type I [16].

The early potential for bone and cartilage formation was confirmed in a later study on the same animal model reaching the 12-month follow-up [17]. In this work, the Agili-C® implant was compared with a defect in which a blood clot extruding from the bone marrow was allowed to form and left untreated. Each operated joint underwent imaging (ultrasound imaging, X-Ray, micro-CT, MRI), histological and immunohistochemical evaluations. At the 12-month sacrifice, only the Agili-C® scaffold group displayed the formation of a hyaline cartilage repair tissue, with little to no signs of neovascularization and inflammation withing the implant. The hyaline cartilage-like features found in the previous study were again confirmed by the presence of proteoglycans and collagen type II, along to the absence of collagen type I.

Those satisfying preclinical results represented the scientific background needed to drive the translation of this specific technology to clinical studies. Interestingly, the early human trial performed by Kon et al. in 2016 confirmed the findings of the aforementioned preclinical studies and helped refine the design and structure of the final implants now available on the market. In this first clinical study, a total of 97 patients younger than 50 years old, presenting with chondral and osteochondral lesions (ICRS grade III-IV) and without severe OA (Kellgren Lawrence I-II) were treated with the implantation of this novel osteochondral scaffold: 21 underwent the implantation of newly optimized tapered implants (2° angulation) and were clinically and radiologically compared to 76 patients previously treated with the implantation of classical cylindrical-shaped implants [19]. Tapered scaffolds maintained the clinical improvement seen in cylindrical implants while dramatically reducing the risk of revision surgery (0 patient underwent revision surgery at the 12 months follow up). Indeed, for the Agili-C® scaffold to be effective, it must remain stable postoperatively and during the subsequent phases of weight-bearing and physical activity. Stability ensures proper graft fixation, which is critical for successful integration with the host bone, maintenance of articular surface congruency, and vascular formation. The tapered design makes the implant more self-centered, avoiding possible damage during plug introduction while also maintaining a better press fit.

Agili-C®: Current Clinical Indications

A variety of chondral and osteochondral scaffolds have been approved for clinical use in recent years, sometimes making it quite tricky for orthopedic surgeons to determine the correct indication. To address this issue and fill in the gap in the literature, a panel of experts belonging to the ICRS (International Cartilage Regenerative & Joint Preservation Society) published in 2021 a consensus statement on the use of scaffolds for knee chondral and osteochondral defect reporting the best indication for different clinical scenarios [26]. They adopted the RAND/UCLA method, a method used to develop guidelines and clinical criteria by achieving expert consensus in situations where the scientific literature is limited or controversial. This specific method aims to systematically incorporate expert opinions while minimizing the influence of social pressure or panel hierarchy, making the guideline development process more transparent and rigorous. The panel’s conclusions can be summarized in 3 levels of appropriateness, detailed in Table 1. Hence, these new guidelines and the clinical results reported in this review, pave the route for a broadened adoption of off-the-shelf scaffolds. Accordingly, Agili-C® scaffold is now indicated and approved from FDA for single and multiple (up to 3) ICRS grade III or IV knee joint surface lesions, with a total treatable area of 1-7cm2, even in the context of non-severe knee OA (Kellgren-Lawrence grade 0–3).

Table 1.

Indications for scaffold implantation to treat chondral/osteochondral defects of the knee

Indications	Contraindications
Joint surface lesion(s) (ICRS grade III or above)	Avascular osteonecrosis
Femoral lesions (trochlear or condylar)	Tibial plateau and patellar lesions
Age 18–75	Associated lesions and/or malalignment (> 8°) if not contextually treated*
Total treatable area 1–7 cm2	OA grade IV
OA 0-III (Kellgren-Lawrence scale)	Bony or systemic infection
Lower limb malalignment < 8°	Uncontained lesions (= lack of surrounding vital bone wall at least 2 mm thick)
BMI < 35	Subchondral bone defect or bone cyst depth deeper than 8 mm
	BMI > 35

OA = osteoarthritis, ICRS = Internation Cartilage Repair Society, BMI = body-mass index

Surgical Technique and Postoperative Care

The Agili-C® surgical technique has been developed and refined to result in an easy and quick procedure benefiting of a limited number of specific surgical instruments and steps.

The lesion is directly exposed through a mini-arthrotomy centered on the cartilage lesion previously identified with MRI (Fig. 2). A cannulated aligner is pointed at the lesion site, and a K wire is passed through so that it goes perpendicular to the lesion floor and right through its center. Before drilling, it must be ensured that the final implant is surrounded by at least 3 mm of intact bone. In case of multiple lesions, it is possible to position multiple implants as far as those 3 mm of bone bridge is preserved between the implants. A manual reamer and a cartilage cutter are then used to prepare the deep floor and the walls of the receiving site. Finally, the implant is manually inserted and pushed to the bottom of the lesion until it is 2 mm below the cartilage surface. The lesion’s margins must be covered with healthy cartilage and stable. If, during surgery, the margins (or “shoulders”) are unsuitable to host the scaffold, the procedure cannot proceed as planned, as the rate of failure of the implant has been seen to be unacceptable. As an example, lesions involving the femoral notch and not providing a sufficient wall between the notch and the implant, have been seen to be associated to high failure rates and should not be treated with this specific surgical solution. Thus, it is always essential to carefully analyze the preoperative MRI to minimize the risk of changing the indication during surgery or risking a surgical failure.

Fig. 2.

Surgical technique. Courtesy of Dr. Seth L Sherman, adapted from https://www.youtube.com/watch?v=WgcyyxI-Xho: (a) Lesions exposure through mini-arthrotomy; (b) Positioning of the cannulated aligner and K wire; (c) Placement of the Drill Sleeve and drilling of the lesion with the Drill Bit over the K-wire; (d) Positioning of the Shaper; (e) Trimming of the peripheral cartilage using the Cartilage Cutter; (f) Manual implant insertion; (g) Final result

Post-operative care and rehabilitation after Agili-C® implantation is not different from the one advised for other cartilage treatment such as OCAs, OAT and ACI: 4 weeks of toe-touch weight bearing followed by 2 weeks of partial weight bearing with crutches are recommended. Continuous passive motion, active-assisted ROM exercises, and quadriceps isometric strengthening are advised during this period even when weightbearing is not allowed. Hydrotherapy is generally allowed and highly recommended after suture removal.

Clinical Results

The clinical results of Agili-C® implantation are derived from six clinical reports [18–23] published after 2016, five of which were published in the last four years.

The first study from 2016 has been already reported above and consisted in a matched cohort analysis of patients treated with 2 different implant designs [19]. Overall, a total of 97 patients younger than 50 years old, with chondral and osteochondral lesions (ICRS grade III-IV) and without severe OA (Kellgren Lawrence I-II) were enrolled and treated: 21 with were treated with a newly optimized tapered implants and were matched to 76 patients previously treated with classical cylindrical-shaped implants [19]. Clinical outcomes were compared using the IKDC subjective score, the Lysholm score, and all five KOOS subscales, administered preoperatively and at 6- and 12-months post-surgery. Nineteen patients in the tapered implants group also had imaging evaluations at the 12-month follow-up (Fig. 3). A statistically significant improvement in all clinical scores and in MRI findings was documented in both the tapered and cylindrical groups with no detectable difference in clinical and radiological scores between the two groups. Nonetheless, tapered implants were found to be associated with lower revision rates (0% vs. 8-10.5%) probably thanks to the ability of this particular design to provide self-centering of the implant, greater press fit forces and greater incorporation.

Fig. 3.

20-year-old patient treated for a significant osteochondral defect in the trochlea. After 12 months of follow-up, his IKDC score improved from 60 to 86, and his overall KOOS increased from 46 to 90

Later, in 2021, Van Genechten et al. published a single-center case series focusing on clinical response, safety outcomes, and MRI imaging results up to 3 years post-surgery [20]. Thirteen subjects with knee joint surface lesions (up to 3 treatable cartilage lesions ICRS III–IV on the femoral condyles or the trochlea) were successfully treated using one or two aragonite-based scaffolds, depending on lesion size. Patients experienced statistically significant symptomatic and functional improvements (KOOS, IKDC, Tegner and Lysholm scores), both shortly after the surgery and in the long term. While they did not fully regain their pre-injury activity levels, significant improvement was still observed at 18 and 24 months following the procedure. No serious adverse events (AEs) were reported during surgery or during the 36-month follow-up period. Potential device-related AEs included joint arthralgia (50%) and joint effusion (33%). No cases of implant loosening, failure, or infection were observed throughout the study. Bony integration and remodeling of the scaffold were completed in 66–100% of cases for 6 implants (40%) at 12 months and 11 implants (78.7%) at the final follow-up as assessed with the MOCART score. MRI frequently revealed a typical pit-like healing pattern, with peripheral ingrowth of newly formed subchondral bone, subsequent scaffold biodegradation, and the formation of a cartilaginous layer above the implant.

Later that year, Kon et al. published the results of a 2-year multicenter prospective study investigating the use of Agili-C® in knees affected by joint surface lesions in the context of mild-to-moderate OA (Kellgren-Lawrence grade 2 or 3) [22]. A total of 86 patients, with a mean age of 37.4 ± 10.0 years, were recruited from 8 medical centers. All patients had JSLs in the context of Kellgren-Lawrence OA grade II and III and a mean defect size of 3.0 ± 1.7 cm². All patients were assessed before surgery and up to 24 months of follow up. The main finding of the study was that Agili-C® could provide significant clinical improvement in patients with JSLs associated to mild to moderate knee OA. Indeed, KOOS and IKDC subjective scores significantly improved after 6 months and continued to increase further during the subsequent follow-up visits at 12, 18, and 24 months. Main AEs included swelling and pain (15/86 patients). During the 2-year follow-up, 8 patients (9.3%) underwent implant removal and were classified as failures: 2 cases were due to procedure-related infections, 5 cases involved partial loosening of the scaffold due to lack of integration, and 1 case experienced progression of osteoarthritis in the patellofemoral compartment, leading to total knee replacement 14 months after scaffold implantation. On MRI, a notable increase in the area of the defect filled with regenerated cartilage was evident. Furthermore, improvement in defect fill was noticeable as early as six months post-implantation, persisting through the 12 and 18-month follow-ups and culminating in its peak after 24 months.

In 2023, Altschuler et al. then published the first multi-center randomized clinical trial comparing the efficacy of Agili-C® aragonite-based scaffolds with surgical standard of care (SSoC, arthroscopic debridement/microfractures) for the treatment of knee chondral and osteochondral lesions [18]. This is the largest study to date on Agili-C® and clearly demonstrated the superiority of aragonite-based scaffolds over the current surgical standard of care. A total of 251 patients, aged 21–75 years old, with a maximum of three joint surface lesions graded IIIa or higher according to the ICRS grading system on the femoral condyles or trochlea were randomly assigned to receive either the aragonite-based implant or undergo debridement/microfracture treatment, with a 2:1 ratio for a total of 167 patients treated with the Agili-C implantation and 84 with the SSoC. To perform a correct randomization, patients with focal defects and Kellgren-Lawrence (KL) scores of 0 or 1 were randomized against similar patients treated with microfracture while patients with mild to moderate OA (KL 2 or 3) were randomized against those treated with arthroscopic debridement. The scaffold group exhibited significantly superior results in all endpoints during each follow-up assessment (6 to 24 months). Specifically, at the two-year follow-up, the magnitude of improvement in the implant group was double the control group in terms of mean KOOS improvement. The same applied to the responder rate, defined as presenting at least a 30-point improvement in overall KOOS, (77.8% vs. 33.6%) and imaging outcomes: at 24 months, 88.5% of patients treated with Agili-C® achieved > 75% defect fill of the treated lesions, compared to just 30.9% of those treated with the standard surgical care. The failure rate was also lower in the Agili-C® group: 7.2% compared to 21.4% in the control group. The most common adverse event was transient knee pain following surgery, experienced by 15.0% of the scaffold group compared to 39.3% of the control group. Moreover, it is important to underline how those encouraging results was also found for patients treated with 2 scaffolds. Indeed, this study illustrates how multiple scaffolds may be used to treat patients presenting either big or multiple lesions, even in the context of mild to moderate knee OA.

Finally, de Caro et al. recently published a small cohort study describing the medium term outcomes of 12 patients followed for at least 5 years of follow up [21]. Patients underwent the implantation of one or two plugs to treat a single condylar or trochlear lesion over grade III of the ICRS grading scale. At a mean of 6.5 years of follow up (range 5–8 years), one patient failed and underwent revision surgery with the implantation of a custom metal implant. For the remaining 11 patients, a statistically significant improvement in all KOOS subscales was reported from baseline to the final follow up with clinical results that appeared stable between the 24 months and final follow up. A subgroup analysis was also performed to evaluate variables that might influence the clinical outcome: acute lesions and previous cartilage surgery or meniscectomy predicted a better improvement, while gender did not influence the outcome. Furthermore, all patients exhibited on MRI a defect filling ranging from 75 to 100%: in 8 cases, a complete integration was found with the surrounding cartilage while in the remaining patients a split-like defect less than 2 mm was present [21].

The most recent clinical evidence on Agili-C® consists in the analysis performed from Conte et al. [23]: a differential analysis of the impact of lesions’ location on four years clinical and radiological outcomes was performed on 247 patients randomized to either Agili-C® implantation or surgical standard of care (SSoC, arthroscopic debridement/microfractures) to treat up to three knee joint surface lesions (ICRS grade IIIa or above). Interestingly, the Agili-C® group significantly outperformed the SSoC group also at the 4 years follow up showing significantly better PROMs (KOOS overall and IKDC), higher responder rates (intended as patients obtaining > 30 improvement in KOOS Overall Score), higher defect filling on MRI and lower treatment failures. When considering exclusively patients treated with Agili-C®, the resulting significant clinical and radiological improvements were found to be independent from lesion locations (either trochlear, condylar or mixed lesions), osteoarthritic state (KL 0-I vs. II-III) or lesion size (≤ 3 cm2 or > 3 cm2). Nonetheless, mixed lesions (trochlear + condylar), despite presenting significant improvements over time, were found to be associated with poorer clinical outcomes when compared to condylar and especially trochlear lesions that lead to the best clinical results.

Discussion

The main finding of the present review is that Agili-C® is an innovative scaffold able to provide symptomatic and functional benefits in patients affected by knee ICRS grade III or IV joint surface lesions even in the context of mild to moderate knee OA (Kellgren-Lawrence grade 0–3).

The biomechanical relationship between the articular cartilage and subchondral bone is well established [27]. In a healthy joint, hyaline cartilage maintains a near-frictionless articulating surface while the subchondral bone distributes joint forces. Nonetheless, after a trauma, damage to the subchondral bone may alter this equilibrium, leading to force distribution changes and cartilage degeneration [28]. Several studies have also explored the concept of biochemical crosstalk between cartilage and bone [29, 30]. The subchondral bone normally supplies cartilage with nutrients. However, during early OA, subchondral bone angiogenesis has been shown to lead to cartilage degradation and innervation. Walsh et al. explored the relationship between new microvasculature and nerve growth in osteochondral tissue and found elevated levels of vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) in the subchondral bone, extending into the noncalcified cartilage [31]. These released factors are able to dive across the fibrovascular structures created by the cartilage damage and may be responsible of symptoms occurrence and persistence [30]. Hence, despite the need of addressing the entire osteochondral unit is undeniable, the dilemma of the choice of the “perfect” scaffold still exists and several solutions have been proposed in the last years.

TruFit® was the first scaffold introduced into clinical practice [32]. This bilayer scaffold is composed of semi-porous polylactic (PLGA), polyglycolic acid (PGA), and calcium sulfate biopolymer. Initially designed to backfill graft donor sites during OAT procedures, TruFit® was later predominantly used as a one-step osteochondral treatment. However, it has now been withdrawn from the market due to poor outcomes, high failure rates, and unfavorable histological outcomes. Indeed, Shivji et al. conducted a long-term follow-up study (121 months) on this scaffold [33] and reported no statistically significant improvements in any scores from baseline. Furthermore, MRI evaluations revealed incomplete or absent plug incorporation and persistent chondral loss.

Maioregen® is a nanostructured biomimetic scaffold that targets the calcified tide mark with a triphasic design (superficial part 100% type I collagen; middle 60% C-I and 40% HA; deep 30% C-I 70% HA). It is also resorbable and osteoconductive, aiding in the regeneration of cartilage, as confirmed by histological analysis. Significant clinical improvement has been reported in almost all studies, with further improvement in clinical scales observed up to 5 years after surgery [34].

As for Agili-C® (CartiHeal, Smith & Nephew), this manuscript integrally reported all the available evidence supporting its use for chondral and osteochondral knee lesions. Initial in vitro studies reported that the bone phase of the bi-phasic aragonite-based scaffold supports osteogenic differentiation and enhanced proliferation of bone marrow-derived MSCs at both the molecular and histological levels given that the scaffold was seen to be colonized by differentiating MSCs, suggesting its suitability for incorporation into bone voids to accelerate bone healing, remodeling and regeneration [14].

Subsequent animal studies further confirmed the osteochondral regenerative potential of this aragonite biphasic scaffold [16, 17], and were then followed by six clinical reports with a total of 375 treated patients [18–23]. All these studies supported the efficacy of Agili-C® in producing significant clinical improvement at short and medium term follow up in patients with knee chondral and osteochondral lesions, its ability of regenerating the osteochondral unit and lastly, in the recent randomized control clinical trial, its superiority over standards of care surgical technique such as debridement and microfractures [18]. Furthemore, Agili-C® implantation was found to lead to statistically significant clinical and radiological improvements over time regardless of lesion locations (either trochlear, condylar or mixed lesions), osteoarthritic state (KL 0-I vs. II-III) or lesion size (≤ 3 cm2 or > 3 cm2) [23].

Data comparing the available osteochondral scaffolds are still not available in the present literature. In 2021, Boffa et al. published a systematic review and meta-analysis on multi-layer cell-free scaffolds collecting all the available evidence on the topic [15]. They focused on articles reporting results of the International Knee Documentation Committee (IKDC) and Tegner scores given the high variability in reported clinical outcomes in the included studies. The scores were analyzed as improvement from baseline to 1, 2, and ≥ 3 years of follow-up. A toal of 34 studies (1022 patients) were included, centered around the three aforementioned scaffolds: TruFit® (11 studies; 9 case series, 2 retrospective comparative techniques), MaioRegen® (20 studies; 19 case series and one RCT), and Agili-C® (3 studies; 2 case series and one retrospective study). Although the findings reported satisfactory outcomes of both MaioRegen® and Agili-C®, it was not possible to get a conclusion of an eventual superiority of one type of scaffold over the other. Indeed, to the author’s knowledge, no previous study performed a direct comparison of the Agili-C® over a different scaffold and the question of its eventual superiority still remains unanswered. Nonetheless, despite the good results achieved by Agili-C® implantation, we have to acknowledge the several limitations of the studies analyzed. Four [19–22] out of six studies analyzed did not include a control group and the overall sample size, although significant from a statistical point of view, still does not address the prevalence of the chondral and osteochondral lesions in the general population. Furthermore, evidences is now limited to short and medium term follow ups, with the longest evaluation represented by the study of de Caro et al. reaching 5 years of follow up while long term efficacy is yet to be determined [21].

In conclusion, further randomized controlled trials with longer follow ups will be needed to confirm the good clinical results and, maybe, proposing a new standard of care for this specific disease.

Conclusion

Agili-C® (CartiHeal, Smith & Nephew) is an innovative porous, biocompatible, and biodegradable bi-phasic scaffold, consisting of interconnected natural inorganic calcium carbonate (aragonite) derived from purified, inorganic, coral exoskeleton. It is an off-the-shelf, cell-free, and cost-effective implant designed to treat knee chondral and osteochondral defects. Its indications are knee joint surface lesions ICRS grade III or IV lesions, with a total treatable area of 1-7cm², without severe knee OA (Kellgren-Lawrence grade 0–3).

Author Contributions

All authors contributed to the review conception and to the production of the manuscript. The first draft of the manuscript was written by PC and GA along with the supervision and guidance of BDM. EK and PV finally contributed to final edits and critical revisions prior to submission. Then, all authors commented on previous versions of the manuscript and help refine it. Finally, all authors read and approved the final manuscript.

Funding

No funding was received for this manuscript.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Competing Interests

Pietro Conte and Giuseppe Anzillotti declare that they have no conflict-of-interest relevant to this manuscript. Berardo Di Matteo, Elizaveta Kon and Peter Verdonk are consultants for Smith and Nephews. Elizaveta Kon and Peter Verdonk both declare they have received consulting fees from and hold stock options in Cartiheal Ltd.