Insights of cartilage imaging in cartilage regeneration

Abstract

Cartilage, as a specialized connective tissue, underpins joint mobility and mechanical load distribution while exhibiting inherently limited self-repair capabilities. This comprehensive review redefines the current landscape of cartilage imaging by exploring conventional and advanced modalities used to assess both the structural and biochemical attributes of cartilage. Whereas conventional radiography and ultrasound offer rudimentary, indirect assessments, cutting-edge techniques - including magnetic resonance imaging (MRI)-based sequences such as T2 mapping, delayed gadolinium-enhanced MRI of cartilage, and sodium MRI - enable early detection of molecular alterations in the cartilage matrix. In addition, hybrid approaches like positron emission tomography-MRI are emerging to provide integrative molecular and structural insights. This article critically appraises imaging strategies in the context of regenerative interventions, highlighting technical innovations, persistent challenges, and future directions to facilitate improved diagnostic accuracy and therapeutic monitoring.

Key Words: Cartilage; Regeneration; Magnetic resonance imaging; Cartigram; Delayed gadolinium-enhanced magnetic resonance imaging of cartilage

Core Tip: Cartilage is crucial for joint mobility and load distribution but has limited self-repair abilities. Traditional imaging like radiography and ultrasound offer basic assessments, while advanced techniques like magnetic resonance imaging (MRI) (T2 mapping, delayed gadolinium-enhanced MRI of cartilage, sodium MRI) and hybrid positron emission tomography-MRI detect early molecular changes. This review highlights innovations, challenges, and future directions in imaging strategies for better diagnostics and regenerative intervention monitoring.

INTRODUCTION

Articular cartilage is an essential tissue that ensures smooth articulation and load distribution across joints, owing to its unique extracellular matrix (ECM) composed primarily of type II collagen, proteoglycans, and interstitial water[1-5]. Despite its critical biomechanical role, cartilage has a negligible regenerative capacity, rendering it susceptible to injuries induced by trauma, degenerative changes, and repetitive mechanical stress. Epidemiological findings, such as those by Cui et al[6], have emphasized the growing global burden of osteoarthritic conditions, especially among aging populations, thereby necessitating accurate diagnostic tools to assess early cartilage deterioration.

Historically, imaging assessments of cartilage have relied on techniques that indirectly infer cartilage integrity through changes in adjacent osseous structures or joint space. Conventional radiography, while accessible and economical, is limited in detecting early matrix alterations because it predominantly visualizes secondary features such as joint space narrowing, osteophytes, and subchondral sclerosis[7,8]. Similarly, ultrasound offers real-time imaging capabilities but is hampered by operator dependency and limited penetration, particularly for deep joint structures[9,10].

In contrast, the advent of magnetic resonance imaging (MRI) has revolutionized cartilage evaluation by providing high-contrast, multi-dimensional views of soft tissues without ionizing radiation[11]. Standard MRI sequences now routinely identify gross morphological changes[12], while advanced compositional techniques - such as T2 mapping, delayed gadolinium-enhanced MRI of cartilage (dGEMRIC), and sodium MRI - detect early biochemical alterations in water content, collagen architecture, and glycosaminoglycan (GAG) concentrations[13-15]. These modalities facilitate earlier intervention by identifying subtle degenerative changes before gross morphological loss occurs[16-19]. Moreover, emerging hybrid techniques like positron emission tomography (PET)-MRI are beginning to integrate metabolic and structural information, offering unprecedented insight into the pathogenesis of cartilage degeneration[20-23].

Given the critical importance of early detection and effective regenerative interventions, this review reexamines the full spectrum of imaging modalities available for cartilage assessment. By synthesizing findings from multiple high-quality studies and integrating novel technical advances, we aim to offer a detailed, state-of-the-art overview of cartilage imaging techniques and their implications for clinical practice.

LITERATURE REVIEW

This review was undertaken as a scoping investigation to capture the diverse imaging approaches used in both diagnosing cartilage pathology and monitoring regenerative therapies. The literature search spanned four principal electronic databases (PubMed, Cochrane Library, EBSCOhost, and Web of Science) from their inception through August 2024. A comprehensive search strategy was constructed utilizing medical subject headings and a range of keywords such as “cartilage”, “cartilage imaging”, “articular cartilage”, “MRI”, “ultrasound”, “CT arthrography”, “T2 mapping”, “dGEMRIC”, “sodium MRI”, “T1ρ imaging”, “gagCEST”, “PET-MRI”, “cartilage repair”, and “osteochondral lesions”. Boolean operators (AND/OR) were applied rigorously to ensure maximal retrieval of relevant literature.

After the initial search, duplicate entries were removed using reference management software. Two independent reviewers then screened the titles and abstracts for relevance based on predetermined inclusion criteria: Studies in English involving human subjects, with a focus on diagnostic imaging or therapeutic monitoring of cartilage, including interventions for cartilage repair and regeneration. Articles such as editorials, conference abstracts without sufficient data, and non-human studies were excluded. Full-text articles deemed potentially relevant underwent further review, and key data - including imaging modality, technical parameters, clinical applications, advantages, limitations, and potential for future innovation - were extracted. The paper is presented to outline the normal architecture and the injury modes of cartilage followed by their injury classification and a detailed review on the available modality to investigate the same with their advantages and disadvantages. We also discussed on the future scope of research in this domain based on the limitations noted with the current technology and the need for future.

CARTILAGE MICROARCHITECTURE AND INJURY CLASSIFICATION

Cartilage microarchitecture

Articular cartilage is a highly specialized tissue, characterized by a complex, hierarchical organization that is fundamental to its biomechanical function. The tissue is predominantly composed of water (65%-85%), which is intricately bound within an ECM composed of collagen fibers, primarily type II collagen, and proteoglycans rich in GAGs[24-26]. The structural organization of cartilage is classically divided into five distinct zones (Figure 1) that are critical to its load-bearing properties.

Figure 1 Normal healthy cartilage structure.

Superficial (tangential) zone: This outermost layer contains flattened chondrocytes and densely packed collagen fibrils aligned parallel to the articular surface. This orientation is critical for resisting shear forces and preserving the smoothness of the joint surface.

Transitional zone: Positioned between the superficial and deep layers, the transitional zone displays a less organized collagen network, providing a gradual change in mechanical properties that mitigates stress concentrations.

Radial (deep) zone: This region is characterized by collagen fibers that are oriented perpendicularly to the joint surface, offering resistance to compressive forces. The deep zone is essential for transferring mechanical loads from the surface to the subchondral bone.

Calcified cartilage zone: Demarcated by the tidemark, this zone consists of mineralized cartilage that secures the uncalcified cartilage to the subchondral bone. The tidemark itself serves as a critical interface where gradual changes in biochemical composition facilitate load dissipation.

Subchondral bone interface: Although not cartilage per se, the underlying subchondral bone plays a crucial role in the overall biomechanics of the joint by providing foundational support and contributing indirectly to the nutritional supply of the cartilage through subchondral vascular channels. This zonal architecture is not static; rather, it undergoes progressive biochemical and structural alterations in response to mechanical stress, aging, and pathological conditions[27,28]. Early degenerative changes are often reflected as a loss of GAG content and a disorganization of the collagen network, which may initially manifest as increased water content and altered T2 relaxation times on compositional MRI sequences[29-33]. These microarchitectural insights have spurred the development of advanced imaging modalities aimed at detecting early biochemical changes that precede gross morphological damage.

Mechanisms of cartilage injury

Cartilage injuries arise from a spectrum of etiological factors, each imposing distinct mechanical and biochemical insults. Acute traumatic injuries, often associated with sports or high-impact incidents, typically result in focal defects characterized by sharp borders and limited transitional zones between injured and healthy tissue[34]. Conversely, degenerative injuries, as observed in osteoarthritis, involve a gradual breakdown of the ECM. In such cases, repetitive microtrauma induces subtle but cumulative disruptions in collagen integrity and proteoglycan depletion, eventually compromising the load-bearing capacity of the tissue[35,36].

Inflammatory processes, as observed in rheumatoid arthritis, may also contribute to cartilage degeneration by altering the synovial environment and accelerating matrix breakdown. Furthermore, biomechanical factors such as malalignment and joint instability can exacerbate cartilage wear by increasing localized stress on articular surfaces. The limited intrinsic healing potential of cartilage exacerbates these injuries, often resulting in the formation of fibrocartilaginous repair tissue that lacks the resilience of native hyaline cartilage[37,38].

Classification of cartilage lesions

The clinical evaluation of cartilage damage has historically relied on direct visualization during arthroscopic procedures. The 1961 Outerbridge classification remains a widely referenced system, grading lesions from: (1) Grade 0: Intact, normal cartilage; (2) Grade 1: Softening and swelling of the cartilage surface; (3) Grade 2: Partial-thickness defects, typically less than 1.5 cm in diameter; (4) Grade 3: Fissuring or fragmentation extending to greater than 1.5 cm in diameter; and (5) Grade 4: Full-thickness loss of cartilage with exposure of the subchondral bone[39].

Subsequently, the International Cartilage Repair Society refined these criteria by incorporating both the depth and surface characteristics of the lesion, thus providing a more nuanced assessment that is critical for treatment planning[40]. Accurate lesion classification is not only essential for prognostication but also guides the selection of appropriate regenerative strategies, such as microfracture, autograft transplantation, or cell-based therapies.

Advanced imaging techniques for lesion characterization

A detailed understanding of cartilage microarchitecture and injury classification is pivotal for guiding imaging protocols. While conventional imaging modalities like radiography and ultrasound offer indirect evidence of cartilage compromise, advanced MRI techniques enable direct evaluation of both structural and biochemical changes. For instance, T2 mapping exploits the sensitivity of T2 relaxation times to water content and collagen orientation, thereby providing a quantitative metric for early degeneration. dGEMRIC, on the other hand, utilizes the distribution of gadolinium-based contrast to inversely reflect GAG concentration, effectively highlighting early degenerative changes before morphological alterations become evident[41-53].

The integration of these modalities with emerging techniques such as sodium MRI, T1ρ imaging, and GAG chemical exchange saturation transfer (gagCEST) has further refined our ability to detect early cartilage pathology. These approaches, although technically demanding, offer the potential to monitor disease progression and response to regenerative therapies with unparalleled precision. Moreover, hybrid imaging systems like PET-MRI are beginning to bridge the gap between molecular imaging and conventional structural assessment, providing a comprehensive overview of the metabolic and structural state of the joint[54-60].

DETAILED ANALYSIS OF IMAGING MODALITIES: TECHNICAL PARAMETERS, CLINICAL APPLICATIONS, AND RESEARCH GAPS

Traditional imaging modalities

Radiography: Radiographic imaging, while historically central to musculoskeletal diagnostics, remains fundamentally limited in its direct visualization of cartilage (Figure 2). Conventional X-rays primarily capture secondary osseous changes - joint space narrowing, osteophyte formation, and subchondral sclerosis - that indirectly suggest cartilage loss[61-67]. Recent advancements, such as diffraction-enhanced X-ray imaging, have attempted to surmount these limitations by enhancing soft-tissue contrast. By employing sophisticated diffraction filters and advanced detector arrays, these techniques promise improved delineation of cartilage contours. However, the clinical translation of such methods remains nascent due to issues of accessibility, radiation exposure, and the need for specialized equipment.

Figure 2 Radiograph of the knee cartilage. A: Conventional; B: Diffraction-enhanced.

Ultrasound: Ultrasound offers distinct advantages in terms of real-time imaging, cost efficiency, and portability, particularly for evaluating superficial cartilage in small joints[68-71]. High-frequency probes (≥ 20 MHz) facilitate the measurement of cartilage thickness and detection of surface irregularities[72-75]. Nevertheless, the inherent limitations - operator dependence, anisotropic artifact generation, and limited penetration depth - hamper its reproducibility, especially when imaging deeper joint structures. Optimizing transducer orientation and adopting standardized protocols may mitigate these issues, yet ultrasound remains less suited for a comprehensive assessment of articular cartilage in large joints (Figure 3).

Figure 3 Ultrasound imaging of cartilage. * indicates hypoechoic cartilage zone.

Computed tomography arthrography and cone-beam computed tomography arthrography: Computed tomography (CT) arthrography (CTA) employs intra-articular iodine contrast to accentuate the cartilage against high-attenuation surrounding tissues, thereby enhancing the detection of osteochondral defects[76-79]. Its high spatial resolution makes it valuable in small joints (e.g., ankle, elbow), but its invasive nature and exposure to ionizing radiation constrain repeated use. Meanwhile, cone-beam CT has emerged as a promising alternative, delivering high-resolution, three-dimensional (3D) reconstructions with a reduced radiation dose (Figure 4). Despite these technical advantages, CT-based methods remain largely supplementary, given their limited soft-tissue contrast compared to MRI.

Figure 4 Cone-beam computed tomography arthrogram of tibiotalar joint with an arrowhead showing the contrast in the joint space and arrow marking the distinct margins of the intact cartilage in the talar dome.

Morphological MRI: MRI has established itself as the gold standard for cartilage imaging due to its superior soft-tissue contrast and multi-planar capabilities. Conventional sequences - spin echo and gradient echo - along with fat-suppressed proton density sequences, enable detailed visualization of cartilage morphology, including thickness, surface integrity, and subchondral bone changes[47,80-86]. 3D techniques such as spoiled gradient echo further enhance spatial resolution, allowing for the detection of subtle focal lesions. Yet, even high-resolution morphological MRI is challenged in capturing early biochemical changes that precede gross structural damage. The summary of comparison of cartilage imaging modalities are tabulated in Table 1.

Table 1 Comprehensive comparison of cartilage imaging modalities.

Imaging modality	Technical requirements	Key strengths	Primary limitations	Clinical utility
Radiography	Basic X-ray systems; optional diffraction-enhanced setups	Widely available; economical; excellent for assessing bony landmarks and joint space	Indirect cartilage evaluation; radiation exposure; limited soft-tissue contrast	Baseline assessment of joint integrity; detection of osteophytes and subchondral changes
Ultrasound	High-frequency transducers (≥ 20 MHz); skilled operator	Real-time imaging; portable; cost-efficient for superficial structures	Operator dependency; anisotropy artifacts; limited penetration for deep joints	Rapid evaluation of superficial cartilage defects, particularly in small joints
CT arthrography	CT scanner; intra-articular contrast; experienced personnel	High spatial resolution; excellent for visualizing osteochondral interfaces	Invasive contrast injection; radiation dose; suboptimal soft-tissue contrast	Detailed assessment of cartilage in small joints; evaluation of osteochondral lesions
MRI (morphological)	1.5 T/3 T MRI systems; dedicated coils; standard sequences	Superior soft-tissue contrast; multi-planar capabilities; non-ionizing	Longer scan times; less sensitive to early biochemical alterations	Detailed structural evaluation; mapping of lesion extent and subchondral involvement
MRI (compositional)	Advanced MRI protocols; specialized sequences (e.g., T2 mapping, dGEMRIC)	Quantitative assessment of biochemical changes; early detection of degenerative markers	Higher cost; technical complexity; standardization challenges	Early diagnosis of cartilage degeneration; monitoring of regenerative therapies

CT: Computed tomography; MRI: Magnetic resonance imaging; dGEMRIC: Delayed gadolinium-enhanced magnetic resonance imaging of cartilage.

Compositional and biochemical MRI techniques: Advances in MRI have led to the development of compositional imaging methods that quantify the biochemical milieu of cartilage: T2 and T2 mapping: By assessing T2 relaxation times, these sequences are sensitive to water content and collagen fiber orientation. Prolonged T2 values indicate disrupted collagen architecture and increased hydration, hallmarks of early degeneration. T2* mapping, with its shorter echo times, facilitates rapid 3D imaging, though its susceptibility to magnetic field inhomogeneities necessitates technical refinements[41-46,48-52,87] (Figure 5).

Figure 5 T2-mapping of the magnetic resonance imaging cartigram sequence done to estimate the cartilage degeneration in knee osteoarthritis.

dGEMRIC: dGEMRIC exploits the negative charge of GAGs to modulate the diffusion of gadolinium contrast. Areas of GAG depletion exhibit increased contrast uptake, reflected as hyperintense regions on T1-weighted images. Despite its efficacy in early degeneration detection, dGEMRIC is constrained by prolonged imaging times and the requirement for contrast administration[53].

Sodium MRI: This technique directly measures sodium ion concentration as a surrogate for proteoglycan content, offering a non-contrast alternative to assess cartilage composition. The inherently low signal-to-noise ratio and need for dedicated hardware currently limit its routine clinical application[17,48,49,88,89].

T1ρ imaging and gagCEST: T1ρ imaging quantifies spin-lattice relaxation in the rotating frame, reflecting interactions between water molecules and proteoglycans. Elevated T1ρ values correlate with early proteoglycan loss, while gagCEST leverages chemical exchange saturation transfer to visualize GAG distribution. Both techniques provide promising biomarkers for early osteoarthritis detection but require further validation and standardization[54-60]. The compositional metrics of advanced MRI for cartilage assessment are summarized in Table 2.

Table 2 Advanced magnetic resonance imaging compositional metrics for cartilage assessment.

Compositional technique	Quantitative parameter	Underlying biophysical principle	Advantages	Current technical challenges	Potential clinical utility
T2 mapping	T2 relaxation time	Reflects water content and collagen fiber orientation within the matrix	Sensitive to early changes; quantitative; non-invasive	Susceptibility to motion artifacts; magnetic field inhomogeneities	Early detection of collagen disruption; monitoring therapeutic response
T2 mapping*	T2* relaxation time	Uses gradient-echo sequences with shorter echo times to capture rapid decay signals	Enables rapid, high-resolution 3D imaging	Sensitive to field inhomogeneities; requires high-field systems	Detailed microstructural assessment with improved spatial resolution
dGEMRIC	T1 relaxation time (post-contrast)	Inverse correlation between GAG concentration and gadolinium uptake	Direct evaluation of GAG content; effective for early degeneration detection	Prolonged imaging protocol; reliance on contrast agents; potential nephrotoxicity	Assessment of cartilage biochemical integrity; predicting osteoarthritis progression
Sodium MRI	Sodium ion concentration	Measures sodium ions linked to proteoglycan density in the extracellular matrix	Contrast-agent free; direct assessment of proteoglycan content	Low signal-to-noise ratio; specialized hardware requirements	Early biomarker for proteoglycan loss; research tool for regenerative interventions
T1ρ imaging	T1ρ relaxation time	Sensitive to interactions between water molecules and macromolecules (proteoglycans)	Early detection of proteoglycan depletion; non-invasive	Limited availability; extended scan times; technical complexity	Early identification of biochemical changes in cartilage; monitoring early degeneration
gagCEST	Chemical exchange saturation transfer effect	Utilizes the exchange of protons between water and GAGs to generate contrast	High specificity to GAG; no contrast agents required	Requires very high field strengths; long scan durations	Promising tool for early osteoarthritis detection and precise regenerative monitoring

dGEMRIC: Delayed gadolinium-enhanced magnetic resonance imaging of cartilage; 3D: Three-dimensional; GAG: Glycosaminoglycan; MRI: Magnetic resonance imaging; gagCEST: Glycosaminoglycan chemical exchange saturation transfer.

Emerging modalities and future directions

Integrated PET-MRI: The fusion of PET and MRI represents a paradigm shift by combining metabolic and structural imaging. PET-MRI can elucidate the molecular underpinnings of cartilage degeneration by identifying specific metabolic markers before structural damage is evident. Despite its high cost and complex data integration requirements, this modality holds the potential to transform early diagnostic and therapeutic monitoring paradigms[90] (Figure 6).

Figure 6 18F sodium fluoride (18F-NaF) served as a one-stop modality to assess whole joint, that is, bone pathology, cartilage, and ligaments (sagittal T1 turbo spin echo) showed osteophyte (orange arrow) and sclerosis (yellow arrow) with corresponding 18F-NaF uptake. A and B: Fused positron emission tomography/magnetic resonance imaging (PET/MRI); C: Sagittal three-dimensional MEDIC did not have any structural abnormality but when fused with PET; D: There was high uptake volume of interest (white arrow) termed as “subchondral magic spot”; E and F: Sagittal T2 spectral attenuated inversion recovery depicted grade 1 bone marrow lesion (blue arrow) with corresponding uptake in fused PET/MRI; G: Axial T2* showed degenerated medial and lateral trochlear cartilage (pink arrow); H: Corresponding fused PET/MRI; I: T2 relaxometry with raised values. A-I: Citation: Jena A, Goyal N, Rana P, Taneja S, Vaish A, Botchu R, Vaishya R. Qualitative and Quantitative Evaluation of Morpho-Metabolic Changes in Bone Cartilage Complex of Knee Joint in Osteoarthritis Using Simultaneous 18F-NaF PET/MRI-A Pilot Study. Indian J Radiol Imaging 2023; 33: 173-182. Copyright© Indian Radiological Association 2023. Published by Thieme Medical and Scientific Publishers. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon (https://creativecommons.org/licenses/by-nc-nd/4.0/).

High-field MRI and advanced sequences: Ultra-high field systems (e.g., 7T MRI) offer enhanced spatial resolution and sensitivity, which can be critical in evaluating the microstructural details of cartilage. Although these systems promise superior detail, their current clinical utility is hampered by high operational costs, safety concerns, and limited accessibility. Future developments in coil design, sequence optimization, and artificial intelligence (AI)-driven image reconstruction may broaden the applicability of high-field imaging.

AI and machine learning: AI-driven algorithms are increasingly being integrated into imaging workflows to facilitate automated segmentation, quantification of cartilage lesions, and predictive modelling of disease progression. These technologies can potentially reduce inter-observer variability and improve diagnostic accuracy by identifying subtle, early changes that may elude human observers.

Research gaps and clinical implications

Despite significant technological advancements, several research gaps persist.

Standardization: Variability in imaging protocols across institutions hampers the generalizability of findings. Establishing standardized acquisition parameters and analysis protocols is critical for multicenter studies and for the routine clinical adoption of advanced techniques.

Validation of novel biomarkers: While compositional imaging methods show promise in detecting early degenerative changes, robust clinical validation against histopathological standards is still required. Longitudinal studies are necessary to establish these biomarkers as reliable predictors of disease progression and treatment outcomes.

Accessibility and cost: High-end imaging modalities such as 7T MRI and integrated PET-MRI, while scientifically intriguing, are limited by cost and accessibility. Future research must focus on developing cost-effective, scalable technologies that can be implemented in routine clinical practice.

Technical challenges: Issues such as motion artifacts, magnetic field inhomogeneities, and the need for specialized hardware continue to challenge the clinical application of advanced imaging techniques. Addressing these technical hurdles through innovative sequence design and robust post-processing algorithms is essential.

Clinical applications and future prospects

The detailed analysis of imaging modalities underscores their critical role in both diagnosing cartilage pathology and monitoring the efficacy of regenerative interventions.

Preoperative planning: Accurate delineation of cartilage lesions informs surgical decision-making, such as the choice between microfracture, autologous transplantation, or cell-based therapies.

Postoperative monitoring: Imaging biomarkers derived from compositional MRI can track the integration and maturation of repair tissue, facilitating early intervention in cases of graft failure.

Precision medicine: Integrating molecular imaging with patient-specific data holds promise for tailoring therapeutic interventions to individual disease profiles, potentially improving outcomes in cartilage regeneration. Cartilage imaging modalities vary significantly in their diagnostic utility, accessibility, and cost-effectiveness. Traditional techniques like X-ray and CT remain widely used for assessing bone involvement but offer limited insights into cartilage health. On the other hand, MRI is considered the gold standard due to its ability to provide detailed visualization of cartilage morphology and biochemical composition. Advanced modalities such as PET-MRI and sodium MRI offer additional insights, albeit with limitations in real-world clinical applicability.

PET-MRI combines metabolic imaging with high-resolution anatomical visualization, making it highly promising for cartilage evaluation. However, its clinical application is restricted to specialized centers due to high costs and operational complexity. Sodium MRI, although valuable for assessing cartilage proteoglycan content, remains a research tool largely due to low signal-to-noise ratio and hardware requirements, limiting its widespread clinical use. Choosing an imaging modality for cartilage assessment often involves balancing cost, diagnostic accuracy, and accessibility. For instance, MRI offers a comprehensive evaluation but comes with higher costs compared to ultrasound, which is more affordable but less detailed. PET-MRI and sodium MRI, while innovative, present cost barriers that restrict their routine use in clinical settings. Reliability and reproducibility are critical factors in selecting an imaging modality for cartilage evaluation. MRI has demonstrated high reproducibility for assessing cartilage morphology and biochemical changes. Conversely, modalities like ultrasound are less reliable for cartilage-specific imaging, although they remain useful for related features such as effusion and synovitis.

IMAGING OF REPAIRED CARTILAGE AND REGENERATIVE STRATEGIES

Imaging evaluation of repaired cartilage

Post-intervention imaging plays a pivotal role in determining the success of cartilage repair procedures. Following regenerative procedures, whether by microfracture, osteochondral transplantation, or cell-based therapies, imaging serves as a non-invasive surrogate for histological assessment. MRI remains the modality of choice owing to its excellent soft-tissue contrast and ability to capture both morphological and compositional details.

Morphological assessment: A successful cartilage repair is characterized by a smooth, continuous articular surface that mirrors the adjacent native cartilage in signal intensity and thickness. High-resolution 3D sequences - such as 3D spoiled gradient echo - enable visualization of the graft-host interface, ensuring that the repair tissue is well integrated with the subchondral bone[91,92]. In contrast, irregular surface contours, focal thinning, or areas of signal heterogeneity may indicate graft delamination, incomplete integration, or early degeneration[93].

Biochemical and compositional imaging: Beyond morphological criteria, advanced compositional MRI techniques have been employed to evaluate the biochemical milieu of repair tissue. Techniques such as T2 mapping and T1ρ imaging provide quantitative biomarkers that correlate with water content, collagen integrity, and proteoglycan concentration. Elevated T2 or T1ρ values in the repair tissue may signal excessive water retention or compromised collagen architecture, serving as early indicators of repair failure[94]. Additionally, dGEMRIC has been utilized to assess GAG content, with lower GAG levels in the graft potentially portending suboptimal long-term outcomes. Such multiparametric assessments afford clinicians a more nuanced understanding of tissue maturation and can guide early re-intervention if adverse changes are detected.

Cartilage regeneration techniques

The clinical management of cartilage defects necessitates a tailored approach that considers lesion size, location, and the patient’s functional demands. Current regenerative strategies can be broadly categorized into local stimulation techniques and transplantation methods.

Local stimulation techniques: Procedures such as microfracture and chondroplasty aim to stimulate the intrinsic healing potential of the subchondral bone. Microfracture involves creating small perforations in the subchondral plate to release marrow elements that differentiate into fibrocartilaginous repair tissue[95-98]. While this method is advantageous for small lesions (typically < 2 cm²) due to its relative simplicity and cost-effectiveness, the resultant fibrocartilage often lacks the biomechanical resilience of native hyaline cartilage[99-102]. Consequently, while short-term functional improvements have been documented, deterioration may occur over time as the repair tissue is subject to mechanical wear[103-106].

Transplantation techniques: Osteochondral autograft transplantation involves harvesting cylindrical plugs from a non-weight-bearing region of the joint and implanting them into the defect site. This single-stage procedure preserves hyaline cartilage architecture and yields promising results for small to medium lesions. However, the risk of donor-site morbidity and the challenge of achieving congruent surface integration limit its broader application[107]. For larger defects, osteochondral allograft transplantation offers an alternative by providing size-matched grafts. Yet, the viability of the graft is time-sensitive, and immunological concerns as well as graft integration remain significant challenges[108-110].

Cell-based and scaffold-assisted techniques: Matrix-induced autologous chondrocyte implantation represents a two-stage procedure where autologous chondrocytes are cultured and then seeded onto a biocompatible scaffold. This technique has been lauded for producing a more uniform repair tissue, but it carries the inherent challenges of a two-stage process, potential graft overgrowth, and the risk of necessitating revision surgery[91,92]. Particulated juvenile allograft cartilage provides a one-stage alternative by using immature cartilage fragments that inherently possess a higher regenerative capacity. While particulated juvenile allograft cartilage circumvents some of the logistical and immunological challenges associated with allograft transplantation, its long-term efficacy remains under investigation[93,94]. The summary of integration of imaging with regenerative strategies are tabulated in Table 3.

Table 3 Integration of imaging with regenerative strategies - diagnostic and prognostic markers.

Regenerative strategy	Imaging modalities utilized	Key imaging biomarkers	Prognostic implications	Future research directions
Microfracture	Morphological MRI; T2 mapping; dGEMRIC	Uniformity and integration of repair tissue; quantitative T2 changes	Early functional gains may be offset by the long-term vulnerability of fibrocartilage	Refinement of imaging protocols to differentiate fibrocartilage from hyaline-like repair tissue
Osteochondral autograft transplantation	Morphological MRI; CT arthrography; high-resolution 3D sequences	Graft congruence; signal homogeneity at the graft-host interface	Potential donor-site morbidity; risk of graft fragmentation or subchondral cyst formation	Development of predictive imaging markers for long-term graft viability and mechanical integration
Osteochondral allograft transplantation	MRI; CT arthrography; T1ρ imaging	Viability of transplanted tissue; early biochemical alterations at the graft interface	Time-sensitive graft viability; immunological responses and delayed integration	Advanced imaging for real-time monitoring of graft immune response and viability
Matrix-induced autologous chondrocyte implantation	High-resolution MRI; T2/T1ρ mapping; dGEMRIC	Restoration of native signal intensity; uniformity in repair tissue; quantitative GAG levels	Risk of graft overgrowth; potential for revision surgery due to suboptimal integration	Standardization of imaging biomarkers to predict early signs of graft failure and guide intervention timing
Particulated juvenile allograft cartilage	3D MRI sequences; T1ρ imaging; sodium MRI	Homogeneity of the repair tissue; integration with adjacent native cartilage; proteoglycan consistency	Uncertain long-term integration dynamics; variable repair tissue maturation	Longitudinal imaging studies correlating early imaging biomarkers with clinical outcomes

MRI: Magnetic resonance imaging; dGEMRIC: Delayed gadolinium-enhanced magnetic resonance imaging of cartilage; CT: Computed tomography; 3D: Three-dimensional; GAG: Glycosaminoglycan.

Future derivatives and concluding insights

The evolving field of cartilage imaging and regenerative medicine is poised for transformative advancements. Future developments are likely to integrate multiple modalities to enhance both diagnostic accuracy and therapeutic efficacy. Advancements in AI and non-invasive imaging technologies present exciting opportunities for revolutionizing cartilage assessment. AI-driven tools such as machine learning algorithms are increasingly being used for automated segmentation, lesion detection, and predictive modeling, with studies showing promising results in improving diagnostic accuracy. For instance, DenseNet and ResNet architectures have demonstrated accuracy levels of over 80% in grading cartilage damage. AI applications can also enhance reproducibility, optimize imaging protocols, and support early detection of subtle degenerative changes, aligning with precision medicine principles.

Advanced molecular imaging: The fusion of PET with MRI continues to show promise, enabling clinicians to detect molecular and metabolic changes in cartilage long before structural degradation becomes apparent. The development of targeted PET tracers may allow for the identification of specific molecular pathways involved in cartilage degeneration, thus facilitating personalized treatment approaches.

Integration with AI: Emerging AI and machine learning algorithms are expected to revolutionize image acquisition and analysis. Automated segmentation and quantification of cartilage lesions, coupled with predictive modeling of disease progression, can reduce inter-observer variability and enable more standardized assessments across institutions. AI-driven approaches could also assist in real-time intraoperative navigation during cartilage repair procedures, thereby improving graft placement and integration.

Innovative imaging sequences and portable devices: Ongoing innovations in MRI technology, including the refinement of ultra-short echo time sequences and the utilization of 7T systems, are anticipated to yield unprecedented resolution of cartilage microarchitecture. Efforts to develop portable high-field MRI devices may also extend the benefits of advanced imaging to settings beyond major academic centers, thus democratizing access to state-of-the-art diagnostics. Current prototypes are being tested for sports-related applications, and future adaptations could focus specifically on knee cartilage imaging. These portable systems offer significant potential to overcome barriers related to cost and accessibility[111].

Augmented reality and 3D printing: The convergence of imaging with augmented reality and 3D printing holds significant promise for surgical planning and patient-specific interventions. Detailed imaging data can be translated into 3D-printed models of cartilage lesions, providing surgeons with tactile references for preoperative planning and intraoperative guidance. These technologies may ultimately improve the precision of cartilage repair procedures and enhance long-term outcomes.

Longitudinal imaging and biomarker validation: To fully elucidate the natural history of cartilage repair and degeneration, long-term longitudinal studies are essential. Standardizing imaging protocols and validating emerging biomarkers against histopathological findings will be critical for integrating these advanced techniques into routine clinical practice. The establishment of robust, multicenter databases can facilitate the comparison of imaging findings with clinical outcomes, thereby refining our understanding of cartilage biology and the efficacy of regenerative interventions.

Novel contrast agents: Additionally, novel contrast agents, including cationic agents such as CA4+, enhance cartilage visualization by targeting proteoglycan distribution[112]. Dual-contrast CT techniques are also being explored to improve the early detection of cartilage degeneration[113]. These innovations could complement existing modalities and provide new avenues for assessing cartilage health. Integrating AI-driven imaging analysis, portable MRI devices, and novel contrast agents into clinical practice could significantly advance the field of cartilage imaging[114]. Future research should focus on validating these technologies through clinical trials and exploring their scalability and cost-effectiveness to ensure broader applicability in clinical settings.

CONCLUSION

The evolution of cartilage imaging, from conventional radiography to advanced molecular techniques, reflects a significant paradigm shift in musculoskeletal diagnostics and regenerative medicine. Imaging is no longer confined to merely depicting anatomical details; it now plays an integral role in evaluating biochemical integrity, guiding therapeutic interventions, and monitoring repair processes over time. While challenges related to standardization, cost, and technical complexity persist, the future of cartilage imaging is bright, driven by innovations in molecular imaging, AI integration, and enhanced hardware capabilities. These advancements will not only improve early diagnosis but also enable personalized, precision approaches to cartilage repair, ultimately transforming patient care in orthopaedic and rheumatologic practices.