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Articular cartilage injuries are common. The diagnosis of these injuries is often delayed and may lead to early osteoarthritis. Treatment depends on many factors but mainly on the stage and size of the lesion. The anatomy of articular cartilage is complex, and it is an avascular, aneural, and alymphatic structure. Recently, more emphasis is laid on its anatomy and biomechanics to understand the regeneration process of articular cartilage.
The main reasons for the increased interest in regeneration are a better understanding of the biomechanics and the science behind degeneration. Availability of diagnostic tools like Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET) has made it easier to confirm the diagnosis, identify the lesion site, size, and morphology.
It is possible to plan the treatment and predict the pathology in the long run, and many treatment modalities are now available. It is essential to plan treatment based on the patients' expectations and the lesion's morphology. Newer techniques have shown promising results in the short and medium-term.
However, long-term results should be analysed to guide the clinical practices on these latest techniques.
In this review, we have analysed the current literature on articular cartilage injuries and regenerative techniques to repair them.
Literature search was performed over the search engines such as PubMed, Scopus, and Google Scholar, on 4th September 2021. The keywords used to extract the relevant articles for this review were cartilage repair, biological reconstruction, joint preservation. Boolean operaters used were AND,OR,NOT. After running the initial query approximately 5000 results were extracted. There were further shortlisted by filtering only full studies, studies performed on humans, Studies only in English language and recent 5 years papers. After the scanning only 19 studies stood out. These were further read and based on the quality of papers using modified coleman criteria they were either accepted or discarded. A narrative review was done with the accepted articles.
3. Results and discussion
Galen was the first to identify the importance of articular cartilage and realised it to be an aneural, alymphatic, and avascular structure.
Cartilage is derived from mesodermal tissue during embryonic development. It is a connective tissue that is smooth in texture. When this is lubricated with synovial fluid, the friction between the surfaces is reduced to a minimum and helps in the smooth movement of the joint surfaces. The articular cartilage is firm and flexible due to water molecules' dynamic entry and exit from its surface. Cartilage is present in various forms in the larynx and respiratory tract, in structures such as the external ear and the articulating surfaces of joints. It is more widespread in the infant skeleton, replaced by bone during growth.
This type of bone formation is called enchondral ossification.
Connective tissue is derived from mesoderm and comprises living cells within the extracellular matrix produced by specialized cells, chondroblasts. The chondroblasts caught in the matrix are called chondrocytes, lying in lacunae spaces.
The cartilage is composed of chondrocytes embedded in its lacunae surrounded by a matrix containing collagen (mainly type 2), hyaluronic acid, and proteoglycans. In addition, it is surrounded by perichondrium (Fig. 1).
3.2 Hyaline cartilage
It derives its name from the Greek word ‘hyalos,’ which means glassy. It is hydrophilic in nature and eosinophilic. It stains red with Safranin O dye compared to elastic cartilage, which is lesser eosinophilic, and stains with a silver dye. Cartilage derives its nutrition from the adjacent synovial fluid by diffusion. When under load, fluid is released in the joint, which lubricates the joint, redistributes the focal load, and cools off the raised temperature. Inefficiencies in its mechanical structure may lead to early disruption in load-bearing and stress-yielding capacity. This disrupted energy may manifest as a rise in temperature or increased friction leading to focal cartilage damage. This is the type of cartilage present at the articular surfaces and can handle shear stresses better.
3.3 The function of articular cartilage
The primary function of articular cartilage is to increase the surface area of load distribution and provide a smooth, frictionless surface that can resist wear. Cartilage is often considered to be a biphasic material consisting of a solid phase and a fluid phase. The interaction of these two phases gives rise to the mechanical behaviour of cartilage. The compressive strength is provided by proteoglycans.
The diagnosis of cartilage lesions can be made by clinical, radiological, and arthroscopic examinations. There are various classifications to quantify the chondral pathology and detecting the severity. The most widely used classification system worldwide is International Cartilage Repair Society classification.
The cases with cartilage lesions may present with pain, swelling, recurrent effusions, catching, and a painful limp (antalgic gait). Once the patient narrates ‘His-story,’ additional leading questions about a differential are asked.
A physical examination should be performed next with more focus on the suspected diagnosis based on history. Also, at the same time, any associated ligamentous injuries which may be present concomitantly should be excluded.
4.2 Radiological evaluation
The advancements in diagnostic imaging have enabled health care workers to diagnose chondral lesions very early instead of earlier times. Even very small lesions can be detected as MRI is a very sensitive diagnostic tool. Hence, these problems are being reported increasingly in young and active individuals who are more health-conscious and aware. This has been shown both in cross-sectional Magnetic Resonance Imaging (MRI) studies of asymptomatic athletes and in patients undergoing arthroscopy of the knee.
The diagnosis of such problems has exponentially increased due to raised awareness and better access to imaging facilities available to the patients.
Plain Radiographs: Imaging is needed next to confirm the diagnosis of cartilage lesions, quantify the problem, and lay down a treatment plan. Once a cartilage defect is suspected, a long leg (Hip-Knee-Ankle) radiograph is required to check the limb alignment. An altered alignment may predispose a chondral pathology.
The patient is scanned in three positions (90, 30, and 0 degrees) of flexion with active quadriceps contraction to assess the patella's tracking. As this is a dynamic measurement, it mimics the movements in real-time and hence finds out the exact point of the problem. It, therefore, helps in formulating a corrective treatment plan by reversing or correcting the pathology.
Magnetic Resonance Imaging (MRI): MRI (Fig. 3) with special cartilage sequencing is valuable to confirm diagnosis also quantify the pathology.
An MRI is an excellent investigation as it is highly sensitive, non-invasive means to localise, measure, and quantify the number of defects in the articular cartilage. This allows laying down the management plan for the patient without having to do an arthroscopy to look for the problem as was carried out in the past years. Furthermore, after the surgery in the postoperative period, it helps to evaluate the quantity and quality of the repaired tissue without the need to perform a second-look arthroscopy and biopsy. In recent times, better MRI-based cartilage-specific sequencing techniques are available for decision making.
These include Intermediate-weighted fast spin-echo (FSE), 3- D fat-suppressed T1-weighted gradient echo (GRE) acquisition, and isotropic 3-D sequences (3-D DESS, d-D FSE SPACE). The pre-operative assessment of cartilage defects is best carried out these days by the International Cartilage Repair Society (ICRS) grading system.
Arthroscopic assessment: Arthroscopy is seldom carried out now for only diagnostic purposes. The imaging advancements have made this possible as almost all information is made available to make a decision. However, it provides the most significant details of the articular cartilage pathology on inspection and probing of the lesion and helps planning a definitive treatment. When the patient had a previous arthroscopic evaluation, the current findings can be used to correlate this episode. Moreover, an arthroscopic examination can detect a concomitant pathology of menisci, cruciate ligament, synovium, etc., of the knee joint.
5. Management of articular cartilage lesion
Restoration of cartilage depends on many variables, and these determine the choice of treatment modality.
Defect size- A smaller lesions heal better and quicker and have a better prognosis when compared to a much larger lesion. Still, overall the healing capacity of the articular cartilage is limited. However, Knutsen (2004), in a randomized control trial (RCT), demonstrated that smaller defects (<4cm
Age- Contrary to a common belief that any surgical procedure would show better functional results in a younger patient, no correlation was found between the outcomes of patients aged between 18-50 years in an RCT. The outcome solely depended on surgical skill and postoperative rehabilitation. Younger patients tend to do better following these surgical procedures probably because they are more likely to comply with the rehabilitation programme and are more active.
Patient activity- The importance of activity and its association in altering the functional outcome after surgery has been recognized. In an RCT, 180 active patients achieved better results no matter what cartilage repair technique was chosen for them.
It highlighted the importance of aggressive postoperative rehabilitation to facilitate better results.
Body mass index (BMI) – High BMI is considered unfavourable for a good result. Asik et al. (2008) in 90 patients showed that BMI >30kg/m2 was associated with poorer functional outcomes after the surgery because the affected limb in a state of single-limb loading transmits around six times the body weight.
However, since this study only considered a microfracture technique that grows fibrocartilage, not hyaline-like cartilage, their result cannot be generalized to other techniques. These authors also stressed that any joint malalignment should be corrected before or simultaneously with the chondral repair surgery to achieve satisfactory results.
Functional requirements- This is an essential factor to consider before surgery. Higher functional demand cases do not do well with procedures like microfracture, where only the fibrocartilage formed does not last long. Mithoefer et al. (2006) reported the results of microfracture in their 32 cases, who regularly indulged in high-impact sports. Only 66% of these reported excellent results, out of which 47% of patients suffered further deterioration.
Cartilage has a poor regenerative potential as it is avascular and aneural. Cartilage damage may disrupt the average load-carrying ability of the tissue and thus the normal lubrication process. Further loading of damaged cartilage may lead to osteoarthritis. A biological knee, hence, is better than a replaced one because it retains its proprioceptive potential. Various available treatment options can be divided into different categories:
Chondroprotection includes strategies directed at preventing disease progression by addressing bio-mechanical or biochemical disrupters of equilibrium.
Chondro stimulation aims to stimulate intrinsic regenerative potential, usually by perforating the subchondral bone (e.g., Pridies' drilling and microfracture). This, in turn, releases mesenchymal stem cells with intrinsic growth factors and, when mixed with blood, forms a super clot. It has excellent regenerative potential.
Chondro conduction uses a scaffold that conducts chondrogenic cells and provides an environment suitable for cartilage formation. A few examples are Trufit, MAIO Regen, Hyaluronic acid gel, Pluronic acid, and Bio-Glass.
Chondral Transplantation uses strategies that transplant cadaveric or autologous osteochondral cores or condyles into the joint surface (e.g., Mosaicplasty and Osteochondral Autograft Transfer System (OATS). As cartilage is aneural, avascular, and alymphatic, cartilage is immunoprotective so that allogeneic cartilage may work in vivo.
Neochondrogenesis looks at strategies that attempt to generate cartilage de-novo at the joint surface. The 2nd generation neochondrogenesis (matrix) techniques combine cell-based therapy with the use of a matrix to generate cartilage de-novo at articular surface includes Membrane Augmented Chondrocyte Implantation (MACI), Gel Augmented Chondrocyte Implantation (GACI), and other hybrid methods (Fig. 4).
Chondral substitution involves substituting the articular surface with an artificial implant. It is time-tested, more reliable, and reproducible. However, it is non-biological, with high chances of complications and burden of wear and tear leading to a revision in the future. These include unicondylar replacement, and total joint arthroplasty.
5.3 Nonoperative measures
A gradual step-wise approach should be adopted to treat cartilage defects. Nonoperative options should be tried thoroughly before invasive methods are advised, whenever possible. Various modalities like medications, physiotherapy, and lifestyle modification to deal with pain and inflammation may be adequate for some patients with small early chondral lesions.
In addition, othet nonoperative treatment options include viscosupplements (injection of hyaluronic acid or HA), which are chondrogenic and provide a scaffold to recreate the joint's internal milieu and stimulate the production of endogenous HA (Greenberg et al., 2006). Kilincoglu Kilincoglu et al. (2015) and Vaishya et al. found intra-articular Platelet Rich Plasma (PRP) administration was more efficient than the HA in early knee osteoarthritis (OA).
Platelets can enhance and modify tissue healing by releasing growth factors (GF) like Platelet-derived GF, Insulin GF, Fibrinogen GF, Vascular endothelium-derived GF, etc., which promotes tissue healing by using PRP.
If all the measures mentioned above fail, only surgery should be considered and should be only reserved for symptomatic cases. The individuals with low functional demand and smaller lesions (<2cm2) respond very well to debridement.
They demonstrated 60% excellent outcomes with this technique. But, they also highlighted that this did not show any additional benefits over conservative treatment. Moseley et al. (2002), from an RCT of 180 patients with knee OA, found no significant differences in functional outcomes between the placebo group and the intervention group, consisting of arthroscopic debridement and lavage.
He concluded that high BMI and lower general satisfaction scores were the only two factors that negatively influenced the functional result. However, the results of this study should be viewed with caution as only fifty percent of patients were followed up for more than two years, and hence the long-term consequences in the rest of the patients are unknown.
Microfracture and ACI (Fig. 5) were considered better for defects sized between 2- 3cm.
He argued that because marrow stimulation techniques form fibrous cartilage, which tends to tolerate shear stresses poorly over time, 91% failures were seen within the first two years and patients with prior treatment with microfracture. Though this case series stands low in the hierarchy of evidence and has limitations such as treatment of lesions performed for different locations in the knee, as the sample size is large and methodology to assess the patients postoperatively is robust, the results can be looked upon with confidence.
For larger lesions (>3cm2), a conventional technique such as ACI has been reported to yield good to excellent results.
However, this study only analysed five patients. Hence, the excellent results may have been a chance event. There is a need to study a much larger sample of patients to determine if the superior results were a chance event or were significant. To discard or extrapolate these results to the clinical practice remains questionable at the moment. At a one-year interval, a second look at arthroscopy and biopsy confirmed good cartilage quality.
Patellofemoral joint (PFJ) defects have constantly shown poor outcomes. One reason for this is limited healing capacity and many defects with the tracking of the extensor mechanism.
In addition, microfracture has shown to have a limited effect on PFJ lesions as the hard bony surface does not allow the new cartilage to grow and integrate simultaneously. This was demonstrated by Kreuz et al. (2006), where deterioration of the ICRS scoring started over one year after surgery.
The best prognostic factors for the outcomes are younger patients with defects on the femoral condyles.
Various techniques are tried to improve the outcomes in PF lesions. These include synthetic resorbable osteochondral scaffold plug, as shown by Joshi et al. (2012), which have shown promising results at two years follow up.
However, since these were non-randomized studies showing good midterm follow-ups, only the long-term outcomes will validate the results of these newer techniques and give direction as to their use in clinical practice.
5.5 Recent advances in chondral repair techniques
More emphasis is laid now on the single staged chondral restoration procedures, either cell or scaffold-based. Recently many RCTs have shown the superiority of one technique over the other.
5.6 Postoperative rehabilitation
After a cartilage repair surgery, the patient is allowed non-weight-bearing mobilisation.. Shorter hospital stay and faster rehabilitation facilitate early return to activities of daily living (ADL).
The rehabilitation regime is not fixed and needs to be altered according to the site and size of the cartilage lesion and the restoration technique used. The cartilage regrowth goes through various stages. Hence, adequate loading and exercising regimes are chosen to allow sufficient growth and regeneration without damaging or overloading the cartilage tissue.
During the first six weeks aim is to reduce inflammation with medications, cryotherapy, and leg elevation and compression. Range of motion is increased on a Continuous Passive Motion (CPM) machine 6–8 h a day as it also stimulates cartilage regeneration and differentiation. Weight-bearing is started partially with the help of crutches and increased gradually over six weeks. In the next 6–12 weeks, full weight-bearing and strength training is achieved. After 12 weeks post-surgery, the patient can return to the pre-injury status of work and continual strengthening of quadriceps. The production of hyaluronic acid (chondrogenic) is stimulated with the cyclical movement of the joint.
The patient is followed up for a wound check at two weeks, then at six weeks for checking the Range of motion, weight-bearing, gait assessment. MRI scans are done at one year, with DESS sequencing and T2 mapping, and 18 months: d-GEMRIC scan (MOCART score) is used to assess articular cartilage repair tissue quality and quantity.
5.7 Surgical complications
Niemeyer (2008) described the complications post cartilage repair.
These can vary from general complications such as haemarthrosis, bleeding, deep vein thrombosis and pulmonary embolism, stiffness to more procedure-specific complications such as hypertrophy of the transplant, disturbed fusion of the regenerative cartilage, and the healthy surrounding cartilage, insufficient regenerative cartilage, and de-lamination. In addition, an increased rate of symptomatic hypertrophy was reported for patellar defects.
Articular Cartilage is a highly specialised structure with limited potential for repair. The degenerative process has biomechanical and biochemical triggers and is self-perpetuating. Repair strategies are only successful with patient selection, based on the understanding of cartilage biology and pathology.
The upsurge in research and publication on articular cartilage repair in the last 10 years.