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. 2021 Sep 21;22:101602. doi: 10.1016/j.jcot.2021.101602

Articular cartilage repair & joint preservation: A review of the current status of biological approach

Ketansinh Solanki a, Saseendar Shanmugasundaram b,∗, Neha Shetty c, Seok-Jung Kim d
PMCID: PMC8488240  PMID: 34631411

Abstract

The articular cartilage of the joint is the thin viscoelastic layer of the connective tissue. It has a unique anatomy and physiology, which makes the repair of the articular cartilage damage more difficult and challenging due to its limited healing capacity. Increasing knowledge regarding the importance of articular cartilage for joint preservation has led to increased attention on early identification of cartilage damage as well as degeneration in order to delay osteoarthritis. There are various treatment modalities ranging from preventive management, physical therapy, pharmacological, non-pharmacological and surgical treatments exist in current literature. However most of the studies have limited long term follow up and mainly consists of small case series and case reports. This is an up to date concise review discussing the available management options for articular cartilage damage starting to lifestyle modification to pharmacotherapy, physiotherapy, and osteobiologics till various joint preservation techniques that have been in use currently.

Keywords: Articular cartilage lesions, Joint preservation, Arthroscopy, Osteoarthritis, Orthobiologics

1. Introduction

Articular cartilage lesions are one of the most demanding and challenging clinical problems faced by the orthopaedic surgeon not only because it is extremely difficult to repair but also because it is the central feature of the progressive degenerative osteoarthritis of the joint. The cartilage is a highly organised connective tissue with significant durability and poor intrinsic healing capacity. Trauma or degeneration commonly results in articular cartilage deterioration, that can result in debilitating joint pain, functional impairment and osteoarthritis (Fig. 1).1

Fig. 1.

Fig. 1

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Cartilage lesion on the medial femoral condyle, 54 year old female.

Management of end-stage joint degeneration is still joint replacement surgery and prevention, early diagnosis and early management still remain to be the need of the hour. Failure to develop a successful therapy for the management of cartilage lesions is due to the inherent property and physiology of this tissue. Various non-surgical and surgical treatment options that include bone marrow stimulation, osteotomy and autologous osteochondral graft transplantation have been proposed to be effective in improving clinical outcomes and preventing rapid progression of arthritis.2

2. Basic science of articular cartilage

Articular cartilage is a thin viscoelastic layer of connective tissue 2–3 mm thick, that is highly hydrated and devoid of nerve supply, blood supply and lymphatic drainage and covering the epiphyseal surfaces of articulating bones.3 It is composed of two forms of contents: 1) collagen (primarily type 2) and 2) fluid. Collagen present as a network of fibres and contributes to the overall shape of the tissue. This framework is filled up with Glycosaminoglycans (GAGs), proteoglycans and glycoproteins. The fluid consists of water and electrolytes and constitutes the extracellular matrix (ECM) that is responsible for the biomechanical properties of the cartilage. The chondrocytes that are populated in the ECM contribute to production of the ECM. The compressive stiffness, resilience, and shear resistance of articular cartilage are primarily characteristics of the ECM.5

3. Events in cartilage injury

Cartilage injuries can occur due to acute trauma or repetitive microtrauma. Cartilage is exposed to mechanical stress during activities of daily living and this increases dramatically to 10–20 times of bodyweight during sports activities.6 Acute osteochondral injury leads to initiation of reparative processes that includes formation of blood clot containing bone marrow cells which forms fibrocartiliginous tissue. However, repetitive microtrauma leads to chondropenia, decreased proteoglycan production and damage to collagen meshwork. Usually, collagen meshwork limits water ingress; hence damage to it leads to swelling and reduced stiffness of the tissue. Response to cartilage injury encompasses both catabolic and anabolic components. Aggrecan-degrading enzyme disintegrin, metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) and collagenase matrix metalloproteinase 13 (MMP-13) which degrades type II collagen all lead to breakdown of cartilage. On the other hand, induction of chondroprotective genes leads to anabolic effects on the cartilage.7

4. Current treatment trends in cartilage repair

Most early stage cartilage lesions do not cause a lot of symptoms and disability. However, in later stages, patients present with pain, swelling and mechanical symptoms like locking, catching and crepitus. Early nonsurgical management of patients with cartilage injury includes patient education regarding underlying pathology and lifestyle modifications.

4.1. Non-operative management

4.1.1. Non-pharmacological management of articular cartilage disease

4.1.1.1. Exercises

Among all the non-pharmacological interventions for cartilage defect, exercise is the most consistent modality. Exercise has been shown to reduce the symptoms of cartilage defect, improve joint movements, and prevent functional disability.8

4.1.1.2. Weight loss

Similarly weight gain increases joint pain symptoms and weight loss is very important to decrease the load on the cartilage of weight-bearing joints. Every 1 kg weight lost decreases 2.2 kg of peak knee load on cartilage.9 Weight loss has also demonstrated decreased rates of cartilage thickness loss and improved quality.10

4.1.1.3. Physical therapy

Physical therapy and resistance training exercises are a commonly prescribed non-operative modality for articular cartilage diseases. However, resistance training exercises have higher evidences as non-operative methods. Core strengthening exercises lead to decreased joint loading and improved joint stability.11 However, other modalities like transcutaneous nerve stimulation and therapeutic ultrasound and interferential therapy have demonstrated no benefits.12

4.1.1.4. Braces

Braces and other orthoses can provide structural support in an effort to reduce pain and improve joint function. Offloading knee braces can reduce forces transmitted through the lateral or medial compartment of the knee and distribute forces more evenly.13

4.1.2. Pharmacological management of articular cartilage injuries

Patients who don't have relief with non-pharmacological modalities are tried with oral and topical analgesics medication for symptomatic relief and for more severe pain opioid analgesics are considered as well.

4.1.2.1. Oral supplements

Pharmacological modalities include supplements like glucosamine and chondroitin sulphate which are used either alone or in combination. Glucosamine is an aminosaccharide used for the synthesis of glycosaminoglycans and glycoproteins. It is highly concentrated in articular cartilage along with chondroitin, which is a glycosaminoglycan.14 However, clinical outcomes of such pharmacological treatment have at best shown mixed results.15

4.1.2.2. Steroid injections

Although cartilage damage is a degenerative process, steroid injections have shown to reduce pain and improve function due to their local anti-inflammatory effect.16 However, results are only short-term and are best suited for acute onset pain in degenerative osteoarthritis or acute cartilage insults.17 Injection site pain, elevated blood sugar, and skin atrophy have been reported after corticosteroid injection.18

4.1.2.3. Injectable viscosupplements

High molecular weight hyaluronic acid (HA) injection has been used to counter the effect of the decreased viscoelasticity of synovial fluid seen in osteoarthritis.19 The clinical improvement is usually slower than following corticosteroid injections. However, pain relief is longer lasting and may be considered a better intermediate-term option due to its lesser side-effect profile.20

Viscosupplementation effects its positive outcomes through various modalities: 1) increasing joint lubrication and shock absorption through improved viscoelasticity, 2) stimulation of endogenous production of hyaluronic acid by synovial cells,19 3) anti-inflammatory effect by inhibiting production of prostaglandin E2 and release of arachidonic acid, 4) protection against cell damage from oxygen free radicals and phagocytosis to the articular cartilage.21 A Cochrane review of 76 RCTs on viscosupplementation for knee osteoarthritis concluded that it effectively improved pain, function, and patient global assessment.20 However using viscosupplements for joints apart from the knee has very little evidence for or against it.

4.1.2.4. Prolotherapy

Prolotherapy uses non-biologic irritant solutions, most commonly dextrose for injection in the joint space.22 The mechanism of action is multi-factorial and not well understood but proposed mechanisms include stimulation of local healing process in tissue of chronic damage of articular cartilage and stimulate cell proliferation.23 Animal studies have suggested cartilage specific anabolic growth and biopsies of the grown tissues have revealed hyaline like cartilage and fibrocartilage mixtures.22 Sit et al. published a meta-analysis of 4 RCTs that demonstrated results of periarticular and intraarticular hypertonic dextrose prolotherapy and concluded that it is superior to exercise for the treatment of knee osteoarthritis.22

4.1.3. Orthobiologics

4.1.3.1. Platelet rich plasma (PRP)

Platelet-rich plasma (PRP) (Fig. 2) has become popular recently in the Orthopaedic community. PRP is autologous blood that is centrifuged to produce a high concentration of platelets than the average.24 It counteracts cartilage erosion by inhibiting the catabolic cytokines IL-1β and TNF-α, and by promoting factors fibroblast growth factor, transforming growth factor-β (TGF-β), and others that are associated with cartilage matrix synthesis.25,26 In animal models in vitro, PRP promotes chondrogenic differentiation and results in enhanced cartilage repair.27 However, similar results have not been published in human subjects. Nevertheless, PRP has shown promising results in the management of knee28 and hip osteoarthritis29 as a standalone treatment modality or in conjunction with surgical treatment. Randomized trials comparing ultrasound-guided PRP versus Hyaluronic Acid injections for hip osteoarthritis have demonstrated significant improvements in functional outcomes in both groups between 1-month and 3-month follow-up. However, the positive outcomes diminished at longer follow up, though still significantly better compared with the baseline.30 No significant differences have been observed between different leukocyte-rich (LR-PRP) and leukocyte-poor PRP (LP-PRP) preparations.31 There are number of studies showing short term results with PRP injections however studies showing long term results are lacking. A recent meta-analysis has shown that intra-articular injection of PRP combined with HA resulted in better functional outcomes than the injection of PRP alone.32

Fig. 2.

Fig. 2

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Preparation of PRP by centrifugation of peripheral blood.

4.1.3.2. Stromal vascular fraction injections (SVF)

Stromal vascular fraction (SVF) is the concentrated heterogeneous population of mononuclear cells, ADSCs, pre-adipocytes, endothelial progenitor cells, adipocytes, fibroblasts, pericytes, T-regulatory cells, monocytes, lymphocytes, vascular smooth muscle cells, and M2 macrophages and also platelets, growth factors, and extracellular matrix materials that remain after separation of the fat cells from adipose tissue. Our systemic review has shown intra-articular injection of SVF to be simple, safe and affordable for the treatment of knee osteoarthritis.33

4.1.3.3. Stem cells

Stem cells are undifferentiated cells that are capable of proliferation, regeneration, self-maintenance, and replication.34 Mesenchymal stem cells (MSCs) are the most popular stem cells for articular cartilage repairs due to their accessibility and their ability to differentiate into chondrocytes given the appropriate environment.35 Soler et al., in their study on 15 patients with knee osteoarthritis treated with a single intra-articular injection of an autologous MSCs, reported significantly improved functional outcomes at 12 months. MRI T2 mapping to assess cartilage quality showed steady improvement in cartilage quality from pre-injection to 12-months follow-up.36 Bone marrow aspirate concentrate (BMAC) is one of the few US Food and Drug Administration (FDA)-approved methods for delivering stem cells and is most often formulated from iliac or tibial bone marrow (Fig. 3).37

Fig. 3.

Fig. 3

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BMAC procedure. A. Bone marrow aspiration, B. Loading bone marrow aspirate to the kit. C. Extraction of BMAC. D. BMAC application to the chondral lesion.

The limitation in the number of stem cells obtainable from bone marrow38 has driven a search for alternative stem cell sources. Adipose tissue obtained by abdominal liposuction appears to be a promising source.39 Synovium-derived stem cells have also been tried in the treatment of isolated cartilage defects with improved clinical and MRI outcomes.40

4.2. Operative management of articular cartilage damage

4.2.1. Microfracture

Microfracture was first introduced in the late 1980s as a method to penetrate the subchondral bones. It is a minimally invasive technique where with standard arthroscopy portals drill holes are made with help of arthroscopic awl. In this technique small holes are made at equal distance over the cartilage lesions at least 3–4 mm apart, 4 mm depth and 3–4 holes in 1 cm area.41 It enhances migration of MSCs from bone marrow to the site of cartilage defect. The technique however results in the formation of fibrocartilage that is both biochemically and biomechanically inferior to hyaline articular cartilage.42 Kreuz et al., in 2006 studied the results of microfracture in the knee joint and showed that the repair tissue is vulnerable to mechanical forces and it gradually deteriorates in 18–24 months of surgery. This is reflected in the modified Cincinnati Rating System for knee and International Cartilage Repair Society (ICRS) scores postoperatively. This effect is more evident in large defects and in defects of the patella femoral joint.43 Due to invasion of subchondral bone osteophytes develop in 20–50% cases.44 However, many author suggest micro-fracture as a gold standard technique but it is only helpful in short term in delaying cartilage degeneration, more than 5 years after the surgery cartilage degeneration is expected irrespective of the size of the lesion (Fig. 4).45

Fig. 4.

Fig. 4

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Microfracture procedure. A. Chondral lesion of medial femoral condyle, B. After microfracture. C. 2nd look arthroscopic finding, post op 2 year.

4.2.2. Nanofracture

This newer technique creates deeper cell channels in a more reproducible manner than the standard microfracture technique and increases bone marrow access and improves cartilage-resurfacing properties.46 It can also combined with autologous matrix induced chondrogenesis techniques.

4.2.3. Subchondral drilling or abrasions

This is an alternative technique to microfracture where cartilage defects are drilled with either drill bit or K wire up to subchondral bone.47 Subchondral abrasions technique uses motorised burr to debride the chondral defect, however there is an evidence of thermal necrosis, hypertrophy or cyst formation with this technique.48 It is considered inferior to microfracture due to the risk of thermal necrosis.49 However, comparison of subchondral drilling and microfracture for the treatment of small to mid-sized osteochondral lesions of the talus has shown similar improvements in clinical outcomes at a mean follow-up of 43 months (Fig. 5).50

Fig. 5.

Fig. 5

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A. Abrasion of sclerotic subchondral bone with burr. B. Multiple drilling.

4.2.4. Osteochondral grafting

Osteochondral grafting is of two types: 1) Mosaicplasty, 2) Osteochondral autograft transplantation system (OATS). Careful patient selection is the key in these procedures. These procedures are performed either by auto graft or allograft.

Allografts have the advantage of providing osteochondral segments that are able to survive transplant, and no associated donor site morbidity.51 They are mainly used in cases of previously failed repair of auto-graft transplantation and very large defects where donor site for autograft is insufficient. Fresh osteochondral allografts stored at physiological temperatures provide high levels of viable donor chondrocytes.52 However, the main problem with allograft is graft host reaction and availability of allograft.53

  • I)

    MOSAICPLASTY:

It was first introduced in early 1990s; cylindrical bone-cartilage grafts are harvested and transplanted into focal chondral or osteochondral defects. A recipient tunnel is created and sized with a drill bit slightly larger than the length of the graft. The harvested graft is placed in the tunnel by a press-fit method. All subsequent grafts are inserted in a similar pattern. Donor sites are routinely left open and fill with cancellous bone and fibrocartilage within 4–8 weeks.54 The advantages of using autograft include graft availability and the absence of disease transmission risk, while disadvantages include donor site morbidity and limited available graft volume.55

  • II)

    OATS:

This procedure is similar to mosaicplasty but involves the use of a single, large plug that fills an entire defect. Increased donor-site morbidity has been reported by some authors with the use of larger, single plugs.55

The limitations of mosaicplasty and OATS include technical difficulty, donor-site morbidity, potential mismatch in the size and shape of the grafts compared with the defect and poorer results for larger defects.55

4.2.5. Cell based therapies

Brittberg et al.56 developed cell-based therapies in the 1970s57 with the purpose of achieving normal hyaline cartilage repair of osteochondral cartilage defects.

  • 1)

    AUTOLOGOUS CHONDROCYTE IMPLANTATION (ACI):

The procedure is performed in two-stages. In the first stage, cartilage is harvested from a non-weight-bearing portion of the joint and in the lab chondrocytes are released from the cartilage by enzymatic digestion (Fig. 6). The chondrocytes are culture-expanded in vitro for 4–6 weeks. The chondrocytes are then implanted into the defect arthroscopically in a second stage.58 Originally, chondrocytes were injected under a periosteal sleeve secured with fine sutures and sealed with fibrin glue. Over the years, the technique has seen several modifications and there are four generations of ACI to-date:

Fig. 6.

Fig. 6

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A. Multiple drilling after cartilage lesion preparion. B. ACI through the patient's rib cartilage culture.

1st generation: Chondrocytes in suspension injected under a periosteal sleeve.

2nd generation: Chondrocytes in suspension injected under a collagen membrane.

3rd generation: Chondrocytes grown on a surface carrier or in a porous matrix/scaffold.

4th generation: Chondrocytes implanted in a one-stage procedure.

Minas et al. described long term outcomes (>10 years follow up) for these procedures which are excellent and they have demonstrated effective and durable treatment option for large cartilage lesions with 71% graft survival at 10 years and 75% improved function54,. However, this procedure is commonly complicated due to hypertrophy of the periosteum leading to clicking sound in 25% of patients.59 Other disadvantages of this procedure include that it is a complex procedure; two staged procedure; it requires longer recovery time for maturation of new tissue. To overcome these issues second generation techniques have been developed.60

  • 2)

    MATRIX-ASSISTED CHONDROCYTE IMPLANTATION (MACI):

This is a second generation technique in which type I/II collagen scaffold is used. Similar to ACI, MACI requires two surgical procedures. In the first stage, autologous cartilage is harvested and chondrocytes are isolated. The cell population is then expanded in vitro and then seeded for 3 days on an absorbable porcine-derived mixed collagen (type I and III) membrane prior to implantation. A mini-arthrotomy is performed and the cell-seeded scaffold is implanted and secured with fibrin glue.58 This technique has an advantage of reduced operative time and avoids complications associated with periosteum.

  • 3)

    AUTOLOGOUS MATRIX-Induced CHONDROGENESIS: Micro-scaffold-induced Chondrogenesis (ACIC/AMIC)

Autologous matrix-assisted chondrogenesis is a procedure which combines microfracture with a collagen scaffold in order to add additional mechanical stability to the fibrin clot which is produced following the microfracture because fibrin clot alone does not have the stability to withstand the tangential forces.61 A randomized controlled trial (RCT) evaluating the use of a chitosan-based scaffold combined with microfracture has shown superior repair tissue quantity and quality over microfracture alone at five years, though with no difference in clinical outcome.62

  • 4)

    HYALURONAN-BASED SCAFFOLDS:

This is another technique of implanting chondrocytes within a three-dimensional biodegradable environment. Similar to collagen-derived matrices, the hyaluronic-acid-based scaffold is intended to promote and maintain the chondrocytic phenotype and collagen type II synthesis during in-vitro culture, as well as after implantation.60 However, long term studies and comparative studies are yet to be proven.

5. Future prospects

  • 1.

    CELL-FREE SCAFFOLDS:

Cell free scaffolds are mechanical support for cell proliferation and viability and are being evaluated as a treatment options for cartilage regeneration. Type I collagen cell free scaffolds implanted in cartilage defect areas have shown promising clinical and radiological results with histological appearance of the articular cartilage with type II collagen's presence in preclinical and phase I clinical trials.63

  • 2.

    GROWTH FACTORS:

There are many growth factors like FGF (fibroblast growth factors), BMP (bone morphogenic proteins) and PDGF (platelet derived growth factors) that can regulate the differentiation and proliferation of cartilage regeneration process. In vitro studies and animal studies have shown their potential of augmenting cartilage regeneration. However, longer studies and human trials are still awaited.64

  • 3.

    GENE THERAPY:

Gene therapy is being investigated as a treatment option. It involves the delivery of genetic material via a vector in an effort to alter cell synthesis or function. Preclinical studies have shown good cartilage regeneration with gene therapy using viral vectors with growth factors like FGF, PDGF65. However, they are yet to be translated into clinical studies.

6. Conclusion

Articular cartilage damage is now diagnosed earlier due to better understanding of pathology and knowledge regarding its consequences. Early diagnosis and its long-term consequences have gained a lot of attention from researchers to have early treatment and focus on preservation and regeneration of articular cartilage. Current techniques result in development of fibrocartilage or hyaline-like cartilage, depending on the type of treatment. Cell-based techniques have shown promising results, though long-term randomised controlled trials and comparative studies with existing techniques are due before their widespread use.

Contributor Information

Ketansinh Solanki, Email: ketansinhs24@gmail.com.

Saseendar Shanmugasundaram, Email: ssaseendar@gmail.com.

Neha Shetty, Email: nehashetty@hotmail.com.

Seok-Jung Kim, Email: orthopland@naver.com.

Learning points

  • 1.

    Articular cartilage is a connective tissue that is devoid of nerve supply, blood supply and lymphatic drainage and is primarily composed of type 2 collagen

  • 2.

    Every 1 kg weight lost decreases 2.2 kg of peak knee load on cartilage

  • 3.

    Clinical outcomes of supplements like glucosamine and chondroitin sulphate have at best shown mixed results

  • 4.

    Steroid injection can reduce pain and improve function, but results are only short-lived and is best suited for acute onset pain in degenerative OA

  • 5.

    High molecular weight hyaluronic acid injection causes longer lasting pain relief and are considered a better intermediate-term option than steroids due to lesser side-effects

  • 6.

    In addition to increasing joint lubrication and shock absorption, injectable viscosupplements stimulate endogenous production of hyaluronic acid and have anti-inflammatory effect by inhibiting production of prostaglandin E2 and release of arachidonic acid and also protect the cartilage from oxygen free radicals

  • 7.

    PRP injection has shown promising results in the management of knee and hip osteoarthritis as a standalone treatment modality or in conjunction with surgical treatment

  • 8.

    Intra-articular injection of PRP combined with HA results in better functional outcomes than the injection of PRP alone.

  • 9.

    Intra-articular injection of SVF is a simple, safe and affordable treatment for knee osteoarthritis

  • 10.

    Mesenchymal stem cells (MSCs) are the most popular stem cells for articular cartilage repairs; sources of MSCs include bone marrow, adipose tissue, synovium

  • 11.

    Microfracture results in improved clinical outcomes in small lesions. Outcomes deteriorate in 2 years in large lesions; Nanofracture creates deeper, more reproducible cell channels and increases bone marrow access and cartilage-resurfacing properties

  • 12.

    Mosaicplasty and Osteochondral autograft transplantation system (OATS) are useful techniques for the treatment of large osteochondral defects

  • 13.

    Autologous chondrocyte implantation (ACI) is a two-stage cartilage reconstruction technique that is now considered gold-standard

  • 14.

    Autologous matrix-induced chondrogenesis combines microfracture with a collagen scaffold in order to add additional mechanical stability to the fibrin clot

  • 15.

    Growth factors and gene therapy are expected to pave new fronts in the reconstruction of articular cartilage

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