Emerging Treatments For Cartilage Damage In Young People Biology Essay

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Depletion of articular cartilage can induce rubbing of two bone condyles, inflicting pain in movement which reduces an individual's ability to perform certain workloads. A prosthesis, knee replacement, is not usually an option for younger patients as it would loosen and wear out with the amount of physical activity undertaken and so has a limited life span (3).

Current treatments for cartilage injuries in young people include subchondral bleeding involving the use of microfractures. More recently autologous chondrocyte implantation has been implemented in some individuals but its effectiveness remains controversial (4). All the procedures reduce the clinical symptoms of articular cartilage defects but long term results require more in depth investigations (5). Future therapies need to create a replacement matching the mechanical properties of articular cartilage (6). Tissue engineering is seen as a promising emerging treatment that is a suitable biomechanical replacement for articular cartilage.

Articular cartilage caps the condylar part of bones to provide a smooth lubricated surface to allow frictionless movement in synovial joints (4). The main components of articular cartilage are specialised cells, chondrocytes, which are situated within an Extra-Cellular Matrix (ECM) containing macromolecules such as proteoglycans, collagen and non-collagenous proteins (7) (see Figure 1). Water also plays a crucial role in acting as a shock absorbent and in lubrication (7) and makes up to 80% of the weight (refer to fig 2).

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This type of cartilage is a vital part of movement in joints especially the knee, a weight bearing joint. The thickness of articular cartilage varies from joint to joint, and in humans it is thickest over ends of the femur and tibia, ranging from 2-4 mm (8). Cartilage is avascular with no lymphatic ducts or nerves innervations and a low metabolic rate (4).

It is possible to identify four zones of articular cartilage (7) (see Figure 3):

Superficial zone

Transitional zone

Radial (deep) zone

Calcified cartilage zone

(Figure 1) Schematic presentation of cartilage extracellular matrix. Hyaluronan is a nonsulfated glycosaminoglycan, aggrecan is a large aggregating proteoglycan (1p)

(Figure 2) The ion concentrations within cartilage. The yellow negative ions are attached to glycosaminoglycans, a component of proteoglycans, attract positive ions that change the osmolality of cartilage (2p)

(Figure 3) Histological organisation of articular cartilage. Four zones are present corresponding to chondrocyte shape and activity, collagen orientation and type, the extent of proteoglycan and water. A histological section of articular cartilage of the knee stained with Alcian Blue and photographed under a light microscope is shown. +: Moderate cell density, ++: high cell density. (3p)

Damage to Articular Cartilage

Articular cartilage has an inability to repair properly (1)(3). Being avascular prevents blood clots forming when damage occurs which is essential to repair as it leads fibrosis and new cells replacing the damaged area. Chondrocytes which are pivotal in synthesising new ECM in cartilage are sparse in population and have low metabolic rates (7). Chondrocyte synthesis of the ECM is insufficient to repair vast areas of tissue defects (7). Differentiated chondrocytes also lack the ability to proliferate (9)(10).

In young people traumatic damage to articular cartilage can result in severe pain and disability (1)(11) increasing the risk of developing osteoarthritis later in life (2). Osteoarthritis is the progressive degradation of articular cartilage leading to a loss in the shock absorbent behaviour of the cartilage.

The extent of pain can be assessed using the Tegner Lysholm Knee Scoring Scale (12) using a set of questions about day-to-day living (12).

Grading

Tegner Lysholm Knee Score

Excellent

<90

Good

84-90

Fair

65-83

Poor

>65

(Figure 4) Tegner Lysholm Knee Scoring Scale. Used to assess the extent of damage to the knee. (4p)

Depletion in articular cartilage can induce rubbing of two bone condyles inflicting pain during movement. The current and emerging treatments for cartilage injuries in young people include cell based therapies and tissue engineering.

Techniques to Restore Painless Joint Function

Cell Based Therapy

Marrow Stimulation

Marrow Stimulation uses surgical techniques to enhance the natural healing response to damage within cartilage (13)(14)(15). Superficial impairment of articular cartilage cannot heal effectively due to its nature of being avascular (4). Techniques such as microfractures, drill into the subchondral bone, where blood vessel are resident to allow the natural healing process to commence (2).

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The natural healing process arises from mediators being released from damaged cells. These mediators encourage local vasodilatation of blood vessels. Inflammatory cells from the immune system respond by removing damaged cells and debris. This promotes the release of bone marrow Mesenchymal Stem Cells (MSCs) to replace and restructure the defects (15). During rehabilitation joint movement distributes MSCs to the articulation surface (15).

(Figure 5) Articular cartilage lesion treated with microfractures. (5p)Microfractures provides small, numerous holes close together limiting the damage to subchondral bone (2) and it not as invasive as it uses an arthroscopic awl (8). It requires little technical skills or specialist equipment providing a low cost therapy (4).

The disadvantages of the procedure include risks associated with an operation, longer recovery period, painful and not applicable as a long term treatment. The main concern with this treatment for young people is that the MSCs that replace the defected articular cartilage differentiate into a fibro-cartilaginous matrix that is disorganised due to the production of collagen Type I (2)(16) (see Figure 5). Fibrocartilage is not as competent mechanically as the native cartilage owing to its structure and has a limited load bearing capacity and restricts frictionless movement (2)(10). Vast areas of defected cartilage cannot be repaired in this manner as a lack of surrounding ECM framework causes new cells to disband with joint movement (2). Extensive rehabilitation can be up to 6 weeks non-weight bearing (6).

Marrow stimulation has been proven to be very effective at removing symptoms of defective articular cartilage such as pain for up to 3-5 years (15) and is therefore a reasonable first step management for articular cartilage injuries in young people (15).

Autologous Chondrocyte Implantation

Autologous Chondrocyte Implantation (ACI) involves utilising the individual's own chondrocytes that are cultured and are then inserted to replace the articular cartilage lesion. Chondrocytes can replenish and synthesis the ECM as it contains large amounts of endoplasmic reticulum and Golgi apparatus within the cell. The therapy involves three steps (2)(see Figure 6):

The collection of cartilage

Isolation of chondrocytes and In vitro expansion of cells in a monolayer culture for 11 to 21 days.

Implantation of the cultured chondrocytes into the articular cartilage lesion

(Figure 6) Diagram of Autologous Chondrocyte Implantation. Located in the right femoral Condyle. (6p)

A periosteal flap is sutured or glued to the encompassing healthy cartilage to try and retain the cells in suspension at the site of defect. Glue is preferred to seal the flap rather than sutures (5) as they can cause an increase in cell death (15). The implanted chondrocytes are injected beneath the periosteal flap into the lesion (see Figure 7). The periosteal flap is in place to prevent hypertrophy of the inserted cells and stimulating collagen Type II fibres, through growth factors (15), which is essential for the ECM framework giving articular cartilage its unique properties of being highly resilient and flexible in response to mechanical stress (3). The layer of periosteum also contains chondrocyte precursor cells (2).

(Figure 7) Autologous Chondrocyte Implantation into lesion below the periosteal flap. (7p)

The beneficial aspects of ACI are that it has shown to regenerate articular cartilage in lesions in clinical trials to emulate normal joint function. ACI has a limited risk of infection as the cells used are corresponding to that individual receiving treatment (3).

The drawbacks of ACI include damage to the area used as a biopsy of healthy cartilage since articular cartilage has an inability to repair properly (2). Only a limited amount of cartilage can be removed from the low weight bearing area meaning less chondrocytes for implantation (4). A critical obstacle with ACI persist during in vitro expansion of chondrocytes as they can become dedifferentiated losing their phenotypic expression (4) giving rise to fibrocartilage that is biomechanically inferior to articular cartilage (2). Another limitation is the implantation of chondrocytes can sometimes lead to hypertrophy to that area of cartilage disrupting the smooth articulation surface creating clinical signs of pain (2). The periosteal flap can sometimes lead to mineralisation of the new cartilage (5).

A long rehabilitation programme of no weight bearing up to the first three months after the procedure can impact a patient's adherence to treatment, as the articular surface is vulnerable to damage (5). ACI is very expensive as the technique is highly skilled and requires specialist equipment for cell culturing (4).

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A recent improvement in second generation ACI is that the cells are implanted with collagen Type II to create a framework similar to healthy cartilage, providing tensile strength (4)(17). ACI is used if other techniques to stimulate cartilage repair, for example, microfractures, are unsuccessful (2).

Further developments of ACI involve three dimensional scaffolds to restructure the ACI that specifically fits the shape of the lesion and has the framework of native cartilage (2). Furthermore, three dimensional cultures, instead of a monolayer, with appropriate growth factors are being investigated to prevent chondrocytes losing phenotypic expression (4). The long term benefits of ACI look promising but are still under investigation (6).

Tissue Engineering

The focus of tissue engineering is on utilising the individual's cells that can be cultured and placed into a three dimensional biomaterial scaffold that resembles the ECM of articular cartilage, to regain biomechanical properties of native cartilage in cartilage lesions. Tissue engineering is increasingly being used as ACI leads to a poor retention of cells at the site of defect (18).

Cell-Scaffolds Composites

An ideal scaffold has many desirable traits to be able to adapt to the environment in a joint.

Biocompatible to prevent an immune response

Three dimensional to provide an environment similar to the ECM of articular cartilage to gain its functional properties and to prevent dedifferentiation

Permeable to allow the uptake of cells to the scaffold and the diffusion of nutrients

Adherence to the lesion or subchondral bone.

Bioactive to allow controlled release of morphogens, such as growth factors and cytokines, to promote maturation of articular cartilage.

Biodegradable to create integration between the implant and native cartilage ensuring long term capacity of the procedure (2).

Cells

Reparative cells need to be cultured to synthesise the ECM at the site of damage. MSCs from bone marrow, periosteum, perichondrium or adipose tissue and chondrocytes originating from articular, nasal or costal regions can be used as a source for cartilage tissue engineering (2). Bone marrow MSCs have the potential to differentiate into cartilage cells in vitro with the correct environment as morphogens encourage the chondrogenic lineage (4)(19). A complication in using chondrocytes is that they are phenotypically instable in a monolayer culture (2). However, a benefit of culturing chondrocytes is that it is the only cell present in cartilage (6). MSCs are preferred as an ideal cell for tissue engineering as chondrocytes can dedifferentiate and have a limited life span.

The autologous cells are removed from the donor sites, as mentioned above, and isolated with the use of enzymes. The cells are then cultured to allow amplification of cells which are then seeded into a three dimensional scaffold (2). The cell-scaffold complex is combined with a carrier such as calcium phosphate to authorise the integration with native cartilage and the production of new articular cartilage containing collagen Type II and proteoglycans (6). This final complex is inserted into the site of the lesion with the use of an arthroscope (see Figure 8).

Cells can be inserted into the defective site in two ways

The cells mature in vitro and then integrate with the cell-scaffold composite

The cells are partially grown in vitro and integrated with the scaffold which is then inserted to allow the maturation of cells in the joint environment (2)(18).

(Figure 8) Plan for Cartilage Tissue engineering. (8p)

Tissue engineering reduces the clinical signs of cartilage damage (6), though it life span of effectiveness is unknown as it is an emerging treatment. A benefit compared to ACI is that the donor site may not involve articular cartilage reducing degradation of the articulation surface (4).

An emerging development involves the use of hydrogels (20). These contain macromolecules that when inserted in the environment within the knee create a cross-linking frame work to act as a three dimensional scaffold. Hydrogels are ideal as they contain water similar to the ECM, are injectable reducing morbidity as it is not invasive and the density of the framework can be adjusted to suit each patient (2).

Conclusion

Articular cartilage's capacity to repair is weak and requires treatments to encourage repairment and without treatment can lead to osteoarthritis (4). Deciding which treatment is currently the most beneficial depends upon a number of variables, for example, the extent of damage, desired outcomes or amount of movement, patient's decision as they will need to adhere to rehabilitation if the therapy is to prove helpful and the multidisciplinary team's decision due to the availability of facilities for treatment from the local primary health trust. It also depends on the person's age and the amount of other attempts that have been unsuccessful to improve the functional capacity of the joint.

Current treatments for cartilage injuries in young people include subchondral bleeding involving the use of microfractures. More recently ACI has been implemented in some individuals but its effectiveness remains controversial (4). All the procedures reduce the clinical symptoms of articular cartilage defects but long term results require more in depth investigations (5). Future therapies need to create a replacement matching the mechanical properties of articular cartilage (6). Tissue engineering is seen as a promising emerging treatment that is a suitable biomechanical replacement for articular cartilage. Alternatively gene therapy is being investigated to allow cells to produce therapeutic proteins when inserted into the joint (2). Ultimately early treatment of cartilage defects may prevent the need for a prosthesis and reduce the risk of osteoarthritis (3).

The essential part of developing an articular cartilage treatment is the production of a macromolecular framework, that collagen Type II does, to institute the biomechanical properties of articular cartilage (3).