User:Shayna tomlinson/sandbox

Team 3: Artificial Cartilage Rough Draft

1. Introduction [5, 10, 14]

Artificial cartilage is a synthetic material made of hydrogels or polymers that aims to mimic the functional properties of natural cartilage in the human body. Tissue engineering principles are used in order to create a non-degradable and biocompatible material that can replace cartilage. While creating a useful synthetic cartilage material, certain challenges need to be overcome. First, cartilage is an avascular structure in the body and therefore does not repair itself. This creates issues in regeneration of the tissue. Synthetic cartilage also needs to be stably attached to its underlying surface, bone. Lastly, in the case of creating synthetic cartilage to be used in joint spaces, high mechanical strength under compression needs to be a property of the material.

1. Natural cartilage

There are three types of cartilage in the human body: fibrocartilage, hyaline cartilage and elastic cartilage. Each type of cartilage has varying concentrations of components such as proteoglycans, collagen and water which determine its functional properties and location in the body. Fibrocartilage is most often found in the intervertebral discs, elastic cartilage is found in the external ear and hyaline cartilage is found on many joint surfaces in the body.

1. 1. Components
      1. Water- Makes up around 80% of cartilage [5].
      2. Chondrocytes
      3. Collagen
      4. Proteoglycans
      5. Glycosaminoglycans
      6. Glycoproteins- Specifically lubricin helps to create a lubricating surface on the collagen for easier joint mobility [5].

1. 1. Structure [14]

There are three transitional zones in articular cartilage including a superficial tangential zone, a middle transitional zone and a deep zone. Between bone and the rest of the transitional zones lies calcified cartilage. In the tangential zone, collagen fibers are aligned parallel to the surface and moving deeper become randomly aligned. Cell arrangement also varies between the zones, in deeper zones chondrocytes are stacked into columns while in the superficial zones they are arranged randomly [14].

1. Synthetic cartilage

Synthetic cartilage can be composed of many different materials that mimic its functional properties, outlined below. In section XX are specific current approaches to synthetic cartilage.

1. 1. Components
      1. Polymers

Examples include poly vinyl alchol and polyethylene

1. 1. 1. Hydrogels
      2. Growth factors

1. Function

Synthetic cartilage will attempt to mimic the functional properties of natural cartilage, which include the following:

1. Load bearing properties [9]
2. Tribological properties [9]

These are important functions of cartilage because of its role as a cushion in bone articulation [2]. These may be achieved depending on the structure and components of the hydrogel created [13]. The optimal properties compared to that of natural cartilage are show in the figure below [9].

An additional function of the hydrogel is that it must have the correct degradation properties. In reference [12], this function was tested by comparing the stress, modulus and water content before and after implantation of 4 different compositions of hydrogels.

1. Poly(2-acrylamide-2-methyl-propane sulfonic acid)/poly(N,N’-dimethyl acrylamide)
2. Poly(2-acrylamide-2-methyl-propane sulfonic acid)/polyacrylamide
3. Cellulose/poly(dimethyl acrylamide)
4. Bacterial cellulose/gelatin

1. Future Work

In terms of future work, there is still a lot to be done in this field. Artificial cartilage is a new research topic and much is still unknown. There is a lot of unknown factors involving ASCPs and more studies need to be conducted to make a more supported conclusion about the regenerative functions of ASCPs [4]. Additionally, growth factors have been thoroughly evaluated, however specific combinations still need to be studied further in order to more effectively generate a tissue that can mimic the properties of natural cartilage [2].

1.     Existing Methods

There are many existing methods concerning regenerative therapies of cartilage as well as developing new artificial cartilage.  First, regenerative therapies for osteoarthritis will be discussed. There have been substantial advances in recent years in the development of these regenerative therapies.  These include anti-degradation, anti-inflammation, and cell and scaffold based cartilage regeneration.

Anti-Degradation

Many biological agents and chemical compounds have been used in order to prevent matrix-degrading enzymes that actively work to degrade cartilage.  Monoclonal antibodies, most commonly studied being 12F4.1H7, work to specifically suppress ADAMTS-5-induced aggrecan release. This in turn helps to slow down cartilage degradation and osteophyte formation [1].    

Anti-inflammation

Inhibiting inflammatory mediators could help prevent osteoarthritis progression.  Cytokines and chemokines are both crucial in stimulating cartilage catabolism and blocking these inflammatory mediators. Studies have shown that treatment with NG-kB pathway inhibitor BAY11-7082 restores IL-1b-inhibited chondrogenesis of cartilage stem cells and in turn postpones progression of OA.  Similarly, ample research shows that combined blockade of TNFa and IL-17 with bispecific antibodies reveals an inhibition of both cytokines for reduced cartilage degradation and proinflammatory responses [1]. 

Cell-and Scaffold-based cartilage regeneration

In order to restore joint cartilage after injury due to chondrocyte loss, cell therapy and chondrocyte replenishment has been shown to work in certain studies.  Lying self-assembled MSCs (mesenchymal stem cells) on top of chondrocyte-laden hydrogel scaffolds has shown cell-mediated regeneration of hyaline-like cartilage. However, one drawback of this is that implantation of these scaffolds requires open-joint surgery to gather donor chondrocytes from non-weight-bearing joint cartilage areas.  This makes it difficult to apply to the elderly [1].

Along with regenerative therapies there are also several studies that show ways to develop new artificial cartilage.  

3D Woven fiber scaffold infiltrated with network hydrogels

One study discussed that the 3d woven fibers provide load bearing tibological properties of native cartilage where they are trying to achieve a near frictionless environment.  Hydrogels are used as cell carriers because they can be readily seeded with cells. However, it is difficult to recreate both the biomechanical and chemical functions of natural tissue.  Hydrogels of interpreting networks (IPN), are two different polymers mixed with one another on a molecular scale. This works to increase fracture toughness. They are ionically-crosslinked networks with a special type of IPN that is capable of scattering mechanical energy while maintaining the shape of a hydrogel after deformation [9].  

Double Network Hydrogels

Similar to the previous study, double network hydrogels are used.  They are composed of two kinds of hydrophilic polymers. At 6 weeks of implantation, the samples compared to those without treatment showed biodegradable properties.  When using poly(2-acrylamide-2-methyl-propane sulfonic acid)/poly(N,N’-dimethyl acrylamide) or PAMPS/PDMAAm ultimate stress and tangent modulus increased. However, when using bacterial cellulose and gelatin, it showed a decrease of ultimate stress and it did not meet the requirements of artificial cartilage [12].  

2.     Clinical Applications

Clinical application is extremely important to consider when looking at the efficacy of artificial cartilage.  The recent clinical approaches for cartilage regeneration in Osteoarthritis treatment is described below.

MSC based therapy

In certain studies, matrix-induces mesenchymal stem cell implantation showed earlier clinical improvements when compared to simple implantation of chondrocytes.  The MSCs promoted cartilage regeneration in knees that had osteoarthritis and also reduced pain and disability [1].

PVP/PVA hydrogels for articular cartilage replacement

Poly(vinyl alcohol) (PVA) hydrogels were used in this study.  It was difficult to meet the mechanical properties of articular cartilage using this hydrogel.  There was no inflammatory or degenerative changes in articular cartilage or synovial membrane surround this artificial PVA cartilage.  PVP hydrogels were also studied. They exhibit high hydrophilicity, biocompatibility, and complexing ability. When used as a blend of PVA/PVP hydrogel, they produced similar internal 3D structure and water content as natural articular cartilage.  The best mechanical properties and friction system were blended hydrogel with 1 wt. % PVP. Due to the greater inter-chain hydrogen bonding, adding PVP to the pure PVA proved a better option. They acted exactly with a characteristic viscoelastic behavior of articular cartilage[13].