Artificial cartilage

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Artificial cartilage is a synthetic material made of hydrogels [1] 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. [2] 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. [3] This creates issues in regeneration of the tissue. Synthetic cartilage also needs to be stably attached to its underlying surface i.e. the bone. Lastly, in the case of creating synthetic cartilage to be used in joint spaces, high mechanical strength under compression needs to be an intrinsic property of the material. [4]

Contents

Natural cartilage

There are three types of cartilage in the human body: fibrocartilage, hyaline cartilage and elastic cartilage. [3] 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. Replacement of hyaline cartilage (articular cartilage) is the most common application of synthetic cartilage.

Articular cartilage

Cartilage is an avascular, aneural and alymphatic tissue within the body. [5] The extracellular matrix (ECM) of collagen is what gives it its high strength. The figure below shows the components of the ECM.

Components

  • Extracellular matrix components of cartilage including proteoglycan aggregates, collagen, integrins and fibronectin. Extracellular Matrix Components of Cartilage.jpg
    Extracellular matrix components of cartilage including proteoglycan aggregates, collagen, integrins and fibronectin.
    Water: Water makes up around 80% of cartilage. [2]
  • Chondrocytes: Chondrocytes are the cells that produce and maintain the cartilaginous matrix. They are sparsely dispersed throughout cartilage and make up only about 2% of the total volume of cartilage. [5] Chondrocytes vary in size, shape and concentration depending on their location in articular cartilage. [5]
  • Collagen: Collagen is a structural protein present in the extracellular matrix of cartilage. Collagen is composed of a triple helix structure of polypeptide chains and offers shear and tensile properties to the cartilage. [5] Type II collagen is the most common type of collagen present in cartilage though types IX, X, XI, and XIV are also present. [2] Overall, collagen is a stabilizing protein present in the ECM.
  • Proteoglycans: Proteoglycans are the second most abundant macromolecule in the ECM of cartilage. [5] Proteoglycans consist of a linker protein along with a core protein to which glycosaminoglycans (GAGs) attach. The most common GAGs are chondroitin sulfate and keratin sulfate. Proteoglycans attach to a central chain, usually hyaluronic acid, via a linker protein, to create larger proteoglycan aggregates. [3] Proteoglycans are hydrophilic and therefore attract and restrain water molecules. This provides cartilage with its intrinsic ability to resist compression.
  • Glycoproteins: Many other glycoproteins are present in cartilage ECM in small amounts that help maintain structure and organization. [5] Specifically, lubricin helps to create a lubricating surface on the cartilage for easier joint mobility. [2] Fibronectin and integrins other glycoproteins present that help in adhesion of chondrocytes to the ECM.
Structural zones in Cartilage including chondrocyte and collagen arrangement. Cartilage Structure.jpg
Structural zones in Cartilage including chondrocyte and collagen arrangement.

Structure

There are three structural zones in articular cartilage including a superficial tangential zone, a middle transitional zone and a deep zone. In the tangential zone, collagen fibers are aligned parallel to the surface and become gradually randomly aligned while moving into the deep zone. Collagen fibers in the superficial zone are aligned parallel to the surface in order to restrict shear stresses. Similarly, collagen fibers are aligned perpendicular to the surface in the deep zone in order to restrict compressive forces. [5] Between bone and the deep zone lies calcified cartilage. Cell arrangement also varies between the zones, in deeper zones chondrocytes are stacked into columns while in the superficial zones they are arranged randomly. [3] In the superficial regions the cells are also more elongated, while in deeper zones they are more spherical in nature. [5]

Artificial cartilage

Synthetic cartilage can be composed of many different materials that mimic its functional properties. Tissue engineering principles include the use of cells, growth factors, and synthetic scaffolds in order to do this. [6]

Components

Structure

Function

Natural articular cartilage is an inhomogeneous, anisotropic, and viscoelastic tissue. [10] The structure, described above 1.1.2. allows the cartilaginous tissue to have superior mechanical properties in order to perform the functions necessary. Synthetic cartilage will attempt to mimic the functional properties of natural cartilage, which can be broken down into two main aspects.

These are important functions of cartilage because of its role as a cushion in bone articulation. [12] When damage and degradation occurs to the articular cartilage, it can no longer withstand the large loads without pain and discomfort of the individual due to the decrease in mechanical properties.

After analyzing the load bearing and tribological properties of natural cartilage, these mechanical properties may be achieved depending on the structure and components of the hydrogel created, which will be discussed further in the Existing Methods section. [13] These optimal properties can then be compared to the synthetic cartilage created. The properties of the hydrogels created can differ dramatically based on the components and the structure. [10] Furthermore, it is extremely difficult to achieve all mechanical functions of natural cartilage, which is the end goal of synthetic cartilage.

When dealing with creating hydrogels, there are additional functions that must be considered. For example, the hydrogel must have the correct degradation properties in order to produce cell regeneration in the correct time frame that the hydrogel will take to degrade. Additionally, the hydrogel must not create toxic waste when degrading. These functions have been tested by comparing the stress, modulus and water content before and after implantation of different compositions of hydrogels. [14]

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. [15]

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 NF-κB 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. [15]

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. [15]

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 tribological 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. [10]

Structure of a double network hydrogel can be seen by combining the blue and red hydrogel shown. Co Hydrogel Structure.jpg
Structure of a double network hydrogel can be seen by combining the blue and red hydrogel shown.

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. [14]

PVA/PAMPS hydrogel

In 2020, developers combined a bacterial cellulose nanofiber network with a poly(vinyl alcohol) (PVA) - poly(2-acrylamido-2-methyl-1-propanesulfonic acid sodium salt) (PAMPS) double network hydrogel. [16] The artificial cartilage displayed the same strength and modulus as natural cartilage in terms of tension and compression, and was the first lab-created option to exhibit cartilage-equivalent tensile fatigue strength. [16] The hydrogel needs to undergo further lab testing before researchers determine if it can be moved to clinical use. [17] PVA hydrogels prepared by several freezing-thawing, without an externally added crosslinking agent, have also exhibited great promises in terms of biocompatibility, wear resistance, shock absorption, friction coefficient, flexibility, and lubrication (due to uptake/excretion of body fluid). [1] A two-year implantation of the PVA gels as artificial meniscus in rabbits showed that they remain intact without degradation, fracture, or loss of properties. [1]

PDMS hydrogel

This method uses a hydrogel that is contained within a porous, silicone-based polymer called polydimethylsiloxane (PDMS). [18] [19] The polymer allows the hydrogel to withstand 14-19 times more force than it could on its own. [18] [19]

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. [15]

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]

Cartilage implants

In July 2016, the U.S. approved the use of a synthetic cartilage implant to treat arthritis in the joint of the big toe. [20] The implant is made of saline and a bio-compatible polymer, and is inserted through an incision between the metatarsophalangeal (MTP) joint where natural cartilage has worn away. [20] It is being researched for use in other joints. [20] A separate orthopedic implant consisting of a hydrated, interpenetrating dual polymer network based on polyether urethane (PEU) was given breakthrough device designation from the U.S. Food and Drug Administration in July 2021. [16]

In September 2021, researchers used nasal chondrocyte-based engineered cartilage to treat osteoarthritic joints in two patients. [21]

Cartilage transplants

In 2021, researchers from Swansea University partnered with the Scar Free Foundation to bioprint 3D transplantable cartilage made of human stem cells and plant-based materials to give a 10-year-old girl an ear transplant. [22] This method eliminated the need to retrieve cartilage from elsewhere on the patient's body. [22]

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 are 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. [23] 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. [12] In 2021, Marc C. Hochberg, head of the division of rheumatology and clinical immunology at the University of Maryland School of Medicine, said that the "holy grail" would be a compound that reduced cartilage degradation and/or restored normal cartilage while reducing pain. [24]

3D printing

In 2017, scientists from Chalmers University of Technology in Sweden demonstrated cartilage tissue engineering using 3D bioprinting. [25] They used two different bioinks with nanofibrillated cellulose (NFC) to conduct the tests: NFC with alginate (NFC/A) and hyaluronic acid (NFC/HA). [25] The bioinks were co-printed with irradiated human chondrocytes [8]. The team had success with NFC/A. [25]

In September 2021, researchers created cartilage repair implants utilizing a process of three-dimensional weaving to combine artificial materials with stem cells. [26] [27] The bioartificial implants are designed to partly dissolve over time, leaving only natural tissues in the repaired joints. [26] [27] As of October 2021, scientists have seen success in treating dogs but further research is required before the technique could move to clinical trials for humans. [28]

Also in September 2021, scientists from the Nakayama Lab at Saga University and Kyoto University in Japan fabricated 3D printed cartilage constructs from stem cells. [29]

Related Research Articles

<span class="mw-page-title-main">Cartilage</span> Resilient and smooth elastic tissue present in animals

Cartilage is a resilient and smooth type of connective tissue. It is a semi-transparent and non-porous type of tissue. It is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck and the bronchial tubes, and the intervertebral discs. In other taxa, such as chondrichthyans, but also in cyclostomes, it may constitute a much greater proportion of the skeleton. It is not as hard and rigid as bone, but it is much stiffer and much less flexible than muscle. The matrix of cartilage is made up of glycosaminoglycans, proteoglycans, collagen fibers and, sometimes, elastin. It usually grows quicker than bone.

<span class="mw-page-title-main">Tissue engineering</span> Biomedical engineering discipline

Tissue engineering is a biomedical engineering discipline that uses a combination of cells, engineering, materials methods, and suitable biochemical and physicochemical factors to restore, maintain, improve, or replace different types of biological tissues. Tissue engineering often involves the use of cells placed on tissue scaffolds in the formation of new viable tissue for a medical purpose, but is not limited to applications involving cells and tissue scaffolds. While it was once categorized as a sub-field of biomaterials, having grown in scope and importance, it can is considered as a field of its own.

<span class="mw-page-title-main">Hyaline cartilage</span> Type of cartilage in animals

Hyaline cartilage is the glass-like (hyaline) and translucent cartilage found on many joint surfaces. It is also most commonly found in the ribs, nose, larynx, and trachea. Hyaline cartilage is pearl-gray in color, with a firm consistency and has a considerable amount of collagen. It contains no nerves or blood vessels, and its structure is relatively simple.

<span class="mw-page-title-main">Chondrocyte</span> Cell that makes up cartilage

Chondrocytes are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word chondroblast is commonly used to describe an immature chondrocyte, the term is imprecise, since the progenitor of chondrocytes can differentiate into various cell types, including osteoblasts.

<span class="mw-page-title-main">Organ printing</span> Method of creating artificial organs

Organ printing utilizes techniques similar to conventional 3D printing where a computer model is fed into a printer that lays down successive layers of plastics or wax until a 3D object is produced. In the case of organ printing, the material being used by the printer is a biocompatible plastic. The biocompatible plastic forms a scaffold that acts as the skeleton for the organ that is being printed. As the plastic is being laid down, it is also seeded with human cells from the patient's organ that is being printed for. After printing, the organ is transferred to an incubation chamber to give the cells time to grow. After a sufficient amount of time, the organ is implanted into the patient.

<span class="mw-page-title-main">Chondrogenesis</span>

Chondrogenesis is the biological process through which cartilage tissue is formed and developed. This intricate and tightly regulated cellular differentiation pathway plays a crucial role in skeletal development, as cartilage serves as a fundamental component of the embryonic skeleton. The term "chondrogenesis" is derived from the Greek words "chondros," meaning cartilage, and "genesis," meaning origin or formation.

Articular cartilage, most notably that which is found in the knee joint, is generally characterized by very low friction, high wear resistance, and poor regenerative qualities. It is responsible for much of the compressive resistance and load bearing qualities of the knee joint and, without it, walking is painful to impossible. Osteoarthritis is a common condition of cartilage failure that can lead to limited range of motion, bone damage and invariably, pain. Due to a combination of acute stress and chronic fatigue, osteoarthritis directly manifests itself in a wearing away of the articular surface and, in extreme cases, bone can be exposed in the joint. Some additional examples of cartilage failure mechanisms include cellular matrix linkage rupture, chondrocyte protein synthesis inhibition, and chondrocyte apoptosis. There are several different repair options available for cartilage damage or failure.

A nerve guidance conduit is an artificial means of guiding axonal regrowth to facilitate nerve regeneration and is one of several clinical treatments for nerve injuries. When direct suturing of the two stumps of a severed nerve cannot be accomplished without tension, the standard clinical treatment for peripheral nerve injuries is autologous nerve grafting. Due to the limited availability of donor tissue and functional recovery in autologous nerve grafting, neural tissue engineering research has focused on the development of bioartificial nerve guidance conduits as an alternative treatment, especially for large defects. Similar techniques are also being explored for nerve repair in the spinal cord but nerve regeneration in the central nervous system poses a greater challenge because its axons do not regenerate appreciably in their native environment.

Articular cartilage repair treatment involves the repair of the surface of the articular joint's hyaline cartilage, though these solutions do not perfectly restore the articular cartilage. These treatments have been shown to have positive results for patients who have articular cartilage damage. They can provide some measure of pain relief, while slowing down the accumulation of damage, or delaying the need for joint replacement surgery.

Autologous chondrocyte implantation is a biomedical treatment that repairs damages in articular cartilage. ACI provides pain relief while at the same time slowing down the progression or considerably delaying partial or total joint replacement surgery.

Nano-scaffolding or nanoscaffolding is a medical process used to regrow tissue and bone, including limbs and organs. The nano-scaffold is a three-dimensional structure composed of polymer fibers very small that are scaled from a Nanometer scale. Developed by the American military, the medical technology uses a microscopic apparatus made of fine polymer fibers called a scaffold. Damaged cells grip to the scaffold and begin to rebuild missing bone and tissue through tiny holes in the scaffold. As tissue grows, the scaffold is absorbed into the body and disappears completely.

A fibrin scaffold is a network of protein that holds together and supports a variety of living tissues. It is produced naturally by the body after injury, but also can be engineered as a tissue substitute to speed healing. The scaffold consists of naturally occurring biomaterials composed of a cross-linked fibrin network and has a broad use in biomedical applications.

Acellular dermis is a type of biomaterial derived from processing human or animal tissues to remove cells and retain portions of the extracellular matrix (ECM). These materials are typically cell-free, distinguishing them from classical allografts and xenografts, can be integrated or incorporated into the body, and have been FDA approved for human use for more than 10 years in a wide range of clinical indications.

The Network of Excellence for Functional Biomaterials (NFB) is a multidisciplinary research centre which hosts over sixty biologists, chemists, scientists, engineers and clinicians. It is based at the National University of Ireland, Galway, and is directed by Professor Abhay Pandit.

The in vivo bioreactor is a tissue engineering paradigm that uses bioreactor methodology to grow neotissue in vivo that augments or replaces malfunctioning native tissue. Tissue engineering principles are used to construct a confined, artificial bioreactor space in vivo that hosts a tissue scaffold and key biomolecules necessary for neotissue growth. Said space often requires inoculation with pluripotent or specific stem cells to encourage initial growth, and access to a blood source. A blood source allows for recruitment of stem cells from the body alongside nutrient delivery for continual growth. This delivery of cells and nutrients to the bioreactor eventually results in the formation of a neotissue product. 

Alpha collagen is specifically designed to deliver specific ratios of α- chain peptides as building blocks. The targeted cells can process the α- chain peptides to form triple helix collagen, and replenish the collagen in the targeted site. Scientists believe that Alpha collagen can help to deliver specific ratios of peptides to benefit the targeted cells.

Hydrogels are three-dimensional networks consisting of chemically or physically cross-linked hydrophilic polymers. The insoluble hydrophilic structures absorb polar wound exudates and allow oxygen diffusion at the wound bed to accelerate healing. Hydrogel dressings can be designed to prevent bacterial infection, retain moisture, promote optimum adhesion to tissues, and satisfy the basic requirements of biocompatibility. Hydrogel dressings can also be designed to respond to changes in the microenvironment at the wound bed. Hydrogel dressings should promote an appropriate microenvironment for angiogenesis, recruitment of fibroblasts, and cellular proliferation.

Bio-inks are materials used to produce engineered/artificial live tissue using 3D printing. These inks are mostly composed of the cells that are being used, but are often used in tandem with additional materials that envelope the cells. The combination of cells and usually biopolymer gels are defined as a bio-ink. They must meet certain characteristics, including such as rheological, mechanical, biofunctional and biocompatibility properties, among others. Using bio-inks provides a high reproducibility and precise control over the fabricated constructs in an automated manner. These inks are considered as one of the most advanced tools for tissue engineering and regenerative medicine (TERM).

Nasal chondrocytes (NC) are present in the hyaline cartilage of the nasal septum and in fact are the only cell type within the tissue. Similar to chondrocytes present in articular cartilage, NC express extracellular matrix proteins such as glycosaminoglycans and collagen.

Farshid Guilak is an American engineer and orthopedic researcher. He is the Mildred B. Simon Professor of Orthopaedic Surgery at Washington University in St. Louis and director of research at Shriners Hospitals for Children. He is also on the faculty of the departments of Biomedical Engineering, Mechanical Engineering & Materials Science, and Developmental Biology at Washington University.

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