Cartilage

• 1. Introduction

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  Cartilage holds tubes open inside your body. The rings of the trachea, the cricoid cartilage, the carina at the branching of the airways. None of these structures could stay open without it. Cartilage is a resilient and smooth type of connective tissue, semi-transparent and non-porous, usually wrapped in a tough fibrous membrane called the perichondrium. It is not as hard as bone, yet much stiffer and far less flexible than muscle or tendon. In tetrapods it caps the ends of long bones at the joints, and forms part of the rib cage, the neck, the bronchial tubes, and the intervertebral discs. In some animals it does far more than that. So what is this material actually made of, why does it almost never heal, and why do sharks build an entire skeleton from it? The answers begin with a single kind of cell trapped in its own matrix.

• 2. A Tissue Without Vessels

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  Specialized cells called chondrocytes do all the manufacturing in cartilage. They produce a large amount of collagenous extracellular matrix, plus an abundant ground substance rich in proteoglycan and elastin fibers. The matrix itself is built from glycosaminoglycans, proteoglycans, collagen fibers and sometimes elastin. Because the relative amounts of collagen and proteoglycan vary, the tissue is classified into three types: elastic cartilage, hyaline cartilage, and fibrocartilage. Cartilage contains no blood vessels and no nerves, which makes it insensitive to pain. Nutrition reaches the chondrocytes only by diffusion, a slow trickle through the matrix rather than delivery by blood. Movement helps that trickle along. Compressing the articular cartilage or flexing the elastic cartilage generates fluid flow, and that flow assists the diffusion of nutrients to the cells. A few exceptions exist, such as the meniscus of the knee, a fibrocartilage with partial blood supply. Compared to other connective tissues, cartilage turns over its extracellular matrix very slowly. It is documented to repair at only a very slow rate relative to other tissues, a limitation that will return with consequences.

• 3. From Mesoderm To Maturity

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  In embryogenesis, the skeletal system is derived from the mesoderm germ layer. The process called chondrification, also known as chondrogenesis, builds cartilage from condensed mesenchyme tissue. That tissue differentiates into chondroblasts, which begin secreting the molecules that form the extracellular matrix, namely aggrecan and collagen type II. In all vertebrates, cartilage is the main skeletal tissue in the early stages of life. In osteichthyans, many cartilaginous elements later ossify through endochondral and perichondral ossification, trading cartilage for bone. After that initial chondrification, growth is mostly a matter of immature cartilage maturing toward a more mature state. Cell division inside cartilage happens very slowly, so growth usually does not come from an increase in the size or mass of the cartilage itself. Researchers have identified non-coding RNAs, such as miRNAs and long non-coding RNAs, as the most important epigenetic modulators that can affect chondrogenesis. The same molecules help explain how non-coding RNAs contribute to cartilage-dependent conditions like arthritis.

• 4. Engineering Of A Joint Surface

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  Aggrecan is the main proteoglycan in cartilage, and its name hints at what it does. It forms large aggregates with hyaluronan and with itself, aggregates that carry a negative charge and hold water inside the tissue. The collagen, mostly collagen type II, constrains those proteoglycans and keeps the structure intact. The whole extracellular matrix responds to the tensile and compressive forces a joint experiences. Stress shapes thickness. Because of the great stress on the patellofemoral joint during resisted knee extension, the articular cartilage of the patella is among the thickest in the human body. Up close, the matrix of articular cartilage divides into three regions: the pericellular matrix, the territorial matrix, and the interterritorial matrix. These layers set the stage for how cartilage behaves under load, the property scientists have measured most intensely.

• 5. Measuring The Resilience

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  Viscoelastic is the word for how cartilage behaves under load, and it makes the material genuinely difficult to test. The tissue carries free-moving interstitial fluid, so engineers turn to a confined compression test to pin its properties down. In that test, a disc of cartilage sits in an impervious, fluid-filled container, covered by a porous plate that forces interstitial fluid to flow only vertically. Run in creep mode, the test measures tissue displacement over time under constant load. Run in relaxation mode, it measures force over time under constant displacement. The deformation shows two regions: a rapid first phase as fluid flows out, then a slow second phase that drifts toward an equilibrium value. Under common loading conditions, reaching that equilibrium can take hours. The numbers describe a specific kind of stiffness. The aggregate modulus of articular cartilage typically falls in the range of 0.5 to 0.9 MPa, and its Young's modulus typically falls between 0.45 and 0.80 MPa. The same test measures permeability, the resistance to fluid flow through the material, typically in the range of 10 to the power -15 to 10 to the power -16 m^4/Ns. Permeability is not uniform. It tends to be highest near the joint surface and lowest near the bone, in the so-called deep zone, and it decreases under increased loading. Indentation testing offers another route, using an indentor usually smaller than 0.8 mm to measure displacement under constant load. For a long time, scientists assumed cartilage was so water-based that its Poisson's ratio was 0.5 and the material was incompressible. Later research disproved that belief. Measured Poisson's ratio is around 0.4 or lower in humans, and ranges from 0.46 to 0.5 in bovine subjects.

• 6. The Gradient To Bone

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  Twenty gigapascals separate bone from soft cartilage, and that gap is a structural problem. The elastic modulus of human bone is roughly 20 GPa, while the softer regions of cartilage sit around 0.5 to 0.9 MPa. Wherever materials with mismatched properties meet, stress concentrates, and over the millions of loading cycles a human joint endures across a lifetime, such interfaces would eventually fail. The body avoids this by building a smooth gradient instead of an abrupt seam. Stiffer, higher-modulus layers near bone hold high concentrations of mineral deposits such as hydroxyapatite. Collagen fibers anchor directly to the bone there, reducing how much the tissue can deform. Moving toward softer tissue, into a region called the tidemark, the density of chondrocytes rises and the collagen fibers rearrange to dissipate stress and lower friction. The outermost layer at the joint surface, the superficial zone, works mainly as a lubrication region. Its dense extracellular matrix is rich in proteoglycans that dispel and reabsorb water to soften impacts, and its thin collagen lies parallel to the surface for excellent shear resistance. Aging attacks this gradient. The earliest changes often appear in the superficial zone, the softest and most lubricating layer, and its degradation loads deeper layers never built to take that strain. Aging also increases the crosslinking of collagen fibers, stiffening the cartilage and making it more prone to fatigue-based failure, while calcified regions accumulate more mineral deposits with the same stiffening effect. The lubrication itself depends on lubricin, a glycoprotein abundant in cartilage and synovial fluid that protects against wear.

• 7. Why It Will Not Heal

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  Chondrocytes are bound in lacunae, tiny chambers in the matrix, and that imprisonment is the heart of the problem. Because they cannot migrate to damaged areas, cartilage damage is difficult to heal. Hyaline cartilage has no blood supply, so the deposition of new matrix stays slow. Complete healing after injury or repair is further hindered by cartilage-specific inflammation, driven by M1 and M2 macrophages, mast cells, and the interactions between them. Surgeons and scientists have responded with a series of cartilage repair procedures meant to postpone the need for joint replacement. A torn meniscus of the knee, for instance, can often be surgically trimmed to reduce problems. Biological engineering aims higher, growing artificial cartilage on a cellular scaffolding material seeded with cultured cells. Freeze-thawed PVA hydrogels have drawn extensive research as a base material. These gels show promise in biocompatibility, wear resistance, shock absorption, friction coefficient, flexibility, and lubrication, and are considered superior to polyethylene-based cartilages. In one trial, PVA hydrogels implanted as an artificial meniscus in rabbits stayed intact for two years, with no degradation, fracture, or loss of properties. One quirk of cartilage makes such transplants unusually forgiving. Its matrix acts as a barrier that blocks lymphocytes and the diffusion of immunoglobulins, allowing cartilage to be transplanted from one individual to another without fear of tissue rejection.

• 8. When The Tissue Fails

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  Bone against bone is the endpoint of osteoarthritis, a disease of the whole joint in which the articular cartilage suffers most. That cartilage thins and eventually wears away entirely, leaving reduced motion and pain. Because it strikes joints under high stress, osteoarthritis is often considered the result of wear and tear rather than a true disease. Treatment is arthroplasty, replacement of the joint with a synthetic one, often built from a stainless steel alloy called cobalt chromoly and ultra-high-molecular-weight polyethylene. Chondroitin sulfate and glucosamine sulfate supplements have been claimed to ease symptoms, but there is little good evidence to support that claim. Inside the diseased tissue, inflammatory cytokines and chemokines push differentiated chondrocytes into excess catabolic activity, mediated by matrix metalloproteinases and aggrecanases. Other disorders take their own forms. Chondrodystrophies disturb the growth and ossification of cartilage. Achondroplasia, a reduced proliferation of chondrocytes in the epiphyseal plate of long bones during infancy and childhood, results in dwarfism. Costochondritis inflames the cartilage in the ribs and causes chest pain. A spinal disc herniation occurs when asymmetrical compression ruptures an intervertebral disc, and the soft hernia presses on adjacent nerves to cause back pain. Relapsing polychondritis, probably autoimmune, destroys cartilage especially in the nose and ears, and can kill by asphyxiation when the larynx loses rigidity and collapses. Cartilage can also turn tumorous: benign growths are called chondroma, malignant ones chondrosarcoma. Seeing any of this is its own challenge, since cartilage does not absorb X-rays under normal conditions. To image it, a dye injected into the synovial membrane absorbs the X-rays, and the void it leaves between bone and meniscus reveals the cartilage.

  Sharks, rays and chimaeras carry a skeleton composed entirely of cartilage. These cartilaginous fish, the Chondrichthyes, show how dominant the tissue can become when it never gives way to bone. Far from the vertebrate line, cartilage turns up in animals most people would never associate with it. It appears in some arthropods such as horseshoe crabs, some mollusks such as marine snails and cephalopods, and some annelids like the sabellid polychaetes. The horseshoe crab Limulus polyphemus carries the most studied arthropod cartilage. Its branchial cartilage is a vesicular, cell-rich tissue built from large, spherical, vacuolated chondrocytes with no homologies in other arthropods. Limulus also has an endosternite cartilage, a fibrous-hyaline tissue whose mucopolysaccharides react with chondroitin sulfate antibodies, and its embryos express ColA and hyaluronan, marking these as fibrillar-collagen-based cartilage. Among mollusks, the cephalopods Octopus vulgaris and Sepia officinalis serve as models, and the cephalopod cranial cartilage most resembles vertebrate hyaline cartilage. In gastropods, attention falls on the odontophore, a cartilaginous structure that supports the radula, studied most in Busycotypus canaliculatus and built from vacuolated cells containing myoglobin. The sabellid polychaetes, the feather duster worms, support their tentacles with cartilage that holds two distinct matrix regions. A cartilage-like matrix, acellular and high in collagen, surrounds an osteoid-like matrix with a highly cellularized core that lacks collagen, studied in Potamilla species and Myxicola infundibulum. One last note guards against confusion. Vascular plants, particularly seeds, and the stems of some mushrooms are sometimes called cartilaginous, though they contain no cartilage at all.