Progress in Cartilage Engineering Over the Past Four Years

Here I'll point you to a recent open access review paper on the use of adult stem cells in the production of cartilage tissue. Cartilage regenerates poorly, and wear and tear in the load-bearing cartilage of joints over the course of aging is the cause of considerable disability and suffering. Any cartilage injuries accumulated along the way only make things worse.

Cartilage is a highly structured tissue, in which the precise arrangement of cells and extracellular matrix molecules provides the mechanical properties necessary to its function. This was perhaps less appreciated than it should have been, at least until researchers started trying in earnest to grow cartilage from stem cells. The complex molecular structure of cartilage has made it a real challenge to engineer this tissue, and only very recently have researchers made inroads into getting the structure right, such as through the mesenchymal condensation technique. Even so production of all of the varied types of cartilage tissue - elastic, hyaline, and fibrocartilage - is yet to be reliably accomplished. It is worth noting that, all this aside, cartilage is one of the "easy" tissues to engineer, being comparatively uniform and lacking in blood vessel networks. Forming and integrating blood vessels is one of the big challenges in building tissues of any significant size, and there is still no good, robust solution to that problem. Until researchers can manage cartilage, muscle, skin, and the like, it is premature to expect much more complex internal organs to be reliably grown from a patient's cells alone.

That said, the process of decellularization will soon allow patient-matched organs to be reliably created from donor organs, and probably even using organs from other species such as pigs. This approach to tissue engineering makes use of the extracellular matrix of the donor organ, stripped of its cells, to guide the patient's cells to reform an organ in the correct fashion. While it is possible to produce a functional organ this way, and this has been demonstrated for a few organs in mice and rats, the research community is still a long way away from being able to fabricate such a matrix or guide its creation by cells. Ultimately we wish to see organ engineering decoupled from the need for donors, which is why decellularization is only a stepping stone to later goals.

Looking back in the Fight Aging! archives, I noticed a very similar review from late 2011 that covers much the same ground as the paper linked below. Four years isn't all that much time in medical research, so the two reviews are much the same in content at a high level. One noteworthy difference is that the number of ongoing, official, by-the-regulations clinical trials for regrowth or regeneration of cartilage has grown considerably in the past few years. But take a look and see what you think; it is clear that this is a field still in the comparatively early stages of developing a practical technology platform for regenerative treatments.

Use of Adult Stem Cells for Cartilage Tissue Engineering: Current Status and Future Developments

Although initially considered as a tissue with a simple structure, reproducing the finely balanced structural interactions of cartilage has proven to be difficult. Articular cartilage is a stable tissue that functions for decades to keep normal joint movement possible. It is a hyaline tissue with no blood, lymphatic or nerve supply. It contains a single type of cells, called chondrocytes, maintained in an abundant connective tissue. This extracellular matrix is composed of collagen fibers, mainly type II collagen, and proteoglycan aggregates, mainly aggrecan, attached along a filament of hyaluronic acid. Collagens provide tensile strength, while proteoglycans are responsible for the compressive strength. The whole forms a viscoelastic structure well suited for both functions of cartilage: the absorption and distribution of forces and the sliding of the joint surfaces with a very low coefficient of friction.

During life, articular cartilage defects may happen and form areas of damaged or missing cartilage. These defects are often caused by acute trauma. Biochemical changes due to age may also stimulate the degradation of cartilage matrix and at term lead to chronic diseases such as osteoarthritis. These defects are the most often irreversible, since articular cartilage has very limited self-repair capability. Cartilage is an attractive candidate for use in tissue-engineering therapies since this tissue is avascular and has a limited capacity for repair.

The use of autologous chondrocyte implantation may represent a promising technology for cartilage repair in orthopedic research. However, we and other investigators have established that, during monolayer expansion of chondrocytes in vitro, this cell population loses its phenotype, as illustrated by a switch in collagen production from type II (typical of hyaline cartilage) toward types I and III (typical of fibrocartilage). The result of these phenotype changes is the production of an extracellular matrix with inferior biomechanical properties. In addition, the limited capacity of the donor site to provide a large amount of chondrocytes, as well as donor site morbidity, are major obstacles for autologous chondrocytes. Therefore, use of stem cells, such as mesenchymal stem cells (MSCs), may be preferred. MSCs can be relatively easily harvested and the procedures using them are less invasive or destructive than articular cartilage harvesting procedures.

Growth factors are essential to induce chondrogenic differentiation of adult stem cells. However, to promote/maintain cartilage differentiation/phenotype in culture, another critical requirement is to provide a 3D microenvironment. Indeed, research has demonstrated that MSCs hardly differentiate into cartilage cell lineage in a 2D culture system. For applications of cartilage tissue replacement, most investigators preferred transplantation of cells combined with scaffold. So, a huge expansion in biomaterial technologies and scaffolds took place to create functional tissue replacement to treat cartilage defects or osteoarthritis. Numerous biomaterials and scaffolds are being developed, influenced by the knowledge of the anatomical and structural complexity of articular cartilage.

Many clinical trials have been registered at regarding application of stem cells for regenerating cartilage. About 40 studies (phase 1 to 3) are in progress or are completed worldwide. Most of them aim to repair cartilage defects or treat degenerative damage, in knee, ankle, or hip, due to osteoarthritis. Some preliminary results have been published and are promising. In spite of the above-mentioned potential, there are some pitfalls associated with MSC application for articular cartilage regeneration. One is the qualities and mechanic properties of neoformed cartilage, and the second is the fabrication of anatomically relevant 3D engineered tissue and its integration into surrounding native joint tissues.


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