Stem Cells and Cartilage

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JB Richardson, JTK Lim, JHP Hui and EH Lee* Introduction

As far back as 1743, William Hunter observed that cartilage, "once destroyed, is not repaired."1 This lack of healing leaves bone exposed in the joint and is a cause of pain. Can stem cell engineering bring a solution?

Osteoarthitis contributes the largest burden to healthcare in the developed world. The extent and involvement of a single cartilage lesion in the development of arthritis is not known. However, in experimental studies, incongruity and articular step-off lead to degenerative changes in the cartilage and subchondral bone that mimic the appearance of arthritis.2 In the clinical setting, the progression of chondral injuries to arthritis is not validated by large prospective studies but rather by anecdotal evidence and smaller studies. One such study is the observation of radiographic evidence of arthritis within 14 years in greater than 50% of patients who sustained a unipolar, unicompartmental injury as adolescents.3

The goal of treating arthritis is to abolish symptoms and restore function. One of the most successful surgical treatments known is artificial joint replacement. Unfortunately, all joint replacements eventually fail if the patient lives long enough. Tissue engineering offers the potential of recreating a "biological joint replacement" which may last a lifetime.

At present, in cartilage repair or regeneration techniques, there are no long term clinical studies as yet. An alternative is to assess how closely the histology or mechanics of a repair tissue resembles normal tissue. The assumption is made that if the normal structure is replicated, then symptom-free joint function can be expected. In the case of cartilage repair it is not merely hyaline cartilage that is the goal but articular cartilage.

* Correspondence: Division of Graduate Medical Studies, Faculty of Medicine, Block MD 5, Level 3, 12 Medical Drive, Singapore 117598. E-mail: [email protected], Tel.: 65 68746576, Fax: 65 6773 1462.

Defining this end-point has involved a lot of hard work by the scientists of the International Cartilage Repair Society.4

Articular cartilage is principally composed of type II collagen, proteogly-cans, and chondrocytes forming a complex, partially hydrated, compressed matrix structure. It is anisotropic and typically composed of four layers, each with different orientations of collagen fibers, varying cell morphology, and varying matrix composition and function (Fig. 1). Articular cartilage is a highly adapted structure that provides resistance against compression and shear, and allows frictionless joint movement, shock absorption and lubrication. It has no pain fibers or blood vessels. Metabolism is anerobic and glucose reaches the cells by diffusion both from the joint surface and

Figure 1. H & E stained section of normal adult articular cartilage showing various zones. (Photomicrograph courtesy of S. Roberts, Oswestry, UK.)

the underlying bone. Even fibrocartilage will stain well for collagen type II, but on polarized light, has clearly no collagen orientation. It appears to give good symptomatic relief in patients if all bone is covered. Hyaline is a term that denotes a glass-like appearance and so is not well defined. Hyaline-like cartilage is a term that has been introduced in cartilage repair5 to denote cartilage that is better than fibrocartilage but not fully normal articular cartilage. An important aspect of histology is that in the normal adult joint, there is variation in the quality of cartilage from one area to another in the same joint.

Fibrous tissue is principally type I collagen and contains vessels and nerves. It does not function well as an articular surface. Success in a repair technique may be usefully measured based on the absence of repair by fibrous tissue.

The best hope for quantification of cartilage repair is in combining absolute measurements of collagen types I and II as well as of proteoglycan with assessments of collagen orientation, integration to bone and to adjacent cartilage and overall thickness. The ability to measure collagen quantity has now been reported on biopsies by Hollander.6

Cartilage does not heal if incised or if a partial thickness of the cartilage is removed. It will, however, heal once it is worn down to bone7 when stem cells are released from the underlyingbone. A good repair response will then produce healing by fibrocartilage. This is not true regeneration of hyaline cartilage but a repair process similar to the formation of scar without blood vessels. The collagens formed are the type II, but under polarized light, the bright effect seen in hyaline cartilage due to the orientation of collagen fibres is not evident.

A useful source of clinical data on this question is to be found in trials of osteotomy at the knee.8 Generally, a third of patients will need total knee replacement within 5 years following osteotomy. Efforts to improve the outcome by adding microfracture or abrasion have found an improvement in histology with a higher proportion of fibrocartilage forming where there was bone-on-bone before.9-12 This tissue has formed where there will still be significant amounts of load applied while the surface heals. The ability to form new tissue under load is important as this opens the way for tissue engineering techniques that depend on tissue growth in the active patient.

The following section provides a review of experimental studies as well as currently available methods of tissue repair, including the use of stem cells.

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