1. Articular cartilage: injury, healing, and regeneration
Sharifi, Ali Mohammad PhD; Moshiri, Ali DVM, DVSc (PhD); Oryan, Ahmad DVM, PhD
Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
Current Orthopaedic Practice
Volume 27(5) pgs September/October 2016

2. INTRODUCTION
Damaged articular cartilage has a poor healing response, and despite innovations in treatment strategy, defects larger than 2-4 mm rarely heal.
Conservative treatment options, such as continuous passive motion, electrical stimulation, laser, and pharmacological agents, aim to enhance cartilage healing.
A variety of surgical treatments have been described and include joint debridement and drilling, microfracture, mosaicplasty, bone marrow stimulation, spongialization, osteotomy, chondrocyte implantation, perichondrial grafting, periosteal grafting, and carbon fiber implants.

3. None are really a complete solution as most are palliative rather than curative and the joint may deteriorate so that total joint arthroplasty remains the only option.
It must be noted that total joint arthroplasty has a higher rate of failure in patients younger than 40 yr or between 40 and 60 yr compared with elderly patients.
Tissue engineering and regenerative medicine (TERM) is a relatively new concept by comparison in the treatment of articular cartilage damage.
By simulating the native tissue environment and regulating the healing process it attempts to regenerate new hyaline cartilage.
The basic concepts regarding cartilage structure and function, injury, healing, and regeneration are discussed in this review as well as the current options and limitations in treating cartilage injuries.

4. STRUCTURE AND FUNCTION OF ARTICULAR CARTILAGE
Articular cartilage is composed of chondrocytes that produce a large amount of extracellular matrix (ECM) which consist of collagen fibers, a considerable amount of ground substance rich in proteoglycan (PG), and elastic fibers.
The collagens (types II and IX) provide tensile strength, assist chondrocytes in attaching to ECM (type VI), contribute to structural support, aid cartilage mineralization, and have a role in nucelate fibril formation.

5. CARTILAGE INJURIES
Osteoarthritis (OA) develops as a result of “wear and tear”.
Traumatic articular cartilage injuries, such as rupture or detachment, can occur from direct mechanical trauma.
Osteochondritis dissecans, which is caused by blood deprivation in the subchondral bone that leads to avascular necrosis and bone resorption.
Cracks may form in the articular cartilage and subchondral bone, resulting in fragmentation of both cartilage and bone, and free movement of these osteochondral fragments within the joint space cause pain and further damage.
Tumors made up of cartilage tissue, either benign (chondroma) or malignant (chondrosarcoma) also may occur.

6. HEALING PROCESS OF ARTICULAR CARTILAGE
The activation of chondrocytes modulates gene expression, resulting in different patterns of protein synthesis, fibroblast dedifferentiation, hypertrophy, or regeneration of mature cartilage.
Injured cartilage heals slowly by scar tissue formation mainly composed of fibrocartilage, which is significantly inferior in its mechanical properties and naturally degrades.
If the injury extends down to the subchondral bone, self-healing processes are initiated by the release of mesenchymal progenitor cells from bone marrow (BM) and periosteum into the defect
Cartilage healing can be accelerated by surgical intervention particularly marrow stimulation techniques

7. DETERMINANT FACTORS IN CARTILAGE HEALING
In a study on horses, it was shown that defects greater than 3 mm in diameter led to complete repair after 9 mo, while larger defects did not repair completely.
The repair response of articular cartilage depends on the extent of injury.
Defects less than 1 cm2 in diameter are less likely to affect stress distribution on the subchondral bone and probably will not enlarge.
Aging reduces cartilage hydration and decreases mitotic and synthetic activities as well as the number of chondrocytes. The depth of injury is age-related.

8. CURRENT OPTIONS IN MANAGING CARTILAGE DEFECTS Conservative Treatment
continuous passive motion (CPM) enhances cartilage healing, the effect is much less obvious in defects greater than 3 mm .
The efficacy of CPM on regeneration of cartilage after periosteal transplantation has been confirmed.
Electrical stimulation (ES) for cartilage-healing has not received as much attention as for fracture-healing that ES improved healing.
Laser therapy may be another option.(no beneficial effect on cartilage-healing with low doses of neodymium doped)
Drugs that might enhance cartilage healing can be administered systemically, intraarticularly, or locally.
corticosteroids impair the physiology of normal cartilage and induce arthropathy.
Hyaluronic acid has been widely used in several countries. It is a lubricant and has a direct biochemical effect. Hyaluronic acid binds to and penetrates damaged articular cartilage, potentially providing a protective coating .

9. Surgical Treatment
Carbon fiber implants (CFI) have been used to treat articular cartilage defects.
Bone marrow stimulation is appropriate for full-thickness chondral defects with exposed subchondral bone.
Penetration of the subchondral bone plate disrupts the subchondral blood vessels, leading to the formation of a fibrin clot on the surface of a chondral defect.
Small subchondral drill holes improved the osteochondral repair more effectively than larger holes.
Joint debridement, which may include articular trimming, meniscectomy, removal of osteophytes or loose bodies, articular abrasions, and even synovectomy, is another option for treatment.

10. Spongialization is a modification of debridement and drilling, being more radical and involving excision of damaged cartilage along with the involved subchondral bone.
Mosaicplasty is another option. Cylindrical osteochondral plugs are harvested from low-weight-bearing areas within the joint.
The gaps between the plugs are filled with fibrocartilage derived from the debrided base of the chondral defect, providing secondary stability to the plugs.
Autologous strips of perichondrium can be used to treat chondral defects, with fibrin glue acting as an adhesive.
Osteotomy is usually a valuable option for early unicompartmental OA because it redistributes the joint load and avoids contact pressure loads on the cartilage surface
In autologous chondrocyte implantation (ACI), a small cartilage segment is harvested from a low weight-bearing area of the joint.

11. Polytherapy
Combining scaffolds, HPFs, and SCs may be a valuable strategy in overcoming the limitations of cartilage healing. The implantation of a gelatin [beta]-TCP sponge loaded with MSCs, BMP-2, and PRP into an experimentally induced osteochondral defect increased subchondral bone and hyaline cartilage density in an equine model.
In designing a desired scaffold, the architecture and type of the selected biomaterials are important.
Each scaffold should be porous with appropriate interconnectivity between the pores, the size of which should be adequate (between µm in diameter).
These characteristics allow regional MSCs to migrate, proliferate, and produce a new matrix inside the scaffold.

12. HEALING PROCESS OF ARTICULAR CARTILAGE
Healing Promotive Factors
HPF can be embedded in articular cartilage scaffolds to be released controllably from the scaffold during particular stages of articular cartilage regeneration with the goal of enhancing biocompatibility and to accelerate and increase the quality of the repaired tissue.

13. Platelet Rich Plasma ( PRP )
Platelets are a simple, cost-effective, and practical source of The most common form of platelets is platelet rich plasma (PRP).
PRP can be produced by one- or two-step centrifugation, resulting in the presence or absence of white blood cells within the solution.
Adding coagulating factors to produce an implantable platelet gel has greater healing potential than a PRP solution, giving platelets a longer life in the body, with prolonged release of GFs from the platelet gel.

14. TISSUE ENGINEERING AND REGENERATIVE MEDICINE
TERM is a newer approach than the classic options described above.
As with other treatments, TERM aims to (1) relieve pain, (2) be a temporary tissue filler to enhance cartilage function, and (3) induce, control, accelerate, and enhance healing to produce a neocartilage with similar structure and function as the original cartilage matrix.
TERM can be divided into four major categories including (1) scaffolds, (2) healing promotive factors (HPFs), (3) stem cells (SCs), and (4) genetic engineering

15. STEM CELLS AND GENE THERAPY
Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) are immortal and pluripotent but require extensive manipulation prior to obtaining chondrogenic cells.
Multipotent adult MSCs have been extensively investigated for cartilage regeneration.
Almost all of the in vivo research performed recently used MSCs for treating the osteochondral defects, showing its beneficial role on cartilage regeneration, regardless of the scaffolds on which the they were seeded.

16. CONCLUSION
Healing of articular cartilage defects is a complicated process and treatment is a state of art.
Despite extensive research, no world-wide accepted method for managing cartilage injuries exists.
Current options include bone marrow stimulation and debridement techniques or management of the injuries with autograft and ACI, resulting in fibrocartilage formation, with favorable short to mid-term outcomes, but disappointing long-term results.
TERM approaches use scaffolds, HPFs and SCs to overcome current limitations.

17. CONCLUSION
Three-dimensional printing, genetic engineering, and scaffold-free strategies together with other technologies are being developed.
It is hoped that a combination of the current options with the TERM approaches would be able to overcome limitations of each strategy and be a proper solution for managing the cartilage injuries.

18. REFERENCES
Ahmed TA, Hincke MT. Strategies for articular cartilage lesion repair and functional restoration. Tissue Eng Part B Rev. 2010; 16:305–329
Baker B, Spadaro J, Marino A, et al.. Electrical stimulation of articular cartilage regeneration. Ann N Y Acad Sci. 1974; 238:491–499