Osteoarthritis is a condition that affects many millions of persons throughout the world. Previously, there has been no effective treatment that specifically targets the chondral lesion associated with the condition and promotes the in situ regeneration of cartilage at that site.
This disease consists of the gradual degeneration and destruction of the articular cartilage due to traumas, structural deformities of the joints, and overweight. This process thins the cartilage through a phenomenon called apoptosis, or programed cell death. When the surface area has disappeared due to the thinning, it is considered grade I osteoarthritis; when the tangential surface area has also disappeared, it is characterized as grade II osteoarthritis. There are other levels of degeneration and destruction, which affect the deep and the calcified layers that border with the subchondral bone.
The clinical manifestations of the development of the condition are: swelling of the joint, pain, crepitation and functional disability that, gradually and steadily, hinders physical mobility, e.g. the taking of lengthy walks and, depending on the affected joint, forced flexion and extension movements. As the condition worsens, pain begins to limit even minimum efforts and can persist at rest making it difficult to sleep. If the condition persists without correction and/or therapy, the joint is totally destroyed, leading the patient to major replacement surgery with total prosthesis, or to disability.
Therapeutic methods for the correction of the articular cartilage lesions that appear during the osteoarthritic disease have been developed, but so far none of them have been able to achieve the regeneration of articular cartilage in situ and in vivo.
The prior art methods include the following:
a) The application of tendinous, periosteal, fascial, muscular or perichondral grafts.
b) The implantation of fibrin or cultured chondrocytes (Osteochondral Grafts Improve Symptoms but May Increase Risk. Of Ostteoarthritis, medscape.com/con/2000/AAOS/story.cfm).
c) The administration of chondrogenic stimulating factors such as “insulin-like growth factors I and TGF-B”.
d) Implantation of synthetic matrices, such as collagen and carbon fiber.
e) Others, such as electromagnetic fields. (J. Buckwalter, M.D., Van C. Mow, Ph. D. and Anthony Ratcliffe, Ph.D. Journal of the American Academy of Orthopaedic Surgery 1994; 2:192-202). All of these have reported minimal and incomplete results with formation of repair, but not regenerative tissue, resulting in a poor quality tissue that can neither support the weighted load nor allow the restoration of an articular function with normal movement.
One treatment that has 74% to 90% effectiveness and produces excellent results, similar to that presented in this invention, is the transplantation of cultured autologous chondrocytes. This method of treatment was first reported in 1987 in Sweden and was introduced in 1995 to the United States of America. It consists of taking chondral cellular material from the patient, sending it to a laboratory where it is seeded in a proper medium for its proliferation, and then, once enough volume is achieved (a variable period that may last from weeks to months), transporting it in a special container, and finally implanting it in the damaged tissues to cover their defects. This is an expensive procedure that requires the patient to be in the operating room for the removal of the necessary cellular material, and subsequently for the implantation of the proliferated material. Furthermore, a significant waiting period is needed for the implant to be ready (VLADIMIR, Bobic, MD AAOS Annual Meeting, Mar. 16, 2000.)
Other, more conventional treatments include antiinflamatories, antirheumatics, systemics, physiotherapy, injection of depot steroids and, recently, viscoprotection has emerged.
Viscoprotection involves the intraarticular application of commercially available sodium hyaluronate viscoelastic materials such as HYLAN G-F 20, SYNVISC, HYALGAN, ARTZ, etc. The sodium hyaluronate substance does affect the rheology of the synovial fluid, producing an almost immediate sensation of free movement and a marked reduction of pain. It has been proven that the change of the intraarticular fluids attendant to sodium hyaluronate instillation produces a blockage of the nociceptors of subsynovial and capsular tissues and that, in addition to the mechanical factors of the osteochondral pathology, the fluids influence these receptors with their lubricating properties. Thus the change in viscosity of these fluids acts favorably on the painful osteochondral symptoms when sodium hyaluronate is instilled. However, the effect of conventional hyaluronate is temporary because the material remains within the articular chamber for only about 72 hours before it is absorbed and/or metabolized. The residual effects of this substance act on the synovial receptors causing a pain reduction that lasts several weeks and even months. However, this isolated effect is counterproductive for the course of the disease and for the viability of the cartilage because, as it masks the symptoms, the joint is used with more intensity and its destruction is accelerated as the original problem is not corrected and the damaged articular cartilage is not restored. Recent studies with a 5 year follow-up with these substances indicate that clinical improvement is significant and that is represents a remission factor of painful symptoms, but only for short and medium term. Also, adverse effects, characterized by severe pain, significant synovial effusion, rash and ankle edema, have been reported in at least 7.2% of the treated patients. In no instance has hyaluronate therapy been reported to effect cartilage regeneration and long term success. The need exists, therefore, for an improved approach to cartilage regeneration.
As an antecedent to this invention, in 1982, the applicant began applying sodium hyaluronate (SH) to thoroughbred race horses at Hipódromo de las Américas (Las Américas Race Track), in Mexico City, Mexico. The knees and ankles are the most commonly injured joints in these horses. Veterinarians at racetracks in the USA had already used this procedure, observing the beneficial reaction that this viscoelastic material produced in the injured knees of the horses. The applicant considered its use in humans, and conceived of adding some substance to cause the restoration of the damaged surface of the cartilage.
The applicant hypothesized that chondroitin sulfate (CS), the most important part of the aggrecan proteglycans which are the basis of chondral support, might have a repaving effect.
In 1996 while visiting Alcon Laboratories in Mexico City, the applicant learned that one of the company's ophthalmic products contained both of the above mentioned substances in a gel suspension (VISCOAT®). The inventor obtained detailed information, including the product monograph for VISCOAT® that states that is has no reported side effects in introacular use; furthermore, there are ample references from efficacy and safety studies of this product (CILCO, In. Summary of safety and efficacy for Viscoat, 1984). It was then that the applicant decided to use it experimentally in patients with osteoarthritis disorders of all degrees, and subsequently analyze the results.
The present study reveals another alternative in the management of osteochondral lesions of the knee through the intraarticular application of a mixture of sodium hyaluronate and sodium chondroitin sulfate. While bound by no theories, it may be that the remarkable effectiveness of this therapy is attributable to the promotion of chondrogenesis synergistically combined with the known benefits of viscoelastic therapy. Implanting an artificial matrix of chondroitin sulfate and sodium hyaluronate may represent an indispensable repair factor, as in it naturally arising chondrocytes can proliferate and restore the continuity of the tissue, regenerating the destroyed cartilage to its original form.
With this matrix, the symptomatic evolution is significantly favorable and long lasting due to the regeneration of cartilage at the chondral lesions. No side effect have been reported except in a patient who reported pain and slight swelling at the site of application, which subsided spontaneously in 24 hours; he was given acetaminophen as an analgesic.
It must be pointed out that in the most preferred usage the product is administered exactly as it is presented for intraocular use and no change is made in the formulation. A change in presentation with a larger capacity syringe is now being proposed, as the current ophthalmic presentation has 0.5 c.c. and 0.75 c.c. syringes.
It must also be pointed out that although this is the same preparation as that used intraocularly, its use for this purpose is totally different as it is applied in a conventional intraaticular manner as an inductor of chondrogenesis, to regenerate the cartilage destroyed by osteoarthritis.
As previously mentioned, experimental application of this composition in humans started in 1996, and excellent results have been noted. These were confirmed later by arthorscopic studies (direct view of the articular cartilage through the insertion of a camera into the joint), pathological anatomy and histophysiological studies, all of them consistent with the clinical findings that the regeneration of normal articular cartilage was achieved. This is why this treatment is presented as the only currently available procedure that can offer up to 955 regeneration of articular cartilage damaged by grade I and II osteoarthritis in any joint of the human body.
USPTO Backgrounds
USPTO Backgrounds