Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1998-12-21
2002-04-09
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C514S825000
Reexamination Certificate
active
06368613
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to therapeutic and diagnostic methods for the management of orthopedic disorders. More particularly, the present invention relates to the administration of fluorocarbons for the treatment or diagnosis of various articular disorders.
BACKGROUND OF THE INVENTION
One of the most significant events in the evolution of animal physiology was the internalization of the skeletal framework. In a broad sense, it allowed for substantial increases in size while retaining the mobility necessary to exploit new environments. Moreover, in higher organisms the skeletal system carries out several important functions. Fundamentally, it provides mechanical support for the tissues of the body and assists in the maintaining the body's natural mineral balance. It also exhibits a protective nature, reducing the potential for harm to delicate internal organs. Perhaps most importantly, the skeletal system is a dynamic structure incorporating numerous joints and providing a framework on which muscles can act to allow motion. Responsive to neural signals, this coordinated interaction is the basis for all voluntary movement.
The adult human skeleton is made up of 206 individual bones. The sites where the bones come together are commonly called joints (arthroses) or points of articulation. In normal operation, joints efficiently function to provide smooth, painless, stable, force transmission between one bone and the next with little effort. For the average adult individual, the joints cycle more than one million times a year, typically without injury or mishap. The hip, knee and ankle joints transmit forces of three times body weight with the simplest of activities such as walking, and over seven times the body weight when undergoing motion related to climbing stairs. Because much of the force transmitted across a joint is due to agonistic muscle contraction, the force per unit area carried by all extremity joints is similar.
Based on the nature of their connective tissue, joints are generally classified as belonging to one of two principal groups. In the first group, connective tissues remain solid (synarthroses). These solid joints are further classified as being fibrous joints or cartilaginous joints based on the most prevalent type of connective tissue. Fibrous joints tend to be articulations in which the surfaces of the bones are fastened together by intervening fibrous tissue. Such joints, including those between cranial bones, tend to allow little appreciable motion. Cartilaginous joints include synchondroses (primary cartilaginous joints) and symphyses (secondary cartilaginous joints) each of which may allow limited movement. The former are essentially growth mechanisms and are found where two separate but adjacent regions of ossification occur within a continuous mass of hyaline cartilage. In most cases, the cartilage is converted ultimately to bone and the synchondrosis is replaced by complete bony union, i.e. a synostosis. Symphyses, including the intervertebral discs, consist of two well-defined, hyaline cartilage-covered bones bonded by a strong, solid connective tissue such as fibrocartilage.
The second major group of joints, the predominant form of joint in the human body, are termed diarthroses or synovial joints. Synovial joints, which allow for a wide range of motion, incorporate a fluid filled cavity (the articular cavity) having a membrane known as the synovium. The synoviurn (or synovial membrane), richly supplied by both blood vessels and lymphatics, terminates at the margin of articular cartilage and is supported by the fibrous tissue defining the cavity or capsule. Only a few cell layers thick under normal circumstances, the synovium helps regulate the amount of liquid in a joint by secreting and absorbing synovial fluid. The synovial fluid plays an important role in lubricating and separating the bone and cartilaginous surfaces comprising the joint. More specifically, the bone surfaces are typically covered by articular cartilage, a specialized form of hyaline cartilage, which has a very low coefficient of friction. Sliding contact is facilitated by the presence of the synovial fluid, which, among other functions, provides for lubrication and maintenance of the living cells in the cartilage. Where the congruity between the bones is low there may also be an articular disc or meniscus of fibrocartilage. The purpose of this fibrocartilage is uncertain although it has been suggested that it plays a part in shock absorption, improvement of fit between surfaces and spreading of weight over a larger area. In any case, the synovial joints allow an impressive array of movements while successfully supporting immense loads.
The presence of healthy cartilaginous tissue is critical for the effective operation of synovial joints. Bathed by synovial fluid, cartilage provides a smooth, relatively malleable surface allowing for almost frictionless movement. Histologically, articular cartilage is a vascular and lacking in nerve structures. It contains a relatively small number of cells (chondrocytes) in a stiff, gel-like extracellular matrix that is permeated by a network of collagen fibers. Synthesis, and to some extent degradation, of the cartilage matrix is undertaken by the chondrocytes. The unusual mechanical characteristics of cartilage are a result of the unique architectural combination as well as chemical interactions between the components. Mechanically, articular cartilage can be considered to be a fluid-filled, permeable, porous solid. It is efficient at resisting the large compressive forces generated by weight transmission during movement and its elasticity dissipates the effect of concussion. During normal joint operation, the cartilage is subjected to both mechanical distortion of the matrix and, as a result of movement of interstitial fluid in and out of the tissue, changes in volume. The movement of synovial fluid, both within the cartilage and in the articular cavity, is extremely important to proper joint function.
Synovial fluid is a dialysate of blood plasma into which hyaluronate, a glycosaminoglycan of high molecular weight is secreted by the synovial membrane. The high levels of hyaluronate dissolved in the synovial fluid tend to make it fairly viscous under normal physiological conditions. In humans, the volume of synovial fluid found in the joints is typically on the order of a few tenths of a milliliter to several milliliters which is deposited on, and permeates, the cartilage and other surfaces within the articular cavity. Besides providing the articular cartilage its smooth texture and appearance, synovial fluid is found in the bursa (small synovium lined cavities associated with ligaments) where it provides lubrication for the tendon sheaths. Collectively, the bursa and articular cavity are known as synovial cavities. The dispersion of the fluid on the critical parts of the joint plays a decisive role in transmuting the dry resistant surfaces into effective load bearing structures exhibiting very low friction. For instance, it has been reported that the friction between articular cartilage surfaces is one third that of ice on ice. Yet, the efficiency of the lubrication depends, at least in part, on the quality and smoothness of the cartilage. In joints exhibiting damaged or degenerate cartilage, surface irregularities impair the lubricating properties of the synovial fluid and increase the rate of wear. Accordingly, while the initial disruption of the cartilage may occur for any one of a number of reasons, destruction of the joint is often due to a reduction in lubrication efficiency and repetitive insult to the tissue.
Several mechanisms have been proposed to explain the degree of lubrication and/or cushioning provided by the synovial fluid. For example, fluid film lubrication, involving a relatively thick layer of liquid interposed between the surfaces, is generally accepted to play a role in joint function. Different forms of fluid film lubrication that act in synovial lubrication, depending on the loading
Hopkins Ronald M.
Klein David H.
Walters Mark A.
Alliance Pharmaceutical Corp.
Knobbe Martens Olson & Bear LLP
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