Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-09-18
2003-10-07
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S002600, C514S008100, C536S053000, C435S243000, C435S253600
Reexamination Certificate
active
06630457
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention is directed to biomaterials for spatially and temporally controlled delivery of bioactive agents such as drugs, growth factors, cytokines or cells. In particular, this invention teaches versatile methods for chemical crosslinking of high molecular weight hyaluronic acid under physiological conditions in situ, to form polymerizable biodegradable materials. The methods are based on the introduction of functional groups into hyaluronic acid (HA) via formation of an active ester at the carboxylate of the glucuronic acid moiety as an intermediate and subsequent substitution with a side chain containing a nucleophilic group on one end and a (protected) functional group on the other end. The introduced functional groups allow for crosslinking of the HA derivatives. Crosslinked hyaluronic acid hydrogels of this invention are useful in various surgical applications and as a temporary scaffold for tissue regeneration, e.g., in cartilage repair.
BACKGROUND OF THE INVENTION
Repair of Articular Cartilage
The failure of regenerating persistent hyaline cartilage by surgical procedures has prompted investigators to attempt repair using biological strategies. The biological repair of articular cartilage is, with a few exceptions, still at an experimental stage. Biological cartilage repair has been approached in two basic ways. First, autologous chondrocytes have been transplanted into a lesion to induce repair (Grande et al.,
J. Orthop. Res
. 7, 208-214 (1989); Brittberg et al.,
New Engl. J. Med
. 331, 889-895 (1994); Shortkroffet al.,
Biomaterials
17, 147-154 (1996)). Chondrocytes may be obtained from a low-loaded area of a joint and proliferated in culture (see Grande; Brittberg; Shortkroff, supra), or mesenchymal stem cells may be harvested, e.g., from the iliac crest marrow, and induced to differentiate along the chondrocyte lineage using growth factors (Harada et al.,
Bone
9, 177-183 (1988); Wakitani et al.,
J. Bone Joint Surg
. 76-A, 579-592 (1994)). The chondrocyte transplantation procedures currently attempted clinically, although promising, are hampered because technically they are very challenging, the cell preparation is very expensive, and the potential patient pool is limited by age, defect location, history of disease, etc. Cells have also been transplanted into cartilage defects in the form of perichondral grafts, e.g., obtained from costal cartilage, but with limited success due to the limit in donor material and the complication of endochondral ossification of the graft site observed in longterm follow-up (Amiel et al.,
Connect. Tissue Res
. 18, 27-39 (1988); O'Driscoll et al.,
J. Bone Joint Surg
. 70-A, 595-606 (1988); Homminga et al.,
Acta Orthop. Scand
. 326-329 (1989); Homminga et al.,
J. Bone Joint Surg
. 72-B, 1003-1007 (1990)). A second approach is aimed at the recruitment of mesenchymal stem cells from the surrounding connective tissue, e.g., synovium, using chemotactic and/or mitogenic factors (Hunziker and Rosenberg,
J. Bone Joint Surg
. 78-A, 721-733 (1996); see also U.S. Pat. No. 5,368,858). The availability of growth factors and cytokines in recombinant form and the lack of complicated cell transplantation make this procedure a very attractive alternative. The shortcoming of both procedures is the difficulty to stably anchor the repair-inducing factors, whether tissue grafts, cells, or growth factors, within the defect site. Also, outlining of the space that is to be repaired, e.g., by filling it with a matrix material, appears to be crucial to recreate a level cartilage surface (Hunziker and Rosenberg, supra). Thus far, the availability of candidate matrix materials has been the limiting factor, and anchoring of materials seeded with chondrocytes and/or chondrogenic factors difficult, explaining the unsatisfactory results obtained with currently available materials such as polylactic acid and polyglycolic acid scaffolds (Freed et al.,
J. Biomed. Mat. Res
. 28, 891-899 (1994); Chu et al.,
J. Biomed. Mat. Res
. 29, 1147-1154 (1995)); calcium phosphate minerals (Nakahara et al.,
Clin. Orthop
. 276, 291-298 (1992)), fibrin sealants (Itay et al.,
Clin. Orthop
. 220, 284-303 (1987)), and collagen gels (Wakitani et al.,
J Bone Joint Surg
. 71-B, 74-80 (1989)). We have developed novel biodegradable materials based on hyaluronic acid which are optimized for the biological requirements posed on a repair material in a synovial joint and which allow in situ polymerization.
Biology of Hyaluronic Acid and its Therapeutic Use
Hyaluronic acid (HA) is unique among glycosaminoglycans in that it is not covalently bound to a polypeptide. HA is also unique in having a relatively simple structure of repeating nonsulfated disaccharide units composed of D-glucuronic acid (GlcUA) and N-acetyl-D-glucosamine (GlcNAc) (Scott et al.,
The Chemistry. Biology and Medical Applications of Hyaluronan and Its Derivatives
, T. C. Laurent (ed.), Portland Press, London, (hereinafter “
Hyaluronan and Its Derivatives
”), pp. 7-15 (1998)). Its molecular mass is typically several million Daltons. HA is also referred to as hyaluronan or hyaluronate, and exists in several salt forms (see formula I).
HA is an abundant component of cartilage and plays a key structural role in the organization of the cartilage extracellular matrix as an organizing structure for the assembly of aggrecan, the large cartilage proteoglycan (Laurent and Fraser,
FASEB J
. 6, 2397-2404 (1992); Mörgelin et al.,
Biophys. Chem
. 50, 113-128 (1994)). The noncovalent interactions of aggrecan and link protein with HA lead to the assembly of a large number of aggrecan molecules along the HA-chain and mediate retention of aggrecan in the tissue. The highly negatively charged aggrecan/HA assemblies are largely responsible for the viscoelastic properties of cartilage by immobilizing water molecules. A number of cell surface receptors for HA have been described and shown to play a critical role in the assembly of the pericellular matrix of chondrocytes and other cells, e.g., isoforms of CD44 and vertebrate homologues of Cdc37 (Knudson and Knudson,
FASEB J
. 7, 1233-1241 (1993); Grammatikakis et al.,
J. Biol. Chem
. 270, 16198-16205 (1995)), or to be involved in receptor-mediated endocytosis and degradation of HA to control HA levels in tissues and body fluids (Laurent and Fraser, supra; Fraser et al.,
Hyaluronan and Its Derivatives
, pp. 85-92 (1998)). Blocking of the interaction of these receptors with HA in prechondrogenic micromass cultures from embryonic limb bud mesoderm inhibits chondrogenesis, indicating that the establishment and maintainance of a differentiated chondrocyte phenotype is at least in part dependent on HA and HA-receptor interactions (Maleski and Knudson,
Exp. Cell. Res
. 225, 55-66 (1996)).
HA and its salts are currently being used in therapy for arthropathies by intraarticular injection (Strachnan et al.,
Ann. Rheum. Dis
. 49, 949-952 (1990); Adams,
Hyaluronan and Its Derivatives
, pp. 243-253 (1998)), in opthalmic surgery for intraocular lens implantation (Denlinger,
Hyaluronan and Its Derivatives
, pp. 235-242 (1998), to promote wound healing in various tissues (King et al.,
Surgery
109, 76-84 (1991)), or more recently, in derivatized and/or crosslinked form to manufacture thin films which are used for tissue separation (for review see Laurent and Fraser, supra; Weiss,
Hyaluronan and Its Derivatives
, pp. 255-266 (1998); Larsen,
Hyaluronan and Its Derivatives
, pp. 267-281 (1998); Band,
Hyaluronan and Its Derivatives
, pp. 33-42 (1998)). Extensive efforts have been made by various laboratories to produce derivatives of HA with unique properties for specific biomedical applications. Most of the developments have been focusing on the production of materials such as films or sponges for implantation and the substitution of HA with therapeutic agents for delayed release and/or prolonged effect (for review see Band, supra; Prestwich et al.,
Hyaluronan and Its Derivatives
, pp. 43-65 (1998); Gustafson,
Hyaluronan and Its Derivatives
, pp
Aeschlimann Daniel
Bulpitt Paul
Fish & Neave
Fonda Kathleen K.
Massaro Jane A.
Orthogene LLC
Rochester S. Craig
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