Methods for tissue repair are provided employing a matrix comprising a biocompatible, bioerodable polymer, said polymer comprising a thermoplastic lactide-containing terpolymer of monomer units derived from lactic acid, glycolic acid, and either caprolactone or valerolactone, which has a water solubility of about 0.01 to about 500 mg/mL at about 25xc2x0 C. and adhesive strength of about 600 to about 150,000 Pa and applying the matrix to a tissue defect. The matrix or adhesive can further comprise a filler or a bioactive agent, or both.

In a matrix for tissue repair comprising a biocompatible, bioerodable polymer, this invention provides the improvement wherein the polymer has a water solubility of about 0.01 to about 500 mg/mL at about 25xc2x0 C. and an adhesive strength of about 600 to about 150,000 Pa so that the matrix is tissue adherent. One such matrix comprises a polymer that also has a glass transition temperature of less than 0xc2x0 C. The improved matrices are useful for repairing tissues such as bone and cartilage, and for administering biologically active substances.
These improved matrices may further comprise a filler, a bioactive agent, or both.
In another aspect, this invention provides a pressure sensitive adhesive for tissue repair comprising (a) a biocompatible, bioerodable polymer which exhibits adhesive strength of about 600 to about 150,000 Pa, (b) a filler and (c) a bioactive agent. Further, this invention provides a pressure sensitive adhesive for tissue repair comprising a terpolymer of an xcex1-hydroxycarboxylic acid which exhibits adhesive strength of about 600 to about 150,000 Pa.
This invention also relates to methods for repairing bone or cartilage which comprise applying to the bone or cartilage an implant matrix of this invention.
In the methods of repairing bone or cartilage using a bioerodable implant matrix, this invention further provides the improvement comprising using a tissue-adherent implant matrix of this invention to repair the defect.
In another aspect this invention relates to implantable articles of manufacture for use in the release of a bioactive agent into a physiological environment, said articles comprising a biologically active agent disbursed in an implant matrix of this invention.
The present invention is directed to improvements in matrices for tissue repair comprising biocompatible, bioerodable polymers. In one improvement, the matrix comprises a polymer which has a water solubility of about 0.01 to about 500 mg/mL at about 25xc2x0 C. and an adhesive strength of about 600 to about 150,000 Pa so that the matrix is tissue adherent. One such matrix comprises a polymer that has a glass transition temperature of less than 0xc2x0 C. The improved matrix can further comprise a filler or a bioactive agent, or both. An especially useful attribute of the improved matrices is that the matrix adheres to tissues such as bone or cartilage. In addition, the matrix has a texture like that of dough or putty; thus, it is particularly suitable for being molded to fit into a site needing repair.
In another aspect, this invention provides pressure sensitive adhesives for tissue repair comprising (a) a biocompatible, bioerodable polymer which exhibits adhesive strength of about 600 to about 150,000 Pa, (b) a filler and (c) a bioactive agent. Further, this invention provides pressure sensitive adhesives for tissue repair comprising a terpolymer of an xcex1-hydroxycarboxylic acid which exhibits adhesive strength of about 600 to about 150,000 Pa.
The implant matrices and adhesives of this invention can be applied to the bone-contacting surfaces of prosthetic appliances (as a cement), or they can be inserted into and around bone defects and cavities or cartilage surfaces (as a filler). The matrix or adhesive biodegrades gradually. As it biodegrades, it is replaced by developing bone or cartilage tissue in a manner which permits a natural healing of the tissue. Thus, it provides an effective means for treating or repairing bone or cartilage.
When the matrix or adhesive further comprises a bioactive agent, it serves as a depot device for release of the bioactive agent. Release of the agent occurs as the matrix or adhesive biodegrades after implantation.
Many attempts have been made to develop a repair matrix that could facilitate bone or cartilage repair and also deliver bioactive agents such as growth factors. Such a matrix could be used instead of bone grafts. Thus far, only matrices comprised of natural products such as collagen have shown promise. Collagen, however, is difficult to manufacture and control in order to meet regulatory standards. In addition, surgeons are not satisfied with collagen matrices because they are difficult to form and/or handle.
Other approaches to replace bone grafts have included conventional bioresorbable polymers, ceramics such as tricalcium phosphate (TCP), natural polymers, such as collagen, proteoglycans, starches, hyaluronic acid and modified bone matrix. To date these efforts have only produced delivery matrices which (a) impede healing, (b) provoke negative tissue reactions, (c) cannot be sterilized, (d) are difficult to use or (e) cannot be manufactured to the satisfaction of regulatory bodies.
For example, one approach was to use conventional bioresorbable polymers such as polylactide-co-glycolide (PLG) to administer growth factors. It was very difficult, however, to combine PLG with the growth factor without inactivating the growth factor. Other disadvantages encountered with PLG were that, when it was implanted, it inhibited the bone healing response and occasionally caused aseptic sinus tract and inflammation and destroyed surrounding bone.
Another attempt to develop an effective bone repair matrix involved implanting a bone growth factor absorbed on a ceramic such as TCP. The problem with this approach was that the TCP particles migrated out of the defect area too quickly to deliver the growth factor effectively.
A major problem encountered with previously tried delivery systems is that the bioerodable material could not be mixed with the growth factor prior to the time of surgery. Mixing the delivery matrix with the bioactive material immediately prior to, or during, the surgery process is very awkward and can lead to inconsistent results.
The bioerodable matrices and adhesives of this invention solve several of the problems encountered with previous delivery systems. They are especially useful in the delivery of bioactive proteins such as growth factors because the polymer component dissolves in solvents which are compatible with proteins. Thus, it is possible to formulate the bioactive component in the polymer adhesive matrix in advance, i.e., well before a surgical procedure, under acceptable regulatory conditions, including sterilization of the product without inactivating the bioactive components. Quality control during the preparation of delivery systems using the present adhesive products is, therefore, greatly improved.
Other advantages of the polymer implant matrices and adhesives of this invention are that they are biocompatible and bioerodable in vivo. The term xe2x80x9cbiocompatiblexe2x80x9d means that the polymer is non-toxic, non-mutagenic and, at most, elicits only a minimal to moderate inflammatory reaction. The term xe2x80x9cbioerodablexe2x80x9d means that the polymer either degrades or is resorbed after implantation into products that are used by, or are otherwise eliminated from, the body by existing biochemical pathways.
The present matrices comprise polymers that are bioerodable within a period of from about three hours to about two years. This period can be varied, depending upon the desired application. A preferred period is from about one day to about one month; another preferred period is from about two weeks to about three months. The period for bioerosion is the time after which the polymer will no longer be detectable at the site of implantation, using standard histological techniques.
Thus, an important advantage of the present polymer implant matrices is that a second surgical procedure to remove the matrix is not required because it degrades with time, and its degradation products are absorbed by the body.
One required feature of certain of the adhesive bioerodable polymers useful in the improved matrices of this invention is their water solubility. They are soluble in water at about 0.01 to about 500 mg/mL of water at about 25xc2x0 C. (ambient temperature). Typically, the polymers are soluble in water at about 0.1 to about 500 mg/mL of water. Preferably they are soluble at about 5 to about 400 mg/mL of water.
Some investigators have reported aseptic necrosis, inflammation, or sinus tracts in animals where poly(xcex1-hydroxycarboxylic acid) implants have been used. It is generally thought that these adverse reactions were caused by local acidosis from the degradation of the polymer. Use of more soluble ionomer forms of the polymers avoids the danger of developing local acidosis at implant sites because the polymers dissolve and are diluted or carried away before quantities of acidic degradation products are produced.
This water solubility allows the polymers to be more readily dissolved by serum at the surface of the implant matrix and thereafter distributed into surrounding body fluids where they can be mobilized for hydrolysis at remote sites. This feature is important because hydrolysis of some polymers results in a localized pH gradient which can be adverse to local cell growth. Hydrolysis occurring at the implant site produces an unnatural concentration of hydrolysis products (and increased acidity) at the surface of the matrix. Such acidity can easily interfere with ongoing tissue repair. The water soluble polymers used in the improved matrices of this invention, therefore, preserve conditions that optimize a localized environment for cell viability and growth at the implant surface.
Certain polymers used in the matrices of this invention, the polyesters, have a glass transition temperature (Tg) of less than 0xc2x0 C. When used with a filler, polymers with a Tg of less than 0xc2x0 C. have excellent handling properties.
A required feature of all the polymers for use in the matrices and adhesives of this invention is a threshold level of adhesiveness. Adhesiveness has been found to be important for optimizing implant performance. Adhesiveness is an intrinsic property that is not readily correlated with polymer properties, but can easily be assessed empirically. Adhesiveness is a characteristic that derives from a wide variety of polymer parameters, including polymer type, i.e., the nature of the covalent linkages linking the monomers, molecular weight and intrinsic structure and as well the nature of the surface to which the matrix will be adhered. Skilled practitioners in the art can readily assess polymer adhesive properties using known techniques, such as those illustrated in the examples infra.
The polymers used in the matrices and adhesives of this invention exhibit adhesive properties on different substrates, such as, for example, dry substrates like glass and water-swollen poly(2-hydroxyethyl methacrylate) (xe2x80x9cpHEMAxe2x80x9d) on glass, which simulates wet tissues. Typically, the polymers withstand a maximum stress on a glass substrate of about 1,000 to about 150,000 Pa, preferably about 10,000 to about 40,000 Pa, and most preferably, about 12,000 to about 16,000 Pa. The polymers withstand a maximum stress on a pHEMA substrates of about 600 to about 90,000 Pa, preferably about 2,500 to about 40,000 Pa, and most preferably about 5,500 to about 8,500 Pa. Thus, the range of adhesive strength is from about 600 to about 150,000 Pa.
The polymers are moldable by hand at a temperature of about 60xc2x0 C. or below. Typically, they are moldable at about 4xc2x0 C. to about 60xc2x0 C., preferably at about 15xc2x0 C. to about 50xc2x0 C., and most preferably at about 20xc2x0 C. to about 30xc2x0 C. The degree of moldability at a selected temperature is dependent upon the characteristics of the polymer selected as well its molecular weight. The matrix containing the polymer remains moldable after it has been implanted within the body.
A variety of polymers can be used in the matrices and adhesives of this invention. The polymers must be biocompatible and susceptible to rapid biodegradation in order to be replaced by new tissue. The polymers may be homopolymers, terpolymers, copolymers, blocked copolymers, or blends of polymers. Bioerodable polymers include polyanhydrides, polyorthoesters, polyesters (such as polylactic acid (PL), polyglycolic acid (PG), polyhydroxybutyric acid, polymalic acid, polyglutamic acid and polylactones) and poly(amino) acids.
One type of polymer especially useful in the matrices and adhesives of this invention is a polyester ionomer, more particularly, a non-toxic salt of a bioerodable carboxy-terminated polyester of the general formula ROxcx9cPExcx9cCOOH or HOOCxcx9cPExcx9cCOOH wherein R is hydrogen or C1-C4 alkyl and xcx9cPExcx9cis a divalent residue of a polyester. The polyester can comprise a homopolymer, copolymer, or terpolymer of biocompatible hydroxy acids, for example, lactic acid, glycolic acid, xcex5-hydroxycaproic acid, and xcex3-hydroxyvaleric acid. Alternatively, the polyester can be formed using copolymerization of a polyhydric alcohol and a biocompatible polycarboxylic acid. Most typically such copolymers are formed between dihydric alcohols, for example, propylene glycol for biocompatibility and biocompatible dicarboxylic acids. Representative carboxylic acids for formation of the polyesters useful for preparing these polyester ionomers include a Kreb""s cycle intermediate such as citric, isocitric, cis-akonitic, xcex1-ketoglutaric, succinic, maleic, oxaloacetic and fumaric acid. Many of such carboxylic acids have additional functionalities which can enable further cross-linking of the polymers if desirable.
The polyesters can be further modified, for example, by reaction with a cyclic carboxylic anhydride to convert residual hydroxy functionality to the carboxy-terminated forms useful for preparation of these polyester ionomers.
The carboxy-terminated polyesters used to prepare the polyester ionomers are selected to have a threshold water solubility between about 0.01 and about 500 mg/mL of water, preferably about 0.5 to about 350 mg/mL of water, at ambient temperature. The polyester precursors have a weight average molecular weight of about 400 to about 10,000, more typically about 1,000 to about 5,000. Conversion of these compounds by neutralization with pharmaceutically acceptable bases produces polyester ionomers having enhanced water solubility relative to the carboxy-terminated polyester precursors but retaining other polymer functionality.
The polyester ionomers are prepared from mono-or bis-carboxy-terminated polyesters. Generally, the carboxy-terminated polyester is dissolved in an organic solvent and neutralized by the addition of a stoichiometric amount of a physiologically acceptable base. In one embodiment, the neutralization is carried out with less than a stoichiometric amount of base to produce a composition comprising a carboxy-terminated polyester and its corresponding ionomer, the ratio of those components being dependent on the degree of neutralization. Suitable bases for use in forming the polyester ionomers include hydroxides of Group Ia or Group IIa metals including preferably the hydroxides of lithium, sodium, potassium, magnesium and calcium, as well as physiologically compatible salt-forming amines. Following neutralization of the carboxy-terminated polyester, the resulting ionomer can be isolated using standard isolation techniques the ionomer is typically dried prior to use in fabrication of implant matrices and adhesives.
The carboxy-terminated polyesters can be prepared using art-recognized procedures for polyester synthesis. The carboxy-terminus (or termini) on such compounds can be formed by reaction of hydroxy functional polyesters with, for example, a stoichiometric amount of a cyclic anhydride of a C1-C6 dicarboxylic acid, such as succinic anhydride.
Bis-hydroxy functional polyesters are readily prepared by reaction of a dihydric alcohol initiator, for example, propylene glycol or ethylene glycol, with one or more cyclic hydroxy acid esters, for example lactide, glycolide or caprolactone. Reaction of such bis-hydroxy functional polyesters with cyclic anhydrides produces bis-carboxy functional polyesters that can be used to prepare the ionomers described supra.
The polyester prepolymers used for the preparation of the ionomers can be prepared using art-recognized polyester-forming reaction chemistry, typically using, for example, metal catalysts to promote ester-forming reactions. One problem with the prior art procedures is the difficulty in removing the metal catalyst from the product polyesters. Removal of the catalyst is particularly crucial when the polyesters are intended for use in medical applications.
It has been found that polyesters of hydroxy acids can be prepared in high yields and high purity with good control over structure/functionality by reacting the corresponding cyclic esters with a hydroxy functional initiator at elevated temperatures under substantially anhydrous conditions. Thus, one preferred method for preparing the polyesters consists of reacting an initiator, for example, a mono-hydric or dihydric alcohol, with at least one cyclic hydroxy acid ester under substantially anhydrous conditions at elevated temperatures. The reaction is preferably carried out neat (an absence of solvent) at a temperature of about 100-180xc2x0 C., more preferably about 120-160xc2x0 C. The term xe2x80x9csubstantially anhydrous conditionsxe2x80x9d means that routine efforts are made to exclude water from the reaction mixture and can typically include such steps as pre-drying the reaction vessel with heat and carrying out the reaction under drying conditions.
The structure of the polyester is controlled by selection and stoichiometry of the cyclic hydroxy acid ester reactant(s) and the amount of initiator used with lower relative initiator amounts leading to higher average molecular weight product and higher relative amounts of initiator leading to lower average molecular weight product.
The hydroxy functional initiator can either be a monohydric alcohol, for example a C1-C4 alkanol, or a di-or polyhydric alcohol. Alternatively, the hydroxy functional initiator can be a hydroxy acid, for example glycolic acid. The product hydroxy-terminated polyesters can be converted to a carboxy-terminated polyester that can be used to prepare the polyester ionomers by reaction with a stoichiometric amount of a cyclic anhydride.
The method for preparing polyester polymers for use in preparing the polyester ionomers can be carried out as well in the presence of a cyclic carboxylic acid anhydride to provide directly the corresponding carboxy terminated polyester compound. The reaction is carried out under the same conditions described supra for preparing the polyester. Most typically the reaction is carried out using about equimolar amounts of a monohydricalcohol initiator and the cyclic anhydride. Where the initiator is a dihydric alcohol, the molar ratio of the cyclic anhydride to the initiator is preferably raised to about 2:1.
Preferred polyester ionomers are those made up of lactide, glycolide and caprolactone or valerolactone. Polymers of lactide/glycolide/caprolactone (PLGC) are especially beneficial. PLGC terpolymers having a molecular weight in the range of about 1,000 to 3,000 are especially preferred. Terpolymers wherein the lactide and glycolide each make up about 35-45% of the terpolymer, and the caprolactone or valerolactone make up about 10 to about 30% of the terpolymer are particularly useful.
Selected poly(amino acids)are another type of polymer useful in the matrices and adhesives of this invention. Certain poly(amino acids) exhibit adhesive properties toward connective tissue, such as cartilage and bone. The poly(amino acid) can be: (1) a classic poly(amino acid) of the formula H2Nxe2x80x94Qxe2x80x94COOR2 in which Q is the divalent residue of a polylactide and R2 is H, a metal cation, or ammonium, or (2) a pseudo-poly(amino acid).
The matrix may comprise two or more different poly(amino acids), each of the formula H2Nxe2x80x94Qxe2x80x94COOR2 wherein:
Q is a divalent residue of a polylactide formed from 1 to 3 species of amino acids;
the amino acid components of Q are represented by the formula aX+bY+cZ;
wherein a, b, and c represent the respective mole fractions of the amino acids X, Y, and Z; a=0 to 1, b=0 to 1, and c greater than 0 but less than 1; and a+b+c=1.0;
X is selected from glutamate, asparagine, aspartate, and glutamine;
Y is selected from lysine and arginine; and
Z is selected from cysteine, methionine, serine, threonine, glycine, alanine, valine, leucine or isoleucine.
Alternatively, the matrix may comprise a divalent or multivalent monomer and a poly(amino acid) of the formula H2Nxe2x80x94Qxe2x80x94COOR2 as defined supra wherein the Q polylactide is formed from 1 to 3 species of amino acids.
A wide variety of polypeptides in a wide variety of ratios may be used to form the useful poly(amino acids). The polypeptides are available commercially from Sigma Chemical Company, P.O. Box 14508, St. Louis, Mo. 63178.
Certain amino acid homopolymers, however, are not useful in the matrices. For example, amino acids with aliphatic side chains do not interact well enough with biological surfaces. They may, however, be used as chain extenders or modulators, along with cysteine, methionine, serine, and threonine, in mixed polymers. Amino acids with aromatic side chains exhibit low rates of diffusion in the body and are, therefore, not suitable to be components of selected poly(amino acids). Histidine is also not a suitable component due to its limited interaction with biological surfaces. Histidine may, however, be used to complex with the polyamino acids as a monomer.
Particular divalent or multivalent monomers may be used in combination poly(amino acids) in the matrices. Amino acids with two or more positive charges at physiological pH, such as lysine, arginine, or histidine, form complexes with poly(amino acids) bearing negative charges at physiological pH. Likewise, amino acids with two or more negative charges, such as aspartate or glutamate, can form complexes with poly(amino acids) bearing positive charges.
In the pseudo-poly(amino acids) that can be selected, the dipeptide monomers are covalently bound through other than normal peptide linkages. Pseudo-poly(amino acids) suitable for use are those having the requisite adhesive character. They can be prepared using the chemistry described, for example, in Kohn, J. and Langer, R., Polymerization Reactions Involving the Side Chains of xcex1-L-Amino Acids, J. Amer. Chem. Soc., 109, 917 (1987) and Pulapura, S. and Kohn, J., Biomaterials Based on xe2x80x9cPseudoxe2x80x9d-Poly(Amino Acids): A Study of Tyrosine-Derived Polyiminocarbonates, J. Polymer Preprints, 31, 23 (1990), which are incorporated by reference. The pseudo-poly(amino acids) can be used alone or in combination with a classic poly(amino acid) or with a different pseudo-poly(amino acid).
As discussed supra, the composition of the polymer, as well as the molecular weight and physical properties, can be varied. Those in the art will also appreciate that compounds can be mixed into, or polymerized with, the polymer as required for additional strength or other desirable physical properties, using materials known in the art. For example, TCP or other ceramic-type materials that provide increased viscosity can be added to the composition.
The dissolution rate of polymers such as the PLGC terpolymers can be varied by end group modification. For example, PLGC terpolymers with OH end groups degrade very slowly; PLGC terpolymers wherein the OH end groups have been partially neutralized, e.g., by neutralization of about 40 to 60% of the end groups with sodium hydroxide, degrade at a moderately slow rate; and PLGC terpolymers wherein most the OH end groups have been neutralized, e.g. by sodium hydroxide, degrade within a few days. Exemplary end groups are OH and COONa+, but any ion or functional group that can be placed on the polymers could be used. The amount of end group modification can have a dramatic effect on the dissolution rate.
In addition to end group changes, variations of molecular weight and composition can be selected to prepare suitable compositions. Increases in molecular weight increase the time to dissolution. Also, blending in a high MW polymer will increase the time to dissolution, or blending in a low MW polymer will decrease the time.
In general, when the matrix is used to repair bone defects, the polymer is selected to degrade over a period of three hours to two years. Preferably, the polymer will degrade in about one month, most preferably in about two weeks. The desired degradation time will depend on the nature of the repair site, including the local tissue type, the support function being served by the implanted matrix, and the nature and concentration of the bioactive component, if any, in the implant matrix. Targeted degradation times can be achieved by selection of polymer/filler combinations on an individual basis.
In the matrix, the polymer may be combined with a bioactive agent, one or more fillers, or both. When the matrix contains a filler, it typically contains about 1 to about 90 weight percent filler, preferably about 30 to about 70 weight percent, and most preferably about 35 to about 50 weight percent of filler.
The filler may be particulate, fibrous, organic, inorganic or a mixture of organic and inorganic. Suitable fillers include bone chips, tricalcium phosphate, hydroxylapatite (xe2x80x9cHAxe2x80x9d), small intestine submucosa (xe2x80x9cSISxe2x80x9d as described in U.S. Pat. No. 4,902,508, issued Feb. 20, 1990, and U.S. Pat. No. 4,956,178, issued Sep. 11, 1990), bioglass granules, synthetic polymers, calcium carbonate, calcium sulfate and collagen, or other extracellular matrix compound, or various mixtures thereof.
When the filler is particulate, the average particle size is from about 20 xcexcm to about 2,000 xcexcm, more preferably about 75 to about 700 xcexcm, and most preferably, about 100 xcexcm to about 500 xcexcm.
As discussed supra, the implant matrix may contain a bioactive agent or agents. A bioactive agent is a compound or material that affects the living cells in its surrounding environment, e.g., it acts to enhance the healing process.
Bioactive agents preferred for use in the present invention are growth factors, growth factor binding proteins or cells. Examples of suitable growth factors include: a fibroblast growth factor, a transforming growth factor (e.g., TGF-xcex21), a bone morphogenetic protein, epidermal growth factor, an insulin-like growth factor or a platelet-derived growth factor.
Examples of growth factor binding proteins are insulin-like growth factor binding proteins (IGFBP""s) such as IGFBP""s 3 and 5. Examples of suitable cells include bone marrow cells and mesenchymal stem cells. The bioactive material can also be an osteogenic agent which stimulates or accelerates generation of bone upon implantation into a bone defect site. Examples of osteogenic agents include demineralized bone powder, morselized cancellous bone, aspirated bone marrow, bone forming cells, and other bone sources.
The bioactive agent may also be an antibacterial substance. Examples of useful antibacterial agents include gentamicin and vancomycin.
When a bioactive agent is included in the matrix or adhesive, it is incorporated in amounts of from about 10xe2x88x925% to about 33% by weight of the matrix. Typically, the agent is incorporated at a rate of from about 10xe2x88x922% to about 20% by weight of the matrix. A preferred rate of incorporation is from about 10xe2x88x921% to about 5% by weight.
When the bioactive agent is a growth factor, it is generally incorporated into the matrix or adhesive in amounts from about 10xe2x88x925% to about 1% by weight of the matrix. When cells are the active component, the range is from about 0.5% to about 50% by weight. When using an agent such as demineralized bone, bone marrow and the like, the range is preferably from about 5% to about 95% by weight. For TGF-xcex21 the preferred range is from about 10xe2x88x924% to about 0.05% of TGF-xcex21 by weight of the matrix.
The percent of bioactive agent should be such that it will release from the implanted matrix in vivo in an effective manner, generally over a period of from about a day to about 30 days and longer, depending on the nature and application of the composition.
The release rate of a bioactive agent, such as TGF-xcex21, can be varied by modification of the polymer as discussed supra, e.g., by varying its end groups, molecular weight or composition.
Other agents that may be added to the matrix include: an extract from whole blood, packed red cells, platelets, plasma (fresh or fresh frozen), serum, skin, bone, cartilage, tendon or microorganisms; synthetic proteins, etc. Suitable proteins can be any one of a wide variety of classes of proteins, such as keratins, collagens, albumins, globulins, hormones, enzymes, or the like. The material can be simple peptides, simple proteins, or conjugated proteins, such as glycoproteins, mucoproteins, lipoproteins, heme proteins, nucleoproteins, or the like.
Antioxidants may also be included in the matrix. Antioxidants suitable for use include tocopherol, citric acid, butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, sodium ascorbate, and other antioxidants which are xe2x80x9cgenerally recognized as safexe2x80x9d by the Food and Drug Administration.
Thus, the implant matrices can be prepared by blending the polymer with one or more bioactive agents and optionally other excipients, for example, additives to optimize retention of biological activity and polymer functionality during sterilization, and then by sterilizing and packaging the implant formulation for surgical use.
Sterilization can be accomplished by radiation with about 1 to about 3 mRad of gamma radiation or electron beam radiation. If the bioactive agent is a protein or peptide, biological activity can be optimized during sterilization by including in the formulation 1) an extraneous protein, for example albumin or gelatin; and 2) a free radical scavenger (antioxidant), for example propyl gallate, 3-tert-butyl-4-hydroxyanisole (BHA) or ascorbic acid, in amounts effective to retard radiation-induced degradation of the biologically active peptide. The sterilization is preferably conducted at low temperature, for example xe2x88x9270xc2x0 C.
When a filler is used in the matrix with a biologically active peptide or protein, it is advantageous to form a mixture of the biologically active compound and an extraneous protein such as albumin or gelatin, and coat the filler with that formulation prior to blending the filler into the polymer.
Preferred matrices for bone repair include the following:
The implant matrices of this invention can be prepared using standard formulation techniques. If the matrix includes a bioactive agent, the polymer can be mixed with the agent or used to encapsulate it, again using known methods such as mixing and compressing and microencapsulation.
This invention also provides an implantable article of manufacture for use in the release of a bioactive agent into a physiological environment comprising a biocompatible tissue-adherent implant matrix of this invention and one or more bioactive agents. Preferred implantable articles are those wherein the bioactive agent is a growth promoting factor.
Although the polymers have been described for use in repairing tissues such as bone and cartilage and in a delivery matrix for a bioactive agent in vivo, these descriptions are illustrative only and are not intended to be limiting in any way. There are many other applications for the bioerodable adhesive polymers of this invention.
For example, the polymers can be used in the treatment of bone tumors. Such treatment typically involves excision of the tumor as well as portions of the surrounding bone, leaving a large cavity in the bone. A graft using autogenous bone (bone harvested from another site in the patient""s body) is the conventional and accepted technique for filling such bony defects. Although use of autogenous bone provides rapid incorporation of new bony ingrowth into a bone cavity, this procedure is associated with a morbidity caused by the required surgical exposure needed to harvest the patient""s bone. Moreover, some patients, particularly osteoporotic individuals, have very limited amounts of bone that are appropriate for use as a graft.
Alternatively, allografts, i.e., bones taken from other individuals, may be used as bone-grafting material. There are certain risks associated with such allografts, however, including the transfer of infections and even unrecognized malignant cells from the harvested patient to the grafted patient as well as the problem of immunologic barriers between all individuals. Furthermore, these processes are complicated and labor-intensive. Thus, the implant matrices of this invention offer a distinct improvement over traditional treatments for bone tumors.
The polymers used in the matrices and adhesives of this invention are typically prepared so that they form a viscous adhesive rather than a conventional solid. When the polymer is mixed with a particulate filler to form the biocompatible matrix or adhesive, the polymer can be used to coat the particles of filler. An example of a suitable particulate filler is a ceramic such as TCP. When the particles are coated with the polymer adhesive, they form a self-adherent dough-like substance that can be conveniently molded to fit surgically into bone defects. When a bioactive agent, such as a protein growth factor, is to be included in the matrix, it can be absorbed onto the particles of the biocompatible solid filler prior to being coated with the polymer adhesive.
This invention also relates to improvements in methods of repairing bone or cartilage using a bioerodable implant matrix, wherein the improvement comprises using a tissue-adherent matrix of this invention to repair the bone or cartilage.
Preferred improvements are those wherein the matrix contains a bioactive agent, particularly those wherein the bioactive agent is a growth-promoting factor.
When using a matrix of this invention to repair bone or cartilage, a surgeon, physician or other caregiver first determines the size of the cavity or void to be filled, or the dimensions of the repair site, and removes the appropriate amount of polymer adhesive matrix from packaging. Typically, the packaging is a barrier package which prevents water vapor from contacting the polymer in the composition; however, it is understood that the packaging may be any one of a wide variety of containers.
Following removal from the packaging, the surgeon then molds the adhesive implant matrix at ambient temperature into dimensions compatible with the repair site. In the case of bone repair, the matrix is molded to the dimensions of the cavity or void to be filled. In the case of connective tissue repair, it is molded to fit the dimensions of the repair site. The adhesive matrix is then applied to the cavity or repair site in a manner which permits it to adhere to the bone or cartilage for a time sufficient to effect its repair. Typically, the surgeon presses the molded matrix against the damaged, and often wet, tissue. Because the matrix has adhesive properties, when it is applied to the surrounding bone or connective tissue with pressure, it will stick and remain in place long enough to effect repair of the bone or tissue.
When the matrix contains a bioactive agent, it is typically implanted in a site in the body where a concentration of the bioactive agent would be beneficial. Thus, for example, in the treatment of an osteoporosis-induced fracture involving a void or bony defect, an implant matrix containing a growth-promoting agent is molded to conform to the bone defect or cavity and is inserted by the surgeon at that location. Similarly, the matrix can be implanted or injected into soft tissue for sustained drug release.
Instrumentation. Gel permeation chromatography (GPC) was used to determine molecular weights and molecular weight distributions, Mw/Mn, of polymer samples with respect to polystyrene standards (Polysciences Corporation). The system configuration was described by R. F. Storey and T. P. Hickey, J. Polymer Sci. 31, 1825 (1993). Throughout this specification, unless otherwise stated, the term xe2x80x9cmolecular weightxe2x80x9d refers to weight average molecular weight.
General Procedure
1. Synthesis of acid-terminated polymers
Glassware was dried at 145-155xc2x0 C. for 24 h, fitted with rubber septa, and cooled under a flow of dry nitrogen. Polymerizations were run in 250-mL Erlenmeyer flasks with 24/40 ground glass joints sealed with evacuated glass stoppers wrapped with teflon tape. To a flask (250 mL) containing a magnetic stir bar were added D,L-lactide (18.17 g, 1.26xc3x9710xe2x88x921 mol), glycolide (14.63 g, 1.26 xc3x9710xe2x88x921 mol), xcex5-caprolactone (7.20 g, 6.30xc3x9710xe2x88x922 mol), glycolic acid (1.66 g, 2.18xc3x9710xe2x88x922 mol), succinic anhydride (2.19 g, 2.18xc3x9710xe2x88x922 mol). The flask was purged with nitrogen and heated in a 135xc2x0 C. constant temperature bath for 20 h with continuous stirring. At 65 h of reaction, the temperature was lowered to 110xc2x0 C. The polymerization was allowed to proceed for 146 h and was then quenched in an ice-water bath.
2. Analytical titration procedure (2,000 g/mol sample)
To a 125-mL Erlenmeyer flask was added a (xcx9c2,000 g/mol) polymer sample (0.30-0.40 g). The polymer sample was completely dissolved in THF (50 mL), and water (15 mL) was added to the solution. Phenolphthalein (1 g/100 mL MeOH) (5 drops) was added to the polymer solution, and the flask was placed in an ice bath. The sample was titrated with an aqueous solution of NaOH (0.5047 N) to a light pink end point. An average equivalent weight was calculated from the values of at least three titrations.
3. Bulk polymer titration procedure (2,000 g/mol sample)
To a 1,000-mL Erlenmeyer flask was added a (xcx9c2,000 g/mol) polymer sample (34.32 g), and the polymer was dissolved in THF (450 mL). The average equivalent weight from analytical titration procedure 2, supra, was used to calculate the exact amount of titrant (85.3 mL, 0.5047 N aqueous NaOH) necessary to completely neutralize the polymer sample. This amount was slowly added to the polymer solution as it was stirred in an ice bath.

Bioerodable polymeric adhesives for tissue repair


Systems and methods for prioritizing transmission control protocol (TCP) flows for communication devices in a network are described herein. The systems and methods herein may further allocate bandwidth to the flows based on the priority of the flows. Further, the systems and methods herein allow devices to determine whether particular flows share a traffic flow constraint or bottleneck that limits the overall available bandwidth to the flows. Therefore, allocation of bandwidth for one flow may be adjusted based on allocation of bandwidth to another flow if the flows share a traffic flow constraint. Further, the systems and methods herein allow for target data rates to be determined for the flows based on shared traffic flow constraints.

1. Field
The present application relates generally to communications, and more specifically to prioritizing transmission control protocol (TCP) flows for communication devices in a network.
2. Background
Communication systems are widely deployed to provide various types of communication (e.g., voice, data, multimedia services, etc.) between communication devices (e.g., mobile handsets, PDAs (Personal Data Assistants), personal computers, smart phones, servers, or any other electronic device capable of communicating via a network). The devices may transmit/receive data between each other via a network of interconnected devices. The data may be sent as different sets of data referred to as flows. For example, communication of a first video stream between a device and another device may be referred to as a first flow, and communication of data packets for a web page between a device and another device may be referred to as a second flow. These data flows may each be associated with a particular application running on the communications device.
Further, the devices are interconnected by wired or wireless connections. The devices may access one or more of these connections via one or more network interfaces. These connections and/or network interfaces may have a finite amount of bandwidth that they are capable of handling. Therefore, there may be a finite available amount of bandwidth for a device to use to communicate. Accordingly, when multiple flows request to use the available bandwidth, the bandwidth can be distributed between flows. Communication of flows of data in the network and allocation of bandwidth to the flows is handled in part by the transmission control protocol (TCP).
Typically, TCP distributes the available bandwidth evenly between the flows. However, different flows may have different minimum throughput requirements and different maximum desired throughputs in order for the application to work well. For example, a video stream flow may require a minimum bandwidth in order for the video to playback in the application smoothly and accurately. Merely evenly distributing available bandwidth between the flows does not ensure the video stream flow is allocated the required minimum bandwidth. Even when minimum and maximum throughput requirements of different flows are equal or unknown, the user may have specific interest in one flow. For example, when a flow is in foreground, the user may pay attention to the respective application, and therefore may desire prioritization of that flow. More generally, different flows may have different requirements, for example intrinsic requirements based on the nature of each flow, or relative to the context in which the device is used. Thus, enhanced systems and methods of bandwidth between flows are needed.

Systems and methods for communicating in a network


An apparatus includes a light source for producing a beam of light, a coupler for coupling the light into a slider waveguide, a beam expander for expanding the beam of light from the waveguide to produce an expanded beam, a collimator for collimating the expanded beam, and a focusing device for concentrating the collimated beam to a focal point. A method of delivering light to a focal point is also described.

Heat assisted magnetic recording (HAMR) generally refers to the concept of locally heating a recording media to reduce the coercivity of the media so that an applied magnetic writing field can more easily direct the magnetization of the media during the temporary magnetic softening of the media caused by the heat source. The heated area in the storage layer determines the data bit dimension. A tightly confined, high power laser light spot is used to heat a portion of the recording media to substantially reduce the coercivity of the heated portion. Then the heated portion is subjected to a magnetic field that sets the direction of magnetization of the heated portion. In this manner the coercivity of the media at ambient temperature can be much higher than the coercivity during recording, thereby enabling stability of the recorded bits at much higher storage densities and with much smaller bit cells.
One way to achieve a small confined hot spot is to use an optical near-field transducer (NFT), such as a plasmonic optical antenna or a metallic aperture, integrated in an optical waveguide of high refractive index contrast. Light propagating in the waveguide is focused by an optical focusing element, such as a planar solid immersion mirror onto the near-field transducer. One example uses a planar solid immersion mirror (PSIM), or lens, fabricated in a planar waveguide; and a near-field transducer in the form of an isolated metallic nanostructure, placed near the PSIM focus. The near-field transducer is designed to reach a local surface plasmon (LSP) condition at a designated light wavelength. At LSP, a high field surrounding the near-field transducer appears, due to collective oscillation of electrons in the metal. Part of the field will tunnel into an adjacent media and get absorbed, raising the temperature of the media locally for recording.
It is desirable to launch light into the waveguide with a low cost apparatus, having good alignment tolerances and high light delivery efficiency.

Laser-in slider light delivery for heat assisted magnetic recording


A high speed rotary hand tool with an adjustable head coupling allows the tool head to be operated at extremely high speeds in a preselected angle in relation to the tool body. A coiled, flexible power drive is carried through a spherical head to transfer power from the motor drive to the tool drive. The spherical head has formed detent recesses in which detent balls are held by a combination of leaf springs and a locking sleeve. A safety pin and groove mechanism prevent the sleeve from being inadvertently released.

The invention relates to hand tools of the type that are power driven, and, more particularly, to such a hand tool having a head that can be angled to allow better access to the work material.
Conventional power hand tools, such as drills, cutters and polishers, are limited in their usefulness due to the rigid axial alignment of the drive, power and tool shafts. Many work areas are inaccessible with these tools because the space is limited to less than the tool length, which cannot be shortened by adjusting the angle of the tool head.
Universal joints have proven unworkable for angled operation at speeds of up to 17,000 to 20,000 rpm, or more. Unless universal joints of constant velocity type are used, they produce unacceptably high angular acceleration of the divers components. Even so, under these high velocity conditions the joint components wear out rapidly, due to heat build-up from the friction of components. They also have objectionably high inertia and suffer from complicated construction.
Known flexible power drives are usable only at significantly lower speeds. At high speeds, due to excessive length, when angled, such flexible drives exhibit a whipping action or other distortion which effectively can cause the drive to fail prematurely or even self-destruct by wearing of the shaft against adjacent structures.
Accordingly, the several objects of the invention include provision of a power tool having a novel coupling assembly which connects the motor drive of a power tool to the tool head drive permitting selection of any of several positions of the tool head, either axially or non-axially; which coupling assembly is of constant velocity type; can be securely locked into the selected position for safety in operation; and which safely can be operated with free-wheeling, free-speeding operation to velocities of at least 17,000 to 20,000 rpm with low inertia and without substantial friction, heat build-up, and resultant rapid wear of the coupling or head components. Among other objects of the invention may be noted the provision of such a power tool which is extremely safe and highly reliable in use; which includes redundant securement of the head in a preselected position and which ensures against inadvertent change in head position.
Briefly, a high speed rotary tool apparatus of the hand-held type comprises a body, a tool head, and swivel means adjustably connecting the tool head to the body in preselected angular orientation; the body, including a motor and a high speed rotary drive shaft; the tool head having a tool shaft for carrying a tool to be rotationally driven by the motor at high speed; the swivel means having a power shaft for coupling power from the motor drive shaft to the tool shaft; the power shaft being a single flexible shaft which is flexibly bent when the tool head is at a non-axial angular orientation to the body; and means for guiding and restraining at least one end of the power shaft when bent to prevent whipping or oscillation of the power shaft when rotating.
Other objects and features will be in part apparent and in part pointed out hereinbelow.
The apparatus of the present invention further accomplishes the above-mentioned objects as follows: A flexible wound power shaft is used with crimped sleeves at each end which each fit into a square (or other polygonally shaped) drive. The square drive ends of the power drive in turn are fitted into the female square (or other correspondingly polygonally shaped) drive bushings of the motor drive and the tool head drive, to avoid the whipping action seen at high speeds with conventional flexible drives. A greater path length is provided from the motor drive shaft to the tool shaft than the overall length of the power drive providing gap spacing which accommodates the excess length of the power shaft which results when bent along an angled path. The swivel means provides a coupling assembly having a substantially spherical coupling to allow the tool head to be positioned at one of a plurality of angles or axially in relation to the tool body. Detent mechanisms comprising a plurality of detent balls and recesses allow the coupling assembly to be stablized in a preselected position. Leaf springs resiliently urge the detent balls into their recesses and a spring-loaded locking sleeve forms the outermost tool surface around the coupling mechanism and prevents the detent balls from slipping out of their positions during tool operation, and until a new head position is selected. A safety locking pin and corresponding groove located on the shoulder or forward portion of the spring-loaded locking sleeve prevent the sleeve from inadvertently being axially shifted from its locked position unless the safety pin and groove are in alignment, as accomplished by selectively rotating the sleeve.

High speed rotary hand tool with adjustable head coupling


An operational amplifier includes: a differential amplifier for differentially amplifying first and second differential input signals to generate first and second output signals through first and second nodes; a driver for driving an output node in response to the second output signal; and a drive current adjuster for adjusting a driving current of the driver in response to the first output signal. The drive current adjuster includes: a first transistor including a drain connected to the output node, a gate, and a source connected to a ground voltage; a second transistor including a gate connected to the first node, a drain, and a source connected to a source voltage; a third transistor including a drain connected to the drain of the second transistor, a source, and a gate connected to a first bias voltage; and a fourth transistor including a drain connected to the source of the third transistor, a source connected to the ground voltage, and a gate connected to a second bias voltage, wherein the gate of the first transistor is commonly connected to the drains of the second and third transistors.

1. Technical Field
The present invention relates to an operational amplifier and, more particularly, to an operational amplifier for an output buffer and a signal processing circuit using the same.
2. Description of the Related Art
An operational amplifier (or op-amp for short) is a high-gain differential amplifier. Generally, an operational amplifier includes two input terminals, one inverting (−) and one noninverting (+), and the output of the amplifier is the difference between the "IN+" and "IN−" voltages multiplied by the gain of the amplifier.
FIG. 1 is a circuit diagram of a basic two-stage operational amplifier. Referring to FIG. 1, a two-stage operational amplifier 100 includes a differential amplifier 110 for differentially amplifying a differential pair of input signals IN+ and IN−, and a driver 120 for driving an output node N11 of the differential amplifier 110 according to a bias voltage Vbias and an output signal of the differential amplifier 110. An output load comprising a resistance component and a capacitance component is connected to the output node N11.
The differential amplifier 110 includes NMOS transistors Q1, Q2 and Q5 and PMOS transistors Q3 and Q4. The noninverted and inverted input signals IN+ and IN− are inputted to gates of the NMOS transistors Q1 and Q2, respectively. The PMOS transistors Q3 and Q4 in a current mirror configuration are connected to NMOS transistors Q1 and Q2, respectively. The bias voltage Vbias is applied to the gate of the NMOS transistor Q5.
The driver 120 includes a PMOS transistor Q6 connected to the output node N11 of the differential amplifier 110 to serve as a current source, and an NMOS transistor Q7 serving as a current sink. The PMOS transistor Q6 charges the output load connected to the output node N11, and the NMOS transistor Q7 discharges the output node N11 according to a bias voltage Vbias applied to its gate. For example, when the noninverted input signal IN+ is higher in voltage than the inverted input signal IN−, the voltage level at the output node N11 is lowered and the PMOS transistor Q6 charges the output load connected to the output node N11. When the noninverted input signal IN+ is lower in voltage than the inverted input signal IN−, the voltage level at the output node N11 is increased, which means the PMOS transistor Q6 is turned off and the output node N11 is discharged by the NMOS transistor Q7.
In the above-described operational amplifier 100, the driving capability of the PMOS transistor Q6 is sufficient for charging the output node N11, but the driving capability of the NMOS transistor Q7 for discharging the output node N11 is limited to the quiescent current (i.e., the current when no load is present).
FIG. 2 is a diagram illustrating, both, an input signal 210 inputted to the input terminal of the two-stage operational amplifier shown in FIG. 1, and an output signal 220 outputted through the output node thereof. Referring to FIG. 2, since the PMOS transistor Q6 is controlled by the output signal of the differential amplifier 110 at a rising edge of the input signal 210, the slew rate of the output signal 220 does not matter. Slew rate refers to the maximum rate of change of an amplifier's output signal with respect to its input signal. In essence, slew rate is a measure of an amplifier's ability to follow its input signal.
However, since the NMOS transistor Q7 is controlled by the constant bias voltage Vbias at a falling edge of the input signal 210, time is required to discharge the electric charge stored in the capacitor of the output load which is connected to the output node N11. Therefore, at the time when the output signal 220 falls, slew rate becomes small.
In conventional op-amps, to improve a driving capability of the NMOS transistor Q7, the quiescent current of the NMOS transistor Q7 must be increased. However when the quiescent current of the NMOS transistor Q7 is increased, the power dissipation through the output node N11 is higher than desirable.
In a liquid crystal display (LCD) source driver for driving pixels of an LCD panel where, for example, the number of output buffers corresponds to the number of horizontal pixels, it is undesirable to increase the quiescent current of the NMOS transistor Q7.

Operational amplifier for output buffer and signal processing circuit using the same


A novel thermoplastic resin composition is here disclosed which contains (I) 99 to 1% by weight of a polysulfone or polyether sulfone; (II) 1 to 99% by weight of an acrylonitrile-butadiene-styrene resin; (III) 0.1 to 100 parts by weight, based on 100 parts by weight of the aforesaid resin (I)+(II), of a multi-phase structure thermoplastic resin which is composed of 5 to 95% by weight of an epoxy group-containing olefin copolymer and 95 to 5% by weight of a vinyl polymer or copolymer obtained from at least one kind of vinyl monomer, either of the polymer or copolymer being in the state of a dispersion phase having a particle diameter of 0.001 to 10 .mu.m; and (IV) 0 to 150 parts of an inorganic filler.. Furthermore, a method for preparing the aforesaid composition is also disclosed.

(1) Field of the Invention
The present invention relates to a thermoplastic resin composition having excellent heat resistance and impact resistance, and a method for preparing the same. This composition of the present case can be widely utilized as materials for electrical and electronic machine parts, automobile parts and the like.
(2) Description of the Prior Art
Polysulfones and polyether sulfones are known as engineering plastics having excellent hot water resistance, heat resistance and demensional stability, but they are not always sufficient in impact resistance, particularly notched impact strength and are poor in flowability and moldability. Thus, attempts have been made to eliminate these faults by mixing an acrylonitrile-butadiene-styrene resin (ABS resin) therewith. In Japanese Patent Publication No. 37896/1971, it is described that when the polysulfone is mixed with the ABS resin, a composition having excellent flowability, impact strength, bending strength and heat resistance can be obtained.
However, such a technique is insufficient to satisfy the requirements of the heightened impact resistance in recent years, and materials having higher impact strength are demanded.

Thermoplastic resin composition and method for preparing the same


A radiation detector comprising a first pair of flat reflective surfces parallel to one another and connected by a second pair of flat rectangular reflective surfaces converging toward one another so as to form a reflective chamber having a relatively wide opening for the entrance of radiation and a relatively narrow opening defining a region for receiving radiaiton, there being a radiation sensor positioned in the receiving region for detecting fluctuations in levels of radiation received from a plurality of detection zones.

In the past numerous optic and catoptric arrangements have been developed for channelling low level radiation to electro-optic sensors for detection purposes. Such devices have been used for detecting motion based on sensing changes in infrared radiation levels at intensities which are very near background levels. Typical catoptric detection devices used in the past are those described in U.S. Pat. Nos. 3,271,575 to Falbel; 3,413,468 to Astheimer; and 4,087,688 to Keller. By way of example, among the devices known in the prior art, there has been disclosed an internal reflecting truncated cone for maximizing the gain in infrared signals provided through the wide opening of the cone to a single immersed detector located beyond the truncated cone end. The maximum possible gain achievable with the internally reflective cone is only comparable to an f/0.5 optical system thus necessitating the positioning of a conical plug having a high refractive index between the truncated cone end and the sensor to further condense radiation which would otherwise be reflected back out the wide end of the cone.
Some of the prior catoptric devices reflect radiation from a continuous field of detection to the sensor. However, it has also been found advantageous to divide an optical field into an alternating pattern of detection zones and passive, i.e., dark zones, in order to more reliably detect minor fluctuations in radiation levels corresponding to the slightest motion of a body through the field. Keller discloses the use of a simple collecting lens in combination with a reflective tube for focusing direct and reflected radiation upon a radiation sensor. The combination, which has been useful in burglary alarm systems, divides an optical field into a plurality of isolated detection zones each separated by a dark zone. During movement of a radiation source through one or a number of the detection zones, the corresponding level of radiation transmitted to the sensor will vary significantly from the background level. In response, the electrical signal provided by the sensor to either a conventional pulse detector or an alternating current voltage detector will also fluctuate resulting in an alarm status.
Generally, motion detection devices known in the prior art are of a complex design, or require expensive lenses, or are physically large. Furthermore, such prior art systems have been difficult to provide adequate numbers of zones of coverage and to eliminate large dark areas. Often, focusing problems are experienced with lenses.


Provided is a method for manufacturing a semiconductor device, including a dual-stage deposition step including: a first stage for introducing tantalum penta-ethoxide containing tantalum as a material gas into a reaction chamber in which a semiconductor substrate on a surface of which a lower electrode is made of ruthenium is placed to thus form a tantalum oxide film by a vapor-phase growth method such as a chemical vapor deposition method and the following second stage for removing from the reaction chamber the material gas introduced into the reaction chamber at the first stage and a byproduct produced at the first stage by introducing a nitrogen gas, and wherein the tantalum oxide film is formed on the semiconductor substrate, by repeating the dual-stage deposition step two or more times.

1. Field of the Invention
The present invention relates to a method for manufacturing a semiconductor device and, more particularly, to the method for manufacturing the semiconductor device having a capacitor as an information storing capacitive element in which a lower electrode is made of a metal that has a catalytic action such as ruthenium (Ru) or a like.
The present application claims priority of Japanese Patent Application No. 2002-220468 filed on Jul. 29, 2002, which is hereby incorporated by reference.
2. Description of the Related Art
Large Scale Integrations (LSIs) known as a representative of semiconductor devices are roughly classified into memory products and logic products, a former of which in particular has been developed remarkably with an up-growth of recent technologies for manufacturing the semiconductor devices. The memory products are further classified into Dynamic Random Access Memories (DRAMs) and Static Random Access Memories (SRAMs), most of which are made up of a Metal Oxide Semiconductor (MOS) transistor excellent in integration density. The DRAMs, in particular, are advantageous over the SRAM in utilization of a higher integration density and so can be reduced in costs, thus being widely used as memories in various kinds of storages in an information processing device such as a personal digital assistant, a personal computer, and a like.
In the DRAM, one memory cell is made up of a memory-cell selecting transistor, that is, a MOS transistor to be operated as a switch and a capacitor connected to the memory-cell selecting transistor so that information may be stored according to whether the capacitor is charged or not. It is to be noted that as an amount of information to be stored increases with a recent advance of an information-oriented society, an area occupied by the capacitor formed on a semiconductor substrate is decreased, so that a capacitance of the capacitor in each of the memory cells needs to be increased. If the capacitor does not have a capacitance large enough to store information, the memory cell readily malfunctions due to an external noise signal or a like, thus readily encountering various errors represented by a soft error.
Conventionally, as a capacitive insulating film of a DRAM capacitor, there has been used a metal oxide film or a like such as a silicon dioxide (SiO2) film, a silicon nitride (SiN) film, or a tantalum oxide (Ta2O5) film. Of these capacitive insulating films, the tantalum oxide film, in particular, is a metal oxide film and has a large dielectric constant as compared to the silicon dioxide film, the silicon nitride film, and so can be used as a capacitive insulating film to make up a capacitor having a large capacitance. Such the tantalum oxide film can be formed typically by Chemical Vapor Deposition (CVD), whereby it is easy to form the film. Further, to increase the capacitance of a capacitor, its lower electrode may be shaped in a form of a three-dimensional structure such as a cylinder in some cases.
Further, in a case where a capacitor is made by forming on the lower electrode a capacitive insulating film having a large dielectric constant such as the tantalum oxide films, such metal as ruthenium is used so that if a surface of the lower electrode is oxidized its oxide film may still have conductivity to thus prevent a decrease in capacitance and further, a Metal Insulator Metal (MIM)-type capacitor is used in which metal such as ruthenium is employed as a material of its upper electrode. For example, Japanese Patent Application Laid-open No. 2001-313379 discloses a method for manufacturing a semiconductor device in which a lower electrode is shaped in a form of a three-dimensional structure such as a cylinder and also a MIM-type capacitor is employed, as described above. The following will describe this semiconductor device manufacturing method along its steps with reference to FIG. 11A-11C.
First, as shown in FIG. 11A, for example, on a P-type semiconductor substrate 121, a memory cell transistor 126 made up of an MOS transistor is formed beforehand and a capacitor contact 129 is formed in a contact hole 128 formed in a silicon oxide film 127 and then a plasma oxidized silicon film 131 is formed throughout a surface via a plasma oxy-nitridized silicon film 130. Next, in a cylindrical trench 132 formed in the plasma oxidized silicon film 131, a lower electrode 134 made of ruthenium is formed via a barrier film 133. Next, on the lower electrode 134, a selective growth film 135 made of ruthenium is formed. A reference numeral 122 indicates an element isolation region 122, a reference numeral 123 indicates gate oxide film 123, a reference numeral 124 indicates a gate electrode 124, and a reference numeral 125 indicates an N-type diffusion region 125.
Next, as shown in FIG. 11B, a capacitive insulating film 136 made up of a tantalum oxide film is formed throughout the surface by CVD. The tantalum oxide film is formed by introducing into a reaction chamber an oxygen gas (O2) and a tantalum compound, for example, a tantalum penta-ethoxide (Ta(OC2H5)5]: hereinafter may be referred simply to as PET) as a material gas. Next, as shown in FIG. 11C, an upper electrode film 137 made of ruthenium is formed and patterned to thus form an upper electrode, thereby forming a capacitor.
A semiconductor device manufacturing method similar to that of the above-described publication is disclosed in, for example, Japanese Patent Application Laid-open No. 2002-26273.
As shown in FIG. 12, after the semiconductor substrate is placed in the reaction chamber kept at a predetermined film formation temperature and a predetermined film formation pressure, at a time t100, a material gas obtained by atomizing and vaporizing PET, which is a tantalum compound, with a nitrogen (N2) carrier gas to vaporize it and an oxygen gas are introduced together into it by the respective predetermined amounts, to start forming a tantalum oxide film. At a time t200 after a predetermined lapse of time, introduction of the material gas and that of the oxygen gas are stopped together. In this case, the oxygen gas is used to fill in oxygen vacancies liable to occur during formation of tantalum oxide films and remove organic matter. Further, by a conventional semiconductor device manufacturing method using the above-described film formation sequence, the material gas is introduced continuously at a time, to form a capacitive insulating film having a finally required film thickness.
However, it is found that by the conventional semiconductor device manufacturing method, the tantalum oxide film grows abnormally depending on a shape of an underlying electrode, that is, the lower electrode 134. It is also found that especially, for example, in a case where the cylindrical trench 132 has a high aspect ratio or the plurality of cylindrical trenches 132 occupies a large area, a capacitive insulating film 136, if made up of the tantalum oxide film by the conventional semiconductor device manufacturing method, grows little in the cylindrical trench 132 but grows abnormally at its upper part during its formation process. Such an abnormal growth has not been observed in a case where the cylindrical trench 132 has a small aspect ratio or the lower electrode 134 has a flat shape instead of a cylindrical shape in construction.
Based on these, the present inventor has concluded that the tantalum oxide film readily grows abnormally owing to the following phenomenon.
If, for example, by the conventional semiconductor device manufacturing method shown in FIGS. 11A-11C, the lower electrode 134 made of ruthenium is formed in the cylindrical trench 132 and then the capacitive insulating film 136 made up of a tantalum oxide film is formed, ruthenium acts as a catalyst to accelerate decomposition of the material gas and hence grow the tantalum oxide film, of which growth is further accelerated by a byproduct containing components of oxygen, carbon, nitrogen, or a like produced by the decomposition. As the decomposition of the material gas goes on, the cylindrical trench 132 is gradually filled with the byproduct until the material gas cannot be supplied into the cylindrical trench 132 any more, whereupon the tantalum oxide film does not grow on a side wall and a bottom of the cylindrical trench 132. At the upper part of the cylindrical trench 132, on the other hand, the byproduct is formed a lot, thereby acting to cause the tantalum oxide film to grow explosively hence abnormally. This deteriorates step coverage drastically.
FIG. 13 is an illustration for schematically showing the capacitive insulating film 136 made up of the tantalum oxide film that has grown abnormally at the upper part of the cylindrical trench 132. If step coverage is deteriorated in such a manner, the upper electrode 137, when subsequently formed on the tantalum oxide film in order to complete a capacitor, short-circuits with the lower electrode 134 readily, thereby resulting in malfunctioning of the capacitor.