The invention disclosed herein relates to biochemical methods for the elimination of corneal collagen fiber disorganization to improve vision. Disorganization of corneal collagen fibers is seen in corneal scars, corneal opacification and corneal haze. In addition, the invention relates to biochemical methods for the elimination of corneal collagen fiber disorganization resulting from accidental traumatic injury to the cornea and from refractive surgery for such as radial keratotomy (RK), photorefractive keratectomy (PRK), and laser in situ keratomileusis (LASIK) so as to improve visual acuity and quality of vision.

The invention disclosed herein relates to biochemical methods for the elimination of corneal scars, opacification and haze.
The cornea is the transparent dome on the front of the eye through which light passes. About eighty percent of the focus, or refracting, power of the eye is in the cornea. A reduction of visual acuity and blindness may result from a lack of corneal clarity caused by corneal traumas, corneal scars, or any other cause of corneal opacification.
The global prevalence of eyes with severe corneal opacities is estimated at more than three million, with over 200,000 new cases being added to this pool every year. The current treatment for corneal opacity associated with significant visual impairment is a form of corneal transplantation, called penetrating or lamellar keratoplasty (PKP, LKP), using tissue from corneal donors. While this surgical technique is generally regarded as safe and effective, associated risks include graft failure or rejection, and infections transmitted through the donor cornea (e.g., rabies, HIV, etc.) or the surgical procedure (e.g., HIV, staph infections, etc.) Notwithstanding the various side-effects, the number of corneal transplant surgeries that can be performed is limited by the number of corneas available for transplantation. To date, the availability of donor corneal tissue suitable for transplant has failed to meet the needs of the patient population.
Present methods of correcting refractive errors of the eye, such as eye glasses, contact lenses, radial keratotomy, photorefractive keratotomy or laser in-situ keratomileusis are not useful in the elimination of corneal opacification. Preliminary evidence suggests that radial keratotomy, photorefractive keratotomy, and laser in-situ keratomileusis may cause corneal haze in some patients.
What is needed to treat the loss of corneal transparency is a biochemical, non-surgical method of treatment that produces a cornea with increase transparency. The methods and compositions taught herein satisfy this long-felt need.
The invention disclosed herein relates to biochemical methods for the elimination of corneal collagen fiber disorganization to improve vision. Disorganization of corneal collagen fibers is seen in corneal scars, corneal opacification and corneal haze. In addition, the invention relates to biochemical methods for the elimination of corneal collagen fiber disorganization resulting from accidental traumatic injury to the cornea or from refractive surgery for such as radial keratotomy (RK), photorefractive keratectomy (PRK), and laser in situ keratomileusis (LASIK) so as to improve visual acuity and quality of vision.
The invention disclosed herein relates to improving corneal clarity using non-surgical, biochemical compositions and methods. The biochemical methods for eliminating corneal scars, corneal opacification, and optical aberrations including corneal haze in the eye of a subject mammal without corneal surgery are achieved by treating the source of the corneal distortion. The compositions and methods of the disclosed invention relate to reducing corneal collagen disorganization by biochemical modification of corneal stromal glycoproteins and proteoglycans.
The cornea is a transparent, multi-component structure of the eye through which light passes to reach the retina. The transparency of the cornea to light results from the unique extracellular matrix of the corneal stroma. The stroma is a tissue layer organized into collagenous lamellae of tightly packed parallel collagen fibers embedded in a hydrated matrix of glycoproteins and proteoglycans. The size, regularity, and precise spacing of the fibrillar structures are the physical characteristics essential for corneal transparency (Maurice, 1957).
The role of corneal glycoproteins and proteoglycans in the establishment and maintenance of corneal transparency is not well understood. Stromal proteoglycans have been hypothesized to play a role in the regulation of collagen fiber spacing. (Hassell et al., 1983). Although the precise role of proteoglycans is still unclear, they are thought to influence the hydration, thickness and clarity of the cornea. (Borcheding et al., 1975). The functional significance of hyaluronan in the cornea, except during development (Toole and Trelstad, 1971) and in some corneal abnormalities (Fitzsimmons et al., 1994) is still unknown.
In some opaque human corneal scars, the scars have been found to contain collagen fibrils with abnormally large diameter and irregular interfibrillar spacing. (Schwarz and Keyserlingk, 1969). However, during wound healing of rabbit corneas, the early opaque scars contain collagen fibrils of generally normal diameter that are irregularly spaced within the tissue. The collagen fibril diameter does not markedly change after a year of healing, but the spacing between the fibrils returns to normal and there is a concomitant decrease in the opacity of the scar. (Cintron and Kublin, 1977 and Cintron et al., 1978).
A 1983 paper authored by Hassell et al., showed that opaque scars that contained large interfibrillar spaces also contained unusually large chondroitin sulfate proteoglycans with glycosaminoglycan side chains of normal size. These opaque scars also lacked the keratan sulfate proteoglycan but did contain hyaluronic acid. The biochemical analysis of proteoglycans in rabbit corneal scars in corneal wounds compared to normal cornea adjacent to the scar demonstrates that the areas synthesize proteoglycans measurably different from one another. (Cintron et al., 1990).
Hassell et al. (1980) analyzed corneal specimens obtained during surgery from patients with macular corneal dystrophy. Hassell et al. found that cells from normal corneas synthesized both a chondroitin sulfate proteoglycan and a keratan sulfate proteoglycan similar to those present in monkey and bovine corneas. Cells in macular corneal dystrophy synthesized a normal chondroitin sulfate proteoglycan, but did not synthesize either keratan sulfate or a mature keratan sulfate proteoglycan. Instead, the cells synthesized a glycoprotein with an unusually large oligosaccharide side chain.
As discussed above, various traumas to the cornea result in the formation of corneal scars or opacification. The opacity of the scar tissue itself results from corneal collagen fibers that have grown during the healing process and lack the same level of organization found in undamaged corneal tissue. Penetrating keratoplasty, which uses corneal tissue from donor corneas in the form of corneal graft is the only surgical technique presently available to eliminate corneal scars or opacification. The challenges associated with penetrating keratoplasty are: (a) availability of human donor corneas for surgery; (b) compatibility of donor corneas and probability of graft survival; (c) donor cornea graft rejection; (d) donor cornea infection. The compositions and methods of the disclosed invention offer a non-surgical alternative to penetrating keratoplasty.
The transparency of the cornea may be altered in a manner more subtle than that seen in the corneal traumas described above. In certain situations the appearance of optical, monochromatic aberrations may decrease the visual acuity (VA) of a subject""s eye. On the basis of the mosaic structures of the retina, the visual acuity of the human eye could be 20/10 or better; however, such good acuity is rarely obtained. Two optical conditions accounting for the sub-optimal level of visual acuity are: diffraction due to pupil size and monochromatic aberrations. (Campbell, et al., 1974). The limitations of visual acuity caused by diffraction decreases with increasing pupil diameter and may play an important role only for pupils smaller than 2 mm. The optical errors of higher order (aberrations) of the human eye, however, demonstrates an opposite behavior and may increase with larger pupil diameter.
The shape of the human cornea and lens is naturally designed in a way that these aberrations are minimized. To our knowledge, the monochromatic aberrations of the human eye so far have not been studied systematically in large series of individuals. (Howland, et al., 1977). Therefore, average values for a standard population are not available. However, loss of visual acuity through the introduction of optical aberrations may become clinically relevant with the advent of refractive corrective surgery.
Refractive surgery for myopia and astigmatism, such as radial keratotomy (RK), photorefractive keratectomy (PRK), and laser in situ keratomileusis (LASIK), induce a non-physiological corneal shape with a flat central area and increasing power towards the periphery. This shape induces an increase in optical aberrations (Seiler T et al., 1993), (Pallikaris I., 1998), and may lead to visual losses that are detected under low lighting conditions (Seiler T, et al., 1994), and by low contrast visual acuity testing (Verdon W., 1996). These side effects of corneal refractive surgery have the potential for public health problems of a yet unknown dimension.
Comparison of corneal wavefront aberrations after PRK and LASIK has been compared in a prospective randomized study of 22 patients with bilateral myopia who received PRK on one eye and LASIK in the other eye. (Oshika T et al., 1999). Before surgery, simulated papillary dilation from 3 mm to 7 mm caused a five to six fold increase in the total aberrations. After surgery, the same dilation resulted in a 25 to 32 fold increase in the total aberrations in the PRK group and a 28 to 46 fold increase in total aberrations in the LASIK. Both photorefractive keratectomy and laser in situ keratomileusis significantly increased the total wavefront aberrations and the values did not return to the preoperative level throughout the 12-month follow-up period.
Corneal wound healing studies in rabbits following LASIK to evaluate the corneal wound healing process were conducted for 1, 2 and 9 months past LASIK surgery. Periodic histopathological evaluation of the rabbit corneas showed disorganized collagen fibers along the interface of the corneal flap even 9 months after the LASIK surgery. These results show that the corneal aberrations and the wound healing process induced by the LASIK surgery continued at 9 months after LASIK. (Kato T, 1999). The methods and compositions of the invention disclosed herein provide the means with which to overcome the optical aberration side-effect of modem refractive surgical techniques.
Without being restricted to any particular mechanism of action, it has been theorized that the various corneal aberrations resulting from RK, PRK, LASIK, and other surgical procedures result from corneal collagen disorganization that occurs during the healing process. For example, following the LASIK procedure, after the flap is positioned to cover the site of the surgical procedure, corneal collagen will be formed to seal the incision. As this collagen is formed it is thought to be arranged in a conformation that is, to one degree or another, less organized than the collagen located in areas of the cornea not affected by the surgery. Reorganization of this material would lead to a reduction in optical aberrations resulting from such surgeries.
Accordingly, the disclosed invention relates to a biochemical method for the elimination of corneal aberrations and corneal collagen fiber disorganization resulting from accidental traumatic injury to the cornea or from refractive surgery for myopia, hyperopia and astigmatism, such as radial keratotomy (RK), photorefractive keratectomy (PRK), and laser in situ keratomileusis (LASIK) so as to improve visual acuity and quality of vision.
Corneal Collagen Reorganizing Enzymes and Agents
The disclosed invention provides for the introduction of particular compositions into a subject""s cornea to improve the visual acuity of the subject. The compositions contemplated for use include a number of enzymes or other agents that result in the reorganization of corneal collagen fibers. Of particular interest are enzymes that act to alter, digest, or otherwise degrade various components that decorate or are in association with the corneal collagen fibers. However, the methods and compositions of the disclosed invention are not limited to the use of these enzymes and agents, and include other chemicals that can be administered to reorganize corneal collagen fibers through various different mechanisms of action.
One embodiment of the disclosed invention provides for the administration of a corneal collagen fiber reorganizing amount of an enzymes which, when contacted with the corneal stroma, will accelerate the rate of breakdown of corneal proteoglycans and lead to the reorganization of corneal collagen. The resulting reorganization will clear corneal scars, corneal opacities and corneal haze.
A variety of glycoaminoglycanase enzymes are contemplated for use with the disclosed invention. These enzymes all exhibit the property of providing a corneal opacity clearing effect as well as the ability to eliminate corneal aberrations and corneal collagen fiber disorganization. Specific enzymes include: hyaluronidase, keratinase, chondroitinase AC, chondroitinase B, chondroitinase ABC, and chondroitin 4 sulfatase.
A variety of metalloproteinase enzymes are contemplated for use with the disclosed invention. These metalloproteinase enzymes exhibit a corneal opacity clearing effect and have the ability to eliminate corneal aberrations and corneal collagen fiber disorganization. Specific examples of suitable enzymes include: matrix metalloproteinase-1, matrix metalloproteinase-2, matrix metalloproteinase-3, and matrix metalloproteinase-9.
Various protein-kinase enzymes that exhibit a corneal opacity clearing effect as well as the ability to eliminate corneal aberrations and corneal collagen fiber disorganization are also contemplated for use with the disclosed invention. Specific examples of such enzymes include: streptokinase and urokinase.
In addition to these enzymes, other enzymes known in the art that alter and modify corneal collagen fibrillar structure may be used with the methods of the disclosed invention. Suitable enzymes induce modifications to corneal collagen or the components thereof that decrease corneal opacification and corneal optical aberrations.
Formulations
The invention disclosed here contemplates a number of different formulations that are effective in producing the reorganization of corneal collagen. One embodiment of the invention contemplates the formulation of an injectable solution containing a corneal collagen reorganizing enzyme. The injectable solution may contain certain inactive ingredients which cause the solution to be substantially isotonic and of a pH which is suitable for injection into the eye. Such solution for injection may be initially lyophilized to a dry state and thereafter, may be reconstituted prior to use.
A general formulation for an injectable thimerosal-free, hyaluronidase preparation, of the present invention is shown in Table I as follows:
This formulation of ingredients is produced by initially dissolving the ingredients in sterile water, sterile filtering the solution and subsequently dispensed as a solution or lyophilized to a dry composition. The lyophilized composition can be packaged for subsequent reconstitution prior to use, in balanced salt solution or sterile isotonic saline solution. Such balanced salt solution typically contains: 0.64% sodium chloride, 0.075% potassium chloride, 0.048% calcium chloride dihydrate, 0.03% sodium acetate trihydrate, 0.17% sodium citrate dihydrate, sodium hydroxide/hydrochloric acid to adjust the pH, and water for injection to 100%.
Many kinds of hyaluronidase enzyme free of thimerosal preservative could be used, however, the term xe2x80x9chyaluronidase ACSxe2x80x9d as used herein describes a preferred hyaluronidase, which is devoid of hyaluronidase molecular weight fractions above 100,000, between 60,000-70,000 and below 40,000 (10% SDS-PAGE). Such hyaluronidase may be derived from ovine testicles and is available on request from Biozyme Biochemicals, 9939 Hilbert Street, San Diego, Calif. 92131-1029. Applicants have determined that this specific molecular weight distribution of the hyaluronidase ACS results in less ophthalmic toxicity than other hyaluronidase preparations, while exhibiting desirable therapeutic efficacy in a number of ophthalmic applications.
The specific molecular weight distribution and specific enzyme activity profile of the preferred hyaluronidase (ACS) of the present invention, and/or the exclusion of thimerosal from its formulation, provides a hyaluronidase preparation which is non-toxic to the eye when administered at dosage levels at which other hyaluronidase preparations preserved with thimerosal would cause toxic effects.
As described in the examples below, the specific preferred formulation as hyaluronidase ACS set forth in Tables II-V (above) may be injected, applied topically, or by contact lens directly into the stroma of the eye at dosage levels which bring about desirable therapeutic effects, including but not necessarily limited to the elimination of a corneal opacity, without causing significant toxicity to the eye.
Determining Suitable Corneal Collagen Reorganizing Enzymes and Agents and their Dosages
The corneal collagen reorganizing chemicals, such as various agents and enzymes, used in the methods of the disclosed invention, in addition to the proper dosages of such agents and enzymes, can be determined by one of skill in the art through routine experimentation. Such experimentation can comprise testing a dose of an enzyme or agent on donor globes (eyes) mounted in plastic model sockets or testing such a dose on laboratory animals. Briefly, to determine whether an enzyme or agent is effective in reorganizing the collagen of a cornea without producing toxicity, the enzyme or agent is first mixed in a carrier vehicle that is pharmaceutically acceptable to a mammal. Preferably, the enzyme or agent is in lyophilized (dry powder) form, and is dissolved in isotonic saline. However, one of ordinary skill in the art will understand that a variety of pharmacologically acceptable carriers which do not interfere with the functioning of an enzyme or agent can be used. Such a procedure is also followed to test various doses of a compound of interest.
A test dose of the enzyme or agent in solution is then administered to a test cornea in order to determine its corneal collagen reorganizing and toxic effects. In one procedure for testing candidates, the test enzyme or agent is first administered to corneas. This procedure is particularly preferred for determining the effect of an enzyme or agent on a human cornea because in this way a human cornea can be tested without subjecting a living person to experimentation.
The test dose of enzyme or agent is then administered to the donor cornea. Such administration can be, for example, by injection of the enzyme into the cornea. Normally, the lens will become opacified following this step due to the introduction of water into the eye and a change in the refractive index of the eye. After a test period of time, the mounted cornea is then examined to determine whether any corneal collagen reorganization has occurred, and if so the extent of such reorganization. Toxicity resulting from the injection is also determined.
The examination of the cornea can be performed, for example, through slit-lamp examination to determine the clarity of the cornea; pachymetry to measure the thickness of the cornea; measurement of the tensile strength of the cornea; measurement of the distensibility of the cornea; and keratometry to measure central corneal curvature. The values determined from these tests are compared to values determined prior to the administration of the agent or enzyme.
In addition, a treated cornea in a mounted globe can be subjected to a number of other tests to determine the strength and viability of the cornea following treatment. For example, light microscopy, scanning, x-ray diffraction analysis, and transmission electron microscopy can be used to examine the morphology of the cornea; tissue culture is prepared to determine the viability of the cells of the cornea following treatment; biochemical studies can be made of the collagens and other structural components of the cornea following treatment.
The foregoing tests of donated globes and corneas can be used to verify that use of a particular enzyme or agent increases the transparency of the cornea, and yet does not decrease the viability of the corneal cells or damage the structural integrity of the cornea. Testing the use of an enzyme or agent on the cornea of a test animal, however, is also desirable in order to make sure that the candidate has no unexpected effect in living mammals that is not discovered during tests of donated eyes. In order to test the effect of a particular test enzyme or agent, a test dose in a pharmacologically acceptable carrier solution is administered to a test animal, in this case a mammal, so as to deliver that agent to the cornea of the animal.
Following the administration of an agent to the cornea of the animal, the animal""s cornea can be subjected to the following examinations: slit lap examination to determine the clarity of the cornea, anterior chamber and iris; pachymetry to measure corneal thickness; computer assisted corneal topography to evaluate the surface topographical change of the cornea; measurement of the elasticity of the cornea; tonometry to measure intraocular pressure; fundoscopic examination in order to evaluate the optic nerve and retina; keratometry to measure central corneal curvature; retinoscopy to measure refractive error; staining with fluorescein or Rose Bengal to identify damage to the corneal epithelium; and indirect ophthalmoscopy. The values determined through these tests can be compared to values determined prior to the administration of the enzyme or agent, as well as to values determined for the untreated eye of the animal.
In addition, a treated cornea of a test animal can be subjected to a number of other tests to determine the clarity, strength, and viability of the cornea following treatment. For example, light microscopy, scanning, and transmission electron microscopy can be used to examine the morphology of the cornea; a tissue culture is prepared to determine the viability of the cells of the cornea following treatment; and biochemical studies can be made of the collagens and other structural components of the cornea following treatment.
Other corneal collagen-modifying enzymes and agents not disclosed herein and proper doses of such known and unknown enzymes and agents can be determined as described hereinabove in relation to determining enzymes and doses of enzymes.
Methods of Administration
Applicant has devised a method for a non-surgical clearance of corneal scars and corneal opacities. These methods generally comprise contacting the cornea with a corneal collagen reorganizing amount of an agent or enzyme in an amount which is effective to accelerate the clearance of corneal opacities. The corneal opacity clearing methods of the disclosed invention may be performed without any other surgical manipulation or removal of the cornea, thereby avoiding the potential risks and complications associated with penetrating keratoplasty.
The foregoing enzymes and agents for reorganizing the collagen of a subject""s cornea may be administered in any way known to the art. For example, in one embodiment, an enzyme or agent is injected directly into the eye in a location proximal to the cornea. In this embodiment, the enzyme or agent should be mixed in a pharmacologically acceptable carrier that will not alter the effectiveness of the enzyme or agent contained therein.
In one particular embodiment of the disclosed invention, the route of administration of a corneal collagen reorganizing enzyme or agent is by intra-stromal injection. In this embodiment, an injectable solution containing one or more of the above-listed corneal collagen reorganizing enzymes or agents is injected, through a needle, directly into the stroma located within the anterior part of the eye.
In another embodiment of the disclosed invention, corneal collagen reorganizing enzymes and agents are administered to the eye of a subject by topical application in the form of eye drops. A sufficient number of drops are applied so as to administer a desired concentration of enzyme or agent to the cornea of the subject. The eye drop method of administration may be superior to injection based administration based on the less discomfort to the cornea of the subject resulting from an injection technique.
In still another embodiment, alternative means of aiding diffusion across the eye into the cornea may be used. Such means include, for example, the use of liposomes to deliver the active enzyme or agent. The enzyme or agent is packaged into liposomes, which can pass across the lipid soluble membrane of the corneal epithelium and into the corneal stroma. Other means of aiding diffusion include the use of an electrical current to make the outer membrane of the eye more permeable to the passage of enzymes and agents, known as iontophoresis.
In another embodiment, iontophoresis is used to administer the corneal collagen reorganizing reagents. Using this procedure, an electrical current traveling through a salt solution causes the agents to pass into the eye as charged particles.
In yet another embodiment of the disclosed invention, corneal collagen reorganizing enzymes and agents are administered to the cornea through use of a contact lens. As an example of one embodiment of the disclosed invention, a corneal collagen reorganizing amount of a corneal collagen reorganizing agent is loaded into a chamber inside a rigid contact lens, preferably one which is gas permeable. Alternatively, the enzyme or agent can be loaded or impregnated into a soft lens capable of taking up the enzyme or agent by soaking the soft lens in a solution containing the enzyme or agent. The enzyme or agent can also be loaded into a combination of a soft and a rigid lens.
In all of the following embodiments of a contact lens for administering a corneal collagen reorganizing enzyme or agent, the enzyme or agent is administered as it diffuses out of (is released from) the chamber in the lens or the material of the lens (if the enzyme or agent is soaked into a soft lens). Dosages for different contact lens delivery vehicles can be optimized through routine experimentation by one of skill in the art.
In accordance with one method of administration through contact lenses of the disclosed invention, corneal collagen reorganizing enzymes and agents can be applied to the eye through the use of rigid contact lenses. These lenses can be made from known fluoro silicone acrylate lens materials, which are gas permeable. The lens is provided with an internal chamber for storing the corneal collagen reorganizing enzyme or agent. The chamber preferably comprises a radially symmetrical space encircling the entire lens between the anterior surface and posterior surface of the lens.
Rigid lenses for the present purpose can conveniently be made by lathe cutting, molding, or milling a posterior component and an anterior component from a contact lens button which, during fabrication, can be secured together to form a unitary lens using bonding techniques or adhesives known in the art. The chamber can be formed by lathe cutting an annular recess into the convex surface of the posterior component of the lens before the final lens fabrication. Any of a variety of dimensions can be used in accordance with the disclosed invention, a preferred lens is provided with an annular chamber having a width of approximately 1.0 mm to about 1.5 mm and a depth of from about 0.05 mm to about 0.10 mm.
A plurality of microscopic holes are provided in the posterior portion of the lens to allow fluid communication between the chamber and the eye, thereby facilitating the timed release of the corneal collagen reorganizing enzyme or agent into the cornea. These holes may be provided by mechanical or laser drilling, or by molding prior to assembling the anterior component and posterior component of the lens. In one embodiment the holes are drilled using a mechanical drill having a microcarbon drill bit.
The pumping action of the eyelids combined with natural tearing assists the release of the corneal collagen reorganizing enzyme or agent through the tiny holes. Preferably, the holes are produced by mechanical drilling with a microcarbon bit and will have a diameter of from about 0.002 mm to about 0.010 mm, and preferably about 0.005 mm. The number and diameter of the holes can be varied to affect the time release characteristics, as will be apparent to one of skill in the art. In general, however, for the diameter ranges specified above, from about 3 to about 10 holes are contemplated to be used.
In one embodiment of the lens, the posterior portion of the lens has a centerpoint thickness of approximately 0.12 mm and an annular recess is lathed to a depth of about 0.075 mm. A number of holes, each having a diameter of about 0.005 mm, are drilled through the bottom of the chamber and spaced equidistantly apart around the periphery of the chamber to provide communication with the posterior surface of the lens. The number of holes in a lens will vary, depending on the desired rate of administration of corneal collagen reorganizing enzyme or agent from the chamber.
The anterior portion of the lens, having a centerpoint thickness of about 0.12 mm is thereafter secured to the posterior portion to enclose the annular recess and form a chamber, thereby forming a lens having an overall center thickness of about 0.24 mm. Bonding can be accomplished by applying a small amount of a bonding agent such as Concise(trademark) enamel bonding system sold by 3M (St. Paul, Minn.). Other means of joining the posterior and anterior portions of the contact lens will be apparent to those of skill in the art.
In another aspect of the disclosed invention, a contact lens is provided which is composed of two layers which are laminated together. In this advantageous design for a contact lens of the disclosed invention, larger chambers for storing corneal collagen reorganizing enzyme or agent can be created.
In this contact lens, an anterior portion of the contact lens may be manufactured having an anterior surface and a posterior surface. A posterior portion of the contact lens may also be manufactured with an anterior surface and a posterior surface. The outer perimeter of the posterior surface of the anterior portion may be designed to have the same radius of curvature as the outer perimeter of the anterior surface of the posterior portion. In this way, when the posterior surface of the anterior portion and the anterior surface of the posterior portion are laminated together, a seal may be formed between the outer perimeters of the anterior and posterior portions.
However, in a central portion of the anterior portion, the posterior surface may have a steeper radius of curvature than the anterior surface of a central portion of the posterior portion. Because of this steeper radius of curvature, when the anterior portion and the posterior portion are laminated together, a chamber is formed between the central portion of the anterior portion and central portion of the posterior portion of the contact lens. The volume of the chamber can be adjusted by changing the radii of curvature of the posterior surface of the central portion and of the anterior surface of the central portion, as will be apparent to one of skill in the art.
Prior to manufacture, one or more holes may be made in the central portion of the posterior portion of the contact lens of this design. The holes may be produced by mechanical drilling with a microcarbon bit or by means of a laser such as an argon laser, and will have a diameter of from about 0.002 mm to about 0.010 mm, and preferably about 0.005 mm. The number and diameter of the holes can be varied to affect the time release characteristics, as will be apparent to one of skill in the art. Thus, the rate at which a dose of a corneal collagen reorganizing enzyme or agent is dispensed from the chamber is largely controlled by the size and number of holes present in the central portion of the posterior portion of the lens. In general, however, for the diameter ranges specified above, from about 3 to about 10 holes are contemplated to be used. These holes may be spaced around the central portion of the posterior portion of the contact lens in order to provide communication between the chamber and the surface of the eye of a subject wearing the lens.
In a preferred embodiment of this lens, the posterior portion of the lens may have a centerpoint thickness of approximately 0.125 mm. The anterior portion of the lens may have a centerpoint thickness of about 0.125 mm. When the anterior portion and the posterior portion are joined, a lens is created having an overall center thickness of about 0.24 mm. Bonding can be accomplished by applying a sufficient amount of a bonding agent such as the Concise(trademark) enamel bonding system sold by 3M (St. Paul, Minn.). Other methods of bonding will also be apparent to one of skill in the art.
A lens of this embodiment of the disclosed invention may be made from known fluoro silicone acrylate lens materials. Such rigid lenses can be made by lathe cutting, molding, or milling a posterior component and an anterior component from a contact lens button. After the anterior and posterior components are manufactured, they can be secured together to form a unitary lens using bonding techniques, adhesives, or any other method of attachment known to the art. For example, an enamel bond system can be used to join the anterior and posterior contact lens portions. An example of such a system is the Concise(trademark) enamel bond system sold by 3M (St. Paul, Minn.).
In an alternate embodiment of a contact lens of this aspect of the disclosed invention, a lens is provided which has a peripheral chamber rather than a chamber in the central portion of the lens. In this embodiment, the lens may be composed of an anterior portion and a posterior portion which are laminated together. In this embodiment, a chamber is provided in an intermediate portion of the lens.
In another embodiment, the chamber may be formed in the intermediate portion of the lens by providing an area of the posterior surface of the anterior portion of the lens, which has a steeper radius of curvature than that found in the remainder of the posterior surface of the anterior portion of the lens. As in the foregoing embodiment of a chambered contact lens, the volume of corneal collagen reorganizing enzyme or agent which can be contained in the lens and thus administered to a subject is largely determined by the radius of curvature of the posterior surface of the interior portion of the lens in the intermediate portion of the lens, as well as by the radius of curvature of the anterior surface of the posterior portion of the lens in the intermediate portion of the lens.
The posterior portion of the lens is also provided with holes through the posterior portion of the lens in the intermediate portion of the lens. These holes serve to allow the transfer of the contents of the chamber from the chamber to the eye of the subject. The number and size of the holes will largely determine the rate at which a corneal collagen reorganizing enzyme or agent is delivered to the eye.
Although the embodiments of a chambered contact lens have been described as being produced by laminating together an anterior portion and a posterior portion of the lens, one of skill in the art will recognize that other methods of forming the previously described chambers are also possible.
In accordance with a further delivery method of the disclosed invention, a soft lens bandage or shield may be soaked or charged with a dose of the corneal collagen reorganizing enzyme or agent. The soft lens may then be properly fit to the cornea and worn for a matter of hours to release the enzyme or agent into the cornea. After the enzyme or agent sufficiently modifies the collagen of the cornea, the soft lens either dissolves or is taken off.
Other types of soft lens materials tend to uptake less of a solution containing an enzyme or agent and also to release it more quickly. Examples of such materials are common hydrophilic soft lens materials such as etafilcon A and phemfilcon A, available from Vistacon and Wesley Jessen. These lenses can be the disposable or long-term wear variety. Lens having an H2O content of between about 58% and about 70% may be found to be useful in the disclosed method.
Fields of Use
One contemplated use of the disclosed invention is to treat corneal opacifications. Corneal opacifications may arise with age, as the corneal collagen loses its organization, or as a result of some trauma. The compositions and methods of the disclosed invention are useful in eliminating such corneal opacifications.
Another contemplated use of the disclosed invention is to rehabilitate irregularities and improve refractive errors that result from various corneal surgeries. The surgeries contemplated include photorefractive keratectomy (PRK), LASIK, radial keratotomy (RK), corneal transplant surgery, and cataract surgery. For example, LASIK is becoming an extremely common procedure worldwide. Although the technique itself is very successful, the incidents of side-effects from the treatment that are attributable to corneal collagen disorganization are growing. The disclosed invention can be used to improve visual acuity of a subject following the surgical reshaping of the cornea using various surgical techniques.
In this embodiment of the invention, a patient who had undergone the LASIK procedure would be identified and an acceptable corneal collagen reorganizing agent would be selected. Administration of the corneal collagen reorganizing agent may occur before, during or after the surgical procedure. In one embodiment, the subject could receive the corneal collagen reorganizing agent after the surgical procedure to facilitate proper healing of the cornea. As discussed above, routes of administration contemplated include injection and topical administration.
Similarly, the disclosed invention may also improve the chances of success for other corneal procedures, such as corneal transplant surgery and cataract surgery. One of the most common reasons for the clinical failure of surgical procedures like corneal transplants, is the existence of residual refractive errors following an otherwise successful surgery. The compositions and methods disclosed here can be used to correct the refractive error that occurs as a result of disease, surgery, or other conditions. Also, the compositions and methods of the disclosed invention, by improving the visual acuity resulting from a surgical procedure, will reduce or eliminate the need for subsequent surgeries that are now required to eliminate unwanted refractive errors.
To use the foregoing methods of the disclosed invention to effect these further clinical benefits, subjects who have corneal opacification, corneal collagen disorganization, or who have under gone a corneal manipulation are first identified. Such identification is normally accomplished by an eye specialist or other practitioner skilled in the art who can diagnose an individual as having corneal opacification, corneal collagen disorganization, or having undergone corneal manipulation. The previously described methods of administration are then used to induce corneal collagen reorganization to produce enhanced visual acuity.

Biochemical methods that eliminate corneal scars, opacification and haze


A cushion arrangement for smoothing stage changes in an hydraulic cylinder and including at least one compression chamber of variable volume with a movable and/or deformable chamber wall element displaceable by at least one of the pistons when approaching the transition zone between first and second stages of displacement. The compression chamber is operatively connected to a gas volume to be compressed upon displacement of the chamber wall element.

The present invention relates to a multi-stage hydraulic cylinder for providing multiple stages of displacement with different cylinder forces, comprising a cylinder housing, a first stage piston slidably received in said cylinder housing to be displaced over a first stage of displacement, a second stage piston coupled to said first stage piston to be displaced, together with said first stage piston, over said first stage of displacement and to be displaced relative to said first stage piston over a second stage of displacement, said first stage piston and said second stage piston having pressure surface areas different from each other to provide for said different cylinder forces, and further comprising a cushion arrangement for smoothening stage changes.
Certain applications of hydraulic cylinders require different displacement forces at different stages of displacement. For example, in large mining trucks, the dumping body for collecting and transporting the mining material is tilted about a horizontal axis to dump the material, said tilting movement requiring a large driving force at the initial stage of tilting, whereas the required driving force is considerably decreased when the dumping body reaches a more upright position with the center of gravity being closer to the tilting axis and a part of the material already having been dumped.
In such hydraulic systems where one or more fixed or variable displacement pumps may be used for operating one or more multi-stage hydraulic cylinders, there exists mechanical contact at the time of stage change. In applications where the force required from the cylinder decreases dramatically as extended length increases, it is desirable to have considerably smaller second stage than first stage, resulting in a large area ratio. However, such large area ratio causes a shock when the first stage piston reaches its mechanical stop. In certain applications of such multi-stage hydraulic cylinders, basically the same pressure is supplied to both the first stage piston and the second stage piston so due to the large area ratio of such pistons a rather hard shock is caused when the first stage piston reaches the end of its displacement path and hits against the mechanical stop.
In order to reduce such shocks, a cushioning arrangement may be used to decelerate the piston at the end of its displacement path before the piston hits said mechanical stop, thereby reducing the velocity of the piston when hitting against the mechanical stop. Various solutions for such cushioning arrangements have been proposed. For example, document U.S. Pat. No. 4,397,218 discloses a cushioning device for decelerating and stopping the piston in a hydraulic cylinder by restricting and throttling the fluid flow from the cylinder. More particularly, the flow of fluid is reduced as the end of stroke in the cylinder is reached. A plunger is slidably received in a flow path, said plunger being pushed deeper into said flow path by the piston approaching its end position, wherein the flow path gets further restricted as the plunger is inserted deeper. However, the downside to this, especially in a fixed displacement system, is any fluid that does not do work on the cylinder is required to flow over a relief valve creating unnecessary heat.
Furthermore, document U.S. Pat. No. 7,104,054 discloses a way to electronically control the speed as a piston reaches the end of its stroke. The hydraulic cylinder system includes a sensor configured to generate a signal indicative of hydraulic cylinder position and a valve coupled to the cylinder to control flow rate of hydraulic fluid to and from the cylinder so that an electronic controller that is coupled to the sensor may command valve opening and closing in response to the hydraulic cylinder position. Such electronic sensing and commanding system is quite expensive, increases complexity and is prone to damages and functional errors under rough environmental conditions.
Furthermore, document US 2006/0151269 discloses a cushioning device that completely prevents the piston from colliding with the end boss. At the end of the piston stroke, a portion of the hydraulic oil to be discharged from the pressure chamber is trapped and may be discharged via a throttle clearance only. In addition, an elastic cushion element made of rubber is positioned between the end boss and the piston to prevent the piston from directly hitting onto the end boss. Such elastic cushion, however, is not advantageous in certain applications due to multiple reasons. In particular, the space required to have an elastic cushion element is not available in certain cylinders such as multi-stage cylinders where a plurality of pistons are to be received within the cylinder housing. Also the forces present in cylinders for large applications such as mining trucks or other large construction equipment prohibit effective use of an elastic cushion element made of rubber. Furthermore, the durability of an elastic cushion element is rather limited in applications where the cylinder is operated at high frequencies and high loads.


A hot melt adhesive including syndiotactic polypropylene having a polymer chain of at least 80% racemic dyads and having a melting point of about 100.degree. C. to 180.degree. C.

A class of adhesive compositions known as thermoplastic or hot melt adhesives have enjoyed continually increasing usage in many industrial applications. These adhesives, or hot melts, as they are commonly designated, are solid or semisolid combinations of film forming resins, tackifying resins, rubbery polymers, plasticizers, waxes and similar materials which are added to the adhesive composition in order to impart various properties thereto.
Adhesive bonds derived from hot melts are particularly useful because (1) they are 100 percent solid materials and (2) they quickly form tough adhesive bonds simply by cooling--i.e. no need for solvent evaporation, etc.
Adhesive derived from hot melts are particularly useful because of their very rapid set up or bonding time. Strong bonds are formed when the adhesive cools below its melt point and crystallizes. There is no long wait for solvent or water evaporation or for chemical curing as with other type adhesives. chemical curing as with other type adhesives. Depending on composition, hot melt adhesives can be prepared having good tack, high bond strength, good flexibility, low temperature properties, good environmental resistance etc.
A typical class of hot melt adhesive composition utilizes polyolefin polymers as the base or carrier material. The polyolefin base is usually blended with other polymers and copolymers, resin tackifiers and with modifiers and additives.


Rolls include a core and a glass outer coating on the core. The glass can be electrically charged and discharged. The outer coatings have smooth finishes and controlled electrical properties. The outer coatings can also provide selected mechanical, chemical and thermal properties. The rolls can be used in various applications in which controlled electrical properties are desired. For example, the rolls can be used as charge donor rolls in electrostatographic imaging apparatus.

1. Field of Invention
This invention relates to rolls, such as for use in electrostatographic imaging devices.
2. Description of Related Art
Electrostatic reproduction involves uniformly charging a photoconductive member, or photoreceptor, and imagewise discharging it, or imagewise exposing it, based on light reflected from an original image being reproduced. The result is an electrostatically-formed latent image on the photoconductive member. The latent image is developed by bringing a charged developer material into contact with the photoconductive member.
Two-component and single-component developer materials are known. Two-component developer materials comprise magnetic carrier particles and charged toner particles that adhere triboelectrically to the carrier particles and are intended to adhere the photoconductive member.
A single-component developer material typically consists of only toner particles. The toner particles typically have an electrostatic charge to adhere to the photoconductive member, and magnetic properties to magnetically convey the toner particles from the sump to the magnetic roll. The toner particles adhere directly to the donor roll by electrostatic charges. The toner particles are attracted to the donor roll from a magnet or developer roll. From the donor roll, the toner is transferred to the photoconductive member in the development zone.
For both types of developer material, the charged toner particles are brought into contact with the latent image to form a toner image on the photoconductive member. The toner image is transferred to a receiver sheet, which passes through a fuser device where the toner particles are heated and permanently fused to the sheet, forming a hard copy of the original image.
A development device is used to bring the charged toner particles into contact with the latent image formed on the photoreceptor, so that the toner particles adhere electrostatically to the charged areas on the latent image. The development device typically includes a chamber in which the developer material is mixed and charged.
One type of two-component development method and apparatus is known as xe2x80x9cscavengeless development.xe2x80x9d In scavengeless development systems, toner is detached from the donor roll by applying an alternating current (AC) electric field to electrodes disposed between the donor roll and the photoconductive member. There is no physical contact between the development apparatus and the photoconductive member. Scavengeless development is useful in apparatus in which different types of toner are supplied to the same photoconductive member.
xe2x80x9cHybridxe2x80x9d scavengeless development apparatus typically includes a mixing chamber that holds a two-component developer material, a developer material developer or magnetic roll, a donor roll, a development zone, and an electrode structure at the development zone between the donor roll and the photoconductive member. The donor roll receives charged toner particles from the developer roll and transports the particles to the development zone. An AC voltage is applied to the electrodes to form a toner cloud in the development zone. Electrostatic fields generated by an adjacent latent image on the photoconductive member surface attract charged toner particles from the toner cloud to develop the latent image on the photoconductive member.
Another variation on scavengeless development uses single-component developer material development systems. As in two-component developer material development systems, the donor roll and electrodes also create a toner cloud.
In both one-component and two-component developer scavengeless development systems, the electrical, chemical and physical characteristics of the donor roll affect the ability of the development apparatus to effectively transport toner particles into the development zone and to achieve high-quality image development. The donor roll should have characteristics that enable charged toner particles to effectively and controllably adhere electrostatically to the donor roll""s outer surface, and be donated to the photoconductive member. It is desirable that the electrical properties of the donor roll be uniform and also tunable. It is also desirable that the donor roll be able to withstand wear and harmful chemicals.
The donor roll outer surface should also have sufficient mechanical properties, including wear resistance, to withstand wear and other types of degradation during service.
It is also desirable that the outer surface of the donor roll have a smooth finish (low roughness).
It is also desirable that the outer surface of the donor roll have good machining characteristics so that a desired surface finish can be formed.
It is also desirable that the outer surface of the donor roll comprises a material that is chemically resistant to withstand exposure to certain chemicals.
It is further also desirable that the outer surface of the donor roll comprises a material that has sufficient thermal properties.
It is still further desirable that the outer surface of the donor roll not be difficult to form and process.
This invention provides rolls, such as donor rolls, that comprise a glass coating that enables charged toner to effectively and controllably adhere electrostatically to the roll, and to be effectively donated to a photoconductive member to form an images.
This invention separately provides rolls having coatings that can be formed using conventional coating techniques.
This invention separately provides rolls having coatings with more uniform, and tunable, electrical properties.
This invention separately provides rolls having coatings with controlled mechanical properties.
This invention separately provides rolls having coatings with high hardness and wear resistance.
This invention separately provides rolls having an outer surface with a smooth finish.
This invention separately provides methods of making such rolls.
Exemplary embodiments of the rolls according to this invention comprise a core and a coating formed over the core. The coating comprises a glass material. Exemplary embodiments of the coating can also provide desired electrical, mechanical, chemical and/or thermal properties.
The properties of the coating make the rolls suitable for use in an electrostatographic imaging apparatus, such as for use in hybrid scavengeless development.
The coatings of the rolls can be applied onto substrates such as cores using conventional coating techniques. Further, the coatings can be processed using conventional finishing techniques.
Exemplary embodiments of the methods of forming the rolls according to this invention comprise applying a glass coating over a core. The coating can be applied over the core by any suitable glass coating process.


A vehicle bumper system, comprises a first bracket fixedly mounted to a bumper. A second bracket is fixedly mounted to a vehicle frame horn, the second bracket including at least one vertical slot. At least one bolt is inserted through an opening in the first bracket and the at least one slot.

Vehicles with relatively high bumpers, such as light trucks, sport utility vehicles, etc., tend to cause more and more serious injuries to pedestrians than other vehicles that have lower bumpers, e.g., sedans. Such injuries, and their frequency and severity, are often result primarily from a greater height of a vehicle bumper. For example, a pedestrian struck by a vehicle with a high bumper may be more likely to stiffer a broken leg, to be dragged under a vehicle on impact, etc.


An adhesive composition comprising: 100 parts by weight of (A) a phenoxy resin having, per molecule, at least one alkoxy silane residue represented by the following formula (I)

A semiconductor device is generally prepared by the following processes:
i) dicing a large-diameter silicon wafer with a circuit pattern formed thereon in silicone chips,
ii) thermocompression bonding the chip on a lead flame via a curable liquid adhesive, i.e., die bonding adhesive, to fix the chip,
iii) wire bonding the electrodes of the chip to pads, and
iv) encapsulating the chip for protecting the chip from the environment and handling facility.
The encapsulating is generally performed by resin transfer molding because of good productivity and low costs.
As miniaturization and multifunctionalization of electric and electronic appliances advances, an area array type package without a lead frame, for example, Chip Size Package (CSP), and stack type packages such as stacked CSP and System in Package (SiP) are more and more used. These packages are required to have higher resistance to thermal shock than those of conventional packages.
In addition, a reflow temperature for lead-free solder is as high as 265° C., requiring higher heat resistance. Among package constituents, a die bonding agent is relatively easy to be modified compared with other constituents, so that the modification of the die bonding agent aiming to lower thermal expansion coefficient, higher adhesion strength, and higher resistance to thermal shock is desired.
A composition comprising a polyimidesilicone resin is known to have excellent properties such as heat resistance from Japanese Patent Application Laid-Open No. 2006-5159. The silicone moiety of the composition contributes to the improved resistance to thermal shock. However, there still is room for improvement in some properties such as thermal expansion coefficient.
Another adhesive composition comprising a silicone moiety is an alkoxy-modified epoxy resin known from Japanese Patent Application Laid-Open No. 2006-111701. The resin is used for adhering a flexible circuit board.

Adhesive composition and adhesive film therefrom

Abstract: wherein R1 may be the same with or different from each other and is a substituted or unsubstituted C1-4 alkyl group, and R2 is a substituted or unsubstituted C1-9 monovalent group comprising a moiety selected from the group consisting of amino, cyanato, glycidoxy and thiol groups; 5 to 200 parts by weight of (B) an epoxy resin; a catalytic amount of (C) catalyst for curing the epoxy resin; and (D) an inorganic filler in an amount of from 33 to 300 parts by weight per total 100 parts by weight of the components (A), (B) and (C).


There is provided a method for calculation of a functional index parameter in at least one blood vessel of a patient, comprises: receiving a dataset of registered functional image data and anatomical image data, wherein the functional image data and the anatomical image data include data indicative of anatomical and functional data for at least one blood vessel of a certain patient; calculating at least one value for at least one functional index parameter for at least one of: (i) at least one blood vessel, and (ii) for the anatomical region of the at least one blood vessel, wherein the at least one value of the at least one functional index parameter is computed based on the functional image data of the dataset; and outputting the calculated at least one value for the at least one functional index parameter for the at least one blood vessel of the certain patient.

The present invention, in some embodiments thereof, relates to methods and systems for computation of a functional index parameter and, more specifically, but not exclusively, to methods and systems for computation of a functional index parameter of blood vessel(s) of a patient.
A stenotic lesion in a blood vessel, for example, a coronary artery, may be treated by coronary revascularization. Lesions are evaluated prior to treatment to determine its potential effectiveness on blood flow within the coronary artery, for example, visually, by Quantitative Coronary Angiography, or by invasive assessment of the fractional flow reserve (FFR). FFR performed at the time of ICA (invasive coronary angiography) provides an additional functional assessment of stenosis significance as compared to anatomical assessment by ICA. It has been shown to be more effective for revascularization guidance than ICA alone with respect to event-free survival. Stenotic lesions associated with FFR values of 0.80 or less are considered clinically significant (ischemia-causing) and for them revascularization can be beneficial.
FFR may be measured invasively using wires with pressure sensors that are inserted into the blood vessel and across the stenosis. However, equipment to invasively measure the FFR may be not universally available, is generally expensive, and the procedure is time consuming to perform.
Less invasive or non-invasive methods of estimating the FFR have been developed. Some methods rely on imaging to estimate the FFR, for example, using computed tomography (CT) images, and/or invasive angiography images. The estimated FFR computed using imaging methods relies partially on data derived from patient populations, and is therefore less accurate in comparison to invasive FFR measurements.

Systems and methods for computation of functional index parameter values for blood vessels


A large-sized and heavy part (1) of plastic material is injection molded. Localized zones are created in which the thermal conductance of the part (1) is higher in the surface impressions (10) at the mold ejectors for the removal of the part after it has been molded. In a preferred embodiment, the outer surface of the part (1) has, at the surface impressions (10), clusters of closed-bottom pits (13) formed by grids of mini-ribs (11) and (12) arranged perpendicularly with respect to each other. The thickness of the part varies from a maximum value (S1) at the periphery of the cavity to a minimum value (S2) at the bottom of a substantial number of the pits (13).

The present invention relates to an improved method for injection-molding parts of plastic materials. In particular, the present invention relates to the production of parts having large dimensions and heavy weight such as the wash tubs of household clothes washing machines, for example the type disclosed in EP 0 601 347 and U.S. Pat. No. 5,329,791.
When production volumes of molded parts are increased, increasing the number of injection molding presses for coping with such volumes would require considerable amounts of money to be invested. To avoid such an increase it would be desirable for the dwelling time of the molded parts in the respective mold to be made as short as possible. The fulfillment of such a requirement is opposed however, in the case of particularly large and heavy parts, by the speed at which the plastic material cools down after injection. The need in fact arises for the ejectors provided in the mold, which exert a localized pressure on the surface of the molded part in view of knocking it out of the mold, to be prevented from deforming it or breaking through it when the plastic material is not sufficiently stiff yet.

Injection molded plastic parts and method of forming

Electrolux Zanussi Elettrodomestici S.p.A.


Disclosed are expanded polytetrafluoroethylene products, such as porous polytetrafluoroethylene tubes, having high axial tear strength and a process for their production. Each expanded polytetrafluoroethylene product has a microstructure, which comprises fibrils and nodes interconnected with each other by the fibrils, and has an axial tear strength of not lower than 6,000 gf/mm as calculated in accordance with the following formula: L/[T×(V/100)] where L (gf) is an axial tear load, T (mm) is a wall thickness, and V (%) is a volume ratio of resin. The process for the production of the expanded polytetrafluoroethylene product includes a high-speed extrusion step.

An expanded polytetrafluoroethylene (hereinafter abbreviated as "PTFE") product formed using PTFE has a microstructure comprising fibrils and nodes interconnected with each other by the fibrils. Expanded PTFE products are porous for such microstructures, and therefore, are also called "porous PTFE products"
Properties of an expanded PTFE product, such as pore size and porosity, can be controlled primarily by relying upon stretching conditions. Among such expanded PTFE products, expanded PTFE tubes which may hereinafter be called "porous PTFE tubes" are provided with properties derived from their porous nature, such as flexibility, fluid permeability, fine particulate capturing capacity, low dielectric constant and low dielectric dissipation factor, in addition to properties such as heat resistance and chemical resistance and surface properties such as low friction coefficient, water repellency and non-tackiness, all of which are possessed by the material PTFE itself. For these unique properties, the utility of expanded PTFE tubes is not limited only to the general industrial field but is also spreading to the medical field and the like.
Taking a porous PTFE tube, for example, it is rich in flexibility and its material PTFE itself is excellent in antithrombic property, and moreover, its porous structure based on a microfibrous structure formed as a result of the stretching and comprising a number of fibrils and a number of nodes interconnected with each other by the fibrils is excellent in biocompatibility. Expanded PTFE tubes, therefore, have found wide-spread utility as substitute blood vessels for maintaining circulation, for example, to replace lesion parts of blood vessels in living bodies, especially to bypass such lesion parts.
A porous PTFE tube is generally produced by mixing a liquid lubricant with unsintered powder of PTFE, forming the resulting mixture into a tubular shape by ram extrusion, drying off the liquid lubricant, and then expanding the tubular extrusion product by stretching in the direction of its axis. Subsequent to the expanding, the expanded extrusion product is heated to a temperature of the melting point of PTFE or higher while holding it to avoid shrinkage, so that the expanded structure is sintered and fixed. When the stretching temperature is sufficiently high, the sintering and fixing is effected concurrently with the expanding step.
Despite such various excellent properties as mentioned above, porous PTFE tubes have a strong molecular orientation in the direction of extrusion and tend to tear in the direction of their longitudinal axes. Porous PTFE tubes are, therefore, accompanied by a problem in that, when blood vessels in living bodies are shunted using porous PTFE tubes as artificial blood vessels, the tubes may tear in the direction of their longitudinal axes by suture needles or sutures to induce hematoma formation or false aneurysm due to blood leakage. This problem becomes particularly pronounced when upon production of porous PTFE tubes, the stretch ratio is increased to make the porosity higher, the pore size is made greater, or the wall thickness is reduced.
As a method for providing an expanded PTFE tube with higher axial tear strength, it may be contemplated to perform the stretching of an extrusion product in biaxial directions, that is, in the longitudinal direction and in the radial direction. With this method alone, however, it is still impossible to achieve any substantial improvement in the axial tear strength.
A process was therefore reported in JP-B-43-20384 and JP-B-7-15022. According to that process, extrusion is conducted while providing an extrusion product with an orientation at an angle with respect to the direction of a longitudinal axis by producing a helical flow in the extrusion product with a helical groove formed on a die or mandrel of a ram extruder.
In the above-described process, however, the extrusion product is stretched in the direction of its longitudinal axis in a subsequent step so that the intersecting angle between the direction of the orientation and the direction of the longitudinal axis becomes too small to expect any substantial improvement in the axial tear strength. Especially when stretching at a high stretch ratio of 4 times or more in the longitudinal direction is needed to produce a porous PTFE tube having a high porosity of 70% or more, the direction of orientation becomes closer to the direction of the longitudinal axis so that practically no effect is expected in increasing the axial tear strength.
With a view to obtaining a porous PTFE tube having high axial tear strength, it was also proposed to reduce the porosity or to reinforce a porous PTFE tube by helically winding an expanded PTFE tape on an outer surface of the porous PTFE tube (JP-B-52-9074). Nowadays, one of two methods is adopted, one being to lower the porosity of a porous PTFE tube, and the other being to helically wind an expanded PTFE tape or filament on the outer surface of a porous PTFE tube such that the porous PTFE tube is reinforced.
However, the method, which relies upon a reduction in the porosity of a porous PTFE tube or a reinforcement by a tape or filament wound on the outer surface of a porous PTFE tube, involves a problem that some inherent characteristics of a porous PTFE tube, such as flexibility and tissue cells invasion, are impaired although the method is effective in increasing the axial tear strength.

Process for production of expanded polytetrafluoroetylene products


The present invention is directed to the combined use of first and second fatty acid amides to improve the softness of a thermoplastic polymer construct. A combination of fatty acid amides is provided in the blend ratio of about 10 to 90 percent by weight of a first fatty acid amide and 90 to 10 percent by weight of a second fatty acid amide. The first and second fatty acid amides are compounded into a thermoplastic polymer carrier resin and, preferentially, produced as concentrate pellets containing 0.5 to 75 percent by weight total fatty acid amide loading. The concentrate pellets are introduced into a thermoplastic polymer base, to form a thermoplastic resin, at a letdown level in the range of about 1 to 15 percent, with the range of 2 to 10 percent being preferred, and the range of 3 to 6 percent being most preferred.

Thermoplastics are becoming an evermore-popular material to be used in the fabrication of disposable and semi-durable goods. The ability of thermoplastics to be formed into specialized fabrics, both woven and nonwoven, and films designed to meet specific performance requirements has resulted in such thermoplastic materials being incorporated into numerous medical, hygiene, and industrial applications. Research and development are ongoing to modify these thermoplastic materials to further improve or otherwise alter the resulting performance of the thermoplastic materials in the fabricated articles.
Particular focus of this research and development has been to the addition of additives to a thermoplastic polymer base, to thus tailor the performance of the thermoplastic resin. Advances in the modification of thermoplastic polymer performance are evident in exemplary performance additive patents directed to changes in hydrophobicity, hydrophilicity, anti-microbial activity, barrier properties, and retention or dissipation of static charge.
While such additives have successfully modified the performance of the thermoplastic polymer, deleterious effects on the softness qualities of a resulting article are expected. The softness of an article, measured in terms of both tactile and ductile performance, is a critical aspect of the user-acceptance of such articles. A number of patents address specifically the improvement of softness in thermoplastic constructs; however, the associated chemistries are such that they are incompatible with the performance additives.
An unmet need remains for a thermoplastic additive that improves the softness of the resulting article, and yet is compatible with performance additives. Due to the criticality of perceived softness in end-use articles, there is also a need for a softness additive that can be favorably compounded with other softness improvement additives, to render thermoplastic constructs of further improved softness.

This patent is subject to a terminal disclaimer.

Thermoplastic constructs with improved softness


There are disclosed an ISE slide element and potentiometric measurement of assaying, using a slide element that is positionally insensitive about an axis of symmetry. This is achieved by accessing one of the electrodes in the center of the slide element, and the other in an annular groove centered on the element center, both for liquid contact and electrometer contact. Preferably, electrometer contact occurs at a side of the electrode opposite to the side contacted with liquid.

Potentiometric slide elements for so-called "dry assays" are well-known, and are described, for example, in U.S. Pat. Nos. 4,184,936 and 4,273,639. Such known elements feature a pair of identical ion-selective-electrodes, hereinafter "ISE's", coupled together with an ion bridge that is generally fibrous in nature. One of the two ISE's is contacted with patient sample liquid, and the other with a reference fluid. The ISE's function to provide a differential charge, depending on the relative ionic concentrations of the analyte, for a differential analysis. The ISE's are exposed at opposite surfaces, so that their ion-selective membranes are exposed to the sample liquid or reference liquid, and their metal layers are exposed to the contacts of an electrometer.
Because of the format of the ISE's and the connecting bridge, the overall slide element has been rectangular in configuration. Although such a configuration has worked well, it is constraining in that it does not lend itself to, e.g., a circular configuration. Indeed, prior to this invention it has been difficult to provide a circular potentiometric slide element using paired ISE's and a connecting ion bridge, precisely because such ISE's and a bridge have not been so configurable.
Circular potentiometric slide elements, on the other hand, become essential if future analyzers are to be converted to slide elements that are circular for all assays (both colorimetric and potentiometric). Unlike those using rectangular frames, slide elements constructed from round frames have no special orientation in an analyzer. This is both a benefit and a possible hindrance. The benefit is that the slide elements can be rotated into any particular station without regard to any particular orientation of a side edge. The possible hindrance is that if there is any feature of the slide element that lacks axial symmetry, it is difficult to position a round slide element to take that asymmetry into account.
Colorimetric slide elements easily lend themselves to a round format; potentiometric elements do not.
Yet another disadvantage of the rectangular ISE slide elements is that the sample deposit must occur off-center. This is contrary to the center depositing of sample that occurs for colorimetric slide elements, necessitating therefore a complicated alteration of the dispenser tip location when the type of slide element changes. For ease in dispensing, it is preferred that all sample dispensing occur at the center of the slide element.

Round potentiometric slide elements and method of using the same


Use of 1-amino-3-N,N-dimethylamino)-propyliden-1,1-bisphosphonic acid of the structural formula: ##STR1## or of its monosodium or other pharmaceutically acceptable salt, as a biological carrier for bone active substances or for the preparation of a medicament for the diagnosis, prophylaxis and/or treatment of bone and/or mineral metabolism disorders.

1. Field of the Invention
Bisphosphonates--synthetic compounds containing two phosphonate groups bound to a carbon and two additional groups R.sub.1 and R.sub.2, respectively (see formula A herebelow)--bind strongly to calcium crystals, inhibit their growth, suppress bone resorption and are used in the treatment of a variety of disorders of calcium and bone metabolism. It is generally considered that the "bone hook" (P-C-P with R.sub.1) is responsible for the binding of these molecules to mineralized matrices, while, in turn, the R.sub.2 group is primarily responsible for its effect on bone resorption. ##STR2##
2. Description of the Related Art
U.S. Pat. No. 4,054,598 discloses a method with sequestering agents, especially for alkaline earth metal ions, having the formula 1-hydroxy-3-amino-alkane-1,1-bisphosphonic acids, useful for the treatment of disturbances of calcium or phosphate metabolism characterized by abnormal deposition of difficultly soluble calcium salts or the abnormal dissolution of hard tissues causing losses of hard bone substance, which cannot be replaced or only by incompletely crystallized tissues, such as Paget's disease, lithiasis, arthritis and others. Spanish Patent No. P910088 discloses pharmaceutical liposome preparations containing bisphosphonates as active compounds. The use of olpadronate as an anabolic agent for the treatment of osteoporosis and other bone metabolism disorders is claimed in the Applicant's earlier PCT application PCT/EP95/05142.
A number of 1,3-diaminoalkane-1,1-bisphosphonic acids including, amongst others, 1-amino-3-(N,N-dimethylamino)-propyliden-1,1-bisphosphonic acid are disclosed in DE-A1-25 34 390. Several applications (medical and non-medical), unrelated to the claimed methods of use of the present application, are mentioned, without giving any specific advantages for 1-amino-3-(N,N-dimethylamino)-propyliden-1,1-bisphosphonic acid.
DE-A1-18 13 659 is directed to compositions for the inhibision of deposition and mobilisation of calcium phosphate in tissues with an effective, but non-toxic content of various polyphosphonates. However, the specific compound of the present application is not mentioned.
In Eur. J. Clin. Invest. 1970, Vol. 1 (1) pp. 12-18 (Fleisch et al.) the inhibitory effect of phosphonates on the formation of calcium phosphate crystals in vitro and an aortic and kidney calcification in vivo is described. However, the specific compound of the present application is not mentioned.
DE-C1-10 02 355 is directed to processes for the production of various bisphosphonates. However, the specific compound of the present application is not mentioned. Moreover, no specific applications for the described compounds are given.
Z. Anorg. Allg. Chem. 389, pp. 119-128 (1972) (Ploger et al.) is directed to different processes for the production of various bisphosphonates, however without mentioning the specific compound of the present application or any specific application of the described compounds at all.
CA-A1-21 20 538 discloses the use of bisphosphonic acid derivatives for promoting bone repair. Although the general formula would also cover the specific compound of the present application, this compound or any related advantages are not mentioned in the description.
It is the object of the invention to provide for specific new medical applications of 1-amino-3-(N,N-dimethylamino)-propyliden-1,1-bisphosphonic acid or its monosodium or other pharmaceutically acceptable salt.

Therapeutic use of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid and its salts


A notch filter circuit includes first and second operational amplifiers, each having a capacitor connected from the amplifier output to the input. A third capacitor is connected between the second-amplifier input and the filter circuit input. A first switched-capacitor resistor is connected between the filter circuit input and the first-amplifier input. A second switched-capacitor resistor is connected between the first amplifier output and the second amplifier input. The second-amplifier output is connected to the filter circuit output. A third switched-capacitor resistor is connected between said filter circuit output and said first amplifier input; First and second programmable capacitor arrays are connected respectively in parallel with the third switched-capacitor resistor and in parallel with the first switched-capacitor resistor, so that a change only in the capacitance of the second capacitor array causes a corresponding change in the filter notch depth and a change only in the capacitance of the first capacitor array causes a corresponding change in the filter notch width. The first and second capacitor arrays each have a group of digital programming terminals that may be connected together for making fixed the ratio of the capacitance values of the two arrays. A digitally programmable voltage divider circuit connected in series with the second programmable capacitor array permits the independent programing of notch depth, i.e. without affecting notch width.

This invention relates to an active notch filter circuit employing switched-capacitor resistors and more particularly to such filter circuits that include simultaneously-digitally-programmable capacitor arrays for controlling notch width and notch depth.
Notch filters are used in analog-signal manipulating circuits for rejecting a particular signal frequency, or narrow range of frequencies. Conventional notch filters have a center or primary rejection frequency w, and a quality factor Q, which when high corresponds to a narrow filter bandwidth and when low corresponds to a relatively wide bandwidth. A high and low Q value also corresponds respectively to a narrow notch and a wide notch, as is further explained below. The transfer function of the conventional notch filter is expressed as ##EQU1##
Notch filters of this kind are described by Alan B. Grebene in his book Bipolar And MOS Analog Integrated Circuit Design, 1984, pages 736-739.
Notch width and notch depth are typically established by the filter manufacturer and are not controllable by the filter user.
It is an object of this invention to provide a notch filter circuit that is programmable with respect to notch width and depth.
It is a further object of this invention to provide such a filter wherein notch width and notch depth are independently programmable by the user.

Switched-capacitor notch filter with programmable notch width and depth


A column of cups guided by their rims in elongated slots is spaced into desired cup pitch by one or more linear stars from which the cups can be transferred for packaging. The linear stars have lugs engaging and spacing the cups. In another aspect of the invention, cups are manipulated into patterns for final grouping and packaging and by a plurality of cup orienting pickers engaging, inverting and re-orienting the cups. In one final packaged cup group of two or more layers, alternating cups in each layer are inverted and a top lid of a cup in an upper layer is disposed on a top lid of a cup in a bottom layer, while a bottom of a cup in an upper layer is disposed on a bottom of a cup in a lower layer, and in an alternating pattern.

Cups for single serve coffee brewing, for example, are formed, filled and sealed and presented in random volume and mixed orientation from forming and filling machines. Typically, such cups are accumulated in random batches and are fed from a feeder drum or bowl into a lid-up, single file line for packaging.
Such cups may vary, at least slightly in shape, in weight and in overall height, depending on whether the typical foil lid or cover outwardly bulges or is somewhat sunken below the cup rim. Generally the cups are slightly tapered from a wider, rounded cross-section at their upper end or mouth at the rim to a narrower rounded cross-section at their bottom ends. The inwardly tapering cup walls from top to bottom may be straight or may have circumferential rings or steps surrounding the upper cup end. Internally, the cups typically contain a filter disposed midway up the cup with coffee between the filter and the upper end or lid. The bottom portion of the cup may define an empty "brew chamber", such that the cup is somewhat top heavy. Depending on construction, a top lid is usually adhesively applied to a radially extending lip or rim extending as a radial flange around the open mouth of the cup. Such lid may bulge outwardly (upwardly) or it may slightly sink below the rim. The cup bottom may be flat, or it too may slightly bulge outwardly, depending on its design and the forming, filling process. As a result, any handling structure downstream of the feeder bowl must be adjustable to handle such cups of a large variety of external shapes, weight and top heaviness, depending on fill.
In a line of cups, guided in a single lane where one cup engages a preceding cup and, in turn, is engaged by a following cup, the cups may not be transported uniformly. For example, if a top guide is adjusted down to engage a sunken cup lid, it may not pass cups with bulging top lids and which hangs up or causes voids in the line of feeding cups, resulting in downstream packaging aberrations, waste, etc. Adjustment of such guides, etc. for cups of different configuration is thus required, takes time and reduces through-put rates when changes are required.
If a handling or guiding system is not "tuned" to a particular cup parameter, cups of even slightly different parameters may upset, fall over or otherwise jam up the feeder once the cups are placed in single file. This results in a high rate of rejection (or lower rate of operational efficiency).
The desire then is to provide apparatus for transferring cups having varied parameters with universal efficiency and comparatively low rejection rates, even when handling cups having a variety of the aforementioned variances.
In addition, the cups are typically presented for cartoning in a line with the cups abutting. For packaging, the cups are typically spaced apart for handling in the packaging process. This is typically accomplished, for example, by one or more timing screws which operate to space the cups apart. These screws are typically configured to the cup shape where handling different cups require a change in the screw.
In handling cups for packaging, it is also desirable to place them into cartons for shipping, transportation and display at the point of sale with as many cups as possible oriented in the given interior volume of any carton. Proper orientation can result in the smallest carton possible for the desired number of cups therein.
Accordingly, it is also desired to reliably orient cups for carton packaging in desired formation but at high speeds and reliable cup through-put.


An elevator hall call registration apparatus automatically registers a destination floor call based on verification information by a personal authentication device. The hall call registration apparatus includes a first personal authentication device which authenticates a user, a hall call registration apparatus main body which performs destination floor call registration based on verification information including personal ID unique to the user verified in the first personal authentication device, and a destination floor changing device which accepts an operation for the user to perform at least one of a change and cancel of the destination floor of a destination floor call registration. If it is judged based on an operation performed in the destination floor changing device that the operation is performed by the user authenticated by the first personal authentication device, the hall call registration apparatus can perform a change and cancel of a destination floor of the destination floor call registration.

In recent years, there have been an increasing number of cases where a security gate is installed in the entrance and the like of a building. This security gate is intended for authenticating a person who is going to pass through the gate. And when the person is authenticated at the security gate, the security gate is opened to permit the person to pass through the gate. And in the case where an elevator is installed in a building where such a security gate is installed, usually, no person can move to an elevator hall in the building unless a person passes through this gate by succeeding in the authentication at the security gate.
As one of conventional hall call registration apparatuses of an elevator installed in a building having such a security gate, there is known a hall call registration apparatus of an elevator which opens a security gate installed on the entrance floor of a building and automatically registers an elevator hall call to the entrance floor when a person is authenticated at the security gate (refer to Patent Literature 1, for example).
In group controller elevators which control a plurality of elevators as a group (a bank) installed in a building having a security gate, there is known a hall call registration apparatus of an elevator which identifies a destination floor of a person who was verified from verification information at the security gate and assigns a car for each identified destination floor (refer to Patent Literature 2, for example). In the hall call registration apparatus of an elevator described in Patent Literature 2, a destination floor is indicated in the hall for each assigned car. And when it is detected that a passenger has boarded a car, in this car, a destination floor call in which the identified destination floor is a desired destination floor, is automatically registered.
Incidentally, in an elevator installed in an apartment house sharing an entrance, there is also known a hall call registration apparatus of an elevator which automatically registers a hall call to a floor when it is detected that a resident of this floor other than the entrance floor has left his or her house (refer to Patent Literature 3, for example). In the hall call registration apparatus of an elevator described in Patent Literature 3, after the arrival of a car at the floor on which the resident left his or her house, a destination floor call is automatically registered in order to cause this car to run to the entrance floor.

Hall call registration apparatus of elevator including a destination floor changing device


A method for forming raised source and drain regions in a semiconductor manufacturing process employs double disposable spacers. A deposited oxide is provided between the first and second disposable spacers, and serves to protect the gate electrode, first disposable spacers and a cap layer during the dry etching of the larger, second disposable spacers. Mouse ears are thereby prevented, while the use of a second disposable spacer avoids shadow-effects during halo ion-implants.

Currently, deep-submicron complementary metal-oxide-semiconductor (CMOS) is the primary technology for ultra-large scale integrated (ULSI) devices. Over the last two decades, reducing the size of CMOS transistors and increasing transistor density on ICs has been a principal focus of the microelectronics industry. A ULSI circuit can include CMOS field effect transistors (FETS) which have semiconductor gates disposed between drain and source regions. The drain and source regions are typically heavily doped with a P-type dopant (boron) or an N-type dopant (phosphorous). The drain and source regions generally include shallow source and drain extension regions that are disposed partially underneath the gate to enhance transistor performance. The shallow source and drain extensions help to achieve immunity to short-channel effects that degrade transistor performance for both N-channel and P-channel transistors. Short-channel effects can cause threshold voltage roll-off and drain-induced barrier-lowering. The shallow source and drain extensions and, hence, controlling short-channel effects are particularly important as transistors become smaller.
As the size of the transistors disposed on ICs decreases, transistors with shallow ultra-shallow source drain extensions become more difficult to manufacture. For example, a small transistor may require ultra-shallow source and drain extensions with a junction depth of less than 30 nanometer (nm). Forming source and drain extensions with junction depth of less than 30 nm is very difficult using conventional fabrication techniques. Conventional ion implantation techniques have difficulty maintaining shallow source and drain extensions because point defects generated in the bulk semiconductor substrate during ion implantation can cause the dopant to more easily diffuse (transient enhanced diffusion, TED). The diffusion often extends the source and drain extensions vertically downward into the bulk semiconductor substrate. Also, conventional ion implantation and diffusion-doping techniques make transistors on the IC susceptible to short-channel effects, which result in a dopant profile tail distribution that extends deep into the substrate.
To overcome these difficulties, source and drain regions can be raised by selective silicon epitaxy to make connections to the source and drain contacts less difficult. The raised source and drain regions provide additional material for a contact silicidation process and reduced deep source/drain junction resistance and source/drain series resistance.
Raised source/drain processes employing disposable spacers have been used, but are not suitable as dimensions decrease, such as 65 nm technology nodes and below. FIGS. 16a-16c and FIGS. 17a-17d depicts some of the concerns with these approaches.
In FIG. 16a, a gate electrode 72 is provided on a substrate 70. A silicon nitride cap 74 serves to protect polysilicon gate electrode 72 from unwanted silicon growth during the selective epitaxial growth (SEG) process. The SEG process is selective towards silicon nitride, and as a result, no silicon will be grown on top of the gate electrode 72 during the SEG process.
An oxide, such as TEOS, or LTO oxide is used to form oxide liner 76. Following the formation of the oxide liner 76, a pair of sidewall spacers 78 are formed, from silicon nitride, for example. Formation of the silicon nitride spacers 78 is typically accomplished by deposition of a silicon nitride layer, followed by dry etching.
Prior to the SEG process, a wet-etch, such as a HF wet-etch, needs to be performed to remove the oxide of the oxide liner 76. Removal of the oxide is necessary since epitaxial silicon only grows on silicon surfaces. Presence of the oxide liner 76 on the substrate 70 would prevent such growth and prevent the formation of raised source/drains.
Since the oxide liner 76 is between the nitride cap layer 74 and the nitride spacers 78, a cavity can be etched during the HF wet-etch. This cavity may reach the polysilicon gate electrode 72. Since TEOS or LTO etches rapidly in HF, the probability of exposing the top left and right corners of the polysilicon gate electrode 72 is high. As a result of this exposure of the corners of the polysilicon gate electrode 72, the formation of the raised source/drain 80 creates mouse-like ears 82 to form, as depicted in FIG. 16b. The ears 82 are highly undesirable.
Referring now to FIG. 16c, the disposable nitride spacers 78 are removed to allow halo and extension implants. However, the ears 82 effectively block the implants from being properly performed. Hence, the device becomes unusable or at least severely impaired.
Another method of forming raised source/drains avoids the use of a deposited oxide liner, but instead uses a thermally grown oxide. However, as will be readily understood, the approach is not scaleable since a thinner nitride cap does not survive a nitride spacer etch, while a thinner nitride spacer results in shadow effects for the halo ion implantation process.
Referring now to FIGS. 17a-17d, a gate electrode 92 is formed on a substrate 90. A nitride cap 94 is provided on top of the polysilicon gate electrode 92. An oxide liner 96 is thermally grown, and does not cover the silicon nitride cap 94. Disposable sidewall spacers 98 are provided on the thermally grown oxide 96.
FIG. 17b depicts the structure of FIG. 17a after the formation of the raised source/drain in an ideal process. However, the top of the cap layer 94 is partially etched in the spacer etch process, so that the cap layer 94 cannot be scaled down as much as desired. The cap layer nitride loss is related to the over etch of the spacer etch process. The result of the nitride cap loss is depicted in FIG. 17c, in which "mouse ears" 102 are formed. In this figure, the nitride spacers 98 are removed by the nitride removal etch process. The mouse ears 102 prevent the halo implantation process from satisfactorily achieved. An alternative to making the cap 94 thicker is to maintain the cap 94 thin, and making the spacers 98 narrower such that the removal of the nitride spacers does not result in an overetch that exposes the top of the polysilicon gate electrode 92 prior to the SEG process. However, as depicted in FIG. 17D, the use of thin nitride spacers results in an insufficient gap between the polysilicon gate electrode 92 and the raised source drain regions 100. The halo implants, which are typically performed with a high tilt, will not be able to be performed efficaciously due to the shadow effects caused by the raised/source drains 100. In other words, the edges of the raised source/drains are too close to the sidewalls of the polysilicon gate electrode 12.

Raised source and drain process with disposable spacers