The present invention relates to the regeneration, reconstruction, repair, augmentation or replacement of organs or tissue structures using scaffolds and autologous cells that are not derived from such organs or tissues.

Several anomalies can cause the bladder to develop abnormally and require surgical augmentation. Conditions such as posterior urethral valves, bilateral ectopic ureters, bladder extrophy, cloacal extrophy, and spina bifida (ie, myelomeningocele) may cause the bladder to be noncompliant, resulting in a small capacity bladder that generates high pressures. Clinically this causes patients to suffer from incontinence while increasing their risk for renal failure due to the high pressures in the genitourinary system. The current standard of therapy for these pediatric patients is bladder augmentation through enterocystoplasty (Lewis et al. Br. J. Urol. (1990); 65:488-491). Bladder augmentation involves the removal of a section of large bowel from the patient who then has that tissue connected to the existing bladder to increase compliance, decrease pressure, and improve capacity. The surgeries are relatively complex and expensive. Even in patients with a good technical result, the procedure is associated with numerous immediate risks and chronic complications. The invasiveness, cost, and complications of these surgeries limit their use to only the most severe bladder deficiencies. A similar surgical procedure is performed in adults who require a bladder replacement, many as a result of bladder cancer. In adults, the entire bladder is resected and replaced with large bowel. Despite the risk of adverse effects, there are approximately 10,000 of these procedures performed per year in the United States, including about 10% in children with congenital abnormalities and 90% in adults with acquired disorders such as bladder cancer. There is clearly a compelling medical need for an improved approach that would eliminate or at least substantially reduce the adverse effects associated with the current standard of care.
The human urinary bladder is a musculomembranous sac, situated in the anterior part of the pelvic cavity that serves as a reservoir for urine, which it receives through the ureters and discharges through the urethra. In a human the bladder is found in the pelvis behind the pelvic bone (pubic symphysis) and is above and posteriorly connected to a drainage tube, called the urethra, that exits to the outside of the body. The urinary bladder is subject to numerous maladies and injuries which cause deterioration of the urinary bladder in patients. For example, bladder deterioration may result from infectious diseases, neoplasms and developmental abnormalities. Further, bladder deterioration may also occur as a result of trauma such as, for example, car accidents and sports injury. Urinary diversions are often necessary in bladder cancer patients. There are over 54,000 new bladder cancer cases each year in the United States of America. Most bladder cancers are of epithelial origin, and worldwide, there are approximately 336,000 new cases of urothelial carcinomas (transitional cell carcinomas (TCC)) annually (Kakizoe (2006) Cancer Sci. 97(9) 821).
Urinary diversion is a way to route and excrete urine from the body when an individual is unable to urinate due to a damaged or non-functional urinary system. In general, any condition that blocks the flow of urine and increases pressure in the ureters and/or kidneys may require a urinary diversion. Some common indications for diversion include cancer of the bladder requiring a cystectomy, a neurogenic bladder that impact renal function, radiation injury to the bladder, intractable incontinence that occurs in women, and chronic pelvic pain syndromes. In general, two major strategies exist for urinary diversion: a urostomy and a continent diversion. A urostomy involves the creation of a stoma in the abdomen which is connected to a conduit inside the body such as a short segment of the small intestine submucosa (SI) such as the ileum, colon or jejunum. In this procedure, the other end of the short SI is connected to the ureters which normally carry urine from the kidney to the bladder. Urine flows through the ureters into the short SI and out the stoma to an external collection reservoir. An alternative of this procedure is the attach the ureters directly to a stoma, also called a ureterostomy. A continent diversion involves the creation of a pouch or reservoir inside the body from a section of the stomach or small or large intestine and the use of a stoma may or may not be required. For example, a continent cutaneous reservoir may be created by obtaining a segment of the bowel and modifying it into a more spherical shape. One end of the modified segment is connected to the ureters and the other to a stoma that leads to an external collection reservoir. Finally, an orthotopic diversion may created by placing the re-shaped segment in place of the original bladder by connecting one end to the ureters and the other end to the urethra so the individual may urinate through the urethra instead of through a stoma.
Although small intestinal submucosa (SI) may be used for urinary diversion, it has been reported that the removal of the mucosa and submucosa may lead to retraction of the intestinal segment (see, e.g., Atala, A., J. Urol. 156:338 (1996)). Other problems have been reported with the use of certain gastrointestinal segments for bladder surgery including stone formation, increased mucus production, neoplasia, infection, metabolic disturbances, long term contracture and resorption. The use of natural materials for urinary diversion has shown that bladder tissue, with its specific muscular elastic properties and urothelial impermeability functions, cannot be easily replaced. In addition, the use of a patient's own bowel segments for urinary diversion requires at least two different surgical procedures where a first surgery is performed to remove a segment and a second surgery to install the urinary diversion. The requirement of multiple surgeries increases the overall cost of the procedures, the risk to the patient, and patient's overall comfort.
Therefore, due to the multiple complications associated with the use of gastrointestinal segments for urinary diversion and requirement for multiple surgical procedures, there exists a need for methods and devices for providing urinary diversion systems to patients in need of such a system.
Urinary incontinence is a prevalent problem that affects people of all ages and levels of physical health, both in the community at large and in healthcare settings. Medically, urinary incontinence predisposes a patient to urinary tract infections, pressure ulcers, perineal rashes, and urosepsis. Socially and psychologically, urinary incontinence is associated with embarrassment, social stigmatization, depression, and especially for the elderly, an increased risk of institutionalization (Herzo et al., Ann. Rev. Gerontol. Geriatrics, 9:74 (1989)). Economically, the costs are astounding; in the United States alone, over ten billion dollars per year is spent managing incontinence.
Incontinence can be attributed to genuine urinary stress (bladder and urethra hypermobility), to intrinsic sphincter deficiency ("ISD"), or both. It is especially prevalent in women, and to a lesser extent incontinence is present in children (in particular, ISD), and in men following radical prostatectomy.
Stress incontinence is an involuntary loss of urine that occurs during physical activities which increase intra-abdominal pressure, such as coughing, sneezing, laughing, or exercise. A person can suffer from one or both types of incontinence, and when suffering from both, it is called mixed incontinence. Despite all of the knowledge associated with incontinence, the majority of cases of urge incontinence are idiopathic, which means a specific cause cannot be identified. Urge incontinence may occur in anyone at any age, and it is more common in women and the elderly.
The detrusor is the bladder wall muscle that contracts to expel the urine from the bladder. Consequences of detrusor malfunction such as hyperreflexia include poor bladder compliance, high intravesical pressure, and reduction in bladder capacity, all of which may result in deterioration of the upper urinary tract.
One current treatment for urge incontinence is injection of neurotoxins, such as botulinum toxin, e.g., Botox®. It is thought that botulinum toxin exerts its effect on bladder hyperactivity by paralyzing the detrusor muscle in the bladder wall or possibly impacting afferent pathways in the bladder and reducing sensory receptors in suburothelial nerves. The large size of the botulinum toxin molecule can limit its ability to diffuse, and thus prohibits it from reaching both afferent and efferent nerve fibers. As a result, current methods of administration for overactive bladder (OAB), for example, require many injections (typically 20 to 50) of botulinum toxin into the bladder muscle wall, thus increasing the number of doctor visits and associated cost of treatment. Moreover, the safety of chronic long-term impact of inhibition of sensory neurotransmitter release from bladder has not yet been determined.
Further approaches for treatment of urinary incontinence involve administration of drugs with bladder relaxant properties, with anticholinergic medications representing the mainstay of such drugs. For example, anticholinergics such as propantheline bromide, and combination smooth muscle relaxant/anticholinergics such as racemic oxybutynin and dicyclomin, have been used to treat urge incontinence. (See, e.g., A. J. Wein, Urol. Clin. N. Am., 22:557 (1995)). Often, however, such drug therapies do not achieve complete success with all classes of incontinent patients, and often results in the patient experiencing significant side effects.
Besides drug therapies, other options used by the skilled artisan prior to the present invention include the use of artificial sphincters (Lima S. V. C. et al., J. Urology, 156:622-624 (1996), Levesque P. E. et al., J. Urology, 156:625-628 (1996)), bladder neck support prosthesis (Kondo A. et al., J. Urology, 157:824-827 (1996)), injection of cross-linked collagen (Berman C. J. et al., J. Urology, 157:122-124 (1997), Perez L. M. et al., J. Urology, 156:633-636 (1996); Leonard M. P. et al., J. Urology, 156:637-640 (1996)), and injection of polytetrafluoroethylene (Perez L. M. et al., J. Urology, 156:633-636 (1996)).
A recent well known approach for the treatment of urinary incontinence associated with ISD is to subject the patient to periurethral endoscopic collagen injections. This augments the bladder muscle in an effort to reduce the likelihood of bladder leakage or stress incontinence.
Existing solutions to circumvent incontinence have well known drawbacks. While endoscopically directed injections of collagen around the bladder neck has a quite high success rate in sphincter deficiency with no significant morbidity, the use of collagen can result in failures that occur after an average of two years and considerations need to be given to its cost effectiveness (Khullar V. et al., British J. Obstetrics & Gynecology, 104:96-99 (1996)). In addition, deterioration of patient continency, probably due to the migration phenomena (Perez L. M. et al.) may require repeated injections in order to restore continency (Herschorn S. et al., J. Urology, 156:1305-1309 (1996)).
The results with using collagen following radical prostatectomy for the treatment of stress urinary incontinence have also been generally disappointing (Klutke C. G. et al., J. Urology, 156:1703-1706 (1996)). Moreover, one study provides evidence that the injection of bovine dermal collagen produced specific antibodies of IgG and IgA class. (McCell and, M. and Delustro, F., J. Urology 155, 2068-2073 (1996)). Thus, possible patient sensitization to the collagen could be expected over the time.
Despite of the limited success rate, transurethral collagen injection therapy remains an acceptable treatment for intrinsic sphincter deficiency, due to the lack other suitable alternatives.
At present, individuals who suffer from Overactive Bladder Disorders or Urge Incontinence are initially treated by physicians with non-invasive pharmaceutical medical products. However, if these non-invasive pharmaceutical products fail, physicians offer a more invasive solution.
Thus, a need exists for a minimally invasive method of enlarging an existing laminarily organized luminal organ or tissue structure, e.g., a bladder.
Tissue engineering principles have been applied to successfully provide implantable cell-seeded matrices for use in the reconstruction, repair, augmentation or replacement of laminarily organized luminal organs or tissue structures, such as a bladder, a portion of a bladder, or a bladder component. As described in Atala U.S. Pat. No. 6,576,019, cells may be derived from the patient's own tissue, including the bladder, urethra, ureter, and other urogenital tissue. However, there are challenges associated with a dependence upon the development and maintenance of cell culture systems from the primary organ site as the basic unit for developing new and healthy engineered tissues. For example, the treatment of a defective bladder poses a particular challenge regarding cell sourcing because it stands to reason that culturing bladder cells from a defective bladder will result in the cultured cells also being defective. Such cells are not a wise choice for populating an implantable neo-bladder scaffold or matrix. As such there is a need for alternative sources of cells that are suitable for seeding on implantable neo-organ/tissue structure scaffold or matrix.
There is a wealth of literature supporting the notion that human adipose tissue is a rich source of adult stem cells (Devlin et al. (2004), Cytotherapy 6:7-14; Awad, et al. (2003), Tissue Engineering 9:1301-12; Erickson et al. (2002), Biochemical and Biophysical Research Communications 290:763-769; Gronthos et al. (2001), Journal of Cellular Physiology 189:54-63; Halvorsen et al. (2001); Metabolism 50:407-413; Halvorsen et al. (2001), Tissue Eng. 6:729-41; Harp et al. (2001), Biochemical and Biophysical Research Communication 281:907-912; Hicok et al. (2004), Tissue Engineering 10:371-380; Safford et al. (2002), Jun. 7, 294(2):371-9; Safford et al, (2004), Experimental Neurology 187:319-28; Sen et al. (2004), Journal of Cellular Biochemistry 81:312-319; Sigal et al. (1994), Hepatology 19:999-1006; Wickham et al. (2003), Clinical Orthopedics and Related Research, 412:196-212; Ashijian et al. (2003), Plast Reconstr Surg. 111:1922-31; De Ugarte et al. (2003), Cells Tissues Organs. 174:101-9; Mizumo et al. (2002), Plast Reconstr Surg. 109:199-209; Morizono et al. (2003), Hum Gene Ther. 14:59-66; Winter et al. (2003), Arthritis Rheum. 48:418-29; Zuk et al. (2001), Tissue Eng 7:211-228; Zuk et al. (2002), Mol Biol 13: 4279-4295, reviewed in Gimble et al. (2003), Cytotherapy 5:362-369). These cells, termed Adipose-Derived Adult Stem (ADAS) cells, exhibit an immunophenotype and differentiation potential comparable to that of MSCs (Gronthos et al. (2001), Journal of Cellular Physiology 189:54-63; Safford et al. (2002), Biochem Biophys Res Commun. 294(2):371-9; Zuk et al. (2002), Mol Biol Cell 13:4279-4295).
Reproducible and efficient methods to isolate adult stem cells from human liposuction specimens are available in the public domain (Aust et al. (2004), Cytotherapy 6:7-14; Halvorsen et al. (2001), Metabolism 50:407-413). The procedure involves collagenase digestion of the tissue, differential centrifugation, and expansion in culture. A single gram of tissue can yield between 50,000 to 100,000 stromal cells within 24 hours of culture (Sen et al. (2001), J Cellular Biochemistry 81:312-319). Analysis of specimens obtained from 20 individual donors resulted in a consistent recovery a mean of 401,000 cells with a viability of 94% from a single ml of liposuction waste (Aust et al. (2004), Cytotherapy 6:7-14). Expansion of these cells can result in a population greater than 500 million cells within a 2 week period from a standard lipoaspirate.
In the presence of dexamethasone, insulin, isobutylmethylxanthine and a thiazolidinedione, the ADAS cells undergo adipogenesis (Sen et al. (2001) Journal of Cellular Biochemistry 81:312-319). The differentiation potential of the ADAS cells is not limited to the adipocyte lineage. Conditions that promote ADAS cell differentiation along the chondrocyte and osteoblast pathways have been reported (Awad, et al. (2003), Tissue Engineering 9:1301-12; Erickson et al. (2002), Biochemical and Biophysical Research Communications 290:763-769; Halvorson et al. (2001), Metabolism 50:407-413; Hicok et al. (2004), Tissue Engineering 10:371-380; Wickham et al. (2003), Clinic Orthopedics and Related Research 412:196-212). In vivo, human ADAS cells combined with a hydroxyapatite biomaterial synthesize osteoid matrix when implanted subcutaneously into immunodeficient mice (Hikok et al. (2004), Tissue Engineering 10:371-380). Substantial data are available to demonstrate that murine or human adipose derived adult stem cells (muADAS and huADAS respectively) cultured in the presence of antioxidants and other mediators undergo morphologic and phenotypic changes consistent with neuronal differentiation (De Ugarte (2003) Cells Tissues Organs. 174:101-9; Safford et al. (2002), 294(2):371-9; Safford et al. (2004), Experimental Neurology 187:319-28).
As described by Jayo et al. Regen. Med. (2008) 3(5), 671-682 (hereinafter referred to as "Jayo I"), attempts to repair organs or tissue have been characterized by incomplete tissue replacement frequently with collagen deposition, and in some cases scar tissue formation. Jayo et al. also observed a more desirable outcome of tissue engineering is regeneration of the original structure and function of a tissue structure or organ. See also Jayo et al., J. Urol. (2008) 180; 392-397 (hereinafter referred to as "Jayo II"). Certain molecules are believed to be associated with the regenerative process in vivo. For example, the chemokine MCP-1 is best known for its ability to recruit mononuclear cells. However, it also appears to be a potent mitogen for vascular smooth muscle cell proliferation. MCP-1 recruits circulating monocytes to the area of vessel injury, which in turn are typically transformed to macrophages that can serve as reservoirs for cytokines and growth factors. Macrophages also ingest cholesterol and oxidize lipids. Macrophages and muscle precursor cells are both believed to be targets for MCP-1 signaling. The CCR-2 receptor is the ligand for MCP-1 (CCL2) and CCR-2 deficient mice show a regeneration defect with enhanced adipogenesis/fibrosis. Sections from CCR-2 deficient mice when challenged with skeletal muscle regeneration demonstrated the following in comparison to normal mice: more interstitial space, a high number of inflammatory cells, large round swollen myofibers, more fibroblast accumulation in interstitial space, fat infiltration with collagen distribution around fat deposits, and fibrosis accompanied by calcium deposition (Warren et al. (2005), FASEB J. 19:413-415; Selzman et al. (2002), Am J Physiol Heart Circ Physiol. 283(4); H1455-H1461; Shannon et al. (2007), Am. J. Cell Physiol. 292:C953-C967; Shireman et al. (2006), J. Surg. Res. 134(1):145-57. Epub 2006 Feb. 20; Amann et al. (1998), Brit. J. Urol. 82:118-121; Schecter et al. (2004), J. Leukocyte Bio1.75:1079-1085; Deonarine et al., (2007), Transl Med. 5:11; Lumeng et al. (2007), J. Clin. Invest. 117(1): 175-184).
The present invention concerns cell populations derived from autologous sources that are different from the organ or tissue structure that is the subject of the regeneration, reconstruction, repair, augmentation or replacement described herein, methods of isolating such cells, neo-organ/tissue structure scaffolds or matrices seeded with such cells (constructs) and methods of making the same, as well as methods of treating a patient in need using such neo-organ/tissue structure constructs.


A flexible, rubber-like member in the shape of a flat "dumbbell" has a pair of holes at either enlarged end thereof for fitment respectively about the opposed knobs or handles of a door with the narrow portion thereof wrapping around the side edge of the door proximal the knobs to prevent closure of the door. In an alternatively preferred embodiment, there is provided a signal generating mechanism for indicating when an attempt is being made to close the door with which it is being used.

1. Field of the Invention
The present invention relates generally to devices for preventing the closure of doors, and more particularly, to a device adapted to be fitted to the handles of a door so as to prevent the door from swinging shut.
2. Description of the Prior Art
Door stops in the form of wedges placed between a door's bottom edge and the floor are age old. Unfortunately, such devices are susceptible of being accidentally kicked free causing a door to close when it is otherwise desired to remain open as, for example, when an infant or child is playing unsupervised in a room and the parent or guardian is in another room or location.
Other prior art attempts at providing a simple, relatively inexpensive yet safe and effective door stop have not been completely successful. Exemplary of these is the door stop shown in U.S. Pat. No. 4,831,688 which shows a one-piece device adapted to be fitted about the edge of a door proximal to the door's hinge so as to serve as a wedge preventing the door from completely closing. This patented device however, is susceptible of being accidentally removed in a relatively easy manner thereby defeating its purpose. Other door stops of various configuration are shown in U.S. Pat. Nos. 4,756,052 (telescopically fitted rods coacting with existing door brace linkage); and 4,462,623 (spring-loaded cylinder in floor recess near door). Also of interest are known devices for engaging doors in one way or another as shown, for example, in U.S. Pat. Nos. 4,181,339 (door knob sleeve of resilient material) and 4,782,553 (bendable door stop screwed into wall).
It is apparent from the above that a need exists for a door stop that may be fitted to a door to maintain the door open and which is not easily removable all of the while being of simple construction and low cost. This need is met by the unique door stop of the present invention as will be made apparent from the following description thereof. Other advantages of the present invention over the prior art also will be rendered evident.


Methods of forming a device isolation structure in a semiconductor device are disclosed. A disclosed method comprises forming a p-type well and an n-type well in a semiconductor substrate; sequentially depositing a gate insulating layer and a gate electrode material layer; depositing a protective layer on the gate electrode material layer; removing a portion of the protective layer, a portion of the gate electrode material layer, and a portion of the gate insulating layer to expose a surface area of the semiconductor substrate; performing ion implantation and heat treatment processes to form a device isolation structure; forming a gate electrode by removing a portion of the gate electrode material layer; forming an LDD region by implanting low concentration impurity ions in the semiconductor substrate; forming a spacers on a sidewall of the gate electrode; and forming a source/drain region by implanting high concentration impurity ions.

A LOCOS (local oxidation of silicon) process has been developed and widely used as a semiconductor device isolation technology. As the LOCOS process has generally been used, new device isolation technologies have been developed to address shortcomings of the LOCOS process. For example, PBL (poly buffer LOCOS) and R-LOCOS (Recessed LOCOS) are widely used. However, these technologies have shortcomings in the context of high-integration of semiconductor devices. For instance, they are complicated processes and cannot fundamentally overcome problems such as bird's beak, which is produced as a result of the lifting of the edges of a nitride layer during subsequent oxidation. Moreover, a planarization process must be carried out after the completion of the LOCOS process because of the level difference between active regions and field regions.
To address the problems of the conventional device isolation technologies, a shallow trench isolation (hereinafter referred to as "STI") process has been developed. The STI process achieves good device isolation characteristics and is suitable for the high-integration of semiconductor devices because the STI structure occupies a small area.
A prior art STI process comprises: forming a trench within a field region of a semiconductor substrate, filling the trench with an oxide layer through a gap filling process, and planarizing the resulting semiconductor substrate by using a chemical mechanical polishing (hereinafter referred to as "CMP") process. The oxide layer to gap-fill the trench is preferably an O3-TEOS (tetra-ethyl-ortho-silicate) layer formed by using APCVD (atmospheric pressure chemical vapor deposition). The oxide layer may be created by HDP CVD (high density plasma chemical vapor deposition).
Sekikawa et al., U.S. Pat. No. 6,489,661, describes a method of forming an element isolation film using LOCOS technology. The Sekikawa et al. Patent uses a pad oxidation film and a pad poly-Si film as an underlying buffer layer of an oxidation resisting film. The pad oxidation film and the pad poly-Si film are used as a gate oxide film and a part of a gate electrode to relax a level difference between the gate electrode and the wiring on the element isolation film.
Jang et al., U.S. Pat. No. 6,153,481, describes a method of forming an element isolation insulating film of a semiconductor device by employing a PBL method to reduce the bird's beak and to increase the length of the effective active region. The Jang et al. Patent comprises: sequentially forming a pad-oxide film, a stack-silicon film, and a nitride film on a semiconductor substrate; forming an element isolation region by selectively patterning the nitride film with an etching process by using an element isolation mask; and forming an element isolation film by field-oxidizing the element isolation region over the semiconductor substrate.
Sun et al., U.S. Pat. No. 5,612,249, describes a method of defining a LOCOS field isolation process after a poly gate is deposited. The Sun et al. Patent comprises: growing a gate oxide on a silicon substrate; depositing poly or amorphous silicon, depositing a thin layer of PECVD or LPCVD oxide on the poly or amorphous silicon, depositing LPCVD nitride as a hard mask, and defining a device active area by using a photoresist mask and performing a plasma etch.
FIGS. 1a and 1b are cross-sectional views illustrating a conventional STI process. Referring to FIG. 1a, a sacrificial layer is formed over the entire surface of a semiconductor substrate 101. The sacrificial layer preferably consists of an oxide layer 102 and a nitride layer 103. At least one opening is formed through the nitride layer 103 and the oxide layer 102 on a field region of the semiconductor substrate 101 by performing a photolithography process. At least one trench is then formed within the field region of the semiconductor substrate 101 by using the nitride layer 103 as an etching mask. An oxide layer 104 is grown along the sidewalls and bottom of the trench(es) 105. The trench(es) are then filled with an insulating layer 105 having good gap-fill characteristics. The insulating layer 105 may be, for example, oxide. Next, a planarization process is performed on the resulting structure.
Referring to FIG. 1b, the nitride layer 103 is etched by a phosphoric acid solution to expose the oxide layer 102. The oxide layer 102 is then etched by an HF solution to expose the surface of the active region of the semiconductor substrate 101. This completes the STI process.
The conventional STI process of FIGS. 1a-1b must remove some portion(s) of the insulating layer 105 through an etching process in order to lower the insulating layer 105 in height compared to the nitride layer 103 after the completion of the planarization process. During this process, the area of the insulating layer 105 which is in contact with the nitride layer 103 is etched more rapidly than the other parts of the insulating layer 105. Thus, after the nitride layer 103 and the oxide layer 102 are etched to expose the surface of the active region of the semiconductor substrate 101, as shown in FIG. 1b, a divot 106 on the upper edge of the trench is deepened. The deepened divot 106 may increase leakage current on the upper edge of the trench.
The above-described STI process may also increase costs as compared to the existing LOCOS process due to the complicated process and the change of the process margin due to the CMP process.

Methods for forming a device isolation structure in a semiconductor device


Laser-scribing brittle substrates along a curvilinear path is effected by impinging and moving at least two laser light beam spots along the substrate surface, the first spot preheating the substrate and the second smaller spot heating the substrate to the laser-scribing temperature below the softening temperature of the substrate. Embodiments include forming dual spots employing a crystal material or employing dual fiber optic cables each optically linked to a lens. In another embodiment, three spot lasers spots are formed employing a three-spot diffractive lens, the third spot formed behind the second laser-scribing spot and heating the surface to a temperature lower than the laser-scribing temperature. Embodiments further include laser-scribing substantially circular glass, ceramic or glass-ceramic substrates for magnetic recording media.

The present invention relates to breaking sheets of brittle materials using a laser-scribing technique. The present invention has a particular applicability in laser-scribing brittle non-magnetic sheets along curvilinear paths to produce substrates for use in manufacturing magnetic recording media.
Conventional techniques for cutting a sheet of brittle material, such as a glass, amorphous glass, glass-ceramic or ceramic material, comprises two principal methods. One such method is mechanical-scribing employing a hard device, such as a diamond tip, to create score marks on the surface of the brittle material which is then broken along the score marks. The second of such conventional techniques is laser-scribing, employing a continuous wave laser, such as a CO2 laser, to continuously heat a zone of a brittle material, such as amorphous-glass, similar to a floating window, up to a localized temperature below the softening point of the material, and then immediately quenching the heated body by applying a coolant, such as air or a liquid such as water. The heating-quenching combination will initiate a tiny surface crack that propagates to localize compression-tension stress effects and the sheet of material will finally be broken under external thermal or mechanical stress. A conventional laser-scribing technique is disclosed by Kondratenko in U.S. Pat. No. 5,609,284, wherein an elliptical target area is impinged with a beam of coherent radiation along the intended direction of the crack, while a stream of fluid coolant is directed at a point on the heated surface on the intended line of the crack. Allaire et al. in U.S. Pat. No. 5,776,220 disclose a laser-scribing technique for brittle materials wherein the laser spot has an extremely elongated elliptical shape such that its major axis is greater than 20 mm to enable rapid scribing.
Conventional substrates for use in manufacturing magnetic recording media include various brittle materials, such as glasses, ceramics and glass-ceramics. In order to form a suitable substrate for use in a magnetic recording medium, two circular scribings must be performed with high precision, one defining the outer diameter and one defining the inner diameter. However, current linear laser-scribing techniques for flat panels can not be directly applied in circular scribings for producing magnetic recording media. For flat panel linear laser-scribing, a circular laser light beam is typically reshaped into a beam with a very elongated cross section, as shown in FIG. 1, with a short axis xe2x80x9caxe2x80x9d of about 1xc2x10.5 mm, and a long axis xe2x80x9cbxe2x80x9d of about 30xc2x110 mm. In FIG. 1, xe2x80x9cxxe2x80x9d represents the scribing direction, xe2x80x9cHxe2x80x9d represents the scribing heating zone, xe2x80x9cQxe2x80x9d represents the quenching zone, xe2x80x9cTspxe2x80x9d represents the material softening point, xe2x80x9cPHxe2x80x9d represents the preheating zone, xe2x80x9cLSxe2x80x9d represents the laser-scribing heating temperature and xe2x80x9cQTxe2x80x9d represents the quenching temperature.
Adverting to FIG. 1, the localized temperature increases from the leading point to the central point where the highest temperature is achieved but below the material""s softening point. The purpose for a long beam axis along the scribing direction and raising a temperature profile is to provide preheating of the surface before reaching the scribing/quenching point. Such an elongated beam is not, however, suitable for substantially circular scribing. Although it may be theoretically possible to modify the lens optics to reshape the elongated beam into an elongated curved beam, any such optical design would be extremely complex in order to meet the various requirements of the outer diameter and inner diameter of magnetic recording media. For example, typical magnetic recording media have an inner diameter of about 20 mm to about 25 mm and an outer diameter ranging from 65 mm to 95 mm, e.g., 84 mm. The difficulty in laser-scribing along a curvilinear path is recognized by Kondratenko (in U.S. Pat. No. 5,609,284) who suggests the use of a score or nick having a gradually increasing depth along the cutting line.
Accordingly, conventional practices for cutting brittle substrates for use in magnetic recording media involve the use of diamond tips to induce mechanical stresses. However, the required high tolerances are not fully satisfied by mechanical scribing. Moreover, after mechanical scribing it is necessary to perform extensive polishing and lapping, thereby significantly increasing manufacturing costs.
There exists a need for a method and apparatus for laser-scribing a brittle substrate along a curvilinear path, particularly a substantially circular path. There exists a particular need for an apparatus and methodology for laser-scribing brittle materials, such as glasses, ceramics and glass-ceramics, along substantially circular paths to form substrates for use in manufacturing magnetic recording media.
An advantage of the present invention is a method of laser-scribing brittle materials along a curvilinear path.
Another advantage of the present invention is an apparatus for laser-scribing brittle materials along a curvilinear path.
Additional advantages and other features of the present invention will be set forth in the description which follows and in part will be apparent to those having ordinary skill in the art upon examination of the following disclosure or may learned from the practice of the present invention. The advantages of the present invention may be realized and obtained as particularly pointed out in the appended claims.
Accordingly to the present invention, the foregoing and other advantages are achieved in part by a method of laser-scribing to separate portions of a sheet of brittle material along a curvilinear path, the method comprising: rotating the sheet; impinging a first laser light beam at a first beam energy on a surface of the sheet to form a first laser spot having a first size to preheat the surface of the sheet to a first temperature; and impinging a second laser light beam at a second beam energy on the surface of the sheet to form a second laser spot having a second size, spaced apart from and behind the first laser spot with respect to the rotating direction, to heat the surface to a second laser-scribing temperature higher than the first temperature; and directing a coolant to an area on the surface of the sheet behind the second spot with respect to the rotating direction.
Another aspect of the present invention is an apparatus for laser-scribing a sheet of brittle material into separate portions along a curvilinear path, the apparatus comprising: means for rotating the sheet; a laser source; a coolant source; means for: impinging a first laser light beam at a first beam energy on a surface of the sheet to form a laser spot having a first size to preheat the surface of the sheet to a first temperature; and impinging a second laser light beam at a second beam energy on the surface of the sheet to form a second laser spot, behind the first laser spot with respect to the rotating direction, to heat the surface of the sheet to a second laser-scribing temperature greater than the first temperature; and means for directing a coolant to an area on the surface of the substrate behind the second spot with respect to the rotating direction.
A further aspect of the present invention is a laser-scribing apparatus for separating portions of a sheet of brittle material along a curvilinear path, the apparatus comprising: a source of a coolant; and means for heating a surface of the sheet to a first preheating temperature and to a second laser-scribing temperature greater than the first preheating temperature.
Embodiments of the present invention comprise the use of a crystal material to form first and second laser light beams. In another embodiment of the present invention, first and second laser light beams are formed employing first and second fiber optic cables each optically linked to a lens. In another embodiment, a three-spot defractive lens is employed to form first and second laser light beams in addition to a third laser light beam which impinges the surface to form a third spot between the second spot and the area impinged by the coolant. Embodiments of the present invention include laser-scribing a glass, ceramic or glass-ceramic material to form a substantially circular disk having an outer diameter and an inner diameter for use in manufacturing magnetic recording media. It should be recognized that the embodiments disclosed herein can be employed for scribing straight lines as well as free-shape lines, such as curvilinear lines and substantially circular lines.
Additional advantages of the present invention will become readily apparent to those having ordinary skill in the art from the following detailed description, wherein embodiments of the present invention are described, simply by way of illustration of the best mode contemplated for carrying out the present invention. As will be realized, the present invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the present invention. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.


The present application provides external bone and tissue fixation systems and related methods. The fixation systems may include an elongate beam element defining an axis with an axially extending threaded track portion. The systems may also include at least one drivable fixation clamp assembly comprising a housing with a central bore, a driving housing rotatably coupled to the housing, a threaded driving member, and a clamp assembly rotatably coupled to the housing configured to clamp to at least one fixation member. The elongate beam element may extend axially through central bore of the housing. The driving member may be movable with respect to the central bore via rotation of the driving housing between engaged and disengaged states with the threaded track portion. Rotation of the driving member in the engaged state may axially translate the clamp assembly along the beam element.

External fixation devices have been used to treat bone and tissue conditions by positioning bone or tissue segments in desired relative positions based on particular clinical needs. One form of external fixation devices is a unilateral or mono-lateral rail based fixation device. These devices are typically comprised of a beam element serving as the structural backbone of the device, along which are slidably attached clamp assemblies that can accept fixation elements such as bone fixation pins or wires. In some embodiments, these clamp assemblies have the ability to be statically locked to the beam element or dynamically driven or translated axially along the beam element. In some embodiments, the clamp assemblies can be rotated about the beam element or angulated relative to the axis of the beam element.
When configured as bone or tissue fixation systems, unilateral fixation systems typically include a multitude of clamp assemblies. In the most basic configurations, there is one static clamp assembly and one drivable clamp assembly coupled to the beam element. In some embodiments, the beam element and the clamp assemblies arranged in this way can be connected to a second beam and clamp assembly through the use of a joint element having 1 or more degrees of freedom, such as a hinge having 1 degree of freedom to a spherical or cardan joint having 3 degrees of freedom. In more complicated configurations, it is sometimes desirable to be able to drive multiple clamp assemblies independently along the beam element such that multiple bone segments can be manipulated thereby. When affixing clamp assemblies to the fixation elements coupled to corresponding bone segments, it is also at times desirable to be able to quickly arrange the clamp assemblies along the beam element. Current unilateral external bone fixation systems do not aloe for such gross and/or quick translation of the clamp assemblies along the beam element, at least without adding or removing parts of the clamp assemblies and/or beam element. Given the small size of many unilateral external bone fixation systems utilized with relatively small bones (e.g., bones of the foot, hand or the like), adding or removing parts of the clamp assemblies and/or beam element can be cumbersome and/or time consuming.
External bone fixation systems with compact, clutch-able, self-contained mechanisms that allows for the rapid buildup and placement of clamp assemblies along the length of a beam element in a variety of positions and angulations to facilitate optimal fixation to bone elements (and thereby corresponding bones or bone segments) is therefore desirable.


A process for preparing torsemide or salts thereof comprising:                a) reacting II with isopropyl isocyanate in the presence of an alkali carbonate or bicarbonate and an organic solvent to form an alkali torsemide mixture,        b) recovering the alkali torsemide mixture, and        c) if desired, recovering the torsemide by acidification of the alkali torsemide mixture.

Torsemide, chemically named N-[[(1-methylethyl)amino]carbonyl]-4-[(3-methylphenyl) amino]-3-pyridinesulfonamide III, is a loop diuretic which has been found to be particularly effective for the treatment of edema associated with chronic renal failure.
The synthesis of torsemide is described in prior art documents including: Delarge et al, Ann. Phann. Fr.31, 467-474 (1973); Delarge et al, Mem. Acad. R. Med. Belg. 47(3), 131-210 (1974); DE 2,516,025 ; U.S. Pat. No. 4,244,950; U.S. RE 30,633; and WO 03/097603 all of which are incorporated herein by reference.
A common process for the preparation of the torsemide III from 4-chloro-3-pyridinesulfonamide I, via intermediate 4-[(3-methylphenyl)amino]-3-pyridinesulfonamide II is depicted in scheme 1 below.

U.S. RE 30,633 (1981, A. Christiaens Societe Anonyme, Belgium) disclose such a synthetic route to torsemide III and an intermediate II. For the preparation of II, the reaction is carried out in the presence of copper powder and at elevated temperature. The purification procedure of II is laborious as well in U.S. RE 30,633. Generally, it is disadvantageous to employ a heavy metal (such as copper) in the later stages of active pharmaceutical ingredient (API) production. Additional purification steps may be required to remove residual traces of the heavy metal from the API or its precursor.
U.S. RE 30,633 further provides for the preparation of torsemide III by the subsequent reaction of 4-[(3-methylphenyl)amino]-3-pyridinesulfonamide II with isopropyl isocyanate in the presence of triethylamine. The solvent system used in U.S. RE 30,633 is dichloromethane, dioxane or neat (i.e. no solvent added). After evaporative removal of the solvent, the mixture is clarified in aqueous sodium carbonate and further addition of acetic acid to furnish torsemide III.
Under such conditions the desired product, torsemide III is isolated in low yields with a high percentage of impurities, thus requiring additional purification steps.
U.S. Pat. No. 6,635,765 (Teva, 2001) discloses a process for preparing torsemide III comprising the step of reacting 3-sulfonamide-4-(3′-methylphenyl)aminopyridine II with isopropyl isocyanate in the presence of triethylamine in a solvent selected from the group consisting of acetonitrile, acetone, ethyl acetate, butyl acetate and mixtures thereof. Upon reaction completion, the pH is adjusted to 4.3 using aqueous hydrogen chloride solution and the precipitated product is isolated by filtration. It is then further purified by trituration in a mixture of acetonitrile and water. Thus, crude torsemide III is obtained with a purity of more than 98% and a chemical yield of 81.5%. In this process, once acidified, a large amount of water has to be added to precipitate the product III. However, many other organic impurities, including the toxic and difficult to remove N,N′-isopropyl urea (from the isopropyl isocyanate), precipitate out as well.
WO 03/097603 (Finetech Laboratories Ltd., 2003) discloses a process for manufacturing torsemide III. However, the process includes the use of isopropyl carbamate. This is not a commercially available compound and is prepared from the toxic and difficult to handle reagent, phenylchloroformate.
Furthermore, excessive exposure to carbamates has been shown to cause fatigue, joint and muscle pain and headaches. Additionally, laboratory experiments indicate that some carbamates have mutagenic or carcinogenic properties.
Furthermore, although WO 03/097603 describes a synthesis for the manufacture of the intermediate II where copper is absent, based on Example 11 the solvent used is methyl ethyl ketone and the reaction does not go to completion. The yield is 91.4% and the purity is only 99.0%, with 0.5% of the 4-chloro-3-pyridine sulfonamide starting material still present.
Once again, the torsemide III is isolated in low yields with an impurity level of toxic material that is difficult to remove.
In summary, some of the disadvantages of the prior art processes include:                i) the purity of the isolated torsemide is low thereby requiring additional steps to obtain pharmaceutically acceptable substance;        ii) the chemical yield of 81.5% for the crude torsemide is low;        iii) because water is introduced to isolate the torsemide during the acidification step, the torsemide is contaminated with N,N′-isopropyl urea;        iv) potential carcinogenic or mutagenic isocarbamate is used;        v) heavy metal usage requires removal thereof, which is difficult.
The yields of the prior art processes are low, highly variable and are unsuitable when transiting to commercial production.
It is therefore necessary to overcome the deficiencies of the prior art and to develop a cost-effective, robust and scalable process to manufacture both torsemide III and torsemide intermediate II. A further objective is to develop a process for making torsemide III meeting the high purity specifications required for an API.
Further and other objects of the invention will become apparent to a person skilled in the art when reading the following.

Process for the preparation of torsemide and related intermediates


A method is disclosed. The method comprising: receiving, by an access control sewer via a directory sewer from an authentication requestor, an authentication request comprising an account identifier, and information regarding a prior authentication method on the account identifier and a current authentication method for the account identifier associated with a transaction; performing, by the access control server, a risk analysis for the transaction based at least in part on the information and a threshold; authenticating, by the access control server, the user of the account identifier using the information, the account identifier, and a result of the risk analysis; modifying, by the access control server, an authentication response to include an authentication indicator, and transmitting, by the access control sewer, the authentication response to the authentication requestor.

Various systems and methods for authenticating users in online transactions exist. In some instances, an authorizing entity such as an issuer may authenticate a user conducting an online transaction with a resource provider such as a merchant. The authorizing entity can verify the user by requesting a password from the user. The user can then supply the password, and the authorizing entity can authenticate the user. After the authorizing entity authenticates the user, the authorizing entity can provide an indication of the authentication (e.g., a positive or negative authentication result) to the resource provider. The resource provider can then provide an authorization request message for the particular amount of the transaction requested by the user to the authorizing entity. The authorizing entity also receive the indication of the authentication, and can use that is its decision to authorize or not authorize the interaction.
While the above described system is suitable for many situations, a number of improvements can be made. For example, the data used to verify the user is limited to a password that we previously supplied to the authorizing entity. If that password had someone been obtained by an unauthorized user, then the unauthorized user could fraudulently perform the transaction with the resource provider. Thus, it would be desirable to provide for a system and method that provides for more effective and efficient authentication during online transactions.
Another problem with the conventional system described above is that the user is always asked for a password by the issuer. This can be cumbersome and requires a number of steps. Further, because the user may be communicating with both a resource provider such as a merchant and the issuer during a single online transaction, it is possible that communications can be hung up or may time out. Accordingly, better ways to streamline processing, by potentially removing the requirement that the user enter an issuer password would be desirable.
Embodiments of the invention address these and other problems, individually and collectively.


The invention relates to a condiment dispensing system for dispensing condiment and the like which includes a gas operated pump for moving condiment(s) from a condiment source to a delivery nozzle through a condiment conduit which includes a draw-back valve to prevent condiment buildup on the delivery nozzle. A gas-operated pump is controlled at the delivery nozzle to effect delivery of the condiment.

The invention relates to a system for dispensing condiments or the like. It is specially adapted to dispense condiments that contain solids or semi solids or particles such as is found in thousand island dressing and various "secret sauces" favored by restaurants without fouling the dispensing system. The invention provides for dispensing condiment rapidly and efficiently and uses a draw-back valve in the condiment dispensing conduit to prevent buildup of the condiment on the dispensing nozzle. The invention is particularly adapted to handle condiments that contain residual air or other gases without causing the condiment to splatter when delivered.
At present, condiment packers are unable to remove all air from the condiment during manufacturing or packing. Additionally, small CO.sub.2 gas or atmosphere air leaks can cause the pump to suck air into the system, literally blending this air with the condiment. The air or gas can cause condiment to splatter at the nozzle when it exits under pressure and to drip and build up on the nozzle if not properly handled.
Typically, this air in prior art systems has been trapped within the condiment between pump condiment outlet and dispensing head on/off valve. When the condiment button is deactivated, the mechanical valve seals off the condiment conduit at the delivery nozzle, which, in turn, stops the condiment flow and thereby stops the pump. At the time of deactivation, pressure is trapped between pump outlet and the valve at the delivery nozzle. When the condiment button in the delivery nozzle is depressed again, and if an air pocket is within a few feet of the nozzle, the air bubble exits the delivery nozzle with sufficient velocity to cause "spitting" (splattering, spraying) within the immediate area. This can soil a customer's clothes and is a problem for the equipment user.
Heretofore there have been many systems developed for dispensing condiments automatically and in controlled portions. For example, U.S. Pat. No. 5,366,117, issued to John M. Mesenbring et al., provides a condiment dispensing system. The Background section of that patent describes many of the prior art methods and systems for dispensing condiments and the problems associated therewith. The Mesenbring et al. patent provides a system for selectively dispensing condiments for items of food, including a plurality of condiment containers, a dispenser head having a plurality of input passages, an outlet nozzle, and valves for controlling fluid flow from each of the input passages to the outlet nozzle, a plurality of fluid flow lines, with a line connecting each condiment container to a corresponding dispenser head input passage, and a fluid pump in each of the fluid flow lines whereby an operator can dispense selected condiments in controlled portions if desired from the nozzle onto a food item. Arrangements for daily and biweekly sanitizing of the system are also provided. The patent provides for the use of a dispensing head having a plurality of input passages which can be fouled during delivery of viscous condiments particularly by condiments that contain solid or semi solid particles.
Another approach to dispensing condiments is disclosed in U.S. Pat. No. 5,158,210 to Benjamin R. Du. The Background section of the Du patent also discusses prior art methods of dispensing condiments. The Du patent provides an improved condiment dispensing system for delivering a measured quantity of condiment as a constant flow rate. The device comprises a pump which is fluidly connected to a condiment source and a dispensing apparatus. The dispensing apparatus includes a valve assembly which is connected to both a pressurized fluid source and to the pump whereby actuation of a valve assembly contained on the surface of the dispensing apparatus causes a measured quantity of condiment to be dispensed from an outlet nozzle contained thereon. The pump of the Du patent is provided with two cavities which in operation alternately withdraw a predetermined quantity of condiment from a condiment source and dispense the predetermined quantity of condiment at a desired location.
There is still need for a condiment dispensing system which can handle condiments including viscous condiments and/or condiments with solid or semi solid particles in an efficient manner without fouling and which may contain air or other gases without splatter at the delivery nozzle and which act to prevent condiment buildup on the dispensing nozzle.

Condiment dispensing system utilizing a draw-back valve


Dioxetanes which couple with organic and biological molecules of the formula: ##STR1## wherein X is a leaving group which is removed by an `activating agent to produce light, wherein A is a coupling substituent, Ar is a substituent selected from the group consisting of phenyl and naphthyl to provide a label are described. R.sub.1 is an optional linker substituent and can have between 1 and 30 carbon atoms with some of the carbon atoms being oxygen, sulfur, nitrogen or phosphorus. Ar as phenyl is preferred. The dioxetane coupled molecules are useful in assays of all types where luminescence can be used as an indicator.

(1) Field of the Invention
The present invention relates to triggerable stable 1,2-dioxetanes which have the ability to bind to organic and biological molecules for use in assays and the like. In particular, the present invention relates to 1,2-dioxetanes which have an ability to react with biological materials without materially altering their essential function.
(2) PRIOR ART
1. Chemical Triggering of Stabilized 1,2-Dioxetanes. Thermally stable dioxetanes which can be triggered by chemical and enzymatic processes to generate chemiluminescence on demand have recently been discovered (A. P. Schaap, patent application Ser. No. 887,139, filed Jul. 17, 1986; A. P. Schaap, R. S. Handley, and B. P. Giri, Tetrahedron Lett., 935 (1987); A. P. Schaap, T. S. Chen, R. S. Handley, R. DeSilva, and B. P. Giri, Tetrahedron Lett., 1155 (1987); and A. P. Schaap, M. D. Sandison, and R. S. Handley, Tetrahedron Lett., 1159 (1987)). To do this, new synthetic procedures to produce dioxetanes with several key features have been developed: (1) the stabilizing influence of spiro-fused adamantyl groups has been utilized to provide dioxetanes that have "shelf lives" of years at ambient temperature and (2) new methods for triggering the chemiluminescent decomposition of the stabilized dioxetanes have been developed.
The required alkenes have been prepared by reaction of adamantanone with aromatic esters of ketones using titanium trichloride/LAH in THF (A. P. Schaap, U.S. Pat. No. 4,857,652). This is the first report of the intermolecular condensation of ketones and esters to form vinyl ethers using these reaction conditions. Although McMurry had earlier investigated the intramolecular reaction of ketone and ester functional groups, cyclic ketones and not vinyl ethers were prepared by this method (J. E. McMurry and D. D. Miller, J. Amer. Chem. Soc., 105, 1660 (1983) and J. E. McMurry, Chem. Rev., 89, 1513 (1989)). ##STR2##
Photooxygenation of these vinyl ethers affords dioxetanes that are easily handled compounds with the desired thermal stability. For example, the dioxetane shown below exhibits an activation energy of 28.4 kcal/mol and a half-life at 25.degree. C. of 3.8 years. Samples of this dioxetane in o-xylene have remained on the laboratory bench for several months with no detectable decomposition. ##STR3##
However, the chemiluminescent decomposition of this dioxetane can be conveniently triggered at room temperature by removal of the silyl protecting group with fluoride ion to generate the unstable, aryloxide form which cleaves to yield intense blue light. The half-life of the aryloxide-substituted dioxetane is 5 seconds at 25.degree. C. The spectrum of the chemiluminescence in DMSO exhibits a maximum at 470 nm which is identical to the fluorescence of the anion of the ester cleavage product (methyl 3-hydroxybenzoate) and the fluorescence of the spent dioxetane solution under these conditions. No chemiluminescence derived from adamantanone fluorescence appears to be produced. The chemiluminescence quantum yield for the fluoride-triggered decomposition measured relative to the luminol standard was determined to be 0.25 (or a chemiluminescence efficiency of 25%). Correction for the fluorescence quantum yield of the ester under these conditions (.O slashed..sub.F =0.44) gave an efficiency for the formation of the singlet excited ester of 57%, the highest singlet chemiexcitation efficiency yet reported for a dioxetane prepared in the laboratory. ##STR4##
2. Enzymatic Triggering of Stabilized 1,2-Dioxetanes. Biological assays such as immunoassays and DNA hybridizations involving enzymes utilized a wide variety of substrates which either form a color (chromogenic) or become fluorescent (fluorogenic) upon reaction with the enzyme. As part of the investigation of triggering methods, the first dioxetanes which can function as chemiluminescent enzyme substrates have been discovered (A. P. Schaap, U.S. patent application Serial No. 887,139; A. P. Schaap, R. S. Handley, and B. P. Giri, Tetrahedron Lett., 935 (1987); A. P. Schaap, T. S. Chen, R. S. Handley, R. DeSilva, and B. P. Giri, Tetrahedron Lett., 1155 (1987); A. P. Schaap, M. D. Sandison, and R. S. Handley, Tetrahedron Lett., 1159 (1897) and A. P. Schaap, Photochem. Photobiol., 47S, 50S (1988)). Use of these peroxides in biological systems requires dioxetanes which are thermally stable at the temperature of the enzymatic reaction and do not undergo rapid spontaneous decomposition in the aqueous buffers. The spiro-fused adamantyl dioxetanes described in the previous section meet these requirements. Dioxetanes have been prepared which can be enzymatically modified to generate the aryloxide form. Decomposition of this unstable intermediate provides the luminescence. Dioxetanes have been synthesized which can be triggered by various enzymes including aryl esterase, acetylcholinesterase, alkaline phosphatase and beta-galactosidase. ##STR5##
For example, enzymatic triggering by alkaline phosphatase has been observed with the phosphate-substituted dioxetane shown above derived from 3-hydroxy-9H-xanthen-9-one and adamantanone. The dioxetane is thermally stable with an activation energy of 30.7 kcal/mol and a half-life at 25.degree. C. of 12 years. The dioxetane is not only stable in organic solvents but also shows very slow spontaneous decomposition in aqueous buffers. Triggering experiments were conducted using alkaline phosphatase from bovine intestinal mucosa and the phosphate-protected dioxetane at pH 10.3 in 0.75M 2-amino-2-methyl-1-propanol buffer. The total light emission was found to be linearly dependent on the dioxetane concentration. The rate of decay of the emission is a function of enzyme concentration while the total light emission is independent of the enzyme concentration. The chemiluminescence spectrum for the phosphatase-catalyzed decomposition was obtained at room temperature in the buffer solution. A comparison of this chemiluminescence spectrum with the fluorescence spectrum of the spent reaction mixture and the fluorescence spectrum of the hydroxyxanthone cleavage product in the buffer indicates that the emission is initiated by the enzymatic cleavage of the phosphate group from the dioxetane to yield the unstable aryloxide dioxetane which generates the singlet excited anion of hydroxyxanthone. ##STR6##
Phosphatase triggering experiments have also been conducted using the phosphate-protected dioxetane shown above derived from methyl 3-hydroxybenzoate and adamantanone with alkaline phosphatase at pH 9.6 in 0.75M 2-amino-2-methyl-1-propanol buffer. Addition of the enzyme to a 10.sup.-4 M solution of dioxetane results in chemiluminescence emitted over several minutes. As a result of the very low background luminescence from slow hydrolysis of the dioxetane in the buffer, less than 10.sup.-18 mol (1 attomol) of alkaline phosphatase can be detected in the presence of enhancers (A. P. Schaap, H. Akhavan and L. J. Romano, Clin. Chem., 35, 1863 (1989) and A. P. Schaap, U.S. patent applications Ser. Nos. 07/224,681 and 07/317,585).
3. Chemiluminescent Direct Labels for Biological Assays.
(a) Luminol and isoluminol. The aminophthalhydrazides, luminol and isoluminol react with H.sub.2 O.sub.2 and a peroxidase enzyme catalyst under basic conditions with emission of light. The reaction is also catalyzed by small amounts of several metal ions including Fe(III), Cu(II) and Cr(III). The first chemiluminescent immunoassay using luminol as a label was reported by Schroeder for an assay of biotin. (H. R. Schroeder, P. O. Vogelhut, R. J. Carrico, R. C. Boguslaski, R. T. Buckler, Anal. Chem. 48, 1933 (1976)). Several applications of the use of luminol derivatives as labels have been reported since then (H. R. Schroeder in Luminescent Immunoassays: Perspectives in Endocrinology and Clinical Chemistry, M. Serio and M. Pazzagli, Eds., Raven Press, New york, pp 129-146 (1982); M. Pazzagli, G. Messeri, A. L. Caldini, G. Monetti, G. Martinazzo and M. Serio, J. Steroid Biochem., 19, 407 (1983); Bioluminescence and Chemiluminescence New Perspectives, J. Scholmerich, et al., Eds., J. Wiley & Sons, Chichester (1987)). Various enhancers have also been employed in conjunction with the use of luminol to increase the intensity of light emitted. These include D-luciferin (T. P. Whitehead, G. H. Thorpe, T. J. Carter, C. Groucutt and L. J. Kricka, Nature, 305, 158 (1983)) and p-iodophenol (G. H. Thorpe, L. J. Kricka, S. B. Mosely and T. P. Whitehead Clin. Chem., 31, 1335 (1985)). ##STR7##
(b) Acridinium and phenanthridinium esters. Aromatic esters of N-methyl acridinium and phenanthridinium carboxylic acid undergo a chemiluminescent reaction upon treatment with H.sub.2 O.sub.2 and a base. The stability of these esters decreases markedly at high pH. Incorporation of a linker group R on the aromatic moiety as shown below allows attachment of the chemiluminescent label to antigens, antibodies or solid supports. This work has been reported in a patent (F. McCapra, D. E. Tutt, R. M. Topping, British Patent No. 1,461,877 (1977)) and in the following papers (I. Weeks, I. Beheshti, F. McCapra, A. K. Campbell, J. S. Woodhead, Clin. Chem., 29, 1474 (1983); I. Weeks, A. K. Campbell, J. S. Woodhead, Clin. Chem., 29, 1480 (1983)). These compounds are used as labels in commercial immunoassay kits for the detection of TSH (LumaTag.TM.; London Diagnostics, Inc.,; Eden Prairie, Minn.) and free thyroxin (Magic Lite System; Ciba-Corning Diagnostics Corp.; Medfield, Mass.). This technology has also been used to label DNA probes (L. J. Arnold, Jr., P. W. Hammond, W. A. Wiese, N. C. Nelson, Clin. Chem., 35, 1588 (1989)). ##STR8##
(c) Adamantylideneadamantane dioxetanes for thermochemiluminescent detection. Derivatives of adamantylideneadamantane dioxetane have been prepared by Wynberg and co-workers for the direct labeling of antibodies and proteins. (J. C. Hummelen, T. M. Luider, H. Wynberg, Pure Appl. Chem., 59, 639 (1987); J. C. Hummelen, T. M. Luider, H. Wynberg, "Thermochemiluminescent Immunoassays", in Complementary Immunoassays, W. P. Collins, Ed., Wiley and Sons, New York, p. 191 (1988); H. Wynberg, E. W. Meijer, J. C. Hummelen, 37 1,2-Dioxetanes as Chemiluminescent Probes and Labels" in Bioluminescence and Chemiluminescence, M. A. DeLuca, W. D. McElroy, Eds., Academic Press, New York, p. 687 (1981)). Detection of chemiluminescence requires that the labeled analyte be immobilized on a plastic disk and heated to 250.degree. to 300.degree. C. These extreme temperatures are incompatible with the development of a homogeneous immunoassay system which is performed in aqueous solution. Since the chemiluminescence quantum yield from the thermolysis of adamantylideneadamantane dioxetane is quite low (.O slashed..sub.CL =10.sup.-4) the technique of energy transfer to a highly fluorescent acceptor must be employed to achieve higher sensitivity of detection. This requires that a second label, a fluorescer, also be chemically attached either to the analyte or to the first label (J. C. Hummelen, T. M. Luider, H. Wynberg, Methods in Enzymology, 133, 531 (1986)). Reaction R groups which were used to chemically bind the dioxetane to proteins included those shown below. ##STR9##
4. Labeling Procedures. A wide variety of procedures for chemically binding labels to organic and biological molecules are described in the literature (see, for example: L. J. Kricka, Ligand-Binder Assays, Marcel Dekker, Inc., New York, 1985, pp. 15-51 and M. Z. Atassi, "Chemical Modification and Cleavage of Proteins," Chapter 1 in Immunochemistry of Proteins, Vol. 1, Plenum Press, New York, 1977, pp. 1-161, and references therein). Antibodies and proteins are conveniently labeled by reaction of certain nucleophilic groups present in proteins (--SH, --OH, --NH.sub.2, --COOH) with labels bearing chemically reactive groups such as those shown below in Table 1. Appropriately functionalized nucleic acids and DNA probes can also be labeled by synthesizing amine or thiol-containing nucleic acids and reacting these molecules with the corresponding reactive group on the dioxetane. Alternatively, nucleic acids (primarily oligonucleotides) can be linked to dioxetanes by the reaction of a hydroxyl with an activated phosphoramidite. In this case the phosphoramidite could be positioned on the nucleic acid and the hydroxyl placed on the dioxetane or vice versa. Other types of molecules which can be labeled include enzymes, protein antigens, haptens, steroids, carbohydrates, fatty acids, prostaglandins, thromboxanes, leukotrienes, nucleosides and nucleotides.
TABLE 1 ______________________________________ Reactive Groups for Chemical Binding of Labels to Organic and Biological Molecules 1) Groups which are reactive towards amines (NH.sub.2). ##STR10## ##STR11## ##STR12## ##STR13## ##STR14## ##STR15## ##STR16## ##STR17## ##STR18## ##STR19## ##STR20## ##STR21## ##STR22## ##STR23## ##STR24## ##STR25## ##STR26## ##STR27## 2) Groups which are reactive towards thiols (SH). ##STR28## CH.sub.2 -Halogen ##STR29## ##STR30## ##STR31## ##STR32## ##STR33## SSR ##STR34## 3) Groups which are reactive towards carboxylic acids (CO.sub.2 H). NH.sub.2 OHNHNH.sub.2 ______________________________________
Bifunctional coupling reagents may also be used to couple labels to organic and biological molecules with moderately reactive groups (see L. J. Kricka, Ligand-Binder Assays, Marcel Dekker, Inc., New York, 1985, pp. 18-20, Table 2.2 and T. H. Ji, "Bifunctional Reagents," Methods in Enzymology, 91, 580-609 (1983)). There are two types of bifunctional reagents, those which become incorporated into the final structure and those which do not and serve only to couple the two reactants. Fluorescein can be used to form a complex with anti-fluorescein. Additionally, psoralen can be used to covalently bind to DNA.
Physical binding or complex formation of a chemiluminescent dioxetane to a molecule of interest may be accomplished as shown below by chemical bonding of the label to a molecule of biotin (vitamin H) and chemical bonding of the organic or biological molecule of interest to either avidin or streptavidin. The latter two compounds are bacterial proteins with four high-affinity binding sites for biotin (R. M. Buckland, Nature, 320, 557-558 (1986) and references therein).

1,2-dioxetane compounds as chemiluminescent labels for organic and biological molecules

Board of Governors of Wayne State University


A backlight display device includes a pixel region, a light-emitting region, a control element, a plurality of first flexible printed circuit board (FPCB) contacts, and a plurality of first driving circuits. The pixel region has a first edge, a second edge opposite to the first edge, a third edge, and a fourth edge opposite to the third edge. A corner region is formed between the first edge and the fourth edge. The light-emitting region is located on the corner region of the pixel region. The control element is located on the corner region of the pixel region and between the light-emitting region and the first edge. The first FPCB contacts are located on the second edge. Each of the first driving circuits is electrically connected to one of the first FPCB contacts and the control element.

1. Field of Invention
The present invention relates to a backlight display device.
2. Description of Related Art
In general, when there is a requirement for displaying an image with large area, plural display devices may be closely arranged to form an assembling display wall with large area, such as a TV wall with large area.
Each of the display devices has plural driving circuits, a display region, and an edge frame. The display region is composed of plural pixel regions, and the driving circuits are located outside of the display region and electrically connected to the pixel regions. The display region is exposed through the display opening of the edge frame, and the edge frame covers and accommodates the driving circuits.
However, since the edge frame outside of the display region needs to cover and accommodate the driving circuits, gaps between adjacent images are formed due to the edge frames of the display devices when the display devices are closely connected. As a result, the images of the display devices are discontinuous, and thereby downgrading visual effect when users watch the display wall.


A cutting member to be connected to a material removing device such as an annular bit, a drilling bit, a cutting bit, a saw and the like, consists of a binder agent, diamond grains and a small amount of hard material particles. The hard material particles reinforce the binder agent and supports the anchorage of the diamond grains.

The present invention is directed to a cutting member for use in material removal tools, such as drills, cutting disks, saws and the like where the cutting member is formed of binder agents, hard material particles and diamond grains.
Material removal tools are used for drilling, cutting and severing of rock and building materials, such as concrete, brick and the like and such tools have cutting edges formed of separate cutting members connected to a carrier in the shape of a hollow cylinder, a disk, a roller and the like. The cutting members consist of binder agents, hard material particles and diamond grains.
A rock drill is disclosed in DE-PS 590 707 which has an annular or core bit formed of sintered hard metal. The hard metal consists of hard metal particles sintered together with the use of a small amount of a binder agent. Diamond grains are embedded in the surface of the annular bit for the purpose of removing material.
The useful life of the rock drill with a core bit or annular bit of the above-mentioned type is determined by the service life of the diamond grains. If the diamond grains are abraded by wear, the bit is no longer able to carry out its material removing function. Further, it should be considered that the core bit formed of sintered hard material provides an extremely hard carrier for the diamond grains, however, it has only a slight toughness or ductility. As a result, all of the blows occurring during the drilling operation are transmitted by the diamond grains, without any damping, to the hard carrier, whereby excessive stresses develop very rapidly, so that the diamond grains fracture prior to their normal wear period with the result that the bit fails prior to the end of its normal useful life.
A hollow drill is disclosed in DE-OS 34 08 092, and has a hollow cylindrical carrier or support with an open end at the drilling end containing cutting members. The cutting members of this known hollow drill consists of a binder with diamond grains embedded in it.
In this hollow drill, the diamond grains are not only present at its surface but also within the entire cutting member comprising the binder. If this drill is used for removing material, the binder is also worn away in addition to the wear of the diamond grains. If a diamond grain has been completely worn away or if it fails, then at the same time some of the binder has been removed, whereby an additional diamond grain is exposed for carrying out the material removing function. The useful life of this known hollow drill ends only after the cutting member is completely worn down. In addition, the binder provides such an elastic carrier or support for the diamond grains that blows developed in the drilling operation can be absorbed without causing overstress and, as a result, does not lead to premature fracture of the diamond grains.
The annular drill bit disclosed in the above-mentioned patent publication has certain advantages as far as useful life is concerned as compared to the bit mentioned at the beginning. These advantages operate within a specific frame of reference and, in particular, are greatly influenced by the material being worked. If such material is a very hard concrete, the wear of the diamond grains and especially of the binder is so great that disadvantages have to be accepted relating to the reduced useful life.


The invention provides a fabrication method for a chalcopyrite powder. The fabrication method includes: (a) mixing a Group IB compound and a Group IIIA compound in a solvent; (b) drying or precipitating the solution of step (a) to obtain a precursor containing Group IB and Group IIIA elements; (c) mixing a solution or powder containing a Group VIA compound with the precursor; and (d) heating the mixture of step (c) to obtain the chalcopyrite powder.

1. Field of the Invention
The present invention relates to a fabrication method for semiconductor materials, and in particular relates to a fabrication method for a chalcopyrite powder.
2. Description of the Related Art
Semiconductor materials have a special band gap which can be regulated by changing the composition of the semiconductor material. Therefore, semiconductor materials are often used as light absorbing layers of a photoelectronic device.
Among the different semiconductor materials used in CIGS solar cell, the Group IB-IIIA-VIA compound, which has a chalcopyrite structure, has been intensely researched. When a thin film made by the Group IB-IIIA-VIA compound is applied to a CIGS solar cell, good photoelectric conversion efficiency of the CIGS solar cell is obtained.
A thin film having the chalcopyrite compound is fabricated by a vacuumed or non-vacuumed process. The vacuum process comprises a co-evaporation or sputtering process. The non-vacuum process comprises an electrodeposition, electroless, coating or chemical spray pyrolysis process. Because, the vacuum process can only be applied to small-scale photoelectronic devices and equipment for the vacuum process is expensive, a non-vacuum process has been developed.
The conventional vacuum process is described as follows. Firstly, a precursor containing the Group IB and IIIA metal ions is deposited on a substrate. The precursor is then subjected to reduction and selenization processes at high temperatures to obtain a chalcopyrite compound. However, the Group IIIA metal has a low melting point, thus non-uniformed thin films are formed at high temperatures due to aggregation. As such, various fabrication methods for forming uniformed thin films with the chalcopyrite compound have been developed.
U.S. Pat. No. 5,445,847 discloses a fabrication method for a chalcopyrite compound. Firstly, a Group IB powder and an IIIA powder are mixed in a ball mill and sintered at a high temperature to obtain an IB-IIIA oxide. The IB-IIIA oxide is heated under gas containing Group VIA elements to obtain the chalcopyrite compound.
U.S. Pat. No. 6,268,014 also discloses a fabrication method for a chalcopyrite compound. The IB-IIIA oxide particles are first fabricated. Then, the IB-IIIA oxide particles are coated on a substrate by a spray process and are heated under the gas containing Group VIA elements to obtain the chalcopyrite compound.
However, both fabrication methods form non-uniformed thin films with the chalcopyrite compound. Accordingly, there is a need to develop a chalcopyrite powder which may be fabricated to form a uniform thin film with small size.

Fabrication method for chalcopyrite powder


Normal column selection signal switching device (20) is provided to switch a signal outputted from normal column selection signal generating device (19) in response to a test-mode signal (TMC1). Even if the normal column selection signal generating device (19) outputs a signal to disable a normal column decoder (3), the normal column selection signal switching device (20) switches the signal to enable the normal column decoder (3) to operate in the test operation. Having this configuration, a semiconductor memory device enables writing of data into all the normal memory cells even after some of the normal memory cells are replaced by spare memory cells.

1. Field of the Invention
The present invention relates to a semiconductor memory device including a spare memory array to compensate for a failure of a normal memory array.
2. Description of the Background Art
FIG. 21 is a conceptional diagram illustrating a background-art semiconductor memory device including a spare memory array. A memory array of FIG. 21 consists of a normal memory array 1 and a spare memory array 2 used to replace the normal memory array 1 if the normal memory array 1 has some defective memory cell. Any normal memory cell in the normal memory array 1 is selected by an address signal. The address signal includes a column address signal and a row address signal. The column address signal is decoded by a normal column decoder 3 and a decoded signal is transmitted to a normal column selection line driving circuit 5. The normal column selection line driving circuit 5 activates one of a plurality of normal column selection lines 11 on the basis of the signal from the normal column decoder 3.
On the other hand, the row address signal is decoded by a normal row decoder 7 and a decoded signal is transmitted to a normal word line driving circuit 9. The normal word line driving circuit 9 activates one of a plurality of normal word lines 12 on the basis of the signal from the normal row decoder 7. FIG. 22 shows one of the normal column selection lines 11 and one of the normal word lines 12 being active in a normal operation. In FIG. 22, signal lines represented by heavy solid lines are active. A specific group of normal memory cells in the normal memory array 1 is selected by the active normal column selection line 11 and the active normal word line 12. Since a plurality of pairs of bit lines are provided with respect to one normal column selection line 11, a plurality of normal memory cells connected to the pairs of bit lines are selected at the same time.
FIG. 26 is a block diagram showing a relation between a selection signal line and pairs of bit lines. In FIG. 26 shown are a column selection line or a spare column selection line 40, sense amplifiers 41a to 41d to be enabled to operate by the column selection line 40, memory cells 42 to 44 which are arranged on separate columns and from which data are read out through one sense amplifier 41a, a pair of bit lines 45 connected to the sense amplifier 41a for reading and writing data from and into the memory cells 42 to 44 and the like, pairs of bit lines 46 to 48 connected to the sense amplifier 41b to 41d respectively, a normal word line 49 connected to the memory cell 42 and the like to select memory cells and spare word lines 50 and 51 connected to the spare memory cells 43 and 44 and the like respectively. When the column selection line 40 is activated, four pairs of bit lines are selected and eventually memory cells associated with an input address are selected.
If some normal memory cell is defective in the normal memory array 1, a normal word line or normal column selection line selecting the defective memory cell is replaced by a spare word line or spare column selection line in order to replace the normal memory cells in the normal memory array 1 by the spare memory cells in the spare memory array 2. For example, if some memory cell which is selected by a column selection line is defective, the column selection line is not activated thus not selecting the normal memory cells and instead a spare column selection line is activated to select the spare memory cells in the spare memory array 2 when the address associated with the defective memory cell is inputted.
For example, when a spare column selection line 13 is used to replace one of the normal column selection lines 11 including some defective memory cell, the normal row decoder 7 and the normal word line driving circuit 9 perform the same operation as in a case of no failure in response to a row address signal specifying a row having no defective memory cell. In this case, given a column address signal specifying one of the normal column selection lines 11 having the defective memory cell, a defective column address detecting circuit 4 detects the column address signal and disable the normal column decoder 3, and a spare column selection line driving circuit 6a outputs a signal to drive the spare column selection line 13. FIG. 23 shows the spare column selection line 13 and one of the normal word lines 12 being active. In FIG. 23, signal lines represented by heavy solid lines are active.
If required, another one of the normal column selection lines 11 is further replacement by, for example, a spare column selection line 14. Receiving a signal from the defective column address detecting circuit 4, a spare column selection line driving circuit 6b drives the spare column selection line 14.
Furthermore, there is a case where one of the normal word lines 12 having some defective memory cell should be replaced by a spare word line 15 or a spare word line 16. In this case, a defective row address detecting circuit 8 detects a row address signal specifying the defective normal memory cell. Detecting this row address signal, the defective row address detecting circuit 8 outputs a spare row selection signal to a spare word line driving circuit 10a or 10b to drive a spare word line 15 or 16 respectively and further outputs a normal row selection signal to disable the normal row decoder 7.
Referring next to FIG. 24, configuration and operation of the defective column address detecting circuit 4 will be discussed. FIG. 24 is a block diagram illustrating a configuration of column selection means. The column selection means refers to the defective column address detecting circuit 4, the normal column selection line driving circuit 5 and the spare column selection line driving circuits 6a and 6b in FIG. 21. A spare comparator 17 stores information regarding a defective column address and compares a column address signal CA with the stored information to detect whether or not the column address signal CA specifies the defective column address. Spare column selection signal generating means 18 generates a spare column selection signal to make a spare column selection line non-active if the spare comparator 17 judges that the defective column address is not specified. Receiving the spare column selection signal, the spare column selection line driving circuit 6 operates to make the spare column selection line non-active. Receiving the spare column selection signal from the spare column selection signal generating means 18, normal column selection signal generating means 19 generates a normal column selection signal to make normal column selection lines active. In response to the normal column selection signal, the normal column decoder 3 and the normal column selection line driving circuit 5 operate to activate only the column selection line associated with this address.
In contrast, the spare column selection signal generating means 18 generates a spare column selection signal to make the spare column selection line active if the spare comparator 17 judges that the defective column address is specified. Receiving the spare column selection signal, the spare column selection line driving circuit 6 operates to make the spare column selection line active. Receiving the spare column selection signal from the spare column selection signal generating means 18, the normal column selection signal generating means 19 generates the normal column selection signal to make the normal column selection lines non-active. In response to the normal column selection signal, the normal column decoder 3 and the normal column selection line driving circuit 5 makes the normal column selection line non-active.
FIG. 25 illustrates a circuit configuration of the normal column selection signal generating means 19 in the semiconductor memory device including a plurality of spare comparators 17 and two spare column selection lines. The normal column selection signal generating means 19 consists of a NAND gate 21 for outputting a negative AND (logical product) of spare column selection signals ZSCS1 and ZSCS2 outputted form spare column selection signal generating means 18a and 18b and an inverter 23c for inverting an output of the NAND gate 21.
The normal column decoder 3 includes a plurality of NAND gates 3a, 3b and the like. For example, each of the NAND gates 3a and 3b receives the address signal CA through a plurality of signal lines. Each of the NAND gates 3a, 3b and the like is enabled to output a signal of "L" when the address signal CA takes a value associated with the corresponding gate. FIG. 25 shows the NAND gates 3a and 3b each having a single input end for receiving the address signal CA, for simple illustration. If a normal column selection signal NCE is "H", one of the NAND gates 3a, 3b and the like which is enabled by the address signal CA outputs the signal of "L". If the normal column selection signal NCE is "L", none of the NAND gates 3a, 3b and the like constituting the normal column decoder 3 outputs the signal of "L".
If no replacement by the spare memory cells is made, the spare column selection signal generating means 18a and 18b generate the spare column selection signals ZSCS1 of "H" and ZSCS2 of "H", respectively. Receiving the spare column selection signals ZSCS1 and ZSCS2, the spare column selection line driving circuits 6a and 6b output signals SCSL1 and SCSL2 being non-active to make the spare column selection lines 13 and 14 non-active, respectively. Receiving the signals ZSCS1 and ZSCS2, the normal column selection signal generating means 19 outputs the normal column selection signal NCE of "H" for controlling the normal column decoder 3 to activate one of signals CSL1 to CSLn to be given the normal column selection lines 11.
Next, a replacement of a defective normal memory cell selected by one of the normal column selection lines 11 by a spare memory cell selected by the spare column selection line 13 will be discussed. When a column address associated with the defective normal memory cell is inputted, the spare column selection signal generating means 18a generates the spare column selection signal ZSCS1 of "L" on the basis of the judgment made by a spare comparator 17a. In response to the signal ZSCS1, the spare column selection line driving circuit 6a outputs the signal SCSL1 which is active to keep the spare column selection line 13 active in association with this address. Furthermore, the spare column selection signal ZSCS2 remains "H" for the spare column selection line 14 which is not used. Then, in response to the spare column selection signal ZSCS1 of "L", the normal column selection signal NCE comes into "L" and the normal column selection lines 11 become non-active in association with this address. Therefore, no memory cell in the memory cell array 1 having some defective memory cell is selected.
In the background-art semiconductor memory device having the above configuration, the normal column selection line or the normal word line which has been once replaced is never selected. Accordingly, a requirement of writing data into the replaced normal column or normal row to observe the effect of interference between memory cells in evaluation of the semiconductor memory device or failure analysis can not be satisfied.


Methods and items useful at least therein are provided for IBS related testing and treatment. Disclosed is a patch useful in determining if one or more test materials can cause allergic contact dermatitis in a patient. A kit containing information on use and that may include such a patch and/or test material(s) is also disclosed. A method of IBS related testing including performing skin patch testing on a patient presenting IBS symptoms using at least one test material that can cause allergic contact dermatitis is provided. A method for the treatment of IBS which includes limiting the intake by a patient presenting IBS symptoms of at least one material that gives a positive skin patch test result in the patient is also disclosed.

IBS is a chronic disorder of the bowel. Its primary symptoms are abdominal pain or discomfort in association with frequent diarrhea or constipation or a change in bowel habits. There may be urgency for bowel movements, a feeling of incomplete evacuation, bloating or abdominal distention. Diarrhea or constipation may predominate, or they may alternate. The exact cause of IBS is currently considered unknown.
There is presently no cure for IBS. Treatments such as change in diet, medication and/or psychotherapy attempt to relieve symptoms, but they are not always very successful.
There are four commonly recognized types of immune reactions or hypersensitivities to foods and other materials, Gell-Coombs Types 1, 2, 3 and 4. Type 1 is characterized by the involvement of IgE antibodies produced in response to a particular material; typically testing here is by injecting or pricking the skin with the suspected allergen. A reaction is indicated if redness or swelling appears at the injection or prick test site.
Types 2 and 3 are characterized by the involvement of IgG, IgM, and some special IgE antibodies. Intradermal testing often fails to produce a reliable immune response in the skin. An elimination diet may be used here instead to detect the suspected material.
The Type 4 reaction involves sensitized lymphocytes or T-cells which respond to a specific material and which are believed to be at least as specific as an antibody to the material producing the immune response. Skin patch testing where one or more possible allergens are brought into contact with the surface of the skin may be used here. This reaction is seen as an allergic contact dermatitis, usually manifesting as a red macule(s), papule(s), plaque(s), vesicle(s) and/or bulla(e) at the patch test site.
U.S. Pat. Nos. 4,543,964 and 4,818,707 to Breneman disclose a device for the detecting of an individual's Gell-Coombs Types 1, 2, 3 and 4 immune response reactions to edible substances that include a mixture of an edible substance and a solution of non-toxic aprotic solvents, such as DMSO and water. The solution acts as a carrier transporting the test substance beneath the skin. The device holds the mixture against the skin and prevents evaporation of the solution. An associated method disclosed includes the preparation of a plurality of mixtures of different edible substances and a solution of a non-toxic aprotic solvent, the application of the mixture to the skin of the individual and the holding of the mixture on the skin for a predetermined period of time. The mixture is subsequently removed, and the site is inspected to determine whether a Type 1, 2, 3 or 4 Gell-Coombs immune response reaction has occurred. Control sites containing the solution only and a control site containing a food substance which causes the skin to fluoresce upon exposure to an ultraviolet light may also be used. Fluorescence indicates whether mixtures have been in sufficient contact with the skin for the required period of time. Several test foods are disclosed, including garlic and onion, but none appear emphasized alone nor are any combinations specified; these patents do not disclose links between allergies to foods or other materials and IBS. Contrary to Brenneman's statements, it is well known that skin patch testing is only used for Type 4 allergic reactions exclusively, and is not used for Type 1-3 allergic reactions. Type 4 reactions may also be referred to as delayed-type hypersensitivity allergic reactions. It is also well known that there are two arms of the immune system, the humoral arm and the cell-mediated arm. The humoral arm encompasses Type 1, 2 and 3 allergies, and the allergic mechanisms for all three of these allergies rely upon antibodies. The cell-mediated arm is limited to Type 4 allergies and relies upon white blood cells called lymphocytes. Testing is thus unique and distinctive for each of these allergy types.
It is estimated that 60-70% of individuals with IBS report that foods cause or aggravate their symptoms. Some believe that an allergic reaction may be involved. Currently, most attention regarding foods and allergy focuses on IgE-mediated (type 1 hypersensitivity) mechanisms.
There is a well-described gastrointestinal disease of infants and young children, food protein-induced enterocolitis, which is felt to be induced by a non-IgE mechanism. Skin patch testing is the only diagnostic testing available for this disease; compared to skin prick testing for diagnosis of IgE-mediated food allergies, patch testing is more specific, although somewhat less sensitive.
Many foods are known to cause allergic contact dermatitis (type 4 hypersensitivity); this is a non-IgE mediated reaction. Of these foods, many are very common in the average diet in the United States as well as in other countries.
The current standard of care in evaluation of individuals with symptoms suggestive of IBS does not include skin patch testing. There is currently no food patch test series targeting evaluation of IBS. Skin patch testing is typically in the realm of the medical specialty of dermatology; IBS is typically within the realm of the medical specialty of gastroenterology. Dermatologists are not trained in and do not typically address IBS issues, and gastroenterologists are not trained in and do not typically use patch testing in their work. These are two different fields of medicine.
IBS is a chronic illness and can dramatically reduce quality of life. Its sufferers have increased medical costs and work absenteeism. It is estimated that 15% of the U.S. population has IBS with similarly high and even higher rates reported for other countries. This high prevalence of IBS produces a very high cost to society. There is a need for new methods and items at least useful therein for IBS related testing and treatment.

IBS CENTERS FOR ADVANCED FOOD ALLERGY TESTING, LLC