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The two new patents are for: interior design elements, and for external screens and speakers. Google has also been awarded a second patent covering a variety of external screens and a speaker, all of which are intended to allow the car to interact with pedestrians and bicyclists. The car could announce sweetly to people waiting to get to the other side of the road, “It is now safe to cross.
James Ayre 's background is predominantly in geopolitics and history, but he has an obsessive interest in pretty much everything. Automakers have recently begun downsizing engines and employing turbocharger technology to provide more power, similar to a bigger engine, while allowing the engine to retain the better fuel economy of a smaller powerplant. Filed last week in Germany’s patent office, BMW has created a design for an electrically-assisted turbocharger.
Simply, what you need to know is that it will increase engine efficiency and power across the engine’s rev range, from idle all the way to its cutoff at the engine’s “redline.” And it will likely be the beginning of the future of an amazing amount of small engine, high power technology.
Continue reading below for an explanation of how turbochargers work and what BMW’s new system does better than existing turbochargers. The great news is that the turbo is only active when you need it, that is, at full throttle.
At low engine speeds, the exhaust turbine doesn’t receive much pressure to move it, which also means that the compressor cannot force more air into the engine to create more power. Where the shaft in the middle connects the turbine and compressor in a traditional turbocharger, the proposed BMW unit has a tiny clutch sandwiched in between the two, decoupling two sides so they don't always have to spin at the same speed. When more power is needed, the electric motor turns on instantly, spinning the power-making compressor. BMW and other manufacturers have already minimized lag in recent years with advancements such as lightweight components, moving the turbine as close as possible to the exhaust, and other tricks, and its recent advancements can be seen in its turbocharged four-, six-, eight-, and twelve-cylinder engines. 13.Singh M and Detamore MS, “Biomechanical properties of the mandibular condylar cartilage and their relevance to the TMJ disc,” Journal of Biomechanics, 42 (4), 405-417, 2009.
Enter keywords & we'll notify you when a new patent matches your request (weekly update). Compositions for regenerating defective or absent myocardiumCompositions of the invention for regenerating defective or absent myocardium comprise an emulsified or injectable extracellular matrix composition.
The Patent Description & Claims data below is from USPTO Patent Application 20150202347, Compositions for regenerating defective or absent myocardium. The invention relates to tissue engineering generally, and more specifically to compositions and methods for regenerating defective or absent myocardium. Medical researchers have transplanted human hematopoetic stem cells, mesenchymal stem cells, endothelial precursor cells, cardiac stem cells, and skeletal myoblasts or bone marrow cells to the myocardium, with however little or mixed success in satisfactory regeneration of the myocardium. After myocardial infarction, injured cardiomyocytes are replaced by fibrotic tissue promoting the development of heart failure. Meanwhile, typical structural abnormalities or damage to the heart that would lend itself to tissue regenerative therapies, were they available, include atrial septal defects, ventricular septal defects, right ventricular out flow stenosis, ventricular aneurysms, ventricular infarcts, ischemia in the myocardium, infarcted myocardium, conduction defects, conditions of aneurysmic myocardium, ruptured myocardium, and congenitally defective myocardium, and these defective conditions remain untreated in humans by any current tissue regenerative techniques. Although tissue regeneration has been accomplished by transplantation in mammalian tissues such as the endocranium, the esophagus, blood vessels, lower urinary tract structures, and musculotendinous tissues, heart tissue regeneration by foreign tissue explant has remained a challenge. It would be beneficial for treatment of heart failure in humans to develop myocardium regenerative strategies using matrices and additives for optimizing the potential results. No experimentation has been conducted to date on regenerating mammalian myocardium using an emulsified or injectable extracellular matrix formulation.
The present invention pioneers compositions and alternatives to prior art solutions for tissue regeneration to provide a biomedical composition (and methods using the composition) for regenerating defective or absent myocardium, particularly for use in humans. An object of the invention is to provide a composition for regenerating defective or absent myocardium and restoring cardiac function.
Accordingly, a composition for regenerating defective or absent myocardium and restoring cardiac function comprising an emulsified or injectable extracellular matrix composition from a mammalian or synthetic source is provided.
Also, a composition for regenerating defective or absent myocardium and restoring cardiac function is provided comprising an extracellular matrix derived from a mammalian or synthetic source, said composition further comprising an additional component selected from the group of: a) a cell, b) a peptide, polypeptide, or protein, c) a vector having a DNA capable of targeted expression of a selected gene, and d) a nutrient, a sugar, a fat, a lipid, an amino acid, a nucleic acid, a ribo-nucleic acid, an organic molecule, an inorganic molecule, a small molecule, a drug, or a bioactive molecule. Also provided is a composition for regenerating defective or absent myocardium and restoring cardiac function comprising at least a portion of an extracellular matrix scaffold derived from a mammalian source and also comprising an additional component selected from the groups consisting of: a) a plurality of synthetic extracellular matrix-like scaffold-forming molecules, b) a cell, c) a peptide, polypeptide, or protein, and d) a vector having a DNA capable of targeted expression of a selected gene, and e) a nutrient, a sugar, a fat, a lipid, an amino acid, a nucleic acid, a ribo-nucleic acid, an organic molecule, an inorganic molecule, a small molecule, a drug, or a bioactive molecule. The invention further provides a method of regenerating defective myocardium and restoring cardiac function, comprising contacting said defective myocardium with a composition of the invention in an amount effective to regenerate the myocardium and restore cardiac function. The invention also provides a method of inducing angiogenesis in myocardium at a site of ischemia, comprising contacting said ischemic myocardium with a composition of the invention in an amount effective to induce angiogenesis in the myocardium at the site of ischemia.
The invention is a composition that regenerates defective or absent myocardium and restores cardiac function.
A composition to accomplish regeneration of myocardium needs to induce complex dynamic interactions and activities at the site of defect.
The expectations for the extracellular matrix scaffold are that it will organize the cells into tissues, both by recruiting endogenous cells and using cells that have been provided as additional components in the composition.
There has been much research recently to elucidate the properties and function of the extracellular matrix: its protein make-up, and its role in the body.
The extracellular matrix of myocardium is made up of collagen types I (which is predominant), III, IV, V, and VI, combined which are 92% of the dry weight of the matrix.
More specifically, when in early regenerative processes, circulating cells or added cells are directed, initial temporary cell adhesion processes occur that result in embryogenesis of the cells, morphogenesis of the cells, regeneration of cell form, eventual maintenance of the cell, possible motility to another site, and organogenesis that further differentiates the cell. Also working as CAMs are integrins, which are proteins that link the cytoskeleton of the cell in which they are lodged to the extracellular matrix or to other cells through alpha and beta transmembrane subunits on the integrin protein.
Specific requirements for the scaffold component of the invention, whether a native scaffold prepared for introduction into a mammal, or a synthetic scaffold formed by synthetic polymerizing molecules, or a combination of the two, are that the scaffold must be resorbable over time as the tissue regeneration ensues, and this resorbtion is at an appropriate degradation rate for optimal tissue regeneration and absence of scar tissue formation. The extracellular matrix scaffold is preferably non-toxic and provides a three-dimensional construction at the site of defect in the myocardium (once delivered to the site). Particular study of the components of the native scaffolds facilitates design of compositions well-suited for regeneration of myocardium. Collagens, the most abundant components of ECM, are homo- or heterotrimeric molecules whose subunits, the alpha chains, are distinct gene products. In the extracellular matrix of the heart, collagen types I and III predominate, together forming fibrils and providing most of the connective material for typing together myocytes and other structures in the myocardium, and thus these molecule types are involved in the transmission of developed mechanical force in the heart. Proteoglycans are grouped into several families, and all have a protein core rich in glycosoaminoglycans.
There are part-time proteoglycans, comprising CD44 (a receptor for hyaluronic acid), macrophage colony stimulating factor, amyloid precursor protein and several collagens (IX, XII, XIV, and XVIII). The last family of proteoglycans is the heparan sulfate proteoglycans, some of which are located in the matrix, and some of which are on cell membranes.
In addition to the structural matrix proteins just discussed, specific interactions between cells and the ECM are mediated by functional proteins of the ECM, including transmembrane molecules, mainly integrins, some members of the collagen family, some proteoglycans, glycosaminoglycan chains, and some cell-surface associated proteins.
Glycosaminoglycans (GAGs) are glycosylated post-translational molecules derived from proteoglycans. The extracellular part of integrins bind fibronectin, collagen and laminin, and act primarily as adhesion molecules. In addition to direct knowledge of protein cell interaction many of the proteins associated with the ECM can initiate binding to proteins that then activate to bind other proteins or cells, e.g. The matrix metalloproteases (MMPs) break down the collagen molecules in the ECM so that new collagen can be used to remodel and renew the ECM scaffold. Structural or functional matrix proteins that can comprise the compositions herein disclosed to facilitate myocardial tissue regeneration include, minimally, collagen I and III, elastin, laminin, CD44, hyaluronan, syndecan, bFGF, HGF, PDGF, VEGF, Fn, tenascin, heparin, heparan sulfate, chondroitin sulfate B, integrins, decorin, and TGF-beta. Native extracellular matrix scaffolds, and the proteins that form them, are found in their natural environment, the extracellular matrices of mammals.
In addition, dermal extracellular matrix material, subcutaneous extracellular matrix material, large intestine extracellular matrix material, placental extracellular matrix material, ornamentum extracellular matrix material, heart extracellular matrix material, and lung extracellular matrix material, may be used, derived and preserved similarly as described herein for the SIS, SS, LBM, and UBM materials. When using collagen-based synthetic ECMs, the collagenous matrix can be selected from a variety of commercially available collagen matrices or can be prepared from a wide variety of natural sources of collagen.
The proportion of scaffold material in the composition when native scaffold used will be large, as the natural balance of extracellular matrix proteins in the native scaffolds usually represents greater than 90% of the extracellular matrix material by dry weight. Native extracellular matrices are prepared with care that their bioactivity for myocardial tissue regeneration is preserved to the greatest extent possible.
Myocardial tissue has been regenerated in vivo in non-humans using native xenogenic extracellular matrix scaffolds in the form of intact patches derived and prepared from mammals, so it can be presumed that at least some of the components required for myocardial tissue regeneration are to be found in these xenogenic patch matrices. The bioactivity of extracellular matrix material can be mimicked in tissue regeneration experiments with combinations of native and synthetic extracellular matrices explanted together, also optionally with additional components such as proteins or cells, in order to provide an optimal myocardial tissue regenerative composition and environment in vivo. When adding proteins to the extracellular matrix composition, be it an emulsified composition, or another formulation of matrix, the proteins may be simply added with the composition, or each protein may be covalently linked to a molecule in the matrix. For decellularization when starting with a whole organ, whole organ perfusion process can be used. Because of the collagenous structure of basement membrane and the desire to minimize degradation of the membrane structure during cell dissociation, collagen specific enzyme activity should be minimized in the enzyme solutions used in the cell-dissociation step. After contacting the liver tissue with the cell-dissociation solution for a time sufficient to release all cells from the matrix, the resulting liver basement membrane is rinsed one or more times with saline and optionally stored in a frozen hydrated state or a partially dehydrated state until used as described below. Basement membrane or other native ECM scaffolds may be sterilized using conventional sterilization techniques including tanning with glutaraldehyde, formaldehyde tanning at acidic pH, ethylene oxide treatment, propylene oxide treatment, gas plasma sterilization, gamma radiation, and peracetic acid sterilization. Synthetic extracellular matrices can be formed using synthetic molecules that polymerize much like native collagen and which form a scaffold environment that mimics the native environment of mammalian extracellular matrix scaffolds. Other examples of suitable biocompatible polymers are polyhydroxyalkyl methacrylates including ethylmethacrylate, and hydrogels such as polyvinylpyrrolidone, polyacrylamides, etc.
The nucleic acids used in the present invention may be modified in a variety of ways, including by cross linking, intra-chain modifications such as methylation and capping, and by copolymerization. Nucleic acids may be used in a variety of crystalline structures both in finished biomaterials and during their production processes. The physical properties of the nucleic acids may also be influenced by the presence of other physical characteristics.
The extracellular matrix can be emulsified for administration to the defective or absent myocardium. An emulsion of mammalian or synthetic extracellular matrix material can be accomplished as is standard for tissue or polymer emulsification in general.
An emulsified extracellular matrix material comprising also cells can have the cultured cells simply added into the matrix emulsion, or the cells may be co-cultured with the matrix for a time before administration to the patient. Unlike skeletal myocytes, cardiomyocytes withdraw from cell cycle shortly after birth, and adult mammalian cardiomyocytes lack the potential to proliferate.
Embryonic stem cells begin as totipotent cells, differentiate to pluripotent cells, and then further specialization.
Myoblasts are another type of cell that lend themselves to transplantation into myocardium, however, they do not always develop into cardiomyocytes in vivo. Other cells which may be employed with the invention are the mesenchymal stem cells administered with activating cytokines. The following list includes some of the cells that may be used as additional cellular components of the composition of the invention: a human embryonic stem cell, a fetal cardiomyocyte, a myofibroblast, a mesenchymal stem cell, an autotransplanted expanded cardiomyocyte, an adipocyte, a totipotent cell, a pluripotent cell, a blood stem cell, a myoblast, an adult stem cell, a bone marrow cell, a mesenchymal cell, an embryonic stem cell, a parenchymal cell, an epithelial cell, an endothelial cell, a mesothelial cell, a fibroblast, a myofibroblast, an osteoblast, a chondrocyte, an exogenous cell, an endogenous cell, a stem cell, a hematopoetic stem cell, a pluripotent stem cell, a bone marrow-derived progenitor cell, a progenitor cell, a myocardial cell, a skeletal cell, a fetal cell, an embryonic cell, an undifferentiated cell, a multi-potent progenitor cell, a unipotent progenitor cell, a monocyte, a cardiomyocyte, a cardiac myoblast, a skeletal myoblast, a macrophage, a capillary endothelial cell, a xenogenic cell, an allogenic cell, an adult stem cell, and a post-natal stem cell. In particular, human embryonic stem cells, fetal cardiomyoctes, mesenchymal stem cells, adipocytes, bone marrow progenitor cells, embryonic stem cells, adult stem cells, or post-natal stem cells together with growth factors or alone with matrix scaffold optimize myocardium regeneration in vivo.
Cells can be seeded directly onto matrix scaffold sheets under conditions conducive to eukaryotic cell proliferation. In addition to a native ECM scaffold, or a synthetic scaffold, or a mixture of the two, peptides, polypeptides or proteins can be added.
Biotechnology scientists must be aware of the broad patent landscape and push for new patent and licensing guidelines, according to a new paper from Rice University's Baker Institute for Public Policy.
Published in the current issue of the journal Regenerative Medicine, the paper is based on the June 2013 U.S. Biotechnological inventions have been patented for several decades, though the criteria for patent eligibility have been refined through numerous court decisions, according to the authors. The authors said the ruling could affect the patentability of other biotechnologies, like stem cells, depending on how the ruling is interpreted.
The authors suggest initial steps to address the current situation, including an outside review of patents before they are granted, reforming the rules of patent licensing to minimize restrictive practices and requiring detailed patent descriptions to prevent expensive and disruptive lawsuits. The Supreme Court announced Friday it will decide whether companies can patent human genes, a decision that could reshape medical research in the United States and the fight against diseases like breast and ovarian cancer. The US Supreme Court heard arguments Monday on whether patents can be enforced for software-created business practices, in a case likely to have a big impact on the tech sector.
Scientists in Spain on Wednesday they had created human sperm from skin cells, a medical feat which could eventually lead to a treatment for infertility. New research published today in the journal Scientific Reports has revealed for the first time that half of the world's farmed fish have hearing loss due to a deformity of the earbone. Honey bee colonies in the United States are in decline, due in part to the ill effects of voracious mites, fungal gut parasites and a wide variety of debilitating viruses. Mesoblast enjoys the patent legacy as the company has also been previously granted patents in Europe (EP1613335) and Japan (2006-503990) originating from the same patent family thus benefiting from exclusive commercial rights in the two other major healthcare markets to a minimum of 29 March 2024.
The US Center For disease Control (CDC) reports that around 10 percent of all diabetes is type one, but it is the most common type of childhood diabetes.Derek Rapp, president of JDRF, formerly the Juvenile Diabetes Research Foundation, said in a ViaCyte statement that the stem cell therapy could make a difference in the quality of treatment and management for diabetes patients. I will wait for you.” Screens mounted on the hood and each door could also indicate to those outside the car when it is safe to cross ahead of it and when it is not, according to a report in the Washington Post.
After an early life spent in the Imperial Free City of Dortmund, James followed the river Ruhr to Cofbuokheim, where he attended the University of Astnide. With the recent focus on turbo technology, it should go without saying that turbo technology has become a wide open field for reinvention. With it, BMW has found a solution that eliminates the turbo “lag” that occurs before normal turbochargers are able to spin fast enough to provide extra power.
If you're just cruising along it doesn't do much of anything, so fuel economy is much better, despite the extra power. If you suddenly put the gas pedal to the floor, it takes time for that exhaust pressure to build up and get everything started.
When coasting on the highway, disconnecting both can leave the electric motor from having to spin either the turbine or compressor, allowing the engine to work as efficiently as a non-turbo engine without any extra load. When the exhaust gas pressure builds up high enough, the clutch reconnects the turbine and the electric motor to link all of the units again, as in a traditional turbocharger.


If this system of miniaturizing a gas-electric hybrid motor within a turbocharger makes it to a production car, it could change the way automakers think about forced-induction engines.
Ingavle GC, Gehrke SH, Detamore MS, “The bioactivity of agarose-PEGDA interpenetrating network hydrogels with covalently immobilized RGD peptides and physically entrapped aggrecan,” Biomaterials, 35(11): 3558-3570, 2014.
Lazebnik M, Singh M, Friis LA, Berkland CJ, Detamore MS, “Biomimetic method for combining the nucleus pulposus and annulus fibrosus for intervertebral disc tissue engineering,” Journal of Tissue Engineering and Regenerative Medicine, EPub, 2011. Wang L, Zhao L, Detamore MS, “Human umbilical cord mesenchymal stromal cells in a sandwich approach for osteochondral tissue engineering,” Journal of Tissue Engineering and Regenerative Medicine, 5(9): 712-721, 2011. Zhao L, Tang M, Weir MD, Detamore MS, Xu HHK, “Osteogenic media and rhBMP-2 induced differentiation of umbilical cord mesenchymal stem cells encapsulated in alginate microbeads and integrated in an injectable calcium phosphate-chitosan fibrous scaffold,” Tissue Engineering Part A, 17(7-8): 969-979, 2011.
Xu HHK, Zhao L, Detamore MS, Takagi S, Chow LC, “Umbilical cord stem cell seeding on fast-resorbable calcium phosphate bone cement,” Tissue Engineering Part A, 16(9): 2743-2753, 2010. Wang Q, Wang J, Detamore MS, Berkland CJ, “Injectable PLGA based colloidal gels for zero-order dexamethasone release in cranial defects,” Biomaterials 31(18): 4980-4986, 2010.
Wang L, Singh M, Bonewald LF, Detamore MS, “Signalling strategies for osteogenic differentiation of human umbilical cord mesenchymal stromal cells for 3D bone tissue engineering,” Journal of Tissue Engineering and Regenerative Medicine,3 (5) 398-404, 2009. Singh M and Detamore MS, “Stress relaxation behavior of mandibular condylar cartilage under high-strain compression,” Journal of Biomechanical Engineering, 131 (6): 061008-1 – 061008-5, 2009. Wang L and Detamore MS, “Insulin-like growth factor-I improves chondrogenesis of predifferentiated human umbilical cord mesenchymal stromal cells,” Journal of Orthopaedic Research, 27 (8): 1109-1115, 2009. Detamore MS and Athanasiou KA, “Use of a rotating bioreactor toward tissue engineering the temporomandibular joint disc,” Tissue Engineering, 11 (7-8), 1188-1197, 2005. Athanasiou KA, Almarza AJ, Detamore MS, Kalpacki KN, Tissue Engineering of Temporomandibular Joint Cartilage, Morgan and Claypool Publishers, San Rafael, CA, 2009, ISBN 1598299964. Another protocol involved injecting transforming growth factor beta preprogrammed bone marrow stem cells to the myocardium, with greater success than transplantation of bone marrow stem cells alone, but without generation of contractile myocardium. On the basis that embryonic stem cells may be directed to differentiate into true cardiomyocytes, transplantation of embryonic stem cells to a site of myocardial infarction may yield success in myocardial tissue regeneration, though the experiments have not yet so proven.
Recently, myocardium has been regenerated using xenogenic extracellular matrix patches in pigs and dogs, and the contractility achieved was at 90% of normal. One problem exists in the preparation of extracellular scaffolds in that they must be non-immunogenic and thus acellular before implantation.
The only known experimental use of extracellular emulsions for tissue regeneration have been with gastroesophageal repair to prevent reflux and urinary bladder sphincter repair. 1 depicts cell-ECM interaction through the matrix proteoglycans, glycoaminoglycans and growth factors. 2 depicts cell-cell adhesions, and cell-matrix adhesions through specific structural and functional molecules of the ECM. 3 depicts a model of matrix scaffold structure including common collagen, proteoglycans, and glycoproteins. For this purpose, an emulsified or injectable extracellular matrix composition can be derived from a mammalian or synthetic source. The present invention provides a composition that creates an environment in vivo to allow these processes to occur.
The extracellular matrix scaffold then coordinates the function of the newly recruited or added cells, allowing also for cell migration within the matrix.
There is a three-dimensional architecture established with proteoglycan molecules, with available cytokines in the microenvironment.
The matrix functional proteins also interact with protein expressing cells during the life and maintenance of the matrix scaffold itself as it rebuilds and maintains its components. Glycosaminoglycans (GAGs) include chondroitin sulfate A and B, heparan, heparin, and hyaluronic acid.
The matrix scaffold is required to have a high surface area so that there is plenty of room for the biological activities required of the tissue regeneration process.
Two main classes of molecules are formed by collagen polymers: the fibril-forming collagens (collagens type I, II, III, V, and XI) and the non-fibrillar collagens that are a more heterogeneous class.
Only collagen types I, II, III, V, and XI self assemble into fibrils, characterized by a triple helix in the collagen molecules. The glycoprotein fibronectin (Fn) is a large dimer that attracts stem cells, fibroblasts and endothelial cells to a site of newly forming matrix. Together with type IV collagen, nidogen, and perlecan, laminin is one of the main components of the basement membrane. These interactions lead to direct or indirect control of cellular activities within the extracellular matrix scaffold such as adhesion, migration, differentiation, proliferation, and apoptosis. Well known GAGs include heparin, hyaluronic acid, heparan sulfate, and chondroitin sulfate A, B, and C. The proteins of the ECM are broken down by matrix metalloproteases, and new protein is made and deposited as replacement protein.
Integrin-ligand binding also triggers cascades of activity for cell survival, cell proliferation, cell motility, and gene transcription.
Cell surface receptors for tenascins include integrins, cell adhesion molecules of the Ig superfamily, a transmembrane chrondroitin sulfate proteoglycan (phosphacan) and annexin II. It is also believed that the proteolytic activity of MMPs augment the bioavailability of growth factors sequestered within the ECM, and can activate latent secreted growth factors like TGF-beta and IGF from IGFBPs and cell surface growth factor precursors.
Other organ tissue sources of basement membrane for use in accordance with this invention include spleen, lymph nodes, salivary glands, prostate, pancreas and other secreting glands.
Collagenous matrix for use in accordance with the present invention comprises highly conserved collagens, glycoproteins, proteoglycans, and glycosaminoglycans in their natural configuration and natural concentration.
Accordingly, for a functional tissue regenerative product, the scaffold component of the composition by weight will be generally greater than 50% of the total dry weight of the composition. Key functions that may need to be preserved include control or initiation of cell adhesion, cell migration, cell differentiation, cell proliferation, cell death (apoptosis), stimulation of angiogenesis, proteolytic activity, enzymatic activity, cell motility, protein and cell modulation, activation of transcriptional events, provision for translation events, inhibition of some bioactivities, for example inhibition of coagulation, stem cell attraction, and chemotaxis. A critical aspect of the decellularization process is that the process be completed with some of the key protein function retained, either by replacement of proteins incidentally extracted with the cells, or by adding exogenous cells to the matrix composition after cell extraction, which cells produce or carry proteins needed for the function of tissue regeneration in vivo. Prudent practice may dictate that the cell extract from the patches be tested for its protein make-up, so that if necessary proteins are removed they can be place back into the matrix composition, perhaps using exogenous proteins at approximately the same amount as those detected in the extraction solution.
What works as the best composition for myocardial tissue regeneration in patients, particularly humans can be tested first in other mammals by standard explanting procedures to determine whether tissue regeneration is accomplished and optimized by a particular composition.
Standard protein-molecule linking procedures may be used to accomplish the covalent attachment. The organ is perfused with a decellularization agent, for example 0.1% peractic acid rendering the organ acellular. For example, liver tissue is typically also treated with a calcium chelating agent or chaotropic agent such as a mild detergent such as Triton 100.
The cell-dissociation step may require several treatments with the cell-dissociation solution to release substantially all cells from the basement membrane. A sterilization technique which does not significantly weaken the mechanical strength and biotropic properties of the material is preferably used. According, such materials as polyethylene terephthalate fiber (Dacron), polytetrafluoroethylene (PTFE), glutaraldehyde-cross linked pericardium, polylactate (PLA), polyglycol (PGA), hyaluronic acid, polyethylene glycol (PEG), polyethelene, nitinol, and collagen from non-animal sources (such as plants or synthetic collagens), can be used as components of a synthetic extracellular matrix scaffold. The FDA has approved these polymers for use in surgical applications, including medical sutures. Other suitable bioabsorbable materials are biopolymers which include collagen, gelatin, alginic acid, chitin, chitosan, fibrin, hyaluronic acid, dextran, polyamino acids, polylysine and copolymers of these materials. For instance, inclusion of hairpin loops may result in more elastic biomaterials or may provide specific cleavage sites. The matrix may also be otherwise liquefied or made into an injectable solution, such as an emulsion, or a liquid, or injectable gel, or semi-gel, other injectable formulation that can be administered with a percutaneous catheter, or other device capable of delivering an injectable formulation.
Generally, the emulsion will be maintained in an emulsified state by control of some component of the composition, for example the pH.
Therefore, in order to regenerate myocardium, the right cells may have to be added to the composition, or the site, or the right molecules to attract the right cells will have to be added to the composition or the site.
They are cultured ex vivo and in the culture dish environment differentiate either directly to heart muscle cells, or to bone marrow cells that can become heart muscle cells. Adult stem cells are yet another species of cell that work in the context of tissue regeneration. Subpopulations of mesenchymal cells have been shown to differentiate toward myogenic cell lines when exposed to cytokines in vitro.
Their function and anticipated change upon implantation, as well as their viability during the process of transplantation need to be considered to determine the number of cells to transplant. The highly porous nature of extracellular matrices in particular will allow diffusion of cell nutrients throughout the membrane matrix. Such components include extracellular structural and functional proteins in admixture so as to mimic either heart ECM, or other native ECMs that are capable of regenerating at least some reasonable percentage of the defective myocardium, for example at least 30%, preferably more than 50%. Myriad Genetics case raises questions about the patent system," said Kirstin Matthews, the Baker Institute fellow in science and technology policy and an expert on ethical and policy issues related to biomedical research and development. Stem cells, like genes, are also isolated from the body although they do require some manipulation after isolation.
Myriad Genetics case will have on the biotech industry or if any patenting requirements will be changed in response to this or other court rulings, the authors said. Supreme Court next week could have major implications for biotechnology research and the public interest in the nation's patent system, according to a University of Michigan expert. Supreme Court decided Friday to hear an appeal of a lower court decision that a federal judge called the "death" of software patents. The definitions vary, but all infer the use of grey matter, whether in a cat or a human, to learn from experience. Patent and Trademark Office based on feedback from scientists, engineers, ethicists and policy scholars as opposed to leaving it up to the courts." I don't think any combination of DNA or RNA should be patentable.
The company has more than 661 patents or patent applications across no less than 72 patent families, thus affording considerable spirited advantages for the commercial development of cellular therapeutic products based on mesenchymal lineage cells. Immunologic and inflammatory – IV administration of cells to impart immuno-modulatory effects. Cardiac and vascular – Local administration of cells to improve heart anatomy and function.
Orthopedic diseases of the spine – Local administration of cells for potential repairmen of intervertebral discs or regeneration of bone. Oncology – Improving outcomes of bone marrow transplantation in patients with cancer or genetic diseases. Yamini Asthana, with an academic background in biochemistry and research expertise in the fields of inorganic biochemistry and material sciences, is the technology specialist for biochemical and pharmaceutical inventions. At the same time, it’s a self-contained system that improves the turbo’s efficiency with a hybrid-like regenerative motor and battery system.
Of course, the opposite is true, too: If you're a leadfoot, you'll wind up burning just as much fuel as you would with a bigger engine. Under really heavy use, such as when the engine is running at full-speed and the turbocharger is at its power-producing limit, the electric motor turns into a generator, using the spinning turbo to generate electricity to help charge the car’s battery. The results of all the effort and cost are disappointing with a 75% five year mortality rate for the heart failure victims. For a related challenge, to induce angiogenesis in ischemic myocardial tissue, transplanting endothelial progenitor cells, with or without angiogenic protein factors has been proposed to generate capillary blood vessels at the site of ischemia in the myocardium. Getting rid of the cells in the matrix may also inadvertently strip the scaffold of key bioactive proteins.
The processes needed to regenerate myocardium include specific phenotypic changes in stem cells that are recruited to the defective site, establishment of cell-cell connections, establishment of vascular supply at the site, beginning of normal tissue specific metabolism, limiting new growth once new tissue is made, coupling electric conduction from new cells to existing cells and pathways, and establishment of cell-extracellular matrix connections by way of cell adhesions to the matrix proteins. The matrix allows and provides for normal metabolism to the cells once the vascular supply delivering nutrients to the cells is established. Cell movement occurs using focal adhesions, and eventually permanent cell adhesions occur called hemidesmosomes. These molecules actually polymerize to form the scaffold or matrix of proteins that exists in dynamic interaction with cells, and closely placed functional proteins (either on the cells, or bound to a structural protein).
Note that some proteins fall into both a structural protein classification and a functional protein classification, depending on the protein's configuration and placement in the whole matrix. Glycoproteins such as fibronectin and entactin, proteoglycans such as decorin and perlecan, and growth factors such as transforming growth factor beta (TGF-beta), fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF), are key players in the activity of a myocardium regenerating matrix.
The CAMs are available either endogenously, or added as an additional component of the composition.
The scaffold must be able to provide cellular signals such as those mentioned herein that facilitate tissue regeneration. The sequence of the alpha chains contains a variable number of classical Gly-X-Y repetitive motifs which form the collagenous domains and noncollagenous domains. Fibril collagen molecules usually have a single collagenous domain repeated the entire length of the molecule, and non-fibrillar collagen molecules have a mixture of collagenous and noncollagenous domains.
The lecticans interact with hyaluronan and include aggrecan, versican, neurocan, and brevican.
Tenascin is a glycoprotein that has Fn repeats and appears during early embryogenesis then is switched off in mature tissue.
Heparin chains stimulate angiogenesis, and act as subunits in a proteoglycan to stimulate the angiogenic effects of fibroblast growth factor-2 (FGF-2) (also known as basic FGF or bFGF). Collagens are mostly synthesized by the cells comprising the ECM: fibroblasts, myofibroblasts, osteoblasts, and chondrocytes. TN-C also interacts with extracellular proteins such as fibronectin and the lecticans (the class of extracellular chondroitin sulphate proteoglycans including aggrecan, versican, and brevican). Other proteoglycans control the hydration of the ECM and the spacing between the collagen fibrils and network, which is believed to facilitate cell migration.
MMPs can proteolytically cleave cell surface growth factors, cytokines, chemokine receptors and adhesion receptors, and thus participate in controlling responses to growth factors, cytokines, chemokines, as well as cell-cell and cell-ECM interactions. In general, any tissue of a mammal that has an extracellular matrix can be used for developing an extracellular matrix component of the invention. Collagens can be from animal sources, from plant sources, or from synthetic sources, all of which are available and standard in the art.


Most typically, the scaffold will comprise an amount of the composition by weight greater than 60%, greater than 70%, greater than 80%, greater than 82%, greater than 84%, greater than 86%, greater than 88%, greater than 90%, greater than 92%, greater than 94%, greater than 96%, and greater than 98% of the total composition. Replacing lost essential proteins may also be necessary with emulsions or injectable solutions of extracellular matrix, particularly those emulsified from mammalian sources. See Badylak, et al, The Heart Surgery Forum, Extracellular Matrix for Myocardial Repair, vol. The cell dissociation step can also be conducted using a calcium chelating agent or chaotropic agent in the absence of an enzymatic treatment of the tissue. The liver tissue can be treated with a protease solution to remove the component cells, and the resulting extracellular matrix material is further treated to remove or inhibit any residual enzyme activity. For instance, it is believed that strong gamma radiation may cause loss of strength in the graft material. The synthetic materials listed are standard in the art, and forming hydrogels and matrix-like materials with them is also standard. An advantage of these synthetic absorbable materials is their degradability by simple hydrolysis of the ester backbone in aqueous environments, such as body fluids.
For example, Na, K, Bi and Ca salts of DNA all have different precipitation rates and different crystalline structures. The nucleic acid polymers and copolymers produced may be used for a variety of tissue engineering applications including to increase tissue tensile strength, improve wound healing, speed up wound healing, as templates for tissue formation, to guide tissue formation, to stimulate nerve growth, to improve vascularization in tissues, as a biodegradable adhesive, as device or implant coating, or to improve the function of a tissue or body part.
Upon delivery of the emulsion the pH is altered to allow the molecules of the matrix to polymerize into a three-dimensional scaffold.
In addition, where proteins such as growth factors, or any other protein, including protein forms such as peptides or polypeptides, or protein fragments, are added into the extracellular matrix, the protein molecules may be added into the matrix composition, or the protein molecules may be covalently linked to a molecule in the matrix. Transplantation cell sources for the myocardium include allogenic, xenogenic, or autogenic sources.
The cultured cells are then transplanted into the mammal, either with the composition or in contact with the scaffold and other components. Adult stem cells are thought to work by generating other stem cells (for example those appropriate to myocardium) in a new site, or they differentiate directly to a cardiomyocyte in vivo. Also the mode of transplantation is to be considered: several modes including intracoronary, retrograde venous, transvascular injection, direct placement at the site, thoracoscopic injection and intravenous injection can be used to put the cells at the site or to incorporate them with the composition either before delivery or after delivery to the defective myocardium. Effective regeneration of the myocardium relies on the extracellular matrix scaffold by its structure and components. She co-authored the paper with Maude Rowland Cuchiara, the Baker Institute scholar for science and technology policy.
Chakrabarty, which determined that "anything under the sun made by man" could be patented, leading to the diverse biotechnology patent landscape seen today, the authors said.
But it is likely that if stem cell patents include detailed procedures for the manipulations beyond isolation, they will be upheld.
Furthermore, auxiliary patent term extension might transpire along with regulatory exclusivity extensions. The prior granted patents include US7514074, US7892829, US8158120, US8158121, US8852570, US8852571, US8852572, US8852573, US8852574 and US8852575.
Meanwhile, the number with Type 2 diabetes, whose bodies make some insulin but don't use it efficiently, is increasing exponentially due to the global epidemic of obesity and sedentary lifestyles. He currently writes for a living, on a broad variety of subjects, ranging from science, to politics, to military history, to renewable energy. If implemented, it's expected to first show up in the next-generation BMW M3, based on the forthcoming 2012 BMW 3 Series sedan. The first pinwheel, called the turbine, runs on pressure from the engine’s hot exhaust gasses.
It’s also why many makers of sports cars have moved to more expensive turbochargers made of ceramic materials.
Treatments for chronic heart failure include medical management with pharmaceutical drugs, diet and exercise, transplantation for a few lucky recipients, and mechanical assist devices, which are costly and risk failure and infection. As yet, the experiments to prove these theories have not worked sufficiently to be attempted in humans.
In order to perform procedures to regenerate human myocardium with fidelity, compositions that mimic the function of extracellular matrices are provided below. Some veterinary use of extracellular matrix emulsions have been reported, but none of those uses were for the repair of myocardium.
An extracellular matrix composition of any formulation can include also an additional component such as: a) a cell, b) a peptide, polypeptide, or protein, or c) a vector expressing a DNA of a bioactive molecule, and d) other additives like nutrients or drug molecules. Additionally, signal transduction pathways for growth, differentiation, proliferation and gene expression are established.
Environmental signals are transmitted, including specific cell signals from growth factors on cell surfaces and disposed within the matrix framework as well. Furthermore, the precise chemical constitution of the matrix appears to play a role in its function, including for example what collagen type is prevalent in the matrix, the pore size established by the matrix scaffold, the forces transmitted to adhesion molecules and mechanoreceptors in the cell membranes of cells at the matrix, and the forces directed from the three-dimensional environment (for example the gene expression in the three-dimensional matrix scaffold environment is very different than in a monolayer environment). CAMs are glycoproteins lodged in the surface of the cell membrane or transmembrane connected to cytoskeletal components of the cell.
Cell migration, embryogenesis, hemostatic, and wound healing are so facilitated by the integrins in the matrix. Finally the scaffold needs to be non-immunogenic so that it is not rejected by the host, and it needs to be non-thrombogenic. The collagenous portions of 3 homologous or heterologous alpha chains are folded together into a helix with a coiled coil conformation that constitutes the basic structure motif of collagens.
Type III collagen dominates in the wall of blood vessels and hollow intestinal organs and copolymerizes with type I collagen. Versican stimulates proliferation of fibroblasts and chondrocytes through the presence in the molecule of EGF-like motifs.
Syndecans have a heparan sulfate extracellular moiety that binds with high affinity cytokines and growth factors, including fibroblast growth factor (FGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), heparin-binding epidermal growth factor (HB-EGF), and vascular endothelial growth factor (VEGF). Chondroitin sulfate B (dermatan sulfate) interacts with TGF-beta to control matrix formation and remodeling. Some collagens are also synthesized by adjacent parenchymal cells or also covering cells such as epithelial, endothelial, or mesothelial cells. For example, material analysis can be used to identify the molecules present in the material composition. Another option would be that the proteins extracted during the cell extraction process can simply be added back after the cell extraction is complete, thus preserving the desired bioactivity in the material.
For example, the resulting basement membrane can be heated or treated with one or more protease inhibitors. Preferred sterilization techniques include exposing the graft to peracetic acid, low dose gamma irradiation and gas plasma sterilization; peracetic acid sterilization being the most preferred method. Their effectiveness can be tested in vivo as sited earlier, by testing in mammals, along with components that typically constitute native ECMs, particularly the growth factors and cells responsive to them. The degradation products are ultimately metabolized to carbon dioxide and water or can be excreted via the kidney. The sequence of the nucleic acid may be irrelevant for many aspects of the present invention. The covalent linking of protein to matrix molecules can be accomplished by standard covalent protein linking procedures known in the art. Accordingly, human embryonic stem cells, neonatal cardiomyocytes, myofibroblasts, mesenchymal cells, autotransplanted expanded cardiomyocytes, and adipocytes can be used as additive components to accompany the scaffold. They may also differentiate into other lineages after introduction to organs, such as the heart.
In all cases, the mode of delivery and whether the cells are first mixed with the other components of the composition is a decision made based on what will provide the best chance for viability of the cells, and the best opportunity for their continued development into cells that can function in the scaffold in vivo in order to signal and promote tissue regeneration. With the emulsified extracellular matrix compositions, or with some of the other formulations, the cells can be co-cultured with the extracellular matrix material before administration of the complete composition to the patient. Mimicking the native explant material as closely as possible thus optimizes the opportunity for regeneration using a composition comprising some native ECM, albeit treated, but also with additional components. The court case and rulings garnered discussion in the public about patenting biological materials. The paper has timely significance in light of President Barack Obama's recent announcements on reforming the nation's patent process, including an initiative announced in February to "crowdsource" the review of patents.
However, biotechnological patents must meet the same requirements as all other patents, and they cannot be laws of nature, physical phenomena or abstract ideas. If you could test the DNA of extinct past organisms you may well find genes and gene combinations not at all present in modern organisms, and those too should not be patentable. Mesoblast Limited is an Australian-based regenerative medicine company, which hunts for providing treatments for inflammatory ailments, cardiovascular disease and back pain. The granted claims envelop the use of the Company’s allogeneic or off-the-shelf MPCs acquired from any source in conditions including ischemic heart disease, stroke and peripheral arterial disease. They deal with allogeneic culture-expanded Mesenchymal Stem Cell product candidates for cardiovascular diseases.
They received a small dose of insulin-producing cells inside their devices and are being closely monitored for two years to see insulin production and other effects.
Thus the landscape for cardiac treatment is turning in recent years to transplantation of tissue or cells. The disadvantage of using intact, non-emulsified extracellular matrix compositions such as patches or strips is that placement of the material requires open surgery, with its coordinate risk of infection, challenge of access to the site, and longer recovery for the patient post-procedure. The matrix itself has structural components and functional components and the line between the two sometimes blurs because some of the moieties of structural components signal and trigger protein activation, and activation of nearby cells. Thus, the outcome of any tissue regenerative processes is determined by the structural and functional components of the matrix scaffold that form the basis of the regenerative process. Specific CAMs include cadherins that are calcium dependent, and more than 30 types are known. Syndecans are proteoglycans that combine with ligands for initiating cell motility and differentiation.
The second type of proteoglycans have a protein core with leucine-rich repeats, which form a horse shaped protein good for protein-protein interactions. The heparan sulfate proteoglycans have been implicated in modulation of cell migration, proliferation and differentiation in wound healing.
Other glycoprotein components of ECM include elastin that forms the elastic fibers and is a major structural component along with collagen; fibrillins which are a family of proteins consisting almost entirely of endothelial growth factor (EGF)-like domains. Virtually all epithelial cells synthesize laminin, as do small, skeletal, and cardiac muscle, nerves, endothelial cells, bone marrow cells, and neuroretina.
The proteoglycan form of chondroitin sulfate B regulates the structure of ECM by controlling collagen fibril size, orientation and deposition. Also, in vitro cell adhesion tests can be conducted to make sure that the fabric or composition is capable of cell adhesion. These polymers are very different from cellulose based materials, which cannot be absorbed by the body. Any combination, copolymer, polymer or blend thereof of the above examples is contemplated for use according to the present invention.
However, special sequences may be used to prevent any significant effects due to the information coding properties of nucleic acids, to elicit particular cellular responses or to govern the physical structure of the molecule. The type of nucleic acid polymer or copolymer used may affect the resulting chemical and physical structure of the polymeric biomaterial.
The adult mammal provides sources for adult stem cells in circulating endothelial precursor cells, bone marrow-derived cells, adipose tissue, or cells from a specific organ. The composition can be placed in contact with the defective or absent myocardium, resulting in myocardial tissue regeneration and restoration of contractility, conductivity, or function to the heart muscle. Laminins affect nearby cells, by promoting adhesion, cell migration, and cell differentiation.
Hyaluronic acid is associated with rapid wound healing and organized deposit of collagen molecules in the matrix.
Using 4M guanidine with pH 7.4 buffer yields a fraction having transforming growth factor beta. The covalent linking may result in an integration of the protein molecules in the matrix scaffold formation once the emulsion converts from the emulsified form to the scaffold form of the extracellular matrix. It is known that mononuclear cells isolated from bone marrow aspirate differentiate into endothelial cells in vitro and are detected in newly formed blood vessels after intramuscular injection. The company is developing a range of regenerative products derived from its proprietary mesenchymal lineage cells, which includes Mesenchymal Precursor Cells (MPCs) and Mesenchymal Stem Cells (MSCs). Extra air means extra fuel can be burned.That’s how a tiny turbocharged four-cylinder engine can make more power than V-8 engines from less than a decade ago. The invention appreciates the importance of the presence of some amount and form of an extracellular matrix, or extracellular matrix-like scaffold, as a framework for the essential activities of cell-cell, matrix-cell, protein-cell, and protein-protein interactions that form the dynamic tissue regenerative process in vivo, potentially optimized by the presence of added cells, proteins, or other bioactive components. Thus, use of cells from bone marrow aspirate may yield endothelial cells in vivo as a component of the composition.
Laminins 5 and 10 occur predominantly in the vascular basement membrane and mediate adhesion of platelets, leukocytes, and endothelial cells. Accordingly, it may behoove a practitioner to decellularize one portion of a matrix, and extract desired proteins to add back in from other different portions. In addition, transforming growth factor beta (TGF beta) interacts with members of this family.
6,379,710, to name some of the extracellular matrix scaffolds presently available for explanting procedures. In addition, collagen from mammalian sources can be retrieved from matrix containing tissues and used to form a matrix composition.
Extracellular matrices can be synthesized from cell cultures as in the product manufactured by Matrigel™.



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