No assignee for this patent application has been made.
News editors obtained the following quote from the background information supplied by the inventors: "In nature, living cells divide and interconnect in the formation of complex biological systems creating structure-function hierarchies that span from the micrometer to meter scales.
"This bottom-up approach leverages genetic programming and environmental stimuli to direct cellular self-assembly and organogenesis into specialized tissues and organs. Capabilities including the parallel processing of neural networks, the combination of force, strain and efficiency of striated muscle and the immune response to pathogens far exceeds what can be achieved in manmade systems. Learning to use living cells as an integral building block in manmade, synthetic systems thus portends the ability to create classes of hybrid devices that combine the advantages of biological and engineering grade materials. Efforts to build biosynthetic materials or engineered tissues that recapitulate these structure-function relationships often fail because of the inability to replicate the in vivo conditions that coax this behavior from ensembles of cells. For example, engineering a functional muscle tissue requires that the sarcomere and myofibrillogenesis be controlled at the micron length scale, while cellular alignment and formation of the continuous tissue require organizational cues over the millimeter to centimeter length scale. Thus, to build a functional biosynthetic material, the biotic-abiotic interface must contain the chemical and mechanical properties that support multiscale coupling."
As a supplement to the background information on this patent application, NewsRx correspondents also obtained the inventors' summary information for this patent application: "Described herein are robust, intrinsically contractile biosynthetic materials actuated by ensembles of molecular motors. The ensembles include one or an array of muscle cells, e.g., skeletal muscle cells, smooth muscle cells, or cardiac muscle cells. Alternatively, the mixtures of cells, e.g., muscle cells and neuronal cells, are used.
"Striated muscle cells include skeletal and cardiac muscle. In nature, striated muscle tissue utilizes high-density arrays of actin-myosin motor complexes organized into contractile subunits, termed, sarcomeres, which assemble serially into myofibrils that span the length of cardiomyocytes and skeletal myoblasts. These muscle cells supply energy for the motor proteins by converting glucose into ATP and controlling excitation-contraction coupling by regulating Ca.sup.2+ concentration. Based on these properties, myocytes have been exploited as a single-cell linear actuator. These actuators are used to synchronize the actuation of motor proteins by interconnecting to form a mechanically and electrically continuous two-dimensional (2D) muscular tissue, such as myocardium. Free-standing, surface-modified thin films formed, e.g., of polydimethylsiloxane (PDMS), support the myocyte self assembly of serially aligned sarcomeres and the parallel bundling of myofibrils using patterned extracellular-matrix (ECM) proteins. While the myocytes provide contractile function, the polydimethylsiloxane thin film provides restorative elasticity and improved handling characteristics. Specifically, the polydimethylsiloxane film thickness dictates muscle sheet bending stiffness, while the structural integrity of the polydimethylsiloxane film allows the muscle sheet to be formed into near any planar shape without disrupting the 2D myocyte tissue.
"These constructs, which are termed, muscular thin films (MTF), are engineered for desired functionalities. For example, specific embodiments include soft robotic actuators and semi-autonomous, motile constructs that swim or walk autonomously or under external electrical stimulation or both. Spatially organized sarcomeres act as efficient linear actuators that have inherent control systems for regulating contraction initiation and propagation. Shortening of myocytes during synchronous, coordinated contraction causes the polydimethylsiloxane thin film to bend during systole and return to its original shape during diastole. The desired performance characteristics of the muscular thin film can be obtained by engineering the size, shape, thickness, tissue microarchitecture and pacing of actuation. In one example, these variables are manipulated to obtain the desired velocity of a swimmer. Furthermore, the spatial and temporal symmetry break utilized herein to generate directed motility in a semi-autonomous swimmer serve as a model for biomimetic anguilliform locomotion. Based on these examples, muscular thin films are useful in prosthetics, tissue engineering, muscle powered microdevices, bench top drug analysis and mechanical and chemical sensors.
"A method for measuring the contractility of a muscle is carried out by providing a muscular thin film comprising a flexible polymer layer coated with the muscle; attaching or clamping an end of the muscular thin film to a mounting structure; applying a stimulus to cause the muscle to contract; and measuring the displacement of the muscular thin film when the muscle is contracted. Measuring the displacement of the film is carried out by detecting a change in a radius of curvature of the muscular thin film when the muscle is contracted compared to when it is relaxed as well as measuring the rate of contraction. The methods are useful to screen for candidate compounds for drugs that promote contraction (e.g., vasocontraction) or relaxation (e.g., vasodilation) for drugs that treat or reduce the severity of disorders that are characterized by aberrant muscular activity (e.g., excessive contraction, excession relaxation, disregulation of contractile function (e.g., heart arrhythmia or vasospasms)). For example, the muscle cells are contact with a candidate compound prior to applying a contractile stimulus and the degree of contraction or the rate of contraction in the presence of the candidate compound is measured and compared relative to displacement in the absence of the candidate compound. The cells on the film are normal wild type cells, diseased cells, physically-damaged cells, or genetically altered cells. A difference between the degree of or rate indicates that the candidate compound alters muscular function, i.e., increases contractile function or decreases contractile function.
"In other embodiments, neurons, fibroblasts, endothelial cells, smooth muscle cells or skin cells are used in place of muscle cells. The cells are functionally active, meaning that the attached cells perform at least one function of that cell type in its native environment. For example, a myocyte cell contracts, e g., a cardiomyocyte cell contracts with particular direction along a single axis. Neural cells transduce or transmit an electrical signal to another neural cell. The neurons are used, e.g., for signal propagation. The fibroblasts are used for ECM deposition. The endothelial cells are used for construction or repair of blood vessels. The smooth muscle cells are used for slow, tonic contractions.
"One use of the engineered tissue structures described herein is to repair and/or reinforce the corresponding tissue in a mammal, e.g., an injured or diseased human subject. For example, the cell-seeded films/polymers are use as or in prosthetic devices, tissue implants, and wound dressing. Such wound dressing offer improved healing of lesions that are often difficult to treat, e.g., burns, bedsores, and abrasions. The structures are also useful to repair other tissue defects, e.g., for organ repair due to birth defects such as gastroschisis or defects due to degenerative diseases. Wound dressing compositions are portable and amenable to both hospital (e.g., operating room) use as well as field (e.g., battlefield) use.
BRIEF DESCRIPTION OF THE DRAWINGS
"FIGS. 1-5 depict a schematic of fabrication steps that may be used to make free-standing films functionalized with cells and/or proteins.
"FIG. 6 is a series of images of cardiomyocytes cultured on different uniform and micro-patterned layers of fibronectin to produce 2D myocardium with different microstructures.
"FIG. 7 depicts an example of an asymmetric film shape and tissue anisotropy.
"FIG. 8 provides illustrations and images for various embodiments of soft robotic actuators created from muscular thin films.
"FIG. 9 provides illustrations, images and charts for a myopod formed from a triangular muscular thin film.
"FIG. 10 provides illustrations of myopods formed from a triangular muscular thin film.
"FIGS. 11-13 depict biological micro-control devices and their uses as valves and/or switches in microfluidic systems.
"FIGS. 14-19 depict application of a muscular thin film in the form of an external cuff or wrap for wound dressings, and its use to seal gun-shot wounds and as a temporary sealant for severed appendages.
"FIGS. 20-25 depict application of a muscular thin film as a graft for repair and/or regeneration of hard and/or soft tissue and its use for fusing and regrowing traumatic muscle injury and as a scaffold to fill voids in muscle tissue.
"FIG. 26 shows a rectangular-shaped muscular thin film with myocytes anisotropically aligned along its length, wherein the muscular thin film is clamped at one end in a PDMS block.
"FIG. 27 shows the clamped muscular thin film of FIG. 26, with the myocytes contracted to produce a radius of curvature in the muscular thin film.
"The foregoing and other features and advantages of the invention will be apparent from the following, more-particular description. In the accompanying drawings, like reference characters refer to the same or similar parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating particular principles, discussed below."
For additional information on this patent application, see: Parker,
Keywords for this news article include: Patents, Peptides, Proteins, Cytoplasm, Myofibrils, Organelles, Sarcomeres, Amino Acids, Engineering, Muscle Cells, Cellular Structures, Intracellular Space.
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