Source: http://www.google.com/patents/US8142990?ie=ISO-8859-1
Timestamp: 2014-10-24 21:40:51
Document Index: 348517141

Matched Legal Cases: ['Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 04', 'Application No. 04760621']

Patent US8142990 - Dermal micro-organs, methods and apparatuses for producing and using the same - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsEmbodiments of the present invention provide Dermal Micro-organs (DMOs), methods and apparatuses for producing the same. Some embodiments of the invention provide a DMO including a plurality of dermal components, which substantially retain the micro-architecture and three dimensional structure of the...http://www.google.com/patents/US8142990?utm_source=gb-gplus-sharePatent US8142990 - Dermal micro-organs, methods and apparatuses for producing and using the sameAdvanced Patent SearchPublication numberUS8142990 B2Publication typeGrantApplication numberUS 12/216,321Publication dateMar 27, 2012Filing dateJul 2, 2008Priority dateNov 5, 2001Also published asCA2523706A1, CA2748659A1, CA2748661A1, CA2748670A1, CA2788000A1, CN1816280A, CN1816280B, CN102816738A, EP1653807A2, EP1653807A4, EP1653807B1, EP2377401A1, EP2377402A1, EP2377403A1, EP2377404A1, US7468242, US8088568, US8293463, US8501396, US8530149, US8685635, US8771291, US20040241148, US20090082717, US20100150878, US20120003276, US20120095557, US20120201793, US20120295245, US20130052240, US20130090669, US20130103151, US20140161859, WO2004099363A2, WO2004099363A3, WO2013118109A1, WO2013118109A8Publication number12216321, 216321, US 8142990 B2, US 8142990B2, US-B2-8142990, US8142990 B2, US8142990B2InventorsStephen F. Bellomo, Itzhak Lippin, Guillermo Alberto Piva, Lior Rosenberg, Mordechay Bukhman, Baruch S. Stern, David Shalhevet, Menachem D. Shavitt, Andrew L. Pearlman, Noam Shani, Einat AlmonOriginal AssigneeMedgenics Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (65), Non-Patent Citations (21), Classifications (34), Legal Events (1) External Links: USPTO, USPTO Assignment, EspacenetDermal micro-organs, methods and apparatuses for producing and using the sameUS 8142990 B2Abstract Embodiments of the present invention provide Dermal Micro-organs (DMOs), methods and apparatuses for producing the same. Some embodiments of the invention provide a DMO including a plurality of dermal components, which substantially retain the micro-architecture and three dimensional structure of the dermal tissue from which they are derived, having dimensions selected so as to allow passive diffusion of adequate nutrients and gases to cells of the DMO and diffusion of cellular waste out of the cells so as to minimize cellular toxicity and concomitant death due to insufficient nutrition and accumulation of waste in the DMO. Some embodiments of the invention provide methods and apparatuses for harvesting the DMO. An apparatus for harvesting the DMO may include, according to some exemplary embodiments, a support configuration to support a skin-related tissue structure from which the DMO is to be harvested, and a cutting tool able to separate the DMO from the skin-related tissue structure. Other embodiments are described and claimed.
CROSS REFERENCE TO RELATED APPLICATIONS This application is a Continuation of U.S. application Ser. No. 10/834,345, filed Apr. 29, 2004, now U.S. Pat. No. 7,468,242, which claims priority from U.S. Provisional Application No. 60/466,793, filed May 1, 2003, and U.S. Provisional Application No. 60/492,754, filed Aug. 6, 2003 and is a Continuation in Part of PCT International Application Numbers PCT/IL02/00877, PCT/IL02/00878, PCT/IL02/00879 and PCT/IL02/00880, all filed Nov. 5, 2002, which claim priority from U.S. Provisional Application No. 60/330,959, filed Nov. 5, 2001, U.S. Provisional Application No. 60/393,745, filed Jul. 8, 2002 and U.S. Provisional Application No. 60/393,746, filed Jul. 8, 2002, the disclosures of all of which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION The invention relates to the field of tissue based micro-organs, therapeutic tissue based micro-organs and methods and apparatuses for harvesting, processing, implanting and manipulating dermal tissue.
A dermal micro-organ (DMO), which can be sustained outside the body (�ex vivo� or �in vitro�) in an autonomously functional state for an extended period of time, and to which various manipulations can be applied, may then be implanted subcutaneously or within the body for the purpose of treating diseases, or disorders, or for plastic surgical purposes. The DMO can be modified to express a gene product of interest. These modified dermal micro-organs are generally referred to as Dermal Therapeutic Micro-Organs (DTMOs).
Skin micro-organs, including layers of epidermal and dermal tissues, for example; as outlined in PCT/IL02/0880, have been observed to be associated with a number of clinical challenges. Harvesting of a skin sample leaves a superficial wound on the patient that may last several weeks and may leave scars. The harvested skin sample requires significant processing to generate micro-organs from this sample. Also, implantation of skin micro-organs subcutaneously or deeper in the body have been found to result in the development of keratin cysts or keratin micro-cysts. Additionally, implantation of skin micro-organs as a graft onto the skin surface in �slits� requires significant technical expertise in order to handle the MO while maintaining its proper orientation.
The term �dermal micro-organ� or �DMO� as used herein, refers in some embodiments of the invention, to an isolated tissue or organ structure derived from or identical to an explant that has been prepared in a manner conducive to cell viability and function, while maintaining at least some in vivo interactions similar to the tissues or organ from which it is obtained. Dermal micro-organs may include plurality of dermal components that retain the micro-architecture of the tissue or organ from which they were derived, and three dimensional structure of the dermal tissue from which they are derived, having dimensions selected so as to allow passive diffusion of adequate nutrients and gases to cells within the MO and diffusion of cellular waste out of the cells of the MO so as to minimize cellular toxicity and concomitant death due to insufficient nutrition and accumulation of waste. Dermal micro-organs may consist essentially of a plurality of dermis components (tissue components of the skin located below the epidermis). These components may contain skin fibroblast, epithelial cells, other cell types, bases of hair follicles, nerve endings, sweat and sebaceous glands, and blood and lymph vessels. Wherever used herein below, the description of the embodiments related to MO relates also to dermal MO whenever the term �dermal tissue� is used, it also relates to �dermal organ�.
The term �donor� as used herein, refers in some embodiments of the invention to a subject, from which the explant is removed and used to form, or which is already in the form of, one or more micro-organs.
The term �therapeutic micro-organ (TMO)� as used herein, refers in some embodiments of the invention to a micro-organ (MO) that can be used to facilitate a therapeutic objective, such as, for example, an MO that has been genetically altered or modified to produce a therapeutic agent, such as a protein or and RNA molecule. The therapeutic agent may or may not be a naturally occurring body substance. Wherever used hereinbelow, the description of the embodiments related to TMO relates also to DTMO which is a therapeutic Dermal MO which may be in some embodiments of the invention genetically modified.
In some embodiments of the invention, the micro-organ is a dermal micro-organ including a plurality of dermis components, for example, fibroblasts and/or epithelial components containing nerve endings and/or sweat glands and/or sebaceous glands and/or blood and lymph vessels and/or elastin fibers and/or collagen fibers and/or endothelial components and/or immune system derived cells and/or extra-cellular matrix. As shown by the test results summarized in the Examples section below (Example 5, FIG. 8), conventional subcutaneous implantation of a micro-organ including epidermal layers (�split thickness skin MO�) in mice and pigs (data in pigs is not shown), may result in formation of keratin cysts or macro-keratin cysts. In contrast, when skin tissue is sampled to obtain a DMO according to exemplary embodiments of the invention, no cysts or macro cysts are observed in mice, pigs or in humans. It should be noted that the biological activity (for example, secretion of a therapeutic protein, e.g., erythropoietin and elevation of hematocrit as a result) of a DTMO according to embodiments of the invention may be comparable to or even higher than split thickness skin derived TMO (see Example 4). Namely, both types of preparation may release the same amount of erythropoietin; however, the DTMO may produce and secrete higher protein levels per unit than those of split thickness derived TMO.
The term �skin-related tissue structure�, as used herein, refers to a structure of tissue components that may be stabilized and/or supported by apparatuses defined herein to enable the harvesting of a dermal micro-organ therefrom. A skin-related tissue structure may include components of the epidermal tissue, and components of the dermal tissue. Optionally, the skin-related tissue structure may include fat tissue and/or muscle tissue in the vicinity of the dermal tissue.
According to some exemplary embodiments, core biopsy devices with similarities to the devices used, for example, in breast cancer biopsy applications, as described below, may be utilized for harvesting a DMO. Apparatus 1800 may include a cutting tool 1808, e.g., as described above, and a Subcutaneous Harvest Trocar (HST) 1806, e.g., a hypodermic needle with a sharpened tip 1804 and a suitable inner diameter, e.g., being slightly larger than the outer diameter of cutting tool 1808, such that cutting tool 1808 may be inserted into and substantially coaxially within HST 1806. HST 1806 may include a notch cutout (�window�) 1802 of a suitable depth, e.g., 1 mm or more, and a suitable length, e.g., substantially equal to the desired length of the DMO to be harvested.
According to some embodiments of the present invention, a system and method are provided for ex-vivo (�in vitro�) handling or processing of dermal micro-organs. Dermal tissue that has been harvested as a direct MO may be left on their inner guide as a mount for the MO. In these embodiments, the inner guide may be used to maintain position and orientation of the MOs during subsequent processing. In other embodiments, the dermal MOs may be removed from the inner guide and directly placed into tissue culture wells or transduction chambers of a bioreactor, as described in detail below, e.g., with reference to FIG. 22. In some embodiments, e.g., if the DMO remains in the coring tube as it is withdrawn from the skin, the DMO may be flushed out of the coring tube by the use of biologically compatible fluid, e.g., saline or growth medium, applied to the back end of the coring tube. The flushing of the DMO may be such that it is flushed directly into a chamber of the bioreactor, e.g., as described below. Alternatively, vacuum may be applied to a back end of the coring tube to �draw out� the DMO, e.g., directly into a chamber of the bioreactor.
According to some exemplary embodiments, lid 2232 may be a removable sterile lid, such as a membrane affixed by a detachable adhesive, silicon plug material, or the like. Lid 2232 may be adapted to maintain a sterile �barrier� between chamber 2202 and the environment. Optionally, a sterile air filter 2234, e.g., a 0.451 μm pore air filter, may be implemented to fluidically connect chamber 2202 and the environment, thus enabling equilibration of pressures while maintaining a sterile barrier between chamber 2202 and the environment. Alternatively, lid 2232 may include a �breathable� material, such that pressure equilibration may be enabled through lid 2232.
Example 7 Autologous Implantation of Miniature Swine Skin Linear Split Thickness TMOs, Expressing Human Erythropoietin (hEPO into Immuno Competent Animals) Linear (30.6 mm long and 0.6 micrometer wide) miniature swine (Sinclar swine) skin micro-organs were prepared from fresh skin tissue samples obtained from live animals under general anesthesia procedures. Tissue samples of 0.9-1.1 mm split skin thickness (depth) were removed using a commercial dermatome (Aesculap GA630) and cleaned using DMEM containing glutamine and Pen-Strep in Petri dishes (90 mm).
In order to generate the linear micro-organs, the above tissue samples were cut by a press device using a blade structure as described above, into the desired dimensions: 30.6 mm �600 micrometers. The resulting linear micro-organs were placed, one per well, in a 24-well micro-plate containing 500 μl per well of DMEM (Biological Industries�Beit Haemek) in the absence of serum under 5% CO2 at 37� C. for 24 hours. Each well underwent a transduction procedure in order to generate a miniature swine skin therapeutic micro-organ (pig skin-TMO) using an adeno viral vector (1�1010 IP/ml) carrying the gene for human erythropoietin (Adeno-hEPO) for 24 hours while the plate was agitated. The medium was changed every 2-4 days and analyzed for the presence of secreted HEPO using a specific ELISA kit (Cat. # DEP00, Quantikine IVD, R&D Systems).
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"Transgenic studies with a keratin promoter-driven growth hormone transgene: prospects for gene therapy" Proc Natl Acad Sci U S A. 4(1):219-26. 1 Jan. 7, 1997.* Cited by examinerClassifications U.S. Classification435/1.1, 623/15.11, 435/325International ClassificationA01N65/00, A61B17/28, C12M, A01N1/00, C12N5/02, A61F2/10, A01N63/00, A61B10/02, A61K48/00, C12N5/00Cooperative ClassificationC12N2502/094, A61B10/0275, A61B2017/2808, C12N5/0698, C12N2502/1323, C12N2510/00, A61B17/322, A61B2017/320052, A61B2017/320064, A61B2017/00969, A61B2017/0023, A61K35/36, A61B2017/3225, A61K38/1816, A61K38/2066, A61K38/215, A61K38/193, A61F2/105, A61K38/27, A61K38/28European ClassificationC12N5/06T2Legal EventsDateCodeEventDescriptionJan 8, 2009ASAssignmentOwner name: MEDGENICS INC., VIRGINIAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BELLOMO, STEPHEN F.;LIPPIN, ITZHAK;PIVA, GUILLERMO ALBERTO;AND OTHERS;REEL/FRAME:022074/0029;SIGNING DATES FROM 20080917 TO 20080929Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BELLOMO, STEPHEN F.;LIPPIN, ITZHAK;PIVA, GUILLERMO ALBERTO;AND OTHERS;SIGNING DATES FROM 20080917 TO 20080929;REEL/FRAME:022074/0029RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google