Dermal micro-organs, methods and apparatuses for producing and using the same

• US 8,142,990 B2
• Filed: 07/02/2008
• Issued: 03/27/2012
• Est. Priority Date: 11/05/2001
• Status: Expired due to Fees

• Current Assignee: Medgenics Medical Israel Ltd.
• Original Assignee: Medgenics Inc. (Avalo Therapeutics, Inc.)
• Inventors: Piva, Guillermo Alberto, Rosenberg, Lior, Bukhman, Mordechay, Stern, Baruch S., Shalhevet, David, Shavitt, Menachem D., Pearlman, Andrew L., Shani, Noam, Bellomo, Stephen F., Almon, Einat, Lippin, Itzhak
• Primary Examiner(s): Noble, Marcia S
• Application Number:
  US12/216,321
• Publication Number:
  US 20090082717A1
• Time in Patent Office: 1,364 Days
• Field of Search: 435/1.1, 435/325, 623/15.11
• US Class Current: 435/1.1
• CPC Class Codes: A61B 10/0275 with sample notch, e.g. on the side of inner stylet
• CPC Class Codes: A61B 17/32053 Punch like cutting instruments, e.g. using a cylindrical or oval knife A61B17/326 takes precedence; trepans A61B17/1695; for use on the cornea A61F9/007
• CPC Class Codes: A61B 17/322 Skin grafting apparatus
• CPC Class Codes: A61B 2017/0023 disposable
• CPC Class Codes: A61B 2017/00969 used for transplantation
• CPC Class Codes: A61B 2017/2808 Clamp, e.g. towel clamp
• CPC Class Codes: A61B 2017/320052 Guides for cutting instruments by marking A61B2090/395
• CPC Class Codes: A61B 2017/320064 with tissue or sample retaining means
• CPC Class Codes: A61B 2017/3225 with processing of harvested tissue
• CPC Class Codes: A61B 2217/005 with suction drainage system
• CPC Class Codes: A61F 2/105 Skin implants, e.g. artificial skin
• CPC Class Codes: A61K 35/36 Skin; Hair; Nails; Sebaceous glands; Cerumen; Epidermis; Epithelial cells; Keratinocytes; Langerhans cells; Ectodermal cells islets of Langerhans A61K35/39
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/2066 IL-10
• CPC Class Codes: A61K 38/215 IFN-beta
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: C12N 2502/094 keratinocytes
• CPC Class Codes: C12N 2502/1323 : Adult fibroblasts
• CPC Class Codes: C12N 2510/00 : Genetically modified cells
• CPC Class Codes: C12N 5/0698 : Skin equivalents
• CPC Class Codes: Y10T 83/929 : Tool or tool with support

Abstract

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.

Claims

1. A dermal micro-organ wherein said dermal micro-organ is an explant of living tissue consisting essentially of a plurality of dermal components and lacking a complete epidermal layer, which substantially maintains the micro-architecture and three-dimensional structure of the dermal tissue from which it is obtained, having dimensions selected so as to allow passive diffusion of adequate nutrients and gases to cells of said dermal micro-organ and diffusion of cellular waste out of said cells so as to minimize cellular toxicity and concomitant death due to insufficient nutrition and accumulation of waste in said dermal micro-organ.

2. The dermal micro-organ of claim 1, wherein said dermal micro-organ includes at least part of a cross-section of the dermis.

3. The dermal micro-organ of claim 1, wherein said dermal micro-organ also includes fat tissue.

4. The dermal micro-organ of claim 1, wherein said dermal micro-organ comprises an in vivo demarcation.

5. A genetically modified dermal micro-organ expressing at least one recombinant gene product, wherein said dermal micro-organ is an explant of living tissue consisting essentially of a plurality of dermal components and lacking a complete epidermal layer, which maintains the micro-architecture and three-dimensional structure of the dermal tissue from which it is obtained, having dimensions selected so as to enable passive diffusion of adequate nutrients and gases to cells of said dermal micro-organ and diffusion of cellular waste out of said cells so as to minimize cellular toxicity and concomitant death due to insufficient nutrition and accumulation of waste in said dermal micro-organ, wherein said dermal micro-organ is 10-60 mm in length and wherein at least one dimension of the cross section of said genetically modified dermal micro-organ is 0.5-3.5 mm, wherein at least some of said cells of said dermal micro-organ express at least a portion of said at least one recombinant gene product and wherein said dermal micro-organ secretes said at least one recombinant gene product.

6. The genetically modified dermal micro-organ of claim 5, wherein said genetically modified dermal micro-organ includes at least part of a cross-section of the dermis.

7. The genetically modified dermal micro-organ of claim 5, wherein said dermal micro-organ also includes fat tissue.

8. The genetically modified dermal micro-organ of claim 5, wherein said at least one recombinant gene product is endogenously produced by the organ or tissue from which the dermal micro-organ is obtained.

9. The genetically modified dermal micro-organ of claim 5, wherein said at least one recombinant gene product is not endogenously produced by the organ or tissue from which the dermal micro-organ is obtained.

10. The genetically modified dermal micro-organ of claim 5, wherein said genetically modified dermal micro-organ comprises an in vivo demarcation.

11. The genetically modified dermal micro-organ of claim 10, wherein said in vivo demarcation comprises an ink or stain on the peripheral surface of said micro-organ.

12. The genetically modified dermal micro-organ of claim 10, wherein said in vivo demarcation comprises a green fluorescent protein (GFP) gene or a luciferase reporter gene expressed by said micro-organ.

13. The genetically modified dermal micro-organ of claim 5, wherein said dermal micro-organ is 20-40 mm in length.

14. A genetically modified dermal micro-organ expressing at least one recombinant gene product, wherein said dermal micro-organ is an explant of living tissue consisting essentially of a plurality of dermal components and lacking a complete epidermal layer, which maintains the micro-architecture and three-dimensional structure of the dermal tissue from which it is obtained, having dimensions selected so as to enable passive diffusion of adequate nutrients and gases to cells of said dermal micro-organ and diffusion of cellular waste out of said cells so as to minimize cellular toxicity and concomitant death due to insufficient nutrition and accumulation of waste in said dermal micro-organ, wherein at least some of said cells of said dermal micro-organ express at least a portion of said at least one recombinant gene product and wherein said dermal micro-organ secretes said at least one recombinant gene product, wherein said at least one recombinant gene product is erythropoietin.

15. The genetically modified dermal micro-organ of claim 14, where said genetically modified dermal micro-organ includes at least part of a cross-section of the dermis.

16. The genetically modified micro-organ of claim 14, wherein said dermal micro-organ also includes fat tissue.

17. The genetically modified micro-organ of claim 14, wherein said genetically modified dermal micro-organ comprise an in vivo demarcation.

18. A genetically modified dermal micro-organ expressing at least one recombinant gene product, wherein said dermal micro-organ is an explant of living tissue consisting essentially of a plurality of dermal components and lacking a complete epidermal layer, which maintains the micro-architecture and three-dimensional structure of the dermal tissue from which it is obtained, having dimensions selected so as to enable passive diffusion of adequate nutrients and gases to cells of said dermal micro-organ and diffusion of cellular waste out of said cells so as to minimize cellular toxicity and concomitant death due to insufficient nutrition and accumulation of waste in said dermal micro-organ, wherein at least some of said cells of said dermal micro-organ express at least a portion of said at least one recombinant gene product and wherein said dermal micro-organ secretes said at least one recombinant gene product, wherein said at least one recombinant gene product is interferon.

19. The genetically modified micro-organ of claim 18, where said genetically modified dermal micro-organ includes at least part of a cross-section of the dermis.

20. The genetically modified micro-organ of claim 18, wherein said dermal micro-organ also includes fat tissue.

21. The genetically modified micro-organ of claim 18, wherein said genetically modified dermal micro-organ comprise an in vivo demarcation.

22. A method of inducing a physiological effect in a subject comprising implanting a genetically modified dermal micro-organ expressing at least one recombinant gene product into or underneath the skin, wherein said dermal micro-organ is autologous with said subject, wherein said dermal micro-organ is an explant of living tissue consisting essentially of a plurality of dermal components and lacking a complete epidermal layer, which maintains the micro-architecture and three-dimensional structure of the dermal tissue from which it is obtained, having dimensions selected so as to enable passive diffusion of adequate nutrients and gases to cells of said dermal micro-organ and diffusion of cellular waste out of said cells so as to minimize cellular toxicity and concomitant death due to insufficient nutrition and accumulation of waste in said dermal micro-organ, wherein at least some of said cells of said dermal micro-organ express at least a portion of said at least one recombinant gene product, and wherein said implanting of said micro-organ induces said physiological effect in said subject.

23. A method of delivering at least one recombinant gene product to a subject comprising implanting into or underneath the skin of said subject a genetically modified dermal micro-organ expressing at least one recombinant gene product, wherein the genetically modified micro-organ is autologous with said subject, wherein said dermal micro-organ is an explant of living tissue consisting essentially of a plurality of dermal components and lacking a complete epidermal layer, which maintains the micro-architecture and three-dimensional structure of the dermal tissue from which it is obtained, having dimensions selected so as to enable passive diffusion of adequate nutrients and gases to cells of said dermal micro-organ and diffusion of cellular waste out of said cells so as to minimize cellular toxicity and concomitant death due to insufficient nutrition and accumulation of waste in said dermal micro-organ, wherein at least some of said cells of said dermal micro-organ express at least a portion of said at least one recombinant gene product, and wherein said implanting of said genetically modified micro-organ delivers said at least one recombinant gene product to said subject.