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

• US 20040241148A1
• Filed: 04/29/2004
• Published: 12/02/2004
• Est. Priority Date: 11/05/2001
• Status: Active Grant

• Current Assignee: Medgenics Medical Israel Ltd.
• Original Assignee: Medgenics Inc. (Avalo Therapeutics, Inc.)
• Inventors: Almon, Einat, Rosenberg, Lior, Pearlman, Andrew L., Bukhman, Mordechay, Lippin, Itzhak, Bellomo, Stephen F., Shani, Noam, Shavitt, Menachem D., Piva, Guillermo Alberto, Shalhevet, David, Stern, Baruch S.
• Granted Patent: US 7,468,242 B2
• Time in Patent Office: Days
• US Class Current: 424/93.21
• 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 comprising 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 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 produces not more than a negligible amount of keratin.

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

4. The dermal micro organ of any one of claims 1, wherein said dermal micro organ further comprises fat tissue.

5. The dermal micro organ of any one of claims 1, wherein said dermal micro organ further comprises tissue from at least one epidermal layer.

6. The dermal micro organ of any one of claims 1, wherein said dermal micro organ is maintainable in-vitro for at least several days.

7. The dermal micro organ of claim 6, wherein said dermal micro organ is maintainable in-vitro in for at least several weeks.

8. The dermal micro organ of any one of claims 1, wherein said dermal micro organ comprises an in-vivo demarcation.

15. A method of inducing a local or systemic physiological effect in a subject comprising implanting in the body a dermal micro organ according to claim 1.

16. The method of claim 15, wherein implanting said dermal micro organ comprises implanting said dermal micro organ into or underneath the skin.

9. A genetically modified dermal micro organ expressing at least one recombinant gene product, said dermal micro organ comprising a plurality of dermal components, which retain the micro-architecture and three dimensional structure of the dermal tissue from which they are derived, 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 express at least a portion of at least one recombinant gene product.

10. The genetically modified dermal micro organ of claim 9, wherein said dermal micro organ includes at least part of the cross-section of the dermis.

11. The genetically modified dermal micro organ of claim 9, wherein said dermal micro organ further comprises fat tissue.

12. The genetically modified dermal micro-organ of claim 9, wherein said at least one recombinant gene product is naturally produced by an organ from which the dermal micro-organ is derived.

13. The genetically modified dermal micro-organ of claim 9, wherein said at least one recombinant gene product is not naturally produced by the organ from which the dermal micro-organ is derived.

14. The genetically modified dermal micro organ of claim 9, wherein said genetically modified dermal micro organ comprises an in-vivo demarcation.

17. A method of delivering a gene product of interest to a subject comprising implanting in the body the genetically modified dermal micro organ of claim 9.

18. The method of claim 17, wherein implanting said genetically modified dermal micro organ comprises implanting said genetically modified dermal micro organ into or underneath the skin.

19. The method of claim 17, wherein said dermal micro organ is derived from said subject.

20. A method of determining the amount of a therapeutic dermal micro organ to be implanted in a patient, the method comprising:

determining a production and/or secretion level of a therapeutic agent by a quantity of the dermal micro organ in vitro;

estimating a relationship between in vitro production and/or secretion and in vivo serum levels of the therapeutic agent; and

determining an amount of therapeutic dermal micro organ to be implanted, based on the determined production and/or secretion level and the estimated relationship.

21. A method of implanting a dermal therapeutic micro organ at an implantation site comprising:

inserting into said implantation site a carrier having said dermal therapeutic micro organ aspirated therein;

withdrawing said carrier while holding said dermal therapeutic micro organ in said implantation site.

22. The method of claim 21, wherein said implantation site is within or under the skin.

23. A method of implanting a dermal therapeutic micro organ at an implantation site comprising:

inserting into said implantation site a carrier having said dermal therapeutic micro organ aspirated therein;

applying pressure on the aspirated dermal therapeutic micro organ such that said dermal therapeutic micro organ exits from said carrier into said implantation site.

24. The method of claim 23, wherein said intended implantation site is intra the body.

25. A method of adjusting the dosage of a therapeutic agent produced by a therapeutic dermal micro organ implanted in a subject and excreting a therapeutic agent, comprising:

monitoring a level of therapeutic agent in the subject; and

controlling the amount of therapeutic dermal micro organ in the subject based on a comparison between said level of therapeutic agent and at least one threshold level.

26. A method according to claim 25, wherein said at least one threshold level comprises a minimum level and a maximum level, and wherein controlling the amount of therapeutic dermal micro organ comprises:

implanting additional therapeutic dermal micro organ if said level of therapeutic agent is lower than said minimum level; and

inactivating or removing a portion of the implanted therapeutic dermal micro organ if said level of therapeutic agent is higher than said maximum level.

27. A method according to claim 26, wherein inactivating or removing said portion comprises ablating said portion.

28. An apparatus for harvesting a dermal micro organ, the apparatus comprising:

a support configuration to support a skin-related tissue structure from which said dermal micro organ is to be harvested; and

a cutting tool able to separate said dermal micro organ from said skin-related tissue structure.

29. The apparatus of claim 28, wherein said support configuration comprises a first tubular element, and wherein said cutting tool comprises a second tubular element adapted to be inserted along and substantially coaxially with said first element.

30. The apparatus of claim 29, wherein said first tubular element comprises an inner guide needle.

31. The apparatus of claim 30, wherein said second tubular element comprises a coring tube able to cut through said skin-related tissue structure when advanced along a cutting axis.

32. The apparatus of claim 31, wherein said coring tube comprises a rotatable coring tube.

33. The apparatus of claim 32, wherein at least one of an inner surface and an outer surface of said coring tube is at least partially coated with a low friction material.

34. The apparatus of claim 28, wherein said support structure comprises a clamping mechanism to support said skin-related tissue structure.

35. The apparatus of claim 28, wherein said support configuration comprises a vacuum chamber having an inner support surface able to maintain said skin-related tissue structure at a desired shape and position to enable said cutting tool to separate said dermal micro organ from said skin-related tissue structure.

36. The apparatus of claim 35 comprising a guiding channel connected to said vacuum chamber and configured to maintain said cutting tool, when inserted into said guiding channel, at a predetermined distance from said support surface.

37. The apparatus of claim 35 comprising one or more vacuum channels to fluidically connect at least part of said surface with at least one vacuum source.

38. The apparatus of claim 35 comprising a clamping configuration for clamping said skin-related tissue structure when said skin-related tissue structure is supported by said support surface.

39. The apparatus of claim 35, wherein said vacuum chamber comprises an elevated protrusion able to maintain a plateau of skin generally above the trajectory of the cutting tool, such that the harvested dermal micro organ is separated from the body with only one lance cut.

40. The apparatus of claim 28 comprising a rotation mechanism able to rotate said cutting tool.

41. The apparatus of claim 28, wherein said dermal micro organ comprises 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 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.

42. A method of harvesting a dermal micro organ from a subject, comprising:

supporting a skin-related tissue structure from which said dermal micro organ is harvested; and

separating said dermal micro organ from said skin-related tissue structure.

43. A method according to claim 42, wherein said supporting comprises inserting an inner guide into said skin-related tissue structure, and wherein said separating comprises inserting a cutting tool along and coaxially with said inner guide.

44. A method according to claim 43 wherein said supporting comprises clamping said skin-related tissue structure.

45. The method of claim 43, wherein said separating further comprises rotating said cutting tool.

46. The method of claim 42, wherein supporting comprises applying to said skin-related tissue structure a vacuum condition.

47. The method of claim 42, wherein said dermal micro organ comprises at least part of the cross-section of the dermis.

48. The method of claim 42 comprising forming at least one lance cut.

49. The method of claims 42, wherein said dermal micro organ comprises 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 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.