WO2010139424A1 - Verwendung von stammzellen aus haarwurzelscheiden und keratinozytenvorläuferzellen zur regeneration gealterter haut - Google Patents
Verwendung von stammzellen aus haarwurzelscheiden und keratinozytenvorläuferzellen zur regeneration gealterter haut Download PDFInfo
- Publication number
- WO2010139424A1 WO2010139424A1 PCT/EP2010/003248 EP2010003248W WO2010139424A1 WO 2010139424 A1 WO2010139424 A1 WO 2010139424A1 EP 2010003248 W EP2010003248 W EP 2010003248W WO 2010139424 A1 WO2010139424 A1 WO 2010139424A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cells
- skin
- hair root
- stem cells
- keratinocyte
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/36—Skin; Hair; Nails; Sebaceous glands; Cerumen; Epidermis; Epithelial cells; Keratinocytes; Langerhans cells; Ectodermal cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
Definitions
- stem cells from hair root sheaths and keratinocyte progenitor cells for the regeneration of aged skin
- the present invention relates to the use of stem cells from hair root sheaths and / or keratinocyte progenitor cells for the regeneration of aged but otherwise healthy and uninjured skin for cosmetic purposes and for the prevention of skin diseases.
- the invention is directed to a cosmetic method for the regeneration of aged skin.
- An aged skin manifests itself in a dilution (atrophy) of both the epidermis (epidermis) and the dermis (Dennis), increased wrinkling and loss of elasticity (Dennis elastosis), skin dryness and turgor loss, and possibly also in pigment irregularities (eg lentigines solar) of the skin ,
- the lifelong renewal (homeostasis) of the skin is based on the one hand on a continuous replacement of the epidermis by dividing the stem cells of the keratinocytes in their lower layer (stratum basale) with subsequent differentiation to horny lamellae while ascending into the outermost layer, the horny layer (stratum corneum).
- the keratinocyte precursor or stem cells that are critically important for homeostasis of the epidermis are localized in the Outer Root Sheath (ORS) sheaths, i. in the depth of the dermis and thus protected from damaging UV radiation (the particularly harmful UVB penetrates only just through the epidermis). From plucked hair in the growth phase, these ORS cells can be isolated and also multiply in the laboratory.
- ORS Outer Root Sheath
- Repigmentation of skin is known as the application of ORS stem cells or derived melanocyte precursor cells from autologous hair root sheaths (Vanscheidt & Hunziker, Dermatology, 904, 2009, WO 2009/049734).
- Epidermal neural crest stem cells are multipotent stem cells derived from the embryonic neural crest and located in hair root sheaths. These stem cells are constantly renewing themselves and are able to differentiate into all the important cell derivatives of the neural crest, including neurons, nerve-supporting cells, smooth muscle cells, bone / cartilage cells and melanocytes. These stem cells can even form cell types that mesoderm-typical. In a mouse model of spinal cord injury, it has been demonstrated that these stem cells can fuse with adult skeletal muscle fibers, that the introduced nuclei are functional, and that adult skeletal muscle is an environment suitable for the long-term survival of stem cell nuclei. (Sieber-Blum & Hu, Stern Cell Rev., 4 (4), 256-60, 2008). The authors conclude from their studies on skeletal muscle in mice that such pluripotent stem cells could be attractive features for future cell replacement therapies and / or biomedical developments.
- This object is achieved by the use of stem cells from hair root sheaths and / or keratinocyte progenitor cells for the regeneration of aged but otherwise healthy and uninjured skin.
- healthy and uninjured skin describes skin without defects, especially without wounds and inflammatory, infectious or degenerative skin diseases, benign or malignant skin tumors or their precursors (eg actinic keratoses, lentigo maligna), post-operative skin changes such as after skin grafts, Etc.
- aged skin in the sense of the invention refers to intrinsically and / or extrinsically aged skin having preferably at least one of the following signs of aging: dilution (atrophy), fine wrinkling, loss of elasticity (elastase), increased vulnerability with a tendency to hemorrhages after slight traumatization as well as pigment irregularities, but also with deep wrinkles or wrinkles, dry, possibly scaly / keratotic skin surface, reduced activity of sebaceous glands, reduced skin turgor, less skin fat content, tendency to tears and pseudo colors, enlargement of small blood vessels (teleang ectasia), loss of regenerative capacity and related wound healing disorders.
- dilution atrophy
- fine wrinkling fine wrinkling
- loss of elasticity elastase
- increased vulnerability with a tendency to hemorrhages after slight traumatization as well as pigment irregularities, but also with deep wrinkles or wrinkles, dry, possibly scaly / keratotic skin surface,
- NF-kappa B transcription factors or tumor suppressor genes
- c-Myc tumor suppressor genes
- p53 transcription factors or tumor suppressor genes
- NF-kappa B in older mice has been shown to block within two weeks for a limited period a biologically younger skin condition triggered.
- the inventive regeneration of aged but otherwise healthy and uninjured skin has cosmetic benefits in addition to medical benefits.
- the keratinocyte progenitor cells which are introduced into the skin, not only thicken the epidermis as differentiated keratinocytes, they also regularly divide and thus displace long-term, slower-dividing "old” cells as well as degenerated cells, as well as affecting the cells in their immediate vicinity (fibroblasts, vascular endothelia, Melanocytes) positively by the excretion of cytokines and growth factors, which overall improves the health and aging of the skin in the long term, whereby the wrinkling decreases (new formation of collagen fibers), the elasticity increases (new formation of elastic fibers) and possibly existing Pigmentunregel bugssstechniken (Regulation By influencing the microcirculation of the skin, the nutritive situation is improved, which also increases, for example, the trophism and the activity of the sebaceous glands, thus normalizing the refatting of the skin According to the invention, the notion of regeneration
- the present invention relates to the purely cosmetic use of stem cells from hair root sheaths and / or keratinocyte progenitor cells for the regeneration of aged but otherwise healthy and uninjured skin of humans and mammals.
- the present invention is directed to the use of stem cells from hair root sheaths and / or keratinocyte progenitor cells for the prevention of skin diseases in humans and mammals, preferably skin diseases selected from the group consisting of skin diseases based on genetic or acquired disorders of skin cohesion , skin homeostasis, skin differentiation and / or skin barrier function, preferably epidermolysis bullosa, xeroderma pigmentosum, progeria, ichthyosis, post surgical status and after X-irradiation and exogenously induced atrophy or hyperplasia, especially hyperplastic scars and keloids, preferably atrophy induced by topical or systemic corticosteroids, etc.
- skin diseases selected from the group consisting of skin diseases based on genetic or acquired disorders of skin cohesion , skin homeostasis, skin differentiation and / or skin barrier function, preferably epidermolysis bullosa, xeroderma pigmentosum, progeria, ichthyosis, post
- autologous and allogeneic and xenogeneic cells can be used, with autologous cells being preferred for avoiding immune reactions.
- the invention is directed to a cosmetic process for the regeneration of aged but otherwise healthy and uninjured skin, comprising the step of applying stem cells from hair root sheaths and / or keratinocyte precursor cells to aged but otherwise healthy and uninjured skin.
- stem cells from hair root sheaths or preferably derived keratinocyte precursor cells of the patient himself so-called autologous keratinocyte precursor cells.
- the hair root root keratinocyte progenitor cells contain pluripotent stem cells, which regenerate the epithelial skin structures lifelong. As a result, they also have a high proliferation potential in older donors.
- These stem cells or progenitor cells can be not only non-invasive, but also win repetitive and without skin biopsy in each donated haired donor. Consequently, the use of such cells results in a less invasive way of sustainably regenerating aged skin, in particular the epidermis.
- stem cells from hair root sheath cells and / or keratinocyte progenitor cells and their recovery, isolation, propagation and storage are well known to those skilled in dermatology.
- the stem cells and / or keratinocyte progenitor cells for the practice of the invention are obtained from hair root sheaths, especially the outer epithelial hair root sheath of hair in the growth phase (anagen).
- the hairs used for cell production can be obtained by plucking out terminal hairs, in particular anagen hairs of the capillaries.
- the hair can advantageously come from the person to be treated or the mammal.
- the term recovery preferably also includes the at least partial isolation and / or enrichment as well as the multiplication or selection of cells in the culture.
- the cells are enzymatically thereto, for example by means of a trypsin solution in a concentration of 0.01 to 10, preferably 0.025 to 0.1 and more preferably about 0.05% trypsin, optionally with EDTA and preferably in PBS preferably 5 to 60, more preferably 10 to 15 minutes at preferably about 20 0 C or more preferably 37 ° C, dissolved from the hair root sheath of a hair removed.
- a trypsin solution in a concentration of 0.01 to 10, preferably 0.025 to 0.1 and more preferably about 0.05% trypsin, optionally with EDTA and preferably in PBS preferably 5 to 60, more preferably 10 to 15 minutes at preferably about 20 0 C or more preferably 37 ° C, dissolved from the hair root sheath of a hair removed.
- PBS preferably 5 to 60, more preferably 10 to 15 minutes at preferably about 20 0 C or more preferably 37 ° C, dissolved from the hair root sheath of a hair removed
- a preferred application is to suspend the cell-containing sediment in a thrombin-containing solution which allows for immediate fixation of the applied cells in a thin layer when applied to fibrinogen pretreated skin, thus allowing a homogeneous, non-occlusive application to skin in each body region , Autologous stem cells from hair root sheaths and / or keratinocyte precursor cells are preferably used in the method according to the invention.
- the cells may be used as a suspension or sediment, or optionally as a cell extract.
- they can be introduced into a biocompatible solution or a biocompatible carrier.
- the application step is preferably carried out by means of a suspension with 10 2 to 10 9 , more preferably 10 3 to 10 5 cells / cm 2 of skin area to be treated, for example by syringe or as a spray or in a biocompatible carrier or nonwoven.
- a biocompatible solution eg PBS 1 cell culture medium, thrombin
- a biocompatible biological eg fibrin, hyaluronan, collagen
- synthetic eg polyurethane, carboxymethylcellulose, polylysine, nanoparticle
- the cells can be used as vital proliferation-capable or growth-arrested cells (eg by means of mitomycin C treatment or X-ray irradiation) or else as cell extracts (such as lyophilisates, sonicates, stimulates). It is also possible to obtain from these cells under different incubation conditions in vitro (eg variable pO 2 and / or pCO 2 concentrations, variable culture media, variable matrix substrates, variable feeder cells in direct cell contact or separated into two-chamber culture systems, submerse or organotypic culture).
- incubation conditions eg variable pO 2 and / or pCO 2 concentrations, variable culture media, variable matrix substrates, variable feeder cells in direct cell contact or separated into two-chamber culture systems, submerse or organotypic culture).
- the term application within the meaning of the invention comprises the simple application of the cells to the skin.
- the cells are thereby fixed on the skin, for example by means of fibrin glue, and protected with a customary occlusion dressing.
- it is also any other suitable form of application for example by integration of the cells in biological or synthetic matrices and subsequent application of these possible.
- the cells can also be introduced directly into the skin.
- the skin to be treated prior to application of the cells physically and / or mechanically deepiderminstrument, preferably by means of dermabrasion, superficial laser application (eg fraxel re: pair ® CO 2 laser, Soltamedical, USA), or superficial needle puncture (eg dermaroller ® , Skintes, CH), whereby flat or preferably punctate, ie grid-like fractional defects are created in the epidermis, which allow the penetration of the applied cells into the skin in the sense of a transepidermal application.
- dermal stimulation or dermal regeneration is also stimulated.
- the epidermis is physically and / or mechanically removed before application of the cells, preferably by means of superficial dermabrasion, laser application and / or superficial needle puncture.
- Cells in the form of partial / fractional deepidermization with different penetration depth are laser abraded in Fraxel modality and / or Dermaroller.
- the stem cells from hair root sheaths and / or keratinocyte progenitor cells are preferably present during application or introduction as enriched or isolated cells as an extract, suspension, solution or incorporated into a biocompatible biological or synthetic carrier.
- the stem cells from hair root sheaths and / or keratinocyte progenitor cells can be propagated by culture in vitro prior to application to or introduction into the skin and / or by means of more specific Culture conditions (eg, variable p ⁇ 2 and / or pC0 2 concentrations, variable culture media, variable matrix substrates, variable feeder cells in direct cell contact or separated in bicameral culture systems, submerged or organotypic culture, etc.) according to favorable criteria such as stem cell content and / or Keratinocyte precursor cells, stem cell potential (mono- versus multi / pluripotent), proliferation capacity, differentiation potential, survivability, etc. are selected.
- Variation conditions eg, variable p ⁇ 2 and / or pC0 2 concentrations, variable culture media, variable matrix substrates, variable feeder cells in direct cell contact or separated in bicameral culture systems, submerged or organotypic culture, etc.
- Selection within the meaning of the invention means the intentional selection of particular stem cells and / or keratinocyte progenitor cells or accompanying cells (no parent or keratinocyte progenitor cells with functions such as interactive stimulation of proliferation or differentiation of stem or keratinocyte progenitor cells in the sense of feeder cells) with advantageous properties.
- the skin treated with cells is preferably occlusively covered after application, in particular when the skin has been mechanically pretreated and is partly "open", in order to protect the skin, but also the applied cells from dehydration, infections and mechanical stress and thus to create an optimal moist environment for the growth of the cells.
- At least one active substance suppressing an (auto) immune reaction preferably a topical or systemic corticosteroid and / or topical calcineurin inhibitor, is administered.
- the method according to the invention relates to the additional application of melanocyte progenitor cells to the skin, before, after or preferably simultaneously with the stem cells and / or keratinocyte progenitor cells. It is most preferable not to separate the melanocyte precursor cells in the recovery of the stem cells and / or keratinocyte progenitor cells at all.
- the cells used according to the invention may preferably also comprise other cells contained in hair root sheaths, in particular other precursor cells.
- the present invention is directed to the above-mentioned method for the prevention of skin diseases in mammals and humans with aged but otherwise healthy and uninjured skin, in particular for the prevention of skin diseases selected from the group consisting of skin diseases based on genetic or acquired disorders of skin cohesion, skin homeostasis, skin differentiation and / or skin barrier function, preferably epidermolysis bullosa, xeroderma pigmentosum, progeria, ichthyosis, status after surgery and x-irradiation and exogenously induced atrophy or hyperplasia, especially hyperplastic scars and keloids, preferably atrophy induced by topical or systemic Corticosteroids, etc.
- Preferred embodiments of this method can be found analogously to the cosmetic method described above.
- the isolated cells were taken up in PBS with Ca / Mg and 5% glucose and then incubated with the CO 2 laser in Fraxel modality (raster-type ablation of ⁇ 20 % of the treated epidermis surface down to the uppermost dermis, penetration depth ⁇ 100 ⁇ m) on the forehead and cheeks (0.1 ml per 5 cm 2 , corresponding to ⁇ 5 x 10 3 cells / cm 2 ).
- Fraxel modality raster-type ablation of ⁇ 20 % of the treated epidermis surface down to the uppermost dermis, penetration depth ⁇ 100 ⁇ m
- the treatment area was then occlusively covered with a modern wound dressing for a total of one week.
- the first dressing change took place after 3 days.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Dermatology (AREA)
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
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Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP10722318A EP2437757A1 (de) | 2009-06-05 | 2010-05-28 | Verwendung von stammzellen aus haarwurzelscheiden und keratinozytenvorläuferzellen zur regeneration gealterter haut |
RU2011153211/10A RU2498809C2 (ru) | 2009-06-05 | 2010-05-28 | Применение стволовых клеток из корневых сумок волос и клеток предшественников (продромальных) кератиноцитов для восстановления постаревшей кожи |
BRPI1011999A BRPI1011999A2 (pt) | 2009-06-05 | 2010-05-28 | "uso de células-tronco de bainhas radiculares do cabelo e células precursoras de queratinócitos para a regeneração de pele envelhecida" |
JP2012513496A JP2012528809A (ja) | 2009-06-05 | 2010-05-28 | 老化した皮膚の再生のための毛根鞘由来幹細胞およびケラチノサイト前駆細胞の使用 |
AU2010256048A AU2010256048B2 (en) | 2009-06-05 | 2010-05-28 | Use of stem cells from hair root sheaths and keratinocyte precursor cells for regenerating aged skin |
MX2011012611A MX2011012611A (es) | 2009-06-05 | 2010-05-28 | Uso de celulas madre de la vaina radicular pilosa y celulas precursoras de queratinocitos para la regeneracion de la piel envejecida. |
CA2763927A CA2763927A1 (en) | 2009-06-05 | 2010-05-28 | Use of stem cells from hair root sheaths and keratinocyte precursor cells for the regeneration of aged skin |
US13/321,385 US20120064049A1 (en) | 2009-06-05 | 2010-05-28 | Use of stem cells from hair root sheaths and keratinocyte precursor cells for the regeneration of aged skin |
CN2010800248134A CN102458424A (zh) | 2009-06-05 | 2010-05-28 | 来自毛根鞘的干细胞和角质形成细胞前体细胞用于老化皮肤再生的用途 |
SG2011083912A SG176066A1 (en) | 2009-06-05 | 2010-05-28 | Use of stem cells from hair root sheaths and keratinocyte precursor cells for regenerating aged skin |
ZA2011/08485A ZA201108485B (en) | 2009-06-05 | 2011-11-18 | Use of stem cells from hair root sheaths and keratinocyte precursor cells for regenerating aged skin |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09007450 | 2009-06-05 | ||
EP09007450.1 | 2009-06-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010139424A1 true WO2010139424A1 (de) | 2010-12-09 |
Family
ID=42813067
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2010/003248 WO2010139424A1 (de) | 2009-06-05 | 2010-05-28 | Verwendung von stammzellen aus haarwurzelscheiden und keratinozytenvorläuferzellen zur regeneration gealterter haut |
Country Status (12)
Country | Link |
---|---|
US (1) | US20120064049A1 (de) |
EP (1) | EP2437757A1 (de) |
JP (1) | JP2012528809A (de) |
CN (1) | CN102458424A (de) |
AU (1) | AU2010256048B2 (de) |
BR (1) | BRPI1011999A2 (de) |
CA (1) | CA2763927A1 (de) |
MX (1) | MX2011012611A (de) |
RU (1) | RU2498809C2 (de) |
SG (1) | SG176066A1 (de) |
WO (1) | WO2010139424A1 (de) |
ZA (1) | ZA201108485B (de) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102011001623A1 (de) * | 2011-03-29 | 2012-10-04 | Euroderm Gmbh | Verfahren zum Herstellen eines Präparats unter Verwendung von Zellen der Haarwurzelscheide, Präparat und Kit |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3010515A1 (de) * | 2013-06-18 | 2016-04-27 | Replicel Life Sciences Inc. | Zusammensetzungen und verfahren zur hautbehandlung |
JP6410343B2 (ja) * | 2014-07-01 | 2018-10-24 | 学校法人順天堂 | 脂肪組織由来幹細胞から表皮角化細胞への誘導 |
Citations (2)
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WO2003024406A2 (en) * | 2001-09-20 | 2003-03-27 | Anticancer, Inc. | Nestin-expressing hair follicle stem cells |
WO2008082525A1 (en) * | 2006-12-19 | 2008-07-10 | National Stem Cell Inc | Umbilical cord stem cell secreted product derived topical compositions and methods of use thereof |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
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US6548058B1 (en) * | 1999-07-20 | 2003-04-15 | Epitech, S.A. | Keratinocyte culture and uses thereof |
DE19917532A1 (de) * | 1999-04-19 | 2000-10-26 | Christian Toloczyki | Trägergebundene kultivierte Stamm-bzw. Vorläuferzellen von Keratinozyten |
PT1198557E (pt) * | 1999-07-20 | 2006-09-29 | Dfb Pharmaceuticals Inc | Cultura melhorada de queeratinocito e suas utilizacoes |
RU2184492C2 (ru) * | 2000-06-13 | 2002-07-10 | Озерская Ольга Сергеевна | Способ дерматохирургического лечения гипотрофических рубцов |
US20030091543A1 (en) * | 2001-10-26 | 2003-05-15 | Klein Matthew B. | Therapeutic cell preparation grafts and methods of use thereof |
KR20040083510A (ko) * | 2002-02-15 | 2004-10-02 | 지엠에스, 엘엘씨 | 생체 의학 적용을 위한 중합 방법 및 재료 |
FR2893502A1 (fr) * | 2005-11-21 | 2007-05-25 | Oreal | Procede cosmetique de soin de la peau utilisant des contraintes mecaniques |
-
2010
- 2010-05-28 JP JP2012513496A patent/JP2012528809A/ja active Pending
- 2010-05-28 CN CN2010800248134A patent/CN102458424A/zh active Pending
- 2010-05-28 RU RU2011153211/10A patent/RU2498809C2/ru not_active IP Right Cessation
- 2010-05-28 US US13/321,385 patent/US20120064049A1/en not_active Abandoned
- 2010-05-28 CA CA2763927A patent/CA2763927A1/en not_active Abandoned
- 2010-05-28 BR BRPI1011999A patent/BRPI1011999A2/pt not_active IP Right Cessation
- 2010-05-28 AU AU2010256048A patent/AU2010256048B2/en not_active Ceased
- 2010-05-28 MX MX2011012611A patent/MX2011012611A/es not_active Application Discontinuation
- 2010-05-28 WO PCT/EP2010/003248 patent/WO2010139424A1/de active Application Filing
- 2010-05-28 SG SG2011083912A patent/SG176066A1/en unknown
- 2010-05-28 EP EP10722318A patent/EP2437757A1/de not_active Withdrawn
-
2011
- 2011-11-18 ZA ZA2011/08485A patent/ZA201108485B/en unknown
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WO2003024406A2 (en) * | 2001-09-20 | 2003-03-27 | Anticancer, Inc. | Nestin-expressing hair follicle stem cells |
WO2008082525A1 (en) * | 2006-12-19 | 2008-07-10 | National Stem Cell Inc | Umbilical cord stem cell secreted product derived topical compositions and methods of use thereof |
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KAMOLZ L P ET AL: "Cultured human epithelium: Human umbilical cord blood stem cells differentiate into keratinocytes under in vitro conditions", BURNS, BUTTERWORTH HEINEMANN, GB LNKD- DOI:10.1016/J.BURNS.2005.08.020, vol. 32, no. 1, 1 February 2006 (2006-02-01), pages 16 - 19, XP024985561, ISSN: 0305-4179, [retrieved on 20060201] * |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102011001623A1 (de) * | 2011-03-29 | 2012-10-04 | Euroderm Gmbh | Verfahren zum Herstellen eines Präparats unter Verwendung von Zellen der Haarwurzelscheide, Präparat und Kit |
Also Published As
Publication number | Publication date |
---|---|
CA2763927A1 (en) | 2010-12-09 |
BRPI1011999A2 (pt) | 2017-06-27 |
US20120064049A1 (en) | 2012-03-15 |
ZA201108485B (en) | 2013-01-30 |
JP2012528809A (ja) | 2012-11-15 |
AU2010256048A1 (en) | 2012-01-12 |
SG176066A1 (en) | 2011-12-29 |
AU2010256048B2 (en) | 2013-08-15 |
RU2498809C2 (ru) | 2013-11-20 |
CN102458424A (zh) | 2012-05-16 |
MX2011012611A (es) | 2011-12-14 |
RU2011153211A (ru) | 2013-07-20 |
EP2437757A1 (de) | 2012-04-11 |
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