Foreskin keratinocyte (neonatal)

Identification

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Name
Foreskin keratinocyte (neonatal)
Accession Number
DB10772
Type
Biotech
Groups
Approved
Biologic Classification
Cell transplant therapies
Other cell transplant therapies
Description

Skin, the largest organ of the human body, plays the main role in protecting the body from mechanical damage. It is composed of epidermal, dermal and hypodermal layers. The barrier function of the skin owed to its avascular epidermal layer, which is made mainly of keratinocytes. The keratinocytes form a stratified epithelium, with growing basal cells at the innermost layer and the keratinized, and mostly impermeable outer stratum corneum layer on the surface 3.

Foreskin keratinocytes are a form of skin cells that are cultured as a skin cell replacement for wounds, to accelerate wound closure and healing 1, 11.

The defining moment in skin culture was in 1975 when Rheinwald and Green successfully grew human keratinocytes on lethally irradiated murine fibroblasts. In 1981, O’Conner and his group utilized cultured autologous epithelium to coat burn defects for the first time. To construct a "living" alternative, a dermal substitute based on collagen I gel was created with mesenchymal cells such as fibroblasts. When an epidermal layer was added, this approach became known as "skin equivalent", "composite culture" or "organotypical culture" 4.

Foreskin keratinocytes are an important ingredient in several skin substitutes 11, used for various indications. Keratinocytes are derived from neonatal foreskins and used to create a drug called Apligraf, a mixture of Foreskin fibroblast (neonatal) and keratinocytes. A gel made of bovine collagen is used as the matrix for cell growth and differentiation. Apligraf has been useful in the treatment of venous leg ulcers and diabetic foot ulcers, by increasing rates of wound healing and decreasing the time required for closure of wounds 3.

Orcel, another skin substitute, is similar to Apligraf since it contains both fibroblasts and keratinocytes derived from neonatal foreskin, but in addition, utilizes a type I collagen sponge as its matrix. It is used for grafting onto partial-thickness wounds, where it offers a favorable matrix for host cell migration 3.

Synonyms
  • foreskin keratinocyte, neonatal
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
GintuitForeskin keratinocyte (neonatal) + Bovine type I collagen + Foreskin fibroblast (neonatal)Cellular SheetTopicalOrganogenesis2012-03-15Not applicableUs
Categories
UNII
ZJO8CP3Q2A
CAS number
Not Available

Pharmacology

Indication

For chronic leg ulcers and diabetic foot 8.

Orcel is indicated for use with standard therapeutic compression for the treatment of non-infected partial and full-thickness skin ulcers due to venous insufficiency of greater than 1 month in duration and which have not effectively responded to conventional ulcer therapy. Orcel is also for use with standard diabetic foot ulcer care for the treatment of full-thickness neuropathic diabetic foot ulcers of greater than 3 weeks in duration which have not effectively responded to conventional ulcer therapy, and which extend through the dermis but without tendon, muscle, capsule or bone involvement 10.

Associated Conditions
Pharmacodynamics

Foreskin keratinocyte grafts lead to the re‐epithelialization of partial deep severe burns, thus allowing complete wound closure, and improves the condition of scars 5.

Mechanism of action

Foreskin keratinocytes promote the proliferation of epithelial (skin) cells. Epidermal keratinocytes (skin cells) are very specialized epithelial cells designed for a very specific function, which is the separation of the organism from its outside environment. To provide this protection, the cells synthesize precursors and assemble them into two distinct structures, the cornified envelope and keratin intermediate filaments. The intermediate filaments are formed by keratin monomers and the cornified envelope is assembled from a protein called involucrin and several other proteins 13.

The following is a description of the mechanism of action of foreskin keratinocytes in various devices, while combined with other types of cells:

Orcel (epidermal keratinocytes and dermal fibroblasts) are cultured in two separate layers into a Type I bovine collagen sponge. Donor dermal fibroblasts are cultured on and within the porous sponge side of the collagen matrix while keratinocytes, from the same donor, are also cultured on the covered, non-porous side of the collagen matrix. Orcel acts as an absorbable matrix, providing a fertile environment for host cell migration and has been shown to contain the following cell-expressed cytokines with growth factors: FGF-1 (bFGF), NGF, GM-CSF, IL-1α, IL-1β, IL-6, HGF, KGF-1 (FGF- 7), M-CSF, PDGF-AB, TGF-α, TGF-β1, TGF-β2, and VEGF. DNA analysis performed on two Orcel treated donor site patient tissue samples demonstrated no trace of allogeneic cell DNA after 2-3 weeks post-treatment. Orcel is manufactured under aseptic conditions from human neonatal foreskin tissue 1.

Apligraf is supplied as a living, bi-layered skin substitute: the epidermal layer is formed by human keratinocytes and has a well-differentiated stratum corneum; the dermal layer is composed of human fibroblasts in a bovine Type I collagen lattice. While matrix proteins and cytokines found in human skin are present in Apligraf, Apligraf does not contain Langerhans cells, melanocytes, macrophages, lymphocytes, blood vessels or hair follicles. In a 10 patient venous leg ulcer study to determine the longevity of Apligraf cells, 2 of 8 patients evaluated at 4 weeks demonstrated Apligraf DNA. Neither of these patients showed Apligraf DNA at 8 weeks 12.

For dental applications, Gintuit (Allogeneic Cultured Keratinocytes and Fibroblasts in Bovine Collagen) is an allogeneic cellularized scaffold product indicated for topical application to a surgically created vascular wound bed in the treatment of mucogingival conditions in adults 9.

TargetActionsOrganism
AFibroblast growth factor 1
agonist
Humans
AEpidermal growth factor receptor
agonist
Humans
AGranulocyte-macrophage colony-stimulating factor receptor subunit alpha
agonist
Humans
AInterleukin-1 beta
agonist
Humans
AInterleukin-6
agonist
Humans
AInterferon gamma
agonist
Humans
UFibroblast growth factor receptor 2
agonist
Humans
APlatelet-derived growth factor receptor alpha
agonist
Humans
ATGF-beta receptor type-2
agonist
Humans
ATransforming growth factor beta-1
agonist
Humans
ATumor necrosis factor
agonist
Humans
AVascular endothelial growth factor A
agonist
Humans
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

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Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

Adverse events in a preclinical study of about 300 subjects were classified as mild, moderate, severe or life-threatening. In the venous leg ulcer study, 1 life-threatening infection and 3 severe infections reported in the Apligraf group occurred, and none in the control group. Of the 4 events, 2 severe infections were related to treatment: however one occurred one month after the last application of Apligraf and the other occurred following application on a pre-existing Pseudomonas infection 12.

Affected organisms
  • Humans
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Pre-Clinical Demo Orcel [Link]
  2. Apligraf document, FDA [Link]
  3. Advances in Skin Substitutes—Potential of Tissue Engineered Skin for Facilitating Anti-Fibrotic Healing [Link]
  4. Skin Substitutes: A Brief Review of Types and Clinical Applications [Link]
  5. Foreskin‐isolated keratinocytes provide successful extemporaneous autologous paediatric skin grafts [Link]
  6. Allogeneic cultured keratinocytes/fibroblasts in bovine collagen (Rx) [Link]
  7. The importance of both fibroblasts and keratinocytes in a bilayered living cellular construct used in wound healing [Link]
  8. Advancement of wound care from grafts to bioengineered smart skin substitutes [Link]
  9. Gintuit [Link]
  10. Orcel [Link]
  11. Advances in keratinocyte delivery in burn wound care [Link]
  12. Apligraf [Link]
  13. Molecular biology of keratinocyte differentiation. [Link]
External Links
Not Available

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Cellular sheetTopical
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
S100 protein binding
Specific Function
Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as potent mitogen in vitro.
Gene Name
FGF1
Uniprot ID
P05230
Uniprot Name
Fibroblast growth factor 1
Molecular Weight
17459.58 Da
References
  1. Pre-Clinical Demo Orcel [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Ubiquitin protein ligase binding
Specific Function
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TG...
Gene Name
EGFR
Uniprot ID
P00533
Uniprot Name
Epidermal growth factor receptor
Molecular Weight
134276.185 Da
References
  1. Pre-Clinical Demo Orcel [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Receptor activity
Specific Function
Low affinity receptor for granulocyte-macrophage colony-stimulating factor. Transduces a signal that results in the proliferation, differentiation, and functional activation of hematopoietic cells.
Gene Name
CSF2RA
Uniprot ID
P15509
Uniprot Name
Granulocyte-macrophage colony-stimulating factor receptor subunit alpha
Molecular Weight
46206.185 Da
References
  1. Pre-Clinical Demo Orcel [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Protein domain specific binding
Specific Function
Potent proinflammatory cytokine. Initially discovered as the major endogenous pyrogen, induces prostaglandin synthesis, neutrophil influx and activation, T-cell activation and cytokine production, ...
Gene Name
IL1B
Uniprot ID
P01584
Uniprot Name
Interleukin-1 beta
Molecular Weight
30747.7 Da
References
  1. Pre-Clinical Demo Orcel [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Interleukin-6 receptor binding
Specific Function
Cytokine with a wide variety of biological functions. It is a potent inducer of the acute phase response. Plays an essential role in the final differentiation of B-cells into Ig-secreting cells Inv...
Gene Name
IL6
Uniprot ID
P05231
Uniprot Name
Interleukin-6
Molecular Weight
23717.965 Da
References
  1. Pre-Clinical Demo Orcel [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Interferon-gamma receptor binding
Specific Function
Produced by lymphocytes activated by specific antigens or mitogens. IFN-gamma, in addition to having antiviral activity, has important immunoregulatory functions. It is a potent activator of macrop...
Gene Name
IFNG
Uniprot ID
P01579
Uniprot Name
Interferon gamma
Molecular Weight
19348.165 Da
References
  1. Pre-Clinical Demo Orcel [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosi...
Gene Name
FGFR2
Uniprot ID
P21802
Uniprot Name
Fibroblast growth factor receptor 2
Molecular Weight
92024.29 Da
References
  1. Pre-Clinical Demo Orcel [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chem...
Gene Name
PDGFRA
Uniprot ID
P16234
Uniprot Name
Platelet-derived growth factor receptor alpha
Molecular Weight
122668.46 Da
References
  1. Pre-Clinical Demo Orcel [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Type iii transforming growth factor beta receptor binding
Specific Function
Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Tran...
Gene Name
TGFBR2
Uniprot ID
P37173
Uniprot Name
TGF-beta receptor type-2
Molecular Weight
64567.1 Da
References
  1. Pre-Clinical Demo Orcel [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Type iii transforming growth factor beta receptor binding
Specific Function
Multifunctional protein that controls proliferation, differentiation and other functions in many cell types. Many cells synthesize TGFB1 and have specific receptors for it. It positively and negati...
Gene Name
TGFB1
Uniprot ID
P01137
Uniprot Name
Transforming growth factor beta-1
Molecular Weight
44340.685 Da
References
  1. Pre-Clinical Demo Orcel [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Tumor necrosis factor receptor binding
Specific Function
Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct ac...
Gene Name
TNF
Uniprot ID
P01375
Uniprot Name
Tumor necrosis factor
Molecular Weight
25644.15 Da
References
  1. Pre-Clinical Demo Orcel [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Vascular endothelial growth factor receptor binding
Specific Function
Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of...
Gene Name
VEGFA
Uniprot ID
P15692
Uniprot Name
Vascular endothelial growth factor A
Molecular Weight
27042.205 Da
References
  1. Pre-Clinical Demo Orcel [Link]

Drug created on December 01, 2015 13:04 / Updated on May 01, 2019 11:01