Identification
- Summary
Foreskin keratinocyte (neonatal) is a treatment of skin cells used to accelerate wound closure and healing.
- Brand Names
- Gintuit
- Generic Name
- Foreskin keratinocyte (neonatal)
- DrugBank Accession Number
- DB10772
- Background
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.
- Type
- Biotech
- Groups
- Approved
- Biologic Classification
- Cell transplant therapies
Other cell transplant therapies - Synonyms
- foreskin keratinocyte, neonatal
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.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Wound of the oral cavity Combination Product in combination with: Bovine type I collagen (DB10771) •••••••••••• ••••• - Contraindications & Blackbox Warnings
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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.
Target Actions Organism AFibroblast growth factor 1 agonistHumans AEpidermal growth factor receptor agonistHumans AGranulocyte-macrophage colony-stimulating factor receptor subunit alpha agonistHumans AInterleukin-1 beta agonistHumans AInterleukin-6 agonistHumans AInterferon gamma agonistHumans APlatelet-derived growth factor receptor alpha agonistHumans ATGF-beta receptor type-2 agonistHumans ATransforming growth factor beta-1 agonistHumans ATumor necrosis factor agonistHumans AVascular endothelial growth factor A agonistHumans UFibroblast growth factor receptor 2 agonistHumans - 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
- Adverse Effects
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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.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- No interactions found.
Products
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Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Gintuit Foreskin keratinocyte (neonatal) + Bovine type I collagen + Foreskin fibroblast (neonatal) Cellular Sheet Topical Organogenesis 2012-03-15 Not applicable US 
Categories
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Humans
Chemical Identifiers
- UNII
- ZJO8CP3Q2A
- CAS number
- Not Available
References
- General References
- Pre-Clinical Demo Orcel [Link]
- Apligraf document, FDA [Link]
- Advances in Skin Substitutes—Potential of Tissue Engineered Skin for Facilitating Anti-Fibrotic Healing [Link]
- Skin Substitutes: A Brief Review of Types and Clinical Applications [Link]
- Foreskin‐isolated keratinocytes provide successful extemporaneous autologous paediatric skin grafts [Link]
- Allogeneic cultured keratinocytes/fibroblasts in bovine collagen (Rx) [Link]
- The importance of both fibroblasts and keratinocytes in a bilayered living cellular construct used in wound healing [Link]
- Advancement of wound care from grafts to bioengineered smart skin substitutes [Link]
- Gintuit [Link]
- Orcel [Link]
- Advances in keratinocyte delivery in burn wound care [Link]
- Apligraf [Link]
- Molecular biology of keratinocyte differentiation. [Link]
- External Links
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 1, 2 Terminated Treatment Edentulous Alveolar Ridge 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Cellular sheet Topical - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Pre-Clinical Demo Orcel [Link]
Drug created at December 01, 2015 20:04 / Updated at May 21, 2021 10:21