Foreskin fibroblast (neonatal)

Identification

Summary

Foreskin fibroblast (neonatal) is a treatment of cells used to treat full-thickness, diabetic foot ulcers that extend through the dermis without tendon, muscle, joint capsule, or bone exposure.

Brand Names

Gintuit

Generic Name

Foreskin fibroblast (neonatal)

DrugBank Accession Number

DB10770

Background

Foreskin fibroblast-like stromal cells (FDSCs) are progenitors isolated from human tissue that can differentiate into various cell types ².

Also known as Dermagraft, this device is a cryopreserved human fibroblast-derived dermal substitute. Composed of fibroblasts, extracellular matrix, and a bioabsorbable scaffold, it effectively supports wound healing ³.

Dermagraft has only been available in the United States as an investigational device (IDE). Dermagraft for the treatment of diabetic foot ulcers was approved for sale in Canada in 1997. Dermagraft was introduced in the United Kingdom in October 1997, and several other European countries, as well as New Zealand and Australia. The device is available for commercial distribution in Australia, Canada, Finland, France, Hong Kong, Ireland, The Netherlands, New Zealand, Singapore, and The United Kingdom ³.

The impact of diabetic foot ulcers (DFU) on individuals and society is devastating. Failure to observe proper wound care in this condition often results in amputation. If wound closure is achieved, it is likely to delay the need for surgical intervention and provide other benefits such as improvements in productivity, mental outlook, social interactions, and time at work, in addition to decreased mortality ¹⁴.

Interestingly, it has been shown that human foreskin cells possess immunosuppressive properties, which are mediated by other processes than that reported for bone marrow/stromal stem cells ¹. Dermagraft has been combined with Foreskin keratinocyte (neonatal) to create a drug beneficial to patients with open burn wounds ¹¹.

Type

Biotech

Groups

Approved

Biologic Classification

Cell transplant therapies
Other cell transplant therapies

Synonyms

foreskin fibroblast, neonatal

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Pharmacology

Indication

This device is indicated for use for the treatment of full-thickness, diabetic foot ulcers greater than six weeks duration which extends through the dermis, but without tendon, muscle, joint capsule or bone exposure. This drug should be used in conjunction with standard wound care regimens and in patients with an adequate blood supply to the involved foot ³.

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Associated Conditions

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: Foreskin keratinocyte (neonatal) (DB10772)	••••••••••••	•••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

This physiologically active dermal substitute is a scaffold upon which tissue can grow, allowing for effective healing of wounds ³.

Dermagraft is made from human fibroblast cells obtained from newborn foreskin tissue. During the manufacturing process, the human fibroblasts are placed onto a bioabsorbable polyglactin mesh scaffold. The fibroblasts grow to fill the interstices of this scaffold and secrete human dermal collagen, matrix proteins, and growth factors, as well as cytokines. This creates a three-dimensional human dermal substitute containing active, living cells. Dermagraft does not contain macrophages, lymphocytes, blood vessels, or hair follicles ³.

Among other cytokines, this device induces the production of interleukin 6 (IL-6). This gene encodes a cytokine that functions in inflammation and the maturation of B type immune cells. In addition the above, the encoded protein has been shown to be an endogenous pyrogen capable of inducing fever in people with autoimmune diseases or infections. The protein is mainly produced at sites of acute and chronic inflammation, where it is secreted into the serum and induces a transcriptional inflammatory response through interleukin 6 receptor, alpha. The function this gene is involved in a wide variety of inflammation-associated disease states, including susceptibility to diabetes mellitus and systemic juvenile rheumatoid arthritis ⁸.

Mechanism of action

Dermagraft is a cryopreserved, human fibroblast-derived dermal substitute that contains fibroblasts, extracellular matrix, and a bioabsorbable polyglactin mesh scaffold ¹¹. The fibroblasts are obtained from human newborn foreskin tissue. The fibroblasts are then placed on a scaffold and progress to proliferate and produce human dermal collagen, matrix proteins, growth factors, and cytokines. The above steps create a three-dimensional human dermal substitute with active human cells. Dermagraft does not contain macrophages, lymphocytes, blood vessels, nor hair follicles. It is available frozen as a single sheet (2 by 3 inches) for a single application ⁶.

Target	Actions	Organism
AVascular endothelial growth factor receptor 1	agonist	Humans
UInterleukin-6	agonist	Humans
UInterleukin-1 receptor type 1	agonist	Humans
UTGF-beta receptor type-2	agonist	Humans
UFibroblast growth factor 1	agonist	Humans
UInterferon gamma	agonist	Humans
UFibroblast growth factor receptor 2	agonist	Humans
UGranulocyte-macrophage colony-stimulating factor receptor subunit alpha	agonist	Humans
UPlatelet-derived growth factor receptor beta	agonist	Humans
UTransforming growth factor beta-1	agonist	Humans
UTumor necrosis factor	agonist	Humans

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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Toxicity

No serious adverse events were attributed to Dermagraft. Of the 314 patients enrolled in a preclinical study, 10.4% (17/163) of the patients developed an infection while 17.9% (27/151) of the control group patients developed an ulcer infection. Overall, 31/163 (19%) of the dermagraft group developed infection, cellulitis, or osteomyelitis. In the control group, 49/151 (32.5%) patients developed the same adverse events. Thus, there was a lower rate of infection, cellulitis, and osteomyelitis in the dermagraft treated group ³.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions: 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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Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Gintuit	Foreskin fibroblast (neonatal) + Bovine type I collagen + Foreskin keratinocyte (neonatal)	Cellular Sheet	Topical	Organogenesis	2012-03-15	Not applicable

Chemical Identifiers

UNII: T34C307W5N
CAS number: Not Available

References

General References

Wada N, Bartold PM, Gronthos S: Human foreskin fibroblasts exert immunomodulatory properties by a different mechanism to bone marrow stromal/stem cells. Stem Cells Dev. 2011 Apr;20(4):647-59. doi: 10.1089/scd.2010.0246. Epub 2010 Oct 12. [Article]
Huang HI, Chen SK, Wang RY, Shen CR, Cheng YC: Human foreskin fibroblast-like stromal cells can differentiate into functional hepatocytic cells. Cell Biol Int. 2013 Dec;37(12):1308-19. doi: 10.1002/cbin.10175. Epub 2013 Sep 16. [Article]
FDA document,: SUMMARY OF SAFETY AND EFFECTIVENESS DATA [Link]
Apligraf document, FDA [Link]
Three-Dimensional Human Tissue Models That Incorporate Diabetic Foot Ulcer-Derived Fibroblasts Mimic In Vivo Features of Chronic Wounds [Link]
Skin Substitutes for Treating Chronic Wounds [Internet] [Link]
Human foreskin fibroblast produces interleukin-6 to support derivation and self-renewal of mouse embryonic stem cells [Link]
IL6 interleukin 6 [ Homo sapiens (human) ] [Link]
IFNλ Stimulates MxA Production in Human Dermal Fibroblasts via a MAPK-Dependent STAT1-Independent Mechanism [Link]
Fibronectin human foreskin fibroblasts [Link]
SUMMARY OF SAFETY AND EFFECTIVENESS DATA, Orcel [Link]
Immortalized human skin fibroblast feeder cells support growth and maintenance of both human embryonic and induced pluripotent stem cells [Link]
Pre-Clinical Demo Orcel [Link]
SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) [Link]
Advancement of wound care from grafts to bioengineered smart skin substitutes [Link]
Premarket Approval (PMA) [Link]

External Links

RxNav: 1427137

MSDS

Download (393 KB)

Clinical Trials

Clinical Trials

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

Solid

Experimental Properties

Property	Value	Source
water solubility	1 mg/mL at 37 °C	MSDS

Targets

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Details1. Vascular endothelial growth factor receptor 1

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Agonist

General Function: Vegf-b-activated receptor activity
Specific Function: Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell ...
Gene Name: FLT1
Uniprot ID: P17948
Uniprot Name: Vascular endothelial growth factor receptor 1
Molecular Weight: 150767.185 Da

References

Pre-Clinical Demo Orcel [Link]

Details2. Interleukin-6

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
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

Human foreskin fibroblast produces interleukin-6 to support derivation and self-renewal of mouse embryonic stem cells [Link]

Details3. Interleukin-1 receptor type 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Agonist

General Function: Transmembrane signaling receptor activity
Specific Function: Receptor for IL1A, IL1B and IL1RN. After binding to interleukin-1 associates with the corecptor IL1RAP to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependen...
Gene Name: IL1R1
Uniprot ID: P14778
Uniprot Name: Interleukin-1 receptor type 1
Molecular Weight: 65401.91 Da

References

Pre-Clinical Demo Orcel [Link]

Details4. TGF-beta receptor type-2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
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]

Details5. Fibroblast growth factor 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
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]

Details6. Interferon gamma

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
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]

Details7. Fibroblast growth factor receptor 2

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]

Details8. Granulocyte-macrophage colony-stimulating factor receptor subunit alpha

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
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]

Details9. Platelet-derived growth factor receptor beta

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Agonist

General Function: Vascular endothelial growth factor binding
Specific Function: Tyrosine-protein kinase that acts as cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic...
Gene Name: PDGFRB
Uniprot ID: P09619
Uniprot Name: Platelet-derived growth factor receptor beta
Molecular Weight: 123966.895 Da

References

Pre-Clinical Demo Orcel [Link]

Details10. Transforming growth factor beta-1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
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]

Details11. Tumor necrosis factor

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
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]

Drug created at December 01, 2015 20:04 / Updated at May 21, 2021 10:21

Foreskin fibroblast (neonatal)

Identification

Pharmacology

Interactions

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Pharmacoeconomics

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