The DOI matches its Crossref record, with a small difference in title or year; 39 of the 40 references it cites were found in a registry or an index; none of the 48 sources its claims cite is checked for support yet.
A review of a bi-layered living cell treatment (Apligraf) in the treatment of venous leg ulcers and diabetic foot ulcers
Open accessAbstract
Apligraf (Organogenesis, Canton, MA) is a bi-layered bioengineered skin substitute and was the first engineered skin US Food and Drug Administration (FDA)-approved to promote the healing of ulcers that have failed standard wound care. Constructed by culturing human foreskin-derived neonatal fibroblasts in a bovine type I collagen matrix over which human foreskin-derived neonatal epidermal keratinocytes are then cultured and allowed to stratify, Apligraf provides both cells and matrix for the nonhealing wound. Its exact mechanism of action is not known, but it is known to produce cytokines and growth factors similar to healthy human skin. Initially approved by the FDA in 1998 for the treatment of venous ulcers greater than one-month duration that have not adequately responded to conventional therapy, Apligraf later received approval in 2000 for treatment of diabetic foot ulcers of greater than three weeks duration. Herein, we review the use of Apligraf in the treatment of chronic venous leg ulcers and diabetic foot ulcers. Our goal is to provide a working understanding of appropriate patient selection and proper use of the product for any physician treating this segment of the aging population.
Overview
CoChat Summary
TL;DR
This narrative review summarizes the use of Apligraf, a bi-layered bioengineered skin substitute of neonatal fibroblasts in bovine type I collagen overlaid with neonatal keratinocytes, for chronic venous leg ulcers (VLU) and diabetic foot ulcers (DFU). It covers the product's history, composition, mechanism, patient selection, application technique, and economic impact, drawing mainly on the two pivotal FDA-approval trials.
Key findings
- In the VLU pivotal trial (293 outpatients), Apligraf plus compression achieved complete healing in 63% versus 49% with compression alone at 6 months, with median time to closure of 61 versus 181 days; benefit was greatest in larger (>10 cm²) and longer-duration (>6 months) ulcers.
- In the DFU pivotal trial (208 patients, 24 US centers), 56% of Apligraf-treated patients achieved complete healing at 12 weeks versus 38% of controls, with median closure of 65 versus 90 days and an odds ratio for complete healing of 2.14 (95% CI 1.23–3.74); osteomyelitis and lower limb amputations were less frequent in the Apligraf group.
- Apligraf is described as immunologically inert with no clinical or laboratory evidence of rejection, though its constituent cells are relatively short-lived (less than 4 weeks in most patients).
- The review reports lower ulcer-related medical costs and improved quality of life (mainly reduced wound pain) with Apligraf versus conventional care, and in one VLU study an average ulcer size decrease of 2.37 cm²/week versus a 0.72 cm²/week increase in controls.
Methods
- Design: narrative review of the literature on Apligraf for VLU and DFU, including its history, composition, mechanism of action, patient selection, proper application, and economic impact.
- Evidence base: primarily the two pivotal randomized controlled trials supporting FDA approval (Falanga et al 1998 for VLU; Veves et al 2001 for DFU), plus additional published studies and case reports of other wound applications.
- The review also synthesizes practical guidance on identifying nonhealing wounds, negative predictive markers, wound bed preparation, and application/dressing technique.
Limitations
- The paper does not state explicit limitations of its own review.
- Evident from the text: this is a narrative (non-systematic) review with no described search strategy or formal quality appraisal, and it relies heavily on the two pivotal trials and on secondary sources for economic and quality-of-life claims.
- The text itself notes that the exact mechanism of action of Apligraf is not known and that its cells do not persist indefinitely, which limits mechanistic conclusions.
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Claims the paper makes
0 Valid · 0 Not valid · 38 Not checked · 18 Own results and interpretations
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It has shown promise as an effective clinical treatment of chronic nonhealing wounds, such as VLU and DFU, and has been utilized in a variety of acute and chronic wounds to facilitate healing.”
§ A review of a bi-layered living cell treatment (Apligraf ®) in the treatment of venous leg ulcers and diabetic foot ulcers > History of Apligraf ®
hedgedstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“It was found to decrease pain at the operative site compared with patients whose wounds were covered with polyurethane film (Muhart et al 1999).”
§ A review of a bi-layered living cell treatment (Apligraf ®) in the treatment of venous leg ulcers and diabetic foot ulcers > History of Apligraf ®
What the sources say
- Not checked yetcites Muhart et al 1999 source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A check of a cited source is scheduled, or we don’t hold its full text yet; the claim is checked once it runs.
In the paper
“Its exact mechanism of action is not known, but it is known to produce cytokines and growth factors similar to healthy human skin.”
§ A review of a bi-layered living cell treatment (Apligraf ®) in the treatment of venous leg ulcers and diabetic foot ulcers > Abstract
What the sources say
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A statement the paper makes itself — it cites no source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Constructed by culturing human foreskin-derived neonatal fibroblasts in a bovine type I collagen matrix over which human foreskin-derived neonatal epidermal keratinocytes are then cultured and allowed to stratify, Apligraf provides both cells and matrix for the nonhealing wound.”
§ A review of a bi-layered living cell treatment (Apligraf ®) in the treatment of venous leg ulcers and diabetic foot ulcers > Abstract
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Living skin equivalent was also compared with autograft or polyurethane film in acute partial thickness donor site wounds and was found to have no toxic effect or clinically apparent rejection.”
§ A review of a bi-layered living cell treatment (Apligraf ®) in the treatment of venous leg ulcers and diabetic foot ulcers > History of Apligraf ®
What the sources say
- Not checked yetcites Muhart et al 1999 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
27 more claims
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Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ A review of a bi-layered living cell treatment (Apligraf ®) in the treatment of venous leg ulcers and diabetic foot ulcers > History of Apligraf ®
“the treatment of epidermolysis bullosa, showing that Apligraf treated areas healed faster than the areas treated with conventional therapy (Falabella et al 1999; Streit et al 2001)”
§ A review of a bi-layered living cell treatment (Apligraf ®) in the treatment of venous leg ulcers and diabetic foot ulcers > References
“33. Streit M Bohlen LM Braathen LR 2001 Ulcerative sarcoidosis successfully treated with Apligraf Dermatology 202 367 70 11455163”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ A review of a bi-layered living cell treatment (Apligraf ®) in the treatment of venous leg ulcers and diabetic foot ulcers > History of Apligraf ®
“ulcerative sarcoidosis that was unresponsive to steroid treatment (Falabella et al 2000)”
§ A review of a bi-layered living cell treatment (Apligraf ®) in the treatment of venous leg ulcers and diabetic foot ulcers > References
“13. Falabella AF Valencia IC Eaglstein WH 2000 Tissue-engineered skin (Apligraf) in the healing of patients with epidermolysis bullosa wounds Arch Dermatol 136 1225 30 11030768”
Citations
Cites
Falanga, V. (1998) · Archives of Dermatology · doi:10.1001/archderm.134.3.293 · Cited by 656
Veves, A., Falanga, V., Armstrong, D. G., Sabolinski, M. L., & Study, T. A. D. F. U. (2001) · Diabetes Care · doi:10.2337/diacare.24.2.290 · Cited by 643
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Healing of Diabetic Foot Ulcers and Pressure Ulcers With Human Skin Equivalent
Brem, H. (2000) · Archives of Surgery · doi:10.1001/archsurg.135.6.627 · Cited by 182
Tissue-Engineered Skin (Apligraf) in the Healing of Patients With Epidermolysis Bullosa Wounds
Falabella, A. F., Valencia, I. C., Eaglstein, W. H., & Schachner, L. A. (2000) · Archives of Dermatology · doi:10.1001/archderm.136.10.1225 · Cited by 173
A Composite Skin Substitute (Graftskin) for Surgical Wounds
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Protocol for the successful treatment of venous ulcers
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Self-citationWaymack, P., Duff, R. G., & Sabolinski, M. (2000) · Burns · doi:10.1016/s0305-4179(00)00017-6 · Cited by 140
The diabetic foot: The importance of biofilms and wound bed preparation
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Self-citationQuality of Life of Adults with Unhealed and Healed Diabetic Foot Ulcers
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Acute Excisional Wounds Treated with a Tissue-Engineered Skin (Apligraf)
Eaglstein, W. H., Alvarez, O. M., Auletta, M., Leffel, D., Rogers, G. S., Zitelli, J. A., Norris, J. E. C., Thomas, I., Irondo, M., Fewkes, J., et al. (1999) · Dermatologic Surgery · doi:10.1046/j.1524-4725.1999.08186.x · Cited by 124
Wounding of Bioengineered Skin: Cellular and Molecular Aspects After Injury
Falanga, V., Isaacs, C., Paquette, D., Downing, G., Kouttab, N., Butmarc, J., Badiavas, E., & Hardin-Young, J. (2002) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.2002.01865.x · Cited by 109
Venous ulcers: pathophysiology and treatment options.
Trent, J. T., Falabella, A. F., Eaglstein, W. H., & Kirsner, R. S. (2005) · PubMed · Cited by 105
Self-citationCurran, M. P., & Plosker, G. L. (2002) · BioDrugs · doi:10.2165/00063030-200216060-00005 · Cited by 99
Hu, S., Kirsner, R. S., Falanga, V., Phillips, T. J., & Eaglstein, W. H. (2006) · Wound Repair and Regeneration · doi:10.1111/j.1743-6109.2006.00148.x · Cited by 93
Self-citationThe Longevity of a Bilayered Skin Substitute After Application to Venous Ulcers
Phillips, T. J., Manzoor, J., Rojas, A., Isaacs, C., Carson, P., Sabolinski, M., Young, J., & Falanga, V. (2002) · Archives of Dermatology · doi:10.1001/archderm.138.8.1079 · Cited by 81
The Use of Tissue-Engineered Skin (Apligraf) to Treat a Newborn With Epidermolysis Bullosa
Falabella, A. F., Schachner, L. A., Valencia, I. C., & Eaglstein, W. H. (1999) · Archives of Dermatology · doi:10.1001/archderm.135.10.1219 · Cited by 79
Orchestrating Wound Healing: Assessing and Preparing the Wound Bed
Hess, C. T., & Kirsner, R. S. (2003) · Advances in Skin & Wound Care · doi:10.1097/00129334-200309000-00015 · Cited by 73
Self-citationMuhart, M., McFalls, S., Kirsner, R. S., Elgart, G. W., Kerdel, F., Sabolinski, M. L., Hardin-Young, J., & Eaglstein, W. H. (1999) · Archives of Dermatology · doi:10.1001/archderm.135.8.913 · Cited by 73
Self-citationNeurovascular disease, antioxidants and glycation in diabetes
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An economic assessment of Apligraf® (Graftskin) for the treatment of hard‐to‐heal venous leg ulcers
Schonfeld, W. H., Villa, K. F., Fastenau, J. M., Mazonson, P. D., & Falanga, V. (2000) · Wound Repair and Regeneration · doi:10.1046/j.1524-475x.2000.00251.x · Cited by 66
Risk assessment of the diabetic foot and wound
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The Cost Effectiveness of Apligraf?? Treatment of Diabetic Foot Ulcers
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The cost-effectiveness of wound management protocols of care
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Apligraf – a Living Human Skin Equivalent for the Treatment of Chronic Wounds
Streit, M., & Braathen, L. R. (2000) · The International Journal of Artificial Organs · doi:10.1177/039139880002301208 · Cited by 48
Repair of cicatricial ectropion in an infant with harlequin ichthyosis using engineered human skin
Culican, S. M., & Custer, P. L. (2002) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(02)01567-2 · Cited by 48
Greenebaum, E. H. (1984) · bepress Legal Repository · Cited by 42
Hydroxyurea-Induced Leg Ulcers Treated with Apligraf
Flores, F., Eaglstein, W., & Kirsner, R. S. (2000) · Annals of Internal Medicine · doi:10.7326/0003-4819-132-5-200003070-00017 · Cited by 30
Self-citationClinical and economic impact of Apligraf® for the treatment of nonhealing venous leg ulcers
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Full-Thickness Burn of The Foot: Successful Treatment with Apligraf
Hayes, D. W., Webb, G. E., Mandracchia, V. J., & John, K. J. (2001) · Clinics in Podiatric Medicine and Surgery · doi:10.1016/s0891-8422(23)01173-4 · Cited by 26
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Self-citationUlcers caused by bullous morphea treated with tissue‐engineered skin
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Self-citationUlcerative Sarcoidosis Successfully Treated with Apligraf
Streit, M., Böhlen, L. M., & Braathen, L. R. (2001) · Dermatology · doi:10.1159/000051685 · Cited by 18
Modulating Diseased Skin with Tissue Engineering: Actinic Purpura Treated with Apligraf
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Self-citationUse of Tissue-Engineered Skin in the Dermal Atrophy Patient With Traumatic Avulsion Injuries
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Skin Wound Healing Process and New Emerging Technologies for Skin Wound Care and Regeneration
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O’Donnell, T. F., Passman, M. A., Marston, W. A., Ennis, W. J., Dalsing, M., Kistner, R. L., Lurie, F., Henke, P. K., Gloviczki, M. L., Eklöf, B. G., et al. (2014) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2014.04.049 · Cited by 720
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Overview of Silk Fibroin Use in Wound Dressings
Farokhi, M., Mottaghitalab, F., Fatahi, Y., Khademhosseini, A., & Kaplan, D. L. (2018) · Trends in Biotechnology · doi:10.1016/j.tibtech.2018.04.004 · Cited by 474
Metadata
- Authors
- Zaulyanov, L., & Kirsner, R. S.
- Affiliations
- University of Miami (US)
- Corresponding author
- Zaulyanov, Larissa
- ORCID
- Kirsner, Robert S
- Venue
- Clinical Interventions in Aging
- Publisher
- Informa UK Limited
- Published
- 2007-03
- Volume
- 2
- Issue
- 1
- Pages
- 93-98
- ISSN
- 1176-9092 (ISSN-L)
- PMC
- PMC2684073
- OpenAlex
- W2067691626
- Cited by
- 266
- References
- 40
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 19 · 2023: 17 · 2022: 15 · 2021: 26 · 2020: 18 · 2019: 14 · 2018: 28 · 2017: 9 · 2016: 17 · 2015: 12 · 2014: 20 · 2013: 14 · 2012: 9
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Clinical Interventions in Aging (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetic Foot Ulcer Assessment and Management
- Health Sciences › Medicine › Surgery › Diagnosis and Treatment of Venous Diseases
- Keywords
- Apligraf, bioengineered skin substitutes, venous leg ulcers, diabetic foot ulcer, chronic wounds, wound healing, human foreskin fibroblasts, keratinocytes, collagen matrix, cytokines and growth factors, patient selection
- MeSH terms
- Collagen, Humans, Varicose Ulcer, Foot Ulcer, Diabetic Foot, Patient Selection
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