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
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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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0 Valid · 0 Not valid · 38 Not checked · 18 Own results and interpretations
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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.
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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.
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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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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
Meerwaldt, R., Links, T. P., Graaff, R., Hoogenberg, K., Lefrandt, J. D., Baynes, J., Gans, R. O. B., & Smit, A. J. (2005) · Diabetologia · doi:10.1007/s00125-005-1828-x · Cited by 185
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
Eaglstein, W. H., Iriondo, M., & LASZLO, K. S. (1995) · Dermatologic Surgery · doi:10.1111/j.1524-4725.1995.tb00709.x · Cited by 156
Protocol for the successful treatment of venous ulcers
Brem, H., Kirsner, R. S., & Falanga, V. (2004) · The American Journal of Surgery · doi:10.1016/s0002-9610(03)00284-8 · Cited by 156
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
Davis, S. C., Martinez, L. C., & Kirsner, R. S. (2006) · Current Diabetes Reports · doi:10.1007/s11892-006-0076-x · Cited by 137
Self-citationQuality of Life of Adults with Unhealed and Healed Diabetic Foot Ulcers
Goodridge, D. M., Trepman, E., Sloan, J. A., Guse, L. W., Strain, L. A., McIntyre, J., & Embil, J. M. (2006) · Foot & Ankle International · doi:10.1177/107110070602700408 · Cited by 127
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Tottoli, E. M., Dorati, R., Genta, I., Chiesa, E., Pisani, S., & Conti, B. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12080735 · Cited by 1,447
Wound Dressings and Comparative Effectiveness Data
Sood, A. K., Granick, M. S., & Tomaselli, N. L. (2013) · Advances in Wound Care · doi:10.1089/wound.2012.0401 · Cited by 835
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
Synthetic polymeric biomaterials for wound healing: a review
Mir, M., Ali, M. N., Barakullah, A., Gulzar, A., Arshad, M., Fatima, S., & Asad, M. (2018) · Progress in Biomaterials · doi:10.1007/s40204-018-0083-4 · Cited by 554
Overview of Silk Fibroin Use in Wound Dressings
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Gaspar‐Pintiliescu, A., Stanciuc, A., & Crăciunescu, O. (2019) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2019.07.155 · Cited by 339
Baltazar, T., Merola, J., Catarino, C. M., Xie, C. B., Kirkiles-Smith, N. C., Lee, V., Hotta, S. Y. K., Dai, G., Xu, X., Ferreira, F. C., et al. (2019) · Tissue Engineering Part A · doi:10.1089/ten.tea.2019.0201 · Cited by 303
Regenerative Scar-Free Skin Wound Healing
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desJardins-Park, H. E., Foster, D. S., & Longaker, M. T. (2018) · Regenerative Medicine · doi:10.2217/rme-2018-0073 · Cited by 265
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Gomes, S. C. V., Leonor, I. B., Mano, J. F., Reis, R. L., & Kaplan, D. L. (2011) · Progress in Polymer Science · doi:10.1016/j.progpolymsci.2011.07.003 · Cited by 265
Bioengineered human blood vessels
Niklason, L. E., & Lawson, J. H. (2020) · Science · doi:10.1126/science.aaw8682 · Cited by 265
Cell Therapy: Types, Regulation, and Clinical Benefits
El-Kadiry, A. E.-H., Rafei, M., & Shammaa, R. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.756029 · Cited by 256
Recent Trends in Decellularized Extracellular Matrix Bioinks for 3D Printing: An Updated Review
Dzobo, K., Motaung, K. S., & Adesida, A. B. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20184628 · Cited by 244
Hydrogels for Tissue Engineering: Addressing Key Design Needs Toward Clinical Translation
Xu, F., Dawson, C., Lamb, M., Mueller, E., Stefanek, E., Akbari, M., & Hoare, T. R. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.849831 · Cited by 235
Instructive microenvironments in skin wound healing: Biomaterials as signal releasing platforms
Castaño, Ó., Pérez‐Amodio, S., Navarro‐Requena, C., Mateos‐Timoneda, M. A., & Engel, E. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.03.012 · Cited by 221
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Dickinson, L. E., & Gerecht, S. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00341 · Cited by 201
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Farina, M., Alexander, J. F., Thekkedath, U. R., Mauro Ferrari, B., & Grattoni, A. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.04.018 · Cited by 194
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Hosseini, M., & Shafiee, A. (2021) · Small · doi:10.1002/smll.202101384 · Cited by 188
Berlanga‐Acosta, J., Cowley, J. G., López-Saura, P. A., González-López, T., Castro‐Santana, M. D., López‐Mola, E., Guillén, G. E., & Herrera-Martínez, L. (2009) · International Wound Journal · doi:10.1111/j.1742-481x.2009.00622.x · Cited by 174
Kirsner, R. S., Marston, W. A., Snyder, R. J., Lee, T. D., Cargill, D. I., & Slade, H. B. (2012) · The Lancet · doi:10.1016/s0140-6736(12)60644-8 · Cited by 172
Self-citationMesenchymal Stem Cells in Chronic Wounds: The Spectrum from Basic to Advanced Therapy
Otero-Viñas, M., & Falanga, V. (2016) · Advances in Wound Care · doi:10.1089/wound.2015.0627 · Cited by 164
Wang, L. L., Janes, M. E., Kumbhojkar, N., Kapate, N., Clegg, J. R., Prakash, S., Heavey, M. K., Zhao, Z., Anselmo, A. C., & Mitragotri, S. (2021) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10214 · Cited by 162
Characteristics and clinical applications of Wharton’s jelly-derived mesenchymal stromal cells
Liau, L. L., Ruszymah, B. H. I., Ng, M. H., & Law, J. X. (2019) · Current Research in Translational Medicine · doi:10.1016/j.retram.2019.09.001 · Cited by 159
Clinical Applications of Naturally Derived Biopolymer-Based Scaffolds for Regenerative Medicine
Stoppel, W. L., Ghezzi, C. E., McNamara, S. L., Black, L. D., & Kaplan, D. L. (2014) · Annals of Biomedical Engineering · doi:10.1007/s10439-014-1206-2 · Cited by 154
Biological Products: Cellular Therapy and FDA Approved Products
Golchin, A., & Farahany, T. Z. (2019) · Stem Cell Reviews and Reports · doi:10.1007/s12015-018-9866-1 · Cited by 154
Highlights on Advancing Frontiers in Tissue Engineering
Ashammakhi, N. A., GhavamiNejad, A., Tutar, R., Fricker, A. T. R., Roy, I., Chatzistavrou, X., Apu, E. H., Nguyen, K., Ahsan, T., Pountos, I., et al. (2021) · Tissue Engineering Part B Reviews · doi:10.1089/ten.teb.2021.0012 · Cited by 151
Patil, P., Russo, K. A., McCune, J. T., Pollins, A. C., Cottam, M. A., Dollinger, B. R., DeJulius, C. R., Gupta, M. K., d’Arcy, R., Colazo, J. M., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abm6586 · Cited by 146
Cheng, L., Zhuang, Z., Yin, M., Lü, Y., Liu, S., Zhan, M., Zhao, L., He, Z., Meng, F., Tian, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54075-7 · Cited by 141
Challenges in the translation and commercialization of cell therapies
Dodson, B. P., & Levine, A. D. (2015) · BMC Biotechnology · doi:10.1186/s12896-015-0190-4 · Cited by 139
Approaches to cutaneous wound healing: basics and future directions
Zeng, R., Lin, C., Lin, Z., Chen, H., Lu, W., Li, H., & Li, H. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2830-1 · Cited by 137
Lower‐extremity ulcers: diagnosis and management
Kirsner, R. S., & Vivas, A. C. (2015) · British Journal of Dermatology · doi:10.1111/bjd.13953 · Cited by 135
Self-citationTissue Engineered Skin Substitutes
Goodarzi, P., Falahzadeh, K., Nematizadeh, M., Farazandeh, P., Payab, M., Larijani, B. A., Tayanloo-Beik, A., & Arjmand, B. (2018) · Advances in experimental medicine and biology · doi:10.1007/5584_2018_226 · Cited by 133
Dixit, S., Baganizi, D. R., Sahu, R., Dosunmu, E., Chaudhari, A. A., Vig, K., Pillai, S., Singh, S. R., & Dennis, V. A. (2017) · Journal of Biological Engineering · doi:10.1186/s13036-017-0089-9 · Cited by 129
Xue, M., Zhao, R., Lin, H., & Jackson, C. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.03.002 · Cited by 125
Dieckmann, C., Renner, R., Milkova, L., & Simon, J. C. (2010) · Experimental Dermatology · doi:10.1111/j.1600-0625.2010.01087.x · Cited by 124
Chasing the Paradigm: Clinical Translation of 25 Years of Tissue Engineering
Hoffman, T., Khademhosseini, A., & Langer, R. (2019) · Tissue Engineering Part A · doi:10.1089/ten.tea.2019.0032 · Cited by 123
3D Bioprinting Constructs to Facilitate Skin Regeneration
Daikuara, L. Y., Chen, X., Yue, Z., Skropeta, D., Wood, F. M., Fear, M. W., & Wallace, G. G. (2021) · Advanced Functional Materials · doi:10.1002/adfm.202105080 · Cited by 118
Recent advances in regenerative medicine strategies for cancer treatment
Mansouri, V., Beheshtizadeh, N., Gharibshahian, M., Sabouri, L., Varzandeh, M., & Rezaei, N. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111875 · Cited by 115
Regenerative Medicine as Applied to General Surgery
Orlando, G., Wood, K. J., Coppi, P. D., Baptista, P. M., Binder, K. W., Bitar, K. N., Breuer, C. K., Burnett, L., Christ, G. J., Farney, A. C., et al. (2012) · Annals of Surgery · doi:10.1097/sla.0b013e318243a4db · Cited by 113
Polymeric wound dressings, an insight into polysaccharide-based electrospun membranes
Gruppuso, M., Turco, G., Marsich, E., & Porrelli, D. (2021) · Applied Materials Today · doi:10.1016/j.apmt.2021.101148 · Cited by 109
Collagen Type I: A Versatile Biomaterial
Chowdhury, S. R., Busra, M. F. M., Lokanathan, Y., Ng, M. H., Law, J. X., Ude, C. C., & Idrus, R. B. H. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-0947-2_21 · Cited by 102
Morimoto, N., Yoshimura, K., Niimi, M., Ito, T., Aya, R., Fujitaka, J., Tada, H., Teramukai, S., Murayama, T., Toyooka, C., et al. (2013) · Tissue Engineering Part A · doi:10.1089/ten.tea.2012.0634 · Cited by 101
Alteration of Skin Properties with Autologous Dermal Fibroblasts
Thangapazham, R. L., Darling, T. N., & Meyerle, J. H. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15058407 · Cited by 101
Hélary, C., Abed, A., Mosser, G., Louedec, L., Letourneur, D., Coradin, T., Giraud‐Guille, M., & Meddahi‐Pellé, A. (2014) · Biomaterials Science · doi:10.1039/c4bm00370e · Cited by 100
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Wu, S., Marston, W. A., & Armstrong, D. G. (2010) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2010.06.009 · Cited by 100
Schneider, C., Stratman, S., & Kirsner, R. S. (2021) · Medical Clinics of North America · doi:10.1016/j.mcna.2021.04.006 · Cited by 91
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Priya, S., Choudhari, M. V., Tomar, Y., Desai, V. M., Innani, S., Dubey, S. K., & Singhvi, G. (2023) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2023.121655 · Cited by 84
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Daristotle, J. L., Lau, L. W., Erdi, M., Hunter, J. W., Djoum, A., Srinivasan, P., Wu, X., Basu, M., Ayyub, O. B., Sandler, A. D., et al. (2019) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10149 · Cited by 83
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Nicholas, M. N., & Yeung, J. (2016) · Journal of Cutaneous Medicine and Surgery · doi:10.1177/1203475416664037 · Cited by 83
Kosaraju, R. S., Rennert, R. C., Maan, Z. N., Duscher, D., Barrera, J. A., Whittam, A. J., Januszyk, M., Rajadas, J., Rodrigues, M., & Gurtner, G. C. (2016) · Tissue Engineering Part A · doi:10.1089/ten.tea.2015.0277 · Cited by 81
O’Donnell, T. F., & Passman, M. A. (2014) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2014.04.058 · Cited by 81
Chemotherapy-Mediated Complications of Wound Healing: An Understudied Side Effect
Słonimska, P., Sachadyn, P., Zieliński, J., Skrzypski, M. T., & Pikuła, M. (2024) · Advances in Wound Care · doi:10.1089/wound.2023.0097 · Cited by 77
Biomaterials and tissue engineering for scar management in wound care
Rahimnejad, M., Derakhshanfar, S., & Zhong, W. (2017) · Burns & Trauma · doi:10.1186/s41038-017-0069-9 · Cited by 76
Piaggesi, A., Läuchli, S., Bassetto, F., Biedermann, T., Marques, A. P., Najafi, B., Palla, I., Scarpa, C., Seimetz, D., Triulzi, I., et al. (2018) · Journal of Wound Care · doi:10.12968/jowc.2018.27.sup6a.s1 · Cited by 76
Development of bioactive conducting polymers for neural interfaces
Poole-Warren, L. A., Lovell, N. H., Baek, S., & Green, R. A. (2009) · Expert Review of Medical Devices · doi:10.1586/erd.09.58 · Cited by 71
Fibroblasts within concentrated collagen hydrogels favour chronic skin wound healing
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Skin substitutes: an overview of the key players in wound management.
Nathoo, R., Howe, N. M., & Cohen, G. (2014) · PubMed · Cited by 68
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Wood, F. M. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.10.025 · Cited by 66
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Yang, H., Fierro, F. A., So, M., Yoon, D. J., Nguyen, A. V., Gallegos, A., Bagood, M. D., Rojo-Castro, T., Alex, A., Stewart, H., et al. (2020) · Stem Cells Translational Medicine · doi:10.1002/sctm.19-0380 · Cited by 56
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Elfawy, L. A., Ng, C. Y., Amirrah, I. N., Mazlan, Z., Wen, A. P. Y., Fadilah, N. I. M., Maarof, M., Lokanathan, Y., & Fauzi, M. B. (2023) · Pharmaceuticals · doi:10.3390/ph16050701 · Cited by 49
Chávez, J. C. P., McGrath, M., O’Connor, C., Dervan, A. G., Dixon, J. E., Kearney, C. J., Browne, S., & O’Brien, F. J. (2025) · Biomaterials Science · doi:10.1039/d4bm01051e · Cited by 49
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Wu, S., Marston, W. A., & Armstrong, D. G. (2010) · Journal of the American Podiatric Medical Association · doi:10.7547/1000385 · Cited by 45
Dabiri, G., Heiner, D., & Falanga, V. (2013) · Expert Opinion on Emerging Drugs · doi:10.1517/14728214.2013.833184 · Cited by 44
Glotzbach, J. P., Wong, V., Gurtner, G. C., & Longaker, M. T. (2011) · Current Problems in Surgery · doi:10.1067/j.cpsurg.2010.11.002 · Cited by 44
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Momeni, M., Fallah, N., Bajouri, A., Bagheri, T., Orouji, Z., Pahlevanpour, P., Shafieyan, S., Sodeifi, N., Alizadeh, A., Aghdami, N., et al. (2018) · Burns · doi:10.1016/j.burns.2018.10.016 · Cited by 37
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Garwood, C. S., & Steinberg, J. S. (2015) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2747 · Cited by 36
Mastrogiacomo, M., Nardini, M., Collina, M. C., Campli, C. D., Filaci, G., Cancedda, R., & Odorisio, T. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.869408 · Cited by 35
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Tsao, C.-T., Leung, M. C., Chang, J. Y., & Zhang, M. (2014) · Journal of Materials Chemistry B · doi:10.1039/c4tb00614c · Cited by 34
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-13, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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Data sources
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
