Trial reportWound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society2020
A bioengineered living cell construct activates metallothionein/zinc/MMP8 and inhibits TGFβ to stimulate remodeling of fibrotic venous leg ulcers.
Trial report in Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01327937 (A Prospective, Randomized, Controlled, Single-Site Post Marketing Study to Identify & Characterize the Molecular Mechanisms of Apligraf in Non-healing Wounds of Subjects With Venous Leg Ulcers), which is not on this map. Cited by 18 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Prospective, Randomized, Controlled, Single-Site Post Marketing Study to Identify & Characterize the Molecular Mechanisms of Apligraf in Non-healing Wounds of Subjects With Venous Leg Ulcers
Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 33 citations in OpenAlex.
- Transcriptomics in Venous Leg Ulcers (VLU): A Systematic Review.Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair SocietyPooled it
- Dysregulated NAMPT signaling underlines the immune-suppressive microenvironment in venous leg ulcers.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Pre-Vascularized 3-Dimensional Skin Substitutes Promote Angiogenesis and Tissue Repair in a Murine Model of Refractory Skin Ulcers.Journal of functional biomaterials · 2025Article
- The role of multi-omics in biomarker discovery, diagnosis, prognosis, and therapeutic monitoring of tissue repair and regeneration processes.Journal of orthopaedic translation · 2025Review
- A Novel Comprehensive Therapeutic Approach to the Challenges of Chronic Wounds: A Brief Review and Clinical Experience Report.Advances in therapy · 2024Review
- Molecular Pathophysiology of Chronic Wounds: Current State and Future Directions.Cold Spring Harbor perspectives in biology · 2023Review
- Bi-layered living cellular construct resulted in greater healing in an alloxan-induced diabetic porcine model.International wound journal · 2023Article
- Skin substitutes as treatment for chronic wounds: current and future directions.Frontiers in medicine · 2023Review
- Calreticulin: a multifunctional protein with potential therapeutic applications for chronic wounds.Frontiers in medicine · 2023Review
- Intrinsic Networks Regulating Tissue Repair: Comparative Studies of Oral and Skin Wound Healing.Cold Spring Harbor perspectives in biology · 2022Review
- Article
- FOXM1 network in association with TREM1 suppression regulates NET formation in diabetic foot ulcers.EMBO reports · 2022Article
- Wound dressings: curbing inflammation in chronic wound healing.Emerging topics in life sciences · 2021Review
- Epigenetic regulation of cellular functions in wound healing.Experimental dermatology · 2021Review
- Glucocorticoid-mediated induction of caveolin-1 disrupts cytoskeletal organization, inhibits cell migration and re-epithelialization of non-healing wounds.Communications biology · 2021Article
- Gut-Skin Axis: Current Knowledge of the Interrelationship between Microbial Dysbiosis and Skin Conditions.Microorganisms · 2021Review
- Genomics of Human Fibrotic Diseases: Disordered Wound Healing Response.International journal of molecular sciences · 2020Review
- Skin Microbiota and its Interplay with Wound Healing.American journal of clinical dermatology · 2020Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 1 institution in 2 countries.
Funding
Abstract
Venous leg ulcers (VLU) represent a major clinical unmet need, impairing quality of life for millions worldwide. The bioengineered bilayered living cell construct (BLCC) is the only FDA-approved therapy demonstrating efficacy in healing chronic VLU, yet its in vivo mechanisms of action are not well understood. Previously, we reported a BLCC-mediated acute wounding response at the ulcer edge; in this study we elucidated the BLCC-specific effects on the epidermis-free ulcer bed. We conducted a randomized controlled clinical trial (ClinicalTrials.gov NCT01327937) enrolling 30 subjects with nonhealing VLUs, and performed genotyping, genomic profiling, and functional analysis on wound bed biopsies obtained at baseline and 1 week after treatment with BLCC plus compression or compression therapy (control). The VLU bed transcriptome featured processes of chronic inflammation and was strikingly enriched for fibrotic/fibrogenic pathways and gene networks. BLCC application decreased expression of profibrotic TGFß1 gene targets and increased levels of TGFß inhibitor decorin. Surprisingly, BLCC upregulated metallothioneins and fibroblast-derived MMP8 collagenase, and promoted endogenous release of MMP-activating zinc to stimulate antifibrotic remodeling, a novel mechanism of cutaneous wound healing. By activating a remodeling program in the quiescent VLU bed, BLCC application shifts nonhealing to healing phenotype. As VLU bed fibrosis correlates with poor clinical healing, findings from this study identify the chronic VLU as a fibrotic skin disease and are first to support the development and application of antifibrotic therapies as a successful treatment approach.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.