The influence of patient and wound variables on healing of venous leg ulcers in a randomized controlled trial of growth-arrested allogeneic keratinocytes and fibroblasts

John C. Lantis, William A. Marston, Alik Farber, Robert Kirsner, Yuxin Zhang, Tommy D. Lee, D. Innes Cargill, Herbert B. Slade

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Objective: To examine patient and wound variables presumed to influence healing outcomes in the context of therapeutic trials for chronic venous leg ulcers. Methods: This double-blind, vehicle-controlled study was conducted with randomized assignment to one of four cell therapy dose groups (n = 46, 43, 44, 45) or vehicle control (n = 50). A 2-week run-in period was used to exclude rapid healers and those with infection or uncontrolled edema. This was a multicenter (ambulatory, private, hospital-based and university-based practices, and wound care centers in North America) study. Adults ≥18 years old with chronic venous insufficiency associated with an uninfected venous leg ulcer (2-12 cm2 area, 6-104 weeks' duration) were included in the study. Excluded were pregnant or lactating women, wounds with exposed muscle, tendon or bone, patients unable to tolerate compression bandages, or patients who had exclusionary medical conditions or exposure to certain products. Exclusion during run-in included patients with infection, uncontrolled severe edema or with healing rates ≥0.349 cm/2 wk. Screen fail rate was 37% (134/362), and the withdrawal rate was ∼10% (23 of 228). Growth-arrested neonatal dermal fibroblasts and keratinocytes were delivered via pump spray in a fibrin sealant-based matrix, plus a foam dressing and four-layer compression bandaging. Treatment continued for 12 weeks or until healed, whichever occurred first. Patient demographic and wound-related variables were evaluated for influence on complete wound healing in all patients, as well as the subsets of treated and control patients. Results: Wound duration (P =.004) and the presence of specific quantities of certain bacterial species (P <.001) affected healing in the vehicle group, while healing in the cell-treated groups was influenced by wound duration (P =.012), wound area (P =.026), wound location (P =.011), and specific quantities of certain bacterial species (P =.002). Age, sex, race, diabetes, HbA1C, peripheral neuropathy, and serum prealbumin did not significantly affect healing. Body mass index was positively associated with healing in cell-treated patients. Conclusions: Wound duration is a quantifiable surrogate for one or more undefined variables that can have a profound negative effect on venous leg ulcer healing. Although cell therapy overcame barriers to healing, the only specific barrier identified was the presence of certain bacterial species. Interventional trials of potentially effective new therapies can be most informative when patients with suspected barriers to healing are included. The specific measurement of candidate barriers such as microbial pathogens, wound inflammatory state, and fibroblast function should be considered in future randomized trials to improve our understanding of the basis for chronicity.

Original languageEnglish
Pages (from-to)433-439
Number of pages7
JournalJournal of Vascular Surgery
Volume58
Issue number2
DOIs
StatePublished - Aug 1 2013

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Varicose Ulcer
Leg Ulcer
Keratinocytes
Randomized Controlled Trials
Fibroblasts
Wounds and Injuries
Growth
Cell- and Tissue-Based Therapy
Edema
Compression Bandages
Venous Insufficiency
Fibrin Tissue Adhesive
Private Hospitals
Prealbumin
Peripheral Nervous System Diseases
Bandages
North America
Infection
Double-Blind Method
Tendons

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

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The influence of patient and wound variables on healing of venous leg ulcers in a randomized controlled trial of growth-arrested allogeneic keratinocytes and fibroblasts. / Lantis, John C.; Marston, William A.; Farber, Alik; Kirsner, Robert; Zhang, Yuxin; Lee, Tommy D.; Cargill, D. Innes; Slade, Herbert B.

In: Journal of Vascular Surgery, Vol. 58, No. 2, 01.08.2013, p. 433-439.

Research output: Contribution to journalArticle

Lantis, John C. ; Marston, William A. ; Farber, Alik ; Kirsner, Robert ; Zhang, Yuxin ; Lee, Tommy D. ; Cargill, D. Innes ; Slade, Herbert B. / The influence of patient and wound variables on healing of venous leg ulcers in a randomized controlled trial of growth-arrested allogeneic keratinocytes and fibroblasts. In: Journal of Vascular Surgery. 2013 ; Vol. 58, No. 2. pp. 433-439.
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AU - Marston, William A.

AU - Farber, Alik

AU - Kirsner, Robert

AU - Zhang, Yuxin

AU - Lee, Tommy D.

AU - Cargill, D. Innes

AU - Slade, Herbert B.

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N2 - Objective: To examine patient and wound variables presumed to influence healing outcomes in the context of therapeutic trials for chronic venous leg ulcers. Methods: This double-blind, vehicle-controlled study was conducted with randomized assignment to one of four cell therapy dose groups (n = 46, 43, 44, 45) or vehicle control (n = 50). A 2-week run-in period was used to exclude rapid healers and those with infection or uncontrolled edema. This was a multicenter (ambulatory, private, hospital-based and university-based practices, and wound care centers in North America) study. Adults ≥18 years old with chronic venous insufficiency associated with an uninfected venous leg ulcer (2-12 cm2 area, 6-104 weeks' duration) were included in the study. Excluded were pregnant or lactating women, wounds with exposed muscle, tendon or bone, patients unable to tolerate compression bandages, or patients who had exclusionary medical conditions or exposure to certain products. Exclusion during run-in included patients with infection, uncontrolled severe edema or with healing rates ≥0.349 cm/2 wk. Screen fail rate was 37% (134/362), and the withdrawal rate was ∼10% (23 of 228). Growth-arrested neonatal dermal fibroblasts and keratinocytes were delivered via pump spray in a fibrin sealant-based matrix, plus a foam dressing and four-layer compression bandaging. Treatment continued for 12 weeks or until healed, whichever occurred first. Patient demographic and wound-related variables were evaluated for influence on complete wound healing in all patients, as well as the subsets of treated and control patients. Results: Wound duration (P =.004) and the presence of specific quantities of certain bacterial species (P <.001) affected healing in the vehicle group, while healing in the cell-treated groups was influenced by wound duration (P =.012), wound area (P =.026), wound location (P =.011), and specific quantities of certain bacterial species (P =.002). Age, sex, race, diabetes, HbA1C, peripheral neuropathy, and serum prealbumin did not significantly affect healing. Body mass index was positively associated with healing in cell-treated patients. Conclusions: Wound duration is a quantifiable surrogate for one or more undefined variables that can have a profound negative effect on venous leg ulcer healing. Although cell therapy overcame barriers to healing, the only specific barrier identified was the presence of certain bacterial species. Interventional trials of potentially effective new therapies can be most informative when patients with suspected barriers to healing are included. The specific measurement of candidate barriers such as microbial pathogens, wound inflammatory state, and fibroblast function should be considered in future randomized trials to improve our understanding of the basis for chronicity.

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