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Diabetes affects more than 100 million people in the United States. Diabetic foot ulcers are a serious complication of this disease, occurring in 15% of people with diabetes. Diabetic foot ulcers (DFU) are non-healing wounds in the lower extremities that occur with loss of sensation, and are often resistant to treatment. This can quickly lead to infection, amputation, and in severe cases, patient morbidity. There is a lack of understanding in the field of the mechanisms of impaired healing in DFU, and very few in vitro models to study it. In order to better understand these non-healing wounds, our lab has fabricated in vitro 3D human skin-like tissues with patient-derived fibroblast cells isolated from the ulcer site. 

Initial characterization of these primary cells showed that diabetic foot ulcer fibroblasts (DFUF) exhibited abnormal fibronectin production (a factor in early wound healing). They also have a distinct gene expression profile compared to normal foot fibroblasts (NFF) from site-matched healthy controls or diabetic foot fibroblasts (DFF) from patients without ulcers. 

Fig. 1: Impaired wound healing and re-epithelialization in DFUF compared to DFF and NFF (Maione et.al, 2015)

Our SA model was used to examine the role of ECM deposition in an ulcer environment. Both diabetic fibroblast lines (DFUF and DFF) in this model exhibit impaired ECM production and assembly compared to the NFF control line.

Fig. 2: Impaired ECM deposition and reduced thickness in DFUF and DFF compared to NFF (Maione et.al, 2015)

This data has shown that we can create an in vitro ulcer environment using only fibroblasts and keratinocytes, however, in vivo wound healing contains many other cell types. Our current work focuses on the involvement of macrophages in wound healing. We incorporated macrophages from patient blood into our in vitro skin systems (HSE and SASE). This enables us to model the complex cross-talk between fibroblasts, macrophages, and keratinocytes during healing. We are looking forward to the results from these new experiments.

DFU Publications

Maione AG, Smith A, Kashpur O, et al. Altered ECM deposition by diabetic foot ulcer-derived fibroblasts implicates fibronectin in chronic wound repair. Wound Repair Regen. 2016;24(4):630–643.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500637/
 

Liang L, Stone RC, Stojadinovic O, et al. Integrative analysis of miRNA and mRNA paired expression profiling of primary fibroblast derived from diabetic foot ulcers reveals multiple impaired cellular functions. Wound Repair Regen. 2016;24(6):943–953. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470742/
 

Maione AG, Brudno Y, Stojadinovic O, et al. Three-dimensional human tissue models that incorporate diabetic foot ulcer-derived fibroblasts mimic in vivo features of chronic wounds. Tissue Eng Part C Methods. 2015;21(5):499–508. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410281/
 

Park LK, Maione AG, Smith A, et al. Genome-wide DNA methylation analysis identifies a metabolic memory profile in patient-derived diabetic foot ulcer fibroblasts. Epigenetics. 2014;9(10):1339–1349. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622843/

Diabetic Foot Ulcer Research

Using 3D skin models to understand the mechanisms behind diabetic ulcers