Tissue Engineering-Based Strategies for Diabetic Foot Ulcer Management.

Significance: Diabetic foot ulcers (DFU) are a mounting problem with the increasingly frail population. Injuries that would otherwise heal are kept open by risk factors such as diabetes, obesity, and age-related conditions, which interferes with the natural wound healing processes. Recent Advances: This review summarizes recent advancements in the field of tissue engineering for the treatment of DFUs. FDA-approved approaches, including signaling-based therapies, stem cell therapies, and skin substitutes are summarized and cutting-edge experimental technologies that have the potential to manage chronic wounds, such as skin printing, skin organogenesis, skin self-assembly, and prevascularization, are discussed. Critical Issues: The standard of care for chronic wounds involves wound debridement, wound dressings, and resolving the underlying cause such as lowering the glycemic index and reducing wound pressure. Current DFU treatments are limited by low wound closure rates and poor regrown skin quality. New adjuvant therapies that facilitate wound closure in place of or in conjunction with standard care are critically needed. Future Directions: Tissue engineering strategies are limited by the plasticity of adult human cells. In addition to traditional techniques, genetic modification, although currently an emerging technology, has the potential to unlock human regeneration and can be incorporated in future therapeutics.

Fibroblast-Generated Extracellular Matrix Guides Anastomosis during Wound Healing in an Engineered Lymphatic Skin Flap.

A healthy lymphatic system is required to return excess interstitial fluid back to the venous circulation. However, up to 49% of breast cancer survivors eventually develop breast cancer-related lymphedema due to lymphatic injuries from lymph node dissections or biopsies performed to treat cancer. While early-stage lymphedema can be ameliorated by manual lymph drainage, no cure exists for late-stage lymphedema when lymph vessels become completely dysfunctional. A viable late-stage treatment is the autotransplantation of functional lymphatic vessels. Here we report on a novel engineered lymphatic flap that may eventually replace the skin flaps used in vascularized lymph vessel transfers. The engineered flap mimics the lymphatic and dermal compartments of the skin by guiding multi-layered tissue organization of mesenchymal stem cells and lymphatic endothelial cells with an aligned decellularized fibroblast matrix. The construct was tested in a novel bilayered wound healing model and implanted into athymic nude rats. The in vitro model demonstrated capillary invasion into the wound gaps and deposition of extracellular matrix fibers, which may guide anastomosis and vascular integration of the graft during wound healing. The construct successfully anastomosed in vivo, forming chimeric vessels of human and rat cells. Overall, our flap replacement has high potential for treating lymphedema.