The Crucial Role of Vascularization and Lymphangiogenesis in Skin Reconstruction

Abstract

Background: The treatment of extensive skin defects and bradytrophic wounds remains a challenge in clinical practice. Despite emerging tissue engineering approaches, skin grafts and dermal substitutes are still the routine procedure for the majority of skin defects. Here, we review the role of vascularization and lymphangiogenesis for skin grafting and dermal substitutes from the clinician’s perspective. Summary: Graft revascularization is a dynamic combination of inosculation, angiogenesis, and vasculogenesis. The majority of a graft’s microvasculature regresses and is replaced by ingrowing microvessels from the wound bed, finally resulting in a chimeric microvascular network. After inosculation within 48–72 h, the graft is re-oxygenated. In contrast to skin grafts, the vascularization of dermal substitutes is slow and dependent on the ingrowth of vessel-forming angiogenic cells. Preclinical angiogenic strategies with adipose tissue-derived isolates are appealing for the treatment of difficult wounds and may markedly accelerate skin reconstruction in the future. However, their translation from bench to bedside is still restricted by major regulatory restrictions. Finally, the lymphatic system contributes to edema reduction and the removal of local wound debris. Therapeutic lymphangiogenesis is an emerging field of research in skin reconstruction. Key Messages: For the successful engraftment of skin grafts and dermal substitutes, the rapid formation of a microvascular network is of pivotal importance. Hence, to understand the biological processes behind revascularization of skin substitutes and to implement this knowledge into clinical practice is a prerequisite when treating skin defects. Furthermore, a functional lymphatic drainage crucially contributes to the engraftment of skin substitutes.

PF-127 hydrogel plus sodium ascorbyl phosphate improves Wharton’s jelly mesenchymal stem cell-mediated skin wound healing in mice

“…This result implied better granulation tissue regeneration in the WJMSCs/PF-127/ SAP group. Angiogenesis, a crucial event occurring during the entire wound healing process from the initial inflammation response stage until the end of the tissue remodeling stage, is involved in the restoration of blood flow and transportation of nutrients to the injured site [40]. In this study, immunohistochemical staining of CD31 was carried out to assess neovascularization.…”

Bioengineered Skin Substitutes: The Role of Extracellular Matrix and Vascularization in the Healing of Deep Wounds

“…Finally, neither elastin nor adnexa were present, and differentiation of fibroblasts in myofibroblasts was observed. On the basis of such findings two main issues affecting the DRT emerge: (i) the lack of vascularization [22,23]; and (ii) the limited capability in inducing regeneration instead of repairing processes [135]. The take of the STSG has huge implications related to the repairing process, patient mortality, and morbidity and healthcare costs.…”

“…Indeed, a low take percentage increases the number of re-grafts and the risk of infection by causing either the death of the patient or an increase of hospitalization time in case of morbidity. To increase the take of STSGs, new emerging strategies involve the use of pre-vascularized DRTs [22,23,33,34,36]. By seeding a DRT with adipose tissue-derived microvasculature fragments, a faster vascularization after implants was observed [138].…”

“…Although further investigations are currently being conducted of a more representative wound model, such data are encouraging. In addition to vascularization, which has been recognized as a critical issue [22,23,25,33,34] affecting the effectiveness of a DRT, the described tissue engineered strategy allows the fabrication of a DRT composed of a native extracellular matrix starting from a small number of fibroblasts derived from the patient. In this way, the risks associated with the allogenic nature of the cells and the impaired ECM assembly during wound closure, can be drastically reduced.…”

“…After this time, it is possible to apply a split thickness skin graft (STSG): an epidermis with a layer of dermis removed from healthy sites of the patient. Both vascularization and fibroblast-secreted ECM molecules affect the take of the STSG that serves to trigger the regeneration of the epidermis due to the lack of adnexa and basal lamina [22][23][24][25][26]. As shown in Figure 2, with a period of two years, the remodeling of the neodermis occurs.…”