Diabetic foot ulcer is a preventable complication of diabetes that imposes a significant burden on the community. It leads to amputation and increased disability if left untreated and thus bears profound implications on the individual, the community and the health system at large. Diabetic foot (DF) is an area of research interest where interdisciplinary researchers are trying to elucidate the best strategy to halt the progression of chronic diabetic wounds. It is an area where tissue engineering research is making a strong impact through the use of scaffolds and skin substitutes for diabetic wound healing. This review aims at discussing the geographical health economics, its impact on healing and factors influencing financial costs of DFU. The upcoming economic and clinical impacts due to disease outbreak such as the 2020 COVID-19 has also been discussed. Finally, it will discuss novel therapy available with emphasis on skin tissue engineering scaffolds with a cost-benefit analysis. The review aims at promoting better management of people with diabetes with emphasis on emerging treatments and technologies.

The primary aim of tissue engineering scaffolds is to mimic the in vivo environment and promote tissue growth. In this quest, a number of strategies have been developed such as enhancing cell–material interactions through modulation of scaffold physico–chemical parameters. However, more is required for scaffolds to relate to the cell natural environment. Growth factors (GFs) secreted by cells and extracellular matrix (ECM) are involved in both normal repair and abnormal remodeling. The direct use of GFs on their own or when incorporated within scaffolds represent a number of challenges such as release rate, stability and shelf-life. Small molecules have been proposed as promising alternatives to GFs as they are able to minimize or overcome many shortcomings of GFs, in particular immune response and instability. Despite the promise of small molecules in various TE applications, their direct use is limited by nonspecific adverse effects on non-target tissues and organs. Hence, they have been incorporated within scaffolds to localize their actions and control their release to target sites. However, scanty rationale is available which links the chemical structure of these molecules with their mode of action. We herewith review various small molecules either when used on their own or when incorporated within polymeric carriers/scaffolds for bone, cartilage, neural, adipose and skin tissue regeneration.

The engineering of polymeric scaffolds for tissue regeneration has known a phenomenal growth during the past decades as materials scientists seek to understand cell biology and cell–material behaviour. Statistical methods are being applied to physico-chemical properties of polymeric scaffolds for tissue engineering (TE) to guide through the complexity of experimental conditions. We have attempted using experimental in vitro data and physico-chemical data of electrospun polymeric scaffolds, tested for skin TE, to model scaffold performance using machine learning (ML) approach. Fibre diameter, pore diameter, water contact angle and Young's modulus were used to find a correlation with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of L929 fibroblasts cells on the scaffolds after 7 days. Six supervised learning algorithms were trained on the data using Seaborn/Scikit-learn Python libraries. After hyperparameter tuning, random forest regression yielded the highest accuracy of 62.74%. The predictive model was also correlated with in vivo data. This is a first preliminary study on ML methods for the prediction of cell–material interactions on nanofibrous scaffolds.

The use of non-invasive scaffold materials which can mimic the innate piezoelectric properties of biological tissues is a promising strategy to promote native tissue regeneration. Piezoelectric and cell instructive electrospun core–shell PDX/PHBV mats have been engineered to promote native tissue and skin regeneration. In depth physicochemical characterisation, in vitro and in vivo studies of a rat model showed that the 20/80 PDX/PHBV composition possessed the right balance of physicochemical and piezoelectric properties leading to enhanced fibroblast stimulation, proliferation and migration, reduced fibroblast-mediated contraction and macrophage-induced inflammation, improved keratinocyte proliferation, proper balance between endothelial cell phenotypes, decreased in vivo fibrosis and accelerated in vivo scarless wound regeneration. Overall, this study highlights the importance of exploiting cell–material interactions to match tissue biological needs to sustain the wound healing cascade.