Review

Nanotechnology in the Future Treatment of Diabetic Wounds

Robert A. Smith

Manuscript submitted June 2, 2020; accepted June 30, 2020.

Keywords: diabetes, nanotechnology, wound healing

Abstract

Diabetic wounds have a large and increasing burden on the healthcare of the UK. Currently, none of the standard treatment options for the treatment of diabetic wounds specifically target the physiological processes behind their enhanced severity. This review evaluated recent studies in the field of nanotechnology concerned with treating diabetic wounds. The studies had each developed novel therapeutics involving nanomedicines that sought to either enhance angiogenesis, the construction of new blood vessels, or increase collagen production, as well as limit the augmented inflammation, in wounds in diabetic rat or mice models. The investigations tended to either target specific anti-inflammatory or pro-proliferative receptors on endogenous cells, or transport growth factors to the wound. Previous studies have shown the beneficial effects of growth factors on healing, but they are easily broken down. By transporting them in nanoscaffolds and liposomes, it has been shown that the longevity of growth factors can be enhanced. Gold nanoparticle matrices have also been shown to have a beneficial effect on healing, by both conveying proliferative factors and independently triggering angiogenesis and collagen production. The most impressive results in the review were achieved by nanomedicines involving multiple growth factors, hence, the review will highlight the beneficial factors to wound healing and suggest a composite therapy to be trialled in the future. The review will evaluate each set of papers using similar nanomedicines and highlight the challenges of transferring this therapy to the clinic.

1. Introduction

Whilst diabetes is generally associated with diet and the gastrointestinal system, the disease also has a detrimental impact on wound healing, with significant clinical consequences if left untreated. Diabetic wounds are characterised by excessive inflammation, which damages healthy tissue and prevents an effective immune response and healing process [1]. Patients with diabetes are also more likely to suffer from an open wound in their lower extremities due to the peripheral neuropathy associated with diabetes [1]. Together, these factors increase the probability of infection, gangrene and amputation in diabetic patients [1].

The health care cost of diabetes is estimated to be $116 billion in the US, with over a quarter of that figure spent on the treatment of chronic diabetic wounds [2]. Furthermore, in the UK, lower limb amputations and aftercare costs almost 1% of the NHS (National Health Service) budget [3]. This problem is likely to intensify, with the Center for Disease Control and Prevention predicting that a third of the US adult population will have contracted diabetes by 2050 [4].

Given that the problems associated with diabetic wounds are so ubiquitous, it is surprising that NHS standard practice for treating diabetic wounds is non-specific; therapy involves cleaning and monitoring the wound [5]. Therefore, the clinical applications of nano-therapy that directly targets the defective healing processes associated with the diabetic wound could be widespread. The following review will seek to critically appraise the various studies in this field and evaluate their clinical applications. The most recent studies in the field will be evaluated, with an emphasis on 3 different therapeutics: Nanofiber scaffolds, gold nanoparticles and liposomes.

To fully outline the mechanisms and limitations of nanotherapy in diabetic wound healing, first a physiological and pathological context must be established concerning inflammation. Inflammation is an immediate and innate response to tissue damage and is usually not a prolonged state [6]. However, in diseases such as diabetes, inflammation can become a chronic phase [6]. This occurs mainly due to the hypoxia in the wound, induced by the high oxidative stress of a glucose rich environment [7]. This hypoxia has two critical effects: it reduces angiogenesis (the formation of new blood vessels) and it reduces the expression of multiple growth factors, thereby preventing the formation of a stable collagen matrix [7]. It is worth noting that whilst the formation of a stable collagen matrix requires multiple factors, such as FGF (fibroblast growth factor), EGF (epidermal growth factor) and PDGF (platelet-derived growth factor) amongst others, the process of angiogenesis is pinned upon the expression of VEGF (vascular endothelial growth factor) [6]. The vast majority of the investigations that are evaluated in this review have therefore looked at upregulating either angiogenesis, by targeting compounds in the VEGF pathway or by applying VEGF itself to the wounds directly, or collagen formation, by attempting to deliver growth factors to the wound or upregulating fibroblast proliferation, the key cell required to move the healing process beyond the inflammatory phase [8].

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