Recent advancements in biopolymer and metal nanoparticle-based materials in diabetic wound healing management

Abstract

Currently, diabetes mellitus (DM) accelerated diabetic foot ulcer (DFU) remains vivacious health problem related with delayed healing and high amputation rates which leads to enormous clinical obligation. Keeping in view of the foregoing, researchers have been made in their efforts to develop novel materials which accelerate delayed wound healing in the diabetic patient and reduce the adversative influences of DFUs. The most prominent materials used for the wound healing application have biocompatibility, low cytotoxicity, excellent biodegradable properties, and antimicrobial activity properties. Utilization of nanoparticles has emerged as a protruding scientific and technological revolution in controlling DFUs. Biopolymers in combination with bioactive nanoparticles having antimicrobial, antibacterial, and anti-inflammatory properties have great potential in wound care to enhance the healing process of diabetic wound infectious. Combination of antibacterial nanoparticles like silver nanoparticles (AgNPs), gold nanoparticles (AuNPs), copper nanoparticles (CuNPs) etc. with polymeric matrix could efficiently inhibit bacterial growth and at the same time fastens the healing process of a wound. This review briefed the recent development of different natural polymers and antibacterial nanoparticles to mitigate the diabetes mellitus based DFU.

Introduction

Diabetes mellitus (DM) is a deficiency of insulin secretion and metabolic disorder of multiple etiologies characterized by a chronic proliferation in blood sugar level with distraction in carbohydrate, fat and protein metabolism resulting in the abnormal functioning of insulin in the body. The long-term action of diabetes as shown in Fig. 1 leads to problems such as impaired wound healing and the development of chronic nonhealing foot ulcerations leading to severe depression and mortality [1].

The epidemiological study between the increased number of patients with diabetes mellitus with some selected years is mentioned in the Table 1. According to the estimation, approximately 50%–70% of all the limb amputations are due to diabetic foot ulcer (DFU) and it was reported that in every 30 s, one leg is amputated due to DFU in worldwide [2,3].

Diabetic extremity ulcers developed in approximately 15% of people with diabetes and are the towering cause of hospitalization and amputation in patients [2].

There are 2 different types of wounds i.e. acute wounds including surgical wounds, traumatic wounds, burns which are healed quickly whereas chronic wounds including pressure ulcers, leg ulcers, diabetic foot ulcers, fungating wounds take a longer time to heal [3,6,7].

As reported [[8], [9], [10]], diabetes is subdivided into 4 types: (1) Type 1 diabetes which occurs from autoimmune beta-cell destruction in the pancreas followed by a deficiency of insulin formation, (2) Type 2 diabetes which occurs due to an uncommon upturn in opposing the action of insulin and inability to create required quantity of insulin to overwhelmed this resistance, (3) Gestational diabetes which arises due to glucose intolerance and mostly resulted in females during pregnancy, (4) other diabetes are resulted by specific genetic defects of beta-cell function, illness of the pancreas, drugs or chemicals etc. [11].

Wound healing takes place in four different phases (i) hemostasis phase, (ii) inflammatory phase, (iii) proliferation phase and (iv) remodeling phase. These phases are represented in Fig. 2 and were well explained by various researchers [[12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]]. As shown in Fig. 2, an acute wound could heal linearly through various healing phases. However, the wound healing process in case of DFU is not as identical as acute wound healing because the healing process may discontinue at any one or more phases. Therefore, it is always recommended to afford a favorable environment to increase the rate of wound healing of DFUs infections and keep away the healing from contamination/infection for a longer period [28,29].

Zhang et al. [31] analyzed that BMI levels were well correlated with DFU and it was suggested that BMI levels of DFU patients are lower than in patients without DFU. Similarly, it was also reported that DFU and retinopathy are very much interconnected [32]. From various studies, it was observed that DFU patients with retinopathy suffered from dysfunctional vasodilation [33], diabetic biomarkers like plasma uric acid and ceruloplasmin in type 2 diabetic patients [[34], [35], [36], [37]].

Therefore, a development in wound healing material which ideally meets the demands of rapid wound closure and complete healing of the wound is a vital issue. An ideal wound healing material should possess several characteristics, as well as conditions at the time of selection such as, it should be cost-effective, biocompatible, non-toxic, low adherence to skin, should provide a moist wound environment, permission of diffusion of gases, thermal insulation (temperature and pH must be controlled), prevention of infection i.e. protection of wound from microorganisms, antibacterial activity [38,39]. Selection of wound healing material is very much subjective because of extreme complications linked to diabetes. The important properties need to consider during the selection of wound healing material are represented in Fig. 3.

The patients with impaired, the hard-to-heal wounds need innovative methods and novel strategies to decrease the infection, accelerating the wound healing process, nourishing the wound, faster wound closing and reducing scar formation. In recent years there has been a rapid increase in drug-resistant microbes and significantly increased resistance to common antibiotics. Therefore, great efforts have been made by researchers for the development of new technologies which could quickly clean the wound from invading bacteria and capable to deliver antibiotics for DFU infections. Among various newly developed technologies, nanotechnology and nanomaterials have been renovating the diagnosis of diabetic wound healing. Biopolymeric materials like cellulose, starch, chitosan, collagen etc., stimulate wound healing by fibrogenesis [[43], [44], [45], [46]]. In recent years, nanoparticles such as silver, gold, and zinc having antibacterial, antibiotic properties along with low in vivo toxicity were contributed an incomparable approach to accelerate the wound healing of delayed acute and chronic wounds. Further, nanoparticle embedded natural polymer based were used as potential wound dressing materials [47]. When nanoparticles incorporated with biopolymeric materials, it acts as a potential wound healing material in the treatment of diabetic ulcer wound.

This review is an attempt to synopsize the potentiality of the natural biopolymers, metal, and metal oxide nanoparticles, and also composite of the biopolymer within the treatment of DFUs infectious.