Antibacterial Cellulose Based Biomedical Hand Sanitizer: Current State and Future Trends

The spread of transmissible disease is considered as one of the main threats to public health [1]. The early symptoms of infection are sometimes non-specific and difficult to recognize, since most infectious diseases are caused by inadvertently contacting with pathogenic bacteria [2]. It therefore created a significant sanitation challenge to health care providers, and the effectiveness of hygiene primarily depends on the public compliance [3]. In general, handwashing is essential to remove the destructive bacterial from hands, thus lowering the threat of transmitting the disease to other individuals. The washing of hand can be implemented by either running water or waterless sanitizers [4]. Of which, handwashing with running water is considered as the most important and effective measure to prevent the transmission of infections. However, recent studies have shown that the compliance with water handwashing by healthcare workers is continuously decreasing to 20%-50% [5]. The deterrence to compliance includes the amount of time required for soap-and-water procedures with heavy workloads, skin irritation and dryness caused by frequently using of soap, and sometimes poor access to sinks [6]. Use of waterless hand sanitizers has thus been demonstrated as an alternative approach to overcome the above barriers to compliance. Hand sanitizers can be classified into two categories, alcohol-based and alcohol-free products. Of which, alcohol-based sanitizers typically contain 60%70% concentration of alcohol or other short-chained alcohols [7]. Received: December 11, 2019

As an effective antibacterial agent, alcohol can immediately denature the target organisms, thus effectively killing most pathogens. However, alcohol is volatile and can cause severe dehydration of skins at its high concentration (>60%). The remained ingredients after the evaporation of alcohol from skin would have very limited antibacterial activity. Another issue is associated with the ingestion of alcohol-based sanitizer [8]. It is toxic and can cause serious poisoning, especially for young children. Miller  while the number increased to 737 of total 1022 cases in 2007 [9].
Furthermore, alcohol-based sanitizer is highly flammable and is forbidden in its large volume for airplane or public transportation.
These data suggest that the use of alternative antibacterial actives might be a benefit in the medical/surgical setting. Alcohol-free formulations were thus been developed.  Paper coated with 0.023 g TCS-loaded NFC, c)

Alcohol-Free Sanitizer
Paper coated with 0.33 g TCS-loaded NFC. Reprinted with permission from Carbohydrate Polymers.
Alcohol-free sanitizer is generally based on disinfectants/antibacterial agents and possesses both immediate and persistent effect. Viable antibacterial agents, such as benzalkonium chloride (BAC) or triclosan, can be used for this purpose and are active at relatively low concentrations (<0.5%) [10]. 72 Shown in ( Figure   1) is a triclosan-based antibacterial formulation reported by Liu et al. [11].The triclosan (TCS) particles were loaded onto nano fibrillated cellulose (NFC) to prepare the antibacterial emulsion, which was then coated on the paper surface to test its antibacterial efficiency against Escherichia coli (E. coli, ATCC 11229). The results showed that 98.7% of the growth inhibition of bacteria (GIB) could be achieved at 0.023 g TCS-loaded NFC (Figure 2), which suggested a great potential of this triclosan-based emulsion for the medical use The alcohol-free sanitizer is mild to hand skin without disrupting its outer protection oil layer. The fragrance-free property is especially favorable for the users who are sensitive to the scent.
Moreover, this type of hand sanitizer is financially superior over the alcohol-based products, especially for consumers who purchase in bulk such as schools or nosocomial offices.

Classification of Antimicrobial Agents
The selection of antimicrobial agents has to consider their antimicrobial activities, stability, side effects and cost [12]. The available antimicrobial agents for sanitizers can be classified into non-biobased and biobased agents. Of which, non-biobased agents, such as metal and their oxides, are widely used due to their unique sterilization activities towards wide variety of microbials [13].
They are usually present in the form of nanoparticles which can disrupt the unicellular membrane of microorganisms, thus leading to a decreased enzymatic activity. Besides metal oxides, Neosporin mupirocin and tetracycline can also be used as non-biobased antibacterial agents for the preparation of sanitizer [12]. As for the biobased antibacterial agents, a large group of low molecular weight compounds which are isolated from animals or plants, such as phenolics, terpenes, bacteriocins, peptides, fatty acids (lipids), organic acids as well as their compounds, can be used as biobased ingredients for antibacterial purpose [14]. Among them, Chitosan and polyphenols have been recognized as promising candidates of antimicrobial agents against a large spectrum of pathogens.
Chitosan (CS) is a natural cationic polysaccharide with excellent biodegradability and nontoxicity [15]. It can be subjected to various chemical modifications due to its abundant surface hydroxyl and amino groups.
Polyphenol, another type of representative antibacterial agent, has a wide range of applications such as pharmaceutical or food additives [16]. Particularly, polyphenol extracted from tea or fruits exhibits good water-solubility, which is especially suitable for the low-fat food and hydrophilic sanitizers. Despite its excellent performance, certain drawbacks still exist with this type of active oxidants, such as poor processing stability and undesired coloration during storage. A large number of studies has been conducted to address these issues, e.g. Sun et al. used sulfated nanocellulose (SCNC) as emulsifiers for stabilizing the gelatin-encapsulated tea polyphenol (G-TPP) and obtained well-entrapped SCNC-G-TPP capsules in their size of 92 ± 1nm (nanoscale) [17]. The residual TPP of SCNC-G-TPP was 85.7 ± 0.8% (HPLC Test) after a 6-day storage, which was much higher than that of G-TPP (44.9 ± 0.5%).
The decrease of TPP after 40 min of storage at high temperature  TEM image of SCNC-G-TPP (after storage for 6 days), showing the stable SCNC-stabilized TPP capsules (measuring bar of 0.5 μm) (TPP concentration of 0.05 g/100 mL for all samples; initial pH of 4 for all test tubes; end pH of 3.9 for tube #1, 3.9 for tube #2 and 3.8 for tube #3, respectively). Reprinted with permission from Cellulose.

Innovative Nanocellulose-Based Sanitizer
As for the selection of continuous phase for sanitizer, celluloseformed colloid can be considered as one of the candidates since it possesses ideal biocompatibility and excellent rheology properties. Cellulose, the most abundant biopolymer, consists of molecular chains of anhydro-D-glucopyranose units (AGU) [19].
Each AGU has three hydroxyl groups at its end ( Figure 4). Its solid state has both low order (amorphous) and high order (crystalline) regions in the molecular structure. Cellulose can be disintegrated into nano-sized particles (nanocellulose) through chemical, mechanical/ enzymatic treatments or their combinations [20][21][22]. Shown in (Figure 4)

Conclusion
The use of hand sanitizer as a supplement to water-washing provides an easy and efficient means of reducing the risk of cross-infection via body contact in the public area. Though the use of alcohol-based hand sanitizer is routine, it is now witnessing a continuous input for the developing of new alcohol-free sanitizer products. In particular, nanocellulose, an emerging biomaterial, is of great importance for the medical use due to its unique rheological properties. The innovative alcohol-free hand sanitizer formulated with nanocellulose, affords long-lasting antibacterial effect without skin dehydration, suits the public demand for green and healthy lifestyle.