Different Types Of Sterilisation Procedures For Hydrogel Dressings In Wound Healing

Give detailed information on the different types of sterilisation procedures followed for hydrogel dressings in wound healing and will also elaborate on the GMP guidelines that must be followed during the production of these wound dressing devices.

Sterilisation and Hydrogel Dressings

Sterilization is a process that is known to eliminate or kills all forms of biological agents like bacteria, fungi, viruses, prions and many others that are found on specified regions of many surgical instruments, medications, biological cultural media and few others (Rutala & Weber, 2014). This process can be achieved by heating, exerting high pressure and filtration. Hydrogel is a hydrophilic network of polymer chain and are highly absorbent. They are extremely flexible due to their 90% of water content. The composition of hydrogel product includes a group of polymers that are proficient of holding water in large amount in their three-dimensional polymeric network. The polymeric network is a cross linkage between dextran and dextran sulphate (Karperien et al., 2015). This is an insoluble polymer and is semi-occlusive in nature. Synthetic hydrogels are more favoured because of their higher capacity of water consumption, longevity in service and availability of raw chemicals of wide varieties. Usually many forms of hydrogel are available, some of them are amorphous hydrogel, which is a free flowing gel, impregnated hydrogel, which is naturally saturated, and another is sheet hydrogel, which is a combination of these gels. There are many biomedical application of hydrogel known today. This is widely used in dressing since it helps to control the exchange of fluid on the surface of the wound (Fan et al., 2014). This provide an excellent moisture to a dry injury and acts by cooling down the lesion. They are known to hydrate wound and there usage should be avoided in wounds from which large amount of exudates are oozing out. This moisturized condition assist in the protection of wound from any bacterial infection and this in turn helps in healing process. Hydrogel provide a soothing effect on burns. The ingredients of hydrogel wound dressing include water and humectants. The main humectant is glycerin that generally attracts and binds to the water or to the product. Beside this, it is also used in producing contact lenses, cell therapeutics, regeneration of cartilage bone and in delivery of drugs as well (Caló & Khutoryanskiy, 2015). Hydrogels are favoured due to their flexibility and serve as scaffolds to provide an integrity in structure during construction of tissues. For producing contact lenses polymeric hydrogel should have some ideal physical properties like luminous transmittance value of minimum 95%, refractive index of 1.3, sufficient oxygen permeability and many others. In regeneration of bones, Alginate hydrogel has been found to be a potential tool due to its biocompatibility nature. In the purpose of cardiac repair injectable hydrogels are also used. This injection attenuates the cardiac function after myocardial infarction. In drug delivery, hydrogels are also used to increase the effect of the drug and to decrease the side effects simultaneously (Yahia et al., 2015).

The process of sterilization involves any procedure that is focused on eliminating, removing or deactivating all forms of life and biological agents in healthcare settings. The primary objective of the research is to identify the importance of hydrogels and the sterilization process that is best suited for this hydrogels.

Hydrogel Dressings and Biomedical Applications

The research objectives are mentioned below:

• To identify the various kinds of sterilization procedures that are utilized at healthcare services
• To recognize the best procedure that can be used for sterilizing hydrogels
• To identify the current Good Manufacturing Practices for a range of medical devices
• To recognize the Australian guidelines that pertain to these Good Manufacturing Practices

The research question forms the fundamental core of a study or project that encompasses a thorough review of literature. This research question helps to focus the study and also facilitates the process of determining the research methodology. The research question was kept succinct and comprehensive and is given below:

What is the best sterilization procedure for hydrogels?

This research question will serve the purpose of guiding all the stages of literature search, and analysis, followed by a reporting of the findings.

There are a range of benefits that can be achieved upon using hydrogel-based dressings in healthcare settings. Hydrogels are primarily used for wound healing. These act as an excellent hydrating source that provides moisture to the skin at the wound site, which might contain a dry lesion. The widespread use of hydrogel as effective dressings for wound cleaning can be attributed to the fact that these polymer gels have self-healing properties, and are able to act at a rapid rate, thereby assisting the wound site to cool down (Kamoun, Kenawy & Chen, 2017). These polymer gels have also been found effectiveness in providing temporary relief to patients undergoing dressings, from the severity of pain. Therefore, hydrogels have been found to exert a temporary analgesic effect at site of injury, for approximately six hours (Boateng & Catanzano, 2015).

Owing to the high amount of moisture that is provided to the lesion or wound site, from the hydrogel polymer dressings, a range of healing phases that encompass stages such as, repair of the epidermal cells, granulation, and removal of an excess dead and damaged tissue get facilitated. In addition to assisting the stages that are an integral part of wound healing, these hydrogels also result in an elimination or reduction of potential discomfort from the site of injury (Dumville et al., 2014). The high prevalence of wound infection that might be deep or superficial signifies the need of administering sterilized dressings to prevent a deterioration of the lesion site (Madaghiele et al., 2014).

Owing to the fact that infections that affect the wound sites are found to significantly contribute to maximum cases of hospital acquired infections that result in an increased rate of mortality and associated morbidity, proper efforts must be taken to recognize manage the spread of pathogens at sites of injury (Fry, 2013). Infection can also occur during direct transfer of the hydrogels at the dressing site, thereby contributing to contamination of the lesion region. Thus, the research is based on discovering the appropriate sterilization procedure that will prevent pathogen infection of the hydrogel, thereby significantly contributing to a reduction in wound infection rates.

To identify the various kinds of sterilization procedures that are utilized at healthcare services

In healthcare services, it is very important to have a proper method of sterilization. Most commonly majority of sterilization process is heat based. The two different types of heat-based method includes moist heat sterilization and dry heat sterilization. Moist heat sterilization or steam heat sterilization is a method that is based on the usage of steam at high temperature (121 degree Celsius to 134 degree Celsius), moisture and are achieved by the help of an enclosed device called autoclave.  An autoclave is known to sterilize various medical devices by utilizing pressurized steam. Another important effect of moist-heat sterilization can be observed on fabricated nanoscale solid lipid particle that contain rasagilinemesylate. The moist heat sterilization process is selected since it is the most effective in maintaining the intact composition of drug and the carrier and in preventing the leakage of drug from its carrier (Viveksarathi&Kannan, 2015). This process of steam sterilization generally involves three stages namely, (1) replacing all air with steam, with the use of vacuum pumps; (2) using temperature control for sterilisation; and (3) utilizing the method of steam evacuation for drying phase (Galante et al., 2017). According to Eljarrat?Binstock et al., (2007) autoclave sterilisation are used for preparing cylindrical HEMA hydrogels with 70% water. While, some hydrogels were left for polymerization for 24 hours, others were left for only 5 hours.

Importance of Sterilisation of Hydrogel Dressings

Dry heat sterilization is another process of sterilization practiced in medical and pharmaceutical industry that is based on the usage of hot air oven method. This method is advantageous to products that are moisture sensitive. This process is involved in the removal of pyrogen completely when done in glass and other laboratory instruments. Hot air oven method was proposed by Louis Pasteur in which products that are exposed to 160⁰ C for one hour. This is performed in an electrically heated oven and acts by denaturation of protein. Articles that are heat sensitive in nature are avoided to undergo this process of stabilization (Purohit & Gupta, 2017). The sterilisation chamber depicted below ensures even heat distribution at all locations. The mechanism of microbial inactivation encompasses cell component oxidation. Bacillus subtilis spores are generally used for validation of the process. Furthermore, this sterilisation method can be used for heat resistant materials such as, metal, glass, and silicone that are impermeable to steam (Galante et al., 2017).                                                                   

Another well-known type of sterilization that is typically followed in case of medical devices, tools and instruments is liquid chemical sterilization process. This is used in articles that are sensitive to heat but are insensitive to liquid. In this process, the object is immersed for a specific amount of time in a sterilizing liquid like peracetic acid, glutaraldehyde or combination of both. This process is very efficient in killing bacterial endospores and microorganisms. Some critical items like surgical instruments, urinary catheters, cardiac catheters, ultrasounds probes can be sterilized by treating with chlorine based products, hydrogen peroxide, phenolic compounds, ammonium compounds and alcohol. Semi critical items like anesthesia and respiratory therapy equipment, laryngoscopes, prostrate biopsy probes, diaphragm fitting rings, endocavity probes should be devoid of all kinds of microorganisms. They minimally require the usage of high level chemical disinfectants like orhto-phthalaldehyde, chlorine, gluteraldehyde and are exposed at 20⁰ C to 25⁰ C for 8 to 45 minutes (Rutala & Weber, 2013).

Few other sterilization processes are toxic gas and radiation sterilization. Toxic gas sterilization is done on objects that are sensitive to heat or liquid. The most efficient and widely used gas is ethylene oxide, which is a highly explosive and toxic even at low concentration. One of the main advantage of this method is that it requires low temperature and can be carried out in some simple containers. The main disadvantage is that they are highly toxic as well as inflammable (Sinclair & Dhingra, 2017).

Radiation sterilization are performed for drug delivery systems that are used to target tissue or organs. Gamma and beta rays are used to sterilize microspheres, liposomal systems, nanospheres and microemulsion by e-sterilization (Abuhano?lu & Özer, 2014). Radioisotope decay like radiation of gamma from cobalt 60 and electron are the most well-known types of ionizing radiation. In case of gamma irradiation, the sterilization conditions referred to a dose of 25 Kg of absorbed radiation. If proper validation process is given, other levels can also be employed. This Gamma irradiation are mostly used in pharmaceutical formulation and in some medical devices like needles, syringes and cannulas. The main advantage of this kind of irradiation are it ensures a good product sterility, it has high penetration power, it can be operated at low temperature, chemical residues are absent and the product is available immediate after sterilization. The disadvantage is that since the process is complex, it always demands well skilled and trained staff along with a specially built and designed installation (Galante et al., 2017). The authors emphasized on the fact that sterile products are generally obtained by terminal sterilization or aseptic processing. Thus, an aseptic process should involve all product manufacturing materials such as, drugs, containers, raw materials, and closures, each one of which will be separately sterilized. This is generally followed by bringing them under operating conditions that help in maintaining the sterility of the wound dressing product, thereby eliminating or preventing all kinds of microbial contamination.

Features	Moist heat sterilization	Dry heat sterilization	Liquid chemical Sterilization	Toxic gas Sterilization	Radiation sterilization
Process	Also known as Steam heat(SH) sterilization and the process includes an autoclave where the materials are exposed to a saturated steam and under high pressure.	In comparison to SH, dry heat sterilization process requires longer time of exposure and higher temperature.	In this process the material is immersed in a sterilizing solution like ethyl alcohol or isopropyl alcohol.	Gases such as ethylene oxide, ozone and hydrogen peroxide are used in this process of sterilization. Steps are vacuum, humidification, admission of gas, sterilization, postvacuum and aeration.	This process use gamma and beta rays to sterilize microspheres and liposomes used in drug delivery system.
Advantage	This process cause the destruction of microorganism effectively. This also maintain the intact composition of the drug and carrier.	It is simple method and are used in heat resistant products.	This process is effective in eliminating microorganisms from materials that are sensitive to heat.	It requires low temperature and can be done in simple container.	It has higher penetration rate, no chemical residue and can be operate at low temperature.
Disadvantage	Substances like powder and oils cannot be sterilized by this process.	Due to the exposure to high temperature and longer time, certain heat sensitive products may melt, distort and degrade.	The sterilant that is used may react with the material that is to be sterilized. This process require safe operation and it remains some toxic residues along with the product.	This process is highly inflammable and explosive.	This is a complex process and requires well skilled and trained staff as well as specially designed installations.

Moist Heat Sterilization and Dry Heat Sterilization

Table 1: Comparison between the sterilisation techniques

To recognize the best procedure that can be used for sterilizing hydrogels

Conventional methods of sterilization like heat or radiation is often sensitive towards hydrogels and sterilizing hydrogel is thus challenging to achieve. Though these techniques are involved in aseptic manufacturing, yet they may alter the original properties and structure. Eljarrat?Binstock et al., (2007) used several modes of hydrogel sterilisation such as, ethylene dioxide, autoclave, and γ-irradiation. Reductions in the dimensions of hydrogels were observed by 0.5mm in each direction (10%), with the use of ethylene dioxide. However, the process failed to bring about any significant impacts on water absorption properties. The hydrogel dimensions were reduced by 0.5mm and 1 mm in each direction, following steam sterilisation in an autoclave for 5 hours and 24 hours, respectively. An increase in weight by 3-5% was also observed. However, there was no significant change in the colour and shape of the dressings. On the other hand, γ-irradiation resulted in a 10-15% reduction in the water absorption capacity of hydrogels that were prepared with 75% water. γ-irradiation failed to induce any significant visual changes in the shape and size of the pore size, upon conducting a SEM imaging comparison (Eljarrat?Binstock et al., 2007).

Research evidences suggested that terminal sterilization is a safer mode of sterilization process to be performed in case of biological terms. This process is overall efficient as well as well accepted and should be done whenever possible. In case of synthetic hydrogels, synthetic polymers present wide degree of uniformity, better reproducibility and enables better detailing of properties. Hydrogels are available for wound dressing or contact lenses and some manufacturers preferred ethylene oxide in the sterilizing process. Researchers suggested that in SH sterilization when carried out in presence of electrolytes, the viscosity, gel adhesiveness, hardness and compressibility decreased (Tichý, Murányi & Pšenková, 2016). Poly vinyl alcohol and poly vinyl pyrrolidone hydrogels were gamma irradiated and an increasing in compressive modulus, tensile and compressive strength with different irradiation dose (Shi, Xiong & Zhang, 2014). Other researchers proposed that mechanical properties and swelling ratio of hydrogel remains unaffected after irradiating with gamma rays (Tohfafarosh et al., 2016). As compared to other materials, hydrogels are specifically more sensitive to sterilization methods. Very few research has been conducted to point out the best procedure for sterilizing hydrogels. Ozone gas terminal sterilization method used in sterilizing silicone based hydrogels are reported to be more potential since it does not leave any toxic residues and is also applicable to materials that are thermo-sensitive. Efficacy of ozone gas sterilization was monitored by analysing swelling, transparency, mechanical, topography and chemical composition of hydrogels. It was observed that sterilization using ozone gas is more effective and can be considered as an efficient and valid method for sterilization of synthetic hydrogels that are used in bio medics (Galante et al., 2017). The authors identified the role of gas sterilisation in decontaminating medical devices that are usually damaged by radiations or high temperatures. The efficiency of the process usually depends on gas concentration, exposure time, humidity, temperature, and load of the bioburden. Depending upon the sterilising agent, oxidation or alkylation of the chemical groups might occur to damage the nucleic acids and proteins. The authors also provided exhaustive information on sterilisation of hydrogel-based dressing devices and emphasized on biocompatibility of the devices for assuring patient safety.

GMP Guidelines for the Production of Wound Dressing Devices

Some of the most relevant characteristics of the hydrogels as identified by the authors include the following:

• Tribologic properties such as, wear friction that is needed for load bearing related biomedical uses
• Surface properties such as, surface chemistry and wettability that influences interaction with the biomolecules and tear film
• Rheological properties to determine flow and deformation
• Zeta potential and size to help in healing of specific organs and tissues (Galante et al., 2017)

In case of natural hydrogel, which are made up of natural polymers, one of the main advantage is their physiological similarity with extra cellular matrix. Natural polymers include polysaccharides such as, hyaluronic acid, cellulose, alginate and proteins such as collagen and gelatin. Research evidence suggested that in case of natural hydrogels containing hyaluronic acid the adverse effects of heat sterilization process could be decreased by controlling the concentration of hyaluronic acid. Researchers developed one of the suitable methods for sterilizing this hydrogel that involves the formation of amide bonds directly between hexamethylenediamine and carboxyl group of hyaluronic acid at a controlled pH (Szabó et al., 2013). Gamma-irradiation, lyophilation, gamma irradiation and ethylene oxide treatment have negative impact on alginate-based hydrogels. Research suggested that washing with ethanol is the best method since it affects mechanical properties and water retention minimally and eliminates persistent bacteria (Stoppel, et al., 2014). This is crucial to select one appropriate technique of sterilization that maintain the structural and biochemical integrity. Any perfect technique having no post sterilization effects has been identified, so, the sterilization technique should be controlled to minimize adverse effects (Dai et al., 2016). According to Galante et al., (2017), synthetic polymers show higher degree of uniformity, when compared to the natural counterparts. The article also suggested that application of γ-irradiation to hydrogels that are cured with thermal free radical initiator does not produce any noticeable adverse effects.

SEM images obtained from horizontally sectioned hydrogels demonstrated a superporous hydrogel comprised of interconnected channels that allowed fast water absorption. The three dimensional matrix interconnection made it difficult to measure the pore size of the freeze-dried HEMA hydrogel (Eljarrat?Binstock et al., 2007). Following a thermal analysis of the normalized DSC traces for dry HEMA hydrogels that had been polymerized for 5 hours and 24 hours, respectively, similar calorimetric behaviours were obtained for the three endothermic peaks at 60 (small), 195 (small), and 382°C (major). This indicated the presence of a transition change in hydrogels due to thermal changes at 382°C. Upon performing mechanical testing for the hydrogels, those with 75% water were found to be more elastic and flexible, when compared to 70% water, which was reflected in the small elastic modulus values.

Furthermore, the authors also indicated that the time of polymerization hydrogels failed to create significant impacts on their elastic property. The fast swelling ability of hydrogels is one of its essential features that can get changed depending on the drug solution. The drug type was thought to influence hydrogel swelling properties, regardless of the molecular charge. The TWC and swelling properties increase upon use of corticosteroids to 87.5%, in comparison to 73.5-76.3% TWC for water and other drugs. Feasibility of the hydrogels were also associated with the swelling time profile that was found to be largely influenced by the kind of drug solution in which the gels were immersed. A major portion (62–91%) of drug absorption was found to occur during the initial 10 minutes of gel immersion. Furthermore, the authors also emphasized on the fact that carboplatin molecules have highest diffusion properties, in the HEMA hydrogel. Approximately 91.2% of maximal drug amounts were found to get absorbed within 10 minutes (Eljarrat?Binstock et al., 2007).

Good Manufacturing Practices is a systemic process that ensures that the products and devices are produced consistently and the quality standards are controlled appropriately. It diminishes the risks involved in pharmaceutical products that cannot be eradicated (Nally, 2016). Good manufacturing practices require trained and qualified personnel, appropriate services and equipment, sufficient space and premises, sanctioned instructions and procedures according to Pharmaceutical Quality System, necessary transport and storage. GMP also require instructional form that should be written in clear and an unambiguous language, trained operators should carry out all the procedures correctly, recording of all the steps of the procedure should be done manually or by the help of some recording instruments. In case of any noteworthy deviations, an investigation of the root cause should be done. Moreover, implementation of suitable corrective and preventive action due to this deviation should be taken. Manufacturing records and distribution records should be retained in an accessible and comprehensible form so that the history of the batch can be traced completely. A good distribution practice should be followed as proper distribution of the pharmaceutical products minimize risk to their quality. For recalling any batch of product from stock or sale, a system should be developed and complaints regarding products should be examined. To prevent the reoccurrence of the quality defects, a proper investigation of defective products should be done. Wound care dressing products are made completely a standardization of naturally occurring food ingredients and are available in market by using guidelines of good manufacturing practices. These natural products are efficient and safe since they have suitable osmotic pressure that is well-suited with optimal healing. These products can also act as a buffer throughout the healing process to maintain an optimal pH and also act as a protective barrier to eliminate and control further irritation of the wound, bacteria, fungi and viruses. They are also known to nourish wounds, prolonged inflammation is controlled and hence scar and allergies are minimized. New food based wound dressing products are not commercially available due to problem in getting standardized Ingredients that are compatible to good manufacturing practices regulations. Though, these are more safe and efficient than recent standard care plan, yet it is not possible to increase their availability in hospitals, retail outlets and health care providers (Mcanalley, Mcanalley& Aguayo, 2009). Research evidence suggested that among all current existing technologies, electrospun drug eluting fibres is effective in healing of wound like ulcers and diabetic wounds. Fibres obtained after electrospinning are considered as an efficient non-healing wound dressing material. They are known to provide physical protection and can incorporate high amount of drugs to the wound. Some natural polymers like combination of chitosan and polyethylene oxide are employed in the process of electrospinning for dressing of wound (Gizaw et al., 2018).Some researchers suggested that using multifunctional device for wound monitoring can be used for improving the process of healing. The device should determine pH, glucose, lactate, temperature, oxygen and should monitor infection feedback and the time to change the dressing of the wound. The sensor in the device should be self-powered and this successful monitoring device will minimize doctor appointment (Brown, Ashley & Koh, 2018).  

The principle behind Australian guideline for manufacturing sterile medicinal products is based on the special requirement for minimizing the contamination of particulate matter, pyrogen and microbes. This special requirement involved skilled and trained personnel who can strictly follow the recognized methods of product preparation. According to Australian guideline for manufacturing sterile products involved a clean areas whose entry should be air locked and a well supply of air in the area that has passed via filters should be maintained. The preparation of any component and product should be done in a clean area for minimizing the risk of microbial contamination (Manufacturing medical devices & IVDs, 2018).            .

There are two categories of manufacturing operations, first one includes the products that are terminally sterilized and the second one includes the products that are sterilized at all stages. Australian guideline distinguish four grades for manufacturing sterile products. Grade A includes all the local zones like filling zones, vials, open ampoules and stopper bowls that are at high risk for operation. A laminar air flow should be arranged at the working position that maintains an homogeneous air flow of speed 0.45m/s. Grade B includes the filling and preparation of aseptic in environment similar to grade A zone. Grade C and D includes the clean areas where less critical stages are carried out for manufacturing sterile products. There is a necessity to provide appropriate filters like HEPA for proper filtration of particulate matter in air system (Bischoff et al., 2107). Monitoring of areas where aseptic operations are done should be performed frequently using methods like volumetric air, settle plates and surface sampling using swabs. Interferences between sampling methods and zone protection should be avoided and monitoring surfaces and personnel after critical operations should be performed. This guideline also mentioned the utilization of isolator technology that reduce the interventions of human and the level of contamination. These isolators are constructed using materials that are more or less inclined to leakage and puncture (Yun & Chen, 2016). Isolator should be validated appropriately by routinely monitoring the integrity of isolator, sanitation of the isolator and the inside and outside air quality of the isolator. A minimum number of personnel should be involved in cleaned areas during aseptic processing. All personnel should be well trained and skilled enough in disciplines related to manufacturing of sterile products correctly, proper hygiene and microbiology. A better standard of hygiene and cleanliness of personnel is very much crucial to minimize the contamination and this include avoiding the usage of wristwatches, jewellery and make-up articles in clean areas. A good quality clothing should be worn to prevent the product from contamination. In changing room, usage of outdoor clothing should be avoided. Usage of face mask, suitable sterilized plastic gloves and disinfected footwear should be used. The premises of health care should be smoothed and unbroken that will help to reduce the accumulation of microorganisms and the premises should be cleaned using disinfectants regularly (Manufacturing medical devices & IVDs, 2018).

The methodology section encompasses actions that are required to be taken for investigating a research problem and the rationale that will help in application of a set of procedures for identifying, selecting, processing and analysing the information applied. This in turn facilitates critical evaluation of the overall reliability and validity of the study. In other words, the methodology section will describe broad philosophical underpinnings to the selected research methods, and will also provide exhaustive information on the use of quantitative or qualitative methods, or a mixture of both of them (Moher et al., 2015). This chapter sets out the different steps involved in conduction of a systematic review. The steps commonly comprise of the following, namely, 1) Research Question Formulation 2) Review of the inclusion and exclusion criteria 3) Literature search 4) Selection of the study and collection of data 5) Data extraction 6) Quality analysis 7) Data analysis, followed by synthesis.

Research design

This refers to a set of procedures and methods that will be used for the collection and analysis of measures of the variables that are mentioned in the research question. This research is a qualitative design that will include observations of non-numerical data that pertain to the concepts, meanings and descriptions of the research questions, to be formulated for the systematic review (Vaismoradi, Turunen & Bondas, 2013).

There is a need of healthcare professionals to rely on best available evidences that help in supporting current healthcare practice. This creates provisions for the patients to rely on the professionals for having adequate and updated clinical expertise. It is imperative to their scope of practice that these healthcare professionals do not participate in making essential healthcare decisions regarding their practice, based on data collected from limited studies. This significantly contributes to several detrimental effects on the patients, provided the research is not confirmed by supporting evidences or lacks reliability (Myers, Well & Lorch Jr, 2013). In other words, systematic reviews are able to provide an overview of studies that are related to the particular research question. These systematic reviews help in conducting a rigorous searching of relevant articles, followed by retrieval of relevant information that is critically appraised and synthesized. Thus, systematic reviews are considered as highest forms of evidence, based on hierarchies of the collected scientific evidence (Schwartz-Shea & Yanow, 2013).

This can be attributed to the fact that evidence based medicine and nursing needs the integration of clinical evidences that are based on recommendations and judgment from best available literature and patient values (McGowan et al., 2016). Placing or organizing the available literature into a predetermined hierarchy creates provisions of a better communication, while discussing the studies and also establishes appropriate recommendations for healthcare practice. These hierarchies of evidence rank the literature according to the extent of validity of the key findings. Systematic review is defined by the Cochrane Library Glossary of Terms as reviews of clearly formulated questions that use explicit and systematic methods for identification, selection, and critical appraisal of relevant research articles. This in turn facilitates the process of collection and analysis of data from the identified studies, included in the review. Meta-analysis or statistical methods might be also used for analysing and summarising results of the included studies. Therefore, the primary objective of a systematic review pertains to allow healthcare professionals and researchers take informed decisions, related to their area of work, with the utilization of best available evidences (Moher et al., 2015).

Quality of the research helps in determining the overall quality of the systematic review. Systematic reviews also take attempts for bias minimization, when compared to literature reviews that have the potential of giving result bias. This can be attributed to the fact that traditional literature reviews generally do not follow a proper strategic research process. Furthermore, these literature reviews also do not synthesise or analyse evidence based data in systematic ways (Lewis, 2015). In addition, they also fail to conduct rigorous quality appraisal of the studies that have been extracted. Furthermore, literature reviews also display an inherent tendency of not dealing with conflicting studies, thereby resulting in bias in the results. However, one of the primary differences between a literature review and a systematic review is that the latter, several rigorous steps are involved in conduction of the review, to reduce bias.

The question that is meant to be answered by the systematic review aims is kept clear, succinct and concise, owing to the fact that the answers extracted from the review will create a major influence on the process of clinical decision making. Formulation of a generalized and broad question will result in bias in the results and might fail to address the exact needs of the literature (Marczyk, DeMatteo & Festinger, 2017). Thus, systematic review question formulation also encompasses the process of including the background information that helps in providing an overview on the reasons for conducting the research and will also ensure delivery of appropriate information. This systematic review will be based on seven questions that are cited below:

1. What is the process of sterilization?
2. What is the importance of sterilization?
3. What are the different methods of sterilization?
4. What are hydro-gel sterilization and its importance in the field of wound dressing?
5. What are the various methods for hydro-gel sterilization and the best methods applied for the same?
6. What are Goods Manufacturing Practices for wound dressing devices?
7. What are the Therapeutic Goods Administration (TGA) guidelines followed in
   Australia for the same?

Formulation of the research question helped in the determination of the inclusion and exclusion criteria, and the search strategy, thereby assisting in the retrieval of appropriate research articles. The aforementioned clinical questions were unambiguous, clear and structured.

Inclusion and exclusion criteria refer to characteristics that prospective studies must contain, if they are to be included or eliminated from the research (Demaerschalk et al., 2016). The inclusion and exclusion criteria were not kept narrow, for extracting enough data that would help in conduction of the systematic review. The inclusion criteria for the following systematic review were the following:

• Articles published in English
• Studies that focused on sterilization process
• Articles containing information on importance of sterilization
• Articles that were published on or after 2010.
• Articles that focused on hydro-gel and their sterilization
• Articles on importance of hydro-gels
• Articles that contained information on GMP practices

The exclusion criteria for the systematic review are given below:

• Unpublished manuscripts
• Abstracts
• Articles published in foreign languages
• Articles published prior to 2010

This is one of the vital steps in conduction of the systematic review and is greatly influenced by the relevance of the articles that are included in the studies. Thus, the literature search was conducted with extreme scientific rigour. Three electronic databases, namely, PubMed, Google Scholar and CINAHL were searched for retrieving relevant data. An appropriate search strategy was employed for extracting articles that met the inclusion criteria, from the database. This search strategy refers to an organised structure of search terms or phrases that were utilized for searching the three databases (Boell & Cecez-Kecmanovic, 2014). The search strategy combined key concepts of the research questions that helped in retrieval of accurate results. The major search terms included ‘sterilisation’, ‘sterilised’, ‘hydrogel’, ‘hydro-gels’, ‘goods manufacturing practices’, ‘GMP’, ‘dressing’, ‘wound’, ‘Australia’, ‘GMP guidelines’, ‘therapeutic’, and ‘methods’. These key terms were combined with the use of Boolean operators ‘AND’, ‘OR’, and ‘NOT’ that helped in connecting between the terms, thereby forming a relationship between the search terms. Use of ‘AND’ narrowed down the search results and helped in retrieving all records that contained the search terms. The operator ‘OR’ broadened the search by forming a connection between two or more synonyms.

On the other hand, the ‘NOT’ operator excluded terms that were irrelevant to the research questions. Truncations (*) were used for retrieving root words that had multiple endings such as, sterilized* gave hits that contained the terms sterilization, sterilization, and sterilize. In addition, wild cards (?) were also used that acted as a substitute for a particular letter in the key phrases such as, sterili?ation gave article hits that contained both British and American spellings of the words.

Following a thorough reading of the article titles and abstracts, the articles that fit the inclusion criteria were selected. Each article were analysed for determining their relevance to the research question. This was followed by exclusion of duplicate articles and those that did not meet the relevant criteria (Machi & McEvoy, 2016). Maintaining precision in this step ensured that all studies included in the review answered the research question appropriately. Appraising the quality of evidence encompassed the procedure of systematically examining these evidences for assessing their validity, and relevance before forming a clinical decision (Turner, 2013). The data obtained from articles selected for the review were later on organized into themes or patterns, for presenting answers to the different research questions. This thematic analysis emphasized on examining and pinpointing patterns that are present within the data. Thus, thematic analysis facilitated the process of identifying specific domains across the dataset.

Biases refer to the consistent deviations from an accurate fact or the truth. Different types of biases that might be encountered in research studies include selection bias, attrition bias, performance bias, publication bias, and outcome reporting bias. Publication bias might have occurred in this systematic review. This generally encompasses instances of including findings that are in favour of the research questions (Dwan et al., 2013). The same might also hold true for specific journals that are considered more beneficial for publication of significant findings. Language bias might have also occurred if some articles, relevant to the research questions were published in foreign languages and excluded from the review.

An analysis of the articles included in the systematic review suggests that all dressings are comprised of a sterile compress or pad that is applied to wound regions, with the ultimate aim of promoting healing from the injury. In addition, the systematic review included articles that focused on the benefits of hydrocolloid dressings for wound healing. Furthermore, the articles included in the study also emphasised on the fact that Good Manufacturing Practices (GMP) encompass a system that ensures consistent production and control of all products, according to the predetermined quality standards. Answers to the seven research questions for the systematic review have been arranged in the form of different themes that will bring together and integrate the obtained findings from the included studies.

One review article illustrated the practices that involve decontamination, sterilisation and disinfection of aesthetic equipment. The authors described sterilisation as the process that eliminates or destroys all kinds of microbial life, which includes bacterial spores, thereby ensuring the levels of sterility that are acceptable (Juwarkar, 2013). The article also elaborated on the fact that medical devices are sterilised with the use of physical or chemical procedures that depend on the degree of contact of the devise with the patients, and healthcare personnel. Exhaustive information was provided on the comparative properties of commonly used sterilising agents such as, glutaraldehyde, alcohols, iodine compounds and orthophthaldehydes. Thus, an analysis of the article helped to identify the drawbacks of iodine compounds for sterilisation owing to their failure in killing hydrophilic viruses and spores. Furthermore, low level sterilising actions of quaternary ammonium compounds and phenols were also elaborated by the authors.

An overview of the process of sterilisation was also provided by another article that emphasised on the fact that all invasive procedures in healthcare settings involve a direct contact of the sterile tissue or mucous membrane in a patient’s body with surgical instruments or other medical devices (Rutala & Weber, 2013). The authors developed a rationale for sterilisation of such medical devices based in the degree of infection risks that are associated with use of the instruments. Furthermore, the article successfully defined the concept of sterilisation as the process that destroys all kinds of microorganisms, including bacterial spores. Exhaustive information was provided on the applications of sterilisation in healthcare such as, heat-tolerant critical and semi critical medical items. Elaborate information was provided on semi-critical items as those that are in contact with non-intact skin or mucous membranes. Showing consistency with the previously cited article, this review also presented a summary of the benefits and drawbacks of a range of chemical agents that are used as sterilising agents namely, hydrogen peroxide, peracetic acid, orthophthaladehyde, and glutaraldehyde. The data presented in the articles emphasised on the advantages of the sterilising agents based on their relative inexpensiveness, material compatibility, rapid sterilisation cycle time, environment friendliness, and removal of endotoxins or organic materials. However, the authors were also successful in proving data for the low sporadic activity, eye irritation, and skin damage.

An article by Rutala and Weber, (2011) emphasised on the fact that failure to perform appropriate sterilisation and disinfection of medical devices and surgical instruments might result in introduction of several pathogens, thereby resulting in severe infection. The methods of sterilization and disinfection depends on intended use of medical devices and surgical instruments such as, critical items that refer to contact sterile tissue, which in  turn must be sterilised before administration on patients. Exhaustive information was also provided on high sterilisation of semi-critical items that include non-intact skin or contact mucous membranes, and low level of sterilisation of non-critical items, namely contact intact. Furthermore, the authors also opined that in order to gain benefits from sterilisation of medical equipment, the process should always be preceded with cleaning. The importance of sterilisation of medical device was established by the links established between transmissions of vancomycin-resistant enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile, and norovirus with environmental contamination. Showing consistency with previously cited articles, the authors were able to develop a rational approach to sterilisation by following the classification scheme of Spaulding. Importance of the process was also explained by the authors by their statements on the contact of surgical instruments and medical devices with mucous membranes and sterile tissues in all kinds of invasive procedures that contribute to introduction of pathogen and subsequent microbial infection in the patient.

The importance of sterilisation and preventing transmission of healthcare associated pathogens in hospitals was also explained by another article that identified the relationship between such infections and associated mortality and morbidity (Weber et al., 2010). The authors accurately recognised the prevalence of 1.7 million HAIs on an annual basis, which contributes to more than 99,000 deaths globally. Need for sterilisation was also associated with the high rates of nosocomial infections attributed to contamination of hands and medical devices. The authors were also successful in providing extensive information on presence of colonized sites I medical equipment, surgical device, bed rails, suction equipment, surfaces of ventilators, sinks, resuscitation equipment, mattresses, slings for lifting, buckets, door handles, incubators, and stethoscopes. Furthermore, the authors also elaborated on the fact that environmental contamination results in frequent hospital outbreaks due to clinical isolates of Acinetobacter spp that has the capability of surviving for prolonged time period. The article also suggested that enhanced disinfection, sterilisation and environmental cleaning should be implemented in the form of intervention programs to control such outbreaks. Frequent contamination of respiratory tract devices and surgical equipment were also recognised in the article, thereby emphasising on the need for sterilising and disinfecting them, with the aim of reducing the rates of nosocomial infections, across healthcare settings.

According to Delgado, Pandit and Zeugolis, (2014) the process of sterilisation for implantable medical devices is integral to prevent all kinds of infection in patients. The author elaborated on the fact that selection of most appropriate sterilisation methods is largely dependent on the physical state and nature of the material that is being sterilised. The article illustrated that sterilisation methods create an influence on the general properties of the medical device. Collagen was identified as the primary structural matrix protein in vertebrates that accounted for more than 20-30% of the body proteins. The authors emphasised on the fact that sterilization methods demonstrate variable biological or cross-linking effects on collagen-based medical devices. This statement was supported by evidences that amino acid analysis signifies intensive reactions of ethylene oxide with residues of lysine and hydroxylysine, thereby resulting in the need of formulating accurate post-treatment steps, with the aim of avoiding cytotoxicity. The article also elaborated on irradiation methods that induce cross-linking and scission of the polypeptide chains in collagen based medical devices. This cross-link formation is attributed to presence of free radicals that are formed on residues of aromatic amino acids. The article identified γ-irradiation as an attractive and reliable method for biopolymer sterilization owing to the high efficacy of the procedure and the absence of residual chemicals, which might lead to cytotoxicity. Another sterilisation method identified in the article focused on use of ethylene oxide that reduces the helix stability of collagen, as observed by a lowering of shrinkage temperature. E-beam irradiation, use of gas plasma and peracetic acid were also identified as potential sterilisation methods in healthcare settings.

Similar findings were reported by Juwarkar, (2013) who elaborated on the different methods of sterilisation such as, steam under pressure, ethylene oxide (ETO) gas, dry heat, and hydrogen peroxide gas plasma. Steam sterilisation is generally done by using saturated steam under pressure and is one of the most non-toxic and inexpensive sterilisation methods used for medical devices that are heat sensitive. Four essential parameters of this process encompass temperature, steam, time, and pressure. The authors focused on the fact that each pack of medical device that undergoes steam sterilisation should be adequately monitored with the ise of chemical indicators such as, strips, or labels. Ethylene oxide was recognised as the best method for sterilising anaesthesia equipment based on the increases susceptibility of microbes for destruction in humid conditions. Factors that limit the use of gas plasma and γ-irradiation were associated with their high costs, presence of protected environment and non-availability at most healthcare centres. Steam sterilisation, use of ethylene oxide gas, chemical sterilants, hydrogen peroxide gas, and dry heat were also recognised as effective sterilisation methods in another article that associated their processing time with healthcare applications (Rutala & Weber, 2013).

Dhivya, Padma and Santhini, (2015) provided information on the benefits of modern wound dressings, which includes hydrocolloids and hydrogels that promote wound healing by keeping the wound from dehydration. These dressings were defined based on their composition of synthetic polymers and were classified as interactive, passive or bioactive products. Hydrogels were defined as dressings that acted as barriers to entry of bacteria at the site of injury. The authors elaborated on hydrogels as insoluble hydrophilic materials, prepared from synthetic polymers such as, polyvinyl pyrrolidine and poly-methacrylates. High water content (70-90 %) of these hydrogels facilitates tissue and epithelium granulation in moist environments. The soft elastic properties of hydrogels helps in application and removal of the dressing, following wound healing, without any significant damage. Furthermore, the hydrogels also reduce the temperature of cutaneous wounds, thereby providing a cooling and soothing effect. The authors also elaborated on the use of hydrogels for necrotic wounds, dry chronic wounds, burns, and pressure ulcers. They also emphasised on the non-reactive and non-irritant properties of hydrogel dressings with biological tissues and their permeability to metabolites. The article also contained information on the difficulties of hydrogel dressings such as, exudate accumulation, which eventually results in maceration and bacterial proliferation.

According to Milne, Ciccarelli and Lassy, (2010) hydrogel dressings that are composed of hydrophilic polymers in dimensional matrices, are frequently used following necrotic material removal, with the aim of providing moisture to wound bed. These hydrogels provide an exogenous moisture source to the physiological mechanisms of the body, thereby achieving wound repair in an optimized environment. They also facilitate maintenance debridement via moisture-facilitated cell migration, in absence of desiccation and thermal insulation. Moreover, the authors also suggested that hydrogels provide intrinsic enzymes in the moist wound bed that participate in selective protein degradation. The article also emphasised on the superiority of hydrogels over saline gauze dressings for wound healing. Another article also elaborated on the role of hydrogels for serving as instructive scaffolds, while promoting neovascularisation and regeneration of skin in third-degree burns. The authors indicated that hydrogel treated burn wounds developed mature epithelial structures with sebaceous glands and hair follicles within 21 days. Following 5 weeks of treatment, hydrogel scaffolds also promoted new hair growth (Sun et al., 2011).

This shows consistency with the sterilisation procedures mentioned in the literature review that encompass several techniques of steam sterilisation, dry heat method, and ethylene oxide. γ-irradiation and e-beam irradiation are less commonly used to prevent alterations in the structural properties of the sensitive biopolymer (Galante et al., 2017) (Eljarrat?Binstock et al., 2007).

As stated earlier in the literature review, the GMP guidelines of Australia expects all therapeutic and medical devices of be of superior quality that is checked based on the adherence to the essential principles of manufacturing. The name and address of manufacturers should always be present on the labels (Manufacture of medical devices: Quality management, 2018).

The wound dressing devices should be manufactured in a way that does not compromise the health and safety of the patients. They should be suitable for the intended purpose of wound healing and should not get adversely affected due to storage and transportation. Furthermore, manufacture of all wound dressing device should meet the PIC/S Guide to Good Manufacturing Practice (GMP) - 01 January 2017, PE009-13 (Manufacturing principles for medicinal products, 2018).

Conclusion and Recommendations

Conclusion

The primary objective of using dressings is to protect the wounded site from further harm. The design of the dressing is made to facilitate its direct contact with the wound, in addition to having self-adhesive properties. It can also be deduced from the articles that application of moist heat in autoclave acts as the best method used for sterilising dressings, thereby preventing all chances of microbial contamination. Materials used during dressings for the drainage of injuries and operation margins. Thus, it is integral for all dressings to have good absorbency, thereby allowing quick drying and sterilisation. Thus, it can be concluded that hydrogel dressings are non-breathable, or biodegradable and adhere to the skin surface, to prevent the need of separate taping. In addition, the active surface of hydrogel dressings are also coated with cross-linked adhesive material that is composed of pectin, gelatin and carboxy-methylcellulose, in combination with other adhesives and polymers, thereby forming a flexible wafer. In addition, the GMPs are designed in a way that aims at minimising all kinds of risks that are involved in production of any pharmaceutical products, food and beverages, dietary supplements and medical devices, which cannot be generally eliminated through the final testing.

Sterilisation of medical devices

The sterilisation of medical and surgical devices and their appropriate packaging is crucial owing to the fact that presence of a single microorganism on any medical instrument that comes in contact with the skin of the patient could have dire ramifications. Thus, there is a need for all healthcare organisations to formulate appropriate protocols and monitor their adherence to ensure contamination free environment.

Using heat sterilisation for hydrogel dressings

The commercial method of steam sterilisation should be used for generating temperatures of 121°C for approximately 15 minutes to disinfect the dressings and other reusable surgical instruments. There is a need to check the temperature suitability of hydrogel and its porosity. Use of air ballasted steam can also be implemented for the purpose. There is a need to explore the mechanism of dry-heat sterilisation at 160°C for two hours for these dressings.

Follow the GMP therapeutic guidelines

The hydrogel dressings should be rationally designed for the mass market, by showing adherence to the good manufacturing guidelines of Australia, to ensure that they are able to bind excess collagen degrading enzymes, thereby promoting wound healing. Furthermore, the guidelines should also be followed in a way that facilitates easy handling of the products, in addition to conferring them the property of being fully absorbable.

Limitations

Although traditional sterilization methods that focus on the use of dry heat or saturated steam under pressure are considered most reliable sterilisation procedures for hydrogel dressings, efforts must be taken to implement other sterilisation techniques as well such as, ionizing radiation (electron-beam and gamma rays), gas plasma (ozone sterilization ethylene oxide, and hydrogen peroxide), peracitic acid and glutaraldehyde. However, there are less number of sterilising agents that do not create adverse impacts on the tissues and organs of the patient being treated.

In spite of adherence to the Australian therapeutic GMP guidelines, heating the hydrogels at high temperature can result in a distortion or corrosion of the dressing products, subsequently leading to their melting. E-beam or γ-irradiation can also prove hazardous as they can degrade the gels and prevent their use. Chemical sterilisation of the hydrogel dressings with the use of glutaraldehyde or peracitic acid might also result in formation of toxic residues that can penetrate the skin and result in adverse health effects. Thus, it is more likely that dry heat and moist steam should be used for sterilisation of all medical and surgical instruments, including hydrogel dressings, for effective wound healing. Compared to the other sterilisation procedures, heat sterilisation is inexpensive, accessible and readily available across the major healthcare settings.

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