Biomaterials of PVA and PVP in medical and pharmaceutical applications: Perspectives and challenges
Petru Poni″ Institute of Macromolecular Chemistry, 41-A Grigore Ghica Voda Alley, 700487 Iasi, Romania
Biotechnology Advances 37(2019)109–131
Contents lists available at ScienceDirect
Research review paper
Poly(vinyl alcohol) (PVA) has attracted considerable research interest and is recognized among the largest vo- lume of synthetic polymers that have been produced worldwide for almost one century. This is due to its ex- ceptional properties which dictated its extensive use in a wide variety of applications, especially in medical and pharmaceutical ﬁelds. However, studies revealed that PVA-based biomaterials present some limitations that can restrict their use or performances. To overcome these limitations, various methods have been reported, among which blending with poly(vinylpyrrolidone) (PVP) showed promising results. Thus, our aim was to oﬀer a systematic overview on the current state concerning the preparation, properties and various applications of biomaterials based on synergistic eﬀect of mixtures between PVA and PVP. Future trends towards where the biomaterials research is headed were discussed, showing the promising opportunities that PVA and PVP can oﬀer.
Advances in biomedical and pharmaceutical ﬁelds gained sig- niﬁcant progress recently due to the development of versatile bioma- terials that can be tailor-made so that to meet even the most exigent requirements. This is due to the high level of control that has been reached in the fabrication steps of these biomaterials, from the stage of polymer synthesis, to materials manufacturing and designing their ﬁnal properties. Among the most explored biomaterials, hydrogels have been largely employed in a variety of applications.
Even since hydrogels were ﬁrst developed, poly(vinyl alcohol) (PVA) demonstrated to be a well suited polymer for the aforementioned applications. One of the earliest papers relating PVA hydrogels was published by Danno (1958), where irradiation method using gamma- rays was reported. However, the weight average molecular weight (Mw) and concentration of polymer in solution were seen to highly inﬂuence the hydrogel formation, which did not occur below a critical overlap concentration even for longer irradiation periods. Foreseeing the ex- traordinary potential of this new kind of materials, many researchers joined their eﬀorts in order to explore the possibilities that PVA hy- drogels can oﬀer (Alves et al., 2011; Bercea et al., 2013; Chiellini et al., 2003; Gupta et al., 2011; Kamoun et al., 2015; Lozinsky and Plieva, 1998; Peppas and Stauﬀer, 1991; Teodorescu et al., 2018a, 2017). Thus, several obtaining methods have been investigated giving rise to such three-dimensional polymeric networks able to absorb considerably high amounts of water or biological ﬂuids without dissolving. Com- bined eﬀects of hydrophilic groups, in addition to polymer composition and the nature of the aqueous medium, lead to the hydration of hy- drogel to diﬀerent degrees, which sometimes can exceed 90 wt%. Their insolubility and capacity to retain a high amount of liquid give a very good blood compatibility of the hydrogels, and also permit a certain degree of elasticity and structural integrity. The superiority of PVA hydrogels over any other kind of synthetic biomaterials is dictated by their faithful resembling properties with that of natural tissues (high water content, soft and rubbery texture, low interfacial tension with water and biological ﬂuids, high elasticity) (Oviedo et al., 2008; Peppas and Mongia, 1997; Rakesh and Deshpande, 2010; Teodorescu et al., 2016).
A considerable number of various polymers have been employed for hydrogels preparation, but PVA proved to form highly interesting bio- materials. This is why our focus was to synthesize the available pub- lished information on the obtaining methods, properties and applica- tions of PVA-based biomaterials. During this survey, we found that although PVA-based hydrogels present very good characteristics, some limitations can restrict their use or performances. To overcome these limitations, various methods have been reported, among which blending with poly(vinylpyrrolidone) (PVP) showed promising results. Therefore, we have analysed some of the published results on PVA/PVP blends and we tried to highlight the advantages they bring. Thus, this review was enriched with valuable information regarding PVP and PVA/PVP biomaterials, their design, properties and applications. Although this study is by no means exhaustive, it traces accurate di- rections towards where the research is heading and can provide pre- cious guidelines for those who want to further develop this ﬁeld.
PVA is recognized among the largest volume of synthetic polymers that have been produced worldwide for almost one century (Haehnel and Herrmann, 1924). It is obtained by free radical polymerization of vinyl acetate, resulting poly(vinyl acetate) (PVAc), followed by a hy- drolysis process of acetate (Ac) groups located along PVAc chains (Buwalda et al., 2014; Hassan and Peppas, 2000a). Due to the fact that this reaction is not always complete, PVA can be obtained with diﬀerent degrees of hydrolysis (DH) – from partially (80.0–98.5%) and highly(> 98.5%), to fully (100.0%) hydrolyzed (see Fig. 1a,b), thus resulting a copolymer of PVA and PVAc (Al-Sabagh and Abdeen, 2010). Thus, it displays a chemical structure having a main C-C atoms macromolecular chain with pendant acetate and hydroxyl groups.
In addition to the DH, the PVA macromolecular chains can possess diﬀerent tacticity (depending on the synthesis method), and a wide range of Mw (usually, Mw = 9 × 103–4× 105 g·mol−1), which is due to the length of initial PVAc chains and the reaction conditions (either acidic or alkaline) (Gaaz et al., 2015). All these aﬀect its physical and chemical properties, such as: solubility in water, diﬀusivity, crystal- linity, biodegradability, adhesion, mechanical strength, etc., char- acteristics which are of high interest for preparation of hydrogels with applicability in biomedical and pharmaceutical ﬁelds (Al-Sabagh and Abdeen, 2010; Buwalda et al., 2014; Cutiongco et al., 2015; Hameed et al., 2015; Juntanon et al., 2008; Paradossi et al., 2002).
As early as 1959, (Hueper, 1959) published a report concerning the biocompatibility of PVA. Studies were also carried out by (DeMerlis and Schoneker, 2003), who summoned up in a comprehensive paper the information on the oral toxicity of PVA, concluding that it is an orally safe polymer. Some other studies concerning preclinical and clinical tests using PVA hydrogels conﬁrm their high in vivo biocompatibility (Batista et al., 2012; Burczak et al., 1996; Hameed et al., 2015; Jiang et al., 2009; Oliveira et al., 2012). In addition, PVA biomaterials showed low level of acute oral toxicity (Nair, 1998), absence of muta- genic activity in the Ames test (Kelly et al., 2003), very weak absor- bance from the gastro-intestinal tract and no agglomeration in the body when administered orally (Alves et al., 2011).
Biodegradation is a very important aspect, especially regarding biomaterials. (Fig. 1. Chemical structures for: (a) fully hydrolyzed PVA, (b) partially hydro- lyzed PVA, (c) PVP.)
Being a typical vinyl polymer and having the main chain consisting of carbon‑carbon bonds, PVA is generally known as non- biodegradable (Alves et al., 2011). So, it is not expected to undergo a signiﬁcant main chain scission upon oral or intra-venous administration, if used in various pharmaceutical formulations. Despite this, in a comprehensive review of literature (Chiellini et al., 2003), it was de- monstrated that several species of bacteria, fungi, and yeasts use PVA as their only source of carbon, thus biodegrading it. In this process, a high inﬂuence is given by the presence of hydroxyl groups along the chains which favour degradability through hydrolysis. However, authors point out that the biodegradation process of PVA is highly dependent on the environment, in the sense that the polymer degrades in aerobic con- ditions in an aqueous environment, while in soil or composting condi- tions biodegradation is much slower or even entirely prohibited (Chiellini et al., 2003). Other studies reported that PVA is prone to microbial attack, and mixed bacterial cultures are able to degrade it (Chiellini et al., 2008; Lozinsky and Plieva, 1998; Solaro et al., 2000). In terms of polymer aﬃnity to water, there are reports mentioning that PVA of all DHs is hydrophilic, but its solubility is dependent on hydrolysis degree as well as tacticity and chains length. Therefore, highly hydrolyzed PVA necessitates high dissolution temperatures (of~100 °C) and holding time of ~30 min to break the strong hydrogen bonds formed intra- and inter- macromolecules (Gaaz et al., 2015). Lower hydrolyzed grades, instead, are poorly dissolved due to the presence of a larger number of hydrophobic Ac groups along the chains (Alves et al., 2011). Moreover, there have been seen that ﬁlms of syn- diotactic PVA are almost insoluble in water (degree of solubility < 4% in water at 80 °C for a degree of polymerization (DP) of 6000, while for a DP = 17,000 the polymer is insoluble) (Lyoo et al., 2003). Instead, for atactic PVA ﬁlms with 6000 and 10,000 DPs there have been registered an almost 100% degree of solubility in the same temperature conditions (Lyoo et al., 2003). However, since high temperature is important in achieving solubility, further caution must be taken into account so that long time exposure of PVA to temperature, which might favour polymer crystallization, to be avoided (Alves et al., 2011).
Crystallinity of cast ﬁlms of PVA with DHs of 88% (PVA88) and 99% (PVA99), respectively, and with close Mw of 1.27 × 105 and 1.24 × 105 g·mol−1, respectively, was investigated by (Cassu and Felisberti, 1997) by using diﬀerential scanning calorimetry method. They showed that ﬁlms of PVA99 present 30% crystallinity, while de- gree of crystallinity dropped by 10% for ﬁlms of PVA88 (Cassu and Felisberti, 1997). This is due to the higher number (12%) of Ac groups present in PVA88, as compared with PVA99 which possesses only 1% Ac groups. Ac groups are bulkier than hydroxyl groups, and thus are re- sponsible for a more diﬃcult packaging of PVA macromolecules, causing the decrease in crystallinity (Cassu and Felisberti, 1997). This could be observed on the thermograms, where the area corresponding to the endothermic peak – showing the enthalpy of fusion of the crys- talline zone – was smaller in PVA88 than in PVA99. Transition tem- peratures were registered at 59 °C for glass temperature (Tg) and 179 °C for melting temperature (Tm), in the case of PVA with DH = 88%, and Tg = 74 °C and Tm = 228 °C, for PVA with DH = 99% (Cassu and Felisberti, 1997).Therefore, it can be concluded that crystallinity is directly inﬂuenced by DH of PVA.
Other interesting properties of PVA which dictated its extensive use in a wide variety of applications are: easy preparation, excellent ﬁlm forming capacity, very good adhesive and emulsifying properties, good mechanical stability, excellent chemical resistance (including grease, oils and solvents), odourless and high barrier properties for oxygen and aroma (Abed and Habeeb, 2013; Attaran et al., 2013; Kim et al., 2002).
Why not (only) PVA?
Depending on the end use of PVA hydrogels, their characteristics must be controlled and tailored so as to better respond to high stan- dards of today advanced materials. For example, their applicability as wound dressing materials is restricted by their very limited hydrophilicity, insuﬃcient elasticity and rigid structure (Kamoun et al., 2015). Moreover, although PVA hydrogels present a mild reaction in contact with body tissues, some studies showed that they are prone to calciﬁcation if exposed for longer period of time to biological ﬂuids (Hill and Whittaker, 2011). This was seen to negatively aﬀect its functionality as artiﬁcial articular cartilages, synthetic nucleus pul- posus, etc. (Joshi et al., 2006; Katta et al., 2007, 2004). For example, PVA hydrogels (SaluCartilage™) clinically tested in Europe as cartilage replacements, were seen to display a poor ﬁxation and underwent dramatic deswelling (Lange et al., 2006). Pervaporation membranes for continuous dehydration of organic solvents were accused of low per- meability, caused by their high degree of crystallinity (Lee et al., 1995; Lu et al., 2003). Furthermore, since PVA is a highly hydrophilic polymer, PVA hydrogels have poor stability in water (Abd El-Mohdy and Ghanem, 2009).
Therefore, to overcome the above mentioned limitations and other that might arise, numerous studies reported the design of enhanced new characteristics of PVA materials through blending with other polymers, clays, low molecules, silver, copolymerization, crosslinking, or grafting (Bahrami et al., 2003; Costa-Junior et al., 2009;Jamnongkan et al., 2014; Jose et al., 2014; Kamoun et al., 2015; Mahdavi et al., 2013; Mishra et al., 2015; Xiao et al., 2010).
Blending with other polymers proved to be a favourable method of modelling the properties of PVA-based materials. Due to PVA's reg- ularly arranged hydroxyl groups along the chains, leading to crystalline regions through hydrogen bonding, another polymer having strong proton-acceptor sites is required to enhance hetero-polymer interac- tions (Ping et al., 1988). PVP has electronegative oxygen and tertiary amide groups, thus making it a potentially good proton-acceptor (Eisa et al., 2012).
PVP – A good choice for synergism with PVA?
PVP is one of the most widely used vinyl polymers with very in- teresting properties, such as: good environmental stability, bio- and hemocompatibility (Wan et al., 2005), biodegradability, extremely low cytotoxicity (Abdelrazek et al., 2010a; Razzak et al., 2001), high Tg (due to the presence of the rigid pyrrolidone ring, see Fig. 1c) (Abdelrazek et al., 2010b), high chemical and thermal resistance, aﬃnity to complex both hydrophilic and hydrophobic substances, very good solubility in water and many organic solvents (such as amines, amides, alcohols, acids, etc.) (Teodorescu and Bercea, 2015).
This polymer is used in a variety of applications, and due to its easy processability, biocompatibility and non-antigenicity, it is approved by the US Food and Drug Administration as a safe polymer for biological experiments, among which most explored are pharmaceutical and biomedical ﬁelds (D'Souza et al., 2004; Ng et al., 2011; Saxena et al., 2006; Smith et al., 2006). Studies have shown that low molecular weight PVP (for example 1.7 × 103 g·mol−1) is easily and completely removed through the kidneys upon oral administration (Robinson et al., 1990). However, high molecular weights are not recommended in parenteral uses, since they cannot be eliminated through the majority of body membranes causing retentions in the tissues (Sneader, 2005).
Due to its remarkable properties, PVP is one of the most explored polymers for various applications. On the other hand, when used alone, it gives rise to materials with poor mechanical strength (Teodorescu and Bercea, 2015). However, this impediment proved to be easily overcome by polymer composites, among which PVA/PVP biomaterials exhibit a signiﬁcant import of valuable additional functionalities as compared with PVP or PVA alone.
Over the last decades, the large volume of research dealing with polymer blending of PVA and PVP has gained increasing interest for designing novel biomaterials with tailored ﬁnal properties that are far superior to those of each parent component. These improved properties result from the modiﬁcation of the microstructure of the PVA/PVP composite and their manifestation is determined by phase behaviour and the established interactions (Abdelrazek et al., 2010a, 2010b). Thus, a good understanding of chemical structures of each homo- polymer and the speciﬁc interactions that might occur between them, can be an important tool in predicting the properties of a future ma- terial, as well as revealing what parameters to tailor to obtain the de- sired characteristics. In this regard, the majority of researches up to this date were being concentrated on experimental investigations. However, there are also some theoretical studies (Dong et al., 2011; Wei et al., 2017, 2016a, 2016b), which not only reduced time and costs associated with experimental studies, but who could oﬀer accurate information concerning interactions and behaviour at molecular level, leading to a very good anticipation of the characteristics that the resulted bioma- terials might possess. One such study focuses on the design and opti- mization of PVA/PVP networks by molecular dynamics simulation (Wei et al., 2016b). This method can be successfully applied to study the equilibrium and dynamic characteristics of potential polymeric struc- tures by simulating them on Materials Studio software, starting from their components molecular structures, possible intra- and inter- molecular interactions, and variations of diﬀerent parameters (e.g. chain length, composition, etc.). Authors report that properties pre- dicted for simulated PVA/PVP blend materials (see Fig. 2) were con- sistent with the experimental ﬁndings for similar polymeric networks prepared in the laboratory (Wei et al., 2016b).
At the molecular level, miscibility of two polymers is possible only when favourable interactions occur between their chains (e.g. hydrogen bonds, charge transfer complexes, π-electrons, ionic or dipole) (Cassu and Felisberti, 1997; Teodorescu et al., 2018b), determining a minimum Gibbs free energy and negative enthalpy of blending (Abdelrazek et al., 2010b). The good blending of PVA and PVP is at- tributed to hydrogen interactions which may occur between hydroxyl groups of PVA and proton-accepting carbonyl groups in pyrrolidone rings.
As it can be observed in Fig. 3, the type of interactions which occur in a PVA/PVP hydrogel are hydrogen interactions established between eOH groups of PVA or eOH and eC]O groups of PVA and PVP, which can be: inter- and intramolecular multiple H-bonds between eOH groups of PVA in crystalline regions, simple hydrogen bonds between eOH groups of PVA chains in amorphous regions, crosslinks between eC]O group of PVP and eOH group of PVA whose oxygen atom is accepting a proton from another eOH group, crosslinks between a eOH group of PVA and a eC]O group of PVP.
Synergistic eﬀects of PVA/PVP blending
There are many published studies demonstrating that PVA and PVP interact through intermolecular hydrogen bonding between hydroxyl groups of PVA and carbonyl ones of PVP, and can form thermo- dynamically miscible blends (Akbar and Sarwar, 2010; Cassu and Felisberti, 1997; Kim et al., 2002;Lewandowska, 2005; Morariu et al., 2016; Ping et al., 1990). During these investigations, various char- acterization techniques have been employed to study interaction parameters and miscibility of PVA/PVP blends both in solution and solid state. One of the frequently used methods is dilute solution vis- cometry (Akbar and Sarwar, 2010; Lewandowska, 2005; Teodorescu et al., 2018b). This method is known as a facile technique that oﬀers information about miscibility of a polymeric blend by comparing the interaction parameters obtained from experimental data with the ideal values: if the deviation between these data is positive, then the system is miscible, and if the deviation is negative, then the system is im- miscible. However, if viscosity measurements cannot oﬀer suﬃcient information to presume PVA/PVP miscibility, some further investiga- tion methods are recommended, as for example rheological analysis for concentrated solutions (Bercea et al., 2016) or a synergistic (Fig. 2. Simulated microstructure of PVA/PVP hydrogel built by using molecular dynamics simulation software Materials Studio (Adapted from (Wei et al., 2016b), with permission from Elsevier).)
combination of their properties into networks (Teodorescu et al., 2016). The hydrogels obtained by applying diﬀerent number of F/T cycles to PVA/PVP aqueous solutions have shown an aging eﬀect at 37 °C and the viscoelastic moduli increased in time (Teodorescu et al., 2016). The samples reach the equilibrium in approx. 2 h; after this period, the values of the viscoelastic parameters remain constant. High values of storage modulus (G') were observed for low content of PVP in the PVA/ PVP mixture after applying a high number of F/T cycles (see Fig. 4), when the volume and mean size of pores were smaller (Teodorescu et al., 2016) and crystallinity is increased (Morariu et al., 2016).
Although they might imply high cost equipment, longer time mea- surement periods and experimental challenges, studies of solid state PVA/PVP blends can also deliver consistent data by using thermal characterization, infrared spectroscopic analysis, X-ray diﬀraction, etc. (Cassu and Felisberti, 1999, 1997; Lewandowska, 2005; Ping et al., 1990, 1988).
Calorimetric method was used to appreciate the miscibility of PVA/ PVP blends, in solid state, by analyzing glass transition and melting temperatures of parent polymers, as compared with their mixtures (Abdelrazek et al., 2010a; Cassu and Felisberti, 1997; Elashmawi and Abdel Baieth, 2012; Kim et al., 2002; Nkhwa et al., 2014). Furthermore, it can give valuable information about the structure of polymeric net- work, its crystalline and amorphous regions. (Fig. 3. Schematic representation of PVA/PVP hy- drogel showing the crystalline regions (a) as well as the possible H-bonds established between polymer components chains: inter- and intramolecular mul- tiple hydrogen bonds between hydroxyl groups of PVA in crystalline regions (b), simple hydrogen bond between PVA macromolecules in amorphous region (c), crosslink between carbonyl group of PVP with hydroxyl group of PVA whose oxygen atom is ac- cepting a proton from another hydroxyl group (d), crosslink between a hydroxyl group of PVA and a carbonyl group of PVP (e).)
However, the transition temperatures were seen to be highly inﬂuenced by the obtaining method of the investigated materials, the polymers concentration and their molecular weight. For example, pure PVA hydrogels obtained by diﬀerent methods were seen to display variations in the recorded
(Fig. 4. The storage modulus as a function of content of PVP in the PVA/PVP mixtures submitted to diﬀerent number of F/T cycles. All samples were kept 2 h at 37 °C (Reprinted from (Teodorescu et al., 2016) with permission from Royal Society of Chemistry).)
temperatures were seen to be highly inﬂuenced by the obtaining method of the investigated materials, the polymers concentration and their molecular weight. For example, pure PVA hydrogels obtained by diﬀerent methods were seen to display variations in the recorded temperatures. Thus, if PVA hydrogels were prepared by air-drying, their Tg varied greatly between 74.25 °C and 58 °C, as the polymer con- centration in the initial solution increased from 10% to 30% PVA (Nkhwa et al., 2014). However, for PVA solutions subjected to one F/ T cycle, only minor variations were recorded between 73.4 °C and 70.5 °C, for the same solution compositions. Instead, Tm values were constant, irrespective of the method adopted for hydrogels preparation or polymer concentration, and slightly approached 230 °C (Nkhwa et al., 2014), which is commonly found in literature (Bajpai and Saini, 2005; Cassu and Felisberti, 1997; Kim et al., 2002). These transitions reﬂect the macromolecular rearrangements with temperature due to the moisture loss and crystallites melting, resulted through hydrogen in- teractions between PVA-water and PVA-PVA macromolecules. It was also observed that F/T method is more eﬃcient than air-drying, leading to stronger crosslinked hydrogels, reﬂected by higher values of Tg. In another study (Cassu and Felisberti, 1997), the measured Tg and Tm values for PVA cast ﬁlms with various DHs were seen to be diﬀerent (i.e. for PVA with a DH = 88% the Tg = 59 °C and Tm = 179 °C, while for PVA with DH = 99% the Tg = 74 °C and Tm = 228 °C). This explains the higher degree of crystallinity (approximately 30 wt% crystallinity for PVA with 99% DH, as compared with 20 wt% crystallinity for PVA with 88% DH) present in the PVA cast ﬁlms with the higher DH, fa- cilitated by strong hydrogen bonds between hydroxyl groups (Cassu and Felisberti, 1997). Due to their smaller dimensions as well as su- periority in number, as compared with acetate groups, hydroxyl ones permit a denser packaging of macromolecules, thus increasing crystal- linity and the associated temperatures.
The transition temperatures of pure PVP are far superior to those of PVA. Thus, it records high Tg values between 100 °C – 190 °C, de- pending on the average molecular weight (Mw = 2.5 × 103 –106 g·mol−1) (Cassu and Felisberti, 1997; Elashmawi and Abdel Baieth, 2012; Nkhwa et al., 2014; Teodorescu and Bercea, 2015). For example, the Tg value recorded for PVP with Mw = 1 × 104 g·mol−1 was 124 °C, while for the higher molecular weight PVP of 36 × 104 g·mol−1 the Tg= 185 °C (Cassu and Felisberti, 1997).
PVA/PVP blends exhibit a small single transition peak (Abdelrazek et al., 2010a; Elashmawi and Abdel Baieth, 2012; Nkhwa et al., 2014), which can be explained by the micro-Brownian motion of the main macromolecular backbone giving the Tg relaxation process (Elashmawi and Abdel Baieth, 2012). For example, PVA/PVP hydrogels obtained from one F/T cycle recorded a Tg value of 112.7 °C, which is situated between Tg values of pure PVA (i.e. 73.4 °C) and pure PVP (i.e.148.5 °C), subjected to a similar cryogenic treatment (Nkhwa et al., 2014). However, this value was seen to constantly decrease as the PVA concentration in the blend increases. Moreover, the peak corresponding to Tm was constantly shifting to higher temperatures, with increasing PVA concentration, showing that the system needs a higher energy to melt crystallites and break the strong hydrogen interactions established between hydroxyl groups of PVA chains (Nkhwa et al., 2014). The thermal proﬁle of a miscible polymeric blend generally exhibits a single Tg or Tm peak, due to the interactions between the macromolecules of the blended components. As expected, Tg and crystallization of the blend are aﬀected by PVA and PVP macromolecules interaction through hydrogen bonds established between hydroxyl and carbonyl groups, respectively.
Infrared spectroscopic analysis
Infrared spectroscopy is a useful technique that can oﬀer valuable information about interactions present in polymer blends, thus it has been used by many research teams to identify and conﬁrm the forma- tion of hydrogen bonds between PVA and PVP (Abd El-Mohdy and Ghanem, 2009; Abdelrazek et al., 2010a, 2010b; Attaran et al., 2013; Awadallah-F, 2014; Eid et al., 2012; Eisa et al., 2012; Elashmawi and Abdel Baieth, 2012; Leone et al., 2011; Morariu et al., 2016; Shi et al., 2014). By analyzing the characteristic absorption bands for stretching and bending vibrations of pure PVA and pure PVP, there can be(Fig. 5. (a) FTIR spectra of PVA/PVP blends with diﬀerent amounts of PVP and subjected to diﬀerent number of F/T cycles and (b) the inﬂuence of the number of F/T cycles on the eOH stretching vibration of PVA (Reprinted from (Morariu et al., 2016) with permission from Elsevier).)
detected the changes exhibited by PVA/PVP blends. In this regard, literature reports that absorption spectra for pure PVA present the following important peaks: eOH stretching (at about 3200–3500 cm−1) and bending (at about 1620–1650 cm−1) vibrations, CH2 asymmetric stretching vibrations (at about 2900 cm−1), CeO stretching (at about 1100–1200 cm−1) of Ac groups on the PVA chains. The spectrum of pure PVP presents a peak assigned to OeH stretching vibration (at about 3300–3400 cm−1), CH2 asymmetric stretching vibrations (at about 2900 cm−1), a peak for carbonyl stretching vibration (at about 1650–1680 cm−1), a small absorption band assigned to C]N (pyridine ring) vibration (at about 1530 cm−1), and CeH bending of out-of-plane rings (at about 960 cm−1) (Abdelrazek et al., 2010a, 2010b; Elashmawi and Abdel Baieth, 2012). For example, infrared spectral analysis (Fig. 5) conducted on PVA/PVP hydrogels obtained by diﬀerent F/T cycles (Morariu et al., 2016) revealed the following:
- At around 3293 cm−1 there was registered an absorption band which is characteristic for eOH stretching of PVA, in accordance with other results (Abdelrazek et al., 2010a, 2010b; Elashmawi and Abdel Baieth, 2012). In PVA/PVP blends, eOH stretching vibration was seen to be seriously aﬀected by the addition of PVP and, with increasing PVP content, the band was constantly widened, reduced and shifted to higher energy regions. For example, the center of gravity of ν(OH) band in PVA/PVP blend with 10% PVP reaches replacement of hydroxyl-hydroxyl bonds present in PVA amorphous zones with mono hydroxyl‑carbonyl interactions (Lewandowska, 2005; Mondal et al., 2013). Also, the PVP concentration aﬀected the eﬃcacy of F/T cycles on hydrogel formation. Thus, the ν(OH) band registered for PVA/PVP blend with 1% PVP subjected to one F/ T cycle rapidly shifted to higher wavenumbers, as compared to pure PVA hydrogel obtained in the same cryogenic conditions, and reaches a stationary domain by increasing the number of F/T cycles up to 20. This plateau was explained by the presence of weak intermolecular hydrogen bonds established between PVA and PVP macromolecules (O − H⋯O = Cbonds) (Morariu et al., 2016). However, by increasing both PVP concentration and the number of F/T cycles (e.g. for PVA/PVP blends with 5% and 10% PVP, re- spectively, subjected to 9 F/T cycles), hydrogels are characterized by strong intermolecular hydrogen interactions established between O − H⋯O − H and reﬂected by a pronounced descending shift.
- The band observed at 1142 cm−1 and attributed to the ν(CeOeC) vibration remained stable both for pure PVA and PVA/PVP hydro- gels, and no variations were seen as a function of PVP concentration or the number of F/T cycles (Morariu et al., 2016). This band was attributed to PVA crystallinity (Kenney and Willcockson, 1966; Lee et al., 2008; Peppas, 1977; Tretinnikov and Zagorskaya, 2012), suggesting that PVP interacts with PVA only in the amorphous re- gions of PVA. Similar results were also reported (Lewandowska, 2005; Lu et al., 2003; Ping et al., 1988). Because high PVP con- centrations negatively aﬀect intermolecular hydrogen interactions in PVA/PVP blends, as compared to pure PVA, it can be suggested that hydrogen forces between PVA and PVP macromolecules act as nucleating nodes (Morariu et al., 2016). At supramolecular level, this results in PVA/PVP hydrogels with a network less dense, thus with larger pores, as compared with pure PVA hydrogels, which are more compact.
- Moreover, the absorption peak assigned to C]O stretching (at about 1650–1680 cm−1) was observed when PVP is added to the blend, and its intensity increases and shifts to the lower frequency region with increasing PVP content. This relative low frequency in contrast with the usual carbonyl frequencies is due to mixed contributions of carbonyl and CeN stretching vibrations (Eisa et al., 2012). For ex- ample, PVA/PVP hydrogel with 1% PVP presents an absorption band at 1661.52 cm−1, with a shoulder around 1675 cm−1. As the PVP concentration increases, this band shifts to lower values (e.g. 1658 cm−1 for PVA/PVP hydrogel with 10% PVP), displaying a narrower and symmetrical aspect, while the 1675 cm−1 shoulder disappears (Morariu et al., 2016). This can be explained by inter- actions which occur between carbonyl groups of PVP with hydroxyl ones present in PVA amorphous regions.
- The characteristic bands of PVP were observed for PVA/PVP hy- drogels with high PVP amount (10%), subjected to high number of cryogenic cycles (> 15 cycles), suggesting that a phase separation occurred due to large PVP content (Morariu et al., 2016).
- Thus, the good compatibility and miscibility of PVA and PVP is supported by Fourier Transform Infrared (FTIR) spectra by the shape modiﬁcation of the hydrogen bonded eOH groups in PVA (at about 3200–3500 cm−1) and C]O peak shifts (at about 1650–1680 cm−1) in PVP, where the dominant intermolecular interactions were seen to occur (Abd El-Mohdy and Ghanem, 2009; Eid et al., 2012; Morariu et al., 2016; Shi et al., 2014).
X-ray diﬀraction (XRD) analysis can oﬀer valuable information re- garding crystallinity of polymers, thus it has been used to characterize PVA and PVP, as well as their mixtures (Morariu et al., 2016; Teodorescu et al., 2016). XRD patterns of pure PVA gels exhibit char- acteristic diﬀraction peaks 2θ located at around 19° – 21° (Fig. 6)(Fig. 6. XRD patterns of pure PVA and PVA/PVP hydrogels with diﬀerent amount of PVP, subjected to a similar cryogenic treatment. The inset ﬁgure presents the dependence of crystallinity degree with the number of F/T cycles and with PVP concentration (Reprinted from (Morariu et al., 2016) with per- mission from Elsevier).)
(Gupta et al., 2011; Morariu et al., 2016; Razzak et al., 1999; Ricciardi et al., 2004; Teodorescu et al., 2016). These strong peaks correspond to the (101) reﬂection, demonstrating the existence of crystalline PVA aggregates. The (101) diﬀraction can be explained by the interference eﬀect between PVA macromolecules in the direction of intermolecular H bonds (Gupta et al., 2011). At higher angles (at about 40.5°), some diﬀused peaks displayed on a broader region can be observed showing the diﬀraction of pure water in the amorphous zones (Gupta et al., 2011; Razzak et al., 1999; Teodorescu et al., 2016).
Thus, it can be concluded that PVA has a semicrystalline nature with domains of structural order and disorder.Gupta et al., (2011) investigated the eﬀect of PVA concentration on the degree of crystallinity of F/T hydrogels and observed that (101) diﬀraction intensities increase with polymer concentration. A higher polymer concentration determines the increase of regularly arranged PVA chains forming crystalline regions, thus degree of crystallinity in- creases.
In comparison, PVP presents two typical weaker peaks on the XRD patterns located at about 2θ ≈ 10° and 20°, showing that it has an amorphous structure (Ragab, 2011; Razzak et al., 1999; Yadav et al., 2013).
XRD proﬁles of PVA/PVP mixtures present also a main crystal peak centred at about 20° Bragg reﬂection due to PVA crystallinity, some small peaks at about 2θ ≈ 12–13°, and a broader amorphous signal of the blended PVA/PVP, showing semicrystalline nature of the blend containing crystals scattered in the amorphous structure (Abdelrazeket al., 2010a; Elashmawi and Abdel Baieth, 2012; Morariu et al., 2016; Ragab, 2011; Razzak et al., 1999). For example, in the case of PVA/PVP hydrogels obtained by F/T method, there was observed that both PVP addition and the number of F/T cycles aﬀect the crystallinity of the resulted samples (Morariu et al., 2016; Teodorescu et al., 2016). Thus, a higher amount of PVP caused a decrease of crystallinity (e.g. 33.73% crystallinity degree for PVA/PVP hydrogels with 1% PVP, compared with 25.29% crystallinity degree for PVA/PVP hydrogels with 10% PVP, subjected to a similar cryogenic treatment), while a higher number of F/T cycles led to more crystalline cryogels (see inset of Fig. 6) (Morariu et al., 2016). Moreover, the crystallites sizes were seen to be inﬂuenced by PVP concentration, in the sense that they become larger with the addition of PVP (e.g. crystallites sizes of 2.95 nm for pure PVA hydrogels, compared with 4.1 nm for PVA/PVP hydrogels with 10% PVP, subjected to a similar cryogenic treatment), while the distance between them does not change (Morariu et al., 2016).
Some properties of PVA/PVP-based biomaterials and how PVP contributes in improving PVA performances will be further analysed. As mentioned earlier, pure PVA leads to materials with a high degree of crystallinity. However, in some applications (e.g. artiﬁcial articular cartilage, nucleus pulposus replacement, etc.), this aspect is rather detrimental. In preclinical tests, these materials demonstrated calciﬁ- cation in contact with body ﬂuids (Hill and Whittaker, 2011) and in- stability in time due to smaller crystallites melting and molecules leaching in the surrounding area (Mallapragada and Peppas, 1996). The incorporation of only minor amounts of PVP (0.5–5%) contributed favourably in polymer network stability (Thomas, 2001). Thus, crystal- linity decreased due to amorphous nature of PVP, triggered by the lower capacity of macromolecules to pack due to pyrrolidone rings.
Although PVA-based hydrogels were demonstrated to possess me- chanical characteristics somewhat similar to natural articular cartilage (Baker et al., 2012), however there are some studies showing that the presence of small amounts of PVP confers better mechanical properties (in compression and shear conditions) and more smoother and less scraggly hydrogel structure (Morariu et al., 2016; Teodorescu et al., 2016; Zheng et al., 2008). Moreover, PVP reduces the coeﬃcient of friction (Ma et al., 2010, 2009; Zheng et al., 2009,2008) due to its lu- bricating inﬂuence (Nkhwa et al., 2014), thus diminishing wear (Guo et al., 2016). However, special care must be given to optimally tailor the ratio between PVA and PVP, since a too high amount of PVP can result in weaker structures with larger pores, which are prone to dis- solution (Bercea et al., 2016; Teodorescu et al., 2016; Thomas, 2001). Another aspect with important implications in biomedical applica- tions is represented by biomaterials ﬂuid swelling, since natural tissues encompass great amount of water. In this regard, pure PVA-based materials were accused of a too compact network with too small por- osity which does not allow them to suﬃciently contain or properly swell liquids. However, PVP used as a pore forming enhancer for the PVA matrix leads to biomaterials with a higher water content (in the range of 60–80%) and adsorption (between 40 and 250%) (Razzaket al., 2001, 1999; Singh and Pal, 2011).
On the other hand, PVP addition has a good inﬂuence on mixture homogeneity and stabilization of biocomposites incorporating an in- organic component (such as carbon nanotubes (CNTs), metal nano- particles (NPs), or clays) into a PVA network. Thus, PVP was seen to be an appropriate surfactant to prohibit the tendency of CNTs (Huang et al., 2011) or silver NPs (AgNPs) (Eisa et al., 2012; Suvorova et al., 2005) to agglomerate, hence uniformly dispersing and stabilizing them in the PVA matrix. Moreover, by adjusting the percentage of PVP in the initial polymer mixture there can be controlled the particle size and distribution (i.e. smaller particles and narrow particle distribution are obtained by a high percentage of PVP) (Eisa et al., 2012). On the other hand, mechanical properties of PVA/PVP-based composites were im- proved by the addition of only small amounts of PVP wrapped CNTs (< 2 wt%) as compared with pure PVA-based composites (Huang et al., 2011). Better properties were registered also for nanocomposites of PVA/PVP containing sodium montmorillonite as compared with pure PVA materials. PVP enhanced the formation of hydrogen bond inter- actions between clay particles and PVA, hence improving thermal sta- bility and mechanical characteristics of the ﬁlms (Mondal et al., 2013). Spectroscopic properties and DC conductivity of PVA biomaterials can also be tuned by blending with PVP so that to broaden their ap- plication as optical components and devices (Mohammed et al., 2018).
Thus, the absorption and reﬂection in the UV–Vis area were seen to signiﬁcantly decrease by adding PVP. Moreover, optical band gap re- gistered for PVA increased when blended with PVP, while refractive index decreased from about 1.4–1.66 (for pure PVA ﬁlms) to 1.24–1.5 for PVA/PVP ﬁlms with a 30% PVP content (Mohammed et al., 2018).
- Biomaterials based on PVA and/or PVP
- Obtaining methods
Having a high number of hydroxyl groups, PVA is known as a polar, hydrophilic polymer that proved to be a very good candidate as main ingredient for the preparation of hydrogels. PVA based hydrogels can be obtained either by chemical or physical means.On one hand, chemical PVA hydrogels can be obtained by using bi- or multifunctional crosslinking agents which contain reactive groups interacting with the hydroxyl ones of PVA. Among the frequently en- countered crosslinkers, there can be mentioned: formaldehyde (Adriaensens et al., 1999; Hill and Whittaker, 2011; Li et al., 2004; Panaitescu et al., 2015), glutaraldehyde (GA) (Attaran et al., 2013; Fundueanu et al., 2010; Gough et al., 2002; Juntanon et al., 2008; Tsai et al., 2010), epichlorohydrin (Al-Sabagh and Abdeen, 2010; He et al., 2014; Savina et al., 2005), sulfosuccinic acid (Huang et al., 2009; Rakesh and Deshpande, 2010; Rhim et al., 2002; Tsai et al., 2010; Xiang et al., 2013), etc.
Although, in general, it is considered that chemically crosslinking of PVA, using the above mentioned crosslinkers, is a cheap and eﬃcient method that allows a high level of control, special care must be taken into account when medical or pharmaceutical applications are targeted. A major drawback is represented by the cytotoxicity of these cross- linking agents which can remain in the ﬁnal product and are often very diﬃcult to remove, causing adverse reactions if used in contact with leaving tissues or can aﬀect the loaded drugs, proteins or cells into the polymer carrier (Gemmell et al., 1997, 1996; Gough et al., 2002). Furthermore, it was reported that these hydrogels are subjected to de- gradation when exposed to high temperatures required for sterilization (Hill and Whittaker, 2011). A way to solve this problem was achieved by replacing these toxic agents with low or non-toxic ones, as for ex- ample natural extracts like genipin, extracted from the fruits of Gar- denia jasmindides Ellis (Aramwit et al., 2010; Bolto et al., 2009; Nand et al., 2007; Ranjha and Khan, 2013), tartaric acid (Altinisik and Yurdakoc, 2014), or silane coupling agents (Islam et al., 2012; Islam and Yasin, 2012; Kariduraganavar et al., 2005).
Also, another method of producing chemically crosslinked PVA hydrogels was introduced in the 1960s, and it involved subjecting aqueous solutions of PVA to gamma radiation (Burczak et al., 1994; Chowdhury et al., 2006; de Oliveira et al., 2013), electron beam (Abd Alla et al., 2006; Bee et al., 2014; Ibrahim and El Naggar, 2013), or UV irradiation (Khan et al., 2006; Nguyen and Liu, 2013; Sheela et al., 2014; Zhou et al., 2009). During this process, free carbon radicals are formed along the macromolecular chains, which are subsequently re- combined forming a chemically crosslinked network. Although it was considered a safer and cleaner technique, allowing simultaneous ster- ilization as the hydrogel is formed, initial attempts were accused of insuﬃcient mechanical strength (Rosiak and Yoshii, 1999). In order to improve their mechanical properties, hydrogels were subsequently subjected to an annealing process, which causes the formation of crystallites, thus reinforcing the PVA network (Peppas and Merrill, 1977).
Another simple, inexpensive and versatile method to produce PVA,PVP and PVA/PVP-based biomaterials is electrospinning. It consists in applying a high voltage electric ﬁeld to a metallic needle or capillary through which a polymer solution or melt is ejected. In contact with air, the solvent evaporates and the polymer jet solidiﬁes forming micro/ nanoﬁbres which are then deposited on a collector. Depending on the collector type, electrospun ﬁbres can form either non-woven mats, with randomly oriented ﬁbres, or arranged networks, with more or less or- iented ﬁbres. The ﬁbres have diameters ranging from a few micro- meters to a few nanometers and very interesting properties (e.g. high porosity with small pore size, large surface area-to-volume ratio) (Gaazet al., 2015). Therefore, they have become research hotspot in a variety of ﬁelds and have largely been employed in many biomedical(Fig. 7. Schematic illustration of the F/T method of obtaining PVA/PVP biomaterials.)
applications as promising materials for tissue engineering implants, drug delivery systems, wound and burn dressings, and many other areas as electronics, catalysis, protective clothing, ﬁltration, etc. (Aytimur et al., 2013; Chaudhuri et al., 2016; Gaaz et al., 2015; Gökmeşe et al., 2013; Ma et al., 2007; Mohammad Ali Zadeh et al., 2014; Pan et al., 2006; Yao et al., 2003).
This technique has been explored by Pan et al. (Pan et al., 2006) to obtain aligned PVA and PVP nanoﬁbres with inﬁnite length. They de- veloped a novel electrospinning method for generating continuous PVA and PVP uniaxially aligned nanoﬁbres, using two oppositely placed metallic needles, connected to positive and negative voltages, respec- tively (Pan et al., 2006). The resulted electrospun nanoﬁbres have op- posite charges, and after they attract each other, they stick together forming a neutral yarn, which is then easily collected by a cylinder collector rotating at a high speed. Authors found that a better ﬁbre alignment is achieved by increasing the collector velocity, and at higher speeds ﬁbres from more concentrated polymer solutions can be col- lected.
Another study conducted by Ma et al. (Ma et al., 2007) was reported for producing electrospun ultraﬁne ﬁbres of PVA/PVP with chitosan. They presented the preparation and characterization of electrospun ultraﬁne ﬁbres from PVA/PVP with chitosan, with a rough surface obtained by etching with CHCl3 (Ma et al., 2007). Authors reported that an increase in electrospinning voltage, from 20 to 30 kV, led to smaller diameter ﬁbres and reduced diameter distribution. The ultraﬁne ﬁbres were obtained from PVA solutions with concentrations ranging from 40 to 50 wt%, and diﬀerent rough surface and fractal surface ﬁbres re- sulted by etching with CHCl3 and adjusting the PVP concentration.
On the other hand, physical PVA hydrogels have been reported to be obtained by cryogenic (subsequent F/T cycles, dry-freezing) or non- cryogenic (solution casting, air drying, using water-miscible solvents) gelation. One of the easiest methods to produce physically crosslinked PVA hydrogels was presented by (Otsuka et al., 2010), and it consisted in storing a plastic dish with PVA solution for 7 days at room tem- perature in a closed environment. During this period, 20 wt% of water content evaporated, resulting stable hydrogels. Physical network was conﬁrmed by XRD and Attenuated total reﬂection FTIR investigations, showing hydrogen bonds formed intra- and inter-PVA chains. Further- more, their stability was tested by immersion in water for 60 days, during which they have kept their structure intact. However, solution casting is very time consuming, especially when larger sized hydrogels are needed. For a more rapid removal of water and gelation, some water-miscible solvents (for example: methanol, ethanol, propanol, acetone) can be used. In this case, the PVA gelation might occur through a solvent-induced dehydration of the polymer chains which rearrange and form PVA-PVA interactions instead of PVA-water bonds (Alves et al., 2011). For example, PVA electrospun ﬁbres were subjected to a 24 h methanol treatment, during which their solubility was in- hibited for > 3 weeks of immersion in water (Yao et al., 2003). Other study reports the obtaining of a PVA hydrogel through solvation-des- olvation method using acetone and drying at 37 °C for 72 h (Oviedo et al., 2008). Diﬀerent amounts of non-solvent were injected into aqueous PVA solutions for water removal. Higher acetone concentra- tion led to a faster entanglement of PVA chains. This method was successfully used to model a drug delivery PVA hydrogel, since the drug release kinetics could be tailored by controlling the physical network and hydrogel swelling.
PVA cryogels prepared by repeated F/T cycles were introduced as early as 1970s (Peppas, 1975), and valuable studies were updated since then by Peppas et al. (Hassan et al., 2000; Hassan and Peppas, 2000a, 2000b; Peppas and Khare, 1993; Peppas and Mongia, 1997; Peppas and Stauﬀer, 1991) and Lozinsky et al. (Damshkaln et al., 1999; Lozinsky,2008; Lozinsky et al., 2007, 2000a, 2000b,1996a, 1996b, 1995, 1992;Lozinsky and Damshkaln, 2001; Savina et al., 2005). Hydrogel, and its applicability in biomedical and biotechnological ﬁelds were described only in the 1990s (Lozinsky et al., 1997; Lozinsky and Plieva, 1998). Cryogenic gelation is a simple, benign and non-harmful technique, which consists in a freezing step of a homogeneous aqueous polymeric solution for a deﬁnite period of time, proceeded by a thawing step (see Fig. 7). During freezing, ice crystals are formed acting as pore formers within the polymer matrix. The ice crystals are pushing the macro- molecular chains, which agglomerate into the still liquid regions. Into these PVA-enriched microphases, intermolecular interactions occur between pendant hydroxyl groups forming polymer crystallites. Thus, a porous three-dimensional network results, where the crystallites act as knots between polymer chains, while the pores are ﬁlled by the free water. There are a number of conditions that must be taken into ac- count when considering the design of PVA cryogels, such as: the number of F/T cycles, freezing time, thawing rate, the polymer con- centration (or Mw) (Hassan and Peppas, 2000b; Holloway et al., 2013a; Lozinsky et al., 2000a, 2000b; Okay, 2014). A higher number of F/ T cycles inﬂuences the increase of physically crosslinked PVA macro- molecules, in the sense that after one F/T cycle only ~50% of PVA chains are bound into a network and ~25% more chains are added during the next ﬁve F/T cycles (Alves et al., 2011), thus reinforcing the stability and elastic properties of the hydrogel up to a limiting value (Bercea et al., 2013).
PVP hydrogels can be obtained by high-energy radiation, such asgamma rays and electron beam, or low-energy radiation, such as UV radiation. High-energy radiation relies on water radiolysis as a primary step that leads to crosslinking. However, high-energy radiation sources are very expensive and not easily available, so UV radiation (UV-A, UV-C) can be used as an alternative. The UV radiation crosslinking of PVP relies on pyrrolidinone moiety photolysis. This process is not very ef- ﬁcient and it was reported that UV-C radiation (λ = 254 nm), from arc mercury lamps, of PVP requires high doses of radiation which leads to the polymer photodegradation before crosslinking (Lopergolo et al.,2003). In order to accelerate the process, so that the crosslinking to appear before photodegradation, a new method was developed for ac- celerating PVP crosslinking through UV radiation (UV-A or UV-C) using hydrogen peroxide and photo-Fenton reactions (Barros et al., 2006; Fechine et al., 2004). It was observed that the exposure time of the PVP sample to a low pressure mercury lamp can be shortened by one order of magnitude, if a low concentration of H2O2 is used, and a similar level of crosslinking results. In this way, UV radiation mimics the high-en- ergy radiation, due to the hydroxyl radicals generated by H2O2 pho- tolysis, which are the same species resulted in water radiolysis re- sponsible for PVP crosslinking.
In general, PVA/PVP-based biomaterials can be prepared using thesame methods as mentioned above. However, depending on the tar- geted application and the properties that it needs to possess, the ob- taining method of the PVA/PVP hydrogel can be adapted (chemical or physical crosslinking, as well as a combination of both) (Abd El-Mohdy and Ghanem, 2009; Abdelrazek et al., 2010a; Ali et al., 2018; Aziz et al., 2017; Choudhary, 2018; Choudhary and Sengwa, 2018; Chougale et al., 2018; Hammannavar and Lobo, 2018; Huang et al., 2011; Jabbari and Karbasi, 2004; Jeyabanu et al., 2018; Kim et al., 2002; Kumar et al., 2017; Lu et al., 2003; Ma et al., 2009; Mohammed et al., 2018; Nho et al., 2004; Nho and Park, 2001; Park and Nho, 2003; Qiao et al., 2010; Ragab, 2011; Shi et al., 2014, 2016a; Shi and Xiong, 2013; Singh and Pal, 2011; Teodorescu et al., 2016; Zheng et al., 2009; Zidan et al., 2018). Chemically crosslinked PVA/PVP materials have been reported by various research teams (Kim et al., 2002; Lu et al., 2003; Qiao et al., 2010). For example, double interpenetrating PVA/PVP networks (IPNs) with pervaporation properties were successfully obtained by using a chemical crosslinker and UV irradiation for the ﬁrst and second polymer component, respectively (Lu et al., 2003). Kim et al. have designed IPNs of PVA and PVP for biomedical applications by polymerization of 1-vinyl-2-pyrrolidone in solution under UV irradia- tion in a PVA matrix (Kim et al., 2002). Solution cast ﬁlms based on PVA/PVP with promising properties for anion-exchange membrane fuel cells were also obtained by a chemical method using GA (Fu et al., 2010). It was reported that the crosslinking time should be up to 6 h in order to obtain the optimum membrane mechanical ﬂexibility.
Physical crosslinking by F/T method proved in many cases to be a good alternative to eliminate harmful chemicals from the process, thus some researchers obtained PVA/PVP hydrogels in this manner (Bercea et al., 2016; Huang et al., 2011; Ma et al., 2009; Morariu et al., 2016; Shi et al., 2016a; Shi and Xiong, 2013; Teodorescu et al., 2016). It was observed that although PVA hydrogels prepared through F/T method, with high-water content, present very good biocompatibility, good chemical stability, and high-mechanical strength, they have insuﬃcient lubrication due to the strong action of the intermolecular hydrogen bonds. Adding PVP to the initial mixture can improve the surface lu- brication, but the mechanical properties decrease because the PVP rigid chains aﬀect the crystallization of PVA and thus the hydrogel forma- tion. Moreover, the PVP molecules in the PVA/PVP hydrogel obtained by F/T method tend to gradually dissolve in water in a physiological environment, aﬀecting the hydrogel performance (Huang et al., 2011; Ma et al., 2009; Shi et al., 2016a; Shi and Xiong, 2013; Teodorescu et al., 2016). For a better ﬁxation of the PVP macromolecules, irra- diation process was also used in addition to F/T (Nho et al., 2004; Park and Nho, 2004,2003; Shi et al., 2014; Zheng et al., 2009). For example, PVA/PVP hydrogels obtained by 60Co gamma-ray irradiation cross- linking were superior in terms of physicochemical properties (water content, degree of water swelling), antimicrobial and antibacterial properties, compared to PVA hydrogels (Razzak et al., 2001). Moreover, PVA/PVP hydrogels crosslinked by a two steps process of F/T cycles followed by gamma-irradiation registered improved gel fraction and mechanical strength than hydrogels obtained only by irradiation which presented weak strength (Nho et al., 2009, 2004; Park and Nho, 2003).
Applications of biomaterials based on PVA and/or PVP
Due to their excellent mechanical properties, good biocompatibility and biodegradability, PVA, PVP and PVA/PVP-based biomaterials have a well-documented history in a wide variety of advanced applications in biomedical, biotechnological, pharmaceutical, food, industrial, and commercial ﬁelds. Among all these, the most explored research areas are tissue engineering (scaﬀolds, articular cartilages, bones, nucleus pulposus, artiﬁcial pancreas, artiﬁcial skin, vascular devices), drug delivery systems, wound and burn dressings, ophthalmic applications (artiﬁcial cornea, contact lenses, synthetic vitreous body (see Fig. 8 and Table 1).
Due to their excellent mechanical properties, good biocompatibility and biodegradability, PVA, PVP and PVA/PVP-based biomaterials have a well-documented history in a wide variety of advanced applications in biomedical, biotechnological, pharmaceutical, food, industrial, and commercial ﬁelds. Among all these, the most explored research areas are tissue engineering (scaﬀolds, articular cartilages, bones, nucleus pulposus, artiﬁcial pancreas, artiﬁcial skin, vascular devices), drug delivery systems, wound and burn dressings, ophthalmic applications (artiﬁcial cornea, contact lenses, synthetic vitreous body (see Fig. 8 and Table 1).
VTissue engineering and regenerative medicine is a promising inter- disciplinary and multidisciplinary research ﬁeld directed towards the production of artiﬁcial substitutes that can restore, maintain, and im- prove tissue functions in various severe injuries which cannot otherwise be treated (Butcher et al., 2014; Ma, 2008; Vedadghavami et al., 2017). Biomimetics played a pivotal role in developing this domain, since it focuses on observing the characteristics and functions of natural tissues in order to understand and extract the principles behind them so that to obtain artiﬁcial tissues that can mimic the natural ones very closely (Jiang et al., 2011). The main elements involved in tissue engineering are a scaﬀold that mimics the natural extracellular matrix, cells, and growth factors. The scaﬀolds are three-dimensional templates with large surface area, high porosity, and interconnected porous structure, on to which the regenerative cells are seeded. Due to their chemical composition and physical structure, scaﬀolds support the cells attach- ment, proliferation, diﬀerentiation, and neo tissue genesis, while the artiﬁcial framework degrades (Butcher et al., 2014; Holzwarth and Ma,2011; Ma, 2008). Therefore, the targeted materials for scaﬀold(Fig. 8. Schematic illustration of PVA/PVP-based biomaterials, their obtaining methods and application ﬁelds.)
High amount of research has been reported in the last few decades on the production of scaﬀolds for tissue engineering using biocompa- tible and biodegradable polymers. Among them, PVA and PVP in
particular have been highly employed as scaﬀolds for tissue en- gineering, due to their great design ﬂexibility allowing them to be tailored so that to meet special requirements (high water content, tissue-like elasticity, biocompatibility, etc.) (Killeen et al., 2012; Ye et al., 2014).
Studies conducted so far on PVA hydrogels have demonstrated that
Biomaterials for medical and pharmaceutical applications with PVA and/or PVP as main ingredients.)
they can be attractive candidates for tissue engineering, since even by simple cryogenic gelation method porous structures with ability to absorb surrounding ﬂuid result, with a high capacity to closely match human tissues (Alves et al., 2011; Nkhwa et al., 2014).
One of the methods used to treat blood vessel diseases is to in- troduce a microcatheter into the region of disease and occluding, or blocking it with an embolic agent. Though they imply several side ef- fects, metallic embolic coils are widely used. In order to eliminate these problems, the possibility of using polymeric materials as embolic coils is explored. In this regard, (Seo et al., 2013) prepared syndiotactic PVA gel-spun ﬁbres via gel spinning and shaped them into coil form by thermal treatment. However, PVA was employed in minimizing blood ﬂow into vessels since 1975 (Tadavarthy et al., 1975), when it was used in the form of embolic microparticles for cancer treatment. A study (Davidson and Terbrugge, 1995), which was published after these dis- coveries, reported that long term (over 8 years) PVA microparticles implantation presented no inﬂammation and successfully diminished the blood ﬂow to the cancerous tissues. Moreover, they can be used as an intra-arterial delivery system for anticancer drugs (Rump et al., 2002).
Another method to treat arterial diseases is replacing the obstructedor restricted blood vessels with new ones. This possibility has been explored by Mathews and co-workers (2007). They designed PVA hy- drogels with incorporated chitosan which presented a very good rate of success for cell adhesion and proliferation of bovine aortic endothelial cells and smooth muscle cells that can be used as artiﬁcial blood vessels. A method to enhance mechanical properties of PVA, PVP and PVA/ PVP biomaterials is the addition of CNTs (Huang et al., 2011; Morimune et al., 2011; Zhang et al., 2003). CNTs present excellent mechanical, electrical and thermal properties, and very good potential for surface functionalization. These characteristics qualiﬁed them as promising reinforcement materials for biocomposites in applications such as tissue engineering scaﬀolds, soft implants, biosensors, drug delivery systems, artiﬁcial cartilage substitutes, etc. One of these studies was reported by Huang et al. (Huang et al., 2011) on the obtaining of PVP wrapped multi-walled carbon nanotubes (MWCNTs) reinforced PVA composite hydrogel, prepared by F/T technique. They tested the resulted materials in terms of tensile strength, modulus, toughness, tear strength and friction coeﬃcient. Knowing that CNTs have a tendency to form bundles, entanglements and agglomerates, phenomenon which lowers their contribution as reinforcement materials, authors reported that PVP acts as a suitable surfactant to uniformly disperse and stabilize them (Huang et al., 2011). Furthermore, even with < 2 wt% of PVP- wrapped MWCNTs, the mechanical properties of PVA hydrogels were signiﬁcantly improved (tensile strength increased with 133%, while tear strength was improved with 63%). There have also been reports on other biocomposites based on PVA/CNTs which mention the good im- pact of CNTs on the mechanical properties of the PVA matrix (Bartholome et al., 2008; Bin et al., 2006; Liu et al., 2005; Zhang et al., 2009). For example, Bin et al. (Bin et al., 2006) obtained PVA/MWCNTs hydrogels with an increase of tensile Young's modulus of 160% for hydrogels with 5 wt% MWCNTs as compared with pure PVA hydrogels. Another study, published by Liu et al. (Liu et al., 2005), presents the properties of single-walled carbon nanotubes (SWCNTs) functionalized PVA ﬁlms. They report that the addition of 0.8 wt% SWCNTs leads to an improvement of 79% in tensile modulus and 47% in tensile yield strength of PVA ﬁlms. It can be concluded that in order to improve mechanical properties of PVA/PVP biomaterials for applications where it is required (such as artiﬁcial cartilage), the addition of CNTs plays an excellent role.
Bone tissue engineering
Natural bone matrix comprises two parts: a collagen network and a mineral one. The collagen network can be mimicked using diﬀerent polymers, and the mineral part by incorporating bone-like minerals (e.g. hydroxyapatite). There have been reports on various ways to produce scaﬀolds resembling the collagen network, among which electrospin- ning and thermally-induced phase separation can be mentioned. In this attempt, scaﬀolds for bone engineering have been designed from var- ious materials and by diverse methods. Among them, both PVA and PVP have been used in this direction.
Some reports (Asran et al., 2010; Butcher et al., 2014; Pan et al., 2006) showed that PVA solutions can be electrospun into beads, beaded ﬁbres, complete ﬁbres and ribbons, and the technique assures a strict control of molecular weight, as well as polymer concentration. This kind of hydrogel ﬁbres can be used as viable solutions for applications in biomedical ﬁeld, as scaﬀolds for bone tissue engineering (Holzwarth and Ma, 2011). One study presenting the obtaining of a hybrid scaﬀold from electrospun nanoﬁbrous PVA mats was reported by Zeng and co- workers (2005). Authors added bovine serum albumin to a PVA solu- tion in order to produce ﬁbres with diameters ranging from 250 to 300 nm. The mats were designed as a controlled delivery system, since their bioactivity was enhanced by incorporating growth factors into the polymer. A poly(p-xylene) coating of diﬀerent thicknesses was used to cover the ﬁbres in order to control the release rate. It could be observed that the thicker coating slowed the long term release of bovine serum albumin, after a burst release within 2 h, thus a greater control was achieved over the release rate of the protein.
Another published study investigated the possibility of creating composite scaﬀolds of PVA hydrogels with carrier function for growth factors and/or plasma rich platelets for bone growth (Nkhwa et al., 2014). Authors used facile physical crosslinking methods (air-drying, F/ T, or combined air-drying and F/T) to produce PVA, PVA/PVP and PVA/gelatine hydrogels. It was concluded that superior gels were ob- tained through air-drying in conjunction with F/T, where PVA con- centration had a clear inﬂuence on the degree of crosslinking. Fur- thermore, equilibrium water uptake was higher for hydrogels where PVP or gelatine was added, in comparison with pure PVA hydrogels. The less eﬃcient crosslinking for PVA/PVP hydrogels also lead to weaker mechanical properties. This was attributed to the presence of bulky side groups in PVP leading to an increase of the amorphous re- gions. However, F/T method was further applied to obtain better per- formances in PVA/PVP hydrogels and very promising results were re- ported recently (Shi et al., 2016b). In these studies, was observed that the DP of PVA plays an important role in creating three-dimensional porous networks very similar to those displayed by microstructure of human bone tissues (see Fig. 9a). Thus, PVA/PVP hydrogels prepared from PVA with longer molecular chains (e.g. DP = 2399) presented a denser network, with smaller porosity, as compared with hydrogels obtained from PVA with shorter molecular chains (e.g. DP = 2099) (Fig. 9b,c). This can be explained by the higher number of physical crosslinking points present on long molecular chains of PVA, hence facilitating more hydrogen interactions, which result in a network structure with increased density (Shi et al., 2016b).
Injectable thermosensitive PVA hydrogels with chitosan were developed by Qi et al., (2010) for bone tissue engineering purposes, and they were seen to facilitate proliferation of rabbit bone marrow me- senchymal stem cells during 3 weeks.
Uni- and multicomponent materials consisting in PVA, PVA/col- lagen and their composites with hydroxyapatite NPs were obtained by electrospinning method (Asran et al., 2010). The resulted composite nanoﬁbrous membranes present a uniform morphology (with diameters ranging from 160 nm for pure PVA, 176 nm for PVA/hydroxyapatite NPs, 245 nm for PVA/collagen and 320 nm for PVA/collagen/hydro- xyapatite NPs), porous structure with adjustable pore size and shape, and with a large number of hydroxyapatite NPs which are preferentially oriented parallel to the longitudinal directions of the nanoﬁbres. Au- thors conclude that all these characteristics suggest that the resulted biocomposite nanoﬁbrous scaﬀolds are great candidates for bone tissue engineering(Fig. 9. Scanning electron micrographs showing: the human bone cellular structure (a) (Reprinted from (Gibson, 2005) with permission from Elsevier), and the microstructure of PVA/PVP hydrogel obtained by F/T method (PVA with DP = 2099 (b); PVA with DP = 2399 (c)) for bone tissue engineering applications (Reprinted from (Shi et al., 2016b) with permission Express Polymer Letters).)
Cartilage replacement in articular and meniscal applications
Natural articular cartilage can be injured as a result of osteoar- thrisis, congenital deformities, accidents or sports, and is unable to self- repair due to its avascular and aneural nature (Shi et al., 2014), thus making articular cartilage replacement one of the most attractive and studied subjects in surgical clinical and biomaterial research (Katta et al., 2007, 2004; Ma et al., 2010, 2009; Shi et al., 2014). Articular cartilage acts as a soft conjoin cushion between bones in human ar- throsis, transferring and distributing equally the laden stress, and re- ducing friction and abrasion (Zheng et al., 2008). These properties have been found to be attributed to a mixed lubrication regime that can be met in hydrogels (Hsu and Gates, 2005; Krishnan et al., 2004; Mow et al., 1980). Natural cartilage itself is a biologic hydrogel made from collagen and glycosaminoglycans, comprising 60–80% water, with a mechanical tensile strength of 17 MPa and a compressive modulus varying between 0.53 and 1.82 MPa (Baker et al., 2012). Another at- tractive reason that makes hydrogels very well suited for replacing natural cartilage is represented by their excellent biocompatibility, ﬂexibility, and biomimetic structure that can easily resemble the lu- brication mechanisms of native articular cartilage (Baker et al., 2012; Batista et al., 2012).
Although PVA hydrogels have been the most widely studied bio- materials for articular cartilage replacement (Baker et al., 2012), re- commended by their biocompatibility (Wang et al., 2008), perme- ability, load-bearing characteristics (Holloway et al., 2013b; Joshi et al., 2006; Wang et al., 2008), and ease of preparation, it was found that they lack the surface lubrication and biomechanical strength re- quired by natural cartilage (Kobayashi et al., 2005, 2003; Lange et al., 2006; Shi et al., 2014; Stammen et al., 2001). This impediment has been removed by adding PVP in the initial mixture which, due to its very high hydrophilicity, contributes to a good lubrication of the resulted hydrogel (Ma et al., 2010, 2009; Shi et al., 2014).
Considering that the human joints bear high loads with minimal or no wear and a low coeﬃcient of friction during one million steps per year that an average person takes (Schmalzried et al., 2000), most studies on PVA/PVP hydrogels for articular cartilage replacement are focused on understanding and improving their tribological properties. Among the ﬁrst studies towards this are the one conducted by Katta and co-workers (2007),(2004), on PVA/PVP hydrogels prepared using the solvent evaporation technique, in which the eﬀects of polymer content, load, and lubricant on the friction and wear characteristics of the hy- drogels were investigated. They managed to observe that the higher the polymer content in the PVA/PVP hydrogel the lower was its wear be- haviour. This can be explained by the formation of a thin skin on the hydrogel surface during solvent evaporation that reduces and controls the rate of further solvent evaporation (Katta et al., 2007). The higher the polymer content in solution, the thicker the skin is, delaying evaporation, thus much time is available for the polymer chains in solution to crosslink (Ngui and Mallapragada, 1999). Also, the friction tests carried out with bovine serum as lubricant showed that the low concentration of proteins, combined with macromolecules like sodium hyaluronate and lubricin present in the serum can produce an eﬀective boundary lubricant that leads to low friction levels (Kattaet al., 2007). Zheng et al., (2009), (2008) published some studies on the obtaining of PVA/PVP hydrogels by F/T method and 60Co gammairradiation, and their mechanical and lubrication characterization. They concluded that the addition of PVP contributes to the hydrogel structure making it smoother and less scraggly (Zheng et al., 2008). Also, the friction coeﬃcient decreased with increasing PVP content. The irradiation process contributed to the modiﬁcation of the gel content (it became larger than that only by F/T), crystallization (it decreased with the increase of irradiation dose), and mechanical properties of the hydro- gels (the crosslinking between PVA and PVP prevented the solubility and exudation of PVP from hydrogels, thus improving the lubricative properties) (Zheng et al., 2009, 2008).
Another team (Ma et al., 2010, 2009) also investigated the factors that inﬂuence the friction properties of PVA/PVP hydrogels, such as polymer content, load, and lubrication conditions, but in this case the hydrogels were prepared by repeating F/T technique. The addition of PVP in the initial mixture proved to improve the mechanical properties of the resulted hydrogels, compared to pure PVA hydrogels, acting with a very similar viscoelastic behaviour as natural articular cartilage does (Ma et al., 2009). The best mechanical properties were registered for blends prepared with 1 wt% PVP. They demonstrated that the friction system composed of PVA/PVP hydrogel and stainless steel ball exhibits a mixed lubrication regime under bovine serum as lubricant (the fric- tion coeﬃcient was half lower than under dry lubrication) (Ma et al., 2009), making this method a good candidate for reducing wear of prosthesis for young and active patients suﬀering from various arthritis injuries (Ma et al., 2010).
Shi et al. (Shi et al., 2014; Shi and Xiong, 2013) conducted somestudies on the mechanical behaviour and tribological properties of PVA/PVP hydrogels for cartilage replacement prepared by F/T method (Shi and Xiong, 2013) and by F/T cycles followed by 60Co gamma-ir- radiation (Shi et al., 2014). They observed that the microstructure of PVA/PVP hydrogels becomes denser and the pore size decreases with the increase of the DP of PVA and polymer concentration, which led to decreasing of the swelling ratio (Shi and Xiong, 2013). Tribological properties were investigated by rubbing against stainless steel, ultra high molecular weight polyethylene (UHMWPE), and PVA/PVP hy- drogel itself. It was concluded that the largest friction coeﬃcient is given by the contact between hydrogel on hydrogel, the second in rank is given by UHMWPE on hydrogel, and the lowest friction coeﬃcient by hydrogel against stainless steel. There was also taken into consideration(Fig. 10. PVA/PVP hydrogels obtained by F/T method showing elastic shape-memory for replacing damaged articular cartilage (Adapted from (Teodorescu et al., 2016) with permission from Royal Society of Chemistry).)
the inﬂuence of irradiation dose on the properties of PVA/PVP hydro- gels, showing that the irradiation dose of 100 kGy leads to the best mechanical characteristics and the lowest friction coeﬃcient (Shi et al., 2014).
However, some PVA/PVP hydrogels with interesting viscoelastic properties were obtained by only applying F/T method (Teodorescu et al., 2016). Thus, after subjecting the polymer blending solutions having 10% PVP to 9 F/T cycles, there have been resulted hydrogels with pronounced elastic shape-memory (Fig. 10). This is a desired property for biomaterials which can be used for in situ developing im- plants (such as articular cartilages).
Nucleus pulposus for intervertebral disc
The intervertebral disc plays a very important role in supporting the body and enabling six degree of freedom motions in the spine (ﬂexion, extension, right and left lateral bending, compression, axial rotation) (Azartash-Namin et al., 2013). Degenerative lumbar intervertebral disc disease is one of the modern age problems, probably one of the most expensive health care issues today (Joshi et al., 2006; Thomas et al., 2004), caused by the deterioration of the nucleus pulposus. This disease severely aﬀects the life of individuals causing them intense lower back pain. In a healthy body, nucleus pulposus has the role of distributing the load in the disc by exerting a hydrostatic intradiscal pressure on the annulus ﬁbrosus ﬁbres (White and Panjabi, 1990). However, in the degenerated disc, the dehydration of nucleus pulposus leads to the decrease of intradiscal pressure on the annulus which can result in cracks and ﬁssures in the annulus, and eventually in nucleus migration towards the periphery (Joshi et al., 2006). A solution in this case con- sists in total disc arthroplasty (Salib and Pettine, 1992) or replacing the damaged nucleus (Joshi et al., 2006; Thomas et al., 2004; Thomas, 2001) with a synthetic one based on polymeric hydrogel. Probably the ﬁrst step in solving this problem was made in the early 1960s by Nachemson, (1962), who injected self-curing silicone into the inter- vertebral disc in cadavers. Although this direction was followed for decades, it could be seen that silicone prostheses present a limited clinical success (Chan et al., 1998). As an alternative for silicone, Bao and Higham studied physically crosslinked PVA hydrogels for nucleus pulposus replacement (Bao and Higham, 1993, 1991). PVA hydrogels present similar mechanical and physiological properties to those of the natural nucleus, and a water content of about 70% is maintained under physiological loading conditions. However, studies have shown that smaller crystallites in PVA hydrogels melt out and the molecules leach into the physiological environment (Mallapragada and Peppas, 1996). In order to stabilize the polymer network, (Thomas and co-workers (2004); Thomas (2001) prepared PVA/PVP blends with small amounts of PVP (0.5–5%), showing that interchain hydrogen bonding between hydroxyl groups of PVA and carbonyl groups of PVP lead to more stable hydrogels. However, when large amounts of PVP were used, the re- sulted hydrogels were weaker, with more open network structures, and they suﬀered dissolution (Thomas et al., 2004; Thomas, 2001). Another factor that inﬂuences the hydrogels properties is the Mw of the in- corporated polymers. The addition of PVA with lower Mw (i.e.9.5 × 104 g·mol−1) leads to obtaining more stable PVA/PVP blends as compared with those which contain PVA with higher Mw (i.e.14.3 × 104 g·mol−1) (Thomas, 2001). Moreover, higher Mw PVA was better stabilized by higher Mw PVP (i.e. 4× 104 g·mol−1), than the lower Mw PVP (i.e. 1× 104 g·mol−1). The blends prepared from 99% PVA (Mw = 14.3 × 104 g·mol−1) and 1% PVP (Mw = 4 × 104 g·mol−1) led to tighter and more stable hydrogels, with best stability under physiological conditions (Thomas, 2001).
Another studies conducted by Thomas et al. (Thomas et al., 2004), presented the mechanical properties of PVA/PVP hydrogels subjected to various levels of dehydration, and subsequently rehydration. They found that the dehydration history of PVA/PVP hydrogels aﬀects the mechanical behaviour of the rehydrated materials, in the sense that the compressive modulus increases with the increasing of the dehydration. Moreover, it was observed the formation of a skin layer during the dehydration process that acted as a barrier against the dehydration of the hydrogel core. The study demonstrates the feasibility of this kind of hydrogels for minimally invasive endoscopic implantation procedure by utilizing PVA/PVP biomaterials with shape-memory properties as nu- cleus replacement.
The obtaining of chemically stable hydrogel polymer systems ofPVA/PVP and their characterization in terms of compressive mechan- ical properties were also reported (Thomas et al., 2003; Joshi et al., 2006). Compression tests showed that even after 10 million cycles of compression-compression fatigue there were none up to 15% mechan- ical behaviour alterations. Moreover, there have been registered mass stability and very little geometrical modiﬁcations which were mostly recoverable. In vitro studies have shown that PVA/PVP implants in the human cadaveric intervertebral discs are able to restore the compres- sive stiﬀness properties of the natural equivalent. These results proved the success of these materials instead of current methods (discectomy and spinal fusion) to treat lower back pain and restoration of normal spinal motion (Joshi et al., 2006).
Azartash-Namin (2013) reported the obtaining of a physically crosslinked hydrogel of 95 wt% PVA and 5 wt% PVP, with successful results in addressing the problem of nucleus pulposus replacement. Authors present various tests performed on a slider-crank mechanism, speciﬁcally designed and constructed to simulate the six degree of freedom motions of intervertebral discs in the spine. Viscoelastic studies on isolated nucleus pulposus of natural bovine specimen and PVA/PVP hydrogel implant performed at 5%, 10%, and 15% strain resulted in elastic modulus of 712.9 Pa, 522.1 Pa, and 363.3 Pa, for the natural bovine specimen, while for hydrogel implant the values registered were 228.6 Pa, 988.8 Pa, and 1794 Pa, respectively (Azartash-Namin et al., 2013).
Traditional drug delivery systems are represented by tablets, injec- tions, syrups and sprays, and they are supposed to assure an optimal drug concentration within the bloodstream for a reasonable time period (Lowman and Peppas, 1999). However, their release is not constant in time, in an initial stage they register a peak after which the drug con- centration falls oﬀ, and another dose is required for maintaining the eﬀectiveness of the drug (Juntanon et al., 2008). Among the side eﬀects it can be mentioned that the traditional drug administration can sometimes reach a toxic level, when it rises above the maximum ther- apeutic range, while in other cases it can be ineﬀective, when it falls below the minimum therapeutic range. In the attempt to design new drug delivery systems, researchers focused their attention on bio- compatible polymers that allow the drug incorporation and the control of their behaviour and release kinetics in biological environment. To this end, hydrogels have shown very good applicability as smart stimuli sensitive materials: pH (Das and Subuddhi, 2013; Fundueanu et al., 2010; Islam and Yasin, 2012; Paradossi et al., 2002), temperature (Fundueanu et al., 2010; Taheri et al., 2011), magnetic (Guowei et al., 2007; Hosseinzadeh et al., 2015; Kamulegeya et al., 2006; Mahdavinia and Etemadi, 2014; Ngadiman et al., 2015), electric (Bercea et al., 2018; Juntanon et al., 2008), etc., biodegradable and biomimetic ma- terials, with several commercial products already available (Colombo, 1993).
Drug delivery systems
PVA or its derivatives hydrogel microparticles and NPs have beenreported in recent years for many kinds of drug delivery systems, in- cluding PVA NPs encapsulated by poly(lactide-co-glycolic acid) (PLGA) microparticles (Wang et al., 1999) and paclitaxel-loaded PVA-g-PLGA NPs for the treatment of restenosis (Westedt et al., 2007), and DNA nanocarriers obtained by modiﬁed solvent displacement method (Oster et al., 2006).PVA in the form of hydrogel NPs have been used since late 1990s with protein/peptide drug delivery purposes (Li et al., 1998). The preparing method consisted in water-in-oil emulsion/cyclic F/T, re- sulting PVA NPs with an average diameter of 675.5 ± 42.7 nm with a skewed or log-normalized size distribution. Bovine serum albumin was loaded in PVA hydrogel NPs and presented a loading eﬃciency of 96.2 ± 3.8% and a diﬀusion-controlled release trend (Li et al., 1998). Another paper, published by Galindo-Rodriguez et al. (Galindo- Rodríguez et al., 2005), reported the production of PVA-based NPs by three methods: salting-out, emulsiﬁcation diﬀusion, and nanoprecipi- tation, for ibuprofen drug release. The NPs mean sizes were in the range from 230 to 565 nm for emulsiﬁcation diﬀusion and from 174 to 557 nm for salting-out, at the pilot-scale stirring rates of 790–2000 rpm. Traynor et al., (2011) proposed a particles engineering method for controlled delivery of drugs by absorption of a vinyl polymer coat to crystalline drug microparticles. The scope was to study the inﬂuence of PVA in drug system coating for in vitro delivery of intranasal lorezapam microparticles. The tests were performed on a series of four, similarly sized (cca. 10 μm), lorezapam-rich microparticles. There could be observed that partially hydrolysed PVA in the microparticles coat leads to a rapid drug release (cca. 80% in 5 min), while fully hydrolysed PVA contributed to the reduction of particle cohesion and retardation of drug release (cca. 15% release in 5 min).
Varshosaz and Koopaie, (2002) proposed a PVA crosslinked system for theophylline, as a model drug, encapsulation. The polymer was synthesized using GA, after which it was mixed with a drug solution in NaOH. Authors found a connection between the polymer concentration and the encapsulation eﬃciency, in the sense that a greater loading of theophylinne drug was registered for a greater proportion of GA.
Since PVA has a low absorption level from gastrointestinal tract into the blood stream, it can be successfully used as non-absorbing carrier matrix for per os administration of drugs (Alves et al., 2011; Moretto et al., (2004). A study conducted by Moretto et al., 2004) reported the application of PVA hydrogels obtained by cryogelation in oral delivery of antibiotics (oxytetracycline hydrochloride and tylosin tartrate) in veterinary uses. They concluded that PVA is a good drug delivery ma- terial for tylosin, since signiﬁcant quantities of this drug were detected in kidneys and muscles. In contrast, it did not register a similar eﬀect for oxytetracyclin delivery.
Ghareeb and Mohammad, (2013) investigated the eﬀects of PVP, and other polymers, on the properties of buccoadhesive PVA patches of 5-ﬂuorouracil for local treatment of oral squamous cell carcinoma. The patches were obtained by solvent casting method and were evaluated in terms of mucoadhesive mechanical properties, and release proﬁle, studies that proved their applicability as good treatment system for oral delivery.
Hydrogels of PVP were proposed by Alsarra et al., (2009) as safe materials for nasal delivery of acyclovir.PVP was also used in combination with ethylcellulose for coating pellets for sparingly water-soluble topiramate delivery (Yang et al., 2014). PVP acted as a binder, changing the physical state of topiramate from amorphous to crystalline when a PVP content in drug layers < 20% was used. This contributed to the modiﬁcation of the drug release proﬁle from ﬁrst-order to zero-order. Moreover, PVP acted as a pore- former enhancing a drug release sensitivity ranging from 23% to 29%. PVA and PVP were used as a coating for beclomethasone dipro- pionate microparticles within a hydroﬂuoroalkane propellant for steroid delivery to the airways from a pressurised metered dose inhaler (Jones et al., 2006). Authors concluded that, in contrast with other polymers, the addition of PVA and PVP signiﬁcantly aﬀected the re- duction of the aggregation of microparticles suspension, contributing to the obtaining of physically stable suspensions with excellent aerosolization properties.
Solid ﬁlms of PVA, PVP and blends of PVA/PVP were used as car- riers for nitric oxide (NO) donor S-nitrosoglutathione (GSNO) (Seabra and De Oliveira, 2004). Due to the fact that the ﬁlms provided a good stabilization eﬀect on the thermal decomposition of GSNO, good me- chanical properties, capacity to smoothly coat metallic surfaces, they are proposed as very good candidates for the local and controlled re- lease of NO in targeted areas.
PVA and PVP in combination with poloxamer 407 was studied for developing a thermally reversible in situ gel forming drug delivery system for recombinant human growth hormone, used for replacement therapy of pediatric hypopituitary dwarﬁsm (Taheri et al., 2011).
Magnetic drug targeting systems
The severe side eﬀects generated by chemotherapy in cancer treatment led to tremendous work aimed to lower the level of systemic cytotoxicity. A viable way to solve this problem seems to be magnetic drug targeting.
Biomedical and bioengineering applications such as drug delivery, detoxiﬁcation of biological ﬂuids, tissue reconstruction, magnetic re- sonance imaging, cell separation, hyperthermia, etc., require the use of magnetic NPs (with high magnetization values and sizes smaller than 100 nm) that have a special surface coating, which possesses besides non-toxicity and biocompatibility, also a capacity to targetable deliver the NPs in a desired area (Gupta and Gupta, 2005). The magnetic NPs can be targeted to a tumour, tissue or an organ by means of an external magnetic ﬁeld, delivering enzymes, proteins, drugs, antibodies, or nucleotides that have previously been attached to the particles. The magnetic elements that have been used to design this kind of NPs are nickel, iron, cobalt and their chemical compounds, such as iron oxides NPs (maghemite, γ-Fe2O3, and magnetite, Fe3O4) (Gupta and Gupta, 2005; Mahdavinia and Etemadi, 2014; Ngadiman et al., 2015). The surface coatings play an important role in biodistribution and bioki- netics inside the body of the resulted magnetic NPs, so choosing the right material is still a challenge. Materials that have been used to cover the magnetic NPs are: silica, graphene or polymers (PVA, PVP, etc.).
Guowei et al., (2007) explored this possibility by synthesizing a magnetic micromolecular drug delivery system based on PVP hydrogel with PVA as crosslinker. They used 25 kGy 60Co gamma-ray irradiation to produce the microparticles for target release of bleomycin. In- vestigations revealed that these magnetic nanospheres present passive drug release and can be used as drug carriers in magnetically guided chemotherapeutic drug delivery. Another research team (Kamulegeya et al., 2006) studied the magnetic pingyangmycin drug targeting of VX2 auricular tumours using self-assembled PVA/PVP magnetic hydrogel microspheres. Authors conﬁrm the success of magnetic drug targeting by PVA/PVP microspheres and recommend them for future studies for improving their eﬃcacy.
Saha and co-workers (Saha et al., 2006) developed a biodegradable composite system based on PVA/PVP modiﬁed with aluminosilicate by solution casting method, with magnetic properties. These systems found applicability in a wide range of uses in biomedical engineering (e.g. implantable drug delivery systems) and microelectronics (e.g. radio- electronic devices to inﬁll the space between electrical circuits). Bio- degradable micro devices are of very great interest lately since they have the capacity to naturally degrade and disappear after accom- plishing their roles in the tissues or other environments.
In a study published by Lee and co-workers (Lee et al., 1996), the obtaining of magnetic NPs by precipitation of iron salts in PVA aqueous solution is presented. Authors reported that by increasing PVA con- centration, the crystallinity of the NPs decreased, with no change in size and morphology of the particles.
Wound and burn dressings
There are two types of wound dressings on the market: ﬁrst are the dry dressings which enable the formation of a crust while the wound is kept dry, and the second type are the wet dressings facilitating the epidermal cells migration for a more rapid healing of the wound (Nho et al., 2004; Nho and Park, 2002; Park and Nho, 2004, 2003). In this context, hydrogels are widely used as wet dressings in the treatment of wounds and burns, due to their intrinsic properties, such as non-toxi- city, protection of the aﬀected area, good adhesion to the wound, moisture retention or removal, and capacity to incorporate and release drugs in a speciﬁc time interval.
PVA and PVP have been investigated as hydrogels for skin re- generation and wound dressing applications using F/T, radiation crosslinking, electrospinning, etc. (Dai et al., 2012; Darwis et al., 1993; Fogaça and Catalani, 2013; Himly et al., 1993; Hu et al., 2017; Ignatova et al., 2007; Kadłubowski et al., 2007; Park and Nho, 2004; Razzak et al., 2001; De Silva et al., 2011; Singh and Pal, 2011). There have been obtained hydrogel membranes with desired properties (e.g. bio- compatibility, elasticity, ﬁxability, transparency, immediate pain re- duction, and impermeability for bacteria) (Darwis et al., 1993; Himly et al., 1993). (1993) have shown that poly(ethylene glycol) (PEG) added as pores-former to the hydrogel composition contributes to its performance by creating a barrier against bacterial growth.Studies published by Razzak and co-workers (Razzak et al., 2001,1999) presented the obtaining of a copolymeric hydrogel of PVA/PVP using 60Co gamma-ray irradiation crosslinking method. They concluded that physicochemical properties of PVA/PVP hydrogels (e.g. water content in the range of 60–80%, water adsorption between 40 and 250%) are signiﬁcantly improved by the addition of PVP. Furthermore, PVA/PVP hydrogels crosslinked by irradiation at 20 kGy meet all conditions for usage as burn and wound dressings due to the formation of a good barrier against microbes and Escherichia coli.
In addition to PVA/PVP mixtures, some studies report the incorporation of another component able to improve the hydrogel properties or the healing process. Among these components, some can be mentioned: chitosan (Ignatova et al., 2007; Morgado et al., 2017; Vimala et al., 2011; Yang et al., 2008), Aloe vera (Park and Nho, 2004; Uslu et al., 2010; Uslu and Aytimur, 2012), charcoal (Nho et al., 2004), hydroxypropyl methylcellulose (HPMC) (Uslu et al., 2010), PEG (De Silva et al., 2011; Uslu et al., 2010), AgNPs (Singh and Singh, 2012; Yu et al., 2007), kappa-carrageenan (De Silva et al., 2011, sterculia gum (Singh and Pal, 2011).
Nho et al. reported a series of studies on the obtaining of hydrogels for wound dressings made from mixtures of PVA/PVP and chitosan (Nho and Park, 2002; Park and Nho, 2003), PVA/PVP and charcoal (Nho et al., 2004) and PVA/PVP and Aloe vera (Park and Nho, 2004). In all cases, the methods used were F/T technique, gamma-ray irradiation, or combined F/T and gamma-ray irradiation. For hydrogels obtained from mixtures of PVA/PVP and chitosan, they studied the eﬀect of ir- radiation dose on the physical properties (such as gelation, degree of water swelling, and gel strength). It could be concluded that the addi- tion of irradiation to the F/T steps inﬂuences the gelation and gel strength, in the sense that these are higher than those of the hydrogels obtained only by F/T (Nho and Park, 2002). Also, with a higher polymer composition and irradiation dose the swelling percent in- creased (Nho and Park, 2002). Moreover, in order to test the usefulness of these hydrogels for wound dressings, there have been performed investigations on rats, with vaseline gauze in comparison with PVA/ PVP and chitosan hydrogel dressing. It could be observed that unlike the vaseline gauze, which dried quickly and stuck to the wound of the rat, the PVA/PVP and chitosan dressing stopped the wound bleeding and had a better curing (Nho and Park, 2002). For charcoal ﬁlled PVA/ PVP hydrogels, the gel content and antibacterial eﬀect were in- vestigated (Nho et al., 2004). The gel content was seen to increase with the increase of irradiation dose or with the number of F/T cycles, while charcoal concentration insigniﬁcantly inﬂuenced the gel percentage. Because it did not inﬂuence the gel content, but it decreased the gel strength, charcoal is supposed to be physically immobilized inside the hydrogel pores. In regard to antibacterial eﬀect, authors reported that the PVA/PVP and charcoal hydrogels had a higher absorption of Sta- phylococcus aureus and Pseudomonas aeroginosa than hydrogels without charcoal (Nho et al., 2004). The physical properties, such as gelation and gel strength, swelling, and degree of water evaporation, were in- vestigated for hydrogels obtained from mixtures of PVA/PVP and Aloe vera (Park and Nho, 2004). It was concluded that using irradiation in addition to F/T leads to a higher gelation and gel strength than when only irradiation was used. Also, these properties increased with the decrease of Aloe vera concentration in the hydrogel, and with the in- crease of irradiation dose or the number of F/T cycles. Hydrogels ob- tained only by irradiation had a much higher swelling degree than hydrogels obtained by F/T and irradiation. With a higher concentration of Aloe vera, or a decrease of irradiation dose and the number of F/ T cycles, the swelling degree of the hydrogel also increased. Some tests were conducted in order to demonstrate the capability of these hy- drogels to be used in wound dressing applications. In this sense, the healing of rat wounds was observed with PVA/PVP and Aloe vera dressing, commercial urethane membrane and without dressing. The PVA/PVP and Aloe vera dressing proved to cure better and heal quicker the wounds than the commercial product, or without any dressing (Park and Nho, 2004).
Another research team that used Aloe vera in preparation of wound dressings was the one conducted by (Aytimur et al., 2013; Uslu and co- workers (2010); Uslu and Aytimur, 2012). They used the electrospin- ning method to obtain PVA/PVP/PEG with Aloe vera (Uslu et al., 2010) and PVA/PVP‑iodine/PEG with Aloe vera and HPMC (Uslu and Aytimur,2012) hybrid nanoﬁbres with very interesting properties such as high surface area-to-volume ratio, high porosity, small pore sizes, anti- bacterial and healing properties. Although PEG was used only in small percentage (1 g PEG per 100 g PVA and 10 g PVP), it is believed that PEG contributes to the improvement of hydrogel barrier performance against bacteria (Uslu et al., 2010). Being one of the oldest herbs used as a healing plant, Aloe vera is also beneﬁcial for wound and burn healing due to its components, such as: polysaccharides, salicylic acid, eight essential amino acids, twelve non-essential amino acids and an- thraquinones, ten enzymes and many minerals and vitamins (Eshun and He, 2004; Hamman, 2008). Furthermore, the addition of Aloe vera in- ﬂuenced the polymer solution properties by increasing viscosity and conductivity. This conducted to the decrease of the ﬁbre diameter, re- sulting ﬁner and beadless nanoﬁbres (Uslu et al., 2010). Thereby the electrospun structure had an increased porosity, facilitating the pene- tration of oxygen and moisture to the wound, which contribute to the healing process and also, prevents the bacteria inﬁltration (Uslu et al., 2010). In the second study, HPMC was used as thickener, stabilizer, emulsiﬁer, excipient, water retention and ﬁlm-forming agent, aspects of very much importance for wound and burn dressing materials (Uslu and Aytimur, 2012).
Another successful study for wound dressing purposes was reported by (Park and Nho, (2003). They developed a new method to synthesize a two-layer hydrogel consisting of a polyurethane membrane cover and a mixture of PVA/PVP-chitosan-glycerin. Some layers of PVA/PVP were crosslinked by gamma irradiation, and others by F/T followed by gamma irradiation. Authors reported that for membranes obtained from two crosslinking steps of F/T cycles followed by irradiation or by in- creasing irradiation dose, an improvement of the physical properties (e.g. gel fraction, mechanical strength) of PVA/PVP hydrogels covered with polyurethane have been observed, compared to hydrogel mem- branes obtained by just one irradiation process, which presented weak strength (Park and Nho, 2003). Furthermore, for these latter PVA/PVP hydrogel membranes, water evaporation speed and permeation rate were reduced when covered by polyurethane membranes (Park and Nho, 2003).
Wounds dressings with antibacterial agent delivery were developed by Singh and Pal, (2011) using radiation crosslinking for PVA/PVP modiﬁed sterculia gum polysaccharide. The addition of PVP and ster- culia gum aﬀected the properties of resulted hydrogel membranes as follows: i) swelling tests revealed that with an increase of amounts of PVP and sterculia gum, the swelling degree of the hydrogel also in- creases, while it decreases when the radiation dose is increased (due to the formation of long crosslinked chains); ii) increasing the amounts of PVP and gum leads to an increase of thermal stability of the hydrogel (Singh and Pal, 2011). Another interesting feature reported was the swelling decrease in simulated wound ﬂuid for hydrogels with low amounts of PVP and gum, explained by the very high ionic strength of the simulated wound ﬂuid (Singh and Pal, 2011).
PVA as well as PVP have been employed in various studies as matrices to stabilize diﬀerent kinds of metal NPs, preventing them from aggregation in the reduction process from the metal salts in aqueous systems. The resultant metal colloids or nanocomposites have sy- nergistic characteristics, combining the magnetic, electrical, optical, electronic, photothermal and photoelectrical properties of metal NPs with degradability, non-toxicity, mechanical and physical properties of the polymers. Among these, AgNPs stabilized by PVP demonstrated their applicability in treating complicated wounds and burns (Suvorova et al., 2005), due to their bactericide properties, anti-bacterial eﬀect against Escherichia coli (Cho et al., 2005; Sondi and Salopek-Sondi, 2004), and potential candidate for optical information (Zheng et al., 2001).
Studies conducted by Abu Bakar et al., (2007) presented the ob- taining of a natural rubber – Ag nanocomposite for potential natural rubber based healthcare products. Authors explained that the AgNPs are obtained on the surface of the latex particle, in the protein-rich region, and at the interstitial region of the merged rubber particles where the amino groups of the protein molecule aﬀect the stabilization of AgNPs. However, in another study (Abu Bakar et al., 2010) they propose grafting PVP onto natural rubber particles, in their attempt to eliminate the protein, but introducing a polymer that can stabilize the natural rubber particles and also interacting in the same way as protein with Ag ions or atoms. They demonstrated that the molecular chains of grafted PVP form a shell around the natural rubber particles in an aqueous environment and act as a swollen hairy layer. In this way, the rubber particles are stabilized by steric repulsion and are prevented from coagulation. By this work, steps are being made towards a proteinfree natural rubber – Ag nanocomposite with antibacterial properties. (Yu et al., (2007)) proposed a type of PVA/PVP hydrogel containing
AgNPs with very good antibacterial properties. They mention that wound infection is the main cause of death in the thermally wounded patients, so the use of eﬀective antimicrobial agents (such as Ag ions) is required. In this regard, authors report the preparation of a PVA/PVP hydrogel (with the weight ratio of PVA to PVP 70:30) by repeated F/T process with incorporated AgNPs, with the Ag particle size between 20 and 100 nm. Studies revealed that this kind of hydrogels possess ex- cellent antibacterial activity against Escherichia coli and Staphylococcus aureus.
Knowing that Ag is non-toxic and harmless to humans and that AgNPs have antibacterial eﬀect interrupting the metabolism of bacteria in various ways, studies have been made in order to produce PVA hy- drogels with AgNPs (Bryaskova et al., 2010; Eid et al., 2012; Pencheva et al., 2012; Yu et al., 2007) by gamma-irradiation. This method re- duces Ag+, leading to AgNPs with sizes that are inversely proportional to the amount of irradiated gamma-rays. It could be observed that a higher number of AgNPs are obtained in PVA hydrogels immersed in AgNO3 solutions with higher concentrations, under the same dose of gamma-rays. Antibacterial tests revealed that the propagation of Es- cherichia coli and Staphylococcus aureus is eﬀectively inhibited in the PVA hydrogels containing AgNPs.
(Eisa et al., (2012)) reported a novel in situ method to synthesize self-organized AgNPs supported within PVA/PVP ﬁlms, for biomedical applications. They characterize the method as a simple, environmental friendly, easy to perform and cost eﬀective, but it requires a long time period for the complete reduction of silver nitrate within the polymer matrix. Authors reported that there is interdependence between the percentage of PVP and the Ag particle size, so that an excess of PVP in the initial polymer mixture leads to smaller size and narrow particle size distribution.
Dry eye syndrome is a common ocular surface disorder caused by excessive tear evaporation, decreased tear production, some medica- tions (such as antidepressants, antihistamines, etc.), that aﬀects about 10–20% in adult population and up to 70% of contact lens wearers (Johnson and Murphy, 2004; Maruyama et al., 2004; Peterson et al.,2006). One of the approaches in addressing this problem is the in- corporation of hydrophilic polymers to contact lens structure, so that their slow release to stabilize the tear ﬁlm, reduce the friction between eye and the lid, and wash out foreign bodies (Baino, 2011; Calonge, 2001; Peterson et al., 2006).
PVA and PVP have already been recognized by the US Food and Drug Administration as two of the six categories of ophthalmic de- mulcents (FDA, 2015), and are already commercially available in soft contact lenses (Schwarz and Nick, 2006; Veys and Meyler, 2006). Nelﬁlcon A (Alcon) lenses are obtained by a patented LightStream™ Technology consisting in polymerizing PVA with N-formyl methyl ac- rylamide. During this process, approximately 0.5% PVA is deliberately left non-bound in the lens matrix which is slowly released into the tear ﬁlm, thus making the Nelﬁlcon A contact lenses very soft and comfor- table due to sustained PVA release during several hours and very good wettability (AquaRelease™) (Peterson et al., 2006; Winterton et al., 2007).
Other commercial contact lenses are Nesoﬁlcon A, which are ob- tained from a copolymer of hydroxyethyl methacrylate and N-vinyl pyrrolidone, and possess high water content (78%), undergo very little dehydration when exposed to air and are able to maintain their shape even in a dehydrated state (Kirchhof et al., 2015).
A study published by Yañez et al., (2008) presented the obtaining of semi-interpenetrating networks of poly(hydroxyethyl methacrylate) with PVP by free radical polymerization of hydroxyethyl methacrylate in the presence of PVP, under anhydrous conditions or after addition of water, for comfortable soft contact lenses. Authors investigated swel- ling, porosity, PVP release rate, air-water surface tension, and friction coeﬃcient, and they concluded that: i) the swelling degree and porosity increased with the increase of the water content during polymerization;ii) slow PVP release by diﬀusion (20% after 9 days); iii) surface tension decreased signiﬁcantly, as well as the friction coeﬃcients, with the increase of PVP content or the higher its molecular weight; iv) higher contents of PVP do not compromise the optical clarity of the lens.
Cataract surgery, one of the most frequently performed surgical interventions, consists in replacing the opaciﬁed natural lens by a polymeric intraocular one (Leone et al., 2011). One of the challenges faced by both conventional rigid poly(methyl methacrylate) and soft foldable (silicone and acrylic) intraocular lenses is that they are too stiﬀ to allow eﬀective accommodation. In order to address this problem, Leone et al. (Leone et al., 2011) developed a new thixotropic PVA/PVP based hydrogel with non-cytotoxic and biocompatible properties, as a good candidate for potential applications in ophthalmology. The rheological studies showed that the behaviour of this viscoelastic ma- terial is similar with that of young human lens in terms of complex shear modulus and accommodation capability (Leone et al., 2011).
Biomaterials ﬁeld is at the forefront of researcher's interest today due to their high potential to positively impact the quality of life, especially when health problems are involved. Eﬀorts concentrated in this direction led to great advances of polymeric biomaterials, which demonstrated to be valuable answers to stringent medical and phar- maceutical problems. Among the polymers used, PVA and PVP proved to be very versatile materials, recommended by their long history as biomaterials, easy processability, and the variety of highly performing applications, previously reviewed. However, in order for these PVA/ PVP-based biomaterials to stay in tune with the biggest trends, we have to take a glimpse into the future in order to see where the research is headed.
Medicine is confronted with an urgent need to solve the problem of donor organs and tissues, patients being forced to wait for agonizing months or years. With the great advancements in regenerative medi- cine, we might hope that in the near future the physicians will be able to send the patient's medical history accompanied by a tissue sample to an organ engineering company and waiting in a matter of days to re- ceive the custom-made organ ready for implantation. We are optimistic that this might become reality, especially after seeing the advancements made by using PVA and PVP in tissue engineering applications as scaﬀolds, artiﬁcial tissues, etc. Moreover, since both polymers men- tioned are biodegradable, they can be used in resorbable matrices, cells transportation in healing enhancement of bone fractures, and many other grafts.
Another alarming problem is raised by the tremendous number of people aﬀected by severe infections provoked by strong resistant viruses and bacteria to current antibiotics. With the conjoint eﬀorts of many research teams, there were registered signiﬁcant developments in the ﬁeld of drug delivery systems based on PVA and PVP containing AgNPs. They clearly demonstrated to be more eﬀective in killing bac- teria, without aﬀecting the surrounding healthy tissues. The advanced functionalities that can be encoded into these polymeric biomaterials, such as stimuli targeted delivery, can eﬃciently treat life-threatening diseases like cancer or diabetes.
In the light of the above mentioned, we envisage a bright future for solving biomaterials scientiﬁc problems and health care challenges, which might greatly beneﬁt from further concentrated research on improving the state-of-the-art of PVA/PVP-based biomaterials. We hope that this paper will be found valuable for researchers interested in this ﬁeld.
The extended amount of information reviewed in this paper serves as a concise outline regarding the applicability of PVA-based bioma- terials over the years. It could be seen that PVA extensive use in medical and pharmaceutical ﬁelds is dictated by its highly interesting properties (e.g. biocompatibility, biodegradability, easy preparation, excellent ﬁlm forming capacity, very good adhesive and emulsifying properties, good mechanical stability, excellent chemical resistance, odourless and high barrier properties, etc.). However, it could be concluded that PVA-based biomaterials present various shortcomings that can restrict their ap- plicability or performance. To overcome these limitations, we have shown that a valuable solution is PVA blending with PVP. In this re- gard, it was analysed a vast range of biomaterials with valuable char- acteristics resulted by the combination of PVA and PVP, and presenting diﬀerent aspects involved in their preparation or synergistic eﬀects of the obtained polymeric structures. Great interest was concentrated on surveying their performances in a wide spectrum of applications, with special emphases on tissue engineering, drug delivery systems, wound/ burn dressings, and ophthalmologic applications. Moreover, we tried to sketch some future trends towards where medical and pharmaceutical research is headed, and how PVA/PVP-based biomaterials can satisfy more and more diﬃcult challenges.
The authors declare no conﬂicts of interest.
This research did not receive any speciﬁc grant from funding agencies in the public, commercial, or not-for-proﬁt sectors.
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