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.


Why PVA?


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., 2014Hassan 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, 2010Buwalda et al., 2014Cutiongco et al., 2015Hameed   et al., 2015Juntanon et al., 2008Paradossi 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., 2012Burczak et al., 1996Hameed et al., 2015Jiang  et al., 2009Oliveira 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., 2008Lozinsky  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, 2013Attaran et al., 2013Kim 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., 2010aRazzak 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., 2004Ng et al., 2011Saxena et al., 2006Smith 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.


PVA/PVP blending


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., 2011Wei et  al., 20172016a2016b), 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, 1997Teodorescu 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, 2010Cassu and Felisberti, 1997Kim et al., 2002;Lewandowska, 2005Morariu et al., 2016Ping 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, 19991997Lewandowska, 2005Ping et al., 19901988).




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., 2010aCassu and Felisberti, 1997Elashmawi and Abdel Baieth, 2012Kim et al., 2002Nkhwa 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, 2005Cassu and Felisberti, 1997Kim 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, 1997Elashmawi and Abdel Baieth, 2012Nkhwa et al., 2014Teodorescu 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., 2010aElashmawi and Abdel Baieth, 2012Nkhwa 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, 2009Abdelrazek et al., 2010a, 2010bAttaran et al., 2013Awadallah-F, 2014Eid et al., 2012Eisa et al., 2012Elashmawi and Abdel Baieth, 2012Leone et al., 2011Morariu et al., 2016Shi 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, 2010bElashmawi 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, 2010bElashmawi 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, 2005Mondal 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 cm1  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,  1966Lee  et al., 2008Peppas, 1977Tretinnikov and Zagorskaya, 2012), suggesting that PVP interacts with PVA only in the amorphous re- gions of PVA. Similar results were also reported (Lewandowska, 2005Lu et al., 2003Ping 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, 2009Eid et al., 2012Morariu  et al., 2016Shi et al., 2014).



X-ray diraction


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., 2011Morariu et al., 2016Razzak et al., 1999Ricciardi et al., 2004Teodorescu 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.,  2011Razzak et al., 1999Teodorescu 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, 2011Razzak et al., 1999Yadav 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., 2010aElashmawi and Abdel Baieth, 2012Morariu et al., 2016Ragab, 2011Razzak 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., 2016Teodorescu 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., 2016Teodorescu et  al., 2016Zheng et al., 2008). Moreover, PVP reduces the coefficient of friction (Ma et al., 20102009Zheng 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., 2016Teodorescu et al., 2016Thomas, 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., 20011999Singh 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., 2012Suvorova 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., 1999Hill and Whittaker, 2011Li et al., 2004Panaitescu et al., 2015), glutaraldehyde (GA) (Attaran et al., 2013Fundueanu et al., 2010Gough et al., 2002Juntanon et al., 2008Tsai et al., 2010), epichlorohydrin (Al-Sabagh and Abdeen, 2010He et al.,  2014Savina et al., 2005), sulfosuccinic acid (Huang et al., 2009Rakesh and Deshpande, 2010Rhim et al., 2002Tsai et al., 2010Xiang 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., 1994Chowdhury et al., 2006de Oliveira et al., 2013), electron  beam  (Abd  Alla et al., 2006Bee et al., 2014Ibrahim and El Naggar, 2013), or UV irradiation (Khan et al., 2006Nguyen and  Liu,  2013;  Sheela  et  al., 2014Zhou 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., 2013Chaudhuri et al., 2016Gaaz et al., 2015Gökmeşe et al., 2013Ma et al., 2007Mohammad Ali Zadeh et al., 2014Pan  et  al.,  2006Yao 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., 2000Hassan and Peppas, 2000a, 2000bPeppas and Khare, 1993Peppas and Mongia, 1997Peppas and Stauer,  1991)  and  Lozinsky  et  al.  (Damshkaln  et  al.,  1999Lozinsky,2008Lozinsky et al., 20072000a2000b,1996a1996b19951992;Lozinsky and Damshkaln, 2001Savina et al., 2005). Hydrogel, and its applicability in biomedical and biotechnological fields were described only in the 1990s (Lozinsky et al., 1997Lozinsky 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, 2000bHolloway et al., 2013aLozinsky  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., 2006Fechine 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, 2009Abdelrazek et al., 2010aAli et al., 2018Aziz et al., 2017Choudhary, 2018Choudhary and Sengwa, 2018Chougale et al., 2018Hammannavar and Lobo, 2018Huang et al., 2011Jabbari and Karbasi, 2004Jeyabanu et al., 2018Kim et al., 2002Kumar  et  al.,  2017Lu et al.,  2003;  Ma  et  al.,  2009;  Mohammed  et  al.,  2018;  Nho  et al., 2004Nho and Park, 2001Park and Nho, 2003Qiao et al., 2010Ragab, 2011Shi et al., 20142016aShi  and  Xiong,  2013;  Singh  and Pal, 2011Teodorescu et al., 2016Zheng et al., 2009;  Zidan  et  al.,  2018). Chemically crosslinked PVA/PVP materials have  been  reported by various research teams (Kim et al., 2002Lu et al., 2003Qiao 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., 2016Huang et al.,  2011Ma et al., 2009Morariu et al., 2016;       Shi et al., 2016aShi and Xiong, 2013Teodorescu 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.,  2011Ma 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., 2004Park and Nho, 2004,2003Shi et al., 2014Zheng 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., 20092004Park 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).


Tissue engineering


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., 2014Ma, 2008Vedadghavami 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., 2014Holzwarth  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.)


production must present biocompatibility and biodegradability, and their mechanical response must be similar to that of the natural tissues (Butcher et al., 2014Hameed et al., 2015).


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

(Table 1

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., 2011Nkhwa 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., 2011Morimune et al., 2011Zhang 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., 2008Bin et al., 2006Liu et al., 2005Zhang 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., 2010Butcher et al., 2014Pan 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., 20072004Ma et al., 20102009Shi 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., 2012Batista 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.,  2013bJoshi et al., 2006Wang 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., 20052003Lange et al., 2006Shi et al., 2014Stammen 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., 20102009Shi 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., 20092008).


Another team (Ma et al., 20102009) 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.,  2014Shi  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., 2006Thomas 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., 2006Thomas 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, 19931991). 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., 2004Thomas, 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., 2003Joshi 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, 2013Fundueanu  et  al., 2010Islam and Yasin, 2012Paradossi et al., 2002), temperature (Fundueanu et al., 2010Taheri et al., 2011), magnetic (Guowei et al., 2007Hosseinzadeh et al., 2015Kamulegeya et al., 2006Mahdavinia and Etemadi, 2014Ngadiman et al.,  2015),  electric  (Bercea  et  al.,  2018Juntanon 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.


  • Ophthalmologic applications


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).


  •  Future trends


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.


  • Conclusions


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.


Competing interests


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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