Bioactive compounds-loaded polyvinyl alcohol hydrogels: advancements in smart delivery media for biomedical applications

The paper initially focuses on the characteristics of Polyvinyl Alcohol (PVA) hydrogel as smart delivery media, such as chemical stability, biocompatibility, and capacity for controlled release of bioactive compounds. Then, it discusses the effect of loading bioactive compounds into PVA hydrogel, considering their stability of delivery media, controlled release, and targeted delivery, enhancing therapeutic outcomes. Loading bioactive compounds such as diphlorethohydroxycarmalol (DPHC), curcumin, carotenoids, andrographolide, and flavonoids into PVA hydrogels can enhance biomedical functionalities. These functionalities include improved drug delivery, wound dressing efficacy, tissue engineering potential, and contact lens applications. Further, while previous review papers have extensively covered aspects such as the source of bioactive compounds, extraction methods, synthesis of PVA hydrogel, and various biomedical applications, there remains a gap in the literature in which no studies have systematically explored the loading of bioactive compounds into PVA hydrogel. This targeted investigation distinguishes our work from previous studies and contributes a novel perspective to the expanding hydrogel market. In light of the projected compound annual growth rate of 7.15% in the hydrogel market from 2021 to 2028, this study provides a pioneering overview of recent advancements in bioactive compound-loaded PVA hydrogels. Finally, this review outlines the challenges in optimizing bioactive compound-loaded PVA hydrogels’ performance and their biomedical application. In the future direction, this review explores their potential in smart delivery media, such as optimizing the loading efficiency and releasing kinetics to specific target therapeutic, crosslinking with double or triple network hydrogels, and convergence of nanotechnology with hydrogel that become frontiers in precision medicine.


Introduction
Hydrogels are produced by crosslinking polymer chains, forming intricate three-dimensional networks.While generally insoluble when immersed in water, they can absorb water thousands of times their dry weight [1][2][3][4].Hydrogels possess attributes that render them sensitive to physiological conditions, being hydrophilic and soft like water while demonstrating favourable flexibility [5][6][7].Notably, hydrogels showcase exceptional reactivity to various stimuli, including pH, temperature, biological molecules, electric and magnetic fields, and solution ionic strength [2,8].These characteristics indicate hydrogels with 'smart' properties, which are especially suitable for various biomedical applications, such as tissue engineering, wound dressings, pharmaceutical applications, contact lenses, and potential edible electronic devices [9][10][11][12][13][14][15][16].Smart hydrogels are advanced materials that can intelligently and controllably release therapeutic agents (bioactive compounds) in response to environmental stimuli.These stimuli can include factors such as pH, temperature, light, specific ions, or the presence of certain molecules.The responsiveness of smart hydrogels allows for targeted and on-demand bioactive delivery, improving the efficacy and precision of therapeutic treatments [17][18][19].
The production of hydrogels entails two fundamental approaches: chemical and physical crosslinking methods [20].Physically crosslinked hydrogels are formed through various physical parameters such as hydrogen and van der Waals bonds or the freeze-thaw technique [11,21].Conversely, chemical crosslinking relies on crosslinking agents like glutaraldehyde, borate-containing species, and glyoxal [22][23][24][25][26].The physical crosslinking method has the advantage of being non-toxic but possessing less long-term stability.In contrast, the chemical crosslinking method offers improved stability, but it may introduce toxic content through the crosslinking agent, if used [11].Hydrogels with physical or chemical crosslinking are derived from natural or synthetic polymers [21,[27][28][29].Polyvinyl alcohol (PVA) is a synthetic polymer with semicrystalline characteristics, known for its biodegradability, non-ionic hydrophilic and non-toxic [30,31].It has extensively been utilized to make solid dispersions to increase the solubility of pharmaceuticals and inhibit crystal transformation [30].PVA hydrogels, with excellent physical properties and chemical resistance, have widely been used in biomedical applications due to their low production costs, appropriate mechanical qualities, and cytocompatibilities [13,32,33].
PVA hydrogel is non-carcinogenic and biocompatible, making it versatile for various biomedical purposes [21].Porosity is another critical factor in hydrogels, impacting drug delivery accuracy and efficiency to the specific target [34].The control of cross-link density within the polymer matrix and its water interaction significantly regulates porosity, allowing precise control of drug release kinetics [35].Cross-linked PVA membranes have demonstrated substantial swelling properties, making them suitable for sustained bioactive compound release at specific targets, which is vital in drug delivery systems [36].Bioactive compounds are chemical compounds found in natural sources that are usually obtained from living things like plants, fruits, vegetables, or bacteria.Noteworthy examples include diphlorethohydroxycarmalol (DPHC) from brown algae, andrographolide from Andrographis paniculata, curcumin from turmeric, carotenoid from carrot, and flavonoids found in various sources like broccoli and onions [37][38][39][40][41].These compounds exhibit multifaceted pharmaceutical functionalities, encompassing antioxidative, antimicrobial, anti-inflammatory, anticancer, and antiviral properties [8].
Hence, the investigation of potential bioactive compounds loaded within PVA hydrogels presents an intriguing avenue for research.The publications on PVA hydrogels and bioactive compounds show a significant increase (figure 1(a)).In previous studies, loading bioactive compounds into PVA hydrogel as smart delivery media enhances their efficacy by protecting against environmental degradation, extending shelf life, enabling controlled release, optimizing therapeutic levels, mitigating adverse effects, and enabling targeted delivery [42][43][44][45][46]. Several review papers have been read thoroughly and it has been found the following keywords, e.g. the source of bioactive compounds [39,47,48], the extraction methods of bioactive compounds [39,41,49], the biomedical applications of the PVA hydrogels [30,50,51], the properties, characterization and synthesis methods of the PVA hydrogels [11,16,52].The studies of loading bioactive compounds into PVA hydrogels are very limited to date.Hence, this review aims to explain recent advances of PVA hydrogels loaded with bioactive compounds, for several biomedical applications (figure 1(b)).

PVA hydrogels as smart delivery media
Smart hydrogels are highly adaptable materials that respond to environmental stimuli, making them suitable for a wide range of applications in medicine and technology.Hydrogels possess distinctive attributes, including their capacity to retain water, biocompatibility, and controlled swelling behaviour, rendering them promising candidates for smart drug delivery systems.They are excellent carriers of bioactive compounds in utilizing targeted, bioadhesive, controlled-release therapeutic agents [53].The release mechanism of bioactive compounds in the hydrogel matrix influences the delivery process [54][55][56].Based on its mechanical properties, biodegradability, biocompatibility, non-toxicity, hydrophilicity, water-solubility, and high ability to form a hydrogel, PVA is one of the most commonly used synthetic polymers in biomedical applications [21,57,58].PVA hydrogels are being extensively researched for their potential as smart media delivery systems.In the previous research, formulated Gel/PVA hydrogels as a pH-sensitive matrix for delivering methotrexate to the colon.The study evaluated their swelling behavior, diffusion coefficient, sol-gel characteristic, porosity, and drug release kinetics [59].Pandit et al developed PVA-based hydrogels using chemically oxidized gum arabic as a cross-linker.These hydrogels displayed high mechanical properties, good porosity, pH sensitivity, and were effective for the sustained delivery of folic acid [60].In the other studies, Lima et al explored a novel pH-sensitive smart hydrogel combining PVA with polyacrylic acid and hydroxyapatite, focusing on its mechanical strength, bioactivity, and their potential for controlled drug release [61].Bakadia et al fabricated silk sericin/polyvinyl alcohol hydrogel-based burn wound dressings synthesized using the freeze-thaw method are a potential biomaterial to accelerate the healing of infected large burn wounds due to their excellent antibacterial, antifungal, and mechanical properties.The addition of silk sericin enhanced the biological characteristics.In contrast, with the addition of genipin and PVA content, the hydrogel's mechanical properties (gelation time, cross-linking density, porosity, swelling degree, and retention water) were enhanced.The hydrogel release capability was demonstrated by sustained silk sericin and azithromycin and the cytocompatibility of fibroblast and keratinocyte.In vivo studies showed that burns from the spleen and liver of mice are more significant and enhance inflammation reactions throughout the body [62].Additionally, Zhang et al created a supramolecular hydrogel using PVA/graphene oxide, and G-quartet/hemin motifs that demonstrated pH-induced reversible phase transitions and peroxidase-like activity, which could be beneficial for drug delivery and biomedical applications [63].These studies highlight the diverse potential of PVA hydrogels in smart media delivery, offering insights into their mechanical properties, drug release behaviors, and suitability for various biomedical applications.The orientation method enhanced hydrogels' mechanical properties, crystallinity, and degree of expansion.Increasing the number of cycles increases polymer alignment. [69] Thawing at 4 °C for 4 h Self modification PVA/HA Mixture PVA/HA at 95 °C until a transparent, viscous and poured into a custom mould.

Increasing hydrophilicity [70]
Freeze-thaw PVA/sericin Four cycles The porous structure of the PVA/sericin hydrogel demonstrated high swelling capacity and hydrophilicity.Incorporating PVA enhanced the thermal stability and mechanical properties. [71] Freezing at −80 °C Thawing at room temperature Physical mixing PVA PVA and tannin mixture at 90 °C for 2 h..The PVA/tannin hydrogels have good mechanical qualities because of their amorphous structure and strong H-bonding.This is shown by their high tensile strengths (up to 2.88 MPa) and high elongations (up to 1100%) [72] Heating at 110 °C to be more homogeneous Reserving PVA/tannin hydrogels at room temperature for 24 h Freeze-thaw PVA/Polyurethane Three cycles The PVA/polyurethane hydrogel exhibits a porous structure with varying surface morphology.Specifically, the hydrogel's surface pore size and swelling ratio increase as the polyurethane content increases.

[73]
Thawing at room temperature for 8 h Freezing at −20 °C for 16 h Freeze-thaw PVA/Polypropylane Freezing at −20 °C for 12 h, thawing at ambient temperature for 12 h Hydrogel was shown a potential to inhibit cell adhesion and good cytocompatibility. [74] Freeze-thaw PVA/Cellulose nanocrystal

Three cycles
The capacity to absorb water increases while the modulus of compression and optical transparency decreases when the concentration of cellulose nanocrystals increases.

[72]
Freeze at −20 °C for 12 h Thaw at RT for 6 h Chemical crosslinking Photo-initiator PVA Photoinitiator: 2-hydroxy-1-The PVA methacrylate hydrogels containing different silk fibroin percentages showed differences in pore size and distribution.The PVA/silk fibroin hydrogel demonstrates that The hydrogel exhibits good compatibility and exhibits the formation of a honeycomb-like structure.The hydrogel exhibited good mechanical and thermal characteristics. [76] Crosslinking agent PVA/Sodium alginate PVA/sodium alginate/Aloe vera mixture at 70 °C, adding (poly(ethylene glycol) diacrylate) into precursor solution, heating at 80 °C for 1.5 h The addition of Aloe vera into PVA/sodium alginate hydrogels exhibited slightly higher thermal stability than the unmodified hydrogels.A rigid and thermally stable three-dimensional structure of the PVA/sodium alginate hydrogel had been obtained.The active substance was released controllable for a week. [77]

Physical and chemical crosslinking
Freeze-thaw and crosslinker agent PVA Mixing PVA/aloe polysaccharide/honey as precursor solution at 70 °C for 30 min, adding borax solution (crosslinking agent) into precursor solution.
PVA/aloe polysaccharide/honey hydrogel has excellent biocompatibility and good mechanical strength.The hydrogels inhibited Staphylococcus aureus, Escherichia coli, and Candida albicans and accelerated wound healing. [78] The final solution freezing for 3 h and thawing for 3 h in two cycles.Freeze-thaw and crosslinker agent PVA PVA hydrogel was cross-linked using glutaraldehyde.Bonded to graphite and nano-hydroxyapatite.
At a concentration of about 1.66 wt% of nHA, there was no change in the shape of the human epithelial cells, and a clot formed around the scaffold during the one-week in vivo placement. [79] Five cycles: freezing at −20 °C for 12 h, thawing at room temperature for 12 h PVA hydrogels as smart delivery media, while advantageous in various biomedical applications, exhibit several disadvantages such as inherent bioinert-ness limiting biomedical effectiveness [64], permeability issues affecting drug release rates [13], hydrophilic properties of PVA hydrogel a restricted drug loading capacity particularly for hydrophobic compounds [65,66], and achieving precise release kinetics is challenging [67].Moreover, PVA hydrogels lack cell adhesion functionalities, which is essential for specific biomedical applications such as tissue engineering and wound healing [15].This limitation points to the need for chemical crosslinking in PVA hydrogels to enhance gel stability and improve endothelialization and hemocompatibility, addressing the common issues attributed to poor cellular interactions [11].These challenges require further modifications for the future development of PVA hydrogel as smart delivery media for biomedical applications.This modification is influenced by the PVA hydrogel fabrication process, which causes changes in characteristics such as shape, size, morphology, and function [68], as explained in table 1.

Characteristic of PVA-based hydrogels
PVA, a synthetic polymer with the formula (C 2 H 4 O) n , is a common raw material for hydrogel synthesis, with molecular weights ranging from 20,000 to 400,000 g mol −1 based on the length of the initial vinyl acetate polymer [80,81].Differing PVA molecular weights yield distinct properties, including variations in pH, band gap, melting point, refractive index, and viscosity [10,13,82].Moreover, the hydroxyl groups within PVA are pivotal in the synthesis of hydrogels, notably in freeze-thaw, where the formation of hydrogen bonds among OH groups in the PVA chain is essential.These hydroxyl groups also promote the formation of intermolecular and intramolecular hydrogen bonds, significantly influencing the rheological and mechanical properties of hydrogels [83].
The utilization of PVA hydrogel as a delivery system exhibits three notable characteristics: significant surface stabilization, chelation qualities, and reduced protein adsorption properties leading to diminished cell adhesion [80,84,85].PVA-based hydrogels find frequent application in the delivery of bioactive compounds through oral, rectal, vaginal, topical, and ocular routes for diverse biomedical purposes [51].These hydrogels have garnered Food and Drug Administration (FDA) approval for a broad spectrum of biomedical applications, spanning wound dressings, tissue engineering, bone regeneration, drug delivery systems, and cardiovascular materials, as evidenced by multiple studies [14,80,86,87].PVA hydrogel has been extensively employed in many non-implanted medicinal applications as a barrier against tissue adhesion, to treat vascular embolisms, and to enhance neurologic regeneration.Also, PVA hydrogel was used in medical materials that could be implanted to restore meniscus tissues and cartilage.Considering their established safety for human use, the diverse applications of PVA highlight its substantial promise across multiple biomedical domains, establishing PVA hydrogels as a subject of extensive research and development within the field [85].

Preparation of PVA hydrogels
The synthesis method significantly influences the physicochemical properties of PVA hydrogel, especially in biomedical applications where hydrophilicity is essential for swelling in biological fluids or water, a crucial factor for drug delivery and compatibility [88].PVA hydrogel preparation employs two primary cross-linking techniques: physical and chemical [89].Physical cross-linking relies on intermolecular interactions, including hydrophobic contacts, ionic/electrostatic interactions, and hydrogen bonding, often achieved through freezethaw cycles and annealing [21].In contrast, chemical cross-linking encompasses diverse methods, such as energy radiation, chemical reactions, and radical polymerization [90].The general crosslinking mechanisms are shown in figure (2).
The freeze-thaw technique is commonly used to create physically crosslinked PVA hydrogels with with -OH group bonds [91], as shown in previous research (figure 3(b)) [14].During this process, PVA macromolecules undergo densification as ice crystals form during freezing and develop a more organized structure during thawing [92].Increasing the number of freeze-thaw cycles enhances crosslinking, resulting in a solid and elastic hydrogel [91,93].PVA hydrogels prepared using this method offer advantages such as ease of processing, nontoxicity, non-carcinogenicity, biocompatibility, and adhesive properties, making them suitable for pharmaceutical and biomedical applications [94].However, these PVA hydrogels exhibit mechanical instability due to their reversible characteristics and lack of fixed junctions among polymer chains [91].In a previous study, PVA hydrogel loaded with red betel extract underwent a freeze-thaw process (figure 3(a)), exhibited antibacterial properties against gram-positive Staphylococcus aureus and gram-negative Pseudomonas aeruginosa, with the clear zone expanding with higher red betel extract concentrations (figure 3(c)).These results suggest that PVA hydrogel loaded with red betel extract through freeze-thawing has the potential as an antibacterial product suitable for biomedical applications, including wound dressings [46].
In contrast, chemical crosslinking enhances the chemical stability of PVA hydrogels by introducing crosslinking agents such as glutaraldehyde, which form covalent bonds between PVA polymer chains [97].
Covalent crosslinking results in durable PVA hydrogels with irreversible linkages, achieved through various chemical reactions, including free radical polymerization, addition and condensation polymerization, Diels-Alder click chemistry, Schiff base reaction, oxime formation, enzyme-induced crosslinking, and photocrosslinking [98].However, this approach raises concerns about the potential toxicity of crosslinkers, byproduct generation during reactions, and the challenges of achieving sterilization.Despite these drawbacks, efforts have been made to substitute toxic crosslinkers with safer alternatives and optimize fabrication  conditions to minimize undesirable by-products [8].In a previous research, synthesizing PVA hydrogel with chemical crosslinking also potentially as smart delivery media for biomedical application (figure 3(d)).The PVA/alginate hydrogel added with glutaraldehyde showed covalent bonds (figure 3(e)).AFM analysis confirmed the presence of spheres in the PVA/alginate hydrogel after loading with bioactive compounds, specifically brown algae extract (figure 3(f)).Over a 12-day observation period, the hydrogel released approximately 69.25% of the bioactive compounds, indicating its suitability as a slow-release material for controlled-release applications [96].In a separate study, the chemical crosslinking method was employed to create PVA hydrogel for transdermal insulin applications, demonstrating its potential for controlled drug release [76].

Classification of PVA hydrogel as smart delivery media
PVA hydrogel serves as a delivery matrix that has garnered considerable attention as an exceptional carrier for targeted delivery systems [86,96].Various influencing factors and parameters are studied to achieve qualified functions.This sub-section discusses the classification of PVA hydrogels used as carrier matrices for bioactive compounds by considering their physicochemical properties and therapeutic effects, as well as several studies of previous research.The flexibility of hydrogels is facilitated by their significantly porous structure, and a porous structure has the potential to load bioactive compounds [80,96].As in previous research, PVA hydrogel as smart delivery shows a porous structure applied for alternative controlled-release fertilizer material (figure 4(a)) and potential wound dressing application (figure 4(b)) [46,96].The physicochemical characteristics in these studies were investigated, including the swelling degree of the PVA/alginate hydrogel, which increased from approximately 430% to 450% after bioactive compound loading (figure 4(c)).The FTIR spectra confirmed that the hydrogel was copolymerized (figure 4(e)), with intermolecular hydrogen bonds between PVA and alginate as the primary crosslinking agents.Adding nutrients to hydrogel significantly decreases the peak intensity of O-H and C-O.This demonstrates that functional groups interact strongly with nutrient ions.The x-ray diffraction patterns revealed that the hydrogel exhibited an amorphous structure (figure 4(f)).The addition of nutrients into the hydrogel caused a significant interaction between the nutrient ions and the hydrogel, leading to an increase in the crystallinity of the hydrogel and an alteration of the spacing between its layers [96].In other research, the swelling degree of PVA hydrogel containing P. crocatum extract ranged from 190% in bioactiveloaded PVA hydrogel to 226% in pure PVA hydrogel (figure 4(d)) [46].The Fourier-transform infrared spectra verified the effective encapsulation of the P. crocatum extract within the PVA hydrogels (figure 4(g)).The band at 1607 cm −1 was characteristic of the P. crocatum extract (C=C stretching vibrations).The x-ray diffraction (XRD) analysis indicates that the profile of the P. crocatum extract powder exhibits a crystalline structure, and the PVA powder exhibits a semicrystalline structure (see figure 4(h)).During the freeze-thaw process, the hydrogel forms cross-links and porous walls, transforming the structure into an amorphous state, as depicted in figure 4(i).Most of the hydrogel structure is pores filled with liquid.
Additionally, the porous characteristics of these materials enable the loading of bioactive compounds into the gel matrix effectively, leading to a controllable release of bioactives based on the diffusion coefficient of the gel network [80,96].The bioactive loaded by hydrogel is gradually released, resulting in a sustained high concentration in the target for a significant amount of time.As a result, this bioactive delivery system has the potential to be used for the systemic administration of various biomedical therapeutics [51,99].For scaffold application, the PVA hydrogel with the addition of polyethilene glycol (PEG) and nano-hydroxyapatite (nHAp) indicated highly porous sponge-like hydrogels [100].Another study investigated a PVA solution with dispersed emulsion droplets (CO 2 ), resulting in the formation of larger pore sizes.A porous structure is highly potentially profitable for cell proliferation in the scaffold [101].In another biomedical application of PVA hydrogels, an invivo test as an artificial meniscus after two-year implantation obtained highly mechanical properties of hydrogels with intact structure without fracture, degradation, or loss of properties [102].In wound dressing application, PVA hydrogel is typically loaded with bioactive compounds with release and pharmaceutical activities [14,31].Curcumin, an anti-inflammatory and antioxidant activity loaded by PVA hydrogel, produced considerable wound healing after two weeks [103].
In hydrogel-based drug delivery, loading and controlled release of bioactive compounds are essential for effective delivery [104,105].PVA hydrogel offers several methods for bioactive compound loading: (1) immersing freeze-dried hydrogels in a bioactive solution, (2) homogeneously mixing bioactive compounds with the polymer in the precursor solution, and (3) covalently tethering bioactive compounds to macromers before hydrogel formation [106].Additionally, the PVA hydrogel provides robust stabilization of bioactive interactions, ameliorates the risk of degradation, and serves as a safeguard against environmental variables like temperature fluctuations, pH changes, the presence of metal ions, and adsorption, all of which may contribute to the deterioration of bioactive compounds [107].
At the molecular or atomistic scale, drugs can interact with polymer chains through various mechanisms [108].The interaction between the hydrogel network and the bioactive-loaded includes hydrogen bonding, covalent bonding, physical encapsulation, surface absorption, precipitation, hydrophobic interaction, and ionic interaction [105,106].Alginate hydrogels, known for their negative charges, have been used in previous studies for delivering cationic growth factors like vascular endothelial growth factor to facilitate tissue regeneration [109,110].In cases where direct electrostatic interactions between the polymer and bioactive agents are insufficient, a third agent can be introduced to facilitate these interactions.For instance, heparin has been employed in hydrogels to achieve controlled release of heparin-binding proteins [97].Another approach involves using sulfonate functional groups, which enhance electrostatic interactions between alginate and protein drugs, extending the duration of drug release [111].Furthermore, the release mechanism of bioactives depends on several key parameters, including bioactive diffusion and dissolution, gel network design, interactions between bioactives and the gel network, and the mesh size of the gel networks [105,106,112].Hydrogels employ various bioactive release mechanisms, including diffusion, swelling, and degradation (figure (5)).In the diffusion-based release process, bioactive molecules move through the hydrogel matrix from a high-concentration reservoir, resulting in constant-rate and timeindependent release profiles.In contrast, hydrogel delivery systems exhibit time-dependent bioactive release profiles [53,113].Typically, diffusion-based release cannot sustain drug release for extended periods, typically lasting only a few hours to a day [53].
In the swell-release mechanism, the delivery system is osmotically controlled and activated with a solvent [114].The hydrogel molecules interact with the solvent, causing a larger pore size than the dimensions of the bioactive substance so that the bioactive substance will be released [115].The release rate is influenced by the swelling rate and the diffusion time of the bioactive substance within the swollen matrix [116,117].For example, Edikresnha et al demonstrated the release of Piper crocatum extract from PVA hydrogel using swelling mechanism.During the first 20 min, approximately 13%-20% of the bioactive was released in a short-term burst.After the initial 20 min, the extract was relatively slow.The swelling polymer chains and the extract's diffusion were influential factors in the release process.The hydrogel with a high extract concentration demonstrates the highest release rate.Conversely, the hydrogel with a low extract concentration demonstrates the lowest diffusion.
In the degradation-release mechanism, the hydrogel crosslinking networks are degraded by chemical, physical, or enzymatic reactions, which lead to the bioactive compounds being released from the hydrogel matrix [117].For example, hydrogels with electrostatic attraction may disintegrate when the pH or ionic strength of the surrounding solution is changed.Additionally, hydrogels composed of proteins or starches may disintegrate when molecules interact with proteases or amylases (digestive enzymes) within specific regions in the body [118].Therefore, the hydrogel matrix's fracture characteristics affected the bioactive compounds' release rate [117].In the degradation-release mechanism, hydrogels commonly involves the copolymerization of hydrophobic polyesters such as poly(lactide) (PLA) and poly(caprolactone) (PCL) with hydrophilic polyethene glycol (PEG), which undergoes degradation by hydrolysis [119].Using these copolymers with high polymer concentrations (20-30 wt%) is desired, as this facilitates controlled release through degradation.An illustrative case involves the utilization of a triblock copolymer composed of PCL-PEG-PCL, which resulted in the sustained release of BSA for two weeks [120].In another studies, Oligopeptide bonds can be degraded by matrix metalloproteinases (MMPs) [120].An MMP-cleavable peptide (GGRMSMPV) was added to a hyaluronic acid hydrogel to deliver a recombinant tissue inhibitor of MMPs in a pig model of myocardial infarction113.External stimuli might trigger degradation in real time.For instance, acidic environments enhance hydrolysis [121].Encapsulated transforming growth factor β1 (TGFβ1) is released when high-energy UV radiation degrades microgels with o-nitrobenzyl ether (NBE) moieties [122].

Bioactive compounds in biomedical function
Bioactive compounds are chemical compounds found in natural sources with unique properties and characteristics.The bioactive compounds contained in the delivery media (PVA hydrogel) need to be investigated for their biomedical function, so that the therapeutic effect is effective.This sub-section discusses the biomedical function of bioactive compounds from various natural sources, including the extraction process carried out to obtain these compounds, as well as several studies of previous research.Natural products cover about 70%-80% of the area of bioactive agents for clinical use during 1981-2018 [123].Bioactive compounds have been widely used in synthesizing materials for biomedical therapeutics.Nowadays, there have been many biomedical therapeutics in the form of synthetic drugs that can treat chronic diseases such as Alzheimer's, cancer or chronic lung disease [8].Bioactive compounds also show therapeutic potential in one of the most chronic diseases (stroke) from the acute to subacute phase [124].However, it frequently leads to adverse effects including complications, pain, and reduced drug effectiveness in certain cases.For instance, cancer patients undergoing chemotherapy could experience side effects such as nerve pain, nausea, constipation, difficulty breathing, and diarrhoea.Furthermore, chemotherapy drugs can lead to drug resistance, potentially resulting in disease recurrence [125].Therefore, an alternative approach is needed to minimize the adverse effects of synthetic drugs, namely by utilizing the therapeutic function of bioactive compounds derived from natural and standardized ingredients.
Bioactive compounds are remarkable molecules obtained from extracts or isolation of herbal plants, including fruit, leaves, stems, seeds, flowers and roots, which have pharmacological functions such as antioxidant, antibacterial, antiviral, anti-diarrhoea, anti-inflammatory, anti-cancer [39].The bioactive compounds highlighted in figure (6), including flavonoids, curcumin, carotenoids, DPHC, and Andrographolide, have been given significant attention in lots of research due to their nutraceutical and technical properties, as shown in table 2. It is abundantly available and can be employed for disease treatment and enhancing the body's resistance as a preventive measure against diseases [126].
Bioactive compounds derived from natural ingredients have many benefits for the human body.However, there are remaining issues such as low solubility, a short biological half-life, a narrow therapeutic index, low bioavailability, poor cell penetration, and susceptibility to degradation in the presence of oxygen, light, heat, and humidity [152].Loading bioactive compounds extracted from natural ingredients into delivery media systems enhances therapeutic functions and overcomes limitations until released at the right target [153].PVA hydrogel is smart delivery media that can maintain the therapeutic function of bioactive compounds for biomedical applications.PVA-based hydrogel delivery systems overcome the problem of low bioavailability and maximize the functionality of bioactive compounds by indicating sustained release of bioactives.In addition, cytotoxicity tests showed that the PVA hydrogel containing the extract was highly biocompatible.Table 3 presents research on PVA hydrogel containing bioactive compounds for wound dressing, tissue engineering, drug delivery, contact lenses, antibacterial devices, anti-biofouling, and artificial muscles.
Comprehensive investigations into PVA hydrogel delivery systems for loading bioactive compounds are essential for understanding the interaction mechanisms between drugs and hydrogels.Such research is vital for elucidating the fundamental principles of controlled drug release under specific conditions.Additionally, there is significant interest in studying the effects of various factors, including PVA molecular weights, crosslinkers and their ratios, and the structural morphology of PVA hydrogels, including mesh size and swelling ratio, on bioactive loading and release [53].The adjustment of mesh size is a crucial factor in the controlled drug delivery, as it directly influences the release profile of the bioactive from the PVA hydrogel.When the mesh diameter exceeds that of the bioactive particles, the diffusion mechanism primarily regulates the release.
Moreover, when bioactive dimensions closely match the mesh size of the delivery system, steric barriers affect drug release.Modifying PVA hydrogel's mesh size can be achieved by adjusting component concentrations or changing the crosslinker.Employing a smaller mesh size is common practice to protect bioactives from the environment and control their release concerning specific enzymes and chemicals.Biological stimuli like enzymes have the capability to break down crosslinked PVA hydrogels, leading to an expansion of their mesh structure [53].Thus, in developing an effective drug delivery system with PVA hydrogel, it is crucial to investigate the impact of mesh size on drug loading and release.
Zakaryan et al showed that flavonoids can inhibit viral infections and have high antioxidant, antibacterial, and other pharmacological activities [164].Quercetin is one of the flavonoids that have beneficial ingredients for biomedical applications such as antibacterial content, anti-inflammatory, antioxidants, anti-carcinogenic, antiobesity, and antiviral [165][166][167][168][169][170].Quercetin can inhibit various types of cancer cells from reproduction (such as colorectal cancer cells, prostate cancer cells, liver cancer cells, pancreatic cancer cells, and lung cancer cells) [171].In another study, Andrographolide demonstrated intense anthelmintic activity against Ascaris lumbricoides infections and effectively neutralized poisonous snake venom in experimental rat models [172,173].
4. Biomedical application of bioactive compound-loaded PVA hydrogels 4.1.Drug delivery Drug delivery involves the controlled and targeted transport of pharmacological chemicals or bioactive compounds into the body to achieve therapeutic effects [174].Conventional drug delivery methods include oral and intravenous administration.In oral delivery, drugs are ingested and absorbed through the digestive system, while intravenous delivery involves direct injection into the bloodstream.Moreover, a significant limitation of conventional drug delivery systems is their inability to effectively control drug levels in the bloodstream.Initially, these systems lead to remarkably high drug concentrations in the bloodstream, potentially resulting in toxicity.Over time, the drug concentration rapidly decreases due to metabolism by the human body, rendering the treatment less effective [175].
Controlled drug delivery systems employing polymer matrices have been developed to address this challenge.The delivery media in a polymer matrix creates slower release conditions due to drug diffusion through the polymer pores [176,177].The presence of porosity and high water content in hydrogels facilitates the transport of hydrophilic drugs and may impact the process of continuous drug dissolution [178].There are two methods to load the drug into the hydrogel matrix: (1) mixing the polymer and the drug using chemical and physical crosslinking methods, and (2) formation of the hydrogel using soaking in a therapeutic solution [179].
Research explores the use of hydrogels for oral drug delivery, protecting drugs or proteins, like insulin, which are vulnerable to proteolysis, including nonsteroidal anti-inflammatory drugs (NSAIDs) [180][181][182].At the Massachusetts Institute of Technology (MIT), a PVA hydrogel device inspired by pufferfish has been developed.This PVA hydrogel degrades rapidly and contains high levels of polyacrylic acid within a PVA hydrogel membrane.It is designed to sense stomach temperature and provide continuous drug release.Another potential  Using the preparative centrifugal partition chromatography (CPC) method.
The process involves an optimized solvent system with specific partition coefficients (K) for DPHC and OPA.This method is noted for its efficiency and simplicity, providing high-purity compounds suitable for further biological and pharmacological studies [128].

Anti-diabetic
Diphlorethohydroxycarmalo effectively prevents the harmful effects of high glucoseinduced glucotoxicity and apoptosis at 10 or 50 μg ml −1 concentrations.Diphlorethohydroxycarmalol also reduces the levels of nitric oxide, intracellular reactive oxygen species production, and the increase of thiobarbituric acid reactive substances caused by high glucose [129].

Anticancer
Diphlorethohydroxycarmalol causes apoptosis in human promyelocytic leukemia (HL60) cells by decreasing the levels of Bcl-2 and activating mitochondrial signaling through Bax, resulting in mitochondrial malfunction [130].

Antibacterial
The turmeric caused damage to the bacterial cell membrane.It exhibited significant antibacterial activity against all tested bacteria, including both Gram-positive and Gram-negative bacteria (Escherichia coli Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis) [133].

Anti-inflammantory
The anti-inflammatory effectiveness of curcumin has mostly been investigated in clinical trials involving patients with osteoarthritis (OA) and rheumatoid arthritis (RA), where the anti-arthritic properties of curcumin have been validate [108].

Antioxidant
Curcumin functions as an antioxidant in the body by scavenging free radicals and also enhances the production of the natural antioxidant glutathione (GSH), which protects cells and tissues from damage caused by free radicals.Curcumin has been observed to enhance the activity of superoxide dismutase (SOD) and raise levels of glutathione (GSH) in cells and serum, as demonstrated by in vitro cell and animal tests.Curcumin administration can effectively eliminate free radicals, hence mitigating the detrimental effects of excessive tissue inflammation [134].Carotenoid Peppers Carotenoids can be extracted from several natural sources using methods such Antioxidant β-Carotene, at a concentration of 10 μM, efficiently eliminated free radicals such as •NO2, thiyl (RS•), and thiyl-sulfonyl (RSO•2), which are known to trigger the lipid peroxidation process.This effect was observed using pulse radiolysis [136].

Antiosteoporosis activity
Decrease the quantity of osteoclast cells, inhibits osteoblast formation, and prevents osteoclast generation.Decrease in bone decomposition, increase in area of mineralized bone, and protection against degradation of bone tissue [137].

Andrographolide
Andrographis paniculata [138] The liquid-liquid fractionation (LLF) method offers a simple, low-cost, and time-efficient methodology.This process involves the extraction of andrographolide using chloroform as the solvent through a Soxhlet apparatus, followed by LLF to isolate the compounds [139].Additionally, supercritical fluid extraction has been utilized as a novel method to isolate andrographolide.This technique optimizes extraction conditions such as temperature and pressure to achieve a high yield of andrographolide [140].

Anti-malarial
The flavonoids extracted from green tea have been observed to reduce the activity of P. falciparum enoyl-ACP reductase (PfENR), with Epigallocatechin Gallate being the most effective inhibitor.Additionally, these flavonoids enhance the effectiveness of triclosan by binding it to PfENR [145].

Antioxidant
Flavonoids can inhibit the enzymes responsible for producing reactive oxygen species (ROS), such as microsomal monooxygenase, glutathione S-transferase, mitochondrial succinoxidase, and NADH oxidase.The antioxidant properties of flavonoids can also be attributed to their ability to activate antioxidant enzymes, including catalase, glutathione peroxidase, and heme oxygenase-1 (HO-1), which can scavenge free radicals [151].The structure and functional groups of diverse phenolic compounds provide hydrogels with customised viscoelastic properties, pH-sensitive swelling behaviour, and low phase transition temperature.
Drug delivery [152] Freeze-thaw PVA/k-carragenan Recombinant mussel protein Pvfp5β In vivo testing was carried out on PVA hydrogel.NIH-3T3 mouse embryonic fibroblasts were placed onto the hydrogels and cultivated for two weeks.The study established the involvement of protein found in the foot of Perna viridis (Pvfp5β)in facilitating cell attachment, spreading, and colonizing the scaffold.
Effective and controlled ascorbic acid release (80% within 8 h) was achieved.

Wound dressing [156]
Freeze-thaw PVA/Polypropylane Rapamycin In vitro cell experiments showed that PVA hydrogel modified was cytocompatible and could suppress cell attachment.The samples had slighter inflammation and looser fibrous tissue around the PVA modified PP than native PP.

Drug delivery [157]
Freeze-thaw Cellulose/PVA Egyptian propolis extract (phenolic) In vitro test cell culture assays showed the highest cell viability, adhesion, and spreading.The PVA/cellulose hydrogels containing Propolis extract (PE) enhanced the antibacterial activity (against Streptococcus mutans, Escherichia coli, Candida albicans, and Salmonella typhimurium) and showed potential anti-inflammatory activity.

Tissue engineering [158]
Freeze-thaw PVA Barbatimão bark extract, Leucaena bark extract, Aloe vera, and Lavender essential oil Lavender essential oil and aloe vera showed the highest release.While Barbatimão and Leucaena samples may have been released due to the swelling, Aloe vera and Lavender samples were released by diffusion regulated by swelling.For Aloe vera, long-term release was dose-dependent, whereas for Lavender essential oil, it was non-Fickian diffusion associated to hydrogel relaxing.
Wound dressing [163] hydrogel application involves monitoring biosignals within the digestive tract, which can be visualized using a microcamera to assess treatment patterns [183].
Diverse drug delivery applications have driven the exploration of PVA hydrogel formulations, including maleic acid-crosslinked PVA for colon-targeted drug delivery, glutaraldehyde-crosslinked PVA for releasing glipizide, and electrically controlled release with glutaraldehyde-crosslinked PVA hydrogels [7,184,185] Researchers have also studied a PVA/tetrahydroxyborate hydrogel for drug delivery systems [186].Current research trends include in situ crosslinked hydrogels and developing in situ scaffolding hydrogels formed by simultaneous hydrogel and cell injection, advancing PVA hydrogel-based drug delivery [187].
Moreover, using PVA hydrogel as smart delivery media can significantly affect drug release characteristics.As demonstrated in prior research, loading bovine serum albumin (BSA) into PVA hydrogel nanoparticles can alter the release mechanism with an impressive 96.2%±3.8%efficiency in protein loading.It is noteworthy that PVA hydrogel nanoparticles expand in aqueous solutions temperature-dependent.In vitro release studies indicate that BSA release from these nanoparticles may take up to 30 h, primarily following a diffusion mechanism.The rate of BSA release is notably influenced by the number of freezing-thawing cycles and the release temperature; fewer cycles or higher temperatures lead to faster drug release [188].In another study, PVA/alginate hydrogel-loaded with extract Glycyrrhiza glabra showed effective release activity against S. mutans and C. albicans within 8 h.Based on its structure, the hydrogel has interconnected pores, hydrophilicity, and excellent water profile, which contribute to its biocompatibility, as demonstrated by direct contact and MTT tests with L929 fibroblasts [189].
Hydrogel drug delivery has clinical use for therapeutic delivery and is constructed to facilitate bioactive compounds' sustained release, enhancing bioactive retention [8].Hydrogels offer a versatile platform characterized by their adjustable physical properties, controllable degradability, and protective capacity against the degradation of sensitive pharmaceuticals, while also facilitating diverse physiochemical interactions that govern the release of bioactive compounds [65].

Wound dressing
Wounds, whether from injury or trauma, can harm internal and external body tissues, particularly the skin, disrupting healthy tissue structure and function [190].The four-phase wound healing process involves hemostasis, inflammation, proliferation, and remodelling [191].Effective wound dressings should maintain moisture around the wound for optimal epithelial cell growth, prevent external contamination, absorb wound fluids, provide elasticity, ensure biocompatibility, support gas exchange, and reduce skin adhesion [192].
PVA hydrogel possesses characteristics suitable for wound dressings, promoting autolytic debridement and dead tissue removal [193].Its impressive water-holding capacity without dissolving in water speeds up wound healing by absorbing wound exudates and reducing infection risk [194,195].Simultaneously, PVA hydrogel accelerates wound healing by promoting fibroblast migration, as depicted in figures 7(a)-(c).
PVA hydrogels hold great potential for advanced wound dressings, given their resemblance to the extracellular matrix, biodegradable nature, and biocompatibility [196].Traditional bandages may adhere to wound tissue, potentially hindering optimal wound healing.Therefore, PVA hydrogels are employed to effectively deliver bioactive compounds in a compatible manner, enabling controlled release at the intended site.Furthermore, these hydrogels offer the advantages of easy disassembly and non-toxicity, making them wellsuited for wound dressing applications [8].
Combining PVA hydrogel with DPHC, a brown alga Ishige okamurae bioactive compound, enhances cellular proliferation and tissue growth and accelerates wound healing [196,197].The PVA/DPHC hydrogels demonstrate a remarkable antimicrobial effect, reducing Staphylococcus aureus and Pseudomonas aeruginosa viability by nearly 99% in ASTM E2149 testing.Importantly, these hydrogels are non-cytotoxic to normal human dermal fibroblast-neonatal (NHDF-Neo) and human keratinocyte (HaCaT) cells, as confirmed by MTT assays and in vitro fluorescein diacetate (FDA) fluorescence analyses.In vivo studies at the Institute of Cancer Research (ICR) mice show that PVA/DPHC hydrogels significantly improve wound healing, achieving a 75% wound closure rate within seven days.By the 14th day, all groups display complete wound healing, as shown in figures 6(d)-(e) [163].
Using bioactive compounds in hydrogel wound dressings represents an innovative approach compared to commercial dressings, usually loading with antibiotics [198].Antibiotics in such dressings, however, can lead to resistance and reduced treatment effectiveness [199].Loading bioactive compounds with antibacterial, antioxidant, or anti-inflammatory properties into PVA hydrogel provides an effective and patient-friendly alternative to antibiotics.Honey, renowned for its rich content of bioactive compounds like phenolic acids, flavonoids (flavanones and flavonols), carotenoids, and organic acids, offers antibacterial and antioxidant benefits conducive to the wound-healing process.Nevertheless, the direct application of honey to wounds can be uncomfortable for patients and hinder its therapeutic effect.
A study by Shamloo et al reveals that the antibacterial efficacy of a PVA hydrogel composite with honey increases with higher honey concentrations, leading to improved cell viability and faster wound healing.However, incorporating honey into the PVA hydrogel composite may result in reduced mechanical strength and quicker degradation of the delivery system, even though the hydrogel maintains sufficient mechanical strength for wound dressing applications [161].
In conclusion, integrating bioactive compounds with PVA hydrogel offers a promising avenue for advancing wound healing technology.Notably, natural extracts such as Lawsonia inermis leaf extract, laden with a spectrum of bioactive components, have shown remarkable potential in accelerating wound healing [162,200].These compounds have exhibited exceptional antibacterial and antioxidant properties and have been effectively delivered through PVA hydrogel, which ensures controlled release and enhances their biocompatibility with the epithelium.The findings by Khan et al serve as a testament to the feasibility of this approach, with over 80% of wounds treated using the PVA/chitosan hydrogel containing Lawsonia inermis leaf extract achieving complete healing within ten days.This result underlines the exciting possibilities of utilizing PVA hydrogel as a vehicle for bioactive compounds, paving the way for enhanced wound healing therapies [162].

Tissue engineering
Tissue engineering involves creating artificial biological tissues or organs to enhance cell function and growth.It is a promising approach for repairing damaged tissues by combining engineering, physics, and life sciences.The concept is to design an environment where specialized cells develop into the desired organ or tissue before transplantation.Scaffolds provide an initial framework for replacement tissue.Organ transplantation is a common approach for tissue repair, but donor shortages challenge healthcare systems [8,[201][202][203][204][205].
The field of tissue engineering employs various scaffold approaches, such as pre-made porous structures, extracellular matrices, cell sheets, and hydrogel encapsulation [206].Hydrogels play a significant role in tissue engineering due to their similarity to the extracellular matrix, providing a three-dimensional structure that influences and guides cell behaviour during tissue development.One prominent application is in bone regeneration, with polymeric hydrogels used for both injection and implantation methods, as depicted in figure 8(a).Researchers have also utilized chondrocyte-derived progenitor cells for creating cartilage in patients with substantial knee cartilage injuries, demonstrating a higher chondrogenic potential compared to mesenchymal stromal/stem cells [207].Studies using pure keratin-based hydrogels as scaffolding materials have shown promise in supporting cell growth and nutritional needs.Keratin is a biocompatible and nonimmunogenic biopolymer that can be sourced from patient hair or nails, making it a versatile material for epithelialization [208].
In previous studies, PVA hydrogel has demonstrated its potential for restoring knee meniscus function [209].The biocompatibility and safety of PVA porous hydrogels were assessed using primary bovine meniscal fibro chondrocytes, as depicted in figure 8(b).Cell viability within these hydrogels was examined through a Live/ Dead assay, with green fluorescence indicating viable cells and red fluorescence indicating non-viable ones (figure 8(c)).Remarkably, after seven days, cell viability remained consistently high.Furthermore, after a 50-day culture, it became evident that PVA hydrogels conformed seamlessly to the inner surface of the natural tissue defect (figure 8(d)).These porous PVA hydrogel-based artificial meniscal implants hold the potential to fully restore natural meniscus function, presenting a promising clinical alternative to meniscus resection [209].
Furthermore, the utilization of PVA/chitosan hydrogel loaded with Hypericum perforatum oil (HPO) demonstrates significant potential in skin tissue regeneration.HPO is renowned for its remarkable antioxidant and anticholinesterase properties.When introduced into a scaffold, this oil contributes to enhancing material characteristics, including hydrophilicity, flexibility, and promoting cell viability [210].
The variation in oil content impacts membrane properties such as water absorption, surface structure, and vapour permeability.To assess the cytocompatibility of this membrane, mouse embryonic fibroblasts (MEF) were subjected to the 3-(4,5-dimethylthiazoyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, conducted for both direct and indirect cell culture evaluations.Results derived from the MTT experiment indicate that scaffolds loaded with Hypericum perforatum oil and crosslinked with Genipin exhibit a notably high level of biocompatibility, thereby facilitating MEF cell attachment and growth.Notably, the genotoxicity test revealed no DNA fragmentation, underscoring the suitability of Hypericum perforatum oil-loaded PVA/chitosan hydrogel for potential applications in skin tissue engineering [210].
Saleh et al conducted a study on the incorporation of quercetin into PVA/chitosan hydrogel, revealing the hydrogel's porous scaffolds to have a significant impact on various microorganisms, including Bacillus subtilis, Klebsiella pneumonia, Escherichia coli, Candida albicans, and Staphylococcus aureus.The biocompatibility and non-toxicity of implanted materials are paramount in biological systems.In this context, HFB4 cell viability notably increased from 52% to 80.26% when cultured on quercetin-containing hydrogel.HFB4 cells exhibited robust growth primarily on hydrogels loaded with quercetin.Furthermore, the hemolysis inhibition assay underscored the hydrogel's ability to protect erythrocytes against hemolysis.These collective findings illuminate the potential of quercetin-loaded PVA/chitosan hydrogel in tissue engineering, offering a low-toxicity solution [158].

Contact lenses
Contact lenses serve various purposes, including vision improvement, medical treatment, and cosmetic enhancement [211].They are directly applied to the cornea to correct refractive errors and safeguard eye health [212].These lenses come in two primary types: rigid and soft.Regulatory agencies like the European Union (EU) and the United States Food and Drug Administration (US-FDA) classify them as medical devices, prioritizing patient safety and effectiveness.The US FDA classifies daily-wear soft and rigid contact lenses as class II, indicating a moderate risk, while extended-wear lenses are class III due to higher risk.In the EU, short-term contact lenses are class IIa with intermediate risk, and long-term lenses are class IIb with high risk [213].
Contact lenses effectively treat refractive disorders like myopia, hypermetropia, presbyopia, and astigmatism [212].They are preferred for correcting refractive issues compared to traditional glasses and surgery, with soft lenses being a popular choice due to their ability to correct astigmatism in over 12% of the market [214].Besides vision correction, contact lenses serve as a cosmetic tool that shields the eyes from harmful ultraviolet (UV) radiation (UV-A and UV-B) and enhances their appearance [215].
Applying a contact lens-based drug delivery system to the eye requires extra caution to maintain visual acuity and homeostasis, considering the sensitive nature of the eye.For contact lens wearers to maintain biocompatibility and normal physiological function, it is necessary to consider the appropriate transparency parameters, oxygen permeability, water diffusion, and mechanical stability [216].Oxygen permeability (Dk), which represents the ability of a lens material to allow oxygen to reach the eyes, is a property of the lens material.
In contrast, depending on the contact lenses, oxygen transmissibility (Dk/t) indicates the extent to which oxygen permeates the lenses of a given thickness [217].Diminished oxygen transmissibility can lead to ophthalmic hypoxia, discomfort, and epithelial acidosis, while a higher Dk/t value correlates with increased comfort and tolerance.Hydrogel is one of the contact lenses with water content, which improves the oxygen permeability.Contact lenses crafted from hydrogels offer a range of desirable properties.They are adept at sustaining a continuous tear film, which is crucial for maintaining clear vision.Additionally, hydrogels exhibit high permeability, permitting the unrestricted movement of ions.Moreover, hydrogel materials exhibit nonirritating characteristics and are resistant to tear accumulation, making them biocompatible and inherently comfortable [35].
Various polymeric hydrogels have been explored as potential carriers for ophthalmic drug delivery via soft contact lenses.Among these, PVA hydrogel is a promising candidate due to its elasticity, collagen-like mechanical properties, and low friction coefficient [218,219].These characteristics make it well-suited for applications in ophthalmic care.Tummala et al have developed PVA/cellulose nanocrystall (CNC) hydrogelbased contact lenses for ocular therapy (figures 9(a)-(b)) [220].The PVA/CNC hydrogel-based contact lenses have a high-water content, transparency, and low light scattering, are biocompatible and are affordable.PVA/ CNC hydrogel biocompatibility is investigated using human corneal epithelial cells (HCE-2).The viability of cells cultured with PVA/CNC hydrogel was well above the cytocompatibility limit of 70% defined by ISO standard 10993:539 and significantly higher than the positive control (5% DMSO in culture medium) (figure 9(c)) [221].
Moreover, bacterial colonization is an obstacle to eye therapy using contact lenses, which reduces the significant therapeutic effect on the eye.Kharagani et al developed a contact lens-based PVA hydrogel containing silver and copper nanoparticles as antibacterial agents (figure 9(d)).PVA hydrogel loaded with silver nanoparticles showed high antibacterial activity but high toxicity, while PVA hydrogel loaded with copper nanoparticles showed minimum toxicity.As the inhibition zone shown in figure 9(e), PVA hydrogel containing silver and copper nanoparticles against Pseudomonas aeruginosa and Staphylococcus aureus bacteria.PVA hydrogel with silver and copper nanoparticles can potentially prevent bacterial infections and minimize bacterial colonization [223].
In order to increase the therapeutic effect of contact lenses, several studies on PVA-based hydrogel used as a matrix to deliver bioactive compounds have been carried out [224].Contact lens-based hydrogels containing bioactive compounds can be done using various techniques, including soaking.In the soaking technique, the lens is immersed in a concentrated aqueous bioactive or drug solution, with bioactive loading accomplished by physical adsorption (figure 9(f)).The concentration gradient results in the non-covalent adsorption of a bioactive onto a polymeric matrix, followed by bioactive release via molecular diffusion.The bioactive concentration in immersion solutions, the water content, and the material's molecular weight significantly impact bioactive loading and release kinetics [225].Soaking is the simplest and most cost-effective method for hydrogel contact lenses with bioactive loading.However, it has limitations such as reduced bioactive loading, burst release, and non-reproducibility.Vitamin E (Vit E) is utilised as a diffusion barrier to address the explosive release.Vitamin E is a powerful antioxidant, biocompatible, and has potential therapeutic applications.Vit E enhances the diffusion path length of a bioactive and delivers controlled drug release kinetics while additionally maintaining practical eye function and drug loading [226].

Future direction
Over the past decade, significant developments in using PVA hydrogels as smart delivery media and promising bioactive compounds for biomedical functions began to emerge.However, several challenges still need to be addressed for further development of PVA hydrogel as smart delivery media in the future: • The freeze-thaw method for synthesizing PVA hydrogel is more economical, easier to use, and non-toxic than other methods; the suitability of the morphological structure and synthesis methods need to be studied.The development of advanced synthesis methods, including modification with nanotechnology and crosslinking with double or triple network hydrogels, can improve mechanical properties, retention of bioactivity, faster response time, and increased loading capacity of bioactive, thereby overcoming some of the current challenges in using PVA hydrogels.
• Synthetic polymers, such as PVA, have demonstrated their potential as a matrix for delivering bioactive compounds in biomedical applications.However, more investigation of natural polymers, including polysaccharides such as starch, cellulose, and zein, as well as from animal-derived sources such as chitosan, hyaluronan, and gelatine, are preferred due to their advantageous characteristics, i.e., low toxicity, biocompatibility, biodegradability, and renewability.
• Although natural polymers are preferred in biomedical applications, some disadvantages, such as low tensile strength, considerable surface tension, and poor solubility, still need to be overcome.Thus, further studies regarding incorporating natural polymers into other materials and synthetic polymers are essential to overcome these disadvantages.
• Further investigations regarding the simulation, modeling, optimization, and prediction of structures such as ash mesh size, swelling kinetic, mechanical deformation, crosslinking molecules, ionic strength, etc, are needed to improve the characteristics of smart delivery media.
• At present, commercial hydrogels are readily obtainable on the market; however, PVA-based hydrogels are not yet established.Meanwhile, commercial market demand for hydrogel continues to increase annually and is predicted to experience significant development.The development of PVA hydrogel as smart delivery media has great potential, with the versatility of PVA hydrogel making it attractive for a broad range of industrial applications such as biomedicine, biosensors, biodegradable packaging, agriculture, and cosmetic applications.
• Achieving successful laboratory-scale to industrial-scale production with cost-effectiveness, consistent quality, and function of PVA hydrogel is a significant challenge.Compositing PVA with natural polymers and modifying the fabrication process is necessary for cost-effectiveness.Controlling process parameters, including mesh size parameters, pH stability, mechanical stability, and thermal stability, is needed to maintain consistent quality and function of hydrogel matrix products as delivery media for biomedical applications on an industrial scale.
As we explained in the previous section, the use of PVA hydrogel as smart delivery media for biomedical applications is also increasing exponentially.Considering the low-cost fabrication process, efficient production, and non-toxicity, PVA hydrogel offers an alternative biomedical material.The biomedical and pharmaceutical industries may become the lead users for the development of loading bioactive compounds into PVA hydrogels for various applications, i.e., delivery of nutraceuticals and pharmaceuticals.However, several challenges still need to be addressed for the future direction of effectiveness, release, and loading of bioactive into PVA hydrogel for biomedical applications: • One of the primary challenges in utilizing PVA hydrogels as smart delivery of bioactive compounds is ensuring the stability and retention of bioactivity over time, particularly in varying physiological conditions.This includes maintaining the efficacy of bioactive compounds, which may be susceptible to degradation or denaturation.High loading efficiency without compromising the stability and bioactive compounds is essential to be developed for biomedical applications.
• Discovery of more sources of bioactive compounds and characterization their properties for biomedical function remains a challenge.Further explorations are important to obtain bioactive compounds from plants, animals, microbes, and marine organisms that are low-cost and prospective.Qualification of bioactive compound also depend on the extraction process; further exploration of effective and efficient extraction methods for bioactive compounds is still needed.
• Achieving a precise and controllable release profile for bioactive compounds is essential for their efficacy in biomedical applications.The suitability of hydrogel properties with release kinetics for biomedical applications, such as drug delivery, wound dressing, or tissue engineering, is a challenge.More investigation of bioactive delivery systems (oral, vaginal, rectal, injection, topical, and eye) is needed to achieve a longer and more controlled release profile of bioactive compounds, including investigating the interaction between the hydrogel matrix and the bioactive compound at the molecular level to perfect the release kinetics.
• More investigations on simulation, modeling, optimization, and prediction of bioactive release are required to enhance the effectiveness of biomedical functions.
• Commercial use of bioactive compounds in society has been widely used.However, the dosage and fabrication processes that need to be standardized are still challenging for researchers and industries.The development of standardized bioactive compounds, including in vitro, in vivo, and clinical testing, is required to minimize side effects and maximize their therapeutic function.So that in industrial-scale production, product safety and qualification are guaranteed.

Conclusion
The recent development of PVA hydrogels as smart delivery media and bioactive-loaded for biomedical applications has been thoroughly reviewed.We summarized many studies that have reported successful attempts in achieving the PVA hydrogel as smart delivery media, demonstrating the remarkable capacity to transport and control the release of bioactive compounds at the designated therapeutic target, effectively addressing concerns related to instability, low water solubility, and vulnerability to decomposition in biological fluids.Furthermore, loading bioactive compounds with biomedical functions in specific matrices will protect against environmental degradation, extend shelf life, enable controlled release, and enable targeted delivery.So it can optimize therapeutic levels and reduce adverse effects.The performance of biocompatibility and non-toxic PVA hydrogel with potential biomedical applications for wound dressings, drug delivery systems, tissue engineering, and contact lenses were also reported.Although several issues related to bioactive loading and the development of PVA hydrogel as smart delivery media for biomedical applications still need to be addressed, PVA hydrogel is a promising smart delivery media for loading and enhancing the function of bioactive compounds as a potential biomedical application.

Figure 1 .
Figure 1.(a) Publication trends analyzed by scopus database (data were collected on August 16, 2023 with keyword input 'Polyvinyl Alcohol Hydrogel' and 'Bioactive Compounds'); (b) The general concept of PVA hydrogel as smart delivery media loaded bioactive compound in biomedical applications.

Figure 5 .
Figure 5. Release mechanism of PVA hydrogel loaded by bioactive compounds.

Figure 6 .
Figure 6.Source and main effects of bioactive compounds from plant extract.

Figure 8 .
Figure 8.(a) Schematic of tissue engineering in bone implant; (b) cytotoxicity test of PVA hydrogel for tissue engineering; (c)-(d) effect of FBS to cell adherence to the scaffolds.Reprinted with permission from [209].Copyright (2018) American Chemical Society.

Table 1 .
Some recent methods of fabricating PVA hydrogel.

Table 2 .
Effect of PVA hydrogels loaded with bioactive compounds.

Table 3 .
Effect of PVA hydrogels loaded with bioactive compounds.