Metal and Metal Oxide Nanoparticle Incorporation in Polyurethane Foams: A Solution for Future Antimicrobial Materials?

With the technological developments witnessed in recent decades, nanotechnology and nanomaterials have found uses in several common applications and products we encounter daily. On the other hand, polyurethane (PU) foams represent an extremely versatile material, being widely recognized for their extensive application possibilities and possessing a multitude of fundamental attributes that enhance their broad usability across various application fields. By combining the versatility of PU with the antimicrobial properties of nanoparticles, this emerging field holds promise for addressing the urgent need for effective antimicrobial materials in various applications. In this comprehensive review, we explore the synthesis methods, properties and applications of these nanocomposite materials, shedding light on their potential role in safeguarding public health and environmental sustainability. The main focus is on PU foams containing metal and metal oxide nanoparticles, but a brief presentation of the progress documented in the last few years regarding other antimicrobial nanomaterials incorporated into such foams is also given within this review in order to obtain a larger image of the possibilities to develop improved PU foams.


Introduction
In addition to the common applications of polyurethane foams, such as insulation for walls and roofs, coatings, elastomers, adhesives and sound insulation materials in the construction and automotive sectors, efforts have been directed towards utilizing these materials in various biomedical applications, like stents, vascular prostheses, breast implants, dressings, antibacterial surfaces, catheters, controlled drug release for cancer treatment, tissue engineering, nerve regeneration, etc. [1].
Polyurethanes constitute a class of polymeric materials primarily synthesized through a polyaddition reaction involving a diisocyanate (such as methylene diphenyl diisocyanate (MDI) or toluene diisocyanate (TDI)) and a mixture of polyols (either polyether or polyester diols), conducted with the aid of catalysts (typically tertiary amines), chain extenders and blowing agents (including CO 2 generated from the reaction of water with an NCO group, as well as pentane, among others).The final characteristics of the resulting polyurethane Polymers 2023, 15, 4570 2 of 31 foam (density, mechanical strength, gelation time, pore structure) can be finely tuned by manipulating factors such as the molecular weight of the polyols, hydroxyl (OH) and isocyanate (NCO) indices, the quantity of the blowing agent, the type and amount of catalyst, the surfactant and so on [2,3].
Obtaining antimicrobial polyurethane foam involves incorporating antimicrobial agents or additives into the polyurethane foam during the manufacturing process.These agents can include metal nanoparticles, quaternary ammonium compounds or other substances known for their ability to inhibit the growth of microorganisms [4,5].Antimicrobial additives are typically mixed with the polyurethane polymer before it is foamed and cured.This ensures that the resulting foam possesses antimicrobial properties, making it suitable for various applications, including medical devices, upholstery and filtration systems, where preventing the growth of harmful microorganisms is essential for safety and hygiene [6,7].
When it comes to the creation of polyurethane foams modified with nanometal particles, the existing literature is relatively limited.This scarcity can be attributed to the use of conventional methods for producing metal nanoparticles, which rely on aqueous solutions.It is widely acknowledged that the precise control of water is crucial in the process of synthesizing polyurethanes with the specific properties for their intended applications.Additionally, achieving an adequate dispersion of these nanoparticle systems presents certain challenges.In specific cases, PUF nanocomposite materials have been generated through different methods, including immersing PU in solutions containing metal ion precursors followed by a chemical reduction [8], immersing PU in solutions with dispersed nanoparticles [9], in situ polymerization [10] or electrospinning [11].
Conversely, an equally significant factor in shaping the characteristics of nanocomposites comprising polyurethane foam and metal nanoparticles is the management of their particle dimensions, arrangement and morphology, alongside the method of their incorporation into the polyurethane foam matrix [12][13][14].
The growing concern over antimicrobial resistance has fueled intense research into novel materials capable of combatting infectious agents.This review article delves into an intriguing prospect for the future: the incorporation of metal and metal oxide nanoparticles into polyurethane foams.By combining the versatility of polyurethane with the antimicrobial properties of nanoparticles, this emerging field holds promise for addressing the urgent need for effective antimicrobial materials in various applications.In this comprehensive review, we explore the synthesis methods, properties and applications of these nanocomposite materials, shedding light on their potential role in safeguarding public health and in environmental sustainability.

PU Foams-A Versatile and Widely Encountered Material
Polyurethane (PU) foams, widely recognized for their extensive application possibilities, possess a multitude of fundamental attributes that enhance their broad usability across various application fields.
As outlined in the Polyurethane Foam Market report [15], the worldwide polyurethane foam market had a valuation of USD 44.02 billion in 2022, with a forecasted trajectory of ascending to USD 64.44 billion by 2028, manifesting a compound annual growth rate (CAGR) of 5.8% within the forecast period spanning 2023 to 2028.The pronounced growth in this market is predominantly driven by the increasing demand for polyurethane foam in various industries, including the construction, automotive, furniture and packaging industries.Figure 1 provides a comprehensive visual representation of the primary applications of polyurethane foams, delineating their respective market shares within various sectors [15][16][17].This graphical depiction highlights the distribution of polyurethane foam usage across sectors such as construction, automotive, furniture and packaging and also summarizes its application in biomedical contexts.
polyurethane foam usage across sectors such as construction, automotive, furniture packaging and also summarizes its application in biomedical contexts.A notable feature of PU foams is their exceptional versatility [5,18].They can be lored through different formulations to acquire specific properties, be that the flexib needed for cushioning or the stiffness essential for insulations.This inherent adaptab enables PU foams to serve in a diverse range of applications, spanning from lightwei thermally insulating construction materials to the comforting support of mattresses 21].
This versatility allows for the incorporation of diverse fillers, a practice that exte the foams' utility by enhancing their intrinsic properties.Among the arsenal of modifi flame retardants stand as a vital component, imparting increased fire resistance to th foams [22][23][24].Different synthetic fibers (e.g., polymers, glass fibers) or natural fillers ( cellulose, chitin, hazelnut and eggshell), on the other hand, reinforce the polyureth foam's structural integrity [25].Incorporating antimicrobial agents into polyureth foams provides them with the ability to combat microbial growth, a feature highly cov in the medical and hygiene industries [26][27][28].Furthermore, the infusion of metal na particles and inorganic oxides (including nano forms) bestows advanced functionali e.g., enhanced thermal conductivities, superior electrical properties, improved mech cal strengths, reductions in noise pollution, and broad-spectrum antimicrobial activ [20][21][22][29][30][31].
In addition to their versatility, PU foams are well known for their lightweight nat Their exceptional thermal insulating properties are highly regarded in the construc and refrigeration industries, where energy efficiency is a key concern [32].The foa ability to dampen sound and reduce noise further broadens their appeal, with app tions in automotive interiors and architectural acoustics [29,30,33].
Durability is another key facet of PU foams.They are designed to withstand w and tear, ensuring long-lasting performance.Additionally, some formulations can exh resistance to various chemicals [34,35].
As sustainability and environmental concerns become increasingly important, eff have been made to develop more eco-friendly alternatives within the area of PU fo [35,36].This ongoing evolution seeks to reduce the environmental footprint of PU f production and application.

Methodology
For the selection of the published works to be included in the review, the Prefe Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA) recomm dations were followed [37].The research strategy was formulated according to the P (Problem, Intervention, Comparison, Outcome) approach (Table 1).A notable feature of PU foams is their exceptional versatility [5,18].They can be tailored through different formulations to acquire specific properties, be that the flexibility needed for cushioning or the stiffness essential for insulations.This inherent adaptability enables PU foams to serve in a diverse range of applications, spanning from lightweight, thermally insulating construction materials to the comforting support of mattresses [19][20][21].
This versatility allows for the incorporation of diverse fillers, a practice that extends the foams' utility by enhancing their intrinsic properties.Among the arsenal of modifiers, flame retardants stand as a vital component, imparting increased fire resistance to these foams [22][23][24].Different synthetic fibers (e.g., polymers, glass fibers) or natural fillers (e.g., cellulose, chitin, hazelnut and eggshell), on the other hand, reinforce the polyurethane foam's structural integrity [25].Incorporating antimicrobial agents into polyurethane foams provides them with the ability to combat microbial growth, a feature highly coveted in the medical and hygiene industries [26][27][28].Furthermore, the infusion of metal nanoparticles and inorganic oxides (including nano forms) bestows advanced functionalities, e.g., enhanced thermal conductivities, superior electrical properties, improved mechanical strengths, reductions in noise pollution, and broad-spectrum antimicrobial activities [20][21][22][29][30][31].
In addition to their versatility, PU foams are well known for their lightweight nature.Their exceptional thermal insulating properties are highly regarded in the construction and refrigeration industries, where energy efficiency is a key concern [32].The foams' ability to dampen sound and reduce noise further broadens their appeal, with applications in automotive interiors and architectural acoustics [29,30,33].
Durability is another key facet of PU foams.They are designed to withstand wear and tear, ensuring long-lasting performance.Additionally, some formulations can exhibit resistance to various chemicals [34,35].
As sustainability and environmental concerns become increasingly important, efforts have been made to develop more eco-friendly alternatives within the area of PU foams [35,36].This ongoing evolution seeks to reduce the environmental footprint of PU foam production and application.

Methodology
For the selection of the published works to be included in the review, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA) recommendations were followed [37].The research strategy was formulated according to the PICO (Problem, Intervention, Comparison, Outcome) approach (    The research was conducted based on the PICO question: "Can metallic and metal oxide nanoparticles provide appropriate antimicrobial properties to PU foams?"As such, the following inclusion/exclusion criteria were defined.

Inclusion Criteria:
- The literature search was conducted using the SCOPUS (as a more exhaustive database) database, using "polyurethane foams" as the primary search term.Further selection of the articles was performed automatically using the inclusion/exclusion criteria defined above, while inclusion in the present review was decided after a full review of the manuscripts.

Results
After applying the above-stated exclusion and inclusion criteria, as well as reading the title, abstract, and full text, a total of 69 articles were selected for inclusion in the present review (Figure 2), covering the modification of polyurethane foams with metallic and metalloid nanoparticles.To the selected articles, other works were added to provide the necessary context.These articles were retrieved by a "search and find"/manual selection approach using the SCOPUS database (by searching using specific keywords) or were suggested by reviewers during the peer review process.

Incorporation of Metal-Based Nanomaterials into PU Foams
When speaking of antimicrobial foams, as the main focus of the present review, one of the main materials that comes to mind is silver.A well-known and widely used antimicrobial material, silver (in very different formulations) represents the subject of a multitude of patents [38] or products already on the market [39].It is no wonder that most of the modifications presented (Table 2-presenting the incorporation of ex situ-formed nanoparticles; Table 3-presenting the in situ formation of nanoparticles in a PU matrix) are based on silver in different forms.Other known antimicrobial metals (such as copper or zinc) are also represented by a significant number of papers.However, several other types

Incorporation of Metal-Based Nanomaterials into PU Foams
When speaking of antimicrobial foams, as the main focus of the present review, one of the main materials that comes to mind is silver.A well-known and widely used antimicrobial material, silver (in very different formulations) represents the subject of a multitude of patents [38] or products already on the market [39].It is no wonder that most of the modifications presented (Table 2-presenting the incorporation of ex situ-formed nanoparticles; Table 3-presenting the in situ formation of nanoparticles in a PU matrix) are based on silver in different forms.Other known antimicrobial metals (such as copper or zinc) are also represented by a significant number of papers.However, several other types of PU foam modifications were also encountered, with, e.g., reinforcement or increasing PU foams' fire resistance or their application in environmental protection, as their main goals.The reason for their inclusion in the present review is the intrinsic antimicrobial properties of the used nanoparticles.
According to the literature data surveyed, three main methods to develop PU foams containing different types of nanoparticles can be identified: mixing the metal salts or nanoparticle solutions in a polyol precursor, the in situ formation of nanoparticles in already constructed PU foams and, finally, physical deposition (i.e., by dipping, spraying, etc.) of NPs on PU foams.All methods have their advantages and shortcomings, which, in our opinion, should be carefully considered when selecting the composite synthesis route, together with the envisaged application.For example, physical deposition of NPs, as an advantage, preserves their morphological and physical properties, although its main disadvantage is represented by insufficient depth penetration into PU foams.The presence of the NPs mostly on the surface also represents a disadvantage of in situ formation, together with supplementary variables that influence the NP's size and shape.The in situ formation of NPs by mixing in a polyol structure usually has, as a main advantage, a homogenous distribution in PU foams, although this, on the other hand, could affect both the properties of the PU foam and the developed NPs.
Considering these aspects, examples regarding the incorporation of NPs into PU foams will be presented considering their synthesis route (ex situ-Table 2, schematically presented in Figure 3; in situ-Table 3, schematically presented in Figure 4). of PU foam modifications were also encountered, with, e.g., reinforcement or increasing PU foams' fire resistance or their application in environmental protection, as their main goals.The reason for their inclusion in the present review is the intrinsic antimicrobial properties of the used nanoparticles.
According to the literature data surveyed, three main methods to develop PU foams containing different types of nanoparticles can be identified: mixing the metal salts or nanoparticle solutions in a polyol precursor, the in situ formation of nanoparticles in already constructed PU foams and, finally, physical deposition (i.e., by dipping, spraying, etc.) of NPs on PU foams.All methods have their advantages and shortcomings, which, in our opinion, should be carefully considered when selecting the composite synthesis route, together with the envisaged application.For example, physical deposition of NPs, as an advantage, preserves their morphological and physical properties, although its main disadvantage is represented by insufficient depth penetration into PU foams.The presence of the NPs mostly on the surface also represents a disadvantage of in situ formation, together with supplementary variables that influence the NP's size and shape.The in situ formation of NPs by mixing in a polyol structure usually has, as a main advantage, a homogenous distribution in PU foams, although this, on the other hand, could affect both the properties of the PU foam and the developed NPs.
Considering these aspects, examples regarding the incorporation of NPs into PU foams will be presented considering their synthesis route (ex situ-Table 2, schematically presented in Figure 3; in situ-Table 3, schematically presented in Figure 4).Among the studies regarding ex situ-synthesized NPs, several present the use of commercially available nanoparticle dispersions [9,10,27,[40][41][42][43]. The main advantage of this approach is a thorough control of the morphology of the nanoparticles, as well as the very good stability of NP solutions, which allows them to be used over long periods of time.Usually, this approach leads to a good dispersion of the nanoparticles in PU foams.
Considering all these potential applications, reinforcement of PU foams with metal or metal oxide NPs can definitively be viewed as a viable approach, making use of their specific properties.However, a particular question arises when modifying an already established material: how are its properties influenced?Fortunately, several studies can provide satisfactory answers.
Several studies (see Table 2) suggest that the incorporation of NPs does not alter the open cell structure of the foam but provides a higher surface area and a smaller pore size (important elements for several applications), preserving or enhancing the foam's mechanical properties.The only significant exception is represented by the study of Khan et al. [76], that revealed, for Al 2 O 3 concentrations above 2%, significant alterations of the PU's structure and properties.This is not, however, a surprise, as most authors define an optimal NP concentration (dependent on the NPs and incorporation route) above which the properties start to decline.Generally speaking, at concentrations under 2% NPs, the foams exhibited pore sizes in the range of 100-500 µm (which reduced with the addition of NPs compared to pure PU foams) and an increase in the compression strength and stability.
Sportelli et al. [12] evaluated the incorporation of CuNPs (obtained by the sacrificialanode electrochemical method) into different types of PU foams (for mattresses and for the automotive industry) by the dipping method in order to develop antimicrobial foams.Their results suggested that the NPs do not affect the pore characteristics, while NP release is favored at a higher initial copper concentration and by the characteristics of the foams (foams with larger pores lead to higher and faster NP release).
Namviriyachote et al. [9] presented the incorporation of different concentrations of AgNPs, together with a herbal compound from Centella asiatica active in wound healing (asiaticoside), in PU foams based on natural polyols (hydroxypropyl methylcellulose, chitosan and sodium alginate) to develop a foam dressing for wound healing.The composite's properties were more related to the type and content of natural polyols than to the NP content; the authors determined an optimal composition for both NP and herbal compound release.The study is important considering the alternative to classical chemical polyols, which opens another important research area.Another alternative for conventional organic-solvent-based polyurethane is represented by waterborne polyurethane.Zhao et al. [40] presented the incorporation of commercial AgNPs (15-40 nm) into waterborne PU foams via mechanical foaming for use as a bacteriostatic agent.Their results revealed the preservation of the open cell structure, with uniformly dispersed NPs.The optimal NP concentration identified by the authors was 2%, at which increases in the pore size, air permeability, water vapor transmission, and thermal and mechanical properties were recorded.Above this concentration, most of the mechanical and physical properties started to decline.
Phytosynthesized AgNP incorporation in PU foams was presented by Morena et al. [13].The phytosynthesis process was applied using phenolated lignin under ultrasound irradiation, leading to nanoparticles with an average diameter of 13.29 nm.Impregnation was performed by dispersing the NPs in a polyol mixture at different concentrations.The addition of NPs preserved the open cell structure and led to a decrease in cell diameter.The optimal NP concentration that led to the highest compression modulus and swelling ratio increase was 0.12%NPs.
A very interesting study is represented by the work of Cheng et al. [21].Although it is more focused on the antibacterial effect of the TiO 2 /Ag/chitosan embedded in the PU foams (an aspect that will be detailed in the next section) than on the NP's characteristics and their influence on the final PU properties, the authors conducted a patient feedback study on a pain-reducing mattress constructed using the composites, with >85% of the responses evaluating it as "excellent".This study offers a glimpse into the possible future applications of the solutions offered at the laboratory level by other works.
Another important application of PU foams is in electromagnetic interference shielding.Selvaraj et al. [78] presented the incorporation of a mixture of commercial NPs (MgO 40-60 nm, Ni 30-50 nm) in a bio-based PU foam via the dipping method.NP incorporation led to a potentially biodegradable, inexpensive, lightweight and flexible shielding material (maximum shielding: 27.56 dB).
Another metal nanoparticle which was evaluated for incorporation in PU foams not commonly encountered in the literature is Pd.Sahoo et al. [71] presented the incorporation of PdNPs obtained via hydrothermal synthesis using PVP as a coating material in commercially available PU foams via dipping.The authors evaluated the efficiency of the developed material as a recyclable catalyst for Suzuki−Miyaura cross-coupling reactions; their findings supported their potential application (the catalysts were viable after 50 catalytic cycles).More importantly, considering the goal of the present review, the authors also evaluated the penetration depth of the NPs (0.1 cm) and the morphology of the evaluated foam, revealing a structure comprising 3D interconnected 100−500 µm pores.The incorporation of SiO 2 nanoparticles could also increase the mechanical durability and stability of the foams by providing water and oil repellency characteristics, as demonstrated by Cho et al. [77].

Medical cushioning
Foams made using a higher compression ratio exhibited an increase in compression strength at higher strains and a higher density compared to PU foam. [27] Polymers 2023, 15, 4570  The second major alternative for the development of NPs containing PU foams is represented by the in situ formation of the nanoparticles in the PU matrix (Figure 4).
Silver nanoparticles are commonly obtained in the PU matrix either by chemical methods or by photoreduction.Their potential applications vary from wound healing and antimicrobial applications [7,8,80,81] to analytical applications [44] or air filtration systems [79].An interesting study is represented by the work of Apyari et al. [44], who comparatively evaluated both methods for incorporation of AgNPs.The reduction of sorbed silver nitrate was achieved by the use of ascorbic acid, and the authors established the optimal conditions as a reaction medium of 0.05 M sulfuric acid and a reaction time of 40 min.Besides these results, the authors concluded that the material obtained was more promising for applications in analytical chemistry for the determination of oxidants and reductants compared with the composite obtained using ex situ-synthesized NPs.
Li et al. [82] evaluated the antimicrobial applications of CuNP/PU foams, as well as the morphology and mechanical characteristics of the developed materials.The authors determined that the cell structure was not significantly influenced by the development of NPs, while the open cell content decreased from 97.42 to 96.64%, accompanied by tensile and compressive strength improvements, thus recommending the materials for antimicrobial and water treatment applications.
An important issue related to the widespread use of PU foams is their highly combustible nature.A study by Meng et al. [85] could provide an alternative solution to this issue.The authors incorporated FeOOH NPs obtained via chemical precipitation on PU foams through in situ surface growth in order to develop an antimicrobial flame-retardant coating.The multifunctional PU foam composite exhibited a limiting oxygen index of 25.5%, a reduction in the peak heat release rate of 45.0% and in the smoke density of 69.1% and a good underwater superoleophobicity.
A more complex study was recently published by Gazil et al. [87], evaluating the in situ development of mono-(Au, Ag, Pd) and bi-metallic (AuPd) nanoparticles in PU foams via microwave irradiation and hydrothermal synthesis for their application as catalytic sponges in semiautomated synthesis.Their conclusions were that the mono-metallic NPs obtained an open cell structure, with smooth surfaces of the cell walls and a homogeneous distribution of nanoparticles on cell walls.Regarding their potential applications, the reaction rate obtained using the materials was comparable to state-of-the-art catalysts.At the same time, for the bimetallic nanoparticles, the open cell structure was preserved; however, the NPs had an inhomogeneous distribution and morphology, while the obtained reaction rates for 4-nitrophenol reduction were inconsistent.Open cell structure, smooth surfaces of the cell walls, nanosized inhomogeneous particles, inconsistent reaction rates for 4-nitrophenol reduction 1 Abbreviations: NPs-nanoparticles, SEM-scanning electron microscopy, TEM-transmission electron microscopy, LOI-limiting oxygen index.
All these examples, alongside the other studies presented in Tables 2 and 3, reveal the possibilities of NP incorporation in PU foams, as well as the many different areas in which the developed composites can find applications.

Antimicrobial Properties and Biocompatibility of Metal-Nanoparticle-Modified PU Foams
As presented in the previous section, most works have highlighted the antimicrobial properties of the developed materials.Therefore, the present section provides the main findings regarding the antimicrobial efficiency reported within these studies, summarized in Table 4.  1 Abbreviations: NP-nanoparticle, ZOI-zone of inhibition, Cu-BTC-copper(II)-benzene-1,3,5-tricarboxylate; CFUs-colony forming units; OD-optical density.
Among all metals, silver-based antibacterial agents are the most widely studied and applied.Although their mechanism of action on microorganisms has not been entirely elucidated, various hypotheses have been proposed.The main antibacterial actions include the continuous release of silver ions, their adherence to the bacterial cell wall and membrane (permeabilization or disruption of the cytoplasmic membrane), oxidative stress induction and modification of signal transduction pathways [95].The accumulation of Ag NPs on the cell surface was observed especially in the case of Gram-negative bacteria.The absence of a thick cell wall and the presence of negatively charged lipopolysaccharides make them much more sensitive to the action of Ag NPs than Gram-positive bacteria [96].Once inside the cell, metal ions can interfere with the signaling pathways of bacterial metabolism and growth by inhibiting ATP production and the synthesis of proteins involved in cell viability and division [46].However, along with their antibacterial properties, metal and metal nanoparticles also have a series of adverse effects on the environment and human health.For example, silver exhibits some potential toxic effects in aquatic ecosystems and against human-friendly soil microbial communities (such as nitrogen-fixing and ammonifying bacteria) [97].
Metal nanoparticles can enter ecosystems through various pathways, such as industrial runoff or the disposal of products containing these nanoparticles.Once released into the environment, they can accumulate in the soil and water, leading to bioaccumulation in plants and animals, potentially causing adverse effects to ecosystem health [98][99][100].Furthermore, these nanoparticles may undergo transformations in the environment, altering their chemical and physical properties and potentially enhancing their toxicity.Their small size and increased surface area can also facilitate their transport over long distances, increasing the risk of widespread environmental contamination [101].
To address these concerns, in addition, there are several reports that describe the biocompatibility of these metal-nanoparticle-modified PU foams with animal cells, exhibiting an efficient wound healing activity.In this way, silver nanoparticles were included in CuraVAC Ag, a device that administers negative pressure wound therapy through a polyurethane foam dressing and discharges ions onto a wound surface where they are saturated with water, providing high efficiency scores of wound healings on rats [45].Also, lignin-based PU foams with silver nanoparticles were applied to full-thickness skin wounds on mice, demonstrating higher wound healing abilities than Tegaderm film, as demonstrated by well-proliferated granulation tissue formation, re-epithelialization, angiogenesis and dense collagen deposition [7].
Polymers 2023, 15,4570 Besides animal studies, there are also several reports on in vitro cytotoxicity assessments of PU foams in order to confirm their benefits for the management of burns, limiting the number of suffering animals.Boonkaew et al. showed that their own developed hydrogel dressing based on a 2-acrylamido-2-methylpropane sulfonic acid sodium salt and silver nanoparticles had lower toxicity to human keratinocytes (immortal cell line HaCaT and primary cells HEK) and fibroblasts (NHF) compared to commercially available silver products (Acticoat TM and Flamazine TM ) after 24 h of incubation in Nunc TM polycarbonate inserts [102].No cytotoxicity to HaCaT cells and BJ5ta fibroblasts was also observed for PU foams with incorporated lignin-capped silver nanoparticles, which had radical-scavenging activity and an ability to reduce the ex vivo myeloperoxidase activity in wound exudate [13].Another cell line used to confirm the cytocompatibility is the 3T3 murine fibroblast line, as reported by Picca et al. for Ag-modified PU foams [79].Further, human-adipose-derived stem cells (hASCs) were cultivated in direct contact with TPU/ZnO nanocomposite foams, displaying the highest cell proliferation for 2 and 5 wt% ZnO [63].This type of cell was also used by Norozi et al. to demonstrate the ability of PU foams with ZnO to help cellular adhesion, proliferation and osteogenic differentiation [103].Mouse embryonic fibroblasts are another type of cell used to test the biocompatibility of PU foams, as in the case of those incorporated with nanosized copper-benzene-1,3,5-tricarboxylate [90].
Novel synergistic dressings, comprising silver nanoparticles and recombinant human epidermal growth factor in PU foams, provided a good cytocompatibility with mice fibroblasts L929 and significantly accelerated the healing of diabetic wounds, with complete re-epithelialization in a diabetic BALB/c mice model [47].Full-thickness wounds treated with PU foams with 5-60 nm silica nanoparticles (with a content of up to 10 wt%) demonstrated accelerated wound closure rates in Sprague-Dawley rats and collagen and elastin fiber regeneration in a newly formed dermis covered by a new epithelial layer [84].In addition, these PU-Si hybrid foams promoted L929 cell proliferation to a greater extent than pure PU (p < 0.05) [84].
A PU foam dressing containing 6% alginate, 1 mg/cm 2 silver and 5% asiaticoside proved its lack of cytotoxicity on human skin fibroblasts (BJ cell line), lack of skin irritation in rabbits and improved wound healing in pigs without any dermatologic reactions [9].
A silver-nanowire-based 3D porous foam dressing developed by Chen et al. [42] showed high levels of live cells after 48 h of incubation with 3T3 cells and promoted wound healing in Bama pigs in combination with exogenous electric fields.This combined therapeutic system facilitated necrotic tissue drainage, downregulated the expression of E-cadherin to weaken intercellular adhesion and promoted angiogenesis, cell migration and proliferation.

Other Types of Modified PU Foams with Antimicrobial Properties
As previously mentioned, the main goal of the presented review is a review of the current state of the art regarding incorporation of metal and metal oxide nanoparticles into PU foams (especially for biomedical and related applications).In order to provide an image of the possibilities in the development of antimicrobial PU foams, the following section will provide a brief presentation of the progress in the last few years regarding other antimicrobial nanomaterials incorporated into PU (summarized in Table 5).Besides the efficiency of inhibiting bacterial growth, several PU foams have been designed for skin applications, exhibiting a good biocompatibility and cell adherence in in vitro studies [104][105][106] and improved wound healing in in vivo murine models [104,107].These types of materials are important to briefly present, as they can be considered as a starting point for future research.As can be seen from the examples provided in Table 5, PU foams can be easily modified with a large variety of other types of materials, although the impregnation/reinforcement routes are similar to those described in previous sections.Also, if, for simpler fillers, the addition can be performed via incorporation into the polyol mixture (without a negative effect on the foam structure and characteristics), for more complex fillers, a deposition strategy should be adopted.The latter case (especially when the reinforcement material forms a second layer and does not diffuse through the foam) raises some issues regarding the different properties of the layers.The issue can be overcome by carefully selecting the most appropriate coating for the PU foam.
All the above examples underline the great potential of modified PU foams, especially regarding antimicrobial applications.

Conclusions and Future Perspectives
As emerging from the literature review, several synthesis methods for NPs were evaluated for reinforcing PU foams.Among those, green synthesis methods were relatively poorly studied, with biosynthesis (using fungi) and phytosynthesis (using natural extracts) being the only evaluated routes.The production processes for metal nanoparticles often involve energy-intensive methods and the use of hazardous chemicals [110], contributing to environmental pollution.The use of alternative nanomaterials, such as nanolignin, nanoclay, chitosan or montmorillonite (as presented in Section 7), could provide increased biocompatibility for skin applications, without posing an environmental threat.Further, the use of green synthesis methods for the development of nanoparticles can constitute a viable approach (some scarce literature data have already been presented on this topic for both ex situ [48,50,52,75] and in situ [80] routes); this leads to the proposal of other green synthesis routes, such as the use of ionizing-radiation-assisted synthesis, a method that our group previously used to provide small-dimension nanoparticles with good antimicrobial properties [111].
Another very important aspect that can be considered in future research is represented by the replacement of conventional organic-solvent-based polyurethane by either waterborne polyurethane or bio-based polyurethane, as several authors have pointed out.Together with the adoption of green synthesis routes for NPs, this would lead not only to PU foams with superior mechanical and physical properties, adapted to the envisaged application, but also to more eco-friendly solutions.

Figure 1 .
Figure 1.Polyurethane foam market share in 2022 and its biomedical applications (source of raw data: [15]).

Figure 3 .
Figure 3. Schematic representation of NP/PU foam composite development using ex situ-synthesized NPs and its applications.

Figure 3 .
Figure 3. Schematic representation of NP/PU foam composite development using ex situ-synthesized NPs and its applications.

Figure 4 .
Figure 4. Schematic representation of NP/PU foam composite development using in situ-synthesized NPs and its applications.

Figure 4 .
Figure 4. Schematic representation of NP/PU foam composite development using in situ-synthesized NPs and its applications.

Table 1 .
Definition of the PICO strategy applied in the present work.

Table 2 .
Incorporation of metal and metal oxide nanoparticles formed ex situ into PU foams and the main non-antimicrobial findings; references are grouped considering the NP type 1 .

Table 3 .
Incorporation of metal and metal oxide nanoparticles formed in situ into PU foams and main non-antimicrobial findings; references are grouped considering the NP type 1 .

Table 4 .
Antimicrobial and cytotoxic properties of metal-nanoparticle-modified PU foams; references are presented in chronological order 1 .

Table 5 .
Antimicrobial properties of other types of nanomaterial-modified PU foams; references are presented in chronological order 1 .