Parthenium argentatum and Taraxacum kok-saghyz species, with the cooperation from rubber product manufacturing companies, has somewhat improved the sustainability of the natural rubber supply chain. Meanwhile, the high demand for synthetic rubber drastically increases the rate of depletion of fossil fuels and amplifies the adverse environmental effect of overexploitation of fossil fuels. Moreover, rubber and plastic products disposal have been a major issue for many decades, causing environmental pollution and the expansion of landfills. Sustainable synthetic rubber products could be realized through the incorporation of materials from biological sources. They are renewable, low cost, and most importantly, biodegradable in nature. In this review, brief introduction to natural and synthetic rubbers, challenges in the rubber industry, alternatives to conventional natural rubber, and recent advances in biodegradable and/or bio-based synthetic rubbers are discussed. The effect of incorporating various types of biologically sourced materials in the synthetic rubbers are also elaborated in detail.Rubber is an amorphous hyperelastic polymer which is widely used in this modern era. Natural rubber is considered the ultimate rubber in terms of mechanical performance, but over the years, some limitations and challenges in natural rubber cultivation that could result in serious shortages in the supply chain had been identified. Since then, the search for alternatives including new natural and synthetic rubbers has been rather intense. The initiative to explore new sources of natural rubber which started during the 1940s has been reignited recently due to the increasing demand for natural rubber. The commercialization of natural rubber from the  Recent progress to improve the sustainability and biodegradability of synthetic rubber by incorporating raw materials from biological sources. The vulcanization process managed to solve the low-temperature brittleness and high-temperature softening of natural rubber,5–7 and subsequently revolutionizes the rubber industry and increases the demand for natural rubber drastically. This induced the Hevea seedling smuggling incident in 1876 to hinder the monopolization of the price of natural rubber as Brazil was the sole natural rubber exporter during that time. The seeds were then replanted in Malaysia, and this sparked the dawn of the natural rubber industry in Southeast Asia as the major natural rubber suppliers even until today. Currently, countries in Southeast Asia inclusive of Thailand, Malaysia, and Indonesia contributed to over 90% of global natural rubber supplies.7,8 The production, harvesting, and processing of natural rubber had matured over these years, bolstered by the suitable climate and growth conditions, cheap labour costs, and the high acreage of land available for rubber plantations in developing countries. However, several limitations and challenges associated with the natural rubber industry had been identified over time and these necessitate the search for new or alternative sources of rubber material, both natural and synthetic.Rubber is a class of polymer categorized as elastomer, an amorphous hyperelastic material having sub-ambient glass transition temperature. Rubber can be divided into 2 types, natural rubber and synthetic rubber, depending on the origin. Natural rubber was first used back in prehistoric times (Olmec and Mayans) as rubber balls in sports, which were important religious and political events during that time.H. brasiliensis plantations in Southeast Asia are of the same origin as the seeds brought in during the 19th century. H. brasiliensis trees have very little genetic variability5,7,9 and have limited resistance to diseases such as South American Leaf Blight (SALB) or white rot disease.7,9,10 It was reported that infection in one of the trees may wipe out the whole plantation in no time and causes a shortage in natural rubber latex supply for future years. Besides the vulnerability to infection, the supply of natural rubber is further constrained by the strict conditions needed for optimal growth of the trees, which include the need for tropical climate that provides warm environment with abundant rainfall and sunlight. This excludes non-tropical countries from cultivating H. brasiliensis and effectively limit the global supply of natural rubber. Moreover, some of the tropical countries such as Malaysia have gradually replaced rubber plantations with palm oil plantations which are more profitable due to the increased biofuel demand,10–12 and this has further exacerbated the natural rubber supply chain problem.Current 13–15 Latex allergy incidents have also been increasing dramatically, with around 6% of the population exhibiting latex sensitization.15 Latex allergy caused by the proteins in natural rubber latex could result in varying reactions ranging from moderate symptoms such as itchy skin and hives, to life-threatening symptoms such as anaphylaxis, difficulty in breathing, and/or severe vomiting16 through direct contact or particle inhalation by sensitized personnel. There has been numerous studies and initiatives to address the latex allergy issue caused by the natural rubber gloves. The complete deproteinization of latex had shown a negative effect on the mechanical property of the rubber, as the non-rubber components, including the allergy-associated proteins were found to be responsible for the formation of island-nanomatrix structure that strengthened the rubber and stabilised the latex.17,18 Other methods developed by the glove manufacturers such as modification of leaching protocol to leach out the soluble proteins near glove surface and/or applying polymer coatings such as hydrogel or silicone polymer on the gloves' surface to prevent direct contact with the wearer have shown varying degrees of effectiveness.19,20 These additional steps are however responsible for the increase in the production cost and the price of latex gloves.17,21The applications of natural rubber cover a wide range of products, including examination and surgical gloves. The use of natural rubber gloves, also known as latex gloves first increased during the HIV epidemic in the 1980s and has grown exponentially with the recent COVID-19 pandemic since 2020.22–24 there is an urgent need to exploit other rubber materials as potential substituents to the current Hevea rubber. The following section of this review details the alternative sources of natural rubber, as well as recent progress in synthetic rubbers.Unfortunately, after more than a century of industrialization, the natural rubber industry still relies on only a single species of natural rubber-producing crop as the predominant source of natural rubber. Given the challenges and constraints to increase the existing natural rubber supply, coupled with the high demand for the natural rubber in various industries,1.125 More than 2500 types of plants were found to be capable of producing latex, but only two, Parthenium argentatum and Taraxacum kok-saghyz were shortlisted as alternative sources of natural rubber with promising potential to be cultivated commercially.25–27Throughout the mid-20th century, there have been many attempts to search for alternatives to Hevea rubber. The main reason behind it was the cut-off of natural rubber supply from Southeast Asia due to the Japanese colonization during World War II.Parthenium argentatum, also known as Guayule is a shrub native to the Chihuahuan desert of Texas and northern Mexico, and it is used as the rubber source for the local population there.11,25 The discovery of Guayule rubber was seen as a promising alternative source for its hypoallergic characteristic due to the lack of proteins associated with the latex allergy.9,11,25,28,29 However, Guayule rubber was found to have inferior quality compared to Hevea rubber, and this includes the presence of high resin content and relatively low molecular weight rubber component.9 Before Guayule rubber can serve as a substituent to Hevea rubber, extensive research and breeding techniques are required to address the abovementioned limitations. Initial research focused on the yield had produced promising results, with significantly higher yield and high-quality guayule rubber obtained. Unfortunately, the yield was rather unstable, and the higher production cost involved compared to producing Hevea rubber has halted the research. It is noteworthy that the price of Hevea rubber was relatively cheap when it became widely available after the World War II period. Nevertheless, Guayule remains as one of the attractive and potential alternatives to Hevea rubber, with its high rubber yield and low water requirement that allows it to be cultivated in non-tropical regions.9,30 Guayule however does not tolerate prolonged freezing temperature which covers the USA and much of Europe during the winter, as this will freeze the latex and greatly inhibits Guayule's growth rate.29,31,32 At present, although not many, there are isolated reports on the use of Guayule rubber in product innovation and these include Guayule/Neoprene blend wetsuits and Guayule-derived tires commercialized by Yulex Corporation and Bridgestone, respectively.Taraxacum kok-saghyz, or Russian dandelion, originates from Kazakhstan and was discovered in the USSR in the effort to search for domestic sources of natural rubber in 1931. It is an annual crop that has a short life cycle of around 6 to 8 months,9 which is significantly shorter compared to Parthenium argentatum (2 years) and Hevea brasiliensis (minimum 10 years growth required before producing rubber). The short life cycle of Russian dandelion plant eases the research and cultivation study, making it one of the prime candidates to substitute Hevea rubber. 11,12 This makes vigorous tilling required for a Russian dandelion plantation to be set up.9 The compositional analysis rubber reveals high-quality of Russian dandelion rubber comparable to that from Hevea brasiliensis by having very high molecular weight. The rubber is as resilient as the Hevea rubber and is better than Guayule rubber. However, it has more associated protein than the Hevea's, making the latex more sensitizing and increases the chances of allergy reaction with symptoms likely to be more serious. With these traits, Russian dandelion rubber is more suitable for non-medical applications or for heavy usage such as tires. Russian dandelion rubber made up 30% of the rubber supply in USSR during World War 2. However, similar to what had happened with Guayule, most if not all research on the cultivation of Russian dandelion was abandoned when the supply of Hevea rubber resumed after World War II.23 The saturation of rubber plantations in the “rubber-belt” area and the irreplaceability of natural rubber by the synthetic alternatives had reignited the world's interest to search for alternative sources of natural rubber to cope with the increasing demand for the rubber. One of the solutions was to source for natural rubber from different rubber producing plant species that can be cultivated and expanded to non-tropical regions. For example, Yulex, a corporation that commercialized Guayule-based products focusing on apparel such as wetsuits, swimming and diving suits, and footwear, has its own Guayule plantation and processing facilities.40 Bridgestone has Guayule research facilities in Arizona since 2012 and has launched racing tires made of guayule-derived rubber.41 Kultevat and KeyGene biotech companies collaborated on the research in Russian dandelion rubber towards the goal of commercialization.42 Continental launched truck tires made from Russian dandelion-derived rubber in 2016.43 Although these initiatives provided some degree of sustainability to the supply of natural rubber, the yield and application of the alternative natural rubbers is considerably low compared to the well-established Hevea rubber. The global distribution of natural rubber plantations, inclusive of Hevea, Guayule and Russian dandelion are shown in The globally rapid expanding economies, especially in China, who is the biggest consumer of natural rubber, have seen a rapid yearly increase in demands for natural rubber over the past decades.2.0Synthetic rubber refers to any artificial rubber synthesized from monomers derived from petroleum by-products or those of natural origin. The former however made-up bulk of the synthetic rubbers that are in use today. Since the first successful synthesis of synthetic polyisoprene in 1887, there were many variations of synthetic rubbers developed throughout history. The brief timeline of the development of synthetic rubbers is shown in 58 Besides, the 6th principle of Green Chemistry, a guidance developed by the United States Environmental Protection Agency for the design of chemical processes of products emphasized the use of renewable raw materials rather than the depletion of the economically available ones.59,60 Both of them targeted sustainability at its source. Unfortunately, this is not the case in the synthetic rubber industry as the raw materials are mostly derived from non-renewable fossil fuels. With the paradigm shift towards sustainable development and green chemistry, the search for sustainable elastomers has been intense in the last 10 years, and the desperation also arises from the ecological and environmental effects of the overexploitation of fossil fuels that had been evidently amplified.Since the 1960s, rapid technology and industrial development had raised global concerns about the detrimental impact on the environment and subsequently sparked the concept of sustainable development later in the 1980s. The primary concept of sustainable development is to ensure that the present needs that could be achieved now should not be compromising the future generations' ability to meet their needs. One of the goals of the United Nation's Sustainable Development Goals (SDGs), “Responsible Consumption and Production”, targeted the efficient use of natural resources can be alternatively defined as the resources that were used in any product development should be able to be replaced naturally.61 In the case of EPDM, ethylene and propylene can be obtained from the bioethanol through dehydration and addition reaction with suitable catalysts.62,63 In recent years, some rubber manufacturing companies incorporated these bio-based monomers in their rubber productions. Companies such as Bridgestone, Goodyear, and Michelin incorporated bio-sourced isoprene into their tire products in the 2010s.64 According to a statistical report, the usage of biomass-derived chemicals was at 2.6% of total usage in year 2020.65 Although the number is increasing steadily in the past 10 years, it is nowhere close to cope with the rate of depletion of fossil fuels anytime soon. Refined protocols that could increase the production efficiency and cost-effectiveness of the bio-sourced monomers, as well as cooperation from large polymer manufacturing companies may be necessary to ensure the viability of this initiative.One of the approaches to foster sustainability was through the incorporation of conventional monomers obtained from biomass sources. Biomass is organic material from biological beings. Some of the common synthetic rubber monomers could be obtained from reprocessing biomass fermentation products. For instance, carbohydrate of biomass waste such as crops and wood is hydrolyzed sequentially by acids and enzymes to produce sugar such as sucrose, which are then fermented to yield bioethanol.Another approach to producing sustainable rubber was achieved with the use of raw materials from natural sources in rubber product development. This includes materials in the form of monomers, as well as compounding materials such as fillers or additives. Incorporation of these non-conventional materials produced novel rubber materials or composites with properties that are of interest and worth investigating. Over the past decade, there are many studies and reports on the use of naturally produced raw materials in the synthetic rubber development. The studies are largely divided into two groups with different focuses; one of them focuses on improving the performance of the rubber  while ensuring its sustainability, and another prioritizes the biodegradability of the novel synthetic rubber. Naturally occurring compounds are known for their ability to be degraded naturally, hence it is reasonable to expect synthetic rubber comprising of such compounds to exhibit a certain extent of biodegradability. Unfortunately, the difference in priorities in the studies are distinct, with many of the studies that investigate the improvement in the performances of the rubber compounded with natural raw materials did not report the biodegradability of the rubber. Due to this, the following review section is divided into two segments, beginning with the review on the recent advances in the use of natural materials to enhance the biodegradability of synthetic rubbers in Section 3.0, and the following Section 4.0 focuses on the sustainability and improvement of the properties of synthetic rubbers using biologically sourced materials.3.066 Many other factors are also known to affect biodegradation activity such as the degradation environment which includes the types of microbial species present, temperature, pH, and aerobic or anaerobic surroundings. The disposal of rubber products after their end-of-life cycle and poor waste disposal management are among the problems faced globally.66–68 The high demand and usage volume for rubber products created a serious problem, as the rate of biodegradation of synthetic rubbers is extremely low, and they persist in landfills or nature for almost indefinitely after being discarded, causing environmental pollution and increase in landfill sizes.69The fact that polymeric materials generally do not decompose easily applies to synthetic rubber as well and they take a long time to be degraded in nature. The synthetic origin of the rubbers is one of the contributing factors to their limited biodegradability, with most of the raw materials used in the production of rubber being derived from fossil fuels. The availability of a wide range of types of monomers that can be used to synthesize rubber has resulted in a vast variety of synthetic rubbers with unique chemical compositions. Besides, various polymerization techniques have been adopted and resulted in rubber with different molecular weight, structure, configuration, and the use of various petroleum-based additives in the rubber compounding process also adds up to the complexation when it comes to the biodegradation of synthetic rubber.66 and ultimately the products can be further digested to produce CO2, H2O and/or CH4. The mechanism of biodegradation involves the secretion of enzymes by the microbes to initiate the breakdown of the material, and it is essential for the microbes to be able to utilize carbon sources from the material substrate. In general, microbes are not able to consume or digest synthetic rubbers, hence the low microbial activity and non-biodegradability of those rubbers.67 This situation is worsened with the use of non-biodegradable additives during the rubber compounding phase. In conventional rubber production, the rubber compounding phase is an inevitable process to render the rubber practically useful for many applications. The most significant part of rubber compounding is the vulcanization process to create crosslinking between rubber chains for the improvement of physical and mechanical properties. Fillers and other additives are often incorporated during this phase; for example, reinforcement fillers for further improving the properties and dyes for changing the appearance of the product. In recent years, there are many reports on the use of renewable materials as additives or as blending components for synthetic rubber, and the incorporation of such materials has resulted with improvement in the biodegradability of the products.In general, biodegradation is defined as the process to breakdown bigger molecules into smaller products by the activity of microorganisms. Naturally occurring materials tend to produce smaller environmentally friendly organic by-products through biodegradation,3.1There is an increase in the number of research that focuses on the incorporation of natural fillers in synthetic rubber, and the purpose of the additive is to not only emulate the conventional role of fillers but to serve as nutrients for the microbes during the biodegradation process as well. One example of such fillers is starch, a type of polymer categorized as carbohydrates and consists of glucose repeating units. Starch is widely available in almost all plants as the product of photosynthesis, and as the energy storage unit in plants. It has been utilized in the development of bioplastics because of its high availability and renewability, low cost, and biodegradability.et al. in 2018.70 Potassium persulfate initiator was included in the blend to induce the grafting of CS to XSBR through the carboxyl group, preventing the agglomeration of starch particles due to the difference in hydrophilicity between the starch and the rubber. In general, the increase in the ratio of CS in the blend resulted in an increase in the rate of soil biodegradation, TS, and water swelling ratio. The highest mass loss of 80% in 1 month was reported with CS/XSBR ratio of 1 : 1. The high TS of 25 MPa was comparable to the conventional synthetic rubber, but EB of the film was considerably low at about 100% only, resulting in a strong but relatively brittle material. The TS, EB and biodegradability could be tuned with different ratio of cassava starch in the blend and a balance in these properties are necessary to produce a sustainable and biodegradable rubber blend with high mechanical performance.Rubber blending with starch is another approach to incorporating biodegradability in synthetic rubber. The blend composite of cassava starch (CS)/carboxylated styrene butadiene rubber (XSBR) was reported by Riyajan 71,72In a separate study, glycerol was used as a plasticizer in CS/XSBR blend to largely improve the EB, and cellulose fibre fillers were introduced to control the moisture content. Although improvement in the mechanical property was observed, the biodegradability of the composite slightly decreased, from full disintegration to 82.6% weight loss within 30 days.73 Modification of starch molecules is often required for good dispersion and subsequently good resultant properties of the rubber.74 In 2019, Daud et al. incorporated acid hydrolyzed sago starch (AHSS) as filler in carboxylated nitrile rubber (XNBR), showing improved biodegradability of the composite.75 The AHSS-filled XNBR showed 22% mass loss in the soil burial test after 3 weeks. The percentage of mass loss in both samples of AHSS-filled or native sago starch-filled XNBR were much higher than the unfilled XNBR (10% mass loss) at 22% and 17%, respectively. However, AHSS is not a good reinforcing filler in XNBR as the mechanical properties such as tensile strength (TS) and elongation at break (EB) of the filled rubber are inferior to the unfilled control. The demotion of mechanical properties is due to the poor interfacial interaction that resulted from the high hydrophilicity difference between hydrophilic starch molecules and the hydrophobic rubber matrix.The presence of rich hydroxyl groups in starch molecules promote agglomeration as a result from the strong hydrogen bonding among starch molecules.et al. by graft copolymerization of starch molecules with acrylonitrile, a monomer containing the same nitrile functional group as XNBR.76 While the introduction of 10 phr ANS filler in XNBR did create starch interstitial region that reduced the crosslink density like in the case of AHSS, the EB of the rubber improved, and TS was insignificantly affected. This was attributed to the glucose ring opening via amino functionalization where the hydrogen bonding between the two sides of the ring-opened glucose units provides reversible points to dissipate external stress in the starch chain before total structure failure occurs. ANS-filled XNBR also has significantly improved biodegradability, with 25% mass loss over 8 weeks of soil burial test. The formation of microbial coaggregation was also observed through a scanning electron microscope (SEM) in the soil burial test samples.Amino-functional starch (ANS) was synthesized by Misman graft-poly(methyl methacrylate) produced through emulsion polymerization between natural corn starch powder and methyl methacrylate as a filler could improve the mechanical properties of SBR through the physical entanglement between SBR matrix and starch grafted PMMA.77 The soft, high strength and bendable material are suggested for applications in tight packaging such as fruit wrapping. The rate of biodegradation increases tremendously at a high filler content of >30 phr but the mechanical strength deteriorates worse than the unfilled SBR due to agglomeration as a consequence of high filler–filler interaction overrides the mechanical reinforcement resulting from the physical entanglement. At optimum 30 phr filler content, 2% mass loss of samples could be obtained after 90 days of soil burial.Starch-3.2d-glucose units and is one of the most abundant organic polymers on earth. In 2019, Taib et al. modified the properties of nanocellulose using gallic acid as antioxidant and subsequently introduced it into synthetic rubber.78 The antioxidant nanocellulose (Aox-NCC) acts as a reinforcement filler and crosslinking agent when incorporated into NBR. The optimum amount of Aox-NCC reported was 3 phr, providing the maximum mechanical strength improvement through the increase in crosslink density, before the decrease in efficiency of reinforcement due to the agglomeration of Aox-NCC particles. The resulting fillers have a negligible mass loss during the soil burial degradation test within 6 months in both filled samples and unfilled control. According to the author, the antioxidant moieties act as radical removers during oxo-biodegradation, slowing down the overall biodegradation process and further investigation is required to conclude the biodegradability of Aox-NCC. Cellulose occurs abundantly in plants as an important constituent of cell walls, hence cellulose fibres can be extracted from many sources, for example, Opuntia Cactaceae cactus trunk, in the form of the mesh-like fibrous network.79 A high extent of degradation approaching complete disintegration can be achieved within 7 months with the incubation of the cellulose fibre network (9 wt%) filled SBR composite in organic soil. Besides plant cellulose sources, bacterial cellulose is also frequently used as filler for synthetic rubber due to its high purity, crystallinity and unique open network structure leading to a large surface area.80 Moreover, hydrolysis of bacterial cellulose resulted in bacterial cellulose whiskers, forming a rigid 3D filler network through hydrogen bonding between whiskers. Water-induced stimuli-responsive SBR reinforced with bacterial cellulose whiskers was reported by Chen et al. They suggested the rupture of the said 3D network occurs during the presence of other competitive hydrogen bonding agents, such as water. This results in a stimuli-responsive composite for the applications such as sensors.81Cellulose is a polysaccharide composed of a linear chain of β-1,4 linked 3.3et al.82 XNBR filled with cattle hair keratin and its acid hydrolysate showed improved crosslink density and higher oil resistance as diesel fuel and leaded petrol compared to unfilled XNBR. Cattle hair keratin showed better mechanical performance reinforcement than hydrolysate due to the higher specific surface area, smaller particle size and the high molecular weight, while in keratin hydrolysate, the large particle size from the formation of aggregates by the small molecular weight scissored chains during acid hydrolysis resulted in poor filler dispersion and lower reinforcement effect. The better filler dispersion is also seen to affect the biodegradability, with the keratin-filled XNBR exhibiting a greater reduction in TS (−30%) and crosslink density after 30 days of burial test in universal soil, indicating the higher decomposition activity by microbes. Keratin hydrolysate from bird feathers  reinforced XNBR and NBR could achieve a faster cure rate, and high strength reinforcement but resulted in lower flexibility composites. However, the process of bird feather hydrolysis should not use highly concentrated alkali as it could further hydrolyse keratin to release free amine and carboxylate ions, resulting in poor water uptake capability and biodegradability of the composite.83Keratin is also one of the natural raw materials that have received attention from the rubber industry. Keratin refers to one of the families under scleroproteins, a type of structural fibrous protein. Keratin consists of peptide chains, forming different functional components in biological organisms for the role of support and protection, such as the epithelial tissues which include skin and nails. Keratin for use in synthetic rubber is usually extracted from the tannery and poultry waste of vertebrate sources such as sheep wool and bird feathers. Even though the occurrence of keratin in these wastes is not as high as collagen, the extraction of keratin from these wastes involves relatively low cost and could reduce the environmental damage and pollution compared to the fossil fuel-based materials. The use of keratin as a biodegradable component in XNBR has been reported by Prochoń et al. in the year 2015 and 2020, respectively.84,85 Generally, the MMT-filled samples have higher TS, while EB and hardness are comparable to PVAL-filled samples at the same amount of keratin fillers. At 10 phr keratin hydrolysate, 3.2% and 5.2% in TS reinforcement were observed in PVAL-filled and MMT-filled samples, respectively. As for the biodegradation test, both samples appeared discoloured, blotchy and uneven surfaces after being buried in soil for 1 month. The discolouration observed through a spectrophotometer was attributed to the biodegradation of the biopolymer part as the colour protection properties were lost. In the MMT-filled XNBR with 5 phr keratin hydrolysate sample, a 50% decrease in TS after 3 months of soil burial was reported. Compared to the negligible change in the TS of the unfilled sample, the reported drop in the filled sample was considerably large, suggesting the use of enzymatic keratin hydrolysate as filler in XNBR could be a very promising approach to produce biodegradable synthetic rubber without compromising the mechanical performance. The effect of inorganic particle-keratin filler blending in NBR was investigated by Prochoń et al.86 The blending of keratin with zinc oxide before the compounding phase decreased the particle size of the filler and improved the water uptake capability and biodegradability. There was a 13.6% increase in TS loss compared to control in 30 days of controlled soil incubation.Keratin hydrolysate could also be obtained through enzymatic hydrolysis. The activity of enzymatic hydrolysate of keratin was investigated in sulphur cured system with different additional fillers, poly, (PVAL) and montmorillonite (MMT) clay by Prochoń 3.487 The incorporation of lignin fibrils filler further improved TS and EB of SBR compared with sole GO filler. The optimum amount of lignin fibrils was reported at 2 wt% for SBR which was pre-compounded with 5 wt% of GO, and a high mass loss of approximately 50% in 50 days of biodegradation was achieved by such composite while benefiting from the maximum mechanical reinforcement. Composite with higher content of lignin fibrils, at 3 wt% further increased the biodegradability but EB was largely reduced to a value slightly lower than GO or pure SBR. In general, altering the amount of biodegradable components in the composite is a simple way to tailor their properties according to the intended application of the biodegradable synthetic rubbers. GO filler used together with elastin collagen was also reported recently, with SBR composite sample containing 1.5 wt% collagen in 5 wt% GO exhibited 19% and 24% increase in TS and EB, respectively.88 The biodegradability of the SBR/GO/collagen composite increased due to the synergistic effect of GO's naturally bonded carbon structure and the presence of biodegradable collagen.The combination of lignin fibrils and graphene oxide (GO) fillers highly improved thermal stability of SBR, making it suitable for applications such as green tires.3.589,90 In general, the biodegradability of the rubber decreased with the increase in the extent of modifications which include the percentage of grafting and amount of silane-modification. The extent of biodegradation of the SBR was less than 5 wt% within 6 months. This implies that the weight loss recorded could be attributed to the biodegradation of the CSP portion in the rubber. PMMA-g-CSP filled SBR composite exhibit higher thermal stability due to lower crystallinity structure of filler, and improved mechanical strength, like the case of PMMA-g-starch mentioned above that resulted from the increased filler–matrix interaction and formation of physical entanglement.Recently, the use of coconut shell powder, CSP as a filler for SBR was reported. CSP contains a high amount of fibre consisting of cellulose, lignin and pentosans. The compatibility of CSP with rubber matrix was improved through silane modification and PMMA grafting.91 However, it did not undergo degradation after 3 months of natural soil burial test even with the use of monomers of natural sources such as succinic, itaconic and sebacic acid. This is due to the combined effect of nanoparticle volume effect, high strength of filler–matrix interaction and the carbon–carbon crosslinks between the polymer chains. On the other hand, linear isosorbide-based polyester with fatty acid dimer undergoes 95.1% degradation in 45 days in a controlled soil compost biodegradation setup according to standard method EN 13432.92 Increasing the amount of fatty acid dimer in the polyester however resulted in a lower degradation rate due to the increase in hydrophobicity and lower amount of degradation susceptible-ester bonds.A tough polyester comprised of peroxide-crosslinked poly has superior mechanical properties after vulcanization and exhibited good compatibility with inorganic fillers.et al. in 2015 and Tran et al. in 2017, respectively.93,94 Although PDMS has excellent thermal stability and can be used for a wide range of operating temperatures, the rubber was found to be degradable in the soil environment through the hydrolysis of siloxane bonds.95 The product of siloxane bond hydrolysis can then be further degraded by radicals and microbes into silica, carbon dioxide and water. The degradation products of PDMS are usually environmentally friendly and PDMS is also non-toxic and biocompatible.95The degradability of synthetic rubber in aqueous medium is also an important consideration as the surface of the earth is covered by almost 70% of water. Disposal of synthetic rubber products could end up in aqueous environments such as rivers, lakes and seas due the unethical disposal or accidental leakage from landfills. The degradation of poly(dimethylsiloxane) (PDMS) which is also known as silicone rubber and characterized by the presence of siloxane (Si–O) bonds in the polymer backbone, in both aqueous and soil media has been reported by Ceseracciu i.e., unmodified corn starch granules and micronized cocoa shell waste (CSW).93,94 In both cases, the filled PDMS have higher biological oxygen demand (BOD) when immersed in Mediterranean seawater, and oxygen consumption increased with higher filler loading. PDMS filled with 70% corn starch experienced 5% volume degradation in 60 days, and the PDMS–starch composite is estimated to be fully degraded in seawater in 3–6 years depending on the starch content. The formation of a porous structure with high CSW content improved water permeation into the PDMS network and this contributed to the improved biodegradability of the material. However, from the EDX analysis, no significant amount of elemental silicon was found in the seawater after the test period of 1 month, implying the initial degradation only proceeded in the CSW. High elastic recovery rates and stress relaxation properties of corn starch-filled PDMS suggested that the composite could be used as mechanical energy dampeners because of the low strain energy dissipation factor. Besides, CSW introduced radical scavenging activity into PDMS due to the presence of a high volume of flavonoid and polyphenol in cocoa, which could be useful in active food packaging, cosmetics or biomedical devices involving drug release.The degradation properties of acetoxy-cured PDMS in Mediterranean seawater had been investigated and reported recently while incorporating different natural fillers, 96 With the increase in RBP content, improvement in TS without adverse effect on the EB was obtained, and this suggests a better performance composite than those filled solely by starch. The rate and amount of antioxidant release, i.e., the antioxidant activity was controllable with the amount of starch granule filler. However, the encapsulation of starch granules in the PDMS network rendered them protected from hydrolytic degradation when immersed in water. Thus, the action of antioxidant betanin release from RBP into the water was through diffusion in the PDMS network. The rate of degradation of synthetic rubber products is affected by the aqueous environment. But in general, degradation of polymeric materials in an aqueous medium is usually slower than in a soil environment due to a lack of suitable degradation conditions for microbial degradation actions.97 Hydrolytic/aqueous degradation tests of elastomers sometimes incorporate different conditions, especially the pH of the aqueous medium and one of the reasons for this is due to the differences in pH in water sources around the globe. However, for elastomeric products containing hydrolysable bonds such as polyurethane and polyester, recovery of monomers through acidic, alkaline or chemical degradation could be more prominent as recyclability of resources also contributes to sustainability.98,99A similar antioxidant property with additional gradual antioxidant release in starch granules–PDMS was achieved with the use of red beetroot powder (RBP) as fillers.A summary of biodegradation of some of the abovementioned synthetic rubbers formulated with natural material is shown in 3.6co-vinyl acetate (EVA) was reported by Ma et al. in 2015. 2,5-Dimethyl-2,5-di(tert-butylperoxy)hexane (AD) was added to the blend as a radical crosslinker to generate interpenetrated network structure of PLA and EVA.100 At 1 wt% of AD, PLA/EVA blend of ratio 40 : 60 exhibited considerably higher TS (21 MPa) than the same ratio blend without AD (8 MPa). However, the EB (210%) was reduced to one-third of the non-crosslinked blend (600%) with the addition of the dynamic crosslinks, but the value was still considerably higher than the petroleum-based thermoplastic blend of PP and EPDM, at which the EB was merely 120%. The reduced tensile set and increased hardness with the AD dynamic crosslink are beneficial for the development of tough and flexible thermoplastic elastomer. The TPV experienced 5% weight loss after being immersed in aqueous alkali for 10 weeks, and from FTIR analysis, absorbance peaks from the PLA components in the blends were no longer visible in the degraded TPV samples. This confirms the partial degradability of the TPV and indicates the degradation proceeded in the PLA phase rather than the blend as a whole.Synthetic rubber could be blended with thermoplastics to produce thermoplastic elastomers (TPE) which exhibit both thermoplastic and elastomeric properties. Thermoplastic properties in TPE enable it to be remolded, providing an advantage over traditional thermoset synthetic rubbers in terms of processability and recyclability. Moreover, some of these thermoplastics are polyesters such as polylactide (PLA) and polycaprolactone (PCL) that contain hydrolysable ester linkages and they exhibit good hydrolytic degradation properties. The incorporation of these biodegradable thermoplastics in conventional synthetic rubber could introduce biodegradability in an otherwise non-biodegradable petroleum-derived synthetic rubber. PLA is a biobased polymer that is commonly produced from corn or sugar beet, and it has been widely used in the development of green plastics, 3D printing filaments, and as a component of polymer blends. Superior mechanical strength of thermoplastic vulcanizates (TPV) produced from blending of polylactide (PLA) with ethylene-101 Recently, Pyo et al. reported the bio-based route for the synthesis of the monomers of PCL through a series of microbial–chemical reactions of biomass, particularly fructose.102 This adds PCL to the list of originally fossil fuel derived polymers with bio-based available monomers, and subsequently improved the sustainability of the material. Tran et al. reported a fully degradable polymer semiconductor with elastomeric behaviour for application in transient electronics, especially skin-inspired electronics.103 Such polymer was obtained by blending polycaprolactone-based polyurethane (E-PCL) which serves as the elastomer matrix, with a polymeric semiconductor. Aldehyde-functionalized diketopyrrolopyrrole (DPP) was polymerized with p-phenyldiamine into a polymer semiconductor containing imine bonded backbone. Resultant biocompatible blend exhibit extremely high EB of more than 1000% with high TS and minor hysteresis at 50% strain for more than 10 cycles. The semiconductor was reported to be able to self-assemble and form nanoconfined fibril aggregates in the elastomer matrix, deriving its ability to depress crystallization and crack formation under applied strain, and consequently produce electrical properties that are stable under strained condition. Imine bonds in the semiconductor can be degraded with acid into monomers, while PCL is known to be hydrolytically degradable. As a result, the film of the blend had about 50% weight loss within 45 days when immersed in an acidic solution of trifluoroacetic acid, proving the degradability of the said blend. The ability of PCL to be degraded in various environments makes it a good candidate for degradable polymer use.PCL is a polyester that is an important material in many medical applications such as surgical implants, bone tissue engineering or drug delivery due to its excellent biocompatibility, high biodegradation rate and mechanical strength. It is noteworthy that production of PCL is achieved through the ring-opening polymerization of ε-caprolactone or polycondensation of 6-hydroxyhexanoic acid, both monomers are usually derived from fossil fuel.et al.104 The longer length of the chain extender makes the TPEU more hydrophobic and lowers the water uptake capabilities. This resulted in a change in the hydrolytic degradation mechanism shifting from bulk to surface erosion, slowing the overall degradation process. Fortunately, the degradability is not severely affected and all investigated TPEU fully degraded within 100 days in aqueous alkali. In a separate study, Gregory and William improved the alkaline hydrolytic degradation of triblock polyester consisting of blocks of poly and PCL by forming ionomers through reaction with a base such as hydroxide of sodium or lithium.105 Carboxylation of the polyester through thiol-ene reaction was initiated by UV between vinyl pendant group of 4-vinylcyclohexene oxide and 3-mercaptopropionic acid. The formation of ionic bonds strengthens the mechanical properties, resulting in high TS, EB and elastic recovery, making the polyester tough, elastic and resilient. Additionally, it was more capable of absorbing water and degrading through alkaline hydrolysis. 75% of sodium–carboxyl group neutralized sample undergoes complete mass loss in 10 hours, while non-neutralized sample shown up to 90% mass loss in 25 hours, and the non-carboxylated samples were not degraded throughout the test period. The thermoplastic behaviour of the ionic polyester was confirmed with high retention of TS and EB after 3 cycles of the hot pressed . The facile modification process enables the properties to tune over a wide range with a straightforward method.Thermoplastic poly(ester urethane) (TPEU) produced from PCL, hydrogenated 4,4′-methylene diphenyl diisocyanate (MDI), and different lengths chain extender (2-ethylurea diol derived from amino acid) was reported by Brannigan 106 Recently, the development of a 3D printable porous elastomeric scaffold of PGS-acrylate has been reported.107 The thermal curing post scaffold fabrication (post-cure) can further enhance and tune the mechanical properties of the scaffold, and the process also affects the scaffold's degradability. When the post-cure duration was little or none, the rate of alkaline hydrolytic degradation of the scaffold was higher than those of PGS, and the rate decreased with the increase in the post-cure duration. The aqueous degradation process of poly--co-(tetramethylene ether)glycol terephthalate (PBT-PTMG) was reported by Diaz et al. using accelerated degradation in distilled water at elevated temperature.108 They found that the degradation process followed a temperature dependant pseudo zero order kinetic, and the mechanical behaviour change during degradation is related to the degradation-induced crystallinity change. Basically, the formation of the crystalline region following the rearrangement of low molecular weight chains scissored by ester bond hydrolysis during degradation increased the storage modulus and shifted the mechanical behaviour of the material from elastomer to brittle after 3 days.Poly(glycerol sebacate) (PGS) is a polyester that is used as a biomaterial in a wide range of medical applications such as tissue engineering, scaffolds and cell culture systems due to its excellent biocompatibility and unique properties.et al. reported a novel bio-based polyester (PLBSI) synthesized through polycondensation of lactic acid, sebacic acid, itaconic acid and 1,4-butanediol.109 Varying the amount of lactic acid in the formulation changed the mechanical behaviour of the resultant material. Reduction in compositional regularity caused by the methyl group side chain from the incorporated lactic acid allows the copolymer to transit from plastic to elastomer. Another linear polyester (PBPSSI) was synthesized by Hu et al. in 2016, involving five bio-based monomers, i.e. 1,3-propanediol, 2,3-butanediol, succinic acid, sebacic acid and itaconic acid.110 The resulting bioelastomer exhibited excellent thermal stability and good biocompatibility. In both PLBSI and PBPSSI, the TS was largely improved when the bioelastomer was reinforced with silica, while EB was not significantly affected compared to the unreinforced counterpart. Both composites have mechanical properties in the acceptable range for many engineering applications. However, the in vitro degradability in phosphate buffer saline was largely inhibited when both bioelastomers were peroxide-crosslinked, with about 35% mass loss in 30 days in unreinforced bioelastomers, to negligible degradation in the crosslinked composites. According to the authors, PBPSSI exhibited high degradability in suitable environment and have properties that could be suitable for a wide range of engineering applications. As for PLBSI, the similar lactate group as in PLA allows both polymers to be highly compatible with each other, and the resultant blend exhibited good toughening effect, improved EB and impact strength by 30 and 15 times, respectively compared to neat PLA.In 2015, Hu 111–113 Mechanisms of various types of environmental degradation are summarized in 112 Oxidative degradation is often triggered by heat or light in the presence of oxygen, causing polymer chain oxidation and chain scission. Consequently, fragmented and lower molecular weight products containing higher concentration of oxygen-carrying groups such as carbonyls and hydroxyls are produced, and this has been reported to facilitate the subsequent biotic degradation.113 Although most of the biobased plastic/synthetic rubber blends summarized here reported improved abiotic degradability of the product, there is a lack of report on the microbial degradability of the rubber blend. Nevertheless, the improvement in the abiotic degradability of the blend is expected to be beneficial to the overall degradability.Degradation process of polymeric materials could be categorized into abiotic and biotic degradation. Biotic degradation is also known as biodegradation, where the degradation process is contributed by the activity of microbes, while abiotic degradation refers to the degradation of polymers triggered by physiochemical conditions, such as photolytic degradation by light or hydrolytic degradation in the presence of water.4.04.173 Modification of starch granules is often carried out to improve this interaction for better compatibility and greater properties enhancement. Sago starch oxidized (OSt) with hydrogen peroxide was investigated for its role as filler in a sulphur-free compounding system.118 The high carboxyl group content (57%) in OSt improved the TS and EB by 304% and 199%, respectively and this improvement was attributed to the formation of ionic crosslink with zinc oxide. The filled elastomers also exhibited improved antibacterial ability with evident inhibition of bacterial growth at low pH. However, this could also imply lower biodegradability of the composite so the selection of materials and the modification technique should depend on the requirement of these properties.Much research had been conducted recently to incorporate renewable materials into the formulation of synthetic rubber to improve their performance and sustainability. Starch is one example of such material and it has been used as green filler in synthetic rubber formulations due to its low cost, high abundance, and excellent biodegradability. Generally, the introduction of filler in a rubber could improve its mechanical performance and one of the reinforcing mechanisms is through the physical entanglement that took place between the fillers and the rubber chains, illustrated in 75,119 It was found that low molecular weight dextrin had low interfacial adhesion with rubber matrix and do not participate in crosslink, but the dextrin filler is expected to improve the biodegradability of the filled rubber because of the ease of consumption of dextrin by microbes. However, no result on biodegradation was presented in the study.119 The use of yeast fermented corn starch (MST) in SBR reduced mechanical properties due to weak interaction between filler and rubber matrix.120 The increase in the concentration of MST up to 100 phr improved the cure rate and crosslink density of the composite as the hydroxyl group take part in crosslinking and MST acts as an activator for vulcanization accelerator. Excellent water absorption and water swelling capability suggested its advantage in agriculture such as controlled fertilizer release and water retention.Modified sago starch through acidic hydrolysis of sago starch solution at elevated temperature results in lower crosslink density in XNBR, and the rubber composite was reported to have poor mechanical properties.g-PMMA was reported by Li et al. The coupling agents used in the study include styrene-co-maleic anhydride (SMA), bis[3-(triethoxysilyl)propyl]tetrasulfide (TESPT), 3-aminopropyl triethoxysilane (APTES), 3-mercaptopropyl triethoxysilane (MPTES) and MDI.121,122 Generally, these coupling agents slightly improved the TS, but produced different effects on EB. Among them, MDI produced the most significant influence on the EB and two possibilities that could have led to the improvement in the filler-matrix adhesion were proposed, i.e., the formation of urethane linkage with starch, and the interaction of aromatic benzene rings between MDI and styrene moieties. MDI coupled composite also exhibits improvement in the initial thermal degradation temperature and thus the thermal stability of the composite. The study of different content of SMA showed improved TS and negligible EB change with increasing SMA content in the starch-g-PMMA/SBR composite up to 5 phr. Urethane polyfunctional monomer based on sucrose molecules was used as a co-agent in electron beam irradiation curing of EPDM rubber.123 Sucrose was diurethane-bonded with hydroxyethyl methacrylate and MDI. At 5 phr loading of the polyfunctional monomer, the crosslink density of the rubber composite improved, resulting in greater swelling resistance and higher thermal stability. A controlled antibacterial material release was incorporated in PDMS/starch blend through a complex formed by povidone-iodine (PVPI) and starch granule fillers.124 Sustained antibacterial activity for more than 1 month can be achieved through controlled release of iodine with the formation of iodine–starch complex when the composite is in contact with water.The effect of using five different coupling agents separately in SBR filled with starch-125 Although the abrasion and wear resistance were slightly reduced when silica filler was replaced with MCC, the improvement in dry grip, heat build-up resistance, and processability make the composites' overall mechanical properties fall within the acceptable range for tire tread application. In 2018, Akbay and Güngör reported the extraction of cellulose from waste banana peels through sequential boiling in water and vinegar, followed by drying and grinding. Based on their report, incorporation of the cellulose in EPDM has resulted in better cure characteristics of the rubber composite.126The use of microcrystalline cellulose (MCC) as a multifunctional material in rubber compounding had been reported by various groups. In the SBR/BR blend, MCC act as a processing aid and reinforcing filler.127 Compared to MCC, NCC was reported to have better interfacial adhesion, compatibility, and dispersion in both NBR and XSBR.127–129 The mechanical reinforcement trend of NCC is similar to that of MCC, in that TS, tear strength, and hardness increased with increasing filler content, whereas EB increased only slightly at a certain filler concentration before decreasing at higher filler loading. The inverse reinforcement between TS and EB was also seen in most conventional synthetic rubber fillers such as carbon black, silica, and clay materials. Cellulose agglomerates easily in the rubber matrix because cellulose contains a high concentration of hydroxyl groups, which is becoming more common when the matrix–filler interaction is weak. By ensuring the optimum concentration of filler in the rubber, a percolated network of NCC was achieved in the SBR. Consequently, the rubber exhibited improved tear strength and this was attributed to the higher force required to break the percolated filler network for crack propagation.130 The use of NCC with zinc oxide as fillers formed Zn–cellulose through the formation of ionic bonds, improving the dispersion of both fillers in the NBR matrix and resulting in a composite with superior mechanical properties than both singly filled-NBR.131 Other recent works involving modification of NCC filler for synthetic rubber is summarized in Acid hydrolysis of MCC produces cellulose nanocrystals or more commonly known as nanocrystalline cellulose (NCC). NCC has a smaller particle size with a higher surface area to volume ratio. The concentration of acid used for MCC hydrolysis greatly affects the yield and filler performance. The optimum concentration of 5 M HCl was reported to produce the smallest particle size while retaining a high yield. The use of excessively high acid concentration should be avoided as it could favour depolymerization of the cellulose and reduce them into amorphous sugar molecules.et al. in 2020 with the aim to reduce petroleum-based materials in the rubber composite.137 The findings suggest that a stronger composite with excellent weathering resistance targeted for automotive sealing applications can be obtained aside from reducing fossil fuel-based material in EPDM rubber. Superior TS vitrimer elastomer based on XNBR could be obtained with the addition of epoxidized soybean oil (ESO).138 Reversible dynamic β-hydroxyl ester bonds formed between the epoxy group of ESO and carboxyl group of XNBR and TCNF gave the composite high mechanical strength retention after recycling and good shape memory ability through thermal treatment.The potential of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) oxidized cellulose nanofibers (TCNF) to produce a blend with EPDM was reported by Kucuk 139 This hybrid filler enhanced the mechanical properties of SBR, improving TS and EB by 110.7% and 39.1% compared to the unmodified lignin-filled SBR of the same filler content. Yu et al. reported the use of lignin to form an interpenetrating network with commercial epoxy resin in NBR to strengthen the rubber composite and improved its oil resistance.140 A thermoplastic composite could be achieved with the addition of GO filler in melt reactive mixing of NBR/lignin (ratio = 1 : 1) blend. The hydrophilic and high surface area GO platelet facilitated the dispersion of lignin fillers in the NBR to produce high TS and moderate EB composite with thermoplastic characteristics.141 The effect of functionalization of lignin and its performance in SBR composite was reported by Jiang et al. in 2018. Unmodified lignin, aldehyde-functionalized lignin, and hydroxylpropyl-functionalized lignin exhibit random aggregate, spherical granule, and supramolecular domains, respectively. The difference in the aqueous alkali aggregation structure made the filler dispersibility in the rubber matrix in the increasing order of unmodified < aldehyde < hydroxylpropyl.142 ENR compatibilizer added in these composites managed to improve the dispersibility of these fillers. Specifically, hydroxylpropyl lignin-filled SBR with ENR compatibilizer had improved mechanical properties compared to the non-compatibilized counterparts, at the same time having a better wet skid resistance and low rolling loss than other samples. The result reflects the potential of hydroxylpropyl lignin filler for the development of green tires.Lignin-based fillers are often used with other chemicals such as hybrid fillers or compatibilizers. Cationic lignin obtained through the reaction of lignin fibrils with glycidyltrimethylammonium chloride, when in use in binary filler systems with MMT formed a lamina of MMT with cationic lignin anchor on two sides of the nanosheet.4.2143 Epoxidized palm oil (EPO) could act as a softener and plasticizer to increase the free volume, reduce the density, and subsequently improve rubber chain mobility.144,145 Mechanical properties of SBR incorporated with EPO improved when the EPO content was below 35 phr. Below this concentration, the mechanical strength and elasticity of the composite increased with increasing EPO content.146 The addition of EPO processing oil reduced the viscosity of the compounded latex, and the crosslink density, as well as mechanical strength of the resultant composite films, was enhanced.Aromatic oils derived from petroleum are often used in rubber processing to increase the processability of the rubber compounds through the action of plasticizing, reducing the viscosity, improving the processability, and enabling better filler incorporation without significantly affecting the final properties of rubber formed. The use of plant oils as rubber processing aids is getting attention because petroleum processing oils are generally toxic and carcinogenic.147 When the GTR/soybean oil mixture is used in the sulphur-cured system, the mixture functions as a reactive plasticizer by facilitating the recombination of broken rubber chains and providing double bonds for sulphur crosslink. Besides, the core–shell structure of carbon black bound by rubber from reclaimed rubber also helps in the reinforcement of mechanical strength. 20 phr substitution of SBR with the reactive plasticizer improved TS by 30% and could provide a new approach to utilizing waste materials, creating added value products. Hydrolysis of soybean oil in alkaline conditions resulted in soybean fatty acid that has a similar plasticizing effect in NBR composite.148 The flowability of the latex improved with reduced Mooney viscosity and resulted in a longer cure time. Incorporation of 4 phr of soybean oil fatty acid resulted in maximum crosslink density (maximum TS with good EB) and higher thermal stability, with the TS of the NBR composite reported to be higher than that incorporated with petroleum oil derivative, dioctyl phthalate (DOP).Soybean oil also can be used in plasticizing ground tyre rubber (GTR) to produce highly reclaimed rubber which can then be reused as a rubber matrix substitute.149 The cure characteristics of the rubber composite improved with the increase in the oil concentration while TS remain unaffected. The fact that these oils are inedible makes them even more attractive as potential replacements to the fossil-based aromatic processing oil. Cardanol is a class of lipid consisting of a phenol group with usually a long alkyl side chain and is the main constituent in cashew nut shell liquid. XNBR grafted with cardanol had been reported recently by Samantarai et al. in 2019.150 The latex had lower Mooney viscosity, and a higher plasticity retention index (PRI), indicating the plasticizing ability of cardanol. Grafting of cardanol through the oligomerized phosphorylated cardanol in NBR reported similar behaviour in the latex, replacing the need for DOP aromatic processing oil.151 Both composites that incorporated cardanol-based plasticizer exhibit low Tg, high thermal stability, and are biocompatible.Castor oil consisting of mainly ricinoleic acid and jatropha oil with high unsaturated fatty acid content has been reported as substitute processing aid oils in SBR composite.4.3152–157 The process of cellulose isolation usually requires a vast amount of chemicals and produces many wastes, and this could be deemed as an obstacle in achieving the sustainability goal. Recent reports of other naturally sourced materials that were obtained without extraction or isolation are tabulated in Recently there are more reports on the use of materials from biological sources that were obtained without extraction or isolation process. This greatly simplifies the material preparation process, making it easier and more practicable to be developed into industrial large-scale manufacturing and involves the usage of lesser chemicals. For example, in recent years, the use of cellulosic materials obtained directly from sources without extraction is gaining attention to evaluate the necessity of pure cellulose extraction.153,158,170 Coconut shell powder is an efficient replacement for the fast extrusion furnace (FEF) filler in NBR, resulting in higher TS. It also contributed to increased water uptake capabilities in NBR/SBR blend, a property which is desirable in improving the biodegradability.154 Coir fibre acts as a nucleating agent for crystallization of polypropylene (PP) in EPDM-g-methyl methacrylate/PP blend, and as physical entanglement compatibilizer between EPDM and PP for high mechanical strength and toughness. Flax fibre has good dispersion in EPDM through melt blending and the resultant material has good thermal stability, comparable to that produced with the petroleum counterpart. Silane modification is commonly performed on fillers to enhance the mechanical properties reinforcement of the filled material, and such modification enabled a wider range of renewable raw materials to be used as filler. Peanut shell powder, waste walnut shell and wood fibre fillers with silane modification resulted in better cure characteristics in SBR, comparable mechanical and thermal properties with largely reduced filler content in EPDM composite, and enhanced stiffness in EPDM, respectively.161,164,165The cost-effectiveness of naturally sourced materials will be more established if the acceptable levels of reinforcement in rubber properties could be achieved with minimal treatment of raw materials. Some of the reported examples include coconut shell powder, coir fibre and flax fibres.5.0Hevea brasiliensis supplying the market predominantly, and the bulk of the rubber plantations are constricted in the Southeast Asia region. A disease wipe could easily cause a serious shortage of natural rubber supply, rendering the search for alternatives necessary. Fortunately, with the help of large rubber manufacturing companies, the commercialization of natural rubber alternatives such as those from Guayule and Russian dandelion has been realized. Although the volume of such rubber is significantly smaller, it is increasing steadily at a slow pace and could possibly serve as a backup supply in times of emergency. Natural rubber had been an excellent rubber material, but some applications require elastomeric materials with durability, chemical resistance, and/or thermal stability that exceed natural rubber. This puts the demand for synthetic rubber high and increases the rate of depletion of fossil fuel sources. Without any corrective action, the current reservoir is expected to be completely depleted in less than a century.Currently, the supply chain of natural rubber is at risk with sole rubber tree species Fortunately, the synthetic rubber and plastic industries have started to replace some of the conventional raw materials in the product development with those derived from natural or biological sources. Although the percentage of this initiative is rather insignificant compared to the enormous production volume of fossil fuels-based counterparts, it had increased steadily over the past 10 years in the hope of at least delaying fossil fuel depletion. The rapid development in fermentation technology has resulted in new varieties of biologically derived raw materials with good cost-effectiveness and high production volume. The biologically derived raw materials are mostly used as fillers in synthetic rubber formulations. While modifications of fillers are inevitable because of the difference in surface chemistry with the rubber matrix that could result in poor compatibility and weak reinforcement, research should be carried out to simplify the process and minimize chemicals used and waste produced.Another major problem is the non-biodegradability of synthetic rubber products which has led to environmental pollution and an increase in landfill areas. In some of the reported works, the biodegradability of synthetic rubbers were enhanced by incorporating biodegradable raw materials in the formulation, usually those which are renewable in nature. Some promising results were reported, with weight loss achieving as high as 90% and tensile strength loss up to 70% throughout the biodegradation process. It is however noteworthy that similar effect of enhanced biodegradation cannot be expected in every synthetic rubber simply by incorporating bio-based ingredients in the formulations. Factors such as modifications of these ingredients or reactions while in the rubber matrix could alter the chemical structure or reactivity, and subsequently limits the biodegradability. It is reasonable to expect that the consumption or digestibility of the material by microbes depends on the newly formed chemical structure, and not the original ones as they were extracted. Biodegradation tests are often not carried out in synthetic rubber research presumably because there is a lack of standard methods to effectively evaluate the biodegradation of rubber materials. This is evident when some recorded TS loss to quantitate the extent of biodegradation, while some reported weight loss. Furthermore, these tests were conducted under different conditions and environments, making it difficult to make any direct comparison. As sustainability is an important topic in synthetic rubber research and industry, it is necessary to come up with biodegradation test methods specifically for rubber so that the effect of those bio-based materials in synthetic rubber can be evaluated more accurately.The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.Zhen Hern Boon: conceptualization, writing-original draft preparation, data curation. Yin Yin Teo: supervision, writing-reviewing and editing. Desmond Teck-Chye Ang: conceptualization, supervision, funding acquisition, writing-reviewing and editing.There are no conflicts to declare.


Objective: Our aim was to present a rare case of a middle-aged male patient, diagnosed with Graves’ orbitopathy, which had an atypical rapid unilateral onset. Initially, the left eye presented exophthalmos, eyelid retraction, corneal ulceration, and pannus formation with an important vascular component due to corneal exposure. The same symptoms developed in the right eye within a short period of time.Methods: A 52-year-old man presented in our department with bilateral proptosis, decrease in visual acuity, and orbital pain, which developed initially in the left eye seven months before the right eye. Slit lamp examination revealed conjunctival hyperemia, purulent discharge, chemosis and inflammation of the caruncle in both eyes. The fluorescein eye stain test was positive due to corneal ulceration with the presence of cells and flare in anterior chamber in the RE (right eye). The LE (left eye) presented a corneal pannus. We documented the changes using a slit lamp biomicroscope, a fundus camera, orbital ultrasonography, and contrast CT (computer tomography) scans. Discussions: The severe Graves’ ophthalmopathy represents a challenge both in active or inactive phase. Medical and surgical therapies should be taken into consideration in order to prevent the complications following corneal perforation or optic neuropathy. Also, ophthalmic, and systemic adverse reactions of systemic steroids used in the treatment of Graves’ disease are important in the prognosis of the visual outcome.Conclusions: The management of Graves’ ophthalmopathy is multidisciplinary and needs a very good therapy adherence in order to achieve a satisfactory prognosis and quality of life. The target cells of the immune process are represented by the pluripotential orbital fibrocytes, which are both found in orbital fat tissue and striated muscle. TRAB (thyrotropin-receptor antibodies), also known as TSH-R (thyroid stimulating hormone receptor) are secreted by an aberrant population of lymphocytes in Graves’ disease. The circulating TRAB binds to CD40+ receptors expressed by the orbital fibrocytes and induces the upregulation of inflammatory cytokines such as IL-6, IL-8, and PGE E2, which increases the production of hyaluronan and glycosaminoglycan. The expansion of orbital fat is caused by a subpopulation of fibrocytes, which differentiates into adipocytes. The clinical features depend on the orbital tissue involved [2]. The most common symptoms and signs of TAO are upper eyelid retraction (75%), lid lag with downgaze (50%), and dull orbital pain (35%). Most TAO patients develop a pattern that involves fat expansion, has a slow progression, and occurs predominantly in young females. This pattern is represented by eyelid retraction, proptosis, and ocular exposure [1]. The muscle centric pattern affects older people, has an increased severity and it is highly associated with smoking and family history of TAO. The enlargement of the extraocular muscles determines restricted ocular ductions, diplopia, edema and congestion of eyelids and conjunctiva and dysthyroid optic neuropathy [1].It is known as the most common orbital disease globally, which has a peak of incidence between fourth and sixth decade. The risk factors for developing TAO are represented by female gender, smokers, family history, life stressors and poorly controlled hypothyroidism following radioactive iodine, whereas male gender, increasing age and a rapid onset of orbitopathy are the predictors of severe thyroid eye disease .The patient was hospitalized for two weeks. A protocol with intravenous methylprednisolone 500 mg weekly for 6 weeks, reduced to 250 mg weekly for 6 weeks was initiated. Topical broad-spectrum antibiotics were instilled in both eyes. Preservative-free lubricants were used in order to relief the symptoms of corneal exposure and a mydriatic was administered 3 times per day in the right eye in order to avoid the formation of posterior synechiae. The IOP of the LE was lowered by using a topical combination of timolol and dorzolamide. Doxycycline was also administered due to its efficiency in the treatment of inflammatory ocular conditions by inhibiting the synthesis and the release of corneal MMPs [4].Patching of both eyes during night was also performed. Thyrozol and propranolol were prescribed to optimize the thyroid function. The patient was also instructed to cease smoking. A target in the management of Graves’ ophthalmopathy is to reduce the modifiable risk factors such as smoking. The patient received effective support in order to cease smoking. A clinical study revealed that cigarette smoking may corelate with increase in retrobulbar venous congestion in thyroid associated ophthalmopathy [5] and an ophthalmologic assessment was recommended by the endocrinologist. At the first month follow-up, the patient showed a suboptimal response to high dose intravenous methylprednisolone. We observed an increase of the CAS score suggested by the exophthalmos, which was similar to the previous examination, a decrease of best corrected visual acuity in RE and perception of hand movements in the LE, while the corneal ulceration showed a slight amelioration . The thyroid function test showed euthyroidism. The liver and renal function were assessed and both were normal. The endocrinologist decided to continue the corticosteroid therapy in order to cease the inflammation. The radiotherapy or decompression surgery were not suitable in this case.A regular follow-up of the thyroid function at four weeks depending on the severity of the disease .Moreover, topical steroids are prescribed in order to manage the symptoms of ocular inflammation consisting of dryness and hyperemia. Likewise, the ocular surface lubricating therapies are an important tool in the treatment of the exposure keratopathy [11]. DES is common even in the early phases of Graves’ ophthalmopathy without exophthalmos. In Graves’ orbitopathy, DES is mainly evaporative due to corneal exposure and it can also be associated with CAS and reduced corneal sensitivity [12]. The alterations of the lacrimal film of these patients are caused by the impairment of the extraocular muscles and the immune-mediated dysfunction of the lacrimal glands [13].The corneal involvement could be related to inflammatory processes including the systemic disease itself and the dry eye syndrome (DES) [7].The severe exposure keratopathy represents an urgence, thus decompression surgery could be indicated. In the active phase, local treatment such as tarsorrhaphies, corneal patches, or gluing can be used in order to avoid corneal perforation or to treat the corneal breakdown, while in the inactive phase, decompression, ophthalmic plastic, and strabismus surgery can be an important tool for the repair of residual damage  [In conclusion, severe forms of Graves’ ophthalmopathy are sight-threatening and need a multidisciplinary approach of the management of the disease and its complications. Also, the therapy adherence and modifiable risk factors, such as smoking, play a major role for the outcome of the Graves’ ophthalmopathy.Conflict of Interest StatementThe authors state no conflict of interest. Informed Consent and Human and Animal Rights statementInformed consent has been obtained from the patient included in the study.Authorization for the use of human subjectsEthical approval: The research related to human use complies with all the relevant national regulations, institutional policies, it is in accordance with the tenets of the Helsinki Declaration and has been approved by the review board of Department of Ophthalmology, “Carol Davila” Central Military University Hospital, Bucharest, Romania.AcknowledgementsNone. Sources of FundingNone. DisclosuresNone. ContributionBoth authors contributed equally to this article.


Giant vesicles (GVs) are closed bilayer membranes that primarily comprise amphiphiles with diameters of more than 1 μm. Compared with regular vesicles , GVs are of greater scientific interest as model cell membranes and protocells because of their structure and size, which are similar to those of biological systems. Biopolymers and nano-/microparticles can be encapsulated in GVs at high concentrations, and their application as artificial cell bodies has piqued interest. It is essential to develop methods for investigating and manipulating the properties of GVs toward engineering applications. In this review, we discuss current improvements in microscopy, micromanipulation, and microfabrication technologies for progress in GV identification and engineering tools. Combined with the advancement of GV preparation technologies, these technological advancements can aid the development of artificial cell systems such as alternative tissues and GV-based chemical signal processing systems. Chemical sciences that mimic biological processes aim to improve our understanding of the exceptional molecular recognition and efficient molecular conversion capabilities of proteins, in addition to the mechanism of information conversion achieved by DNA and RNA. Supramolecular and systems chemistry  has led Giant vesicles (GVs) have drawn attention as one of the cell-sized molecular self-assemblies . GV is aWhen vesicles are composed of phospholipids, which are the primary components of the cell membrane, they are labeled liposomes . VesicleTo increase the level of GV functions aimed at the hierarchy of cellular functions, it is important to increase the structural hierarchy of GVs. The assembly of GVs has attracted attention as a basis for highly functionalized supramolecular chemical systems. In assembling technology for GVs, it is indispensable to determine the kind of GV to be assembled and identify each of the GVs. Therefore, in this review, we introduce the recent identification and characterization methods of GV and the progress of the manipulation methods developed by microfabrication technology. In addition, we discuss the process of constructing GV-based cell mimicry devices with higher-order functions.GVs have diameters of 1 μm or greater and can be observed in situ without staining or fixing under an optical microscope due to the difference between the refractive index of the membrane and that of water. Conventional research on GVs has aimed to clarify the mechanism of cell shape using GVs as cell models, and thus, microscopic observation has been an important identification method for GV morphology . For exaAlthough detailed optical microscopy observation of individual GVs is effective for scrutinizing the GV structural morphology, it is difficult to statistically and quantitatively evaluate the morphologies of large amounts of GV. Flow cytometry has been used to measure the GV population. While Vorauer-Uhl et al. first reported the flow cytometric evaluation of the size distribution of nanometer-sized fluorescence-labeled vesicles , Yomo’s Lamellarity of GV is defined as the number of bilayer membranes contained in individual GVs. The film swelling method, which is a standard preparation method for GVs, usually affords a mixture of GUVs (with a lamellarity of 1) and GMVs . The recent development of GV preparation methods, including the water-oil-emulsion templating method, enables GUV production and the encapsulation of water-soluble molecules and particles into GUVs . A membrA quantitative attempt to evaluate GV lamellarity was recently performed by Ishiwata’s group . The groThe membrane bending rigidity or membrane modulus of GV is one of the most important characteristic parameters that have been measured historically in many studies from the biophysical viewpoint of cell membranes. Many measurement studies have been conducted to observe vesicular membrane deformation caused by the suction of a glass capillary (micropipette) under a microscope . The micIn addition, visualization of membrane bending rigidity using fluorescent dyes for GV membranes has been developed . A speciAs explained previously, the membranes of GVs are semipermeable, that is, water-soluble molecules with large molecular weights and ions scarcely permeate the membrane, while water molecules can permeate. Membrane permeability is another important physical parameter for measuring GVs through cell membranes. A single GUV observation for membrane permeation of encapsulated water-soluble fluorescence dyes under a microscope is repeatedly and quantitatively performed to determine the reliability of the permeation rate. Yamazaki’s group applied this method to clarify the mechanism of bioactive substances, such as magainin 2, which interacts with cell membranes to enhance membrane permeation upon chemical stimulus of such substances . The appThe ion current of the GV membrane has drawn attention in the construction of model nerve cells based on GVs. The physiological measurement of ion currents in the nerve cell membrane, called the patch-clamp technique, also enables us to measure those in the GV membrane. Hamada et al. and Fukuda et al. independently applied the whole-cell patch-clamp technique to measure the ion currents of GV membranes inserted with membrane proteins ,48. VelaOther properties of vesicles, such as the zeta potential and heat of transition of the vesicular membrane, are significant physical properties in terms of not only the model cell membrane, but also the drug delivery carrier. These properties have been measured for nanometer-sized vesicles because such vesicles, called small or large vesicles (<1000 nm), can be uniform through ultrasonication and filtration ,51. HoweThe more detailed the observation of each GV under a high-resolution optical microscope, the longer the observation time. This sometimes causes difficulties in capturing 3D images of individual GVs owing to Brownian motion or membrane fluctuation. The current technical problem has been solved through the development of high-speed scanning confocal laser fluorescence microscopy  and lighw/v. Lira et al. observed that the lateral displacement of GUVs in agarose gels was completely suppressed [A commonly used method is to modify GVs with biotin-tagged phospholipids. This results in GVs that are heavier than their surroundings, which settle onto a substrate coated with avidin. For example, encapsulation of sucrose inside GVs and addition of same osmolarity glucose on the outside . In contppressed .The preparative technology for GVs has advanced not only in controlling lamellarity but also in fabricating uniform sizes ,62,63. IIn addition, size sorting techniques for GVs using microfluidic devices have recently been proposed following cell sorting microfluidic technology . KazayamThe trapping and morphological change induction of GVs by hydrodynamic fields have become popular in microfluidic device development as well as the GV preparation method. As already mentioned, GVs are likely to be captured by simply pouring the GV dispersion into a microfluidic device equipped with cup-shaped microstructures with a narrow gap. Ditrrich’s group developed a device that created a curtain of air bubbles around each GV-trapping microstructure to protect the trapped GV from the surrounding flow field . Yamada The advantage of using microfluidic devices is that, owing to the development of materials and hydrodynamic methodologies for microfluidic devices, it is possible to freely design shapes and pour GV dispersions for observation and manipulation. For instance, by devising the shape of the trapping structure, Schwille’s group held to trap the prolate-shaped GVs and found a novel pattern formation of the encapsulated protein, FtsZ, that self-assembles in response to the GV shape . Dekker’As mentioned above, measurement of the membrane bending rigidity of GVs is conventionally performed using a glass capillary as a micropipette. Micropipette aspiration can hold them and allow morphological changes in GVs. When the tip of the micropipette is sufficiently narrower than the GV and the suction pressure is sufficiently strong, the GV membrane stretches to form a tubular structure . FurtherOrwar’s group extended the micropipette technique to morphological changes in GVs . The groLaser technology has advanced research in the scientific and engineering fields, and the optical tweezers (or laser trapping) have had a great impact on GV manipulation. In the initial research on optical tweezers on GVs, the transformation of GVs was observed due to the light radiation pressure of a laser applying a GV membrane, which has a higher refractive index than water ,86. GVs GV manipulation is also realized using sound pressure. The advantage of sound waves is irradiation variation, that is, squeezing sound pressure in a relatively small area or creating a periodic pattern of sound pressure in a limited space. In the former case, pore formation in the GV membrane occurs . In the The electric and magnetic fields directly affect the properties of the lipid molecules, so that GV manipulation, including shape change of GVs, is easily performed c. The el2O2 inducing cell death in the vicinity of the assembly (GUV colony) under glucose exposure [GVs respond to a magnetic field that is a result of diamagnetic susceptibility of the lipid bilayer membrane. Historically, Helfrich’s first report on GV morphology suggested the perturbation of GV shapes by a magnetic field . Recentlexposure .3D printing technology has sparked a revolution in the micro-construction of molds for fundamental material research and industrial applications . One of In this paper, we review recent developments in GV identification and manipulation methods and summarize the advantages of basic techniques for assembling GVs as building blocks. Several approaches overlap with cell manipulation techniques. However, GVs have no cytoskeleton or cell wall and therefore require careful handling of their physical properties. Imminent enhanced development of artificial cell construction is expected due to these methods, leading to the construction of elaborate artificial tissues and information processing systems composed of GVs ,117,118.


This paper is motivated by Bitcoin’s rapid ascension into mainstream finance and recent evidence of a strong relationship between Bitcoin and US stock markets. It is also motivated by a lack of empirical studies on whether Bitcoin prices contain useful information for the volatility of US stock returns, particularly at the sectoral level of data. We specifically assess Bitcoin prices’ ability to predict the volatility of US composite and sectoral stock indices using both in-sample and out-of-sample analyses over multiple forecast horizons, based on daily data from November 22, 2017, to December, 30, 2021. The findings show that Bitcoin prices have significant predictive power for US stock volatility, with an inverse relationship between Bitcoin prices and stock sector volatility. Regardless of the stock sectors or number of forecast horizons, the model that includes Bitcoin prices consistently outperforms the benchmark historical average model. These findings are independent of the volatility measure used. Using Bitcoin prices as a predictor yields higher economic gains. These findings emphasize the importance and utility of tracking Bitcoin prices when forecasting the volatility of US stock sectors, which is important for practitioners and policymakers. Previous studies tend to consider the relationship between Bitcoin prices and the aggregate US stock market index  , and ecoWe can formally determine the statistical significance of the observed difference between the forecast errors of the contending models using the CW test, which compares the predictive accuracy of two competing models. The CW framework is as follows:The data set includes daily Bitcoin prices and 20-day annualized realized volatility of the US S&P 500 composite index returns and its 11 sector stock returns . The motivation for using stock sector indices in addition to the aggregate composite index stems from the diverse reaction of US stock sectors to exogenous variables and risk factors , which is computed as Table Two robustness analyses are performed. In the first step, we re-estimate the US sectoral stock realized volatility–Bitcoin nexus using a model-based volatility measure derived from the GARCH model’s conditional variance. In the second, we use an 80:20 data split instead of the 75:25 data split used in the main analysis. We report the in-sample predictability and the forecast performances using the relative RMSE and the CW  statistiTables This study examines the relationship between realized volatility of US stock returns across sectors and Bitcoin prices. Using the WN-Type predictive model, this is an attempt to determine the predictive potential of Bitcoin prices for the realized volatility of US stock returns while controlling for potential biases arising from model mis-specification and/or variable omission. The analyses are carried out for both in-sample and out-of-sample periods and multiple forecast horizons. The relative RMSE and the pairwise CW  test staOur results are summarized below. First, Bitcoin prices have an inverse relationship with the realized volatility of US stocks. This indicates that falling Bitcoin prices may increase volatility in the US sector stock market due to improved trading in the latter. Second, in terms of out-of-sample forecast performance, the analysis shows that our predictive model that accounts for Bitcoin prices and other observed salient data features consistently outperforms the benchmark historical average model that does not consider these data. This conclusion holds true across multiple sectors of the US stock market and forecast horizons. Third, in terms of economic significance, incorporating Bitcoin prices as a predictor yields higher economic gains in a larger proportion of US sector stocks under alternative leverage ratio assumptions. Based on the foregoing, we can conclude that using Bitcoin prices to forecast the realized volatility of US stocks will not only improve forecasts but will also result in higher economic gains. Accordingly, investors and portfolio managers seeking to maximize returns in the US stock market should pay attention to the price dynamics in the Bitcoin market, as they have the potential to significantly influence the volatility formation of US stocks. This assists market participants in fine-tuning their forecasting models, which has implications for risk management, financial derivatives, and market efficiency. Similarly, practitioners and academics who are constantly involved in financial market analyses may find our proposed model and the various conclusions interesting, especially in terms of producing more accurate forecasts when analyzing the riskiness of the US stock market. This is important given the recent view and evidences that cryptocurrencies in general and Bitcoin in particular are becoming mainstream and thus closer to the global financial system, including the US stock market. Accordingly, these digital assets should be monitored carefully by central banks and regulatory bodies as they can pose risk to the financial system and thus to financial stability, which also requires a tighter regulation of cryptocurrencies in the same way as stock markets, without ignoring some of their particular features.Future research should consider whether the above findings can be generalized to other stock markets in Europe and Asia. In addition, it could be interesting to assess the response of emerging markets to the dynamics of the Bitcoin market, while also investigating whether markets’ responses are symmetrical or asymmetrical, given the bullish and bearish nature of financial markets.


Viral infection of peripheral and central nervous systems  is usually accompanied by disease associated with high morbidity and mortality. Neurological disease upon viral infection is the consequence of both direct viral cytopathic effect and the response of the innate and adaptive immune responses. In some instances, even peripheral infection with viruses that do not enter the CNS or PNS results in high expression of cytokines and neuropeptides that cause neuroinflammation, impacting the function of the nervous system, as it has been observed during COVID-19 . Interestingly, as discussed by Adonis and colleagues in this Special Issue, other zoonotic virus like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause posttraumatic stress disorder (PTSD).Some neurotropic human viruses, like herpes simplex virus (HSV), establish latent infections in peripheral ganglia. However, several reports suggest a role for this virus in cognitive disorders, including Alzheimer's disease (AD), as discussed by Horn and MacLean. Other viruses, like human alphaherpesviruses, travel inside neurons using cellular motor proteins. In the case of the highly virulent rabies virus (RABV), the most accepted view is that it employs synaptic connections to spread between neurons. Whether this is true or not may require further experimental evidence, as discussed in the review by Beier.The mechanisms that lead to neuroinfection are not well understood for many viruses. Colonization of the PNS and CNS occurs through different routes, including hematogenous transmission and transport within neurons. The role of extracellular vesicles (EV) in viral transmission to the CNS through the blood brain barrier (BBB) and its pathogenic consequences is becoming evident, as discussed in a review by In this “Special Issue”, we assembled five reviews and one original research article that deal with the highly relevant topics mentioned above.Beier explores the immune evasion mechanisms underlying the RABV infiltration of the CNS and highlights gaps in the most accepted model of RABV spreading, which exclusively considers viral transmission among neurons through synapses. After analysis of evidence supporting or rejecting this synaptically-restricted viral transmission, the initial infection of astrocytes by RABV emerges as an interesting hypothesis to explain the basal interferon-based response detected during infection.In their mini review, Miranda D. Horn and Andrew G. MacLean summarize the role of EV in viral infection of the CNS, a very interesting, but rather unexplored field. They report on the function of EV during homeostasis and disease, focusing on the misuse of EV by viruses to modulate the immune response, increase virus spread and tropism, facilitating crossing of the BBB, infection of resident CNS cells and modulation of their activity, inducing neuroinflammation and neurodegeneration. More research on this topic is clearly needed to provide novel therapeutic strategies to treat neurological disease caused by viruses.RM) rapidly respond to repeated viral antigen exposure driving to neuroinflammation. They now report that this prolonged antigen re-challenge of bTRM drives to dysregulation of the surrounding microglia, which could have important neurotoxic effects. This study identifies a cellular mechanism that might contribute to neuropathogenesis after reinfection or viral reactivation.Some studies have linked re-challenge of neurotropic viruses with neurodegeneration. Prasad et al.  previousYong et al. review the current knowledge about the potential involvement of HSV-1 in AD, paying special attention to the neuroanatomical point of view. In this regard, the authors explore the special vulnerability of the hippocampus to HSV-1 infections, as the hippocampus is a key area involved in learning and memory, and one of the main areas affected in AD.Sfera et al. thoroughly review the current literature on PTSD, its association with SARS-CoV-2 and discuss the potential mechanisms leading to this neurological disorder in this infection setting. These include the role of BBB leakage, brain derived neurotrophic factor and the fibrinolytic system.A substantial percentage of survivors of Ebola virus and human immunodeficiency virus infections develop PTSD. This is also observed in about one third of individuals that recover from coronavirus-induced disease 2019 caused by SARS-CoV-2. King and Irigoyen debate about the different ZIKV strains and their involvement in the Congenital Zika Syndrome (CZS). Their discussion is focused on the molecular mechanisms underlying CZS and on the potential capacity of ZIKV lineages to employ these mechanisms.In conclusion, this Special Issue highlights the state-of-the-art and recent advances in viral infection of the nervous system and its pathological consequences. The complexity of this interdisciplinary topic requires the cooperation of virologists, immunologists, and neurologists. Only through this cooperation we will be able to face the challenges ahead in an aging society exposed to old and novel viruses that cause neurological disease.All authors listed have equally contributed to this work and approved it for publication.The laboratory of AV-B was funded by the Deutsche Forschungsgemeinschaft  under Germany's Excellence Strategy – EXC 2155 RESIST – Project ID 39087428. BH lab is funded by the Spanish Ministry of Science and Innovation, and European Union  grant RTI2018-097581-B-I00.JC declares he holds a Project Management position at Labcorp Drug Development. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.