On a worldwide scale, food demand is increasing as a consequence of global population growth. This makes companies push their food supply chains’ limits with a consequent increase in generation of large amounts of untreated waste that are considered of no value to them. Biorefinery technologies offer a suitable alternative for obtaining high-value products by using unconventional raw materials, such as agro-industrial waste. Currently, most biorefineries aim to take advantage of specific residues  provided by agro-industry in order to develop high-value products for either in-house use or for sale purposes. This article reviews the currently explored possibilities to apply biorefinery-known processes to banana agro-industrial waste in order to generate high-value products out of this residual biomass source. Firstly, the Central and Latin American context regarding biomass and banana residues is presented, followed by advantages of using banana residues as raw materials for the production of distinct biofuels, nanocellulose fibers, different bioplastics, and other high-value products Lastly, additional uses of banana biomass residues are presented, including energy generation and water treatment. The rising development of industries all over the world has brought a consequential increase in their residue generation, especially in the field of agro-industry. This waste can be denominated as “food supply chain waste” (FSCW) and can be defined as “organic material produced for human consumption lost or degraded primarily at the manufacturing and retail stages” . This coAgro-industries have slowly come to realize that valorization of biomass residues  is not only beneficial from an environmental perspective, but can also help to minimize economic losses or even raise the net value of companies.Inadequate treatment of these biomass residues has a negative impact on the environment, mainly generating greenhouse gases, contaminating water sources, and causing ecological problems ,4. BioreWaste valorization converts polymeric substrates into useful products such as chemicals, materials, and fuels, often by extraction, chemical conversion, or degradation. Historically, the utilization of complex biomasses led the way in pulp and paper production, or biotechnological production of furfural, ethanol, or short chain organic acids since the 19th century . HoweverOut of the many published definitions for the term “biorefinery”, perhaps the one from the American National Renewable Energy Laboratory (NREL) seems to fit best the approach of this review: “A biorefinery is a facility that integrates biomass conversion processes and equipment to produce fuels, power, and chemicals from biomass” . DefinitIn addition to lignocellulosic biomass-based industries, more sectors have shown interest in applying biorefinery approaches to organic waste, for instance: food waste , nonedib2 and CH4 . No. No32]. Even though further technological improvements are still required, bioethanol yield from banana waste presents a promising alternative for the production of this biofuel. Further research on improved enzymatic cocktail formulations, more robust microorganism strains, as well as optimization of industrial conditions, such as reaction time, water content, and ethanol separation technologies , are stiBanana fiber has traditionally found a place in a number of manufactured products such as paper, ropes, table mats, and handbags . Though LCMNFs from banana leaf residue have been used to restore mechanical properties of recycled fluting paper. A study found that incorporation of only 1.5 wt% of LCMNF can restore the original properties of fluting paper, with a low impact in pulp drainability, while increasing the life span of the resulting recycled products .Banana residues are a great source of cellulosic materials see ; celluloNCFs exhibit many attractive physicochemical properties such as a high bending strength (~10 GPa), a Young’s modulus of approximately 150 GPa, a high aspect ratio, and a high specific surface area. Therefore, NCFs have been used as reinforcements for polymer matrixes , and as Acid hydrolysis of cellulose is the most common process for obtaining NCFs , as fracBacillus sp. able to yield up to 27 w/w % of PHB content after the fermentation of hydrolyzed banana peel residues [Burkholderia sacchari IPT101 [Poly-hydroxybutyrates (PHBs) are value-added biocompatible, biodegradable, thermoplastic biopolymers that can be synthesized by microorganisms from diverse carbon sources. Polysaccharides in banana peel can be either chemically or microbiologically transformed into PHBs , these bresidues . PHB proi IPT101 .l-lactic acid) (PLA) is a biodegradable and renewable polyester with many industrial and biomedical applications, including drug delivery systems, bioabsorbable fixation devices, bone regeneration, and tissue engineering scaffolds [Lactobacillus casei (subspecies rhamnosus), and further microwave-assisted polymerization, as reported by Jiménez-Bonilla and collaborators [Poly-, and exo-1,4-β-D-glucanase using banana wastes as solid substrate fermentation. Both microorganisms originated comparable levels of enzyme activities and patterns of production. Banana stalk residues have been valorized in the bio assisted production of enzymes like laccase, different oxidases, and endoglucanases too . For insLeaf biomass was found to be an appropriate substrate (compared to pseudostems) for enzyme production . Banana There seems to be a worldwide agreement on shifting towards green energy production and lessening the current dependence on fossil fuels. Agro-industrial biomass sources are a natural choice when it comes to exploring environmentally friendly ways to produce energy, and banana wastes are no exception to this. Banana residues have made it into the energy production sector only in recent times and their potential as energetic biomass is becoming evident; for instance, energy generation from dry banana peel can yield up to 18.89 MJ/kg . The reaCurrently, there are two approaches for the conversion of banana biomass into energy: thermal and biological conversion . The forTheoretical estimates for potential power generation based on both banana waste and banana peels in Malaysia (by Tock and coworkers for the period 2003–2008) suggest that banana biomass is a suitable renewable energy source in this one and other similar tropical nations. This study calculated potential power assuming that 1 PJ can be converted into 46 MW of electrical energy with 21% electrical conversion efficiency. This study estimates that using whole banana residues might generate some 80–95 MW yearly, while banana peels only would generate 12–25 MW per year (15% and 25% of energy production using the whole residue) as detailed in Banana peel has been reported to be used as a bio adsorbent for the removal of contaminants such as heavy metals, dyes, and organic pollutants from wastewaters . A studyBanana plants exhibit high growth rates and carbon neutrality; therefore, their agro-industrial residues are a promising alternative to be used as feedstock for biorefinery technologies, though challenges regarding composition variations in the wastes must be addressed, i.e., geographic location, plant variety, ripening stage, among others that difficult standardization for biorefinery processing . Current technologies require further developments in order to extract as much value as possible from banana waste, for instance, by achieving positive energy balances by full integration of different biorefinery processes. Efforts involving the production of bioethanol and biogas are currently moving in this direction ,24. Alth


Key pathological features of cerebral small vessel disease (cSVD) include impairment of the blood brain barrier (BBB) and the progression of white matter lesions (WMLs) amongst other structural lesions, leading to the clinical manifestations of cSVD. The function of endothelial cells (ECs) is of major importance to maintain a proper BBB. ECs interact with several cell types to provide structural and functional support to the brain. Oligodendrocytes (OLs) myelinate axons in the central nervous system and are crucial in sustaining the integrity of white matter. The interplay between ECs and OLs and their precursor cells (OPCs) has received limited attention yet seems of relevance for the study of BBB dysfunction and white matter injury in cSVD. Emerging evidence shows a crosstalk between ECs and OPCs/OLs, mediated by signaling through the Wingless and Int-1 (WNT)/β-catenin pathway. As the latter is involved in EC function  and oligodendrogenesis, we reviewed the role of WNT/β-catenin signaling for both cell types and performed a systematic search to identify studies describing a WNT-mediated interplay between ECs and OPCs/OLs. Dysregulation of this interaction may limit remyelination of WMLs and render the BBB leaky, thereby initiating a vicious neuroinflammatory cycle. A better understanding of the role of this signaling pathway in EC–OL crosstalk is essential in understanding cSVD development. Cerebral small vessel disease (cSVD) is an umbrella term used to describe different pathological processes that affect the small vessels of the brain, including small arteries, arterioles, capillaries, and small veins, and is associated with brain structural lesions and eventual cognitive impairment . With cSBBB dysfunction has been evidenced in experimental animal models of cSVD as well as in cSVD patients ,7,8. EndAlthough both ECs and OLs (and their precursor cells) are involved in BBB integrity, studies examining these cells and their interaction in the context of cSVD are limited. This review aimed to summarize the published findings on the crosstalk between ECs and OPCs/OLs, and in particular the role played by WNT/β-catenin signaling in this interaction. First, we briefly address the respective roles of WNTs in ECs and OPCs/OLs. Second, we discuss the current knowledge on EC–OL interaction. Third, we present studies found via a systematic search that have identified a role for WNT signaling in this crosstalk. Finally, we discuss the potential implications of these findings for cSVD pathology before we formulate a conclusion.cSVD is a heterogeneous disease that includes genetic and sporadic forms. Sporadic cSVD, the most prevalent form of cSVD, can be further subdivided into amyloidal and non-amyloidal subtypes ,10,16. STaken together, our current knowledge on cSVD pathology indicates a role for ECs and OLs in maintaining the integrity of the white matter and the BBB, and suggests that their dysfunction could be critical in the course of cSVD development.Brain ECs harbor specific features compared to peripheral ECs, namely the presence of TJ proteins. This is a key feature in maintaining the central nervous system (CNS) microenvironment and to protect the brain from invading pathogens, immune cells, toxic compounds, or alternating ionic concentrations that can affect normal cerebral function . PericytECs also play a key role in regulating local cerebral blood flow in response to neuronal activity and their underlying metabolic needs. This is regulated by the relaxation of smooth muscle cells and pericytes surrounding the larger vessels and capillaries, respectively, mediated by the release of nitric oxide (NO), synthesized by the endothelial NO synthase (eNOS). Upon eNOS deactivation, or impaired vasodilation, the cerebrovascular tone is increased, potentially leading to hypoxia in the corresponding areas . This hiMicrovascular dysfunction has been proposed as an early sign of cSVD, preceding the occurrence of structural lesions, such as WMLs. Endothelial dysfunction causes BBB leakage and inflammation, which has been suggested to cause lacunar strokes, white matter hyperintensities, and cerebral microbleeds seen in cSVD ,24,27,30OLs are the cells responsible for the production of myelin, the isolating fatty sheath surrounding axons that provides structural protection, and facilitate fast electrical signal transduction along CNS axons. In addition to this role in action potential conduction, recent work has revealed additional roles in various processes, including trophic and metabolic support of neurons ,33,34,35Myelinating OLs are generated through a sequence of developmental steps involving four stages: OPCs, late OPCs, immature OLs, and mature myelinating OLs . During Consequently, the emergence of a local or global brain hypoperfusion can affect both OPC/OL function and the factors secreted by these cells under these conditions. One group of these secreted factors are the WNT proteins and their signaling molecules, an upregulation of which was found after exposure of OPCs to hypoxic conditions, suggesting that they may play major roles in brain hypoxia . In factWNT signaling is typically categorized into two pathways: The β-catenin- and non-β-catenin-mediated pathways, with the latter being further sub-categorized. The non-beta-catenin-mediated pathways involve all WNT pathways that do not lead to the stabilization of β-catenin and plays a role in processes including cell polarization, cell fate, inflammatory response, and cell migration . The β-cβ-catenin is essential for the formation and maintenance of vascular integrity and controls BBB TJ formation ,56. The Taken together, this demonstrates the essential role of WNT/β-catenin signaling in the formation and integrity of the BBB. Interestingly, WNT7a and WNT7b, which drive angiogenesis, are the predominant WNT proteins expressed by OPCs ,62.plp expression levels, while a three-fold increase in the expression of this myelin gene protein was observed following WNT/β-catenin activation by WNT1 [WNT/β-catenin signaling was initially suggested to exert an inhibitory effect on oligodendrogenesis and differentiation, although it is now clear that this pathway regulates multiple events during the OPC developmental stages ,63,64. W by WNT1 . Myelin Apc allele or containing a complete deletion of the Axin2 gene, which both caused an increase in β-catenin levels [Apc single-allele conditional knockout nor one-allele nonsense truncated mutation differed in the levels of WNT/β-catenin signal when compared to wild type (WT) mice [Apc deletion. On the contrary, an increase in the WNT transcription mediator gene, transcription factor-4 ), was reported following white matter demyelination in rodents and in active areas of MS lesions, indicating a beneficial role for WNT signaling in remyelination [After demyelination, activation of WNT/β-catenin seems to inhibit OPC differentiation and to decrease myelin density. Fancy et al. reported a decrease in PLP-expressing OLs, 14 days after a lysolecithin (LPC)-induced lesion in Olig2Cre;Da-Cat mice. They also found a decrease in remyelination after LPC-induced demyelination in mice lacking one n levels . In linen levels . HoweverWT) mice . This sulination . It was,lination ,71. Thislination , as a reAlthough sometimes contradictory at first sight, these results highlight a crucial role for WNT/β-catenin in OL function that may largely depend on the timing, context, and cellular environment. Taken together, activation of WNT/β-catenin signaling in demyelination appears to inhibit OL development and decreases myelin production, resulting in a remyelination failure that could contribute to the development of the WML seen in cSVD.Although both ECs and OPCs/OLs are of importance for the BBB integrity, the interaction between ECs and OPCs/OLs and their role in cSVD remain largely unclear. It has been suggested that EC dysfunction might alter OL function, and vice versa . There iAria and Lo were the first to describe a clear interaction between ECs and OLs in an in vitro model by culturing rat OPCs in human brain EC-conditioned medium, which induced an increased OPC proliferation rate. They suggested that EC-secreted factors, such as fibroblast growth factor (FGF) and BDNF, mediated these effects . In turnMore recently, abnormal WNT signaling was suggested to alter the EC–OPC interaction, leading to abnormal OPC migration and dysfunction of both ECs and OLs ,83. HencPublications on ECs and OPCs/OLs and interaction related to cSVD were exclusively identified through PubMed search engine and reported following the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) . The seaDuplicate papers were removed, and studies underwent an initial screen based on their title, followed by a screening of their abstract. Studies using the following terms were included during title screening: Endothelial cells; oligodendrocytes and/or oligodendrocyte precursor cells; and cerebral small vessel disease. Papers using the following terms were included after screening the abstract: Interaction EC–OPC/OL; inflammation; vasculature; cerebrovascular; animal and human studies. We excluded publications matching the following topics: Review, methodology, periphery, oncology, and cancer. Furthermore, studies were excluded if they referred to EC interaction with OPCs or OLs in the context that was not related to the brain or irrelevant for cSVD  after full text reviewing. There were no commentaries, editorials, rectifications, or non-English publications in our search results. Screening and extraction of articles was performed by the first author (NM) under the guidance of the other authors. For each study, the following variables were recorded: Language, year of publication, type of disease, clinical design, experimental design, animal model, and results. The results are described in a flow diagram .The key role of WNT/β-catenin signaling in various brain cells is subject to complex regulation. Miyamoto et al. reviewed recent findings indicating a WNT-dependent single cell migration of adult OPCs from the subventricular zone to damaged areas under the guidance of ECs, which may contribute to white matter recovery . Other fIn cSVD animal models and patients, increased OPC proliferation and migration has been observed following EC dysfunction ,90. RajaOPC clustering, and the dysfunctional overexpression of WNT signaling seen in Olig2-cre: APC floxed/floxed mice, in turn lead to EC dysfunction, BBB disruption, and inflammation in non-injury settings . A key cHypoxic conditions lead to the upregulation of WNT7a and WNT7b, mediated by the stabilization of hypoxia-inducible factor (HIF)1/2α, which resulted in decreased myelination in mouse white matter ,91. ThesIn summary, direct and indirect evidence suggests an interplay between ECs and OPCs/OLs driven by WNT/β-catenin signaling. The mechanistic/molecular hypothesis of their interaction may differ between physiological and pathological conditions as proposed below . We suggIt this review, we identified an important role for WNT signaling in the EC–OPC/OL interplay, whose contribution (both autocrine and paracrine) should be further investigated. The use of animal and post-mortem human material will be determinative to decipher the pleiotropic role of WNT in this interaction and its relevance for cSVD pathobiology and other cerebrovascular disorders. Beyond a greater pathological understanding, it may bring therapeutic opportunities to seal an impaired BBB, reverse OPC clustering, and repair white matter injuries in cSVD.


Background: β-catenin plays a crucial role in the progression of osteosarcoma. However, the clinical significance of β-catenin over-expression in osteosarcoma still remains unclear. Thus, we performed a meta-analysis of studies that evaluated the impact of β-catenin on metastasis and overall survival (OS) in osteosarcoma.Methods: We searched PubMed, The Cochrane Library, Embase, Springer, Science Direct, OVID, Weipu, Wanfang and China National Knowledge Internet (CNKI) databases from their start year up to Aug.2019. Individual hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted and pooled HRs with 95% CIs or odd ratio (OR) were used to evaluate the relationships between β-catenin over-expression and metastasis and overall survival in osteosarcoma.Results: Eight related studies involving 521 patients were qualified for this meta-analysis. Results showed that over-expression of β-catenin was significantly correlated with metastasis  and overall survival .Conclusion: The meta-analysis revealed that over-expression of β-catenin might be associated with distant metastasis and overall survival in osteosarcoma, which reminds that β-catenin acts as a prognostic biomarker and it can guide the clinical therapy in osteosarcoma patients. Osteosarcoma is one of the most common primary malignant bone tumors in children and young adults , mainly Biomarkers can be used to predict the prognosis and metastasis of cancer. β-Catenin is a multifunctional protein and plays an important role in the regulation of cell proliferation, differentiation, and apoptosis. It is widely distributed in endothelial cells, fibroblasts, osteoblasts, and other types of cells . Plenty Numbers of reported studies suggested that overexpression of β-catenin was associated with a high risk of distant metastasis and poor prognosis in patients with osteosarcoma , 14. HowOver the internet, the PubMed, Cochrane Library, EMBASE, Springer, Science Direct, OVID, China National Knowledge Internet, Weipu, and Wanfang literature databases were searched to obtain the relevant literature published before August 2019. Articles were identified using the following search terms: “Beta-catenin, β-catenin, or CTNNB1,” “osteosarcoma, Osteogenic Sarcoma, or bone tumor,” and “prognosis, prognostic or survival.”The studies were included in our meta-analysis if they met the following inclusion criteria: (1) patients with osteosarcoma were diagnosed based on histopathological examination; (2) studies regarding β-catenin expression were detected using an immunohistochemistry method; (3) studies provided sufficient information on evaluation of the relationships between β-catenin expression and overall survival (OS) pathological features or prognosis; (4) sufficient information provided to estimate the hazard ratio (HR) and its 95% confidence interval (CI) and information used to calculate the HR; (5) articles were published in English or Chinese with the full text.Exclusion criteria were as follows: (1) osteosarcoma diagnosed without a biopsy and there was no clear cutoff value in the literature; (2) similar studies from the same author and multiple replicates from different literatures exclude earlier and smaller sample data; (3) animal experiments, reviews, correspondences, case reports, talks, letters, expert opinions, and editorials without original data.http://digitizer.sourceforge.net); HR and 95% CI were calculated as described by Tierney et al.  . Each ofy et al. .www.stata.com). The HR and 95% CI were used to estimate the relationship between β-catenin expression and OS in patients with osteosarcoma, and odds ratio (OR) was used to estimate lung metastasis. The χ2 test and the I2 statistic were used to examine heterogeneity between selected studies. Random-effects or fixed-effects models were used based on the results of heterogeneity test; P < 0.1 or I2 > 50% was considered to be significant for heterogeneity, and a random-effects model was used to conduct the meta-analysis; otherwise, a fixed-effects model was used. Begg test and Egger test were used to analyze the publication bias; P < 0.05 was considered statistically significant. All the P values were used for a two-sided test with significance at P < 0.05.Statistical analyses were conducted with Stata version 12.0 . Meta-analysis with random-model β-catenin overexpression was associated with metastasis in osteosarcoma patients . To explore the heterogeneity, the literature that has a significant impact on heterogeneity is mainly in the study of Bao et al. . Meta-analysis indicated that β-catenin overexpression was associated with poor OS in osteosarcoma patients , which is consistent with the research by Yao et al. (P = 0.02), favoring the hypothesis that β-catenin overexpression is associated with a poor prognosis in patients with osteosarcoma.In this meta-analysis, the association between β-catenin overexpression and OS or metastasis in patients with osteosarcoma was comprehensively reviewed. Overexpression of β-catenin was significantly associated with metastasis and contributes to distant metastasis (OR, 3.31; 95% CI, 2.08–5.24; o et al. . Nevertho et al. . We subsThis meta-analysis suggests that overexpression of β-catenin was associated with distant metastasis. Simultaneously, the patients with β-catenin overexpression compared with low-expression showed poorer prognosis, which suggests that β-catenin may be used as a prognostic biomarker to guide the clinical therapy in osteosarcoma. Moreover, overexpression of β-catenin can be used as one of the risk factors for assessing early lung metastasis and survival prognosis in patients with osteosarcoma. And we expect more new molecular targeted therapies in osteosarcoma.This meta-analysis has some limitations. First, studies published only in English or Chinese are included in this meta-analysis, which may affect our conclusion. Second, the sample size of individual studies included in the study is small. Third, the β-catenin expression was detected by immunohistochemical staining and different detection reagents, and immunohistochemical cutoff values for β-catenin–positive expression in each article may be different, which may lead to some heterogeneity in this article. However, this conclusion still requires more and large-sample positive–negative control studies to obtain more precise and sufficient results.All datasets generated for this study are included in the article/supplementary material.XX and TF contributed to the conception and design of the research. XX and ZK contributed to acquisition of data. XX, HZ, and DC contributed to data analysis and the interpretation and completion of the figures and tables. YL and TF contributed to revision of manuscript for important intellectual content. All authors read and approved the final manuscript.The 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.


In this review, we summarize the role of Wnt proteins in cardiomyogenesis. More specifically, we focus on how the development of cardiomyocytes from precursor cells involves a complex interplay between Wnt canonical β‐catenin signaling pathways and Wnt noncanonical signaling pathways involving PCP and JNK. We also describe recent literature which suggests that endogenous Wnt inhibitors such as the Sfrp and DKK proteins play important roles in regulating the cardiomyocyte differentiation. Srfp2 mediates cardiomyocyte differentiation by inhibiting Wnt3a. Wnt3a is a canonical Wnt that activates b‐catenin and inhibits cardiac specification. In contrast, Wnt11 is a noncanonical Wnt, inhibits b‐catenin and promotes differentiation into cardiomyocytes. The addition of Sfrp2 upsets this balance as it binds, and sequesters, Wnt3a but not Wnt11; thereby leaving Wnt11 free to bind to Fzd5 and activate the noncanonical pathway resulting in cardiac differentiation. Their main function is to provide the contractile force necessary for the heart to pump blood. In mammals, cardiomyocytes appear early in the developing fetus where they develop from undifferentiated precursors. In this review, we will discuss the importance of the Wnt signaling pathway for cardiomyocyte differentiation.2Currently, 19 Wnt proteins have been identified in humans and rodents  or β‐catenin independent  signaling pathway.3.1The β‐catenin‐dependent pathway is regulated by a cytoplasmic complex comprised of Axin, glycogen synthase kinase 3β (GSK3 β), adenomatous polyposis coli (APC), and casein kinase 1α (CK1α). The role of this complex is to phosphorylate β‐catenin. Following phosphorylation, β‐catenin associates with E3‐ubiquitin and is degraded  and protein kinase C (PKC)  pathway Adler, . In the 4Early expression in the developing heart of canonical Wnts  and non‐canonical Wnts  suggests that both the β‐catenin‐dependent and β‐catenin independent signaling pathways are necessary for normal heart development  and Dickkopf (DKK) proteins. Both Sfrp and DKK proteins play important roles in cardiac differentiation.6.1Xenopus by inhibiting the canonical Wnt6 pathway . These Sfrps have cysteine‐rich (CRD) domains with 10 conserved Cys residues. As their name suggests, Sfrps have a strong ~30% to 50%) homology with Fzd receptors and their function is to compete with Fzd receptors for Wnt binding. In essence, Sfrps act as Wnt inhibitors  and β‐ctenin independent  regulation. Wnt/β‐catenin activation in the mesodermal stage promotes the formation of progenitor cells and their differentiation. Critical roles have been ascribed to LRP5/6 and Wnt3a. Inhibition of β‐catenin by Wnt non‐canonical pathways is then necessary for the cardiac progenitors to differentiate into cardiomyocytes. Important roles have been ascribed to Wnt5a and Wnt11. Importantly, Wnt inhibitors such as DKK1, Sfrp1, and Sfrp2 also play important roles in switching signaling from β‐catenin activation to β‐catenin inhibition. This bi‐phasic switch in β‐catenin signaling has already found use in differentiating of induced pluripotent stem cells (iPSCs) into cardiomyocytes , and in part by discretionary research funds from the Vanderbilt University Medical Center.


This review reports the wealth of studies that aim to enhance transdermal delivery of biopharmaceutics using MNs. The true potential of MNs as a drug delivery device for biopharmaceuticals will not only rely on acceptance from prescribers, patients and the regulatory authorities, but the ability to upscale MN manufacture in a cost-effective manner and the long term safety of MN application. Thus, the current barriers to clinical translation of MNs, and how these barriers may be overcome are also discussed.The success of protein, peptide and antibody based therapies is evident - the biopharmaceuticals market is predicted to reach $388 billion by 2024 [1], and more than half of the current top 20 blockbuster drugs are biopharmaceuticals. However, the intrinsic properties of biopharmaceuticals has restricted the routes available for successful drug delivery. While providing 100% bioavailability, the intravenous route is often associated with pain and needle phobia from a patient perspective, which may translate as a reluctance to receive necessary treatment. Several non-invasive strategies have since emerged to overcome these limitations. One such strategy involves the use of microneedles (MNs), which are able to painlessly penetrate the  The increasing development and use of protein based therapies over the last few decades can be attributed to the improvement of protein expression and synthesis on the scale required for widespread manufacturing ,2. ProteProtein and peptide based drugs are primarily administered via the parenteral route, as this provides rapid drug delivery, and in the case of the intravenous route, 100% bioavailability. Such high bioavailability is required particularly for proteins and peptides because of the potential for rapid degradation and clearance once in the bloodstream ,6. AlthoHowever, long-term administration of protein and peptide based drugs via the parenteral route is not without its disadvantages and complications, despite it being the traditional method. From a patient perspective, repeated intravenous drug delivery may be associated with needle phobia, pain, and more complex issues, for example phlebitis and tissue necrosis ,9. The nTo improve the bioavailability and stability of protein, peptide and antibody based drugs, alternative routes of administration have been sought. Ideally, these routes should allow patients to self-administer the drug and therefore should be minimally invasive and ideally, painless. Additionally, the route should allow rapid onset of drug action with potential for sustained drug delivery, to reduce the need for repeated administration. Alternative administration routes investigated include the pulmonary –16, oculstratum corneum barrier by creating temporary microscopic aqueous channels within the epidermis, through which drug molecules can diffuse into the dense microcirculation, present in the dermis. MNs were first conceptualised by Gerstel and Place in 1971 (Microneedle (MN) arrays consist of multiple micro-projections assembled on one side of a supporting base, ranging in height from 25 to 900 μm. MN arrays effectively bypass the  in 1971 , but werEach type of MN has its own distinct advantages and disadvantages and therefore it is important to determine the type of MN required for maximised transdermal delivery of a specific drug. Solid MNs may be combined with any conventional drug formulation for passive diffusion , however, the two-step application process is more impractical than other methods and may discourage patient use.The use of coated MNs removes the two-step application process, however, the finite surface area of the needle array limits the amount of drug that can be applied. Thus, coated MNs are typically limited to use with potent drugs.Dissolving MNs use biocompatible polymers mixed with the drug to form the needle tips. As the needle tips dissolve once applied to the skin, there is no risk of accidental re-piercing of the skin and no need for sharps disposal, a potential problem associated with solid, coated and hollow MNs. Additionally, dissolving MNs provide potential for controlled drug release - the release kinetics of the drug are dependent upon the constituent polymers’ dissolution rate . By adjuAs an alternative, biodegradable polymers, such as poly(lactic acid), chitosan, poly(glycolic acid), or poly(lactide-co-glycolide) (PLGA), have been explored, which degrade, rather than dissolve, to release the drug. Carbohydrates have also been used as a dissolving MN material. They are cheap, safe, and can sufficiently pierce the skin –35. HoweHollow MNs allow a greater volume of drug to be delivered into the skin, either by passive diffusion, or by infusion using pressure or electricity to drive the direction of drug flow into the skin . HoweverHydrogel-forming MNs are the most recent type of MN to be formulated ,43. MNs As briefly discussed above, the type of material used to make MNs in dissolving and hydrogel-forming systems will influence the drugs ability to diffuse into the skin. There has been numerous studies that explore the material types used to create MNs and their biocompatibilities. MNs were initially manufactured from silicon , but havSilicon was the first material used for MN fabrication, prior to the development of more complex fabrication techniques ,52. It iVarious types of metals, such as stainless steel, titanium, palladium, palladium-cobalt alloys and nickel have been used to fabricate MNs . Metals 2O3), calcium sulfate dihydrate (CaSO4·2H2O) and calcium phosphate dihydrate (CaHPO4·2H2O)  ,63. AlumO4·2H2O) . CeramicO4·2H2O) , and ultTo summarise, MNs are a minimally invasive drug delivery device, which combines the benefits of a transdermal patch with the drug delivery capabilities of a hypodermic needle. Their application is painless with minimalised skin trauma and bleeding compared to that of a hypodermic needle, a highly attractive attribute for patients ,66. In a2 patch containing 100 units/mL was deemed sufficient to meet the basal needs of many diabetics.Diabetes affects 422 million people worldwide . The firA secondary study exploring the ability of solid MNs to deliver insulin transdermally was completed by Martanto et al. (2004). Similarly to McAllister et al. (2003), MNs increased skin permeability to insulin, to an extent equal to a 0.05–0.5 units of insulin injected subcutaneously. Blood glucose levels in diabetic rats were lowered by as much as 80% .Zhou et al. (2010) investigated the effects of differing metal MN lengths  on the transdermal delivery of insulin. For all three needle lengths, blood glucose levels rapidly decreased in 1 h and continued to decrease until 3 h. Glucose levels slowly increased thereafter, this was associated with the closure of the temporary micropores created by the MNs, confirmed by transepidermal water loss (TEWL). Furthermore, the rate of elevation in blood glucose levels was inversely proportional to the length of the needle .2. The minimal blood glucose levels were found to be 29% at 5 h, compared to 19% at 1.5 h from a subcutaneous insulin injection. The authors concluded that the use of MNs may be beneficial when a delayed reduction in blood glucose is required  created solid MNs from poly(lactic acid) (PLA) to combine the advantages of MNs with the added benefit of a biodegradable system, an attractive prospect from a commercial point of view. The study systematically investigated the effects of MN dimensions, drug (insulin) concentration, viscosity of drug formulation and the administration time of drug on its transdermal delivery. Increasing insulin concentration increased the permeation amount, but not rate, of drug in vitro. Increasing formulation viscosity decreased permeation rate. In vivo studies were then conducted on diabetic mice, using solid PLA MNs with a height of 600 μm and a density of 100 MNs per cmrequired .2/h and 353.17 ng/cm2/h in vitro for maltose and metal MNs respectively. Cmax was recorded as 7.27 ng/mL and 9.33 ng/mL at 24 h for maltose and metal MNs respectively. The ability of the DermaRoller™ to create wider MN channels was attributed to the increase in both flux and Cmax  investigated the effects of solid MN  pre-treatment on the transdermal delivery of human immunoglobulin G (IgG) in vivo (5 mg/mL applied concentration). Flux was recorded as 45.96 ng/cmand Cmax .Cui et al. (2011) evaluated the extent to which pre-treatment with MNs  could enhance skin permeation of ovalbumin-conjugated nanoparticles in vitro and in vivo. For in vitro studies, MN pre-treatment increased ovalbumin permeation significantly more than the control. Furthermore, 28.3 ± 6.5% of ovalbumin was delivered transdermally from ovalbumin in solution compared to 13.6 ± 2.4% ovalbumin delivery from ovalbumin nanoparticles. This was attributed to the greater size of the ovalbumin nanoparticles hindering diffusion. When applied as a 70 μg/mouse dose, transcutaneous immunisation from ovalbumin nanoparticles following MN pre-treatment was greater than the same dose given subcutaneously .Han and Das (2013) combined sonophoresis and MNs to enhance the delivery of BSA across porcine ear skin. Permeability of BSA was found to be 0.43 and 0.40 μm/s from MNs and sonophoresis alone, however, when the two physical methods of permeation enhancement were combined , permeability increased to 1 μm/s. This was reported as approximately 10 times higher than that achievable by passive diffusion of BSA .Zhang et al. (2014) determined transdermal permeation of four model peptides following a 150 μm solid silicon MN pre-treatment across porcine ear skin. Similarly to Cui et al. (2011), molecular weights of the peptides influenced their ability to permeate transdermally. MN pre-treatment significantly enhanced permeation of all peptides, although increasing the molecular weight of the peptides decreased the amount delivered transdermally .Many studies that use coated MNs focus on the field of vaccination . MinimalSaurer et al. (2010) successfully coated stainless steel MNs with DNA and protein-containing polyelectrolyte films in a layer-by-layer approach. The authors cited five key advantages of using these types of films – there is precise control over film thickness and therefore drug concentration; organic solvents are not required in the fabrication process, improving the safety of the MNs; fabrication of films provides control over the release of defined amounts of multiple different agents; auxiliary agents may be incorporated into the films (e.g. cationic polymers); and the fabrication process is able to coat objects having irregular shapes such as medical devices or implantable materials. In this study, the release of both protein and DNA from the coated MNs was characterised by fluorescence and optical microscopy following 2 h insertion into porcine cadaver skin. Post insertion fluorescence images demonstrate the capability of the coated layer to be released almost completely from the solid MNs and to be delivered into the epidermal and dermal layers of skin .Acknowledging that MN mediated drug delivery focused mainly on hydrophilic molecules, Zhao et al. (2017) developed a novel formulation for the coating of MNs for delivery of hydrophobic auto antigen peptides, which are being investigated for antigen specific immunotherapy of type 1 diabetes. The formulation was comprised of three co-solvents  and PVA 2000, which could dissolve both hydrophilic and hydrophobic peptide auto-antigens at relatively high, and clinically relevant, concentrations. The formulation coating and procedure did not adversely affect the biological activity of the peptides. Both in vitro (human skin) and in vivo (mouse skin) studies were completed to demonstrate the ability of hydrophobic peptides to be delivered via coated MNs. Delivery was maximised when electropolishing the underlying metal MN array, reducing the thickness of peptide coating and utilising peptides with greater aqueous solubility .2) across full thickness porcine skin following 5 min MN insertion was found to be 45% at 24 h. FITC-BSA appeared to be concentrated in the epidermis, upper layers of the dermis, and around sites of microneedle penetration, with little fluorescent signal observed in the lower dermis. The effectiveness of the MNs was attributed to the needle density and needle length  utilised PEG MNs for the delivery of BSA in vitro and in vivo. MNs were inserted into a solution-filled coating mask device, then withdrawn and allowed to dry before piercing the skin. In vitro permeation of FITC-BSA loaded MNs  coated the surface of individual metal MNs with various compounds  to allow delivery of a variety of therapies within the same MN patch. The compounds chosen represented drugs of different sizes and both particles and free drugs, in order to represent almost any type of therapy which may be utilised within MN systems. MNs were applied to full thickness porcine skin for 5 s and removed after 2 min. The protein used in the in vitro experiment was FITC-BSA, and was delivered alongside free fluorescein sodium dye and fluorescently labelled nanoparticles. Results showed that all three compounds were successfully delivered, but at differing rates. FITC-BSA delivery sat between the three compounds, with fluorescein sodium dye diffusing the fastest and fluorescently labelled nanoparticles diffusing the slowest. FITC-BSA fluorescent intensity declined to ~40% after 4 h and trace remains were left at the end of the 2 day experiment .Similarly to coated MNs, dissolving MNs have been investigated extensively for vaccine delivery –104, andMönkäre et al. (2015) developed monoclonal IgG loaded hyaluronan-based dissolving MNs for intradermal delivery in vitro. Following 10 min application to human skin (280 μm length), the majority of the original tip length (65%) was dissolved and IgG and hyaluronan were co-deposited until a depth of 150–200 μm in the skin. The authors noted that the low molecular weight of the hyaluronan likely improved the dissolution rate compared to other studies using hyaluronan for the basis of their dissolving MNs .max and Tmax of 11.58 ng/mL at 40 min. The dissolving MNs showed sufficient stability for 2 months. The authors reported that the bioequivalence was similar between dissolving MNs and an intramuscular (IM) injection control, suggesting that IM injections of interferon-α-2b could be replaced with MNs for self-administration and increased patient compliance  formulated interferon-α-2b containing dissolving MNs (680 μm length) for transdermal drug delivery. In vitro drug release efficiency was 49.2%. In vivo studies reported a Cmpliance .A dissolving MN system, comprised of PVA and trehalose to encapsulate active pharmaceutical peptides within the MN matrix was created by Dillon et al. (2017). Polymyxin B loaded MNs were applied to porcine ear skin for 30 s. The rate of drug delivery was found to be greater than the control (drug loaded disc without MNs) for the first 4 h post MN application, after which rate of permeation was equal to the control, but the percentage of drug delivered transdermally was significantly greater. At the end of the 22 h Franz cell experiment, 66.9 ± 11.59% of polymyxin B was delivered transdermally, compared to 54.14 ± 3.01% for the control .3 microparticles and PVP. Each patch contained 10 × 10 array of needles, 250 μm needle length. When compared to pure PVP MNs, mechanical strength was increased and solubility was slower, providing controlled release properties. Similarly to the study completed by Li et al. (2017) discussed above, delivery of insulin from the MNs was slower than that of a control subcutaneous injection. The 5 IU subcutaneous injection lowered blood glucose levels to 29.5 ± 5.2 mg/dL 2 h post injection, compared to 39.7 ± 7.5 mg/dL at 5 h post MN insertion containing the same units of insulin  fabricated insulin-loaded dissolving MNs for glucose regulation in diabetic rats. A two-step centrifuging and moulding process was used to form a dissolving composite containing insulin-loaded CaCO insulin .It is clear that numerous parameters can be changed to optimise the stability and activity of drugs encapsulated within a dissolving MN system. Lahiji, Jang, Huh, et al. (2018) and Lahiji, Jang, Ma, et al. (2018) evaluated the effects of polymer type, concentration, drying conditions and storage temperature on the activity of lysozyme (model protein) loaded in dissolving MNs. The activity of lysozyme was preserved up to 99.8 ± 3.8% for 12 weeks when fabricated at 4°C, allowed to dry naturally and when fabricated within the presence of stabilising agents such as trehalose ,110.2 was delivered from the dissolving MNs. Therefore, the authors demonstrated for the first time the potential of the carbohydrate biopolymer pullulan for fabrication of dissolving MNs for the successful delivery of high molecular weight compounds such as FITC-BSA  acknowledged that there is a limited range of water soluble, biodegradable polymers that can be used to manufacture dissolving MNs. They therefore used a carbohydrate biopolymer (pullulan) for the first time to facilitate delivery of FITC-BSA across dermatomed neonatal porcine skin. After assuring stability of FITC-BSA remained intact in the formulation, in vitro studies were used to assess transdermal delivery of FITC-BSA from the novel dissolving MNs (600 μm needle length). FITC-BSA was detectable as soon as 15 min post-MN insertion, and at 28 h, 1105 ± 123 μg/cmFITC-BSA .Most studies regarding hollow MN arrays have focused on fabrication aspects, including design and characterisation studies. As a result, less attention has been given to their actual efficiency in delivering drug molecules across the skin . Again, Delivery of high molecular weight compounds into the skin was questioned by Chen et al. (2010). The authors believed the answer to this question might lie in the combination of sonophoresis, a technique that uses low frequency ultrasound to induce acoustic cavitations in the lipid layers of the SC, and MNs. The transdermal delivery of calcein and BSA was measured passively, with either sonophoresis or hollow MNs (300 μm length) alone, or when the two methods were combined (SEMA). For both compounds, transdermal delivery was in the order of; SEMA > sonophoresis alone > hollow MNs alone > passive diffusion . AlthougA “pocketed” MN device design was created by Torrisi et al. (2013) for the intradermal delivery of botulinum toxin A to reduce pain, improve therapeutic targeting and to streamline the administration procedure. Pockets were cut into stainless steel MN shafts for liquid drug reservoir loading. Microneedle-mediated intradermal delivery of β-galactosidase and formaldehyde-inactivated botulinum toxoid revealed effective deposition and subsequent diffusion within the dermis .In vitro intradermal delivery of synthetic mRNA using hollow MNs was demonstrated by Golombek et al. (2018). High levels of humanised Guassia luciferase (hGLuc) protein were detectable following hollow MN penetration. Levels after 24 h and 48 h were significantly higher than the control “naked mRNA” .Hydrogel-forming MNs are a relatively newer type of MN compared to those discussed above . Thus, mTo improve adhesion to the skin, Seong et al. (2017) formulated double layered MN arrays with swellable needles inside a non-swelling patch, which are able to interlock upon skin insertion. This interlocking behaviour was attributed to the sustained release of insulin in vivo. Over 12 h, 60% of the applied insulin was delivered transdermally, 70% of which had a stable confirmation. The authors suggest this novel MN design could be used in the future where sustained release kinetics are required .max at a faster rate (488.7 ng/mL at 6 h) compared to the hydrogel-forming MNs (81.2 ng/mL and 358.2 ng/mL at 48 h for the hydrogel-forming MNs containing 5 mg and 10 mg of bevacizumab respectively). The differences in the pharmacokinetic profile was attributed to the molecular weight of bevacizumab . It was suggested that diffusion of the large macromolecule through the tortuous hydrogel network was likely to have been the cause of the delayed Cmax compared to dissolving MNs  compared dissolving and hydrogel-forming MNs (500 μm needle length) for the transdermal delivery of bevacizumab in vivo. The dissolving MNs delivered a higher CThe field of MNs has grown immensely since they were first conceptualised by Gerstel and Place in 1971 Fig. . ExtensiClinicalTrial.gov search reports 106 studies for the keyword microneedle (March 2020), 67 of which have been completed worldwide. Studies that focus on intradermal vaccination, diabetes and anaesthesia are the most common. Of the completed studies, only four have reached Phase IV trials, one of which involves the intradermal delivery of the influenza vaccine. However, the use of protein, peptide and antibody based therapies transdermally faces numerous challenges that must be addressed before they can achieve their full potential.The transdermal drug delivery market is predicted to grow by $1.79 billion between 2019 and 2023 , and theMNs now harbour the ability to deliver drugs that require high doses and are of low potency , as oppo2 in the skin. Assuming a patch size of 10 cm2, 50–100 mg of polymer would be deposited into the skin each time a patch is applied. This is unlikely to be a concern for vaccinations, however, most therapeutic agents, particularly biologics discussed in this review, require repeated administration. This supports the ongoing use of hydrogel-forming MNs .The authors of this study repeatedly applied a hydrogel-forming MN array to the upper arm of human volunteers over a 5 day period. Safety of repeated MN application was assessed by measuring skin barrier integrity and the presence of systemic inflammatory biomarkers  in blood. The results demonstrated that repeat hydrogel-forming MN application does not lead to prolonged skin reactions or prolonged disruption of skin barrier function.In vivo studies revealed that repeat application of both dissolving (once daily for 5 weeks) and hydrogel-forming (twice daily for 3 weeks) MNs did not alter skin appearance or barrier function and caused no measurable disturbance of serum biomarkers of infection, inflammation or immunity . More reFurthermore, concentrations of systemic inflammation biomarkers were all found to be within the normal range . It appep > 0.05), indicating that the formulations are nonimmunogenic.However the question still remains, could repeated delivery of protein, peptide and antibody based therapies eventually result in an immune response from the host? Proteins and peptides present in infusions may trigger an immune response if the body recognises them as antigens ,13, and Whilst it seems unwanted immunogenic effects from protein and peptide drugs delivered via MNs are unlikely, long-term studies exploring the immune response following repeated application of MNs containing biological drugs are required before clinical acceptance can be assured, and will likely have to be shown on a drug-by-drug basis.The success of MN based products is also dependent on the acceptability to patients and healthcare professionals. A prescriber must be willing to prescribe the product, and patients must accept the product and be able to apply the MN array correctly. Patient benefits, including reduced pain, blood, and needle stick injuries, increased acceptability by people with needle phobia and the potential for self-administration were the most important factors influencing the opinion of MNs in various groups such as in children and the elderly ,139,140.Appropriate MN application is of particular importance for cases such as global pandemics or bioterrorism incidents, where necessary treatment may be dependent on the ability to self-apply the device. Previous studies have shown that patients can successfully apply MNs to their own skin following instruction provided by pharmacist counselling in conjunction with a patient information leaflet . FurtherQualitative studies demonstrate the complex and multifaceted nature of end-user acceptance. Thus, such studies will undoubtedly aid industry in taking the necessary action to address concerns and develop informative labelling and patient counselling strategies to ensure safe and effective use of MN devices. Marketing strategies will also be vital in achieving maximum market share relative to existing and widely accepted conventional delivery systems.The likely considerations and potential requirements from a regulatory standpoint that must be addressed for MNs to be accepted for clinical use are summarised in Table These issues are somewhat intensified when considering the need for scale up manufacture of MNs, as the large scale requires further investment to overcome issues associate with formulating biologics alongside, and within, MNs. Laboratory-based processes are often difficult to scale-up initially, with problems of cost-efficiency of mass manufacture and turnaround time . TurnaroQC tests differ from those that are presented in Table One must ask the question therefore: what are the basic requirements of MNs? The answer to this question dictates the acceptance criteria, and thus the QC tests which must be undertaken to assure the manufacturers that the MNs are meeting this basic requirement. MNs must adequately pierce the skin, penetrate, and be able to be removed intact. Where dissolving MNs are used, they must be able to sufficiently release their drug cargo within a reasonable period. Hollow MNs must remain “open” for the duration of drug delivery, and hydrogel-forming MNs must swell appropriately for delivery of the drug through the associated drug cargo. The MNs must not harm the patient. Lutton et al.  demonstrDespite the ongoing questions surrounding MN manufacture and acceptance, it is interesting to note that the US FDA recently published draft guidance on “microneedling” for cosmetic applications , and PATTo conclude, numerous studies have illustrated the ability to deliver therapeutic doses of protein, peptide and antibody based therapies using MNs as an alternative drug delivery device. The advantages of MNs over traditional routes of drug delivery are apparent, and thus, it appears likely that MNs will be used as a drug delivery device within the next ten years. The use of these devices could vastly improve the quality of life for patients, improve public health, and increase the economic productivity of developing countries.Future success of MNs will be contingent on their long-term safety profile, methods of manufacture, and their ability to comply with standardised GMP guidelines. Furthermore, marketing strategies will also be vital in achieving maximum market share relative to existing and widely accepted conventional delivery systems. In the meantime, academia and industry must work together to address concerns, and thereby push MN technology into the clinic, where its potential can be truly realised.At present, MNs are primarily viewed as vaccine delivery systems for the developing world despite a plethora of published articles demonstrating their ability to deliver of a wide range of therapeutic molecules. Consequently, many pharmaceutical companies are unwilling to make investments in the field. For this reason, it is vitally important to change this mind set by proving that MNs offer far more than acting as simple vaccine delivery devices. Indeed, MNs have made important advancements in removing the need for needle and syringe in the treatment of diseases such as HIV, diabetes, Alzheimer’s and cancer ,150,151.Moving forward, pharmaceutical companies must view drug containing MNs as commercially viable. One way to achieve this is through focussed collaboration between academia, industry, healthcare professionals and patients. In particular, it is vitally important that the views and opinions of patients are respected and considered fully, as many products have failed in the past as they have forgotten about the end user. In this regard, MNs have shown to help overcome needle phobia through painless application, thus improving patient compliance ,66. As aAaron R.J. Hutton is a PhD candidate funded by Department for the Economy (N. Ireland) studentship. Additionally, the authors would like to express their sincere gratitude to William Kerr for his assistance with the creation of Fig. I.


We characterized the coatings’ wettability, morphology and average surface roughness and discussed the influence of surface wettability and morphology on the coefficient of friction and the wear resistance. Experiments were performed in dry, distilled water and in a simulated physiological solution (Hank’s solution). In the case of dry sliding, a lower coefficient of friction is achieved for both TiO2 coatings compared to the pure epoxy coating. In a water environment the same level of friction is shown for all three coatings, whereas in Hank’s solution the friction is reduced for the hydrophilic epoxy/TiO2/epoxy coating, increased for the hydrophobic epoxy/FAS-TiO2/epoxy coating and has no effect on the pure epoxy coating. The results show that the corrosion resistance is significantly improved for the hydrophobic epoxy/FAS-TiO2/epoxy coating compared to the hydrophilic pure epoxy and epoxy/TiO2/epoxy coatings.An AISI 316L surface was functionalized by the adsorption of hydrophilic epoxy and epoxy/TiO An efficient way to protect metallic surfaces against adhesive wear and corrosion is the application of various polymer coatings, with epoxy resin being the most commonly used polymer matrix ,2. This −, O2 or H+ and therefore improve the corrosion resistance and prolong the lifetime of metallic substrates. Pure epoxy coatings are, however, characterized by a highly cross-linked structure, which is responsible for the susceptibility to surface abrasion, scratching and poor resistance to the propagation of cracks in pure epoxy coatings [Epoxy coatings, in general, exhibit superior mechanical properties, chemical resistance, good electrical insulation properties and strong adhesion to heterogeneous substrates. Based on a low surface shear resistance and favorable friction characteristics they provide good anti-sticking and anti-galling properties . Furthercoatings ,10.2, CuO, ZnO). Their properties are tailored via surface multiscale roughness for specific applications [2 nanoparticles produced by aerosol synthesis also demonstrated self-cleaning and self-disinfecting properties, as reported by De Falco et al. [2 nanoparticles, on the other hand, led to the photoinduced superhydrophilicity of TiO2 thin films [In the past few years, researchers in the field of coatings have, therefore, focused on improving the properties of pure epoxy coatings by implementing various nanofillers ,14,15,16ications ,18. Wateications ,19. Supeo et al. . The phoin films ,22 with in films  or with in films .2 nanoparticles to study the reinforcement, surface roughness and wettability effect on tribological and corrosion properties of the coated contact surface. A wear analysis of the polymer coatings is performed in dry conditions, distilled water and a physiological Hank’s solution. The coefficient of friction was analysed for a pure epoxy coating in comparison with the sandwich-structured epoxy coatings (epoxy/nanoparticles/epoxy) filled with dual-size, as-received TiO2 and fluoroalkylsilane functionalized FAS-TiO2 nanoparticles, leading to moderately hydrophilic and hydrophobic surfaces, respectively. The aim of this work was to study the effect of TiO2 nanoparticles implementation and functionalization on the tribological and corrosion behaviour of epoxy coatings, not the stainless-steel substrate and therefore detailed analysis of the bare stainless-steel substrate was not carried out.The modification and ability to control the surface properties, surface roughness and wettability, are, on the other hand, extremely important for various friction applications in different media. Surface properties can be tailored by the application of various inorganic/organic coatings with desirable target properties. However, in general these coatings show low wear resistance. As not a lot of attention has been paid to the combined effect of nanoparticles implementation, roughness and wettability on the surface behaviour of polymer coatings, in this paper we focus on stainless-steel surface functionalization based on the adsorption of polymer coatings with implemented TiO2 nanoparticles with mean diameters of 30 nm (anatase) were provided by Cinkarna Celje , whereas those with 100 nm (rutile) mean diameter were supplied by US Research Nanomaterials, Inc. . The nanoparticles were dispersed in ethanol to prepare 3 wt.% TiO2 nanoparticle ethanolic solution. The 3 wt.% loading of was chosen to lead to optimized coatings preparation with desirable properties as reported in our previous work [Materials—Austenitic stainless steel AISI 316L  was used as the substrate. A two-component USP Class-VI biocompatible epoxy EPO-TEK 302-3M  was mixed in the wt.% ratio 100:45. TiOous work ,25.2 particles were functionalized in a 1% vol ethanolic fluoroalkylsilane (FAS), C16H19F17O3Si solution to ensure the hydrophobic effect.Surface modification—TiOSubstrate preparation—1.5 mm-thick steel sheet was cut into discs with a diameter of 25 mm. The steel discs were diamond polished following a standard mechanical procedure and finally ultrasonically cleaned in ethanol.2/epoxy (shortly TiO2 coating) and epoxy/FAS-TiO2/epoxy (shortly FAS-TiO2 coating), were prepared on a diamond-polished AISI 316L substrate. The first layer of epoxy was spin-coated on the steel surface to ensure the good adhesion of the nanoparticles. In the next step, four double layers of 30 nm and 100 nm TiO2/FAS-TiO2 nanoparticles were spin-coated on the pre-prepared epoxy layer and finally covered with another thin layer of epoxy for the particle fixation. The coatings were then cured for 3 h at 65 °C. A pure epoxy coating was used as a reference.Coating preparation—Sandwich-like structured coatings, epoxy/TiOSurface characterization—A JEOL JSM-6500F field-emission scanning electron microscope (SEM) with an energy-dispersive X-ray spectrometer  was used for the morphology evaluation of all the coatings before and after the tribological testing.The wettability of the coatings was evaluated with static water and Hank’s solution contact-angle measurements. Droplets of water/Hank’s solution with V = 5 µL were deposited on at least three different spots on the coatings to avoid the influence of roughness and gravity on the shape of the droplet. Advex Instruments s.r.o.  was used to analyse the droplets and determine the contact angles.2. The average surface roughness, Sa, was evaluated from the general surface-roughness equation: xL and yL are the acquisition lengths of the surface in the x and y directions and z is the height.Surface roughness was characterized with an optical 3D metrology system, model Alicona Infinite Focus , and IF-MeasureSuite (Version 5.1) software. At least three measurements on each coating were performed at 20x magnification with a lateral and vertical resolution of 0.9 μm and 50 nm, respectively. The size of the analysed area was 1.337 × 0.993 mmTribological measurements—Tribological testing was performed under a reciprocating sliding motion using a pin-on-disc configuration, where a flat-ended AISI 316L steel pin with a diameter of 5 mm was loaded against a coated stainless-steel plate. Tests were performed at a normal load of 1 N, corresponding to a nominal contact pressure of 20 MPa and an average sliding speed of 5 mm/s. The total sliding distance was up to 1 m, achieved in a sliding time of up to 200 s. Each test was repeated at least three times in order to obtain statistically relevant results. To ensure smooth and parallel contact between the pin and the plate, the pin surface was smoothened before each test using grinding paper (grit 4000) attached to the plate surface and sliding at a load of 12 N for 60 s. After that, the grinding paper was removed and the test continued under the pre-defined contact conditions mentioned above. Regarding the environment, the investigation was focused on three cases. Dry sliding in air in room conditions , sliding in distilled water and lastly in the physiological Hank’s solution (the composition is defined below) in order to check applicability of coatings in biomedical applications. In both lubricated cases, the coated steel plate was fully submerged in the lubricant. The test results were evaluated in terms of the sliding time when steady-state friction conditions were reached, the average value of the steady-state coefficient of friction and a wear-scar analysis.−1. We repeated all the measurements three times.Potentiodynamic measurements—Measurements were performed in a simulated physiological Hank’s solution at pH = 7.8, which contained 8 g/L sodium chloride, 0.40 g/L potassium chloride, 0.35 g/L sodium bicarbonate, 0.25 g/L sodium dihydrogen phosphate dihydrate, 0.06 g/L disodium hydrogen phosphate dihydrate, 0.19 g/L calcium chloride dihydrate, 0.41 g/L magnesium chloride hexahydrate, 0.06 g/L magnesium sulfate heptahydrate and 1 g/L glucose. For measurements a BioLogic Modular Research Grade SP-300 instrument  was used. The samples were applied as a working electrode. A saturated calomel electrode  was used as the reference electrode and a platinum net as the counter electrode. The samples were stabilized 1 h prior to the measurement at the open-circuit potential (OCP), after which potentiodynamic curves were recorded using a scan rate of 1 mV s2/epoxy and epoxy/FAS-TiO2/epoxy, were revealed by SEM imaging  and Hank’s solution (θHank) at different spots on the coatings. As shown in 2 coatings both have a moderately hydrophilic nature in both environments, the water and Hank’s solution, whereas the FAS-TiO2 coating is moderately hydrophobic. In addition, the differences in the contact angles between the water/coating and Hank’s solution/coating are not significant, since Hank’s solution is also water based. Surface wettability was analysed by performing three static contact-angle measurements, θ, with 5 µL droplets of distilled water , which was achieved after 100 s  without any surface reactions. However, in the Hank’s solution the hydrophilic/hydrophobic nature of the coating together with the reactions between the elements of the coating  and the solution affect the friction level. For the base epoxy coating, no reactions could be identified, while for the TiO2-containing coating with a hydrophilic nature formation of low shear strength hydroxides, i.e., calcium hydroxide [2 coating with a hydrophobic nature more detrimental compounds (which still need to be identified) are formed, increasing friction to over 0.5.The results show that TiOentation ,27. In oydroxide  have a p2/epoxy, epoxy/TiO2/epoxy and epoxy coatings on AISI 316L stainless steel in Hank’s solution (corrv) and the corrosion current density (icorr) according to ASTM G102-89 [Ecorr) for the epoxy coating was approximately −204 mV vs. SCE. After the Tafel range, the specimen displayed a wide passive region, followed by the breakdown potential (Eb) at 800 mV vs. SCE. The corrosion rate was 0.23 µm/year. To achieve improved corrosion properties, we prepared coatings by the addition of the as-received and surface-modified TiO2 nanoparticles. The increased corrosion resistance of these samples was observed with a significantly wider range of passivation, which was shifted to lower corrosion-current densities (icorr). For the epoxy/TiO2/epoxy-coated AISI 316L sample, the Ecorr was −329 mV vs. SCE and the Eb was shifted to 1000 mV vs. SCE. The corrosion rate was 0.8 nm/year. For the epoxy/FAS-TiO2/epoxy-coated AISI 316L sample, the Ecorr was −479 mV vs. SCE and the Eb was 1000 mV vs. SCE. The corrosion rate was 0.4 nm/year. The results show the significantly improved corrosion resistance of the AISI 316L stainless steel after the addition of nanoparticles to the epoxy coating compared to the pure epoxy coating; this effect was especially noticeable for the hydrophobic epoxy/FAS-TiO2/epoxy coating. The key advantage is the presence of nanoparticles within the coating, which inhibits the permeation of aggressive ions and increases the corrosion performance of the substrate.We studied the potentiodynamic behaviour of the epoxy/FAS-TiOsolution . The qua G102-89 . The sur2/epoxy and hydrophilic as-received epoxy/TiO2/epoxy coatings. Experiments were performed in dry conditions, distilled water and in Hank’s solution. In the case of dry sliding, a lower coefficient of friction was achieved for both TiO2 reinforced coatings in comparison to the base epoxy coating due to the abrasive wear of the top epoxy layer and accumulation of the coating material around TiO2 nanoparticles forming larger load-carrying low-friction patches. In the water environment the same level of friction was shown for all three coatings, indicating that the friction level is defined by the water itself. In the Hank’s solution, however, we observed that the wettability and the implementation of the TiO2 nanoparticles regulate the friction level through the reactions between the solution and the elements of the coating revealed by abrasive wear. Friction was reduced for the hydrophilic epoxy/TiO2/epoxy coating, increased for the hydrophobic epoxy/FAS-TiO2/epoxy and had no effect on the pure epoxy coating. Finally, the results have shown that the reinforcement with the TiO2 nanoparticles provides better polymer coating resistance to mechanical and tribological loading provided by the formation of the patches of the coating material rich in Ti. The nanoparticle implementation within the coating also resulted in an enhanced corrosion resistance for the hydrophobic epoxy/FAS-TiO2/epoxy coating compared to the hydrophilic pure epoxy and the epoxy/TiO2/epoxy coatings.We studied the influence of surface morphology and wettability on the friction and wear resistance of hydrophilic pure epoxy, hydrophobic epoxy/FAS-TiO


Polymer blends is a well-established and suitable method to produced new polymeric materials as compared to synthesis of a new polymer. The combination of two different types of polymers will produce a new and unique material, which has the attribute of both polymers. The aim of this work is to analyze mechanical and morphological properties of bio-phenolic/epoxy polymer blends to find the best formulation for future study. Bio-phenolic/epoxy polymer blends were fabricated using the hand lay-up method at different loading of bio-phenolic  in the epoxy matrix whereas neat bio-phenolic and epoxy samples were also fabricated for comparison. Results indicated that mechanical properties were improved for bio-phenolic/epoxy polymer blends compared to neat epoxy and phenolic. In addition, there is no sign of phase separation in polymer blends. The highest tensile, flexural, and impact strength was shown by P-20(biophenolic-20 wt% and Epoxy-80 wt%) whereas P-25 (biophenolic-25 wt% and Epoxy-75 wt%) has the highest tensile and flexural modulus. Based on the finding, it is concluded that P-20 shows better overall mechanical properties among the polymer blends. Based on this finding, the bio-phenolic/epoxy blend with 20 wt% will be used for further study on flax-reinforced bio-phenolic/epoxy polymer blends. Currently, the needs of high-performance materials have driven researchers to studies on various methods, such as polymer synthesis and modification. There are several techniques in polymer modification such as blending, copolymerization, and reinforcing . PolymerSeveral research studies have been reported in polymer blending using various combinations of polymers. Chen et al.  has studMohamed et al.  has a stThe selection of the polymer to blend depends on its application and the drawback of the polymer that needs improvement. Phenolic resin was used in many areas, such as molding compound, wood products industry, foundry, composite materials, structural integrity, thermal insulation materials, coating, thermal stability, and solvent resistance ,13,14,15In this study, bio-phenolic resin was blended with epoxy resin and both were commercially available. Therefore, there is no issue regarding the supply for both resins for industrial usage. The purposed of this study is to investigate the effect of different loadings of bio-phenolic resin on tensile, flexural, impact, and morphological properties of epoxy composite. Based on literature, it was expected that the mechanical properties of bio-phenolic/epoxy polymer blends were improved compared to neat epoxy and phenolic composites. The finding in this study will be used in a future study for ballistic helmet application by using flax and carbon/kevlar as reinforcement.Epoxy resin D.E.R * 331 and epoxy hardener jointmine 905-3S was procured from Tazdiq Engineering Sdn Bhd. . While Bio-phenolic (PH-3507) was obtained by Chemovate Girinagar, Banglore, India. The Teflon sheet was supplied by Evergreen Sdn Bhd. . Epoxy resin was stirred using mechanical stirring and, at the same time, bio-phenolic resin was added slowly to avoid bio-phenolic resin agglomerate. The mixture was stirred for about 10 min so that the powder was evenly distributed in the epoxy. Then epoxy hardener was poured into the mixture and the stirring continued for about another 2–4 min. This mixing process was done at room temperature. A Teflon sheet was placed in between the mould and steel plate. The mixture was poured into the stainless steel mould with dimensions of 150 mm × 150 mm × 3 mm. The mould was transferred into the hot press with a temperature of 150 °C for 15 min. After 15 min, the polymer blend was removed from the mould and cooled at room temperature. The polymer blends were put in the oven at 105 °C for 2 h. The formulation of the polymer blends was shown in Tensile testing was conducted as per ASTM D 3039 using a 30 kN Bluehill INSTRON 5567 universal testing machine . The samples were cut using bandsaw JETMAC JMWBS-14 with dimension 120 mm × 20 mm × 3 mm. The testing speed used was 2 mm/min and 60-mm gauge length was used. The sample was put in a condition chamber for 24 h at 23 ± 3 °C and a relative humidity of 50 ± 10%. In every formulation, five replications were tested, and the average value was tabulated.Flexural testing was conducted as per ASTM D 790 using a 30 kN Bluehill INSTRON 5567 universal testing machine . The samples were cut using a bandsaw JETMAC JMWBS-14 with dimension 127 mm ×12.7 mm × 3 mm. The support span used was 16 times the depth of the sample and the crosshead speed used was calculated using Equation (1). The sample was put in a condition chamber for 24 h at 23 ± 3 °C and a relative humidity of 50 ± 10%. In every formulation, five replications were tested, and the average value was tabulated.R = rate of crosshead motion, mm/min,L = support span, mm,d = depth of beam, mmImpact testing was conducted as per ASTM D 256 using a Ray Ran advanced universal pendulum impact tester (RR/IMT)  The samples were cut using bandsaw JETMAC JMWBS-14 with dimension 63.5 mm ×12.7 mm × 3 mm. In every formulation, five replications were tested, and the average value was tabulated.The fracture surface of polymer blends, epoxy, and phenolic from the tensile test were examined using an EM-30AX scanning electron microscope  with an acceleration voltage of 20 kV. The samples were coated with a thin layer of gold prior to the testing.The ability of bio-phenolic/epoxy polymer blends to resist breaking under tensile stress and its rigidity were studied by examining the tensile strength and modulus. The effect of bio-phenolic material on the tensile modulus of epoxy were shown in Scanning electron microscopy was carried out on a fracture surface of the tensile test. The ability of bio-phenolic/epoxy polymer blends to withstand bending forces perpendicular to its longitudinal axis, which resist to bending forces, were studied by evaluating the flexural strength and modulus. The ability of a material to absorb and dissipate energy under impact or shock loading were studied by evaluating the impact property . Figure The highest tensile strength improvement was shown by P-20 (66 MPa), which is 1.27 times compared to epoxy (52 MPa). The obtained results showed that neat epoxy have higher tensile strength compared to bio-phenolic material, which is 53 MPa and 32 MPa, respectively, whereas P-5 display the lowest (3.1 GPa) and P-25 show the highest tensile modulus (3.7 GPa). A morphological study of tensile fracture samples supported this finding based on SEM images showing a multilevel facture with ridges and a wavy crest while fracture surface paths of a bio-phenolic material mostly showed straight and constitute failure bands. The findings showed that bio-phenolic/epoxy polymer blends have higher flexural strength compared to neat epoxy and bio-phenolic material. Bio-phenolic/epoxy polymer blends at 25 wt% showed the highest flexural modulus (3.9 GPa), which is 27.45% improvement compared to neat epoxy material. The highest impact resistance (18 J/m) was shown by a bio-phenolic/epoxy polymer blend with 20 wt%. The findings showed that a bio-phenolic/epoxy polymer blend has potential to be utilized for an application since it showed a positive result. Based on this result, P-20 showed the best overall properties. We concluded from this study that blends of bio phenolic resin with epoxy resin can improve the overall mechanical properties of bio phenolic/epoxy polymer blends. Thus, bio-phenolic/epoxy polymer blends with 20 wt% bio-phenolic material will be used in a future study for a ballistic helmet application by using flax and carbon/Kevlar as reinforcement.