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1.
Molecules ; 28(8)2023 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-37110587

RESUMEN

Contemporary pharmacology dating back to the late 19th/early 20th centuries has benefitted largely from the incorporation of metal complexes. Various biological attributes have been successfully realized using metal/metal complex-based drugs. Among anticancer, antimicrobial, and antiviral applications, anticancer applications have extracted the maximum benefit from the metal complex, Cisplatin. The following review has compiled the various antiviral benefits harnessed through inputs from metal complexes. As a result of exploiting the pharmacological aspects of metal complexes, the anti-COVID-19 deliverables have been summarized. The challenges ahead, the gaps in this research area, the need to improvise incorporating nanoaspects in metal complexes, and the need to test metal complex-based drugs in clinical trials have been discussed and deliberated. The pandemic shook the entire world and claimed quite a percentage of the global population. Metal complex-based drugs are already established for their antiviral property with respect to enveloped viruses and extrapolating them for COVID-19 can be an effective way to manipulate drug resistance and mutant issues that the current anti-COVID-19 drugs are facing.


Asunto(s)
Antineoplásicos , COVID-19 , Complejos de Coordinación , Humanos , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , Antineoplásicos/farmacología , Cisplatino , Antivirales/farmacología , Antivirales/uso terapéutico
2.
Molecules ; 28(5)2023 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-36903395

RESUMEN

After decades of research and development concerning cancer treatment, cancer is still at large and very much a threat to the global human population. Cancer remedies have been sought from all possible directions, including chemicals, irradiation, nanomaterials, natural compounds, and the like. In this current review, we surveyed the milestones achieved by green tea catechins and what has been accomplished in cancer therapy. Specifically, we have assessed the synergistic anticarcinogenic effects when green tea catechins (GTCs) are combined with other antioxidant-rich natural compounds. Living in an age of inadequacies, combinatorial approaches are gaining momentum, and GTCs have progressed much, yet there are insufficiencies that can be improvised when combined with natural antioxidant compounds. This review highlights that there are not many reports in this specific area and encourages and recommends research attention in this direction. The antioxidant/prooxidant mechanisms of GTCs have also been highlighted. The current scenario and the future of such combinatorial approaches have been addressed, and the lacunae in this aspect have been discussed.


Asunto(s)
Anticarcinógenos , Catequina , Neoplasias , Humanos , Té/química , Antioxidantes , Catequina/química , Neoplasias/tratamiento farmacológico , Anticarcinógenos/farmacología
3.
Trends Analyt Chem ; 150: 116569, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35221399

RESUMEN

MALDI-TOF-MS has essentially delivered more than expected with respect to clinical pathogens. Viruses are the most versatile entities of clinical pathogens that have challenged well-established microbiological methodologies. This review evaluates the existing scenario with respect to MALDI TOF-MS analytical technique in the successful analysis of viral pathogens. The milestones achieved with respect to detection and identification of COVID-19 has been presented. The fact that only a handful of scattered applications for COVID-19 exist has been pointed out in the review. Further, the lapses in the utilization of the available state-of-the art MALDI-TOF-MS variants/benchmark sophistications for COVID-19 analysis, are highlighted. When the world is seeking for rapid solutions for early, sensitive, rapid COVID-19 diagnosis, maybe MALDI-TOF-MS, may be the actual 'gold standard'. Reverting to the title, this review emphasizes that there is a need for extrapolating MALDI-TOF-MS for COVID-19 analysis and this calls for urgent scientific attention.

4.
Molecules ; 27(13)2022 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-35807336

RESUMEN

Of the biologically active components, polysaccharides play a crucial role of high medical and pharmaceutical significance. Mushrooms have existed for a long time, dating back to the time of the Ancient Egypt and continue to be well explored globally and experimented with in research as well as in national and international cuisines. Mushroom polysaccharides have slowly become valuable sources of nutraceuticals which have been able to treat various diseases and disorders in humans. The application of mushroom polysaccharides for anticancer mycotherapy is what is being reviewed herein. The widespread health benefits of mushroom polysaccharides have been highlighted and the significant inputs of mushroom-based polysaccharides in anticancer clinical trials have been presented. The challenges and limitation of mushroom polysaccharides into this application and the gaps in the current application areas that could be the future direction have been discussed.


Asunto(s)
Agaricales/química , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Polisacáridos/uso terapéutico , Antineoplásicos/farmacología , Suplementos Dietéticos , Humanos , Polisacáridos/farmacología
5.
Crit Rev Food Sci Nutr ; 60(22): 3725-3736, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32056467

RESUMEN

As much as nanotechnology hit the headlines decades ago, currently nanotoxicity has become more than a reality than a threat. Even as nanotechnology is proven, nanotoxicity is well accomplished too. This review specifically concentrates on the area that is close to the consumers, that is the effect of nanomaterials (NMs) on staple food crops. Nanoimpacts impacting primary producers of the food pyramid, cannot be overlooked. Crucial issues on this topic, that have not caught the attention nor action of those concerned has been highlighted in this review. The amount of data and research in this direction was found to be scanty and scattered. Strong emphasis has been made to the fact that NMs when exposed to plants are accumulated and passed on to the second generation seeds and plant parts. This is perhaps a critical concern, that will not just have consequences as of now, but will have permanent and long lasting impacts on the future progenies too. The lack of life cycle assessment of the NMs prior to releasing them to plant interactions and the eventual bioaccumulation and corroborative effects on the plant system if not evaluated, will have more serious implications. This review is aimed at creating a public awareness, that the possibility of nanomaterials entering the consumers and other trophic levels of the food chain is inevitable under the current circumstances. Mitigation methods and check points prior to releasing the NMs to plants systems and risk assessment of specific NMs to specific plants under specified environments is suggested to give a clear overview and insights to prevention rather than a delayed and expensive cure strategy.


Asunto(s)
Nanoestructuras , Nanotecnología , Productos Agrícolas , Semillas
6.
Int J Mol Sci ; 21(15)2020 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-32759789

RESUMEN

Despite multitudes of reports on cancer remedies available, we are far from being able to declare that we have arrived at that defining anti-cancer therapy. In recent decades, researchers have been looking into the possibility of enhancing cell death-related signaling pathways in cancer cells using pro-apoptotic proteins. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Mu-2/AP1M2 domain containing, death-inducing (MUDENG, MuD) have been established for their ability to bring about cell death specifically in cancer cells. Targeted cell death is a very attractive term when it comes to cancer, since most therapies also affect normal cells. In this direction TRAIL has made noteworthy progress. This review briefly sums up what has been done using TRAIL in cancer therapeutics. The importance of MuD and what has been achieved thus far through MuD and the need to widen and concentrate on applicational aspects of MuD has been highlighted. This has been suggested as the future perspective of MuD towards prospective progress in cancer research.


Asunto(s)
Complejo 1 de Proteína Adaptadora/genética , Subunidades mu de Complejo de Proteína Adaptadora/genética , Proteínas Reguladoras de la Apoptosis/genética , Neoplasias/tratamiento farmacológico , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Complejo 1 de Proteína Adaptadora/antagonistas & inhibidores , Subunidades mu de Complejo de Proteína Adaptadora/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias/genética , Neoplasias/patología , Transducción de Señal/efectos de los fármacos , Ligando Inductor de Apoptosis Relacionado con TNF/antagonistas & inhibidores
7.
Int J Mol Sci ; 21(24)2020 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-33302373

RESUMEN

Glycosylation plays a crucial role in various diseases and their etiology. This has led to a clear understanding on the functions of carbohydrates in cell communication, which eventually will result in novel therapeutic approaches for treatment of various disease. Glycomics has now become one among the top ten technologies that will change the future. The direct implication of glycosylation as a hallmark of cancer and for cancer therapy is well established. As in proteomics, where bioinformatics tools have led to revolutionary achievements, bioinformatics resources for glycosylation have improved its practical implication. Bioinformatics tools, algorithms and databases are a mandatory requirement to manage and successfully analyze large amount of glycobiological data generated from glycosylation studies. This review consolidates all the available tools and their applications in glycosylation research. The achievements made through the use of bioinformatics into glycosylation studies are also presented. The importance of glycosylation in cancer diagnosis and therapy is discussed and the gap in the application of widely available glyco-informatic tools for cancer research is highlighted. This review is expected to bring an awakening amongst glyco-informaticians as well as cancer biologists to bridge this gap, to exploit the available glyco-informatic tools for cancer.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Glicómica/métodos , Glicoproteínas/metabolismo , Neoplasias/metabolismo , Animales , Glicosilación , Humanos , Neoplasias/diagnóstico , Neoplasias/terapia , Procesamiento Proteico-Postraduccional
8.
Rev Med Virol ; 27(3): e1930, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-31211498

RESUMEN

Nature's providences are rather the choicest remedies for human health and welfare. One such is quercetin, which is nature's nominee for cancer cure and recently demonstrated against influenza attack. Quercetin is highly recognized for its anticancer applications. This review emphasizes on yet another gift that this compound has to offer for mankind, which is none other than combating the deadly evasive influenza virus. The chemistry of this natural bioflavonoid and its derivatives and its modus operandi against influenza virus is consolidated into this review. The advancements and achievements made in the anti-influenza clinical history are also documented. Further, the challenges facing the progress of this compound to emerge as a predominant anti-influenza drug are discussed, and the future perspective for breaking its limitations through integration with nanoplatforms is envisioned.

9.
Phys Chem Chem Phys ; 18(28): 18670-7, 2016 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-27355696

RESUMEN

The development of thin film coatings has been a very important development in materials science for the modification of native material surface properties. Thin film coatings are enabled through the use of sophisticated instruments and technologies that demand expertise and huge initial and running costs. Nano-thin films are yet a furtherance of thin films which require more expertise and much more sophistication. In this work for the first time we present a one-pot straightforward carbon thin film coating methodology for glass substrates. There is novelty in every single aspect of the method, with the carbon used in the nanofilm being obtained from turmeric soot, the coating technique consisting of a basic immersion technique, a dip-dry method, in combination with the phytosoot-derived carbon's inherent ability to self-assemble to form a uniform and continuous stable coating. The carbon nanofilm has been characterized using field emission scanning electron microscopy (FESEM), Energy Dispersive X-ray (EDAX) analysis, a goniometer and X-ray diffraction (XRD). This study for the first time opens a new school of thought of using such naturally available free nanomaterials as eco-friendly green coatings. The amorphous porous carbon film can be coated on any hydrophilic substrate and is not substrate specific. Its added advantages of being transparent and antibacterial in spite of being green and parsimonious are meant to realize its utility as ideal choices for solar panels, medical implants and other construction applications.


Asunto(s)
Antibacterianos/química , Carbono/química , Nanoestructuras/química , Titanio/química , Vidrio , Microscopía Electrónica de Rastreo , Propiedades de Superficie , Difracción de Rayos X
10.
Sci Total Environ ; 861: 160463, 2023 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-36503651

RESUMEN

COVID-19 pandemic has been the talk of the globe, as it swept across the world population, changing enumerable aspects. The pandemic affected all sectors directly or indirectly. The food sector took a direct hit. The food packaging sector rose to the occasion to serve and feed the pandemic affected, but there were interactions, reactions, and consequences that evolved through the course of the journey through the pandemic. The aim of this perspective is to address the importance of the food packaging industry (from the COVID-19 point of view) and to highlight the unpreparedness of the food packaging materials, for times as these. As the world has been asked to learn to live with Corona, improvisations are definitely necessary, the lapses in the system need to be rectified, and the entire packaging industry has to go through fortification to co-exist with Corona or confront something worse than Corona. This discussion is set out to understand the gravity of the actual situation, assimilating information available from the scattered shreds of reports. Food packaging materials were used, and plastic wastes were generated in bulks, single-use plastics for fear of contamination gained prominence, leading to an enormous turnover of wastes. Fear of Corona, sprayed overloads of sanitizers and disinfectants on food package material surfaces for surface sterilization. The food packages were tailored for food containment needs, never were they planned for sanitizer sprays. The consequences of these sanitization procedures are unprecedented, neglected and in the post-COVID-19 phase no action appears to have been taken. Corona took us by surprise this time, but next time atleast the food packaging industry needs to be fully equipped. Speculated consequences have been reviewed and plausible suggestions have been proposed. The need for extensive research focus in this direction in exploring the ground-reality has been highlighted.


Asunto(s)
COVID-19 , Desinfectantes , Humanos , Embalaje de Alimentos , COVID-19/epidemiología , Pandemias , Plásticos
11.
Polymers (Basel) ; 15(3)2023 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-36772001

RESUMEN

Electricity consumption is an integral part of life on earth. Energy generation has become a critical topic, addressing the need to fuel the energy demands of consumers. Energy storage is an offshoot of the mainstream process, which is now becoming a prime topic of research and development. Electrochemical energy storage is an attractive option, serving its purpose through fuel cells, batteries and supercapacitors manipulating the properties of various materials, nanomaterials and polymer substrates. The following review presents a comprehensive report on the use of carbon-based polymer nanocomposites, specifically graphene and fullerene-based polymer nanocomposites, towards electrochemical energy storage. The achievements in these areas, and the types of polymer nanocomposites used are listed. The areas that lack of clarity and have a dearth of information are highlighted. Directions for future research are presented and recommendations for fully utilizing the benefits of the graphene/fullerene polymer nanocomposite system are proposed.

12.
RSC Adv ; 13(25): 17297-17314, 2023 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-37304772

RESUMEN

MALDI-TOF MS has decades of experience in the detection and identification of microbial pathogens. This has now become a valuable analytical tool when it comes to the identification and detection of clinical microbial pathogens. This review gives a brief synopsis of what has been achieved using MALDI-TOF MS in clinical microbiology. The major focus, however, is on summarizing and highlighting the effectiveness of MALDI-TOF MS as a novel tool for rapid identification of food crop microbial pathogens. The methods used and the sample preparation methodologies reported thus far have been highlighted and the challenges and gaps and recommendations for fine tuning the technique have been put forth. In an era where anything close to the health and welfare of humanity has been considered as the top priority, this review pitches on one such relevant research topics.

13.
Int J Biol Macromol ; 253(Pt 5): 127162, 2023 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-37788732

RESUMEN

Anticancer therapies have been the continual pursuit of this age. Cancer has been ravaging all across the globe breathing not just threats but demonstrating them. Remedies for cancer have been frantically sought after. Few have worked out, yet till date, the available cancer therapies have not delivered a holistic solution. In a world where the search for therapies is levitating towards natural remedies, solutions based on phytochemicals are highly prospective attractions. A lot has been achieved with inputs from plant resources, providing numerous natural remedies. In the current review, we intensely survey the progress achieved in the treatment of cancer through phytochemicals-based programmed cell death of cancer cells. More specifically, we have further reviewed and discussed the role of phytochemicals in activating apoptosis via Tumor Necrosis Factor-Alpha-Related Apoptosis-Inducing Ligand (TRAIL), which is a cell protein that can attach to certain molecules in cancer cells, killing cancer cells. The objective of this review is to enlist the various phytochemicals that are available for specifically contributing towards triggering the TRAIL cell protein-mediated cancer therapy and to point out the research gaps that require future research motivation. This is the first review of this kind in this research direction.


Asunto(s)
Neoplasias , Humanos , Estudios Prospectivos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Apoptosis , Proteínas Reguladoras de la Apoptosis , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Línea Celular Tumoral
14.
Antibiotics (Basel) ; 12(4)2023 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-37107027

RESUMEN

Chitosan derivatives and composites are the next generation polymers for biomedical applications. With their humble origins from the second most abundant naturally available polymer chitin, chitosan is currently one of the most promising polymer systems, with wide biological applications. This current review gives a bird's eye view of the antimicrobial applications of chitosan composites and derivatives. The antiviral activity and the mechanisms behind the inhibitory activity of these components have been reviewed. Specifically, the anti-COVID-19 aspects of chitosan composites and their derivatives have been compiled from the existing scattered reports and presented. Defeating COVID-19 is the battle of this century, and the chitosan derivative-based combat strategies naturally become very attractive. The challenges ahead and future recommendations have been addressed.

15.
Plants (Basel) ; 12(23)2023 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-38068573

RESUMEN

Extensive growth of microscopic algae and cyanobacteria results in harmful algal blooms (HABs) in marine, brackish, and freshwater environments. HABs can harm humans and animals through their toxicity or by producing ecological conditions such as oxygen depletion, which can kill fish and other economically or ecologically important organisms. This review summarizes the reports on various HABs that are able to bring about marine fish kills. The predominant HABs, their toxins, and their effects on fishes spread across various parts of the globe are discussed. The mechanism of HAB-driven fish kills is discussed based on the available reports, and existing mitigation methods are presented. Lapses in the large-scale implementation of mitigation methods demonstrated under laboratory conditions are projected. Clay-related technologies and nano-sorption-based nanotechnologies, although proven to make significant contributions, have not been put to use in real-world conditions. The gaps in the technology transfer of the accomplished mitigation prototypes are highlighted. Further uses of remote sensing and machine learning state-of-the-art techniques for the detection and identification of HABs are recommended.

16.
Foods ; 11(24)2022 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-36553718

RESUMEN

While plastics are already notorious for their accumulation in the environment, which poses environmental challenges, invisible microplastics (MPS) are an even greater challenge. This review focuses on consolidating the reports available on MP accumulation in edible marine and freshwater fishes, shrimps, and crabs. The reality as to whether MPs in these edible aquatic organisms are really a cause of high concern is questioned and discussed. While the entrails of aquatic organisms are reported to contain high levels of MPs, because these products are consumed after the removal of the entrails and gut area in the majority of cases, the MP threat is questionable. The existence of MPs in these aquatic sources is validated but their potency in harming humans, aquatic organisms, and other interlinked species is unassessed. To overcome the difficulty in tracing the movement of MPs in a bigger ecosystem, this review proposes laboratory-based pilot studies mimicking real-world conditions, which will help us to understand the kinetics of MPs in the food chain. The effects of MPs on human welfare and health are yet to be assessed, and this is another gap that needs attention.

17.
Nutrients ; 14(18)2022 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-36145076

RESUMEN

Mushrooms are the gifts of the non-green revolution; they are not limited by land demand or specific growth requirements. Nearly 14,000 species of mushrooms are on record thus far; of these, only 2200 species are deemed edible. Only 650 species from this list have been cultivated and consumed. Farmed on waste, mushrooms are rich reservoirs of proteins, polysaccharides, metabolites, minerals and vitamins. In the following review, various edible mushrooms have been listed and their nutritional aspects and their associated contributions have been discussed. Furthermore, the commercial mushroom-based products that are on the market have been surveyed. The challenges facing the use of mushroom and mushroom products as foods, functional foods and nutraceuticals have been presented. The need to seek options to troubleshoot the current limitations has also been discussed.


Asunto(s)
Agaricales , Agaricales/metabolismo , Suplementos Dietéticos , Polisacáridos/metabolismo , Vitaminas/metabolismo
18.
Anal Methods ; 15(1): 87-98, 2022 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-36484165

RESUMEN

MALDI-MS was used for studying the impact of zinc oxide (ZnO) nanomaterials on Pseudomonas aeruginosa and Staphylococcus aureus. The growth patterns of both these bacterial pathogens in the presence of the ZnO nanomaterials and the subsequent lipidomic changes were assessed using an optimized simple, rapid MALDI-MS based methodology. All three nanostructures tested exhibited differential bactericidal activity unique to P. aeruginosa and S. aureus. The results indicated that the ZnO nanomaterials were highly inhibitory to S. aureus even at 70 mg L-1, while in the case of P. aeruginosa, the ZnO nanomaterials were compatible for up to 10 h and beyond 10 h only marginal growth inhibition was observed. The results proved that the shapes of the ZnO nanomaterials did not affect their toxicity properties. MALDI-MS was applied to study the lipidomic changes of P. aeruginosa and S. aureus after nanomaterial treatment, in order to throw light on the mechanism of growth inhibition. The results from the MALDI-MS studies showed that the ZnO nanostructures exhibited only marginal changes in the lipidomic profile both in the case of P. aeruginosa and S. aureus. These preliminary results indicate that the mechanism of growth inhibition by the ZnO nanomaterial is not through lipid-based interactions, but apparently more so via protein inhibitions.


Asunto(s)
Nanotubos , Puntos Cuánticos , Óxido de Zinc , Óxido de Zinc/farmacología , Óxido de Zinc/química , Staphylococcus aureus , Puntos Cuánticos/toxicidad , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Antibacterianos/farmacología , Antibacterianos/química , Lípidos
19.
Polymers (Basel) ; 14(11)2022 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-35683804

RESUMEN

Chitosan has come a long way in biomedical applications: drug delivery is one of its core areas of imminent application. Chitosan derivatives are the new generation variants of chitosan. These modified chitosans have overcome limitations and progressed in the area of drug delivery. This review briefly surveys the current chitosan derivatives available for biomedical applications. The biomedical applications of chitosan derivatives are revisited and their key inputs for oral drug delivery have been discussed. The limited use of the vast chitosan resources for oral drug delivery applications, speculated to be probably due to the interdisciplinary nature of this research, is pointed out in the discussion. Chitosan-derivative synthesis and practical implementation for oral drug delivery require distinct expertise from chemists and pharmacists. The lack of enthusiasm could be related to the inadequacy in the smooth transfer of the synthesized derivatives to the actual implementers. With thiolated chitosan derivatives predominating the oral delivery of drugs, the need for representation from the vast array of ready-to-use chitosan derivatives is emphasized. There is plenty to explore in this direction.

20.
Polymers (Basel) ; 14(8)2022 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-35458335

RESUMEN

Chitosan and its allies have in multiple ways expanded into the medical, food, chemical, and biological industries and is still expanding. With its humble beginnings from marine shell wastes, the deacetylated form of chitin has come a long way in clinical practices. The biomedical applications of chitosan are truly a feather on its cap, with rarer aspects being chitosan's role in tissue regeneration and artificial organs. Tissue regeneration is a highly advanced and sensitive biomedical application, and the very fact that chitosan is premiering here is an authentication of its ability to deliver. In this review, the various biomedical applications of chitosan are touched on briefly. The synthesis methodologies that are specific for tissue engineering and biomedical applications have been listed. What has been achieved using chitosan and chitosan composites in artificial organ research as well as tissue regeneration has been surveyed and presented. The lack of enthusiasm, as demonstrated by the very few reports online with respect to chitosan composites and artificial organs, is highlighted, and the reasons for this lapse speculated. What more needs be done to expand chitosan and its allies for a better utilization and exploitation to best benefit the construction of artificial organs and building of tissue analogs has been discussed.

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