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1、TRAILBLAZINGTHE FUTURE WITHEMERGINGBIOMATERIALS国家自然科学基金委员会NATIONAL NATURAL SCIENCE FOUNDATION OF CHINA1986Project PlanningWestlake University:Yigong Shi,Jiaxing HuangCAS,a division of the American Chemical Society:Manuel Guzman,Gilles Georges,Michael Dennis,Craig Stephens,Dennis McCullough,Dawn Ried

2、el,Dawn George,Caroline MaResearch&AnalysisWestlake University:Yutao Zhan,Xinning Wang,Wen XiaoCAS:Angela Zhou,Kevin Hughes,Chia-Wei Hsu,Rumiana Tenchov,Julian Ivanov,Yi Deng,Eva Nesbit,Robert Bird,Janet Sasso,Leilani Lotti DiazACS International India Pvt.Ltd:Kavita Iyer,Krittika Ralhan,Magesh Ganes

3、an,Saswata Banerjee,Ankush MaindPublicity and Promotion:CAS:Caroline Ma,Jinying Zhang,Peter Carlton,Peter Jap,Tina Tomeo,Erica Brown,Chris Cotton Project Management:Westlake University:Yutao Zhan,Xinning WangCAS:Sunny Yu,Li Zheng,Jennifer Sexton,Christopher Barbosky,Dharmini Patel,Sabrina LewisConsu

4、ltantsWestlake University:Jianjun Cheng,Bowen Zhu,Chengchen Guo,Huaimin Wang,Lei Wang,Yue ZhangProject TeamAcknowledgementsThis report has also received contribution from Menghua Gao,Yuan Yao,Ran Jin and Zijie Yang of Westlake University and others.We would like to express our heartfelt thanks to al

5、l the help!Trailblazing the future with emerging biomaterials|1Synopsis2Introduction3Antibacterial Materials6Lipid-Based Materials29Bioinks52Programmable materials75Protein-Based Materials100Self-Healing materials120Bioelectronic Materials143Sustainable Materials for Biomedical Applications 169Concl

6、usions194Methods197Trailblazing the future with emerging biomaterials|1Table of ContentsI.II.III.IV.V.VI.VII.VIII.IX.X.XI.SynopsisHealth stands as the bedrock of human existence and the linchpin for a high-quality life,therefore research in this area represents a vital global aspiration for a health

7、ier future.Yet,the evolving societal landscape and environmental shifts have ushered in diverse health challenges.Issues such as the rapid transmission of infectious diseases like COVID-19 and environmental pollution pose significant threats to human well-being.Modern lifestyles further elevate the

8、risks of chronic diseases and mental health concerns.Confronting these shared health challenges has become an urgent global imperative.Materials silently influence our quality of life,continually enhancing human health,from commonplace consumer goods to intricate medical devices and surgical materia

9、ls.Materials science,through its involvement in cutting-edge medical equipment,improved drug delivery systems,innovative diagnostic tools,and the development of intelligent monitoring and sustainable materials,emerges as a key element in improving human health.Strides in material science have become

10、 pivotal in propelling advancements in healthcare,and the future augmentation of human health will increasingly hinge on progress in materials science.Ongoing fundamental research and the application of novel materials are not only steering the future trajectory of the health industry but also shapi

11、ng the industries of the future,catalyzing the formation of transformative productive forces.This report is a collaborative effort between Westlake University and CAS,a division of the AmericanChemical Society.Together,teams from these two organizations delved into the dynamic landscape ofthe future

12、 development of materials used in biomedical applications.Westlake University focuses on cutting-edge scientific research,dedicates itself to breakthroughs in advanced technology,emphasizes interdisciplinary collaboration,and consistently places the promotion of human health and well-being as one of

13、 its core missions.CAS,with its diverse reservoir of expert scientific knowledge,extensive collection of indexed content,and state-of-the-art data analytics capabilities,stands as a singular hub uniquely positioned to generate panoramic insights into scientific trends.These two organizations have co

14、llaborated to explore the role of materials to address the challenges confronting human health,with the goals of unraveling future trends in materials development to provide foresight for pertinent scientific research and industrial advancement,and to spark profound discussions and facilitate extens

15、ive exchanges within the scientific,industrial,and investment community,contributing to build a healthy future together.Trailblazing the future with emerging biomaterials|3I.IntroductionOver the past two decades,the realm of biomaterials has undergone a surge in research and development.These materi

16、als,which are designed to interact with the human body to perform therapeutic and diagnostic functions,hold the promise of revolutionizing the landscape of healthcare.In this report,you will find materials that allow antitumor drugs to target tumor cells,then release drug payloads;materials that can

17、 heal themselves autonomously after being cut or sheared;implantable devices that are safely absorbed by the body over time;and conductive,soft,stretchable composite materials that are used to make two-way electrical interfaces bridging dynamic human tissue and precision electronics.This reports unp

18、recedented level of detail and expansive scope is made possible through a dynamic fusion of interdisciplinary expertise at Westlake University and CAS,coupled with the CAS Content CollectionTM,the largest human-curated collection of scientific data in the word.This database,housing nearly 60 million

19、 journal and patent records across chemistry,biomedicine,materials science,and more,has been analyzed by specialists to unveil the substances,chemical reactions,and scientific concepts discussed in each.The eight emerging research areas in this report were identified using the approach described in

20、the Methods section as a representation of the most active and fast-growing fields of biomaterials research(where a field is often signified by its most prominent feature,where the feature may be a specific material type,application,or function).The selection of these fields was the result of a seam

21、lessly integrated research process among data scientists and biomaterial scientists.This process involved utilizing cutting-edge natural language processing methods,with iterative adjustment and refinement by biomaterial scientists,to identify emerging research areas.The report has also undergone mu

22、ltiple peer review cycles,ensuring that each revelation within it stands as a pinnacle of scientific rigor.In this report,each research area has its own chapter and begins by recent publication trends,with information including:Comparison of the growth of journal and patent publications as an indica

23、tor of research,development,and commercialization interest in the field.Leading research institutions for journal publications.Leading patent assignees and their geographical distribution.Time trends in patent publications broken down by geography.Chronological flow of filing initial patent applicat

24、ions within patent families,leading eventually to individual patent publications in national patent offices.Next,the materials used in each of the topic areas and their key applications are presented and discussed.Throughout this discussion,examples from literature are provided to illustrate promine

25、nt trends.Most chapters also include additional data to address topics that were found to be especially relevant for that chapter.(The chapter on self-healing materials,for example,contains a breakdown of the chemical mechanisms used to provide self-healing properties.)To highlight recent examples o

26、f innovative biomaterials research,each chapter includes tables of notable journal articles and patent publications from 2018-2023.These examples represent the range of materials identified through data analysis,and were selected based on journal impact factor,number of citations,and the assignee(fo

27、r patents).Finally,the most difficult challenges facing each topic are identified.The report has yielded a series of fascinating insights,exploring the ongoing innovation and evolution in the field of biomaterials.Some of the topic areas,for example protein-based materials,have been well known to sc

28、ience for more than 20 years,but have shown continued research interest in recent years.Others,like bioinks,are relatively new fields of research that have undergone rapid expansion,with the majority of research having been published in the past 5 years.In at least two areas,lipid-based materials an

29、d sustainable biomaterials,research interest has increased significantly due to the use of these materials in the response to the COVID-19 pandemic.1,2 Antibacterial materialsProgrammableLipid-basedSustainableHydrogelsProtein-basedDrug deliveryWound healingBiosensorsImplantsElectronic skinTissue eng

30、ineeringSelf-healing materialsBioelectronicsMetalsCarbon nanomaterialsNanocompositesSilkPVAGelsFilmsBioinksNatural polymersPiezoelectric sensorsLiposomesAMPsBioprintingGelMAStem cellsSelf-assemblyPorosityBiocompatibilityChitosanGelatinDNAStimuli-responsiveMultifunctionalPDMSExosomesPEGGrapheneSilico

31、nBiodegradableSynthetic polymersLigninNon-covalent interactionsThe diversification in biomaterial research encompasses both applications and the substances used in them.A representative list of substances that appear in this report includes naturally-derived polymers,such as silk,chitosan,and DNA,ch

32、emically modified naturally-derived polymers,stem cells,synthetic polymers including PEDOT:PSS,metals,alloys,and nanoscale materials such as carbon nanotubes.In addition,a strong trend in many of the topic areas is combining individual substances to make highly engineered composites or hybrid materi

33、als that can perform complex functions,while maintaining biocompatibility.Notable applications that appear throughout the eight chapters include drug delivery,wound healing,tissue engineering,implantable devices,and sensors,among others.A significant fraction of the research efforts in biomaterials

34、today involves combining or modifying existing materials,or discovering new materials,to achieve improved performance for these applications,with the goal of developing them to the point of clinical use.The materials used in these applications can have several synergistic properties.For example,drug

35、 delivery materials can possess both the ability to self-heal,preserving their physical form after placement inside the body,combined with a stimulus-response profile that triggers the release of a drug payload at a specific location,such as tumor or infection sites.3 Multi-functional biomaterials c

36、an also cross between application areas,such as self-healing antimicrobial materials developed for wound healing.4,5Overall,this report aims to provide a thorough overview of the rapidly advancing field of biomaterials research,including insightful guidance on the expected future research trajectori

37、es in this field.Additionally,we aspire for the information contained herein to serve as a valuable resource for professionals involved in the development and commercialization of emerging biomaterial technologies.By offering data-supported insights into anticipated growth areas,challenges,and oppor

38、tunities for new materials and applications,we aim to facilitate informed decision-making within this dynamic industry.Figure 1.Word cloud representing key concepts in this report.(blue:8 chapters in the report,light blue:applications,purple:broad material categories,red:specific materials,dark purp

39、le:forms,black:properties).Terms were chosen to be representative of the content of this report and are purely illustrative.Trailblazing the future with emerging biomaterials|5References(1)Patrcio Silva,A.L.;Prata,J.C.;Walker,T.R.;Duarte,A.C.;Ouyang,W.;Barcel,D.;Rocha-Santos,T.Increased plastic poll

40、ution due to COVID-19 pandemic:Challenges and recommendations.Chemical Engineering Journal 2021,405,126683.DOI:https:/doi.org/10.1016/j.cej.2020.126683.(2)Tenchov,R.;Bird,R.;Curtze,A.E.;Zhou,Q.Lipid Nanoparticles-From Liposomes to mRNA Vaccine Delivery,a Landscape of Research Diversity and Advanceme

41、nt.ACS Nano 2021,15(11),16982-17015.DOI:10.1021/acsnano.1c04996.(3)Wu,M.;Chen,J.;Huang,W.;Yan,B.;Peng,Q.;Liu,J.;Chen,L.;Zeng,H.Injectable and Self-Healing Nanocomposite Hydrogels with Ultrasensitive pH-Responsiveness and Tunable Mechanical Properties:Implications for Controlled Drug Delivery.Biomacr

42、omolecules 2020,21(6),2409-2420.DOI:10.1021/acs.biomac.0c00347.(4)Zhao,X.;Liang,Y.;Huang,Y.;He,J.;Han,Y.;Guo,B.Physical Double-Network Hydrogel Adhesives with Rapid Shape Adaptability,Fast Self-Healing,Antioxidant and NIR/pH Stimulus-Responsiveness for Multidrug-Resistant Bacterial Infection and Rem

43、ovable Wound Dressing.Advanced Functional Materials 2020,30(17),1910748.DOI:https:/doi.org/10.1002/adfm.201910748.(5)Hu,C.;Zhang,F.;Long,L.;Kong,Q.;Luo,R.;Wang,Y.Dual-responsive injectable hydrogels encapsulating drug-loaded micelles for on-demand antimicrobial activity and accelerated wound healing

44、.Journal of Controlled Release 2020,324,204-217.DOI:https:/doi.org/10.1016/j.jconrel.2020.05.010.Trailblazing the future with emerging biomaterials|5II.Antibacterial MaterialsIntroductionAntibacterials are a class of antimicrobials that target bacteria.Depending on their effect on bacterial cells,an

45、tibacterials can be classified either as bactericidal,which kill the bacterium,or bacteriostatic,if they arrest the bacterial growth.1 Since the discovery of Penicillin G in the 1940s,various classes of antibiotics have been developed.Lack of regulation and overuse of antibiotics in both humans as w

46、ell as animals has led to various bacteria becoming unresponsive to numerous classes of existing antibiotics and this phenomenon is referred as multidrug resistance(MDR).2-4 The development of resistance towards existing drugs is an urgent problem crippling the world with the World Health Organizati

47、on(WHO)declaring antimicrobial resistance as one of the top 10 global health threats.5 According to data presented by the Centers for Disease Control and Prevention(CDC),more than 2.8M antimicrobial-resistant(AMR)bacterial infections occur each year leading to 35K+deaths per year.6 Amongst resistant

48、 bacteria,ESKAPEE pathogens(an acronym for a group of Gram-positive and Gram-negative bacteria such as Enterococcus faecium,Staphylococcus aureus,Klebsiella pneumoniae,Acinetobacter baumannii,Pseudomonas aeruginosa,Enterobacter species,and E.coli)are responsible for the largest fraction of hospital-

49、acquired infections(HAIs).7-9 To create awareness about the diverse and prevalent resistant bacterial species,the CDC has published a list of microbes and classified them as either urgent antimicrobial resistance threats,serious AMR threats,or AMR watchlist(microbes that could become serious threats

50、 in the future due to their propensity to become multidrug resistant)in 2019.10,11 The serious AMR threat category comprises of drug-resistant Acinetobacter,Neisseria gonorrhoeae,Clostridioides difficile,and Enterobacterales.Resistant variants of bacteria such as Staphylococcus aureus,Pseudomonas ae

51、ruginosa,Enterococcus,Mycobacterium tuberculosis,Salmonella,Shigella,Campylobacter,and Streptococcus pneumoniae are featured in the CDCs serious AMR threat list.Drug-resistant Mycoplasma genitalium and Bordetella pertussis are included in the CDCs watch list as they have the potential to become mult

52、idrug-resistant in the near future.To counter the problem of increasing drug resistance,traditional small molecule-based antibiotics continue to be developed.However,development has been slow,and novel classes remain elusive.A continued necessity for newer antibiotics and a lack of newer classes of

53、small-molecule antibiotics have led researchers to explore other avenues.In addition to traditional antibiotics,biomaterials with antibiotic functions,such as antimicrobial polymers,antimicrobial peptides(AMPs),antimicrobial enzymes,nanomaterials,bacteriophages can reduce(not replace)antibiotics usa

54、ge and biomaterials which are biocompatible as scaffolds for antibiotics,such as glass,ceramics,polymers,can help more effective drug delivery and act,in a way reducing the load of drugs.12-17 This interest is exemplified by the increase in journal publications in the field of antibacterial biomater

55、ials over the last two decades(Figure 1).Growth in patent publications appears to be more modest indicating a gap between research and commercialization of antibacterial biomaterials(Figure 1).In this chapter,we showcase our findings with regards to publication trends from extensive analysis of more

56、 than 90,000 documents(journals and patents)from the CAS Content Collection,spanning two decades of research(2003-2023)in the field of antibacterial biomaterials.In addition to a publication trend overview,we also identified emerging materials in the field,their forms,and applications.Trailblazing t

57、he future with emerging biomaterials|7JournalPatent2003200420052008200720062009200202000021Publication year02,0004,0006,000Number of publications*8,00010,000Figure 1.Number of journal and patent publications per year in the field of antibacterial materials

58、(shown as blue and yellow bars,respectively)for the last two decades(2003-2023).*The data for 2023 only include months from Jan to Aug.Journal and patent publication trendsRanking research institutions firstly by the volume of journal publications followed by the average number of citations per publ

59、ication allowed identification of the leading organizations in antibiotic research.The top 15 organizations show a diverse spread across different countries or regions(Figure 2).The United States of America(USA)and China(CHN)led by a small margin,each contributing 3 organizations to the top 15,respe

60、ctively.This was closely followed by the Republic of Korea(KOR)and Singapore(SGP),each contributing 2 organizations.While the University of British Columbia ranked relatively low in terms of the actual number of journal publications(little more than 60),the average number of citations per publicatio

61、n was 90 indicating the scientific impact of those publications.An example of a journal publication from the University of British Columbia with a high number of citations is“Anti-adhesive antimicrobial peptide coating prevents catheter-associated infection in a mouse urinary infection model”.18 The

62、 geographical distribution of commercial and non-commercial entities in terms of patent documents published shows overlapping members(Figure 3).China(CHN)leads by a wide margin for both commercial and non-commercial organizations accounting for 50%of patents published.The United States of America(US

63、A)accounts for a much smaller fraction as compared to its contribution to patent publications for other biomaterials discussed in this report.This may indicate low interest in antibiotic development because of the high costs associated with antibiotic discovery and development and limitations on the

64、 use of new antibiotics which reduce their market size and thus potential earnings.Additionally,bacterial infections,especially of the multi-drug resistant variety,are perceived to be more prevalent in and therefore a bigger problem in developing or low-and middle-income countries as compared to dev

65、eloped or high-income countries.19 However,this perception might be flawed as due to extensive globalization the world has become extremely interconnected and increasingly diseases affecting human beings can no longer be contained in any given geographical area,perhaps best exemplified by the COVID-

66、19 pandemic.Other key countries or regions in the University of British ColumbiaSharif University of TechnologyMassachusetts Institute of TechnologyXian Jiaotong University The University of Hong KongSeoul National UniversityBar-Ilan UniversityNanyang Technological UniversityChonbuk National Univers

67、ityUniversity of CaliforniaNational University of SingaporeHubei UniversityUniversity College LondonHarvard UniversityNanjing UniversityAverage number of citations per publicationNumber of journal publicationsCitations per publicationNumber of journal publications(CAN)Number of journal publications(

68、USA)Number of journal publications(IRN)Number of journal publications(GBR)Number of journal publications(CHN)Number of journal publications(SGP)Number of journal publications(KOR)Number of journal publications(ISR)Number of journal publications(HKG,CHN)commercial and non-commercial sectors include:J

69、apan(JPN),Republic of Korea(KOR),Germany(DEU),Russia(RUS),India(IND),Italy(ITA),United Kingdom(GBR)and France(FRA).Japan in particular appears to have a more favorable contribution in patent publications by commercial organizations as compared to non-commercial organizations(Figure 3).Among the comm

70、ercial patent assignees,Chinese companies led the way accounting for 60%of the top 15.This was followed by Japan with 25%and the United States which made up the remainder.The Japanese companies Lion Corporation and Kao Corporation appear to have been more active in the early part of the 2010s with p

71、atent publications related to the use of antibiotics in oral hygiene including incorporating antibacterial agents in dentifrices(JP2010150155A20 and JP2011136956A21).Similarly,Colgate-Palmolive,a US-based company,also has patents mostly focused on antibacterial agents in oral care(US20190185490A122)

72、.The Chinese company Guangdong Taibao Medical Technology Co.,Ltd.applied for patents starting in 2013 for the use and incorporation of biomaterials such as chitosan and alginate among others in medical dressings aimed at wound healing(CN103356692A23 and CN106267309A24).Other Chinese commercial organ

73、izations part of the top 15 such as Suzhou BEC Biology Technology Co.,Ltd.as well as Guangzhou Rainhome Pharm&Tech Co.,Ltd.also appeared to have similar commercial pursuits i.e.use of chitosan and other biomaterials in wound healing(CN105617451A25 and CN107970488A26).In terms of non-commercial organ

74、izations,the leading entities all originate from China with Sichuan University,South China University of Technology,and Zhejiang University leading of the rest by a modest margin(Figure 3).Sichuan University appears to have been more prolific after 2010 with patents revolving around diverse areas in

75、cluding iron oxide nanoparticles for targeted delivery of antibacterial agents(CN115040662A27)and use of a polymer,polyurethane,in antibacterial coatings(CN103214646A28).The overall growth of patent publications shows a distinct upward trend for the Republic of Korea and Japan post-2020 and India po

76、st-2018(Figure 4A).Germany and the United Kingdom also show modest increases in the number of patents published.While the US showed an increase in patent publications in the early 2000s(between 2003 and 2008),this was followed by a decrease in 2009-2010 with a more or less flat trajectory until the

77、present year.Among the leading countries or regions,China is the only one that shows a sharp and dramatic increase in patent publications,Figure 2.Leading research organizations in the field of antibacterial biomaterials over the last two decades(2003-2023)from the CAS Content Collection.Bar graphs

78、have been color coded by country/region with standard three letter codes used to represent countries/regions.Trailblazing the future with emerging biomaterials|9Number of patent publicationsEast China University of Science and TechnologyLion Corp.Hainan Weikang Pharmaceutical(Qianshan)Co.,Ltd.Guangz

79、hou Rainhome Pharm&Tech Co.,Ltd.Guangdong Taibao Medical Technology Co.,Ltd.Suzhou BEC Biology Technology Co.,Ltd.Wuxi Zhongke Guangyuan Biomaterials Co.,Ltd.Jinan Kangquan Pharmaceutical Science and Technology Co.,Ltd.Toyobo Co.,Ltd.Kao Corp.Toray Industries,Inc.Kimberly-Clark Worldwide,Inc.Colgate

80、-Palmolive CompanyNon-commercialCommercialPatent assignees2504045Suzhou Koumei New Materials Co.,Ltd.South China University of TechnologyZhejiang Sci-Tech UniversitySichuan UniversityDonghua UniversityJinan UniversityChina Pharmaceutical UniversitySoochow UniversityJilin UniversityInstitu

81、te of Metal Research,Chinese Academy of SciencesSouthwest UniversityJiangnan UniversityZhejiang UniversitySoutheast UniversityBeijing University of Chemical TechnologyNumber of patent publications0120Patent assigneesUSACHNDEUKORFRA(1%)JPNRUSGBR(2%)INDTop 10patent assignees%11%9

82、%3%Others3%9%USACHNDEU(2%)KORFRAINDITA60%7%11%6%2%Top 10patent assignees2003-2023JPNRUSOthers2%3%ITA(2%)5%BRZ(1%)3%4%2%Dalian Sansheng Technology Development Co.,Ltd.Jinan Shuaihua Pharmaceutical Science and Technology Co.,Ltd.Figure 3.Leading patent assignees in the field of antibacterial biomateri

83、als over the last two decades(2003-2023)as reflected in the CAS Content Collection.Patent assignees have been separated in to two groups:commercial and non-commercial.Bar graphs have been color coded by country/region to match color scheme used in donut charts.Standard three letter codes used to rep

84、resent countries/regions.almost doubling between 2012 and 2016.This growth appears to have continued beyond 2016 to the present year at a fast rate.In terms of the sheer volume of patent publications,China clearly dominates having 16 times as many patent publications in 2021-2022 as USA.An analysis

85、of patent family activity data in Figure 4B shows the flow from the patent assignee country(left)to the patent office where the first application in a given family is filed(center)and finally to the destination patent office for individual patent publications within the family.For China,the country

86、leading in terms of sheer volume of patent publications,an overwhelming majority of patent applications appear to have been filed and granted at their home office.The US and UK had a greater number of patent filings at the World Intellectual Patent Office(WIPO)than at their respective home offices.O

87、n the other hand,Japan,Republic of Korea,and India showed a distinct preference for their respective home offices both for the initial and destination patent filings.Germany and Italy appear to only show preference for their respective home offices for the initial patent filing(A)USA:8,928CHN:15,587

88、DEU:1,690ITA:642KOR:1,618JPN:2,644CAN:557FRA:919USA:4,875CHN:16,107EUR:2,106CAN:1,050JPN:2,489BRZ:415KOR:1,533DEU:260MEX:313IND:906Others:1,567(B)Publication yearNumber of patent publications-20-20-20-20-2022JPNRUSKORINDUSA2,00

89、01,50002,5003,0005001,0-20-20-20-20-2022USACHN0500KORGBR:1,135IND:963WIPO:8,807KOR:1,423USA:3,184EPO:667ITA:367CHN:15,624FRA:543JPN:1,881IND:788DEU:1,174JPNINDRUSDEUGBRGBRDEUOTH:495Figure 4.(A)Growth in patent publ

90、ications in the field of antibacterial biomaterials for the leading countries or regions over the last two decades(2003-2022)from the CAS Content Collection.(B)Sankey graph depicting flow of patent families in the antibacterial biomaterials field between assignee countries or regions(left),office wh

91、ere the first application in a family is filed(center)and the office where individual patent publication activities take place(right).Trailblazing the future with emerging biomaterials|11StaphylococciEscherichiaPseudomonasBacilliKlebsiellaSalmonellaeStreptococciEnterococciAcinetobactersProteiHaemoph

92、ili(0.1%)Burkholderia(0.2%)Saccharomyces(0.3%)Citrobacteria(0.4%)Clostridia(0.4%)Helicobacters(0.4%)Aeromonas(0.5%)Serratia(1%)Mycobacteria(1%)Lactobacilli(1%)Shigellae(1%)Micrococci(1%)Enterobacteria(1%)Vibrios(1%)Listeria(1%)(A)(B)27%27%12%5%3%3%3%7%2%2%21%19%9%4%4%3%6%4%3%2%2%2%2%2%2%2%1%2%1%2%2%

93、1%0.5%(C)Staphylococcus aureusAcinetobacter baumanniiKlebsiella pneumoniaePseudomonas aeruginosaEnterobacter spp.Enterococcus faeciumRelative publication growth(%)0-20-20-20-20-2010Publication year-201

94、-20-20-20-2010Publication yearRelative publication growth(%)004080Carbapenem-resistant EnterobacteralesDrug-resistant Neisseria gonorrhoeaeClostridioides difficileCarbapenem-resistant AcinetobacterFigure 5.(A)Distribution of publi

95、cations(journals and patents)in the field of antibacterial biomaterials across various bacterial species.Growth in publications(journals and patents)associated with(B)ESKAPEE pathogens and bacteria classified as(C)“urgent”threats by the CDC in the field of antibacterial biomaterials.Data includes bo

96、th journal and patent publications from the CAS Content Collection for the last two decades(2003-2022)in the field of antibacterial biomaterials.with a more or less even spread across various patent offices worldwide in terms of the final destination.We analyzed both journal and patent publications

97、in our dataset exhaustively in an effort to identify the research interest distribution across different bacterial species(Figure 5A).The two genera,Staphylococcus and Escherichia account for half of all publications associated with bacterial species.Other key bacterial species that appear to be of

98、interest in the field of antibacterial biomaterials include Pseudomonas,Bacillus,Klebsiella,Salmonella,Streptococcus,Enterococcus,Acinetobacter,and Proteus(Figure 5A).Drug-resistant strains for several of these species have been identified and classified as threats by authorities such as the WHO and

99、 CDC.Publications associated with the ESKAPEE pathogens show steady and consistent growth for the last two decades(Figure 5B).Similarly,publications associated with bacterial species classified as“Urgent”threats by the CDC also show steady growth(Figure 5C).Overall,these trends are indicative of the

100、 interest in developing antibacterial biomaterials to combat the very real and growing threat of multidrug-resistant bacteria.Key materials,properties/forms and applicationsData mined from the CAS Content Collection allowed the identification and classification of biomaterials occurring/used frequen

101、tly in the field of antibacterial biomaterials into the following broad categories:Polymers Organic molecules Metals and metal oxides Carbon-based materials Protein-based materials OthersThe quantitative distribution of identified materials and their breakdown across various categories are shown in

102、Figure 6.Three of the bigger categories have been further sub-divided to give a more nuanced/granular view of emerging materials polymers into synthetic,natural,and conductive,organic molecules into antibiotics,and others(consisting of substances such as steroids,quaternary ammonium compounds,zinc c

103、hloride,silver chloride,etc.)and metal into noble and transition metals.Relative growth in publications of a few shortlisted materials identified as emerging across the last two decades are shown in Figure 7A.Graphene shows a sharp and continued increase in publications post-2014.The use of graphene

104、 oxide29 and graphene-based hybrid nanocomposites in the form of hydrogels for antibacterial effect has been reported.30,31 Other emerging materials include polycaprolactone(PCL)and chitosan a synthetic and a natural polymer,respectively;metals such as zinc,copper,and silver known for their antibact

105、erial properties;antimicrobial peptides(AMP)and quaternary ammonium-containing compounds.Chitosan is among the few biomaterials that possess inherent antimicrobial activity.32 This along with other favorable properties such as biocompatibility,biodegradability,and abundance along with reduced propen

106、sity of development of resistance by bacterial species means that chitosan has been explored in novel ways including as a carrier for drug delivery,33 in combination with other materials34 and incorporated into hydrogels along with other polymers and loaded with antibiotics for drug delivery and wou

107、nd healing.35 Recently,a light-responsive chitosan nano-assembly36 and a synthetic analog of chitosan with improved antimicrobial efficacy have been developed.37 Chitosan and its derivatives continue to be of high interest in the field of antibacterial biomaterials.The synthetic biodegradable polyme

108、r,polycaprolactone,is often used in conjunction with other biomaterials such as gelatin,38 silica,39 and others40 fashioned into nanostructures,41-43 hydrogels,etc.for applications such as targeted drug delivery44 and wound healing.41 Despite the antimicrobial effect/activity of metals such as silve

109、r,45,46 copper,47,48 and zinc49 being well-known,interest in these materials has sustained over the years with efforts being made to use these metals in combination with other biomaterials in novel ways.Silver in particular continues to be utilized along with other biomaterials in combating multi-dr

110、ug resistant strains50,51 including for the disruption of biofilms.52 In addition,dead bacteria with accumulated silver appear to retain the ability to kill other living bacteria in its vicinity,53,54 an effect that can be exploited for increased/greater antimicrobial effect.AMPs are small peptides

111、of variable length composed of natural amino acids55 which are classified by their structures,sources,activities,and other properties.56 Interest in AMPs has been consistent with several AMP candidates currently in clinical trials.57 A large majority of the protein-based materials identified in our

112、dataset result from AMPs.In terms of growth in publications,we see a steady growth over the last two decades.This is in agreement with the overall sustained interest in AMPs as alternatives to traditional antibiotics.A few examples of AMPs in the context of biomaterials include the use of AMPs as an

113、ti-biofilm agents for medical implants and devices58-60 as well as incorporation of AMPs in hydrogels61 and AMP-polymer conjugates.62-64 Ceramics loaded with antibiotics have been used for local/targeted delivery of antibiotics for prolonged periods of time(up to several days),especially in bone-rel

114、ated applications.65,66 Biomaterials such as bamboo,which are naturally antibacterial,are being explored in their natural or composite forms for biomedical applications such as designing medical gauze and would dressing for accelerated wound healing.67-69Trailblazing the future with emerging biomate

115、rials|13PolymersOrganicmoleculesMetals andmetal oxidesOthersProtein-basedCarbon-basedNaturalSyntheticConductiveAntibioticsOthersTransitionmetalsOthersNoblemetalsMetaloxides*Figure 6.Distribution of materials in the field of antibacterial biomaterials over the last two decades(2003-2022)from the CAS

116、Content Collection.Size of the circle corresponds to number of publications(journals and patents).Growth of materials marked with an asterisk are shown in Figure 7.Established classes of antibiotics such as tetracyclines,macrolides,and others have reportedly been used in conjunction with biomaterial

117、s often to aid in their delivery and to boost their antibacterial effectiveness in applications such as tissue engineering and wound healing.70-73 Among the various classes of antibiotics,we identified a few that appear to be most prolific and show a steady rate of increase in publications(Figure 7B

118、).These classes of antibiotics are most often formulated/incorporated into either hydrogel,nano-based systems such as nanoparticles,nanofibers,nanosheets,etc.,or liposomes.Among the various forms listed,nano-based systems appear to dominate(Figure 8A).All the forms show steady growth more so over th

119、e last decade.Hydrogels and quantum dots in particular show a sharp growth in publications post-2016(Figure 8B).Liposomes,a subtype of nanocarriers was originally focused on packaging and delivery of anticancer drugs,but is increasingly being explored for effective delivery of antibiotics.74-76 For

120、instance,a hydrogel comprising lignin and silver nanoparticles has shown antibiotic activity against S.aureus,a Gram-positive bacterium,and E.coli,a Gram-negative bacterium indicating its applicability and versatility.77 In another recent example,a self-assembled peptide hydrogel made from naphthyl

121、anthranilamide capped,short cationic peptides that showed promising antibacterial activity against S.aureus and E.coli.78 The high surface area to volume ratio of nanoparticles allows them to deliver antibacterial drugs effectively.79,80 Nanoparticles made using silver,gold,selenium,calcium oxide,co

122、pper,titanium dioxide,iron oxide,poly(lactic-co-glycolic acid)(PLGA),chitosan,etc.are widely used in the field of antibacterials.81-86To understand the preference for a particular form,we searched for various classes of antibiotics and forms and generated a Sankey graph to visually represent these c

123、o-occurrences(Figure 9).Among the different classes of antibiotics,a majority had a higher number of co-occurrences with nano-based systems as compared to other forms,the exceptions being oxazolidinones,glycylcyclines,phosphonic acids,amphenicols,and aminocyclitol which showed co-occurred more or le

124、ss evenly across hydrogels,nano-based systems,and liposomes(Figure 9).We generated a heat map to effectively showcase co-occurrences between specific bacterial species and the classes -20-20-20-20-20-20162017-201

125、-20-20-20082009-2010Publication yearPublication yearRelative publication growth(%)Relative publication growth(%)(B)(A)AmphenicolsPenicillins&Beta lactamsLincosamidesTetracyclinesSulfonamidesQuinolones&fluoroquinolonesNitroimidazolesMacrolidesCarbapenemAnth

126、racyclines0555GraphenePolycaprolactoneZincChitosanAntimicrobial peptidesSilverCeramicLigninQuaternary compoundsCopperPhosphonic acidsGlycylcyclinesAnsamycinsAminoglycosidesOxazolidinonesAminocyclitols45Figure 7.Growth in publications for(A)emerging materials and(B)major classes

127、 of antibiotic drugs in the field of antibacterial biomaterials from the CAS Content Collection for 2003-2022.Data includes both journal and patent publications.Trailblazing the future with emerging biomaterials|15of antibiotics deployed against them(Figure 10).The bacterial species we chose to focu

128、s on were based on our findings described earlier i.e.,the most prevalent bacterial species in the current dataset of antibacterial materials(Figure 5A).Discussed below are a few observations from the heat map:1.The bacterial species that co-occurred most frequently across the different classes of a

129、ntibiotics are Staphylococcus,Escherichia,Pseudomonas,and Klebsiella.This is unsurprising since drug-resistant strains of Staphylococcus,Pseudomonas,and Klebsiella have long been identified.2.Certain classes of antibiotics are more effective against Gram-negative bacteria while some have a preferent

130、ial effect against Gram-positive bacterial species.For instance,carbapenems(including imipenem,doripenem,and meropenem)are mostly effective against Gram-negative bacteria belonging to genera such as Acinetobacter,Escherichia,Klebsiella,Pseudomonas,Enterobacter etc.87,883.Certain broad-spectrum antib

131、iotics such as tetracycline and their derivatives like glycylcycline are effective against both Gram-positive(Staphylococcus)and Gram-negative bacteria(Escherichia)which also correlates well with literature.89,90The distribution of applications that antibacterial biomaterials can be utilized for is

132、shown in Figure 11A.One of the biggest applications is the use of biomaterials to effectively target and deliver antibiotics accounting for nearly 12K publications in the last two decades(2003-2023).Biomaterials such as antimicrobial peptides,enzymes,and biopolymers are being used effectively in the

133、 field of antibiotics.12 Another major application involves the use of antibacterial biomaterials in the design and fabrication of medical apparatuses,devices,and implants to reduce the risk of infections.Various polycationic polymers(including quaternary ammonium salt-containing polymers),zwitterio

134、ns,polyethylene glycol(PEG),and antibacterial peptides are used to design antimicrobial coatings for preventing bacterial infections.91-93 Besides these,other notable Nano-basedQuantum dotsLiposomesHydrogels-20-20-20-20-2022Pub

135、lication year050Relative growth in publications(%)(B)(A)Nano-basedHydrogelsLiposomesQuantum dotsNumber of publications(Journals and patents)K5.6K3K522354045Figure 8.(A)Distribution of various forms in the field of antibacterial biomaterials and(B)relative growth in publications

136、 related to chosen forms in the field of antibacterial biomaterials over the last two decades from the CAS Content Collection.applications of antibacterial biomaterials appear to be in the food industry and as antifouling agents.PEG-based materials,zwitterions,hydrogels,cationic,and fluoropolymers a

137、re some commonly used antifouling agents94,95 used to coat surfaces in order to prevent bacterial infections.In the food industry,antibacterial biomaterials are Penicillin and beta lactams:3,822Fluoroquinolones:1,671Quinolones:1,542Others:1,338Tetracyclines:1,155Aminoglycosides:1,031Macrolides:711An

138、thracyclines:461Carbapenems:373Ansamycins:417Sulfonamides:357Lincosamides:270Nitroimidazoles:236Oxazolidinone:122Glycylcyclines:75Phosphonic acids:62Amphenicols:31Aminocyclitol:42Nano-based:9,979Hydrogels:1,894Liposomes:1,843Figure 9.Sankey graph showing co-occurrences between various classes of ant

139、ibiotics and the forms such as nano-based,hydrogels and liposomes.Data is for publications(journals and patents)in the field of antibacterial biomaterials from the CAS Content Collection for the period 2003-2023.used to increase the shelf-life of perishable food products by preventing bacterial infe

140、ctions.Phenolic compounds,enzymes such as lysozyme,and antimicrobial peptides are a few examples of biomaterials being actively utilized to design more effective and safer food preservatives.95-97 Trailblazing the future with emerging biomaterials|1726.714.07.88.76.010.23.72.80.51.61.82.62.51.50.60.

141、38.7Penicillin&lactamsQuinolones&fluoroquinolonesTetracyclinesCarbapenemMacrolidesAminoglycosidesAnsamycinLincosamideAnthracyclinesOxazolidinoneGlycylcyclineSulfonamidePhosphonic acidNitroimidazoleAminocyclitolAmphenicolsOthersStaphylococcus24.917.915.36.516.313.019.218.324.021.67.114.214.812.28.08.

142、517.5Escherichia16.517.916.615.112.815.712.110.324.29.315.217.918.511.910.016.917.8Pseudomonas12.615.610.917.211.417.49.29.210.67.77.713.514.06.89.36.911.0Bacillus4.14.85.81.65.44.74.74.68.62.91.44.01.55.04.85.85.2Klebsiella8.38.37.014.85.99.15.25.54.25.316.57.78.04.05.53.26.9Streptococcus2.93.34.21

143、.95.42.64.36.03.16.02.33.03.17.75.29.03.6Salmonella3.03.34.62.04.03.73.23.73.62.82.53.23.33.14.66.34.1Enterococcus3.94.35.53.16.94.46.37.43.911.33.54.14.36.54.85.35.1Proteus2.12.52.22.81.92.52.02.01.42.23.12.22.31.43.21.62.0Enterobacter4.23.63.39.52.64.52.73.40.83.811.64.44.62.34.11.63.4Acinetobacte

144、r4.84.84.110.43.26.33.93.71.93.59.85.15.32.33.91.63.5Micrococcus0.60.60.80.31.00.70.80.61.10.10.20.50.50.40.70.50.9Mycobacterium0.91.41.71.22.31.97.02.42.53.41.71.71.72.84.62.63.2Lactobacillus1.01.12.20.52.61.22.13.70.31.50.51.51.65.32.11.61.7Vibrio1.01.22.50.81.91.52.12.30.61.70.92.11.12.14.37.91.8

145、Listeria1.01.01.70.82.11.31.82.41.71.70.51.31.41.82.12.11.7Shigella1.11.21.80.91.81.31.81.71.41.41.71.31.41.72.70.51.7Clostridium0.90.81.71.01.91.12.83.61.43.31.52.12.18.24.34.21.3Burkholderia0.70.91.21.11.11.21.41.20.61.70.91.92.01.12.71.61.1Serratia1.41.41.32.71.21.51.21.30.31.63.51.92.01.03.01.11

146、.3Helicobacter1.00.71.40.53.50.61.71.40.81.50.91.01.07.12.11.11.1Aeromonas0.80.91.50.91.40.91.11.50.61.00.72.12.10.41.85.31.3Citrobacter1.61.41.43.40.91.81.11.00.31.54.51.71.81.02.52.61.4Haemophilus0.70.91.00.91.60.81.61.91.42.71.41.11.22.43.42.10.9Saccharomyces0.30.30.50.20.70.40.70.80.80.40.30.60.

147、61.70.50.00.4LowHighFigure 10.Heat map showing co-occurrences between major antibiotic classes and bacterial species.Data is for publications(journals and patents)in the field of antibacterial biomaterials from the CAS Content Collection for the period 2003-2023.Values shown are in percentages.(B)(A

148、)-20-20-20-20-2022HydrogelsDrug deliveryWound healingTissue engineeringFood industryAnti-foulingMedical apparatus0500025003000Publication yearNumber of publicationsNumber of publications(Journals and patents)2003-202

149、3Drug deliveryMedical apparatusHydrogelsWound healingTissue engineeringFood industryAntifouling12K11K5.6K5.4K1.7K1K1KFigure 11.(A)Distribution of applications in the field of antibacterial biomaterials and(B)and growth in publications related to chosen applications in the field of antibacterial biom

150、aterials over the last two decades from the CAS Content Collection.Notable journal articles and patents Table 1 consists of a set of research articles published from 2020-2023 that are representative of emerging trends in this field.Articles were selected on the basis of collective factors such as j

151、ournal impact factor,citations,and type of study and describe the usage of different antibacterial materials for various bacterial species.Notable examples from Table 1 include an article titled“Graphdiyne-modified TiO2 nanofibers with osteoinductive and enhanced photocatalytic antibacterial activit

152、ies to prevent implant infection”published in 2020 in Nature Communications.The article describes the use of a stable carbon allotrope-based nanomaterial(GDY),that forms a composite with titanium oxide(TiO2)nanofibers to improve the antibacterial properties of titanium oxide.TiO2/GDY nanofibers have

153、 enhanced photocatalytic and ROS production activity.98 Another example includes a recent publication titled Injectable wound dressing based on carboxymethyl chitosan triple-network hydrogel for effective wound antibacterial and hemostasis”which describes the synthesis of a hydrogel comprising carbo

154、xymethyl chitosan(CMCS),oxidized dextran(OD),and poly-glutamic acid(-PGA).Components of CMCS-OD-PGA(COP)hydrogel such as CMCS and OD are responsible for antibacterial action while-PGA is responsible for wound healing and maintaining homeostasis at the wound site.Furthermore,researchers at Westlake U

155、niversity have developed chitin and cellulose nanofibril-based adhesive tape which can be incorporated with antibiotics.In this article,nanofibril-stabilized latex(poly-2-ethylhexyl acrylate-co-polymethyl acrylate)was infused with the antifungal drug miconazole nitrate.The resultant antibiotic-loade

156、d tape was used to effectively inhibit the growth of Staphylococcus aureus.99Table 2 shows notable patents in the field of antibacterial biomaterials published from 2018 to 2023.Patents were selected based on relevance,novelty,applicability,and field of study.Most of these involve different forms of

157、 biomaterials and their diverse applications.For instance,US10662203B2 by Hoffmann La Roche Inc.describes the synthesis of heterocyclic compounds that can be used as DNA gyrase/topoisomerase inhibitors thereby eliminating bacterial infections.100In another example,US11234997B2 describes the topical

158、formulation that comprises varying ratios of galactooligosaccharide and xylitol(ranging from 1:10 to 10:1).These formulations selectively inhibited the formation of biofilm by Staphylococcus aureus and helped to reduce atopic dermatitis without causing skin inflammation and irritation.101In a recent

159、 example,CN113277563B describes a composite powder made using molybdenum-doped cesium tungsten bronze/montmorillonite where montmorillonite acts as a carrier for molybdenum doped cesium tungsten bronze which is loaded on to the surface of the film.These composites were used to inhibit the growth of

160、E.coli.102Trailblazing the future with emerging biomaterials|19Table 1.Notable journal articles in the field of antibacterial biomaterials in recent years.YearTitleJournalResearch InstituteApplication2020Designing a 0D/2D S-scheme heterojunction over polymeric carbon nitride for visible-light photoc

161、atalytic inactivation of bacteria103Angewandte ChemieWuhan UniversityAntibacterial coating effective against S.aureus.2020Graphdiyne-modified TiO2 nanofibers with osteoinductive and enhanced photocatalytic antibacterial activities to prevent implant infection98Nature CommunicationsGuangzhou Laborato

162、ry and Wuhan UniversityGraphdiyne(GDY)composite TiO2 nanofiber with antibacterial properties.2021Dual-Dynamic-Bond Cross-Linked Antibacterial Adhesive Hydrogel Sealants with On-Demand Removability for Post-Wound-Closure and Infected Wound Healing104ACS NanoXian Jiaotong UniversitySelf-healing antiba

163、cterial containing quaternized chitosan(QCS)for wound healing after methicillin-resistant Staphylococcus aureus(MRSA)infection.2021Anti-bacterial and wound healing-promoting effects of zinc ferrite nanoparticles105Journal of NanobiotechnologyUniversity of CaliforniaSynthesis and testing antibacteria

164、l activity of zinc ferrite(ZnFe2O4)nanoparticles against S.aureus and E.coli.2020Near-Infrared Light-Triggered Nitric-Oxide-Enhanced Photodynamic Therapy and Low-Temperature Photothermal Therapy for Biofilm Elimination106ACS NanoChongqing UniversityAnti-biofilm activity of AI-MPDA Nanoparticles cont

165、aining mesoporous polydopamine(MPDA),L-arginine(l-Arg),and indocyanine green(ICG).2021Dy2BaCuO5/Ba4DyCu3O9.09 S-scheme heterojunction nanocomposite with enhanced photocatalytic and antibacterial activities107Journal of the American Ceramic SocietyUniversity of KashanNanoparticles made from a semicon

166、ductor combination(Dy2BaCuO5/Ba4DyCu3O9.09)were synthesized and tested for antibacterial activity against E.faecalis,S.aureus,K.pneumonia,and E.coli.2022Facile formation of injectable quaternized chitosan/tannic acid hydrogels with antibacterial and ROS scavenging capabilities for diabetic wound hea

167、ling108International Journal of Biological MacromoleculesWenzhou Medical UniversityAntibacterial activity of hydrogel made by introducing tannic acid(TA)into quaternized chitosan(QCS)matrix against S.aureus and E.coli.2022Promoting the healing of infected diabetic wound by an anti-bacterial and nano

168、-enzyme-containing hydrogel with inflammation-suppressing,ROS-scavenging,oxygen,and nitric oxide-generating properties109BiomaterialsZhejiang UniversityAntibacterial activity of Poly(PEGMA-co-GMA-co-AAm)(PPGA)based hydrogels crosslinked with hyperbranched poly-L-lysine(HBPL)-modified manganese dioxi

169、de(MnO2)against methicillin-resistant S.aureus(MRSA)infection.2022Cellulose or chitin nanofibril-stabilized latex for medical adhesion via tailoring colloidal interactions99Carbohydrate PolymersWestlake UniversityUsing cellulose and chitin nanofibrils to form adhesive tapes which exhibit antibacteri

170、al activity 2022Multi-crosslinking hydrogels with robust bio-adhesion and pro-coagulant activity for first-aid hemostasis and infected wound healing110Bioactive MaterialsSichuan UniversityHydrogels comprising carboxymethyl chitosan(CMCS),sodium alginate(SA),and tannic acid were tested for antibacter

171、ial activity against S.aureus and E.coli.2023Injectable wound dressing based on carboxymethyl chitosan triple-network hydrogel for effective wound antibacterial and hemostasis111International Journal of Biological MacromoleculesShanghai UniversityAntibacterial effect of a hydrogel comprising carboxy

172、methyl chitosan(CMCS)/oxidized dextran(OD)/poly-glutamic acid(-PGA).Table 2.Notable patent publications in the field of antibacterial biomaterials in recent years.Patent numberPublication yearPatent assigneeTitleDescription of patented technologyJP2018159860A1122018Tokai Optical Co LtdOptical produc

173、t containing metal ion-carrying zeoliteAn optical multilayer product with an antireflective film coated with an organic antibacterial agent.CN107536725A1132018Guangzhou Weimeizi Industrial Co LtdA kind of multiple-effect oral cavity composition and its application containing hyaluronic acid mixtures

174、Oral care composition comprising different combinations of hyaluronic acid(in some cases with zinc citrate)used as antibacterials.JP2019065375A1142019Harada Metal Industry Co.,Ltd.,National Institute of Advanced Industrial Science&Technology,JapanCopper alloy powder having antibacterial properties a

175、nd antivirus properties and article using the sameAntibacterial coating formulation containing copper alloy powder(comprising 0.10%tin,0.01%phosphorus and remaining copper).US10662203B21002020Hoffmann La Roche IncNovel pyrido 2,3-b indole compounds for the treatment and prevention of bacterial infec

176、tionsHeterocyclic compound to inhibit bacterial DNA gyrase and/or topoisomerase IV,in turn inhibiting bacterial growth.US11065223B21152021University of Texas System,USAAntibacterial composition and its useAntimicrobial composition in the form of wound ointment containing esterified polygalacturonic

177、acid and a C6-12 fatty acid.CN110067042B1162021Donghua UniversityKonjac glucomannan-based antibacterial hydrogel fiber and preparation method thereofAntibacterial hydrogel fiber comprising Konjac glucomannan polymerizable monomer,alginate,guanidine salt polymerizable monomer,deionized water,and poly

178、merization initiator.US11459296B21172022Infex Therapeutics Ltd Medivir ABPreparation of sulfamoyl pyrrolecarboxylic acids as antibacterial agentsNitrogen-containing heterocyclic compounds that act as Metallo-lactamase inhibitors.US11234997B21012022Rottapharm SpAAntibacterial activity of galactooligo

179、saccharide and xylitol in dermatological treatmentsAnti-biofilm activity of topical formulation comprising galactooligosaccharide and xylitol in different ratios.US11691967B21182023The Board of Trustees of the University of Illinois,USAAntibiotics effective for gram-negative pathogensOrganic compoun

180、ds with antibiotic activity,selectively against gram-negative bacteria.CN113277563B1022023Nanjing Zhouninglin Advanced Materials Technology Co Ltd,Nanjing Normal UniversityMolybdenum doped cesium tungsten bronze/montmorillonite composite powder and preparation method and application thereofSynthesis

181、 and antibacterial activity of molybdenum doped cesium tungsten bronze/montmorillonite composites.Trailblazing the future with emerging biomaterials|21Challenges and perspectivesDevelopment of novel antibiotics requires a thorough understanding of the host immune system and the interaction of host c

182、ells with antibiotics.There are various traditional antibiotic approaches/materials being used to treat bacterial infections but the major challenges in this area are:One common challenge in this field is the development of antimicrobial resistance in bacterial species,which happens at a much faster

183、 pace as compared to the of development of any novel antibiotic.1,119 The same levels of antibiotic treatment produce varied results in different individuals in any population,due to the differences in the host immune system.120 The development of antibiotics is more challenging for highly infectiou

184、s,Gram-negative bacteria as compared to Gram-positive ones,due to the presence of a lipopolysaccharide(LPS)rich,outer membrane.The outer membrane acts as a barrier and prevents the entry of various drug molecules inside the bacterial cell.121,122 The limited market size,short treatment duration,and

185、reduced price of antibiotic agents reduce the willingness of pharmaceutical companies to invest in antibiotic drug development.123 Another major challenge is the treatment of bacterial infections if the bacteria is prone to biofilm formation,which is a densely packed community of bacteria embedded w

186、ithin an extracellular matrix.Biofilms prevent the entry of antibiotics and the lowest concentration of antibiotics entering the biofilm can promote the rapid development of antimicrobial resistance.14,124Various emerging approaches such as the use of antimicrobial peptides,enzymes,bacteriophages,an

187、d CRISPR-Cas technology are being tried to enhance the efficacy of antibiotics and counter the problem of rapid antimicrobial resistance development.Artificial intelligence(AI)has slowly started entering the field of antibiotics where machine-learning based algorithms are being leveraged to identify

188、 successful antibiotic candidates.However,the widespread use of AI is still in the nascent stages,and it requires more research endeavors in the future.123 In addition,continued advancements are needed in translating more antibiotic-based materials into various clinical applications.Trailblazing the

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275、,C.;Czako,Z.;Muresan,L.;Ismaiel,A.;Dumitrascu,D.I.;Leucuta,D.C.;Stanculete,M.F.;et al.Artificial Intelligence and Antibiotic Discovery.Antibiotics 2021,10(11),1376.(124)Liu,J.;Gefen,O.;Ronin,I.;Bar-Meir,M.;Balaban,N.Q.Effect of tolerance on the evolution of antibiotic resistance under drug combinati

276、ons.Science 2020,367(6474),200-204.DOI:doi:10.1126/science.aay3041.Trailblazing the future with emerging biomaterials|29Iiposomedrug-loadedliposometargetedliposome“stealth”liposomemRNA-carryinglipid nanoparticlesolid lipidnanoparticlenanostructuredlipid carriercubosomeIII.Lipid-based materialsIntrod

277、uctionThe field of pharmaceuticals has witnessed remarkable progress recently,driven by innovations in drug delivery technologies.Traditionally,drug delivery has been a complex puzzle,often challenged by the limited solubility,stability,and bioavailability of many therapeutic agents.These constraint

278、s have led researchers on a quest to find more effective ways to deliver drugs to their intended targets within the body.Therefore,drug delivery systems play a crucial role in optimizing the therapeutic benefits of medications while minimizing side effects and improving patient compliance.Among the

279、transformative advancements in drug delivery technologies,lipid-based drug delivery systems have emerged as a formidable force in the world of pharmaceutical science and practice offering a dynamic range of solutions that transcend traditional pharmaceutical boundaries.Lipid-based drug delivery syst

280、ems are ingeniously designed carriers,benefitting from the inherent biocompatibility and versatility of lipids and tailored to encapsulate,transport,and release a wide array of therapeutic agents,including small molecule drugs,genes,and biologics.Their elegance lies in their ability to overcome some

281、 of the most pressing challenges in drug delivery.These challenges include improving the solubility of poorly water-soluble drugs,protecting labile compounds from degradation,and precisely targeting disease sites within the body.1-9Lipid nanocarriers can be divided into various categories,including

282、solid lipid nanoparticles(SLNs),nanostructured lipid carriers(NLCs),liposomes,lipid-based micelles,and lipid prodrugs(Figure 1).SLNs consist of solid lipids,while NLCs combine solid and liquid lipids,offering enhanced drug-loading capacity and Figure 1.Schematic representation of various types of li

283、pid nanoparticles.Adapted from Tenchov et al.1flexibility.Liposomes are spherical vesicles with lipid bilayers surrounding an aqueous core,while lipid-based micelles have amphiphilic molecules forming micellar structures.Lipid nanocarriers offer several advantages,such as improved drug solubility,en

284、hanced bioavailability,controlled drug release,targeted delivery,and protection of labile drugs from degradation.1,5,8,10,11 Exosomes are similar to liposomes but originating from biological systems and secreted by most eukaryotic cells.They possess unique properties such as innate stability,low imm

285、unogenicity,biocompatibility,and good bio-membrane penetration capacity,making them superior natural nanocarriers for efficient drug delivery and diagnostics.12-15Lipid nanocarriers have revolutionized drug delivery by overcoming limitations related to drug solubility,stability,bioavailability,and t

286、argeted delivery.They continue to play a pivotal role in improving drug delivery,expanding treatment options,and enhancing patient outcomes across a wide spectrum of diseases and conditions.Their versatility,biocompatibility,and ability to address specific drug delivery challenges make them valuable

287、 tools in pharmaceutical research and development.Besides drug delivery,lipid-based materials have also found applications in other fields such as cosmetics16,17 and agriculture18,19 among others.These diverse applications have led to a sustained interest in lipid-based materials as seen by the more

288、 or less steady increase in journal publications(Figure 2).Growth in patent publications have been more modest indicating unmet commercial potential(Figure 2).In the present report we showcase our findings with regards to publication trends from extensive analysis of more than 46,000 documents(journ

289、als and patents)spanning across two decades(2003-2023)in the field of lipid-based materials from the CAS Content Collection.In addition to a publication trend overview,we also identified emerging materials in the field and their applications.Figure 2.Number of journal and patent publications per yea

290、r in the field of lipid-based materials(shown as blue and yellow bars respectively)over the period of the last two decades(2003-2023).*The data for 2023 only include months from Jan to Aug.JournalPatent2003200420052008200720062009200202000021Publication ye

291、ar05001,0001,5002,000Number of publications*2,5003,0003,500Trailblazing the future with emerging biomaterials|31Journal and patent publication trendsFrom the top 150 organizations in terms of volume of journal publications,we identified leading organizations involved in research related to lipid-bas

292、ed materials on the basis of average number of citations per publications.Nearly half of the top 15 organizations originate in the USA which is followed closely by China contributing 4 institutions(Figure 3).The University of Alberta,the only organization originating in Canada leads the pack with an

293、 average number of citations per publication of 160(Figure 3).One such highly cited article from the University of Alberta titled“Spray-freeze-dried liposomal ciprofloxacin powder for inhaled aerosol drug delivery”describes the formation and characterization of liposomal-encapsulated ciprofloxacin,a

294、 broad-spectrum antibiotic designed to be delivered via inhalation to prevent bacterial infections.20The trends in geographical distribution of patent assignees separated into commercial and non-commercial organizations show a high degree of overlap,a trend echoed in other biomaterials addressed in

295、this report(Figure 4).Across both categories,the USA and China dominate with the former contributing greater numbers of patent publications in terms of commercial organizations.On the other hand,non-commercial organizations in the USA and China have published similar numbers of patent documents.Othe

296、r important/key countries or regions in terms of volume of patent publications include:Germany(DEU),Japan(JPN),the Republic of Korea(KOR),France(FRA),Italy(ITA),India(IND)and Switzerland(CHE).More than 65%of the leading commercial organizations involved in research in lipid-based materials originate

297、 in the USA.Patents from ModernaTX,a biotechnology company from the USA,appear to be related to the use of lipid nanoparticles to deliver active payloads including drug molecules,proteins and mRNA for the treatment of cancer and other disorders(WO2021243207A1,21 WO2023076605A122)as well as developme

298、nt and delivery of vaccines(WO2018170260A1,23 WO2023154818A124).Other US based companies such as Codiak Biosciences and Transdermal Biotechnology have filed patent applications relating to the use of lipid-based materials such as exosomes for drug and vaccine delivery(WO2023056468A1,25 WO2020191361A

299、226)and transdermal delivery(US20160136169A127)and wound healing(WO2014159986A228),respectively.The Japanese company,Konica Minolta Medical&Graphic,Inc.appears to have been more active in the late 2000s and was focused on the Figure 3.The top 15 research institutions in terms of average citation num

300、bers per journal publication between 2003-2023.delivery of X-ray contrast agents using liposomes(JP200520654029)and the use of liposomes in photodynamic therapy(EP2374825A130).Lipotec,a Spanish company,has explored the use of liposomes in cosmetics(US20130078295A1,31 EP2740484A1,32)such as for the d

301、elivery of peptides and botulinum toxin.Distribution for the top 15 commercial organization appears to split between China and the USA with 9 organizations originating in China(Figure 5).Among the non-commercial organizations in China,Shenyang Pharmaceutical University leads with 90 patent publicati

302、ons,closely followed by China Pharmaceutical University.Patents by Shenyang Pharmaceutical University appear to be centered around manufacturing liposomes(CN102552142A33)as well as their application in drug delivery(WO2021043231A134)especially cancer therapy(CN109718228A,35 CN116440287A36).Examples

303、of patent publications by China Pharmaceutical University include designing remdesivir liposomes to be administered by inhalation route(CN111991375A37),liposomes for targeted delivery(CN111001011A38),as well as other drug delivery applications(CN107837234A39).Patent documents filed by the University

304、 of California seem to be related to use of lipid nanocarriers for drug delivery for cancer immunotherapy(WO2021076630A140)as well as Alzheimers disease(WO2018081085A141)and viral infections(WO2021207632A142).The overall growth in patent publications across the last decade shows a positive upward tr

305、end pronounced more so for the USA,China,the Republic of Korea,Germany,and India(IND)(Figure 5A).On the other hand,Italy and France display a more modest growth in patents over the last decade.Despite this upward trend,the actual number of patents for lipid-based materials is relatively low.Detailed

306、 analysis of patent family data showing the complex flow of patents from patent assignee countries or regions(left)to the patent office wherein the first application in a given family is filed(center)and the patent office where the individual patent publication activity takes place(right)is shown in

307、 Figure 5B.Unlike other biomaterials,for patents related to lipid-based materials a majority of applications were first filed at the European Patent Office(EPO).This is especially true for the USA,Germany,Japan,Canada,Israel(ISR)and the United Kingdom(GBR)wherein nearly half of the patent applicatio

308、ns were filed at the EPO first(Figure 5B).In contrast,patent applications originating from China and Spain(ESP)appear to show only a minor preference for home office(CHN)and EPO,respectively,while a majority of the patents were filed more or less evenly across WIPO,their respective home offices as w

309、ell as other patent offices across the world(Figure 5B).For USA,the rest of the patent application filings are split between their home office(US)and the World Intellectual Patent Office(WIPO).In terms of the final destination patent office,more than a third of the patents initially filed at the EPO

310、 make their way to the United States Patent Office(USA)followed by the EPO itself.Other important/key/major destinations offices include the Japanese,Canadian,Chinese,Korean,Indian,Spanish,Mexican,and Brazilian patent offices.Trailblazing the future with emerging biomaterials|33Figure 4.Geographical

311、 distribution(top panel)and leading patent assignees in the field of lipid-based materials in terms of numbers of patent publications between 2003-2023.Patent assignees have been separated in to two groups:commercial and non-commercial.Bar graphs have been color coded by country/region to match colo

312、r scheme used in donut charts.Standard three letter codes used to represent countries/regions.(A)USA:23,286CAN:1,743CHN:1,100ITA:931JPN:2,210CHE:1,139GBR:1,052FRA:1,371USA:11.308CHN:2,485EUR:5,398CAN:3,218JPN:3,255BRZ:853KOR:1,362MEX:804ESP:869IND:1,236OTH:4,267(B)Publication yearNumber of patent pu

313、blications-20-20-2022ITADEUINDFRA5004000800200USACHN04080120160KORISR:1,134ESP:833EPO:18,024US:8,771WIPO:4,846CHN:1,560ESP:660CAN:711JPN:722Others:1,212DEU:586FRA:440ITA:264JPN-20-20-2022DEU:2,997Figure 5.(A)Growth

314、 in patent publications over the last decade(2011-2022)in the field of lipid-based materials.(B)Sankey graph depicting flow of patent families in the lipid-based materials field between assignee countries(left),office where the first application in a family is filed(center)and the office where indiv

315、idual patent publication activities take place(right).Trailblazing the future with emerging biomaterials|35Key materials,forms and applicationsA detailed and comprehensive exploration of our document and substance data from the CAS Content Collection aided in the identification of key materials acro

316、ss three major categories utilized in the development and application of lipid-based materials.Broadly speaking,these include:Lipids Payloads EmulsifiersFigures 6 and 7 show a detailed breakdown of materials across these categories.The category of lipids was further sub-classified into the following

317、 general classes:Sphingolipids Sterols Phospholipids Glycerides Cationic lipids Oil and waxes PEG-lipid conjugates In order to identify lipids that have seen an increase in interest over time,we plotted the relative publication growth rates for 50 lipids over 2012-2023 and used this information to s

318、hortlist key lipids shown in Figure 8.The biggest takeaway from our data analysis was that of the identified lipids,cationic lipids such as 2,3-dioleyloxy-N-2-(sperminecarboxamido)ethyl-N,N-dimethyl-1-propanaminium(DOSPA;CAS number:282533-23-7),dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium(DM

319、RIE;CAS number:153312-64-2),1,2-dioleoyl-sn-glycero-3-ethylphosphocholine(EDOPC;CAS number:183283-20-7)and dioctadecylamidoglycylspermine(DOGS;CAS number:124050-77-7)and the PEG-lipid conjugate DMPE-mPEG(CAS number:474922-82-2)show a sharp increase in publications post 2018(Figure 8A).Phospholipids

320、such as 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine(DOPE,CAS number:4004-05-1)and 1,2-dioleoylphosphatidylserine(DOPS,CAS Number:70614-14-1)and sphingomyelin(CAS number:85187-10-6),a sphingophospholipid,also show an increase in publications after 2018 but the increase was of a more modest magnitud

321、e as compared to the cationic lipids listed above(Figure 8A).Finally,publications related to the phospholipid 1,2-dierucoyl-sn-glycero-3-phosphatidylcholine(DEPC,CAS number:51779-95-4)grew rapidly from 2018 to 2020 and then appears to have plateaued(Figure 8A).During the COVID-19 pandemic,a number o

322、f lipids were utilized in the delivery of vaccines being developed.The growth in interest(in terms of relative growth in publications)for these diverse lipids belonging to classes such as cationic lipids,PEG-lipid conjugate,phospholipids and sterols are shown in Figure 8B.Of particular note are the

323、cationic lipids ALC-0315(CAS number:2036272-55-4)and SM-102(CAS number:2089251-47-6)and the PEG-lipid conjugates 2-(Polyethylene glycol)-2000-N,N-ditetradecylacetamide(ALC-0159,CAS number:18496164-2-7)and DMG-PEG(CAS number:160743-62-4)which show a 5-6-fold and 3-fold increase in publications,respec

324、tively.The above-mentioned lipids can all be utilized to form various types of lipid nanocarriers including liposomes,lipid nanoparticles,exosomes,and emulsions,among others.We conducted a systematic search for the various types of lipid nanocarriers and their associated terms and showcase their dis

325、tribution and growth in the lipid-based materials document dataset in Figure 9.Liposomes,consisting of vesicles,PEGylated,echogenic,stimuli-responsive,and bubble liposomes account for more than half while lipid nanoparticles comprising of solid nanoparticles(solid NPs),nanostructured lipid carriers(

326、nanostructured LCs),ethosomes,cubosomes,and hexosomes account for a quarter of publications of the overall distribution(Figure 9A).Exosomes,a type of nanosized vesicles enclosed by a lipid bilayer membrane that can be used as drug delivery systems,and emulsions account for about 12%and 10%of publica

327、tions.Virus-like particles(VLPs),well-ordered complex structures composed of viral proteins that do not retain the pathogenicity of viruses,have been increasing explored in nanomedicine.43,44 While first discovered in the late 1960s,45 the use and exploration of VPNs appears to have proceeded in a m

328、odest fashion and accounts for a small fraction of overall publications in our dataset.Noteworthy,recently a selective endogenous encapsulation platform for cellular delivery has been developed based on mammalian capsid protein homologs that form virus-like particles,and a long terminal repeat retro

329、viral-like protein,which preferentially binds and facilitates vesicular secretion of its own mRNA.46 This modular platform,engineered to package,secrete,and deliver specific RNAs,has been demonstrated to be suitable for development as an efficient therapeutic delivery unit,which potentially provides

330、 an endogenous vector for RNA-based gene therapy.In terms of growth and time trends,among the subtypes of liposomes,stimuli-responsive liposomes47,48 show a sharp growth after 2016 while vesicles show a more controlled/modest but sustained growth for the last two decades(Figure 9B).Interest in PEGyl

331、ated liposomes49 appears to be more or less steady with neither a sharp increase nor decrease.Finally,echogenic and bubble liposomes appear to show a slight decline in interest around the same time(i.e.,post 2018)however the volume of publications associated with these subtypes are much smaller than

332、 the others.The diverse stimuli that have been utilized in the context of lipid nanocarriers can be broadly categorized into exogenous and endogenous with the former accounting for nearly 2/3rd of publications related to stimuli-induced release(Figure 10A).Of the various exogenous stimuli magnetic f

333、ield based50,51 and light or photosensitive/photo responsive52 release systems appear to be more popular than temperature53 and ultrasound54,55 based signaling.In terms of growth over time,publications related to endogenous stimuli,especially enzyme56,57 and redox,58,59 appear to show a sharp growth after 2014(Figure 10B)while those related to pH60 showed a more modest increase.Publications relate