Introduction to nanomedicine with emphasis on carrier-mediated drug targeting
Lecturer: Rimona Margalit (TAU) "Summer School on Nanomedicine and Innovation", The Marian Gertner Institute for Medical Nanosystems, Tel Aviv University, Ju...
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Introduction to nanomedicine with emphasis on carrier-mediated drug targeting - Video
European Nanomedicine Characterisation Laboratory
Our Mission is to provide a trans-disciplinary testing infrastructure covering a comprehensive set of preclinical characterisation assays (physical, chemical, in-vitro and in-vivo biological testing) allowing researchers to fully comprehend the bio distribution, metabolism, pharmacokinetics, safety profiles and immunological effects of their Med-NPs.
We are fostering the use and deployment of standard operating procedures (SOPs), benchmark materials, and quality management for the preclinical characterisation of Med-NPs (nanoparticles used for medical applications).
As nanomedicine is a fast evolving field of research, it is a key objective for EUNCL to constantly refine and adapt its assay portfolio and processes in order maintain the provision of state-of-the-art TNA to the scientific community. Therefore, we will progressively implement additional assays to increase our characterisation capacity, for instance in terms of medical application or route of administration.
The emphasis of the EUNCL is to serve as a nexus for trans-disciplinary research, development and clinical applications of nanotechnology. Therefore, lessons-learned, best practices, knowledge, tools and methods will be made available to the scientific community such as academic researchers, industry, regulatory bodies, metrology institutes and others. However, care will be taken to ensure that proprietary information and materials disclosed to the EUNCL by the TNA users are protected.
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EUNCL | Nanomedicine Characterisation Laboratory
LOS ANGELES, Feb. 4, 2020 /PRNewswire/ --Immix Biopharma, Incannounced today that the first patient in the USA was dosed successfully in its flagship phase 1b/2a clinical trial testing Imx-110 in patients with refractory solid tumors.To-date, the trial has accrued patients across tumor types. The expansion of the study to the US builds upon Immix' results from Australia, wherein six cohorts were dosed with no treatment-related serious adverse events observed and dose escalation is continuing.
The first US patient was dosed at Sarcoma Oncology Research Center in Santa Monica, California - led by Dr. Sant Chawla, a world renowned expert in sarcoma treatment and clinical research. Based on his extensive experience with anthracycline-based experimental therapies for sarcoma, including CytRx' Aldoxorubicin, Dr. Chawla shared his optimism for Imx-110 as an investigational candidate both from the standpoint of superior efficacy and a lower risk of cardiac complications associated with older formulations of doxorubicin.Dr. Chawla's colleague, Dr. Erlinda Gordon is the Principal Investigator leading the study at Sarcoma Oncology Research Center in Santa Monica.
Dr. Gordon is a Diplomate of the American Board of Pediatric Hematology/Oncology and previously a Tenured Associate Professor for 24 years at USC and currently a Professor Emeritus at the USC Keck School of Medicine, Los Angeles, California. She is a co-inventor of more than 150 patents in biomedical research, and patented the first targeted gene delivery system for cancer in the USA, Europe and the Philippines. She has authored more than 100 original peer-reviewed articles and served as Editor-in-Chief of the International Journal of Pediatric Hematology-Oncology, Director of the Red Cell Defects Program and the NIH-funded Comprehensive Hemophilia Center at Children's Hospital of Los Angeles and the NIH-funded Children's Oncology Group. Dr. Gordon was co-founder of two biotechnology companies and is a pioneer in the development of targeted gene therapy products.
For more information on the Imx-110 study, please visit clinicaltrials.gov: https://clinicaltrials.gov/ct2/show/NCT03382340.
Immix also has an open call for investigator initiated studies where the company will provide Imx-110 at no charge.
About Imx-110Imx-110 is a first-in-class combination therapy designed to inhibit cancer resistance and evolvability while inducing apoptosis. Imx-110 contains NF-kB/Stat3/pan-kinase inhibitor curcumin combined with a small amount of doxorubicin encased in a nano-sized delivery system for optimal tumor penetration. The nanoparticle is tunable in that it can be bound to various targeting moieties, allowing it to deliver even more payload to tumors or other cell populations of interest, if needed. Imx-110 showed preclinical efficacy in glioblastoma, multiple myeloma, triple-negative breast, colorectal, ovarian, and pancreatic tumor models with the mechanism of action being a 5x increase in cancer cell apoptosis compared to doxorubicin alone, and a wholesale shift in the tumor microenvironment post administration.
About the CompanyImmix Biopharma, Inc. is a privately-held, biopharmaceutical firm focused on developing safe and effective therapies for cancer patients. The company was founded by Vladimir Torchilin, Ph.D., D.Sc., Director of the Center for Pharmaceutical Biotechnology and Nanomedicine at Northeastern University; physician-scientist and clinical researcher Ilya Rachman, MD, PhD, MBA; and Sean D. Senn, JD, MSc., MBA, a senior biotechnology patent attorney. Immix's founding investor is a family office focused on harnessing scientific advances in order to engineer transformative and effective cancer treatments. For more information visit http://www.immixbio.com.
Media ContactRyan Witt+1 (888) 958-1084info@immixbio.com
View original content:http://www.prnewswire.com/news-releases/immix-doses-first-patient-in-usa-in-its-phase-1b2a-trial-in-patients-with-advanced-solid-tumors-300998208.html
SOURCE Immix Biopharma, Inc.
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Immix Doses First Patient in USA in its Phase 1b/2a Trial in Patients with Advanced Solid Tumors - BioSpace
Profiles in Nanomedicine Research: Sakaguchi
By: ISUengineering
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Profiles in Nanomedicine Research: Sakaguchi - Video
We are pleased to announce that the 2018 Nanomedicine and Drug Delivery Symposium will be hosted in Portland, Oregon.The objectives of this symposium are to highlight new groundbreaking discoveries and developments in nanomedicine and drug delivery. Revolutionary advances in this area require collaboration amongst researchers working in a diverse array of fields including nanotechnology, materials science, imaging, cell biology, tissue engineering, gene editing, drug and gene delivery as well as clinical research.
The symposium will take place at the Collaborative Life Science Building (CLSB), a next-generation health and science education and research facility that combines the resources and brainpower of three Oregon universities under one roof Oregon State University (OSU),Oregon Health & Science University (OHSU) and Portland State University (PSU).
College of Pharmacy, Oregon State University/Oregon Health Science University, Portland, OregonDr. Gaurav Sahay, Assistant ProfessorDr. Conroy Sun, Assistant ProfessorDr. Oleh Taratula, Assistant ProfessorDr. Adam Alani, Associate ProfessorDr. Olena Taratula, Research Assistant ProfessorDr. Mark Zabriskie, Professor and Dean
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NANODDS 2018 | 16th International Nanomedicine & Drug ...
New Jersey, United States,- The in-depth research report on Healthcare Nanotechnology (Nanomedicine) Market added to its huge repository by Verified Market Research provides brilliant and comprehensive market research. The report offers an in-depth study of key market dynamics including growth drivers, restraints, and opportunities. It mainly focuses on current and historical market scenarios. It includes market competition, segmentation, geographic expansion, regional growth, market size, and other factors. The Healthcare Nanotechnology (Nanomedicine) research study is sure to benefit investors, market players and other market players. You will gain an in-depth understanding of the global market and industry.
This report focuses on Healthcare Nanotechnology (Nanomedicine) market trends, future forecast, growth opportunities, key end-user industries and market players. The aim of the study is to present the most important developments of the market in the world.
The following Manufacturers are covered in this report:
Healthcare Nanotechnology (Nanomedicine) Market Report Contains:
Market Scenario Growth, Constraints, Trends, and opportunities Segments by value and volume Status of supply and demand Competitive analysis Technological innovations Analysis of the value chain and investments
This is an up-to-date report covering the current impact of COVID-19 on the market. The coronavirus pandemic (COVID-19) has affected all aspects of life around the world. This resulted in several changes in market conditions. The rapidly changing market scenario along with the initial and future assessment of the impact is covered in the report. The report discusses all major aspects of the market with expert opinions on the current state of the market as well as historical data. This market report is a detailed study of growth, investment opportunities, market statistics, growing competitive analysis, key players, industry facts, key figures, sales, prices, revenue, gross margins, market share, business strategies, major regions, demand and developments.
The report further studies the segmentation of the market based on product types offered in the market and their end-use/applications.
Furthermore, the market research industry provides a detailed analysis of the Healthcare Nanotechnology (Nanomedicine) market for the estimated forecast period. The market research provides in-depth insights into the various market segments based on end-use, types, and geography. One of the most important characteristics of a report is the geographic segmentation of the market which includes all the key regions. This section mainly focuses on various developments in the region including the main development and how these developments will affect the market. Regional analysis provides in-depth knowledge of business opportunities, market status and forecast, possibility of generating sales, regional market by different end-users along with future types and forecast for the coming years.
Geographic Segmentation
The report offers an exhaustive assessment of different region-wise and country-wise Healthcare Nanotechnology (Nanomedicine) markets such as the U.S., Canada, Germany, France, U.K., Italy, Russia, China, Japan, South Korea, India, Australia, Taiwan, Indonesia, Thailand, Malaysia, Philippines, Vietnam, Mexico, Brazil, Turkey, Saudi Arabia, U.A.E, etc. Key regions covered in the report are North America, Europe, Asia-Pacific, Latin America, and the Middle East and Africa.
The report includes:
Market overview Complete market analysis Analysis of the latest market developments Events of the market scenario in recent years Emerging and regional markets Segmentations up to the second and/or third level Historical, current and estimated market size in terms of value and volume Competitive analysis with an overview of the company, products, sales, and strategies. impartial market assessment Strategic recommendations to increase the presence in the business market
The study analyzes numerous factors influencing supply and demand in the Healthcare Nanotechnology (Nanomedicine) market and further assesses market dynamics that boost the market growth during the forecast period. Furthermore, the Healthcare Nanotechnology (Nanomedicine) market report offers a comprehensive analysis of the SWOT and PEST tools for all major regions such as North America, Europe, Asia Pacific, Middle East and Africa. The report offers regional expansion of the industry with product analysis, market share, and brand specifications. Furthermore, the Healthcare Nanotechnology (Nanomedicine) market research provides a comprehensive analysis of the political, economic, and technological factors which are driving the market growth in these economies.
Some Points from Table of Content
1. Study coverage2. Summary3. Healthcare Nanotechnology (Nanomedicine) Market Size by Manufacturer4. Production by region5. Consumption by region6.Healthcare Nanotechnology (Nanomedicine) Market Size by Type7. Healthcare Nanotechnology (Nanomedicine) Market size according to application8. Manufacturer profiles9. Production forecasts10. Consumption forecasts11. Analysis of customers upstream, industrial chain and downstream12. Opportunities and challenges, threats and influencing factors13. Main results14. Appendix
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Healthcare Nanotechnology (Nanomedicine) Market 2020: COVID19 Impact on Industry Growth, Trends, Top Manufacturer, Regional Analysis and Forecast to...
Dai M, Wu Z, Qi S, et al. Int J Nanomedicine. 2020;15:18631870.
The Authors, Editor and Publisher of International Journal of Nanomedicine have agreed to retract the published article. Concerns were raised by the Editor following the authors request to make several corrections to the published article. Many of the requested corrections related to data descriptions in the Materials and Methods and the Results and Discussion. Readers should note the Editor confirms the retraction is not due to academic misconduct but owing to the number of corrections reported within the article which were too numerous to be corrected in a standard corrigendum. The authors may consider republishing a corrected version of the article. The authors agreed with the decision to retract the article to maintain the preciseness of the publication record and wish to apologise for the number of corrections that were reported.
Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction.
The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as Retracted.
This retraction relates to this paper
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.
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Retraction for the article Implementation of PPI with Nano Amorphous O | IJN - Dove Medical Press
013 Sharing Science Explaining a Nanomedicine Breakthrough
By: Sophia Wight
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013 Sharing Science Explaining a Nanomedicine Breakthrough - Video
Nanomedicine Market Overview:
Reports and Data has recently published a new research study titled Global Nanomedicine Market that offers accurate insights for the Nanomedicine market formulated with extensive research. The report explores the shifting focus observed in the market to offer the readers data and enable them to capitalize on market development. The report explores the essential industry data and generates a comprehensive document covering key geographies, technology developments, product types, applications, business verticals, sales network and distribution channels, and other key segments.
The Nanomedicine Market is projected to grow at a rate of 12.6% to reach USD 387.11 billion in 2027 from USD 149.53 billion in 2019.
The report is further furnished with the latest market changes and trends owing to the global COVID-19 crisis. The report explores the impact of the crisis on the market and offers a comprehensive overview of the segments and sub-segments affected by the crisis. The study covers the present and future impact of the pandemic on the overall growth of the industry.
Get a sample of the report @ https://www.reportsanddata.com/sample-enquiry-form/1048
Competitive Landscape:
The global Nanomedicine market is consolidated owing to the existence of domestic and international manufacturers and vendors in the market. The prominent players of the key geographies are undertaking several business initiatives to gain a robust footing in the industry. These strategies include mergers and acquisitions, product launches, joint ventures, collaborations, partnerships, agreements, and government deals. These strategies assist them in carrying out product developments and technological advancements.
The report covers extensive analysis of the key market players in the market, along with their business overview, expansion plans, and strategies. The key players studied in the report include:
Arrowhead Pharmaceuticals Inc. AMAG Pharmaceuticals, Bio-Gate AG, Celgene Corporation, and Johnson & Johnson.
An extensive analysis of the market dynamics, including a study of drivers, constraints, opportunities, risks, limitations, and threats have been studied in the report. The report offers region-centric data and analysis of the micro and macro-economic factors affecting the growth of the overall Nanomedicine market. The report offers a comprehensive assessment of the growth prospects, market trends, revenue generation, product launches, and other strategic business initiatives to assist the readers in formulating smart investment and business strategies.
To read more about the report, visit @ https://www.reportsanddata.com/report-detail/nanomedicine-market
Product Outlook (Revenue, USD Billion; 2017-2027)
Drug Delivery System Outlook (Revenue, USD Billion; 2017-2027)
Application Outlook (Revenue, USD Billion; 2017-2027)
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Key Coverage in the Nanomedicine Market Report:
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This article was originally published here
Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2020 Nov 10:e1677. doi: 10.1002/wnan.1677. Online ahead of print.
ABSTRACT
Non-small cell lung cancer (NSCLC) is the primary cause of cancer death worldwide. Despite developments in chemotherapy and targeted therapies, the 5-year survival rate has remained at approximately 16% for the last four decades. NSCLC is a heterogeneous group of tumors that, through mutations and drivers, also demonstrate intra-tumor heterogeneity. Thus, current treatment approaches revolve around targeting these oncogenes, often using small molecule inhibitors and chemotherapeutics. However, the efficacy of these therapies has been crippled by acquired and inherent drug-resistance in the tumor, accompanied by increased therapeutic dosages and subsequent devastating off-target effects for patients. Evidently, there is a critical need for developing treatment methodologies more effective than the current standard of care. Fortunately, RNA interference, particularly small interfering RNA (siRNA), presents an alternative of silencing specific oncogenes to control tumor growth. Although siRNA therapy is subject to rapid degradation and poor internalization in vivo, nanoparticles can serve as nontoxic and efficient delivery vehicles, even introducing combinational delivery of multiple therapeutic agents. Indeed, siRNA-nanoconstructs possess extraordinary potential as an innovative modality to address clinical needs. This state-of-the-art review summarizes the recent advancements in the development of novel nanosystems for delivering siRNA to NSCLC tumors and analyzes the efficacy of representative examples. By illuminating the most promising biomarkers for silencing, we hope to streamline current therapeutic efforts and highlight powerful translational opportunities to combat NSCLC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology-Inspired Nanomaterials > Lipid-Based Structures Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
PMID:33174364 | DOI:10.1002/wnan.1677
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A review on RNAi therapy for NSCLC: Opportunities and challenges - DocWire News
Transfection is a process that involves production of genetically modified cells with utilization of foreign nucleic acid (DNA and RNA). This technology helps the cells in mutation of cancer cells, protein metabolism by affecting the nuclear genes and regulation of gene therapy. Transfection is an integral equipment used in investigation studies for gene function and the modulation of gene expression. Thus, it contributes in the advancement of basic cellular research, drug discovery, and target validation. The transfection reagent and equipment market is driven by rising prevalence of infectious disease, utilization of biopharmaceuticals in the production of proteins, growing obese population, and increasing prevalence of cancer. Various government initiative accentuated the growth of transfection reagent and equipment market. However, high cost of transfection reagents and equipment, risk factors during insertion of the reagents and cytotoxic effect associated with transfection technology are the major factors restraining the transfection reagents and equipment market.
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The transfection reagent and equipment market can be segmented on the basis of various methods such as physical methods and biochemical methods. The biochemical method accounts for the largest share in the overall transfection market. The biochemical based method is further segmented as calcium phosphate, DEAE-dextran, lipid mediated transfection (Lipofection), catonic polymers, activated dendrimers and magnetic beads. The physical based method includes electroporation, biolistic technology, microinjection, laserfection and others (gene gun, sonoporation). Electroporation technique is likely to account for the largest share in the equipment based transfection. The transfection reagent market, by application is segmented into biomedical research, protein product, and therapeutic delivery. The biomedical research segment was observed as one of the largest segment of the transfection reagent market.
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Geographically, North America is the largest transfection reagents and equipment market in the world due to rising prevalence of various cancers (such as cervical cancer, breast cancer, colon cancer, and prostate cancer). Moreover, rising demand for proteomics and genomics technology and upfront initiatives taken by government related to preventive healthcare have supported the growth of transfection reagents and equipment market in this region. Europe was the second largest market due to rising trend of utilization of targeted drug delivery, nanomedicine in diagnostics, clinical trials and drug development studies drive the demand of transfection reagents and equipment market. Asia-Pacific is observed to be an emerging market in transfection reagents and equipment market and is still in the initial stage. One of the important factors driving the growth of transfection reagent and equipment in the Asia-Pacific market is outsourcing of clinical trials to Asian countries by majority of the drug development companies. Moreover, development of in transfection technology, rise in demand of protein therapeutics, developing healthcare infrastructure in emerging markets such as India and China, and increasing demand from applied markets. Latin American countries such as Brazil and Mexico are the regions that have significant potential for growth due to emerging medical infrastructure, high disposable income and rising prevalence of infectious diseases. Transfection equipment and reagents market is in introductory stage especially in Latin American and African countries.
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Some of the major players in the global transfection reagent and equipment market include
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Transfection Reagents And Equipment Market Share to Witness Steady Rise in the Coming Decade - Scientect
This analysis provides the insights which bring marketplace clearly into the focus and thus help organizations make better decisions. The data and the information regarding the industry are taken from consistent sources such as websites, annual reports of the companies, and journals which is then checked and validated by the market experts. report has been structured with transparent research studies which makes it of supreme quality. By exactly understanding customer requirement, one or more methods are used to construct this finest market research report. The report provides with CAGR value fluctuation during the forecast period of 2020 2025 for the market.
Global nanomedicine marketis registering a healthy CAGR of 15.50% in the forecast period of 2019-2026. This rise in the market value can be attributed to increasing number of applications and wide acceptance of the product globally. There is a significant rise in the number of researches done in this field which accelerate growth of nanomedicine market globally.
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Key Market Competitors
Few of the major market competitors currently working in the global nanomedicine market are Abbott, Invitae Corporation, General Electric Company, Leadiant Biosciences, Inc., Johnson & Johnson Services, Inc., Mallinckrodt, Merck Sharp & Dohme Corp., NanoSphere Health Sciences, Inc., Pfizer Inc., CELGENE CORPORATION, Teva Pharmaceutical Industries Ltd., Gilead Sciences, Inc., Amgen Inc., Bristol-Myers Squibb Company, AbbVie Inc., Novartis AG, F. Hoffmann-La Roche Ltd., Luminex Corporation, Eli Lilly and Company, Nanobiotix, Sanofi, UCB S.A., Ablynx among others.
Competitive Landscape
Global nanomedicine market is highly fragmented and the major players have used various strategies such as new product launches, expansions, agreements, joint ventures, partnerships, acquisitions, and others to increase their footprints in this market. The report includes market shares of nanomedicine market for global, Europe, North America, Asia-Pacific, South America and Middle East & Africa.
Key Insights in the report:
Complete and distinct analysis of the market drivers and restraints
Key Market players involved in this industry
Detailed analysis of the Market Segmentation
Competitive analysis of the key players involved
Market Drivers are Restraints
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Market Segmentation:-
By Product Type
By Application
By Indication
By Modality
To comprehend Global Nanomedicine market dynamics in the world mainly, the worldwide Nanomedicine market is analyzed across major global regions.
Actual Numbers & In-Depth Analysis, Business opportunities, Market Size Estimation Available in Full Report.
Some of the Major Highlights of TOC covers:
Chapter 1: Methodology & Scope
Definition and forecast parameters
Methodology and forecast parameters
Data Sources
Chapter 2: Executive Summary
Business trends
Regional trends
Product trends
End-use trends
Chapter 3: Industry Insights
Industry segmentation
Industry landscape
Vendor matrix
Technological and innovation landscape
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Nanomedicine Market report effectively provides required features of the global market for the population and for the business looking people for mergers & acquisitions, making investments, new vendors or concerned in searching for the appreciated global market research facilities. It offers sample on the size, offer, and development rate of the market. The Nanomedicine report provides the complete structure and fundamental overview of the industry market.
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Global nanomedicine market Is Projected To Witness Vigorous Expansion By 2026 |DBMR insights - The News Brok
New Jersey, United States,- The most recent Nanomedicine Market Research study includes some significant activities of the current market size for the worldwide Nanomedicine market. It presents a point by point analysis dependent on the exhaustive research of the market elements like market size, development situation, potential opportunities, and operation landscape and trend analysis. This report centers around the Nanomedicine business status, presents volume and worth, key market, product type, consumers, regions, and key players.
The COVID-19 pandemic has disrupted lives and is challenging the business landscape globally. Pre and Post COVID-19 market outlook is covered in this report. This is the most recent report, covering the current economic situation after the COVID-19 outbreak.
Key highlights from COVID-19 impact analysis:
Unveiling a brief about the Nanomedicine market competitive scope:
The report includes pivotal details about the manufactured products, and in-depth company profile, remuneration, and other production patterns.
The research study encompasses information pertaining to the market share that every company holds, in tandem with the price pattern graph and the gross margins.
Nanomedicine Market, By Type
Nanomedicine Market, By Application
Other important inclusions in the Nanomedicine market report:
A brief overview of the regional landscape:
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Nanomedicine Market 2020 Size by Product Analysis, Application, End-Users, Regional Outlook, Competitive Strategies and Forecast to 2027 - Owned
New Jersey, United States,- The most recent Healthcare Nanotechnology (Nanomedicine) Market Research study includes some significant activities of the current market size for the worldwide Healthcare Nanotechnology (Nanomedicine) market. It presents a point by point analysis dependent on the exhaustive research of the market elements like market size, development situation, potential opportunities, and operation landscape and trend analysis. This report centers around the Healthcare Nanotechnology (Nanomedicine) business status, presents volume and worth, key market, product type, consumers, regions, and key players.
The COVID-19 pandemic has disrupted lives and is challenging the business landscape globally. Pre and Post COVID-19 market outlook is covered in this report. This is the most recent report, covering the current economic situation after the COVID-19 outbreak.
Key highlights from COVID-19 impact analysis:
Unveiling a brief about the Healthcare Nanotechnology (Nanomedicine) market competitive scope:
The report includes pivotal details about the manufactured products, and in-depth company profile, remuneration, and other production patterns.
The research study encompasses information pertaining to the market share that every company holds, in tandem with the price pattern graph and the gross margins.
Healthcare Nanotechnology (Nanomedicine) Market, By Type
Healthcare Nanotechnology (Nanomedicine) Market, By Application
Other important inclusions in the Healthcare Nanotechnology (Nanomedicine) market report:
A brief overview of the regional landscape:
Reasons To Buy:
About Us:
Market Research Intellect provides syndicated and customized research reports to clients from various industries and organizations with the aim of delivering functional expertise. We provide reports for all industries including Energy, Technology, Manufacturing and Construction, Chemicals and Materials, Food and Beverage, and more. These reports deliver an in-depth study of the market with industry analysis, the market value for regions and countries, and trends that are pertinent to the industry.
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Healthcare Nanotechnology (Nanomedicine) Market 2020 Size by Product Analysis, Application, End-Users, Regional Outlook, Competitive Strategies and...
Everything about Chinas drive to become a leading innovator works on a giant scale. Ambitions are enormous, budgets are vast and the focus is widespread. And in many fields, its beginning to close the gap with U.S. and European institutions. But its in the study of materials on the scale of a billionth of a meter nanoscience that China is already fast overtaking its international rivals.
From cloning to cancer research, China is using nanoscience and nanotechnology innovation to drive some of the worlds biggest breakthroughs. In July, an international team of researchers led by Chinese scientists developed a new form of synthetic, biodegradable nanoparticle. Capable of targeting, penetrating and altering cells by delivering the CRISPR/Cas9 gene-editing tool into a cell, the nanoparticle can be used in the treatment of some single-gene disorders, as well as other diseases including some forms of cancer.
In a separate project, scientists at Chinas Nanjing University haveused nanoparticles to target and destroy abnormal proteins known to causebreast cancer. Tests in mice showed the treatment reduced the size of tumors byhalf compared to the control group. At the University of Science and Technologyof China, a team of researchers claims to have given mice infrared night visionby injecting nanoparticles into their eyes.
And at the State Key Laboratory of Robotics in the northeast city of Shenyang, researchers have developed a laser that produces a tiny gas bubble. This bubble can be used as a tiny robot to manipulate and move materials on a nanoscale with microscopic precision. The technology promises new possibilities in the field of artificial tissue creation and cloning.These innovations are backed up by a scale of research thats unmatched. In 2018, Chinese researchers were on their own responsible for 40 percent of all global scientific papers in the field, with the U.S. (15 percent) a distant second.
Nanotechnology supports biomedicine and quantum technology development and makes its way into everyday life through advancements in consumer electronics and artificial intelligence, all areas where China seeks global dominance. Being at the forefront of cutting-edge nano research greatly improves Chinas prospects for success, especially in biomedicine, where it has long trailed rivals.
Drug delivery, nanomedicine and tissue engineering are rapidly growing fields that rely on our ability to engineernanoparticles and biomaterialstargeted at specific cells, such as cancer cells,to enhance the therapeutic efficacy, says Dr. Omid Kavehei, deputy director of the University of Sydney Nano Institute.
Chinas gains could help it win critical patents in advanced research in fields like cancer, where the U.S. has historically led.
Strong state support in nanoscience as in tech fields such as artificial intelligence and robotics is also a key advantage for China, Bai Chunli, president of the Chinese Academy of Sciences (CAS), conceded publicly in August. The importance the government places on competitiveness in the field is underlined by its inclusion as a strategic industry in Chinas 13th Five-Year Plan, ensuring state funding and legislative and regulatory support. Nanotech research is also a key component of the ambitious Made in China 2025 initiative aimed at turning China into a high-tech manufacturing powerhouse.
Thats allowing China to find success in myriad areas of nanotechnology. A new nanomaterial invented by CAS scientists promises to eliminate millions of metric tons of liquid pollution and emissions from organic chemicals used in printing plates and ink. It is one of the headline acts for CAS as it drives to apply nanotechnology innovation to the development of consumer tech. So far, the project has landed $780 million in investment.
China still relies on collaborations with foreign institutions in most of the subfields of nanoscience and nanotechnology.
Shengfu Yang, University of Leicester
In an October 2019 paper published by science journalNano Energy, Dalian Institute of Chemical Physics announced the creation of a tiny lithium battery that is resilient to low temperatures, capable of operating at 80 percent efficiency at temperatures of -40 degrees Celsius. While the battery presents huge potential for industries from electric cars to mobile devices, the ability of the battery to operate at extreme temperatures is particularly important to the future of space technology.
Industry experts point to the return of foreign-trained Chinese researchers to the Middle Kingdom, lured by the promise of readily available funding, as an important factor of Chinas progress. The next step is for China to become self-sufficient in developing talent. Currently China still relies on collaborations with foreign institutions in most of the subfields of nanoscience and nanotechnology, says Shengfu Yang, nanochemistry professor at the University of Leicester. The nanoparticle that delivers the gene-editing tool into cells was developed in partnership with scientists at Tufts University in the United States, for instance.
Enhancing innovation in the private sector will also help China kick on, says Zheng Xiao Guo, professor of chemistry and mechanical engineering at the University of Hong Kong. State-funded institutions have played a far bigger role in nanotechnology innovations, and private institutions or enterprises in this area are not as strong, he says.
But the number of private companies driving nanotech product innovation is rapidly growing, Zheng concedes. Nanopolis, the worlds largest nanotech industrial zone, located in the eastern city of Suzhou, houses several private multinationals and new Chinese startups across nanotech fields. China now also leads the globe in newly established nanotech companies. In 2018, Tencent founder Ma Huateng joined a number of high-profile businesspeople in financing the establishment ofChinas first private research institute,Westlake University, with nanotech a main focus for research.
Private-sector involvement opens new and unique pools of funding and talent, and the focus is on applicable research even in a country like China, where state-sponsored institutions still dominate, say experts.
That combination of a growing talent pool and a state-sponsored desire to become a global leader, with an expanding private-sector ecosystem, will be hard for other countries to match. Chinas big leap in small science is just starting.
Abstract
Conventional thrombolytic drugs for vascular blockage such as tissue plasminogen activator (tPA) are challenged by the low bioavailability, off-target side effects and limited penetration in thrombi, leading to delayed recanalization. We hypothesize that these challenges can be addressed with the targeted and controlled delivery of thrombolytic drugs or precision drug delivery. A porous and magnetic microbubble platform is developed to formulate tPA. This system can maintain the tPA activity during circulation, be magnetically guided to the thrombi, and then remotely activated for drug release. The ultrasound stimulation also improves the drug penetration into thrombi. In a mouse model of venous thrombosis, the residual thrombus decreased by 67.5% when compared to conventional injection of tPA. The penetration of tPA by ultrasound was up to several hundred micrometers in thrombi. This strategy not only improves the therapeutic efficacy but also accelerates the lytic rate, enabling it to be promising in time-critical thrombolytic therapy.
Blood vessel occlusion partly or completely blocks the flow of blood in a blood vessel, often resulting in life-threatening diseases such as coronary infarction, ischemic stroke, and pulmonary embolism (13). While infusion of thrombolytic drugs such as tissue plasminogen activator (tPA) through either systematic administration or catheter placement has greatly improved the survival rates and the life quality of the patients, challenges emerge such as the low bioavailability of tPA, poor delivery efficiency, and the resistance of fibrin and platelet-rich thrombi to thrombolytic drugs, resulting in stepwise or slow recanalization (47).
The targeted and controlled delivery of thrombolytic drugs has been proposed to address the challenges, aiming at improving the bioavailability of tPA, targeted delivery, and clot lysis acceleration (811). For example, shear-stress responsive carriers targeting the narrowed or obstructed blood vessels could lower the required doses of tPA and minimize the side effects (12). Rotating magnetic nanomotors elevate tPA transport at the interface of blood and clot, resulting in accelerated lytic rate and improved thrombolytic efficacy (13). Acoustically trigged release of tPA from tPA-loaded echogenic liposomes enhance the thrombolytic activity due to cavitation or acoustically driven diffusion effects (14, 15). While these advancements are encouraging, they only partially address the above challenges and have not been translated into clinical practice.
There are three keys in this process, i.e., maintenance of drug activity, selected accumulation in the clots, and diffusion/penetration throughout the clot tissue (1618). Although shear-activated nanotherapeutics is promising to improve the delivery efficiency specifically to clots, the loaded tPA by surface conjugation tend to be deactivated by the inhibitors in the blood (12). Ultrasound can trigger the tPA release from tPA-loaded echogenic liposomes directly to the site of a clot visualized by ultrasound imaging; however, it has been limited because of the lack of targeted strategy (14, 15). The thrombolysis efficacy of these methods was also challenged by the limited clot penetration of released tPA. Magnetically targeted delivery of tPA and rotating enhanced mass transfer (diffusion) of tPA have been achieved by magnetic porous micromotors (19). This method addressed the challenges mentioned above and improved the therapeutic efficacy of blood clot in the mice middle cerebral, thereby representing a potential solution for accelerating thrombolysis. Despite promising, a trigger of the release of tPA from carriers will reduce the unwanted leakage during circulation. Meanwhile, facilitating the penetration of tPA rapidly during the treatment will initiate the enlarged interaction area between tPA and clots, probably further improving the thrombolysis efficacy.
To address this unmet need, we propose a precision delivery strategy using the magnetic targeting and ultrasound-triggered release. Specifically, this strategy uses a multifunctional nanosystem with responsiveness to the magnetic field and ultrasound by synergizing different functions of its components (Fig. 1A). This system stably maintains the tPA activity during circulation. When guided by a magnet, it directly targets to the thrombi and then is remotely activated for drug release using low-intensity ultrasound. The ultrasound stimulation also rapidly improves drug penetration into thrombi tissue within several minutes.
(A) Illustration of targeted delivery and controlled release for thrombolysis. (B) Illustration of the synthesis of nanomedicine-shelled microbubble (i.e., MMB-SiO2-tPA).
As a proof of concept, we have developed a nanoparticle-shelled microbubble (MMB-SiO2-tPA) for the targeted delivery of tPA to clots. The microbubbles were made through nanoparticle self-assembly at the liquid-air interface (Fig. 1B). The prepared microbubbles have a layer of nanoparticles that are densely packed around the air core, sealing the air and preventing the release of loaded tPA in circulation. The magnetic component of the shell facilitates the targeting of the microbubbles to clots under a magnetic field. Upon ultrasound stimulation, microbubbles oscillate, and shelled nanoparticles are released from the bubbles following the microstreaming. The momentum received from the oscillation allows the nanoparticles to penetrate into the agarose-fibrin gel and femoral vein clots up to 1 cm and hundred micrometers, respectively. The penetrated tPA accelerates the mass transfer into the interior of the clots, thereby improving the lytic rate and thrombolysis efficacy.
Nanoparticle-shelled microbubbles (MMB-SiO2-tPA) are composed of a gas core and a shell of nanoparticles. The core is air, while the nanoparticles are a mixture of magnetic iron oxide nanoparticles (50 nm; MMB) and tPA-containing mesoporous silica nanoparticles (50 nm; SiO2-tPA). Under the presence of anionic surfactant (e.g., SDS) and agitation, gas is encapsulated within the surfactant, and nanoparticles assemble at the air-liquid interface. Their size can be precisely controlled by adjusting the agitation speed and the concentration of nanoparticles (20).
The structure and morphology of prepared MMB-SiO2-tPA were shown in Fig. 2A. The mean thickness of the nanoparticle shells was around 1.5 m, accounting for approximately 20 to 30 layers of assembled nanoparticles (fig. S1). Elemental mapping confirmed the presence of Fe, Si, and O on the shell of the MMB-SiO2-tPA with homogeneous distribution (Fig. 2B). The microbubbles were compacted with spherical shape and had a mean diameter of 5.36 1.44 m (Fig. 2C), similar to the microbubbles used in clinics (2 to 8 m usually) (21). To identify whether the mesoporous silica nanoparticles were loaded in the microbubble shell, SiO2-tPA nanoparticles were replaced with SiO2-Cy5.5 nanoparticles. In a confocal image, red fluorescence surrounded the shell of most microbubbles, while no fluorescence was found in the air core, suggesting the structure of nanoparticle-shelled microbubble and the efficient assembly of silica nanoparticles (fig. S2). Being out of the focal plane resulted in centered fluorescence and smaller sizes of the microbubbles in the same confocal image. Quantitative element analysis by inductively coupled plasma optical emission spectrometry (ICP-OES) revealed the contents of Fe and Si in MMB-SiO2-tPA samples (Fig. 2D), and the content of tPA was quantified by bicinchoninic acid (BCA) assay (Fig. 2E). After the number of MMB-SiO2-tPA in different volume of solutions was counted (Fig. 2F), the amounts of Fe, Si, and tPA were determined as 1.25 108, 2.99 1010, and 6.63 1012 g per MMB-SiO2-tPA, respectively. The encapsulation efficiency of tPA was 47.9%.
(A) Environmental scanning electron microscope image of MMB-SiO2-tPA in bright field mode. Scale bar, 10 m. (B) Scanning electron microscopy and elemental mapping of a single MMB-SiO2-tPA. Scale bar, 5 m. (C) The diameter distribution of the MMB-SiO2-tPA; n = 200. (D) Contents of iron and silicon in different volumes of MMB-SiO2-tPA quantified by ICP-OES. (E) Content of thrombolytic drug (tPA) in different volumes of MMB-SiO2-tPA by BCA assay. (F) Counting MMB-SiO2-tPA in different volumes of solutions. (G) In vitro enzymatic activity of native tPA, SiO2-tPA, and MMB-SiO2-tPA versus time in the presence of plasminogen activator inhibitor-1 (PAI-1). (H) The retained activity of tPA after 3 and 12 hours in the presence of PAI-1. (I) Cumulative release profiles of thrombolytic drug tPA from MMB-SiO2-tPA at different acoustic pressure of ultrasound. Error bars in all figures indicated the standard divisions by at least triplicate experiments.
tPA has a relatively short half-life (about 2 to 6 min) in circulation as there are inhibitors such as plasminogen activator inhibitor1 (PAI-1; the major inhibitor of tPA) (22). When it was loaded in the mesoporous silica nanoparticles, its stability can be substantially improved. For example, we compared the availability of tPA under the presence of the PAI-1 for three formulations (i.e., native tPA, SiO2-tPA, and MMB-SiO2-tPA). The activity of tPA in all groups decreased with time when exposed to PAI-1 (Fig. 2G). The retained activity of native tPA decreased to 25% when exposed to PAI-1 for 60 min, while more than 50% of tPA in both SiO2-tPA and MMB-SiO2-tPA maintained their activity at the same time. After 12 hours of incubation with PAI-1, MMB-SiO2-tPA still maintained 36% of the tPA activity, which was higher than 16 and 8% obtained by SiO2-tPA and native tPA, respectively (Fig. 2H). It is worth noting that the close packing of shelled nanoparticles on the microbubble surface prevented the release of tPA from silica nanocarriers without an ultrasound trigger, resulting in the higher retained activity of MMB-SiO2-tPA than that of SiO2-tPA.
This microbubble-based drug delivery system is expected to release the drug upon the ultrasound stimulation. Traditionally, most microbubbles are stabilized by a rigid shell formed by polymer, silica, or protein (21, 23). The release of cargos depends on the bubble inertial expansion and explosion, a phenomenon called cavitation that usually requires high acoustic-driven force (i.e., high-intensity ultrasound) (24). To reduce the risk of tissue injury in cavitation, drug release by stable microbubble oscillations (fig. S3) that activated by low-intensity ultrasound is an alternative (20, 25, 26).
We compared tPA release under both microbubble stable oscillations and cavitation. Stable oscillation was achieved when the ultrasound intensity was set below the threshold of activating microbubble cavitation (0.4 bar or 0.04 MPa in our experiment) (20). Shelled nanoparticles are then released by these microbubble oscillations accompanied by the microstreaming. For example, approximately 5% of tPA were released when ultrasound was applied for five cycles with the acoustic pressure of 0.05 bar (i.e., 0.005 MPa; Fig. 2I). If the ultrasound was kept on applying for another 60 cycles, then the amount of released tPA reached a plateau to around 90%. Owing to the stable oscillations of MMB-SiO2-tPA that without microbubble collapse, a stepwise release of tPA was achieved with increasing the number of cycles of applied ultrasound. When most nanoparticles were released, MMB-SiO2-tPA gradually dissolved in solution. By increasing the acoustic pressure to 0.1 and 0.15 bar, more rapid release kinetics were observed compared to that by 0.05 bar, suggesting that more intense oscillations happened. If the acoustic pressure (i.e., 0.5 bar or 0.05 MPa) was higher than the cavitation threshold, then almost 90% of tPA were released at the first five cycles of ultrasound due to the bubble collapse by the cavitation effect. On the basis of these findings, on-demand release of tPA can only be achieved by stable microbubble oscillations under low-intensity ultrasound.
We first validated the response of MMB-SiO2-tPA toward the magnetic guidance in an in vitro vessel system. The MMB-SiO2-tPA were dissolved in cell culture medium and pumped by a syringe into a polyethylene vessel (diameter of 3 mm) with a speed (1.2 cm s1) that mimics the blood flow. When a magnet was placed adjacent to the vessel, MMB-SiO2-tPA accumulated to the magnet in approximately 2 s (fig. S4). Once the magnet was removed, the accumulated MMB-SiO2-tPA swiftly dispersed and circulated with the liquid flow without noticeable attachment to the vessel wall.
Next was to confirm this magnetically guided targeting in vivo. Ultrasound imaging was used to track this process, as the microbubbles can enhance the contrast in ultrasound imaging. As shown in Fig. 3B, the B mode acoustic intensity of a phantom was enhanced by three times after injection of MMB-SiO2-tPA into the phantom. The enhancement of contrast mode was much more significant, which is increased by 17 times after injection (Fig. 3D).
(A) Schematic illustration of the ultrasound imaging and magnetic targeting process in a femoral vein thrombosis model. (B) In vitro ultrasound phantom images of MMB-SiO2-tPA in B mode and contrast mode. (C) In vivo ultrasound images of femoral vein thrombi before and after MMB-SiO2-tPA injection in B mode and contrast mode. A magnet was placed adjacent to the femoral vein after 5 min after MMB-SiO2-tPA injection. (D) The acoustic intensities of the interested area (red frame) quantified in ultrasound phantom images. a.u., arbitrary units. (E) The acoustic intensities of the interested area (red frame) quantified in ultrasound images of the mouse model. Error bars in all figures indicated the standard divisions by at least triplicate experiments.
The animal model was built on mice through ferric chloride infiltration of the femoral vein. We imaged the mice before and after the intravenous injection with MMB-SiO2-tPA. A magnet was placed adjacent to the thrombi for magnetic targeting (Fig. 3A). The acoustic intensities of both B mode and contrast mode of the thrombi in the femoral vein were slightly increased after intravenous injection of MMB-SiO2-tPA for 5 min, which might be attributed to the presence of small amounts of MMB-SiO2-tPA at the thrombi lesion through blood circulation (Fig. 3C). Once a magnet was applied, significant enhancement of the acoustic intensities of both B mode and contrast mode was observed (increased by 1.4 and 2.6 times, respectively), suggesting the accumulation of MMB-SiO2-tPA at the thrombi site by magnetic targeting (Fig. 3E). Therefore, MMB-SiO2-tPA can be magnetically guided to the thrombi and used as ultrasound contrast agents for thrombi diagnosis, simultaneously monitoring the delivery efficiency of therapeutic agents noninvasively.
In the fibrinolysis process, tPA activates plasminogen and converts it into plasmin, which is able to cleave fibrin into a soluble product (27). To validate the effectiveness of fibrin lysis and the penetration of tPA in three dimensions, a vertical-channel gel system composed of fibrinogen, thrombin, plasminogen, and agarose was developed. Fibrin formed by the reaction of fibrinogen and thrombin were dispersed within the agarose gel with good homogeneity and appeared pale white throughout the gel (Fig. 4A, top left). Once fibrin interacted with tPA, degraded products will make the gel transparent (dark area), indicating the lysis area by tPA. As shown in Fig. 4, following the addition of tPA from the top of the vertical channel, a stepwise enlargement of the lysis area with time is presented from the top of the gel (Fig. 4A, bottom left). The stepwise lysis by tPA, the standard thrombolysis process in clinics, was attributed to the mass transfer dynamics of tPA at the liquid-gel (or liquid-thrombi) interface, suggesting limited penetration of tPA in the gel. A similar finding was also found in the group treated by SiO2-tPA (Fig. 4A, top right), where retarded lysis compared to native tPA was observed because of the delayed release of tPA from SiO2 nanocarriers (fig. S5). To facilitate the penetration of SiO2-tPA into the gel, MMB-SiO2-tPA (equivalent amount of tPA with the groups of native tPA or SiO2-tPA) were concentrated at the liquid-gel interface by a magnet and then irrigated by low-intensity ultrasound (0.2 bar, i.e., 0.02 MPa) for stable oscillations. The penetration of both iron oxide and silica nanoparticles throughout the gel was observed immediately once the stable oscillations happened, where black dots appeared deep inside the gel along the vertical channel (Fig. 4A, bottom right). The enlargements of dark areas at multiple locations indicated that the lysis happened not only at the liquid-gel interface but also around the nanocarriers that penetrating into the gel. Consequently, the fibrinolytic efficacy (quantified by fibrinolytic areas; Fig. 4B) of MMB-SiO2-tPA was higher than native tPA after 6-hour treatment. The mean fibrinolytic rate obtained by MMB-SiO2-tPA markedly increased during the period from 6 to 12 hours after treatment (Fig. 4C). However, the fibrinolytic rate obtained by native tPA decreased with time because of the consumption or degradation of tPA. It is worth noting that these improvements of both fibrinolytic efficacy and fibrinolytic rate by MMB-SiO2-tPA compared to native tPA were achieved in a confinement space without blood flow. Considering the blood flow in vivo that resulted in fast clearance of tPA, the improvement of tPA penetration will retain the delivered tPA within the clots and, lastly, accelerate thrombolysis and improve the efficacy of tPA treatment.
(A) Schematic diagrams and representative photographs of the fibrinolytic process of the agarose-fibrin gel incubated with saline, native tPA, SiO2-tPA, and MMB-SiO2-tPA at different thrombolysis times, respectively. (B) Quantification of fibrinolytic area of fibrin over time incubated with saline, native tPA, SiO2-tPA, and MMB-SiO2-tPA (n = 5; ***P < 0.001). (C) The mean fibrinolytic rate of fibrin at different time intervals incubated with native tPA, SiO2-tPA, and MMB-SiO2-tPA (n = 5).
The thrombolysis efficacy was further evaluated in the ex vivo blood clots, which were prepared by fresh mice blood and thrombin (Fig. 5A). With dissolution, the clots in tubes shrank, and the supernatants became red. As expected, clots treated by saline barely lysed in a period of 12 hours, suggesting the stability of prepared clots. When clots were treated with native tPA, SiO2-tPA, or MMB-SiO2-tPA, all clots lysed stepwise into smaller sizes, while the supernatants gradually changed from colorless into blood red (Fig. 5B). The black color presented in MMB-SiO2-tPAtreated group was generated by the released iron oxide nanoparticles. The dissolution efficiencies were quantified by measuring the mass loss of the clots at 3 and 12 hours after treatments. During the first 3 hours (Fig. 5C), clots treated by MMB-SiO2-tPA exhibited similar dissolution efficiency (approximately 32%) to those by native tPA (approximately 27%), which was higher than those obtained by SiO2-tPA or saline treatments (17 and 7%, respectively). After 12 hours (Fig. 5D), MMB-SiO2-tPA treatment achieved the highest dissolution efficiency, which was approximately 93%, compared to those obtained by native tPA, SiO2-tPA, or saline treatments (68, 51, and 16%, respectively). The amounts of hemoglobin (released during clot lysis) in the supernatants at 12 hours after treatments exhibited similar trends to the dissolution efficiencies, confirming the results obtained in the ex vivo experiments. As this experiment was performed in a static situation without blood flow, the improvement of dissolution efficiency in the MMB-SiO2-tPAtreated group might be attributed to the enhanced penetration and retained activity of tPA.
(A) Schematic illustration of the blood clot dissolution treatment process under the magnetic field combined with low-intensity ultrasound. (B) Representative images of the thrombolysis processes at 0, 3, 6, 9, and 12 hours after being treated by saline, native tPA, SiO2-tPA, and MMB-SiO2-tPA, respectively. (C) Quantification of the dissolution efficiency by measuring the mass loss of the blood clot at 3 hours after treatments. (D) Quantification of the dissolution efficiency by measuring the mass loss of the blood clot at 12 hours after treatments. (E) Absorbance values ( = 540 nm) of the supernatants at 12 hours after treatments; n = 5; *P < 0.05, **P < 0.01, and ***P < 0.001.
To investigate whether the clot-penetrating strategy was applicable to in vivo animal models, we performed different treatments to the femoral vein thrombi of a mouse model. Male C57/BL6J mice were pretreated with FeCl3 for infiltration to form the clots, then were injected with MMB-SiO2-tPA through the tail vein, and were treated with magnetic targeting and the low-intensity ultrasound in sequence (Fig. 6A). Control groups included mice injected with saline, native tPA, and SiO2-tPA, respectively. The images of the thrombi were recorded every 3 hours before the mice were sacrificed at 12 hours after treatments. As shown in Fig. 6B, the femoral vein exhibited dark areas where FeCl3 filter paper was placed, indicating the successful formation of the blood clots. The dark areas of the femoral vein treated by saline became longer with time, suggesting the progression of venous thrombosis. When native tPA were intravenously injected, the dark areas shrank in size and became shallow, indicating that clot lysis happened gradually with time. By this dosage of native tPA (100 l, 10 g ml1), the blocked veins were not thoroughly recanalized, as shallow shadows still presented at 3 and 12 hours after treatment. Although SiO2-tPA holds the ability to protect native tPA against its inhibitors in blood, SiO2-tPA treatment only achieved similar thrombolysis efficacy to that of native tPA treatment, suggesting the low delivery efficiency of SiO2-tPA to clots. With the equivalent amount of tPA, the dark areas of MMB-SiO2-tPAtreated veins faded completely even at 3 hours after treatment. The histological results (Fig. 6C) of the femoral veins were in good agreement with the results in Fig. 6B. Ideally, the thrombus is considered to be a cylinder, and the quantification of the volume of the clots reveals the thrombolysis efficacy. Alternatively, quantification of the thrombus area (% vein lumen) by measuring the cross-sectional areas of the clots and the veins in the histological images provides a rough estimate of the thrombosis area (28). Still, MMB-SiO2-tPA treatment achieved the optimal thrombolysis efficacy, resulting in the least thrombus area (approximately 13%), whereas the percentages were 66, 40, and 50% for treatments with saline, native tPA, or SiO2-tPA, respectively (Fig. 6D). It is worth noting that, according to the histological analysis (Fig. 6C and fig. S7), two of four femoral veins treated by MMB-SiO2-tPA achieved complete recanalization. Furthermore, the improved penetration of released nanoparticles was evidenced by the histological images of the clots (Fig. 6E). The shelled nanoparticles (black dots) mainly attached to the periphery of the clots without an ultrasound trigger. When triggered by low-intensity ultrasound, shelled nanoparticles were released and penetrated into the interior of the clots, resulting in a relatively homogenous distribution of nanoparticles within the clots.
(A) Schematic illustration of the treatment procedures of a femoral vein thrombosis mouse model. (B) Representative images of thrombolysis evaluation after treatment with saline, native tPA, SiO2-tPA, and MMB-SiO2-tPA, respectively. The white arrows indicate the inducted thrombi (n = 4). (C) Representative histological analysis of the femoral vein after treatment with saline, native tPA, SiO2-tPA, and MMB-SiO2-tPA for 12 hours, respectively (n = 4). Scale bar, 50 m. (D) Quantification of the thrombus area (% vein lumen) in femoral vein in different treatment groups (n = 4). (E) Representative histological analysis of the femoral vein after administration and magnetic targeting of MMB-SiO2-tPA with or without low-intensity ultrasound. The red arrow indicates the enrichment of MMB-SiO2-tPA, and the red circles indicate the MMB-SiO2-tPA with an intact structure. Scale bars, 50 m.
To evaluate the safety of the precision delivery strategy in vivo, MMB-SiO2-tPA were intravenously administrated to the mice, and the major organs were collected. As shown in the histological images (fig. S8A), no obvious organ damage or inflammatory lesion appeared in both short-term (i.e., 1 day) and long-term (i.e., 7 days) periods. Meanwhile, serum biochemistry assay and complete blood panel tests were studied by comparison between healthy mice and MMB-SiO2-tPAinjected mice (after 7 days) (fig. S9). The results showed no significant differences in all measurement indicators between the two groups, suggesting the good biocompatibility of MMB-SiO2-tPA. The SiO2 nanoparticles were mainly accumulated in the liver and kidney after 24 hours after injection, while the distribution mainly in the spleen was observed for iron oxide nanoparticles (fig. S10). The biodistribution of MMB-SiO2-tPA in mice suggested their clearance by the reticuloendothelial system.
In addition, the thrombolytic drug always results in bleeding complications because of the off-target action. For example, the circulating tPA breaks down the fibrinogen in the blood, leading to abnormal hemostatic and hemorrhagic side effects (29). To evaluate the influence on hemostasis of the MMB-SiO2-tPA, tail bleeding time was tested on a mouse model. Mice were first intravenously injected with saline, native tPA, or MMB-SiO2-tPA (with the equivalent amount of tPA), respectively, and then their tails were cut by a scalpel (fig. S8B). The tail bleeding time of mice treated with native tPA (approximately 7.6 min) was almost fourfold as much as that of saline-treated group (approximately 1.8 min), indicating the significant abnormal hemostatic side effect. In contrast, the administration of MMB-SiO2-tPA without an ultrasound trigger presented a similar bleeding time (approximately 2.2 min) to the saline group, suggesting the limited off-target action and bleeding complication.
Last, but not the least, the safety assessment of ultrasound intensity on mice vascular injury was performed. The applied high-intensity ultrasound (above 0.04 MPa, i.e., 0.4 bar) used to activate cavitation might cause endothelial injury and intracerebral hemorrhage (in treatment of stroke), which raised safety issues (3032). MMB-SiO2-tPA were intravenously injected into the mice and targeted to the tail vein, followed by ultrasound treatment with the intensity to trigger bubble cavitation (0.5 bar) and stable oscillations (0.2 bar), respectively. As shown in fig. S8C, deformation of the vascular wall treated by high-intensity ultrasound was observed because of the bubble cavitation effect. The vascular wall became wrinkled and thinner or even ruptured at the thinnest locations (the black arrow in fig. S8C). In contrast, as the ultrasound intensity decreased by more than a half, the vascular wall remained intact with no deformation of the structure. Thus, the precision delivery strategy by low-intensity ultrasound exhibited satisfactory safety with limited bleeding complication and vascular injury.
This work proposed a precision delivery strategy to achieve the targeted and controlled delivery of thrombolytic drugs for thrombolysis. There are three criteria that must be met in this process, i.e., activity maintenance in circulation, targeting to clots, and penetration into clots.
To keep the activity of drugs in circulation, we first loaded tPA into mesoporous silica nanoparticles, which protect the activity of tPA against its inhibitors in the blood. Besides, the stability of nanomedicine in circulation is also important for the activity maintenance and the bioavailability of tPA. In our design, nanoparticles with different functions were integrated into an ultrasound-responsive microbubble through self-assembly and stabilized by the buckling effect. Specifically, when a strong shear flow is created during agitation of the mixture solution, microbubbles first form because of air entrainment and fragmentation. Because of the hydrophobic surface property, the nanoparticles self-assemble on the microbubble interfaces. When the resultant solution was stored in the ambient, the microbubbles shrink because of gas diffusion, while the nanoparticles remain attached to the interfaces. Until the bubble size reduces to sufficiently small for close packing, the nanoparticles buckle (Fig. 1B). On one hand, this buckling resists the bubble surface area reduction; on the other hand, the multilayered packing also shields the gas diffusion from the gas core. Eventually, these microbubbles reach an equilibrium size with a multilayered nanoparticle shell resulting in superior stability. The close packing of nanoparticles also prevents the release of loaded tPA to the blood, decreasing the contact possibility between tPA and its inhibitors. Comparing to the delivery strategy using surface conjugation of tPA or noncontrolled release of tPA, this strategy can improve the delivery efficiency of active tPA to the clots (12, 19). The activity of tPA is maintained with a half-life of 1 hour in the presence of its inhibitors in vitro (Fig. 2H), which is much longer than that of native tPA (approximately 5 min). The stability of MMB-SiO2-tPA in circulation was evidenced by the US imaging in a mouse model, where enhanced contrast was observed in the blood vessel even after 30 min after injection. Thereby, the precision delivery strategy meets the first criteria in the thrombolysis process of a nanomedicine, i.e., maintained the activity of tPA in blood circulation.
Targeted delivery improves delivery efficiency and specificity, thus reduces the required dose and side effects. Targeting strategies using RGD (Arg-Gly-Asp) motif (binding to active platelet integrin GPIIb/IIIa) or anti-fibrin antibody are still challenged by the relatively low targeting efficiency due to the protein corona of the nanomedicine formed in the blood and the heterogeneity of different clots from individuals (3335). For example, there was no significant difference in the recanalization rate of the rabbit aorta thrombus model by injection of tPA-loaded echogenic liposomes with or without ultrasound treatment (15). The ultrasound was speculated to potentiate the catalytic activity of exposed liposome-associated tPA, rather than cause the release of the enzyme into the clots. The improvement of the thrombolysis efficacy might be compromised by the poor delivery efficiency without targeting strategy and the limited penetration of tPA within the clots. Magnetically targeted delivery of tPA to the blood clot in mouse middle cerebral artery has been achieved in the reported work by porous magnetic microrods as carriers (19). In our strategy, magnetic targeting can be simply applied to the adjacent tissue of the thrombi diagnosed by ultrasound imaging (Fig. 3E), enabling it to meet the second criteria and to be promising and clinically feasible.
There is limited clot-penetrating strategy that have been reported because of the structure of thrombi, consisting of abundant platelet and well-organized fibrin. Rotating magnetic microrods might generate mechanical force to the cross-linked fibrin, disrupting the structure of the clots and facilitating the penetration of released tPA (19). Blood flow of a cerebral artery occlusion mouse model was restored in 25 min by tPA-loaded microrods [tPA (0.13 mg kg1)], which is faster than 85 min required by tPA only with high concentration [tPA (10 mg kg1)]. The significant improvement of the lytic rate and the much less required dosage of tPA were attributed partially to the increased release rate and improved mass transport of tPA and partially to the disruption of the fibrin network by mechanical rotation force leading to the improved penentration of tPA (19). In the present work, we aim to show the direct evidence of enhanced penetration of tPA nanocarrier within the clot tissue by low-intensity ultrasound. Previously, we have demonstrated improved tissue penetration of nanoparticles by stable microbubble oscillations (20). Briefly, self-assembled nanoparticles form an elastic shell due to the weak hydrophobic interaction between nanoparticles. When activated by their resonance frequency with the ultrasound intensity below the threshold of cavitation, microbubbles undergo stable oscillations. As illustrated in fig. S3, under high acoustic pressure, a microbubble shrinks in size, while its shelled nanoparticles are densely packed. Whereas under low acoustic pressure, the microbubble swells, and its shelled nanoparticles are loosely packed, accompanying by the nanoparticles shedding at the outermost layer. Subsequently, the loosely packed nanoparticles reassembled to form the buckled shell when the acoustic pressure increases again. This reassembling of shelled nanoparticles was recorded by a charge-coupled device camera in supplementary movie. The movements of fluorescent silica nanoparticles in the shell revealed the nanoparticle reassembling process during stable microbubble oscillations. It is worth noting that silica nanoparticles were released and moved along with the microstreaming induced by the stable oscillations, suggesting the possibility of penetration improvement in tissues. The penetration of released nanoparticles can be up to 1 cm in the agarose-fibrin gel (Fig. 4A). According to literature (13), the lysis process can be described as followsS+TKTST(SP)KPS+Pwhere S, T, ST, SP, and P is the exposed lysine site, the tPA molecule, tPA-lysine complex, tPA-product complex, and the product, respectively, KT and KP are the tPA absorption rate and product desorption rate, respectively. Assuming that the transport-facilitated tPA binding is the rate-limiting step at CtPA = 10 g ml1 (KT < < KP), then the thrombolysis rate v = KT[S][T]. In all the experiment groups, KT can be assumed to be a constant. For tPA group, the v decreased with time, which was the result of the decrease of [T] due to the consumption of tPA molecules. According to the release profile of SiO2-tPA, the initial [T] of SiO2-tPA group is smaller than that of tPA group, which results in slower thrombolysis rates of SiO2-tPA (0 to 6 hours) than those of tPA. As SiO2-tPA continuously replenish the tPA to the surrounding medium, the [T] of SiO2-tPA (depends on the release and consumption kinetics) might be not change as significant as that of tPA. Thus, the values of v in SiO2-tPA group were observed at similar level after 3 hours. For MMB-SiO2-tPA group, the magnet concentrated the microbubbles (together with the SiO2-tPA) at the interface of the gel, and then stable microbubble oscillation (by ultrasound for 3 min) released the nanoparticles and facilitated the penetration of SiO2-tPA into the gel, resulting in increased number of exposed lysine site (i.e., [S]) from the interior of the gel. Considering the smaller [T] of MMB-SiO2-tPA (the same with SiO2-tPA) than that of tPA, the observed v of both MMB-SiO2-tPA and tPA are similar in 0 to 3 hours. The penetration effect on the thrombolysis rate is more prominent for MMB-SiO2-tPA after 6 hours due to the different changes of [T] for MMB-SiO2-tPA and tPA groups. Notably, the improved penetration can only be achieved by MMB-SiO2-tPA under ultrasound. Free tPA and MMB-SiO2 under ultrasound did not change the lysis speed and manner (from top to the bottom), which are the same with those of tPA group (fig. S6).
In the mouse model, the released nanoparticles can easily reach the center of a venous thrombus with the diameter of 300 m (Fig. 6E). Thereby, the lysis happened not only at the interface of a clot but also at many interior locations, resulting in accelerated thrombolysis. In a mouse model of venous thrombosis, the residual thrombus decreased by 67.5% when treated with MMB-SiO2-tPA [tPA (0.03 mg kg1)] compared to conventional injection of tPA [tPA (0.03 mg kg1)]. Note that such a low tPA dosage of MMB-SiO2-tPA can achieve complete recanalization (two of four femoral veins). The therapeutic efficacy and lytic rate can be further improved by increasing the dosage of loaded tPA for time-critical thrombolytic therapy. The improved penetration of tPA lastly meets the third criteria of the thrombolysis process.
The delivery of the thrombolytic drugs to complex locations such as cerebral embolism, pulmonary embolism, and myocardial infarction is more challenged in comparison to femoral vein thrombus. Although promising results have been shown in both in vitro and in vivo, the present delivery strategy can be further improved for application in embolism at complex locations. First, the size of MMB-SiO2-tPA can be reduced to avoid fast clearance by the reticuloendothelial system. Last, the circulation time of MMB-SiO2-tPA is challenged due to its hydrophobic surface property. Cell membrane (e.g., red blood cells and platelets)coating technology can be applied to prolong the circulation of MMB-SiO2-tPA, thereby improving the delivery efficiency and therapeutic efficacy (3639).
In summary, we conclude that our precision delivery strategy can complete three important steps of nanomedicine for thrombolysis, i.e., activity maintenance in circulation, targeting to clots, and penetration into clots. The accelerated lytic rate and the improved therapeutic efficacy are attributed to the increased effective concentration of tPA at the site of clots, a result by tPA activity maintenance, magnetic targeting, and improved penetration of tPA within the clots. Thus, this strategy holds great promise in thrombi diagnosis and accelerating thrombolysis while reducing the complication risk of tPA and the vascular injury by high-intensity ultrasound.
tPA was purchased from Merck (USA). SDS, thrombin from human plasma, plasminogen from human plasma, and the protease substrate H-d-isoleucyl-l-prolyl-l-arginine-p-nitroaniline (S-2288) were purchased from Sigma-Aldrich (USA). Mesoporous silica nanoparticles (SiO2) were purchased from Shanghai So-Fe Biomedical (China). Fe3O4 nanoparticles were purchased from Alfa Aesar (USA). Fibrinogen from human plasma was purchased from Shanghai Yuan Yu Bio-Tech Co. Ltd. (China). Agarose was purchased from BD (USA). All the other chemicals and solvents were purchased from Sigma-Aldrich.
The nanoparticle-shelled microbubbles were prepared by the previous method (20). Briefly, magnetic nanoparticles (Fe3O4) were dispersed in deionized water to form a stock solution (10 mg ml1) and treated with ultrasound for 20 min before use. Next, a mixture solution including 150 l of SiO2-tPA nanoparticles (0.2 mg ml1), 150 l of SDS (10 mM1), and 400 l of Fe3O4 nanoparticle (10 mg ml1) was homogenized at 20,000 rpm for 3 min. After stirring, the nanoparticle-shelled microbubbles were stabilized overnight for close packing of nanoparticles and then purified with deionized water by magnetic separation for three times.
The morphology and the size were observed by a microscope (Olympus IX71, Japan) and an environmental scanning electron microscope (Philips XL30, The Netherlands). The diameters were manually measured from the photos and counted at least for 200 microbubbles. The fluorescent nanoparticle-shelled microbubbles were imaged by the laser scanning confocal microscope (Olympus FV1000MPE, Japan). The content of iron and silicon in different volumes of MMB-SiO2-tPA was measured by ICP-OES (PerkinElmer, USA). The content of the tPA loaded in MMB-SiO2-tPA was tested by the BCA protein assay kit.
The fibrinolytic activity of the tPA was tested using a chromogenic substrate, S-2288, as previously reported (40). The native tPA was added to the microtiter plate containing assay buffer [0.1 M1 of tris-HCl (pH 7.4)] and S-2288 (1.0 mM1) at 37C. The fibrinolytic activity was calculated by Abs per min at 405 nm for 30 min of reaction. The inhibition efficiencies of tPA were determined by incubation of the same amount of tPA (10 g ml1) and active PAI-1 (0.5 nM1) in 200 l of assay buffer in a microplate at 37C for predetermined periods. Then, the residual activities of tPA were then measured by the method described above.
The release of tPA from MMB-SiO2-tPA by ultrasound with different intensities was tested in vitro. Briefly, the ultrasound frequencies from 10 to 900 kHz with amplitudes starting from 2 to 20 Vpp (peak-to-peak voltage) were adjusted by a function generator (Keysight, USA), while the powers of ultrasound were adjusted from 0.1 to 10% by an amplifier (T&C, USA). The ultrasound was applied through a homemade focused transducer, and each cycle contained 5 s of duration time with a time interval of 1 s. The output ultrasound intensities at the focus of the transducer were monitored by an oscilloscope (Keysight, USA). After different cycles of ultrasound, the supernatants were collected, and the amounts of released tPA were quantified by the BCA protein assay kit.
A gel mold with a hole was used as the ultrasound phantom, and 1 ml of MMB-SiO2-tPA solution was added. The phantom was imaged by a high-resolution microimaging system (VisualSonics Vevo 2100, Canada) using the transducer at 18 MHz with a static state using both B mode and contrast mode. The center frequency, intensity power, and contrast gain were set as 18 MHz, 10%, and 35 dB, respectively. The mean video intensity in the regions of interest (ROIs) was analyzed by a ultrasound image software.
For in vivo ultrasound imaging, the femoral veins of male C57/BL6J mice were treated with 20% ferric chloride solution. Then, the mice were anesthetized by 10% chloral hydrate solution and imaged by a ultrasound imaging system. After intravenously injected with 100 l of MMB-SiO2-tPA for 5 min, the femoral veins were imaged again, followed by magnet placement. The accumulations of MMB-SiO2-tPA by magnet were monitored by ultrasound imaging with time. The mean video intensity in ROI was analyzed by a ultrasound image software.
Ten milliliters of agarose solution (0.5%) containing 20 l of thrombin solution (250 U ml1) was thoroughly mixed with 1 ml of fibrinogen solution (10 mg ml1) and 10 l of plasminogen solution (1 mg ml1). Subsequently, the mixed solution was uniformly added to a vertical channel and incubated at 37C for 2 hours to form the fibrin gel. The concentrations of native tPA, SiO2-tPA, and MMB-SiO2-tPA used in the in vitro, ex vivo, and in vivo experiments were fixed with the equivalent amount (1 g) of tPA (native tPA, 100 l of 10 g ml1; SiO2-tPA, 100 l of 50 g ml1; MMB-SiO2-tPA, 100 l of concentrated MMB-SiO2-tPA with the number of 1.5 106 ml1). Afterward, 100 l of saline, native tPA, SiO2-tPA, or MMB-SiO2-tPA with the equivalent concentration of tPA (10 g ml1) was added to the channel at the top of the gel and incubated at 37C for 3, 6, 9, and 12 hours, respectively. For the MMB-SiO2-tPAtreated group, a magnet was placed at the bottom of the channel, and ultrasound was applied for 3 min with the intensity of 0.2 bar. Last, the fibrinolytic activity of each sample was evaluated by comparing the dark areas of the gel. Briefly, images were first processed to eliminate background and converted into binary (black and white) images. The area of black pixels represents the lysis area, while the area of white pixels represents the agarose-fibrin gel. To identify the boundary, a threshold was determined by processing the images of tPA group. Threshold value was adjusted to include all of the black area within the threshold of the selected area. Then, the same threshold value was applied to the processing for all the other images.
The blood clots were prepared via the previous protocol (41). Male mice of C57/BL6J (8 to 10 weeks old) were anesthetized via isofluoride gas. One hundred microliters of fresh blood was obtained from the orbital vein and distributed in several centrifuge tubes containing 50 U of thrombin solution. The tubes were placed at 37C for 3 hours and then were moved to 4C for 3 days.
The prepared blood clots were placed into centrifuge tubes containing 1 ml of saline. Then, saline (100 l), native tPA, SiO2-tPA, and MMB-SiO2-tPA with the equivalent concentration of tPA (10 g ml1) were added into the solution and incubated at 37C, respectively. During the incubation, the lysis process was monitored at predetermined time points. For the MMB-SiO2-tPAtreated group, a magnet was placed beneath the clots, and ultrasound was applied for 5 min with the intensity of 0.2 bar. The weight of blood clots during the lysis was recorded, and the clot lysis efficiencies were calculated. Besides, the supernatants of all samples after 12 hours were collected and measured at OD540 (optical density at 540) (optical absorbance).
All procedures involving animals were approved by the Institutional Animal Care and Utilization Committee at Nanyang Technological University. Male C57/BL6J mice (6 to 8 weeks old) were obtained from Nanjing Qinglongshan Animal Breeding Field. The femoral vein thrombosis was induced according to the previous protocol. Briefly, mice were anesthetized with 10% chloral hydrate (100 l) by intraperitoneal injection. The left femoral veins of the mice were exposed with a scalpel and forceps. After exposure, a filter paper infiltrated with 20% ferric chloride solution was placed on the surface of the femoral vein vessel for 1 to 2 min. Then, the filter paper was removed, and the vessel was washed with sterilized phosphate-buffered saline. In the end, the visible femoral vein thrombi were formed.
To study the thrombolysis efficacy in vivo, 100 l of saline, native tPA, SiO2-tPA, and MMB-SiO2-tPA with the equivalent amount of tPA (10 g ml1) was intravenously injected (n = 4 for each group). For the MMB-SiO2-tPAtreated group, a magnet was placed adjacent to the clots for 25 min, and then ultrasound was applied for 5 min with the intensity of 0.2 bar. The thrombolysis processes were monitored by taking photos in the next 12 hours. After being euthanized, the vessel tissues were excised from the mice and collected for histological analysis (n = 4 for each group). Sections were processed and analyzed using the Image J software by an investigator blinded to the treatment. The areas of clots were measured, and thrombolytic efficiency was determined by the area ratio of vascular occlusion to total vasculature.
To evaluate the improvement of nanoparticle penetration in clots in vivo, the femoral vein thrombibearing mice were divided into two groups (n = 3 for each group). One hundred microliters of MMB-SiO2-tPA was administrated by intravenous injection, and a magnet was placed adjacent to the thrombi for 25 min. Subsequently, the two groups were treated with or without low-intensity ultrasound (0.2 bar), respectively. After being sacrificed, the vessel tissues were excised from the mice and collected for histological analysis.
Male C57/BL6J mice (6 to 8 weeks old) were intravenously injected with 100 l of MMB-SiO2-tPA. Then, the mice were euthanatized after 1 or 7 days, and the main organs were collected for histological analysis. Healthy mice intravenously injected with saline were selected as control group (n = 3 for each group).
Tail bleeding assay was performed via previous methods (29). Male C57/BL6J mice were anesthetized with 10% chloral hydrate by intraperitoneal injection. Subsequently, 100 l of saline, native tPA, and MMB-SiO2-tPA at the equivalent concentration of tPA (10 g ml1) was administered (n = 3 for each group). After 5 min, 1 cm of the distal tail was removed from the mice using a scalpel. The time for hemostasis (bleeding fully stopped for at least 1 min) was recorded.
To investigate the vascular injury by ultrasound, male C57/BL6J mice were anesthetized with 10% chloral hydrate by intraperitoneal injection. Hereafter, 100 l of MMB-SiO2-tPA at the equivalent concentration of tPA (10 g ml1) was administered. Then, a magnet was placed in the middle of the mice tail. Ultrasound with different intensities (0.2 and 0.5 bar) was applied, respectively. Last, 5 cm of the distal tail was removed from the mice for histological analysis.
All data were expressed as means SD. Inter- and intragroup comparisons and analysis in each experiment were performed by unpaired Students t test and one-way analysis of variance (ANOVA) using the SPSS software. Probability (P) values of <0.05 were considered statistically significant.
Acknowledgments: Funding: This work was supported by the National Key Research and Development Program of China (2017YFA0205302), the National Natural Science Foundation of China (81601608, 21475064), the Natural Science Foundation of Jiangsu Province of China (BK20160919), the Key Research and Development Program of Jiangsu (BE2018732), the Natural Science Key Fund for Colleges and Universities in Jiangsu Province (17KJA430011), and NUPTSF (NY216024). Author contributions: Y.G., S.W., and L.W. designed the study. S.W. carried out microbubble synthesis, characterization, and all in vitro assays. S.W., X.G., W.X., L.R., and H.X. performed the ex vivo and animal experiments. Y.L. and F.Y. helped with the ultrasound imaging experiments. C.X. helped and gave valuable suggestions for the animal experiments. Y.G., S.W., C.X., and L.W. wrote the manuscript. All authors discussed the results and commented on the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.
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Accelerating thrombolysis using a precision and clot-penetrating drug delivery strategy by nanoparticle-shelled microbubbles - Science Advances
Introduction
Over the last years, nanotechnology has been introduced in our daily routine. This revolutionary technology has been applied in multiple fields through an integrated approach. An increasing number of applications and products containing nanomaterials or at least with nano-based claims have become available. This also happens in pharmaceutical research. The use of nanotechnology in the development of new medicines is now part of our research and in the European Union (EU) it has been recognized as a Key Enabling Technology, capable of providing new and innovative medical solution to address unmet medical needs (Bleeker et al., 2013; Ossa, 2014; Tinkle et al., 2014; Pita et al., 2016).
The application of nanotechnology for medical purposes has been termed nanomedicine and is defined as the use of nanomaterials for diagnosis, monitoring, control, prevention and treatment of diseases (Tinkle et al., 2014). However, the definition of nanomaterial has been controversial among the various scientific and international regulatory corporations. Some efforts have been made in order to find a consensual definition due to the fact that nanomaterials possess novel physicochemical properties, different from those of their conventional bulk chemical equivalents, due to their small size. These properties greatly increase a set of opportunities in the drug development; however, some concerns about safety issues have emerged. The physicochemical properties of the nanoformulation which can lead to the alteration of the pharmacokinetics, namely the absorption, distribution, elimination, and metabolism, the potential for more easily cross biological barriers, toxic properties and their persistence in the environment and human body are some examples of the concerns over the application of the nanomaterials (Bleeker et al., 2013; Tinkle et al., 2014).
To avoid any concern, it is necessary establishing an unambiguous definition to identify the presence of nanomaterials. The European Commission (EC) created a definition based on the European Commission Joint Research Center and on the Scientific Committee on Emerging and Newly Identified Health Risks. This definition is only used as a reference to determine whether a material is considered a nanomaterial or not; however, it is not classified as hazardous or safe. The EC claims that it should be used as a reference for additional regulatory and policy frameworks related to quality, safety, efficacy, and risks assessment (Bleeker et al., 2013; Boverhof et al., 2015).
According to the EC recommendation, nanomaterial refers to a natural, incidental, or manufactured material comprising particles, either in an unbound state or as an aggregate wherein one or more external dimensions is in the size range of 1100 nm for 50% of the particles, according to the number size distribution. In cases of environment, health, safety or competitiveness concern, the number size distribution threshold of 50% may be substituted by a threshold between 1 and 50%. Structures with one or more external dimensions below 1 nm, such as fullerenes, graphene flakes, and single wall carbon nanotubes, should be considered as nanomaterials. Materials with surface area by volume in excess of 60 m2/cm3 are also included (Commission Recommendation., 2011). This defines a nanomaterial in terms of legislation and policy in the European Union. Based on this definition, the regulatory bodies have released their own guidances to support drug product development.
The EMA working group introduces nanomedicines as purposely designed systems for clinical applications, with at least one component at the nanoscale, resulting in reproducible properties and characteristics, related to the specific nanotechnology application and characteristics for the intended use (route of administration, dose), associated with the expected clinical advantages of nano-engineering (e.g., preferential organ/tissue distribution; Ossa, 2014).
Food and Drug Administration (FDA) has not established its own definition for nanotechnology, nanomaterial, nanoscale, or other related terms, instead adopting the meanings commonly employed in relation to the engineering of materials that have at least one dimension in the size range of approximately 1 nanometer (nm) to 100 nm. Based on the current scientific and technical understanding of nanomaterials and their characteristics, FDA advises that evaluations of safety, effectiveness, public health impact, or regulatory status of nanotechnology products should consider any unique properties and behaviors that the application of nanotechnology may impart (Guidance for Industry, FDA, 2014).
According to the former definition, there are three fundamental aspects to identify the presence of a nanomaterial, which are size, particle size distribution (PSD) and surface area (Commission Recommendation., 2011; Bleeker et al., 2013; Boverhof et al., 2015).
The most important feature to take into account is size, because it is applicable to a huge range of materials. The conventional range is from 1 to 100 nm. However, there is no bright line to set this limit. The maximum size that a material can have to be considered nanomaterial is an arbitrary value because the psychochemical and biological characteristics of the materials do not change abruptly at 100 nm. To this extent, it is assumed that other properties should be taken in account (Lvestam et al., 2010; Commission Recommendation., 2011; Bleeker et al., 2013; Boverhof et al., 2015).
The pharmaceutical manufacturing of nanomaterials involves two different approaches: top down and bottom down. The top down process involves the breakdown of a bulk material into a smaller one or smaller pieces by mechanical or chemical energy. Conversely, the bottom down process starts with atomic or molecular species allowing the precursor particles to increase in size through chemical reaction (Luther, 2004; Oberdrster, 2010; Boverhof et al., 2015). These two processes of manufacturing are in the origin of different forms of particles termed primary particle, aggregate and agglomerate (Figure 1). The respective definition is (sic):
Figure 1. Schematic representation of the different forms of particles: primary particle, aggregate, and agglomerate (reproduced with permission from Oberdrster, 2010).
particle is a minute piece of matter with defined physical boundaries (Oberdrster, 2010; Commission Recommendation., 2011);
aggregate denotes a particle comprising strongly bound or fused particlesand the external surface can be smaller than the sum of the surface areas of the individual particles (Oberdrster, 2010; Commission Recommendation., 2011);
agglomerate means a collection of weakly bound particles or aggregates where the resulting external surface area are similar to the sum of the surface areas of the individual components (Oberdrster, 2010; Commission Recommendation., 2011).
Considering the definition, it is understandable why aggregates and agglomerates are included. They may still preserve the properties of the unbound particles and have the potential to break down in to nanoscale (Lvestam et al., 2010; Boverhof et al., 2015). The lower size limit is used to distinguish atoms and molecules from particles (Lvestam et al., 2010).
The PSD is a parameter widely used in the nanomaterial identification, reflecting the range of variation of sizes. It is important to set the PSD, because a nanomaterial is usually polydisperse, which means, it is commonly composed by particles with different sizes (Commission Recommendation., 2011; Bleeker et al., 2013; Boverhof et al., 2015).
The determination of the surface area by volume is a relational parameter, which is necessary when requested by additional legislation. The material is under the definition if the surface area by volume is larger than 60 m2/cm3, as pointed out. However, the PSD shall prevail, and for example, a material is classified as a nanomaterial based on the particle size distribution, even if the surface area by volume is lower than the specified 60 m2/cm3 (Commission Recommendation., 2011; Bleeker et al., 2013; Boverhof et al., 2015).
Nanomaterials can be applied in nanomedicine for medical purposes in three different areas: diagnosis (nanodiagnosis), controlled drug delivery (nanotherapy), and regenerative medicine. A new area which combines diagnostics and therapy termed theranostics is emerging and is a promising approach which holds in the same system both the diagnosis/imaging agent and the medicine. Nanomedicine is holding promising changes in clinical practice by the introduction of novel medicines for both diagnosis and treatment, having enabled to address unmet medical needs, by (i) integrating effective molecules that otherwise could not be used because of their high toxicity (e.g., Mepact), (ii) exploiting multiple mechanisms of action (e.g., Nanomag, multifunctional gels), (iii) maximizing efficacy (e.g., by increasing bioavailability) and reducing dose and toxicity, (iv) providing drug targeting, controlled and site specific release, favoring a preferential distribution within the body (e.g., in areas with cancer lesions) and improved transport across biological barriers (Chan, 2006; Mndez-Rojas et al., 2009; Zhang et al., 2012; Ossa, 2014).
This is a result of intrinsic properties of nanomaterials that have brought many advantages in the pharmaceutical development. Due to their small size, nanomaterials have a high specific surface area in relation to the volume. Consequently, the particle surface energy is increased, making the nanomaterials much more reactive. Nanomaterials have a tendency to adsorb biomolecules, e.g., proteins, lipids, among others, when in contact with the biological fluids. One of the most important interactions with the living matter relies on the plasma/serum biomoleculeadsorption layer, known as corona, that forms on the surface of colloidal nanoparticles (Pino et al., 2014). Its composition is dependent on the portal of entry into the body and on the particular fluid that the nanoparticles come across with (e.g., blood, lung fluid, gastro-intestinal fluid, etc.). Additional dynamic changes can influence the corona constitution as the nanoparticle crosses from one biological compartment to another one (Pearson et al., 2014; Louro, 2018).
Furthermore, optical, electrical and magnetic properties can change and be tunable through electron confinement in nanomaterials. In addition, nanomaterials can be engineered to have different size, shape, chemical composition and surface, making them able to interact with specific biological targets (Oberdrster et al., 2005; Kim et al., 2010). A successful biological outcome can only be obtained resorting to careful particle design. As such, a comprehensive knowledge of how the nanomaterials interact with biological systems are required for two main reasons.
The first one is related to the physiopathological nature of the diseases. The biological processes behind diseases occur at the nanoscale and can rely, for example, on mutated genes, misfolded proteins, infection by virus or bacteria. A better understanding of the molecular processes will provide the rational design on engineered nanomaterials to target the specific site of action desired in the body (Kim et al., 2010; Albanese et al., 2012). The other concern is the interaction between nanomaterial surface and the environment in biological fluids. In this context, characterization of the biomolecules corona is of utmost importance for understanding the mutual interaction nanoparticle-cell affects the biological responses. This interface comprises dynamic mechanisms involving the exchange between nanomaterial surfaces and the surfaces of biological components (proteins, membranes, phospholipids, vesicles, and organelles). This interaction stems from the composition of the nanomaterial and the suspending media. Size, shape, surface area, surface charge and chemistry, energy, roughness, porosity, valence and conductance states, the presence of ligands, or the hydrophobic/ hydrophilic character are some of the material characteristics that influence the respective surface properties. In turn, the presence of water molecules, acids and bases, salts and multivalent ions, surfactants are some of the factors related to the medium that will influence the interaction. All these aspects will govern the characteristics of the interface between the nanomaterial and biological components and, consequently, promote different cellular fates (Nel et al., 2009; Kim et al., 2010; Albanese et al., 2012; Monopoli et al., 2012).
A deeper knowledge about how the physicochemical properties of the biointerface influence the cellular signaling pathway, kinetics and transport will thus provide critical rules to the design of nanomaterials (Nel et al., 2009; Kim et al., 2010; Albanese et al., 2012; Monopoli et al., 2012).
The translation of nanotechnology form the bench to the market imposed several challenges. General issues to consider during the development of nanomedicine products including physicochemical characterization, biocompatibility, and nanotoxicology evaluation, pharmacokinetics and pharmacodynamics assessment, process control, and scale-reproducibility (Figure 2) are discussed in the sections that follow.
Figure 2. Schematic representation of the several barriers found throughout the development of a nanomedicine product.
The characterization of a nanomedicine is necessary to understand its behavior in the human body, and to provide guidance for the process control and safety assessment. This characterization is not consensual in the number of parameters required for a correct and complete characterization. Internationally standardized methodologies and the use of reference nanomaterials are the key to harmonize all the different opinions about this topic (Lin et al., 2014; Zhao and Chen, 2016).
Ideally, the characterization of a nanomaterial should be carried out at different stages throughout its life cycle, from the design to the evaluation of its in vitro and in vivo performance. The interaction with the biological system or even the sample preparation or extraction procedures may modify some properties and interfere with some measurements. In addition, the determination of the in vivo and in vitro physicochemical properties is important for the understanding of the potential risk of nanomaterials (Lin et al., 2014; Zhao and Chen, 2016).
The Organization for Economic Co-operation and Development started a Working Party on Manufactured Nanomaterials with the International Organization for Standardization to provide scientific advice for the safety use of nanomaterials that include the respective physicochemical characterization and the metrology. However, there is not an effective list of minimum parameters. The following characteristics should be a starting point to the characterization: particle size, shape and size distribution, aggregation and agglomeration state, crystal structure, specific surface area, porosity, chemical composition, surface chemistry, charge, photocatalytic activity, zeta potential, water solubility, dissolution rate/kinetics, and dustiness (McCall et al., 2013; Lin et al., 2014).
Concerning the chemical composition, nanomaterials can be classified as organic, inorganic, crystalline or amorphous particles and can be organized as single particles, aggregates, agglomerate powders or dispersed in a matrix which give rise to suspensions, emulsions, nanolayers, or films (Luther, 2004).
Regarding dimension, if a nanomaterial has three dimensions below 100 nm, it can be for example a particle, a quantum dot or hollow sphere. If it has two dimensions below 100 nm it can be a tube, fiber or wire and if it has one dimension below 100 nm it can be a film, a coating or a multilayer (Luther, 2004).
Different techniques are available for the analysis of these parameters. They can be grouped in different categories, involving counting, ensemble, separation and integral methods, among others (Linsinger et al., 2012; Contado, 2015).
Counting methods make possible the individualization of the different particles that compose a nanomaterial, the measurement of their different sizes and visualization of their morphology. The particles visualization is preferentially performed using microscopy methods, which include several variations of these techniques. Transmission Electron Microscopy (TEM), High-Resolution TEM, Scanning Electron Microscopy (SEM), cryo-SEM, Atomic Force Microscopy and Particle Tracking Analysis are just some of the examples. The main disadvantage of these methods is the operation under high-vacuum, although recently with the development of cryo-SEM sample dehydration has been prevented under high-vacuum conditions (Linsinger et al., 2012; Contado, 2015; Hodoroaba and Mielke, 2015).
These methods involve two steps of sample treatment: the separation of the particles into a monodisperse fraction, followed by the detection of each fraction. Field-Flow Fractionation (FFF), Analytical Centrifugation (AC) and Differential Electrical Mobility Analysis are some of the techniques that can be applied. The FFF techniques include different methods which separate the particles according to the force field applied. AC separates the particles through centrifugal sedimentation (Linsinger et al., 2012; Contado, 2015; Hodoroaba and Mielke, 2015).
Ensemble methods allow the report of intensity-weighted particle sizes. The variation of the measured signal over time give the size distribution of the particles extracted from a combined signal. Dynamic Light Scattering (DLS), Small-angle X-ray Scattering (SAXS) and X-ray Diffraction (XRD) are some of the examples. DLS and QELS are based on the Brownian motion of the sample. XRD is a good technique to obtain information about the chemical composition, crystal structure and physical properties (Linsinger et al., 2012; Contado, 2015; Hodoroaba and Mielke, 2015).
The integral methods only measure an integral property of the particle and they are mostly used to determine the specific surface area. Brunauer Emmet Teller is the principal method used and is based on the adsorption of an inert gas on the surface of the nanomaterial (Linsinger et al., 2012; Contado, 2015; Hodoroaba and Mielke, 2015).
Other relevant technique is the electrophoretic light scattering (ELS) used to determine zeta potential, which is a parameter related to the overall charge a particle acquires in a particular medium. ELS measures the electrophoretic mobility of particles in dispersion, based on the principle of electrophoresis (Linsinger et al., 2012).
The Table 1 shows some of principal methods for the characterization of the nanomaterials including the operational principle, physicochemical parameters analyzed and respective limitations.
Another challenge in the pharmaceutical development is the control of the manufacturing process by the identification of the critical parameters and technologies required to analyse them (Gaspar, 2010; Gaspar et al., 2014; Sainz et al., 2015).
New approaches have arisen from the pharmaceutical innovation and the concern about the quality and safety of new medicines by regulatory agencies (Gaspar, 2010; Gaspar et al., 2014; Sainz et al., 2015).
Quality-by-Design (QbD), supported by Process Analytical Technologies (PAT) is one of the pharmaceutical development approaches that were recognized for the systematic evaluation and control of nanomedicines (FDA, 2004; Gaspar, 2010; Gaspar et al., 2014; Sainz et al., 2015; European Medicines Agency, 2017).
Note that some of the physicochemical characteristics of nanomaterials can change during the manufacturing process, which compromises the quality and safety of the final nanomedicine. The basis of QbD relies on the identification of the Quality Attributes (QA), which refers to the chemical, physical or biological properties or another relevant characteristic of the nanomaterial. Some of them may be modified by the manufacturing and should be within a specific range for quality control purposes. In this situation, these characteristics are considered Critical Quality Attributes (CQA). The variability of the CQA can be caused by the critical material attributes and process parameters (Verma et al., 2009; Riley and Li, 2011; Bastogne, 2017; European Medicines Agency, 2017).
The quality should not be tested in nanomedicine, but built on it instead, by the understanding of the therapeutic purpose, pharmacological, pharmacokinetic, toxicological, chemical and physical properties of the medicine, process formulation, packaging, and the design of the manufacturing process. This new approach allows better focus on the relevant relationships between the characteristics, parameters of the formulation and process in order to develop effective processes to ensure the quality of the nanomedicines (FDA, 2014).
According to the FDA definition PAT is a system for designing, analzsing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality (FDA, 2014). The PAT tools analyse the critical quality and performance attributes. The main point of the PAT is to assure and enhance the understanding of the manufacturing concept (Verma et al., 2009; Riley and Li, 2011; FDA, 2014; Bastogne, 2017; European Medicines Agency, 2017).
Biocompatibility is another essential property in the design of drug delivery systems. One very general and brief definition of a biocompatible surface is that it cannot trigger an undesired' response from the organism. Biocompatibility is alternatively defined as the ability of a material to perform with an appropriate response in a specific application (Williams, 2003; Keck and Mller, 2013).
Pre-clinical assessment of nanomaterials involve a thorough biocompatibility testing program, which typically comprises in vivo studies complemented by selected in vitro assays to prove safety. If the biocompatibility of nanomaterials cannot be warranted, potentially advantageous properties of nanosystems may raise toxicological concerns.
Regulatory agencies, pharmaceutical industry, government, and academia are making efforts to accomplish specific and appropriate guidelines for risk assessment of nanomaterials (Hussain et al., 2015).
In spite of efforts to harmonize the procedures for safety evaluation, nanoscale materials are still mostly treated as conventional chemicals, thus lacking clear specific guidelines for establishing regulations and appropriate standard protocols. However, several initiatives, including scientific opinions, guidelines and specific European regulations and OECD guidelines such as those for cosmetics, food contact materials, medical devices, FDA regulations, as well as European Commission scientific projects (NanoTEST project, http://www.nanotest-fp7.eu) specifically address nanomaterials safety (Juillerat-Jeanneret et al., 2015).
In this context, it is important to identify the properties, to understand the mechanisms by which nanomaterials interact with living systems and thus to understand exposure, hazards and their possible risks.
Note that the pharmacokinetics and distribution of nanoparticles in the body depends on their surface physicochemical characteristics, shape and size. For example, nanoparticles with 10 nm in size were preferentially found in blood, liver, spleen, kidney, testis, thymus, heart, lung, and brain, while larger particles are detected only in spleen, liver, and blood (De Jong et al., 2008; Adabi et al., 2017).
In turn, the surface of nanoparticles also impacts upon their distribution in these organs, since their combination with serum proteins available in systemic circulation, influencing their cellular uptake. It should be recalled that a biocompatible material generates no immune response. One of the cause for an immune response can rely on the adsorption pattern of body proteins. An assessment of the in vivo protein profile is therefore crucial to address these interactions and to establish biocompatibility (Keck et al., 2013).
Finally, the clearance of nanoparticles is also size and surface dependent. Small nanoparticles, bellow 2030 nm, are rapidly cleared by renal excretion, while 200 nm or larger particles are more efficiently taken up by mononuclear phagocytic system (reticuloendothelial system) located in the liver, spleen, and bone marrow (Moghimi et al., 2001; Adabi et al., 2017).
Studies are required to address how nanomaterials penetrate cells and tissues, and the respective biodistribution, degradation, and excretion.
Due to all these issues, a new field in toxicology termed nanotoxicology has emerged, which aims at studying the nanomaterial effects deriving from their interaction with biological systems (Donaldson et al., 2004; Oberdrster, 2010; Fadeel, 2013).
The evaluation of possible toxic effects of the nanomaterials can be ascribed to the presence of well-known molecular responses in the cell. Nanomaterials are able to disrupt the balance of the redox systems and, consequently, lead to the production of reactive species of oxygen (ROS). ROS comprise hydroxyl radicals, superoxide anion and hydrogen peroxide. Under normal conditions, the cells produce these reactive species as a result of the metabolism. However, when exposed to nanomaterials the production of ROS increases. Cells have the capacity to defend itself through reduced glutathione, superoxide dismutase, glutathione peroxidase and catalase mechanisms. The superoxide dismutase converts superoxide anion into hydrogen peroxide and catalase, in contrast, converts it into water and molecular oxygen (Nel et al., 2006; Arora et al., 2012; Azhdarzadeh et al., 2015). Glutathione peroxidase uses glutathione to reduce some of the hydroperoxides. Under normal conditions, the glutathione is almost totally reduced. Nevertheless, an increase in ROS lead to the depletion of the glutathione and the capacity to neutralize the free radicals is decreased. The free radicals will induce oxidative stress and interact with the fatty acids in the membranes of the cell (Nel et al., 2006; Arora et al., 2012; Azhdarzadeh et al., 2015).
Consequently, the viability of the cell will be compromised by the disruption of cell membranes, inflammation responses caused by the upregulation of transcription factors like the nuclear factor kappa , activator protein, extracellular signal regulated kinases c-Jun, N-terminal kinases and others. All these biological responses can result on cell apoptosis or necrosis. Distinct physiological outcomes are possible due to the different pathways for cell injury after the interaction between nanomaterials and cells and tissues (Nel et al., 2006; Arora et al., 2012; Azhdarzadeh et al., 2015).
Over the last years, the number of scientific publications regarding toxicological effects of nanomaterials have increased exponentially. However, there is a big concern about the results of the experiments, because they were not performed following standard and harmonized protocols. The nanomaterial characterization can be considered weak once there are not standard nanomaterials to use as reference and the doses used in the experiences sometimes cannot be applied in the biological system. Therefore, the results are not comparable. For a correct comparison, it is necessary to perform a precise and thorough physicochemical characterization to define risk assessment guidelines. This is the first step for the comparison between data from biological and toxicological experiments (Warheit, 2008; Fadeel et al., 2015; Costa and Fadeel, 2016).
Although nanomaterials may have an identical composition, slight differences e.g., in the surface charge, size, or shape could impact on their respective activity and, consequently, on their cellular fate and accumulation in the human body, leading to different biological responses (Sayes and Warheit, 2009).
Sayes and Warheit (2009) proposed a three phases model for a comprehensive characterization of nanomaterials. Accordingly, the primary phase is achieved in the native state of the nanomaterial, specifically, in its dry state. The secondary characterization is performed with the nanomaterials in the wet phase, e.g., as solution or suspension. The tertiary characterization includes in vitro and in vivo interactions with biological systems. The tertiary characterization is the most difficult from the technical point of view, especially in vivo, because of all the ethical questions concerning the use of animals in experiments (Sayes and Warheit, 2009).
Traditional toxicology uses of animals to conduct tests. These types of experiments using nanomaterials can be considered impracticable and unethical. In addition, it is time-consuming, expensive and sometimes the end points achieved are not enough to correctly correlate with what happens in the biological systems of animals and the translation to the human body (Collins et al., 2017).
In vitro studies are the first assays used for the evaluation of cytotoxicity. This approach usually uses cell lines, primary cells from the tissues, and/or a mixture of different cells in a culture to assess the toxicity of the nanomaterials. Different in vitro cytotoxicity assays to the analysis of the cell viability, stress, and inflammatory responses are available. There are several cellular processes to determine the cell viability, which consequently results in different assays with distinct endpoints. The evaluation of mitochondrial activity, the lactate dehydrogenase release from the cytosol by tretazolium salts and the detection of the biological marker Caspase-3 are some of the examples that imposes experimental variability in this analysis. The stress response is another example which can be analyzed by probes in the evaluation of the inflammatory response via enzyme linked immunosorbent assay are used (Kroll et al., 2009).
As a first approach, in vitro assays can predict the interaction of the nanomaterials with the body. However, the human body possesses compensation mechanisms when exposed to toxics and a huge disadvantage of this model is not to considered them. Moreover, they are less time consuming, more cost-effective, simpler and provide an easier control of the experimental conditions (Kroll et al., 2009; Fadeel et al., 2013b).
Their main drawback is the difficulty to reproduce all the complex interactions in the human body between sub-cellular levels, cells, organs, tissues and membranes. They use specific cells to achieve specific endpoints. In addition, in vitro assays cannot predict the physiopathological response of the human body when exposed to nanomaterials (Kroll et al., 2009; Fadeel et al., 2013b).
Another issue regarding the use of this approach is the possibility of interaction between nanomaterials and the reagents of the assay. It is likely that the reagents used in the in vitro assays interfere with the nanomaterial properties. High adsorption capacity, optical and magnetic properties, catalytic activity, dissolution, and acidity or alkalinity of the nanomaterials are some of the examples of properties that may promote this interaction (Kroll et al., 2009).
Many questions have been raised by the regulators related to the lack of consistency of the data produced by cytotoxicity assays. New assays for a correct evaluation of the nanomaterial toxicity are, thus, needed. In this context, new approaches have arisen, such as the in silico nanotoxicology approach. In silico methods are the combination of toxicology with computational tools and bio-statistical methods for the evaluation and prediction of toxicity. By using computational tools is possible to analyse more nanomaterials, combine different endpoints and pathways of nanotoxicity, being less time-consuming and avoiding all the ethical questions (Warheit, 2008; Raunio, 2011).
Quantitative structure-activity relationship models (QSAR) were one the first applications of computational tools applied in toxicology. QSAR models are based on the hypothesis that the toxicity of nanomaterials and their cellular fate in the body can be predicted by their characteristics, and different biological reactions are the result of physicochemical characteristics, such as size, shape, zeta potential, or surface charge, etc., gathered as a set of descriptors. QSAR aims at identifying the physicochemical characteristics which lead to toxicity, so as to provide alterations to reduce toxicology. A mathematical model is created, which allows liking descriptors and the biological activity (Rusyn and Daston, 2010; Winkler et al., 2013; Oksel et al., 2015).
Currently, toxigenomics is a new area of nanotoxicology, which includes a combination between genomics and nanotoxicology to find alterations in the gene, protein and in the expressions of metabolites (Rusyn et al., 2012; Fadeel et al., 2013a).
Hitherto, different risk assessment approaches have been reported. One of them is the DF4nanoGrouping framework, which concerns a functionality driven scheme for grouping nanomaterials based on their intrinsic properties, system dependent properties and toxicological effects (Arts et al., 2014, 2016). Accordingly, nanomaterials are categorized in four groups, including possible subgroups. The four main groups encompass (1) soluble, (2) biopersistent high aspect ratio, (3) passive, that is, nanomaterials without obvious biological effects and (4) active nanomaterials, that is, those demonstrating surface-related specific toxic properties. The DF4nanoGrouping foresees a stepwise evaluation of nanomaterial properties and effects with increasing biological complexity. In case studies that includes carbonaceous nanomaterials, metal oxide, and metal sulfate nanomaterials, amorphous silica and organic pigments (all nanomaterials having primary particle sizes smaller than 100 nm), the usefulness of the DF4nanoGrouping for nanomaterial hazard assessment has already been established. It facilitates grouping and targeted testing of nanomaterials, also ensuring that enough data for the risk assessment of a nanomaterial are available, and fostering the use of non-animal methods (Landsiedel et al., 2017). More recently, DF4nanoGrouping developed three structure-activity relationship classification, decision tree, models by identifying structural features of nanomaterials mainly responsible for the surface activity (size, specific surface area, and the quantum-mechanical calculated property lowest unoccupied molecular orbital), based on a reduced number of descriptors: one for intrinsic oxidative potential, two for protein carbonylation, and three for no observed adverse effect concentration (Gajewicz et al., 2018)
Keck and Mller also proposed a nanotoxicological classification system (NCS) (Figure 3) that ranks the nanomaterials into four classes according to the respective size and biodegradability (Mller et al., 2011; Keck and Mller, 2013).
Due to the size effects, this parameter is assumed as truly necessary, because when nanomaterials are getting smaller and smaller there is an increase in solubility, which is more evident in poorly soluble nanomaterials than in soluble ones. The adherence to the surface of membranes increases with the decrease of the size. Another important aspect related to size that must be considered is the phagocytosis by macrophages. Above 100 nm, nanomaterials can only be internalized by macrophages, a specific cell population, while nanomaterials below 100 nm can be internalized by any cell due to endocytosis. Thus, nanomaterials below 100 nm are associated to higher toxicity risks in comparison with nanomaterials above 100 nm (Mller et al., 2011; Keck and Mller, 2013).
In turn, biodegradability was considered a required parameter in almost all pharmaceutical formulations. The term biodegradability applies to the biodegradable nature of the nanomaterial in the human body. Biodegradable nanomaterials will be eliminated from the human body. Even if they cause some inflammation or irritation the immune system will return to the regular function after elimination. Conversely, non-biodegradable nanomaterials will stay forever in the body and change the normal function of the immune system (Mller et al., 2011; Keck and Mller, 2013).
There are two more factors that must be taken into account in addition to the NCS, namely the route of administration and the biocompatibility surface. When a particle is classified by the NCS, toxicity depends on the route of administration. For example, the same nanomaterials applied dermally or intravenously can pose different risks to the immune system.
In turn, a non-biocompatibility surface (NB) can activate the immune system by adsorption to proteins like opsonins, even if the particle belongs to the class I of the NCS (Figure 3). The biocompatibility (B) is dictated by the physicochemical surface properties, irrespective of the size and/or biodegradability. This can lead to further subdivision in eight classes from I-B, I-NB, to IV-B and IV-NB (Mller et al., 2011; Keck and Mller, 2013).
NCS is a simple guide to the evaluation of the risk of nanoparticles, but there are many other parameters playing a relevant role in nanotoxicity determination (Mller et al., 2011; Keck and Mller, 2013). Other suggestions encompass more general approaches, combining elements of toxicology, risk assessment modeling, and tools developed in the field of multicriteria decision analysis (Rycroft et al., 2018).
A forthcoming challenge in the pharmaceutical development is the scale-up and reproducibility of the nanomedicines. A considerable number of nanomedicines fail these requirements and, consequently, they are not introduced on the pharmaceutical market (Agrahari and Hiremath, 2017).
The traditional manufacturing processes do not create three dimensional medicines in the nanometer scale. Nanomedicine manufacturing processes, as already mentioned above, compromise top-down and bottom-down approaches, which include multiple steps, like homogenization, sonication, milling, emulsification, and sometimes, the use of organic solvents and further evaporation. In a small-scale, it is easy to control and achieve the optimization of the formulation. However, at a large scale it becomes very challenging, because slight variations during the manufacturing process can originate critical changes in the physicochemical characteristics and compromise the quality and safety of the nanomedicines, or even the therapeutic outcomes. A detailed definition of the acceptable limits for the CQA is very important, and these parameters must be identified and analyzed at the small-scale, in order to understand how the manufacturing process can change them: this will help the implementation of the larger scale. Thus, a deep process of understanding the critical steps and the analytical tools established for the small-scale will be a greatly help for the introduction of the large scale (Desai, 2012; Kaur et al., 2014; Agrahari and Hiremath, 2017).
Another requirement for the introduction of medicines in the pharmaceutical market is the reproducibility of every batch produced. The reproducibility is achieved in terms of physicochemical characterization and therapeutic purpose. There are specific ranges for the variations between different batches. Slight changes in the manufacturing process can compromise the CQA and, therefore, they may not be within a specific range and create an inter-batch variation (Desai, 2012; Kaur et al., 2014; Agrahari and Hiremath, 2017).
Over the last decades, nanomedicines have been successfully introduced in the clinical practice and the continuous development in pharmaceutical research is creating more sophisticated ones which are entering in clinic trials. In the European Union, the nanomedicine market is composed by nanoparticles, liposomes, nanocrystals, nanoemulsions, polymeric-protein conjugates, and nanocomplexes (Hafner et al., 2014). Table 2 shows some examples of commercially available nanomedicines in the EU (Hafner et al., 2014; Choi and Han, 2018).
In the process of approval, nanomedicines were introduced under the traditional framework of the benefit/risk analysis. Another related challenge is the development of a framework for the evaluation of the follow-on nanomedicines at the time of reference medicine patent expiration (Ehmann et al., 2013; Tinkle et al., 2014).
Nanomedicine comprises both biological and non-biological medical products. The biological nanomedicines are obtained from biological sources, while non-biological are mentioned as non-biological complex drugs (NBCD), where the active principle consists of different synthetic structures (Tinkle et al., 2014; Hussaarts et al., 2017; Mhlebach, 2018).
In order to introduce a generic medicine in the pharmaceutical market, several parameters need to be demonstrated, as described elsewhere. For both biological and non-biological nanomedicines, a more complete analysis is needed, that goes beyond the plasma concentration measurement. A stepwise comparison of bioequivalence, safety, quality, and efficacy, in relation to the reference medicine, which leads to therapeutic equivalence and consequently interchangeability, is required (Astier et al., 2017).
For regulatory purposes, the biological nanomedicines are under the framework set by European Medicines Agency (EMA) This framework is a regulatory approach for the follow-on biological nanomedicines, which include recommendations for comparative quality, non-clinical and clinical studies (Mhlebach et al., 2015).
The regulatory approach for the follow-on NBCDs is still ongoing. The industry frequently asks for scientific advice and a case-by-case is analyzed by the EMA. Sometimes, the biological framework is the base for the regulation of the NBCDs, because they have some features in common: the structure cannot be fully characterized and the in vivo activity is dependent on the manufacturing process and, consequently, the comparability needs to establish throughout the life cycle, as happens to the biological nanomedicines. Moreover, for some NBCDs groups like liposomes, glatiramoids, and iron carbohydrate complexes, there are draft regulatory approaches, which help the regulatory bodies to create a final framework for the different NBCDs families (Schellekens et al., 2014).
EMA already released some reflection papers regarding nanomedicines with surface coating, intravenous liposomal, block copolymer micelle, and iron-based nano-colloidal nanomedicines (European Medicines Agency, 2011, 2013a,b,c). These papers are applied to both new nanomedicines and nanosimilars, in order to provide guidance to developers in the preparation of marketing authorization applications.The principles outlined in these documents address general issues regarding the complexity of the nanosystems and provide basic information for the pharmaceutical development, non-clinical and early clinical studies of block-copolymer micelle, liposome-like, and nanoparticle iron (NPI) medicinal products drug products created to affect pharmacokinetic, stability and distribution of incorporated or conjugated active substances in vivo. Important factors related to the exact nature of the particle characteristics, that can influence the kinetic parameters and consequently the toxicity, such as the physicochemical nature of the coating, the respective uniformity and stability (both in terms of attachment and susceptibility to degradation), the bio-distribution of the product and its intracellular fate are specifically detailed.
After a nanomedicine obtains the marketing authorization, there is a long way up to the introduction of the nanomedicine in the clinical practice in all EU countries. This occurs because the pricing and reimbursement decisions for medicines are taken at an individual level in each member state of the EU (Sainz et al., 2015).
In order to provide patient access to medicines, the multidisciplinary process of Health Technology Assessment (HTA), is being developed. Through HTA, information about medicine safety, effectiveness and cost-effectiveness is generated so as support health and political decision-makers (Sainz et al., 2015).
Currently, pharmacoeconomics studies assume a crucial role previous to the commercialization of nanomedicines. They assess both the social and economic importance through the added therapeutic value, using indicators such as quality-adjusted life expectancy years and hospitalization (Sainz et al., 2015).
The EUnetHTA was created to harmonize and enhance the entry of new medicines in the clinical practice, so as to provide patients with novel medicines. The main goal of EUnetHTA is to develop decisive, appropriate and transparent information to help the HTAs in EU countries.
Currently, EUnetHTA is developing the Joint Action 3 until 2020 and the main aim is to define and implement a sustainable model for the scientific and technical cooperation on Health Technology Assessment (HTA) in Europe.
The reformulation of pre-existing medicines or the development of new ones has been largely boosted by the increasing research in nanomedicine. Changes in toxicity, solubility and bioavailability profile are some of the modifications that nanotechnology introduces in medicines.
In the last decades, we have assisted to the translation of several applications of nanomedicine in the clinical practice, ranging from medical devices to nanopharmaceuticals. However, there is still a long way toward the complete regulation of nanomedicines, from the creation of harmonized definitions in all Europe to the development of protocols for the characterization, evaluation and process control of nanomedicines. A universally accepted definition for nanomedicines still does not exist, and may even not be feasible at all or useful. The medicinal products span a large range in terms of type and structure, and have been used in a multitude of indications for acute and chronic diseases. Also, ongoing research is rapidly leading to the emergence of more sophisticated nanostructured designs that requires careful understanding of pharmacokinetic and pharmacodynamic properties of nanomedicines, determined by the respective chemical composition and physicochemical properties, which thus poses additional challenges in regulatory terms.
EMA has recognized the importance of the establishment of recommendations for nanomedicines to guide their development and approval. In turn, the nanotechnology methods for the development of nanomedicines bring new challenges for the current regulatory framework used.
EMA have already created an expert group on nanomedicines, gathering members from academia and European regulatory network. The main goal of this group is to provide scientific information about nanomedicines in order to develop or review guidelines. The expert group also helps EMA in discussions with international partners about nanomedicines. For the developer an early advice provided from the regulators for the required data is highly recommended.
The equivalence of complex drug products is another topic that brings scientific and regulatory challenges. Evidence for sufficient similarity must be gathered using a careful stepwise, hopefully consensual, procedure. In the coming years, through all the innovation in science and technology, it is expected an increasingly higher number of medicines based on nanotechnology. For a common understanding among different stakeholders the development of guidelines for the development and evaluation of nanomedicines is mandatory, in order to approve new and innovative nanomedicines in the pharmaceutical market. This process must be also carried out along with interagency harmonization efforts, to support rational decisions pertaining to scientific and regulatory aspects, financing and market access.
CV conceived the original idea and directed the work. SS took the lead in writing the manuscript. AP and JS helped supervise the manuscript. All authors provided critical feedback and helped shape the research, analysis and revision of the manuscript.
This work was financially supported by Fundao para a Cincia e a Tecnologia (FCT) through the Research Project POCI-01-0145-FEDER-016648, the project PEst-UID/NEU/04539/2013, and COMPETE (Ref. POCI-01-0145-FEDER-007440). The Coimbra Chemistry Center is supported by FCT, through the Project PEst-OE/QUI/UI0313/2014 and POCI-01-0145-FEDER-007630. This paper was also supported by the project UID/QUI/50006/2013LAQV/REQUIMTE.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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CLINAM 9 / 2016 Conference and Exhibition
European & Global Summit for Cutting-Edge Medicine
June 26 29, 2016
Clinical Nanomedicine and Targeted Medicine -
Enabling Technologies for Personalized Medicine
Scientific Committee: Chairman Prof. Dr. med. Patrick Hunziker, University Hospital Basel (CH). MEMBERS Prof. Dr. Yechezkel Barenholz, Hebrew University, Hadassah Medical School, Jerusalem (IL). Dr. med. h.c. Beat Ler, MA, European Foundation for Clinical Nanomedicine, Basel (CH) Prof. Dr. Gert Storm, Institute for Pharmaceutical Sciences, Utrecht University, (NL) Prof. Dr. Marisa Papaluca Amati, European Medicines Agency, London (UK). Prof. Dr. med. Christoph Alexiou, University Hospital Erlangen (D) Prof. Dr. Gerd Binnig, Nobel Laureate, Munich (DE) Prof. Dr. Viola Vogel, Laboratory for Biologically Oriented Materials, ETH, Zrich (CH). Prof. Dr. Jan Mollenhauer, Lundbeckfonden Center of Excellence NanoCAN, University of Southern Denmark, Odense (DK). Prof. Dr. med. Omid Farokhzad, Associate Professor and Director of Laboratory of Nanomedicine and Biomaterials, Harvard Medical School and Brigham and Women's Hospital; Founder of BIND Therapeutics, Biosciences and Blend Therapeutics, Cambridge, Boston (USA) Prof. Dr. Dong Soo Lee, M.D. Ph. Chairman Department of Nuclear Medicine Seoul National University Seoul, Korea (invited) Prof. Dr.Lajos Balogh, Editorin in Chief, Nanomedicine, Nanotechnologyin, Biology and Medicine, Elsevier and Member of theExecutive Board, American Society for Nanomedicine in, Boston(USA) and other members.
Conference Venue: Congress Center, Messeplatz 21, 4058 Basel, Switzerland, Phone + 41 58 206 28 28, This email address is being protected from spambots. You need JavaScript enabled to view it. Organizers office: CLINAM-Foundation, Alemannengasse 12, P.B. 4016 Basel Phone +41 61 695 93 95, This email address is being protected from spambots. You need JavaScript enabled to view it.
In the previous eight years, the CLINAM Summit grew to the largest in its field with 12 presenting Noble Laureates and more than 500 participants from academia, industry, regulatory authorities and policy from over 40 different countries in Europe and worldwide. With this success and broad support by well beyond 20 renowned collaborating initiatives, the CLINAM-Summit is today one of the most important marketplaces for scientific exchange and discussions of regulatory, political and ethical aspects in this field of cutting edge medicine.
In particular, the CLINAM Summit emerged as exquisite forum for translation from bench to bedside, for European and international networking, and for industrial collaboration between companies, with academia, and point-of-contact with customers. The summit is presently the only place to meet the regulatory authorities from all continents to debate the needs of all stakeholders in the field with the legislators.
CLINAM 9/2016continues with its successful tradition to cover the manifold interdisciplinary fields of Clinical and Targeted Nanomedicine in major and neglected diseases. As special focus area, CLINAM 09/2016 adds translation and enabling technologies, including, for example, cutting-edge molecular profiling, nano-scale analytics, single cell analysis, stem cell technologies, tissue engineering, in and ex vivo systems as well as in vitro substitute systems for efficacy and toxicity testing.
CLINAM 09/2016covers the entire interdisciplinary spectrum of Nanomedicine and Targeted Medicine from new materials with potential medical applications and enabling technologies over diagnostic and therapeutic translation to clinical applications in infectious, inflammatory and neurodegenerative diseases, as well as diabetes, cancer and regenerative medicine to societal implications, strategical issues, and regulatory affairs. The conference is sub-divided into four different tracks running in parallel and provides ample possibilities for exhibitors as indicated by steadily increasing requests:
Track 1: Clinical and Targeted Nanomedicine Basic Research Disease Mechanisms and Personalized Medicine Regenerative Medicine Novel Therapeutic and Diagnostic Approaches Active and Passive Targeting Targeted Delivery (antibodies, affibodies, aptamers, nano drug delivery devices) Accurin Technology Nano-Toxicology Track 2: Clinical and Targeted Nanomedicine: Translation Unsolved Medical Problems Personalized Medicine and Theranostic Approaches Regenerative Medicine Advanced Breaking and Ongoing Clinical Trials Applied Nanomedical Diagnostics and Therapeutics Track 3: Enabling Technologies Nanomaterial Analytics and Testing Molecular Profiling for Research and Efficacy/Toxicology Testing (Genomics, Proteomics, Glycomics, Lipidomics, Metabolomics) Functional Testing Assays and Platforms Single Cell Analyses Cell Tracking Stem Cell Biology and Engineering Technologies Microfluidics Tissue Engineering Tissues-on-a-Chip Bioprinting In vivo Testing Novel Imaging Approaches Medical Devices Track 4: Regulatory, Societal Affairs and Networking Regulatory Issues in Nanomedicine Strategy and Policy The Patients` Perspective Ethical Issues in Nanomedicine University Village Cutting-Edge EU-Project Presentations Networking for International Consortium Formation
For CLINAM 9 / 16 Last Summit the number of exhibitors increased without investment of acquisition.As from the 9th Summit the CLINAM-Foundation has stepped in to a Partnership with The Congress Center Basel which will invest in a proactive acquisition and management for large foyer exhibition. Based on last years exhibition it is expected to have about 50 Exhibitors at thenext Summit. Exhibitors can profit of the possibility to meet their target visitors on one single spot in Basel at CLINAM 9 / 2016. With this new concept for the exhibition, the international CLINAM-summit becomes also the place for the pulse of the market and early sales in the field of cutting-edge medicine.
The exhibitors are invited to participate in the below in the nomenclature described fields. The list is topic to extensions so that by proposals from exhibitors it will constantly be updated. Strong focus of the exhibition relates to the topics of the conference in which Nanomedicine and Targeted Medicine - presently the most important building blocks in novel Medicine - are debated. The organizers look forward to the interest of the exhibitors to at a moderate investment take the opportunity to meet the community of Nanomedicine, Targeted Medicine and those investing into cutting edge Medicine tools and applications.
The CLINAM- Summit has every year 150 presentations. Many young mist skilled young researchers, young starting entrepreneurs, Engineers and scientists apply for posters and oral presentations. CLINAM offers a first Deadline for those, submitting their work before February 15, 2016 a discount of 20% on the registration fees for Submitters (610.00 ; for students 430.00 ) . The second Deadline after that is April 25, 2016
The Exhibitors at CLINAM 8/2015
The European Foundation for Clinical Nanomedicine is a non-profit institution aiming at advancing medicine to the benefit of individuals and society through the application of nanoscience. Aiming at prevention, diagnosis, and therapy through nanomedicine as well as at exploration of its implications, the Foundation reaches its goals through support of clinically focussed research and of interaction and information flow between clinicians, researchers, the public, and other stakeholders. The recognition of the large future impact of nanoscience on medicine and the observed rapid advance of medical applications of nanoscience have been the main reasons for the creation of the Foundation.
Nanotechnology is generally considered as the key technology of the 21st century. It is an interdisciplinary scientific field focusing on methods, materials, and tools on the nanometer scale, i.e. one millionth of a millimeter. The application of this science to medicine seeks to benefit patients by providing prevention, early diagnosis, and effective treatment for prevalent, for disabling, and for currently incurable medical conditions.
Link:
CLINAM - The Foundation
Our recent research article "In-vitro Topographical Model of Fuchs Dystrophy for Evaluation of Corneal Endothelial Cell Monolayer Formation" appeared on theBack cover of Advanced Healthcare Materials latest issue.
Several diseases have been known to be caused by microstructural changes in the extracellular microenvironment. Therefore, the knowledge of the interaction of cells with the altered extracellular micro-structures or surface topography is critical to develop a better understanding of the disease for therapeutic development. One such disease is Fuchs corneal endothelial dystrophy (FED). FED is the primary disease and major reason of corneal endothelial cell death. If left untreated, corneal blindness will be resulted; thus, FED is the leading indication for corneal transplantation. In the USA, 4% of population over the age of 40 is believed to have compromised corneal endothelium due to FED, which will further increase due to increasing life expectancy and rapidly ageing population. A diagnostic clinical hallmark of FED is the development of discrete pillar or dome-like microstructures on the corneal endothelial basement membrane (Descemet membrane). These microstructures are called corneal guttata or guttae. Cell therapies have been proposed as an alternative treatment method for Fuchs dystrophy patients. However, currently, no in-vitro or in-vivo FED disease model is available to study the cell therapies before clinical trials.
In this study, the pathological changes in the micro-structure of basement membranes resulting from FED disease was analyzed, to identify geometrical dimension to develop an in-vitro disease model of synthetic corneal guttata pillars/domes by using microfabrication techniques. This model was used to study the monolayer formation of donor-derived human corneal endothelial cells to test the effectiveness of the corneal endothelial cell regenerative therapies. The results suggest that the corneal cell therapies may not be equally effective for patients at different stages of disease progression. The pre-existing guttata in patients could interfere with the cells thus hampering monolayer formation within the eye. Surgical removal of the guttata from the diseased Descemet membrane prior to cell regenerative therapy could increase the success rate of monolayer formation, which could potentially increase the chances of cell therapy success. This study also demonstrate how biomaterial design can be employed to mimic the pathological microstructural changes in basement membranes for better understanding of cellular responses in disease conditions.
The rest is here:
Regenerative Nanomedicine Lab - yimlab.com
About JournalEditorsPublishing Fees Peer Reviewers Articles Open Outlook: Nanomedicine Aims and ScopeCall For PapersInterview: Dr Webster
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Yours sincerelyDr Thomas J WebsterEditor-in-ChiefInternational Journal of Nanomedicine
Email: Editor-in-Chief
Excerpt from:
International Journal of Nanomedicine | Call For Papers ...