11 research outputs found
Toxicity of nanomaterials
Nanoscience has matured significantly during the last decade as it has transitioned from bench top science to applied technology. Presently, nanomaterials are used in a wide variety of commercial products such as electronic components, sports equipment, sun creams and biomedical applications. There are few studies of the long-term consequences of nanoparticles on human health, but governmental agencies, including the United States National Institute for Occupational Safety and Health and Japan’s Ministry of Health, have recently raised the question of whether seemingly innocuous materials such as carbon-based nanotubes should be treated with the same caution afforded known carcinogens such as asbestos. Since nanomaterials are increasing a part of everyday consumer products, manufacturing processes, and medical products, it is imperative that both workers and end-users be protected from inhalation of potentially toxic NPs. It also suggests that NPs may need to be sequestered into products so that the NPs are not released into the atmosphere during the product’s life or during recycling. Further, non-inhalation routes of NP absorption, including dermal and medical injectables, must be studied in order to understand possible toxic effects. Fewer studies to date have addressed whether the body can eventually eliminate nanomaterials to prevent particle build-up in tissues or organs. This critical review discusses the biophysicochemical properties of various nanomaterials with emphasis on currently available toxicology data and methodologies for evaluating nanoparticle toxicity
Advanced polymer nanocapsules with enhanced capabilities for controlled-release of payloads
The main objective of this thesis was to prepare polymer nanocapsules with improved capability for controlled-release of payloads. To fulfill this objective, new strategies were developed to (i) hinder non-controlled leakage and (ii) enhance controlled-release of payloads from these nanocapsules. Nanocapsules with either oily or aqueous core containing hydrophilic or hydrophobic payloads were prepared by miniemulsion technique.
In the first part (section 4.1), the release of hydrophilic payloads from polyurea nanocapsules was programmed by varying the osmotic pressure in the core of these nanocapsules. The results exhibited that the initial release of the payloads from the aqueous core was largely dependent on the concentration of osmotic pressure agents. The analysis showed that the correlation between the release of the dye and the concentration of the co-encapsulated salts (i.e. osmotic pressure agents) is non-linear. Further measurements displayed that the swelling of nanocapsules is the responsible mechanism for the observed differences between the release profiles of the dye from the nanocapsules loaded with osmotic pressure generating species and non-loaded ones. To diminish the burst release of the payload, nanocapsules with crosslinked shell were synthesized using crosslinker. Crosslinking had an influence on shell rigidity and, thus, decreased release kinetics by obstructing the swelling of nanocapsules despite of an osmotic pressure. Finally, we illustrated how this strategy can be utilized to induce triggered release or sustained release profiles through two different applications.
In the next set of experiments (section 4.2), the non-controlled leakage of hydrophilic payloads from the core due to osmotic pressure difference could be suppressed by varying the physicochemical properties of nanocapsule membranes thereby decreasing release kinetics. The shell thickness of polyurea nanocapsules was tuned by changing the monomer concentration used for the preparation of these nanocapsules. A significant increase of shell thickness could largely decrease the non-controlled leakage of the hydrophilic payloads. In addition, this significant increment of shell thickness slowed down the release kinetics and thereby suppressed a precisely targeted delivery of the payload in desired time. Therefore, reduction-responsive unit were introduced into the thick shell to enable triggered release of the payload. Triggered-release of the payload was successfully upon application of reducing agent. In this work, the concept of stimulus-induced release of hydrophilic payloads from nanocapsules was demonstrated for redox-responsive nanocapsules.
The concept of using block copolymers responsive to one stimulus for the preparation of stimulus responsive capsules was extended to triblock terpolymers responsive to three independent stimuli (section 4.3). Novel triple stimuli-responsive nanocapsules consisting of PVFc-b-PDMAEMA-b-PMMA triblock terpolymer were prepared by the solvent evaporation process from miniemulsion droplets. The nanocapsules could encapsulate the dye in the core and perfectly protect it from non-controlled leakage. The triggered release of the payload was achieved because the nanocapsules shell was addressable by three different stimuli: pH change, oxidizing agent, and temperature. Alternatively, nanocapsules were synthesized with a mixture of responsive diblock copolymers, where their shell had the same chemical composition in terms of molar amount of blocks with nanocapsules synthesized from triblock terpolymer. However, the microphase separation between the responsive diblock copolymer across the shell hampers the release performance of the payloads from the nanocapsules. This configuration of diblock copolymers across the shell, thus, made these nanocapsules stimulus-responsive instead of triple stimuli-responsive.
Finally, the concept of utilizing pro-active payloads in order to significantly increase the selective release of small size payloads from mesoporous nanocapsules was demonstrated (section 4.4). Silica nanocapsules were synthesized by the miniemulsion technique. The non-controlled release of payload largely decreased the efficiency of these silica nanocapsules for the precise delivery of the payload. To overcome the problem of non-controlled release, a pro-active payload was synthesized. A pro-active payload is defined as a compound that is converted to an active functional molecule in the environment where it is needed. The pro-active payload could not diffuse through the silica shell due to its larger molecular size compared to the payload. The combination of the encapsulation of the pro-active payload and the responsive behavior of the silica nanocapsules led to significant increase in the final released amount of payload while almost the entire payload in the release medium could be selectivity delivered from the silica nanocapsules.Das Hauptaugenmerk dieser Dissertation lag auf der Herstellung von Polymer-Nanokapseln mit verbesserter Fähigkeit zur kontrollierten Freisetzung ihrer Beladung. Zur Erreichung dieses Ziels wurden neue Strategien entwickelt, um (i) unkontrolliertes Austreten zu verhindern und (ii) die kontrollierte Freisetzung des Inhaltes dieser Nanokapseln zu verbessern. Es wurden Nanokapseln, sowohl mit öligen als auch mit wässrigen Kernen, die hydrophile oder hydrophobe Beladungen enthalten, mithilfe der Miniemulsionstechnik hergestellt.
Im ersten Teil (section 4.1) wurde die Freisetzung von hydrophilen Beladungen aus Polyurea-Kapseln durch Variation des osmotischen Drucks im Inneren dieser Nanokapseln angepasst. Die Ergebnisse zeigten, dass die anfängliche Freisetzung der Beladungen aus dem wässrigen Kern stark von der Konzentration der osmotischen Druck-Agenzien abhängt. Die Analyse zeigte, dass die Korrelation zwischen der Freisetzung des Farbstoffs und der Konzentration des mit eingekapselten Salzes (i. e. des osmotischen Druck-Agens) nicht linear ist. Weitere Messungen wiesen darauf hin, dass das Anquellen der Nanokapseln der verantwortliche Mechanismus ist für die beobachteten Abweichungen zwischen dem Freisetzungsprofil des Farbstoffs aus den, mit osmotischen Druck generierenden Spezies geladenen, und den ungeladenen Kapseln. Um die Ladungs-Freisetzung durch Aufplatzen zu verringern, wurden Nanokapseln mit quer-vernetzten Schalen durch Einsatz eines Vernetzers hergestellt. Die Vernetzung hat Einfluss auf die Stabilität der Schale, was trotz des osmotischen Drucks zu einer Blockade des Anschwellens der Nanokapseln führt und damit eine reduzierte Freisetzungskinetik bewirkt. Abschließend haben wir anhand zwei verschiedener Anwendungen veranschaulicht, wie diese Strategie einsetzbar ist, um ein gesteuertes oder dauerhaftes Freisetzungsprofil zu erhalten.
In der nächsten Reihe von Experimenten (section 4.2) konnte durch Veränderung der physikochemischen Eigenschaften der Nanokapselmembran das unkontrollierte Austreten der hydrophilen Beladungen aus dem Kern wegen des osmotischen Druckunterschieds unterdrückt und dadurch die Freisetzungskinetik verringert werden. Die Schalendicke der Polyharnstoff-Nanokapseln wurde durch Veränderung der Monomer-Konzentration, die zu deren Herstellung verwendet wurden, eingestellt. Ein merklicher Anstieg der Schalendicke konnte die unkontrollierte Freisetzung der hydrophilen Beladungen deutlich senken. Außerdem reduzierte diese starke Erhöhung der Schalendicke die Freisetzungskinetik, wodurch die präzis-gezielte Abgabe der Beladung in gewünschter Zeit unterdrückt wurde. Deshalb wurden reduktionssensitive Einheiten in die dicke Schale eingebracht, um eine steuerbare Freisetzung der Beladung zu ermöglichen. Dies gelang erfolgreich nach Einsatz eines Reduktionsmittels. In dieser Arbeit wurde das Konzept der stimulus-induzierten Freisetzung von hydrophilen Beladungen aus Nanokapseln für Redox-sensitive Nanokapseln demonstriert.
Das Konzept des Einsatzes von Blockcopolymeren, die auf einen Stimulus reagieren, für die Herstellung von stimulus-responsiven Kapseln, wurde auf Triblockcopolymere, die sensitiv für drei unabhängige Stimuli sind, erweitert (section 4.3). Neuartige, dreifach stimuli-responsive Nanokapseln aus PVFc-b-PDMAEMA-b-PMMA Triblockterpolymer wurden mittels des Lösungsmittelverdampfungsverfahren aus Miniemulsionströpfchen hergestellt. Die Nanokapseln waren in der Lage den Farbstoff im Kern einzukapseln und ihn gegen unkontrolliertes Austreten zu sichern. Die steuerbare Freisetzung der Beladung wurde erzielt, weil die Nanokapsel durch drei unterschiedlichen Stimuli adressierbar war: durch Änderung des pH-Werts, durch Zugabe eines Oxidationsmittel und durch Variation der Temperatur. Als eine Alternative wurden Nanokapseln mit einer Mischung aus responsiven Diblockcopolymeren hergestellt, deren Schale dieselbe chemische Zusammensetzung, bezogen auf den molaren Anteil der Blöcke, besitzt wie die Nanokapseln aus Triblockcopolymeren. Allerdings hemmt die Mikrophasenseparation zwischen den responsiven Diblock-copolymeren die Freisetzung der Beladungen aus den Nanokapseln. Die Konfiguration der Diblockcopolymere innerhalb der Schale wiederum machte diese Nanokapseln stimulus-responsiv, im Gegensatz zu den dreifach stimuli-responsiven Kapseln.
Zuletzt wurde das Konzept des Einsatzes von proaktiven Beladungen für einen signifikanten Anstieg der selektiven Freisetzung der kleinen Beladungen aus mesoporösen Nanokapseln demonstriert (section 4.4). Die Silika-Nanokapseln wurden mittels Miniemulsionstechnik hergestellt. Die unkontrollierte Ladungsfreisetzung verringerte die Effizienz dieser Silika-Nanokapseln für die präzise Abgabe der Beladungen erheblich. Um das Problem der unkontrollierten Freisetzung zu umgehen, wurde eine sogenannte proaktive Beladung hergestellt. Eine proaktive Beladung ist definiert als eine Verbindung, die erst in der entsprechenden Umgebung, wo es benötigt wird, in ein aktives, funktionelles Molekül umgesetzt wird. Dank der gewachsenen Größe, verglichen zur Beladung, konnte die proactive Beladung nicht mehr durch die Silika-schale diffundieren. Die Kombination aus der Einkapselung der proaktiven Beladung und des responsiven Verhalten der Silika-Nanokapseln führte zu einem signifikanten Anstieg des endgültig freigesetzten Anteils der Beladung, welches selektiv aus den Silika-Nanokapseln abgeben wurde
Toxicity of nanomaterials
Nanoscience has matured significantly during the last decade as it has transitioned from bench top science to applied technology. Presently, nanomaterials are used in a wide variety of commercial products such as electronic components, sports equipment, sun creams and biomedical applications. There are few studies of the long-term consequences of nanoparticles on human health, but governmental agencies, including the United States National Institute for Occupational Safety and Health and Japan's Ministry of Health, have recently raised the question of whether seemingly innocuous materials such as carbon-based nanotubes should be treated with the same caution afforded known carcinogens such as asbestos. Since nanomaterials are increasing a part of everyday consumer products, manufacturing processes, and medical products, it is imperative that both workers and end-users be protected from inhalation of potentially toxic NPs. It also suggests that NPs may need to be sequestered into products so that the NPs are not released into the atmosphere during the product's life or during recycling. Further, non-inhalation routes of NP absorption, including dermal and medical injectables, must be studied in order to understand possible toxic effects. Fewer studies to date have addressed whether the body can eventually eliminate nanomaterials to prevent particle build-up in tissues or organs. This critical review discusses the biophysicochemical properties of various nanomaterials with emphasis on currently available toxicology data and methodologies for evaluating nanoparticle toxicity (286 references)
Pyrolytic carbon coating for cytocompatibility of titanium oxide nanoparticles: A promising candidate for medical applications
Biodegradable Harmonophores for Targeted High-Resolution In Vivo Tumor Imaging
Optical imaging probes have played a major role in detecting and monitoring a variety of diseases. In particular, nonlinear optical imaging probes, such as second harmonic generating (SHG) nanoprobes, hold great promise as clinical contrast agents, as they can be imaged with little background signal and unmatched long-term photostability. As their chemical composition often includes transition metals, the use of inorganic SHG nanoprobes can raise long-term health concerns. Ideally, contrast agents for biomedical applications should be degraded in vivo without any long-term toxicological consequences to the organism. Here, we developed biodegradable harmonophores (bioharmonophores) that consist of polymer-encapsulated, self-assembling peptides that generate a strong SHG signal. When functionalized with tumor cell surface markers, these reporters can target single cancer cells with high detection sensitivity in zebrafish embryos in vivo. Thus, bioharmonophores will enable an innovative approach to cancer treatment using targeted high-resolution optical imaging for diagnostics and therapy
Engineering of Mature Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Using Substrates with Multiscale Topography
Producing mature and functional cardiomyocytes (CMs) by in vitro differentiation of induced pluripotent stem cells (iPSCs) using only biochemical cues is challenging. To mimic the biophysical and biomechanical complexity of the native in vivo environment during the differentiation and maturation process, polydimethylsiloxane substrates with 3D topography at the micrometer and sub-micrometer levels are developed and used as cell-culture substrates. The results show that while cylindrical patterns on the substrates resembling mature CMs enhance the maturation of iPSC-derived CMs, sub-micrometer-level topographical features derived by imprinting primary human CMs further accelerate both the differentiation and maturation processes. The resulting CMs exhibit a more-mature phenotype than control groups—as confirmed by quantitative polymerase chain reaction, flow cytometry, and the magnitude of beating signals—and possess the shape and orientation of mature CMs in human myocardium—as revealed by fluorescence microscopy, Ca2+ flow direction, and mitochondrial distribution. The experiments, combined with a virtual cell model, show that the physico-mechanical cues generated by these 3D-patterned substrates improve the phenotype of the CMs via the reorganization of the cytoskeletal network and the regulation of chromatin conformation
Temperature: The “Ignored” Factor at the NanoBio Interface
Upon incorporation of nanoparticles (NPs) into the body, they are exposed to biological fluids, and their interaction with the dissolved biomolecules leads to the formation of the so-called protein corona on the surface of the NPs. The composition of the corona plays a crucial role in the biological fate of the NPs. While the effects of various physicochemical parameters on the composition of the corona have been explored in depth, the role of temperature upon its formation has received much less attention. In this work, we have probed the effect of temperature on the protein composition on the surface of a set of NPs with various surface chemistries and electric charges. Our results indicate that the degree of protein coverage and the composition of the adsorbed proteins on the NPs’ surface depend on the temperature at which the protein corona is formed. Also, the uptake of NPs is affected by the temperature. Temperature is, thus, an important parameter that needs to be carefully controlled in quantitative studies of bionano interactions