Randall A. Meyer

Biodegradable Nanoellipsoidal Artificial Antigen Presenting Cells for Antigen Specific T‐Cell Activation

Non-spherical nanodimensional artificial antigen presenting cells (naAPCs) offer the potential to systemically induce an effective antigen-specific immune response. In this report it is shown biodegradable ellipsoidal naAPCs mimic the T-Cell/APC interaction better than equivalent spherical naAPCs. In addition, it is demonstrated ellipsoidal naAPCs offer reduced non-specific cellular uptake and a superior pharmacokinetic profile compared to spherical naAPCs.

Biomimetic particles as therapeutics

In recent years, there have been major advances in the development of novel nanoparticle- and microparticle-based therapeutics. An emerging paradigm is the incorporation of biomimetic features into these synthetic therapeutic constructs to enable them to better interface with biological systems. Through the control of size, shape, and material consistency, particle cores have been generated that better mimic natural cells and viruses. In addition, there have been significant advances in biomimetic surface functionalization of particles through the integration of bio-inspired artificial cell membranes and naturally derived cell membranes. Biomimetic technologies enable therapeutic particles to have increased potency to benefit human health.

Noninvasive Targeted Transcranial Neuromodulation via Focused Ultrasound Gated Drug Release from Nanoemulsions

Targeted, noninvasive neuromodulation of the brain of an otherwise awake subject could revolutionize both basic and clinical neuroscience. Toward this goal, we have developed nanoparticles that allow noninvasive uncaging of a neuromodulatory drug, in this case the small molecule anesthetic propofol, upon the application of focused ultrasound. These nanoparticles are composed of biodegradable and biocompatible constituents and are activated using sonication parameters that are readily achievable by current clinical transcranial focused ultrasound systems. These particles are potent enough that their activation can silence seizures in an acute rat seizure model. Notably, there is no evidence of brain parenchymal damage or blood-brain barrier opening with their use. Further development of these particles promises noninvasive, focal, and image-guided clinical neuromodulation along a variety of pharmacological axes.

Shaping the future of nanomedicine: anisotropy in polymeric nanoparticle design

Nanofabrication and biomedical applications of polymeric nanoparticles have become important areas of research. Biocompatible polymeric nanoparticles have been investigated for their use as delivery vehicles for therapeutic and diagnostic agents. Although polymeric nanoconstructs have traditionally been fabricated as isotropic spheres, anisotropic, nonspherical nanoparticles have gained interest in the biomaterials community owing to their unique interactions with biological systems. Polymeric nanoparticles with different forms of anisotropy have been manufactured using a variety of novel methods in recent years. In addition, they have enhanced physical, chemical, and biological properties compared with spherical nanoparticles, including increased targeting avidity and decreased nonspecific in vivo clearance. With these desirable properties, anisotropic nanoparticles have been successfully utilized in many biomedical settings and have performed superiorly to analogous spherical nanoparticles. We summarize the current state-of-the-art fabrication methods for anisotropic polymeric nanoparticles including top-down, bottom-up, and microfluidic design approaches. We also summarize the current and potential future applications of these nanoparticles, including drug delivery, biological targeting, immunoengineering, and tissue engineering. Ongoing research into the properties and utility of anisotropic polymeric nanoparticles will prove critical to realizing their potential in nanomedicine.

Continuous Microfluidic Assembly of Biodegradable Poly(beta‐amino ester)/DNA Nanoparticles for Enhanced Gene Delivery

Translation of biomaterial-based nanoparticle formulations to the clinic faces significant challenges including efficacy, safety, consistency and scale-up of manufacturing, and stability during long-term storage. Continuous microfluidic fabrication of polymeric nanoparticles has the potential to alleviate the challenges associated with manufacture, while offering a scalable solution for clinical level production. Poly(beta-amino esters) (PBAE)s are a class of biodegradable cationic polymers that self-assemble with anionic plasmid DNA to form polyplex nanoparticles that have been shown to be effective for transfecting cancer cells specifically in vitro and in vivo. Here, we demonstrate the use of a microfluidic device for the continuous and scalable production of PBAE/DNA nanoparticles followed by lyophilization and long term storage that results in improved in vitro efficacy in multiple cancer cell lines compared to nanoparticles produced by bulk mixing as well as in comparison to widely used commercially available transfection reagents polyethylenimine and Lipofectamine® 2000. We further characterized the nanoparticles using nanoparticle tracking analysis (NTA) to show that microfluidic mixing resulted in fewer DNA-free polymeric nanoparticles compared to those produced by bulk mixing.

An automated multidimensional thin film stretching device for the generation of anisotropic polymeric micro- and nanoparticles

Anisotropic polymeric particles are of growing interest for biomaterials applications due to their unique properties. These include the ability for these particles to evade nonspecific cellular uptake and to have enhanced targeted cellular uptake and interaction. One of the most widely used methods for generating anisotropic polymeric particles is the thin film stretching procedure. Despite its theoretical simplicity, this procedure, as it has been implemented to date, can be difficult due to the inconsistent nature of the manual operation of machinery used to stretch the film. We have constructed an automated thin film stretcher for control over biomaterials via thin film stretching in 1D and 2D and as a result, have enabled precise generation of anisotropic polymeric particles. We demonstrate that this device can be utilized to produce anisotropic biodegradable particles of different size, shape, and material consistency. Furthermore, we show that this machine has enabled the scaled up and rapid production of anisotropic polymeric particles, including polymeric microparticles that mimic the shape of red blood cells. Further application of this automated thin film stretching device could allow for significant impact to diverse biomaterial and biomedical applications such as biomimetic particles for immunoengineering and long-circulating particles for controlled release of drugs.

Surface engineering for lymphocyte programming

ABSTRACT The once nascent field of immunoengineering has recently blossomed to include approaches to deliver and present biomolecules to program diverse populations of lymphocytes to fight disease. Building upon improved understanding of the molecular and physical mechanics of lymphocyte activation, varied strategies for engineering surfaces to activate and deactivate T‐Cells, B‐Cells and natural killer cells are in preclinical and clinical development. Surfaces have been engineered at the molecular level in terms of the presence of specific biological factors, their arrangement on a surface, and their diffusivity to elicit specific lymphocyte fates. In addition, the physical and mechanical characteristics of the surface including shape, anisotropy, and rigidity of particles for lymphocyte activation have been fine‐tuned. Utilizing these strategies, acellular systems have been engineered for the expansion of T‐Cells and natural killer cells to clinically relevant levels for cancer therapies as well as engineered to program B‐Cells to better combat infectious diseases. Graphical abstract Figure. No Caption available.

Biodegradable polymer iron oxide nanocomposites: the future of biocompatible magnetism

Superparamagnetic iron oxide nanoparticles (SPIONs) have become increasingly popular for various biomedical applications. The superparamagnetic properties of these nanoparticles enable their magnetic manipulation of biological targets such as cells, proteins and nucleic acids. In addition, SPIONs allow for MRI contrast for cells and tissues. Although generally nontoxic, these particles on their own are not sufficiently biocompatible due to their inorganic nature. One strategy to circumvent this compatibility issue is to coat the SPIONs with a biocompatible polymer. Although polymer coating is effective at mitigating potential complications at the SPION/biological interface, this only scratches the surface of the functionality that can be enabled by polymer-SPION nanocomposites. For example, polymeric nanostructures can have multifunctional drug delivery abilities, including control of the delivery of biological payloads in both space and time. An emerging strategy is to combine the advantages of inorganic SPIONs with the drug delivery capabilities of biodegradable polymeric particles to create multifunctional theranostic polymer-SPION nanocomposites. By treating the SPIONs as a cargo to be loaded into larger biodegradable polymeric nanostructures, new nanocomposites can be created to unite the beneficial features of paramagnetism and controlled drug release into one single nanoparticle. Biodegradable polymer iron oxide nanoparticles are promising for applications to many areas of medicine.

Entanglement-Based Thermoplastic Shape Memory Polymeric Particles with Photothermal Actuation for Biomedical Applications

Triggering shape-memory functionality under clinical hyperthermia temperatures could enable the control and actuation of shape-memory systems in clinical practice. For this purpose, we developed light-inducible shape-memory microparticles composed of a poly(d,l-lactic acid) (PDLLA) matrix encapsulating gold nanoparticles (Au@PDLLA hybrid microparticles). This shape-memory polymeric system for the first time demonstrates the capability of maintaining an anisotropic shape at body temperature with triggered shape-memory effect back to a spherical shape at a narrow temperature range above body temperature with a proper shape recovery speed (37 < T < 45 °C). We applied a modified film-stretching processing method with carefully controlled stretching temperature to enable shape memory and anisotropy in these micron-sized particles. Accordingly, we achieved purely entanglement-based shape-memory response without chemical cross-links in the miniaturized shape-memory system. Furthermore, these shape-memory microparticles exhibited light-induced spatiotemporal control of their shape recovery using a laser to trigger the photothermal heating of doped gold nanoparticles. This shape-memory system is composed of biocompatible components and exhibits spatiotemporal controllability of its properties, demonstrating a potential for various biomedical applications, such as tuning macrophage phagocytosis as demonstrated in this study.

Artificial Antigen-Presenting Cells: Biomimetic Strategies for Directing the Immune Response

Antigen-specific immune modulation and bioengineered immunotherapy have many applications in medicine. One promising technology to achieve the goal of immune control is the use of artificial antigen-presenting cells (aAPCs). aAPCs are synthetic constructs that mimic natural APCs in their ability to direct and maintain a T cell response. Several design criteria are important in the construction of an aAPC including its biomaterial composition, the size and shape of the aAPC for T cell interaction, the type and density of surface proteins presented, the delivery of soluble signals, and the recreation of the dynamic immunological synapse. Various aAPCs have been developed as therapeutics including those that activate the immune system against cancer or infectious disease and others that suppress the immune system in the context of autoimmunity. Additional research into the design and application of aAPCs could unlock the full potential of this technology to direct the immune response.