fabrication-anisotropic-polymeric-artificial-antigen-presenting-cells

Fabrication of Anisotropic Polymeric Artificial Antigen Presenting Cells for CD8+ T Cell Activation

Artificial antigen presenting cells (aAPC) are a promising platform for immune modulation due to their potent ability to stimulate T cells. Acellular ...

Johns Hopkins University School of Medicine

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.

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

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.

Shaping the future of nanomedicine: anisotropy in polymeric nanoparticle design.

Biodegradable polymer iron oxide nanocomposites: the future of biocompatible magnetism.

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.

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

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. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1813-1825, 2017.

Continuous microfluidic assembly of biodegradable poly(beta-amino ester)/DNA nanoparticles for enhanced gene delivery.

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.

Article	Year
An automated multidimensional thin film stretching device for the generation of anisotropic polymeric micro- and nanoparticles. Journal of biomedical materials research. Part A\| PubMed ID: 25641799	2015
Shaping the future of nanomedicine: anisotropy in polymeric nanoparticle design. Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology\| PubMed ID: 25981390	2016
Biodegradable polymer iron oxide nanocomposites: the future of biocompatible magnetism. Nanomedicine (London, England)\| PubMed ID: 26608843	2015
Noninvasive Targeted Transcranial Neuromodulation via Focused Ultrasound Gated Drug Release from Nanoemulsions. Nano letters\| PubMed ID: 28094959	2017
Continuous microfluidic assembly of biodegradable poly(beta-amino ester)/DNA nanoparticles for enhanced gene delivery. Journal of biomedical materials research. Part A\| PubMed ID: 28177587	2017
Surface engineering for lymphocyte programming. Advanced drug delivery reviews\| PubMed ID: 28501510	2017

Randall A. Meyer

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