Perforated red blood cells enable compressible and injectable hydrogels as therapeutic vehicles

Hydrogels engineered for medical use within the human body need to be delivered in a minimally invasive fashion without altering their biochemical and mechanical properties to maximize their therapeutic outcomes. In this regard, key strategies applied for creating such medical hydrogels include formulating precursor solutions that can be crosslinked in situ with physical or chemical cues following their delivery or forming macroporous hydrogels at sub-zero temperatures via cryogelation prior to their delivery. Here, we present a new class of injectable composite materials with shape recovery ability. The shape recovery is derived from the physical properties of red blood cells (RBCs) that are first modified via hypotonic swelling and then integrated into the hydrogel scaffolds before polymerization. The RBCs' hypotonic swelling induces the formation of nanometer-sized pores on their cell membranes, which enable fast liquid release under compression. The resulting biocomposite hydrogel scaffolds display high deformability and shape-recovery ability. The scaffolds can repeatedly compress up to ~87% of their original volumes during injection and subsequent retraction through syringe needles of different sizes; this cycle of injection and retraction can be repeated up to ten times without causing any substantial mechanical damage to the scaffolds. Our biocomposite material system and fabrication approach for injectable materials will be foundational for the minimally invasive delivery of drug-loaded scaffolds, tissue-engineered constructs, and personalized medical platforms that could be administered to the human body with conventional needle-syringe systems

Zwitterionic 3D- Printed Non- Immunogenic Stealth Microrobots

Microrobots offer transformative solutions for non- invasive medical interventions due to their small size and untethered operation inside the human body. However, they must face the immune system as a natural protection mechanism against foreign threats. Here, non- immunogenic stealth zwitterionic microrobots that avoid recognition from immune cells are introduced. Fully zwitterionic photoresists are developed for two- photon polymerization 3D microprinting of hydrogel microrobots with ample functionalization: tunable mechanical properties, anti- biofouling and non- immunogenic properties, functionalization for magnetic actuation, encapsulation of biomolecules, and surface functionalization for drug delivery. Stealth microrobots avoid detection by macrophage cells of the innate immune system after exhaustive inspection (>90 hours), which has not been achieved in any microrobotic platform to date. These versatile zwitterionic materials eliminate a major roadblock in the development of biocompatible microrobots, and will serve as a toolbox of non- immunogenic materials for medical microrobot and other device technologies for bioengineering and biomedical applications.Zwitterionic stealth microrobots avoid detection and capture by immune cells. Zwitterionic microrobots with anti- biofouling, stealth, and non- immunogenic properties are 3D- printed via two- photon- polymerization, and are functionalized for magnetic actuation, encapsulation of biomolecules, and drug delivery. The microrobots remain undetected by macrophages and other immune cells for at least 90 hours, overcoming a major roadblock in medical microrobotics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163416/3/adma202003013-sup-0001-SuppMat.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163416/2/adma202003013.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163416/1/adma202003013_am.pd

Magnetic Resonance Imaging-Compatible Optically Powered Miniature Wireless Modular Lorentz Force Actuators

Minimally invasive medical procedures under magnetic resonance imaging (MRI) guidance have significant clinical promise. However, this potential has not been fully realized yet due to challenges regarding MRI compatibility and miniaturization of active and precise positioning systems inside MRI scanners, i.e., restrictions on ferromagnetic materials and long conductive cables and limited space around the patient for additional instrumentation. Lorentz force-based electromagnetic actuators can overcome these challenges with the help of very high, axial, and uniform magnetic fields (3-7 Tesla) of the scanners. Here, a miniature, MRI-compatible, and optically powered wireless Lorentz force actuator module consisting of a solar cell and a coil with a small volume of 2.5 x 2.5 x 3.0 mm(3) is proposed. Many of such actuator modules can be used to create various wireless active structures for future interventional MRI applications, such as positioning needles, markers, or other medical tools on the skin of a patient. As proof-of-concept prototypes toward such applications, a single actuator module that bends a flexible beam, four modules that rotate around an axis, and six modules that roll as a sphere are demonstrated inside a 7 Tesla preclinical MRI scanner.ISSN:2198-384

Multifunctional Bacteria-Driven Microswimmers for Targeted Active Drug Delivery

High-performance, multifunctional bacteria-driven microswimmers are introduced using an optimized design and fabrication method for targeted drug delivery applications. These microswimmers are made of mostly single <i>Escherichia coli</i> bacterium attached to the surface of drug-loaded polyelectrolyte multilayer (PEM) microparticles with embedded magnetic nanoparticles. The PEM drug carriers are 1 μm in diameter and are intentionally fabricated with a more viscoelastic material than the particles previously studied in the literature. The resulting stochastic microswimmers are able to swim at mean speeds of up to 22.5 μm/s. They can be guided and targeted to specific cells, because they exhibit biased and directional motion under a chemoattractant gradient and a magnetic field, respectively. Moreover, we demonstrate the microswimmers delivering doxorubicin anticancer drug molecules, encapsulated in the polyelectrolyte multilayers, to 4T1 breast cancer cells under magnetic guidance <i>in vitro</i>. The results reveal the feasibility of using these active multifunctional bacteria-driven microswimmers to perform targeted drug delivery with significantly enhanced drug transfer, when compared with the passive PEM microparticles

Microrobots: Zwitterionic 3D- Printed Non- Immunogenic Stealth Microrobots (Adv. Mater. 42/2020)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163415/1/adma202070312.pd

Improving Pancreatic Islet In Vitro Functionality And Transplantation Efficiency By Using Heparin Mimetic Peptide Nanofiber Gels

Pancreatic islet transplantation is a promising treatment for type I diabetes. However, viability and functionality of the islets after transplantation are limited due to loss of integrity and destruction of blood vessel networks. Thus, it is important to provide a proper mechanically and biologically supportive environment for enhancing both in vitro islet culture and transplantation efficiency. Here, we demonstrate that heparin mimetic peptide amphiphile (HM-PA) nanofibrous network is a promising platform for these purposes. The islets cultured with peptide nanofiber gel containing growth factors exhibited a similar glucose stimulation index as that of the freshly isolated islets even after 7 days. After transplantation of islets to STZ-induced diabetic rats, 28 day-long monitoring displayed that islets that were transplanted in HM-PA nanofiber gels maintained better blood glucose levels at normal levels compared to the only islet transplantation group. In addition, intraperitoneal glucose tolerance test revealed that animals that were transplanted with islets within peptide gels showed a similar pattern with the healthy control group. Histological assessment showed that islets transplanted within peptide nanofiber gels demonstrated better islet integrity due to increased blood vessel density. This work demonstrates that using the HM-PA nanofiber gel platform enhances the islets function and islet transplantation efficiency both in vitro and in vivo. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.Wo

Microemulsion-Based Soft Bacteria-Driven Microswimmers for Active Cargo Delivery

Biohybrid cell-driven microsystems offer unparalleled possibilities for realization of soft microrobots at the micron scale. Here, we introduce a bacteria-driven microswimmer that combines the active locomotion and sensing capabilities of bacteria with the desirable encapsulation and viscoelastic properties of a soft double-micelle microemulsion for active transport and delivery of cargo (<i>e</i>.<i>g</i>., imaging agents, genes, and drugs) to living cells. Quasi-monodisperse double emulsions were synthesized with an aqueous core that encapsulated the fluorescence imaging agents, as a proof-of-concept cargo in this study, and an outer oil shell that was functionalized with streptavidin for specific and stable attachment of biotin-conjugated <i>Escherichia coli</i>. Motile bacteria effectively propelled the soft microswimmers across a Transwell membrane, actively delivering imaging agents (<i>i</i>.<i>e</i>., dyes) encapsulated inside of the micelles to a monolayer of cultured MCF7 breast cancer and J744A.1 macrophage cells, which enabled real-time, live-cell imaging of cell organelles, namely mitochondria, endoplasmic reticulum, and Golgi body. This <i>in vitro</i> model demonstrates the proof-of-concept feasibility of the proposed soft microswimmers and offers promise for potential biomedical applications in active and/or targeted transport and delivery of imaging agents, drugs, stem cells, siRNA, and therapeutic genes to live tissue in <i>in vitro</i> disease models (<i>e</i>.<i>g</i>., organ-on-a-chip devices) and stagnant or low-flow-velocity fluidic regions of the human body

Microemulsion-Based Soft Bacteria-Driven Microswimmers for Active Cargo Delivery

Biohybrid cell-driven microsystems offer unparalleled possibilities for realization of soft microrobots at the micron scale. Here, we introduce a bacteria-driven microswimmer that combines the active locomotion and sensing capabilities of bacteria with the desirable encapsulation and viscoelastic properties of a soft double-micelle microemulsion for active transport and delivery of cargo (<i>e</i>.<i>g</i>., imaging agents, genes, and drugs) to living cells. Quasi-monodisperse double emulsions were synthesized with an aqueous core that encapsulated the fluorescence imaging agents, as a proof-of-concept cargo in this study, and an outer oil shell that was functionalized with streptavidin for specific and stable attachment of biotin-conjugated <i>Escherichia coli</i>. Motile bacteria effectively propelled the soft microswimmers across a Transwell membrane, actively delivering imaging agents (<i>i</i>.<i>e</i>., dyes) encapsulated inside of the micelles to a monolayer of cultured MCF7 breast cancer and J744A.1 macrophage cells, which enabled real-time, live-cell imaging of cell organelles, namely mitochondria, endoplasmic reticulum, and Golgi body. This <i>in vitro</i> model demonstrates the proof-of-concept feasibility of the proposed soft microswimmers and offers promise for potential biomedical applications in active and/or targeted transport and delivery of imaging agents, drugs, stem cells, siRNA, and therapeutic genes to live tissue in <i>in vitro</i> disease models (<i>e</i>.<i>g</i>., organ-on-a-chip devices) and stagnant or low-flow-velocity fluidic regions of the human body