Advanced medical micro-robotics for early diagnosis and therapeutic interventions

Recent technological advances in micro-robotics have demonstrated their immense potential for biomedical applications. Emerging micro-robots have versatile sensing systems, flexible locomotion and dexterous manipulation capabilities that can significantly contribute to the healthcare system. Despite the appreciated and tangible benefits of medical micro-robotics, many challenges still remain. Here, we review the major challenges, current trends and significant achievements for developing versatile and intelligent micro-robotics with a focus on applications in early diagnosis and therapeutic interventions. We also consider some recent emerging micro-robotic technologies that employ synthetic biology to support a new generation of living micro-robots. We expect to inspire future development of micro-robots toward clinical translation by identifying the roadblocks that need to be overcome

Custom-Designed Biohybrid Micromotor for Potential Disease Treatment

Micromotors are recognized as promising candidates for untethered micromanipulation and targeted cargo transport. Their future application is, however, hindered by the low efficiency of drug encapsulation and their poor adaptability in physiological conditions. To address these challenges, one potential solution is to incorporate micromotors with biological materials as the combination of functional biological entities and smart artificial parts represents a manipulable and biologically friendly approach. This dissertation focuses on the development of custom-designed micromotors combined with sperm and their potential applications on targeted diseases treatment. By means of 2D and 3D lithography methods, microstructures with complex configurations can be fabricated for specific demands. Bovine and human sperm are both for the first time explored as drug carriers thanks to their high encapsulation efficiency of hydrophilic drugs, their powerful self-propulsion and their improved drug-uptake relying on the somatic-cell fusion ability. The hybrid micromotors containing drug loaded sperm and constructed artificial enhancements can be self-propelled by the sperm flagella and remotely guided and released to the target at high precision by employing weak external magnetic fields. As a result, micromotors based on both bovine and human sperm show significant anticancer effect. The application here can be further broadened to other biological environments, in particular to the blood stream, showing the potential on the treatment of blood diseases like blood clotting. Finally, to enhance the treatment efficiency, in particular to control sperm number and drug dose, three strategies are demonstrated to transport swarms of sperm. This research paves the way for the precision medicine based on engineered sperm-based micromotors

From microfluidics to hierarchical hydrogel materials

Over the past two decades, microfluidics has made significant contributions to material and life sciences, particularly via the design of nano-, micro- and mesoscale materials such as nanoparticles, micelles, vesicles, emulsion droplets, and microgels. Unmatched in control over a multitude of material parameters, microfluidics has also shed light on fundamental aspects of material design such as the early stages of nucleation and growth processes as well as structure evolution. Exemplarily, polymer hydrogel particles can be formed via microfluidics with exact control over size, shape, functionalization, compartmentalization, and mechanics that is hardly found in any other processing method. Interestingly, the utilization of microfluidics for material design largely focuses on the fabrication of single entities that act as reaction volume for organic and cell-free biosynthesis, cell mimics, or local environment for cell culturing. In recent years, however, hydrogel design has shifted towards structures that integrate a large variety of functions, e.g., to address the demands for sensing tasks in a complex environment or more closely mimicking architecture and organization of tissue by multiparametric cultures. Hence, this review provides an overview of recent literature that explores microfluidics for fabricating hydrogel materials that go well beyond common length scales as well as the structural and functional complexity of microgels necessary to produce hierarchical hydrogel structures. We focus on examples that utilize microfluidics to design microgel-based assemblies, on microfluidically made polymer microgels for 3D bioprinting, on hydrogels fabricated by microfluidics in a continuous fashion, like fibers, and on hydrogel structures that are shaped by microchannels

Biohybrid robotics: From the nanoscale to the macroscale

Biohybrid robotics is a field in which biological entities are combined with artificial materials in order to obtain improved performance or features that are difficult to mimic with hand-made materials. Three main level of integration can be envisioned depending on the complexity of the biological entity, ranging from the nanoscale to the macroscale. At the nanoscale, enzymes that catalyze biocompatible reactions can be used as power sources for self-propelled nanoparticles of different geometries and compositions, obtaining rather interesting active matter systems that acquire importance in the biomedical field as drug delivery systems. At the microscale, single enzymes are substituted by complete cells, such as bacteria or spermatozoa, whose self-propelling capabilities can be used to transport cargo and can also be used as drug delivery systems, for in vitro fertilization practices or for biofilm removal. Finally, at the macroscale, the combinations of millions of cells forming tissues can be used to power biorobotic devices or bioactuators by using muscle cells. Both cardiac and skeletal muscle tissue have been part of remarkable examples of untethered biorobots that can crawl or swim due to the contractions of the tissue and current developments aim at the integration of several types of tissue to obtain more realistic biomimetic devices, which could lead to the next generation of hybrid robotics. Tethered bioactuators, however, result in excellent candidates for tissue models for drug screening purposes or the study of muscle myopathies due to their three-dimensional architecture

Biofabrication: an overview of the approaches used for printing of living cells

The development of cell printing is vital for establishing biofabrication approaches as clinically relevant tools. Achieving this requires bio-inks which must not only be easily printable, but also allow controllable and reproducible printing of cells. This review outlines the general principles and current progress and compares the advantages and challenges for the most widely used biofabrication techniques for printing cells: extrusion, laser, microvalve, inkjet and tissue fragment printing. It is expected that significant advances in cell printing will result from synergistic combinations of these techniques and lead to optimised resolution, throughput and the overall complexity of printed constructs

Soft tubular microfluidics for 2D and 3D applications

Microfluidics has been the key component for many applications, including biomedical devices, chemical processors, microactuators, and even wearable devices. This technology relies on soft lithography fabrication which requires cleanroom facilities. Although popular, this method is expensive and labor-intensive. Furthermore, current conventional microfluidic chips precludes reconfiguration, making reiterations in design very time-consuming and costly. To address these intrinsic drawbacks of microfabrication, we present an alternative solution for the rapid prototyping of microfluidic elements such as microtubes, valves, and pumps. In addition, we demonstrate how microtubes with channels of various lengths and cross-sections can be attached modularly into 2D and 3D microfluidic systems for functional applications. We introduce a facile method of fabricating elastomeric microtubes as the basic building blocks for microfluidic devices. These microtubes are transparent, biocompatible, highly deformable, and customizable to various sizes and cross-sectional geometries. By configuring the microtubes into deterministic geometry, we enable rapid, low-cost formation of microfluidic assemblies without compromising their precision and functionality. We demonstrate configurable 2D and 3D microfluidic systems for applications in different domains. These include microparticle sorting, microdroplet generation, biocatalytic micromotor, triboelectric sensor, and even wearable sensing. Our approach, termed soft tubular microfluidics, provides a simple, cheaper, and faster solution for users lacking proficiency and access to cleanroom facilities to design and rapidly construct microfluidic devices for their various applications and needs. Keywords: flexible microfluidics, elastomeric microtubes, microfluidic assemblies, inertial focusing chip, microfluidic sensorSingapore-MIT Alliance for Research and Technology (SMART

Carbon-Nanotube-Embedded Hydrogel Sheets for Engineering Cardiac Constructs and Bioactuators

We engineered functional cardiac patches by seeding neonatal rat cardiomyocytes onto carbon nanotube (CNT)-incorporated photo-cross-linkable gelatin methacrylate (GelMA) hydrogels. The resulting cardiac constructs showed excellent mechanical integrity and advanced electrophysiological functions. Specifically, myocardial tissues cultured on 50 μm thick CNT-GelMA showed 3 times higher spontaneous synchronous beating rates and 85% lower excitation threshold, compared to those cultured on pristine GelMA hydrogels. Our results indicate that the electrically conductive and nanofibrous networks formed by CNTs within a porous gelatin framework are the key characteristics of CNT-GelMA leading to improved cardiac cell adhesion, organization, and cell–cell coupling. Centimeter-scale patches were released from glass substrates to form 3D biohybrid actuators, which showed controllable linear cyclic contraction/extension, pumping, and swimming actuations. In addition, we demonstrate for the first time that cardiac tissues cultured on CNT-GelMA resist damage by a model cardiac inhibitor as well as a cytotoxic compound. Therefore, incorporation of CNTs into gelatin, and potentially other biomaterials, could be useful in creating multifunctional cardiac scaffolds for both therapeutic purposes and in vitro studies. These hybrid materials could also be used for neuron and other muscle cells to create tissue constructs with improved organization, electroactivity, and mechanical integrity.United States. Army Research Office. Institute for Soldier NanotechnologiesNational Institutes of Health (U.S.) (HL092836)National Institutes of Health (U.S.) (EB02597)National Institutes of Health (U.S.) (AR057837)National Institutes of Health (U.S.) (HL099073)National Science Foundation (U.S.) (DMR0847287)United States. Office of Naval Research (ONR PECASE Award)United States. Office of Naval Research (Young Investigator award)National Research Foundation of Korea (grant (NRF-2010-220-D00014)

Design, Actuation, and Functionalization of Untethered Soft Magnetic Robots with Life-Like Motions: A Review

Soft robots have demonstrated superior flexibility and functionality than conventional rigid robots. These versatile devices can respond to a wide range of external stimuli (including light, magnetic field, heat, electric field, etc.), and can perform sophisticated tasks. Notably, soft magnetic robots exhibit unparalleled advantages among numerous soft robots (such as untethered control, rapid response, and high safety), and have made remarkable progress in small-scale manipulation tasks and biomedical applications. Despite the promising potential, soft magnetic robots are still in their infancy and require significant advancements in terms of fabrication, design principles, and functional development to be viable for real-world applications. Recent progress shows that bionics can serve as an effective tool for developing soft robots. In light of this, the review is presented with two main goals: (i) exploring how innovative bioinspired strategies can revolutionize the design and actuation of soft magnetic robots to realize various life-like motions; (ii) examining how these bionic systems could benefit practical applications in small-scale solid/liquid manipulation and therapeutic/diagnostic-related biomedical fields

Active Stimuli-Responsive Polymer Surfaces and Thin Films: Design, Properties and Applications: Active Stimuli-Responsive Polymer Surfaces and Thin Films: Design, Properties and Applications

Design of 2D and 3D micropatterned materials is highly important for printing technology, microfluidics, microanalytics, information storage, microelectronics and biotechnology. Biotechnology deserves particular interest among the diversity of possible applications because its opens perspectives for regeneration of tissues and organs that can considerably improve our life. In fact, biotechnology is in constant need for development of microstructured materials with controlled architecture. Such materials can serve either as scaffolds or as microanalytical platforms, where cells are able to self-organize in a programmed manner. Microstructured materials, for example, allow in vitro investigation of complex cell-cell interactions, interactions between cells and engineered materials. With the help of patterned surfaces it was demonstrated that cell adhesion and viability as well as differentiation of stem cells1 depend of on the character of nano- and micro- structures 2 as well as their size. There are number of methods based on optical lithography, atomic force microscopy, printing techniques, chemical vapor deposition, which have been developed and successfully applied for 2D patterning. While each of these methods provides particular advantages, a general trade-off between spatial resolution, throughput, “biocompatibility of method” and usability of fabricated patterned surfaces exists. For example, AFM-based techniques allow very high nanometer resolution and can be used to place small numbers of functional proteins with nanometer lateral resolution, but are limited to low writing speeds and small pattern sizes. Albeit, the resolution of photolithography is lower, while it is much faster and cheaper. Therefore, it is highly desirable to develop methods for high-resolution patterning at reasonably low cost and high throughput. Although many approaches to fabricate sophisticated surface patterns exist, they are almost entirely limited to producing fixed patterns that cannot be intentionally modified or switched on the fly in physiologic environment. This limits the usability of a patterned surface to a single specific application and new microstructures have to be fabricated for new applications. Therefore, it is desirable to develop methods for design of switchable and rewritable patterns. Next, the high-energy of the ultraviolet radiation, which is typically used for photolithography, can be harmful for biological species. It is also highly important to develop an approach for photopatterning where visible light is used instead of UV light. Therefore, it is very important for biotechnological applications to achieve good resolution at low costs, create surface with switchable and reconfigurable patterns, perform patterning in mild physiologic conditions and avoid use of harmful UV light. 3D patterning is experimentally more complicated than 2D one and the applicability of available techniques is substantially limited. For example, interference photolithography allows fabrication of 3D structures with limited thickness. Two-photon photolithography, which allows nanoscale resolution, is very slow and highly expensive. Assembling of 3D structures by stacking of 2D ones is time consuming and does not allow fabrication of fine hollow structures. At the same time, nature offers an enormous arsenal of ideas for the design of novel materials with superior properties. In particular, self-assembly and self-organization being the driving principles of structure formation in nature attract significant interest as promising concepts for the design of intelligent materials 3. Self-folding films are the examples of biomimetic materials4. Such films mimic movement mechanisms of plants 5-7 and are able to self-organize and form complex 3D structures. The self-folding films consist of two materials with different properties. At least one of these materials, active one, can change its volume. Because of non-equal expansion of the materials, the self-folding films are able to form a tubes, capsules or more complex structure. Similar to origami, the self-folding films provide unique possibilities for the straightforward fabrication of highly complex 3D micro-structures with patterned inner and outer walls that cannot be achieved using other currently available technologies. The self-folded micro-objects can be assembled into sophisticated, hierarchically-organized 3D super-constructs with structural anisotropy and highly complex surface patterns. Till now most of the research in the field of self-folding films was focused on inorganic materials. Due to their rigidity, limited biocompatibility and non-biodegradability, application of inorganic self-folding materials for biomedical purposes is limited. Polymers are more suitable for these purposes. There are many factors, which make polymer-based self-folding films particularly attractive. There is a variety of polymers sensitive to different stimuli that allows design of self-folding films, which are able to fold in response to various external signals. There are many polymers changing their properties in physiological ranges of pH and temperature as well as polymers sensitive to biochemical processes. There is a variety of biocompatible and biodegradable polymers. These properties make self-folding polymer highly attractive for biological applications. Polymers undergo considerable and reversible changes of volume that allows design of systems with reversible folding. Fabrication of 3D structures with the size ranging from hundreds of nanometers to centimeters is possible. In spite of their attractive properties, the polymer-based systems remained almost out of focus – ca 15 papers including own ones were published on this topic (see own review 8, state October 2011). Thereby the development of biomimetic materials based on self-folding polymer films is highly desired and can open new horizons for the design of unique 3D materials with advanced properties for lab-on-chip applications, smart materials for everyday life and regenerative medicine