Intestinal retentive systems - recent advances and emerging approaches.

Intestinal retentive devices (IRDs) are devices designed to anchor within the lumen of the intestines for long-term residence in the gastrointestinal tract. IRDs can enable impactful medical device technologies including sustained oral drug delivery systems, indwelling sensors, or real-time diagnostics. The design and testing of IRDs present a myriad of challenges, including precise deployment of the device at desired intestinal locations, secure anchoring within the gastrointestinal tract to allow for natural function, and safe removal of the IRD at user-defined times. Advancing the state-of-the-art of IRD is an interdisciplinary effort that requires innovations such as new materials, novel anchoring mechanisms, and medical device design with consistent input from clinical practitioners and end-users. This perspective briefly reviews the current state-of-the-art for IRDs and charts a path forward to inform the design of future concepts. Specifically, this article will highlight materials, retention mechanisms, and test beds to measure the efficacy of IRDs and their mechanisms. Finally, potential synergies between IRD and other medical device technologies are presented to identify future opportunities.

Miniature battery-free bioelectronics.

Miniature wireless bioelectronic implants that can operate for extended periods of time can transform how we treat disorders by acting rapidly on precise nerves and organs in a way that drugs cannot. To reach this goal, materials and methods are needed to wirelessly transfer energy through the body or harvest energy from the body itself. We review some of the capabilities of emerging energy transfer methods to identify the performance envelope for existing technology and discover where opportunities lie to improve how much-and how efficiently-we can deliver energy to the tiny bioelectronic implants that can support emerging medical technologies.

Edible Origami Actuators Using Gelatin-Based Bioplastics.

The potential of ingestible medical devices can be greatly enhanced through the use of smart structures made from stimuli-responsive materials. While hydration is a convenient stimulus for inducing shape changes in biomaterials, finding robust materials that can achieve rapid actuation, facile manufacturability, and biocompatibility suitable for ingestible medical devices poses practical challenges. Hydration is a convenient stimulus to induce shape changes in smart biomaterials; however, there are many practical challenges to identifying materials that can achieve rapid actuation and facile manufacturability while satisfying constraints associated with biocompatibility requirements and mechanical properties that are suitable for ingestible medical devices. Herein, we illustrate the formulation and processability of a moisture-responsive genipin-crosslinked gelatin bioplastic system, which can be processed into complex three-dimensional shapes. Mechanical characterization of bioplastic samples showed Young's Modulus values as high as 1845 MPa and toughness values up to 52 MJ/m3, using only food-safe ingredients. Custom molds and UV-laser processing enabled the fabrication of centimeter-scale structures with over 150 independent actuating joints. These self-actuating structures soften and unfold in response to surrounding moisture, eliminating the need for additional stimuli or actuating elements.

Villi Inspired Mechanical Interlocking for Intestinal Retentive Devices.

Intestinal retentive devices have applications ranging from sustained oral drug delivery systems to indwelling ingestible medical devices. Current strategies to retain devices in the small intestine primarily focus on chemical anchoring using mucoadhesives or mechanical coupling using expandable devices or structures that pierce the intestinal epithelium. Here, the feasibility of intestinal retention using devices containing villi-inspired structures that mechanically interlock with natural villi of the small intestine is evaluated. First the viability of mechanical interlocking as an intestinal retention strategy is estimated by estimating the resistance to peristaltic shear between simulated natural villi and devices with various micropost geometries and parameters. Simulations are validated in vitro by fabricating micropost array patches via multistep replica molding and performing lap-shear tests to evaluate the interlocking performance of the fabricated microposts with artificial villi. Finally, the optimal material and design parameters of the patches that can successfully achieve retention in vivo are predicted. This study represents a proof-of-concept for the viability of micropost-villi mechanical interlocking strategy to develop nonpenetrative multifunctional intestinal retentive devices for the future.

Poisson-Nernst-Planck framework for modelling ionic strain and temperature sensors.

Ionically conductive hydrogels are gaining traction as sensing and structural materials for use bioelectronic devices. Hydrogels that feature large mechanical compliances and tractable ionic conductivities are compelling materials that can sense physiological states and potentially modulate the stimulation of excitable tissue because of the congruence in electro-mechanical properties across the tissue-material interface. However, interfacing ionic hydrogels with conventional DC voltage-based circuits poses several technical challenges including electrode delamination, electrochemical reaction, and drifting contact impedance. Utilizing alternating voltages to probe ion-relaxation dynamics has been shown to be a viable alternative for strain and temperature sensing. In this work, we present a Poisson-Nernst-Planck theoretical framework to model ion transport under alternating fields within conductors subject to varying strains and temperatures. Using simulated impedance spectra, we develop key insights about the relationship between frequency of the applied voltage perturbation and sensitivity. Lastly, we perform preliminary experimental characterization to demonstrate the applicability of the proposed theory. We believe this work provides a useful perspective that is applicable to the design of a variety of ionic hydrogel-based sensors for biomedical and soft robotic applications.

Gelatin-Based Ingestible Impedance Sensor to Evaluate Gastrointestinal Epithelial Barriers.

Low-profile and transient ingestible electronic capsules for diagnostics and therapeutics can replace widely used yet invasive procedures such as endoscopies. Several gastrointestinal diseases such as reflux disease, Crohn's disease, irritable bowel syndrome, and eosinophilic esophagitis result in increased intercellular dilation in epithelial barriers. Currently, the primary method of diagnosing and monitoring epithelial barrier integrity is via endoscopic tissue biopsies followed by histological imaging. Here, a gelatin-based ingestible electronic capsule that can monitor epithelial barriers via electrochemical impedance measurements is proposed. Toward this end, material-specific transfer printing methodologies to manufacture soft-gelatin-based electronics, an in vitro synthetic disease model to validate impedance-based sensing, and tests of capsules using ex vivo using porcine esophageal tissue are described. The technologies described herein can advance next generation of oral diagnostic devices that reduce invasiveness and improve convenience for patients.

Hysteresis-free and high sensitivity strain sensing of ionically conductive hydrogels.

Hydrogels are promising materials for soft and implantable strain sensors owing to their large compliance (E<100 kPa) and significant extensibility (εmax >500%) compared to other polymer networks. Further, hydrogels can be functionalized to seamlessly integrate with many types of tissues. However, most current methods attempt to imbue additional electronic functionality to structural hydrogel materials by incorporating fillers with orthogonal properties such as electronic or mixed ionic conduction. Although composite strategies may improve performance or facilitate heterogeneous integration with downstream hardware, composites complicate the path for regulatory approval and may compromise the otherwise compelling properties of the underlying structural material. Here we report hydrogel strain sensors composed of genipin-crosslinked gelatin and dopamine-functionalized poly(ethylene glycol) for in vivo monitoring of cardiac function. By measuring their impedance only in their resistive regime (>10 kHz), hysteresis is reduced and the resulting gauge factor is increased by ~50x to 1.02±0.05 and 1.46±0.05 from approximately 0.03-0.05 for PEG-Dopa and genipin-crosslinked gelatin respectively. Adhesion and in vivo biocompatibility are studied to support implementation of strain sensors for monitoring cardiac output in porcine models. Impedance-based strain sensing in the kilohertz regime simplifies the piezoresistive behavior of these materials and expands the range of hydrogel-based strain sensors.

Recent Progress in Materials Chemistry to Advance Flexible Bioelectronics in Medicine.

Designing bioelectronic devices that seamlessly integrate with the human body is a technological pursuit of great importance. Bioelectronic medical devices that reliably and chronically interface with the body can advance neuroscience, health monitoring, diagnostics, and therapeutics. Recent major efforts focus on investigating strategies to fabricate flexible, stretchable, and soft electronic devices, and advances in materials chemistry have emerged as fundamental to the creation of the next generation of bioelectronics. This review summarizes contemporary advances and forthcoming technical challenges related to three principal components of bioelectronic devices: i) substrates and structural materials, ii) barrier and encapsulation materials, and iii) conductive materials. Through notable illustrations from the literature, integration and device fabrication strategies and associated challenges for each material class are highlighted.

Control Release and Diffusion-Reaction Kinetics of Genipin-Eluting Fibers Using an in Vitro Aneurysm Flow Model.

The minimally invasive treatment of intracranial aneurysms by endovascular coiling is attractive yet faces challenges related to the degradation of fibrin clots in the aneurysm sac over time. Fibrin gels cross-linked with genipin exhibit enhanced mechanical and chemical stability, but there are many unknowns related to best practices for delivery from endovascular devices and subsequent integration of cross-linkers with the nascent clot. Here, we describe the in vitro characterization of genipin-eluting polymer fibers prepared by coextrusion with poly(ethylene-co-vinyl acetate). Genipin incorporation and release from these fibers are characterized by various gravimetric and spectroscopic techniques. Genipin release adheres to Higuchi kinetics with Higuchi constants varying between (2.44 ± 0.83) × 10-7 and (8.41 ± 0.82) × 10-7 mol·h-0.5 depending on genipin loading and vinyl acetate concentration in the polymer matrix. The diffusion-reaction kinetics of genipin released from polymeric fibers within fibrin hydrogels was investigated using an in vitro aneurysm flow model. Spatiotemporal maps of genipin cross-linking density in fibrin gels produced by absorbance measurements suggest that genipin cross-link concentrations up to 9,993.87 ± 909.01 µM can be achieved. This work describes relevant diffusion-reaction parameters of genipin in fibrin gels and establishes the viability of genipin-eluting fibers as a platform for improving endovascular embolization of intracranial aneurysms.

Recent advances in neural interfaces-Materials chemistry to clinical translation.

Implantable neural interfaces are important tools to accelerate neuroscience research and translate clinical neurotechnologies. The promise of a bidirectional communication link between the nervous system of humans and computers is compelling, yet important materials challenges must be first addressed to improve the reliability of implantable neural interfaces. This perspective highlights recent progress and challenges related to arguably two of the most common failure modes for implantable neural interfaces: (1) compromised barrier layers and packaging leading to failure of electronic components; (2) encapsulation and rejection of the implant due to injurious tissue-biomaterials interactions, which erode the quality and bandwidth of signals across the biology-technology interface. Innovative materials and device design concepts could address these failure modes to improve device performance and broaden the translational prospects of neural interfaces. A brief overview of contemporary neural interfaces is presented and followed by recent progress in chemistry, materials, and fabrication techniques to improve in vivo reliability, including novel barrier materials and harmonizing the various incongruences of the tissue-device interface. Challenges and opportunities related to the clinical translation of neural interfaces are also discussed.

Dynamic Contributions to the Bulk Mechanical Properties of Self-Assembled Polymer Networks with Reconfigurable Bonds.

Soft materials that contain dynamic and reversible bonds exhibit unique properties including unusual extensibility, reversible elasticity, and self-healing capabilities, for example. Catechol motifs are of particular interest owing to their ability to form many kinds of reversible bonds; however, there are few reports on the role of hydrogen bonds between catechols. Here, physically crosslinked self-assembled networks composed of catechol-functionalized ABA triblock co-polymers are synthesized and characterized to elucidate the role of intermolecular bonding between catechol motifs on bulk mechanical properties. The Young's moduli of equilibrated networks range from 16 to 43 MPa. Furthermore, the concentration of intermolecular interaction is controlled indirectly by synthesizing polymers with prescribed catechol concentrations on each A block. Further, network dynamics are characterized by measuring the relaxation spectrum, and it is found that the network mean relaxation time is inversely related to catechol density. Finally, networks exhibit time-dependent recovery after uniaxial strain. These findings establish important relationships between molecular design, network composition, and macroscopic mechanical properties of model soft matter networks with dynamic intermolecular bonds. Furthermore, this insight has the potential to guide the design of dissipative materials for use in applications ranging from consumer products to surgical materials.

Zwitterionic polymer/polydopamine coating reduce acute inflammatory tissue responses to neural implants.

The inflammatory brain tissue response to implanted neural electrode devices has hindered the longevity of these implants. Zwitterionic polymers have a potent anti-fouling effect that decreases the foreign body response to subcutaneous implants. In this study, we developed a nanoscale anti-fouling coating composed of zwitterionic poly (sulfobetaine methacrylate) (PSB) and polydopamine (PDA) for neural probes. The addition of PDA improved the stability of the coating compared to PSB alone, without compromising the anti-fouling properties of the film. PDA-PSB coating reduced protein adsorption by 89% compared to bare Si samples, while fibroblast adhesion was reduced by 86%. PDA-PSB coated silicon based neural probes were implanted into mouse brain, and the inflammatory tissue responses to the implants were assessed by immunohistochemistry one week after implantation. The PSB-PDA coated implants showed a significantly decreased expression of glial fibrillary acidic protein (GFAP), a marker for reactive astrocytes, within 70 µm from the electrode-tissue interface (p < 0.05). Additionally, the coating reduced the microglia activation as shown in decreased Iba-1 and lectin staining, and improved blood-brain barrier integrity indicated by reduced immunoglobulin (IgG) leakage into the tissue around the probes. These findings demonstrate that anti-fouling zwitterionic coating is effective in suppressing the acute inflammatory brain tissue response to implants, and should be further investigated for its potential to improve chronic performance of neural implants.

Electrochemical-Mediated Gelation Of Catechol-Bearing Hydrogels Based On Multimodal Crosslinking.

Catechol-bearing polymers form hydrogel networks through cooperative oxidative crosslinking and coordination chemistry. Here we describe the kinetics of cation-dependent electrochemical-mediated gelation of precursor solutions composed of catechol functionalized four-arm poly(ethylene glycol) combined with select metal cations. The gelation kinetics, mechanical properties, crosslink composition, and self-healing capacity is a strong function of the valency and redox potential of metal ions in the precursor solution. Catechol-bearing hydrogels exhibit highly compliant mechanical properties with storage moduli ranging from G' = 0.1-5 kPa depending on the choice of redox active metal ions in the precursor solution. The gelation kinetics is informed by the net cell potential of redox active components in the precursor solution. Finally, redox potential of the metal ion precursor can differentially alter the effective density of crosslinks in networks and confer properties to hydrogels such as self-healing capacity. Taken together, this parametric study generates new insight to inform the design of catechol-bearing hydrogel networks formed by electrochemical-mediated multimodal crosslinking.

Advances in Materials and Structures for Ingestible Electromechanical Medical Devices.

Ingestible biomedical devices that diagnose, prevent, or treat diseases has been a dream of engineers and clinicians for decades. The increasing apparent importance of gut health on overall well-being and the prevalence of many gastrointestinal diseases have renewed focus on this emerging class of medical devices. Several prominent examples of commercially successful ingestible medical devices exist. However, many technical challenges remain before ingestible medical devices can achieve their full clinical potential. This Minireview summarizes recent discoveries in this interdisciplinary topic including novel materials, advanced materials processing techniques, and select examples of integrated ingestible electromechanical systems. After a brief historical perspective, these topics will be reviewed with a dedicated focus on advanced functional materials and fabrication strategies in the context of clinical translation and potential regulatory considerations. Future perspectives, challenges, and opportunities related to ingestible medical devices will also be summarized.

Multimodal Underwater Adhesion Using Self-assembled Dopa-bearing ABA Triblock Copolymer Networks.

Self-assembled mechanically robust Dopa-bearing triblock copolymer networks improve underwater adhesion through both energy dissipation and interfacial bonding. Polymer networks that incorporate energy dissipating motifs could improve the performance of high-performance wet adhesives rather than only by interfacial bonds.

Texture-Dependent Adhesion in Polydopamine Nanomembranes.

The conformal nature of in situ polymerization of adhesive dopamine molecules permits the strong underwater adhesion between polydopamine (PDA) nanomembranes and the target substrates. However, the adhesive interaction between the postdeposit PDA nanomembranes and other macrobodies is strongly influenced by the texture of PDA nanomembranes. Here we report the texture-dependent adhesion of PDA nanomembranes both in air and aqueous environments. Despite the nanometer-scale roughness of PDA nanomembranes, interfacial adhesion between PDA nanomembranes and elastomeric bodies are the strong function of the root-mean-square roughness of PDA nanomembranes, root-mean-square gradient of PDA nanomembranes, and the elasticity of the bulk materials. Reduced adhesion due to increased texture is intensified in hydrated conditions, possibly hinting that the conventional explanation of the negative effect of water to adhesion from a molecular level needs to be revisited. These findings can inform the role of adhesive interaction in conformal coatings and provide an explanation for the differential adhesion observed in freestanding PDA nanomembranes.

Recent advances in materials and flexible electronics for peripheral nerve interfaces.

Peripheral nerve interfaces are a central technology in advancing bioelectronic medicines because these medical devices can record and modulate the activity of nerves that innervate visceral organs. Peripheral nerve interfaces that use electrical signals for recording or stimulation have advanced our collective understanding of the peripheral nervous system. Furthermore, devices such as cuff electrodes and multielectrode arrays of various form factors have been implanted in the peripheral nervous system of humans in several therapeutic contexts. Substantive advances have been made using devices composed of off-the-shelf commodity materials. However, there is also a demand for improved device performance including extended chronic reliability, enhanced biocompatibility, and increased bandwidth for recording and stimulation. These aspirational goals manifest as much needed improvements in device performance including: increasing mechanical compliance (reducing Young's modulus and increasing extensibility); improving the barrier properties of encapsulation materials; reducing impedance and increasing the charge injection capacity of electrode materials; and increasing the spatial resolution of multielectrode arrays. These proposed improvements require new materials and novel microfabrication strategies. This mini-review highlights selected recent advances in flexible electronics for peripheral nerve interfaces. The foci of this mini-review include novel materials for flexible and stretchable substrates, non-conventional microfabrication techniques, strategies for improved device packaging, and materials to improve signal transduction across the tissue-electrode interface. Taken together, this article highlights challenges and opportunities in materials science and processing to improve the performance of peripheral nerve interfaces and advance bioelectronic medicine.

Polydopamine Nanostructures as Biomaterials for Medical Applications.

Polydopamine is a versatile and organic material that can be deposited as a conformal film with nanometer thickness on virtually any substrate. Much of the initial foundational work regarding polydopamine synthesis and processing was reported during the 2000s. Latter years have witnessed increasing interest and widespread adoption of polydopamine as a material for many applications including medicine. Conformal polydopamine coatings confer unique chemical and physical properties to many substrate materials including metals, ceramics, polymers, and beyond. Polydopamine-modified surfaces permit facile bioconjugation of many biomedical materials for potential use as bioadhesives, contrast agents, drug delivery systems, and protein-adsorption resistant interfaces. Polydopamine-based materials and interfaces may improve the performance of biomedical devices used in neurotechnology, diagnostics, and cardiovascular applications. This highlight article reviews recent advances in polydopamine processing capabilities. The use of polydopamine as a material in various biomedical applications is also discussed. Finally, challenges and opportunites in translating polydopamine for future biomedical technologies are summarized.

Polymeric peptide pigments with sequence-encoded properties.

Melanins are a family of heterogeneous polymeric pigments that provide ultraviolet (UV) light protection, structural support, coloration, and free radical scavenging. Formed by oxidative oligomerization of catecholic small molecules, the physical properties of melanins are influenced by covalent and noncovalent disorder. We report the use of tyrosine-containing tripeptides as tunable precursors for polymeric pigments. In these structures, phenols are presented in a (supra-)molecular context dictated by the positions of the amino acids in the peptide sequence. Oxidative polymerization can be tuned in a sequence-dependent manner, resulting in peptide sequence-encoded properties such as UV absorbance, morphology, coloration, and electrochemical properties over a considerable range. Short peptides have low barriers to application and can be easily scaled, suggesting near-term applications in cosmetics and biomedicine.