RESUMO
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.
RESUMO
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.
Assuntos
Catecóis/química , Polietilenoglicóis/química , Polímeros/química , Módulo de Elasticidade , Elasticidade , Ligação de Hidrogênio , Metacrilatos/química , Modelos Moleculares , Polímeros/síntese químicaRESUMO
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.
Assuntos
Materiais Biocompatíveis/química , Técnicas Biossensoriais , Equipamentos e Provisões Elétricas , Técnicas Biossensoriais/instrumentação , Eletrônica , Humanos , Estrutura MolecularRESUMO
Stimulus-responsive hydrogels make up an important class of programmable materials for a wide range of biomedical applications. Ultrasound (US) is a stimulus that offers utility because of its ability to permeate tissue and rapidly induce chemical alterations in aqueous media. Here we report on the synthesis and US-mediated disintegration of stimulus-responsive telechelic Dopa-modified polyethylene glycol-based hydrogels. Fe3+-[PEG-Dopa]4 hydrogels are formed through Fe3+-induced cross-linking of four-arm polyethylene glycol-dopamine precursors to produce networks. The relative amounts of H-bonds, coordination bonds, and covalent bonds can be controlled by the [Fe3+]:[Dopa] molar ratio in precursor solutions. Networks formed from precursors with high [Fe3+]:[Dopa] ratios create mechanically robust networks (G' = 6880 ± 240 Pa) that are largely impervious to US-mediated disintegration at intensities of ≤43 W/cm2. Conversely, lightly cross-linked networks formed through [Fe3+]:[Dopa] molar ratios of <0.73 are susceptible to rapid disintegration upon exposure to US. Pulsatile US exposure allows temporal control over hydrogel disintegration and programmable self-healing. Sustained US energy can also stabilize hydrogels through the formation of additional cross-links via free radical-mediated coupling of pendant catechols. Taken together, the diverse ranges of mechanical behavior, self-healing capability, and differential susceptibility to ultrasonic disintegration suggest that Fe3+-[PEG-Dopa]4 hydrogels yield a class of application-specific stimulus-responsive polymers as smart materials for applications ranging from transient medical implants to matrices for smart drug delivery.
Assuntos
Hidrogéis/química , Ferro/química , Ultrassom , Dopamina/química , Sistemas de Liberação de Medicamentos , Polietilenoglicóis/químicaRESUMO
Biodegradable electronics represents an attractive and emerging paradigm in medical devices by harnessing simultaneous advantages afforded by electronically active systems and obviating issues with chronic implants. Integrating practical energy sources that are compatible with the envisioned operation of transient devices is an unmet challenge for biodegradable electronics. Although high-performance energy storage systems offer a feasible solution, toxic materials and electrolytes present regulatory hurdles for use in temporary medical devices. Aqueous sodium-ion charge storage devices combined with biocompatible electrodes are ideal components to power next-generation biodegradable electronics. Here, we report the use of biologically derived organic electrodes composed of melanin pigments for use in energy storage devices. Melanins of natural (derived from Sepia officinalis) and synthetic origin are evaluated as anode materials in aqueous sodium-ion storage devices. Na(+)-loaded melanin anodes exhibit specific capacities of 30.4 ± 1.6 mAhg(-1). Full cells composed of natural melanin anodes and λ-MnO2 cathodes exhibit an initial potential of 1.03 ± 0.06 V with a maximum specific capacity of 16.1 ± 0.8 mAhg(-1). Natural melanin anodes exhibit higher specific capacities compared with synthetic melanins due to a combination of beneficial chemical, electrical, and physical properties exhibited by the former. Taken together, these results suggest that melanin pigments may serve as a naturally occurring biologically derived charge storage material to power certain types of medical devices.
Assuntos
Técnicas Eletroquímicas , Eletrodos , Melaninas/química , Nanoestruturas/química , Animais , Microscopia Eletrônica de Varredura , Espectroscopia Fotoeletrônica , Sepia/química , Sódio/química , Análise Espectral Raman , Relação Estrutura-Atividade , Água/químicaRESUMO
The facile preparation of conformal polydopamine (PDA) films on broad classes of materials has prompted extensive research into a wide variety of potential applications for PDA. The constituent molecular species in PDA exhibit diverse chemical moieties, and therefore highly variable properties of PDA-based devices may evolve with post-processing conditions. Here we report the use of redox-inactive cations for oxidative post-processing of deposited PDA films. PDA films incubated in alkaline CaCl2 solutions exhibit accelerated oxidative evolution in a dose-dependent manner. PDA films incubated in CaCl2 solutions exhibit 53% of the oxidative charge transfer compared to pristine PDA films. Carboxylic acid groups generated from the oxidation process lower the isoelectric point of PDA films from pH = 4.0 ± 0.2 to pH = 3.1 ± 0.3. PDA films exposed to CaCl2 solutions during post-processing also enhance Fe2+/Fe3+ chelation compared to pristine PDA films. These data illustrate that the molecular heterogeneity and non-equilibrium character of as-deposited PDA films afford control over the final composition by choosing post-processing conditions, but also demands forethought into how the performance of PDA-incorporated devices may change over time in salt solutions.
Assuntos
Cálcio/química , Indóis/química , Quelantes de Ferro/química , Ferro/química , Polímeros/química , Indóis/síntese química , Oxirredução , Polímeros/síntese químicaRESUMO
Macroscopic structures that undergo rapid and reversible stiffness transitions can serve as functional polymeric materials for many applications in robotics and medical devices. Thermomechanical phase transitions can provide a suitable mechanism for transient control of mechanical properties. However, the characteristic time scale for actuation is large and dictated by the dimensions of the structure. Embedding vascular networks within bulk polymers can reduce the characteristic length scale of the material and permit rapid and reversible thermomechanical transitions. Here we report perfusable bulk materials with embedded microvascular networks that can undergo rapid and reversible stiffness transitions. Acrylate-based thermoplastic structures exhibit storage moduli with a dynamic range between E' = 1.02 ± 0.07 GPa and E' = 13.5 ± 0.7 MPa over time scales as small as 2.4 ± 0.5 s using an aqueous thermal perfusate. The spatiotemporal evolutions of temperature profiles were accurately predicted using finite element simulation and compared to experimental values. Rigid-compliant transitions were leveraged in a demonstration in which a microvascularized device was used to grasp an external object without the aid of moving parts.
RESUMO
Stimuli-responsive polymers play an important role in many biomedical technologies. Light responsive polymers are particularly desirable because the parameters of irradiated light and diverse photoactive chemistries produce a large number of combinations between functional materials and associated stimuli. This Review summarizes recent advances in utilizing photoactive chemistries in macromolecules for prospective use in biomedical applications. Special focus is granted to selection criterion when choosing photofunctional groups. Synthetic strategies to incorporate these functionalities into polymers and networks with different topologies are also highlighted herein. Prospective applications of these materials are discussed including programmable matrices for controlled release, dynamic scaffolds for tissue engineering, and functional coatings for medical devices. The article concludes by summarizing the state of the art in photoresponsive polymers for biomedical applications including current challenges and future opportunities.
Assuntos
Materiais Biocompatíveis/química , Substâncias Macromoleculares/química , Polímeros/química , Animais , Pesquisa Biomédica/métodos , Humanos , Luz , Engenharia Tecidual/métodosRESUMO
Skin is the body's largest organ and is responsible for the transduction of a vast amount of information. This conformable material simultaneously collects signals from external stimuli that translate into information such as pressure, pain, and temperature. The development of an electronic material, inspired by the complexity of this organ is a tremendous, unrealized engineering challenge. However, the advent of carbon-based electronics may offer a potential solution to this long-standing problem. In this Account, we describe the use of an organic field-effect transistor (OFET) architecture to transduce mechanical and chemical stimuli into electrical signals. In developing this mimic of human skin, we thought of the sensory elements of the OFET as analogous to the various layers and constituents of skin. In this fashion, each layer of the OFET can be optimized to carry out a specific recognition function. The separation of multimodal sensing among the components of the OFET may be considered a "divide and conquer" approach, where the electronic skin (e-skin) can take advantage of the optimized chemistry and materials properties of each layer. This design of a novel microstructured gate dielectric has led to unprecedented sensitivity for tactile pressure events. Typically, pressure-sensitive components within electronic configurations have suffered from a lack of sensitivity or long mechanical relaxation times often associated with elastomeric materials. Within our method, these components are directly compatible with OFETs and have achieved the highest reported sensitivity to date. Moreover, the tactile sensors operate on a time scale comparable with human skin, making them ideal candidates for integration as synthetic skin devices. The methodology is compatible with large-scale fabrication and employs simple, commercially available elastomers. The design of materials within the semiconductor layer has led to the incorporation of selectivity and sensitivity within gas-sensing devices and has enabled stable sensor operation within aqueous media. Furthermore, careful tuning of the chemical composition of the dielectric layer has provided a means to operate the sensor in real time within an aqueous environment and without the need for encapsulation layers. The integration of such devices as electronic mimics of skin will require the incorporation of biocompatible or biodegradable components. Toward this goal, OFETs may be fabricated with >99% biodegradable components by weight, and the devices are robust and stable, even in aqueous environments. Collectively, progress to date suggests that OFETs may be integrated within a single substrate to function as an electronic mimic of human skin, which could enable a large range of sensing-related applications from novel prosthetics to robotic surgery.
Assuntos
Pele/química , Transistores Eletrônicos , Materiais Biocompatíveis , Engenharia/métodos , HumanosRESUMO
Synthetic biodegradable elastomers are a class of polymers that have demonstrated far-reaching utility as biomaterials for use in many medical applications. Biodegradable elastomers can be broadly classified into networks prepared by either step-growth or chain-growth polymerization. Each processing strategy affords distinct advantages in terms of capabilities and resulting properties of the network. This work describes the synthesis, processing, and characterization of cross-linked polyester networks based on Diels-Alder coupling reactions. Hyperbranched furan-modified polyester precursors based on poly(glycerol-co-sebacate) are coupled with bifunctional maleimide cross-linking agents. The chemical and thermomechanical properties of the elastomers are characterized at various stages of network formation. Experimental observations of gel formation are compared to theoretical predictions derived from Flory-Stockmayer relationships. This cross-linking strategy confers unique advantages in processing and properties including the ability to fabricate biodegradable reconfigurable covalent networks without additional catalysts or reaction byproducts. Reconfigurable biodegradable networks using Diels-Alder cycloaddition reactions permit the fabrication of shape-memory polymers with complex permanent geometries. Biodegradable elastomers based on polyester networks with molecular reconfigurability achieve vastly expanded properties and processing capabilities for potential applications in medicine and beyond.
Assuntos
Plásticos Biodegradáveis/síntese química , Elastômeros/síntese química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Plásticos Biodegradáveis/química , Reagentes de Ligações Cruzadas/química , Reação de Cicloadição , Decanoatos/química , Elastômeros/química , Glicerol/análogos & derivados , Glicerol/química , Maleimidas/química , Maleimidas/metabolismo , Poliésteres/química , Polímeros/químicaRESUMO
Photodegradable physically cross-linked polymer networks are prepared from self-assembly of photolabile triblock copolymers. Linear triblock copolymers composed of poly (o-nitrobenzyl methacrylate) and poly(ethylene glycol) (PEG) segments of variable molecular weights were synthesized using atom transfer radical polymerization. Triblock polymers with low-molecular-weight PEG segments form solid films upon hydration with robust mechanical properties including a Young's modulus of 76 ± 12 MPa and a toughness of 108 ± 31 kJ m⻳. Triblock polymers with high-molecular-weight PEG segments form physically cross-linked hydrogels at room temperature with a dynamic storage modulus of 13 ± 0.6 kPa and long-term stability in hydrated environments. Both networks undergo photodegradation upon irradiation with long wave UV light.
Assuntos
Metacrilatos/química , Polietilenoglicóis/química , Polímeros/química , Fotólise , Polímeros/efeitos da radiação , Raios UltravioletaRESUMO
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.
Assuntos
Hidrogéis , Temperatura , Íons/química , Transporte de Íons , Condutividade Elétrica , Hidrogéis/químicaRESUMO
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.
Assuntos
Equipamentos e Provisões , Trato GastrointestinalRESUMO
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.
RESUMO
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.
Assuntos
Sistemas de Liberação de Medicamentos , Mucosa IntestinalRESUMO
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.
RESUMO
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.
Assuntos
Esofagite Eosinofílica , Refluxo Gastroesofágico , Animais , Suínos , Gelatina , Impedância Elétrica , Cápsulas , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/patologia , Esofagite Eosinofílica/diagnósticoRESUMO
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.
Assuntos
Transferência de Energia , Miniaturização , Próteses e Implantes , Dispositivos Eletrônicos Vestíveis , Tecnologia sem Fio , Humanos , Corpo HumanoRESUMO
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.
Assuntos
Dispositivos Eletrônicos Vestíveis , Eletrônica , HumanosRESUMO
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.