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This feature article is an overview of the recent research activity in the area of enzyme-based biofuel cells implanted and operating in vivo in living creatures (insects, mollusks, rats, rabbits, etc.). The electrical power extracted from these biological sources presents use for activating microelectronic devices for biomedical applications (e.g. pacemakers) or sensors/biosensors for environmental monitoring. The inequality of the voltage generated by the biofuel cell (which is thermodynamically limited by the redox potentials of the biomolecular fuel and oxygen) and the voltage demanded by the electronic devices requires special attention and can be resolved by specific interfacing with charge pumps and DC-DC converters. The paper focuses on the problems in the present technology as well as offers their potential solutions.Lastly, perspectives and future applications of the implanted biofuel cells are also discussed. Broader contextImplantable devices harvesting energy from biological sources and based on electrochemical, mechanical and other energy transducers are currently receiving a high amount of attention. The energy collected from the body can be utilized to activate various microelectronic devices. While some microelectronic devices can work within a fairly broad range of electrical operating conditions, others such as pacemakers require precise voltage levels and voltage regulation for correct operation. Thus, certain classes of electronic devices powered by implantable energy sources will require careful attention not only to energy and power considerations, but also to voltage scaling and regulation. This requires appropriate interfacing between the energy harvesting device and the energy consuming microelectronic device. The present feature article provides an overview of the recent research activity in the area of implanted biofuel cells operating in vivo. Challenges and perspectives in these studies are addressed, giving particular attention to the interfacing between biofuel cells and microelectronic devices. The future holds the prospect for implanted biofuel cells that extract electrical energy directly from the human body, for the powering of implantable biomedical devices. These bioelectronic synergistic systems lay the foundation for bionic human hybrids as well as autonomously operating self-powered "cyborgs".

Biocatalytic electrodes made of buckypaper were modified with PQQ-dependent glucose dehydrogenase on the anode and with laccase on the cathode and were assembled in a flow biofuel cell filled with serum solution mimicking the human blood circulatory system. The biofuel cell generated an open circuitry voltage, Voc, of ca. 470 mV and a short circuitry current, Isc, of ca. 5 mA (a current density of 0.83 mA cm(-2)). The power generated by the implantable biofuel cell was used to activate a pacemaker connected to the cell via a charge pump and a DC-DC converter interface circuit to adjust the voltage produced by the biofuel cell to the value required by the pacemaker. The voltage-current dependencies were analyzed for the biofuel cell connected to an Ohmic load and to the electronic loads composed of the interface circuit, or the power converter, and the pacemaker to study their operation. The correct pacemaker operation was confirmed using a medical device - an implantable loop recorder. Sustainable operation of the pacemaker was achieved with the system closely mimicking human physiological conditions using a single biofuel cell. This first demonstration of the pacemaker activated by the physiologically produced electrical energy shows promise for future electronic implantable medical devices powered by electricity harvested from the human body.

Biocatalytic electrodes made of buckypaper were modified with PQQ‐dependent glucose dehydrogenase on the anode and with laccase on the cathode. The enzyme modified electrodes were assembled in a biofuel cell which was first characterized in human serum solution and then the electrodes were placed onto exposed rat cremaster tissue. Glucose and oxygen dissolved in blood were used as the fuel and oxidizer, respectively, for the implanted biofuel cell operation. The steady‐state open circuitry voltage of 140±30 mV and short circuitry current of 10±3 µA (current density ca. 5 µA cm−2 based on the geometrical electrode area of 2 cm2) were achieved in the in vivo operating biofuel cell. Future applications of implanted biofuel cells for powering of biomedical and sensor devices are discussed.

An “abiotic” biofuel cell composed of catalytic electrodes modified with inorganic nanostructured species was used to activate a pacemaker. The catalytic nanoparticles of various compositions, AuxPty, deposited on carbon black (CB) were prepared and extensively characterized to select the species with selectivity for glucose oxidation and oxygen reduction. Then two kinds of 3D‐electrode materials with different morphology, buckypaper composed of carbon nanotubes (ca. 50 nm diameter) and carbon paper made of carbon fibers (ca. 7 µm diameter), were used in a combination with different catalytic species. Finally, Au/CB nanospecies deposited on buckypaper were selected for catalyzing glucose oxidation (composing the biofuel cell anode) and Au60Pt40/CB species deposited on carbon paper were selected for catalyzing oxygen reduction (composing the biofuel cell cathode). The catalytic electrodes were characterized by cyclic voltammetry in an aqueous buffer solution and the polarization function for the biofuel cell was studied in a human serum solution. The open circuit voltage, Voc, short circuit current density, jsc, and maximum power produced by the biofuel cell, Pmax, were found as 0.35 V, 0.65 mA cm−2 and 104 µW, respectively (in human serum at 5.4 mM glucose). The biofuel cell produced the steady state open circuit voltage over 10 hours with its slow decrease over 50 hours originating from the glucose depletion and slow mass‐transport within the 3D‐electrode. The voltage produced by the biofuel cell was amplified with an energy harvesting circuit and applied to a pacemaker resulting in its proper operation. The present study continues the research line where different implantable (enzyme‐based or abiotic) biofuel cells are used for the activation of biomedical electronic devices, e.g., pacemakers.

The present study aims at integrating drug-releasing materials with signal-processing biocomputing systems. Enzymes alanine transaminase (ALT) and aspartate transaminase (AST)-biomarkers for liver injury-were logically processed by a biocatalytic cascade realizing Boolean AND gate. Citrate produced in the system was used to trigger a drugmimicking release from alginate microspheres. In order to differentiate low vs. high concentration signals, the microspheres were coated with a protective shell composed of layer-by-layer adsorbed poly(L-lysine) and alginate. The alginate core of the microspheres was prepared from Fe 3+ -cross-linked alginate loaded with rhodamine 6G dye mimicking a drug. Dye release from the core occurred only when both biomarkers, ALT and AST, appeared at their high pathophysiological concentrations jointly indicative of liver injury. The signal-triggered response was studied at the level of a single microsphere, yielding information on the dye release kinetics. ________________________________________________________________________ An integrated system logically processing biomarkers and releasing a drug-mimicking material was developed to demonstrate a new "Sense-Act-Treat" concept.

A biofuel cell composed of catalytic electrodes made of "buckypaper" modified with PQQ-dependent glucose dehydrogenase and FAD-dependent fructose dehydrogenase on the anode and with laccase on the cathode was used to activate a wireless information transmission system. The cathode/anode pair was implanted in orange pulp extracting power from its content (glucose and fructose in the juice). The open circuit voltage, Voc, short circuit current density, jsc, and maximum power produced by the biofuel cell, Pmax, were found as ca. 0.6 V, ca. 0.33 mA·cm(-2) and 670 μW, respectively. The voltage produced by the biofuel cell was amplified with an energy harvesting circuit and applied to a wireless transmitter. The present study continues the research line where different implantable biofuel cells are used for the activation of electronic devices. The study emphasizes the biosensor and environmental monitoring applications of implantable biofuel cells harvesting power from natural sources, rather than their biomedical use.

This review outlines advances in designing modified electrodes with switchable properties controlled by various physical and chemical signals. Irradiation of the modified electrode surfaces with various light signals, changing the temperature of the electrolyte solution, application of a magnetic field or electrical potentials, changing the pH of the solutions, and addition of chemical/biochemical substrates were used to change reversibly the electrode activity. The increasing complexity in the signal processing was achieved by integration of the switchable electrode interfaces with biomolecular information processing systems mimicking Boolean logic operations, thus allowing activation and inhibition of electrochemical processes on demand by complex combinations of biochemical signals. The systems reviewed range from simple chemical compositions to complex mixtures modeling biological fluids, where the signal substrates were added at normal physiological and elevated pathological concentrations. The switchable electrode interfaces are considered for future biomedical applications where the electrode properties will be modulated by the biomarker concentrations reflecting physiological conditions.