WO2010029297A1

WO2010029297A1 - Photo-ionic pacemakers

Info

Publication number: WO2010029297A1
Application number: PCT/GB2009/002166
Authority: WO
Inventors: Leon Sergot; Nicholas Oliver; Patrick Degenaar; Nir Grossman
Original assignee: Imperial Innovations Limited
Priority date: 2008-09-10
Filing date: 2009-09-10
Publication date: 2010-03-18
Also published as: GB0816501D0

Abstract

A pacemaker for controlling contraction of a heart comprises a light source (107), light guide means (112), (113) for directing light from the source at a target region of the heart, sensing means (104,111) arranged to sense activity of the heart, and control means (100) arranged to receive signals from the sensing means and control operation of the light source.

Description

PHOTO-IONIC PACEMAKERS Field of invention

This invention relates to devices for regulating or restoring cardiac cycle rate and rhythm.

Background of the invention

The heart

The heart is a muscular organ that works as a pump. Anatomically it is divided into a right and left side which do not communicate in the normal heart. Each side is comprised of an atrium and a ventricle. Heart contraction starts in the atrium, pushing blood into the ventricle from where it is distributed through large blood vessels to either the pulmonary circulation of the lungs for oxygenation or to the peripheral tissues. The heart receives blood with reduced levels of oxygen (deoxygenated blood) from peripheral veins in the right atrium, and delivers it to the lungs through contraction of the right ventricle. Oxygenated blood from the lungs is delivered to the left atrium by the pulmonary veins, and is pumped into the aorta to be distributed throughout the body. In order for efficient flow of blood through the chambers of the heart, atrial and ventricular contractions are co-ordinated with tight regulation to maintain appropriate cardiac contraction and heart rate. Contraction is controlled by a system of electrical impulses.

The sino-atrial node (SA node) is the pacemaker of the heart. It has the ability to 'fire' regularly due to channels in the membrane which allow ions to cross freely. This passage of ions changes the voltage across the cell wall and, when a threshold voltage is reached, the cell fires or depolarises. This depolarisation is then propagated through the left and right atria, causing contraction. The depolarisation cannot freely propagate through to the ventricles due to a non-conducting fibrous band between the atria and ventricles. Propagation is controlled by the atrioventricular node (AV node) . This prevents free propagation of the electrical impulse and induces a delay of around 120 microseconds before ventricular contraction to allow for adequate ventricular filling. When the AV node depolarises, the electrical impulse travels between the ventricles in the intra-ventricular septum and divides into bundles serving the right and left ventricles, causing synchronous contraction of the two major pumping chambers.

The muscle cells in the heart are called cardiac myocytes and can be divided into work cells and pacemaker cells. The work cells have a large stable resting membrane potential and display a prolonged action potential with a plateau phase. The pacemaker cells have smaller unstable resting potentials and spontaneously depolarize, generating the intrinsic electrical activity of the heart. Pacemaker cells are found in the SA and AV nodes.

In cardiac myocytes, the release of calcium ions (Ca²⁺) from the intracellular store (sarcoplasmic reticulum) is induced by Ca²⁺ influx into the cell through voltage-gated calcium channels on the cell membrane (sarcolemma) . This phenomenon is called calcium-induced calcium release and increases the intracellular free Ca²⁺ concentration, causing muscle contraction. After a delay, (the absolute refractory period) , potassium channels reopen and the resulting flow of potassium ions (K⁺) out of the cell causes repolarization to the resting state. The mechanism that couples excitation - an action potential in the plasma membrane of the muscle cell - and contraction of heart muscle is an increase in the cell's calcium concentration. This calcium combines with the regulator protein troponin, initiating cross-bridge formation between actin and myosin. Cross-bridge formation between actin and myosin is the mechanism of muscular contraction. Current Pacemakers & ICD

An electronic artificial pacemaker is a medical device which uses electrical impulses, delivered by electrodes contacting the interior membrane of the heart, to regulate the beating of the heart. The primary purpose of a pacemaker is to maintain an adequate heart rate and blood pressure and prevent complications associated with abnormal heart rhythms . Pacemakers are used in the following conditions:

• Sick sinus syndrome • Symptomatic bradycardia

• Tachy-brady syndrome

• Atrial fibrillation with a slow ventricular response

• 2^nd or 3^rd degree atrioventricular block

• Long QT syndrome • Chronotropic incompetence

• Hypertrophic obstructive cardiomyopathy

• Cardiomyopathy

• Syncope

• Paroxysmal atrial fibrillation • Congestive cardiac failure

Conventional pacemakers consist of a housing device which contains a battery and the electronic circuitry that runs the pacemaker, along with one or two long thin electrical wires that travel from the pacemaker housing device to the heart. Impulses are transmitted to the heart by means of a lead, which is attached to the pulse generator via the connector block. The lead is either unipolar or bipolar. A unipolar lead contains one insulated coil, while a bipolar lead contains two coils, separated by an inner insulation. An outer insulation shields a lead from the environment. The tip of a lead, which contains an electrode, is implanted into the inner, endocardial surface of the heart; the actual location depends on the type of pacemaker. The pacemaker unit is usually implanted in the pectoral region (below the collar bone), with the lead running through the subclavian vein to the internal surface of the heart (Trohman, R. G., M. H. Kim, et al. (2004) . "Cardiac pacing: the state of the art. " Lancet 364(9446) : 1701-19, Borek, P. P. and B. L. Wilkoff (2008). "Pacemaker and ICD leads: Strategies for long-term management. " J Interv Card Electrophysiol) .

Complications associated with current pacemakers include device related failures such as failure to sense or capture properly (typically lead or connection malfunction), venous thrombosis, nerve damage, pneumothorax (collapsed lung), endocarditis (heart valve infections), pericarditis (inflammation of the heart) , skin erosion, lead dislodgement, and ventricular puncture (Trohman, Kim et al. 2004; Borek and Wilkoff 2008, Cowan, D. B. and F. X. McGowan, Jr. (2006) . "A paradigm shift in cardiac pacing therapy?" Circulation 114(10) : 986-8) .

An implantable cardioverter-defibrillator (ICD) is a small battery- powered electrical impulse generator which is implanted in patients who are at risk of sudden cardiac death due to ventricular fibrillation. The device is programmed to detect ventricular fibrillation and administer an electric shock to the heart muscle to correct it. The process of implantation of an ICD is similar to implantation of a pacemaker. Similar to pacemakers, these devices typically include electrode wires which pass through a vein to the right chambers of the heart, usually being lodged in the apex of the right ventricle. The difference is that pacemakers are designed to correct slow heart rhythms (bradycardia) and over-ride fast heart rhythms (tachycardia) when required, while ICDs are permanent safeguards against sudden, potentially fatal abnormalities. Photosensitization Technology

Recent advances in biochemistry that enable the optical excitation of cells have started a new era in the study of neural physiology, especially at the network level. The photo-stimulation concept was first demonstrated in 1971 by Richard Fork (Fork, R. L. (1971) . "Laser Stimulation of Nerve

Cells in Aplysia. " Science 171 (3974) : 907-908) who used a high power laser to stimulate action potentials in the abdominal ganglion of the marine mollus. Since then scientists have exploited developments in nanotechnology and genomics to photosensitize cells. These sensitization methods can be divided into three categories of useful techniques.

The first category is photolysis of caged neurotransmitters, which was also the first modern photo-stimulation technique (Kaplan, J. J. H. , B. B. Forbush, et al. (1978). "Rapid photolytic release of adenosine 5¹- triphosphate from a protected analogue: utilization by the Na:K pump of human red blood cell ghosts. " Biochemistry 17(10): 35). Neurotransmitters, rendered inactive with covalently bonded blocking ligands are released into the solution around the neurons. The blocking moiety bonds with the neurotransmitters are then broken with the use of UV light. The result is a great localized increase in the neurotransmitter concentration in the vicinity of the light spot, which can excite a neuron cell. Due to its wide expression in the central nervous system (CNS) neurons, caged-glutamate is the most commonly used caged neurotransmitter. The uncaging process has a very good temporal and spatial resolution (approximately 3 ms and 5 μm, respectively) - the later mainly limited by the diffusion of the uncaged molecules (Kaplan, Forbush et al. 1978) . The release of such caged molecules can be used not only to stimulate neuron cells, but also to stimulate non-neuronal cells and can be useful for potential drug screening. The second category involves the incorporation of photoswitch-linked ion channels on the cell membrane. These can come in the form of modified ion-channels with light gated opening mechanisms. The modification method can be fully genetic, fully chemical, or a mix of the two. Existing ion channels and receptors can be genetically modified to receive photo- switchable arms which can act to open or close the active site. Examples include hyperpolarizing shaker channels and depolarizing modified glutamate channels. Presently, while it is conceivable to chemically induce photosensitivity into existing membrane receptors, no such system exists without genetic manipulation. Such a process would involve matching a targeted amino acid sequence to bind to the outside of an anchor point, and the use of a photoisomerisable arm which can insert or retract an agonist into the active core.

The third category is based on genetically incorporated light sensitive functional proteins which either react directly or indirectly to the action of light. Directly gated ion channels and pumps such as channelrhodopsin2 (ChR2) and halorhodopsin (NpHR) (Nagel G. , Szellas T. , Huhn W. , Kateriya S. , Adeishvili N. , Berthold P. , Ollig D. , Hegemann P. , Bamberg E. (2003) Channelrhodopsin-2, a directly light- gated cation-selective membrane channel. Proc. Natl. Acad. Sci. USA 100:13940-13945) and (Banghart, M. , K. Borges, et al. (2004) . "Light- activated ion channels for remote control of neuronal firing. " Nature Neruoscience 7(12) : 1381-1386, Zhang, F. , L. -P. Wang, et al. (2007) . "Multimodal fast optical interrogation of neural circuitry. " Nature 446(7136): 633-639 act directly on light action, i.e. an absorbed photon will open an ion channel, or cause a pumping action. ChR2 and NpHR can depolarize and hyperpolarize cells respectively. It is also conceivable that modified receptor groups such as glutamate, acetylcholine and GABA could act on light stimulation to stimulate or inhibit neuro-electric activity. Such receptors would need to incorporate light sensitive moieties such as retinal to function. In addition, amplifying cascades could be used for depolarisation and hyperpolarisation. G-Protein linked cascades such as Melanopsin are particularly applicable. Additionally it is conceivable that existing cascades in the heart such as the G-protein linked Adrenergic receptor system could be used to modulate cAMP activity and thereby cardiac activity. These light sensitization methods can be implemented via genetic manipulation of the cells. The advantage of such genetic manipulation is that the active agents will be continuously produced by the cellular machinery circumventing any decay over time. Delivery methods include plasmid and viral (e.g. Adeno Associated virus and lenti virii) transfection.

Summary of the Invention

This invention relates to a device to pace or restore cardiac cycle rate or rhythm with light. It is based on photosensitization of the cardiac myocytes and uses a light source to induce or inhibit contraction of these cells. One or several areas of cardiac myocyte cells (selected according to the specific medical indication) may be transfected with light sensitive moieties such as light sensitive ion channels and/or light sensitive ion pumps, or made light sensitive in other ways. Light may be guided into

(or directly illuminated on) these areas. The illumination can trigger these moieties for example by opening the light sensitive ion channels (or the activation of the light sensitive ion pumps) in the sensitized cells (a difference in the spectral sensitivity enables independent activation of the ion channels and the ion pumps), resulting in depolarization or hyperpolarization of the cells and the initiation or inhibition of synchronous contraction.

Contrary to present artificial pacemaker technology that is based on the application of a current or an electric field to or toward the cardiac myocytes, in some embodiments the cardiac cycle is controlled by the opening and closing of ion channels or ion pumps which is much closer to the normal physiology of the heart's conducting system. Using light to trigger the contractions, any required heart rate can be achieved simply by pulsing the light. Since the light can be pulsed with high temporal resolution, the rate can be precisely controlled.

Using light instead of electricity enables also remote stimulation (no direct contact or close proximity to the heart is required) . The stimulating light source can therefore be placed outside the heart. This introduces a significant reduction in the invasiveness and, potentially, in the operative complexity of pacemakers and may avoid some of the major complications of the traditional approach.

The heart's electrical activity may be sensed and fed to a control unit of the device. The sensing can be electrical by an electrocardiography (ECG) electrode that is placed on the outside or inside of the heart chambers. Since no stimulating electrode is required to be inserted into the heart in the light-based system, an external recording electrode is naturally preferable. There is no interference between light stimulation and the electrical recording, so they can be performed simultaneously on any desired area. Other sensing capabilities can be used to modulate the light stimulus of the device this include mechanical sensors such as accelerometers , further ECG analysis including QT-interval, minute- ventilation sensors, and biochemical sensor for analytes such as glucose, lactate, pH, free fatty acids, amino acids, carbon dioxide and oxygen.

The device may comprise two major modules: a control unit and one or more interfacing units. The control unit may comprise one or more of: a power supply; data acquisition and processing; an oscillatory controller for the light emitters; light sources; optics to extract the light from the source; optical sensors; and a communications interface to the outside world (e.g. an RF or IR link). This unit may be sealed in a biocompatible and electromagnetically isolated capsule and can be placed distant from the heart. It may also be small enough to be implanted subcutaneously so as not to interfere with the user's daily life. The interfacing unit(s) may comprise any one or more of: optics, light sources and local power supply/storage (optional) , sensing facilities and potentially local processing, and positioning and fixation facilities. In addition this unit may comprise transfection facilities to reduce the operative steps and to improve the overlaying of transfected cells and illumination.

The present invention further provides any one or more of the following:

• Use of light to modulate cardiac cycle rate and rhythm.

• A device to modulate and restore cardiac electrical activity that is based on impartment of light sensitivity to the heart cells and a light source.

• Imparting light sensitivity on the cardiac myocytes.

• Use of light to increase heart rate.

• Use of light to slow/delay heart rate. • Use of light to depolarize or hyperpolarize cardiac myocytes.

• Use of light to repair/bypass a failed sino-atrial or atrioventricular node.

• Use of light and a photosensitization process to make an artificial sino-atrial or atrioventricular node at specific locations in the heart.

• Use of light to inhibit abnormal circuitry (such as aberrant reentrant pathways) in the heart.

• A rate modulation pacemaker device that is based on impartment of light sensitivity to the heart and the use of light source. • A rhythm modulation pacemaker device that is based on impartment of light sensitivity to the heart and the use of light source.

• An Implantable cardioverter defibrillator (ICD) device that is based on impartment of light sensitivity to the heart and the use of light source.

• Imparting light sensitivity on cardiac myocyte cells.

• Use of light sensitive ion channels and light sensitive ion pumps to modulate heart beats. • Genetic modification of heart cells such as cardiac myocyte to express photosensitive activity.

• Genetic expression of ion channels to express photosensitive activity enhancement or inhibition with light.

• Genetic expression of ion pumps to express photosensitive activity enhancement or inhibition with light.

• Genetic expression of light gated G-protein cascades to express photosensitive activity enhancement or inhibition with light.

• Genetic manipulation of the heart with light sensitive proteins using viral transfection, electroporation, or chemical means to impart photosensitivity.

• Imparting light sensitivity on cardiac cells by administration of molecular/chemical agents, or molecularly /chemically delivered ion channels and pumps.

• Delivery of light sensitization agents to the heart by needle injection during open surgery, by endoscopic procedure, by the transcutaneous route or by intravascular means.

• Delivery of light sensitization agents to the heart via a delivery chip. The chip can be micro-fluidic, silicon based or other.

• Delivery of light sensitization agents to the heart by coating fibre tip with the reagents or transfection material. • The use of a light emissive element to modulate heart rate.

• The use of a light emissive element to modulate the heart rate of a heart with photosensitized cardiac cells. • The use of light emitting diodes to modulate heart rate.

• The use of Gallium Nitride or organic LED's to modulate heart rate.

• The use of miniature lasers to modulate heart rate.

• The use of quantum dot emitters to modulate heart rate. • The use of any light emissive device in the wavelengths between

350nm and lOOOnm with energy densities of between IpJ and 10OnJ to modulate heart rate.

• Using different light wavelengths to individually control contraction and relaxation of the heart or part of the heart. • A device for optically modulating heart rate whereby the use of optical stimulation of acetylcholine or norepinephrine neurotransmitter activity is used to modulate heart function.

• A device for optically modulating heart rate whereby the use of electrocardiogram recordings is used to sense heart function. • A device for optically modulating heart rate whereby the use of accelerometers , QT-interval, minute- ventilation sensors, metabolic analytes, and blood gas sensors is used to sense heart function.

• A device for optically modulating heart rate whereby the use of vagus nerve recordings is used to sense heart function. • A device for optically modulating heart rate whereby the sensing of acetylcholine or norepinephrine neurotransmitter activity is used to sense heart function.

• A device for optically modulating heart rate whereby the sensing of heart activity above is carried out by electrical means. • A device for optically modulating heart rate whereby the sensing of heart activity above is carried out by optical means.

• A device for optically modulating heart rate whereby the sensing of sensing of oxygenated and free haemoglobins activity is used to sense heart function.

• A device for optically modulating heart function which consists of an electronic chip or plurality of electronic circuits to drive a light emissive system.

• A device for optically modulating heart function which exhibits a circuit with inputs from a plurality of sensors to define the optical stimulation waveforms required for ideal cardiac opto-modulation.

• A device for optically modulating heart function which exhibits inbuilt learning circuitry to modulate the optical stimulation signal for cardiac optical modulation. • A device for optically modulating heart function which exhibits an electronic control chip which is combined with an LED array in a flip chip or other close proximity arrangement.

• A device for optically modulating heart function which exhibits circuitry to extract energy from communication signals. • A device for optically modulating heart function which exhibits a mechanical-electrical device to extract electrical energy from the mechanical energy of a beating heart.

• A device for optically modulating heart function which exhibits inbuilt light sensors and surface optical modifications to act as a cardiac sensor.

Preferred embodiments of the present invention will now be described by way of example only with reference to the accompanying drawings. Brief Description Of The Drawings

Figure 1 is a general schematic of a pacemaker device according to one embodiment of the invention;

Figure 2 is a diagram of a control unit of the device of Figure 1 ;

Figures 3a to 3e show interfacing units of various further embodiments of the invention;

Figure 4 is a diagram of an interfacing unit of a further embodiment of the invention;

Figure 5 is a diagram of a driving circuits of an embodiment of the invention; and

Figure 6 is a diagram of a driving circuit of a further embodiment of the invention;

Figures 7a, 7b, 8a and 8b show the results of experiments carried out to demonstrate the light sensitization of cardio-myocyte cells.

Detailed description of the preferred embodiments General

The components of a photonic pacemaker according to some embodiments of the invention will be:

1. Control unit containing a. Battery b. Processing c. Driving/control circuit d. Light source e. Optics with light guides f. Sensing components g. Communication link h. Casing i. Fixation facilities 2. Interfacing Unit containing a. Optics b. ECG sensing electrode c. Alternative modality sensors d. Transfection module e. Light source with power supply and driving circuit

(optional)

Implantation of a functional photonic pacemaker according to some embodiments of the invention will require the following steps (steps may be combined, and the order can vary):

1. Confirmation of diagnosis

2. Selection of required stimulation or inhibition points

3. Preparation of transfection solution

4. Transfection of light sensitive gene 5. Implantation of control unit

6. Implantation of interfacing unit(s)

7. Programming of control unit

8. Testing

Referring to Figure 1 , a pacemaker according to one embodiment of the invention comprises a control unit 100 and a plurality of interfacing units 114 each of which is connected to the control unit by a communications cable 112. The control unit 100 comprises a power supply module 101, a processing module 102, alight source driving module 103, a sensing module 104 and a communication (e.g. RF) module 105. The control unit further comprises a cooling system 106, a light source array 107, light coupling connectorslOδ, optic fibres 109, sensor interface connectors or bonding 110, and sensor cable 11.

The light sources of the array 107 are connected via the connectors 108 to the optic fibres 109 which extend through the communications cable to the interfacing units 114. Each of the interfacing units is connected to a respective one or more of the light sources so that light to each of the interfacing units can be turned on and off independently. The cooling system 106 is connected to the light source array 107 so as to cool it and prevent over heating of the device. The light sources in the array are controlled by the light source driving module 103 in a manner determined by the processing module 102. The sensor cables 111 connect sensors on the interface modules 114 through the communications cable 112 to the sensing module 104 via the connectors 110. The processing module 102 is connected to the sensors on the interfacing units via the sensor cables 111 and is arranged to control the light sources 107 in response to the sensor signals. The interfacing cable 113 between each of the interfacing units 114 and the main communications cable 112 therefore includes the optic fibre and sensor cable for that interfacing unit 114. The communications module 105 allows RF communication with the processing module 102.

In operation, the processing unit 102 receives data from sensing units 114 and preprocessing components 104 which may be at the subcutaneous module, the interface unit or both. The processor signals the optical driver 103 to define the required light stimulation waveforms to be emitted from the light emissive module 107. The cooling system 106 is used to remove excessive thermal energy from the light emissive module, the electronics or both. It can be fixed to the light emissive module, or the electronics module and connected to the unit casing for optimal thermal dissipation. The light from the array 107 is coupled via the optic guides 109 to the interfacing units (for example units 114) via the main cable 112 this cable consists of optic fibres for the optical stimulation and sensing, and electrical connectors for electrical sensor and power. The functionality of the device can be monitored and changed via a RF/magnetic communication link 5.

Referring to Figure 2, one implementation of the control unit 101 of Figure 1 will now be described. The control unit comprises a power source in the form of a battery 201, a communication system 202, e.g. RF or IR, a cardiac sensing/processing chip 203, a power extraction component 204, a communication decoding/encoding component 205, a learning algorithm/neural network block 206, a main processing block 207, a memory block 208, an ECG signal acquisition and preprocessing block 209, an electronic sensor acquisition and pre-processing block 210, an optical sensor driver, data acquisition and preprocessing module 111 a cardiac photomodulation driver 212, a sensor optical system 213, and light emitters 214 for cardiac photomodulation.

The power source 201 can be a battery, or other charge storage system and possibly an additional energy scavenging system. The communication device 202 can be an RF coil or infrared optical system including emitters and receivers. The cardiac sensing/processing chip 203 comprises electronic components which can be integrated into a monolithic electronic chip. The memory storage system 208 could also be part of this chip, but may be better kept external. The power extraction component 204 includes circuitry to extract power from the communication system. The main processing block 207 takes signals from the ECG 209, electronic sensor 210 and optical sensor 211 pre-processing units. If it determines that conditions have been met that indicate that it should intervene, it will also determine how to intervene, and will signal action to the cardiac photomodulation driver 212. It can use learning circuitry 206 and memory 208 to help in the final decision. Optical signals are then driven out via the photomodulation light emitters for cardiac stimulation/inhibition 214 and the emitters for the optical sensing systems 213. On the return path, light will return via the sensor optical system 213 to optical sensors either externally in that system or inbuilt into the sensor circuitry 11.

Referring to Figure 3a, an interfacing-unit forming part of the embodiment of Figure 1 comprises an interfacing cable a which includes an optical fibre and a sensor cable, a chip b which forms a support for the other components, clamps c which are arranged to secure the interfacing unit to the tissue of the heart, a sensor electrode d which is mounted on the underside of the chip and connected to the sensor cable, and a lens e which is also mounted on the underside of the chip and connected to the optical fibre and includes a transparent surface on its underside which is arranged to be held against the tissue of the heart and through which light from the optical fibre can be directed into the heart.

In use, stimulating light is fed via the optic fibre in cable a and focussed or imaged on the target tissue with micro-lens e. The extracellular electrode d records the ECG signal and feeds it back to the control unit via the sensor cable in the interface cable a. The electrode d and the optic fibre tip are held together using the small chip b that is secured onto the heart by means of the clamping facilities c.

Referring to Figure 3b, a penetrating interfacing-unit arranged to form part of another embodiment of the invention comprises parts corresponding to those of the unit of Figure 3a indicated by the same letters. In this case the lens is replaced by a penetrating light guide e which comprises a rigid transparent rod, tapered slightly from its base where it is attached to the chip c to its tip, and of circular cross section. The tip is domed so as to form a lens for directing light into the tissue of the heart. The light guide therefore acts as an extension of the optic fibre and is aligned with it so that light from the optical fibre enters the light guide e at its base and propagates along it to its tip where the light is emitted into the target region of the heart tissue. The light guide e is designed to penetrate inside tissue layer to overcome opaque tissues.

Referring to Figure 3c, an interface for a third embodiment of the invention again comprises corresponding parts indicated by the same letters. In this case the unit is a stand-alone interfacing unit in which the light source e is built into the unit with the lens f mounted directly on it. The interface cable a therefore carries electric control signals from the control module which control operation of the light source e on the interfacing unit. The light source is driven by a flip-chip module g which may include an internal battery.

Referring to Figure 3d, in a further embodiment the interfacing unit is similar to that of Figure 3b, but in this case it further comprises a micro- reservoir f connected to a micro-needle h, with control electronics g controlling the flow of transfection reagents, or other light sensitizing materials, from the reservoir through the micro-needle h into the target region of the heart. The micro needle h and the penetrating light guide e are located adjacent to each other, substantially parallel to each other, and are substantially the same length so that the light guide directs light into the same region of tissue as the transfection reagent. It will be appreciated that it is important for the micro-needle to direct transfecting reagents into the same target region as the light guide directs light at. To achieve this the tips of the micro needle and light guide are arranged adjacent to each other. The exact length and shape of the two components can vary while still achieving this result. Referring to Figure 3e, an interfacing unit for a further embodiment of the invention is an interfacing unit similar to that of Figure 3a, but with the addition of a transfecting system f, g, h similar to that of the embodiment of Figure 3d.

Referring to Figure 4, an interfacing unit according to a further embodiment of the invention comprises a light emissive module 401, a surface modified sensor or MEMS component 402, surface electrodes 403 for connecting to external sensor units and a power supply, surface patterned micro-optics 404, a surface patterned optical filter 405, transparent dielectric layers 406 of a CMOS chip, a CMOS silicon base 407 of the chip, a photodiode 408, processing elements 409 and flip chip interconnects 410.

In this embodiment, the monolithic CMOS chip integrates all the processing components and is bonded in a flip-chip or other arrangement with the light emissive elements of the module 401. This allows for miniaturized operation. The light emissive module 401 comprises a light emitting diode array chip which is bonded to the CMOS chip 406, 407 via the interconnecting wires 410. The CMOS chip typically has a semiconductor base 407 which can include the processing circuits 409 and photodiode sensors 408. It also has a transparent dielectric stack 406 which can be used for interconnecting wires, which can come to the surface to interface with the external components 403 of the chip. Surface modification such as MEMS sensors 402 can be incorporated in addition to optical filters 405 and microlenses 404. In this arrangement a heat sink may be best placed at the back of the chip 411 or in a ring 412 around the light emitters 401.

Referring to Figure 5, the main driving circuit for the light emitters 401, which forms part of the processing circuits 409, includes in one embodiment an information stream decoder and line and column control 501, and for each of the LED light emitters, a current source 502, LED power line 503, a memory unit and/or oscillator circuitry 504 and a ground connection 505. The driver circuit is formed on an active driver chip 506 which is flip chip bonded to the GaN LED chip. This circuit therefore provides individual oscillation control at each pixel. In this active driver case signal information can be converted into the appropriate oscillation controls by the line and column decoders 501. These then send information to a memory unit or oscillator circuit 504 which determine whether or not current from the current source 502 passes through the LED power line 503 to ground 505. The LED power line can protrude external to the chip to the light emitters for which a flip chip 506 and associated bonding process is highly appropriate. The memory unit configuration 504 can be a simple latch which switches between on and off operation, whereas an oscillator 504 configuration would drive at a certain frequency for a period according to instruction.

Referring to Figure 6, in a passive version of the driver circuit, an LED chip 607 has the control wires 603 to the LEDs on it, and the control electronics are provided on a passive control unit 608. The control unit 608 is arranged to scan the LED elements in raster fashion. In this passive configuration the controller 608 can simply address a particular LED either on an individual basis or in an array. For the duration of the control current will pass through the light emitter allowing photons to be emitted.

While some specific embodiments of the invention have been described above it will be appreciated that these can be used in various ways, and that they can be varied and modified in many ways. Some examples of the implanting, operation, and variations in design details of the embodiments described above will now be described. The light triggering mechanism

The triggering or delaying of the heart beats with light can be achieved via light sensitive ion channels and light sensitive ion pumps. Presently the channelrhodopsin (ChR) family, which are light gated ion channels provide the best method of optical triggering, whereas the halorhodopsin (HR) family of light gated ion pumps provide the best method of delay. When depolarizing light (light that activates the ion channel) is turned on it triggers the opening of the light sensitive ion channels and the influx of positive ions (cations) into the cytoplasm. The result is depolarization of the myocytes that, when it overcomes a specific threshold, activates the natural spiking and contraction mechanism of the cells. Typically this mechanism involves a strong influx of Ca²⁺ into the cell from the activation of the voltage-gated calcium channels. The rise of the internal Ca²⁺ concentration triggers the release of the internal reservoir of Ca²⁺ from the sarcoplasmic reticulum by the calcium-induced calcium release mechanism. That significant increase in the free intracellular Ca²⁺ concentration causes the muscle to contract. In the opposing inhibitory scenario, when hyperpolarizing light (light that activates the sensitive ion pumps) is turned on it triggers the pumping of the light sensitive ion pumps and an influx of negative ions (anions, such as chloride) that hyperpolarize the cells. This inhibits or delays contraction of the cells. By artificially controlling the depolarizing and hyperpolarizing of the cardiac myocyte cells the cardiac cycle rate and rhythm can be precisely regulated or restored.

As an example, cardiac myocytes can be photosensitized by expressing a light sensitive ion channel ChR2 and a light sensitive ion pump NpHR that can be independently activated due to a difference in their wavelength sensitivity. A pulse of blue light ( ~ 470nm) will trigger the opening of ChR2 and an influx of monovalent (such as sodium) and bivalent (such as calcium) cations that depolarizes the cell. A pulse of yellow light ( ~ 580nm) will selectively activate the NpHR and an influx of anions, hyperpolarizing the cell.

Light Sensitization

The light sensitive proteins can be introduced to the cells via transfection. This can be done for example with viral transfection technique using Adeno-associated virus (AAV), electroporation technique or other transfection techniques. The transfection reagents can be injected to the required area during or before implantation of the light source. It can be also integrated into the interfacing unit in order to improve the overlay between the transfected cells and the light beam. This can be realized with micro-fluidic or silicon chips that have micro-containers where the transfection solution is kept and released by electrical or optical signal mechanism. In this case the transfection solution can contain agents to enhance transfection probability such as lipof ectamine . The transfection means can be also introduced by coating the optic fibre tip or lenses with the transfection material (in this case, the transfection material will be covered with a removable inert covering until it reaches the location) or by drug delivery. In the case of electroporation surface electrodes on the interface module can be used to create the appropriate electric fields. The transfection reagent can be blocked by light sensitive moieties and locally released with light, thereby improving the overlaying of light sensitive cells and light stimulus.

Alternatively, the light sensitive reagent (such as light sensitive ion channels) can be produced outside the body (for example in bacteria) and administered to the cells via for example drugs, micro-fluidic chip or direct injection. Implantation

There are several potential methods for implantation of the photonic pacemaker device. The control unit can be implanted as for present pacemaker technology, using the subscapular fossas. This is an easily accessible area of the body, requiring local anaesthesia only. There are no important nerves or blood vessels at risk from minor surgery to this region. Implantation of the light delivery device and transfection of the cardiac myocytes would ideally occur simultaneously to minimise procedures and to ensure accurate overlay of light with the transfected cells. This can be achieved in several ways.

Following cardiac surgery it is common for patients to require temporary pacemaker devices and, in this population with intrinsic cardiac disease, permanent pacemakers are more frequently required in later life. At the time of cardiac surgery, transfection and implantation of a light source can occur. This does not add to the procedure and provides an available, programmable method of cardiac rate and rhythm modulation postoperatively without the requirement for temporary pacing wires or further surgery to implant a pacemaker.

In patients not undergoing cardiac surgery, the photonic pacemaker could be implanted by open cardiac surgery but this is overly invasive. Video assisted thoracic (VATS) procedures are keyhole surgical procedures into the chest. They may be done as day-case surgery and require a short general anaesthetic. Using this procedure it is possible to access the outside of the heart for implantation of one or multiple units containing both transfection and light delivery devices. Optic fibres may then be passed through the thoracic cavity or tunnelled under the skin to the control device. A transcutaneous needle approach may be used to access the outside of the heart using ultrasound guidance and fine-bore needles inserted between the ribs. This technique would require local anaesthetic only and would allow transfection. Finally transfection may be achieved using an intravascular approach during coronary angiography.

Light source & optics

Due to the low efficiency of the light sensitive proteins, i.e. low change in membrane potential vs. light flux, high photon flux is required for the photostimulation process at present. This can be realized for example with miniature high power light sources such as light emitting diodes (LED) or lasers. Organic light emitting diodes (OLED) are highly efficient and thus would provide an ideal candidate if they can achieve good long-term durability and sufficient brightness. At present however gallium nitride based light emitting diodes provide the best solution. Each stimulation spot can be covered with multiple light sources to address the difference in the spectral sensitivity of the proteins and to enable safe redundancy in illumination. Typically optical power density in the range of lpW/μm² to lOOnW/μm² is required depending on the efficacy of genetic manipulation, the efficiency of the photosensitization agent, and the efficiency of the optical delivery system.

The light sources can be placed in the interfacing unit or in the distant control unit. In the second case the light is coupled to light guides such as optic fibres and directed to the interfacing unit where it is focused/imaged on the required area. Microlenses and photonic crystals can be used to increase the light extraction yield in both the coupling and illuminating ends.

As an example, an array of high-power semiconductor based blue 470nm and 570nm micro-LEDs can be used to stimulate ChR2 and NpHR (Poher, V., N. Grossman, G. Kennedy, K. Nikolic, H. Zhang, Z. Gong, E. Drakakis, E. Gu, M. Dawson, P. French, P. Degenaar, and M. Neil, 2008. Micro-LED arrays: a tool for two-dimensional neuron stimulation. J. Phys. D 41:094014.) The two wavelengths can be realized on a single chip with sophisticated growth procedure, by the use of a fluorescent shifting technique, or can be realized on separate chips and combined optically.

The light is coupled out from the control unit casing and guided to the interfacing units using optic fibres for example. A depolarizing light source (blue in case of ChR2) and a hyperpolarizing light source (yellow in case of NpHR) -if required, are dedicated to a single interfacing point

(a redundancy of LEDs per interface unit can be realized for safety reason) . The two light sources are coupled to a single optic fibre using micro-lenses, optic fibre fusion or photonic crystals waveguides.

Alternatively, separate optic fibres can be used and their illumination can be optically overlaid in the interfacing unit.

The system can be cooled with heat sinks and Peltier cooling in order to reduce the temperature and increase the efficiency of the light sources.

In the interfacing units the light from the optic fibres is directed to the transfected cells using for example a micro-lens structure on the fibres tips. The optic fibres can inserted through the pericardial sac or any interfering tissue to increase the illumination efficiency.

Sensing

The heart's activity will be monitored primarily by single lead ECG electrodes, with potential for a combination of further sensors. The information is used to activate/deactivate the interfering stimulus and also to tune the stimulus to the required cardiac cycle rate and rhythm. ECG recording requires a minimum of two electrodes to measure the voltage changes associated with cardiac cycle. These can be placed far apart and, in clinical scenarios, electrodes are frequently placed on the ankles. The electrical activity of the heart can be sensed with electrodes, one of which can be placed in the interfacing units, the other of which can be incorporated into the control unit. Since no interference exist between optic stimulation and the electrical recording these two can be perform simultaneously in each location. Further or alternative sensing capabilities can be integrated to the device such as accelerometers , QT-interval, minute- ventilation sensors, metabolic analytes, and blood gas sensors.

Being an electro-optic device, it is feasible that an optical blood gas sensor can be incorporated, sensing the difference in the absorption of oxygenated and free haemoglobins at near-infrared light (600nm-800nm) . To achieve this, the light is introduced into the heart in the same manner as the depolarizing light, i.e. by a light source located on the interfacing unit or on the control unit, and suitable light guide means, and its absorption is monitored with a photodiode on the interface unit, for example similar to that of Figure 4.

In addition to such spectroscopic methods it is also possible to use localised release of optically active materials that change their optical characteristics upon interaction with a target. It is thus possible to sense the presence of the target optically. Such optically active materials can exhibit luminescent, fluorescent or absorption based changes. The interaction can be immunological or more low level, e.g. with aptamers or amino acid sequences. Additionally carbon fibre electrodes offer the potential for long term sensing without fouling. In this situation, the carbon fibre electrode can be used in cyclic voltametric mode to determine the concentrations of targets via oxidation and reduction potentials. In normal physiology, heart rate is a dynamic variable, falling during sleep and rising during periods of exercise or stress. The change in heart rate is affected by the autonomic nervous system which comprises parasympathetic and sympathetic neurons. Increases in heart rate are caused by a combination of decreased parasympathetic and increased sympathetic activity. The vagus nerve innervates the SA node of the heart and, via the neurotransmitter molecule acetylcholine, reduces heart rate. Sympathetic innervation of the heart comes from the sympathetic ganglionic chain, a network of nerves from the spine. The sympathetic nervous system increases heart rate by direct innervation of the heart with the neurotransmitter norepinephrine and by increasing circulating epinephrine. In sinoatrial node failure we propose using transfected light sensitive proteins to repair the node or create a new node at a distant location. However, physiological heart rate control may be lost in achieving this. By sensing vagal activity or sympathetic chain activity using nerve recording electrodes it is possible to add a physiological input to the processing unit and appropriately modulate heart rate. Alternatively combining acetylcholine or norepinephrine cellular receptors with a light sensitive moiety may provide a mechanism to recruit cellular machinery to modulate heart rate as required.

Power supply

Due to the relatively slow temporal resolution of the heart (in comparison to the optoelectronic switching time) and due to the required delays between the different interfacing locations, it is likely that only a single light source will be required at a given moment, relieving the peak power requirements. Thus, the system can be powered via a small battery.

Additionally, as the control component of some embodiments can be implanted subcutaneously, a radiofrequency or infra-red recharging system can be used to maintain battery levels. In addition, it is possible for energy scavenging to be used to help in the return of power to the energy storage unit (e.g. battery or charge capacitor) . Such energy scavenging can include mechanical energy scavenging via MEMS systems optimized to the frequency of the heart, and/or chemical scavenging which extract energy from glucose, ATP or other sources in the blood stream. In the case of the mechanical system, the heart would provide the most ideal location.

In one embodiment individual micro-LEDs are pulsed between 0.5-1OmA at 5-7 V for 1-lOms. The total energy consumption of the light emitter in this case is 2.5microJ - 700microJ, resulting in a continuous power consumption of 2.5 - 700 microW when pulsed at 60 pulses/minute. The variation is dependent on the efficiency of the emitter, the optics and the level of sensitization of the cells. This is smaller than the present requirement for current electrical based pacemakers (Mallela, 2004) .

In the case of ICD devices, present electrical ICD consumes several joules of energy, while in most cases of the photogentic ICD device several millijoules will be enough. Thus the present invention has considerable advantages with regards battery power consumption. Thus it will subsequently be possible to reduce the size of the required device.

The power requirement can be easily realized with conventional batteries such as lithium iodine or lithium carbon monofluoride (CFx) that have a very low self-discharge rate resulting in a long shelf life and a stable voltage throughout their lifespan, resulting in safe prediction of working time. Control Electronics

In general, the device requires electronics to interpret the sensing modules and control the optical stimulation. The system can be built from discrete components or from a single monolithic chip. Additionally individual processing components can be implemented either in analog or digital processing modes. The advantages of the former are extremely low power consumption and the advantages of the latter are accuracy and tunability. Examples of digital processing platforms include programmable logic such as CPLD (complex programmable logic device) , PIC (Programmable interface controllers) or FPGA (Field Programmable Gated Arrays) and ASIC (Application Specific Integrated Circuits) platforms such as CMOS Complementary Metal Oxide Semiconductor) .

Some of the system components may remain dormant for much of the time in order to save power. Thus it is preferable to maintain power to the sensor and preprocessing components. These can be operated using low power analog circuit methods. Alternatively they can be formed from analog to digital conversion and digital processing elements. A threshold can be implemented to only ensure the transmission of information to the main processing block when a safety limit is indicated. Alternatively this information can be transmitted directly.

The sensor processing component can have electrical isolation to ensure no electrolytic discharge into the solution. The ECG/EKG requires frequency analysis, and additionally, high, low and bandpass filtering to determine the health of the heart rate, and processing providing these functions can therefore be included. For other sensors, specific processing modalities include frequency, phase, amplitude, time domain, and differential analysis can be provided. Differential analysis is usually performed via a comparison between the main sensor and a control. Additionally for specific cases such as signal analysis from carbon fibre electrodes signals need to be analysed with variation in drive voltages. Furthermore, in the case of optical analysis, the signal may be analysed via the driving of a light based system and analysing the returning photons through a transducer such as a photodiode. Photodiodes in particular can be built into CMOS electronics. Furthermore in some cases inbuilt electrically controlled wavelength tuning systems can be provided which can be used to help perform spectroscopic sensing studies. In this case sensing occurs in conjunction with electronic scanning of the wavelength emitted or received.

The higher level processing module can compare the desired frequencies of cardiac activity, which can be stored in memory, with the sensor based information and the desired cardiac activity. An intervention signal can be subsequently generated if the sensed cardiac activity meets certain defined conditions. The intervention processing circuitry can be tunable via instructions stored in a memory module. This memory can be included in a dedicated ASIC but can also be part of a separate module with low power non-volatile memory. An appropriate stimulation frequency signal can then be sent to the light emitter controllers. The processing in the first instance simply analyzes whether the heart rate falls into a specific frequency range and phase, but can also be expanded to consider all the features of the ECG signal in conjunction with other sensor information from the various sensor systems described above. Additionally fuzzy logic and hysteresis can be implemented to ensure stability when the signals are on the borderline between intervention and non-intervention

Given manufacturing variances between light emissive systems, the level of sensitivity of the photosensitized tissue, the electronics and how these change with time, a learning algorithm may be required. The learning algorithm circuitry can act to modify the stimulation signal in order to obtain maximum benefit. Thus, the learning circuits can in effect be part of a closed loop control. Alternatively the control can be fixed and adjustments modulated by the user using an external controller. The specifics of such learning circuits can be as simple as offset enhancement based on the difference between cardiac instruction and sensor reading, or much more complicated neural networks.

The light stimulator controller can be operated using an active latching system, a simple passive raster control between light emitters or an oscillatory circuit controlling each light emissive device. Pulse widths can be from 10 microseconds to 100 milliseconds but are most ideal in the couple of millisecond range. Thus, the most convenient way to control the LED' s is then by supplying a constant current which is pulsed with time. Latching circuits can turn on the signal and keep it on until a new signal switches it off. Passive circuits can act to drive the circuit only when a drive signal is present. It may however be useful to also modulate the drive voltage and current. In the latter case, oscillatory circuitry needs to be designed accordingly. If the oscillator is developed using analog circuitry, the capacitor required to achieve IHz may need to be external to the chip. Alternatively it can be created on-chip, but will require a large surface area.

The chip may have a communication component which is connected to an RF or IR emitter /recorder. Both RF and IR signals can permeate the skin, and are thus the most ideal transmission methods. This component may also be used to extract power from the external signal in order to recharge the battery. The communication bandwidth may be limited, and the energy cost of return transmission from the device could be significant. Thus pre-processing of the return signal from the chip can be important. Such a link allows the user to modify the system to fine-tune the signalling, and to extract data where necessary. Casing

The casing of the control unit functions as housing for the battery, electronics and light sources.

The case can be made from a material such as titanium, a metal that is ten times as strong as steel, but much lighter. Titanium and two of its alloys, niobium and tantalum, are biocompatible and they exhibit physical and mechanical properties superior to many other metals. The modulus of elasticity (measure of stiffness) of titanium and its alloys range between 100-120GPa. A titanium case can help to shield the internal components and reduce the external electromagnetic interference. In addition, titanium casing shields from ground level cosmic radiation. Furthermore, while titanium is weakly paramagnetic, it is nevertheless considered MRI compatible.

Expression of Channelrhodopsin-2 in Cardiomyocytes

In order to investigate transfection of the HL-I Cardiomyocyte cell line with the light-gated channel protein Channelrhodopsin-2 (ChR2) , the following experiment was performed.

Materials & Method: β-actin-ChR2-YFP plasmid was used to transfect HL-I cardiomyocyte cells by the process of lipofection. The cells were cultured in two sterile wells and were also plated onto three microelectrode arrays (MEA) from which recordings of cell activity would then be tested.

Two transfection methods were implemented.

Protocol A: the growth medium was removed from the culturing cells and the cells were washed once with 37⁰C DMEM (Dulbecco's Modified Eagle's Medium) . Then, ImI of DMEM was pipetted carefully into the

MEA/well. The transfection solution was then prepared by mixing 200μl DMEM, 5μl lipofectamine ™, and 3.6μg of DNA in a sterile eppendorf tube. The transfection solution was mixed well and left for 20 minutes at room temperature. After 20 minutes, the transfection solution was added, drop- wise, to the MEA/well of culturing cells with ImI of DMEM and mixed very gently. The sample was then incubated for 4 hours at 37° C. After 4 hours, the medium was removed and growth medium was added (growth medium, 10% Foetal Bovine Serum, and Pen/Strep) .

Protocol B: the second protocol adjusted from Cormier-Regard et al. (Cormier-Regard S. , Nguyen S.V., Claycomb W. C. (1998) Adrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes. J Biol Chem 273(28) : 17787-17792) . Here, the transfection solution - (i)10μl lipofectamine ™ was added to 90μl DMEM (37° C) and incubated for 30 minutes at room temperature; (ii)3.5μg DNA was mixed with 100ml DMEM (37⁰C) and added to solution (i) and then again incubated for 30 minutes at room temperature; (iii) 800μl DMEM (37° C) was then added. The medium was removed from the plated cells which were then washed with DMEM (37° C) . ImI of transfection solution was added to each culture well/MEA and incubated at 37°C (95% air, 5% CO₂) for 6 hours. ImI of HL-I medium ( + 20% Foetal Bovine Serum without Pen/Strep antibiotic) was then added and the solution again incubated for a further 16 hours. The medium was then replaced with normal HL-I medium and incubated for 8 hours and then treated at 37° C (95% air, 5% CO₂) for a further 12 hours.

One MEA and one well were transfected using each method. The remaining MEA was not subject to transfection, but was used as a control in the result of experiment failure to establish possible causes of cell death. Results & Discussion:

Figure 7 A shows a cluster of HL-I cells, plated on to an MEA and then transfected by lipofection with the plasmid β-actin-ChR2-YFP. The cells are fluorescing as they are expressing the protein channelrhodopsin (ChR2) which carries with it a fusion tag, in this case Yellow Fluorescent Protein (YFP) . Figure 7B: shows the same cells under a normal filter and therefore not emitting any fluorescence. The arrows in both A and B indicate the same cell.

Figure 8A shows fluorescence images of the Microelectrode Arrays (MEA) plated with HL-I cells and then transfected with the plasmid β- actin-ChR2-YFP. The cells were transfected according to protocol B.

Figure 8B: shows the MEA transfected according to protocol A.

The cardiomyocyte cells were successfully transfected with ChR2 that impart light sensitivity. The transfection was stable for several days. The existence of ChR2 in the cells and the photostimulaiton did not seem to harm the cells. Cells with ChR2 did not loose their beating capability and no damage to the cells was seen. The two protocols used to transfect the HLl differed mainly in the length of time the plated cells were incubated in the transfection solution (i.e. the lipofection time) . Both transfections were initiated on the same concentration of cells and both yielded a transfection efficiency of 3-5%. This is to be expected of any initial transient transfection, and the skilled man will understand that the transfection conditions need to be optimized.

Claims

1. A pacemaker for controlling contraction of a heart, comprising a light source, light guide means for directing light from the source at a target region of the heart, sensing means arranged to sense activity of the heart, and control means arranged to receive signals from the sensing means and control operation of the light source.

2. A pacemaker according to claim 1 wherein the light guide means has a transparent external surface through which light can be directed into a region of the heart.

3. A pacemaker according to claim 1 or claim 2 comprising a control module and an interface unit, wherein the light source is located in the control module and the light guide means includes an optical fibre extending between the control module and the interface unit.

4. A pacemaker according to any foregoing claim wherein the light source is arranged to generate light of two different wavelengths, and the light guide means is arranged to direct light of each of the wavelengths at the same target region.

5. A pacemaker according to claim 4 wherein the control means is arranged to control the light source to generate the two different wavelengths of light alternately so that they can induce and inhibit respectively contraction of the heart.

6. A pacemaker according to any foregoing claim wherein the light source comprises at least one LED.

7. A pacemaker according to any foregoing claim wherein the light source comprises an array of light source elements.

8. A pacemaker according to claim 7 wherein the light guide means is arranged to guide light from the light source elements to a plurality of different target regions.

9. A pacemaker according to any foregoing claim wherein the sensing means is arranged to sense electrical activity of the heart.

10. A pacemaker according to claim 9 wherein the sensing means is arranged to sense activity of the vagus nerve.

11. A pacemaker according to claim 9 or claim 10 wherein the sensing means is arranged to sense acetylcholine or norepinephrine neurotransmitters .

12. A pacemaker according to any of claims 9 to 11 wherein the sensing means is arranged to sense oxygenated and free haemoglobin activity.

13. A pacemaker according to any foregoing claim wherein the sensing means includes optical sensing means.

14. A pacemaker according to any foregoing claim wherein the sensing means includes at least one of: an accelerometer; a QT-interval sensor; a minute ventilation sensor; a metabolic analyte; and a blood gas sensor.

15. A pacemaker according to any foregoing claim further comprising light sensitizing material supply means for supplying light sensitizing material to the target region.

16. A pacemaker according to claim 15 wherein the light sensitizing material supply means comprises an injecting needle and flow control means arranged to control the flow of light sensitizing material through the needle into the target region.

17. A method of controlling contraction of a heart comprising providing a pacemaker according to any of claims 1 to 16, sensing activity of the heart with the sensing means, and controlling operation of the light source to control contraction of the heart.

18. A method according to claim 17 wherein the target region of the heart contains myocytes which have been made light sensitive by means of a light sensitizing material.

19. A method of controlling contraction of a heart comprising sensitizing one or more myocytes in the heart to light by means of a light sensitizing material and exposing the sensitized myocytes to light.

20. A method of producing a sinoatrial node in a heart comprising sensitizing one or more myocytes in the heart to light by means of a light sensitizing material.

21. A method according to any of claims 18 to 20 wherein the light sensitizing material is a light sensitive ion channel and/or a light sensitive pump.

22. The method of claim 21 wherein the light sensitive ion channel is a channelrhodopsin .

23. The method of claim 22 wherein the channelrhodopsin is channelrhodopsin 2.

24. The method of any of claims 18 to 23 wherein the light sensitive pump is a halorhodopsin.

25. The method of any of claims 18 to 24 wherein the myocytes are sensitized to light by genetically engineering the myocytes to express the light sensitive ion channel and/or light sensitive pump.

26. The method of claim 19 wherein the light is provided by a pacemaker device according to any of claims 1 to 16.

27. The method of claim 25 wherein the one or more myocytes are genetically engineered by introducing a gene encoding a light sensitive ion channel and/or a gene encoding a light sensitive pump.

28. The method of claim 27 wherein a gene is introduced by transfecting one or more myoctes with a vector comprising a gene encoding a light sensitive ion channel and/or a gene encoding a light sensitive pump.

29. The method of claim 28 wherein the vector is a viral vector, a plasmid or a phage.

30. The method of claim 27, 28 or 29 wherein the gene encoding the light sensitive ion channel and/or the gene encoding the light sensitive pump is operably linked to a promoter constitutively or inducible active in the myocyte.

31. A pharmaceutical composition for use in controlling contraction of a heart comprising one or more of (i) a nucleic acid encoding a light sensitive ion channel wherein the nucleic acid is operably linked to a promoter constitutively or inducibly active in a myocyte, and (ii) a nucleic acid encoding a light sensitive pump wherein the nucleic acid is operably linked to a promoter constitutively or inducibly active in a myocyte.

32. A pacemaker according to claim 15 or claim 16 wherein the light sensitizing material is a pharmaceutical composition according to claim 31.