Neuroprosthetics

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Neuroprosthetics

Neuroprosthetics (also called neural prosthetics) is a discipline related to neuroscience and biomedical engineering concerned with developing neural prostheses. They are sometimes contrasted with a brain–computer interface, which connects the brain to a computer rather than a device meant to replace missing biological functionality.

Neural prostheses are a series of devices that can substitute a motor, sensory or cognitive modality that might have been damaged as a result of an injury or a disease. Cochlear implants provide an example of such devices. These devices substitute the functions performed by the eardrum and stapes while simulating the frequency analysis performed in the cochlea. A microphone on an external unit gathers the sound and processes it; the processed signal is then transferred to an implanted unit that stimulates the auditory nerve through a microelectrode array. Through the replacement or augmentation of damaged senses, these devices intend to improve the quality of life for those with disabilities.

These implantable devices are also commonly used in animal experimentation as a tool to aid neuroscientists in developing a greater understanding of the brain and its functioning. By wirelessly monitoring the brain's electrical signals sent out by electrodes implanted in the subject's brain, the subject can be studied without the device affecting the results. 

Accurately probing and recording the electrical signals in the brain would help better understand the relationship among a local population of neurons that are responsible for a specific function. 

Neural implants are designed to be as small as possible in order to be minimally invasive, particularly in areas surrounding the brain, eyes or cochlea. These implants typically communicate with their prosthetic counterparts wirelessly. Additionally, power is currently received through wireless power transmission through the skin. The tissue surrounding the implant is usually highly sensitive to temperature rise, meaning that power consumption must be minimal in order to prevent tissue damage.

The neuroprosthetic currently undergoing the most widespread use is the cochlear implant, with over 300,000 in use worldwide as of 2012.

History

The first known cochlear implant was created in 1957. Other milestones include the first motor prosthesis for foot drop in hemiplegia in 1961, the first auditory brainstem implant in 1977 and a peripheral nerve bridge implanted into the spinal cord of an adult rat in 1981. In 1988, the lumbar anterior root implant and functional electrical stimulation (FES) facilitated standing and walking, respectively, for a group of paraplegics.

Regarding the development of electrodes implanted in the brain, an early difficulty was reliably locating the electrodes, originally done by inserting the electrodes with needles and breaking off the needles at the desired depth. Recent systems utilize more advanced probes, such as those used in deep brain stimulation to alleviate the symptoms of Parkinson's disease. The problem with either approach is that the brain floats free in the skull while the probe does not, and relatively minor impacts, such as a low speed car accident, are potentially damaging. Some researchers, such as Kensall Wise at the University of Michigan, have proposed tethering 'electrodes to be mounted on the exterior surface of the brain' to the inner surface of the skull. However, even if successful, tethering would not resolve the problem in devices meant to be inserted deep into the brain, such as in the case of deep brain stimulation (DBS). 

Visual prosthetics

A visual prosthesis can create a sense of image by electrically stimulating neurons in the visual system. A camera would wirelessly transmit to an implant, the implant would map the image across an array of electrodes. The array of electrodes has to effectively stimulate 600-1000 locations, stimulating these optic neurons in the retina thus will create an image. The stimulation can also be done anywhere along the optic signal's path way. The optical nerve can be stimulated in order to create an image, or the visual cortex can be stimulated, although clinical tests have proven most successful for retinal implants.

A visual prosthesis system consists of an external (or implantable) imaging system which acquires and processes the video. Power and data will be transmitted to the implant wirelessly by the external unit. The implant uses the received power/data to convert the digital data to an analog output which will be delivered to the nerve via micro electrodes.

Photoreceptors are the specialized neurons that convert photons into electrical signals. They are part of the retina, a multilayer neural structure about 200 um thick that lines the back of the eye. The processed signal is sent to the brain through the optical nerve. If any part of this pathway is damaged blindness can occur.

Blindness can result from damage to the optical pathway (cornea, aqueous humor, crystalline lens, and vitreous). This can happen as a result of accident or disease. The two most common retinal degenerative diseases that result in blindness secondary to photoreceptor loss is age related macular degeneration (AMD) and retinitis pigmentosa (RP).

The first clinical trial of a permanently implanted retinal prosthesis was a device with a passive microphotodiode array with 3500 elements. This trial was implemented at Optobionics, Inc., in 2000. In 2002, Second Sight Medical Products, Inc. (Sylmar, CA) began a trial with a prototype epiretinal implant with 16 electrodes. The subjects were six individuals with bare light perception secondary to RP. The subjects demonstrated their ability to distinguish between three common objects (plate, cup, and knife) at levels statistically above chance. An active sub retinal device developed by Retina Implant GMbH (Reutlingen, Germany) began clinical trials in 2006. An IC with 1500 microphotodiodes was implanted under the retina. The microphotodiodes serve to modulate current pulses based on the amount of light incident on the photo diode.

The seminal experimental work towards the development of visual prostheses was done by cortical stimulation using a grid of large surface electrodes. In 1968 Giles Brindley implanted an 80 electrode device on the visual cortical surface of a 52-year-old blind woman. As a result of the stimulation the patient was able to see phosphenes in 40 different positions of the visual field. This experiment showed that an implanted electrical stimulator device could restore some degree of vision. Recent efforts in visual cortex prosthesis have evaluated efficacy of visual cortex stimulation in a non-human primate. In this experiment after a training and mapping process the monkey is able to perform the same visual saccade task with both light and electrical stimulation.

The requirements for a high resolution retinal prosthesis should follow from the needs and desires of blind individuals who will benefit from the device. Interactions with these patients indicate that mobility without a cane, face recognition and reading are the main necessary enabling capabilities.

The results and implications of fully functional visual prostheses are exciting. However, the challenges are grave. In order for a good quality image to be mapped in the retina a high number of micro-scale electrode arrays are needed. Also, the image quality is dependent on how much information can be sent over the wireless link. Also this high amount of information must be received and processed by the implant without much power dissipation which can damage the tissue. The size of the implant is also of great concern. Any implant would be preferred to be minimally invasive.

With this new technology, several scientists, including Karen Moxon at Drexel, John Chapin at SUNY, and Miguel Nicolelis at Duke University, started research on the design of a sophisticated visual prosthesis. Other scientists have disagreed with the focus of their research, arguing that the basic research and design of the densely populated microscopic wire was not sophisticated enough to proceed. 

Auditory prosthetics

Cochlear implants (CIs), auditory brain stem implants (ABIs), and auditory midbrain implants (AMIs) are the three main categories for auditory prostheses. CI electrode arrays are implanted in the cochlea, ABI electrode arrays stimulate the cochlear nucleus complex in the lower brain stem, and AMIs stimulates auditory neurons in the inferior colliculus. Cochlear implants have been very successful among these three categories. Today the Advanced Bionics Corporation, the Cochlear Corporation and the Med-El Corporation are the major commercial providers of cochlea implants. 

In contrast to traditional hearing aids that amplify sound and send it through the external ear, cochlear implants acquire and process the sound and convert it into electrical energy for subsequent delivery to the auditory nerve. The microphone of the CI system receives sound from the external environment and sends it to processor. The processor digitizes the sound and filters it into separate frequency bands that are sent to the appropriate tonotonic region in the cochlea that approximately corresponds to those frequencies. 

In 1957, French researchers A. Djourno and C. Eyries, with the help of D. Kayser, provided the first detailed description of directly stimulation the auditory nerve in a human subject. The individuals described hearing chirping sounds during simulation. In 1972, the first portable cochlear implant system in an adult was implanted at the House Ear Clinic. The U.S. Food and Drug Administration (FDA) formally approved the marketing of the House-3M cochlear implant in November 1984.

Improved performance on cochlear implant not only depends on understanding the physical and biophysical limitations of implant stimulation but also on an understanding of the brain's pattern processing requirements. Modern signal processing represents the most important speech information while also providing the brain the pattern recognition information that it needs. Pattern recognition in the brain is more effective than algorithmic preprocessing at identifying important features in speech. A combination of engineering, signal processing, biophysics, and cognitive neuroscience was necessary to produce the right balance of technology to maximize the performance of auditory prosthesis.

Cochlear implants have been also used to allow acquiring of spoken language development in congenitally deaf children, with remarkable success in early implantations (before 2–4 years of life have been reached). There have been about 80,000 children implanted worldwide.

The concept of combining simultaneous electric-acoustic stimulation (EAS) for the purposes of better hearing was first described by C. von Ilberg and J. Kiefer, from the Universitätsklinik Frankfurt, Germany, in 1999. That same year the first EAS patient was implanted. Since the early 2000s FDA has been involved in a clinical trial of device termed the "Hybrid" by Cochlear Corporation. This trial is aimed at examining the usefulness of cochlea implantation in patients with residual low-frequency hearing. The "Hybrid" utilizes a shorter electrode than the standard cochlea implant, since the electrode is shorter it stimulates the basil region of the cochlea and hence the high-frequency tonotopic region. In theory these devices would benefit patients with significant low-frequency residual hearing who have lost perception in the speech frequency range and hence have decreased discrimination scores.

For producing sound see Speech synthesis. 

Prosthetics for pain relief

The SCS (Spinal Cord Stimulator) device has two main components: an electrode and a generator. The technical goal of SCS for neuropathic pain is to mask the area of a patient's pain with a stimulation induced tingling, known as "paresthesia", because this overlap is necessary (but not sufficient) to achieve pain relief. Paresthesia coverage depends upon which afferent nerves are stimulated. The most easily recruited by a dorsal midline electrode, close to the pial surface of spinal cord, are the large dorsal column afferents, which produce broad paresthesia covering segments caudally. 

In ancient times the electrogenic fish was used as a shocker to subside pain. Healers had developed specific and detailed techniques to exploit the generative qualities of the fish to treat various types of pain, including headache. Because of the awkwardness of using a living shock generator, a fair level of skill was required to deliver the therapy to the target for the proper amount of time. (Including keeping the fish alive as long as possible) Electro analgesia was the first deliberate application of electricity. By the nineteenth century, most western physicians were offering their patients electrotherapy delivered by portable generator. In the mid-1960s, however, three things converged to ensure the future of electro stimulation.

1. Pacemaker technology, which had it start in 1950, became available.
2. Melzack and Wall published their gate control theory of pain, which proposed that the transmission of pain could be blocked by stimulation of large afferent fibers.
3. Pioneering physicians became interested in stimulating the nervous system to relieve patients from pain.

The design options for electrodes include their size, shape, arrangement, number, and assignment of contacts and how the electrode is implanted. The design option for the pulse generator include the power source, target anatomic placement location, current or voltage source, pulse rate, pulse width, and number of independent channels. Programming options are very numerous (a four-contact electrode offers 50 functional bipolar combinations). The current devices use computerized equipment to find the best options for use. This reprogramming option compensates for postural changes, electrode migration, changes in pain location, and suboptimal electrode placement.

Motor prosthetics

Devices which support the function of autonomous nervous system include the implant for bladder control. In the somatic nervous system attempts to aid conscious control of movement include Functional electrical stimulation and the lumbar anterior root stimulator. 

Bladder control implants

Where a spinal cord lesion leads to paraplegia, patients have difficulty emptying their bladders and this can cause infection. From 1969 onwards Brindley developed the sacral anterior root stimulator, with successful human trials from the early 1980s onwards. This device is implanted over the sacral anterior root ganglia of the spinal cord; controlled by an external transmitter, it delivers intermittent stimulation which improves bladder emptying. It also assists in defecation and enables male patients to have a sustained full erection.

The related procedure of sacral nerve stimulation is for the control of incontinence in able-bodied patients.

Motor prosthetics for conscious control of movement

Researchers are currently investigating and building motor neuroprosthetics that will help restore movement and the ability to communicate with the outside world to persons with motor disabilities such as tetraplegia or amyotrophic lateral sclerosis. Research has found that the striatum plays a crucial role in motor sensory learning. This was demonstrated by an experiment in which lab rats' firing rates of the striatum was recorded at higher rates after performing a task consecutively.

To capture electrical signals from the brain, scientists have developed microelectrode arrays smaller than a square centimeter that can be implanted in the skull to record electrical activity, transducing recorded information through a thin cable. After decades of research in monkeys, neuroscientists have been able to decode neuronal signals into movements. Completing the translation, researchers have built interfaces that allow patients to move computer cursors, and they are beginning to build robotic limbs and exoskeletons that patients can control by thinking about movement.

The technology behind motor neuroprostheses is still in its infancy. Investigators and study participants continue to experiment with different ways of using the prostheses. Having a patient think about clenching a fist, for example, produces a different result than having him or her think about tapping a finger. The filters used in the prostheses are also being fine-tuned, and in the future, doctors hope to create an implant capable of transmitting signals from inside the skull wirelessly, as opposed to through a cable.

Prior to these advancements, Philip Kennedy (Emory and Georgia Tech) had an operable if somewhat primitive system which allowed an individual with paralysis to spell words by modulating their brain activity. Kennedy's device used two neurotrophic electrodes: the first was implanted in an intact motor cortical region (e.g. finger representation area) and was used to move a cursor among a group of letters. The second was implanted in a different motor region and was used to indicate the selection.

Developments continue in replacing lost arms with cybernetic replacements by using nerves normally connected to the pectoralis muscles. These arms allow a slightly limited range of motion, and reportedly are slated to feature sensors for detecting pressure and temperature.

Dr. Todd Kuiken at Northwestern University and Rehabilitation Institute of Chicago has developed a method called targeted reinnervation for an amputee to control motorized prosthetic devices and to regain sensory feedback. 

In 2002 a Multielectrode array of 100 electrodes, which now forms the sensor part of a Braingate, was implanted directly into the median nerve fibers of scientist Kevin Warwick. The recorded signals were used to control a robot arm developed by Warwick's colleague, Peter Kyberd and was able to mimic the actions of Warwick's own arm. Additionally, a form of sensory feedback was provided via the implant by passing small electrical currents into the nerve. This caused a contraction of the first lumbrical muscle of the hand and it was this movement that was perceived.

In June 2014, Juliano Pinto, a paraplegic athlete, performed the ceremonial first kick at the 2014 FIFA World Cup using a powered exoskeleton with a brain interface. The exoskeleton was developed by the Walk Again Project at the laboratory of Miguel Nicolelis, funded by the government of Brazil. Nicolelis says that feedback from replacement limbs (for example, information about the pressure experienced by a prosthetic foot touching the ground) is necessary for balance. He has found that as long as people can see the limbs being controlled by a brain interface move at the same time as issuing the command to do so, with repeated use the brain will assimilate the externally powered limb and it will start to perceive it (in terms of position awareness and feedback) as part of the body.

Amputation techniques

The MIT Biomechatronics Group has designed a novel amputation paradigm that enables biological muscles and myoelectric prostheses to interface neurally with high reliability. This surgical paradigm, termed the agonist-antagonist myoneural interface (AMI), provides the user with the ability to sense and control their prosthetic limb as an extension of their own body, rather than using a prosthetic that merely resembles an appendage. In a normal agonist-antagonist muscle pair relationship (e.g. bicep-tricep), when the agonist muscle contracts, the antagonist muscle is stretched, and vice versa, providing one with the knowledge of the position of one's limb without even having to look at it. During a standard amputation, agonist-antagonist muscles (e.g. bicep-tricep) are isolated from each other, preventing the ability to have the dynamic contract-extend mechanism that generates sensory feedback. Therefore, current amputees have no way of feeling the physical environment their prosthetic limb encounters. Moreover, with the current amputation surgery which has been in place for over 200 years, 1/3 patients undergo revision surgeries due to pain in their stumps. 

An AMI is composed of two muscles that originally shared an agonist-antagonist relationship. During the amputation surgery, these two muscles are mechanically linked together within the amputated stump. One AMI muscle pair can be created for each joint degree of freedom in a patient in order to establish control and sensation of multiple prosthetic joints. In preliminary testing of this new neural interface, patients with an AMI have demonstrated and reported greater control over the prosthesis. Additionally, more naturally reflexive behavior during stair walking was observed compared to subjects with a traditional amputation. An AMI can also be constructed through the combination of two devascularized muscle grafts. These muscle grafts (or flaps) are spare muscle that is denervated (detached from original nerves) and removed from one part of the body to be re-innervated by severed nerves found in the limb to be amputated. Through the use of regenerated muscle flaps, AMIs can be created for patients with muscle tissue that has experienced extreme atrophy or damage or for patients who are undergoing revision of an amputated limb for reasons such as neuroma pain, bone spurs, etc. 

Obstacles

Mathematical modelling

Accurate characterization of the nonlinear input/output (I/O) parameters of the normally functioning tissue to be replaced is paramount to designing a prosthetic that mimics normal biologic synaptic signals. Mathematical modeling of these signals is a complex task "because of the nonlinear dynamics inherent in the cellular/molecular mechanisms comprising neurons and their synaptic connections". The output of nearly all brain neurons are dependent on which post-synaptic inputs are active and in what order the inputs are received. (spatial and temporal properties, respectively).

Once the I/O parameters are modeled mathematically, integrated circuits are designed to mimic the normal biologic signals. For the prosthetic to perform like normal tissue, it must process the input signals, a process known as transformation, in the same way as normal tissue. 

Size

Implantable devices must be very small to be implanted directly in the brain, roughly the size of a quarter. One of the example of microimplantable electrode array is the Utah array.

Wireless controlling devices can be mounted outside of the skull and should be smaller than a pager. 

Power consumption

Power consumption drives battery size. Optimization of the implanted circuits reduces power needs. Implanted devices currently need on-board power sources. Once the battery runs out, surgery is needed to replace the unit. Longer battery life correlates to fewer surgeries needed to replace batteries. One option that could be used to recharge implant batteries without surgery or wires is being used in powered toothbrushes. These devices make use of inductive coupling to recharge batteries. Another strategy is to convert electromagnetic energy into electrical energy, as in radio-frequency identification tags. 

Biocompatibility

Cognitive prostheses are implanted directly in the brain, so biocompatibility is a very important obstacle to overcome. Materials used in the housing of the device, the electrode material (such as iridium oxide), and electrode insulation must be chosen for long term implantation. Subject to Standards: ISO 14708-3 2008-11-15, Implants for Surgery - Active implantable medical devices Part 3: Implantable neurostimulators. 

Crossing the blood–brain barrier can introduce pathogens or other materials that may cause an immune response. The brain has its own immune system that acts differently from the immune system of the rest of the body. 

Questions to answer: How does this affect material choice? Does the brain have unique phages that act differently and may affect materials thought to be biocompatible in other areas of the body? 

Data transmission

Wireless Transmission is being developed to allow continuous recording of neuronal signals of individuals in their daily life. This allows physicians and clinicians to capture more data, ensuring that short term events like epileptic seizures can be recorded, allowing better treatment and characterization of neural disease.

A small, light weight device has been developed that allows constant recording of primate brain neurons at Stanford University. This technology also enables neuroscientists to study the brain outside of the controlled environment of a lab.

Methods of data transmission must be robust and secure. Neurosecurity is a new issue. Makers of cognitive implants must prevent unwanted downloading of information or thoughts from and uploading of detrimental data to the device that may interrupt function. 

Correct implantation

Implantation of the device presents many problems. First, the correct presynaptic inputs must be wired to the correct postsynaptic inputs on the device. Secondly, the outputs from the device must be targeted correctly on the desired tissue. Thirdly, the brain must learn how to use the implant. Various studies in brain plasticity suggest that this may be possible through exercises designed with proper motivation. 

Technologies involved

Local field potentials

Local field potentials (LFPs) are electrophysiological signals that are related to the sum of all dendritic synaptic activity within a volume of tissue. Recent studies suggest goals and expected value are high-level cognitive functions that can be used for neural cognitive prostheses. Also, Rice University scientists have discovered a new method to tune the light-induced vibrations of nanoparticles through slight alterations to the surface to which the particles are attached. According to the university, the discovery could lead to new applications of photonics from molecular sensing to wireless communications. They used ultrafast laser pulses to induce the atoms in gold nanodisks to vibrate.

Automated movable electrical probes

One hurdle to overcome is the long term implantation of electrodes. If the electrodes are moved by physical shock or the brain moves in relation to electrode position, the electrodes could be recording different nerves. Adjustment to electrodes is necessary to maintain an optimal signal. Individually adjusting multi electrode arrays is a very tedious and time consuming process. Development of automatically adjusting electrodes would mitigate this problem. Anderson's group is currently collaborating with Yu-Chong Tai's lab and the Burdick lab (all at Caltech) to make such a system that uses electrolysis-based actuators to independently adjust electrodes in a chronically implanted array of electrodes.

Imaged guided surgical techniques

Image-guided surgery is used to precisely position brain implants.

Artificial organ

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Artificial_organ

 

An artificial organ is an engineered device or tissue that is implanted or integrated into a human — interfacing with living tissue — to replace a natural organ, to duplicate or augment a specific function or functions so the patient may return to a normal life as soon as possible. The replaced function does not have to be related to life support, but it often is. For example, replacement bones and joints, such as those found in hip replacements, could also be considered artificial organs.

Implied by definition, is that the device must not be continuously tethered to a stationary power supply or other stationary resources such as filters or chemical processing units. (Periodic rapid recharging of batteries, refilling of chemicals, and/or cleaning/replacing of filters would exclude a device from being called an artificial organ.) Thus, a dialysis machine, while a very successful and critically important life support device that almost completely replaces the duties of a kidney, is not an artificial organ.

Purpose

Constructing and installing artificial organs, an extremely research-intensive and expensive process initially, may entail many years of ongoing maintenance services not needed by a natural organ.:

• providing life support to prevent imminent death while awaiting a transplant (e.g. artificial heart);
• dramatically improving the patient's ability for self care (e.g. artificial limb);
• improving the patient's ability to interact socially (e.g. cochlear implant); or
• improving a patient's quality of life through cosmetic restoration after cancer surgery or an accident.

The use of any artificial organ by humans is almost always preceded by extensive experiments with animals. Initial testing in humans is frequently limited to those either already facing death or who have exhausted every other treatment possibility. 

Examples

Artificial limbs

A prosthetic arm

 

Artificial arms and legs, or prosthetics, are intended to restore a degree of normal function to amputees. Mechanical devices that allow amputees to walk again or continue to use two hands have probably been in use since ancient times, the most notable one being the simple peg leg. Since then, the development of artificial limbs has progressed rapidly. New plastics and other materials, such as carbon fiber have allowed artificial limbs to become stronger and lighter, limiting the amount of extra energy necessary to operate the limb. Additional materials have allowed artificial limbs to look much more realistic. Prostheses can roughly be categorized as upper- and lower-extremity and can take many shapes and sizes. 

New advances in artificial limbs include additional levels of integration with the human body. Electrodes can be placed into nervous tissue, and the body can be trained to control the prosthesis. This technology has been used in both animals and humans. The prosthetic can be controlled by the brain using a direct implant or implant into various muscles.

Bladder

The two main methods for replacing bladder function involve either redirecting urine flow or replacing the bladder in situ. Standard methods for replacing the bladder involve fashioning a bladder-like pouch from intestinal tissue. As of 2017 methods to grow bladders using stem cells had been attempted in clinical research but this procedure was not part of medicine.

Brain

A diagram of a hippocampal prosthesis

Neural prostheses are a series of devices that can substitute a motor, sensory or cognitive modality that might have been damaged as a result of an injury or a disease.

Neurostimulators, including deep brain stimulators, send electrical impulses to the brain in order to treat neurological and movement disorders, including Parkinson's disease, epilepsy, treatment resistant depression, and other conditions such as urinary incontinence. Rather than replacing existing neural networks to restore function, these devices often serve by disrupting the output of existing malfunctioning nerve centers to eliminate symptoms.

Scientists in 2013 created a mini brain that developed key neurological components until the early gestational stages of fetal maturation.

Corpora cavernosa

To treat erectile dysfunction, both corpora cavernosa can be irreversibly surgically replaced with manually inflatable penile implants. This is a drastic therapeutic surgery meant only for men who suffer from complete impotence who have resisted all other treatment approaches. An implanted pump in the (groin) or (scrotum) can be manipulated by hand to fill these artificial cylinders, normally sized to be direct replacements for the natural corpora cavernosa, from an implanted reservoir in order to achieve an erection.

Testes

Men whom have sustained testicular abnormalities through birth defects or injury have been able to replace the damaged testicle with a testicular prosthesis. Although the prosthetic does not restore biological reproductive function, the device has been shown to improve mental health for these patients.

Ear

An illustration of a cochlear implant

In cases when a person is profoundly deaf or severely hard of hearing in both ears, a cochlear implant may be surgically implanted. Cochlear implants bypass most of the peripheral auditory system to provide a sense of sound via a microphone and some electronics that reside outside the skin, generally behind the ear. The external components transmit a signal to an array of electrodes placed in the cochlea, which in turn stimulates the cochlear nerve.

In the case of an outer ear trauma, a craniofacial prosthesis may be necessary.

Eye

A bionic eye

The most successful function-replacing artificial eye so far is actually an external miniature digital camera with a remote unidirectional electronic interface implanted on the retina, optic nerve, or other related locations inside the brain. The present state of the art yields only partial functionality, such as recognizing levels of brightness, swatches of color, and/or basic geometric shapes, proving the concept's potential.

Various researchers have demonstrated that the retina performs strategic image preprocessing for the brain. The problem of creating a completely functional artificial electronic eye is even more complex. Advances towards tackling the complexity of the artificial connection to the retina, optic nerve, or related brain areas, combined with ongoing advances in computer science, are expected to dramatically improve the performance of this technology. 

Heart

An artificial heart

 

Cardiovascular-related artificial organs are implanted in cases where the heart, its valves, or another part of the circulatory system is in disorder. The artificial heart is typically used to bridge the time to heart transplantation, or to permanently replace the heart in case heart transplantation is impossible. Artificial pacemakers represent another cardiovascular device that can be implanted to either intermittently augment (defibrillator mode), continuously augment, or completely bypass the natural living cardiac pacemaker as needed. Ventricular assist devices are another alternative, acting as mechanical circulatory devices that partially or completely replace the function of a failing heart, without the removal of the heart itself.

Besides these, lab-grown hearts and 3D bioprinted hearts are also being researched. Currently, scientists are limited in their ability to grow and print hearts due to difficulties in getting blood vessels and lab-made tissues to function cohesively.

Kidney

It has been reported that scientists at the University of California, San Francisco, are developing an implantable artificial kidney. As of 2018, these scientists have made significant advancements with the technology but are still identifying methods to prevent the blood clotting associated with their machine.

Liver

HepaLife is developing a bioartificial liver device intended for the treatment of liver failure using stem cells. The artificial liver is designed to serve as a supportive device, either allowing the liver to regenerate upon failure, or to bridge the patient's liver functions until transplant is available. It is only made possible by the fact that it uses real liver cells (hepatocytes), and even then, it is not a permanent substitute.

Researchers from Japan found that a mixture of human liver precursor cells (differentiated from human induced pluripotent stem cells [iPSCs]) and two other cell types can spontaneously form three-dimensional structures dubbed “liver buds.”

Lungs

An artificial lung by MC3

With some almost fully functional, artificial lungs promise to be a great success in the near future. An Ann Arbor company MC3 is currently working on this type of medical device. 

Extracorporeal membrane oxygenation (ECMO) can be used to take significant load off of the native lung tissue and heart. In ECMO, a one or more catheters are placed into the patient and a pump is used to flow blood over hollow membrane fibers, which exchange oxygen and carbon dioxide with the blood. Similar to ECMO, Extracorporeal CO2 Removal (ECCO2R) has a similar set-up, but mainly benefits the patient through carbon dioxide removal, rather than oxygenation, with the goal of allowing the lungs to relax and heal.

Ovaries

The ground work for the development of the artificial ovary was laid in the early 1990s.

Reproductive age patients who develop cancer often receive chemotherapy or radiation therapy, which damages oocytes and leads to early menopause. An artificial human ovary has been developed at Brown University with self-assembled microtissues created using novel 3-D petri dish technology. In a study funded and conducted by the NIH in 2017, scientists were successful in printing 3-D ovaries and implanting them in sterile mice. In the future, scientists hope to replicate this in larger animals as well as humans. The artificial ovary will be used for the purpose of in vitro maturation of immature oocytes and the development of a system to study the effect of environmental toxins on folliculogenesis. 

Pancreas

An artificial pancreas is used to substitute endocrine functionality of a healthy pancreas for diabetic and other patients who require it. It can be used to improve insulin replacement therapy until glycemic control is practically normal as evident by the avoidance of the complications of hyperglycemia, and it can also ease the burden of therapy for the insulin-dependent. Approaches include using an insulin pump under closed loop control, developing a bio-artificial pancreas consisting of a biocompatible sheet of encapsulated beta cells, or using gene therapy.

Thymus

An implantable machine that performs the function of a thymus does not exist. However, researchers have been able to grow a thymus from reprogrammed fibroblasts. They expressed hope that the approach could one day replace or supplement neonatal thymus transplantation.

As of 2017, researchers at UCLA developed an artificial thymus that, although not yet implantable, is capable of performing all functions of a true thymus.

Trachea

The field of artificial tracheas went through a period of high interest and excitement with the work of Paolo Macchiarini at the Karolinska Institute and elsewhere from 2008 to around 2014, with front-page coverage in newspapers and on television. Concerns were raised about his work in 2014 and by 2016 he had been fired and high level management at Karolinska had been dismissed, including people involved in the Nobel Prize.

As of 2017 engineering a trachea—a hollow tube lined with cells—had proved more challenging then originally thought; challenges include the difficult clinical situation of people who present as clinical candidates, who generally have been through multiple procedures already; creating an implant that can become fully developed and integrate with host while withstanding respiratory forces, as well as the rotational and longitudinal movement the trachea undergoes.

Enhancement

It is also possible to construct and install an artificial organ to give its possessor abilities that are not naturally occurring. Research is proceeding in areas of vision, memory, and information processing. Some current research focuses on restoring short-term memory in accident victims and long-term memory in dementia patients.

One area of success was achieved when Kevin Warwick carried out a series of experiments extending his nervous system over the internet to control a robotic hand and the first direct electronic communication between the nervous systems of two humans.

This might also include the existing practice of implanting subcutaneous chips for identification and location purposes (ex. RFID tags).

Microchips

Organ chips are devices containing hollow microvessels filled with cells simulating tissue and/or organs as a microfluidic system that can provide key chemical and electrical signal information.

This information can create various applications such as creating "human in vitro models" for both healthy and diseased organs, drug advancements in toxicity screening as well as replacing animal testing.

Using 3D cell culture techniques enables scientists to recreate the complex extracellular matrix, ECM, found in in vivo to mimic human response to drugs and human diseases. Organs on chips are used to reduce the failure rate in new drug development; microengineering these allows for a microenvironment to be modeled as an organ.

Lanthanide probes

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Lanthanide_probes

Lanthanide probes are a non-invasive analytical tool commonly used for biological and chemical applications. Lanthanides are metal ions which have their 4f energy level filled and generally refer to elements cerium to lutetium in the periodic table. The fluorescence of lanthanide salts is weak because the energy absorption of the metallic ion is low; hence chelated complexes of lanthanides are most commonly used. The term chelate derives from the Greek word for “claw,” and is applied to name ligands, which attach to a metal ion with two or more donor atoms through dative bonds. The fluorescence is most intense when the metal ion has the oxidation state of 3+. Not all lanthanide metals can be used and the most common are: Sm(III), Eu(III), Tb(III), and Dy(III).

History

EuFOD, an example of a europium complex

 

It has been known since the early 1930s that the salts of certain lanthanides are fluorescent. The reaction of lanthanide salts with nucleic acids was discussed in a number of publications during the 1930s and the 1940s where lanthanum-containing reagents were employed for the fixation of nucleic acid structures. In 1942 complexes of europium, terbium, and samarium were discovered to exhibit unusual luminescence properties when excited by UV light. However, the first staining of biological cells with lanthanides occurred twenty years later when bacterial smears of E. coli were treated with aqueous solutions of a europium complex, which under mercury lamp illumination appeared as bright red spots. Attention to lanthanide probes increased greatly in the mid-1970s when Finnish researchers proposed Eu(III), Sm(III), Tb(III), and Dy(III) polyaminocarboxylates as luminescent sensors in time-resolved luminescent (TRL) immunoassays. Optimization of analytical methods from the 1970s onward for lanthanide chelates and time-resolved luminescence microscopy (TRLM) resulted in the use of lanthanide probes in many scientific, medical and commercial fields.

Techniques

There are two main assaying techniques: heterogeneous and homogeneous. If two lanthanide chelates are used in the analysis one after the other—it is called heterogeneous assaying. The first analyte is linked to a specific binding agent on a solid support such as a polymer and then another reaction couples the first poorly luminescent lanthanide complex with a new better one. This tedious method is used because the second more luminescent compound would not bind without the first analyte already present. Subsequent time resolved detection of the metal-centered luminescent probe yields the desired signal. Antigens, steroids and hormones are routinely assayed with heterogeneous techniques. Homogeneous assays rely on direct coupling of the lanthanide label with an organic acceptor.

The relaxation of excited molecules states often occurs by the emission of light which is called fluorescence. There are two ways of measuring this emitted radiation: as a function of frequency (inverse to wavelength) or time. Conventionally the fluorescence spectrum shows the intensity of fluorescence at different wavelengths, but since lanthanides have relatively long fluorescence decay times (ranging from one microsecond to one millisecond), it is possible to record the fluorescence emission at different decay times from the given excitation energy at time zero. This is called time resolved fluorescence spectroscopy.

Mechanism

Lanthanides can be used because their small size (ionic radius) gives them the ability to replace metal ions inside protein complex such as calcium or nickel. The optical properties of lanthanide ions such as Ln(III) originate in the special features of their electronic [Xe]4fⁿ configurations. These configurations generate many electronic levels, the number of which is given by [14!/n!(14- n)!], translating into 3003 energy levels for Eu(III) and Tb(III).

The energies of these levels are well defined due to the shielding of the 4f orbitals by the filled 5s and 5p sub-shells, and are not very sensitive to the chemical environments in which the lanthanide ions are inserted. Inner-shell 4f-4f transitions span both the visible and near-infrared ranges. They are sharp and easily recognizable. Since these transitions are parity forbidden, the lifetimes of the excited states are long, which allows the use of time resolved spectroscopy, a definitive asset for bioassays and microscopy. The only drawback of f-f transitions are their faint oscillator strengths which may in fact be turned into an advantage.

The energy absorbed by the organic receptor (ligand) is transferred onto Ln(III) excited states, and sharp emission bands originating from the metal ion are detected after rapid internal conversion to the emitting level. The phenomenon is termed sensitization of the metal centered complex (also referred to as antenna effect) and is quite complex. The energy migration path though goes through the long-lived triplet state of the ligand. Ln(III) ions are good quenchers of triplet states so that photobleaching is substantially reduced. The three types of transitions seen for lanthanide probes are: LMCT, 4f-5d, and intraconfigurational 4f-4f. The former two usually occur at energies too high to be relevant for bio-applications.

Applications

Cancer research

Screening tools for the development of new cancer therapies are in high demand worldwide and often require the determination of enzyme kinetics. The high sensitivity of lanthanide luminescence, particularly of time-resolved luminescence has revealed to be an ideal candidate for this purpose. There are several ways of conducting this analysis by the use of fluorogenic enzyme substrates, substrates bearing donor/acceptor groups allowing fluorescence resonance energy transfer (FRET) and immunoassays. For example, guanine nucleotide binding proteins consist of several subunits, one of which comprises those of the Ras subfamily. Ras GTPases act as binary switches by converting guadenosine triphosphate (GTP) into guadenosine diphosphate (GDP). Luminescence of the Tb(III) complex with norfloxacin is sensitive to determine the concentration of phosphate released by the GTP to GDP transformation.

pH probes

Protonation of basic sites in systems comprising a chromophore and a luminescent metal center leads the way for pH sensors. Some initially proposed systems were based on pyridine derivatives but these were not stable in water. More robust sensors have been proposed in which the core is a substituted macrocycle usually bearing phosphinate, carboxylate or four amide coordinating groups. It has been observed that lanthanide luminescent probe emission increases about six-fold when decreasing the pH of the solution from six to two.

Hydrogen peroxide sensor

Hydrogen peroxide can be detected with high sensitivity by the luminescence of lanthanide probes—however only at relatively high pH values. A lanthanide-based analytical procedure was proposed in 2002 based on the finding that the europium complex with various tetracyclines binds hydrogen peroxide forming a luminescent complex.

Estimating molecule size and atom distances

FRET in lanthanide probes is a widely used technique to measure the distance between two points separated by approximately 15–100 Angstrom. Measurements can be done under physiological conditions in vitro with genetically encoded dyes, and often in vivo as well. The technique relies on a distant- dependent transfer of energy from a donor fluorophore to an acceptor dye. Lanthanide probes has been used to study DNA-protein interactions (using a terbium chelate complex) to measure distances in DNA complexes bent by the CAP protein.

Protein conformation

Lanthanide probes have been used to detect conformational changes in proteins. Recently the Shaker potassium ion channel, a voltage-gated channel involved in nerve impulses was measured using this technique. Some scientist also have used lanthanide based luminescence resonance energy transfer (LRET) which is very similar to FRET to study conformational changes in RNA polymerase upon binding to DNA and transcription initiation in prokaryotes. LRET was also used to study the interaction of the proteins dystrophin and actin in muscle cells. Dystrophin is present in the inner muscle cell membrane and is believed to stabilize muscle fibers by binding to actin filaments. Specifically labelled dystrophin with Tb labelled monoclonal antibodies labeled were used.

Virology

Traditional virus diagnostic procedures are being replaced by sensitive immunoassays with lanthanides. The time resolved fluorescence based technique is generally applicable and its performance has also been tested in the assay of viral antigens in clinical specimens.

Medical imaging

Several systems have been proposed which combine MRI capability with lanthanides probes in dual assays. The luminescent probe may for instance serve to localize the MRI contrast agent. This has helped to visualize the delivery of nucleic acids into cultured cells. It should be noted in this case that lanthanides are not used for their fluorescence but their magnetic qualities.

Biology - Receptor-ligand interactions

Lanthanide probes displays unique fluorescence properties, including long lifetime of fluorescence, large Stokes shift and narrow emission peak. These properties is highly advantageous to develop analytical probes for receptor-ligand interactions. Many lanthanide-based fluorescence studies have been developed for GPCRs, including CXCR1, insulin-like family peptide receptor 2, protease-activated receptor 2, β2-adrenergic receptor, and C3a receptor.

Instrumentation

The emitted photons from excited lanthanides are detected by highly sensitive devices and techniques such as single-photon detection. If the lifetime of the excited emitting level is long enough, then time-resolved detection (TRD) can be used to enhance the signal-to-noise ratio. The instrumentation used to perform LRET is relatively simple, although slightly more complex than conventional fluorimeters. The general requirements are a pulsed UV excitation source and time-resolved detection.

Light sources which emit short duration pulses can be divided into the following categories:

• Flash tubes
• Mechanically or electronically chopped discharge lamps
• Spark gaps
• Pulsed lasers

The most important factors in the selection of the pulsed light source for are the duration and intensity of the light. Pulsed lasers for the 300 to 500 nm range have now replaced spark caps in fluorescence spectroscopy. There are four general types of pulsing lasers used: lasers with pulsed excitation, lasers with G-switching, mode locked lasers and cavity dumped lasers. Pulsed nitrogen lasers (337 nm) have often been used as an excitation source in time resolved fluorometry.

In time resolved fluorometry the fast photomultiplier tube is the only practical single photon detector. Good single photon resolution is also an advantage in counting photons from long decay fluorescent probes, such as lanthanide chelates.

These commercial instruments are available in the market today: Perkin-Elmer Micro Filter Fluorometer LS-2, Perkin-Elmer Luminescence Spectrometer Model LS 5, and LKB-Wallac Time-Resolved Fluorometer Model 1230.

Ligands

Lanthanide probes ligands must meet several chemical requirements for the probes to work properly. These qualities are: water solubility, large thermodynamic stability at physiological pHs, kinetic inertness and absorption above 330 nm to minimize destruction of live biological materials.

The chelates which have been studied and utilized to date can be classified into the following groups:

1. Tris chelates (three ligands)
2. Tetrakis chelates (four ligands)
3. Mixed ligand complexes
4. Complexes with neutral donors
5. Others such as: phthalate, picrate, and salicylate complexes.

The efficiency of the energy transfer from the ligand to the ion is determined ligand-metal bond. The energy transfer is more efficient when bonded covalently than through ionic bonding. Substituents in the ligand which are of electron-donating such as hydroxy, methoxy and methyl groups increase the fluorescence. The opposite effect is seen when an electron-withdrawing group (such as nitro) is attached. Furthermore, the fluorescence intensity is increased by fluorine substitution to the ligand. The energy transfer to the metal ion increases as the electronegativity of the fluorinated group makes the europium-oxygen bond of a more covalent nature. Increased conjugation by aromatic substituents by replacing phenyl by naphtyl groups is shown to enhance fluorescence.