A biological pacemaker is one or more types of cellular components that, when "implanted or injected into certain regions of the heart," produce specific electrical stimuli that mimic that of the body's natural

pacemaker cells 350px, Image showing the cardiac pacemaker or SA node, the primary pacemaker within the electrical_conduction_system_of_the_heart">SA_node,_the_primary_pacemaker_within_the_electrical_conduction_system_of_the_heart. The_muscle_contraction.htm ...

. Biological pacemakers are indicated for issues such as

heart block Heart block (HB) is a disorder in the heart's rhythm due to a fault in the natural pacemaker. This is caused by an obstruction – a block – in the electrical conduction system of the heart. Sometimes a disorder can be inherited. Despite the se ...

slow heart rate Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...

, and asynchronous heart ventricle contractions. The biological pacemaker is intended as an alternative to the

artificial cardiac pacemaker An artificial cardiac pacemaker (or artificial pacemaker, so as not to be confused with the natural cardiac pacemaker) or pacemaker is a medical device that generates electrical impulses delivered by electrodes to the chambers of the heart ei ...

that has been in human use since the late 1950s. Despite their success, several limitations and problems with artificial pacemakers have emerged during the past decades such as

electrode An electrode is an electrical conductor used to make contact with a nonmetallic part of a circuit (e.g. a semiconductor, an electrolyte, a vacuum or air). Electrodes are essential parts of batteries that can consist of a variety of materials de ...

fracture or damage to

insulation Insulation may refer to: Thermal * Thermal insulation, use of materials to reduce rates of heat transfer ** List of insulation materials ** Building insulation, thermal insulation added to buildings for comfort and energy efficiency *** Insulated ...

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

, re-operations for

battery Battery most often refers to: * Electric battery, a device that provides electrical power * Battery (crime), a crime involving unlawful physical contact Battery may also refer to: Energy source *Automotive battery, a device to provide power t ...

exchange, and

venous thrombosis Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...

. The need for an alternative is most obvious in children, including premature

newborn babies An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...

, where size mismatch and the fact that pacemaker leads do not grow with children are a problem. A more biological approach has been taken in order to mitigate many of these issues. However, the implanted biological pacemaker cells still typically need to be supplemented with an artificial pacemaker while the cells form the necessary electrical connections with cardiac tissue.

History

The first successful experiment with biological pacemakers was carried out by Arjang Ruhparwar 's group at

Hannover Medical School The Hannover Medical SchoolAlthough the English spelling of the city name is "Hanover", this form of the name, using the German spelling of the city name, is used as the English-language name of the school, for example . (german: Medizinische Ho ...

in Germany using transplanted

fetal A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal develo ...

heart

muscle cells A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscle ...

. The process was first introduced at the scientific sessions of the

American Heart Association The American Heart Association (AHA) is a nonprofit organization in the United States that funds cardiovascular medical research, educates consumers on healthy living and fosters appropriate cardiac care in an effort to reduce disability and death ...

Anaheim Anaheim ( ) is a city in northern Orange County, California, part of the Los Angeles metropolitan area. As of the 2020 United States Census, the city had a population of 346,824, making it the most populous city in Orange County, the 10th-most p ...

in 2001, and the results were published in 2002. A few months later, Eduardo Marban's group from

Johns Hopkins University Johns Hopkins University (Johns Hopkins, Hopkins, or JHU) is a private university, private research university in Baltimore, Maryland. Founded in 1876, Johns Hopkins is the oldest research university in the United States and in the western hem ...

published the first successful gene-therapeutic approach towards the generation of pacemaking activity in otherwise non-pacemaking adult

cardiomyocytes Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...

using a

guinea pig The guinea pig or domestic guinea pig (''Cavia porcellus''), also known as the cavy or domestic cavy (), is a species of rodent belonging to the genus ''Cavia'' in the family Caviidae. Breeders tend to use the word ''cavy'' to describe the ani ...

model. The investigators postulated latent pacemaker capability in normal

heart muscle Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...

cells. This potential ability is suppressed by the inward-rectifier potassium current Ik1 encoded by the

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

Kir2 which is not expressed in

. By specific inhibition of Ik1 below a certain level, spontaneous activity of cardiomyocytes was observed with resemblance to the action potential pattern of genuine pacemaker cells. Meanwhile, other genes and cells have been discovered, including heart muscle cells derived from

embryonic stem cell Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consi ...

s, "HCN" genes which encode the

wild type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...

pacemaker current I(f). Michael Rosen's group demonstrated that transplantation of HCN2-transfected human mesenchymal

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

s (hMSCs) leads to expression of functional HCN2 channels

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

and

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

, mimicking overexpression of HCN2 genes in cardiac

myocyte A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscl ...

s. In 2010, Ruhparwar's group again demonstrated a type of biological pacemaker, this time showing that by injection of the "Adenylate Cyclase" gene into the heart muscle a biological cardiac pacemaker can be created. In 2014, a gene called TBX18 has been non-invasively applied to speed up heart rates caused by heart block. More recent studies in 2015, has been experimented

optogenetic Optogenetics is a biological technique to control the activity of neurons or other cell types with light. This is achieved by expression of light-sensitive ion channels, pumps or enzymes specifically in the target cells. On the level of individ ...

approach in the rats heart, where a light sensitive

transgene A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...

(

Channelrhodopsin Channelrhodopsins are a subfamily of retinylidene proteins ( rhodopsins) that function as light-gated ion channels. They serve as sensory photoreceptors in unicellular green algae, controlling phototaxis: movement in response to light. Express ...

-2) injected to several sites of rat's ventricular, which, furthermore, can simultaneously stimulate the injection sites by a blue light irradiation.

References

{{DEFAULTSORT:Biological pacemaker American inventions Cardiac electrophysiology Embedded systems Implants (medicine) Neuroprosthetics Prosthetics