Biomimicry 101: Cardiovascular Medicine: Part 1: Thinking Outside the – Stem Cell – Box

anat-stent-ekg-monarch-caterpillarFigure 1: Anatomy of the heart, with blood flow schematic (top left panel); profile of a coronary artery stent application (top right panel); the electrocardiogram – abbreviated ECG or EKG – representing the heart’s conduction system (center panel); and the monarch caterpillar (bottom panel).

When you ponder biomimicry, think design, intelligent design, and creation, but please don’t think evolution. And when considering biomimetic applications, let your imagination know no bounds.

The previous article in our biomimicry series introduced several key issues describing the feasibility and use of engineered tissue in different health and medical fields. Presently, this article (in two installments) will focus on various examples concerning bioengineering and biomimicry in the field of cardiovascular medicine. For example, we address the ethics and challenges concerning the regeneration of cardiac tissue via stem cell therapy. At the same time, however, we draw the spotlight away from a stem cell model to survey other novel clinical cardiology and endovascular biomimetic research. What is more, a first principle that continues to serve as motivation for exploring biomimetic applications that deal with cardiac tissue is our viewpoint that the heart is uniquely and deliberately designed, as emphasized with respect to tissue scaffolds in our prior article, as follows:

Because of the unique makeup of cardiac tissue, the work surrounding cardiac tissue scaffolds has focused on mimicking the physiological properties of the heart itself. This fact is true whether we are talking about designing artificial heart valves that mimic the mechanical properties of native heart valve tissue (Capulli et al., 2017), or boldly seeking to engineer myocardial tissues that elicit the unique mechanical, biological, and electrical properties existing at cell-tissue interfaces throughout the heart (Kaiser & Coulombe, 2015). (“Three examples of biomimicry applied to tissue engineering,” para. 3)

Once again, the aim of this series, and in particular this subject matter, is to bring glory to God and His creation, which includes human beings as a special creation. We begin our discussion with an overview on heart anatomy and physiology.

Anatomy and physiology of the heart

Tissues that make up the heart integrate a distinct blend of mechanical, biological, and electrical properties. To best examine these properties, we first review this unique organ.

— Location, Location, Location —

The heart is centered within the chest cavity, just left of midline between our two lungs. In fact, our bodies accommodate its exact location because our left lung is comprised of only two lobes, whereas our right lung has three. This means our hearts are nuzzled into the space made available by the “missing” part of our left lung. What is more, an intimate vascular network exists between our heart and lungs, and when taken together these organs and their connections comprise our cardiopulmonary system (i.e., the heart-lung system).

— Circulation —

Our circulatory system, which includes the associated vasculature of the heart, is a closed-loop system that is responsible for moving blood through our bodies. With the heart serving as the system’s pump, there are three types of blood vessels: the arteries, the capillaries, and the veins.

  • Arteries are specialized blood vessels composed of three individualized layers: the innermost layer, the tunica intima; the middle layer, the tunica media; and the outermost layer, the tunica adventitia. Within the tunica media are smooth muscles that control the diameters of arteries via influence of the autonomic nervous system. Arteries function as conduits that, in all but one circumstance, carry oxygenated blood away from the heart. In addition, healthy arteries are well-known for their resilient, elastic nature. A very large artery known as the aorta is the first artery in the circulatory system.
  • Capillaries facilitate the exchange of oxygen, nutrients, and waste by-products resulting from cellular respiration and metabolism.
  • Veins are characterized by their one-way valves that help direct blood flow toward the heart (and thus prevent the back-flow of blood).

— The Big Squeeze —

The heart’s squeezing action is what circulates blood throughout our vasculature. What is more, a heart cycle is easily detected via the heart’s squeezing sounds, the so-called lub-dub sound of the heart. The lub sound represents simultaneous contraction of the two top chambers (i.e., the atria), and the dub sound represents simultaneous contraction of the two bottom chambers (i.e., the ventricles). Blood has four main components: oxygen-carrying cells called red blood cells; functional immunity cells called white blood cells; cell fragments that are important for clotting called platelets; and a liquid constituent called plasma. What follows is the path our blood takes within the cardiopulmonary system:

  • After a red blood cell releases its oxygen content to our muscles and organs, it is called deoxygenated. Deoxygenated red blood cells, together with the aforementioned constituents, make their way back to the heart through our systemic venous system (i.e., our veins). As this pathway draws closer to the heart, it converges to form two large venous trunks known as vena cava. The superior vena cava brings back blood from the upper part of the body, and the inferior vena cava brings back blood from the lower part of the body. This returning systemic flow of blood then enters the first of our heart’s four chambers – the right atrium.
  • Once inside the right atrium, blood passes through the tricuspid valve into the second chamber of the heart – the right ventricle. This occurs in synchrony with the first of the two squeezing sounds, the so-called lub sound associated with atrial contraction.
  • As a result of ventricular contraction (i.e., the dub sound), the blood then passes from the right ventricle through the pulmonary semi-lunar valve and flows toward our lungs via both pulmonary arterial trunks, the right and the left pulmonary arteries. The pulmonary arteries carry the blood to the lungs where red blood cells are oxygenated within the lung’s capillary beds. The oxygenated blood will now flow back towards the heart by way of the pulmonary veins, a process returning this pulmonary flow of blood to the heart’s third chamber – the left atrium.
  • Once in the left atrium, the blood passes through the mitral valve into the fourth and final chamber of the heart – the left ventricle. Again, this occurs in synchrony with atrial contraction.
  • Finally, with contraction of the left ventricle, the oxygenated blood enters systemic circulation as it passes through the aortic semi-lunar valve (i.e., flowing out of the left ventricle and into the aorta).

TECHNICAL INSERT: Arteries and veins are recognized by the directional flow of blood that they facilitate away from – or toward – the heart, respectively, and not by whether or not the blood within the artery or vein is oxygenated or deoxygenated.

What is more, each squeezing action initiating a new cardiac cycle will simultaneously generate a pressure spike within our vessels, causing the blood to effectually pulsate through the circulatory system. Notably, this spike or wave of pressure is called systole, whereas the underlying pressure is referred to as diastole. Both systole and diastole make up our body’s systemic blood pressure. Normal systemic systolic pressure is 120 mmHg, and normal systemic diastolic pressure is 80 mmHg.

The term that describes the volume of blood pumped through the body is cardiac output, and this volume is seen as a marker of efficiency of cardiac mechanics and hemodynamics. To adequately deliver oxygen to our body’s tissues (called perfusion), cardiac output is approximately five liters per minute. In fact, investigations looking into cardiac output during cardiopulmonary resuscitation (CPR) led to guidelines from the American Heart Association to favor compression-only CPR to better achieve adequate blood flow and perfusion (Wininger, 2007). Investigators discovered that two different theories describing CPR-related chest compression – the cardiac pump theory and the thoracic pump theory – actually work together and in tandem depending on the physiological situation. One study helping investigators reach this level of insight was a review of the use of CPR for emergent care during coronary angiography. Today, there are even mechanical chest compression devices that heart catheterization labs can use, if necessary, during interventional care (Wagner et al, 2010).

Perspectives such as this illuminate how far we have come. Currently, a prototype of a ventricular assist device that mimics the natural squeezing/compression action of the heart has proven feasible. The device is a soft robotic sleeve that wraps around the heart, and it is being devised for those patients with severe heart failure (Roche et al, 2017). A major benefit of this particular device is that it never contacts blood, unlike traditional assistive devices, and thus eliminates the need for patients to be on blood thinners for prolonged periods of time.

— The Conduction of Electricity: The Conduction Pathway —

Cardiac squeezing action is controlled by the heart’s electrical activity. In fact, the conduction pathway that exists for this electrical activity is what we observe when looking at electrocardiogram tracings (abbreviated ECG, or colloquially known as EKG rhythm strips). ECG tracings show three main waves: the P-wave, the QRS-complex, and the T-wave. Crucially, analysis of these waves provides cardiologists with critical diagnostic information. The conduction pathway begins in the right atrium with a group of “like-minded” heart cells known as the sinoatrial node (abbreviated SA node and also called the heart’s “pacemaker cells”). Once the SA node fires, electrical charge disperses across the atrium and arrives at the aterioventricular (AV) node. At the AV node, the electrical charge then travels down through the intraventricular septum (a tissue that separates the chambers associated with the left and right ventricles), traveling down and along the bundle of His.

Continuing on – the charge follows the pathway that is made available by the bundle of His, a fibrous tissue pathway that splits within the septum and forms a right bundle branch and a left bundle branch. Here the electrical charge flows through the right and left bundle branches within the septum. Finally, both the right and left bundle branches divide and carry the electrical charge into terminal filaments of delicate, feathery-like fibers called Purkinje fibers.

The conduction pathway within the heart, not to mention the heart itself, is an electrochemical process. In fact, a physiological redundancy has been designed into the cardiac electrical system. By this I mean that the heart’s muscle cells, the cardiac myocytes, have the capacity to fire at sustained rates, and thus each contract individually on their own accord. However, specified regions exist throughout the myocardium, as well as along the conduction pathway, that are designed to fire in a hierarchal fashion, with each region firing at determined rates and led by the SA node, or in other words, the so-called pacemaker cells.

— The Arteries That Crown the Heart —

Coronary arteries are special arteries that crown the heart. These arteries are important because they provide the heart with oxygen so that it pumps effortlessly. Notably, all coronary arteries stem from two main divisions, aptly named the right coronary artery and the left main coronary artery. Of these two divisions, the left main coronary artery further divides into the left anterior descending artery and the left circumflex artery (with the latter known simply as the circumflex artery). However, the coronary arteries are important not only because they supply the heart with oxygen, but because they are also susceptible to inflammation and injury that may lead to an occlusive artery disease known as coronary artery disease, a condition that restricts oxygen delivery.

Coronary artery disease is a silent, chronic process that has two phases. The first phase begins when white blood cells respond to inflammation between the innermost and middle layers (the tunica intima and tunica media layers, respectively) of one or more of the coronary arteries. As more and more white blood cells arrive, over time they form a viable bump called an atheroma within the inner wall (i.e., the luminal lining) of the affected artery. If the surface of the lumen over the bump bursts, then the second phase of coronary artery disease is initiated. In the second phase, the rupture or burst triggers platelets to aggregate around the injured tissue in an attempt to clot off the injury. In fact, this clot formation is called a thrombus. If the clot (or thrombus) significantly occludes the vessel, or if the clot formation occludes the vessels at just the right place within the coronary artery vasculature, a person may suffer from a heart attack. Heart attacks are a life threatening situation because the surrounding heart tissue, or the so-called mycocardium, that is normally supplied with oxygen by the flow of blood from the effected artery, will no longer receive its supply.

TECHNICAL INSERT: The lumen of the artery (i.e., the inner passageway of the artery) is characterized by a clean, smooth lining. This luminal lining is made up of endothelial cells, and it is these cells themselves that compose the innermost arterial layer (i.e., the tunica intima). This layer is much more delicate compared to the middle and outermost layers, the tunica media and the tunica adventia, respectively. Notably, the tunica media contains bands of smooth muscle, whereas the tunica adventia contains connective tissue. However, all three layers play an important role in the elastic nature of all arteries, but in the coronary arteries particularly.

One of the best ways to guard against coronary artery disease is to observe Virchow’s triad. Although a comprehensive exam of the three aspects of Virchow’s triad is beyond the scope of this article, it is interesting to note that the prevention of endothelial injury, or the reduction of endothelial dysfunction, is plausible through proper diet and exercise. When taken together, proper diet and adequate exercise can reduce or even counteract the inflammatory process that endothelial cells endure. And again, endothelial cells are those cell types that make up the tunica intima layer of arteries, and thus, it is these cells that are responsible for the smooth luminal lining of coronary arteries (i.e., the smooth inner-wall of the passageway of an artery).

virchow's-triadFigure 2: The three sides of Virchow’s triad.

And, indeed, diet and exercise are important since a luminal narrowing of 20%, as evidenced by coronary catheterization studies, is considered normal (Bovin, Klausen, & Petersen, 2013). What is more, studies show that between 30% – 50% of patients undergoing coronary CT angiography can have a stenosis (or a luminal narrowing) of up to 50% and not indicate signs of ischemic disease detectable by myocardial perfusion imaging, such as SPECT imaging (Cremer, Hachamovitch, & Tamarappoo, 2014).

— The Husk of Life: Glycocalyx —

The word glycocalyx is shaped from the prefix glyco or “sweet” and the suffix kalyx or “husk.” Because the glycocalyx forms a sugary, slimy coating of certain cell types in various animals, as well as several different cell types of the human body, we may think of it as the sweet husk (i.e., coating) of life. What is more, the prefix refers to the coating’s composition, which is carbohydrate-based. Microscopically, gylcocalyx looks like feathery fibers. First-year anatomy and physiology students would recognize the coating as the feathery elements of the microvilli of our intestinal tracts (recalling that the microvilli are actually the lining of the villi). However, important for our purposes, a glycocalyx coating is present on the innermost layer of our vasculature (i.e., on the luminal surface of the endothelial cells that comprise the tunica intima). In fact, a protective barrier made up of glycocalic fibers functions as a vital component to our cardiovascular health (Sieve, Munster-Kuhnel, & Hilfiker-Kleiner, 2018). Moreover, researchers investigating the embryonic stages of certain bird species have shown that a glycocalyx layer is present and viable as soon as blood flow starts (Henderson-Toth, Jahnsen, Jamarani, Al-Roubaie, & Jones, 2012).

For you formed my inward parts; you knitted me together in my mother’s womb. I praise you, for I am fearfully and wonderfully made. Wonderful are your works; my soul knows it very well.

– Psalm 139:13,14 (ESV)

— A Unique Thing About Cardiac Myocytes: The Heart’s Muscle Cells —

From organ to tissue to the cellular level, the cardiac myocytes are rather specialized muscle cells. According to Ferrari’s comprehensive review (2002) of these cells:

The myocytes are extraordinary cells. They are immortal and contract for a lifetime, supporting the peripheral circulation. In order to do so, they have a unique ultrastructure and unique biochemical machinery that allows them to produce enough adenosine triphosphate to support the contraction. This article deals with the ultrastructure of cardiac muscle and myocytes, and with our current understanding of cardiac metabolism. In addition, the process of contraction is taken into consideration, as well as the mechanisms that allow the adult myocyte to be a terminal cell. However, even the myocytes can die; this can happen by necrosis as a result of an external insult (e.g. a lack of oxygen due to an abrupt occlusion of a coronary artery) or by apoptosis – a genetically programmed type of death that is operative in foetal life. Interestingly, and quite amazingly, under pathological conditions such as acute myocardial infarction or congestive heart failure, this genetic programme is reinstated and apoptosis can then occur, thus resembling features that occur in the embryonic phenotype. The metabolic alterations that occur under pathological conditions such as myocardial ischaemia are also addressed in depth, with several references to the so-called ‘new ischaemic syndromes’, such as stunning, hibernation and reperfusion paradox. The review is presented in light of an understanding of the biochemical and biomolecular changes that occur in pathological conditions, with the hope that this will provide room for innovative therapeutic intervention.

Thinking outside the embryonic stem cell box

In her 2007 article “Stem Cells: Does Their Origin Matter?” published in Answers Magazine, Dr. Georgia Purdom, a molecular geneticist with Answers in Genesis, presented several key points:

  • Stem cells are classified as either totipotent or pluripotent/multipotent.
  • Totipotent stem cells are taken from embryonic tissue, an action that kills the embryo in the process. These cells are capable of forming any cell type in the body, but carry certain risks for the recipient.
  • Pluripotent and multipotent stem cells are harvested from adult tissue, and notably, the process does no harm to the adult. These stem cell types are capable of forming almost every cell type in the body.
  • Ethical issues concerning life and its preservation can be easily reconciled through a biblical worldview.
  • Interestingly, an alternate approach to using embryonic stem cells taps the potential to reprogram adult cells to become more like embryonic stem cells. Here Dr. Purdom cited the work by Silva, Chambers, Pollard, and Smith (2006) with the protein Nanog on nervous system cells, published in the journal Nature.

Optimistic remarks concerning the reprogramming of adult cells surfaced ten years later in an interview with acclaimed materials scientist Buddy Ratner, PhD of the University of Washington. The interview appeared in a 2017 issue of the biotechnology journal Future Science, and celebrated Dr. Ratner’s forty-nine years of work in biomaterials science. When asked about exciting advances we should look for in the next five years within the biomaterials arena, Dr. Ratner’s response touched on the plasticity of adult cells. What follows is the relevant excerpt of that interview:

Another interesting area is a new concept I call ‘cell plasticity’. Through most of Modern Biology we have used the term ‘terminally differentiate’ – a mature cell cannot go any place. Now people are getting the idea that cells are actually very plastic, they change from one cell type to another, and the ability to control these transformations means almost any cell has a stem cell-like ability. We do have defined stem cells but I think the ability to take an adult cell and to crank it back to a more plastic, stem-like state, then direct it, gives us tremendous options in the area we call regenerative medicine. Within the initial biomaterials ideas we said ‘well if a part fails we’ll replace it with plastic and metal’ – the regenerative medicine field says ‘if a part fails we’ll just regrow it’. Regenerative medicine interest is increasing and efforts in that area are rightly accelerating. The interesting thing is, this still requires an extensive use of biomaterials in many different forms such as scaffolds and drug delivery platforms, so biomaterials are an important foundation technology to make regenerative medicine a reality. (“Question #5,” para. 2)

Part 2 will focus on biomimetic applications in cardiovascular medicine!

Keeping the preceding paragraphs in mind, we now outline the second installment of our focus on cardiovascular medicine (part two of our article) in this biomimicry series. First, discussion related to tissue engineering and regenerative science in cardiovascular research will center specifically on multipotent and pluripotent stem cell therapy. Second, we will briefly expand on cell plasticity related to cardiovascular medicine. Third, we will draw attention to the interesting, evolving role of protein therapy in cardiology, such as efforts to treat heart attack (i.e., myocardial infarction) by reprogramming/regenerating heart muscle cells (i.e., the cardiac myocytes). Fourth, we will highlight a novel approach to reperfusion therapy by Singh and Wang (2014), who introduced the concept of using coronary artery stents mimicked after the skeletal structure of the monarch caterpillar. Finally, we will explore a variety of other biomimetic applications that have promising potential to impact cardiac and endovascular patient care.

monarch-caterpillar-cvcuFigure 3: The segmented structure of the monarch caterpillar has inspired a novel coronary stent concept that offers segmented movement relative to pulsatile blood flow through the coronary arteries, as well as movement related to the heart’s squeezing action.

References

Bovin, A., Klausen, I.C., & Petersen, L.J. (2013). Myocardial perfusion imaging in patients with a recent, normal exercise test. World Journal of Cardiology, 5(3), 54-59. [View in article] [View in PubMed]

Cremer, P., Hachamovitch, R., & Tamarappoo, B. (2014). Clinical decision making with myocardial perfusion imaging in patients with known or suspected coronary artery disease. Seminars in Nuclear Medicine, 44(4), 320-329. [View in PubMed]

Ferrari, R. (2002). Healthy versus sick myocytes: Metabolism, structure and function. European Heart Journal Supplements, 4 (supplement G), G1-G12. [View in article]

Henderson-Toth, C.E., Jahnsen, E.D., Jamarani, R., Al-Roubaie, S., & Jones, E.A. (2012). The glycocalyx is present as soon as blood flow is initiated and is required for normal vascular development. Developmental Biology, 369(2), 330-339. [View in article] [View in PubMed]

Purdom, G. (2007, January 1). Stem cells: Does their origin matter? Answers Magazine. [View in online article]

Ratner, B. (2017). Forty-nine years in Biomaterials Science: An interview with Buddy Ratner. Future Science OA, 3(1), FSO158. [View in article] [View in PubMed]

Roche, E.T., Horvath, M.A., Wamala, I., Alazmani, A., Song, S.E., Whyte, W., … Walsh, C.J. (2017). Soft robotic sleeve supports heart function. Science Translational Medicine, 9(373), eaaf3925. [View abstract] [View in PubMed]

Sieve, I., Munster-Kuhnel, A.K., & Hilfiker-Kleiner, D. (2018). Regulation and function of endothelial glycocalyx layer in vascular diseases. Vascular Pharmacology, 100, 26-33. [View in article] [View in PubMed]

Silva, J., Chambers, I., Pollard, S., & Smith, A. (2006). Nanog promotes transfer of pluripotency after cell fusion. Nature, 441, 997-1001. [View abstract] [View in PubMed]

Singh, C., & Wang, X. (2014). A biomimetic approach for designing stent-graft structures: Caterpillar cuticle as design model. Journal of the Mechanical Behavior of Biomedical Materials, 30, 16-29. [View abstract] [View in PubMed]

Wagner, H., Terkelsen, C.J., Friberg, H., Harnek, J., Kern, K., Lassen, J.F., & Olivecrona, G.K. (2010). Clinical arrest in the catheterization laboratory: A 5-year experience of using mechanical chest compressions to facilitate PCI during prolonged resuscitation efforts. Resuscitation, 81(4), 383-387. [View abstract] [View in PubMed] [View in article]

Wininger, K.L. (2007). Chest compressions: biomechanics and injury. Radiologic Technology, 78(4), 269-274. [View abstract] [View in PubMed]

Wininger, K.L. (2018, September 14). Biomimicry 101: Biomaterials and tissue engineering. [blog post]. Retrieved from https://studiesoncreation.org/2018/09/14/biomimicry-101-biomaterials-and-tissue-engineering/.

Previous articles in this series:

Stay tuned as we continue our focus on cardiovascular medicine!

In our next installment, we not only continue our discussion on cardiac tissue engineering, but we will also highlight novel biomimetic applications across various areas of clinical cardiology and endovascular research.