Biomimicry 101: Cardiovascular Medicine: Part 2: Cardiac Tissue Engineering and Other Novel Biomimetic Research

coronary-angioFigure 1: Coronary angiogram depicting adequate perfusion of the myocardium via the left coronary vasculature: the left main trunk branching out to form the left anterior descending and circumflex arteries. Among the areas of the heart that these arteries perfuse, the left-sided vasculature ultimately feeds – supplies oxygen to – the left ventricle.

Cardiovascular disease accounts for more deaths per year than all forms of cancer combined.

– American Heart Association, 2016

Given the complex yet interrelated structure and physiological design of the heart, we now center our discussion on biomimicry and bioengineering in cardiovascular medicine. First, we discuss multipotent and pluripotent stem cell therapy with respect to tissue engineering and regenerative science in cardiovascular research. Second, we expand briefly on the concept of cell plasticity related to cardiovascular medicine. Third, we point out the 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 highlight a novel approaches to reperfusion therapy. Finally, we explore a variety of other biomimetic applications that have promising potential to impact cardiac and endovascular patient care.

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.

Multipotent and pluripotent (induced pluripotency) stem cell therapy for tissue engineering and regenerative science in cardiovascular research

Cardiovascular disease (both coronary and cerebrovascular disease) accounts for more deaths per year than all forms of cancer combined (American Heart Association, 2016). Given that cardiomyocytes have a rate of turnover of 1% in youth to 0.5% in old age (Tchao et al., 2013), the heart is one of the least regenerative organs in the body. Currently, efforts remain ongoing for repopulating damaged/injured cardiac muscle tissue (the myocardium) via stem cell therapy (Naumova & Yarnykh, 2014). Moreover, it is often the case that tissue injury or damage results from ischemic events, such as heart attacks (also known as a myocardial infarctions). In fact, therapeutic goals and clinical outcomes driving much of the work behind regenerative cardiovascular research have to do with preventing the post-infarct heart from sliding into a low-functioning state of utility by regenerating the cardiomyocytes. One such approach gaining favor in recent years is the use of multipotent and pluripotent stem cells, as opposed to totipotent stem cells. Whereas totipotent stem cells are taken from embryonic tissue, multipotent and pluripotent stem cells (as well as induced pluripotency stem cells) are harvested from adult tissue and are less problematic to the recipient heart (Baldassarre, Cimetta, Bollini, Gaggi, & Ghinassi, 2018; Hirt, Hansen, & Eschenhagen, 2014; Purdom, 2007). However, because of the ability to perpetually divide, pluripotency is more advantageous with respect to the heart. Below we survey progress made in the use of pluripotent-derived cardiomyocytes. In addition, we review advances made in cardiac DTI that allow this non-invasive imaging technique to gain favor as the leading platform for the evaluation of infarct healing (via stem cell therapy) after ischemic injury in patients post-heart attack.

— Multipotent and (induced) Pluripotent Stem Cell Therapy —

With each ischemic insult that fully manifests as a heart attack, the myocardium will lose approximately one billion cardiomyocytes (i.e., the cardiac muscle cells) (Naumova & Yarnykh, 2014). What is more, such robust, immediate loss of myocardial tissue dramatically affects cardiac hemodynamics (including reduced cardiac output). Furthermore, after the initial ischemic injury, as well as the initial change in hemodynamics, a functional decline occurs over time (such as further reduced cardiac output) that can limit the physical capacity of a patient due to left ventricular remodeling. Such anatomical and physiological decline is termed heart failure. However, therapeutic strategies based on “patching” the cardiac muscle damage at or near the time of event onset (given that the patient is hemodynamically stable) by means of stem cell therapy can curb the detrimental progression of heart attack-induced heart failure, and this is especially the case with induced pluripotent-derived cardiomyocytes (Baldassarre, Cimetta, Bollini, Gaggi, & Ghinassi, 2018).

What do we mean when we say totipotent, multipotent, pluripotent, or induced pluripotent?

Totipotent – The state of a cell that is capable of giving rise to all types of differentiated cells found in an organism, as well as the supporting extra-embryonic structures of the placenta. A single totipotent cell could, by division in utero, reproduce the whole organism.

Multipotent – Having the ability to develop into more than one cell type of the body.

Pluripotent – The state of a single cell that is capable of differentiating into all tissues of an organism, but not alone capable of sustaining full organismal development. In other words, pluripotent stem cells can give rise to any type of cell in the body except those needed to support and develop a fetus in the womb.

Induced pluripotent stem cell – A type of pluripotent stem cell, similar to an embryonic stem cell, formed by the introduction of certain embryonic genes into a somatic cell, in which somatic cells are differentiated, mature cells. What is more, somatic cells are commonly referred to as “adult” cells.

Why pluripotent is important!

According to the National Institutes of Health website (n.d.):

In late 2007, scientists identified conditions that would allow some specialized adult human cells to be reprogrammed genetically to assume a stem cell-like state. These stem cells are called induced pluripotent stem cells (iPSCs). IPSCs are adult cells that have been genetically reprogrammed to an embryonic stem cell–like state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells. Although these cells meet the defining criteria for pluripotent stem cells, it is not known if iPSCs and embryonic stem cells differ in clinically significant ways. Mouse iPSCs were first reported in 2006, and human iPSCs were first reported in late 2007. Mouse iPSCs demonstrate important characteristics of pluripotent stem cells, including expressing stem cell markers, forming tumors containing cells from all three germ layers, and being able to contribute to many different tissues when injected into mouse embryos at a very early stage in development. Human iPSCs also express stem cell markers and are capable of generating cells characteristic of all three germ layers.

Although additional research is needed, iPSCs are already useful tools for drug development and modeling of diseases, and scientists hope to use them in transplantation medicine. Viruses are currently used to introduce the reprogramming factors into adult cells, and this process must be carefully controlled and tested before the technique can lead to useful treatments for humans. In animal studies, the virus used to introduce the stem cell factors sometimes causes cancers. Researchers are currently investigating non-viral delivery strategies.

Non-embryonic (including adult and umbilical cord blood) stem cells have been identified in many organs and tissues. Typically there is a very small number of multipotent stem cells in each tissue, and these cells have a limited capacity for proliferation, thus making it difficult to generate large quantities of these cells in the laboratory. Stem cells are thought to reside in a specific area of each tissue (called a “stem cell niche”) where they may remain quiescent (non-dividing) for many years until they are activated by a normal need for more cells, or by disease or tissue injury. These cells are also called somatic stem cells.

— Bioengineering Applications of Engineered Heart Tissue —

  • Screening for drug discovery (i.e., pharmacodynamics) and cardiotoxicity testing
  • Cardiovascular disease modeling
  • Regenerative medicine: cell-based heart regeneration
    • Importance of avoiding arrhythmias
    • Immunological favorability
  • Evidence indicates that immunological tolerance to iPSC-derived tissues is favorable for utilization. Moreover, the evidence suggests that such tissues may actively participate in their own survival.

Examples of adult tissue-derived, pluripotent-derived stem cells

Cardiac progenitor cells naturally form functional, fully-fledged cardiomyocytes. However, harvesting suitable numbers of cardiac progenitor cells for the treatment of injured or failing myocardium is an insurmountable task via cardiac biopsy. For this reason, various adult stem cell sources have been identified from other human tissue, including bone marrow, adipose tissue, connective tissue, umbilical cord blood, and skeletal muscle. Notably, given these tissue types, stem cells induced from skeletal muscle present an intriguing opportunity for the treatment of debilitating myocardial ischemia that leads to myocardial infarction. In fact, stem cells associated with skeletal muscle cells are resistant to hypoxia, fibrosis, and easily achieve contractile characteristics (Tchao et al., 2013).

From myocyte to pluripotent-derived cardiomyocyte stem cell

Tchao et al. (2013) investigated the practicality of using human muscle cells (i.e., myocytes) for engineering cardiac muscle tissue by means of pluripotency induction given that cardiac and skeletal muscle share major transcription factors as well as sacromere proteins that are generally regarded as significant to either cardiac or skeletal muscle tissue but not both muscle types. In fact, skeletal muscle and cardiac muscle are known to have similar embryonic developmental pathways. What is more, according to Lewandowski et al. (2018), this similarity implies that skeletal muscle cells induced for pluripotency have what it takes to achieve greater myocardial development, compared to other tissue types, such as, for example, fibroblast cells from connective tissue.

The state of plasticity of a cell: review of Lewandowski et al.’s attempt to derive heart cells from muscle cells

In this section, we look closely at a study conducted by Lewandowski et al. (2018), who investigated the feasibility, significance, and practicality of cardiomyocytes derived from induced pluripotent stem cells of myogenic origin.

  • The work by Lewandowski et el. (2018):
  • Biochemical (regulatory) pathways and epigenetic memory
    • Importance of the Wnt signaling
    • Importance of the epigenetic memory
  • Morphological and functional properties, including electrophysiological analysis
    • Importance of mismatches between iPSC and native cardiac muscle cells
  • Paracrine effects
  • Study limitations

Cardiac muscle microarchitecture: innovative evaluation of stem cell therapy structural outcomes by cardiac DTI

Introduced in the mid-1990’s, diffusion tensor imaging (DTI) is a MRI technique capable of visualizing cardiac microstructure (Naumova & Yarnykh, 2014). One distinguishing feature of DTI is its ability to image fiber trajectories – a method known as tractography. Although tractography has been widely used in brain imaging (as well as musculoskeletal imaging), Sosnovik et al. (2014) recently published a landmark study showing the capacity of cardiac DTI tractography to characterize the integrity and spatial organization of cardiac myofibers in live mice after stem cell therapy for ischemic heart damage. According to Naumova and Yarnykh (2014):

The study [by Sosnovik et al. (2014)] establishes DTI as a new approach for assessment of the effect of stem cell therapy in a preclinical setting, in which it could prove whether cardiomyocytes derived from stem cells are actually aligned with host myofibers to regenerate heart structure and function. (p. 1720)

Furthermore, Naumova and Yarnykh (2014) stated the following:

Collectively, the present [study by Sosnovik et al. (2014)] and earlier studies have established the feasibility of DTI tractography in the human heart in vivo. However, a significant amount of work remains to translate this challenging technology to serial applications in clinical trial settings. (p.1721)

What is more, quality control protocols are a critical part of all imaging programs. With respect to protocols for cardiac DTI tractography, a dedicated phantom has only recently been developed that incorporates microtubules that allow the phantom to mimic the heart itself, specifically, the microarchitecture of the heart (Teh, Zhou, Hubbard Cristinacce, Parker, & Schneider, 2016). Testing of this phantom has been successful, and it is our conjecture that the device will help bring clinical trials utilizing serial cardiac DTI tractography a step closer to reality for assessment of the myocardium for patients with post-ischemic heart damage treated by regenerative stem cell therapy (preferably, pluripotent-derived cardiomyocytes).

Protein therapy in cardiology

Whereas protein engineering refers to various ways of modifying proteins, the benefit of protein therapy is its affinity for targeted interventions.

Protein-mediated paracrine effects identified through stem cell-derived cardiac muscle analysis, have spurred interest in protein therapy as a viable approach for cardiac muscle proliferation and myocardium repair (Jay & Lee, 2013).

Detecting artieral stenosis/occlustion: coronary angiography, coronary CT angiography, myocardial perfusion imaging, and reperfusion therapy and biomimicry

Conventional coronary angiography is the gold standard for detecting and treating coronary artery stenosis (Jiangping et al., 2013). Nevertheless, recent advances made in non-invasive, diagnostic methodologies, such as coronary CT angiography (with slice standards of 64 slices or greater) and myocardial perfusion imaging studies, are contributing to the earlier detection of the underlying pathology (i.e., earlier detection of coronary artery disease) (Gorenol, Schönermark, & Hagen, 2012; Tamarappoo et al., 2010). With respect to stress and rest myocardial perfusion imaging, according to Smith (2018):

If the coronary artery narrows less than 50% of the original vessel diameter, the effect on blood flow is clinically insignificant, but at 70% narrowing, blood flow is significantly affected during stress. During rest, the vessel must be narrowed 90% or more to reduce blood f low significantly. A cardiac event is not likely to be detected unless the coronary artery is narrowed to these degrees under stress or rest. Myocardial perfusion studies detect stress-induced myocardial schemia approximately 80% to 90% of the time, which is more sensitive than exercise electrocardiography at 60% to 70% sensitivity. This is because of the high rate of patients that undergo nondiagnostic exercise ECG tests because of baseline electrocardiographic abnormalities or inadequate stress.

What is more, a luminal stenosis at 70% to 80%, as assessed by coronary CT angiography, was correlated with electrocardiographic rhythm strips that revealed robust ST-segment depression (Lipinski, Morise, & Froelicher, 2002).

— Stents/Camouflaged Coating of Sugar —

Significant coronary artery narrowing is quantified as luminal narrowing at 70% or greater, although 50% narrowing is significant for the left main coronary artery (Bovin, Klausen, & Petersen, 2013). Given this percentage of narrowing (and the chronic nature of coronary artery disease), when cardiologists talk with patients and family members about reperfusion interventions, such as coronary artery ballooning and stenting, the discussion inevitably comes around to the likelihood of restenosis of treated vessels (including in-stent restenosis). One way to reduce the potential of in-stent restenosis, however, is a stent design that mimics the luminal lining of the tunica intima (the innermost layer of the coronary artery comprised entirely of endothelial cells) (Perez et al., 2009). In fact, such biomimetic-inspired stents have been modeled on the native coating found on endothelial cells of the tunica intima (i.e., the native glycocalyx). Production of these stents involves laser-etching technology that patterns the inside surface of the stent’s struts after these glycocalic fibers. This means that the surface area inside the stent effectually becomes camouflaged against vascular inflammatory and injury cycles that are associated with the patients’ coronary disease. The net-outcome for this design has reduced the body’s foreign body response to the stent.

monarch-caterpillar-cvcuFigure 2: 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.

— Stents/Dynamical, Flexible Cardionature and the Caterpillar’s Skeleton —

At rest, average heart rate is approximately 72 beats per minute, and with exercise, the typical range falls between 112 and 146 beats per minute. Therefore, we are clearly beneficiaries of the heart’s dynamical nature (including the constant movement of its surface) (Jiangping et al., 2013). What is more, the heart’s constant movement places high mechanical loads (i.e., mechanical stress and strain) on the functionality of stents, and this movement can ultimately damage the stent’s integrity. In their efforts to support the demands of this environment, Singh and Wang (2014) introduced a “flexible” stent that offers an unparalleled advantage over common, “stiff” stents. Their design mimics the flexible yet rigid skeletal structure of a monarch caterpillar. The end product is a biomimetic stent capable of flexing and bending with the movement of the heart, which, once again, is dynamical in nature as the heart adapts to the demands to supply oxygen to the body’s muscles and organs.

Endovascular angiography: reperfusion therapy and biomimicry

— Stents/High Shear Wall Flows and the Swirling Flow of Water Currents —

What about biomimicry in peripheral vascular studies? Has any attention been given to reperfusion therapy in this area of medicine? The answer to both of these questions is “yes.” For example, the superficial femoral artery (SFA) is a lower extremity artery susceptible to luminal narrowing secondary to atheromas and plaque build-up. Moreover, stents indicated for this vessel can be quite long, with lengths up to 15 cm commonly deployed. Recently, a novel stent design for the reperfusion of an occluded segment of the SFA was modeled on the flow of blood through the aorta, given that the aorta is quite resistant to atherosclerotic disease (Gaines, 2015). This intrinsic resistance identified with the aorta has been correlated with high-grade, pulsatile blood flow, which in part is also associated with the structural nature of the aortic arch. In other words, hemodynamics at the aorta not only imposes a high shear wall stress on the aorta’s inner wall (the tunica intima layer of this artery), but blood flow analysis reveals that the curvature of the aortic arch also helps give rise to a swirling, turbulent component of this high-grade, pulsatile flow.

TECHNICAL INSERT: For a conceptual image of the aforementioned dynamics in the healthy aorta, imagine that the turbulent and swirling nature of blood flow through the aortic arch repeatedly washes and rinses the luminal lining in this region of the artery. The best analogy comes from the flow of water that washes the banks along a somewhat sharp, curving bend (effectually, a U-turn) of a river as the current transits downstream.

With respect to the SFA, the stent that captures the nature of aortic blood flow has a subtle corkscrew design. Notably, such design helps impose a swirling effect on the flow of blood through the stented region of the SFA that also induces higher shear wall stress, which reduces the chances for in-stent restenosis.

— Stents/Vascular Smooth Muscle Cell Biomimetic Surface Patterns —

Because normal wound healing in the tissues surrounding a deployed stent is delayed, design schemes for stents have included antibody coatings to attract endothelial progenitor cells as a means to promote healing. However, testing of these stents has revealed that the associated lesions are often more complex than those associated with other stents, such as drug-eluting stents (whereas drug-eluting stents are known to be cytotoxic). Therefore, to address these challenges, and in a novel design twist to the aforementioned glycocalyx-mimicked stent, researchers recently introduced a stent that is designed to mimic vascular smooth muscle cells (VSMCs) at the nanometer level on the stent struts (Liang, et al., 2016). Methods similar to those used to obtain the glycocalic coating (i.e. laser-etching) were used to achieve the VSMC pattern. Testing performed on the iliac arteries of rabbits showed that a VSMC-biomimetic surface pattern was effective for rapid re-endothelialization (which translates as distinctly effective for promoting normal wound healing), as well as reducing the likelihood of in-stent restenosis.

Clearly the heart is uniquely designed! Can you imagine a career researching and developing engineered heart tissues?

The Heart is Uniquely Designed: Part of God’s Special Creation!

Quintessentially Mimicking the Structure and Function of the Human Heart:

Christian scholarship extending into professional roles is sincerely needed in education and culture, including mathematics and the sciences (including medicine). Chemical engineering and bioengineering can be a promising career for those who like to study physiology, microbiology, and biochemistry. And a well-developed understanding of anatomy and physiology plays a crucial role.

Insert: myocardial squeezing problem or atrial/ventricular filling problem

For many years echosonographers and cardiologists understood heart failure as a mechanical-type squeezing problem due to myocardial remodeling or enlargement; only recently did they learn it may also be a filling problem. The latter became known as diastolic heart failure.

As Christians, we ought to ask ourselves if we walk around with filling defects. In fact, the sermon “Why is my Heart not Filling?” given at Maranatha Baptist Church by Pastor Todd Grover (2018), gives us perspective on whether or not our own hearts might be suffering spiritually.

Consider 2 Corinthians 6:11-13 (ESV), in which the Apostle Paul expressed to the Christians living in Corinth: “We have spoken freely to you, Corinthians; our heart is wide open. You are not restricted by us, but you are restricted in your own affections. In return (I speak as to children) widen your hearts also.”

According to Pastor Grover (2018): “Here Paul revealed his heart’s condition to the Corinthians, that his heart is wide-open or enlarged, or that his heart is full and does not suffer from a filling problem.” Grover also pointed out that Paul stated he has spoken freely, and reminded listeners that Jesus said, “What comes out of the mouth proceeds from the heart.” However, Pastor Grover acknowledged that verse 11 of 2 Corinthians 6 is also clearly implying that Paul has a welcoming spirit toward the Corinthians, but not because Paul is outgoing, and has a warm and inviting personality. Rather, the reason is spiritual, since only a couple of years earlier Paul would have been killing these same Corinthians for their faith he is now trying to nurture.

So, a natural question to ask is what fills the heart. Some at Corinth were blaming Paul for their bad spiritual condition, but Paul is telling them that it is not he that should be blamed. Then, how did Paul’s heart become filled? To answer this, Pastor Grover quoted three verses from the very same epistle, and offered the applications of these verses, as follows:

  • The Spirit unveils, as we read according to 2 Corinthians 3:16 (ESV), “But when one turns to the Lord, the veil is removed.” Thus, if we don’t understand, then we can turn to the Lord, and the Lord will remove our veil of not understanding.
  • The Spirit writes, since we learn from 2 Corinthians 3:3 (ESV), “And you show that you are a letter from Christ delivered by us, written not with ink but with the Spirit of the living God, not on tablets of stone but on tablets of human hearts.” Therefore, we cannot live in the flesh and expect the Spirit to teach us.
  • Finally, the Spirit does not mix with sin, as we know according to 2 Corinthians 4:2 (ESV), “But we have renounced disgraceful, underhanded ways. We refuse to practice cunning or to tamper with God’s word, but by the open statement of the truth we would commend ourselves to everyone’s conscience in the sight of God.” And thus, we cannot allow sin to soil our hearts.

To summarize, Pastor Grover remarked: “So if our heart is not filling properly, we must develop a skill set as a Bible reader, because a heart fills as we read, learn, and know that the Spirit unveils, the Spirit writes, and the Spirit does not mix with sin.”

May the God of hope fill you with all joy and peace in believing, so that by the power of the Holy Spirit you may abound in hope.

– Romans 15:13 (ESV)

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Previous articles in this series:

Other medical applications are featured in the next installment in our biomimicry series!

In our next installment on biomimicry, we will touch finally on cardiac function and fractal behavior via the area of concentration we have coined mathematical cardiology. We then move forward from our focus on the heart, as we turn our attention to two unrelated fields in medicine where biomimetic solutions have garnered exciting outcomes: diabetic solutions and work towards spinal cord regeneration.