Hello everyone!

Welcome to the third part of this series covering biomaterials, biocompatibility, and how it all relates to Foregen’s work. If you haven’t read the last entry, I recommend doing so before tackling this one. Initially, this was intended to be a three-part series; however, after some feedback I received on the first two parts, there appears to be more of an appetite for this material than I originally anticipated. I have decided to provide something of a “peek behind the curtain” of tissue engineering. Not to scare anyone, but in trying to satiate the appetite for information and providing this peek behind the curtain, this article is mathematically dense; I invoke many equations and models that are fundamental to the field. I don’t expect most of you to understand them, though I will explain what they mean—my intention is not to scare anyone away from learning more about this material. I hope that showing these will help ground the work Foregen does with many of you; to show that there’s nothing magical in tissue engineering; this field is anything but “science fiction.”

We will primarily look at how cells interact with polymers: adhesion, migration, degradation, and how that fits in with the extracellular matrix (ECM). I recommend taking this article slow and not reading it all in one sitting.

Let’s get to it.

Cell Interactions with Polymers for Tissue Engineering

Ultimately, we’re exploring how the body responds to foreign materials that it encounters. The response we’re interested in—from a macro perspective—is tissue regeneration, so it makes sense to take a look first at how cells even sense and interact with their environment. Let’s first look at one of the most fundamental concepts in tissue engineering, as it underlies nearly each of its subsequent sections.

Cell-Surface Ligand-Receptor Kinetics

Not to state the obvious, but cells do not have eyes, so how do they see? They don’t have hands, fingers, or legs, so how do they grab onto things and get around? For tissues and organs to function correctly, the cells that compose them need to communicate and work cooperatively, so how do they communicate? The simple answer is through receptors suspended in the cell’s plasma membrane. These receptors are specialized proteins that chemically bind with some specific target molecule or ligand, which, in turn, initiates a specific cellular response (Figure 1).

Figure 1: Basic Ligand-Receptor Model [Khan Academy]

There is an enormous variety of receptors and corresponding ligands, as cells use this paradigm for communication, sensation, locomotion, material exchange, gene expression, differentiation, and more [9, 15]⁠. I have listed examples of the four different types of surface receptors in Table 1.

Because the whole event of a ligand binding to a receptor is a chemical reaction, we must also consider the kinetics of the reaction, which is, more-or-less, the rate at which a reaction occurs, or more simply, its behavior (given some set of initial conditions). Generally speaking, ligand-receptor binding can be treated as a reversible reaction [43]⁠, which means that the product (bound-complex) can form the original reactants (unbound ligand and receptor) given the proper conditions, such as if the system is pushed beyond chemical equilibrium in the forward direction [10]⁠. For our consideration, the ligand-receptor binding process can be expressed by the following chemical equation:

Suppose we want to get a sense of the concentration of bound-complex at any given point in time for the most basic of these interactions. In that case, the following kinetic model expresses the accumulation of bound-complex as the difference between the ligand-receptor binding and the dissociation of the complex:

Where k₁ is the association rate coefficient (M⁻¹ min⁻¹ or M⁻¹ s⁻¹), k₋₁ is the dissociation rate coefficient (min⁻¹ or s⁻¹), and , , and Cᴄ are the concentrations of receptor, ligand, and bound-complex, respectively [43:524]⁠.

Cell Adhesion

The ligand-receptor model describes numerous ways that cells interact with their surroundings, but one of the most important examples for tissue engineers and biomaterials scientists is cell adhesion; if a cell cannot stick to the material you're using, you're not going to have much luck with your application. Admittedly, sometimes you don't want cells to adhere to something. Regardless, cell adhesion is essential because it is a critical process that often precedes and influences other events such as differentiation, migration, and ingrowth within natural or synthetic polymeric scaffolds [44]⁠.

A Sticky Situation

We'll come back to the concept of ligand-receptor complexes from the previous section shortly, but first, let's think about how things stick to each other generally. If we consider the four different types of fundamental forces that exist, one of which is electromagnetism. I assume everyone is familiar with magnets, where positive poles attract negative poles and repel other positives, and vice-versa for negative poles. And by no coincidence, electric charges behave in this same manner (though an exploration of the connection between magnetism and electric charge is far beyond the scope of this article). The electrostatic potential of two electrically charged particles at rest is directly proportional to the magnitude of their charge and inversely proportional to the dielectric constant D and the distance separating the two charged species (Figure 2).

Figure 2: Coulomb’s Law

Coulomb's law formally characterizes this:

where Z₁ and Z₂ represent two unit charges, e is the charge of a proton (1.602×10⁻¹⁹ C), D is the material's dielectric constant separating the two charges, and r is the distance between the two charged species [12]⁠.

The electromagnetic force is responsible for the entirety of chemical phenomena and, by extension, all biochemical phenomena. These electrical charges allow for interactions to occur, as things like chemical bonds depend on the negative charge that electrons carry. Moreover, this attractive property is why things stick together through static electricity. But more importantly, for our conversation here, cells use electrostatic, steric stabilization, and dipole (van der Waals forces) interactions to adhere to various surfaces (and even other cells), and the degree of adhesion is dependent on the surface chemistry of a material. Just as they teach in Physics 101 with static, rigid bodies, if the sum of the forces in each direction is equal to zero, that is to say, that they are balanced, the cell will adhere to the surface [27]⁠.

When engineering biomaterials, numerous surface modification approaches can be employed, which can alter the surface chemistry or the surface topography, and, as a result, change the thermodynamics of the surface, giving engineers a significant amount of control over cell adhesion and, subsequently, the following biological processes the cells might undertake [23, 39]⁠⁠. Table 2 lists a number of acrylic copolymer materials and how effectively cells can attach to and grow on them. The ability for cells to adhere to a surface is often paired with the surface free energy of a material and its hydrophobicity. Contact angle analysis is typically used to measure this property. Cells often behave much like a bead of water on a surface, which is why this characterization method is so popular. Though it might seem counter-intuitive at first, a highly hydrophilic surface (water-loving) is generally a poor decision for tissue engineering. The cells will stick to the surface and be unable to migrate as the adhesive forces are too great for them to overcome. Likewise, a surface that is not attractive enough will cause them to slide off; a happy medium needs to be found [39]⁠.

Now, let's consider the ligand-receptor complex from the last section. We can gain a relatively complete, though surface level, understanding of how cells adhere to biomaterials. Although cells can attach to each other through gap junctions and desmosomes, and the ECM and biomaterials by hemidesmosomes [40]⁠, I specifically want to focus on what are called focal contacts, which are localized sites of attachment and are influenced by the diffusion-limited reversible binding of receptors and ligands on the cell surface [44]⁠. There are five classes of adhesion molecules:

  1. Cadherins
  2. The immunoglobulin (Ig) superfamily
  3. Integrins
  4. Selectins
  5. Mucins [44]

For the sake of this article, I'm only going to speak about integrins, as they are the principle adhesion molecule that binds to ECM proteins. Integrins are transmembrane proteins involved in both cell-cell and cell-matrix contacts. They are connected to the microfilaments of a cell's cytoskeleton, which allows for intracellular signaling. Under the framing of the ligand-receptor complex from earlier, an integrin is the receptor component, and the ligands that it can bind with are ECM proteins, such as fibronectin, laminin, and collagen [40]⁠. This binding allows cells to adhere to the ECM, as the binding can be thought of as a "gripping" action. This binding of adhesion proteins and Integrins occurs at the aforementioned focal contacts. For a more complete picture, we can consider Figure 3 to get a good sense of what this roughly looks like, as cells adhere at multiple focal contacts, which will be important in the next section on migration.

Figure 3: Cell binding to extracellular matrix [Khan Academy]

After a cell begins to adhere to a suitable material, it will start to spread out and make more adhesion contacts. On a flat surface, this looks a bit like cracking an egg into a frying pan: when in the shell, the whites and yolk are relatively spherical; though after cracking the egg, the whites and yolk spread out and flatten; cells do something rather similar. However, the degree of spreading will depend upon the surface's hydrophobicity. Very hydrophobic materials will see that the cells remain spherical like a bead of water. By spreading, cells can maximize the surface area they are in contact with and reduce drag force that might displace the cell [44]⁠. This is important to note that these adhesions are not unbreakable, and cells can become displaced. For completeness, we can consider a fraction of a cell population per unit area at a given shear stress τ and exposure time t:

where the integrand is the probability distribution of shear stresses at which cells detach and is represented by a lognormal distribution [44]⁠. I will leave this topic there. Otherwise, we will need to get into some complicated Vector Calculus and Fluid Dynamics, and I have probably spent more time on this section than I should have. Now, let's look at the next step in these cellular processes.

Cell Migration

From adhesion, the next logical event to consider is migration. Obviously, this is relevant for Foregen’s work, as we want a patient’s cells to be able to invade the decellularized ECM scaffold, where they will then proliferate. Migration is conceptually simple, though technically incredibly complicated, as to give a relatively complete description of a migrating cell population in a single direction (x), it requires the use of dense, second-order partial differential equations, such as:

where the chemotaxis coefficient χ is defined as:

with boundary and initial conditions:

Many models exist that describe this cellular process [5:271–278, 6:321–324, 32]⁠, however, the above cell flux model from Saltzman [29:216–218]⁠is one of the most descriptive migration models that I’m aware of; admittedly, I did not define each variable or constant (as is proper form), though we will come back to a rudimentary version of this model. No doubt, I’m sure many of you are relieved that I’m holding out and not invoking these more complex models for this article.

Migration is an action that numerous cell types are able to perform (Table 3). And luckily for Foregen’s purposes, some of the most relevant cell types can migrate:

Under the context of Foregen’s work, cell migration is characteristic of the type seen in wound healing in the presence of biomaterial scaffolds as depicted in Figure 4.

Figure 4: Cell migration in wound healing in the presence of a biomaterial scaffold.

Cell Locomotion   

The actual process of cell locomotion occurs in distinct steps and uses the adhesion mechanisms that we just discussed. Locomotion can be delineated into four stages: protrusion, attachment, translocation, and release. Protrusion is a process driven by actin polymerization within the cell, where a projection is extended from the cell body. This process is likened to an exploratory process, where the cell is “feeling” around and “determines” the direction of motion. Attachment is simply what we discussed in the last section. In the context of migration, following the protrusion phase, the cell will adhere to a stable anchoring point. Translocation, the third step, can be thought of as though the cell were “pulling” itself forward as the cell body moves in the direction of attachment. Lastly, release is merely a detachment from the trailing end of the cell [16]⁠.

Cell Wrangling

Cells, on their own, are kind of clueless about what to do; they often need to be told what to do at any given time. For instance, in a completely uniform environment, cells migrate similarly to a gradient of particles that exhibit random, Brownian motion. Quantitatively, we can describe the cell migration in the generalized form:

Where μ is the random motility coefficient, and c is the cell density with respect to the spatial dimensions x, y, and z (in Cartesian coordinates anyhow) and with respect to time t, and effectively tells us that, over a period of time, cells will move from a region of high concentration to low concentration. Those of you that are familiar with Fick’s Second Law of Molecular Diffusion will recognize this as being analogous [29]⁠; just like particles in a gradient, these cells will “bounce” around until there’s a nice even distribution across some area.

The point of me detailing this is not to introduce anyone to the class of parabolic partial differential equations commonly referred to as “diffusion-type” equations [7]⁠, as interesting as that might be. The point I’m trying to get at is that cells are aimless without any external guidance; they behave almost like inanimate particles suspended in a medium. However, cells can be directed to migrate to specific locations based on chemical compounds known as chemoattractants. Suppose there is a gradient of a particular chemoattractant. Cells may sense the gradient and direct their migration towards the source [16]⁠. In fact, gradients of nutrients and waste will also induce certain behaviors within cells, which is important for understanding when designing tissue engineered constructs [18]⁠. Cells don’t just respond to chemical gradients in this manner, as mechanical and porosity gradients can also directly influence their behavior, which is something that my advisor and mentor at Illinois Institute of Technology, Georgia Papavasiliou, studied quite a bit in her lab; for example, designing scaffolds with these sorts of gradient characteristics can promote vascular network formation [45]⁠.

To keep this section brief: the important part here is that cell behavior can be controlled based on scaffold design. The introduction of chemical and mechanical cues can direct cell motion and behavior towards a desired result [16, 29]⁠. If the conditions are appropriate, the cells, with time, will aggregate and sort themselves into a tissue [30]⁠.

An Entropic Excursion

Although I'd like to discuss polymer biodegradation next, before we can properly discuss this, we first need to make a detour and examine a fundamental concept from thermodynamics. Thermodynamics describes the forces that govern molecular behavior, which, by extension, govern the behavior of biomolecules. These biomolecules comprise cells, which assemble into functional tissues, which come together to form organs that comprise us. These principles from thermodynamics underlie all of the concepts that we have already explored.

Though it may seem like a significant tangent, it is necessary to adequately characterize polymer biodegradation, which is vital for the next section on extracellular matrix remodeling and repair. Hopefully, it will become clear why I am choosing to spend a significant amount of time with this.

Despite how much we might like it to be, our world is not static and unchanging; everything is transitory. If we examine the flow of time, we only ever find "what has been," which, by the time we experience it, we are already in the next moment, and what was has departed and exists no more [34]⁠. In this regard, time flows the way a river does: though we may be standing in the current, at no point are we in contact with the same water more than once. The Roman Stoics of old, such as Marcus Aurelius, have much to teach us regarding the transitory nature of all things and their relation to the human condition. Because the universe is constantly in flux, those external things are outside our absolute control. Of course, one can try to deny this and struggle against the flow of time, but this is akin to swimming against a river's current: one can fight against it, but eventually, you will exhaust yourself.

What gives directionality to the flow of time is entropy. Entropy is a thermodynamic quantity and a rather abstract one at that; it isn't easy to accurately describe it unless we speak in terms of statistical mechanics. Regardless, it is often described as a "measurement of disorder" (despite how much I dislike this definition, though, for this article, I will stick with it). For a system with a large number of molecules, the most precise description for entropy S is given by the statistical postulate formulated by Ludwig Boltzmann

where k is known as Boltzmann’s constant, and Ω (U, V, N) represents the number of distinct microstates of a system with a number of molecules N, volume V, and internal energy U [24]⁠.

The peculiar attribute that entropy carries with it is described by the Second Law of Thermodynamics, which states that the total entropy for the entire universe is continuously increasing. Rudolf Clausius, one of the founders of thermodynamics (and owner of fine mutton chops—which was the style at the time), formally expressed this in his eponymous inequality in 1865, that the while the energy of the universe remains at a constant, the entropy of the universe “tends to a maximum.” Mathematically, this is expressed as

which, the cyclic integral δQ/T can be viewed as the sum of all of the different amounts of heat transfer divided by the temperature at some boundary [3]⁠.

Temporality is an intrinsic characteristic of entropy; just as we cannot ever escape from the current of time, so too are we unable to be liberated from entropy's influence truly. Because the Second Law of Thermodynamics dictates that the universe's entropy is continually increasing, everything within the world of phenomena tends toward disorganization. This is why material objects, with time, wear out, break down, or otherwise "fall apart," so to speak.

One can "order" things within an open system and decrease the system's entropy, though this is something of a zero-sum game. To do this, it requires an input of some of energy, such as heat or from the energy released by the breaking of chemical bonds, but this, in turn, will increase entropy outside that system by at least as much, contributing to the overall increase within the universe [25]⁠.

Being that I'm a Schopenhauerian, I'm inclined to abstract this discussion further into the realm of metaphysics, wherein the tendency for entropy to increase is merely the phenomenal mechanism by which die Wille zum Leben (the Will to Life) makes itself known to us [35]⁠. However, that is a discussion for another time. At any rate, I genuinely hope that I've made this challenging concept relatively easy to follow, despite only scratching the surface of entropy. If you are lost and confused, you're in luck because we're now going to look at polymer biodegradation, which is a practical example of this material.

Polymer Biodegradation   

Because the world of phenomena tends towards disorganization via the gradual increase of entropy, material breakdown is inevitable. For instance, the degradation of metals that everyone is familiar with is corrosion, resulting from the coupling of redox (reduction and oxidation) reactions. This is ultimately a consequence of the material interacting with its environment [41]⁠. The amount of free energy in the system will dictate whether the process can occur [13]⁠. Understanding how these materials will interact with the environments they’re placed into informs our selection when designing biomedical devices. Sticking with the example of metals for the moment, one option could be to select non-reactive (cathodic) metals like gold, silver, or platinum. Though these metals are relatively soft and deform easily, their usefulness in many cases is limited. A compromise can be made by selecting metals that form passive oxide coatings, which offer corrosion resistance while providing sufficient mechanical strength [41]⁠.

In many biomedical applications, like orthopedic implants, degradation is undesirable as it leads to device failure, so we try to mitigate it as much as possible. But this is not always the case, as sometimes we want the material to degrade, which is often the case in tissue engineering and drug delivery applications, where the overall goal is tissue replacement and/or release of bioactive factors. The issue here is designing a biomaterial device such that it degrades in a controlled manner because uncontrolled degradation often leads to structural breakdown of the material and premature failure of said device [41]⁠; keep this in mind for when we finally talk about biocompatibility next time.

Though many physiological factors can contribute to or influence polymeric biomaterial degradation, as things like water, proteins, and inflammatory cells, we will only look at the two primary mechanisms of biodegradation, swelling/dissolution and random chain scission, as well as one other that will be important specifically for the final section.        

Swelling & Dissolution

If we remember from part 1 that polymeric materials are composed of long chains that branch and network with each other. Between these branches is open space. Some polymers are such that these open spaces are regions of hydrophilicity or are water-loving, meaning that water exhibits an attractive behavior towards them. Much like a sponge, water will be absorbed by the polymer and occupy the space between the macromolecular chains, and the polymer will begin to swell. This swelling makes the material more pliable and will alter other mechanical and thermal properties. In some cases, this is desired, depending on one’s application. But in extreme cases, if the polymer chains are soluble enough and if there are relatively few bonds between the chains, the polymer may ultimately dissolve completely [41]⁠.

Random Chain Scission

Random chain scission can occur in one of two ways: hydrolysis or oxidation [41]⁠. Hydrolysis is where a water molecule facilitates the cleavage of certain bonds within a macromolecule and proceeds according to the reaction

The kinetics of this simple model assumes that the rate of the reaction of the ester bonds is proportional to time [8]⁠. The extent or progress of the hydrolytic reaction can depend on the reactivity of the polymer backbone groups, the extent of interchain bonding, and the amount of water in the system [41]⁠. I should clarify that the extent or progress of a reaction is a technical concept. One way to define it, for a single reaction, such as the hydrolysis of a polymer, at least in terms of fractional conversion of J, XJ [26]⁠:

The chemical mechanism behind oxidation is a bit more complex, but it occurs when a highly reactive species (typically free radicals) attack and break bonds in susceptible side chains. The extent of oxidation depends on the number of susceptible groups in the material. Moreover, it’s important to note that lower molecular weight polymers are less tightly crosslinked by their very nature and thus degrade quicker as they have fewer primary and secondary interactions that hold the material together [41]⁠.

Enzyme-Catalyzed Degradation

Concerning biomaterials as a whole, this mechanism is not as prominent. It mainly involves enzymes suspended in the fluid around a biomedical implant. An enzyme is merely a protein that catalyzes a reaction. Some of these have a particular affinity for chemical groups present in polymers, where they may bind and cause either hydrolytic or oxidative degradation of polymers, where they break bonds of polymer chains, much like a scissor cutting a string [41]⁠.

But in the domain of tissue engineering, this mechanism is crucial, as cells use a family of enzymes known as matrix metalloproteinases (MMPs) to degrade ECM components. These enzymes are typically secreted by the cell. Still, some are membrane-bound, and they degrade natural polymers usually. Still, synthetic materials can be formulated with bonds susceptible to these enzymes. They can be effectively tuned to degrade at precise rates [11]⁠.

Extracellular Matrix Maintenance and Repair   

Physiologically speaking, the body has two aims: reproduction and maintaining homeostasis. Homeostasis is defined as the normal and most desirable condition of body functioning. Loss of homeostasis always leads to some type of pathology—temporary or permanent [19]⁠. As cold and indifferent as it sounds, the goal is to maintain homeostasis just long enough for an organism to reproduce and pass its genetic information on; in his essay Über den Willen in der Natur (On Will in Nature), Schopenhauer provides us with countless examples of this truth [33]⁠.

Because all things slowly break down, including our bodies, that poses the question: how do we maintain homeostasis? The full answer to this question is exceedingly complicated and should be considered on a system-by-system basis. One explanation that I can provide is that the body has evolved biological processes to repair itself and correct deviations from homeostasis. These dynamics can be described through Process Control theory—the same type that controls your thermostat uses to regulate temperature—to control and model biological systems [36]⁠. I find it a fascinating topic, and I had the pleasure to learn from one of the great researchers in biological controls at Illinois Institute of Technology, Dr. Ali Cinar. Much like other topics, if there is enough interest, I would not mind coming back to discuss this more. In the meantime, I have included some analogies between biological systems and more traditional systems in Table 4.

But for this article, we’re merely interested in how cells interact with polymers for tissue engineering applications. If we recall from part 1, the ECM is an amalgamation of different polymers. These can all break down from mechanical stresses. But even if they are not subjected to these stresses, they will degrade themselves with time. The half-life of a reactant is the time it takes for some concentration of the chemical species to degrade to half its initial value. For a first-order reaction, this is described as:

where kᵣ is the reaction rate constant [1:230]⁠.

Without some repair mechanism, our tissues would fall apart with time. The process in question is matrix maintenance, which is essential for tissue regeneration. For instance, in damaged tissue, injury signals are converted into regenerative signals, which trigger wound healing, cell proliferation, differentiation, and ECM building. Much like ECM biology as a whole, this topic can become exceedingly complicated, so we will only consider it at a surface level. Over time, cells will break down the ECM in their environment and, in turn, deposit new matrix fibers to maintain normal tissue function and hence, homeostasis. Cells will also respond to external stimuli, like mechanical stresses, and remodel the matrix in response to them. A classic example is hypertension-induced arterial remodeling [37]⁠. Hypertension is a condition where one has high blood pressure that is beyond ordinary. In response, cells that make up the arteries will begin to thicken the ECM to prevent the arteries from bursting because of the high pressure. The problem with this is that it narrows the vessels and decreases their elasticity, decreasing functionality. As we age, our bodies become less efficient in remodeling, so we begin to see things such as arthritis and skin sagging. The reason behind this is more of a discussion of cell biology, so I won’t go into too much more detail on that front.

To describe the dynamics of ECM growth and remodeling, it is best to utilize a continuum approach. If we consider an arbitrary control volume (Figure 4), that represents some section of tissue:

Differential mass balance on a characteristic element. This diagram shows a simple mass balance in a Cartesian coordinate system. [31]

Where molecules of species A can enter through any face of this control volume, but they can also be generated or consumed by chemical reaction and accumulate within the volume. Thus, we say that mass is conserved:

Where A is some chemical species of interest (such as collagen). For the above control volume, if we take a general mass balance we obtain:

The bracketed terms serve to account for the movement of species A through the faces of the control volume we have defined. ΨA accounts for the generation or consumption of A per unit volume, and ρA is the mass density of A within the volume. If we divide each term by the volumes on the right-hand side of the equals sign and then take the limit of the resulting expression as the differential volumes become infinitesimally small presents us with the equation of continuity

Unfortunately, the above equation only describes binary systems [31]⁠. And if we remember the composition of the ECM from part 1, we know that it and tissues are far from binary. We must instead consider the equations of change for multicomponent systems:

where α = 1, 2, 3, …, N are each different species within a mixture [2]⁠. I know I’ve just thrown a lot of very advanced mathematics at all of you without doing much to describe what any of it means. The continuity equation that I listed above effectively accounts for all of the mass of different materials within some defined volume; it describes something so elementary that we all know it fundamentally: mass cannot spontaneously appear and must come from somewhere. The amount of mass that accumulates can enter or leave through convective and diffusive mass transport, or it can be generated or consumed in a chemical reaction. This is the more precise mathematical way of stating the conservation of mass equation from earlier. All physical systems, and by extension all chemical and biological systems, are subject to this fundamental law. As a result, this gives us an excellent foundation for being able to consider ECM growth and remodeling.

I’m not going to derive it for you all (unless there is interest), as the mathematics that the next model involves is incredibly advanced—especially compared to what we just went over; I assume that most of you would look at me with blank expressions if I asked you to tell me what a Cauchy-Green tensor is or to define the Lagrangian for me. Therefore, I will merely show the primary model and then discuss its use in Tissue Engineering, save for one example.

The model that I appreciate most is the constrained mixture model (CMM) that Humphrey and Rajagopal developed in 2002 [14]⁠. Not only does it describe remodeling of the ECM as well as growth, but it can describe and accurately predict how an engineered tissue will behave based upon scaffold scaffold characteristics. In its general form, the mass balance for each individual component k is defined as

With the energy density of each component having the following form

For brevity’s sake, I’m not going to define each term (though they can be found in the paper I cited), so take my word for it, please. Still, the above model is merely a generalized version of the model. For specific applications, it needs to be altered.

Although its derivation is long and complicated, one application this model has been used for is predicting the remodeling of implanted engineered, collagenous tissues. Nevertheless, it accurately describes the degradation of a polymer (PGA) implant:

Which is then replaced by collagen

and collagen removal

in matrix remodeling [22]⁠. Said model has proven to be as powerful as it is versatile. It has seen use in designing [17, 21]⁠ and optimizing scaffold design for tissue-engineered blood vessels [38]⁠. In another, application, it’s been used to predict the vascularization of polymeric scaffolds [20]⁠. Work such as this will become invaluable when we formally begin our work in fabricating foreskin scaffolding. There are many other applications, though these are the ones I find the most exciting and relevant.

Understanding the kinetics, or rates, of tissue remodeling and scaffold degradation is extremely important in designing tissue engineering scaffolds. As the scaffold is degraded and new tissue forms, the mechanical properties should remain constant. Ideally, a scaffold’s degradation should be inversely proportional to the rate at which ECM is deposited, and tissue is regenerated (Figure X) [4]⁠. If the scaffold degrades too quickly, its mechanical properties may be compromised, and the implant might fail (fall apart) [41]⁠. Conversely, a scaffold that degrades too slowly might trigger an inflammatory immune response [42]⁠.

Figure 6: Relationship between mechanical properties of a scaffold and progression of degradation with time [4]

For the work that Foregen is currently doing, this aspect is not as vital, as the kinetics are already “prefabricated” into the decellularized donor tissue. However, this concept will be fundamental regarding our future work involving bioprinting scaffolds, which I hope to discuss more shortly!

Concluding Remarks

This article undoubtedly was far longer and more detailed than I expected. I hope that this was able to shed some light on the inner workings of the tradition of tissue engineering that I come from (as opposed to that of a biologist or a physician). I expect this article will generate many questions, as I do not doubt that there may be some confusion because I tried to give a surface-level explanation with peaks beneath the hood; I hoped that doing this helped ground much of these concepts beyond these notions of “science fiction.” Moreover, there were undoubtedly many things that I skipped over that I might return to in a future article if the demand is there.

We have but one more, though short, concept to look at before we finally consider biocompatibility formally. And we shall do it all next time, finishing off this series in particular.


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