As you all may have no doubt noticed, we made some fairly significant announcements recently. In December, we released the abstract for our human clinical trial proposal, which we have scheduled for April 2023; then, earlier this month, we released a brief overview of the rat model results. This round of research was what is known as a biocompatibility study. We’ve received many questions asking for clarification and noticed some confusion among supporter discourse regarding these results.
This comes as no surprise to me, as I am well aware of how esoteric the fields of Tissue Engineering and Regenerative Medicine can seem to even laypeople. Admittedly, this is further compounded when we consider that biocompatibility is a relatively nebulous and difficult to define concept—though it may not appear that way at first—and even seasoned researchers have a habit of misusing the term . I am somewhat delighted that we’ve received these questions because, for a while now, I have wanted to write a piece that lays down some of the fundamental principles that Foregen’s work is built on and then explore and simplify the underlying concepts of our work; hopefully on a level that everyone can follow.
My goal for this post, if I am successful, is to provide some needed clarification for those of you that have asked or would appreciate more context with regards to our work. I’m not exactly made for this type of writing because it tends to lack the technical depth that I’m used to dealing with, though I will do my best to keep things as simple as possible, as this topic can become highly complicated quickly, and without straying too far from the more relevant aspects of the case at hand.
Before we can even consider discussing biocompatibility, we need to lay down the groundwork for the concept of biomaterials; as we shall see, biomaterials are one-half of the coin, while biocompatibility is the other. Regarding this first section, we’ll first briefly discuss what a biomaterial is and then move on to the more specific area of polymeric biomaterials for tissue engineering applications. Then, we’ll be able to briefly discuss decellularized extracellular matrices (ECMs) and the rationale behind our 2018 study. In this, we will briefly consider each step of our 2018 study, and I will try to describe what was done and why for laypeople to understand. After this, we are then in a position to consider biocompatibility and our recent study with rats finally.
Due to the length, I will be splitting this into three different parts. The first will be biomaterials, the second will be our 2018 study, and the third will be on biocompatibility and the rat study. This will serve as an introduction to these concepts and as an overview of Foregen’s research up until this point.
A Brief History
In keeping with tradition, every introduction to biomaterials begins with a short overview of the discipline’s history. However, nearly every text I’ve found almost entirely focuses on the 20th-century, when the domain formally took off, as the Second World War resulted in a significant increase in synthetic materials, which then found use in biomedical applications . This is all well-and-good and exciting enough; however, I find history that dates before the 20th-century far more interesting concerning biomaterials. Although the term “biomaterial” is relatively new, materials that fit in this category have been used in medical applications since prehistory: in the primitive medicine of the Neanderthal man, the most frequent surgical interventions concerned bone repair, teeth replacements, and head trepanation. This is where we see the first biomaterials being used, which were derived from nature, such as wood, nacre, and ivory. However, xenogenic bone was used for early orthopedic constructs. Moreover, teeth substitutes were procured from different animals, particularly dogs, calves, seals, and narwhals. Later, in Classical Antiquity, we begin to see the Greeks, Romans, Etruscans, Celts, Egyptians, Phoenicians, the indigenous peoples of Meso- and South America, and over the world begin to utilize materials, such as gold, iron, and dog or calf teeth for dental restorations and bone reconstruction .
What are Biomaterials?
Now, as many of you will have noticed, I haven’t really defined what a biomaterial is, so much as I have just pointed out examples of them. Unfortunately, I have bad news, as there hasn’t been a total consensus on what constitutes a biomaterial, as the definition has evolved over the decades, and depending on who you ask today, you may get a wide range of answers . The most widely accepted definition—which is the one that my undergraduate biomaterials textbook provides—I imagine, is quite a bit in line with what you all are likely considering, which is:
A material intended to interface with biological systems to evaluate, treat, augment, or replace any tissue, organ or function of the body. 
Now, this is a definition that is fair enough. However, as David Williams, a leading thought leader in the field, argues, this definition is inadequate as the traditional conception of a material does not fit some of the more modern things, such as highly active nanoparticles, hydrogels, soluble contrast agents, self-assembled biological systems, and cells and viruses. More conventional notions of materials leave out these entities. As Williams suggests, it’s better to think of biomaterials as substances or systems instead of merely tangible things, which is admittedly a rather abstract way of conceptualizing this class of things. The definition that Williams provides that I am partial to suggests
A biomaterial is a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure, in human or veterinary medicine. 
Generally speaking, materials as a whole are considered either a metal, a ceramic, or a polymer, and biomaterials are no different in this regard. What distinguishes these three comes down to chemistry and what type of chemical bonding holds the material together. It would take almost a whole semester of general chemistry to understand the differences between metallic, ionic, and covalent bonding and why these lead to such vastly different types of materials.
In any case, in biomedical applications, metals, like cobalt-chromium and titanium alloys, are used in artificial heart valves, dental implants, vascular stents, and artificial joints. Ceramics, such as aluminum oxides, calcium phosphates, and bioactive glasses, also see general use in orthopedics, dental implants, and bone graft substitute materials and bone cements .
Polymers are the most relevant to this article, so I will spend slightly more time on them. What characterizes a polymer is the covalent bonding of individual “mer” (Greek for “part”) units into long chains (Figure 1).
Figure 1: Basic polymer chain
For those more mathematically inclined, we can consider a polymer formed by linkage of X units of monomer m:
Then, the overall chemical structure of this complex molecule can be written in reference to the structure of the monomer, which is signified as m. This repetition is what distinguishes polymers from the other two classes of materials. These chains can also form branches and link up with other chains, which can then develop into networks; this branching is one way polymers obtain their properties as it dictates how they interact with their surroundings. The number of combinations that these polymeric chains can assemble into is upwards of infinite, which is why we find so many different types of materials made from them, which all have very different properties. Moreover, even materials made from the same polymer can have drastically different properties based on molecular weight and crosslinking density .
Generally speaking, polymeric materials are divided into two separate classes: naturally-derived and synthetic. Numerous examples of both natural and synthetic polymers in biomedical applications are shown below in Table 1. However, there are hybrids, but I won’t discuss those for our purposes unless there is some demand for more information.
Table 1: Synthetic and Naturally Derived Polymers Commonly Used in Biomedical Applications 
Nature appears to be rather fond of polymers. We can find them everywhere in biology; one notable example is deoxyribonucleic acid, or DNA. As I mentioned above, polymers can branch out and even network with other polymers (something that DNA does with complementary strands to give us the iconic double-helix shape (Figure 2).
For our purposes, they also allow single cells to come together and form tissues, which is where the extracellular matrix (ECM) comes in. The ECM is a very particular type of biological polymer network. The composition and structure of the ECM in a specific tissue are directly related to its function . The protein fibers of the matrix give a tissue its tensile strength (collagen) and elasticity (elastin), and adhesion molecules allow cells to bind to the matrix and migrate [6,7]. The ECM is beyond complicated—I took a graduate course in extracellular matrix biology. The complexity of the ECM is almost beyond words. It is just as intricate as the biology of the cells that inhabit it. If there is a high enough demand for it, I can discuss another article. Still, until then, the important takeaway is that the ECM is a polymer network that gives tissues and organs their structure, but also that it plays a fundamental role in how tissues function, how cells sense and interact with the environment, and various other cellular behaviors, including migration, growth, and differentiation [8,9].
Biomaterials for Tissue Engineering
Looking back at Table 1, we can see that biomaterials are used in a wide variety of biomedical applications. Tissue Engineering, of course, carries its own unique considerations when it comes to biomaterial selection. When it comes to tissue engineering and replacing tissues, one method is to use some sort of biomaterial scaffolding for cells to grow on. Which material you choose depends entirely upon your application. Ultimately, you want the scaffolding to resemble as closely as possible the tissue or organ that you are working to replace ; this is with regards to structural, mechanical, chemical, and topographical characteristics; if it does not, the engineered tissue will not develop properly and consequently will not function correctly. This requirement of biomimicry is not limited to only tissue engineering, though many of the underlying principles are the same. For instance, a project I worked on years ago required an imaging phantom that mimicked brain tissue's viscoelastic behavior and mechanical properties . Though the application was different, these same principles are applied. The suitable formulation of silicone elastomers was found with trial and error, resulting in the peculiar blob in Figure 3.
Suppose we are working on engineering a soft tissue and assuming that we know all of the characteristics mentioned above of the tissue of interest. In that case, the first thing we need to do is decide if we want to use a naturally derived or a synthetic material. Both classes have advantages and disadvantages, and there may not necessarily be a single best material. As a general rule, particularly with tissue engineering applications, naturally-derived materials tend to integrate better than synthetic materials, as their chemical composition is usually closer to the tissues they are replacing. For example, the ECM is primarily composed of collagen, so repairing a defect with a collagen scaffold might yield the best outcome. However, where synthetic materials have some advantages of their own. It is much easier to tune the properties of synthetic materials, and manufacturers tend to be more consistent batch-to-batch and are far more readily available than natural materials, which, in contrast, can be challenging to obtain in significant amounts . Personally, the polymer that I have the most experience with is poly(ethylene glycol) (Figure 4), which is a fantastic synthetic material because of how versatile it is, as well as how it is relatively inert in its unmodified state when introduced to the body, giving you a large amount of control.
For replacing relatively simple tissues, like skin, an engineered equivalent can be produced by suspending dermal cells within gels made from ECM components . However, as the complexity of the target tissue increases, the more difficult it will be to design an appropriate scaffold, and the more design considerations need to be taken. For instance, the human foreskin is a composite tissue consisting of skin, mucosa, nervous tissue, and smooth muscle, is highly vascularized, and carries a distinct mechanical function. There is also the ridged band that must be considered. Each one of these characteristics needs to be accounted for when designing a scaffold. Moreover, each material is polymerized by a specific type of reaction, which means that planning for small structures becomes very difficult; this is one reason why advances in 3D-bioprinting have been so critical.
As with all engineering projects, the cost is another consideration that will dictate much of the approach. One of the biggest hindrances at the moment is the price: many commercial biomaterials are incredibly expensive, which can severely limit the scope of projects and applications (Table 2).
Table 2: Commercial biomaterials and current pricing. Price ranges take into account any options of size format 
Thankfully, materials scientists and engineers are looking to overcome this hurdle by looking towards nature. As I mentioned, naturally-derived materials have better integration. However, they are relatively inconsistent and less available than their synthetic counterparts. One solution is by having recombinant plants produce human collagen . The other has been through using plant cellulose as scaffolding materials, as plant tissue is inexpensive and highly available. One lab has found that decellularized apple tissue functions effectively as a tissue engineering scaffolding .
Similarly, another lab has grown functioning cardiac cells on decellularized spinach leaves . I have some experience in this area : several years ago, I took inspiration from these works to develop an MRI imaging phantom using decellularized asparagus stalks (Figure 5) in an effort to mimic the microvasculature of cardiac tissue. I also experimented with spinach (Figure 6) and ginkgo leaves (Figure 7). Though it’s a bit of a novelty at the moment, I believe that plant-derived materials will be essentially where natural biomaterials shift to in the future. The ease at which one can create their own plant-derived tissue engineering scaffold, such as with the apple mentioned above, is such that you can even do it at home with simple dish soap .
Decellularized Extracellular Matrices
This, of course, brings us to the periphery of Foregen's work. In 2018, we published our work on decelluarizing adult donor foreskin tissue . I mentioned decellularization in the previous section, but I did not really define it. Decellularization is precisely what the name implies: a removal of cells (namely a tissue or organ). There are numerous methods of decellularizing tissues and organs, and each is tissue-specific. Moreover, since the genetic material is removed, there is some flexibility regarding where the tissue is derived from; it's not imperative that human tissue be sourced, which is why you will often see ECM taken from bovine or porcine dermis (as seen in the table above) used in humans. At the same time, there are distinct differences in the ECM components in these animals. Generally speaking, there is enough similarity that they can be interchanged (though this comes with some caveats beyond this article's scope). After subjecting a donor tissue (animal or human) to a decellularization process—if the process is adequate—the ECM itself typically remains unaltered with all of its structural, chemical, and mechanical properties. Though a bit of an umbrella term, ECMs are common biomaterials. After decellularization, they are typically processed into sheets or powdered for more general applications .
With all of her experience, Nature is often far better at design and has production methods that dwarf those of humans. Though there are many that one can point to, the classic example that I like to cite is thermal efficiency. However, despite my affinity for the subject, I will do my best to keep this from diverging into a Thermodynamics essay. The most straightforward way to consider efficiency is as the ratio of some desired output and its required input :
If we consider things in terms of engine efficiency, we can consider the desired output to be work, and the required input is the energy potential of the fuel source. Your average gasoline automobile engine typically has an efficiency of ~25% efficiency. However, in comparison, the thermodynamic efficiency of ATP synthesis in oxidative phosphorylation (the chief biochemical process for energy in the human body) is estimated to be 40-41% . For specific applications, the best approach is to take advantage of Nature's products.
Now, if you’re very clever, you’ll have already noticed something about this decellularization approach that’s fundamentally different than the more traditional biofabrication approach I detailed in the last section. Ignoring the step where the decellularized ECM is processed into sheets and whatnot, I said that the process leaves us with an acellular scaffolding with the same structural, chemical, and mechanical properties of the original tissue. I also said the most critical thing about designing a tissue engineering scaffold is that it mimics the target tissue as closely as possible. Moreover, the more complicated the target tissue is, the more complicated and subsequently more difficult it is to design an appropriate scaffold. What this “minimally manipulated” decellularization approach does is entirely sidestep the traditional problems of biofabrication and, indeed, yields what could be considered the gold standard of tissue engineering scaffolds. We must remember that the human prepuce is a highly specialized construct, is composed of multiple tissue types, has distinct structures, and carries a specific mechanical function . To fabricate a scaffold through traditional means would be an ambitious project, indeed, as each particular feature must be considered and designed with the others in mind. By decellularizing human donor tissue, Nature has done the heavy lifting for us, as the resulting matrix already has the necessary properties in all correct places.
We are beyond fortunate to have Dr. Bondioli on our team because the decellularization method that she and her colleagues in Italy developed has repeatedly shown that it is exceptional for soft tissue engineering applications [24–32]. Moreover, for our purposes, similar types of matrices have already been used to reconstruct penile shaft skin (sans prepuce) with outstanding results [33,34], which spells success for our efforts.
If you’ve made it this far, I appreciate your perseverance. I’m going to leave it here for part 1. In the next part, we will take a closer look at our 2018 decellularization study, which I promise will be much shorter than this.
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