Regenerative medicine

The fact that our body has memory of how all tissues should be built and can regenerate things is incredible.

Personally excited about developments of Foregen & am donating to the cause. Being able to regenerate any body part we need at will is matter of time.

Michael Levin does great research on the subject.

Most notes/links below I got from Cunningham.

With regards to Foregen, optimal vascularization is the biggest challenge. Without proper blood flow, regenerated construct will die.

Vascularization is great book on the subject.

Also Biomaterials: The Intersection of Biology and Materials Science & Biomaterials: Foreign Bodies or Tuners for the Immune Response are great reads.

DNA is not encoding the size of regenerated tissue.

Notes

Adequate vascularization is required for the survivability of tissue engineered constructs. Additionally, it’s often a prerequisite for other cell types to migrate into a scaffold. The challenge for this project is ensuring adequate vascularization is achieved before necrotization begins to occur. The desired level of vascularity is such that all of the tissues have an adequate level of heat and material transfer. This principle is reflected in the body.
If the body of the cell remains intact and alive, severed axons can be regenerated. The nerve that innervates the foreskin is the pudendal nerve, and it innervates the entire penis (skin, glans, etc.), various pelvic muscles, the urethral sphincter, the external anal sphincter, and is the main nerve of the perineum. If circumcision killed this nerve or there was significant atrophy, it would be incredibly obvious and problematic. Therefore, it is highly likely a regenerated foreskin can be reinnervated.
The nerve for the penis (and whole perineum) is the pudendal nerve that is located in the spine. There might be some Wallerian degeneration distal to the site of injury, but the cell bodies of these neurons in the dorsal root ganglia generally remain intact. In reality, circumcision just cuts some of the branches from this nerve off, but the integrity of the pudendal nerve itself should be fine. Regenerating nerve cells for new branches is already a proven technique.
It is true that if a nerve is severely damaged it may atrophy or die back to the spine. However, if the body of the cell remains intact and alive, severed axons can be regenerated. You can repair severed axons.
Axons can migrate into scaffolding if provided the right conditions. For example, chemotactic gradients can direct growth ones, which can be incorporated into the scaffold design.
Keratin on epithelial tissues is nothing more than a layer of dead cells that is built up to prevent mechanical friction from damaging underlying tissues.
Nerves connect through the process of Angiogenesis. It's process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis.
Unlike with other types of cells, neurons can be quite large in size, and span half the length of the body. In the case of circumcision, entire neurons are not being removed, rather, the endings are being cut; conceptually this is kind of like the neuron's fingers being removed. They are still alive and functional, but are limited in the sensory information that they can take in. The simple explanation is that the properties of the scaffolding promote regeneration at the severed end of the neuron, which regrows and extends into the neotissue.
Neurons do not divide, so when a neuron dies, the body has no mechanism to replace it. Peripheral nervous system has the capacity for regeneration and repair, while the central nervous system does not. However, this means that the peripheral neuron must survive the trauma being inflicted, as if the damage is severe or close to the cell body, it may die. However, if the cell body remains intact, then severed axons of peripheral nerves can be regenerated.
Biological tissues, like skin and muscle, behave viscoelastically, that is to say, they deform instantaneously (like ideal elastic materials) when subjected to loading, but they also continue to plastically deform slowly after the initial period, exhibiting a time-dependent property called creep. Moreover, when the same material is rapidly deformed, the amount of force needed to maintain said deformed state decreases gradually, which is a process known as stress relaxation. With small tensile deformations, soft biological tissues behave as elastic materials. With these small tensile deformations, the fibers are not stretched nor are there any large structural changes to the matrix. However, as the strain on the matrix increases, the fibers begin to deform and straighten out normal to the tension vector; under these conditions we see the stiffness of the tissue increasing as a result. In deformations that are just less than the ultimate tensile strength, the fibers are aligned uniaxially in the direction of the applied load. When the tension is removed, and so long as no plastic deformation has occurred, the matrix fibers will spontaneously return to their original conformation. Otherwise, they will recoil into whichever conformation is most thermodynamically favorable based upon the shifting of the matrix fibers. When these biological tissues, like skin, begin to plastically deform, which is an irreversible deformation, we see a characteristic not found in other viscoelastic materials. Conventional materials, when plastically deformed, will not return to their original state, and as a result, have altered mechanical properties. However, when a biological tissue is strained beyond its elastic limit, mechanosensing receptors in the local cells are activated, which triggers a cascade of cellular processes known as mechanotransduction. To lessen the strain on the tissue, the cells begin to expand the tissue normal to the tension vector. This is the tissue expansion process that non-surgical foreskin restoration takes advantage of. At no point are elastic fibers “broken,” and when plastic deformation does occur, the body works to mitigate it. Second, when engineering a tissue, the scaffold must be designed to mimic the desired tissue—structurally, topographically, chemically, and mechanically—as closely as possible. Failing to do so will result in an engineered tissue that will either function poorly or will fail. This is precisely why minimally-manipulated decellularized matrices are considered the gold standard when it comes to tissue engineering scaffolds; if the decellularization process is adequate, then all of those desired properties of the native tissue will be retained in the scaffolding, which enables the engineering of complex and intricate tissues with relative ease.
ECM is not static, as it is constantly being remodeled, that is to say it is broken down and built back up. The materials the cells use in constructing the matrix and use for their own cellular maintenance are, likewise, constantly being cycled out. After a time, any materials that were once part of the donor's body are replaced by new materials brought in from one's diet.
As far as mammals go, we find that the glanular tissue is the primary erogenous area, and the prepuce serves primarily as a structure to house the phallus when not in use for sexual intercourse (although there is a wide variety of secondary functions in different mammals, though that is neither here nor there). In this regard, humans and non-human primates are unique, as the prepuce functions as the primary erogenous tissue. That is not to say that the glans has no erogenous properties though, as sensitivity in the glans is indeed decreased through keratinization after circumcision. The nerve endings in the penis that contribute to fine-touch, and are primarily concentrated in the foreskin, are stimulated through mechanical deformation, hence why the gliding action of the foreskin is so important for normal function. The distributed and concentration of these fine-touch receptors was mapped out in great detail back in 2007, and gives us at least some empirical data on the sensitivity of the foreskin versus the glans.
Regeneration process is initiated by the growth factors present in the PRP. Generally speaking, growth factors are chemical signaling molecules that instruct cells to begin the healing process. They are critical for normal wound healing, let alone tissue regeneration. As I said, our method in the grand scheme is not terribly different, as the decellularization method developed by Dr. Bondioli and her colleagues in Italy has this unique property where the original cells generate and embed the ECM with an abundance of growth factors. In fact, in our article published in 2018 on foreskin decellularization, we found that the growth factor content doubled as a result of the decellularization process, which indicates a high degree of bioactivity and regenerative capabilities.
Interactions between the immune system and biomaterials is incredibly complicated, however, the short explanation is that whenever something is implanted, the immune system is going to analyze it. If it doesn't like it, it will attack it (this can look like a couple of different things). Even though the ECMs are acellular, there will be an initial immune response. Ideally, you want this to be mild and short.
Thermodynamics dictates how everything in biology proceeds. Specifically polymer conformations and cell binding affinities.
Nerve axon regeneration is a relatively slow process compared to reepithelialization or neoangiogenesis.
The specific decellularization process Foregen is using has a peculiar effect of having the cells produce large amounts of bFGF, which are embedded into the matrix. Moreover, certain ECM components are conducive to tissue remodeling, and hence regeneration.
Reattachment of a whole host of parts and organs has been done with relative ease since, well, modern medicine. Severed fingers, whole arms, transplantation of organs, etc. The body is the opposite of a static, unmoving thing, and essentially your body will try to heal most damage to the peripheral nervous system to some degree (albeit poorly). The basic unit of the nervous system is the Axon, and a series of axons form the structure of the nerves in our body. You can think of them like a series of extension chords that all plug into each other in long threads of tissue, and send electrical pulses to communicate with the brain and spinal chord (which together are the central nervous system). When a part of the body is cut or damaged, the nearest axons are usually irreparably harmed and nonfunctional without intervention, and are removed by your body's recycling system when they die. The closest undamaged axons are essentially capped to form the new "end" of the chain. What Foregen is looking into is taking the foreskins of deceased or otherwise willing people and treating the foreskins so that all cellular material of the donor is removed (this would theoretically help remove the risk of rejection). The only thing left would be the Extracellular Matrix (ECM), which is all of the non-cellular material (collagen, enzymes, glycoproteins and hydroxyapatite, etc.). It looks like a thin piece of tissue paper, but is still foreskin shaped. From this, the ECM is seeded with stem cells of the person who will be receiving the new foreskin. Stem cells show a striking ability to diversify based upon the structure of the organ they are placed into, which is how they will theoretically fill in the new structures of the foreskin (ridged band, frenulum, inner and outer mucosa, etc.) with blood vessels, nerves, and tissue. Once the newly reseeded foreskin is ready, the penile scar of the recipient will be reopened, and the foreskin attached. Over a period of weeks, months, and years, the repair system of your body (notably neuroglia and other repair cells), along with the natural growth of blood and nervous tissue, will over time reconnect so long as (or since, rather) your body begins to recognize it as part of yourself. again, people have had limbs and extremities severed, but reattached with enough speed and intervention. This is the same principle in that you are providing new "plug in" cites before the outermost cells die. With any luck, both function and feeling will return. Likely not 100%, but any progress would be monumentally impactful.

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