Evolution of therapeutic techniques utilising the human body's self-healing system: From PRP to PRF

PRP (Platelet - rich plasma)

The first generation of products inspired by the human body's regenerative (self-healing) mechanism at the end of the last century is called PRP. Its principle is to extract a super-physiological dose of growth factors from human blood and inject it at the site of the injury, using the signaling mechanism of the body's self-healing mechanism to stimulate the production of fibroblasts needed for tissue repair to induce faster wound healing

Since growth factors are mainly concentrated within platelets in human blood, the extraction process is not complicated. First, blood needs to be extracted from the patient and placed in a centrifuge. It is then spun at a certain angle and speed, and particles of different weights in the blood will sink or float under the influence of gravity, forming layers of different colors. Among them, the heavier red blood cells will sink, and the lightest serum will float to the top, while blood platelets, white blood cells, and fibrin, which are of similar weight, will aggregate in the middle layer, which is the part that needs to be extracted for PRP.

For a long time, the emergence of PRP technology as a new treatment method has promoted the healing of skin wounds on the body surface faster than other treatment methods, and has provided the possibility of using autologous blood cell therapy to directly target human body lesions. We already know that the first problem that the body's self-regeneration (self-healing) mechanism needs to solve is how to "send signals" to the body. Only when bleeding occurs and the concentration of platelets in the blood locally increases sharply, the body will produce signals. The reason why the lesions in the body cannot regenerate (self-heal) for a long time is precisely because the relevant lesions do not produce a large number of platelet aggregates, send signals, and produce "positive feedback". PRP technology solves this problem of "sending signals" with the simplest thinking, which is a very direct small step, but it opens the door to a new treatment concept. This treatment technology was once popular all over the world, especially in the treatment of sports injuries. Even today, due to its earlier discovery and use, there are quite a lot of literature and case contributions at home and abroad. After a lot of data accumulation and several upgrades and improvements, it has gradually been widely accepted and used by mainstream hospitals and medical institutions.

Currently, there are three main problems with PRP technology, mainly due to the complicated preparation process of PRP and the use of chemical additives during preparation.

The first problem is that during the preparation process of PRP, blood coagulates rapidly at normal temperature after leaving the human body, making it impossible to centrifuge and obtain PRP.

To solve this problem, the PRP commonly used in the market during the entire preparation process usually involves storing blood in tubes with added anticoagulants (such as sodium citrate and heparin). When separating platelets using a centrifuge, two centrifugation steps are required, and the total separation time takes approximately 30 minutes.

The second problem arises as clinical research deepens, due to the addition of anticoagulants during the preparation of PRP. After injecting PRP into the lesion, it is quickly diluted by the body. Although PRP is rich in high concentrations of platelets, the duration of stay is not long enough to sustain "signal release" to stimulate continuous cell regeneration, resulting in unsatisfactory effects. Therefore, a significant proportion of early PRP cases have been found to be ineffective after comparative observation. Scientists have analyzed and found that the PRP extract lacks fibrous protein adhesive agents necessary for the "positive feedback loop" during the human body's regeneration (self-healing) process.

To solve this problem, the upgraded generation of BRP technology adds thrombin and calcium to PRP after separation and before injection back into the human body. This technique is called Fibrin technologies in clinical surgery, and it is believed that the biochemical characteristics of surgical additives are a necessary condition to ensure the effectiveness of PRP treatment. Moreover, the "3-dimensional fibrin architecture" heavily relies on the clinically polymerized process after artificial intervention, such as the use of a large amount of bovine thrombin addition. The expected result after injection is to achieve a longer duration of stay and strengthen the treatment effect.

The third problem is that to solve the first and second problems, chemical additives such as anticoagulants and thrombin must be added to PRP during the entire preparation and injection process. As it enters the human body, some hidden risks exist, namely the body's "rejection" characteristics of non-endogenous substances. Rejection not only makes it impossible for PRP to achieve the expected effect in the body but also increases the possibility of postoperative allergic reactions and even the possibility of acquired coagulation disorders and other diseases caused by the added chemical additives. Due to the large individual differences in the human body, it is difficult to accurately predict and control these side effects.Academia has raised concerns about this risk: "Although fibrin glue has a good track record in many field-related schemes over the past 30 years, it remains controversial due to the complexity of production schemes (compared to autologous adhesives) or the risk of cross-infection (for commercial adhesives)." (Dohan et al., 2006)

In essence, although PRP is a groundbreaking technology that takes a crucial step in utilizing the human body's self-healing mechanism to help humans overcome pain and illness, it is not a perfect "safe" treatment technology in the eyes of scientists and medical professionals. There are still some areas where the treatment effect falls short of satisfying both medical professionals and patients.

PRF（Platelet-rich fibrin）：

As the new century arrived, the biggest weakness of PRP technology remained unsolved. In order to improve treatment safety, the medical community needed an upgraded treatment option that could obtain PRP or even better components without adding any "non-autologous" additives. With the efforts of scientists and medical professionals, a new technique called "second-generation platelet concentrate" was discovered and introduced into clinical practice.

In this new technique, Platelet-rich fibrin (PRF) was discovered as an upgraded version of Platelet-rich plasma (PRP) technology. The centrifuge parameters were updated and adjusted in the preparation process, allowing for a faster and shorter centrifugation and separation time without the use of any anticoagulants or other additives. At the same time, fibrin and white blood cells in the blood were effectively retained. Due to the lack of inhibition of the clotting process, the PRF extract quickly formed into a gel.

Compared to PRP, this new discovery has two significant advantages:

First, no chemical or other living additives are added during the preparation process, significantly reducing the risk.

Second, PRF contains more "fibrin" than PRP, making up for the deficiency of autologous adhesives in PRP. When PRF is injected into the body tissue, not only do the platelets obtain a scaffold to rely on, but the PRF, rich in fibrin, can stay and act in the affected area for a longer time, continuously sending healing signals to the body, promoting positive circulation. In comparative treatment effectiveness, PRP often has short-term and immediate effects, unable to release healing signals for a long time, resulting in limited therapeutic effects. PRF can extend the action time of signal factors to 5-10 days, significantly improving the therapeutic effect of this self-healing technique.

In the above figure, we can see the schematic diagram of the matrix and cellular structure of four types of platelet concentrates very intuitively. Two key parameters are important: white blood cell content (blue spheres), fibrin density (light brown fibrous lines), and platelet aggregates (light gray shapes) always attach to fibrin. In typical P-PRP and L-PRP preparations, the fibrin network is thin, fragile, and immature. Although composed of fibers, this fibrin network dissolves rapidly like fibrin glue due to simple fiber polymerization and small diameter (red arrows). Although this fibrin network supports platelet application during surgery, it is quickly dissolved. In P-PRF and L-PRF preparations, the fibrin is thicker and sturdier (black arrows) and constitutes a resistant matrix due to the assembly of multiple fibers, which can be considered as a fibrin biological material.

In clinical practice, the "safety" of PRF itself is beyond doubt. Because no non-human-derived additives are used in the preparation of the entire PRF technology, the possibility of rejection reactions or cross-infection during surgery is eliminated, and the postoperative efficacy has made greater progress compared to PRP.

However, PRF technology also has its limitations. First, the preparation time and surgery time must be very short after the blood leaves the body, otherwise, the PRF will turn into a gel within a limited time. This means several problems:

The first problem is that the clotting of blood into a gel means that PRF cannot be injected into deeper tissues, and the treatment range is limited to the surface of the skin. Although solid PRF has medical value in the treatment of postoperative dental repairs or other auxiliary treatments for surface wounds, its use is greatly discounted compared to PRP.

The second problem is that the poor injectability of PRF means that doctors need to use thicker needles to inject patients. Using thick needles may cause additional damage to human tissue when entering the body, bringing new risks, while patients will face greater pain. In some treatments, even anesthesia may be applied to the patient's injection site before PRF injection. This once again uses non-human-derived additives, which reduces the safety that has already been improved, creating a kind of reverse effect.

Summary:

With the efforts of medical researchers and advancements in technology, there has been significant progress in harnessing the human body's self-healing system. The evolution from the first-generation technique PRP to PRF has addressed concerns such as increased surgical risks due to anticoagulants and suboptimal treatment outcomes. However, PRF still has limitations, including the inability to prevent blood clotting, resulting in compressed surgical time. These limitations have restricted the application of PRF in certain areas. Therefore, UCHON aspires to address the unresolved challenges and difficulties in self-regeneration therapy, aiming to further enhance this beneficial treatment technique for humanity.

Reference:

Dohan, D. M., Choukroun, J., Diss, A., Dohan, S. L., Dohan, A. J., Mouhyi, J., & Gogly, B. (2006). Platelet-rich fibrin (PRF): a second-generation platelet concentrate. Part I: technological concepts and evolution. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, 101(3), e37-e44.

Ehrenfest, D. M. D., Rasmusson, L., & Albrektsson, T. (2009). Classification of platelet concentrates: from pure platelet-rich plasma (P-PRP) to leucocyte-and platelet-rich fibrin (L-PRF). Trends in biotechnology, 27(3), 158-167.