Regenerative Medicine: The New Frontier Platelet-Rich Plasma to the Promise of Exosomes
The medical community is in a constant state of refinement when it comes to therapies that accelerate healing, repair and rejuvenation of tissue. In dermatology, in orthopedics, and to an even greater degree, in the emotionally fraught world of hair restoration, it is a race toward a master set of molecular keys and signals that will reliably unlock the body’s potential to repair itself. For the past decade, Platelet-Rich Plasma or PRP has been leading the charge. The top of the ladder. A mainstream tool for speeding the healing process, and especially for improving the survival rate and efficacy of hair transplants. But while PRP has been maturing as a clinical product, a new horizon of regenerative medicine is already showing on the horizon. The tools and techniques of the best and brightest research labs are beginning to converge into a single, groundbreaking, and very promising approach. An approach so powerful and nascent that it has no standard treatment parameters, no FDA-approved uses, and not even an agreed-upon name. We are at the bleeding edge, the raw frontier, of the “next gen” in regenerative and hair growth therapy. And the name we are using right now for that frontier is “exosome therapy”.
Platelet-Rich Plasma (PRP): The Established Workhorse
Before we dig into exosome therapy, it will help to take a quick look at PRP, which is where we started on this regenerative journey. A lot of the groundwork has already been done there. The concept is simple. Take the body’s own complex system of growth factors, cytokines and platelets (blood clotting agents) and concentrate and return them to the area in need of help. That usually involves first drawing the patient’s blood (15-60 milliliters, about a half cup or so—no more than a standard blood draw). This is placed in a centrifuge and spun at high RPMs, in a process called “differential centrifugation”. The blood separates into layers: red blood cells at the bottom, a thin “buffy coat” layer in the middle of white blood cells and platelets, and a PPP (platelet poor plasma) supernatant at the top. The process is then repeated to further separate out platelets from the other blood components. Platelets are disc-shaped cell fragments in our blood that circulate until activated, then perform the dual tasks of triggering coagulation and degranulating, or releasing all the healing goodies they contain. PRP has been used for a decade to “supercharge” the body’s own healing signals and boost the success rate of hair restoration surgery. By concentrating and injecting the patient’s own platelets directly into the scalp, PRP gives a concentrated dose of growth factors and cytokines to the hair follicles and blood vessels in the treatment area. The idea is that the cocktail of dozens of different growth factors will increase blood supply, extend the growth phase of the hair cycle, recruit and activate local stem cells in the hair follicles, and basically supercharge the scalp into healing and regrowing hair. Platelet concentrations in PRP solutions are usually about 3-5 times the baseline level in normal blood. Once prepared, it is activated by adding calcium chloride or thrombin, which triggers the platelets to release their contents, including the many growth factors and bioactive proteins they contain, directly on to the target tissue or injury site.
The Actions of PRP in Hair Restoration
PRP is used to treat androgenetic alopecia, or pattern hair loss, which is the most common cause of hair loss in both men and women. It is thought to have multiple mechanisms of action in the scalp and hair follicles. The flood of growth factors it supplies to hair follicles and surrounding tissue can lengthen and extend the anagen phase, or “growth” phase of the hair cycle, and “wake up” dormant hair follicles. It stimulates the formation of new capillaries, bringing more blood and nutrients to a scalp and follicles under attack. PRP can also target the stem cells found in the “bulge” area of the hair follicle, in the follicle’s outer root sheath, and activate them to proliferate and migrate, essentially “commanding” the follicle to re-build itself. These actions make PRP a potentially useful treatment on its own for early hair loss and a powerful adjuvant to hair transplant surgery. It can be injected into the scalp recipient area during or immediately after hair transplant surgery to potentially make a better environment for graft survival (“better soil for the seeds”) and speed up post-operative recovery, reduce inflammation, and improve graft survival and eventual density.
PRP’s Drawbacks and The Next Step
PRP, as the leading standard of regenerative hair restoration, is far from perfect. In fact, there is a lot about it that is far from perfect. First and most obviously is the variability in results, from person to person. This can be influenced by the patient’s age and overall health and more, but is also connected to the variability in the PRP preparation protocol itself. The procedure is an art as much as a science right now. Depending on the lab and the practitioner, the process of drawing the patient’s blood and spinning it in a centrifuge to separate the platelets from other blood components can result in wildly different concentrations of platelets, white blood cells and other components in the end product. A couple of other important factors include the skill and experience of the practitioner preparing the PRP and the medical team performing the injections, and most critically the fact that PRP is entirely dependent on the health and “juiciness” of the patient’s own blood supply. This is an autologous procedure (meaning it uses the patient’s own cells). Platelets are less potent in older patients, in patients who smoke, are obese, or have underlying medical issues like cardiovascular disease or diabetes. If your blood is just not that good, the PRP will not be either.
It is this last point that is the critical one, the source of both PRP’s best feature (absolute safety and low risk of allergic reaction and rejection) and its major, major drawback. While PRP takes advantage of a much larger and more powerful toolbox of growth factors and cytokines, it is limited by both the available supply in the patient’s body and the effectiveness of the procedure itself in using those tools in the most efficient and effective way. This is where exosomes enter the picture, as a potential solution and a method of re-writing the body’s own cellular language.
Exosome Therapy: The New Frontier
An exosome is not a cell. It is a tiny, nanoscale (thousands of times smaller than a human cell), extracellular vesicle (bubble) surrounded by a lipid bilayer membrane. Exosomes are natural products of all cells in the body, excreted (expelled or pushed out from the inside of the cell) as part of a process of cellular housekeeping and communication. To visualize an exosome, think of the cell’s nucleus like a small city and the nucleus’ DNA the city’s central computer. The computer (DNA) is too busy and too important to do every single job in the city (cell), so it creates specialized departments (proteins), each one tasked with handling specific jobs. These departments don’t just “know” what to do because they are physically constructed and shaped by the central computer in specific ways and given specific directions encoded in the DNA itself. The nucleus has to take a DNA strand and use special enzymes to “copy” that strand into a smaller working set of instructions, called messenger RNA, or mRNA. mRNA is then given the job of delivering copies of specific DNA instructions to a specific protein building machine in the cell, or ribosome. The ribosome reads the mRNA instructions and begins to assemble that protein using the raw materials available inside the cell.
The ribosome, in addition to building the protein, also reads the DNA instructions on the mRNA and assembles the complete protein, including all the correct molecular machinery and little amino acid “hooks” and “handles” that connect it to the ribosome and other proteins and structures in the cell and which allow it to travel to the correct place in the cell and perform its specific functions. Now think of that protein building process not just as a factory floor, but as an entire factory building, full of tools, employees and instructions. If you were to take that factory building and pop it into a bubble, seal it up and float it out of the cell, you basically have an exosome. Exosomes are very similar to another kind of cellular vesicle called an “apoptotic body” or an “apoptotic vesicle”. Both are cellular “buildings” floating in a bubble outside the cell. But the difference is that, while apoptotic vesicles are basically cellular trash cans, tossed out and left to be degraded by macrophages and immune cells in the extracellular space, exosomes are informational FedEx packages. They are loaded with information, “tucked inside” in the form of specialized proteins, enzymes, lipids and very specific forms of genetic information. This genetic information is different from DNA, and much more potent. The cell inserts not only mRNA (copies of DNA), but miRNA (microRNA, snippets of RNA that are not DNA copies, but instead can program and re-program cells) into exosomes. An exosome can thus be loaded with a specific program, function, or set of tools and sent off into the extracellular space where it will travel in the blood and body fluids to the target cell, and be absorbed by the target cell, which will act on the instructions and the tools provided by the exosome to do a specific job.
Exosomes in Hair Restoration
For hair growth, it is these extra sets of information, extra tools, and these extra messages that make exosomes so powerful. So how does all this relate to hair growth? Hair restoration surgery takes advantage of hundreds of tiny pieces of hair and follicle tissue that are cut out of the back of the head where they are genetically resistant to hair loss and transplanted to the thinning areas on the scalp where hair loss has already begun. Doctors use a fine needle to punch hundreds of tiny holes in the scalp. This is the soil. The punchings will be replaced by the donor tissue, or the seeds. Exosomes have been used in a number of research studies to show increased hair density, and in several clinical cases that have shown results comparable to traditional hair transplants with much less downtime. The process works like this: Doctors extract mesenchymal stem cells (MSCs) from sources like fat or bone marrow, culture them, extract and purify the exosomes, and repackage the exosomes into an injectable solution. Doctors then inject this preparation into the scalp using a fine needle, much like they would with PRP.
The first and most important benefit to exosome treatment over PRP is potency. Since exosomes are carrying not only growth factors, but more importantly extra copies of RNA (miRNA, messenger RNA) which can reprogram target cells and their function, they are more powerful, and effective at commanding cells to do specific jobs than PRP. A 2020 study in the Journal of Cosmetic Dermatology noted the importance of this effect, finding that exosomes can not only promote hair follicle regeneration, but they are better at triggering activation of hair growth-specific signaling pathways, such as Wnt/β-catenin, than some existing treatments for hair loss. A second important consideration is that while PRP is a made-to-order product, specific to each individual patient and each blood draw, exosome solutions can be manufactured in bulk and stored in huge, consistent, quality-controlled batches. This means that each vial of exosomes has a known, measurable, standard amount of active exosomes. It also means that there are dozens, if not hundreds of options for patients to choose from, each with a known source, production protocol, concentration and information on ingredients and more.
Thirdly, and perhaps most critically, exosomes for these treatments are usually allogeneic, not autologous (from the patient). There is a very high safety profile for this use of exosomes because exosomes are acellular (made of lipid bilayers, not cells) and are more “stealth” to the immune system because their lipid membranes have certain molecular “flags” on them that allow them to hide in plain sight from the immune system. Doctors take a blood draw from a donor (donated in accordance with strict screening and ethical protocols) to isolate the MSCs they want to use. The MSCs are cultured, the exosomes extracted and purified in a lab, and the whole batch packaged into an injectable preparation which is administered by injection just like PRP. This means that it is a potentially much more powerful, potent, consistent treatment than PRP, because it is not limited to what the patient already has in their system. It is a “fresh start” or a “blueprint” for the patient’s own cells to follow to help them rebuild and repair damaged tissue. The fact that it is an off-the-shelf, not patient-specific treatment, also means that it can be much less invasive and involved for the patient (no blood draw), can be stored and administered by clinics as needed, and manufactured by labs in standardized, quality-controlled batches. The therapy itself involves injections in a single session, and because of the reduced post-operative downtime, can be used in conjunction with PRP to create a potentially synergistic cocktail of powerful cellular signals (exosomes) to enhance a powerful set of growth factors (PRP). The best way to think of it is that while PRP may be like getting a collection of first aid tools and bringing them directly to the site of the injury, exosome treatment may be more like rebuilding and reconstructing the site from the ground up.
The Future: Beyond “Versus”
In practice, in a clinical setting, the use of exosome therapy for hair loss is nearly identical to the use of PRP. The purified solution is injected just below the surface of the scalp, superficially and in an evenly distributed pattern across the treatment area. Patients receive an initial series of treatments, and in some cases maintenance treatments, as part of a total hair restoration regimen. Results can vary from person to person, but in our experience early exosome treatment can result in improvements in density, thickness, and overall scalp coverage, with consistent results, often more robust and lasting than PRP or hair transplant surgery alone. The use of exosomes in hair restoration is also being tested as a means to create a more optimal environment for hair graft survival, and to speed up the post-operative healing and recovery period, reducing downtime and recovery time after surgery.
It should be emphasized, however, that while PRP is an established procedure with substantial clinical support, research, and regulation for a variety of applications, and while exosomes have been studied and are used in hair restoration as well as other therapies, it is important to emphasize the distinction. In the U.S. at least, exosome therapy for hair loss, much less any of the myriad other applications and potential uses, is a still an “experimental” or “investigational” procedure. The FDA has yet to provide clear regulatory and classification guidance on the issue, much less approve exosome products for hair loss or most other applications in dermatology and orthopedics. This is likely to change as better and more advanced exosome products are manufactured and submitted for FDA review, and as research continues to establish and validate the efficacy and safety of the treatments. At the moment, however, the legal/regulatory situation is a rapidly moving target, and patients need to be extremely well informed and cautious about providers offering exosome therapy for hair loss. At least in the U.S., the current standard of regulatory compliance and quality control for exosomes is that they are sourced from an FDA-registered and compliant laboratory (for manufacturing, storage and distribution, not specifically hair loss indications), and that the companies offering the product are transparent about its investigational nature and limitations and are registered with the FDA as part of the process of developing exosome therapies. To reiterate: This does not make the treatment FDA-approved, or approved for hair loss, or dermatology or orthopedics in general. It does mean, however, that the providers have a higher standard of quality control, source verification, and registration that provides a starting point for regulatory and legal compliance. For a patient, choosing an exosome product means first choosing a provider, and choosing a provider who is fully transparent about the nature of the product, its sourcing, and its expected and acceptable range of results and outcomes.
As for the future of this therapy, there is a lot of potential, and also a lot of headroom for improvement and enhancement of exosome treatment. At the moment, the natural and logical next step for many practitioners is to combine the two. Exosomes and PRP are complementary rather than exclusive, and “super-charging” a patient’s own PRP with a standardized dose of allogeneic exosomes is a logical and straightforward next step. It combines the relative safety of a fully autologous treatment (albeit one that does not include the isolation of MSCs) with the massive added benefit of exosomal cellular signaling that is more standardized, more powerful, and more consistent than PRP alone.
To sum up, from PRP to exosomes is the journey of hair growth and regenerative therapy over the past ten years. PRP has proven itself as an established and valuable treatment that can be used on its own for early to moderate hair loss or as an adjunct and powerful booster to hair transplant surgery. It is a mainstream tool in hair restoration clinics, and is an important and often used therapy in a variety of other fields, including orthopedics and sports medicine. Exosomes represent a much newer, much more nascent tool and approach. An approach so new and so wide open that there is not even consensus on a name for the thing we are all talking about! Exosomes have a similar mechanism of action to PRP, taking advantage of one of the body’s existing communication methods to trigger a repair and regrowth signal that is more direct, more powerful and more standardized than PRP. As the process matures, as the protocols and “machinery” of the labs behind exosome products becomes more standardized, consistent and automated, it is a potential game-changer in hair restoration and an extremely promising treatment for all kinds of regenerative and restorative therapies.
FAQ
What are Exosomes?
Exosomes are naturally occurring nanoscale extracellular vesicles (bubbles) that are released by nearly every cell in the body. An exosome contains proteins, enzymes, lipids, growth factors and special forms of genetic material that are specifically packaged by the cell into the exosome, and which are loaded with instructions, tools and resources for the recipient cell. In this way, an exosome is like a cellular FedEx package or a fully-stocked, fully-manned tool truck sent by a cell to do a specific job.
Can Exosome Therapy be Used as a Stand-Alone Treatment?
Yes, exosome therapy has been used as a stand-alone treatment for hair loss in some clinics, often as part of a clinical study or trial. There is currently some research into the effects and outcomes of exosome treatment, but more and better information is still needed before the therapy becomes fully standardized and well-established. We recommend exosomes be used in conjunction with existing and established hair restoration treatments.
What are the Possible Side Effects of Exosome Treatment?
Exosomes are acellular, meaning they are not made of cells but of lipid membranes, and this is one of the main reasons for their safety profile. The lipid bilayer membrane has certain molecular “flags” on it that are recognized by the immune system as “self”, making it much more difficult for the immune system to find and react to the exosomes. Some side effects, including itching, slight swelling and tenderness, and transient hair shedding, are possible but all are mild and temporary. Exosomes should not cause serious, dangerous or even common allergic reactions since they are not a foreign cellular product like an allogeneic stem cell treatment would be.
How Long Before I See Results and How Long Will the Results Last?
The process is usually done in a single session, although multiple sessions may be required or recommended, and some clinics provide a maintenance treatment after some period of time as well. Some patients experience faster results than others, but results are usually seen around three months. This is true for exosomes used in conjunction with hair transplant surgery as well, although some results, such as less post-operative downtime, are available sooner.
Exosome Treatment in Combination with Hair Transplant Surgery
Exosome treatment can be used in combination with hair transplant surgery in a number of ways. Patients can receive exosome treatments alone, as part of a total hair restoration protocol. We use exosomes not only as a primary treatment for early and moderate hair loss, but also as an adjunct and powerful booster to hair transplant surgery, either to help improve the microenvironment in the recipient area and improve graft survival, or to speed up and reduce post-operative downtime. The procedure is virtually identical to PRP, and involves a series of superficial scalp injections of the exosome solution in a grid pattern across the treatment area.
