Regenerative medicine for hair loss patients includes high-quality lysed platelets, prescriptions for topical finasteride with minoxidil, dutasteride, amniotic membrane, adipose-derived stem cells, Acell, appropriate vitamins, whey protein, low-level laser caps, and other nutritional supplements. There are some additional products on the market, which may offer benefits including RU58841, however, they lack supporting studies.
WHAT CAUSES ANDROGENIC ALOPECIA HAIR LOSS?
Hair loss is caused by multiple factors with a genetic predisposition. The origin of the gene for hair loss may be acquired from the father or the mother’s side of the offspring. If the father has no hair loss, the gene most likely comes from the mother’s side. In this case, the gene may skip a few generations passing down from grandmother to mother without any affected males. With female pattern hair loss, the female’s mother often exhibited signs of hair loss.
In androgenic alopecia there is a shortening of the normal cell cycle or growth (anagen), decay (catagen), and rest (telogen). At the end of telogen, follicles awaken, push the old resting hair out, and initiate a new growth phase. This resumption of growth results from a protein interaction between cells derived from the secondary germ, which is derived from the dermal papilla during catagen, and cells higher up at the bulge area of the follicle. To initiate the new cycle a protein called noggin suppresses the production of an inhibitory protein called BMP or bone marrow protein. Once BMP is suppressed cells at the bulge area up-regulate the WNT pathway, a new dermal papilla is formed, and the hair shaft begins to elongate and thicken.
A new anagen hair is fine, but gradually that follicle thickens. The hair becomes longer until the next resting cycle begins. The hair shaft becomes more elliptical in shape as it elongates. Prior to the new hair cycle, the follicle becomes less elliptical for reasons we do not comprehend. The hair then enters a new catagen phase, followed by a telogen phase.
All cells have a limited number of cycles of growth. Thus, with each cycle, the hair follicle’s life span shortens. The amount of pigment, melanin, in the follicle decreases, and the hair begins to thin and grow shorter due to a much shorter growing phase. Following the final phase, the stem cells necessary to initiate a new growth cycle are lost, and the follicle can no longer initiate a new growth phase. Hence, even though the follicle remains, it can no longer elongate and remains in a perpetual resting phase.
YOUNG HAIR VS. OLD HAIR
Hair follicles are like a cat with nine lives. The stem cells necessary to initiate a new cycle undergo a shortening of the telomeres with each new cycle. Once the critical number of cycles is reached, the follicle no longer returns to growth. There are marked differences between young hair and old hair. The concept of regenerative medicine is to slow the aging process of the hair follicle.
A young hair has a prolonged growth phase, produces a darker color, and is in its thickest diameter. Young hairs cover the scalp much better than older hairs. Older hairs begin to lose color, diameter, and potential length due to a shortening of the hair growth phase. In androgenetic alopecia, one’s hair ages much faster in the areas where hair loss will occur. Those with male pattern hair loss will have younger hair on the backs and the sides of the scalp, but physically much older hair on the top.
Older hair produces a lighter color and less coverage. The contrast in color between the older hairs on the top of the scalp and younger hairs on the sides of the scalp is one of the signs that one is losing their hair. Older hair begins to exhibit signs of thinning. As the hair continues to age, the coverage becomes less, and frank signs of balding emerge. Balding results from a loss of hair follicles. Although the follicle is still there, the very old follicle loses the capacity to regenerate a new hair follicle.
Eventually, even the hair on the back and sides of the scalp gets older and begins to thin. In fact, thinning occurs in all men and all women due to the aging process of hair that begins at age 35. Men in their 20s will have about 10 to 15% more hair than a man in his 70s. Although hair restoration surgeons preached for decades that hair transplanted from the back to the top would survive indefinitely, this is not the case. All hair transplants will lose 10 to 15% of the transplanted hair over time.
WHAT CAN YOU DO TO SLOW HAIR LOSS?
The best way to combat hair loss is to keep the hair follicles young for as long as possible. This is the principle of anti-aging medicine and regenerative medicine. Other factors such as inflammation occur during the transition from growing to resting and during the resting phase. The inflammation attacks the stem cells necessary to initiate a new growth cycle. Over time, this repetitive attack on stem cells causes a loss of stem cells. As hair loss progresses, the resting phase of the follicle increases in duration, so the stem cells are exposed to this inflammation for longer periods of time. The best way to keep hair youthful is to prolong the growing phase, which will prolong the duration of each cycle. In this way, the hair is protected from aging as long as possible. Hair will still age, but not as rapidly.
It is important to note that regenerative medicine works best when you begin the treatment as early as possible. As an example, consider that a person 80 years of age will never look and feel like he is 60 years of age when he begins regenerative medicine at age 80. Hair is similar, but hair loss is accelerated aging. A person with advanced hair loss in his 20s may have hair that is chronologically 60 years old. Thus, it is important for these individuals to begin treatment perhaps in the late teens. Those, who respond best to regenerative medicine begin minimal hair loss. Those with advanced hair loss, respond the least to regenerative medicine. One can think of it as training the body. A person in his late teens and early 20s can train to become outstanding athletes. However, if one waits until they are 40 to begin a strong exercise program, this person will never be able to perform as well as the 20-year-old. Consider Tom Brady, who just won his seventh Superbowl at age 42. Tom Brady began a rigorous exercise program at an early age and continued this into his 40s. Tom Brady also followed a stringent diet along with supplements to slow the tick tock of aging. If you want Tom Brady hair in your 40s and 60s, you need to begin early in life and continue a stringent anti-aging program.
IS HAIR CLONING POSSIBLE?
Some might shun the concept of maintaining the youthful nature of one’s hair and wait on cloning. These individuals are doing themselves a grave disservice because we have been waiting for the cloning of hair for over 30 years without any significant progress in the process. Considerable scientific research continues in the hopes that we may one day find a way to clone hair. The initiation of the growth cycle is exceedingly complex with cells from two different embryological origins, ectoderm and mesoderm. The interaction of various proteins is poorly understood, which makes the prospects of hair cloning unlikely. What holds more promise is to discover a way to repopulate stem cells into the dormant follicle so that a new cells cycle can begin. The ideal scenario would be to add young stem cells into an old follicle so that the follicle can return to its youthful state.
WHAT ARE THE MORE LIKELY MEANS TO POPULATE THE BALD SCALP WITH HAIR SHORT OF A SURGICAL SOLUTION?
Remember there is young hair and there is old hair. All hairs cycle – they grow, rest, fall out, and then regrow. All hairs have a limited number of cycles. All cells have a limited number of cycles. With each cycle, the telomers shorten and the lifetime of the hair and cell declines. In androgenic alopecia, hair begins to cycle more rapidly. The hair begins to lose color, then diameter, and finally, the hair is lost. Once the hair is lost, there is nothing that will bring that hair back. The hair is still there, but the hair ceases to grow. Jumpstarting these dormant hairs is the most promising solution for baldness and a much better possibility than hair cloning. However, that solution may be many years away. The prospect of awakening a dormant hair follicle is far more likely than hair cloning.
WHAT ARE YOUR OPTIONS TO TREAT HAIR LOSS IN 2021?
capacity to increase in number and diameter. Younger hair is more influenced by growth factor-rich mediums along with stem cell treatments. Hence, we want to catch hair loss as early as possible. Remember a person in his 20s will look and feel younger in his 60s should that person begin regenerative medicine in their 20s. One wants to begin treating younger hair rather than older hair.
WHAT ARE THE OPTIONS TO BEGIN AN ANTI-AGING PROGRAM FOR HAIR?
First, start at an early age. If you want Tom Brady’s hair later in life, you need to begin maintaining your hair at an early age. Here are some options to consider.
- 1. Oral 5 alpha-reductase inhibitors (finasteride and dutasteride)
- 2. Saw Palmetto (a natural weak 5 alpha-reductase inhibitor
- 3. Topical Minoxidil with or without Retin A to increase absorption
- 4. Oral Minoxidil
- 5. Topical finasteride with topical or oral minoxidil
- 6. Topical dutasteride with topical or oral minoxidil
- 7. Nutrafol
- 8. Low-level laser Caps
- 9. Whey protein
- 10. RU58841
- 11. Regenerative injections:
- a. Platelet-rich plasma (PRP)
- b. Lysed platelets.
- c. Amniotic Membraned.
- d. Exosomes.
- e. Adipose-derived mesenchymal stem cells
Let’s discuss 5 alpha-reductase inhibitors first. The oral forms have been out for many years. These products inhibit the conversion of testosterone into dihydrotestosterone (DHT), a hormone implicated in hair loss. There are two enzymes that can produce DHT. Type 1 isoenzyme is found in the skin where hair follicles reside. Type 2 resides in the prostrate. Finasteride blocks only one of these enzymes (type 2), while dutasteride blocks both enzymes. Circulating DHT levels will be lower with oral dutasteride. Both products slow the progression of hair loss. In my experience, neither product produces significant hair growth in most men. Furthermore, circulating DHT has other roles in the body such as the development of body hair. We are uncertain of other functions, but over time patients on these products can experience brain fog, depression, reduced sex drive, breast enlargement, and impotence. These products also reduce sperm count, semen volume, and sperm movement. Male fertility may be negatively impacted.
These oral forms are better than nothing, but there are better options today. Furthermore, these products work better when combined with minoxidil.
Topical finasteride with minoxidil is very cost-effective and efficacious in treating hair loss. This product actually grows hair on more individuals. Again, nothing will grow hair on bald skin. You must have hair on your head to respond to any of these products in a meaningful way. There are many ways to deliver topical finasteride and dutasteride. They can be delivered in a gel with a liposomal agent to increase absorption or in a solution with Retin A, azelaic acid, or other agents to increase absorption. Circulating DHT levels are not decreased as much with the topical forms of these DHT blockers, and side effects are less common with the topical versions. Topical concoctions work better when combined with minoxidil. The primary drawback to these topical options is a higher cost compared to the generic forms of finasteride and dutasteride. These products must be compounded in a compounding pharmacy, which leads to a higher cost.
LOW-LEVEL LASER THERAPY
There are a variety of laser devices on the market. Almost all of these devices are manufactured in China. The energy delivered varies significantly between devices. These devices are good for stimulating the hair follicle, but new hair growth is minimal. They are useful devices but do not expect to restore your thinning hair. The only cap Dr. Cole recommends is the Laser Cap, which has the highest energy of all the devices on the market.
REGENERATIVE MEDICINE FOR HAIR LOSS
PRP (PLATELET-RICH PLASMA)
Platelet-rich plasma (PRP) is a concentration of platelets. Platelets have two functions. When the body is cut, platelets clump to help stop the bleeding. As platelets clump, they release growth factors to initiate the healing process. In the late 1990s, the dental field and orthopedic surgery field decided to concentrate the platelets and use them in dental procedures and orthopedic injuries. PRP spread from these fields to plastic surgery and later to hair restoration procedures. In 2005, Dr. Ubel put PRP in hair transplant grafts prior to transplanting them to the scalp. He found that the survival rate of hair was 15% higher if the grafts treated with PRP. Subsequent to this, physicians began injecting PRP into the scalp during a hair transplant and to regenerate hair in people with hair loss.
When blood is spun with a centrifugal force, the cells will fall into layers based on weight. The red blood cells are the heaviest and lie at the bottom. Then there is a layer of white blood cells called the buffy coat. Above the buffy coat are the lighter platelets. Above the platelets is the serum with still lighter anions and cations of sodium, potassium, chloride, calcium, etc. PRP is further concentrated platelets. The normal concentration might be 150,000 to 250,000 per milliliter in the whole blood. Concentrating the platelets up to 5X increases them often over 1 million platelets per milliliter. These concentrated platelets have much higher concentrations of growth factors.
There is high-quality PRP and low-quality PRP. It is possible to prepare PRP in a very inexpensive way by spinning a tube of blood and drawing off the platelet fraction. However, this is usually a 1X concentration (150,000 to 250,000 per milliliter) of platelets with lower concentrations of platelets. Concentrating platelets up to 5X requires much more expensive equipment and supplies. However, there is also a difference in the quality of the PRP even with equipment that is more expensive. Thus, you need to know the specific cell counts of the equipment you are using. These cell counts include monocytes and granulocytes. Monocytes are positive, while granulocytes are negative. Then there also appears to be a difference between the quality of the platelets that is seen only by evaluating the growth factor concentration profile of the equipment you are using. The physician needs to know all of this. Higher concentrations of growth factors are optimal. Better quality platelets and higher concentrations of platelets will lead to a higher concentration of growth factors.
A comparison of good quality PRP and poor quality PRP for hair density and follicular unit density.
After preparing the PRP, the platelets can be injected without activation (not activated PRP) or with activation of the platelets. Not activated PRP has the lowest concentration of growth factors and is least desirable. Platelets can be induced to clump by adding a 1:10 concentration of calcium gluconate or calcium chloride just prior to injecting them into the area of hair loss. This means of inducement produces similar concentrations as activating the platelets with thrombin and is acceptable. Bovine thrombin cannot be used on humans due to the risk of hypernasality, disease transmission, or transfer of plasmids. Recombinant thrombin made from bacteria may be used but adds to the cost and offers no benefit over calcium gluconate.
Dr. Cole has studied this extensively and found that different PRP preparation systems produce different concentrations of growth factors. Furthermore, studies show that dermal papilla proliferation is greater when the concentration of growth factors is higher. The response of dermal papilla is dose dependent.
PRP VS. CRP
For this reason, Dr. Cole performed a study where he lysed the platelets using high energy sound waves that costs over $23,000.00 to purchase. He studied different protocols of lysis and found that subjecting platelets to sound energy in 30 second increments while chilled in a bath at 4 degrees Celsius for a total of 30 minutes of sonication produced 5X the concentration of high molecular weight growth factors. Higher concentrations of growth factors are desirable. Preparing PRP from the blood draw to the injection of the platelets requires about 2 hours using Dr. Cole’s method. Lysis of the platelets is preferred due to the higher concentration of platelets. Other methods can be completed in less than one hour, but do not produce similar results. Because this method of lysing platelets is much different other forms of PRP on the market, Dr. Cole called this method cytokine rich plasma (CRP).
Dr. Cole further studied the impact on hair loss following injection of the PRP. Dr. Cole found that with PRP prepared by the Angel System (hematocrit set at 2% and platelets set at 5X), the hair density increased by 50% at 6 months. Using the Regen system and a 5X concentration of platelets, hair density decreased by 25% at 6 months. Thus, the system of preparation produces different quality of platelets, as well. Again, no product will grow hair on bald skin so do not use these methods to treat bald skin. You can protect areas where you are thinning from the aging process, but at this time, only hair transplants will grow hair on bald skin.
Before good quality PRP or CRP.
Same patient 9 months after treatment with good quality PRP or CRP.
Platelets and cytokines have one more use in hair transplant surgery. Platelets and cytokines may be turned into a gel called platelet rich fibrin (PRF). PRF may be combined with Acell to improve the healing of the donor area extraction sites following FUE surgery. This is an excellent option to add the healing power of cytokines and growth factors to Acell.
Acell can be combined with PRP and does increase density and diameter slightly more with conventionally activated platelets. Acell may also be added to the donor area to improve healing and promote hair regeneration following minimal depth FUE graft extraction. Acell is a biphasic product derived from porcine bladder. This makes Acell a xenologous product, derived from a different species. Acell is FDA approved and is used by dentists, plastic surgeons, podiatrists, orthopedic surgeons, and ophthalmologists. Acell is an extracellular matrix that functions to direct tissue repair, cellular proliferation, and cellular differentiation following injury.
The amniotic membrane is derived from the placenta of pregnant women. This makes the amniotic membrane a true biologic and would be called homologous since it comes from the same species. This is unlike PRP, which comes from the same person and is termed autologous. However, there are some forms of PRP from some companies, which are homologous products. During pregnancy, the company producing the homologous amniotic membrane tests the female for every known infectious disease and then irradiates the product prior to packaging it for use on humans. These products are FDA-approved products. Amniotic membrane is another growth factor-rich medium that induces hair growth. This is an excellent product to consider and is reasonably priced. Amniotic membrane is used in numerous other health-related fields on humans.
Exosomes are small (50-150 nm) membrane-bound particles called extracellular vesicles that influence a number of signaling pathways that modulate cellular functions including proliferation, differentiation, migration, and even cell death. Exosomes begin as invaginations of the cell membrane termed endosomes. Endosomes may contain multiple vesicles. When the endosome is secreted into the extracellular space, it is called an exosome. Exosomes function as carriers of proteins, lipids, and genetic material to other tissues. The cellular machinery that produces exosomes is cell specific. The most promising exosomes might be those created by the dermal papilla. In the mouse model, dermal papilla derived exosomes the beta-catenin and sonic hedgehog levels, which induce anagen, in the mouse model. Exosomes from bone marrow can induce the dermal papilla, prolong cell survival, activate growth factors, and promote hair growth. The exosome can bind with the messenger RNA of a cell to produce growth factors and cytokines.
In theory exosomes can bind to receptors in the cells and influence the cells in a positive manner. Once injected the exosome may last between 30 minutes and three weeks.
Unfortunately, there are no good studies to show that exosomes of bone marrow origin increase hair density or prolong hair survival. Exosomes of chorionic membrane origin may function better because the cells may have more pluripotency or the capacity to influence more cells lines such as the hair follicle.
The exosome is an important area for future research, but they are very expensive because they are difficult to manufacture. Furthermore, there are regulatory issues that manufacturers should follow to ensure the quality of the exosomes and that exosomes are not produced by mutant cells. Hence the specific manufacturer their production protocol and, quality control measures must be known by the dispensing physician. Due to the high cost and lack of proof of efficacy, other products should be considered first before attempting the exosome as a treatment modality.
ADIPOSE DERIVED MESENCHYMAL STEM CELLS
Adipose-derived mesenchymal stem cells (ADMSC) is an autologous product derived from the patient’s own adipose. Adipose has the most abundant supply of stem cells in the human body. These stem cells include differentiated stem cells along with progenitor cells capable of becoming other cells like cartilage. While 85% of the cells in adipose are fat cells, the remaining 15% consist of mesenchymal and endothelial stem cells, leukocytes, lymphatic cells, pericytes, vascular smooth muscle cells, and extracellular matrix.
Adipose is easily aspirated from the legs, abdomen, or back using a cannula under local anesthesia. For the purposes of treating hair loss, 40 to 60 cc of lipoaspirate is all that is required. That is 3 to 4 tablespoons of adipose.
ADMSC secret growth factors including VEGF, HGF, PDGF, IGF, etc. ADMSC stimulates the dermal papilla, induces a new hair growth cycle, increases in hair density and diameter have been noted following injections of ADMSC in male and female patients with hair loss. Furthermore, angiogenesis (new blood vessel formation) is a benefit of ADMSC.
During anagen, the population of adipose cells and blood vessels increases and can double the thickness of the skin. There is a relationship between the adipocyte and the hair follicle. Adipose cell derivatives also exhibit an anti-inflammatory capacity. This may be important in the treatment of scarring alopecias like lichen planopilaris and telogen effluvium including alopecia areata. Androgenic alopecia also has an inflammatory component, which the immune-modulating effects of ADMSC may reduce.
Adipose and circulation increase during anagen.
DERMAL PAPILLA RESPONSE TO GROWTH FACTOR RICH MEDIA
We performed a study to evaluate the proliferation of cultured dermal papilla in response to a variety of growth factor-rich products. We also measured FGF-7, a potent stimulator of the cell cycle, levels in response to the products. We designed the study with positive control and negative control. The positive control included the base culture media with the addition of fetal calf serum, insulin, FGF, and bovine pituitary extract. The negative control was the base culture medium alone. In our first study, we evaluated lysed platelets from a single patient, commercial-grade lysed platelets from homologous sources, and commercial-grade amniotic membrane from homologous sources. We found the proliferation responded in a dose-dependent manner with the best response at the highest concentration of growth factors. The best response was with the addition of an amniotic membrane followed by lysed platelets.
We evaluated FGF-7 production by the dermal papilla, as well. FGF-7 production was also dose-dependent and the highest levels were produced by an amniotic membrane.
Hence, you need to begin regenerative medicine as early as possible in the hair loss cascade. You need to determine your budget for regenerative medicine and chose the best solution for you based on cost. Every patient with advanced hair loss will eventually run out of donor hair so begin regenerative medicine as early as possible and continue with those treatments. High blood pressure does not go away with one dose of an antihypertensive. Similarly, hair loss will not cease with a single dose of a regenerative product. Topical finasteride should be used daily or as frequently as possible. Injections should be given every 6 to 8 months. Perhaps adipose stem cell treatments can be delivered less frequently when combined with microfat and nanofat.
REGENERATIVE MEDICINE AT FORHAIR
Finally, if you are bald, no regenerative medicine is going to bring your hair back. You can reduce the loss in the periphery of your hair loss along the back and sides, but you are not going to fill in your bald areas. Currently, the only way to restore your hair in balding areas is FUE hair restoration surgery. Dr. Cole plans to open an office in Manhattan, New York in May 2021. Initially, this office will focus on regenerative medicine, but eventually, Dr. Cole will offer smaller hair restoration surgery procedures in Manhattan. As the team grows, Dr. Cole will offer larger procedures. Dr. Cole has the most FUE experience of any surgeon in the world and has focused exclusively on FUE surgery since 2003. Dr. Cole offers the most advanced regenerative medicine in the world for hair restoration including adipose-derived stem cells. Adipose has the largest supply of stem cells in the body. Adipose is easy to harvest through a minimally invasive procedure and easy to deliver.