11
Apr
2019

The Basics of Hair

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Introduction

Hair and hair restoration terminology can be confusing on the surface. This article will better acquaint you with the details of hair and language that is used by professionals. Reviewing this article should help you better understand the advice and descriptions provided by your hair restoration surgeon as well as prepare you for asking questions so that you get the most accurate information. We at Seager want you to feel informed and comfortable throughout the entire process of hair restoration.
In this article we will go over follicle anatomy and the role of different parts of the follicle. Next we will discuss how hair grows and what that means for baldness. We will next talk about the characteristics of hair and how it is pigmented and why hair maintains a curl. Hair density and the permanence of hair will be discussed and finally common hair disorders.

The hair follicle

Each hair follicle is considered a mini organ with different components that each possesses a distinct function (Figure 1). The root sheath of the follicle is a specialized layer of cells that house the hair bulb and growing hair fibre. The hair fibre is what you see protruding from the scalp and it is composed of three distinct cell types all of which are dead by the time the hair fibre grows out of the root sheath. The hair bulb contains the dividing cells that grow into the hair fibre. Along the length of the root sheath we find a small anchoring muscle, the arrector pili, which is responsible for making the hair stand up in response to emotional stimuli (e.g., fear or surprise) or physical stimuli (e.g., chill). Also attached to the root sheath is the sebaceous gland which is responsible for coating the hair with sebum. Sebum is necessary to prevent the hair fibre from becoming too dry as well as lubricating it as it emerges from the hair follicle.

 

Follicular units

If we observe from the level of the scalp we see that hairs appear to protrude from the scalp in irregular groups. It turns out that follicles tend to arrange in groups of 1-4 resulting in what are called follicular units. Follicular units share usually the same pore or pores very close together. In rare instances up to 7 hairs have been observed in single follicular units. The hair follicles of the body do not tend to group together to such a high number with 2 being the typical maximum count.
The distribution of the follicular unit density is not uniform throughout the scalp. Hair restoration surgeons have observed that 1-2 hair containing follicular units are normally found at the hair line with higher density follicular units (i.e., >3 hairs per follicular unit) found in the mid scalp and vertex (i.e., the crown) (Figure 2). The distribution of follicular units of different densities contributes to the natural fullness of scalp hair and the softness of the hair line. Natural looking hair line restoration requires the placement of single hairs followed by greater density implantation to prevent an artificial “too dense” hair line that can be produce by in-experienced practitioners. Hair restorations surgeons take immense care to study the density of a patient’s hair to plan the appropriate hair line so that a natural-looking hair is restored.

Hair growth cycle

Human hair grows asynchronously which is to say that it does not grow and shed all at once. Most other mammals have synchronous hair growth to accommodate changes in season. The random distribution of hair, in various points of the hair growth cycle, ensures that there are always 85% of our available follicles containing hair (1). Any given follicle can grow hair for between 3-10 years, with this number varying between people. With hair growing about 1.3 cm per month (2), human hair reaches an average maximum length of 101 cm. Some people’s hair grows faster but for less time and some people’s hair grows slowly for a longer time.
The hair cycle is described by 4 distinct steps; anagen, catagen, early telogen, and late telogen. Anagen is the growth part of the cycle and lasts roughly 6 years. Anagen is followed by the brief catagen phase, where the follicle stops producing additional hair. In early telogen, the follicle prepares to shed the hair. The final step of the hair growth cycle is the late telogen where the follicle rests.

Chemical communication occurs between the hair follicle and the nearby fat layer of the skin, which appears to play a crucial role in perpetuating the hair cycle. Maintaining or reinitiating this communication, is the subject of intense research. Platelet-rich plasma (PRP) (3) and transplantation of fat-derived stem cells (4) aim to coax the hair follicle back into the anagen step of the hair cycle.

Hair fibre and curl

The hair fibre is composed of three layers; the outermost cuticle, the cortex, and the innermost medulla (5) (Figure 4A). The cuticle is the protective layer that surrounds the inner cells of the hair. The cuticle itself does not have any colour. The bulk of the hair fibre is made up of the cortex cells that provide the structure of the hair by contain large amounts of the protein keratin. The cortex cells also contain the pigment that imparts colour to the hair fibre. The function of the medulla is bot well understood.
The curl of hair is created by the shape of the follicle beneath the skin (6,7). A curved follicle produces a curled hair fibre. As the hair bulb produces cortex cells, they fill up all of the space of the root sheath. The cells at the outside of the curve tend to be longer while the cells at the inside of the curve tend to be shorter. The shape is made permanent once the cortex cells die as the hair fibre emerges from the follicle. The shape of the exit of the pore also has been implicated in the hair curl. A more round pore exit is associated with straight hair, while an elliptical pore exit is associated with curly hair.
Modification to the curl of hair can be induced by heat, humidity, or chemicals. Heating of the hair fibre with blow dryers or hair irons cause changes to hydrogen bonds within the keratin of the cortex cells. Throughout the day the hair continuously absorbs humidity from the environment which reverses the hydrogen bond breakage.

Permanent hair straightening or curling is performed with chemicals that are able to break the disulfide bonds of the hair fibre. The disulfide bonds of hair are much stronger than the hydrogen bonds that can be simply heat treated. The chemical agents used in permanent straining or curling are very harsh and may damage the scalp is incorrectly handled.

Hair colour

Human hair colour is the product of a ratio of two melanin molecules; eumelanin and pheomelanin (8) (Figure 4B). All of the ranges of hair colour from blonde, red, brown, to black are created by the ratio of eumelanin and pheomelanin. As one ages the cells responsible for making the pigment become less effective and produce less pigment resulting in grey or white hair.
Hair may be coloured artificially with different levels of permanence. The cuticle of the hair fibre prevents environmental chemicals from entering into the hair but it also possesses properties that we can harness for artificial colouring. Temporary hair dye is designed to bind to the cuticle and is typically composed of large pigments molecules. Due to the loose association of the large pigment molecules with cuticle, they can easily be washed out. Semi-permanent hair dye functions like temporary dye, in that is able to interact with the rough texture of the cuticle but is instead composed of small pigment molecules that are more difficult to wash out of the rough cuticle. Permanent hair dye requires a different approach where the pigment molecules absorb into the cortex of the hair fibre where it cannot be washed out easily. To allow passage of the dye into the cortex of the hair fibre the hair is made to swell by applying an oxidizing agent and an alkaline agent.

Hair density and hair caliber

Humans possess roughly 100 000 hair follicles throughout the body and 20 000 of those are located on scalp. The appearance of a dense head of hair is the sum of multiple aspects of hair. The scalp of average person has roughly 80 follicular units/cm2 (5).
The apparent density is the result of the relationship of hair growing out of the scalp. Follicle units that contain greater numbers of hairs (e.g., 3-4 hairs) tend to impart greater density. The density of hair is highest at the top of the head and at the crown. The density of the hair at the hairline is considerably less with many follicular units containing only one or two hairs. Hair restoration surgeons take this fact into account, reserving 1 and 2 hair grafts for the hairline and greater hair grafts for space filling.
Hair caliber describes the relationship between the number of hair and hair diameter. Thick hair fibres have a thickness of 90-100 μm, medium hair has a thickness of 50-80 μm, and thin hair has a thickness of 30-40 μm. When determining hair caliper we take into account both the hair thickness and follicular density. A person with 50 units/cm2 and a thickness of 100 μm has roughly double the hair mass of a person with 85 units/cm2 with a hair thickness of 30 μm.
In male and female pattern baldness hair density is lost through the follicles miniaturizing and converting to produce vellus hairs. Vellus hairs are different from the thick pigmented terminal hair of the scalp because they do not contain pigment, are thin, and only grow a few centimeters.

Permanent and non-permanent hair

Not all of the hair of the scalp is vulnerable to male or female pattern baldness. Hair restoration surgeons have observed innumerable cases of hair loss and have determined the regions of the scalp where hair is deemed permanent. Specifically this is hair on the back of the head between the middle of the neck. The permanent region continues in a band from this region to over the ears and onto the temples. Any harvesting of hair grafts occurs from these permanent regions as any harvesting performed outside of these regions may end up falling out as male pattern baldness progresses.

Hair disorders

Androgenetic alopecia

Androgenetic alopecia is the medical name for the common age related hair loss that affects both men and women. Treatment for the condition can be performed pharmaceutically through the administration of topical minoxidil for men and women or oral finasteride for men. Finasteride is only indicated for use in men due to complications that could arise should pregnancy occur. Androgenetic alopecia presents in different ways in men and women. Men experience a distinct pattern called male pattern baldness where the hairline recedes accompanied a thinning of the crown. Female pattern baldness presents as diffuse thinning of the hair.

Alopecia areata

Alopecia areata is a rare auto-immune disease that causes patchy hair loss. Alopecia areata is treated with immune modulatory pharmaceuticals and corticosteroids (1,9). Alopecia areata affects men and women equally and can vary dramatically in severity. Alopecia totalis is a form of alopecia areata that affects the entire scalp. Alopecia universalis is the more severe form of alopecia where then entire body does not have hair. Alopecia areata can in some patients be permanent but is often temporary or cyclical. Individuals with alopecia areata may be eligible for a hair transplant if a region of hair loss has been stable without further hair loss for one year.

Conclusion

This review hopes to give you the basics of hair biology and inform you of aspects of hair anatomy that are relevant in how you hair restoration surgeon makes decisions about your treatment.

References

1. Unger WP, Shapiro R, Unger R, Unger M, editors. Hair Transplantation. 5th ed. Informa Healthcare; 2011. 538 p.
2. How hair grows [Internet]. American Academy of Dermatology, Inc; 2018 [cited 2019 Mar 19]. Available from: https://www.aad.org/public/kids/hair/how-hair-grows
3. Alves R, Grimalt R. A Review of Platelet-Rich Plasma: History, Biology, Mechanism of Action, and Classification. Skin Appendage Disord. 2018 Jan;4(1):18–24.
4. Guerrero-Juarez CF, Plikus MV. Emerging nonmetabolic functions of skin fat. Nat Rev Endocrinol. 2018 Mar;14(3):163–73.
5. Lam SL. Hair Transplant 360. Vol. 1. Jaypee Brothers Medical Publishers (P) LTD; 2011.
6. Tirado-Lee L. The Science of Curls [Internet]. Helix Magazine; 2014 [cited 2019 Mar 19]. Available from: https://helix.northwestern.edu/blog/2014/05/science-curls
7. Plowman JE, Harland DP, Deb-Choudhury S, editors. The Hair Fibre: Proteins, Structure and Development. Springer Nature Singapore Pte Ltd.; 2018. 224 p. (Advances in experimental medicine and Biology; vol. 1054).
8. Ito T. Recent advances in the pathogenesis of autoimmune hair loss disease alopecia areata. Clin Dev Immunol. 2013;2013:348546.
9. AAD. Alopecia areata: Diagnosis and Treatment [Internet]. American Academy of Dermatology, Inc; 2018 [cited 2019 Mar 22]. Available from: https://www.aad.org/public/diseases/hair-and-scalp-problems/alopecia-areata#treatment

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21
Mar
2019

Fat Cells for Hair Regeneration

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Introduction

Hair is one of the most important symbols of youth and vitality. People throughout history have sought methods to maintain and restore ones hair. Hair loss, especially in the young, can be psychologically devastating (1). For sufferers of male- and female-pattern baldness there is the potential for surgery to move healthy hair bearing follicles to bald scalp. Surgery however is not always possible in cases where the cause of hair loss is autoimmune as is the case in alopecia areata and scarring alopecia.
New research into the hair growth cycle and its associated phases has revealed the striking link between dermal adipose tissue (fat tissue) and the hair follicle (2–5). Fat tissue, it seems, is a multi-functional tissue that performs essential tasks outside of the scope of simple energy storage.
Fat tissue has also demonstrated its potential as a source of stem cell with the capability of being harnessed for therapeutic treatments. Here we present some of the exciting science of hair regeneration using adipose derived stem cells.

The Hair Cycle

Hair growth in humans is the result of the asynchronous growth of the follicles of the scalp (6). Each follicle undergoes four distinct phases: anagen, where the hair follicle grows; catagen, where the hair follicle ceases producing hair; early telogen, where the follicle is in a resting phase; and late telogen, where the follicle has shed its hair and is awaiting a signal to commence growth of a new hair. Humans are unlike other mammals in that they do not shed all of their hair at once. The anagen phase of hair growth can last between 3 to 10 years resulting in an average maximum length of hair of 100 cm. At any given time roughly 80% of follicles are in anagen and the remaining 20% are shedding, or resting. The combination of short growing hairs, full length (trimmed to desired length), and resting follicles results in the appearance of a full head of hair.
Investigations into the anatomy of the hair follicle in relation to the hair growth cycle have demonstrated that the follicle undergoes great changes in size. The follicle is at its largest during anagen and begins to recede during catagen. During telogen, the follicle is at its smallest. Along with these changes in size was the observation that the fat that lies under the skin, the dermal adipose tissue, would increase in size with the follicle such that the two tissues would physically touch. This observation was made in other mammal including mice and rabbits.

Fat tissue as a source of stem cells

Fat tissue is composed of more cell types than previously thought. Primarily the fat tissue is composed of adipocytes that contain the white fat that define the tissue. The other cells that reside in adipose tissue are circulating blood cells, fibroblasts, pericytes, endothelial cells, and pre-adipocytes. Pre-adipocytes are the most sought after cells because of their characteristic of being stem cells. For simplicity, pre-adipocytes are typically referred to as adipose derived stem cells. Adipose derived stem cells, it turns out, are one of the primary cell types responsible for driving the hair cycle.
When we think of stem cells, we think of the ability of specialized cells to change their function and become other types of tissue. While adipose derived stem cells have the ability to be coaxed into various cell types under lab specific conditions, during the hair cycle these cells don’t actually become hair follicle cells. They instead chemically communicate with the follicle in the creation of a feedback loop (discussed below). For a stem cell to make a good therapeutic treatment it must adhere to some basic characteristics. These include: obtainability through minimally invasive procedures, possess the ability to differentiate into multiple cell types reproducibly, be in high abundance, and be able to handle transplantation. Adipose derived stem cells are relatively abundant in fat tissue at roughly 3% which is significantly higher than other stem cell sources such as bone marrow who are only composed of roughly 0.01% stem cells (7,8). Adipose derived stem cells are easily transplanted and in high abundance making them an excellent candidate for therapeutics for these reasons (4,5).

Hair Follicle Anatomy

Hair follicles produce hair by going through distinct phases that involve the chemical feedback loop between adipose derived stem cells, mature adipocytes (fat cells) and the hair follicle. The anagen phase when the hair is growing sees the hair follicle grown to its largest size. At this point the adipose tissue also expands to engulf the root of the follicle. The cells of the hair follicle communicate with the adipose derived stem cells within the fat tissue. This indicates to the adipose derived stem cells to begin differentiation into fat cells. Differentiation is the act of a stem cell committing to a cell type. The hair follicle signals also tell the surrounding adipocytes to begin growing and increase their size.
During catagen, the hair follicle undergoes programmed cell death resulting in its overall shrinkage. At this time the hair follicle stops signaling for the fat tissue to grow and maintain its size resulting in the two tissues separating.
In early telogen, the hair follicle conversely, begins to be influenced by the fat cells. The fat cells send inhibitory signals to the hair follicle that encourage it to remain in a resting state, not producing hair. During this time the follicle has reached its smallest size but we still see a full length hair.
At the end of telogen, the hair is shed and the signaling environment begins to change. Induced by an unknown factor, the ASCs cells begin to send growth signals to the hair follicle inducing its grown and entry into the anagen phase. The signals of the fat cells are potentially blocked or out competed by the pro-growth signals of the adipose derived stem cells. Once the hair begins growth the follicle is back in the anagen phase.
The role of adipose in the form of adipose derived stem cells (stimulatory) and fat cells (inhibitory) then becomes clear. While the role of adipose derived stem cells is only half of the communication, it presents the question of whether it is possible to induce follicle entry into anagen (growth phase) by transplanting adipose derived stem cells into bald scalp.

Adipose derived stem cells used therapeutically

Fat cells and adipose derived stem cells compete for influence over the hair follicle. Transplantation of complete fat tissue into the scalp may not influence the microenvironment of the hair follicle because of this inherent competition. For effective use as a therapeutic the cell transplantation should contain an enriched population of adipose derived stem cells. Adipose tissue is harvested easily and routinely through liposuction procedures. To process the tissue and enrich the adipose derived stem cells population they must be separated from the fat cells. Centrifugation forces non-fat containing cells to the bottom of a sample tube thus making separation of the cells easy. Fat cells contain large quantities of white adipose making them unable to sink. These floating cells can then be discarded leaving only active cells. The cells can used in this state or undergo further processing. The optimal procedure for preparing and administering adipose derived stem cells has not been yet been determined.

Ongoing in clinical trials

The gold standard for developing a treatment is to perform clinical trials. Clinical trials are composed of a few crucial components that prove efficacy and safety of a given intervention. The two exciting trials discussed below are registered with the National Institute of Health (NIH, http://clinicaltrials.gov/) and are great examples with use of placebo (no active ingredient in the intervention) and participant blinding (preventing the patient or physician from knowing the true identity of the intervention). The world of stem cell research is expanding quickly and regulatory bodies like the FDA are responding in kind to create investigatory pipelines that expedite the approval of novel therapies (9).
The first trial (NCT02849470) is being undertaken by Healeon Medical in the treatment of male and female pattern baldness (10). The trial utilizes adipose derived stem cells that are further processed enriched, and administered to the scalp. The trial is currently enrolling patients 18 and older and is estimated to have 60 participants. The study began in 2016 and is slated to be completed in 2023.
The second trial (NCT03078686) is being undertaken by Dr. Ryan Welter of Regeneris Medical (11). This trial tests the hypothetical abilities of ASCs even further by utilizing them to treat scarring alopecia and alopecia areata. Both scarring alopecia and alopecia areata being autoimmune related with patients having reduced options for treatment. The trial is set to be completed in June 2019.

Non-FDA approved uses of stem cells

The FDA is extremely cautious when it comes to approval of new therapeutics. Current the only approved use of stem cell is in the transplantation of bone marrow (9,12). For any treatment to attain approval they must be backed up by a large body of clinical trials. The status of most stem cell applications are either for use with patients with terminal conditions, who have exhausted their options, or in experimental treatments whose efficacy and safety have not been determined. The hype around the potential uses of stem cell therapies have led to innumerable unscrupulous businesses administering and marketing untested and potentially dangerous treatments to naïve patients.
If a treatment sounds too good to be true then it probably is! Certainly make sure to question any treatment that does not report potential adverse reactions. If you find yourself unsure of an offered treatment, the FDA provides excellent resources for patients on a wide range of treatments and medical devices (https://www.fda.gov/).

Conclusion

We at Seager Hair Transplant Centre are excited about the future of adipose derived stem cell treatments. With the methods and safety still in the experimental stage, we are not ready to provide stem cell treatments at this time. The results of the clinical trials discussed above will greatly increase our understanding of stem cell use in hair regeneration.

References

1. Liu LY, King BA, Craiglow BG. Health-related quality of life (HRQoL) among patients with alopecia areata (AA): A systematic review. J Am Acad Dermatol. 2016 Oct;75(4):806–812.e3.
2. Chase HB, Montagna W, Malone JD. Changes in the skin in relation to the hair growth cycle. Anat Rec. 1953 May;116(1):75–81.
3. Festa E, Fretz J, Berry R, Schmidt B, Rodeheffer M, Horowitz M, et al. Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell. 2011 Sep 2;146(5):761–71.
4. Bunnell BA, Flaat M, Gagliardi C, Patel B, Ripoll C. Adipose-derived stem cells: isolation, expansion and differentiation. Methods San Diego Calif. 2008 Jun;45(2):115–20.
5. Gimble JM. Adipose tissue-derived therapeutics. Expert Opin Biol Ther. 2003 Aug;3(5):705–13.
6. Unger WP, Shapiro R, Unger R, Unger M, editors. Hair Transplantation. 5th ed. Informa Healthcare; 2011. 538 p.
7. De Ugarte DA, Morizono K, Elbarbary A, Alfonso Z, Zuk PA, Zhu M, et al. Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs. 2003;174(3):101–9.
8. National Institutes of Health , U.S. NIH Stem Cell Information Home Page. In: Stem Cell Information [Internet]. Bethesda, MD: Department of Health and Human Services; 2016 [cited 2019 Mar 6]. Available from: https://stemcells.nih.gov/info/Regenerative_Medicine/2006Chapter2.htm
9. Marks P, Gottlieb S. Balancing Safety and Innovation for Cell-Based Regenerative Medicine. N Engl J Med. 2018 08;378(10):954–9.
10. Healeon Medical Inc. AGA BioCellular Stem/Stromal Hair Regenerative Study (STRAAND) (NCT02849470) [Internet]. NIH U.S. National Library of Medicine; 2019 [cited 2019 Mar 1]. Available from: https://clinicaltrials.gov/ct2/show/NCT02849470
11. Welter R. Biocellular-Cellular Regenerative Treatment Scaring Alopecia and Alopecia Areata (SAAA) (NCT03078686) [Internet]. NIH U.S. National Library of Medicine; 2018 [cited 2019 Mar 1]. Available from: https://clinicaltrials.gov/ct2/show/NCT03078686
12. Marks PW, Witten CM, Califf RM. Clarifying Stem-Cell Therapy’s Benefits and Risks. N Engl J Med. 2017 Mar 16;376(11):1007–9.

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