19 May

Clinical Applications of Acell

Acell AppAcell is a FDA approved bi-modal extracellular matrix useful in regeneration of tissue.  For this reason I began working with this product in FUE extraction sites.  The objective of this presentation is to stimulate interest in Acell by other physicians with the hope that we will eventually generate clinically significant data to prove or disprove the early clinical findings as they relate to Acell.

With this in mind, let us contemplate how might we multiply the donor area?  For years we have focused on hair multiplication and hair cloning.  Neither has offered much in the way of hope other than the prospect that we might succeed in the next five years.  Unfortunately, we have been saying “in the next five years” for the past 15 years, yet we are no closer to the objective.  During this same time frame, those interested in multiplying the donor area have vastly overlooked the role regenerative medicine might play in overcoming this seemingly insurmountable obstacle.  Indeed tissue engineering might be the primrose path.

The ineluctable modality of the ineluctable visuality is that we are cannot possibly substantially cover a scalp that has lost 50% or more of the hair that originally covered the scalp with the 50% or less hair that remains on the scalp.    It is a mathematical inequality that will result in a significant disparity.    Lotus-eaters have for years substantiated their efforts to begin hair restoration in the young patient with hopes of scientific breakthroughs in hair cloning or hair multiplication.  Confabulated opinions are simply inexorable efforts pined on the relict of the confused majority, who fail to comprehend the calculus involved with covering the scalp with a consubstantial donor supply with no scientific breakthrough on the horizon.

Recent cognitive efforts in medicine attempt to understand developmental biology.  Such an understanding may help us capitalize on the potential of regenerative medicine.   It is well known that a fetus develops organs and structures by maturation of germ cells.  Specific proteins play a role in the development of structures and organs.  For instance, targeted deletion of fibronectin in the murine embryo results in embryonic death with disruption of normal blood vessel and cardiovascular development.  An understanding of developmental biology may help us in the quest to regenerate organs and structures in the mature mammal.

The extra cellular matrix (ECM) is the structural tissue between cells. While it may seem insignificant, the ECM does not simply hold all the cells together.  It is an information highway.  The ECM tells cells what to do, where to go, when to divide, etcetera.  Furthermore, it is chemotactic.  Cells are attracted to it.  Most importantly stem cells are attracted to the ECM.  As such ECM is a scaffold for such progenitor cells to accumulate and dictate the formation of specific structures and organs.

Take for example the salamadar arm.  Should this arm be amputated, an entire limb will regrow in 6 weeks.  When the arm is cut off, fibroblasts migrate into that area and they become stem cells that change from a differentiated cell to an undifferentiated cell.  These cells form a cluster called a blastema. A blastema is a pre-programmed cluster of stem cells that know what they should be, for example an arm.  Over a 6 week period these cells will form a completely fully functional new arm composed of muscles, nerves, bones, blood vessels, and external tissue. The question remains how we might replicate this process in man.

The answer resides in part in an application of ECM.  ECM is composed of varieties of components. These include collagen, fibronectin, laminin, and glycosaminoglycans (GAGs).  These components  encompass many proteins.  Some of the proteins such as fibronectin play both a functional and structural role.  ECM provides a structural scaffold that attracts stem cells and stimulates them to differentiate into specific structures.  ECM also contains a normal concentration of growth factors that promulgate regeneration of normal tissue.

When tissue injury occurs in mammals, there is first hemorrhage, then clotting (hemostatsis), followed by inflammatory cell infiltration.  This process is followed by cell death, fibroblast migration, new host ECM deposition, ECM organization and finally scarring.  This results in tissue repair and healing under normal circumstances.  In regenerative medicine there is tissue injury followed by hemorrhage with clotting.  This is followed by removal of injured tissue and subsequent re-growth of a new body part.

This is a complex process that is still poorly understood.  We are in the infancy of regenerative medicine.  Currently we are not able to regrow entire body parts or organs.  However, it appears that current science allows us the opportunity to regenerate portions of organs or tissues using ECM.

ECM is currently derived from the submucossa or basement membrane of the intestine or the bladder.  ACELL is derived from this basement membrane of the pig and is termed porcine in origin.  This form of ECM is isolated, purified, and sterilized.  It is FDA approved in humans.  The primary concern is a risk of reaction to pig tissue, which is uncommon.  There are notable successes with regeneration of muscle, cardiac muscle, nerves, esophagus, tympanic membrane (ear drum), bladder, tendons, and skin.  In two examples the tip of an amputated thumb have been regenerated.  While it is unlikely that we might regrow an entire limb or organ with present technology, we are successful in regenerating parts of organs or tissue with ACELL.

We have three interests in ACELL.  One is to regrow normal tissue in the donor area following our method of FUE, which is termed CIT.  Our second goal is to regenerate hair follicles in the donor area in the extraction sites.  The final goal is to regenerate or heal any transected or amputated hair follicles as a result of FUE.

We have followed ACELL since 2007.  We did not incorporate ACELL into our treatment protocol until we heard of potential success by Cooley and Hitzig with regard to hair restoration surgery.  While we view their success as inconclusive to date, we are inspired by their reports.  Their reports are primarily limited to strip based therapy.  We view this as a much lower probability of success than our method of FUE for the regeneration of normal skin tissue and donor hair follicles.

While cloning and hair multiplication may have the flutiest voice, tissue regeneration may be the apotheosis (epitome) of donor area expansion.   Hair cloning may be miles away.  It depends on the proper combination and sequence of genetic expression from two different tissue sources: epidermal and mesenchymal cells.  One might say that we can clone a sheep so why can’t we clone a hair?  In response one might consider that should all the ingredients be mixed in a bowl and then placed in an oven, it is quite simple to make a cake thought the gastronomical quality might vary from one chef to another.  Suppose that someone mixed all the ingredients in the bowl and then was told to make pure sugar.  This would be a much more challenging feat.  Such is the state of hair cloning.  It requires the proper sequence of genetic expression from two different embryological tissues.  Hair multiplication thus far focuses on multiplying cells in vitro and then re-injecting them into the scalp with the hope that they might induce follicular neogenesis.  Such efforts thus far have been a failure and may continue to fail indefinitely.  It is difficult to measure success in hair multiplication because new hair growth might be a recycling of hair that was in the exogen phase at the time cells were injected.  This would account for the fine, vellus like hairs that have resulted from hair multiplication studies to date.  Such fine, sparsely pigmented hairs provide inconsequential coverage that aptly parallels the accomplishment of hair multiplication presently.  Tissue regeneration of the donor area, however is a new concept that is in its infancy and may hold a greater potential for success, which I will expound on in due course.

Thus far the greatest success in follicular neogenesis is credited to cell multiplication.  As I have pointed out, it is impossible to know whether their successes are indeed true achievements.  Rather they might be failures that are actually natural cell cycling.  It is not uncommon to see a single or multiple terminal hairs in an otherwise desert of hair lost due to androgenic alopecia.  We have always wondered what factors allowed these single isolated hairs to survive the relentless onslaught of androgenic alopecia.  These hairs are not immune to normal cell cycling, however.  Suppose a few cycle out and while in their state of dormancy a renowned researcher injects a concoction of stem cells.   Imagine that miraculously this dormant hair cycles back into the growing stage.  The researcher notes the new hair(s) and claims false success.  The hair(s) would have re-grown regardless of the study or the injection of stem cells.   Such an occurrence would fully explain the variable and inconsistent findings of cell multiplication research.  This scenario also fully explains why the predominance follicles attributed to cell based neogenesis are fine, short, and lightly pigmented.  This explanation also explains the occurrence of occasional terminal hair.

Androgenic alopecia is a progressive miniaturization, reduction in length, and loss of pigmentation of affected hair.  Injection of stem cells into this wasteland of alopecia is presumed to cause what?  Is the miniaturized hair suddenly stimulated to metamorphose into a terminal hair?  Alternatively, are new terminal hairs induced to grow de novo?  What if a terminal hair arises from stem cell induction of a miniaturized hair?  Might that hair subsequently succumb to the same affects of androgentic alopecia in the next hair cycle, as this induced hair is genetically the same biologic structure?  The failure to achieve consistency and aesthetically substantial coverage from cell based therapy coupled with the unknown consequences should a breakthrough occur may limit the potential for cell based follicle induction in the recipient area.  Such limitations suggest we might prudently focus on tissue regeneration in the donor area.

Hair restoration surgery is a proven method of restoring hair on the bald scalp.  Despite the lack of imagination or progress by the founding father of hair restoration surgery, whose focus remained on cosmetically disfiguring plugs and the thirty-year span from the inception of hair restoration surgery to the origin of hair restoration utilizing natural groupings of hair follicles by Bobby Limmer in 1988, hair transplantation today is capable of creating a natural result.  Just as the old “plugers” went kicking a screaming into the new age of follicular unit transplantation, the old “strippers” are hanging on to their strip scars in the most ingenious, yet doomed means.  As published in the ISHRS practice survey from 2008, FUE is now 10.8% of all hair restoration surgeries, which is up from essentially 0% in 2002.  The fact is that hair restoration surgery continues to close the gap aesthetically with Mother Nature.

Dr. Cooley suggests that we should consider ECM to improve strip scars.  This philosophy is simply the natural progression of the morose delectation of the strip surgeon as strip surgery provides the least contribution of time and effort by the physician, yet brands the patient indefinitely with a linear strip scar.  Who is the beneficiary in such a procedure, the rancher or the cow?  Furthermore, a strip excision is often 1 cm or more in depth, one centimeter or more in width, and thirty or more centimeters in length.  Such a procedure removes at least 30 square centimeters of tissue and at least 2400 follicular units provided the strip averages 80 follicular units per square centimeter.  Suppose that you apply ECM into the wound margin prior to closure.  ECM is known to work best in partial circumference esophageal excisions where esophageal stricture is absent, whereas in complete circumferential excisions the esophagus heals with unacceptable stricture.  With complete excision of the strip to a depth of 1cm or more, we are asking ECM to regenerate structurally and functionally normal host adipose, dermis, epidermis, and hair follicles along a margin 30 centimeters or long in length.  Should ECM prove successful in all parameters, the most you might hope for is an additional one or two follicular units at a similar density as the pre-surgical density or a range of 240 to 480 follicular units.  Such a full thickness result might be asking too much of ECM.  Regardless, replacing 2400 donor area follicular units with no more than 240 to 480 follicular units via follicular neogeneis is hardly an acceptable mathematical trade off.  Should follicular neogeneis fail to occur, the best you might hope for is a structurally similar tissue along the suture line, but you would still have the resulting alteration in hair growth angles that are a necessary consequence of strip surgery.  You simply cannot drop the top half of a glass mosaic on the bottom half and expect the artist’s creation to tell the same story.  One would never consider doing this to an artist’s conception so why should we contemplate it with God’s creation when a more aesthetic method is possible.  Wouldn’t individual removal of isolated pieces of the mosaic result in an aesthetically more similar appearance to the original?

Before proceeding, lets focus on the biologic and physiologic potentials of ECM.  There are multiple manufacturers of ECM.  Some examples include products and companies such as Restore, CuffPatch, GraftJacket, TissueMend , and ACELL.  Suppose you cut your arm off and then applied ACELL’s ECM.  You are not going to re-grow your arm.  If you cut off your thumb at its origin and then applied ACELL, you are not likely to re-grow your thumb.  Alternatively, should you cut off the tip of your thumb, select trials have shown that you might regrow the distal 5 millimeters.  It is fully understood that a should a child cut off the tip of his thumb, such an amputation is far more likely to occur without biologic assistance.  The same would occur with a fetus.  An elderly man might under select circumstances regrow the tip of an amputated thumb, but it is far less likely to occur without some sort of modulation. The application of topical ACELL is linked with two occurrences where the tip of the thumb re-grew in elderly men.  While this may have occurred naturally, such an occurrence without induction is less likely in that it occurred in two cases.  As mentioned above, partial resection of the esophagus result in normal host healing without stricture.  Full circumferential resection of the esophagus result in healing with stricture.  ACELL is a tissue scaffold.  It attracts undifferentiated stem cells and induces them to produce local host tissue.  The scaffold then degenerates and is replaced by normal host scaffold.  The normal host scaffold then attracts and induces the production of natural host tissue that is structurally and functionally the same as the original host tissue.  In essence the smaller job is more likely to come to fruition, while the larger job is more likely to fail with the formation of some scar tissue.  In summary, a smaller project is more likely to bear fruit.

Follicular unit extraction or more appropriately termed individual follicular group harvesting (IFGH), results in the removal of the superficial surface of the skin and the follicles.  The adipose is left intact, as is the lower portion of the dermis.  In such an instance, the application of ECM has the requirement to regenerate only a partial thickness of skin and hair follicles.  Furthermore, the total surface area of skin excised is measure in square millimeters rather than square centimeters.  Studies conclude that ECM functions far better when expectations are minimized.

In addition, ECM might induce 2400 follicular units to re-grow provided that 2400 are removed.  Such possibilities far exceed the potential from strip surgery.  Should ECM fail to grow hair follicles, it is far more likely that ECM will induce normal tissue to grow in the FUE extraction site than in the full length of a strip harvest.  Regardless, the maximal potential for ECM is with FUE.

It is with this in mind that I began using ACELL, a specific brand of ECM.  Currently, I am applying it topically to the extraction sites and then adding platelet rich factor (PRP) exterior to the ACELL.  The concentration of growth factors function to further amplify the natural concentration of existing growth factors on the ECM and help seal the extraction site while externally coating the ECM so that the ECM has the greatest potential to attract and induce host cells to form their own natural matrix followed by regeneration of normal host tissue.  It may be that I must later mix the ECM with host dermal and follicular stem cells along with the infiltration of the extraction sites with PRP.  Regardless, my mission is to improve the probability of full hair coverage while leaving an intact donor area.

Suppose you were to take your fingers and sink them into a bowl of Jell-O.  If you removed your fingers rapidly, you would have Jell-O on your fingers and you would leave skin cells in the bowl of Jell-O.  This mimics the removal of hair follicles from the skin.  Some cells will remain behind in the subcutaneous fat.  Application of ECM might induce some residual stem cells to produce dermis, epidermis, and skin, as well as follicles.   Should we fail to produce follicles, I will follow up this attempt by mixing follicle stem cells, which Jimenez has shown to exist on the superficial 1.6mm of the follicle with normal dermal cells in the PRP.  I will then inject this mixture each extraction site.  Should this fail, I will subsequently come up with an alternative plan.

Patients who have a limited donor supply and a need for hair restoration deserve such efforts.  Ultimately, the goal is to help these individuals overcome their hair loss through advancements in science.  Many individuals are struggling with their hair loss mentally and emotionally.  They are out of hope.  My mission is to somehow overcome the limitations of the donor area so that we might provided a glimmer of hope and a potential resolution to the problems facing these individuals.  We were not always successful with body hair, but perhaps this new modality will offer an escape from the disgrace of hair loss that far too many men and women face today.

Jerry Cooley recently published a paper summarizing his experience with Acell:

Dr. Jerry Cooley’s Presentation on ACell MatriStem in Hair Restoration and Autocloning (Hair Regeneration)

Dr. Hitzig recently published the following paper on the benefits of combining Acell and PRP:

Dr. Hitzig- Benefits of combining Acell and PRP

I have submitted two papers for publication regarding my clinical experience with Acell (Nect Page):



Body Hair Yield following Acell Administration

John P. Cole, MD

1-25-10

Scalp donor area is the ideal source of hair for transplantation in Androgenic Alopecia.1,2 Unfortunately, the scalp donor area is limited in all individuals.  For this reason, the availability of alternative sources of donor area is desirable.  One source is body hair.  Regrettably, the yields and coverage potential of body hair are often unpredictable and often produce results that are not ideal.1,2 Therefore, it is potentially beneficial for us to identify means to improve the survival rate and coverage value of body hair.  One potential way to improve coverage of body hair is through the application of Acell, an extracellular matrix.

I compared the yield from beard hair transplanted to a donor area strip scar pretreated with Acell to the yield of chest hair transplanted to a donor area strip scar that was not pretreated with Acell.  The objectives of the study were to evaluate the yield of two different sources of hair and to see if Acell offered any potential increase in the survival rate of body hair.

Findings: The use of Acell resulted in a 92% yield for beard hair in the donor area scar at 6 months.  The absence of Acell resulted in a 0% yield for chest hair in the donor area scar at 6 months.

Methods:

I made all the recipient sites with a 1.3 mm solid core needle attached to a counting incision device available from Cole Instruments (CI). (Figure 1).  I obtained 50 anagen beard hair grafts using a 0.9 mm punch (CI) punch set at 2.3 mm depth on a (CI) minimal depth handle. (Figure 2).  I extracted 25 beard hair grafts from the right side of the neck and 25 beard hair grafts from the left side of the neck.  I then obtained 6 anagen chest hair grafts using the same 0.9 mm CI punch on a CI depth control handle set at 2.4 mm.

I chose a patient with 4 different strip scars.  I treated a 0.5 cm X 7 cm donor area strip scar located in the mid-line of the donor area, which was the superior most of 4 other strip scars, with 50 evenly spaced beard grafts.  This scar was located in Boxes 1 and 5 as I defined in Donor Area Mapping.3,6 (Figure 3).  I treated the 3rd most superior strip scar that measured 0.4 cm X 3.5 cm that was located in Box 6 with six chest hair grafts that were evenly spaced.

I pre-treated the scar that received 50 beard hair grafts with 2 cc of a solution containing 1mg/cc of Acell.  I injected the Acell into the full layer of the scar.  I did not pre-treat the scar that received 6 chest hair grafts.

Results:

After six months I evaluated the growth in each scar.  I counted the growing hairs by attaching the tip of a Gentian Violet marker to a Counting Incision Device (CID). (Figure 4).  Each time I counted a hair, I made a mark on the scalp at the base of the graft.  The CID recorded each mark accurately.

The growth of the beard hair was 46 out of 50 grafts.  The growth of the chest hair was 0 out of 6 grafts.

Discussion:

Anagen body hair grafts are identified by a characteristic pigmented shadow that is present just below the surface of the skin.  Anagen body hair grafts may also be identified by wet shaving the area one or two days prior to the transplant.  Wet shaving the body hairs against the grain cuts the hair even with the surface of the skin.  Anagen hairs will elongate over the ensuing day or two.  Telogen hairs will remain even with the surface of the skin.  Pre-operative shaving one day before the procedure is adequate for beard hair.  Other sources of body hair should be shaved two days prior to the procedure because other sources of body hair grow at a slower rate.

In the past I have noted a variety of differences in the survival rates of anagen body hair.1,2 Most of my studies where minimal density was attempted suggest an optimal rate of growth is 38 - 60% for body hair of any type.1,2 On occasion, body hair yield may be as high as 86%.1 Intact scalp hair yields vary between 72.5% and 133% depending on he study.4,5 With higher densities, body hair survival rates may be as low as 4%.1 We did not use Telogen hair body hair grafts because the yields are generally much lower than with anagen body hair grafts.1

Survival rate studies often are impaired by the lack of means to accurately record the number of hairs that grow.  The use of the Counting Incision Device, CID, equipped with a gentian marker on the tip allowed me to accurately record the number of hairs that grew.   I placed a purple mark at the base of each hair that grew.  (Figure 5).  In this manner I was able to insure that no hair was neither counted twice nor missed.  I was also able to insure that the recorded count was absolutely accurate.

This study shows both a difference in the survival rate of beard hair as compared to chest hair, as well as a difference in the survival rates for grafts placed into a recipient area pre-treated with Acell compared to a recipient area that was not pre-treated with Acell.  I performed an informal investigation to evaluate the survival of chest hair grafts placed into a strip scar that was pre-treated with Acell a year ago.  I noted that the growth of chest hair in the recipient area of this patient was not as good as the growth of his beard hair from a procedure performed 1 year before.  As a result I wanted to see if pre-treating the scalp with Acell had an improvement in the growth of chest hair.  The donor area scar was transplanted with beard hair one year prior to this study.  In the follow up procedure, I transplanted only chest hair to the donor area scar.  I treated the donor area scar with an injection of several cc of Acell 1mg/ cc.  I anecdotally found that the Acell improved the survival of chest hair in follow up 3 months later.  The natural follow up to this evaluation was to objectively evaluate the survival rate of body hair in donor scars in the absence and presence of Acell.

Strip scars are often devoid of hair growing in them.  Even with trichophytic closure, hair is often absent in strip scars.  Without the trichophytic closure one can usually count on these scars to be predominately devoid of hair.  The advantage of such a barren area is that they are useful for measuring transplant yields.  While it is true these areas are not normal skin, strip scars readily accept grafts and produce good yields.  Bald areas due to androgenic alopecia on the other hand often have dormant hairs that may resume growth at any point following the start of a hair yield study.  Unknown variables such as exogen hairs in an otherwise bald zone that resume growth prior to follow up may confuse hair growth yield studies.  Such regrowth may produce spurious results that are higher than actual yields.  Similarly existing hairs in a predominantly bald zone that are counted at the beginning of a study might evolve into the exogen phase prior to the follow up evaluation and result in an inaccurate lower yield than expected.  Scars rarely have such exogen hair issues.  Thus they are truly bald skin and potentially ideal for analyzing hair growth yields.

The use of a donor template allows us to more precisely define regions of the donor area and allow us to follow specific regions in the donor scar to evaluate hair growth yield. (Figure 6).  Each zone or box is predictable based on 8 major regions and 6 minor regions.  The presence of scar in any box may be easily annotated prior to a procedure.  Furthermore, any action in a specific box may be recorded during a procedure so that a physician can follow the consequences of any action, as well as monitor the density of follicular units in any given region.  Procedures may include removal of grafts via FUE or the location of any scar.  It could also allow for the annotation of a skin lesion that is present prior to a procedure.

Prior body hair survival rates suggest that a 60% yield is quite good.  Higher densities can negatively impact the yield.1,2 Conversely, lower densities can result in better yields.1,2 High body hair densities can occasionally produce high yields.  In this instance we did not seek a higher density, as we did not want to evaluate this variable.  Therefore all body hair densities were kept low in this study.

The length of hair growth for the beard hair suggested that many of the beard hairs began growing at the time of implantation based on a mean growth rate of 0.4 mm/day, which is similar to scalp hair (rate 0.37 – 0.42 mm/day).7 Most body hair grows at a rate of 0.23 mm/day, but increases to 0.33 mm/day upon transplantation to the scalp.1 Beard hair grows at a much faster rate than most other types of body hair.  Many of the beard hairs in this study were 6 cm in length, which implies a very fast rate of growth or an early resumption of anagen following transplantation for many of the hairs. It is unknown whether Acell played any role in the rate of growth or the onset of growth with these grafts.

The advantage of using beard hair for transplantation is that it produces a better cosmetic result even when different sources produce a similar or slightly higher yield.  The rational for such improved coverage is the increased diameter of the hair shaft, which results in improved hair volume.  Doubling the diameter of a hair shaft quadruples the volume of hair coverage since the volume of a cylinder of hair is equivalent to the formula: V = Õ r2 h.  Furthermore, body hair often seems to become finer upon transplantation to the scalp whereas beard hair seems to retain its larger diameter.  Finally, beard hair generally grows with a characteristic wave that adds to the coverage or volume in the scalp.  These features make beard hair more ideal to produce a cosmetic benefit to the coverage of the scalp than other sources of body hair.  Unfortunately, the added curl or wave can produce an unacceptable contrast in the grafted hair compared to the scalp hair in those with straight hair particularly when the scalp hair is straight and fine.

Beard hair often produces a yield of only 60%.1 In this instance the yield was 92%.  The 0% yield of chest hair in the donor scar was well below the expected yield.  Because the scalp donor area is finite and many patients often seek more hair than the donor area typically contains, sources such as body hair are desirable.   Unfortunately, many studies have suggested that the results and yields are quite variable.1 For this reason, it would be beneficial for us to find means to improve not only the coverage, but also the yield from any given source of body hair.  It appears in this evaluation that the application of Acell by injection may have improved the survival of the beard hair over previous beard hair survival studies and significantly improved the survival rate over alternative sources of body hair that were not treated with Acell.  It is not uncommon for different sources of body hair to produce different yields and there is no way to determine which source will produce a better yield or a better cosmetic result at this time.1,2 Never the less, it is not common for two different sources to have such a dramatic difference in yields.  The significant difference in yield between chest and beard hair in this study suggests that other variables such as Acell may play a role in positively modifying the yield of body hair.

This study suggests that we should further study the benefits of Acell in body hair transplantation to see if we can further improve the survival rate of the body hair grafts.   A good follow up study might compare the survival of body hair grafts of the same source in different regions of the scalp to see if Acell has an impact on the survival rate of the same source of body hair.  In this brief study it appears that Acell had a benefit on the survival of beard hair.  Acell was delivered by injection in this study.  One might also consider adding Acell powder to the grafts prior to re-implantation.

Bibliography:

  1. Cole, J. Body to Scalp, Hair Transplantation, W.P. Unger, R.M. Shapiro, R. Unger, M. Unger, S. Zarl, eds. Informa Healthcare: London, 2010; 304-306.
  2. Cole, J. Harvesting the Fallows, ISHRS meeting, San Diego, CA 2006.
  3. Cole, J. Donor Area Mapping, ISHRS meeting Amsterdam, Holland, 2009.
  4. Beehner, M. Hair Growth Studies in Follicular Units/ Micrografts (Seager and Beehner), In: Hair Transplantation. W.P. Unger and R.M. Shapiro, eds. Marcel Dekker: New York, 2004; p 263.
  5. Beehner, M. Mayer: FU Survival Rates for Different Recipeint Spacing, In: Hair Transplantation. W.P. Unger and R.M. Shapiro, eds. Marcel Dekker: New York, 2004; p 268.
  6. Devroye, Cole’s FUE safe area, Hair Transplantation, W.P. Unger, R.M. Shapiro, R. Unger, M. Unger, S. Zarl, eds. Informa Healthcare: London, 2010; 258.
  7. Abell E. Follicular data, Disorders of Hair Growth Diagnosis and Treatment, E Olsen, ed, McGraw Hill, 1994; p7.



Acell Survival Study

John P. Cole, MD

Introduction:  Acell has gained significant exposure as an adjunct to hair transplant surgery the past couple of years.  Dr. Cooley has reported that treatment of FUE extraction sites, as well as larger trephine punch biopsy sites does not result in follicle regrowth unless some transeted follicles were left in the extraction sites.  I have reported in the past that follicle regrowth following treatment of Acell FUE extraction sites has occurred in my hands.  In addition, I have seen improvement in the appearance of some hypopigmented extraction sites even in the absence of hair regrowth.  In this case study, I attempted to objectively evaluate the regrowth of follicles in the extraction sites that I treated with Acell following the removal of intact follicular groups.

Methods:  I divided the donor area into 8 major regions and 6 minor regions using my donor template. Figure 1.  I harvested a specific number of intact follicular groups from each quadrant and annotated the exact number on my donor extraction sheet.    I noted the transection rate for the patient following removal of the grafts.  The patient returned 14 months later for follow up.  I then once again divided the donor area into 8 major regions and 6 minor regions.  I then counted the number of hypopigmented extraction sites that lacked any follicles on the left side of the patient’s donor area.  Figure 2.  I counted each site using a Counting Incision Device (Cole Instruments) that I loaded with a gentian violet marker. Figure 3.  I placed a purple dot in each hypopigmented extraction site so that I avoided inadvertently counting each site more than once.  Figure 4.

Results:

Region

Extractions

Hypopigmented

Spots

Difference

Percent

Regrowth

5

95

44

51

54%

6

91

49

42

51%

7

70

34

36

51%

8

90

20

70

78%

9

10

11

-1

-10%

10

13

11

2

15%

Total

369

169

200

54%

Discussion:  Until now there have been no objective studies performed attempting to document the potential benefits of Acell.  Prior reports have been conflicting regarding the benefits of treating FUE extraction sites with Acell.  Dr. Cooley has found no benefit from treating FUE extraction sites with Acell, while my anecdotal evaluations suggested a benefit from using Acell in my extraction sites.

In this study I attempted to document the regrowth of follicles in my extraction sites.  There is not always hypopigmentation of extraction sites, but when there is hypopigmentation, extraction sites are easy to see because they are hypopigmented and have no follicles growing in them.  Even when one follicle is transected and there is regrowth of the follicle, it is usually evident that it is an extraction site when there is hypopigmentation.

I found there was an overall regrowth of 54%.  This mark is more important than the regrowth of each region because it is possible there was a slight shift in the exact location of each region even though I used a donor area template.  In all 200 out of 369 extraction sites had follicle regrowth.  It is possible that there was some regrowth due to a rare transected hair, but this is cause of study error would be small due to the very low follicle transection rate, which was 1.4%, in this patient during his FUE procedure.

One possible reason I find better regrowth in my anecdotal studies to date is that I use a minimal depth approach to my extraction sites, whereas many other physicians use a full or nearly full depth incision technique with a focus on extracting the surrounding adipose tissue.  The minimal depth approach allows me to ease or tease the follicles out from their original resting place.  This technique may leave behind some follicle stem cells that have the capacity to evolve into intact follicular units or groups following administration of Acell.

The lack of full regrowth and the variability in growth from each region may result from the difficulty in delivering the Acell to each extraction site when the powder is placed into each site using a jewler’s forceps.  This method makes it extremely difficult to determine which sites have already been treated and which have not.  This is especially true when the non-shaven extraction approach is taken as in this case report.

More recently I have been delivering the Acell in a mixture of hyaluronic acid and a more viscous form of methylcellulose.  I mix 15 mg of fine powder Acell in 1 cc of viscous fluid.  I then deliver this using a 25 gauge catheter tip.  This method makes it much easier to ensure that each site is treated.  Unfortunately, I do not have any data back from this method of treatment so that I can evaluate whether this form of delivery works as well as delivery of the product by itself.   Note that Dr. Cooley delivered the product by mixing it in saline.  I have not found that it is possible to create a paste using Acell and saline as practiced by Dr. Cooley, but it may be that mixtures are not as affective as the product delivered directly to the wound.

Current research of Acell suggests that it may have many potential benefits in hair transplant surgery.  We still need more scientific research to confirm these findings including statistically significant data.  To date, we lack statistically significant data to support the benefits of Acell.  In summary application of Acell has shown the following benefits.

  1. Potential regeneration of follicles in minimal depth FUE extraction sites treated with Acell.
  2. Potential improvement in pigmentation in FUE extraction sites in those individuals most prone to hypopigmentation.
  3. Potential improvement of survival rates and yield in plucked hair follicles.  Scalp hair harvested by FUE survival rates have not been studied yet.
  4. Potential improvement in survival rates and yields for grafts harvested by strip surgery methods.
  5. Potential improvement in the survival rates and yield of body hair grafts.
  6. Potential improvements in coverage from native hair when combined with PRP.
  7. Potential improvement in the consistency of scar tissue following closure of a strip harvest.
  8. Potential improved survival rates of follicles transected during punch harvesting or FUE.

Acell has shown no benefit in the pigmentation of full thickness punch harvesting ranging between 1 mm and 4 mm in diameter.  Acell has shown no capacity to regenerate follicles harvested by strip excision.


Autoclonning?

My thoughts on autoclonnig as described by Dr. Cooley and Dr. Hitzig are as follows:

Hair restoration surgeons have long demonstrated their mastery of double entendre.  In 1984 Headington first defined the follicular unit as a histological structure as disclosed at the mid-dermal level.1 Later in 1995 others popularized the use of the term follicular unit to describe a gross anatomical structure as disclosed on the surface of the skin.2 The term follicular unit thus took on a dual meaning with the latter one being far more ambiguous as it is often impossible to determine if the surface structures are one or more than one true follicular unit.  The bulge is the location of the attachment for the arrector pili muscle or an anatomical structure, but it is also the location of the stem cell niche, which is the entire length of the isthmus.3 The locations and importance of each are different.  Cloning has a well-recognized meaning.   Cloning means duplicating so that we have more than one identical structure.  Cloning is the ultimate grail to patients with hair loss as it implies an unlimited supply of donor hair.   More recently some have used the term auto-cloning to suggest that we are able to create more than one hair from a single plucked hair without providing evidence that an exact duplication occurs.4,5,6,7,8,9

Dr. Hitzig first used the term auto-cloning at the ISHRS meeting in New York.4 In this lecture he described the capacity to pluck beard hair and transplant it on the scalp.  We are all well aware that a plucked hair has the capacity to grow back as both men and women must repeatedly groom unwanted hair by plucking them repeatedly.  Therefore, when Dr. Hitzig presented his work on plucked hairs, the natural tendency for all is to assume that Dr. Hitzig was plucking hair in the usual sense.5 Dr. Cooley gave us a better understanding of what Dr. Hitzig was accomplishing in his forum editorial in 2006.7 In this editorial Dr. Cooley informed us that Dr. Hitzig was not plucking follicles in the usual sense.  Rather, Dr. Hitzig was plucking intact follicles.  Dr. Cooley was excited enough about Dr. Hitzig’s hair plucking technique that Dr. Cooley suggested Dermatology books should be updated because the literature had not previously demonstrated the capacity to pluck intact follicles.7 One might expect intact follicles to grow following transplantation.  One would be less certain that the plucked intact follicles would also regrow in the donor area.

Despite these early notes on auto-cloning, the subject was vastly over-looked until both Dr. Cooley and Dr. Hitzig raised the same topic in Boston last October.   Their work was commendable and noteworthy.   At this time both resurrected the term auto-cloning.  In their presentations they treated both plucked beard and plucked scalp hair with Acell prior to transplantation.  Both concluded that they had achieved auto-cloning as a result.  In other words, they were able to create two hairs from a single plucked follicle.  Unfortunately, just as in the original 2004 presentation, both failed to demonstrate that a plucked hair follicle from any source is able grow in both the transplanted recipient area and also re-grow in the donor area.  There was no evidence of hair duplication.  A cloned follicle in the truest sense would be the physically the same as the original follicle.  In that Dr. Cooley has demonstrated that his plucked follicles may grow finer than his transplanted FUE grafts in the same patient, he has shown that plucked follicles may not always be physically identical to the other donor follicles.  Hence I feel that auto-cloning is too strong a term to use at this time.

If we suggest that we have a new FDA approved product that may be combined with plucked hairs and produce two hairs from a single hair, we may expect a euphoric response from both patients and physicians.  When we have not demonstrated the capacity to duplicate hair, however, we should be careful to avoid the implication that we have discovered a means to clone hair.  I’m not suggesting that Dr. Cooley and Dr. Hitzig will not produce subsequent evidence, however.   In the interim, we should exercise greater caution.

I suggest we stick to evidence based medicine that depends on the following: hypothesis, methods, and results, followed by conclusions based on the results.  We should create an objective study to evaluate the potential for duplication of plucked hair grafts.  How can we do this?  It will not be easy and it may be nearly impossible to prove.  There are many obstacles in the way to obtaining useful data.  The greatest challenge will be to differentiate which of the more than 20,000 to 30,0000 follicles in a donor area might be the original plucked follicle. Finding a needle in a haystack might be easier simply because the needle looks different than the hay.

A theory that predicts everything predicts nothing.   There are infinite probabilities from plucking hairs so there are infinite potential outcomes.  Dr. Cooley has stated that sometimes he plucks an intact follicle, but other times he plucks a nearly intact follicle.  When an intact follicle is plucked, we can anticipate very little regrowth in the donor as my hair plucking efforts with FUE have demonstrated.  When we pluck a nearly intact follicle, the total amount of residual tissue remaining in the donor area has infinite uncontrollable outcomes such that regrowth is unpredictable.  In fact, Dr. Cooley has provided insight that nearly intact follicles from the beard and scalp may have a higher yield when treated with Acell.  How much tissue remains in the donor area?  Is there only outer root sheath and follicular sheath, or is there some inner root sheath and dermal papilla that remains?  Does the amount of tissue and embryological origin have any affect on regrowth?  Take for example Figure 1.  The upper follicle is an intact follicle.  The lower follicle is a plucked nearly intact follicle that lacks only a tiny fraction of the outer root sheath and dermal papilla.   The residual fraction in the donor area is estimated by the orange outline in Figure 2.  Suppose that only this tiny amount of tissue represented by the orange color remains in the donor area.  What is the probability that his tiny fraction can produce a follicle that is an exact duplication of the original follicle especially without Acell treatment?  We do know from transection studies that we often leave far more tissue in the donor area than is depicted by this orange fill, but we do not get 100% regrowth of transected follicles.  With so little tissue remaining in the donor area, how can we imply that we are duplicating hair follicles?

We have already redefined the follicular unit and the bulge with more ambiguous definitions, while over looking the established definitions.  Trying to establish a double entendre with the term cloning puts us at risk of becoming the subject of humor noir.  We have no evidence that nearly intact plucked follicles are capable of duplication and limited ways to prove this theory.  I suppose we could put an entire donor area at risk without knowing the yield from transplanting nearly intact follicles to the recipient area to prove the theory, but such an effort is dangerous.

Dr. Hitzig suggests that a combination of PRP and ACell can improve natural coverage of existing hair in those suffering from androgenic alopecia.  I have seen an improvement in coverage with PRP combined with Acell, but like Dr. Hitzig all these examples are purely anecdotal at this time.  Dr. Greco has suggested that PRP can improve the diameter of hairs undergoing miniaturization secondary to androgenic alopecia.10 This very well may be true, but the use of a Starrit Digital micrometer to evaluate follicle diameter is not the ideal method to evaluate changes in hair diameter.  Dr. Greco further states that a combination of PRP and an extracellular matrix that acts as a scaffold can result in improved coverage in up to 70% of patients.11 Acell does provide such an ECM.  Dr. Hitzig does present a few examples suggesting a response to PRP and Acell, but statistically significant data is lacking.  We have an absence of information as to whether PRP derived from arterial blood provides a better potential result than venous PRP and no data that suggests platelet concentrations are higher in arterial blood.  Again what we need in this instance is a well-defined study to draw any conclusions.

The use of Acell certainly has some exciting potential.  We still need far more documentation and scientific study before we jump to any firm conclusions.  I do suggest we refrain from use of terms such as cloning or auto-cloning until we have more definitive evidence.  The term has a connotation that is too euphoric without more conclusive evidence.

Bibliography

1. Headington JT: Transverse Microscopic Anatomy of the Human Scalp. Arch Dermatol 1984; 120:450.

2. Bernstein RM., Rassman WR, Szaniawski W, Halperin AJ: Follicular Transplantation, Intl Jl of Aesthetic and Rest Surgery, 1995; 3:119-132.

3. Jimenez F: Personal Communication 2011.

4. Hitzig G: International Society of Hair Restoration Surgery, New York 2003

5. Beehner M: Hair Transplant Forum Volume 13, Number 5 2003.

6. Hitzig G: Hair Transplant Forum, Volume 16, Number 2, 2006, p55.

7. Cooley J: Hair Transplant Forum, Volume 16, Number 2, 2006, p39.

8.  Cooley J: International Society of Hair Restoration Surgery, Boston, 2010.

9. Hitzig G: International Society of Hair Restoration Surgery, Boston, 2010.

10. Greco J, Brandt R: Hair Transplant Forum, vol 19, num 2, 2009, p9.

11. Greco J, Personal communication, October 2010.

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