Acell is an FDA approved bi-modal extracellular matrix useful in the regeneration of tissue. For this reason, I began working with this product on 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 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 the maturation of germ cells. Specific proteins play a role in the development of structures and organs. For instance, the targeted deletion of fibronectin in the murine embryo results in embryonic death with the disruption of a 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 extracellular 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 salamander 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 a variety 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 the regeneration of normal tissue.
When tissue injury occurs in mammals, there is first hemorrhage, then clotting (hemostasis), 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 the 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 submucosa 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 the risk of reaction to pig tissue, which is uncommon. There are notable successes with the regeneration of muscle, cardiac muscle, nerves, esophagus, tympanic membrane (eardrum), bladder, tendons, and skin. In two examples the tip of an amputated thumb has 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 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 single or multiple terminal hairs in an otherwise desert of hair loss 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 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 effects of androgenetic 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 excision the esophagus heals with an 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 neogenesis is hardly an acceptable mathematical trade-off. Should follicular neogenesis 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, let’s 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 resulting in healing with a 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 a 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 a platelet-rich factor (PRP) exterior to the ACELL. The concentration of growth factors functions 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 into 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 provide 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. Hitzig recently published the following paper on the benefits of combining Acell and PRP:
I have submitted two papers for publication regarding my clinical experience with Acell (Next Page):