Researchers from Columbia University Medical Center received a $2.5 million grant from the National Institute of Biomedical Imaging and Bioengineering to use stem cells to engineer soft tissue, developing a process that should ultimately allow scientists to use a patient’s own stem cells to develop tissue for facial reconstruction following disfiguring injuries from war, cancer surgery or accidents.

The Columbia research team, led by Jeremy Mao, D.D.S., Ph.D., associate professor of dental medicine, aims to create long-lasting soft tissue implants from mesenchymal stem cells harvested from the patient’s own bone marrow or adipose tissue. Mesenchymal stem cells can differentiate into bone, fat, cartilage and other types of cells.

“Our research has shown that mesenchymal stem cells can create tissue that is biocompatible with the host and that the continuous generation of these cells can replenished the implant to reduce shrinkage,” said Dr. Mao.

Currently, surgeons often graft from the patient’s own tissue, which creates additional wounds. Grafted cells also fail to stay alive, causing implants to shrink up to 70 percent and lose their shape and volume. Attempts have also been made to use fat cells left over after liposuction, but those cells also have a limited lifespan.

The Columbia team of biologists, biomedical engineers, biomaterial scientists, imaging experts and surgeons has shown that human mesenchymal stem cells can create long-lasting implants in mice. The implant is created by placing the stem cells into an FDA-approved scaffold that mimics the conditions needed to turn stem cells into fat cells. Because stem cells have the ability to replicate and differentiate, they can regenerate the soft tissue, keeping the implant from shrinking. In mice, these cells have successfully created fat cells that could be implanted and retained their size and shape for at least a month.

Because the implants can be molded into any size or shape, they could also be used for breast reconstruction.

While this research program does not directly impact hair loss, it shows how advances are being made in the field of tissue engineering.   Advances like this will ultimately lead to future developments in hair follicle cloning technology.

Cambridge, UK - Intercytex Group plc, the cell therapy company focused on aesthetic medicine and tissue repair, announces today a clinical breakthrough in regenerative medicine following the conclusion of a clinical trial in which laboratory-made living human skin has been fully and consistently integrated into the human body for the first time. ICX-SKN contrasts with all other living skin graft alternatives which biodegrade in situ after a matter of weeks.

In the trial - which is published in the July issue of Regenerative Medicine - a full-thickness skin sample was excised from the upper arm of six volunteers and replaced with Intercytex’ skin graft replacement product, ICX-SKN. After 28 days both visual and histological analysis showed that in all volunteers the ICX-SKN grafts were rapidly vascularised and overgrown with the hosts’ own cells, resulting in a fully integrated skin graft that had closed and healed the wound site.

ICX-SKN comprises a collagen-based matrix produced by the same skin cells - human fibroblasts - that are responsible for laying down the collagen in natural skin. The fibroblasts weave a collagen structure which mimics that found in skin and which shares many of the structural attributes of skin. Intercytex’ scientists believe that the combination of living human fibroblasts in a human fibroblast-produced matrix underpins the integration and acceptance of ICX-SKN by the host skin. To date, other living regenerative medicine skin constructs have degraded too quickly to act as skin grafts when implanted in the human body.

In certain wounds and burns the use of skin grafts taken from a different part of the patient’s own body is the optimal treatment to obtain wound closure. However, their use is avoided wherever possible because skin grafting itself is a painful and traumatic process that creates an additional wound. ICXSKN represents a potential alternative which could be of enormous benefit to patients and physicians.

The next stage of clinical development will involve application of ICX-SKN to larger wounds with a view to generating data that would enable rapid progress to pivotal trials and granting of a marketing licence.

Dr Paul Kemp, Intercytex’ Founder, Chief Scientific Officer and senior author of the paper, said:

‘Intercytex intends to develop a range of cell-based implants that can regenerate lost tissue and this research is an important milestone in the pursuit of that objective. For regenerative medicine to fulfil its promise, scientists need to develop cellular implants that are accepted and integrated into the human body. So far this has proved elusive but today’s research shows, for the first time, that it can be achieved.”

Dr Stephen L Minger, Director, Stem Cell Biology Laboratory, Wolfson Centre for Age Related Diseases, King’s College London and an acknowledged world expert in regenerative medicine, commented:

‘I think these results are a real breakthrough in the field of wound healing and regenerative medicine in general. To have an off-the-shelf skin replacement product that can be used in large numbers of patients will revolutionise the treatment of burned and skin damaged patients.”

Mr Ken Dunn, Consultant burns and plastic surgeon at University Hospital of South Manchester, said:
“Surgeons have long had a need for a skin graft replacement. The data described in this paper offer real promise to provide surgeons with a product that could be used ‘off-the-shelf’to help to heal patients.”

A recent U.S. DHSS report states that regenerative medicine is in ‘the vanguard of 21st century healthcare” with a ‘worldwide market for regenerative medicine conservatively estimated to be $500 billion by 2010″. However, the field has been limited by an inability to create tissues in the laboratory that are recognised as natural and can be fully integrated into the body.

InterCytex has signed a licensing agreement with BioLife Solutions Inc., a leading developer and marketer of proprietary hypothermic storage and cryopreservation media products for cells and tissues.

Terms of the 10-year agreement include an intellectual property escrow provision which guarantees Intercytex access under certain conditions to BioLife’s HypoThermosol storage and preservation media when used in the production of Intercytex’ VAVELTA (ICX-RHY), a facial rejuvenation product and ICX-TRC, their hair regeneration product, as well as annual license fees payable to BioLife.

Intercytex Chief Executive Nick Higgins commented on the selection of BioLife’s technology and the licensing agreement: “We completed a thorough evaluation of several commercial and generic hypothermic storage and preservation media products. HypoThermosol clearly outperformed all competing alternatives, so securing long-term access to the product was a priority.”

BioLife Chief Executive Mike Rice stated: “We are extremely pleased to be providing Intercytex with key enabling technology for the commercialization of their new cell therapy products. As a growing number of companies have realized, when used as a transportation and preservation media for biologic source material and finished cell therapy products, HypoThermosol provides optimal post preservation cell viability and function. This agreement validates the diverse applications potential of our intellectual property portfolio and the benefits our products provide to the cell therapy market.

Intercytex is the leading cell therapy company focused on the restoration and regeneration of skin and hair. Intercytex is using its fully integrated cell technology platform to develop living, human cell-based products, at commercially viable scale in attractive markets. Intercytex commenced operations in 2000 and currently employs around 75 staff. In addition to its head office in Cambridge, UK, it has a GMP clinical production facility plus research and development laboratories in Manchester, UK. Additional laboratories are located in Boston, USA.

Intercytex is asked many questions about ICX-TRC, so in response, they have created a new web-page to provide some answers.

Please note: ICX-TRC is at an early stage of its development and there are still many unknowns which will become clearer as their clinical program develops and the regulatory environment matures. The answers given below are provided by Intercytex in good faith based on current knowledge, but they are subject to change due to clinical trial results, scientific research or other factors which influence the development of new healthcare products. Therefore, anyone reading the information below is asked to do so in the same spirit and should not alter any current or future medication or hair treatment plan as a result.

Their web-site is frequently updated so please see the relevant pages for the latest information on ICX-TRC.

When this or any other info is updated an alert will be sent to everyone who has registered via their alert service, which can be found at this link: http://www.intercytex.com/icx/services/alert/

Frequently Asked Questions about ICX-TRC

1. How can I receive ICX-TRC?

ICX-TRC is currently in Phase II clinical trials in the UK, so it is not yet widely available.

2. When will ICX-TRC be on the market?

ICX-TRC is classified as a medicine by the regulatory authorities and hence has to undergo a series of clinical trials before it can be offered on the market. We currently estimate that the earliest that ICX-TRC would be available on the market is 2010 although we don’t know in which country it will be launched first.

3. How can I stay in touch with ICX-TRC’s progress?

Please watch our website for news and announcements about ICX-TRC and sign up via the news alert so you can stay up-to-date with our progress.

4. When will the Phase II trial be completed?

It is a rolling trial which will optimise the formulation and delivery as well as studying safety and efficacy. We expect some data will become available during 2007. We anticipate the current trial will complete during 2008.

5. Will there be a Phase II or III trial in the US?

At the moment the Phase II trial will be conducted in the UK only. Phase III trials may be conducted in both the US and the UK but plans to do so have not been finalised.

6. May I take part in the Phase II clinical trial?

The trials are being conducted at the Farjo Medical Centre in Manchester so all volunteers need to come from that area of the UK, partly for safety reasons but mainly because of their evaluation at the clinic for 48 weeks after the procedure has been undertaken. If you live in the Manchester area and would like to be considered for participation in the trial, please contact clinicaltrials@intercytex.com.

7. How much will ICX-TRC cost?

It is too early to be able to determine the likely price.

8. Will ICX-TRC be available on the NHS or covered by insurance?

We don’t know if ICX-TRC will be available on the NHS, however most procedures regarded as “cosmetic” are not covered by NHS or medical insurance.

9. Do you have before and after photos?

There are no before or after pictures yet. This is because the first clinical trial, the Phase I trial, was to test for safety not efficacy. Although hair growth was observed, it was not the primary purpose of the trial.

10. Will it be possible to grow a full head of hair using ICX-TRC?

Theoretically yes. If a person has enough hair at the back of the head from which to take a small sample of cells, we believe that ultimately it may be possible for their entire head to be re-populated with hair using the procedure.

11. If I have had a transplant will it prevent me from using ICX-TRC at a later date?

No, not at all. It may well be that ICX-TRC will work very well with a transplant and could be used to “top-up” a transplant if there is insufficient hair for a whole transplant to be carried out.

12. Would I need several treatments with ICX-TRC?

ICX-TRC will not stop the natural process of hair loss so what you might need is a series of “top-up” treatments over time so that a full head of hair could always be maintained as you continued to lose your own hair. We anticipate that only one small biopsy would be required at the start though as the cells would be cryopreserved and thawed as needed.

13. Would new hair grow in the same direction as the old?

In the ICX-TRC procedure we are not transplanting hair follicles, instead we are implanting cells into the skin which induce new hair growth, so there is no reason for these hairs to grow in a different direction from before.

14. Could ICX-TRC be used to treat the hair loss found in alopecia areata and totalis?

We do not know if ICX-TRC could be used to treat these conditions. These conditions are thought to be caused by an autoimmune mechanism. Since ICX-TRC is autologous (meaning it uses the patient’s own cells) it may be that the underlying autoimmunity might attack and destroy ICX-TRC cells just as it attacked and destroyed intact hair follicle cells to cause the initial hair loss.

15. Would new hair be resistant to the hormones that cause hair loss in the first place?

Male pattern baldness, the most common type of hair loss, is caused by hormones which generally affect the central and frontal areas of hair but not the entire head. Hair at the back and sides remains and it is cells from this part of the head – cells which are resistant to the hormones, that are used in the ICX-TRC process.

16. Could ICX-TRC be used to treat female diffuse alopecia?

We hope so. If ICX-TRC is successful in Phase II trials for male pattern baldness, we plan to begin trials for female diffuse alopecia.

17. Would it be possible to use donor hair for the ICX-TRC procedure if for example, someone had lost all their hair, wanted different coloured hair or a different textured hair?

In short the answers are maybe, no and no. The use of allogeneic or donor cells is a long-term goal but it is many years away. The colour of the hair comes from the epidermis and not the dermal papilla cells so the cells that are cultured have no influence on hair colour. Different textured hair would also require allogeneic cells which is currently not possible.

18. How will ICX-TRC be administered?

ICX-TRC will be administered by a healthcare specialist; a dermatologist, plastic surgeon or similarly qualified individual who will need to take a biopsy (a small sample of cells from the back of the patient’s head) during the first part of the treatment and to inject cells into the patient’s scalp during the second part of the procedure.

19. Does the ICX-TRC procedure result in the regeneration of miniaturised follicles or the growth of new follicles (neogenesis)?

Studies indicate that both of these mechanisms may be active. “Intrafollicular” implantation would take advantage of the follicle structure retained by the miniaturised follicles – these follicles would already be aligned in the appropriate direction so rejuvenating or reactivating such pre-existing hairs may be easier than forming new ones in the case of “interfollicular” implantation. Intercytex is looking at both neogenesis and regeneration.

For more info on this techonlogy click on the link below to access the following publication:

Follicular Cell Implantation: An Emerging Cell Therapy for Hair Loss by Jeff’ Teumer PhD and Jerry Cooley MD, Seminars in Plastic Surgery/Volume 19, Number 2, 2005
http://www.thieme-connect.com/ejournals/abstract/sps/doi/10.1055/s-2005-871735

Aderans Research Institute, Inc., has just been issued a patent for their bioabsorbable scaffolds.  These scaffolds are used in hair cloning procedures to ensure that the cultured cells are kept in place in order for a new hair follicle to be formed.

The patent, number 7,198,641, which was initially filed on August 7, 2001 and has subsequently been revised, was finally issued on April 3, 2007.

According to the patient, the “bioabsorbable scaffolds are useful for the tissue engineering of new hair follicles and to methods for their manufacture and to methods of their use in creating new hair. More specifically it relates to new and useful bioabsorbable porous structures that have the correct architecture to facilitate culturing of the appropriate follicle progenitor cells and their development into normal, functional, hair-producing follicles. The invention also relates to methods of making and using bioabsorbable scaffolds to implant and grow new hair follicles in vitro and in vivo.”

These tiny scaffolds are essentially the key to being able to grow new hair follicles because without them the cells cannot be held together after being injected into the scalp.   New hair follicles get created in a specific process that results from the interaction between different cells.   If these cells cannot be held together in the same place by some mechanism, then they will simply disperse from the point of injection and no new hair follicle will be formed. 

The process for using the scaffolds to grow new hair follicles goes something like this:

Human hair follicles are dissected to obtain the dermal papilla, which are transferred to a culture flask containing culture media. After several weeks in culture, the dermal papilla cells multiply and grow over the surface of the cell culture flask. These cells are detached from the flask by treatment with an enzyme and concentrated by centrifugation.

The cells are then transferred, after re-suspension, by pipette into the scaffolds and the cell-seeded scaffolds placed in a culture flask with media for several days to allow the cells to adhere to the surfaces of the scaffolds. Culturing of the cell-seeded scaffolds is then continued in another flask of media with gentle stirring until the scaffolds are fully populated with cells.

Scaffolds that have been seeded are implanted into the scalp of a human experiencing hair loss. Over time, as new hair follicles are created, new hairs grow from the implants, and the scaffolds bioabsorb.

Intercytex recently released their annual report which includes details of their hair cloning technique dubbed ICX-TRC.

The Phase II trial of ICX-TRC, their cell therapy product for hair regeneration in male-pattern baldness, began in September 2006.  The process involves taking a biopsy from the subject, separating out the relevant cells, and growing them in their facility using a proprietary process.

All biopsies from the first group of 9 patients have been taken and most of these patients have been treated.  Further groups will follow to investigate variations in the delivery technique.   Intercytex expect to report preliminary data from this trial around the middle of 2007.

In the Phase I trial, which had 7 subjects, there were no safety issues and 5 out of the 7 patients had an increased number of hairs after treatment.  The Phase II trials have 10 patients per group and is ongoing.  It is an efficacy trial designed to look for new hair growth.

Intercytex has also received a £1.8m grant from the British government to assist in the commercialization of their process.

Newswise — A newly discovered small molecule called IQ-1 plays a key role in preventing embryonic stem cells from differentiating into one or more specific cell types, allowing them to instead continue growing and dividing indefinitely, according to research performed by a team of scientists who have recently joined the stem-cell research efforts at the Keck School of Medicine of the University of Southern California. Their findings are being published today in an early online edition of the Proceedings of the National Academy of Sciences.

This discovery takes scientists another step closer to being able to grow embryonic stem cells without the “feeder layer” of mouse fibroblast cells that is essential for maintaining the pluripotency of embryonic stem cells, says the study’s primary investigator, Michael Kahn, Ph.D., who was recently named the first Provost’s Professor of Medicine and Pharmacy at USC. Such a layer is needed because it is currently the only proven method to provide the stem cells with the necessary chemical signals that prompt them to stay undifferentiated and to continue dividing over and over.

Still, growing human embryonic stem cells on a layer of mouse fibroblasts has never made much sense to the scientists forced to do just that. “Stem cells that grow on feeders are contaminated with mouse glycoproteins markers,” Kahn says.

“If you use them into humans, you’d potentially have a horrible immune response.”

And so, in order to take any eventual stem cell-based treatments from the laboratory to the clinic, there needs to be a way to keep the cells growing and dividing without the use of mouse fibroblasts. The discovery of IQ-1, says Kahn, is a significant step in that direction.

What IQ-1 does, Kahn explains, is to block one arm of a cell-signaling pathway called the Wnt pathway, while enhancing the signal coming from the other arm of the Wnt pathway. The Wnt pathway is known to have dichotomous effects on stem cells i.e. both proliferative and differentiative. More specifically, IQ-1 blocks the coactivator p300 from interacting with the protein ß-catenin; this prevents the stem cells from being ‘told’ to differentiate into a more specific cell type. At the same time, IQ-1 enhances the interaction between the coactivator CBP and ß-catenin, which signals the cells to keep dividing and to remain as fully potent stem cells.

“This way, you can essentially maintain the stem cell’s growth and potency for as long as you want,” Kahn says.

The studies of IQ-1 and its effects reported in the newly published PNAS paper were performed at the University of Washington in Seattle by Kahn and his colleagues (along with collaborators from the Asahi Kasei Corporation in Shizuoka, Japan) using mouse embryonic stem cells, but Kahn notes that subsequent pilot studies using human embryonic stem cells, in collaboration with Dr. Qilong Ying at the Center for Stem Cell and Regenerative Medicine at the Keck School of Medicine, have confirmed that IQ-1 plays a similar role in that system as well.

“If we can create a totally chemically defined system for growing human embryonic stem cells without any risk of contamination, it would make life much easier for scientists than it is at the moment,” says Kahn. “And that’s our goal.”

“Kahn’s study provides us with striking new insights into the molecular regulatory machinery inside embryonic stem cells,” adds Martin Pera, Ph.D., director of the Center for Stem Cell and Regenerative Medicine at the Keck School of Medicine. “His team has identified a chemical that controls a critical switch that enables stem cells to multiply indefinitely in the laboratory. These findings will help lead to the development of new techniques to propagate pure populations of embryonic stem cells on a large scale, an essential prerequisite to the successful development of stem cell based therapies.”

Tomoyuki Miyabayashi, Jia-Ling Teo, Masashi Yamamoto, Michael McMillan, Cu Nguyen, Michael Kahn, “Wnt/ß-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency.” PNAS Early Edition, Mar. 19, 2007, http://www.pnas.org/.
 

Researchers in Japan have just published a study where they succeeded in culturing dermal papilla cells for more than 30 passages (generations).

Usually when cells are cultured they lose their properties after only a few passages rendering them useless.  Therefore being able to culture cells for more than 30 passages means that the amount of cells you can clone from a single source is significantly greater.   

They were also able to induce the formation of new hair follicles by injecting these cells together with epidermal cells into mice.

Based on their study they concluded that fibroblast growth factor-2 is essential for the culturing of dermal papilla cells.

Long-Term Culture of Mouse Vibrissal Dermal Papilla Cells and De Novo Hair Follicle Induction

Tissue Eng. 2007 Mar 6
Osada A, Iwabuchi T, Kishimoto J, Hamazaki TS, Okochi H.
Department of Tissue Regeneration, Research Institute, International Medical Center of Japan, Shinjuku-ku, Tokyo, Japan.

We have succeeded in culturing dermal papilla (DP) cells long term and developed new techniques that enhance their hair follicle-inducing efficiency in a patch assay.

The outgrowing DP cells from mouse vibrissae were markedly stimulated by 10% fetal bovine serum-Dulbecco’s modified essential medium that included fibroblast growth factor-2 (FGF-2). Moreover, the potency of proliferation was maintained during serial cultivations (more than 30 passages).

We combined these established DP cells with epidermal cells and implanted them subcutaneously into athymic mice to examine their hair follicle-inducing ability.

New hair follicles were induced by dissociated DP cells at earlier passages (under passage 4), but the cells from later passages could not induce follicles. We next aggregated the DP cells to form spheres and then injected them with epidermal cells. Unlike the dissociated DP cells, the spheres made from the later passaged cells (more than 10 passages) did induce new hair follicles.

We examined several genes specific for DP of anagen follicles and confirmed that their expression level was elevated in the spheres compared with their expression level in adherent DP cells.

These results suggest that FGF-2 is essential for dermal papilla cell culture and that sphere formation partially models the intact DP, resulting in hair follicle induction, even by later passaged cells.

According to an article in the Italian newspaper “La Corriere Della Sera”, two Italian plastic surgeons have created a process to create several hair follicles from one single hair follicle.

The surgeons, Prof. Pierluigi Santi and his colleague Prof. Edoardo Rapposio, claim that in about 12 days they can create ten to fifteen new growing hairs from one single hair follicle.

This technique has been attempted before where surgeons have taken a hair follicle and sliced it into two halves and both halves of the follicles have been able to successfully grow a new hair.   However there have been problems with consistency with this type of procedure and it’s never been successfully marketed before.

In the latest attempt at this primitive form of hair cloning, the parts of the dissected hair follicle are soaked in a cell culture medium before being re-implanted into the scalp.  It will be interesting to see what type of success this method yields.   While it’s not hair cloning in its truest sense, if successful it could create hope for men who have very little hair for a conventional hair transplant.

The doctors plan on getting their procedure ISO certified and will be opening a clinic dedicated to performing this procedure in early 2008.   Initially the treatment will be offered to burn victims like firefighters and later on it will be open to everyone else.

For more discussion on this topic visit http://www.hairlosshelp.com/forums/messageview.cfm?catid=10&threadid=65455