Review of Manstein D, et. al. Selective cryolysis: a novel method of non-invasive fat removal

http://www.ncbi.nlm.nih.gov/pubmed/18951424

Lasers Surg Med. 2008 Nov;40(9):595-604

Selective cryolysis: a novel method of non-invasive fat removal.

Manstein D, Laubach H, Watanabe K, Farinelli W, Zurakowski D, Anderson RR.

Department of Dermatology, Wellman Center for Photomedicine , Massachusetts General Hospital , Harvard Medical School , Boston , Massachusetts , USA .

Manstein et. al. present the first animal study results with prototype  Zeltiq devices for non-invasive cold-induced fat destruction.   Note that Manstein is the inventor of the technology and receives royalties from Zeltiq. This report provides critical insight into the device-tissue interaction, the rationale for device parameter selection, and the mechanism of tissue response to the procedure.

Non- invasive surface cooling lowers the temperature of epidermis, dermis and subcutaneous fat via thermal conduction.  Because fat cells are more easily damaged by cold temperatures than are skin cells, this approach attempts to cool the subcutaneous fat below its damage threshold, while keeping the epidermis and dermis above their dermal damage thresholds.  Because cold is delivered from the surface through the dermal layers to the fat, the challenge is to make the dermis cold enough (for long enough) to adequately cool the fat, while keeping the dermal layers from frostbite.

Three animal studies (female black yucatan pigs, age 2-3, ca. 100 lb.) are presented in this paper.  All treatments were performed with the animals under general anesthesia, so treatment pain (e.g. signs of distress) could not be evaluated.

In the first study, a lab prototype was applied to eleven locations (abdomen, flank, buttock) on one animal.  This prototype provided contact cooling of the skin surface to -7C, and attempted to apply sufficient pressure to inhibit blood flow in the skin (which would warm the subcutaneous fat and thus prevent fat cooling below the damage threshold).  Durations varied from 5 to 21 minutes.  This pig was observed for 3.5 months, and except for some slight hyperpigmentation, no apparent skin injury was seen.  The highest degree of fat loss was seen as an easily visible indentation in the skin corresponding to the shape of the applicator.  This occurred at a buttock location with a cooling duration of 10 minutes, and where dermal blood flow was felt to be well inhibited.  By histology, 40% of the total fat layer thickness was removed in this area.  This n=1 experiment demonstrated initial feasibility of this approach.

In the second study, two prototype Zeltiq devices were applied to a total of 60 locations on 4 animals, to test the effect of various device temperature settings and the need for blood-flow suppression.   The first device was a flat cold applicator that could be held against the skin surface (“flat” applicator) but would not inhibit blood flow.  The second device clamped a fold of skin between two cold plates (“fold” applicator), enabling compression of the skin fold, effective suppression of blood flow within the fold and an improved cooling geometry.  Ten control sites were treated with applicators set to skin temperature (20C).  At some treatment sites, thermocouples were used to measure in vivo tissue temperatures during the procedure, demonstrating that significantly colder fat temperatures were achieved with the “fold” applicator, even at the same temperature as the “flat” applicator.  In this study, no clinical or histological evidence of damage to the epidermis or dermis was found, thus demonstrating that it is possible to provide cooling to the fat without damaging the overlying skin layers.  By histology, fat damage was significantly greater at lower applicator temperatures, with the lowest temperature applicator (-7C) achieving the best results.  At 1 month post treatment, most of the “fold” applicator sites showed obvious visible skin indentation (up to 3mm reduction in fat thickness), while none of the “flat” applicator sites showed such indentations.  It is not known if 3mm reduction could be routinely obtained.

This study also provided data regarding the biological mechanism of fat destruction.  At one day post treatment, no damage was seen on histology at either control or treatment sites.  At two days, inflammation (clusters of neutrophils around the fat cells) was seen in the top 3-4 mm of the subcutaneous fat.  At 14 days, fat cell size was reduced, inflammation was more intense and occasional macrophages were observed.  At 30 days, fat cell size was further reduced, and multinucleated giant macrophage cells could be seen.  As mentioned above, no histological damage to overlying skin layers was seen.

The purpose of the third study, in six pigs, was to monitor blood lipids at six time points (1 hour, 1 day, 1 week, and 1, 2, and 3 months) following treatment of a very large portion (approximately 15%) of the body area. This treatment varied from prior studies in three ways.  First, the applicator was flat, had a more efficient cooling plate, and was weighted to apply 38mm Hg pressure to the skin (surface temperatures varied from -5C to -8C).  Second, ultrasound gel was applied to the skin beneath the applicator to enhance thermal conduction.   Third, a 1-minute vibrating massage was performed immediately after the cold exposure.   No significant changes in serum lipids associated with this treatment were seen, indicating the safety of the procedure despite the very large dose.  However, in this study, about 30% of the treatment sites suffered skin freezing, resulting in epidermal necrosis, transient hypopigmentation, but no scarring or ulceration.  It is unknown which of the three changes to the treatment above might have caused this freezing.

Together, these three studies showed that in pigs, it is possible to selectively cool fat below its damage threshold without damaging overlying skin.  While it is not surprising that lower applicator temperatures and effective blood flow suppression provide more cooling of fat and more effective fat destruction, it should be noted that these parameters also bring dermal temperatures closer to their damage thresholds.  The authors note that pig fat may be more sensitive to cold than human fat, because pigs have higher concentration of saturated fatty acids which may enable fat damage.

Because the approach appears to be operating close to the margin of skin damage, it may make sense to consider a study of multiple applications using a slightly lower cold dose (less likely to freeze overlying skin and slightly less damage to the fat).  Multiple applications of cold are likely to do additive damage to fat cells, while the overlying skin should be unharmed by each application.  The applications could be separated by just a few minutes, long enough for the treatment area to return to normal temperature, so that multiple applications could be applied in one treatment session.

If a 3mm fat thickness reduction could be routinely obtained, and the applicator was applied uniformly around the circumference of a body area, a circumference reduction of approximately a 2cm would be achieved.  These results would be considered clinically significant.  Of course, clinical techniques (e.g. layering) would need to be developed to provide cosmetically pleasing results.  No one wants a series of indentations in their skin.  Here again, multiple overlapping lower-dose applications may prove useful.

The need for 10-minute exposures may result in relatively long treatment times.  This would be increased if multiple applications of the device were needed in a single session.  The level of pain associated with this technique and the need for pain management techniques is also unknown.  While the prospect of holding a large piece of ice against the skin for 10 minutes may seem painful, simultaneous pressure on the skin is known to have analgesic effects.

While there are still many unknowns, this report provides critical insight into the device-tissue interaction, the rationale for device parameter selection, and the mechanism of tissue response to the procedure.  Aesthetic device users should demand analogous animal studies for every device that claims to have a novel tissue effect.  Subsequent to the performance of the studies in this paper, Zeltiq has carried out further device modifications and has begun two human clinical studies.

http://clinicaltrials.gov/ct2/show/NCT00762437

http://clinicaltrials.gov/ct2/show/NCT00762307

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One Response to Review of Manstein D, et. al. Selective cryolysis: a novel method of non-invasive fat removal

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