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Synthetic Ice Modulators (SIMs)*


High cooling rates are required to suppress crystallization in cryopreservation by vitrification. Due to the underlying principles of heat transfer, there is a size limit above which vitrification becomes impractical at the center of the specimen. The high cooling rates required for vitrification may give rise to thermo-mechanical stress, driven by the physical property of thermal expansion. Due to the underlying principles of solid mechanics, the thermo-mechanical stress also increases with the specimen size for a given cooling rate. When the stress exceeds the strength of the material, structural damage follows with fracture formation as its most dramatic outcome.


Synthetic ice modulators can help alleviate cooling rate and size limitations in vitrification. When the cryoprotective agent (CPA) is mixed with SIMs, the cooling rates necessary to control ice formation decrease and, thereby, the resulting stresses.

SIB bonding labeled

In broad terms, SIMs are compounds that influence the formation and growth of ice nuclei and crystals by various purported mechanisms [PubMed]. This general classification embraces several categories of molecules that have been shown to modulate ice formation and growth. For example, molecules such as 1,3-cyclohexanediol (1,3-CHD) that specifically attenuates the growth of ice crystals by virtue of its chemical structure have been referred to as synthetic ice blockers (SIBs).  Other SIMS such as 2,3-butanediol (2,3-BD) and polyethylene glycol (PEG400) facilitate the stability of the amorphous state by virtue of their interactions with water. As such, ice modulators make useful stabilizing supplements to vitrification solutions to enhance their amorphous stability and help reduce both the concentrations of other cryoprotectant solutes necessary and the likelihood of ice formation.


* Terminology: While the synthetic ice blocker (SIB) is a more common term in the literature, the synthetic ice modulator (SIM) has been termed by our research group. To a large extent, the SIM classification is a practical one—it is derived from the outcome of adding the corresponding compounds into the cryopreservation cocktail, rather than attributing that outcome to a unique physical mechanism.


Selected publications:

       Solanki, P.K., Rabin, Y. (2017): Thermal expansion of the cryoprotective agent cocktail DP6 in combination with various synthetic ice modulators, ASME Bioengineering and Biotransport Conference, Tucson, AZ, USA (June 21-24) BTTL Depository

       Ehrlich, L.E., Malen, J.A., Fahy, G.M, Wowk, B.G.,  Rabin, Y. (2017): Thermal analyses of a human kidney and a rabbit kidney during cryopreservation by vitrification, ASME Journal of Biomechanical Engineering, doi:10.1115/1.4037406 PubMed, HHS Public Access, ASME Digital Collection, BTTL Depository

       Eisenberg, D.P., Bischof, J.C., Rabin, Y. (2015): Thermo-mechanical stress in cryopreservation via vitrification with nanoparticle heating as a stress-moderating effect, ASME Journal of Biomechanical Engineering, 138(1), doi: 10.1115/1.4032053 PubMed, ASME Digital Collection

       Eisenberg, D.P., Rabin, Y. (2015): Stress-strain measurements in vitrified arteries permeated with synthetic ice modulators, ASME Journal of Biomechanical Engineering, 137(8):0810071-0810077, doi:10.1115/1.4030294. PubMed, HHS Public Access, ASME Digital Collection

       Eisenberg, D.P., Taylor, M.J., Jorge L. Jimenez-Rios, Rabin, Y. (2014): Thermal expansion of vitrified blood vessels permeated with DP6 and synthetic ice modulators, Cryobiology, 68(3):318-26 PubMed, HHS Public Access, ScienceDirect

       Rabin, Y., Taylor, M.J., Feig, J.S.G., Baicu, S., Chen, Z. (2013): A new cryomacroscope device (Type III) for visualization of physical events in cryopreservation with applications to vitrification and synthetic ice modulators, Cryobiology 67(3):264-73 PubMed, HHS Public Access, ScienceDirect

       Eisenberg, D.P., Taylor, M.J., Rabin, Y. (2012): Thermal expansion of DP6 combined with synthetic ice blockers in presence and absence of biological tissues. Cryobiology, 65(2):117-125 PubMed, HHS Public Access, ScienceDirect

       Eisenberg, D.P., Rabin, Y. (2011): The effect of synthetic ice blockers on thermal expansion of the cryoprotective cocktail DP6. ASME 2011 Summer Bioengineering Conference - SBC 2011, Farmington, PA, USA (June 22-25) ASME Digital Collection



This research has been supported, in part, by:

       National Heart Lung and Blood Institute (NHLBI) Grant R01HL127618

       US Army – Defense Health Program Contract H151-013-0162

       National Institute of Biomedical Imaging and Bioengineering (NIBIB) Grant R21EB011751

       National Center for Research Resources (NCRR) Grant R21RR026210

       National Institute of General Medical Sciences (NIGMS) Grant R21GM103407