Современные подходы к медицинскому использованию сополимерных рН- и температурно-чувствительных гидрогелей (обзор)

Аннотация

В этой статье приведен обзор медицинского использования рН- и температурно-чувствительных полимерных гидрогелей. Такие полимеры характеризуются термо- и pH-чувствительностью в водных растворах при температуре функционирования живых организмов и могут реагировать на малейшие изменения условий окружения. По причине этого поведения они получили название стимул-чувствительные полимеры. Такой отклик на внешний раздражитель происходит за счет амфифильности (дифильности) этих (со)полимеров. Термин гидрогели включает в себя несколько
понятий макро- и микрогели. Микрогели, в отличие от макрогелей, представляют собой полимерные частицы, которые находятся в диспергированном состоянии в жидкости и являются нано- или микрообъектами. В обзоре представлены работы, отражающие основные пути получения таких полимерных материалов, среди них осадительная полимеризация, как основной, наиболее простой и доступный способ, миниэмульсионная полимеризация, микрофлюидика и послойная адсорбция полиэлектролитов. Подобные системы, несомненно, будут перспективны для использования их в биотехнологии и медицине, из-за того, что они представляют собой набухшие жидкостью частицы, способные связывать и нести внутри себя различные вещества, от низко- до высокомолекулярных.
Также важным фактором является то, что небольшое нагревание и охлаждение
или незначительное изменение рН среды переводит систему из гомогенного в гетерогенное состояние и обратно. Именно это дает возможность использовать данные полимеры как средства направленной доставки лекарств, позволяющие снизить негативное влияние токсичных веществ, используемых для лечения, на весь организм и направить это действие в определенную
точку. Помимо этого, такие полимеры можно использовать для создания «умных» покрытий имплантируемых материалов, а также искусственного матрикса для регенерации клеток и тканей, способствуя значительному повышению вероятности приживаемости и скорости восстановления клеток и тканей

ЛИТЕРАТУРА

1. Gisser K. R. C., Geselbracht M. J., Cappellari A.,
Hunsberger L., Ellis A. B., Perepezko J., et al. Nickeltitanium
memory metal: A "Smart" material exhibiting
a solid-state phase change and superelasticity. Journal
of Chemical Education. 1994;71(4): 334. DOI: https://doi.org/10.1021/ed071p334
2. Erman B., Flory P.J.. Critical phenomena and
transitions in swollen polymer networks and in linear
macromolecules. Macromolecules. 1986;19(9): 2342–
2353. DOI: https://doi.org/10.1021/ma00163a003
3. Tanaka T., Fillmore D., Sun S.-T., Nishio I.,
Swislow G., Shah A. Phase transitions in ionic gels.
Physical Review Letters. 1980;45(20): 1636–1639. DOI:
https://doi.org/10.1103/physrevlett.45.1636
4. Polymer Gels. DeRossi D., Kajiwara K., Osada Y.,
Yamauchi A. (eds.). Boston, MA: Springer US; 1991.
354 p. DOI: https://doi.org/10.1007/978-1-4684-5892‑3
5. Ilmain F., Tanaka T., Kokufuta E. Volume
transition in a gel driven by hydrogen bonding. Nature.
1991;349(6308): 400–401. DOI: https://doi.org/10.1038/349400a0
6. Kuhn W., Hargitay B., Katchalsky A., Eisenberg
H. Reversible dilation and contraction by changing the
state of ionization of high-polymer acid networks.
Nature. 1950;165(4196): 514–516. DOI: https://doi.org/10.1038/165514a0
7. Steinberg I. Z., Oplatka A., Katchalsky A.
Mechanochemical engines. Nature. 1966;210(5036):
568-571. DOI: https://doi.org/10.1038/210568a0
8. Tian H., Tang Z., Zhuang X., Chen X., Jing X.
Biodegradable synthetic polymers: Preparation,
functionalization and biomedical application. Progress
in Polymer Science. 2012;37(2): 237–280. DOI: https://doi.org/10.1016/j.progpolymsci.2011.06.004
9. Gonçalves C., Pereira P., Gama M. Self-Assembled
hydrogel nanoparticles for drug delivery applications.
Materials. 2010;3(2): 1420–1460. DOI: https://doi.org/10.3390/ma3021420
10. Pangburn T. O., Petersen M. A., Waybrant B.,
Adil M. M., Kokkoli E. Peptide- and Aptamer-functionalized
nanovectors for targeted delivery of therapeutics.
Journal of Biomechanical Engineering. 2009;131(7):
074005. DOI: https://doi.org/10.1115/1.3160763
11. Caldorera-Moore M. E., Liechty W. B., Peppas
N. A. Responsive theranostic systems: integration
of diagnostic imaging agents and responsive controlled
release drug delivery carriers. Accounts of Chemical
Research. 2011;44(10): 1061–1070. DOI: https://doi.org/10.1021/ar2001777
12. Das M., Sanson N., Fava D., Kumacheva E.
Microgels loaded with gold nanorods: photothermally
triggered volume transitions under physiological
conditions†’. Langmuir. 2007;23(1): 196–201. DOI:
https://doi.org/10.1021/la061596s
13. Oh J. K., Lee D. I., Park J. M. Biopolymer-based
microgels/nanogels for drug delivery applications.
Progress in Polymer Science. 2009;34(12): 1261–1282.
DOI: https://doi.org/10.1016/j.progpolymsci.2009.08.001
14. Oh J. K., Drumright R., Siegwart D. J.,
Matyjaszewski K. The development of microgels/
nanogels for drug delivery applications. Progress in
Polymer Science. 2008;33(4): 448–477. DOI: https://doi.org/10.1016/j.progpolymsci.2008.01.002
15. Talelli M., Hennink W. E. Thermosensitive
polymeric micelles for targeted drug delivery.
Nanomedicine. 2011;6(7): 1245–1255. DOI: https://doi.org/10.2217/nnm.11.91
16. Bromberg L., Temchenko M., Hatton T. A. Smart
microgel studies. Polyelectrolyte and drug-absorbing
properties of microgels from polyether-modified
poly(acrylic acid). Langmuir. 2003;19(21): 8675–8684.
DOI: https://doi.org/10.1021/la030187i
17. Vinogradov S. V. Polymeric nanogel formulations
of nucleoside analogs. Expert Opinion on Drug Delivery.
2007;4(1): 5–17. DOI: https://doi.org/10.1517/17425247.4.1.5
18. Vinogradov S. V. Colloidal microgels in drug
delivery applications. Current Pharmaceutical Design.
2006;12(36): 4703–4712. DOI: https://doi.org/10.2174/138161206779026254
19. Kabanov A. V., Vinogradov S. V. Nanogels as
pharmaceutical carriers: finite networks of infinite
capabilities. Angewandte Chemie International Edition.
2009;48(30): 5418–5429. DOI: https://doi.org/10.1002/anie.200900441
20. Lee E. S., Gao Z., Bae Y. H. Recent progress in
tumor pH targeting nanotechnology. Journal of
Controlled Release. 2008;132(3): 164–170. DOI: https://doi.org/10.1016/j.jconrel.2008.05.003
21. Dong H., Mantha V., Matyjaszewski K.
Thermally responsive PM(EO)2MA magnetic microgels
via activators generated by electron transfer atom
transfer radical polymerization in miniemulsion.
Chemistry of Materials. 2009;21(17): 3965–3972. DOI:
https://doi.org/10.1021/cm901143e
22. Nayak S., Lyon L. A. Soft nanotechnology with
soft nanoparticles. Angewandte Chemie International
Edition. 2005;44(47): 7686–7708. DOI: https://doi.org/10.1002/anie.200501321
23. Hennink W. E., van Nostrum C. F. Novel
crosslinking methods to design hydrogels. Advanced
Drug Delivery Reviews. 2012;64: 223–236. DOI:
https://doi.org/10.1016/j.addr.2012.09.009
24. Motornov M., Roiter Y., Tokarev I., Minko S.
Stimuli-responsive nanoparticles, nanogels and capsules
for integrated multifunctional intelligent systems.
Progress in Polymer Science. 2010;35(1-2): 174–211. DOI:
https://doi.org/10.1016/j.progpolymsci.2009.10.004
25. Saunders B. R., Laajam N., Daly E., Teow S.,
Hu X., Stepto R. Microgels: From responsive polymer
colloids to biomaterials. Advances in Colloid and
Interface Science. 2009;147-148: 251–262. DOI:
https://doi.org/10.1016/j.cis.2008.08.008
26. Landfester K. Miniemulsion polymerization
and the structure of polymer and hybrid nanoparticles.
chemInform. 2009;40(33). DOI: https://doi.org/10.1002/chin.200933279
27. Seo M., Nie Z., Xu S., Mok M., Lewis P.C.,
Graham R., et al. Continuous microfluidic reactors for
polymer particles. Langmuir. 2005;21(25): 11614–
11622. DOI: https://doi.org/10.1021/la050519e
28. Nie Z., Li W., Seo M., Xu S., Kumacheva E. Janus
and ternary particles generated by microfluidic
synthesis: design, synthesis, and self-assembly. Journal
of the American Chemical Society. 2006;128(29): 9408–
9412. DOI: https://doi.org/10.1021/ja060882n
29. Seiffert S., Thiele J., Abate A. R., Weitz D. A.
Smart microgel capsules from macromolecular
precursors. Journal of the American Chemical Society.
2010;132(18): 6606–6609. DOI: https://doi.org/10.1021/ja102156h
30. Rossow T., Heyman J. A., Ehrlicher A. J.,
Langhoff A., Weitz D. A., Haag R., et al. Controlled
synthesis of cell-Laden Microgels by Radical-Free
Gelation in Droplet Microfluidics. Journal of the
American Chemical Society. 2012;134(10): 4983–4989.
DOI: https://doi.org/10.1021/ja300460p
31. Perry J. L., Herlihy K. P., Napier M. E.,
DeSimone J. M. PRINT: A novel platform toward shape
and size specific nanoparticle theranostics. Accounts
of Chemical Research. 2011;44(10): 990–998. DOI:
https://doi.org/10.1021/ar2000315
32. Caruso F., Sukhorukov G. Coated Colloids:
Preparation, characterization, assembly and utilization.
In: Decher G., Schlenoff J. B., editors. Multilayer
Thin Films. Weinheim, FRG: Wiley-VCH Verlag GmbH
& Co. KGaA; 2002. p. 331-362.
33. Sauzedde F., Elaïssari A., Pichot C. Hydrophilic
magnetic polymer latexes. 2. Encapsulation of
adsorbed iron oxide nanoparticles. Colloid & Polymer
Science. 1999;277(11): 1041–1050. DOI:
https://doi.org/10.1007/s003960050488
34. Sauzedde F., Elaïssari A., Pichot C. Hydrophilic
magnetic polymer latexes. 1. Adsorption of magnetic
iron oxide nanoparticles onto various cationic latexes.
Colloid & Polymer Science. 1999;277(9): 846–855. DOI:
https://doi.org/10.1007/s003960050461
35. Pich A., Richtering W. Microgels by Precipitation
Polymerization: Synthesis, Characterization, and
Functionalization. In: Pich A., Richtering W. (eds.)
Chemical Design of Responsive Microgels. Springer
Heidelberg Dordrecht London New York; 2011. p. 1–37.
DOI: https://doi.org/10.1007/978-3-642-16379-1
36. Yamada N., Okano T., Sakai H., Karikusa F.,
Sawasaki Y., Sakurai Y. Thermo-responsive polymeric
surfaces; control of attachment and detachment of
cultured cells. Die Makromolekulare Chemie, Rapid
Communications. 1990;11(11): 571–576. DOI:
https://doi.org/10.1002/marc.1990.030111109
37. Kushida A., Yamato M., Konno C., Kikuchi A.,
Sakurai Y., Okano T. Decrease in culture temperature
releases monolayer endothelial cell sheets together
with deposited fibronectin matrix from temperatureresponsive
culture surfaces. Journal of Biomedical
Materials Research. 1999;45(4): 355–362. DOI:
https://doi.org/10.1002/(sici)1097-4636(19990615)45:4<355::aid-jbm10>3.0.co;2-7
38. Sekine H., Shimizu T., Dobashi I., Matsuura K.,
Hagiwara N., Takahashi M., et al. Cardiac cell sheet
transplantation improves damaged heart function via
superior cell survival in comparison with dissociated
cell injection. Tissue Engineering Part A. 2011;17(23-
24): 2973–2980. DOI: https://doi.org/10.1089/ten.tea.2010.0659
39. Nishida K., Yamato M., Hayashida Y.,
Watanabe K., Yamamoto K., Adachi E., et al. Corneal reconstruction with tissue-engineered cell sheets
composed of autologous oral mucosal epithelium. The
New England Journal of Medicine. 2004;351(12): 1187–
1196. DOI: https://doi.org/10.1056/nejmoa040455
40. Kanzaki M., Yamato M., Yang J., Sekine H.,
Kohno C., Takagi R., et al. Dynamic sealing of lung
air leaks by the transplantation of tissue engineered
cell sheets. Biomaterials. 2007;28(29): 4294–4302.
DOI: https://doi.org/10.1016/j.biomaterials.2007.06.009
41. Iwata T., Yamato M., Tsuchioka H., Takagi R.,
Mukobata S., Washio K., et al. Periodontal regeneration
with multi-layered periodontal ligament-derived cell
sheets in a canine model. Biomaterials. 2009;30(14):
2716–2723. DOI: https://doi.org/10.1016/j.biomaterials.2009.01.032
42. Sawa Y., Miyagawa S., Sakaguchi T., Fujita T.,
Matsuyama A., Saito A., et al. Tissue engineered
myoblast sheets improved cardiac function sufficiently
to discontinue LVAS in a patient with DCM: report of
a case. Surgery Today. 2012;42(2): 181–184. DOI:
https://doi.org/10.1007/s00595-011-0106-4
43. Ohki T., Yamato M., Ota M., Takagi R.,
Murakami D., Kondo M., et al. Prevention of esophageal
stricture after endoscopic submucosal dissection using
tissue-engineered cell sheets. Gastroenterology.
2012;143(3): 582–588. DOI: https://doi.org/10.1053/j.gastro.2012.04.050
44. Ebihara G., Sato M., Yamato M., Mitani G.,
Kutsuna T., Nagai T., et al. Cartilage repair in
transplanted scaffold-free chondrocyte sheets using
a minipig model. Biomaterials. 2012;33(15): 3846–
3851. DOI: https://doi.org/10.1016/j.biomaterials.2012.01.056
45. Sato M., Yamato M., Hamahashi K., Okano T.,
Mochida J. Articular cartilage regeneration using cell
sheet technology. The Anatomical Record. 2014;297(1):
36–43. DOI: https://doi.org/10.1002/ar.22829
46. Kuramoto G., Takagi S., Ishitani K., Shimizu T.,
Okano T., Matsui H. Preventive effect of oral mucosal
epithelial cell sheets on intrauterine adhesions. Human
Reproduction. 2014;30(2): 406–416. DOI: https://doi.org/10.1093/humrep/deu326
47. Yamamoto K., Yamato M., Morino T.,
Sugiyama H., Takagi R., Yaguchi Y., et al. Middle ear
mucosal regeneration by tissue-engineered cell sheet
transplantation. NPJ Regenerative Medicine. 2017;2(1):
6. DOI: https://doi.org/10.1038/s41536-017-0010-7
48. Gan D., Lyon L. A. Synthesis and Protein
adsorption resistance of PEG-modified poly(Nisopropylacr
ylamide) core/shell microgels.
Macromolecules. 2002;35(26): 9634–9639. DOI:
https://doi.org/10.1021/ma021186k
49. Veronese F. M., Mero A. The impact of
PEGylation on biological therapies. BioDrugs.
2008;22(5): 315–329. DOI: https://doi.org/10.2165/00063030-200822050-00004
50. Sahay G., Alakhova D. Y., Kabanov A. V.
Endocytosis of nanomedicines. Journal of Controlled
Release. 2010;145(3): 182–195. DOI: https://doi.org/10.1016/j.jconrel.2010.01.036
51. Nolan C. M., Reyes C. D., Debord J. D.,
García A. J., Lyon L. A. Phase transition behavior,
protein adsorption, and cell adhesion resistance of
poly(ethylene glycol) cross-linked microgel particles.
Biomacromolecules. 2005;6(4): 2032–2039. DOI:
https://doi.org/10.1021/bm0500087
52. Scott E. A., Nichols M. D., Cordova L. H., George
B. J., Jun Y.-S., Elbert D. L. Protein adsorption and cell
adhesion on nanoscale bioactive coatings formed from
poly(ethylene glycol) and albumin microgels.
Biomaterials. 2008;29(34): 4481–4493. DOI:
https://doi.org/10.1016/j.biomaterials.2008.08.003
53. South A. B., Whitmire R. E., García A. J.,
Lyon L. A. Centrifugal deposition of microgels for the
rapid assembly of nonfouling thin films. ACS Applied
Materials & Interfaces. 2009;1(12): 2747–2754. DOI:
https://doi.org/10.1021/am9005435
54. Wang Q., Uzunoglu E., Wu Y., Libera M. Selfassembled
poly(ethylene glycol)-co-acrylic acid
microgels to inhibit bacterial colonization of synthetic
surfaces. ACS Applied Materials & Interfaces. 2012;4(5):
2498–2506. DOI: https://doi.org/10.1021/am300197m
55. Wang Q., Libera M. Microgel-modified surfaces
enhance short-term osteoblast response. Colloids and
Surfaces B: Biointerfaces. 2014;118: 202–209. DOI:
https://doi.org/10.1016/j.colsurfb.2014.04.002
56. Tsai H.-Y., Vats K., Yates M. Z., Benoit D. S. W.
Two-dimensional patterns of poly(N-isopropylacrylamide)
microgels to spatially control fibroblast
adhesion and temperature-responsive detachment.
Langmuir. 2013;29(39): 12183–12193. DOI:
https://doi.org/10.1021/la400971g
57. Lynch I. , Miller I. , Gallagher W. M. ,
Dawson K. A. Novel method to prepare morphologically
rich polymeric surfaces for biomedical applications
via phase separation and arrest of microgel particles.
The Journal of Physical Chemistry B. 2006;110(30):
14581–14589. DOI: https://doi.org/10.1021/jp061166a
58. Li Y., Chen P., Wang Y., Yan S., Feng X., Du W.,
et al. Rapid assembly of heterogeneous 3D cell
microenvironments in a microgel array. Advanced
Materials. 2016;28(18): 3543–3548. DOI: https://doi.org/10.1002/adma.201600247
59. Bridges A. W., Singh N., Burns K. L., Babensee
J. E., Andrew Lyon L., García A. J. Reduced acute
inflammatory responses to microgel conformal
coatings. Biomaterials. 2008;29(35): 4605–4615. DOI:
https://doi.org/10.1016/j.biomaterials.2008.08.015
60. Bridges A. W., Whitmire R. E., Singh N.,
Templeman K. L., Babensee J. E., Lyon L. A., et al.
Chronic inflammatory responses to microgel-based
implant coatings. Journal of Biomedical Materials Research Part A. 2010;94A(1): 252–258. DOI:
https://doi.org/10.1002/jbm.a.32669
61. Gutowski S. M., Templeman K. L., South A. B.,
Gaulding J. C., Shoemaker J. T., LaPlaca M. C., et al.
Host response to microgel coatings on neural
electrodes implanted in the brain. Journal of Biomedical
Materials Research Part A. 2014;102(5): 1486–1499.
DOI: https://doi.org/10.1002/jbm.a.34799
62. da Silva R. M. P., Mano J. F., Reis R. L. Smart
thermoresponsive coatings and surfaces for tissue
engineering: switching cell-material boundaries.
Trends in Biotechnology. 2007;25(12): 577–583. DOI:
https://doi.org/10.1016/j.tibtech.2007.08.014
63. Schmidt S., Zeiser M., Hellweg T., Duschl C.,
Fery A., Möhwald H. Adhesion and mechanical
properties of PNIPAM microgel films and their
potential use as switchable cell culture substrates.
Advanced Functional Materials. 2010;20(19): 3235–
3243. DOI: https://doi.org/10.1002/adfm.201000730
64. Uhlig K., Wegener T., He J., Zeiser M., Bookhold
J., Dewald I., et al. Patterned thermoresponsive
microgel coatings for noninvasive processing of
adherent cells. Biomacromolecules. 2016;17(3): 1110–
1116. DOI: https://doi.org/10.1021/acs.biomac.5b01728