Biocompatibility of a Sonicated Silk Gel for Cervical Injection During Pregnancy

Abstract

Objective:

To evaluate the biocompatibility of silk gel for cervical injection.

Study Design:

Silk gel was injected into the cervix of pregnant rats on day 13 (n = 11) and harvested at day 17. Histology of silk gel was compared with suture controls. Also, human cervical fibroblasts were cultured on silk gel and tissue culture plastic (TCP) in vitro. Cell viability, proliferation, metabolic activity, gene expression (COL1A1, COL3A1, and COX2), and release of proinflammatory mediators (interleukin [IL] 6 and IL-8) were evaluated.

Results:

In vivo, a mild foreign body response was seen surrounding the silk gel and suture controls. In vitro, cervical fibroblasts were viable, metabolically active, and proliferating at 72 hours. Release of IL-6 and IL-8 was similar on silk gel and TCP. Collagen and COX2 gene expression was similar or slightly decreased compared with TCP.

Conclusions:

Silk gel was well tolerated in vivo and in vitro, which supports continuing efforts to develop silk gels as an alternative to cervical cerclage.

Keywords

cerclage cervix injectable biomaterial silk preterm birth

Get full access to this article

View all access options for this article.

References

Martin

Hamilton

Sutton

. Births: final data for 2007. Natl Vital Stat Rep. 2010;58(24):1–85.

Institute of Medicine. Preterm Birth: Causes, Consequences, and Prevention. Washington, DC: National Academies Press; 2006.

Liu

Johnson

Cousens

. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet. 2012;379(9832):2151–2161.

Mathews

MacDorman

. Infant mortality statistics from the 2007 period linked birth/infant death data set. Natl Vital Stat Rep. 2011;59(6):1–30.

Berkowitz

Papiernik

. Epidemiology of preterm birth. Epidemiol Rev. 1993;15(2):414–443.

Boyle

Poulsen

Field

. Effects of gestational age at birth on health outcomes at 3 and 5 years of age: population based cohort study. BMJ. 2012;344:e896.

Fawke

Lum

Kirkby

. Lung function and respiratory symptoms at 11 years in children born extremely preterm: the EPICure study. Am J Respir Crit Care Med. 2010;182(2):237–245.

O'Connor

Wilson

Fielder

. Ophthalmological problems associated with preterm birth. Eye (Lond). 2007;21(10):1254–1260.

Marlow

Wolke

Bracewell

Samara

, Group EPS. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med. 2005;352(1):9–19.

10.

Greenough

. Long term respiratory outcomes of very premature birth (<32 weeks). Semin Fetal Neonatal Med. 2012;17(2):73–76.

11.

Hagberg

Beckung

Uvebrant

. Changing panorama of cerebral palsy in Sweden. VIII. prevalence and origin in the birth year period 1991-94. Acta Paediatr. 2001;90(3):271–277.

12.

Singer

Salvator

Guo

Collin

Lilien

Baley

. Maternal psychological distress and parenting stress after the birth of a very low-birth-weight infant. JAMA. 1999;281(9):799–805.

13.

Chang

Larson

Blencowe

. Preventing preterm births: analysis of trends and potential reductions with interventions in 39 countries with very high human development index. Lancet. 2013;381(9862):223–234.

14.

Norwitz

Caughey

. Progesterone supplementation and the prevention of preterm birth. Rev Obstet Gynecol. 2011;4(2):60–72.

15.

Fonseca

Celik

Parra

. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med. 2007;357(5):462–469.

16.

Hassan

Romero

Vidyadhari

. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2011;38(1):18–31.

17.

U. S. Food and Drug Administration/Center for Drug Evaluation and Research. Background Document for Meeting of Advisory Committee for Reproductive Health Drugs, January 20, 2012. NDA 22-139. Washington, DC: Author.

18.

Alfirevic

Heath

. Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial. Lancet. 2004;363(9424):1849–1853.

19.

Owen

Hankins

Iams

. Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length. Am J Obstet Gynecol. 2009;201(4):375 e371–378.

20.

Landy

Laughon

Bailit

. Characteristics associated with severe perineal and cervical lacerations during vaginal delivery. Obstet Gynecol. 2011;117(3):627–635.

21.

Berghella

Odibo

Rust

Althuisius

. Cerclage for short cervix on ultrasonography: meta-analysis of trials using individual patient-level data. Obstet Gynecol. 2005;106(1):181–189.

22.

Norman

Mackenzie

Owen

. Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis. Lancet. 2009;373(9680):2034–2040.

23.

March of Dimes, PMNCH, Save the Children, WHO. Born Too Soon: The Global Action Report on Preterm Birth. In: Howson

Kinney

Lawn

, eds. Geneva: World Health Organization; 2012.

24.

Iams

Berghella

. Care for women with prior preterm birth. Am J Obstet Gynecol. 2010;203(2):89–100.

25.

Goya

Pratcorona

Merced

. Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial. Lancet. 2012;379(9828):1800–1806.

26.

Heard

Socrate

Burke

Norwitz

Kaplan

House

. Silk-based injectable biomaterial as an alternative to cervical cerclage: an in vitro study. Reprod Sci. 2013;20(8):929–936.

27.

Wang

Kluge

Leisk

Kaplan

. Sonication-induced gelation of silk fibroin for cell encapsulation. Biomaterials. 2008;29(8):1054–1064.

28.

Kim

Park

Kim

Wada

Kaplan

. Three-dimensional aqueous-derived biomaterial scaffolds from silk fibroin. Biomaterials. 2005;26(75):2775–2785.

29.

House

Sanchez

Rice

Socrate

Kaplan

. Cervical tissue engineering using silk scaffolds and human cervical cells. Tissue Eng Part A. 2010;16(6):2101–2112.

30.

House

Daniel

Elstad

Socrate

Kaplan

. Oxygen tension and formation of cervical-like tissue in two-dimensional and three-dimensional culture. Tissue Eng Part A. 2012;18(5-6):499–507.

31.

Pereira

Cotter

Gomez

. Expectant management compared with physical examination-indicated cerclage (EM-PEC) in selected women with a dilated cervix at 14(0/7)-25(6/7) weeks: results from the EM-PEC international cohort study. Am J Obstet Gynecol. 2007;197(5):483.e481–e488.

32.

Poellmann

Chien

McFarlin

Wagoner Johnson

. Mechanical and structural changes of the rat cervix in late-stage pregnancy. J Mech Behav Biomed Mater. 2013;17:66–75.

33.

Akins

Luby-Phelps

Bank

Mahendroo

. Cervical softening during pregnancy-regulated changes in collagen cross-linking and composition of matricellular proteins in the mouse. Biol Reprod. 2011;84(5):1053–1062.

34.

Read

Word

Ruscheinsky

Timmons

Mahendroo

. Cervical remodeling during pregnancy and parturition: molecular characterization of the softening phase in mice. Reproduction. 2007;134(2):327–340.

35.

Bucknall

Teare

Ellis

. The choice of a suture to close abdominal incisions. Eur Surg Res. 1983;15(2):59–66.

36.

Lugo

Putong

. Metaplasia. an overview. Arch Pathol Lab Med. 1984;108(3):185–189.

37.

Cotran

Collins

Robbins

. Pathologic Basis of Disease. 6th ed. Philadelphia, PA: WB Saunders Co; 1999.

38.

Sennstrom

Ekman

Westergren-Thorsson

. Human cervical ripening, an inflammatory process mediated by cytokines. Mol Hum Reprod. 2000;6(4):375–381.

39.

Meinel

Hofmann

Karageorgiou

. The inflammatory responses to silk films in vitro and in vivo. Biomaterials. 2005;26(2):147–155.

40.

Wray

Gallego

. Effect of processing on silk-based biomaterials: reproducibility and biocompatibility. J Biomed Mater Res B Appl Biomater. 2011;99(1):89–101.

41.

Kaplan

Cebe

. Determining beta-sheet crystallinity in fibrous proteins by thermal analysis and infrared spectroscopy. Macromolecules. 2006;39(18):6161–6170.

42.

Kaplan

Cebe

. Dynamic protein-water relationships during beta-sheet formation. Macromolecules. 2008;41(11):3939–3948.