Diagnóstico y Tratamiento de Aneurisma Aórtico Abdominal Infrarrenal Guía de Referencia Diagnóstico y Tratamiento de Aneurisma Aórtico Abdominal Infrarrenal Guía de Práctica Clínica Catálogo maestro de guías de práctica clínica: IMSS-XXX-XX Diagnóstico y Tratamiento de Aneurisma Aórtico Abdominal Infrarrenal Guía de Referencia Rápida 171.4 Aneurisma abdominal (aorta)
UntitledRCAS1 Decidual Immunoreactivity during Stillbirth: Immune CellPresence and Activity Krystyna Galazka1, Lukasz Wicherek2, Jerzy Sikora3, Artur Czekierdowski4, Tomasz Banas5, WieslawaBednarek4, Bogdan Obrzut6, Pawel Blecharz2, Alfred Reron5, Jaroslaw Kalinka7 1Department of Pathomorphology, Jagiellonian University, Krakow, Poland;2Department of Gynecology and Oncology, Jagiellonian University, Krakow, Poland;3Department of Gynecology and Obstetrics, Medical University, Katowice, Poland;4Department of Gynecology and Oncology, Medical University Lublin, Lublin, Poland;5Department of Perinatology, Jagiellonian University, Krakow, Poland;6Clinical Department of Obstetrics and Gynecology, University of Rzeszow, State Hospital, Rzeszow, Poland;7Medical and Environmental Pregnancy Health Hazards Unit, Department of Perinatology, I Chair of Gynecology and Obstetrics, Medical University of Lodz, Lodz, Poland Decidua, immune cells, RCAS1, stillbirth Alterations in RCAS1 (a receptor-binding cancer antigen expressed onSiSo cells) expression in the placenta and decidua may be related to the regulation of the process of maternal immune tolerance against fetal Lukasz Wicherek, Department of Gynecology,Obstetrics and Oncology, Jagiellonian antigens. Moreover, it has been demonstrated that the occurrence of the University, 23 Kopernika Str, 31-501 Krakow, spontaneous beginning of stillbirth is related to a decrease in the placental expression of RCAS1. There are no data currently available on the immune processes in decidua during stillbirth. The aim of this study was toevaluate the RCAS1 immunoreactivity level in decidua and to identify the Submitted May 13, 2008; cytotoxic immune cells present during labor, induced after intrauterine accepted July 28, 2008.
fetal death either with a combination of oxytocin (OT) and prostaglandins or with OT alone; a further objective was to assess the potential impact of Galazka K, Wicherek L, Sikora J, Czekierdowski these molecular alterations on the effectiveness of stillbirth induction.
A, Banas T, Bednarek W, Obrzut B, BlecharzP, Reron A, Kalinka J. RCAS1 decidual immunoreactivity during stillbirth: immune cell The immunoreactivity of RCAS1, CD3, CD56, CD69, and CD25 was presence and activity. Am J Reprod Immunol assessed by immunohistochemistry in 31 decidual samples derived from 2008; 60: 513–522 patients in whom the stillbirth occurred before the onset of labor.
ResultsThe RCAS1 immunoreactivity level was higher in a statistically signifi-cant manner in decidual tissue samples derived from patients in whomOT alone proved insufficient to induce labor after the diagnosis of intra-uterine fetal death but required additionally the use of prostaglandinswhen compared with samples from women in whom stillbirth wasinduced successfully with OT alone. However, we did not observe anydifferences either in CD56 and CD3 positive cell presence or in CD25and CD69 antigen immunoreactivity in the respective decidua of thesetwo groups of patients.
ConclusionThe level of RCAS1 in decidua seems to influence the effectiveness ofstillbirth induction.
American Journal of Reproductive Immunology 60 (2008) 513–522 ª 2008 The Authors Journal compilation ª 2008 Blackwell Munksgaard GALAZKA ET AL.
The initiation of labor is associated not only with the increase in OT, oxytocin receptor (OTR), and PG Stillbirth continues to be an important public health expression,10–18 but also with a complex molecular issue. In recent decades, the development of health- response leading to a brief activation of the maternal care has reduced the incidence of sudden infant immune system with an accompanying capacity to death syndrome,1 but the problem of stillbirth, restrict this very activation.21–26 Szekeres-Bartho which entails fetal death prior to labor, remains et al.21 have observed an increase in lymphocyte unresolved.2 There is a significant difference in the activity during labor while Abadia-Molina et al.22 incidence of stillbirth between the developed and have found lymphocytes with a prominent expres- the developing countries. The rate of stillbirth ranges sion of antigens (such as CD25+, CD69+, and human from three per 1000 in developed countries when leukocyte antigen class II-DR) in the decidua basalis compared with 100 per 1000 births in developing during labor at term. During labor at term, an alter- countries.2,3 Difficulty in accessing proper medical care is the most likely reason for the high stillbirth CD56+ CD16) and CD56+ CD16+) has been observed rate found in the developing countries. Moreover, between the decidua basalis and decidua parietalis.23 overall improvements in medical care have influ- In recent reports, it has been suggested that the enced the outcome more for intra-partum than for maternal immune system is not solely responsible for ante-partum stillbirth.4 Yet, regardless of the circum- the proper initiation of labor, but fetal macrophages stances, delivery is always the most hazardous part have also been determined to play an important role of the medical care that the patient receives. In most in this process.27 At the beginning of stillbirth, both cases, spontaneous labor will not occur after a diag- the fetal immune system and fetal adrenals probably nosis of intrauterine fetal death, but will have to be fail to function properly. For this reason, we have induced, and this induction has an effect on mater- chosen stillbirth as a way to analyze the involvement nal morbidity. There is currently limited statistical of the maternal decidua in immunoregulation during information on the relationship between maternal the course of labor. In our recent studies, we have mortality ⁄ morbidity and the course of stillbirth.2 demonstrated that the placenta retains some suppres- Thus, the method of labor induction together with sory activity against maternal immune cytotoxic cells access to medical care may significantly affect the even after fetal death and, depending on this sup- outcome of treatment. Whether or not the method pressory activity, either spontaneous stillbirth will of effective labor induction is related to molecular occur or labor will have to be induced.28 The proper changes at the maternal–fetal interface would seem function of the phenomenon of maternal immune to be an important issue given that such changes in tolerance, however, is conditioned by the suppresso- physiological conditions determine the course of ry activity of both the placenta and the decidua. The labor.5 As with the physiological labor, normal uter- ability to suppress the activity of the immune cells ine contractions with cervical remodeling are essen- present within the maternal–fetal interface, particu- tial to the proper course of stillbirth. Myometrial larly during labor, is realized mainly through pro- activation may be stimulated via the paracrine and teins originating from the decidual cells, as placental endocrine pathways by uterotonic agonists (includ- physiological suppressory activity diminishes.29–31 In ing oxytocin (OT) and prostaglandins (PGs).6 How- our previous study, we have demonstrated that ever, the beginning of labor is determined not only RCAS1, one of the proteins in decidua, is responsible by the proper myometrial contractility pattern, but for the inhibition of activated cytotoxic immune cells also, most likely, by the activity of the fetal adrenals in decidua during labor at term29,30 and also during and related cofactors,7–9 not to mention molecular the course of such pathological conditions as pre- changes at the maternal–fetal interface that cause term placental abruption32 and pre-eclampsia.33,34 alterations in the level of maternal immune toler- Moreover, because of its ability to inhibit the growth ance against fetal antigens.5 As the involvement of and activation of NK cells and T and B lympho- endocrine signals from the fetal adrenals during the cytes,35 RCAS1 has previously been shown to be initiation of labor is well known,7–9 we have focused responsible for the escape of cancer cells from host our study on the maternal–fetal interface—that is, immunological surveillance.36–42 It has also been the interface of the maternal decidua and its immu- shown that RCAS1 interaction with the receptor on the effector cell may lead to Fas-associated death American Journal of Reproductive Immunology 60 (2008) 513–522 ª 2008 The Authors Journal compilation ª 2008 Blackwell Munksgaard DECIDUAL RCAS1 AND STILLBIRTH domain activation and may induce effector cell apop- patients were divided into two subgroups, according tosis through the caspases cascade.43 In uterine cervi- to the method of labor induction following the diagnosis of intrauterine fetal death. Group 1 con- lymphocytes (mainly CD3+) surrounding RCAS1 sisted of patients in whom stillbirth was induced positive-cancer cells and RCAS1-positive metastatic using an intravenous infusion of diluted OT (5 U in cancer cells in lymph nodes has been observed.36 0.5 L of normal saline), at an initial dose of 2 drops Recently, Han et al.44 has determined that RCAS1 per min increased every 5 min by 2 drops per min until regular uterine contraction occurred; when immune cells in vitro; this indicates that the changes OT proved insufficient (after 24 hr of observation), in its expression in the decidua and placenta may be PGs were administered intravaginally. Group 2 con- associated with the reversible restriction of the activ- sisted of patients in whom stillbirth was induced ity of the immune system during labor. Alterations using OT, and Misoprostol (PGE1) was used addi- in RCAS1 expression in the placenta and decidua as tionally until delivery occurred (a 200 lg in every well as its presence within the serum of pregnant 6 hr). The patients in whom fetal death was related women may be related to the regulation of immune to an infection acquired during the birth process tolerance against fetal antigens during pregnancy.29 (as confirmed by histopathological examination of This seems to be one of the physiological homeo- the fetal membranes and chorionic plate) were static mechanisms in a woman's reproductive tract excluded from this study. Patients with anti-phos- responsible for the proper activation of the immune pholipids syndrome were also excluded from the system during labor. In our previous study,28 we study. The tissue samples derived from patients in demonstrated that the occurrence of the spontaneous whom stillbirth was induced were immediately beginning of stillbirth is related to a decrease in fixed in 10% buffered formaldehyde solution and RCAS1 placental expression when compared with sent to the Pathomorphology Department of the cases in which labor needed to be induced following Jagiellonian University. An experienced pathomor- the diagnosis of intrauterine fetal death. The aim of phologist (K.G.) evaluated the routinely stained (HE this study, therefore, was to evaluate the RCAS1 – hematoxylin and eosin) slides prepared from the immunoreactivity in decidua and to identify the paraffin-embedded tissue material and also selected cytotoxic immune cells present during stillbirth – sufficient material for further analysis. Last, selected induced either with a combination of OT and PGs or paraffin blocks were cut and used for immuno- with OT alone – to assess the potential impact of these molecular alterations on the effectiveness of The consent of the patient was obtained in each case. Prior to this study, we also obtained theapproval of the Jagiellonian University Ethical Com-mittee for our research program (KBET ⁄ 89 ⁄ B ⁄ 2005).
The decidual tissue samples evaluated in our study Immunohistochemical analysis was performed in the were obtained from 31 pregnant women in whom Pathomorphology Department of the Jagiellonian stillbirth occurred before the onset of labor (ante- University. Four-lm slides from each case, including partum stillbirth). These patients were hospitalized the deciduas, prepared routinely for immunohisto- during the period between December 2004 and chemistry, were stained to visualize the expression December 2006 either in the Department of Gyne- of RCAS1- and CD3-, CD69-, CD25-, and CD56-posi- cology, Obstetrics and Oncology at the Jagiellonian tive cells (lymphocytes).
University, Krakow, Poland, or in the Clinical In each case, immunohistochemistry was perfor- Department of Obstetrics and Gynecology at the med by using the Envision method using Dako State Hospital in Rzeszow, Poland. The main causes of fetal ante-partum death included fetal anomalies RCAS1 immunostaining, the slides were treated (congenital and karyotypic) (60% of cases), growth with the mouse monoclonal antibody anti-RCAS1 restriction (10%), placental thrombosis (10%), and Nagoya, Japan in DAKO Antibody Diluent with American Journal of Reproductive Immunology 60 (2008) 513–522 ª 2008 The Authors Journal compilation ª 2008 Blackwell Munksgaard GALAZKA ET AL.
Background Reducing Components – DAKO, dilu- tion 1:1000) in a moist chamber overnight. Further,the following antibodies were also used: CD56 Clinical Comparison of the Two Groups of Patients (NCAM; NCL-CD56-504; Novocastra, MA, US) in Analyzed in Whom, Following the Diagnosis of dilution 1:100, CD69 (NCL-CD69; Novocastra) in Intrauterine Fetal Death, Labor was Induced Either dilution 1:25, CD25 (interleukin-2 receptor, NCL- with a Combination of OT and PGs or with OT CD25-305; Novocastra) in dilution 1:25, CD3 (NCL- CD3p, rabbit polyclonal antibody; Novocastra) indilution 1:100, according to the manufacturer's As stillbirth can take place at any of the different instructions. The visualization of reaction products stages of pregnancy, it seems appropriate to compare was performed using AEC (3-amino-9-ethyl-carba- the parameters characterizing the course of preg- zole) as a chromogen (AEC Substrate Chromogen nancy in the different groups of patients considered ready-to-use; DAKO) for 10 min at room tempera- (Table I). The profile of the clinical parameters of ture. Sections were counterstained with hematoxy- patients enables us to compare the levels of the anti- lin and mounted in glycergel. As a positive control gens studied in these two groups of patients, evalu- for RCAS1, a breast cancer specimen was used. For ated according to the method of stillbirth induction.
method were used as for the positive one, but with- Immunohistochemical Analysis of the Immune out the primary antibody. RCAS1 reactivity was Cells Present and their Activity evaluated in an entire slide from the decidua asfollows: 0 (no reactivity), +1 (any staining pattern CD3-positive cells were identified in all the decidual in up to 10% of the cells), +2 (positive staining in tissue samples derived from patients in whom still- 11–30% of the cells), and +3 (more than 30% of birth was induced by oxytocin and in 85% of the positive cells). The various types of lymphocytes in decidual tissue samples derived from patients in the decidua were also evaluated. The number of whom stillbirth was induced by a combination of OT immune cells in an entire specimen was counted and PGs (Fig. 1).
and an average cell number per 1 hpf (high power CD56-positive cells were observed in 42% of the field, objective magnification ·40) calculated. The decidual tissue samples derived from those patients following scale was used to evaluate the number of induced by OT and in 31% of the decidual tissue CD3-positive lymphocytes semi-quantitatively: 0 –lack of positive cells or only single positive cells inthe entire specimen; +1 – 2 to 5 positive cells ⁄ 1 hpf; Table I Clinical Characteristics of Patients Who Underwent +2 – 6 to 10 positive cells ⁄ 1hpf, +3 – 11 to 20 posi- Stillbirth in Relation to the Method of Labor Induction Followingthe Diagnosis of Intrauterine Fetal Death tive cells ⁄ 1 hpf; +4 – more than 20 positive cells ⁄1 hpf. Because of the scarcity of CD25-, CD69-, CD56-positive lymphocytes, the other three-pointed scale was applied to evaluate their number: 0 – lack of positive cells, +1 – presence of single cells, up to Maternal age (median, IQR) two per 1 hpf, +2 – more than two positive lym- Parity (median, IQR) phocytes per 1 hpf.
Fetal birth weight Statistical analysis Duration of the labor – hours The distribution of variables in the groups of women studied, checked by performing Shapiro-Wilk test, Number of diluted oxytocin showed that each of the women was different from infusion (median, IQR) normal. Non-parametric testing was therefore carried Number of PGE1 doses out. Statistical significance between the groups was determined by the Mann–Whitney U-test. The data IQR, intraquartile range; OT, oxytocin; PGs, prostaglandins; PGE1, were presented in terms of median value and intra- quartile range.
American Journal of Reproductive Immunology 60 (2008) 513–522 ª 2008 The Authors Journal compilation ª 2008 Blackwell Munksgaard DECIDUAL RCAS1 AND STILLBIRTH Fig. 1 Multiple CD3 lymphocytes in the infiltrate of deciduas (·40).
Fig. 3 Immunoreactivity of CD69 antigen in lymphocytes in deciduas(·60).
Table II Immunoreactivity of CD3, CD56, CD69, and CD25Antigens within Decidua-Derived from Patients Who UnderwentStillbirth in Relation to the Method of Labor InductionFollowing the Diagnosis of Intrauterine Fetal Death Immunoreactivity per cent(number of cases) OT alone (n = 16) Fig. 2 CD56 positive cells in deciduas (·60).
samples derived from those induced by a combina- OT, oxytocin; PGs, prostaglandins.
aPercentage of cases (n, number of tissue samples).
tion of OT and PGs (Fig. 2).
CD69 antigen immunoreactivity was observed in 21% of the tissue samples derived from patients in Comparison of RCAS1 Alterations within Decidua whom stillbirth was induced by OT and in 31% of Derived from Stillbirth According to the Method of the tissue samples derived from patients induced by Stillbirth Induction a combination of OT and PGs (Fig. 3). CD25 antigenimmunoreactivity was comparably weak in both the RCAS1-positive cells (Fig. 4) were identified in 14% groups studied (Table II).
of the decidual tissue samples derived from patients We found no statistically significant differences in in whom stillbirth was induced by OT and in 54% of the immunoreactivity levels of the antigens CD3, the decidual tissue samples derived from patients in CD56, CD25, and CD69 between the two examined whom stillbirth was induced by a combination of OT groups that consisted of those patients who under- and PGs (Fig. 4, Table IV).
went stillbirth induced by OT and of those who We have identified statistically significant differ- underwent induction with a combination of OT and ences in RCAS1 decidual immunoreactivity level in PGs (Table III).
patients in whom stillbirth was induced by OT when American Journal of Reproductive Immunology 60 (2008) 513–522 ª 2008 The Authors Journal compilation ª 2008 Blackwell Munksgaard GALAZKA ET AL.
Table III Analysis of Immunoreactivity of CD3, CD56, CD69, Table IV Immunoreactivity of RCAS1 within Decidua Derived CD25 Antigens and RCAS1 within Decidua in Relation to the from Patients Who Underwent Stillbirth in Relation to the Method of Labor Induction Following the Diagnosis of Method of Labor Induction Following the Diagnosis of Intrauterine Fetal Death Intrauterine Fetal Death RCAS1 immunoreactivity per cent (number of cases) CD3 (median, IQR) CD56 (median, IQR) OT alone (n = 16) CD69 (median, IQR) Combination of OT CD25 (median, IQR) RCAS1 (median, IQR) OT, oxytocin; PGs, prostaglandins.
a IQR, intraquartile range; OT, oxytocin; PGs, prostaglandins.
Percentage of cases (n, number of tissue samples).
compared with those in whom stillbirth was induced positive cell presence or in CD25 and CD69 antigen by a combination of OT and PGs (Fig. 5, Table III).
immunoreactivity in the respective decidua of thesetwo groups of patients. To our knowledge, this is thefirst investigation to focus on RCAS1 decidual immunoreactivity in patients in whom stillbirth has The RCAS1 immunoreactivity level was significantly been induced.
higher statistically in decidual tissue samples derived In our previous study, we showed that the sponta- from patients in whom OT alone proved insufficient neous course of stillbirth is related to a lower level to induce labor following intrauterine fetal death, so of RCAS1 placental expression than that is found in PGs were also used, when compared with the patients in whom labor needed to be induced after the diagnosis of intrauterine fetal death.28 This dif- derived from those in whom stillbirth was induced ference indicates that the spontaneous course of still- successfully with OT alone. However, we did not birth may result from the increasing activity of the observe any differences either in CD56 and CD3 maternal immune cytotoxic cells in response to the Fig. 4 Decidual RCAS1 immunoreactivity dur- ing stillbirth in relation to the method of laborinduction following the diagnosis of intrauter- ine fetal death: a combination of oxytocin andprostaglandins (a,b,c) or oxytocin alone (d).
(a) Moderate RCAS1 expression – an area ofthe decidua with the strongest positive reac-tion in the entire specimen (·40). (b) Weakexpression of RCAS1 – an area of the speci-men with the strongest RCAS1 expression indecidual cells (·40). (c) Moderate (+2) expres-sion of RCAS1 in decidual cells (·20). (d) Weak(+1) expression of RCAS in decidual cells(·20).
American Journal of Reproductive Immunology 60 (2008) 513–522 ª 2008 The Authors Journal compilation ª 2008 Blackwell Munksgaard DECIDUAL RCAS1 AND STILLBIRTH in the number of immune cells infiltrating the P = 0.019
decidua.12,20–24,26,46–48 The number of these cells in the decidua has been found to be significantly higher following the spontaneous initiation of labor than after elective cesarean section.23The increase is most prominent during the spontaneous beginning of labor, whereas the further progression of labor is characterized by an actual decrease in the activity of immune cytotoxic cells in the decidua.26,29 This decrease is a response to the increasing suppressory activity of decidual cells as labor progresses, because RCAS1 imm
the inhibitory activity of the placenta diminishes with the advancement of labor.30 This decidual func- tion may be related to the expression of RCAS1. In this study, we have shown for the first time that the decrease in RCAS1 immunoreactivity, even when a Combination of OT with PGs
comparable number of cytotoxic immune cells were Fig. 5 Comparison of RCAS1 immunoreactivity level within decidua present, enabled the induction of stillbirth by OT derived from patients who underwent stillbirth in relation to the alone (mainly by inducing myometrial activation).
method of labor induction following the diagnosis of intrauterine fetal By contrast, patients with a high level of cytotoxic death: a combination of oxytocin (OT) and prostaglandins (PGs) or oxy- immune cell suppression in the decidua and a corre- tocin alone (OT).
spondingly high level of RCAS1 immunoreactivity,needed an additional application of PGs to be decrease in expression of inhibitory factors (such as induced following intrauterine fetal death. We spec- RCAS1) in the placenta.30 The maternal immune tol- ulate that, if alterations in RCAS1 levels in decidua erance during pregnancy phenomenon is controlled are found, they will correlate with alterations in the by both placental and decidual cells. We confirmed number and activity of immune cells, and then still- this finding in our previous study that analyzed birth will spontaneously begin. However, these alter- RCAS1 expression in both eutopic and ectopic ations in immune cells are related not only to decidua with concomitant consideration of the pres- decreased decidual RCAS1 levels, but also to the pla- ence and activity of the immune cells during cesar- cental RCAS1 level, and in our study, we did not ean section.45 Investigating ectopic decidua allowed observe any differences in the number and activity us to study the immunomodulating activity of of immune cells in the decidua according to the decidua free from the suppressory influence that the method of stillbirth induction.
placenta exerts on decidua within the uterine cavity.
The more the level of OTR expression in the my- We clearly demonstrated that the activity of ectopic ometrium rises with the increase in myometrial con- decidua is effective enough to inhibit the infiltrating tractility,10 the more stretching will occur with immune cells during cesarean section.45 Our reason uterine contraction; this in turn will increase cyclo- for choosing the stillbirth was to show that decidua oxygenase (COX-2) and PGs production.11,12 How- and its associated cofactors are essential to the course ever, alterations in the level of immune tolerance as of labor, during which the function of both the fetal the course of labor progresses are related to both adrenals and fetal immune system is disrupted. Pla- OTR expression and an increase in COX-2 activ- cental suppressory activity may also be observed ity.12,13 Interleukin-1beta (IL-1beta) increases the during stillbirth, but probably does not exhibit the secretion of OT in decidua as well as the production alterations that typically occur with the various of prostaglandins through COX-2, but at the same stages of physiological labor. This is most likely time decreases OTR expression.14 During normal related to the necessity for inducing stillbirth when physiological labor, PGs would be released by the the RCAS1 level in the placenta is observed to be membranes in response to stretching and pro-inflam- still elevated even after intrauterine fetal death. Fur- matory cytokine activity.12,15,19,20,49 Furthermore, it thermore, it has been demonstrated that the initia- has been shown that the typical blockade of immune tion of vaginal labor at term is related to an increase responses during labor results in a decrease in PGs American Journal of Reproductive Immunology 60 (2008) 513–522 ª 2008 The Authors Journal compilation ª 2008 Blackwell Munksgaard GALAZKA ET AL.
production.50,51 Prostaglandins are important media- developing and developed countries. Int J Gynaecol tors of the immune system reactions that accompany Obstet 2007; 96:139–146.
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beginning of labor to be terminated by both the 7 Beshay VE, Carr BR, Rainey WE: The human fetal maternal and fetal immune systems. The results of adrenal gland, corticotropin-releasing hormone, and our study indicate that the increase in PGs in a parturition. Semin Reprod Med 2007; 25:14–20.
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We wish to thank Professors A. Basta and A. Skret 12 Osman I, Young A, Jordan F, Greer IA, Norman JE: for their advice, helpful discussions, and friendly Leukocyte density and proinflammatory mediator words of support. I would also like to thank Chris- expression in regional human fetal membranes and tine Maisto and Dr Magdalena Dutsch-Wicherek for decidua before and during labor at term. J Soc Gynecol their assistance. This work was funded by the Polish Investig 2006; 13:97–103.
13 Loudon JA, Elliott CL, Hills F, Bennett PR: 31 ⁄ 0201 and 0888/B/P01/2008/35 in 2008 ⁄ 2009.
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Imaging an adapted dento-alveolar complex Ralf-Peter Herber1 , Justine Fong2, Seth A. Lucas1, Sunita P. Ho2* 1 Division of Orthodontics, Department of Orofacial Sciences, University of California, San Francisco, CA 94143, USA 2 Division of Biomaterials and Bioengineering, Department of Preventive and Restorative Dental Sciences, University of California San Francisco, San Francisco, CA 94143, USA