
==== Front
Aesthet Surg J
Aesthet Surg J
asj
Aesthetic Surgery Journal
1090-820X
1527-330X
Oxford University Press US

38857184
10.1093/asj/sjae128
sjae128
Original Article
AcademicSubjects/MED00987
Asj/12
Oxylipins in Breast Implant–Associated Systemic Symptoms
Khan Imran PhD
Timsina Lava PhD
Chauhan Ruvi MD
Ingersol Christopher MD
Wang David R MPH
Rinne Ethan BS
Muraru Rodica MD
Mohan Ganesh PhD
Minto Robert E PhD
https://orcid.org/0000-0003-1792-1247
Van Natta Bruce W MD
Hassanein Aladdin H MD
Kelley-Patteson Christine MD
https://orcid.org/0000-0002-9222-1921
Sinha Mithun PhD
Dr Khan and Dr Mohan are postdoctoral researchers; Dr Chauhan and Dr Ingersol are plastic surgery residents; Mr Wang is a medical student; Mr Rinne is a research technician; Dr Hassanein is an associate professor; and Dr Sinha is an assistant professor, Department of Surgery, Division of Plastic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.

Dr Timsina is a senior biostatistician, International Drug Development Institute, Raleigh, NC, USA.

Dr Muraru is a database coordinator, Department of Surgery, Surgical Outcomes and Quality Improvement Center, Indiana University School of Medicine, Indianapolis, IN, USA.

Dr Minto is an associate professor, Department of Chemistry and Chemical Biology, Indiana University–Purdue University Indianapolis, Indianapolis, IN, USA.

Dr Van Natta and Dr Kelley-Patteson are plastic surgeons in private practice at Meridian Plastic Surgeons, Indianapolis, IN, USA.

Corresponding Author: Dr Mithun Sinha, Indiana University School of Medicine, 975 W Walnut St, Medical Research Library Building, Suite # 444A, Indianapolis, IN 46202, USA. E-mail: mitsinha@iu.edu
10 2024
10 6 2024
10 6 2024
44 10 NP695NP710
28 5 2024
30 7 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of The Aesthetic Society.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

Abstract

Background

A subset of females with breast implants have reported a myriad of nonspecific systemic symptoms collectively termed systemic symptoms associated with breast implants (SSBI). SSBI symptoms are similar to manifestations associated with autoimmune and connective tissue disorders. Breast tissue is rich in adipose cells, comprised of lipids. Insertion of an implant creates an oxidative environment leading to lipid oxidation. Oxylipins can influence immune responses and inflammatory processes.

Objectives

In this study we explored the abundance of a spectrum of oxylipins in the periprosthetic tissue surrounding the breast implant. Because oxylipins are immunogenic, we sought to determine if they were associated with the SSBI patients. We have also attempted to determine if the common manifestations exhibited by such patients have any association with oxylipin abundance.

Methods

The study included 120 patients divided into 3 cohorts. We analyzed 46 patients with breast implants exhibiting manifestations associated with SSBI; 29 patients with breast implants not exhibiting manifestations associated with SSBI (control cohort I, non-SSBI); and 45 patients without implants (control cohort II, no-implant tissue). Lipid extraction and oxylipin quantification were performed with liquid chromatography mass spectrometry (LC-MS/MS). LC-MS/MS targeted analysis of the breast adipose tissue was performed.

Results

Of the 15 oxylipins analyzed, 5 exhibited increased abundance in the SSBI cohort when compared to the non-SSBI and no-implant cohorts.

Conclusions

The study documents the association of the oxylipins with each manifestation reported by the patient. This study provides an objective assessment of the subjective questionnaire, highlighting which symptoms may be more relevant than the others.

Level of Evidence: 4

US National Institutes of Health 10.13039/100000002 R01AI165958 R21AI171932 Plastic Surgery Foundation 10.13039/100002280 831458 Aesthetic Surgery Education and Research Foundation 10.13039/100003559
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pmcNearly 300,000 females have breast implant surgeries every year in the United States.1 A subset of females with breast implants report a myriad of nonspecific systemic symptoms.2,3 The symptoms described include fever, myalgias, chronic fatigue, arthralgias, and other manifestations often associated with autoimmune illnesses.4-11 This constellation of symptoms related to implants has been named breast implant illness (BII) or systemic symptoms associated with breast implants (SSBI).

The number of patients who opt for breast implant explantation due to complications including systemic symptom concern is over 30,000 annually.1 Therefore, SSBI is a growing concern to patients and surgeons alike, with more than 10 million females worldwide currently living with breast implants.4 Despite the increased concern regarding SSBI, existing scientific literature does not show a link between breast implants and autoimmune or connective tissue diseases.

SSBI is poorly understood, and the etiology is unknown.11 Many studies have reported a pattern of systemic autoimmune symptoms and casual association between breast implants and an increase in immunological reactions.6,12,13 These responses are similar to autoimmune reactions against adjuvants after vaccinations.14,15 Reports have linked breast implants to malignancies like breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) and breast implant–associated squamous cell carcinoma (BIA-SCC).13,16 Some studies have linked breast implants to carcinomas at other sites, and other studies have shown breast implants not to be associated with cancer at other sites.17-19 This may be due to limited evidence on pathophysiological mechanisms secondary to differences in patient lifestyle, demographics, and reproductive age in comparison to the general population.11,12,20,21

Different hypotheses have been postulated to explain the origin of systemic symptoms in SSBI patients, but rarely explore the role of the implant–host breast adipose tissue interface. Lipids once were merely considered energy stores and structural blocks.22 Recently, due to the work done by several laboratories, it has become evident that adipose tissue communicates and controls many physiological and pathological processes in the rest of the body by synthesizing adipokines, which are circulating endocrine factors.23,24

Tissue-material integration and biostimulation studies demonstrate significant local complications.25,26 Currently available studies of mice or rats exposed to various antigens associated with implant materials indicate that implant material can act as an adjuvant and elicit a localized immune response that is notably weak.27-29 From the implant perspective, the injury created during the surgical procedure initiates an immune reaction to maintain homeostasis, which may lead to bioacceptance through resolution.30 The surgical injury at the implant site initiates a local inflammation and creates a multitude of factors that impact adipose tissue (increased inflammation, decreased adipose-derived hormone expression). These acute stress responses activate pathways that are involved in lipid peroxidation, generating oxylipins, which are involved in inflammatory, nociceptive, and vascular responses to injury.31,32

Oxylipins are oxygenated metabolites derived from ω−3 and ω−6- poly unsaturated fatty acids (PUFAs) by the activity of lipoxygenase (LOX), cyclooxygenase (COX), and cytochrome P450 (CYP) enzymes.33 Oxylipins are shown to have a complex function, with a role in both ameliorating and progressing illnesses. The ω−6-PUFA–derived oxylipins are more proinflammatory than ω−3-PUFAs, by promoting the synthesis of chemokines and cytokines that induce the triad of inflammation (edema, pain, and fever), resulting in the clearing of invasive pathogens and wound healing. Because oxylipins are associated with several human diseases, including diabetes, obesity, cancer, autoimmunity, and cardiovascular diseases, they are targeted by nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (aspirin) for many pharmaceutical actions.34,35

Despite oxylipins being associated with inflammatory activities, we know relatively little about their influence and concentrations in the periprosthetic tissue associated with breast implants. Because the breast tissue is rich in lipids, we hypothesized that they could be associated with the pathogenesis of SSBI. To test this hypothesis, we established a lipidomic profile to quantify 14 different lipid metabolites simultaneously derived from oxygenation of PUFAs synthesized through the activity of LOXs, COXs, and CYPs in the adipose tissue from the patients participating in the study. Here we report the changes in oxylipin profile of the SSBI patients and the correlations of these changes with systemic symptoms of concern.

METHODS

Human Patients

Patients participating in the study included 3 subsets. The first group consisted of patients with breast implants exhibiting manifestations associated with SSBI. Two additional groups of patients were evaluated as controls, implanted patients without symptoms of SSBI (non-SSBI cohort) and breast tissue without implant (no-implant cohort). Demographic characteristics of the patients are presented in Table 1. Patients exhibiting manifestations underwent clinical evaluation that included a detailed medical history interview, review of a comprehensive symptom inventory (Table 2), and a physical examination as outlined in previous SSBI studies.4-10,36 This was a single visit study in which samples were collected at the time of breast implant explantation (for SSBI and non-SSBI cohort) and breast procedures such as breast reduction (for no-implant cohort). The study was conducted over a period of 2 years and 2 months. All human studies were approved by the Indiana University School of Medicine Institutional Review Board (IRB no. 2003674175). Declaration of Helsinki protocols were followed, and patients gave their written informed consent.

Table 1. Sample Characteristics and Demographics

Characteristics	Total	SSBI	Non-SSBI	No-implant	P value	
Group						
 SSBI	46 (38.33%)					
 Non-SSBI	29 (24.17%)					
 No-implant	45 (37.50%)					
Age, mean (SD)	46.79 (13.31)	47.39 (9.73)	57.84 (12.27)	39.07 (12.03)		
BMI, median (IQR)	26.52 (23.17, 30.27)	24.80 (21.63, 29.05)	24.69 (22.86, 26.12)	29.12 (26.62, 33.65)	.0001	
Duration of implant, months, median (IQR)	193.08 (126, 264.57)	196.63 (105.6, 243)	195.58 (157.75, 307.22)		.421	
Duration of implant by decades					<.0001	
 No-implant	44 (36.67)	0 (0.00)	0 (0.00)	44 (97.78)		
 <10years	16 (13.33)	13 (28.26)	3 (10.34)	0 (0.00)		
 10-20 years	34 (28.33)	21 (45.65)	13 (44.83)	0 (0.00)		
 >20 years	24 (20.00)	12 (26.09)	12 (41.38)	0 (0.00)		
Race					.013	
 White	96 (80%)	40 (86.96%)	26 (89.66%)	30 (66.67%)		
 African American	7 (5.83%)	0 (0%)	0 (0%)	7 (15.56%)		
 Other	1 (0.83%)	0 (0%)	0 (0%)	1 (2.22%)		
 No response	16 (13.33%)	6 (13.04%)	3 (10.34%)	7 (15.56%)		
Medical history					.01	
 None	29 (24.17%)	6 (13.04%)	7 (24.14%)	16 (35.56%)		
 1-3	71 (59.17%)	26 (56.52%)	19 (65.52%)	26 (57.78%)		
 4+	20 (16.67%)	14 (30.43%)	3 (10.34%)	3 (6.67%)		
Medical History						
 Cardiovascular	25 (20.83%)	11 (23.91%)	8 (27.59%)	6 (13.33%)	.271	
 Respiratory	16 (13.33%)	8 (17.39%)	4 (13.79%)	4 (8.89%)	.522	
 Endocrine	25 (20.83%)	13 (28.26%)	4 (13.79%)	8 (17.78%)	.331	
 Gastrointestinal/genitourinary	27 (22.50%)	17 (36.96%)	5 (17.24%)	5 (11.11%)	.009	
 Rheumatology	16 (13.33%)	12 (26.09%)	1 (3.45%)	3 (6.67%)	.007	
 Hematology/oncology	28 (23.33%)	15 (32.61%)	10 (34.48%)	3 (6.67%)	.002	
 Neurologic	35 (29.17%)	17 (36.96%)	9 (31.03%)	9 (20%)	.199	
 Psychologic	55 (45.83%)	25 (54.35%)	11 (37.93%)	19 (42.22%)	.315	
History of mastitis (n = 84)	15 (17.86%)	11 (25%)	3 (16.67%)	1 (4.55%)	.112	
Smoking (n = 118)					.106	
 Never	111 (94.07%)	40 (88.89%)	27 (93.1%)	44 (100%)		
 Current	5 (4.24%)	3 (6.67%)	2 (6.9%)	0 (0%)		
 Past	2 (1.69%)	2 (4.44%)	0 (0%)	0 (0%)		
Alcohol (n = 118)					.568	
 None	109 (92.37%)	40 (88.89%)	27 (93.1%)	42 (95.45%)		
 Social	9 (7.63%)	5 (11.11%)	2 (6.9%)	2 (4.55%)		
Medications					.007	
 None	48 (40%)	12 (26.09%)	10 (34.48%)	26 (57.78%)		
 At least 1	72 (60%)	34 (73.91%)	19 (65.52%)	19 (42.22%)		
BMI, bone mass index; IQR, interquartile range; SD, standard deviation; SSBI, systemic symptoms associated with breast implants.

Table 2. Distribution of Questionnaire Responses by Domain

Domain and questions	Total
n (%)	SSBI
n (%)	Non-SSBI
n (%)	No-implant
n (%)	P value	Bonferroni adjusted	
LOCAL CHEST AREA							
Pain around implant and/or upper or outer chest (n = 75)				<.001	0.007	
 None	26 (34.66%)	6 (13.63%)	7 (41.17%)	13 (92.85%)			
 Low	24 (32%)	18 (40.9%)	5 (29.41%)	1 (7.14%)			
 High	25 (33.33%)	20 (45.45%)	5 (29.41%)	0 (0%)			
Pain and swelling around armpit (n = 76)					.036	>0.99	
 None	46 (60.52%)	18 (41.86%)	14 (82.35%)	14 (87.5%)			
 Low	18 (23.68%)	14 (32.55%)	2 (11.76%)	2 (12.5%)			
 High	12 (15.78%)	11 (25.58%)	1 (5.88%)	0 (0%)			
GENERAL							
Feel fatigued (n = 85)					<.001	<0.001	
 None	23 (27.05%)	0 (0%)	10 (52.63%)	13 (61.9%)			
 Low	21 (24.70%)	8 (17.77%)	6 (31.57%)	7 (33.33%)			
 High	41 (48.23%)	37 (82.22%)	3 (15.78%)	1 (4.76%)			
Have brain fog (n = 85)					<.001	<0.001	
 None	27 (31.76%)	0 (0%)	11 (57.89%)	16 (76.19%)			
 Low	17 (20%)	7 (15.55%)	6 (31.57%)	4 (19.04%)			
 High	41 (48.23%)	38 (84.44%)	2 (10.52%)	1 (4.76%)			
Feel inflamed (n = 81)					<.001	<0.001	
 None	36 (44.44%)	4 (10.25%)	14 (87.5%)	18 (85.71%)			
 Low	9 (11.11%)	8 (20.51%)	0 (0%)	1 (4.76%)			
 High	31 (38.27%)	27 (69.23%)	2 (12.5%)	2 (9.52%)			
IMMUNE SYSTEM							
Frequent viral infections (n = 85)					<.001	<0.001	
 None	34 (40%)	5 (11.11%)	12 (63.15%)	17 (80.95%)			
 Low	40 (47.05%)	29 (64.44%)	7 (36.84%)	4 (19.04%)			
 High	11 (12.94%)	11 (24.44%)	0 (0%)	0 (0%)			
Have night sweats (n = 83)					<.001	0.0004	
 None	22 (26.50%)	4 (9.09%)	7 (36.84%)	11 (55%)			
 Low	26 (31.32%)	19 (43.18%)	8 (42.1%)	9 (45%)			
 High	25 (30.12%)	21 (47.72%)	4 (21.05%)	0 (0%)			
MUSCULOSKELETAL							
Joint pain/swelling (n = 84)					<.001	<0.001	
 None	22 (26.19%)	0 (0%)	12 (66.66%)	10 (45.45%)			
 Low	17 (20.23%)	5 (11.36%)	4 (22.22%)	8 (36.36%)			
 High	45 (53.57%)	39 (88.63%)	2 (11.11%)	4 (18.18%)			
Muscle pain and weakness (n = 84)					<.001	<0.001	
 None	24 (28.57%)	1 (2.27%)	12 (66.66%)	11 (50%)			
 Low	30 (35.71%)	15 (34.09%)	5 (27.77%)	10 (45.45%)			
 High	30 (35.71%)	28 (63.63%)	1 (5.55%)	1 (4.54%)			
SKIN							
Have dry skin and hair (n = 86)					<.001	<0.001	
 None	22 (25.58%)	3 (6.66%)	5 (26.31%)	14 (63.63%)			
 Low	31 (36.04%)	13 (28.88%)	10 (52.63%)	8 (36.36%)			
 High	33 (38.37%)	29 (64.44%)	4 (21.05%)	0 (0%)			
Have hair loss (n = 85)					<.001	<0.001	
 None	30 (35.2%)	5 (11.36%)	7 (36.84%)	18 (81.81%)			
 Low	31 (36.4%)	18 (40.9%)	10 (52.63%)	3 (13.63%)			
 High	24 (28.23%)	21 (47.72%)	2 (10.52%)	1 (4.54%)			
EYES							
Have puffy eyes (n = 86)					<.001	<0.001	
 None	38 (44.18%)	6 (13.33%)	13 (68.42%)	19 (86.36%)			
 Low	23 (26.74%)	14 (31.11%)	6 (31.57%)	3 (13.63%)			
 High	25 (29.06%)	25 (55.55%)	0 (0%)	0 (0%)			
RESPIRATORY							
Nasal discharge (n = 86)					<.001	0.0002	
 None	47 (54.65%)	12 (26.66%)	15 (78.94%)	20 (90.9%)			
 Low	21 (24.41%)	15 (33.33%)	4 (21.05%)	2 (9.09%)			
 High	18 (20.93%)	18 (40%)	0 (0%)	0 (0%)			
HEART							
Palpitations (n = 84)					<.001	<0.001	
 None	41 (48.80%)	8 (17.77%)	14 (77.77%)	19 (90.47%)			
 Low	32 (38.09%)	26 (57.77%)	4 (22.22%)	2 (9.52%)			
 High	11 (13.091%)	11 (24.44%)	0 (0%)	0 (0%)			
GASTROINTESTINAL							
Food intolerance/allergies (n = 83)					<.001	<0.001	
 None	36 (43.37%)	6 (13.63%)	12 (66.66%)	18 (85.71%)			
 Low	24 (28.91%)	18 (40.9%)	3 (16.66%)	3 (14.28%)			
 High	23 (27.71%)	20 (45.45%)	3 (16.66%)	0 (0%)			
Constipation (n = 84)					.001	0.048	
 None	30 (35.71%)	7 (15.55%)	10 (55.55%)	13 (61.9%)			
 Low	32 (38.09%)	19 (42.22%)	5 (27.77%)	8 (38.09%)			
 High	22 (26.19%)	19 (42.22%)	3 (16.66%)	0 (0%)			
Diarrhea (n = 84)					.001	0.031	
 None	30 (35.71%)	7 (15.55%)	11 (61.11%)	12 (57.14%)			
 Low	40 (47.61%)	25 (55.55%)	7 (38.88%)	8 (38.09%)			
 High	14 (16.67%)	13 (28.88%)	0 (0%)	1 (4.76%)			
Bloating (n = 84)					<.001	<0.001	
 None	22 (26.19%)	2 (4.44%)	9 (50%)	11 (52.38%)			
 Low	26 (30.95%)	10 (22.22%)	7 (38.88%)	9 (42.85%)			
 High	36 (42.85%)	33 (73.33%)	2 (11.11%)	1 (4.76%)			
ENDROCRINE/HORMONAL							
Low libido (n = 84)					<.001	<0.001	
 None	25 (29.76%)	1 (2.22%)	11 (61.11%)	13 (61.9%)			
 Low	18 (21.42%)	6 (13.33%)	4 (22.22%)	8 (38.09%)			
 High	41 (48.88%)	38 (84.44%)	3 (16.66%)	0 (0%)			
Abnormal menstrual cycles (n = 74)					.012	0.763	
 None	43 (58.1%)	17 (42.5%)	14 (93.33%)	12 (63.15%)			
 Low	18 (24.32%)	11 (27.5%)	0 (0%)	7 (36.84%)			
 High	13 (17.56%)	12 (30%)	1 (6.66%)	0 (0%)			
NEUROLOGICAL							
Numbness and tingling in arms, hands, fingers, legs, feet (n = 84)				<.001	0.0005	
 None	26 (30.95%)	4 (8.88%)	10 (55.55%)	12 (57.14%)			
 Low	27 (32.14%)	13 (28.88%)	6 (33.33%)	8 (38.09%)			
 High	31 (36.90%)	28 (62.22%)	2 (11.11%)	1 (4.76%)			
PSYCHOLOGICAL							
Feel depressed (n = 85)					<.001	0.027	
 Never	26 (30.59%)	5 (11.11%)	11 (57.89%)	10 (47.62%)			
 Rarely	18 (21.18%)	11 (24.44%)	4 (21.05%)	3 (14.29%)			
 Sometimes	27 (31.76%)	15 (33.33%)	4 (21.05%)	8 (38.1%)			
 Often	11 (12.94%)	11 (24.44%)	0 (0%)	0 (0%)			
 Always	3 (3.53%)	3 (6.67%)	0 (0%)	0 (0%)			
Feel anxious (n = 85)					<.001	0.0004	
 Never	21 (24.71%)	3 (6.67%)	9 (47.37%)	9 (42.86%)			
 Rarely	9 (10.59%)	4 (8.89%)	3 (15.79%)	2 (9.52%)			
 Sometimes	23 (27.06%)	9 (20%)	6 (31.58%)	8 (38.1%)			
Often	22 (25.88%)	19 (42.22%)	1 (5.26%)	2 (9.52%)			
Always	10 (11.76%)	10 (22.22%)	0 (0%)	0 (0%)			
SSBI, systemic symptoms associated with breast implants.

Sample Size

The study included 120 patients divided into 3 cohorts. Analysis was performed of 46 patients with breast implants exhibiting manifestations associated with SSBI; 29 in control cohort I, patients with breast implants not exhibiting manifestations associated with SSBI (non-SSBI); and 45 in control cohort II, patients without implants (no-implant normal tissue). Post hoc power analysis revealed that this sample size could detect an effect size of 0.2870 with 0.08 between-group variance at 80% statistical power and 5% type I error rate. Patients were diagnosed with SSBI by the clinical parameters outlined in previous studies.4-10 As a part of the diagnosis, the patients were required to complete a questionnaire. The questionnaire screened for commonly reported symptoms associated with SSBI.4-10 Implant-associated capsules, periprosthetic breast tissue, and peripheral blood were collected from these patients. The mean age of SSBI (n = 46) patients was 47 years. Two groups were considered controls. Control group I (non-SSBI, n = 29) included patients with breast implants without SSBI symptoms who underwent explantation of the breast implant. The mean age of non-SSBI patients was 58 years. Control group II (no-implant, normal tissue, n = 45) was comprised of females without an implant, whose breast tissue was removed in clinically indicated surgical procedures such as mastopexy or breast reduction. The mean age of control group II (cohort with no-implant tissue) patients was 39 years. The demographics of the patients have been provided in Table 1.

Lipid Profiling

Lipid extraction and oxylipin quantification was performed with liquid chromatography mass spectrometry (LCMS). LC-MS/MS targeted analysis from the breast adipose tissue was carried out through Cayman Chemical Company (Ann Arbor, MI). Samples were weighed and transferred to 2-mL Precellys vials with ceramic beads and PBS/methanol 1:1 (v/v) containing a mixture of deuterated oxylipin standards (0.5 ng/mL for each oxylipin). Samples were homogenized with Precellys 24 tissue homogenizer (Bertin Technologies, Rockville, MD) and extracted using Strata-X 96 well solid phase extraction plates (Phenomenex, Torrance, CA). The total volume of the homogenate was extracted with ethyl acetate in a 1:1 volume ratio. Samples were vortexed for 1 minute and centrifuged at 14.000 rpm for 10 minutes. The organic phase was collected and transferred to a new vial to be evaporated and stored at −80 °C until analysis. The dried lipid extracts were reconstituted with 50 μL of mobile phase A (water/acetonitrile 6:4, v/v, 0.2% acetic acid for targeted quantification by liquid chromatography tandem MS (LC/MS/MS). The LC column was an Acquity UPLC BEH Shield RP18 column 1.7-µm particle size,2.1 × 100 mm (Waters, Milford, MA) fitted with an Acquity UPLC BEH Shield RP18 VanGuard pre-column 130Å, 1.7 μm, 2.1 X 5 mm (Waters, Milford, MA). The binary pump flow rate was set at 0.3 mL/min in an ExionLC integrated system (Sciex, Framingham, MA) with acetonitrile/isopropanol 1:1 (v/v) as mobile phase B. The LC column was pre-equilibrated with 80% A for 1 minute. A linear gradient to 55% B was run from 0.1 to 8 minute. The binary pump was set in a linear gradient to 99% B in 9 minutes brought back to 0.1% B at 10.1 minute, and reequilibrated for 12 minute. Samples were analyzed on a Sciex QTrap 6500+ mass spectrometer, using multiple reaction monitoring in negative-ion mode . In the mass spectrometer the ion spray voltage was -4000 V in the negative ion mode; declustering potential, -60V; entrance potential, -10V; exit potential, -11V; curtain gas 20 psi; collison gas 8 psi, ion source gas 1, 2 and 30 psi. the gas temperature was 350 °C, concentrations in pg/mg of tissue were obtained by normalizing by the dried weight of the sample homogenized and by the concentration of the deuterated internal standard. To quantify various oxylipins, calibration curves were constructed with 15 serial dilutions of the stock solution. Data processing was carried out with software MutliQuant (Sciex).

Quantification and Statistical Analysis

The quantification and analysis of the abundance of oxylipins were performed on n = 120 patients who were categorized by 3 cohorts: patients with breast implants exhibiting manifestations associated with SSBI, patients with implants without manifestations (non-SSBI), and those without implants (no-implant). Patient-reported symptoms were analyzed for all patients who responded to questions related to the manifestations with Likert-type questionnaires to examine the correlation of oxylipins and clinical manifestations as experienced by the 3 cohorts. Duration of implant was grouped into categories such as <10 years, 10 to 20 years, >20 years, and no-implant, and this was analyzed in relation to the abundance of oxylipin. Normality of the distribution of each oxylipin abundance and other continuous variables were evaluated with the Shapiro-Wilk test and also evaluated with Q-Q plot. Descriptive statistics by groups (SSBI, non-SSBI, and no-implant) were calculated with mean (standard deviation) for normally distributed data and median (interquartile range) for those deviating from normality. Parametric bivariate analyses were performed with analysis of variance (ANOVA), and nonparametric bivariate analyses were performed with the Kruskal-Wallis test followed by Dunn's test for pairwise comparisons, with Bonferroni multiple testing adjusted P values to minimize the false discovery rate. Analysis of 2 categorical variables was by bivariate analysis chi-square test or, if the expected cell count was <5, Fisher's exact tests with family-wise error rate (FWER)–adjusted P value by Bonferroni methods were used. Continuous variables describing the sample characteristics were analyzed to examine the difference among the cohorts with ANOVA or Kruskal-Wallis test as appropriate, based on the test of normality of these variables. Graphical presentation of each oxylipin by cohort was created with a bar diagram, including the standard error around the mean (SEM). A line plot was created for the oxylipin abundance by duration of implant when no-implant was the reference category. For the questionnaire, we grouped the 5-point Likert scale by 3 categories: those reporting no symptom manifestations were grouped as none, intermediate responses were grouped as low, and quite a bit, very much or often, and always as high. All analyses were performed with Stata/MP 16.1, and the level of significance was set at P < .05.

RESULTS

Sample Characteristics

Of the 120 females, 38% were patients with breast implants who exhibited manifestations associated with SSBI, and 24% were without SSBI (non-SSBI). As a healthy control, about 38% of the females provided no-implant breast tissue (no-implant (normal tissue)), without any SSBI symptoms. The mean age was 47 (+/−13) years in the SSBI sample, with a significantly older population in the non-SSBI group, with a mean age (SD) of 58 (+/−12) years. The median ages (interquartile ranges, IQR) by group were, respectively, 46 (40-54) for SSBI, 59 (48-65) for non-SSBI, and 37 (31-48) for the no-implant (normal) cohort. The population had a median BMI that was significant in the overweight range (IQR: 23.17-30.27) in the no-implant (normal) cohort. Among those who had an implant, the median range of duration of implant was significantly observed to be within 10 to 20 years. Irrespective of cohort, the majority of the study population was white (P = .013). About 25% of the study population had no comorbidity history (P = .01). Among those who had a history of comorbidity, the majority of them had 4+ comorbidities in the SSBI group. Compared to non-SSBI patients, SSBI patients were significantly more likely to report a history of at least 1 medication (P = .007) (Table 1).

Symptom Manifestations by Cohorts

The descriptive analysis of the manifestation domains on the questionnaire and comparison by chi-square test or Fisher's exact test with FWER-adjusted P value by Bonferroni methods is presented in Table 2.36 For ease of interpretation, we presented intermediate responses as low category, and quite a bit, very much or often, and always as high category in the response levels for symptom manifestations. Pain around the implant was found to be significantly higher in the SSBI cohort, whereas non-SSBI and no-implant (normal) cohorts reported having no symptoms associated with pain around the implant (P = .007). Pain and swelling around the armpits were not different (P > .99) between cohorts; however, a feeling of discomfort was more prevalent in the SSBI group (P = .01). Feeling fatigued, having brain fog, unexplained weight gains, and feeling inflamed were some of the general major manifestations consistently reported by the SSBI group (P < .001) compared to others. Compared to other cohorts, there were some indications, although less frequent (lower rating levels), of symptom manifestations related to viral infections, swelling of tender lymph nodes, having chills, and night sweats in the SSBI cohort (P < .05). The overall pain rating as evaluated by Kruskal-Wallis test was found to be significantly higher in the SSBI cohort compared to the non-SSBI and no-implant cohorts (P = .0089). Similarly, higher levels of manifestations were reported in the SSBI cohort for joint pain or swelling, muscle pain and weaknesses, and having dry skin and hair loss (P < .001) compared to other cohorts. Muscle twitching and slow recovery after exercise were reported to occur rarely or sometimes significantly among the SSBI cohort, while these symptoms were not reported by most of the non-SSBI and no-implant cohorts (P < .001). Having skin rashes and acne or acne-like eruptions were not found to be associated with the 3 cohorts. Most of the respondents in both the no-implant and non-SSBI cohorts reported having none of the manifestations related to vision change or distortions, puffy eyes, or sensitivity to light. The SSBI cohort reported having these manifestations more consistently (P < .001). More than three-quarters of the non-SSBI and no-implant cohorts did not express any respiratory or cardiac symptoms, whereas the SSBI cohort frequently reported experiencing quite a bit or very much nasal discharge, palpitations, and chest pain (P < .001). Most of the gastrointestinal symptoms (food intolerance or allergies, constipation, diarrhea, bloating, abdominal pain, reflux or gastritis, and dry mouth) were reported to be frequent by the SSBI cohort compared to the non-SSBI and no-implant cohorts (P < .05). Temperature intolerance and low libido were also frequently reported in the SSBI cohorts (P < .001). Heavy or abnormal menstrual bleeding were found to be similar across all 3 cohorts (P > .05). Other common symptoms reported by the SSBI cohort were numbness and tingling in the arms, hands, fingers, legs or feet (P = .0005) and headaches (typical or tension; P = .0001). Studies have reported that psychological testing has demonstrated that patients exhibiting SSBI symptoms have an increased level of anxiety compared to non-SSBI patients.37 Responses on the questionnaire regarding feeling anxious (P = .0004) and feeling depressed (P = .027) were significantly associated with the study cohort. All 14 (31.1%) patients who responded that they were often or always depressed were from the SSBI cohort. Only 11% of the SSBI cohort never felt depressed, compared to 57.89% in the non-SSBI and 47.62% in the no-implant cohorts. Similarly, about 19 patients who said they were often and 10 always anxious were from the SSBI cohort (64.4%) (Table 2). No significant difference in migraines was observed across all 3 cohorts (P > .99). No statistically significant association between mastitis and oxylipin abundance between the cohorts was observed (Supplemental Table 1, located online at www.aestheticsurgeryjournal.com).

Oxylipin Abundance by Cohort for Each Symptom Manifestation

The oxylipins from the breast tissue of the no-implant group (normal) were measured, and breast tissue surrounding the implant (periprosthetic tissue) was analyzed for the SSBI and non-SSBI groups. The oxylipins were not measured from periprosthetic capsules. The baseline oxylipin from the no-implant breast tissue was compared with the periprosthetic breast tissue of the SSBI and non-SSBI cohorts. Upon analyses of 15 oxylipins (Table 3), altered oxylipin in periprosthetic tissue of SSBI patients was observed for 5 oxylipins. Compared to the non-SSBI and no-implant cohorts, a significantly increased abundance of 5 oxylipins (9-HODE; 12,13-DiHOME; 9,10-DiHOME; 13-HODE; and 10-HOME) in the SSBI cohort were observed through pairwise comparisons. These oxylipins also had significant higher abundance in the SSBI cohorts compared to the non-SSBI cohorts, as observed from the pairwise Bonferroni adjusted P values (P < .05) in Figure 1A-E; and Supplemental Figure 1 and Supplemental Table 2, located online at www.aestheticsurgeryjournal.com. In some cases, difference was observed between the non-SSBI versus no-implant cohorts for oxylipins like 5-HETE and 14,15-DiHETrE. In these cases, no difference was found between the SSBI and non-SSBI cohorts. The change in these oxylipins could possibly be because of the breast implant itself.

Figure 1. Altered oxylipin in periprosthetic tissue of SSBI patients. (A-E) Fifteen oxylipins were analyzed. Nonparametric Dunn's pairwise comparison was performed to analyze the abundance of oxylipins across 3 cohorts—SSBI, non-SSBI, and no-implant (normal). We observed increased abundance of 5 oxylipins (A) 9-HODE; (B) 12,13-DiHOME; (C) 9,10- DiHOME; (D) 13-HODE; and (E) 10-HOME in the SSBI cohort when compared to the non-SSBI and no-implant cohorts. For (A) 9-HODE there were n = 45 (SSBI), 29 (non-SSBI), and 44 (no-implant) patients; for (B) there were n = 46 (SSBI), 29 (non-SSBI), and 45 (no-implant) patients; for (C) there were n = 46 (SSBI), 29 (non-SSBI), and 45 (no-implant) patients; for (D) there were n = 45 (SSBI), 29 (non-SSBI), and 43 (no-implant) patients; and for (E) there were n = 46 (SSBI), 29 (non-SSBI), and 44 (no-implant) patients. The P value displayed is the adjusted P value for multiple pairwise comparison with Bonferroni methods.

Table 3. List of Oxylipins Analyzed in Periprosthetic Breast Tissue

	Oxylipin	Abbreviation	
1	5-hydroxyeicosatetraenoic acid	5-HETE	
2	11-hydroxyeicosatetraenoic acid	11-HETE	
3	12-hydroxyeicosatetraenoic acid	12-HETE	
4	15-hydroxyeicosatetraenoic acid	15-HETE	
5	9-hydroxyoctadecadienoic acid	9-HODE	
6	17-hydroxydocosahexaenoic acid	17-HDoHE	
7	13-hydroxyoctadecadienoic acid	13-HODE	
8	9,10-dihydroxyoctadecenoic acid	9,10-DiHOME	
9	12,13-dihydroxyoctadecenoic acid	12,13-DiHOME	
10	8,9-dihydroxyeicosatrienoic acid	8,9-DiHETrE	
11	11,12-dihydroxyicosatrienoic acid	11,12-DiHETrE	
12	14,15-dihydroxyicosatrienoic acid	14,15-DiHETrE	
13	Thromboxane B2	TXB2	
14	Prostaglandin F2α	PGF2α	
15	10-hydroxy-8-octadecenoic acid	10-HOME	

We subsequently assessed altered oxylipin abundance as a function of implant duration for the oxylipins (9-HODE, P = .0011; 12,13-DiHOME, P = .0198; 9,10-DiHOME, P = .0019; 13-HODE, P = .0014; and 10-HOME, P = .0032) (Figure 2A-E; Supplemental Figure 2 located online at www.aestheticsurgeryjournal.com). Duration of implant was found to be significantly associated with an increase in the median value of oxylipin abundance in the first 10 years. However, after a decade with an implant, the level dropped off for 5 types of oxylipins and became equivalent to the levels expressed for the no-implant group in 10 to 20 years and 20+ years, except for 13-HODE, which still dropped off in the 10 to 20 years window but remained significant until 20+ years, when it became equivalent to the abundance of the no-implant group.

Figure 2. Altered oxylipin abundance as a function of implant duration. (A) 9-HODE; (B) 12,13-DiHOME; (C) 9,10- DiHOME; (D) 13-HODE; and (E) 10-HOME. Following implantation, the median values of oxylipin abundance were found to significantly increase in the first 10 years, with P values (A) = 0.0011, (B) = 0.0198, (C) = 0.0019, (D) = 0.0014, and (E) = 0.0032, as observed after Bonferroni-adjusted Dunn's pairwise comparisons. The level then dropped in all 5 types of oxylipins and became equivalent to the levels expressed for the no-implant group in 10 to 20 years and 20+ years, except for 13-HODE, which still dropped off in 10 to 20 years but remained significant until 20+ years, when it became equivalent to the no-implant group's abundance levels.

The group-bar diagrams in Figures 3, 4 and Supplemental Figures 3, 4 (located online at www.aestheticsurgeryjournal.com) demonstrate significant association (P < .05) of oxylipins 9-HODE; 12,13-DiHOME; 9,10- DiHOME; 13-HODE; and 10-HOME with patient-reported symptoms. More specifically, patients with increased oxylipin levels reported having significantly higher manifestation of (Supplemental Figure 3A) feeling fatigued, (Supplemental Figure 3B) myalgia, (Supplemental Figure 3C) joint pain/swelling, (Supplemental Figure 4A) brain fog, (Supplemental Figure 4B) pain around implant, (Supplemental Figure 4C) dryness of skin, (Supplemental Figure 3A) numbness and tingling, (Supplemental Figure 3B) nasal discharge, (Supplemental Figure 4A) abnormal menstrual cycles, (Supplemental Figure 4B) bloating, (Supplemental Figure 4C) food intolerance/allergies, (Supplemental Figure 4D) low libido, (Supplemental Figure 4E) palpitations, and (Supplemental Figure 4F) hair loss. Comparisons of the oxylipins and levels of other symptom manifestations are reported in Supplemental Figures 5-25, located online at www.aestheticsurgeryjournal.com. A history of anxiety and depression has been reported to be associated with SSBI.38,39 Of the 15 oxylipins, 9-HODE and 13-HODE were found to be associated with anxiety, and 12,13-DiHOME was found to be associated with depression (Supplemental Figure 3C, D, Supplemental Figures 26, 27, located online at www.aestheticsurgeryjournal.com). In addition to the psychological comorbidities mentioned above, others such as a history of cancer, diabetes, thyroid activity, asthma, or migraines, were obtained from the chart review of the patients. In this study, no statistically significant difference was observed for them (Supplemental Table 3, located online at www.aestheticsurgeryjournal.com). There were 26 of the 79 patients with breast implants in the study who had grade 3 or 4 capsular contracture and 1 patient with grade 2. In the SSBI cohort 10/46 (21%) had capsular contracture, whereas in the non-SSBI cohort it was 17/29 (58%). Of the 15 oxylipins, no association was observed for 10 of them. Five oxylipins (9-HODE; 9,10-DiHOME; 13-HODE; 12-HETE; and 11,12-DiHETrE) showed a lower abundance in capsular contracture patients (Supplemental Figures 28, 29, located online at www.aestheticsurgeryjournal.com).

Figure 3. The group-bar diagrams present the oxylipins versus patient-reported symptoms categorized by none, low, or high score levels of individual oxylipin abundance and error bars for standard error around the mean. Overall P values indicating significant association between oxylipins and symptoms' score categories were obtained with the Kruskal-Wallis test. There was significant association of oxylipins 9-HODE; 12,13-DiHOME; 9,10- DiHOME; 13-HODE; and 10-HOME. Patients with increased oxylipins levels reported higher manifestations of (A) feeling fatigued; (B) muscle pain and weakness; and (C) joint pain or swelling.

Figure 4. The group-bar diagrams present the oxylipins versus patient-reported symptoms categorized by none, low, or high score levels of individual oxylipin abundance and error bars for standard error around the mean. Overall P values indicating significant association between oxylipins and symptoms' score categories were obtained with the Kruskal-Wallis test. Significant association of oxylipins 9-HODE; 12,13-DiHOME; 9,10- DiHOME; 13-HODE; and 10-HOME were noted. Patients with increased oxylipins levels reported higher manifestations of (A) brain fog; (B) pain around the implant; and (C) dryness of skin and hair.

DISCUSSION

Lipids are regulators of cellular functions, and their metabolism is altered due to pathological manifestations similar to those of genetic transcripts and proteins.40 Bioactive lipids can influence immune responses and inflammatory processes.41,42 In the case of proinflammatory lipid activity, these lipids also contribute to the transition from acute to chronic inflammation.41 Lipidomics is the analysis of lipid metabolism, which is assessed by spectrophotometric techniques or mass/gas chromatography.43,44 Nutritional and epidemiological studies have shown that high consumption of trans fatty acids can lead to autoimmune responses and cardiovascular diseases.45,46 Breast tissue is rich in lipids. Recent reports have implicated the involvement of the breast lipids in pathological conditions associated with the tissue. Oxidative stress–mediated increase in breast endothelial lipase (LIPG) was reported to support proliferation, tumorigenicity, and metastasis of breast cancer cells.47 Implantation of the prosthetic device leads to an oxidative environment in the breast tissue.48 In this study we explored the abundance of oxidized lipids in the periprosthetic tissue surrounding the breast implant. Because oxylipins are immunogenic, we assessed whether they were associated with the SSBI patients. We also identified whether the common manifestations exhibited by these patients had any association with the oxylipin abundance.

Of the 15 oxylipins analyzed, 5 exhibited increased abundance in the SSBI cohort compared to the non-SSBI and no-implant cohorts. These were 9-HODE; 12,13-DiHOME; 9,10-DiHOME; 13-HODE; and 10-HOME. It is to be noted that 9-HODE and 13-HODE are oxidized products of linoleic acid. They have been reported to be associated with inflammatory conditions of tissues, including progression of atherosclerotic plaques.49 The oxylipin 9,10-DiHOME, derived from oxidation of linoleic acid, leads to oxidative stress through activation of NF-kB and AP1 transcription factors, and 12,13 Di-HOME has been associated with increased risk of asthma in mouse models.50,51 It is important to note that many SSBI patients reported endocrinal manifestations. It has been reported in a study that a mixture of 9,10- and 12,13-DiHOME disrupted the estrous cycle of female rats but did not affect the sexual behavior of male rats.52

The abundance of a majority of oxylipins barring 2 increased with the duration of implant. The maximum abundance was observed at around 10 years of implant duration. Subsequently, a reduction in the level of oxylipins was observed in the periprosthetic tissue. This was possibly due to the foreign body response that resolved in cases in which implants remained for a longer time. The observation is consistent with an earlier study which reported that the foreign body response to silicone injection resulted in the “Vroman effect,” which peaked around 10 years and subsequently declined.53 This also is consistent with the fact that the majority of females describing manifestations associated with SSBI are within 10 years of receiving the implants.

Causation of SSBI is believed to be multifactorial in nature. The research in this field is evolving and the etiology is primarily unknown. In this study we investigated whether oxylipins might be associated with the condition. The rationale for focusing on oxylipins included the adipose microenvironment of breast tissue and the oxidative environment due to the breast implant. This study documented association of the oxylipins with each manifestation reported by patients. The intensity of some manifestations was positively corelated with oxylipin levels, whereas with other manifestations it was not. Analysis of comorbidities and psychological conditions were considered. This study has provided an objective assessment of the subjective questionnaire, highlighting which symptoms may be more important than others. A limitation of the study was that it was not longitudinal. A longitudinal study of 2 years or more, following oxylipin levels postexplantation, will be helpful. Because the study was cross-sectional by design, causation could not be established, however we can infer association from the study design.

CONCLUSIONS

In summary, this is the first report that exhibits possible association of a panel of oxylipins with manifestations reported by patients with SSBI. Further studies are required to assess whether this association can be related to SSBI etiology. Also, mechanistic immunological cause-effect studies will be required to understand the molecular pathway.

Supplemental Material

This article contains supplemental material located online at www.aestheticsurgeryjournal.com.

Supplementary Material

sjae128_Supplementary_Data

Acknowledgments

Dr Khan and Dr Timsina contributed equally to this work as co-first authors.

Disclosures

Dr Sinha participated in the SSBI scientific research advisory meeting held by AbbVie in November 2023. This was a meeting of scientists working in the field of breast implants to share their research developments. The organization had no influence on this study or its outcomes.

Funding

This work was supported by the National Institutes of Health (NIH) grants R01AI165958 and R21AI171932 to Dr Sinha; Plastic Surgery Foundation (PSF) grant 831458 to Dr Sinha; and The Aesthetic Foundation (Garden Grove, CA) (previously referred to as the Aesthetic Surgery Education and Research Foundation [ASERF]) research grant to Dr Sinha.
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