Adipose-Derived Mesenchymal Stem Cells for the Prevention of Capsular Contracture

doi:10.21203/rs.3.rs-4719643/v1

Download PDF

Research Article

Adipose-Derived Mesenchymal Stem Cells for the Prevention of Capsular Contracture

https://doi.org/10.21203/rs.3.rs-4719643/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background

Capsular contracture (CC) is the most common complication associated with implant-based breast surgery, with particularly high risk in patients undergoing alloplastic reconstruction surgery followed by radiation therapy. Revision surgery, the only currently effective treatment, carries a high risk of recurrent CC and secondary complications. This work assessed the prophylactic potential of human adipose-derived mesenchymal stem cells (hAD-MSCs) in a novel animal model of radiation-induced CC.

Methods

A total of 36 female C57Bl/6 mice, were randomly assigned to three groups: (1) IMP (silicone implants only), (2) IMP + RAD (silicone implants and irradiation therapy to promote CC); (3) IMP + RAD + MSCs (silicone implants, irradiation therapy and local administration of hAD-MSCs). On day 42 post-implantation, animals were euthanized and capsular tissue was subjected to histological and gene expression analyses. In addition, serum transforming growth factor beta (TGF-β) levels were measured.

Results

Targeted radiotherapy induced significant CC. In contrast, on day 42 post-irradiation, capsular thickness in the IMP + RAD + MSCs group was significantly lower, comparable to that of non-irradiated mice. hAD-MSCs treatment also resulted in a significant downregulation of pro-fibrotic and pro-inflammatory genes in the capsular tissue.

Conclusion

hAD-MSCs demonstrated significant prophylactic potential in preventing radiation-induced CC. Further research is necessary to investigate the underlying mechanisms and to assess the efficacy and safety of this approach.

Capsular Contracture

Radiation

Adipose-Derived Mesenchymal Stem Cells

Capsular contracture (CC) is the most common complication of implant-based aesthetic and reconstructive breast surgery.^1–5 While the incidence of CC following primary breast augmentation surgery ranges from 0.57–15%,^1,2,6,7 the risk is higher in patients undergoing implant-based breast reconstruction (5–55%)^1,8–12 and even higher in patients who undergo postmastectomy radiation therapy (PMRT). A recent meta-analysis reported CC rates of up to 50% in this high-risk group,¹³ while other authors report rates of between 68% and 100%. ^1,3,4,14,15

CC is thought to occur due to an excessive fibrotic reaction to the implant, resulting in excessively firm, painful and deformed breasts.^4–6 Notably, thin capsule formation is a normal response to foreign bodies, whereas CC is not.⁵ Numerous experimental and clinical studies have attempted to understand the risk factors, clinical features and management of CC. The underlying etiology and optimal treatment of CC remain elusive.^16,17 Feasible etiological factors include biofilm, hematoma, implant type, silicone leakage and individual susceptibility.¹ Proposed risk factors for CC include incision site, implant surface texture and radiotherapy.¹⁸

The extensively documented correlation between radiation and CC has been ascribed to radiotherapy-induced tissue damage, which leads to increased inflammation, fibrosis and collagen deposition, ultimately contributing to the formation of a contracted capsule. Transforming growth factor beta (TGF-ß) has been identified as a pivotal cytokine involved in the development of radiation-induced fibrosis,³ through its stimulation of the production of extracellular matrix, leading to capsular fibrosis and contracture.¹⁹

Thus far, no interventions have satisfactorily prevented or treated CC.^20–26 Currently, the only effective treatment for CC is surgery, which includes capsulotomy or capsulectomy with implant removal or replacement. Yet, the procedure carries a high risk for CC recurrence and secondary complications.^1,27

In recent years, stem cells, particularly adipose-derived stem cells, have attracted considerable attention as promising candidates for anti-fibrosis treatment and regenerative medicine.^28–30 Stem cells can be isolated from adipose tissue with less invasive techniques and at higher yields as compared to bone marrow aspirates, and have significant proliferative capacity and a longer life span in culture.²⁹ Their anti-fibrotic, immunomodulatory and angiogenic effects, among others, render them unique and suitable for treating a variety of fibrosis-related diseases.^30,31 To the best of our knowledge, no studies have examined the prophylactic potential of human adipose-derived mesenchymal stem cells (hAD-MSCs) for the prevention of radiation-induced CC.

To date, most animal experimental models in this realm have been exploited to evaluate the outcome of different interventions on normal capsule formation and have failed to accurately replicate the development of CC.^32–34 Adams et al. were one of the first to study a pathological CC animal model that mimicked the formation of the CC response in humans.³⁵ Their study demonstrated a correlation between CC severity and the thickness of the capsule surrounding a saline implant. However, it was limited by the use of fibrin glue to induce CC, which does not replicate clinical reality. Katzel et al. were the first to study the effect of radiation on CC induction in a mouse model.³⁶ Radiation was shown to cause consistent reproducible changes with micro–computed tomography and histology. The model utilized gamma radiation, similar to the radiation used in therapeutic breast cancer treatment, making it more representative of real-life conditions.¹³

The current work assessed the potential of locally administered hAD-MSCs in the prevention of radiation-induced CC in mice.

Study design:

This study was approved by the Sourasky Medical Center - Institutional Animal Care and Use Committee, Israel. Eight-week-old, female C57Bl/6 mice, weighing 20 g, on average, were randomly assigned to three groups (12 mice per group): (1) IMP (silicone implants only), (2) IMP + RAD (silicone implants and irradiation therapy), (3) IMP + RAD + MSCs (silicone implants, irradiation therapy and local administration of hAD-MSCs). All mice underwent an acclimatization week upon arrival. On day 0, they were weighed and marked.

Human adipose-derived mesenchymal stem cell isolation:

Adipose tissue samples were obtained from patients undergoing liposuction surgery. All procedures were performed in accordance with the Declaration of Helsinki and approved by the ethics committee of Tel Aviv Sourasky Medical Center, Israel (Approval No. 0369-12-TLV). Signed informed consent was obtained from patients before surgery. Cells were isolated from lipoaspirates using 0.1% collagenase (Sigma, St. Louis, MO, USA), and separated from the fat by centrifugation (15 min, 400x g). hAD-MSCs were grown in high-glucose Dulbecco’s modified Eagle’s medium (DMEM) (Gibco, Paisley, Scotland, UK), supplemented with 10% fetal calf serum (Thermo Scientific HyClone, Tauranaga, New Zealand), 60 µg/ml penicillin, 100 µg/ml streptomycin, 50 µg/ml kanamycin, 1 mM sodium pyruvate, 2 mM L-glutamine and non-essential amino acids, under 10% CO₂ and atmospheric oxygen conditions. After 72 h, nonadherent cells were removed, while adherent cells were grown for 13 days.

Flow cytometry was performed to confirm that the cultured hAD-MSCs express stem cell markers. Cells were harvested and incubated (1 h, in the dark) with a 7-color panel containing anti-CD31, anti-CD34, anti-CD29, anti-CD105, anti-human-73 and anti-CD45 antibodies. To exclude dead cells, the samples were stained with ViViD (violet viability dye, Molecular Probes, Invitrogen, Eugene, OR, USA), according to the manufacturer’s protocol. Appropriate single-stained and isotype control samples were prepared and analyzed by flow cytometry (FACSCanto II, BD Biosciences). Flow-Jo software (Tree star, Ashland, OR USA) was used for data analysis.

In-vivo model:

Mice were anesthetized with an intraperitoneal injection of ketamine (2 mg/0.47 mg) and xylazine (200 µl/mouse). Following anesthesia, the surgical site was shaved and prepared with iodine solution. A 1.5-cm transverse incision was made on the dorsal aspect of the mouse at the level of the sacral spine, followed by dissection of a cranial pocket, and subcutaneous placement of a smooth silicone mini-implant device (Polytech Health and Aesthetics, Germany). The incision was closed with interrupted 4 − 0 nylon sutures (Ethicon, Inc., Somerville, N.J., USA).

Following surgery and while still under anesthesia, animals in the radiation arms (IMP + RAD and IMP + RAD + MSCs) received a 10 Gy dose, delivered with a linear accelerator with 6 MeV x-ray beam (Varian True Beam). The radiation was targeted to induce CC around the silicone implants while avoiding systemic effects of radiation.

Following surgery and radiation, 3x10⁶ harvested hAD-MSCs suspended in 400 µL phosphate-buffered saline were locally administered by microinjection into the breast implant pocket of animals in the therapeutic group (IMP + RAD + MSCs).

Follow-up included daily evaluations for 5 consecutive days, and then once every 3 days. Each evaluation included assessment of general well-being and signs of distress, a physical examination and weight measurement.

On postoperative day 42, total capsulectomy was performed and the capsules were sent for histological analysis. Gene expression was analyzed by real-time polymerase chain reaction (PCR). Intracardiac blood was collected to determine serum transforming growth factor beta (TGF-β) levels by enzyme-linked immunosorbent assay (ELISA). Mice were then euthanized by CO2 asphyxiation followed by cervical dislocation. The work has been reported in line with the ARRIVE guidelines 2.0.

Histopathological examination:

Capsules were harvested from all mice on postoperative day 42. Harvested tissues were fixed in 10% neutral buffered formalin and then embedded in paraffin blocks. Serial longitudinal sections were prepared and stained with hematoxylin and eosin for histological analysis of capsular thickness. All slides were scanned and capsular thickness in the three thickest and the three thinnest areas of the capsules was measured by a blinded pathologist.

Quantitative real-time PCR:

RNA was isolated from capsules with Tri-Reagent (Sigma, USA) and reverse-transcribed with the High-Capacity cDNA Reversed transcription kit (Applied Biosystems, USA), according to the manufacturer’s instructions. PCRs were performed with the SYBER Green PCR Master Mix (Applied Biosystems, USA). Quantification was performed using Step One software (V2.2). Levels of TGF-β, collagen type 1 (Coll1), alpha-smooth muscle actin (αSMA), tissue inhibitor of metalloproteinase 1 (TIMP1), interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNFα) gene expression were compared with those of the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) housekeeping gene. The primer sequences (forward and reverse) are listed in Table 1.

Table 1

Primer sequences used for quantitative Real-Time Polymerase Chain Reaction (PCR).
Gene	Forward	Reverse
Coll-1	5′-GAGAGCATGACCGATGGATT-3′	5′-CCTTCTTGAGGTTGCCAGTC-3’
TGFβ	5′-ATTCAGCGCTCACTGCTCTT-3'	5'- GTTGGTATCCAGGGCTCTCC-3'
Timp-1	5' -TCCCCAGAAATCAACGAGAC-3'	5'-CTGGGACTTGTGGGCATATC-3'
αSMA	5′-CCCCTGAAGAGCATCGGACA-3′	5′-TGGCGGGGACATTGAAGGT-3′
TNFα	5'-CGAGTGACAAGCCTGTAGCC-3'	5'-CCTTGTCCCTTGAAGAGAACC-3'
IL-1β	5’-GACCTTCCAGGATGAGGACA-3’	5’-AGCTCATATGGGTCCGACAG-3’
GAPDH	5’-AACGACCCCTTCATTGAC-3’	5’-TCCACGACATACTCAGCAC-3’

Enzyme-linked immunosorbent assay (ELISA):

Intracardial serum levels of TGF-β were measured using the TGF beta-1/LAP Mouse Uncoated ELISA Kit (INVITROGEN, USA) according to the manufacturer’s protocol.

Sample size calculation:

Sample size was calculated using G-power software with the following assumptions: type 1 error of 5%, and minimum desired power of 80%. The primary endpoint to determine the sample size is the reduction in the capsular thickness and formation following the treatment in stem cells. Following a similar study conducted by Sutthiwanjampa et al., (2021), we assume a moderate effect size of this reduction. Specifically, using a mixed-model ANOVA examining the interaction between time and group (Time X Group), that is different pattern of changes between the four groups. Under these assumptions, the required sample size is 12 subjects in each group.

F tests - ANOVA: Repeated measures, between factors

Analysis: A priori: Compute required sample size

Input: Effect size f = 0.4

α err prob = 0.05

Power (1-β err prob) = 0.80

Number of groups = 4

Number of measurements = 4

Corr among rep measures = 0.5

Output: Noncentrality parameter λ = 12.2880000

Critical F = 2.8164658

Numerator df = 3.0000000

Denominator df = 44.0000000

The required sample size is 12 subjects in each group. Total number of animals for the study − 36 mice.

Statistical analysis

Variables are expressed as mean ± standard error of the mean (SEM). Differences between values were tested by one-way analysis of variance followed by Tukey’s test for multiple comparisons. If values were not normally distributed (determined by the D’Agostino Pearson omnibus normality test), the non-parametric Kruskal-Wallis test was used. p values of < 0.05 were considered statistically significant. All statistical analyses were performed with GraphPad Prism version 9.00 (GraphPad Software, La Jolla, CA, USA).

Targeted radiation induced capsular contracture in mice

When compared to the IMP group, mean capsular thickness on day 42 in the IMP + RAD group was significantly increased (233.7 ± 30 µm vs. 483.8 ± 81 µm (p = 0.004) (Fig. 1). Radiotherapy also significantly upregulated the expression of pro-fibrotic genes TGF-β, Coll1, αSMA and TIMP1 in capsular tissue (Fig. 2). Furthermore, pro-inflammatory genes, such as IL-1β and TNFα, were significantly upregulated in the capsular tissues of irradiated mice, suggesting an aggravated local inflammatory response induced by radiation. Finally, a significant systemic increase in serum TGF-β concentrations was observed in irradiated mice compared with IMP controls (144,771 ± 12,417 pg/ml vs.108,879 ± 6,513 pg/ml (p = 0.04)) (Fig. 3). Taken together, targeted radiotherapy in mice with a subcutaneous silicone mini-implant induced significant CC along with elevated pro-fibrotic and pro-inflammatory responses.

Human adipose-derived mesenchymal stem cells reduced capsular thickness and the expression of pro-fibrotic and pro-inflammatory genes

When compared to IMP + RAD mice, mice receiving hAD-MSCs treatment showed significantly reduced mean capsular thickness by day 42 after radiation therapy (483.8 ± 81 µm vs. 298.1 ± 25 µm (p = 0.045)) (Fig. 1). Notably, hAD-MSC treatment restored capsular thickness to levels similar to those observed in IMP mice (298.1 ± 25 vs. 233.7 ± 30; p = 0.624) (Fig. 1).

hAD-MSCs treatment significantly downregulated the expression of pro-fibrotic genes TGF-β, Coll1, αSMA and TIMP1 in capsular tissue (Fig. 2), as well as the expression of the pro-inflammatory genes IL-1β and TNFα. As demonstrated for capsular thickness, the pro-fibrotic gene expression levels returned to baseline in hAD-MSCs-treated mice and were similar to those seen in IMP mice (Fig. 2). Circulating TGF-β concentrations were lower in mice treated with hAD-MSCs compared to untreated mice, yet the difference was not statistically significant (123,505 ± 11,715 vs.144,771 ± 12,417; p = 0.349)) (Fig. 3).

In summary, hAD-MSCs administered immediately after implant insertion and irradiation prevented the increase in capsular thickness and reduced the local pro-fibrotic and pro-inflammatory responses induced by radiotherapy.

CC is the most common complication of breast augmentation and is likely the primary cause of implant-based breast reconstruction failure, particularly in irradiated patients.^3,6 Radiation therapy has been shown to induce fibrosis of the capsule and pectoralis muscle, which results in capsular thickening, contracture and cephalad displacement of the implant. These events are further aggravated by the absence of glandular soft-tissue coverage and by skin flap contracture over the muscle and capsule.³

The current work demonstrated induction of significant CC following targeted radiotherapy in mice bearing a subcutaneous silicone mini-implant, as demonstrated by a significantly increased implant capsular thickness 42 days following the procedure.

TGF-ß is a key factor in the development of radiation-induced CC and has been termed the “master switch” of the TGF-β/Smad axis. Dysregulation of this axis is thought to be central to the development of pathological fibrosis. ^19,30 Indeed, the current work demonstrated a significant upregulation of pro-fibrotic gene (TGF-β, Coll1, αSMA, and TIMP1) and pro-inflammatory gene (IL-1β and TNFα) expression in the capsular tissue of irradiated as compared to control mice. Katzel et al. showed that reduced TGF-β signalling in Smad3 knockout mice eliminated nearly all the signs of CC. A parallel histological analysis showed that blocking TGF-β signalling by Smad3 also significantly reduced implant capsule thickness.¹⁹

in a recent study Sutthiwanjampa et al. found that hAD-MSCs successfully suppressed fibrotic and inflammatory responses around breast implants in rats, as measured by capsule thickness, collagen density and myofibroblast and fibroblast counts.³³

In their evaluation of the effect of mouse adipose-derived mesenchymal stem cells (mAD-MSCs) around customized silicone implants on CC, Park et al. measured reduced capsule thickness, decreased myofibroblast and macrophage counts in the capsule and decreased mRNA levels of fibrogenic genes within the peri-implant tissue.³⁴

Diehm et al. developed a novel technique for cell-assisted hybrid breast reconstruction (CA-HBR) in a rat model, which had a lower rate of CC. Stem-cell-enriched fat grafting significantly reduced the thickness of and collagen density of the capsules and reduced collagen I and TGF-β levels in the capsule tissue.³⁷ These findings verified the contribution of adipose-derived mesenchymal stem cells to prevention of CC after breast implantation.

However, none of the above models^33,34,37 applied any factors to induce CC. The current work demonstrated induction of CC by irradiation which better resembled that of clinical practice. In the present study, hAD-MSCs treatment significantly reduced capsular thickness (p < 0.05), and significantly downregulated the expression of pro-fibrotic and pro-inflammatory genes in the capsular tissue. Notably, hAD-MSCs treatment restored capsular thickness and gene expression to levels similar to those seen in mice with implants who did not receive any radiation at all.

This work had several limitations. The data were acquired using a mouse model, which may not fully represent human responses. In addition, it utilized customized silicone implants rather than implants specifically designed for human applications. Furthermore, irradiation was administered within the same anesthetic procedure, thus not fully replicating clinical practice. Additionally, the 42-day follow-up period may have been too short to capture long-term outcomes or CC recurrence; longer term investigations will be necessary. Further, while hAD-MSCs were found to decrease capsular thickness and downregulate pro-fibrotic and pro-inflammatory genes, their exact mode of action remains to be determined. Finally, the potential long-term safety and adverse effects of stem cells warrant further investigation.

Targeted radiotherapy in implanted mice induced significant CC along with elevated pro-fibrotic and pro-inflammatory responses. This effect was significantly ameliorated by introduction of hAD-MSCs, as shown by prevention of radiation-induced increases in capsular thickness and in local pro-fibrotic and pro-inflammatory responses. The novel animal model used here demonstrated the therapeutic potential of hAD-MSCs in the prevention of breast implant CC.

Capsular contracture (CC)

human adipose-derived mesenchymal stem cells (hAD-MSCs)

transforming growth factor beta (TGF-β)

postmastectomy radiation therapy (PMRT)

real-time polymerase chain reaction (PCR)

enzyme-linked immunosorbent assay (ELISA)

collagen type 1 (Coll1)

alpha-smooth muscle actin (αSMA)

tissue inhibitor of metalloproteinase 1 (TIMP1)

interleukin-1 beta (IL-1β)

tumor necrosis factor alpha (TNFα)

glyceraldehyde 3-phosphate dehydrogenase (GAPDH)

Ethics approval and consent to participate

The study Adipose-Derived Mesenchymal Stem Cells for the Prevention of Capsular Contracture, was approved by the Sourasky Medical Center - Institutional Animal Care and Use Committee, Israel, 3/2022 (Approval No. TLVMC - IL - 2203 - 111 - 4).
The study- Fat samples for use in current and future medical laboratory research, was approved by the ethics committee of Tel Aviv Sourasky Medical Center, Israel (Approval No. 0369-12-TLV, 1/2020). All procedures were performed in accordance with the Declaration of Helsinki.
Patients or their guardians/legally authorized representatives/next of kin provided written informed consent for participation in the study and/or the use of samples.

Consent for publication

All authors confirm their consent for publication.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Data supporting the results reported in the paper are archived in Zenodo DOI 10.5281/zenodo.12788885

Competing interests

The authors declare that they have no competing interests

Funding

We did not receive financial support for this study. Polytech Health and Aesthetics (Germany) provided the mini silicone implants gratis.

Authors' contributions

OGY (Department of Plastic and Reconstructive Surgery, Tel Aviv Sourasky Medical Center): Conceptualization, methodology, project administration, supervision, surgeries in the animals, writing—original draft, critical revision of the manuscript.
YK (Institute of Radiation Therapy, Tel Aviv Sourasky Medical Center): Radiation therapy consultation, data curation, investigation, provision of study materials, writing—review and editing.
YZ (Institute of Pathology, Tel Aviv Sourasky Medical Center): Pathological analysis, interpretation of pathological data, investigation, writing—review and editing.
NC (The Faculty of Medicine, Tel Aviv University): Data curation, investigation, resources, writing—review and editing.
RYB (The Faculty of Medicine, Tel Aviv University): Formal analysis, statistical analysis, software, data visualization, interpretation of data, writing—review and editing.
DR (The Faculty of Medicine, Tel Aviv University): Methodology, laboratory experiments, validation, data acquisition, writing—review and editing.
YGY (The Faculty of Medicine, Ben-Gurion University of the Negev): Conceptualization, methodology, resources, supervision, oversight of the study, writing—review and editing.
EG (Department of Plastic and Reconstructive Surgery, Tel Aviv Sourasky Medical Center): Supervision, project administration, provision of study materials, writing—review and editing.
IS (Department of Plastic and Reconstructive Surgery, Tel Aviv Sourasky Medical Center): Methodology, laboratory experiments, validation, data acquisition, writing—review and editing.
YB (Department of Plastic and Reconstructive Surgery, Tel Aviv Sourasky Medical Center): Project administration, resources, patient recruitment, writing—review and editing.
All authors read and approved the final manuscript.

Disclosures

Yoav Barnea participates in educational lectures for Johnson (Mentor) Corporation. All other authors have no conflict of interest.

Acknowledgements:

We would like to thank Polytech (Dieburg, Germany) for providing the mini silicone implants.
The authors declare that they have not used Artificial Intelligence in this study.

Susini P, Nisi G, Pierazzi DM, et al. Advances on Capsular Contracture - Prevention and Management Strategies: A Narrative Review of the Literature. Plast Reconstr Surg Glob Open. 2023;11(6). doi:10.1097/GOX.0000000000005034
Wagner DS, Mirhaidari SJ. Capsulectomy, Implant Exchange, and Placement of Acellular Dermal Matrix Is Effective in Treating Capsular Contracture in Breast Augmentation Patients. Aesthet Surg J. 2021;41(3). doi:10.1093/asj/sjz358
Haran O, Bracha G, Tiosano A, et al. Postirradiation Capsular Contracture in Implant-Based Breast Reconstruction: Management and Outcome. Plast Reconstr Surg. Published online 2020. doi:10.1097/PRS.0000000000007453
Hammond JB, Kosiorek HE, Cronin PA, et al. Capsular contracture in the modern era: A multidisciplinary look at the incidence and risk factors after mastectomy and implant-based breast reconstruction. Am J Surg. 2021;221(5). doi:10.1016/j.amjsurg.2020.09.020
Larsen A, Rasmussen LE, Rasmussen LF, et al. Histological Analyses of Capsular Contracture and Associated Risk Factors: A Systematic Review. Aesthetic Plast Surg. 2021;45(6). doi:10.1007/s00266-021-02473-3
Boyd CJ, Chiodo M V, Lisiecki JL, et al. Plastic and Reconstructive Surgery Advance Online Article Systematic Review of Capsular Contracture Management Following Breast Augmentation: An Update. doi:10.1097/PRS.0000000000010358
Venkataram A, Lahar N, Adams WP. Enhancing Patient Outcomes in Aesthetic Breast Implant Procedures Using Proven Antimicrobial Breast Pocket Irrigations: A 20-Year Follow-up. Aesthet Surg J. 2023;43(1). doi:10.1093/asj/sjac238
Hölmich LR, Breiting VB, Fryzek JP, et al. Long-term cosmetic outcome after breast implantation. Ann Plast Surg. 2007;59(6). doi:10.1097/SAP.0b013e31803c7c78
Handel N, Cordray T, Gutierrez J, Jensen JA. A long-term study of outcomes, complications, and patient satisfaction with breast implants. Plast Reconstr Surg. 2006;117(3). doi:10.1097/01.prs.0000201457.00772.1d
Araco A, Caruso R, Araco F, Overton J, Gravante G. Capsular contractures: A systematic review. Plast Reconstr Surg. 2009;124(6). doi:10.1097/PRS.0b013e3181bf7f26
Marques M, Brown SA, Oliveira I, et al. Long-term follow-up of breast capsule contracture rates in cosmetic and reconstructive cases. Plast Reconstr Surg. 2010;126(3). doi:10.1097/PRS.0b013e3181e5f7bf
Cordeiro PG, Albornoz CR, McCormick B, Hu Q, Van Zee K. The impact of postmastectomy radiotherapy on two-stage implant breast reconstruction: An analysis of long-term surgical outcomes, aesthetic results, and satisfaction over 13 years. Plast Reconstr Surg. 2014;134(4). doi:10.1097/PRS.0000000000000523
Ricci JA, Epstein S, Momoh AO, Lin SJ, Singhal D, Lee BT. A meta-analysis of implant-based breast reconstruction and timing of adjuvant radiation therapy. Journal of Surgical Research. 2017;218. doi:10.1016/j.jss.2017.05.072
Rosato RM, Dowden R V. Radiation therapy as a cause of capsular contracture. Ann Plast Surg. 1994;32(4). doi:10.1097/00000637-199404000-00002
Gross E, Hannoun-Levi JM, Rouanet P, et al. Evaluation of immediate breast reconstruction and radiotherapy: Factors associated with complications. Cancer/Radiotherapie. 2010;14(8). doi:10.1016/j.canrad.2010.05.004
Rohrich RJ, Kenkel JM, Adams WP. Preventing capsular contracture in breast augmentation: In search of the Holy Grail. Plast Reconstr Surg. 1999;103(6). doi:10.1097/00006534-199905000-00033
Bachour Y, Verweij SP, Gibbs S, et al. The aetiopathogenesis of capsular contracture: A systematic review of the literature. Journal of Plastic, Reconstructive and Aesthetic Surgery. 2018;71(3). doi:10.1016/j.bjps.2017.12.002
Luvsannyam E, Patel D, Hassan Z, Nukala S, Somagutta MR, Hamid P. Overview of Risk Factors and Prevention of Capsular Contracture Following Implant-Based Breast Reconstruction and Cosmetic Surgery: A Systematic Review. Cureus. Published online 2020. doi:10.7759/cureus.10341
Katzel EB, Koltz PF, Tierney R, et al. The impact of Smad3 loss of function on TGF-β signaling and radiation-induced capsular contracture. Plast Reconstr Surg. 2011;127(6). doi:10.1097/PRS.0b013e3182131bea
Graf R, Ascenço ASK, Freitas RDS, et al. Prevention of capsular contracture using leukotriene antagonists. Plast Reconstr Surg. 2015;136(5). doi:10.1097/PRS.0000000000001683
Gancedo M, Ruiz-Corro L, Salazar-Montes A, Rincón AR, Armendáriz-Borunda J. Pirfenidone prevents capsular contracture after mammary implantation. Aesthetic Plast Surg. 2008;32(1). doi:10.1007/s00266-007-9051-4
Caffee HH. Capsule Injection for the Prevention of Contracture. Plast Reconstr Surg. 2002;110(5). doi:10.1097/01.prs.0000025628.86133.ee
Planas J, Migliano E, Wagenfuhr J, Castillo S. External ultrasonic treatment of capsular contractures in breast implants. Aesthetic Plast Surg. 1997;21(6). doi:10.1007/s002669900143
Johnson JD, Glat PM, Scarlett WL. Low-Level Laser Therapy: An Alternative Treatment for Capsular Contraction. The American Journal of Cosmetic Surgery. 2015;32(1). doi:10.5992/ajcs-d-14-00036.1
Diehm YF, Hirche C, Berger MR, et al. The Collagenase of the Bacterium Clostridium histolyticum in the Treatment of Irradiation-Induced Capsular Contracture. Aesthetic Plast Surg. 2019;43(3). doi:10.1007/s00266-018-1267-y
Lombardo GAG, Tamburino S, Magano K, et al. The effect of omega-3 fatty acids on capsular tissue around the breast implants. Plast Reconstr Surg. Published online 2020. doi:10.1097/PRS.0000000000006553
Wan D, Rohrich RJ. Revisiting the Management of Capsular Contracture in Breast Augmentation: A Systematic Review. Plast Reconstr Surg. 2016;137(3). doi:10.1097/01.prs.0000480095.23356.ae
Evans GRD, Widgerow AD. Stem cells and tissue engineering in plastic surgery: an update. Plast Aesthet Res. 2020;7. doi:10.20517/2347-9264.2019.53
Gimble JM, Katz AJ, Bunnell BA. Adipose-derived stem cells for regenerative medicine. Circ Res. 2007;100(9). doi:10.1161/01.RES.0000265074.83288.09
Li ZJ, Wang LQ, Li YZ, et al. Application of adipose-derived stem cells in treating fibrosis. World J Stem Cells. 2021;13(11). doi:10.4252/wjsc.v13.i11.1747
Shukla L, Yuan Y, Shayan R, Greening DW, Karnezis T. Fat Therapeutics: The Clinical Capacity of Adipose-Derived Stem Cells and Exosomes for Human Disease and Tissue Regeneration. Front Pharmacol. 2020;11. doi:10.3389/fphar.2020.00158
Vieira VJ, D’Acampora A, Neves FS, et al. Capsular contracture in silicone breast implants: Insights from rat models. An Acad Bras Cienc. 2016;88(3). doi:10.1590/0001-3765201620150874
Sutthiwanjampa C, Shin BH, Ryu NE, Kang SH, Heo CY, Park H. Assessment of human adipose-derived stem cell on surface-modified silicone implant to reduce capsular contracture formation. Bioeng Transl Med. Published online 2021. doi:10.1002/btm2.10260
Park BY, Wu D, Kwon KR, et al. Implantation and tracing of green fluorescent protein-expressing adipose-derived stem cells in peri-implant capsular fibrosis. Stem Cell Res Ther. 2023;14(1). doi:10.1186/S13287-023-03248-0
Adams WP, Haydon MS, Raniere J, et al. A rabbit model for capsular contracture: Development and clinical implications. Plast Reconstr Surg. 2006;117(4):1214-1219. doi:10.1097/01.prs.0000208306.79104.18
Katzel EB, Koltz PF, Tierney R, et al. A novel animal model for studying silicone gel-related capsular contracture. Plast Reconstr Surg. 2010;126(5):1483-1491. doi:10.1097/PRS.0b013e3181ef8b8e
Diehm YF, Thomé J, Will P, et al. Stem Cell-Enriched Hybrid Breast Reconstruction Reduces Risk for Capsular Contracture in a Hybrid Breast Model. Plast Reconstr Surg. 2023;152(3):572-580. doi:10.1097/PRS.0000000000010260

ARRIVEChecklistFilled.pdf

Download PDF

Version 1

posted

You are reading this latest preprint version

Adipose-Derived Mesenchymal Stem Cells for the Prevention of Capsular Contracture

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

BACKGROUND

MATERIALS & METHODS

Study design:

Human adipose-derived mesenchymal stem cell isolation:

In-vivo model:

Histopathological examination:

Quantitative real-time PCR:

Enzyme-linked immunosorbent assay (ELISA):

Sample size calculation:

Statistical analysis

RESULTS

Targeted radiation induced capsular contracture in mice

DISCUSSION

CONCLUSION

Abbreviations

Declarations

References

Supplementary Files

Status:

Version 1