Experimental and Clinical Investigation of the Implant Surface Roughness Reduction Effect on Early-stage Fibrosis

Immunological Analysis of Capsular Tissue Formed Around Expanders With Varying Surface Topography in Women Undergoing Bilateral Nipple or Skin Sparing Mastectomy

The goal of this single-center, randomised double-blinded trial is to compare the early stage fibrosis progression around conventional textured expander and the SmoothSilk® expander with reduced surface roughness in women undergoing bilateral nipple or skin sparing mastectomy in a prophylactic setting followed by tissue-expander based breast reconstruction. Researchers will compare intra-individually, the conventional textured expander CPX®(Mentor) and the SmoothSilk® (Motiva) expander (i) to gain a comprehensive insight into immunological mechanisms occurring at the timepoint of expander insertion (within the first days after implantation) based on WBF analysis in vitro, (ii)to determine the role and function of immune cells in a rather early stage of capsule formation (6-8 months after implantation) and under well-defined conditions in humans as well as (iii)to analyze the aesthetic outcome and clinical parameters after bilateral implant-based reconstruction using two expanders with varying surface topography within the individual patient (intra-individually).

Study Overview

• Status: Completed
• Conditions: Wounds and Injuries; Foreign-Body Reaction; Tissue Expander Disorder; Capsular Contracture Associated With Implant
• Intervention / Treatment: Other: Patient Satisfaction Questionnaire; Diagnostic test: Pregnancy test; Procedure: Blood draw; Procedure: Expander based breast reconstruction; Procedure: Ultrasound of breast; Other: S(AE )monitoring

Detailed Description

Expander Immunology trial is a single-center, randomized double-blinded trial. A total of 14 patients, undergoing prophylactic bilateral simultaneous NSME (nipple sparing mastectomy) and implant based breast reconstruction, will receive either SmoothSilk® (Motiva Flora) or other routinely used expander (Mentor CPX™4), randomised to left or right breast after mastectomy. Patient and laboratory expert will be double-blinded. Clinical follow-up visits will be scheduled at 2, 4, 5, 6, 7, 8 and 16 weeks post procedure. Biological sample collection of wound bed fluid will take place daily from day 1 to 5 after expander implantation. Ultrasound will be performed -28 to-1 day before re-operation. Capsule tissue will be harvested and blood draw will be performed during re-operation between 24 to 28 weeks after initial expander implantation.

Directly postoperatively at day 1-5 after expander implantation, wound bed fluid will be collected and proteinaceous and cellular components will be analyzed via FACS (flow cytometry), molecular (RNA, protein) assays and microbiome testing platform.

Phenotypical and functional analyses will be performed for capsular tissue and blood as well as PCR (polymerase chain reaction) assays for bacterial antigens when expanders are changed to definite implants. Expanders will also undergo sonication to check for bacterial contamination. Peri-capsular tissue samples will be evaluated using scanning electron microscopy-energy dispersive x-ray spectroscopy (SEM-EDS) to identify sites with/without titanium particles (Titan-Bra debris). And breast ultrasound will be performed to detect capsular thickness before the reoperation.

During regular clinical examinations patients will go through a short questionnaire at week 4 and 16 to check patient satisfaction with expanders and adverse events will be monitored. (S)AE evaluation will be performed from Visit 1 (Day 0 = Expander implantation) to Visit 15 (Day 168-196 = Reoperation) according to visit plan.

The main question[s] it aims to answer are:

1. Does the immune cell profile differ within the wound-bed fluid (WBF) directly after implantation? Do the investigators see different activation patterns or distribution patterns of immune cells within the WBF on the conventional expander reconstructed side versus the SmoothSilk® (Motiva) reconstructed side?
2. Does the immune cell profile differ within the capsular tissue formed around conventional expanders versus SmoothSilk® (Motiva) expanders?
3. Which cytokines are mainly expressed in the early capsular tissue (conventional expander versus SmoothSilk® (Motiva) and do the investigators see differences in comparison with those of peripheral blood?
4. Does the cellular composition (histology) show different distribution patterns of immune cells and ECM proteins in these capsules?
5. Do the investigators see differences concerning bacterial & fungi contamination in WBF and on expander shells at the time point of explantation (sonication and PCR as well as next-generation DNA sequencing for bacteria and fungi)
6. Do the investigators see titanium wear particle incorporation into peri-capsular tissue? Is there a difference between the conventional expanders versus SmoothSilk® (Motiva) expanders after 6-8 months?
7. Do the investigators see any differences in outcome analysis between the conventional expanders versus Motiva nano-textured expanders after 6-8 months (Seroma formation, Implant dislocation, thickness of capsule)?

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Austria
  • Tyrol
    • Innsbruck, Tyrol, Austria, 6020
      • Medical University of Innsbruck, Department for Plastic, Aethetic and Reconstructive Surgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 97 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age > 18 years
• Female sex
• High risk family history for mammary and/or ovarian cancer
• Planned prophylactic mastectomy with simultaneous breast reconstruction
• Signed informed consent form

Exclusion Criteria:

• Confirmed sever Coagulation disorder, representing a potential contraindication for the elective surgery
• Confirmed Rheumatic disease accompanied by obligatory intake of immunomodulating therapeutic agents
• Confirmed severe renal functional disorder: Renal insufficiency status IV or V
• Active hematological or oncological disease
• HIV-Infection
• Hepatitis-Infection
• Pregnancy or breast feeding
• Intake of anti-inflammatory drugs
• Carrier of silicone implants (e.g. gastric banding, mammary implants)
• Subject is currently participating or intends to participate in another clinical trial that may interfere with the protocol of this study
• Patients who have implanted devices that could be affected by a magnetic field (e.g., pacemakers, drug infusion devices, artificial sensing devices) * patients with removable devices such as removable diabetes pumps, sensors and transmitter might still part take,
• Patients with alteration in hematologic and serum protein reference values post-chemotherapy.
• When there is a residual malignancy in the intended expansion site.
• Existing tissue at the intended expansion site is not adequate according to the surgeon's criteria, because of previous radiation therapy, ulcerations, vascular compromise, history of compromised wound healing, or scar deformity.
• Radiation therapy before or after the expander placement can be associated with a higher rate of complications during the expansion and final implantation phases of the reconstructive process.
• Abscess or infection in the body in general.
• Participants with autoimmune diseases (e.g., lupus, scleroderma) or whose immune system is compromised (e.g., currently receiving immunosuppressive therapy such as steroids).
• Unsuitable tissue due to radiation damage on the chest wall, tight thoracic skin grafts or radical resection of the pectoralis major muscle.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: the conventional expander Mentor CPX4 (MENTOR); intraindividual comparison of two differentially rough tissue expanders Arm description: women undergoing prophylactic bilateral NSME and simultaneous tissue-expander based reconstruction with conventionally textured expander with surface roughness 60µM Ra	Other: Patient Satisfaction Questionnaire; During regular clinical examinations patient will go through a short questionnaire at week 4, 16 and 24 to check patient satisfaction with expanders; Diagnostic test: Pregnancy test; Pre-op; to sufficiently check pregnancy as exclusion criteria; Procedure: Blood draw; pre- expander implantation, alongside anaesthesia pre- expander explantation and exchange with definite implant alongside anaesthesia - no additional vein irritation needed; Procedure: Expander based breast reconstruction; implantation of 2 different expanders intraindividually; Procedure: Ultrasound of breast; Measurement of capsular thickness pre- expander removal; Other: S(AE )monitoring; (S)AE evaluation will be performed from Visit 1 (Day 0 = Expander implantation) to Visit 15 (Day 168-196 = Reoperation) according to visit plan.
Active Comparator: the expander SmoothSilk(Motiva) with reduced surface roughness; intraindividual comparison of two differentially rough tissue expanders Arm description: women undergoing prophylactic bilateral NSME and simultaneous tissue-expander based reconstruction with reduced textured expander with surface roughness 4µM Ra	Other: Patient Satisfaction Questionnaire; During regular clinical examinations patient will go through a short questionnaire at week 4, 16 and 24 to check patient satisfaction with expanders; Diagnostic test: Pregnancy test; Pre-op; to sufficiently check pregnancy as exclusion criteria; Procedure: Blood draw; pre- expander implantation, alongside anaesthesia pre- expander explantation and exchange with definite implant alongside anaesthesia - no additional vein irritation needed; Procedure: Expander based breast reconstruction; implantation of 2 different expanders intraindividually; Procedure: Ultrasound of breast; Measurement of capsular thickness pre- expander removal; Other: S(AE )monitoring; (S)AE evaluation will be performed from Visit 1 (Day 0 = Expander implantation) to Visit 15 (Day 168-196 = Reoperation) according to visit plan.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
wound bed fluid Immune cell profile (composition)	immediately after implantation wound drain fluid will be immune profiled for cell populations by flow cytometry to gain a comprehensive insight into immunological mechanisms occurring at the time-point of expander insertion (within the first days after implantation) and evaluate potential effects of expander surface roughness	1 to 5 days post expander implantation
wound bed fluid wound proteome composition	immediately after implantation wound drain fluid will be proteomically profiled by Mass Spectrometry for tissue repair and foreign body response to gain a comprehensive insight into immunological triggers and mechanisms occurring at the time-point of expander insertion (within the first days after implantation) and evaluate potential effects of expander surface roughness	1 to 5 days post expander implantation
wound bed fluid Immune cell activity	immediately after implantation wound drain fluid will be immune profiled for cell activity by qPCR analysis of cytokine expression to gain a comprehensive insight into immunological mechanisms occurring at the time-point of expander insertion (within the first days after implantation) and evaluate potential effects of expander surface roughness	1 to 5 days post expander implantation
wound bed fluid wound microbiome composition	will be NextGen sequenced for microbiome colonisation, population, and biofilm formation to gain a comprehensive insight into immunological triggers and mechanisms occurring at the time-point of expander insertion (within the first days after implantation) and evaluate potential effects of expander surface roughness	1 to 5 days post expander implantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracapsular immune cell composition	After 6-8 months, collected capsular tissue formed around both expanders will be analyzed for immune cell profile and composition by flow cytometry	At reoperation; 6-8 months post expander implantation
Clinical evaluation of aesthetic outcome and postoperative complications	In follow-up visits 2, 4, and 16 W post-expander implantation; Breast will be clinically evaluated for symmetry and complications through clinical evaluation by the senior surgeon.	2, 4 and 16 weeks and at reoperation; 6-8 months post expander implantation
Intracapsular immune cell activity	After 6-8 months, collected capsular tissue formed around both expanders will be analyzed for immune cell activity and cytokine secretion and expression by qPCR	At reoperation; 6-8 months post expander implantation
Ultrasound evaluation of capsular thickness and postoperative complications	Directly before the expanders are exchanged (6-8 months post implantation), an experienced radiologist will perform non-invasive ultrasound evaluation of capsular thickness and seroma formation.At last cosmetic outcome will be evaluated (breast symmetry, nipple areola complex).	At reoperation; 6-8 months post expander implantation
Expander Satisfaction and comfortability evaluation by Questionnaire	Directly before the expanders are exchanged (6-8 months post implantation),, and expander comfortability as well as practicability during filling and expansion will be evaluated by the patient and senior surgeon on a scale from 0 to 10.	At reoperation; 6-8 months post expander implantation

Collaborators and Investigators

• Sponsor: Medical University Innsbruck
• Investigators: Principal Investigator: Dolores Wolfram-Raunicher, Dr., Medical University of Innsbruck, Department for Plastic Surgery

Publications and helpful links

General Publications

• Schoberleitner I, Augustin A, Egle D, Brunner C, Amort B, Zelger B, Brunner A, Wolfram D. Is It All about Surface Topography? An Intra-Individual Clinical Outcome Analysis of Two Different Implant Surfaces in Breast Reconstruction. J Clin Med. 2023 Feb 7;12(4):1315. doi: 10.3390/jcm12041315.
• Schoberleitner I, Faserl K, Sarg B, Egle D, Brunner C, Wolfram D. Quantitative Proteomic Characterization of Foreign Body Response towards Silicone Breast Implants Identifies Chronological Disease-Relevant Biomarker Dynamics. Biomolecules. 2023 Feb 6;13(2):305. doi: 10.3390/biom13020305.

Helpful Links

• Results reference
• Results reference

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2021
• Primary Completion (Actual): January 1, 2024
• Study Completion (Actual): February 13, 2024

Study Registration Dates

• First Submitted: November 10, 2022
• First Submitted That Met QC Criteria: December 5, 2022
• First Posted (Actual): December 13, 2022

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: prophylactic NSME (nipple sparing mastectomy); implant-based breast reconstruction; medical grade silicone; SMI (silicone mammary implants); Foreign body response to SMI; SMI encapsulation; immunoreactivity of SMI surface topography; capsular fibrosis; immunomodulation by SMI-surface roughness
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Wounds and Injuries; Contracture; Foreign Bodies; Foreign-Body Reaction
• Other Study ID Numbers: EIT2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

The sponsor Medical University Innsbruck and Principal investigator Assoc. Prof. PD. Dr. Wolfram intent to publish the results of this clinical investigation. The ownership of the data shall at all times be held by Medical University Innsbruck and the PI, who will be the main author of all publications by this trial.

For the avoidance of doubt, positive and negative results may be published.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No