Breast enhancement using Macrolane™: A report of complications in three patients and a review of this new product

A 34-year-old female underwent bilateral breast enhancement with 120 ml Macrolane™ to each breast. One week later she developed bilateral painful swelling. This had been treated with Augmentin to no effect. On presentation she was clinically-unwell with a pyrexia of 38.2 °C and bilaterally infected breasts. Blood cultures were positive for Staphylococcus epidermis. The breasts were explored surgically. Macrolane™ was found in multiple pockets within the breast parenchyma and was removed by infusing the breast with saline and squeezing out the HA. The patient made a full recover after a week of antibiotics (Cefuroxime and Metronidazole).

A 27-year-old female had bilateral breast augmentation with 100 ml Macrolane™ to each breast. She presented 3 months later complaining of rapid and asymmetrical volume loss together with breast lumpiness that was both visible and palpable. At surgery Macrolane™ was found in multiple pockets within the breast parenchyma. It was clear and granular, like tapioca, and was enclosed by a capsule similar to that around breast implants. The Macrolane™ deposits were approached in a sub-mammary plane, each pocket was incised and the Macrolane™ squeezed out. The capsules were not excised. Anatomical cohesive silicone gel implants were then placed in a sub-muscular plane. The patient made an uneventful recovery.

A 36-year-old female had Macrolane™ 100–120 ml injected bilaterally. She presented 4 months later complaining of asymmetrical lumpiness of the breasts. On examination she had visible lumpiness of both breasts particularly in the lower lateral quadrant (Figure 1). She underwent surgical evacuation of the Macrolane™ and simultaneous augmentation with a cohesive gel implants. Each deposit of Macrolane™ was contained within a well-developed capsule (Figure 2). On the right side the deposits were predominantly located above the pectoralis muscle, within breast parenchyma and subpectorally. On the left side the Macrolane™ was located completely below the pectoralis major muscle with the capsule extending towards the axilla. Also noted were multiple pockets with a surrounding fibrous capsule empty of Macrolane™ which presumably had been resorbed. Histological examination of the capsule surrounding the Macrolane™ deposits showed a fibrous capsule with synovial-like cells on the luminal surface similar to the capsule surrounding a silicone breast implant (Figure 3). Irregular HA was located in the adjacent connective tissue, fat and muscle and a foreign body tissue response was noted.

We present three patients who developed complications following breast shaping using Macrolane™ shortly after this product was introduced into the UK. One suffered infection and two had visible and palpable lumpiness as a result of capsular contracture.

Breast augmentation using prosthetic implants is a widely used and largely satisfactory procedure. The concept of using a liquid or semi-liquid injectable material to increase breast volume is an attractive one since it would avoid a formal surgical procedure, is quick and could be carried out in a minor surgical facility without general anaesthetic. Previous experience with alloplastic injectable fillers for this purpose has not been free of complications. There is an extensive clinical experience of HA as a filler in the face, using relatively small volumes up to 10 cc or so. If this could be extended safely to breast augmentation it would be attractive and convenient to women seeking to enlarge their breasts, who wished to avoid an operation and would have obvious commercial potential for the manufacturer and those who injected it. Macrolane™ was developed for this purpose.

An unpublished pilot study investigating the effects of Macrolane™ in the breasts of 20 patients reported that eight (40% of the group) were assessed at 6 months and between 70% and 80% of these rated their breast shape improved. The average volume used was 97.8 ml. No information is given about the 12 patients not assessed. Sixteen patients (80%) reported a total of 44 adverse events, the most common which was injection site pain (8 events) and capsular contracture (6 events). There were no instances of infection or inflammation.

The 30% rate of capsular contracture rate at 6 months is a concern particularly since the injection technique results in multiple collections each potentially with their own capsule. This was confirmed by our findings during the surgical removal of Macrolane™ where each deposit was surrounded by a thick capsule. For comparison, the prevalence of capsular contracture after breast augmentation with traditional encapsulated breast implants in large-scale studies ranges from 4 to 17% but this is over a 10-year period.

Two of the patients in our report presented with multiple visible and palpable lumps resulting from capsular contractures. This could cause difficulty with clinical examination of the breast as well as having implications for mammography. The manufacturer states that Macrolane™ resorbs over 12–18 months and recommends top up injections at 12 months. However, in a pilot study, MRI scans showed that Macrolane™ underwent only minor degradation between 3 months and 12 months. This suggests that unlike the small volumes in the face, large volumes of Macrolane™ remain in the breast for a much longer indeterminate time.

The long-term effect on breast screening is unknown. In another pilot study the visualisation of breast tissue behind Macrolane™ was investigated. In this study 19 women with a mean age of 31 underwent augmentation for both breasts with a mean of 211 ml in total. The five patients over 35 years of age then underwent mammography. All 19 patients were scheduled for MRI (Magnetic resonance imaging) and US at 3, 12 and 24 months. Hyaluronic acid was visible on all five mammograms located deeply and partly within pectoralis muscle. Compared to no implant there was a reduction in visualisation of the glandular tissue but visualisation was higher compared to silicone or saline implants. This is, however, not a valid comparison as with surgical breast augmentation the implant is behind all the breast tissue and so using the Eklund maneuver allows the breast to be visualised without loss of sensitivity as mammograms are taken at two different angles whilst squeezing the breast tissue in front of the implant. This would clearly not be possible with Macrolane™ as the hyaluronic acid is dispersed throughout the breast. Therefore the suggestion that macrolane is less radioopaque than a silicone or saline implant may not be clinically relevant. A further level of difficulty in breast cancer detection may arise from the long-term effects of high capsule rate. Any capsule in the breast has a tendency to show calcification over time and as yet long-term studies of the change in radiographic appearance with time due to the effects of calcification in the capsule are lacking. Until these long-term scientific results are available patients should be aware that Macrolane™ breast shaping may impact on the diagnosis of breast cancer.

The only published report on the use of injectable HA for breast enhancement was a Japanese paper that used a different type of HA. This paper reviewed 1100 patients that were augmented with Restylane SubQ™. An average of 40 ml was injected per breast with multiple injections. The time period of follow-up, the number of patients followed up, patient satisfaction and long-term outcomes were not stated in the paper. There were only three complications mentioned, two cases of infection and a single patient where HA causes a nodular lump under the hypodermis at the injection site. It was mentioned that excessive infusion can cause the breast to look unnatural and feel hard. This was not quantified. Capsular contracture and the effects on breast cancer screening were not discussed except for patient consent which contained the general statements that HA injections into the breast may delay the diagnosis of breast cancer and that patients would need regular breast screening after augmentation.

Macrolane™ was authorised in 2006 for use as a soft tissue filler in Europe by the CE mark and the basis of approval for use is likely to have included research data on HAs used as fillers in facial aesthetic surgery. The question must be asked is the approval process of new implantable medical devices in Europe and the UK adequate. In Europe this is determined by the CE mark. In the UK this responsibility falls upon the MHRA (Medicines and Healthcare products Regulatory Agency) however if a device has CE approval it can still be marketed in the UK despite not being recommended by the MHRA. In contrast to the European approval, Macrolane™ does not have FDA (Food and Drug Administration) approval for use in the USA and Canada and is unlikely to be approved based on currently available research. In order to obtain FDA authorisation clinical performance data is required. This data must be collected from clinical trials that are subject to FDA regulations as laid out in the Investigational Device Exemption (IDE) booklet.

This does raise the specter of the European regulatory authorities having a much lower standard of proof for safety and efficacy with regard to new implantable medical products compared to the FDA. This has previously had significant clinical impact in breast enhancement in the past. Trilucent breast implants, a soybean oil-filled implant were first marketed in 1995 and over 9000 implants were sold in the UK, and implanted into almost 5000 women. This implant, was not FDA approved. It was subsequently withdrawn from the UK in 1999 by the Medical Device Agency due to concern that the soybean oil filler could degrade into a genotoxic carcinogen and cause quite severe inflammation when the implant ruptured. The MHRA has recommended that these implants should be explanted or removed.

These serious health issues with the Trilucent implants only became apparent after their introduction and may have been avoided if the burden of proof for efficacy and safety was at a higher standard requiring greater clinical research and trial data. With the introduction of Macrolane™ it is important to gather clinical data in order to establish its safety, although this would ideally have been performed before release to the market. In the UK, the MHRA is functioning as a reactionary regulator rather than ensuring that new implantable devices are safe based on a high-level of evidence.

The idea of a breast enhancement product that is minimally invasive, non-permanent, technically reliable and produces the desired results has a lot of appeal. There is no perfect procedure and all techniques have limitations and complications some more so than others. Unfortunately history has shown us that many breast augmentation products have not lived up to their initial promise. The only way to know whether a new product is safe is to undergo scientific research and clinical trials. Here we present the first published report on Macrolane™ detailing our findings in three patients that presented with complications. All three complications were rectified via surgical intervention and as such we suggest the following recommendations for macrolane use:

• 1.
  All patients in the UK that have had Macrolane injected should be followed up long-term and the results of their outcome published.
• 2.
  Hyaluronic acid breast augmentation should not be used in patients with a history of breast carcinoma, cystic breast lesions, precancerous lesions and those with a family history of breast or ovarian cancer until the implications for breast screening are known.
• 3.
  Specific study should be made of the long-term radiographic changes on mammography in order to establish the sensitivity and specificity of breast screening especially in those patients with capsule formation.
• 4.
  A review of the regulation of new implantable medical devices so that there is a greater burden of proof on efficacy and safety. It is worth considering adopting the FDA process thus creating a single universal standard. New products released onto the market should receive a preliminary authorisation and undergo a trial period during which the outcomes are audited at the end of the allotted time. This is the procedure adopted by the FDA.

We would like to thank Asako and Adrian Castelino-Prabhu for their assistance with the preparation and interpretation for this manuscript.

The authors have no conflict of interest to declare.

None.