Transformation of Breast Reconstruction via Additive Biomanufacturing.

Breast cancer is a major cause of illness for women, with an estimated number of 300,000 new cases diagnosed in 20131,2. Unfortunately, currently available clinical treatments and filler materials for breast reconstruction or augmentation sometimes yield unsatisfying results3,4. Reconstructions using silicone-based implants may lead to complications such as fibrous capsule formation around the implant. In some cases this may be associated with pain, soft tissue irritation via capsular contracture and lead, from a cosmetic point of view, to an undesirable appearance to the breast5. Additional corrective surgeries may be required to remove the capsule–resulting in amplified costs for the patient and the healthcare system. A second reconstruction method termed lipotransfer, first described by the German surgeon Neuber6, is also used routinely for both reconstructive and aesthetic surgeries. In this case, the surgeon isolates fat from a donor site within the patient’s body via liposuction and injects it back into the breast region. However, without a structural support, the newly injected fat quickly gets remodelled by the body and a significant originally regenerated tissue volume is lost after 2–3 months–thus requiring 3–4 additional lipotransfer sessions before the tissue stabilises7. Furthermore, lipotransfer of large amounts of adipose tissue bears the risk of adipose tissue necrosis owing to insufficient vascularisation–ultimately leading to formation of oil cysts. Therefore, impetus has been gradually growing towards regenerative medicine-based approaches for breast reconstruction8,9,10,11. Therapy concepts based on application of adult stem cells were thought to be promising for complete regeneration of breast tissue in the early days in the field; however, those concepts also have considerable disadvantages impeding their clinical translation–ranging from complexities and cost with scaling up of tissue culture to requiring complex GMP-certified laboratories for the processing12,13,14,15,16,17,18. Furthermore, it is challenging to efficiently vascularise large clinically relevant breast scaffolds (>75 cc) using cell culture-based concepts. In order to solve the problems of vascularisation and adipose tissue remodelling in the field of breast tissue engineering, we have devised a unique concept based on the combination of an additive biomanufactured and patient-specific biodegradable scaffold in combination with a delayed fat injection. In this method of implantation, a scaffold additive biomanufactured from medical grade polycaprolactone (mPCL) is first implanted into the implantation site. The well-designed fully interconnected large pore network in combination with a surface etching process19 allows the formation of a blood clot inside the scaffold architecture20. The clot consists of platelets embedded in a mesh of cross-linked fibrin fibres, together with a growth-factor rich cocktail of fibronectin, vitronectin and thrombospondin. It is well known in the literature that the fibrin network and the associated growth-factor cocktail stimulates a strong angiogenic response and induce highly organised connective tissue to penetrate into the affected region21,22. After 14 days of implantation, when this angiogenic response is at its peak, fat is isolated from a donor site within the patient’s body and injected into the scaffold (see Fig. 1 for a visualisation of this concept). Figure 1 Overall concept of the prevascularisation and delayed fat injection concept. From a clinical perspective, the amount of fat that can be harvested from the patient without encountering donor site morbidity depends on the body composition of the patient–whereby a larger volume of fat can be extracted from patients with higher body fat percentage. In this study, based on the expertise of our surgical team and an extensive literature search23,24,25,26, 4 cm3 of adipose tissue was considered to be the maximum amount that can be harvested from a patient with a very low body fat percentage without encountering donor-site complications. Therefore, a study design was chosen in which the scaffolds were injected with 4 cm3 of autologous harvested fat–representing 5.2% of the total volume of the implanted scaffold. We further hypothesise that the presence of a pre-formed bed of connective tissue and vasculature would allow the injected fat to remodel within the highly porous scaffold architecture with minimal tissue necrosis and graft resorption. This study characterised adipose tissue retention in 75 cm3 sized patient-specific mPCL scaffolds subjected to a delayed fat injection implanted in a large animal model (pigs) for a period of 24 weeks. The results from this study move the field towards addressing the important clinical question of how to regenerate clinically relevant volumes of adipose tissue by integrating the clinically routinely applied technique of lipotransfer with scaffold-guided regeneration.