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  • br Patients and Methods br

    2018-11-09


    Patients and Methods
    Results No complications such as infection, device exposure, hematoma or seroma were observed throughout the trial. All patients, except one (patient 3), tolerated the chamber adequately with early low-grade pain that resolved spontaneously without any further interventions. After chamber removal, all patients recovered uneventfully. MRI findings are summarized in Table 3. Flap and chamber details are summarized in Table 4. In patient 2, MRI at six months showed flap enlargement, so she was offered the opportunity to keep the chamber in place for another six months to allow for further growth. At 12months, the chamber was removed and the 210ml space was filled with tissue in its entirety (Fig. 2). While the tissue in the lateral component (i.e. next to the pedicle) had a macroscopic appearance and palpable texture very similar to that of native fat (Fig. 3), tissue in the medial aspect was firmer and looked more fibrotic. When punctured, all regions of the newly formed tissue bled, showing good vascularization of the construct. Encapsulation around the exterior of the chamber caused the flap to be embedded into a thick wall resulting in a flattening effect and reduced projection compared with the immediate post implantation appearance. Even though the final volume did not completely match the opposite breast, a decision was made not to insert an implant. At six months follow-up the tissue remained stable and had softened to a “fat-like” consistency (Fig. 4). Patient 3, who had the lowest body mass index of the cohort and consequently received the smallest chamber (140ml), had the chamber removed at 7weeks due to continuous pain from rubbing of the chamber rim over her rib at one point. Upon removal, the cavity was approximately half full of flimsy, haemovascular and fibrous adipose-like tissue. Once the “thread-like” tissue projections into the chamber holes were released, the tissue compacted to an estimated volume of 25ml, which was roughly four times that of the original flap (6ml). The piece was removed en-bloc and sent for histological analysis, showing viable fat containing perfused blood vessels (Fig. 5). A silicone implant was inserted and the postoperative course was unremarkable. Patients 1, 4 and 5 failed to grow tissue beyond the initial flap\'s dimensions. On exploration at six months, their chambers were densely encapsulated and embedded into the pectoral muscle. Upon removal, a thick fibrous UNC1999 covering the flap and compressing it into a discoid flat patch was observed (Fig. 6). Histological analysis of these specimens using perilipin and CD31 staining revealed the presence of viable well-vascularized fat inside the chamber (Fig. 7). Reconstruction in these cases was carried out with silicone implants, without further complications.
    Discussion The traditional paradigm of tissue engineering is based on the use of scaffolds and cells in different combinations to create tissues or enhance their growth. First-in-human studies have used this approach for the repair of tissues such as the bladder, vaginal vault, blood vessels, and nasal nostril (Atala et al., 2006; Raya-Rivera et al., 2014; Fulco et al., 2014; Olausson et al., 2012). Although attractive, we cannot rush into thinking that this approach can be readily applied to the engineering of other important tissues such as muscle or fat. The bladder wall, vaginal wall and cartilage are tissues either thin enough to rely on nutrient diffusion until neo-vascularization occurs or with a low metabolic rate that allows them to survive under hypoxic conditions. By contrast, a 210ml volume of adipose tissue is a different challenge. Due to its thickness, dimensions and metabolic requirements, such a block of tissue needs a reliable source of blood supply from the beginning. This is achieved with the TEC: growth and expansion of tissue concomitantly with angiogenesis and the development of a reliable vasculature. This first-in-human pilot study represents an important upscale in the research and clinical application of tissue engineering, as it reports on the largest block of well differentiated vascularized tissue grown so far. Birchall and Seifalian in their Comment published in Lancet in 2014 pose the important question: Is it possible to scale up the volume of organs and tissues replaced using tissue-engineering technologies? (Birchall and Seifalian, 2014) We believe that such upscale is indeed achievable and that the TEC may hold promise for the development and growth of sizeable tissues and organs. In the current trial we have tested the chamber in a breast reconstruction setting, which is a fairly standardized model for soft tissue reconstruction. By no means the tissue-engineering chamber is specifically devised as an alternative to breast restoration but offers a solution for soft tissue defects elsewhere in the body as well as for the generation of tissues other than fat. In fact, using the TEC model, our group has been able to grow functional specialized tissues such as heart, thymus and liver, albeit with the inclusion of specific cell types (Morritt et al., 2007; Seach et al., 2010; Forster et al., 2011). Despite the unquestionable observation that human tissue did grow inside the chamber, the difference in the consistency of results compared with those obtained in animals needs further investigation. One clear difference is that small animals and pigs continue to grow throughout life and during the experiment, whilst mature human tissue is homeostatic. Additionally, wounds in animals are made de novo whereas in patients scarring from previous surgeries, might affect the tissues\' vascularization and growth potential.