Biodegradation of poly(urethane)s (PU)s using single enzymes in vitro was assessed by measuring radiolabel release from model poly(ester-urea-urethane) (PESU) and poly(ether-urea-urethane) (PETU) materials synthesized with 14C-labelled monomers. Cholesterol esterase (CE), an enzyme found in monocyte-derived macrophages (MDM), has been reported to cause a significant level of radiolabel release from both of these PUs. Previous work has shown that CE activity could be inhibited by the serine protease/esterase inhibitor, phenylmethylsulfonyl fluoride. Since many serine proteases are present in circulating blood and can be released by cells other than MDM, this study investigated the ability of serine proteases relative to that of CE to cause the degradation of PUs. In addition, the possible role of several oxidative enzymes in the breakdown of PUs was investigated. Proteinase K, chymotrypsin and thrombin, when incubated with PESU, coated on glass slips, caused significant radiolabel release, with proteinase K giving the highest values. However, the highest radiolabel release which proteinase K could elicit was ten times less than CE. Thrombin and then chymotrypsin were progressively worse in their biodegradative activity. Only CE, and not the serine proteases, could elicit a detectable radiolabel release from PETU. Although the release of reactive oxygen species and molecular oxygen occur around an implanted biomaterial, several oxidative systems (peroxidase, xanthine oxidase, catalase), known to produce one or more of these molecular species, were unable to induce radiolabel release from these PUs. The process of biodegradation as assessed by radiolabel release appears to be a specific hydrolytic process, while the role of oxidative enzymes remains less clear.
Although biodegradation of model poly(ester-urethane)s and poly(ether-urethane)s has been demonstrated using a single enzyme system (cholesterol esterase (CE) in vitro, in vivo biodegradation most likely involves many processes acting together. In this study, the physical (film vs textured surface) and chemical (poly(urethane)s containing polycaprolactone (PCL) vs poly(tetramethylene oxide) (PTMO)) nature of the materials as well as the products of enzymatic reactions known to occur during the inflammatory response (CE and phospholipase A2 (PLA)) were assessed for their effects on poly(urethane) (PU) biodegradation in vitro. A mixed micelle (phosphatidylcholine (PC):lysoPC (LPC):oleic acid (OA): 2:1:1) significantly increased the release of radiolabelled products from a C-labelled poly(ester-urethane) (TDI/PCL/ED) caused by CE. This effect was further enhanced when this material was cast as a textured surface. A model poly(ether-urethane) showed no significant enhancement of CE-mediated hydrolysis in the presence of phospholipids and their breakdown products whether cast as a film or a textured surface. PLA caused a small but significant release of radiolabel from TDI/PCL/ED which was enhanced in the presence of its substrate, PC, and a mixture of PC with its breakdown products, LPC and OA. Based on the results of this study, it may be possible to hypothesize that during the inflammatory response when PLA is activated, enhancement of the biodegradation of a PU could occur by direct action of PLA on the poly(ester-urethane) and by stimulation of CE due to the formation of LPC and OA occurring when PLA hydrolyses PC, its natural substrate
Introduction: Breast conserving surgery (BCS) is the most common procedure performed in breast cancers, but it can often result in breast deformities that can have negative impacts on quality of life. With better treatments, more breast cancer survivors are expected to live longer, the demand for achieving optimal cosmetic outcomes has also increased accordingly. Currently, oncoplastic techniques involving local tissue rearrangement with or without contralateral balancing procedures are used in specialized centers to achieve breast symmetry in some patients. When a breast deformity occurs, corrective options include: fat grafting, autologous flap procedures and completion mastectomy with immediate reconstruction. These techniques have long operative times, longer length of hospital stay and higher complication rates. Commercially-available synthetic implants are fabricated in pre-determined sizes and thus are not suitable to reconstruct partial breast deformities of varying size and shape. We explored the use of amino-acid based biodegradable polyurethanes as tissue fillers for BCS due to their chemical versatility, superior mechanical properties and tailored biocompatibility. Objective: To evaluate novel biodegradable polymer constructs, referred to as ReFilx, as soft tissue fillers for BCS defects. Hypothesis: Implantation of ReFilx during BCS will maintain breast shape and size and promote tissue regeneration in and around the biodegradable biomaterial, in contrast to sham controls. Methods: Two ReFilx formulations with high porosity, mechanical properties (compressive modulus=45±6 kPa and 31±9 kPa) comparable to native breast tissue and a moderate degree of swelling (202±6% and 248±6%) were selected for implantation in porcine BCS defects. Three female Yucatan Minipigs (age=4 years, weight=100-120 kg, 12 breasts per pig) received BCS to remove normal breast tissue of approximately 2 cm diameter, after which the defects were filled with ReFilx Formulation A, ReFilx Formulation B, or no filler (sham control). At 6, 12, 24, and 36 weeks post-implantation (n=3 per group), ultrasound breast examinations and mastectomies of each selected group of breasts were performed. Samples were fixed in 10% buffered formalin and stained with H&E, Masson's Trichrome and immunohistomchemistry using CD31. Results: ReFilx formulations maintained breast size and shape, with similar stiffness to native breast tissue, while sham controls collapsed over 36 weeks. The ReFilx fillers supported cell and tissue infiltration and neovascularization, as indicated by Masson's Trichrome and CD31 staining, respectively, without eliciting foreign body giant cell formation, fibrosis, or chronic inflammation, commonly associated with implanted medical devices. Conclusions: ReFilx are promising soft tissue fillers for breast volume restoration, representing a simple, versatile, permanent, and aesthetically superior solution to prevent soft tissue deformities. Acknowledgements: MaRS PoP fund, grant # MI 2011-170, NSERC # SYN 430828. Haynes Connell Foundation Breast Cancer Fund. Citation Format: Leong WL, Sharifpoor S, Battiston K, Charleton D, Corrigan M, McCready DR, Done SJ, Santerre JP. ReFilx- synthetic biodegradable soft tissue fillers for breast conserving surgery in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-12-15.
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