Full length articleLong term efficacy and fate of a right ventricular outflow tract replacement using an elastomeric cardiac patch consisting of caprolactone and D,L-lactide copolymers
Graphical abstract
Introduction
Some synthetic materials, such as polyethylene terephthalate fabric (DACRON) and expanded polytetrafluoroethylene (ePTFE, e.g., Gore-Tex or IMPRA), are commonly used for reconstruction of tissue deficiencies in cardiovascular surgery. These materials are not clinically ideal since each has drawbacks, for instance unsuitable mechanical properties for cardiac tissue, lack of biodegradation resulting in lack of native tissue growth, and risks of calcification and infection.
Previously, we reported that applying a cardiac patch made of biodegradable polyester urethane urea (PEUU) onto an infarcted area could prevent further cardiac dilation and preserve cardiac function after myocardial infarction, due to the material's suitable elasticity and strength [1], [2], [3]. Further, this material induced muscle cellularization in which the cells had characteristics of early cardiomyocytes, contributing to cardiac regeneration. Unfortunately, PEUU has not yet been approved by the US Food and Drug Administration (FDA) for clinical usage.
We have focused on polylactic acid (PLA) and poly-ε-caprolactone (PCL) which have already been widely used clinically in the construction of artificial bone, tendon, skin, and sutures, and are expected to be utilized in the cardiovascular field. Our objective is to develop a biodegradable material with suitable mechanical properties for cardiovascular reconstruction and to apply this material to cardiac tissue in vivo to prove its long-term efficacy.
To create the cardiac biomaterial, we used four-armed poly(ε-caprolactone-co-D,L-lactide) (i.e., P(CL-DLLA)), which was reported in previous papers [4], [5], [6]. In general, PCL and PLA are quite mechanically rigid; however, the elasticity of our P(CL-DLLA) material has been tuned for tissue compatibility and biodegradability [6]. We were able to use this tunable material platform in tissue-engineering scaffolds for nerve generation, spheroid culture, and the creation of biomaterials for cancer therapy [7], [8], [9].
In this study, we used an elastomeric patch composed of P(CL-DLLA), which has more optimal material properties for use as a cardiac patch. The right ventricular outflow tract (RVOT) in rats was replaced with P(CL-DLLA), and the RVOT material was then examined in terms of degradation, angiogenesis, and endothelium and tissue formation after implantation periods of 8, 24, and 48 weeks. It was thought that the endpoint of 48 weeks would demonstrate the fate of the implanted biomaterial. This is the first study to report such long-term observation of biodegradable material in the heart.
Section snippets
Experimental animals
Adult male Sprague-Dawley rats (Japan SLC, Inc. Shizuoka, Japan) weighing 300 g to 350 g were used for the RVOT replacement procedure. The research protocol followed the National Institutes of Health guidelines for animal care and was approved by the Institutional Animal Care and Use Committee of the Animal Experiment Advisory Committee of the Nagoya University School of Medicine (No. 20383).
Mechanical properties of P(CL-DLLA)
Briefly, four-armed P(CL-DLLA) was synthesized by ring-opening polymerization of CL and D,L-lactide
Characterization of P(CL-DLLA)
Fig. 1a shows the stress-strain curve of crosslinked P(CL-DLLA). The curve with a CL/DLLA ratio of 80/20 was strongly temperature-dependent, and the elastic moduli were 71 ± 12 MPa at 25°C and 230 ± 25 kPa at 37°C, respectively. On the other hand, the curve with a CL/DLLA ratio of 60/40 showed polymeric, rubber-like stress-strain curves, with elastic moduli of 252 ± 37 kPa at 25°C and 238 ± 25 kPa at 37°C, respectively. A temperature-independent mechanical property of P(CL-DLLA) with a CL/DLLA
Discussion
We previously developed PCL-based materials with tunable thermal and mechanical properties as well as shape memory ability [8,11,12]. Despite being composed of only crosslinked P(CL-DLLA), this biodegradable polymeric material possesses high elasticity and strength. We already utilized this material platform as a scaffold for nerve regeneration and spheroid cell culture [7,8]. Given this material's superior characteristics, we assumed it could serve as an elastic patch for tissue reconstruction
Conclusion
This study evaluated the potential of an elastomeric cardiac patch made of biodegradable cross-linked P(CL-DLLA) copolymers for in vivo RVOT repair. This patch had unique mechanical properties, particularly elasticity, that made it suitable for long-term cardiac patches. The P(CL-DLLA) successfully induced new muscle tissue growth during the initial 24-week period, as manifested by the appearance of myofibroblasts, immature cardiomyocytes, endocardial endothelialization, and vascularization,
Funding
This study was supported in part by a Grant-in-Aid for Science Research (No. 26462086) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and Japan Agency for Medical Research and Development (AMED)-PRIME, AMED to K.U under Grant Number JP19gm5810017.
Declaration of Competing Interest
The authors declare no conflicts of interest.
Acknowledgments
The authors thank the Division for Experimental Animals, Nagoya University Graduate School of Medicine, for managing the animals used in this study. The authors would like to thank the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine, for the use of a cryomicrotome (Leica) and FSX100 microscope (Olympus).
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