Cancan Xu

ORCID Identifier(s)

0000-0001-6597-2562

Graduation Semester and Year

2018

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Biomedical Engineering

Department

Bioengineering

First Advisor

Yi Hong

Abstract

Biodegradable polyurethanes have been applied in biomedical field since 1960s. In recent years, biodegradable polyurethanes have been widely investigated for tissue repair and regeneration because of their good mechanical properties, elasticity, biodegradability, biocompatibility and processability. Compared with some commonly used biodegradable polymers, such as poly(glycolide) (PGA), poly(lactide) (PLA), poly(ε-caprolactone) (PCL) and polyhydroxyalkanoates (PHA), the favorable aspects of biodegradable polyurethane are its mechanical, physicochemical and biological properties can be tailored by varying the three blocks in polyurethane backbone, diisocyanate, diol and chain extender. In this thesis, we focus on the development of different functional biodegradable polyurethanes to study their structure-property relationships and satisfy different requirements in cardiac tissue repair and regeneration. We firstly designed a series of degradation-controllable polyurethanes containing various amounts of disulfide bonds in the backbones (PU-SS), which made the polyurethane selectively sensitive to antioxidants. Glutathione (GSH) is a natural antioxidant existing in intracellular and extracellular fluids as well as in extracellular matrices (ECM). The in vivo degradation of the PU-SS can be initiated by the GSH existing in the cardiac ECM and accelerated via intramuscular injection of GSH to induce the fast degradation of the implant on demand. The PU-SS polymer can be processed into films and electrospun fibrous scaffolds. Synthesized materials exhibited robust mechanical properties and high elasticity. Accelerated degradation of the materials was observed in the presence of GSH, and the rate of such degradation depends on the amount of disulfide present in the polymer backbone. The polymers and their degradation products exhibited no apparent cell toxicity while the electrospun scaffolds supported fibroblast growth in vitro. The in vivo subcutaneous implantation model showed that the polymers prompt minimal inflammatory responses, and as anticipated, the polymer with the higher disulfide bond amount had faster degradation in vivo. Secondly, we developed series of electroactive biodegradable elastomeric polyurethanes as potential cardiac patch because electromechanical coupling of myocytes is crucial for their synchronous response to electrical pacing signals and conductive material can improve the ability of cardiac patch to contract effectively as a unit. First of all, a biodegradable conductive polyurethane (CPU) was synthesized from polycaprolactone diol (PCL), hexadiisocyanate (HDI), and aniline trimer and subsequently doped with (1S)-(+)-10-camphorsulfonic acid (CSA). The electrical conductivity of the CPU films, as enhanced with increasing amounts of CSA, ranged 4.2±0.5 × 10-8 to 7.3±1.5 × 10-5 S/cm in a wet state. The initial moduli of CPU films increased from 7±1 MPa to 35±11 MPa with increased CSA amount. The doped CPU film could maintain 87% of initial conductivity after 150 hours charge under physiological environment. After 7 days of enzymatic degradation, the conductivity of all CSA-doped CPU films had decreased to that of the undoped CPU film. Furthermore, most CPU films showed high cell viability except for the group with highest CSA amount. Hence, we found the addition of dopant, CSA, can increase the polymer stiffness and deteriorated its electrical stability and biocompatibility due to the dopant leaching-out. To address this issue, we improved our design by introducing the dopant molecule into the polyurethane backbone via covalent bonding to form a biodegradable, dopant-free conductive polyurethane (DCPU) without adding extra dopant, which possessed improved mechanical properties, electrical conductivity and conductive stability, compared with the CPU polymer. Specifically, a biodegradable PCL, conductive aniline trimer, and dopant dimethylolpropionic acid (DMPA) were linked into DCPU polymer chain through HDI. The electrical conductivities of DCPU s increased with increasing DMPA amounts, ranging from 4.4 ± 0.4 × 10–7 to 4.7 ± 0.8 × 10–3 S/cm in wet state, which were higher than those of CPU polymers doped with different amounts of CSA. The initial moduli of CPU films ranged from 3.0±0.6 MPa to 5.2±1.1 MPa with decreasing DMPA content, which were lower than those of CPU films. The DCPU film showed excellent electrical stability (264% of initial conductivity after 150h charge) under a physiological condition. Furthermore, mouse 3T3 fibroblasts proliferated on these films exhibiting good cytocompatibility. DCPU can also be processed into a porous scaffold using salt leaching. In vivo mouse subcutaneous model exhibited good tissue compatibility with extensive cell infiltration over 4 weeks of the DCPU scaffold compared to PCL porous scaffold. Subsequently, because tissue engineered cardiac patch is also required to have mechanical and bioactive properties mimicking the native myocardium, we firstly developed a family of biodegradable elastomeric polyurethanes (PU) with low initial moduli to mechanically mimic the native myocardium. Specifically, random copolymers poly(δ-valerolactone-co-ε-caprolactone) (PVCL) and hydrophilic poly(ethylene glycol) (PEG) were combined into a triblock copolymer, PVCL−PEG−PVCL, and was used as a soft segment in the polyurethane backbone. The triblock copolymers were varied in chemical components, molecular weights, and hydrophilicities. The mechanical properties of polyurethanes in dry and wet states can be tuned by altering the molecular weights and hydrophilicities of the soft segments. Increasing the length of either PVCL or PEG in the soft segments reduced initial moduli of the polyurethane films and scaffolds in dry and wet states. The polymer films are found to have good cell compatibility and to support fibroblast growth in vitro. Selected polyurethanes were then processed into anisotropic porous scaffolds by a thermally induced phase-separation technique and their mechanical properties can be tailored by altering the soft segment molecular weight in the polyurethane backbone, and subsequently by varying the polymer concertation parameters during the scaffold fabrication process. The uniaxial mechanical properties, suture retention strength, ball-burst strength and biaxial mechanical properties of the polyurethane anisotropic porous scaffolds were optimized to mechanically match the native myocardium. The optimal PU-PEG1K-PVCL6K-10% scaffold had ball burst strength (20.7 ± 1.5 N) comparable to that of native porcine myocardium (20.4 ± 6.0 N) and showed anisotropic mechanical behavior close to the biaxial behavior of the native porcine myocardium. Furthermore, the optimized synthetic polyurethane scaffold was combined with myocardium-derived hydrogel to form a biohybrid scaffold to improve its bioactivity. The biohybrid scaffold had morphologies similar to the decellularized porcine myocardial scaffold. The mechanical testing results showed the combination of the myocardium-derived hydrogel with the synthetic polyurethane scaffold did not affect the optimizal mechanical properties of the synthetic scaffold. In vivo rat subcutaneous implantation of the biohybrid scaffold showed minimal immune response and exhibited higher cell penetration than the synthetic polyurethane scaffold, indicating its good tissue compatibility and high bioactivity. Based on the above three aims, our future study will focus on exploring the biological function of these developed polyurethanes for cardiovascular application. For example, C2C12 cells have been cultured on the DCPU films and the abilities of this electroactive polymer to support cell proliferation, promote myogenic differentiation and maturation, and induce cell-to-cell interactions are studied at present. Also, in our future work, combining those desired functions into one polymer, which is degradation-controllable, electroactive biodegradable polyurethane with mechanical properties and bioactivities comparable to native myocardium, will be a promising method to create ideal cardiac patch. In summary, this work demonstrates the design and synthesis of functionalized biodegradable polyurethanes for cardiac repair and regeneration from three different aspects: degradation controllability, electroactivity, and mechanical match with native myocardium. These functionalized polyurethane-based scaffolds are not just physical templates for cell growth and tissue formation, but can also provide various signals (e.g., electrical and mechanical signals) to cells, thus can regulate cell proliferation and tissue regeneration. These exciting functionalized polyurethanes may find great opportunities not only for cardiac tissue regeneration, but also for other soft tissue repair and regeneration, such as skeletal muscle, nerve and skin.

Keywords

Biodegradable polyurethane, Biomaterials

Disciplines

Biomedical Engineering and Bioengineering | Engineering

Comments

Degree granted by The University of Texas at Arlington

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