Rational design of biodegradable thermoplastic polyurethanes for tissue repair

Abstract

As a type of elastomeric polymers, non-degradable polyurethanes (PUs) have a long history of being used in clinics, whereas biodegradable PUs have been developed in recent decades, primarily for tissue repair and regeneration. Biodegradable thermoplastic (linear) PUs are soft and elastic polymeric biomaterials with high mechanical strength, which mimics the mechanical properties of soft and elastic tissues. Therefore, biodegradable thermoplastic polyurethanes are promising scaffolding materials for soft and elastic tissue repair and regeneration. Generally, PUs are synthesized by linking three types of changeable blocks: diisocyanates, diols, and chain extenders. Alternating the combination of these three blocks can finely tailor the physio-chemical properties and generate new functional PUs. These PUs have excellent processing flexibilities and can be fabricated into three-dimensional (3D) constructs using conventional and/or advanced technologies, which is a great advantage compared with cross-linked thermoset elastomers. Additionally, they can be combined with biomolecules to incorporate desired bioactivities to broaden their biomedical applications. In this review, we comprehensively summarized the synthesis, structures, and properties of biodegradable thermoplastic PUs, and introduced their multiple applications in tissue repair and regeneration. A whole picture of their design and applications along with discussions and perspectives of future directions would provide theoretical and technical supports to inspire new PU development and novel applications.

Keywords: Biodegradable polyurethane; Elastic; Synthesis; Thermoplastic; Tissue repair.

Graphical abstract

Fig. 1

Biodegradable polyurethanes: chemistry, functionalization, and tissue repair applications.

Fig. 2

Typical synthesis routine of biodegradable polyurethane and polyurethane urea via a two-step method.

Fig. 3

List of component parameters that affect mechanical properties and degradation of biodegradable polyurethanes.

Fig. 4

Functional biodegradable polyurethane design. (A) Dopant-free conductive polyurethane. Structural design (left); Electrical stability (right): Relationship between electrical current and incubation time in the electrical stability test of DCPU-0.3/1 film in cell culture medium. Camphor doped PU-trimer film was used as a control. Reprinted with permission from [87]. Copyright 2016 Springer Nature. (B) Thermally triggered shape-memory polyurethane. Structural design (left); Shape memory behavior (right): Polyurethane cylinder was compacted into a flower shape at 40 °C and then cooled to room temperature immediately, and it returned to the original shape when immersed in 40 °C water. Adapted with permission from [109]. Copyright 2005 American Chemical Society. (C) Anionic waterborne polyurethane. Structural design (left); Porous polyurethane sponge fabricated from polyurethane/water dispersion via freeze-drying (right). Reproduced with permission from [122]. Copyright 2014 Elsevier B.V. (D) AAK-peptide conjugated polyurethane. Structural design (left); Polyurethane enzymatic degradation manipulation by introducing elastase sensitive AAK sequence and varying the feeding ratio of polyether/polyester (PEG/PCL) in the soft segment (right). Reprinted with permission from [67]. Copyright 2005 American Chemical Society. (E) Positively charged GQAS conjugated anti-bacterial polyurethane. Structural design (left); Antibacterial activities (right): live bacteria attached on surfaces with and without GQAS and PEG. No live E. coli or S. aureus cells detected on all surfaces of the polyurethanes containing different GQASs compared with the PCLPU0 without GQAS, indicating the antibacterial property of GQAS. Reprinted with the permission from [167]. Copyright 2017 Royal Society of Chemistry. (F) Non-thrombogenic polyurethane. Structural design (left); Ovine blood platelet deposition on polyurethane films observed by scanning electron microscopy after blood contact for 2 h (right): PSBUU-0 was control group without SB content which had relatively high platelet deposition, while PSBUU-100 contained the highest SB content showing sparse platelet deposition. Reprinted with the permission from [176]. Copyright 2014 American Chemical Society. (G) Reduction sensitive polyurethane. Structural design (left); Electrospun polyurethane scaffold controllable degradation (right): Scaffolds were immersed in PBS for 14 d and then in 10 mM GSH for another 14 d, where the scaffold degradation rate increased obviously after transferring from PBS to GSH solution. * represents significantly different groups (p < 0.05). Reprinted with the permission from [31]. Copyright 2015 American Chemical Society.

Fig. 5

Typical morphologies of biodegradable thermoplastic polyurethane scaffolds fabricated by various methods. (A) Salt leaching. Reprinted with permission from [52]. Copyright 2010 Elsevier B.V (B) Phase separation. Top: random pores. Reprinted with permission from [196]. Copyright 2005 Elsevier B.V.; Bottom: aligned pores Reprinted with permission from [197]. Copyright 2020 American Chemical Society. (C) Freeze drying. The aligned (top) and random (bottom) scaffolds were prepared using WBPU emulsion by freeze-drying at different concentrations. Reprinted with permission from [210]. Copyright 2019 Oxford University Press. (D) Electrospinning. Top: random fibers. Reprinted with permission from [31]. Copyright 2015 American Chemical Society. Bottom left. Aligned fibers. Reprinted with permission from [213]. Copyright 2012 Elsevier B.V. Bottom right: orthogonally aligned fibers. Reprinted with permission from [214]. Copyright 2015 Wiley. (E) 3D printing. Melt extrusion printing. Reprinted with permission from [206]. Copyright 2020 Elsevier B.V. (F) Combination. A bilayer scaffold from phase separation and electrospinning. Reprinted with permission from [208]. Copyright 2010 Elsevier B.V.

Fig. 6

Biodegradable polyurethane cardiac patch implanted in a porcine MI model. Digital (A) and SEM (B) images of biodegradable polyurethane cardiac patch. (C) The polyurethane patched left ventricle wall (n = 7) was significantly thicker than the sham surgery wall (n = 8). *p < 0.01. (F) Hematoxylin and eosin staining and immunostaining for a-smooth muscle actin (αSMA) and CD31. The polyurethane patched wall exhibited an aSMA rich layer (s) beneath the implanted PEUU patch (p). Below the αSMA rich layer was a vascular rich layer (v) and then a myocardial remnant (r) region at the endocardial side. A higher magnification of the boundary area between the polyurethane patch and αSMA rich layer showed that the PEUU partially degraded and cellular infiltration occurred with αSMA-positive cells (G and H). (I and J) are the junction between αSMA and vascular rich layers, and (K and L) are the center of the vascular rich layer. Reprinted with permission from [221]. Copyright 2013 American Association for Thoracic Surgery.

Fig. 7

In vivo evaluation of the effects of polyurethane scaffold encapsulating rhBMP-2 on bone reparation in a rat femoral plug model. Four treatment groups included: PUR control (no rhBMP-2), PUR/rhBMP-2 (no PLGA microspheres), PUR/PLGA-L-rhBMP-2 (rhBMP-2 released from large PLGA microspheres), and PUR/PLGA-S-rhBMP-2 (rhBMP-2 released from small PLGA microspheres). The PUR cylinders (5 mm*3 mm) were implanted into rat femoral plug defects (A) and harvested for mCT imaging at week 2 (B) and 4 (C), respectively. All rhBMP-2 treated groups showed significantly higher new bone formation than the control (PUR) (p < 0.05). Reprinted with permission from [277]. Copyright 2009 Elsevier. Ltd.

Fig. 8

PC12 cells growth on (A) polyurethane nanofibers; (B) gold nanoparticle decorated polyurethane nanofibers; (C) gold nanoparticle decorated aligned polyurethane nanofibers; (D) gold nanoparticle decorated aligned PU nanofibers after NGF and electrical stimulation. The neurite elongation of PC-12 cells was significantly promoted on gold nanoparticle decorated aligned PU nanofibers with the synergistic effect of NGF and electrical stimulation. Reprinted with permission from [293]. Copyright 2018 Wiley Periodicals, INC.

Fig. 9

In vivo evaluation of effects of polyurethane/siloxane dressing on wound healing in a rat skin wound model. Two treatment groups include: NESiPU4 (no aniline trimer, nonconductive), and EASiPU2 (containing aniline trimer, conductive). Photographs (A) and closure rate (B) of wounds treated with gauze (control), NESiPU4, and EASiPU2 during the wound healing process for 20 days. *p < 0.05. H&E and Masson's Trichrome staining at day 14 (C) and day 20 (D). Scale bars: 60 μm. Arrows indicate capillaries. The results suggested that the electroactive wound dressing could promote fast wound healing by complete re-epithelialization of the wound, enhanced vascularization, and collagen deposition. Reprinted with permission from [304]. Copyright 2015 American Chemical Society.