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生物可降解聚氨酯因為其良好的生物相容性，可降解性，以及優(yōu)異的力學性能 （柔軟且有彈性）而被廣泛應用于軟組織修復。本篇綜述從生物可降解熱塑性聚氨酯的化學結構， 理化性質(zhì)，功能性聚氨酯，以及其在組織再生修復中的實際應用作了一個綜合闡述， 并指出了新型聚氨酯的研究和應用方向。

 

01研究內(nèi)容簡介

 

聚氨酯在生物醫(yī)學領域的應用最早可以追溯到1960年代：一種用于心血管修復的 不可降解的聚氨酯。隨后為了滿足組織再生修復的需求，可降解型聚氨酯預1990年代開始進入人們的視野。生物可降解型聚氨酯具有良好的力學強度，柔軟度，和彈性，使其成為軟組織修復的理想材料。此外，熱塑性聚氨酯擁有良好的可加工性，可以被加工成各種形狀，使其更廣泛的應用于組織修復。通常生物可降解型熱塑性聚氨酯由三元結構組成：二異氰酸酯，可降解二元醇，和小分子擴鏈劑。調(diào)節(jié)這個三元結構的組成成分，可以賦予聚氨酯多樣的理化性能和功能性， 進而適用于不同組織修復和再生 （圖1）。

 

 

Fig. 1. Biodegradable polyurethanes: chemistry, functionalization, and tissue repair applications.

 

一、生物可降解型熱塑性聚氨酯合成

 

熱塑性聚氨酯可以通過一步或者兩步法制成。其中，兩步法因為能夠更好的控制其鏈段結構而得到更為廣泛的應用 （圖2）。如前所述，調(diào)節(jié)聚氨酯鏈段的三元結構成分可以得到不同的理化性質(zhì)， 賦予其不同的功能性。比如使用聚酯或者聚酰胺之類的生物可降解多元醇作為軟段可以確保聚氨酯具有生物可降解性。亦或者增加軟段的鏈段長度或者使用無定形態(tài)聚合物作為軟段可以降低聚氨酯的模量。擴鏈劑通常是小分子量的二醇或者是二胺，這樣有助于聚氨酯硬段的有序排列。而二胺和異氰酸酯鍵形成的聚氨酯脲由于更多的氫鍵結合，會比二醇和異氰酸酯鍵形成的聚氨酯具有更強的力學性質(zhì)。三元結構對于所形成的聚氨酯的理化性能的影響如圖3所示。

 

 

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.

 

二、功能性生物可降解型熱塑性聚氨酯

 

如前所述，通過調(diào)節(jié)展聚氨酯的三元結構成分，可以賦予其不同的功能性。比如，本文作者的課題組曾用苯胺三聚體作為擴鏈劑合成了具有導電性能的生物可降解聚氨酯，可以用于電信號響應的組織，如肌肉，神經(jīng)，皮膚等組織的修復。此外，本課題組還曾經(jīng)將二硫鍵引入聚氨酯鏈段中，使得聚氨酯具有還原敏感性， 可以用于還原敏感型藥物載體制備以及降解可控型生物支架的制備。除此之外，還有很多其他功能型的聚氨酯，比如形狀記憶型聚氨酯，水性聚氨酯，抗菌、抗凝血聚氨酯，詳情如圖4所示。

 

 

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 poly- urethane. 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) AAKpeptide 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.

 

三、生物可降解型熱塑性聚氨酯支架的制備以及組織工程應用

 

生物可降解型熱塑性聚氨酯因其良好的可加工性，可以通過多種方式制備成多孔支架，比如鹽析法， 相分離，凍干，靜電紡絲，3D 打印等 （圖5）。聚氨酯多孔支架也被廣泛應用于多種組織的修復和再生。

 

 

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.

 

  3.1 聚氨酯支架用于心血管修復

 

聚氨酯因其優(yōu)異的力學性能被廣泛地用作心肌補片， 血管支架和心臟瓣膜材料。甚至有一些基于聚氨酯的心血管修復產(chǎn)品已然面世， 比如Vectra ® graft， 是一款基于聚醚型聚氨酯的血管支架產(chǎn)品早在2000年已經(jīng)得到美國FDA認證上市。聚氨酯心肌補片也被植入多種心肌梗死動物模型中，印證了其對于受損心肌功能恢復的促進作用 （圖6）。此外，通過加入天然多肽或者蛋白來增加聚氨酯的生物活性，調(diào)節(jié)改善聚氨酯支架力學性能使其更趨近于天然心肌的力學性能，以及導電聚氨酯的應用都是當前聚氨酯心血管支架的研究方向。另一方面，可降解聚氨酯也被廣泛用于小直徑血管和瓣膜材料

 

 

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.

 

3.2 聚氨酯支架用于肌肉骨骼修復

 

聚氨酯支架也被廣泛應用于半月板，骨和軟骨的修復。很多可降解聚氨酯半月板支架得以進入臨床試驗階段，且實驗追蹤期不小于五年。實驗結果證明聚氨酯半月板可以促進膝關節(jié)功能修復，減少疼痛。但是植入失敗率高達40%， 且對于軟骨的保護能力受到了質(zhì)疑。聚氨酯支架也被廣泛應用于骨修復中，一些生物活性因子 （如骨形態(tài)發(fā)生蛋白 rhBMP-2）會被加入聚氨酯骨支架中增加其生物活性，從而促進骨損傷修復 （圖7）。

 

 

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.

 

3.3 聚氨酯支架用于神經(jīng)修復

 

由于神經(jīng)細胞的電學活性，使得導電性聚氨酯成為極具潛力的神經(jīng)修復材料。參雜了金納米粒子的聚氨酯納米纖維可以促進PC-12 細胞的貼附和增殖。同時在神經(jīng)生長因子和電刺激下， PC-12細胞神經(jīng)突的生長和伸長也得到了促進 （圖8）。

 

 

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.

 

3.4 聚氨酯支架用于傷口修復

 

聚氨酯因其良好的氧透過性而被用于傷口修復， 但其抗菌性和親水性需要得到改善從而阻止細菌感染和提高細胞黏附。提高聚氨酯的抗菌性可以通過引入抗菌物，如金、銀、氧化鋅、季銨鹽、抗生素等得以實現(xiàn)。而親水性可以通過混入親水物質(zhì)或者增加聚氨酯親水鏈段組分得到改善。此外，抗氧化物也可以加入聚氨酯中以促進傷口修復進程 （圖9）。

 

 

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.

 

最后作者指出雖然有很多體內(nèi)體外的實驗驗證的生物可降解型聚氨酯的良好的生物相容性， 但市面上生物可降解型聚氨酯產(chǎn)品并不多。很多有潛力的可降解型聚氨酯產(chǎn)品在被FDA認證之前仍然還有許多工作需要完成。值得注意的是，對于產(chǎn)品體內(nèi)體外安全性和功能性的取證一定要形成完善的證據(jù)鏈。此外，本文作者也提出了幾個新的可生物降解的聚氨酯研究方向，比如相較于單一功能聚氨酯，多功能性的聚氨酯也許更能滿足組織修復的需求。此外，可用于3D 打印的水性/水溶性聚氨酯，以及免疫調(diào)節(jié)性聚氨酯也是極具潛力的可用于生物醫(yī)學領域的新型聚氨酯材料。

 

總之，可降解聚氨酯材料可以通過化學結構設計調(diào)節(jié)它的物化性質(zhì)， 力學和生物學性能，以達到組織修復的材料要求。它們也非常有希望用于臨床應用。