Department of Hand Surgery, China-Japan Union Hospital, Jilin University, Changchun, People's Republic of China.
J Neural Eng. 2019 Jun;16(3):036030. doi: 10.1088/1741-2552/ab17a0. Epub 2019 Apr 9.
Currently commercially available nerve conduits have demonstrated suboptimal clinical efficacy in repairing peripheral nerve defects. Although tissue-engineered nerve grafts (TENGs) with sustained release of neurotrophic factors (NTFs) are experimentally proved to be more effective than these blank conduits, there remains a lack of clinical translation. NTFs are typically immobilized onto scaffold materials of the conduit via adsorption, specific binding or other incorporation techniques. These scaffold-based delivery strategies increase complexity and cost of conduit fabrication and lack flexibility in choosing different drugs. Therefore, to facilitate clinical translation and commercialization, we construct a TENG using a scaffold-independent drug delivery system (DDS).
This study adopted a scaffold-independent DDS based on methoxy-poly (ethylene glycol)-b-poly(γ-ethyl-L-glutamate) (mPEG-PELG) thermosensitive hydrogels that undergo sol-to-gel transition at body temperature. In addition, TENG, a chitosan scaffold filled with nerve growth factor (NGF)-loaded mPEG-PELG that gel in the lumen upon injection during surgery and function as a drug-releasing conduit-filler, was designed. Subsequently, the efficacy of DDS and therapeutic effects of TENG were assessed.
The results demonstrated that NGF-loaded mPEG-PELG controllably and sustainably released bioactive NGF for 28 d. When bridging a 10 mm rat sciatic nerve gap, the morphological, electrophysiological, and functional analyses revealed that NGF-releasing TENG (Scaffold + NGF/mPEG-PELG) achieved superior regenerative outcomes compared to plain scaffolds and those combined with systemic delivery of NGF (daily intramuscular injection (IM)), and its effects were relatively similar to autografts.
This study has proposed a TENG using thermosensitive hydrogels as an injectable implant to controllably release NGF, which has promising therapeutic potential and translatability. Such TENGs obviate the need for conduit modification, complex preloading or binding mediators, therefore they allow the ease of drug switching in clinical practice and greatly simplify the manufacturing process due to the independent preparation of drug delivery system.
目前市售的神经导管在修复周围神经缺损方面的临床效果并不理想。虽然实验证明，具有神经营养因子（NTFs）持续释放功能的组织工程神经移植物（TENGs）比这些空白导管更有效，但仍缺乏临床转化。NTFs 通常通过吸附、特异性结合或其他结合技术固定在导管的支架材料上。这些基于支架的递药策略增加了导管制造的复杂性和成本，并且在选择不同药物时缺乏灵活性。因此，为了促进临床转化和商业化，我们构建了一种使用无支架药物递送系统（DDS）的 TENG。
本研究采用了一种基于甲氧基聚（乙二醇）-b-聚（γ-乙基-L-谷氨酸）（mPEG-PELG）温敏水凝胶的无支架 DDS，该水凝胶在体温下发生溶胶-凝胶转变。此外，设计了一种壳聚糖支架填充神经生长因子（NGF）负载的 mPEG-PELG，在手术中注射时在管腔中凝胶化，并作为药物释放导管填充剂。随后，评估了 DDS 的疗效和 TENG 的治疗效果。
结果表明，NGF 负载的 mPEG-PELG 可控制并持续释放具有生物活性的 NGF 长达 28 天。当桥接 10mm 大鼠坐骨神经间隙时，形态学、电生理学和功能分析表明，释放 NGF 的 TENG（支架+NGF/mPEG-PELG）与单纯支架和与 NGF 全身给药（每天肌内注射（IM））结合相比，具有更好的再生效果，其效果与自体移植物相当。
本研究提出了一种使用温敏水凝胶作为可注射植入物的 TENG，以可控方式释放 NGF，具有有前途的治疗潜力和转化能力。这种 TENG 不需要对导管进行修饰，也不需要复杂的预加载或结合介质，因此在临床实践中便于药物转换，并且由于独立制备药物递送系统，大大简化了制造过程。
