應用於創傷性腦損傷修復之兩性離子聚合物PAGPs

Abstract

創傷性腦損傷（TBI）因中樞神經系統再生能力有限及膠質細胞引發的慢性發炎反應，至今仍是一大臨床挑戰。為同時促進神經軸突再生並抑制膠質細胞貼附，本研究開發並合成一種新型兩性離子聚合物——具備胍基與磺酸基的poly(3-(3-allylguanidino)propane-1-sulfonic acid)（PAGPs）。PAGPs的兩性結構不僅提升材料親水性，亦強化其抗細胞貼附特性；其成功磺酸化經 FTIR、NMR與元素分析驗證。 抗貼附測試顯示，PAGPs對星狀膠細胞（CTX-TNA2）具有顯著抑制效果。小鼠初代小腦神經細胞培養實驗進一步證實，PAGPs 可有效促進軸突延伸並提升 GAP-43表現與細胞活性。此現象亦符合文獻中指出含磺酸根之聚合物能抑制 PTPRσ活性、進而促進神經再生的觀察結果。 為提升材料之可降解性，本研究將 PAGPs 塗佈於 PLGA/PEG可降解共聚膜上。結果顯示，複合膜在具備良好降解性的同時，亦能維持 PAGPs 的神經促生長及抗膠質細胞貼附功能。 綜合以上結果，PAGPs展現出促進神經修復並抑制膠質反應的潛力，未來有望應用於 TBI 損傷修復，提供患者更安全有效的治療選項。

Traumatic brain injury (TBI) remains a major clinical challenge due to the limited regenerative capacity of the central nervous system and the persistent inflammatory response triggered by glial cells. To simultaneously promote axonal regeneration and suppress glial adhesion, we developed and synthesized a novel zwitterionic polymer, poly(3-(3-allylguanidino)propane-1-sulfonic acid) (PAGPs), which contains both guanidinium (positive) and sulfonate (negative) groups. The zwitterionic structure of PAGPs enhances its hydrophilicity and anti-adhesive properties, and successful sulfonation was confirmed by FTIR, NMR, and elemental analysis. Adhesion assays showed that PAGPs effectively suppressed astrocyte (CTX-TNA2) attachment. Further culture of primary cerebellar neurons from mice demonstrated that PAGPs significantly promoted axonal outgrowth, enhanced GAP-43 expression, and increased neuronal viability. These findings are consistent with reports that sulfonated polymers inhibit PTPRσ activity, a receptor known to block axon regeneration, thus facilitating neural repair. To address the non-degradable nature of PAGPs, the polymer was coated onto biodegradable PLGA/PEG membranes. The composite membrane not only retained the biofunctionality of PAGPs but also exhibited excellent degradation profiles. In summary, PAGPs exhibit dual functionality in enhancing neuronal regeneration and suppressing glial responses. This material shows strong potential for application in TBI repair, offering a promising strategy for safe and effective neural tissue regeneration.