本研究旨在設計具有藥物釋放功能之高分子材料，以便作為神經導管。研究方法係將甲基丙烯酸-2-羥基乙酯(HEMA)與聚乳酸(PLA)溶於N-甲基吡咯烷酮(NMP)，並加入交聯劑乙二醇二甲基丙烯酸酯(EGDMA)及光起始劑2-羥基-2-甲基-1-苯基-1-丙酮(PI-1173)，再以紫外光照射，使HEMA與PLA形成半互穿網狀高分子結構(semi-interpenetrating network, SIPN)。再將SIPN浸入維他命B12 (Cobalamin)之溶液中，吸收藥物。藉由不同比例的HEMA與PLA，探討其機械性質，以及包覆維他命B12後之生物相容性質。研究結果顯示出，此SIPN混合物有良好的生物相容性與機械性質。除此之外，吸收藥物後的SIPN有著較高的蛋白質吸附。因此，本論文所研究之包覆維他命B12的HEMA/PLA之SIPN具有製作神經導管的開發潛力。

In this study, a semi-interpenetrating network (SIPN) polymer was synthesized for nerve conduits with drug delivery functionality. This SIPN was synthesized by polymerizing 2-hydroxyethyl methacrylate (HEMA) in polylactic acid (PLA) dissolved in N-methylpyrrolidone (NMP) using ethylene glycol dimethacrylate (EGDMA) as the crosslinking agent and 2-hydroxy-2-methyl-1-phenyl-1-propanone (PI-1173) as the photoinitiator. After curing with ultraviolet light, the mechanical properties and biocompatibility of the resultant SIPN were evaluated. Furthermore, the SIPN was loaded with vitamin B12 (cobalamin) to investigate the drug release behavior. The results show that this SIPN exhibited suitable biocompatibility and mechanical properties. In addition, this vitamin B12 loading SIPN showed higher protein adsorption. Therefore, these HEMA/PLA SIPN polymers will be promising for making drug-delivery nerve conduit.

參考文獻
[1] Carvalho CR, Chang W, Silva-Correia J, Kohn J, Engineering Silk Fibroin-Based Nerve Conduit with Neurotrophic Factors for Proximal Protection after Peripheral Nerve Injury, Advanced Healthcare Materials, vol 10, no. 1, pp. 1-14, 2020
[2] Houshyar S, Bhattacharyya A, Shanks R, Peripheral Nerve Conduit: Materials and Structures, ACS Chem. Neurosci, vol 10, no. 8, pp. 3349-3365, 2019
[3] Rodrigues MCO, Rodrigues AA, Glover LE, Voltarelli J, Borlongan CV, Peripheral nerve repair with cultured Schwann cells: getting closer to the clinics, The Scientific World Journal, vol. 2012, pp. 1-10, 2012.
[4] Jenkins AD, Kratochvíl P, Stepto RFT, Suter UW, Glossary of basic terms in polymer science, Pure Appl. Chem., vol 68, no. 12, p. 2305, 1996
[5] Sperling LH, Klempner D, Utracki LA (Eds.), Sperling Interpenetrating polymer networks, Advances in Chemistry Series, vol. 239, pp. 3-38, 1994
[6] Lauralee S, Human Physiology (9th ed.), USA, New York, McGraw-Hill Press, 2006
[7] Seddon HJ, A Classification of nerve injuries. Br. Med. J., vol 2, no. 4260, pp. 237-239, 1942
[8] Sunderland S, A classification of peripheral nerve injuries producing loss of function. Brain, vol 74, no. 4, pp. 491–516, 1951
[9] Gaudet AD, Popovich PG, Ramer MS, Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury, Journal of Neuroinflammation, vol 8, no. 110, pp. 1-14, 2011
[10] Davis EN, Chung KC, The Tinel sign: a historical perspective, Plastic and Reconstructive Surgery, vol 114, no. 2, pp.494-499, 2004
[11] Pfister LA, Papaloïzos M, Merkle HP, Gander B, Hydrogel nerve conduits produced from alginate/chitosan complexes, J. Biomed. Mater. Res., Part A, vol 80, no. 4, pp. 932-937, 2007
[12] Wang H, Zhao Q, Zhao W, Liu Q, Gu X, Yang Y, Repairing rat sciatic nerve injury by a nerve-growth-factor-loaded chitosan-based nerve conduit. Biotechnol. Appl. Biochem., vol 59, no. 5, pp. 388-394, 2012
[13] Lai ES, Anderson CM, Fuller GG, Designing a tubular matrix of oriented collagen fibrils for tissue engineering, Acta Biomater., vol 7, no. 6, pp. 2448-2456 ,2011
[14] Xie F, Li QF, Gu B, Liu K, Shen GX, In vitro and in vivo evaluation of a biodegradable chitosan-PLA composite peripheral nerve guide conduit material, Microsurgery., vol 28, no. 6, pp.471-479, 2008
[15] Matsumoto K, Ohnishi K, Kiyotani T, Sekine T, Ueda H, Nakamura T, Peripheral nerve regeneration across an 80-mm gap bridged by a polyglycolic acid (PGA)–collagen tube filled with laminin-coated collagen fibers: a histological and electrophysiological evaluation of regenerated nerves, Brain Res., vol 868, no. 2, pp.315-328, 2000
[16] Lee BK, Ju YM, Cho JG, Jackson JD, Lee SJ, Atala A, End-to-side neurorrhaphy using an electrospun PCL/collagen nerve conduit for complex peripheral motor nerve regeneration, Biomaterials, vol 33, no. 35, pp. 9027-9036, 2012
[17] Quigley AF, Bulluss KJ, Kyratzis IL, Gilmore K, Mysore T, Schirmer KS, Engineering a multimodal nerve conduit for repair of injured peripheral nerve, J. Neural Eng., vol 10, no. 1, pp. 1-17, 2013
[18] Tran PA, Zhang L, Webster TJ, Carbon nanofibers and carbon nanotubes in regenerative medicine, Adv. Drug Delivery Rev., vol 61, no. 12, pp.1097-1114, 2009
[19] Almansoori A, Hwang C, Lee SH, Kim B, Kim HJ, Lee J, Tantalum – poly (L-lactic acid) nerve conduit for peripheral nerve regeneration, Neurosci. Lett., vol 731, pp. 1-9, 2020
[20] Dalton PD, Flynn L, Shoichet MS, Manufacture of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) hydrogel tubes for use as nerve guidance channels, Biomaterials, vol. 23, no. 18, pp. 3843-3851, 2002.
[21] Fu Y, Kao WJ, Drug Release kinetics and transport mechanisms of non-degradable and degradable polymeric delivery systems, Exp. Opin. Drug Deliv., vol 7, pp. 429-444, 2010
[22] Sackett CK, Narasimhan B, Mathematical modeling of polymer erosion: Consequences for drug delivery, Int. J. Pharma., vol 418, pp. 104-114, 2011
[23] Sun J, Yu H, Zhuang X, Chen X, Jing X, Crystallization behavior of asymmetric PLLA/PDLA blends, J. Phys. Chem. B, vol 115, pp. 2864– 2869, 2011
[24] Farah S, Anderson DG, Langer R, Physical and mechanical properties of PLA, and their functions in widespread applications - A comprehensive review, Adv. Drug Delivery Rev., vol 107, pp. 367-392, 2016
[25] Montheard JP, Chatzopoulos M, Chappard D, 2-Hydroxyethyl methacrylate (HEMA): chemical properties and applications in biomedical fields. Journal of Macromolecular Science, Part C: Polymer Reviews, vol 32, no. 1, pp. 1-34, 1992
[26] Omidian H, Park K, Kandalam U, Rocca JG, Swelling and Mechanical Properties of Modified HEMA-based Superporous Hydrogels, Journal of Bioactive and Compatible Polymers, vol 25, no. 5, pp. 483-497, 2010
[27] Dotson NA, Galvan R, Laurence RL, Tirrell M, Polymerization process modeling, USA, New York, Wiley-VCH, 1996
[28] Akhtar MF, Hanif M, Ranijha NM, Methods of synthesis of hydrogels, A review, Saudi Pharm J, vol 24, no. 5, pp. 554-559, 2016
[29] Eagland D, Crowther NJ, Butler CJ, Complexation between polyoxyethylene and polymethacrylic acid-the importance of the molar mass of polyethylene, Eur. Polym. J., vol 30, pp. 767-773, 1994
[30] Mathur AM, Hammonds KF, Klier J, Scranton AB, Equilibrium swelling of poly(methacrylic acid-g-ethylene glycol) hydrogels, J. Control. Rel., vol 54, pp. 177-184, 1998
[31] Förster S, Antonietti M, Amphiphilic block copolymers in structure-controlled nanomaterial hybrids, Adv. Mater., vol 10, pp. 195-217, 1998
[32] Bezemer JM, Grijpma DW, Dijkstra PJ, van Blitterswijk CA, Feijen J., Control of protein delivery from amphiphilic poly(ether ester) multiblock copolymers by varying their water content using emulsification techniques, J. Control. Rel., vol 66, pp. 307-320, 2000
[33] Yokoyama F, Masada I, Shimamura K, Morphology and structure of highly elastic poly(vinyl alcohol) hydrogel prepared by repeated freezing-and-melting, Colloid Polym. Sci., vol 264, pp. 595-601, 1986
[34] Goosen MF, O'Shea GM, Gharapetian HM, Chou S, Sun AM, Optimization of microencapsulation parameters: semipermeable microcapsules as a bioartificial pancreas, Biotechnol. Bioeng., vol 27, pp. 146-150, 1985
[35] Zu YG, Zhang Y, Zhao XH, Shan C, Zu SC, Wang KL, Li Y, Ge YL, Preparation and characterization of chitosan-polyvinyl alcohol blend hydrogels for the controlled release of nano-insulin, Int. J. Biol. Macromol, vol 50, pp. 82-87, 2012
[36] Coviello T, Grassi M, Rambone G, Santucci E, Carafa M, Murtas E, Riccieri FM, Alhaique F, Novel hydrogel system from sceroglycan: synthesis and characterization, J. Control. Rel., vol 60, pp. 367-378, 1999
[37] Debajyoti R, Gils PS, Guru PM, Manavalan R, Prafulla KS, Comparative delivery of diltiazem hydrochloride through synthesized polymer: hydrogel and hydrogel microspheres, J. Appl. Polym. Sci., vol 116, no. 2, pp. 959-968, 2010
[38] Martin BD, Linhardt RJ, Dordick JS, Highly swelling hydrogels from ordered galactose-based polyacrylates, Biomaterials, vol 19, pp. 69-76, 1998
[39] Hubbell JA, Hydrogel systems for barriers and local drug delivery in the control of wound healing, J. Control. Rel., vol 39, pp. 305-313, 1996
[40] Andreopoulos FM, Beckman EJ, Russell AJ, Light-induced tailoring of PEG-hydrogel properties, Biomaterials, vol 19, pp. 1343-1352, 1998
[41] Zhu L, Liu F, Yu X, Xue L, Poly(Lactic Acid) Hemodialysis Membranes with Poly(Lactic Acid)-block-Poly(2-Hydroxyethyl Methacrylate) Copolymer As Additive: Preparation, Characterization, and Performance, ACS Appl. Mater. Interfaces, vol 7, pp. 17748-17755, 2015
[42] Li DJ, Zhang T, Xu C, Ji B, Effect of pH on the interaction of vitamin B12 with bovine serum albumin by spectroscopic approaches, Spectrochim. Acta A Mol. Biomol. Spectrosc., vol 83, no. 1, pp. 598-608, 2011
[43] Nishimoto S, Tanaka H, Okamoto M, Okada K, Murase T, Yoshikawa H, Methylcobalamin promotes the differentiation of Schwann cells and remyelination in lysophosphatidylcholine-induced demyelination of the rat sciatic nerve, Front Cell Neurosci, vol 9, Article 289, 2015