Delivery of Brain-Derived Neurotrophic Factor by 3D Biocompatible Polymeric Scaffolds for Neural Tissue Engineering and Neuronal Regeneration
Biopolymers are increasingly employed for neuroscience applications as scaffolds to drive and promote neural regrowth, thanks to their ability to mediate the upload and subsequent release of active molecules and drugs. Synthetic degradable polymers are characterized by different responses ranging from tunable distension or shrinkage to total dissolution, depending on the function they are designed for. In this paper we present a biocompatible microfabricated poly-ε-caprolactone (PCL) scaffold for primary neuron growth and maturation that has been optimized for the in vitro controlled release of brain-derived neurotrophic factor (BDNF). We demonstrate that the designed morphology confers to these devices an enhanced drug delivery capability with respect to monolithic unstructured supports. After incubation with BDNF, micropillared PCL devices progressively release the neurotrophin over 21 days in vitro. Moreover, the bioactivity of released BDNF is confirmed using primary neuronal cultures, where it mediates a consistent activation of BDNF signaling cascades, increased synaptic density, and neuronal survival. These results provide the proof-of-principle on the fabrication process of micropatterned PCL devices, which represent a promising therapeutic option to enhance neuronal regeneration after lesion and for neural tissue engineering and prosthetics.
KeywordsMicrofabrication Biopolymer Drug delivery Primary neurons BDNF Neural tissue engineering
The work was supported by the King Abdullah University of Science and Technology start-up funding and by research grants from the European Union FP7 “Neuroscaffolds” (grant number 604263 to FB), Compagnia di San Paolo-Italy (to FC).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no competing interest.
- 12.Shirian S, Ebrahimi-Barough S, Saberi H, Norouzi-Javidan A, Mousavi SM, Derakhshan MA, Arjmand B, Ai J (2016) Comparison of capability of human bone marrow mesenchymal stem cells and endometrial stem cells to differentiate into motor neurons on electrospun poly(epsilon-caprolactone) scaffold. Mol Neurobiol 53(8):5278–5287. https://doi.org/10.1007/s12035-015-9442-5 CrossRefPubMedGoogle Scholar
- 13.Limongi T, Miele E, Shalabaeva V, Rocca RL, Schipani R, Malara N, Angelis FD, Giugni A, Fabrizio ED (2015) Development, characterization and cell cultural response of 3D biocompatible micro-patterned poly-ε-caprolactone scaffolds designed and fabricated integrating lithography and micromolding fabrication techniques. J Tissue Sci EngGoogle Scholar
- 17.Liechty WB, Kryscio DR, Slaughter BV, Peppas NA (2010) Polymers for drug delivery systems. Annu Rev Chem Biomol Eng 1:149–173. https://doi.org/10.1146/annurev-chembioeng-073009-100847 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Sanna V, Siddiqui IA, Sechi M, Mukhtar H (2013) Resveratrol-loaded nanoparticles based on poly(epsilon-caprolactone) and poly(D,L-lactic-co-glycolic acid)-poly(ethylene glycol) blend for prostate cancer treatment. Mol Pharm 10(10):3871–3881. https://doi.org/10.1021/mp400342f CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Siafaka PI, Barmpalexis P, Lazaridou M, Papageorgiou GZ, Koutris E, Karavas E, Kostoglou M, Bikiaris DN (2015) Controlled release formulations of risperidone antipsychotic drug in novel aliphatic polyester carriers: data analysis and modelling. Eur J Pharm Biopharm 94:473–484. https://doi.org/10.1016/j.ejpb.2015.06.027 CrossRefPubMedGoogle Scholar
- 22.Limongi T, Pagliari G, Allione P, Candeloro FD (2017) Fabrication and applications of micro/nanostructured devices for tissue engineering. Nano-Micro Letters 9(1)Google Scholar
- 24.Cesca F, Yabe A, Spencer-Dene B, Scholz-Starke J, Medrihan L, Maden CH, Gerhardt H, Orriss IR et al (2012) Kidins220/ARMS mediates the integration of the neurotrophin and VEGF pathways in the vascular and nervous systems. Cell Death Differ 19(2):194–208. https://doi.org/10.1038/cdd.2011.141 CrossRefPubMedGoogle Scholar
- 27.Limongi T, Giugni A, Tan H, Bukhari EM, Torre B, Allione M, Marini M, Tirinato L et al (2015) Fabrication, mercury intrusion porosimetry characterization and in vitro qualitative analysis of biocompatibility of various porosities polycaprolactone scaffolds. J Tissue Sci Eng 6. https://doi.org/10.4172/2157-7552.1000159
- 29.Wilhelm JC, Xu M, Cucoranu D, Chmielewski S, Holmes T, Lau KS, Bassell GJ, English AW (2012) Cooperative roles of BDNF expression in neurons and Schwann cells are modulated by exercise to facilitate nerve regeneration. J Neurosci 32(14):5002–5009. https://doi.org/10.1523/JNEUROSCI.1411-11.2012 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Revest JM, Le Roux A, Roullot-Lacarriere V, Kaouane N, Vallee M, Kasanetz F, Rouge-Pont F, Tronche F et al (2014) BDNF-TrkB signaling through Erk1/2 MAPK phosphorylation mediates the enhancement of fear memory induced by glucocorticoids. Mol Psychiatry 19(9):1001–1009. https://doi.org/10.1038/mp.2013.134 CrossRefPubMedGoogle Scholar
- 31.Chikar JA, Hendricks JL, Richardson-Burns SM, Raphael Y, Pfingst BE, Martin DC (2012) The use of a dual PEDOT and RGD-functionalized alginate hydrogel coating to provide sustained drug delivery and improved cochlear implant function. Biomaterials 33(7):1982–1990. https://doi.org/10.1016/j.biomaterials.2011.11.052 CrossRefPubMedGoogle Scholar