Controlled drug delivery from 3D printed two‐photon polymerized poly(ethylene glycol) dimethacrylate devices

ABSTRACT Controlled drug delivery systems have been utilized to enhance the therapeutic effects of many drugs by delivering drugs in a time‐dependent and sustained manner. Here, with the aid of 3D printing technology, drug delivery devices were fabricated and tested using a model drug (fluorophore: rhodamine B). Poly(ethylene glycol) dimethacrylate (PEGDMA) devices were fabricated using a two‐photon polymerization (TPP) system and rhodamine B was homogenously entrapped inside the polymer matrix during photopolymerization. These devices were printed with varying porosity and morphology using varying printing parameters such as slicing and hatching distance. The effects of these variables on drug release kinetics were determined by evaluating device fluorescence over the course of one week. These PEGDMA‐based structures were then investigated for toxicity and biocompatibility in vitro, where MTS assays were performed using a range of cell types including induced pluripotent stem cells (iPSCs). Overall, tuning the hatching distance, slicing distance, and pore size of the fabricated devices modulated the rhodamine B release profile, in each case presumably due to resulting changes in the motility of the small molecule and its access to structure edges. In general, increased spacing provided higher drug release while smaller spacing resulted in some occlusion, preventing media infiltration and thus resulting in reduced fluorophore release. The devices had no cytotoxic effects on human embryonic kidney cells (HEK293), bone marrow stromal stem cells (BMSCs) or iPSCs. Thus, we have demonstrated the utility of two‐photon polymerization to create biocompatible, complex miniature devices with fine details and tunable release of a model drug.

[1]  K. Anseth,et al.  Poly(ethylene glycol) hydrogels formed by thiol-ene photopolymerization for enzyme-responsive protein delivery. , 2009, Biomaterials.

[2]  Xiaoxiang Zheng,et al.  Thiol-ene Michael-type formation of gelatin/poly(ethylene glycol) biomatrices for three-dimensional mesenchymal stromal/stem cell administration to cutaneous wounds. , 2013, Acta biomaterialia.

[3]  Ibrahim T. Ozbolat,et al.  Controlled and Sequential Delivery of Fluorophores from 3D Printed Alginate-PLGA Tubes , 2016, Annals of Biomedical Engineering.

[4]  A. Salem,et al.  Biotinylated biodegradable nanotemplated hydrogel networks for cell interactive applications. , 2008, Biomacromolecules.

[5]  Niklas Sandler,et al.  3D printed UV light cured polydimethylsiloxane devices for drug delivery , 2017, International journal of pharmaceutics.

[6]  Clive J Roberts,et al.  3D extrusion printing of high drug loading immediate release paracetamol tablets. , 2018, International journal of pharmaceutics.

[7]  B. Tucker,et al.  Neuronal Differentiation of Induced Pluripotent Stem Cells on Surfactant Templated Chitosan Hydrogels. , 2016, Biomacromolecules.

[8]  Brian Derby,et al.  Mechanical properties of porous ceramic scaffolds: Influence of internal dimensions , 2015 .

[9]  T. Kissel,et al.  The effect of porosity on drug release kinetics from vancomycin microsphere/calcium phosphate cement composites. , 2011, Journal of biomedical materials research. Part B, Applied biomaterials.

[10]  Preparation and characterization of polymers based on PDMS and PEG-DMA as potential scaffold for cell growth. , 2017, Materials science & engineering. C, Materials for biological applications.

[11]  Hannah L. Cebull,et al.  Tuning the Mechanical Properties of Poly(Ethylene Glycol) Microgel-Based Scaffolds to Increase 3D Schwann Cell Proliferation. , 2016, Macromolecular bioscience.

[12]  J. Fischer,et al.  Elastic Fully Three‐dimensional Microstructure Scaffolds for Cell Force Measurements , 2010, Advanced materials.

[13]  Michael A Repka,et al.  Coupling 3D printing with hot-melt extrusion to produce controlled-release tablets. , 2017, International journal of pharmaceutics.

[14]  P. Turecek,et al.  PEGylation of Biopharmaceuticals: A Review of Chemistry and Nonclinical Safety Information of Approved Drugs. , 2016, Journal of pharmaceutical sciences.

[15]  Kristi S. Anseth,et al.  PEG Hydrogels for the Controlled Release of Biomolecules in Regenerative Medicine , 2009, Pharmaceutical Research.

[16]  Abdul W. Basit,et al.  3D printing of drug‐loaded gyroid lattices using selective laser sintering , 2018, International journal of pharmaceutics.

[17]  J. Siepmann,et al.  How porosity and size affect the drug release mechanisms from PLGA-based microparticles. , 2006, International journal of pharmaceutics.

[18]  A. Castro,et al.  Partial inhibition of Cdk1 in G2 phase overrides the SAC and decouples mitotic events , 2014, Cell cycle.

[19]  Budd A Tucker,et al.  Two-photon polymerization for production of human iPSC-derived retinal cell grafts. , 2017, Acta biomaterialia.

[20]  Ricky D. Wildman,et al.  3D printing of tablets using inkjet with UV photoinitiation. , 2017, International journal of pharmaceutics.

[21]  M. Vallet‐Regí,et al.  Influence of pore size of MCM-41 matrices on drug delivery rate , 2004 .

[22]  P. Wagner Type II photoelimination and photocyclization of ketones , 1971 .

[23]  Paul N Manson,et al.  Variable cytocompatibility of six cell lines with photoinitiators used for polymerizing hydrogels and cell encapsulation. , 2005, Biomaterials.

[24]  M. Yavuz,et al.  Biocompatible thermoresponsive PEGMA nanoparticles crosslinked with cleavable disulfide-based crosslinker for dual drug release. , 2015, Journal of biomedical materials research. Part A.

[25]  Charles E. Hoyle,et al.  The Effect of Monomer Structure on Oxygen Inhibition of (Meth)acrylates Photopolymerization , 2004 .

[26]  T. Braun,et al.  Patient-specific iPSC-derived photoreceptor precursor cells as a means to investigate retinitis pigmentosa , 2013, eLife.

[27]  Charlotte K. Williams,et al.  Biocompatible Initiators for Lactide Polymerization , 2008 .

[28]  B. Schweighardt,et al.  PEGylated Biopharmaceuticals , 2015, Toxicologic pathology.

[29]  E. Stone,et al.  Use of a Synthetic Xeno‐Free Culture Substrate for Induced Pluripotent Stem Cell Induction and Retinal Differentiation , 2013, Stem cells translational medicine.

[30]  Stephanie J Bryant,et al.  Controlling the spatial distribution of ECM components in degradable PEG hydrogels for tissue engineering cartilage. , 2003, Journal of biomedical materials research. Part A.

[31]  Pamela Robles Martinez,et al.  Fabrication of drug-loaded hydrogels with stereolithographic 3D printing. , 2017, International journal of pharmaceutics.

[32]  Anh-Vu Do,et al.  3D Printing of Scaffolds for Tissue Regeneration Applications , 2015, Advanced healthcare materials.

[33]  Nicholas A. Peppas,et al.  A simple equation for description of solute release I. Fickian and non-fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs , 1987 .

[34]  O. Gavet,et al.  Progressive activation of CyclinB1-Cdk1 coordinates entry to mitosis. , 2010, Developmental cell.

[35]  Benjamin M. Wu,et al.  Photocurable poly(ethylene glycol) as a bioink for the inkjet 3D pharming of hydrophobic drugs , 2018, International journal of pharmaceutics.

[36]  F. Melchels,et al.  A review on stereolithography and its applications in biomedical engineering. , 2010, Biomaterials.

[37]  A. Deiwick,et al.  3D in vitro platform produced by two-photon polymerization for the analysis of neural network formation and function , 2016 .

[38]  Jonathan Goole,et al.  3D printing in pharmaceutics: A new tool for designing customized drug delivery systems. , 2016, International journal of pharmaceutics.