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A 3D Printed Self-Sustainable Cell-Encapsulation Drug Delivery Device for Periocular Transplant-Based Treatment of Retinal Degenerative Diseases

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A 3D Printed Self-Sustainable Cell-Encapsulation Drug Delivery Device for Periocular Transplant-Based Treatment of Retinal Degenerative Diseases micromachines Article A 3D Printed Self-Sustainable Cell-Encapsulation Drug Delivery Device for Periocular Transplant-Based Treatment of Retinal Degenerative Diseases Hideto Kojima 1, Bibek Raut 1 , Li-Jiun Chen 1, Nobuhiro Nagai 2, Toshiaki Abe 2 and Hirokazu Kaji 1,3,* 1 Department of Finemechanics, Graduate School of Engineering, Tohoku University, 6-6-01 Aramaki, Aoba-ku, Sendai 980-8579, Japan; [email protected] (H.K.); [email protected] (B.R.); [email protected] (L.-J.C.) 2 Division of Clinical Cell Therapy, United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba-ku, Sendai 980-8575, Japan; [email protected] (N.N.); [email protected] (T.A.) 3 Department of Biomedical Engineering, Graduate School of Biomedical Engineering, Tohoku University, 6-6-01 Aramaki, Aoba-ku, Sendai 980-8579, Japan * Correspondence: [email protected]; Tel.: +81-22-795-4249 Received: 27 March 2020; Accepted: 18 April 2020; Published: 21 April 2020 Abstract: Self-sustainable release of brain-derived neurotrophic factor (BDNF) to the retina using minimally invasive cell-encapsulation devices is a promising approach to treat retinal degenerative diseases (RDD). Herein, we describe such a self-sustainable drug delivery device with human retinal pigment epithelial (ARPE-19) cells (cultured on collagen coated polystyrene (PS) sheets) enclosed inside a 3D printed semi-porous capsule. The capsule was 3D printed with two photo curable polymers: triethylene glycol dimethacrylate (TEGDM) and polyethylene glycol dimethylacrylate (PEGDM). The capsule’s semi-porous membrane (PEGDM) could serve three functions: protecting the cells from body’s immune system by limiting diffusion (5.97 0.11%) of large molecules like ± immunoglobin G (IgG)(150 kDa); helping the cells to survive inside the capsule by allowing diffusion (43.20 2.16%) of small molecules (40 kDa) like oxygen and necessary nutrients; and helping in the ± treatment of RDD by allowing diffusion of cell-secreted BDNF to the outside environment. In vitro results showed a continuous BDNF secretion from the device for at least 16 days, demonstrating future potential of the cell-encapsulation device for the treatment of RDD in a minimally invasive and self-sustainable way through a periocular transplant. Keywords: retinal degenerative disease; cell-encapsulation device; periocular implant; growth factors; brain-derived neurotrophic factor (BDNF); cell sheet engineering; 3D printing; minimally invasive device 1. Introduction Retinal degenerative diseases (RDD), such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), causes progressive damage to the photoreceptor cells of the retina leading to gradual visual decline [1]. Although no permanent cure or prosthetic exists to date, cell culture and animal experiments done with tropic factors, such as brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), have shown that they can revive the damaged photoreceptor cells [2–4]. However, their delivery to the retina is very challenging [5,6]. For instance, intravenous injection cannot deliver the required amount of BDNF to the retina because BDNF has a very short half-life in blood (0.92 min) [7], and it is impermeable to the blood-retinal barrier [8]. Likewise, topical Micromachines 2020, 11, 436; doi:10.3390/mi11040436 www.mdpi.com/journal/micromachines Micromachines 2020, 11, 436 2 of 12 Micromachines 2020, 11, x 2 of 12 installation is equally ineffective due to low permeability through multi-cellular cornea and sclera [9,10]. Moreover,[10]. Moreover, intravitreal intravitreal injection injection is highly is invasivehighly invasive during longduring term long treatment term treatment that requires that periodicrequires pokingperiodic of poking the eyeball of the which eyeball can which risk infectioncan risk infection [9]. Although [9]. Although minimally minimally invasive invasive delivery delivery of drugs of throughdrugs through the blood-retina the blood barrier-retina usingbarrier focused using focused ultrasound ultrasoun [11] hasd been[11] has proposed, been proposed, a minimally a minimally invasive wayinvasive of sustained way of sustained and localized and druglocalized delivery drug is delivery desirable. is desirable. WeWe havehave previouslypreviously developeddeveloped transscleraltransscleral (periocular)(periocular) implantsimplants asas aa minimallyminimally invasiveinvasive wayway toto deliverdeliver drugsdrugs toto thethe retinaretina [12[12–15–15].]. TheseThese implantsimplants areare generallygenerally placedplaced outsideoutside thethe eyeballeyeball (subconjunctival,(subconjunctival, sub-tendon,sub-tendon, peribulbar,peribulbar, posteriorposterior juxta-scleral,juxta-scleral, andand retrobulbarretrobulbar spaces)spaces) withoutwithout performingperforming aa complicatedcomplicated surgery.surgery. Additionally,Additionally, suchsuch implantsimplants useuse aa shortershorter transscleraltransscleral routeroute thatthat allowsallows relativelyrelatively highhigh permeabilitypermeability ofof largerlarger drugsdrugs (up(up toto 7070kDa) kDa) [16[16,17,17].]. InIn addition,addition, wewe designeddesigned thesethese devicesdevices withwith aa singlesingle sidedsided permeablepermeable membranemembrane facingfacing thethe sclera,sclera, whichwhich increasedincreased thethe drugdrug deliverydelivery effiefficiencyciency by by reducing reducing drug drug elimination elimination by conjunctival by conjunctival clearance. clearance Although. theseAlthough minimally these invasiveminimally devices invasive allowed devices long-term allowed (18 long weeks-term [13 (18]) release weeks of [13] pre-loaded) release of drugs, pre-loaded they had drugs, to be replacedthey had onceto be thereplaced drug ranonce out. the Itdrug was ran also out. diffi Itcult was to also pre-determine difficult to pre the-determine exact time the for exact device time replacement. for device Thus,replacement a self-sustainable. Thus, a self way-sustainable of drug delivery way of drug is desirable. delivery is desirable. AA promisingpromising wayway toto achieveachieve self-sustainableself-sustainable drugdrug deliverydelivery isis toto replacereplace thethe drugsdrugs inin thethe devicedevice withwith geneticallygenetically modifiable modifiable cells cells that that cancan continuouslycontinuously secrete secrete trophic trophic factor factor proteins proteins [ 18[18]].. In In fact,fact, thisthis techniquetechnique hashas nownow gainedgained widewide popularitypopularity amongstamongst manymany researchresearch groups groups [ [55,19,19].]. Herein,Herein, wewe utilizedutilized aa retinalretinal pigmentpigment epithelium (RPE) cell cell line line (ARPE (ARPE-19;-19; [20] [20]).). The The RPE RPE cells cells play play an an important important role role in inthe the health health of of the the retina retina including including,, but but not not limited limited to, to, the the transport transport of of ions, nutrients, and water;water; absorptionabsorption ofof light; and protection against against photooxidation photooxidation [21 [21,22,22].]. RPE RPE cells cells can can also also be be modified, modified, in inprinciple, principle, to toproduce produce almost almost any any trophic trophic factors factors [18] [18],, which which makes makes it highly valuablevaluable forfor treatingtreating regenerativeregenerative diseases. diseases. Here,Here, wewe culturedcultured thethe ARPE-19ARPE-19 cellscells onon collagencollagen coatedcoated polystyrenepolystyrene (PS)(PS) sheetssheets andand transferredtransferred these cell cell-loaded-loaded sheets sheets to to a a3D 3D printed printed capsule capsule (Figure (Figure 1).1 ).Using Using the thedeveloped developed cell- cell-encapsulationencapsulation device, device, we wetested tested the the efficacy efficacy of ofthe the device device in in defending defending the the ARPE ARPE-19-19 cells fromfrom thethe body’sbody’s immuneimmune responseresponse (limiting(limiting didiffusionffusion of ofmolecules molecules biggerbigger thanthan 150150 kDa),kDa), whilewhile simultaneouslysimultaneously allowingallowing didiffusionffusion ofof oxygenoxygen andand nutrientsnutrients insideinside thethe device,device, andand releaserelease ofof BDNFBDNF toto thethe outsideoutside environmentenvironment (molecules (molecules smaller smaller than than 40 kDa). 40 kDa) Thus,. byThus, utilizing by utilizing advancement advancement in cell sheet in engineering cell sheet andengineering 3D printing, and we3D developedprinting, we a self-sustainable developed a self cell-encapsulation-sustainable cell- deviceencapsulation that has device the potential that has to the be usedpotential as a minimallyto be used invasiveas a minimally periocular invasive transport periocular for the transport treatment for of the retinal treatment diseases. of retinal diseases. Figure 1. Overview of the cell-encapsulation device. (A) A 3D printed capsule with ARPE-19 cells enclosedFigure 1. inside Overview the device. of the ARPE-19cell-encapsulation cells were device. cultured (A in) A polystyrene 3D printed (PS) capsule sheets. with (B) ARPE Cross-section-19 cells ofenclosed device insi in A.de Thethe device. 3D printed ARPE capsule-19 cells with were semi-porous cultured in polystyrene membrane (PEGDM)(PS) sheets allowed. (B) Cross selective-section permeabilityof device in ofA. brain-derived The 3D printed neurotrophic capsule with factor semi (BDNF;-porous 27 kDa),
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