@article{sheets_ewend_mohiti-asli_tuin_loboa_aboody_hingtgen_2020, title={Developing Implantable Scaffolds to Enhance Neural Stem Cell Therapy for Post-Operative Glioblastoma}, volume={28}, ISSN={["1525-0024"]}, DOI={10.1016/j.ymthe.2020.02.008}, abstractNote={Pre-clinical and clinical studies have shown that engineered tumoricidal neural stem cells (tNSCs) are a promising treatment strategy for the aggressive brain cancer glioblastoma (GBM). Yet, stabilizing human tNSCs within the surgical cavity following GBM resection is a significant challenge. As a critical step toward advancing engineered human NSC therapy for GBM, we used a preclinical variant of the clinically utilized NSC line HB1.F3.CD and mouse models of human GBM resection/recurrence to identify a polymeric scaffold capable of maximizing the transplant, persistence, and tumor kill of NSC therapy for post-surgical GBM. Using kinetic bioluminescence imaging, we found that tNSCs delivered into the mouse surgical cavity wall by direct injection persisted only 3 days. We found that delivery of tNSCs into the cavity on nanofibrous electrospun poly-l-lactic acid scaffolds extended tNSC persistence to 8 days. Modifications to fiber surface coating, diameter, and morphology of the scaffold failed to significantly extend tNSC persistence in the cavity. In contrast, tNSCs delivered into the post-operative cavity on gelatin matrices (GEMs) persisted 8-fold longer as compared to direct injection. GEMs remained permissive to tumor-tropic homing, as tNSCs migrated off the scaffolds and into invasive tumor foci both in vitro and in vivo. To mirror envisioned human brain tumor trials, we engineered tNSCs to express the prodrug/enzyme thymidine kinase (tNSCstk) and transplanted the therapeutic cells in the post-operative cavity of mice bearing resected orthotopic patient-derived GBM xenografts. Following administration of the prodrug ganciclovir, residual tumor volumes in mice receiving GEM/tNSCs were reduced by 10-fold at day 35, and median survival was extended from 31 to 46 days. Taken together, these data begin to define design parameters for effective scaffold/tNSC composites and suggest a new approach to maximizing the efficacy of tNSC therapy in human patient trials. Pre-clinical and clinical studies have shown that engineered tumoricidal neural stem cells (tNSCs) are a promising treatment strategy for the aggressive brain cancer glioblastoma (GBM). Yet, stabilizing human tNSCs within the surgical cavity following GBM resection is a significant challenge. As a critical step toward advancing engineered human NSC therapy for GBM, we used a preclinical variant of the clinically utilized NSC line HB1.F3.CD and mouse models of human GBM resection/recurrence to identify a polymeric scaffold capable of maximizing the transplant, persistence, and tumor kill of NSC therapy for post-surgical GBM. Using kinetic bioluminescence imaging, we found that tNSCs delivered into the mouse surgical cavity wall by direct injection persisted only 3 days. We found that delivery of tNSCs into the cavity on nanofibrous electrospun poly-l-lactic acid scaffolds extended tNSC persistence to 8 days. Modifications to fiber surface coating, diameter, and morphology of the scaffold failed to significantly extend tNSC persistence in the cavity. In contrast, tNSCs delivered into the post-operative cavity on gelatin matrices (GEMs) persisted 8-fold longer as compared to direct injection. GEMs remained permissive to tumor-tropic homing, as tNSCs migrated off the scaffolds and into invasive tumor foci both in vitro and in vivo. To mirror envisioned human brain tumor trials, we engineered tNSCs to express the prodrug/enzyme thymidine kinase (tNSCstk) and transplanted the therapeutic cells in the post-operative cavity of mice bearing resected orthotopic patient-derived GBM xenografts. Following administration of the prodrug ganciclovir, residual tumor volumes in mice receiving GEM/tNSCs were reduced by 10-fold at day 35, and median survival was extended from 31 to 46 days. Taken together, these data begin to define design parameters for effective scaffold/tNSC composites and suggest a new approach to maximizing the efficacy of tNSC therapy in human patient trials.}, number={4}, journal={MOLECULAR THERAPY}, author={Sheets, Kevin T. and Ewend, Matthew G. and Mohiti-Asli, Mahsa and Tuin, Stephen A. and Loboa, Elizabeth G. and Aboody, Karen S. and Hingtgen, Shawn D.}, year={2020}, month={Apr}, pages={1056–1067} }
 @article{tuin_pourdeyhimi_loboa_2016, title={Creating tissues from textiles: scalable nonwoven manufacturing techniques for fabrication of tissue engineering scaffolds}, volume={11}, ISSN={["1748-605X"]}, DOI={10.1088/1748-6041/11/1/015017}, abstractNote={Electrospun nonwovens have been used extensively for tissue engineering applications due to their inherent similarities with respect to fibre size and morphology to that of native extracellular matrix (ECM). However, fabrication of large scaffold constructs is time consuming, may require harsh organic solvents, and often results in mechanical properties inferior to the tissue being treated. In order to translate nonwoven based tissue engineering scaffold strategies to clinical use, a high throughput, repeatable, scalable, and economic manufacturing process is needed. We suggest that nonwoven industry standard high throughput manufacturing techniques (meltblowing, spunbond, and carding) can meet this need. In this study, meltblown, spunbond and carded poly(lactic acid) (PLA) nonwovens were evaluated as tissue engineering scaffolds using human adipose derived stem cells (hASC) and compared to electrospun nonwovens. Scaffolds were seeded with hASC and viability, proliferation, and differentiation were evaluated over the course of 3 weeks. We found that nonwovens manufactured via these industry standard, commercially relevant manufacturing techniques were capable of supporting hASC attachment, proliferation, and both adipogenic and osteogenic differentiation of hASC, making them promising candidates for commercialization and translation of nonwoven scaffold based tissue engineering strategies.}, number={1}, journal={BIOMEDICAL MATERIALS}, author={Tuin, S. A. and Pourdeyhimi, B. and Loboa, E. G.}, year={2016}, month={Feb} }
 @article{tuin_pourdeyhimi_loboa_2016, title={Fabrication of novel high surface area mushroom gilled fibers and their effects on human adipose derived stem cells under pulsatile fluid flow for tissue engineering. applications}, volume={36}, ISSN={["1878-7568"]}, DOI={10.1016/j.actbio.2016.03.025}, abstractNote={The fabrication and characterization of novel high surface area hollow gilled fiber tissue engineering scaffolds via industrially relevant, scalable, repeatable, high speed, and economical nonwoven carding technology is described. Scaffolds were validated as tissue engineering scaffolds using human adipose derived stem cells (hASC) exposed to pulsatile fluid flow (PFF). The effects of fiber morphology on the proliferation and viability of hASC, as well as effects of varied magnitudes of shear stress applied via PFF on the expression of the early osteogenic gene marker runt related transcription factor 2 (RUNX2) were evaluated. Gilled fiber scaffolds led to a significant increase in proliferation of hASC after seven days in static culture, and exhibited fewer dead cells compared to pure PLA round fiber controls. Further, hASC-seeded scaffolds exposed to 3 and 6dyn/cm(2) resulted in significantly increased mRNA expression of RUNX2 after one hour of PFF in the absence of soluble osteogenic induction factors. This is the first study to describe a method for the fabrication of high surface area gilled fibers and scaffolds. The scalable manufacturing process and potential fabrication across multiple nonwoven and woven platforms makes them promising candidates for a variety of applications that require high surface area fibrous materials.We report here for the first time the successful fabrication of novel high surface area gilled fiber scaffolds for tissue engineering applications. Gilled fibers led to a significant increase in proliferation of human adipose derived stem cells after one week in culture, and a greater number of viable cells compared to round fiber controls. Further, in the absence of osteogenic induction factors, gilled fibers led to significantly increased mRNA expression of an early marker for osteogenesis after exposure to pulsatile fluid flow. This is the first study to describe gilled fiber fabrication and their potential for tissue engineering applications. The repeatable, industrially scalable, and versatile fabrication process makes them promising candidates for a variety of scaffold-based tissue engineering applications.}, journal={ACTA BIOMATERIALIA}, author={Tuin, Stephen A. and Pourdeyhimi, Behnam and Loboa, Elizabeth G.}, year={2016}, month={May}, pages={220–230} }
 @misc{tuin_pourdeyhimi_loboa_2014, title={Interconnected, microporous hollow fibers for tissue engineering: Commercially relevant, industry standard scale-up manufacturing}, volume={102}, ISSN={["1552-4965"]}, DOI={10.1002/jbm.a.35002}, abstractNote={Abstract Significant progress has been achieved in the field of tissue engineering to create functional tissue using biomimetic three‐dimensional scaffolds that support cell growth, proliferation, and extracellular matrix production. However, many of these constructs are severely limited by poor nutrient diffusion throughout the tissue‐engineered construct, resulting in cell death and tissue necrosis at the core. Nutrient transport can be improved by creation and use of scaffolds with hollow and microporous fibers, significantly improving permeability and nutrient diffusion. The purpose of this review is to highlight current technological advances in the fabrication of hollow fibers with interconnected pores throughout the fiber walls, with specific emphasis on developing hollow porous nonwoven fabrics for use as tissue engineering constructs via industry standard processing technologies: Spunbond processing and polymer melt extrusion. We outline current methodologies to create hollow and microporous scaffolds with the aim of translating that knowledge to the production of such fibers into nonwoven tissue engineering scaffolds via spunbond technology, a commercially relevant and viable melt extrusion manufacturing approach that allows for facile scale‐up. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 3311–3323, 2014.}, number={9}, journal={JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A}, author={Tuin, Stephen A. and Pourdeyhimi, Behnam and Loboa, Elizabeth G.}, year={2014}, month={Sep}, pages={3311–3323} }