Browsing by Author "Lin, Fang-Yi"

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    Dissolvable microgel-templated macroporous hydrogels for controlled cell assembly
    (Elsevier, 2022) Jiang, Zhongliang; Lin, Fang-Yi; Jiang, Kun; Nguyen, Han; Chang, Chun-Yi; Lin, Chien-Chi; Biomedical Engineering, School of Engineering and Technology
    Mesenchymal stem cells (MSCs)-based therapies have been widely used to promote tissue regeneration and to modulate immune/inflammatory response. The therapeutic potential of MSCs can be further improved by forming multi-cellular spheroids. Meanwhile, hydrogels with macroporous structures are advantageous for improving mass transport properties for the cell-laden matrices. Herein, we report the fabrication of MSC-laden macroporous hydrogel scaffolds through incorporating rapidly dissolvable spherical cell-laden microgels. Dissolvable microgels were fabricated by tandem droplet-microfluidics and thiol-norbornene photopolymerization using a novel fast-degrading macromer poly(ethylene glycol)-norbornene-dopamine (PEGNB-Dopa). The cell-laden microgels were subsequently encapsulated within another bulk hydrogel matrix, whose porous structure was generated efficiently by the rapid degradation of the PEGNB-Dopa microgels. The cytocompatibility of this in situ pore-forming approach was demonstrated with multiple cell types. Furthermore, adjusting the stiffness and cell adhesiveness of the bulk hydrogels afforded the formation of solid cell spheroids or hollow spheres. The assembly of solid or hollow MSC spheroids led to differential activation of AKT pathway. Finally, MSCs solid spheroids formed in situ within the macroporous hydrogels exhibited robust secretion of HGF, VEGF-A, IL-6, IL-8, and TIMP-2. In summary, this platform provides an innovative method for forming cell-laden macroporous hydrogels for a variety of future biomedical applications.
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    Facile Synthesis of Rapidly Degrading PEG-Based Thiol-Norbornene Hydrogels
    (American Chemical Society (ACS), 2021-02-09) Lin, Fang-Yi; Lin, Chien-Chi; Biomedical Engineering, School of Engineering and Technology
    An alternate synthesis route was developed to prepare norbornene-functionalized poly(ethylene glycol) (PEG) from reacting multiarm PEG with carbic anhydride. The macromer, PEGNBCA, permits photo-cross-linking of thiol-norbornene hydrogels with kinetics comparable to conventional PEGNB macromer. In addition, PEGNBCA provides an additional carboxylate group for further conjugation with amine-bearing molecules. Interestingly, PEGNBCA thiol-norbornene hydrogels are highly susceptible to hydrolytic degradation through enhanced ester hydrolysis. The ester linkage is further weakened after the secondary conjugation, resulting in extremely rapid degradation of PEGNB hydrogels. More importantly, the degradation can be readily adjusted via tuning macromer compositions, with complete degradation time ranging from hours to weeks. The PEGNBCA hydrogels are also highly cytocompatible toward various cell types, providing opportunities for future applications in tissue engineering and advanced biofabrication.
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    Injectable Acylhydrazone-Linked RAFT Polymer Hydrogels for Sustained Protein Release and Cell Encapsulation
    (Wiley, 2022) Lin, Fang-Yi; Dimmitt, Nathan H.; Moraes de Lima Perini, Mariana; Li, Jiliang; Lin, Chien-Chi; Biomedical Engineering, School of Engineering and Technology
    A new class of temperature responsive polymer, termed PADO, is synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization. Synthesized from copolymerization of diacetone acrylamide (DAAM), di(ethylene glycol) ethyl ether acrylate (DEGA), and oligo(ethylene glycol) methyl ether acrylate (OEGA), PADO polymer phase separates at temperature above its LCST (36°C to 42°C) due to enhanced hydrophobic interactions between the short ethylene glycol side chains. Solution of PADO polymers exhibited injectable shear-thinning properties and reached sol-gel transition rapidly (< 5 min) at 37°C. When the ketone moieties on DAAM were linked by adipic acid dihydrazdie (ADH), PADO polymers formed crosslinked and injectable acylhydrazone hydrogels, which were hydrolytically degradable at a mild acidic environment owing to the pH sensitive acylhydrazone bonds. The pH-responsive degradation kinetics could be controlled by tuning polymer contents and ketone/hydrazide ratio. Importantly, the injectable PADO hydrogels were highly cytocompatible and could be easily formulated for pH-responsive sustained protein delivery.
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    Viscoelastic hydrogels for interrogating pancreatic cancer-stromal cell interactions
    (Elsevier, 2023-02-04) Lin, Fang-Yi; Chang, Chun-Yi; Nguyen, Han; Li, Hudie; Fishel, Melissa L.; Lin, Chien-Chi; Pediatrics, School of Medicine
    The tumor microenvironment (TME) is known to direct cancer cell growth, migration, invasion into the matrix and distant tissues, and to confer drug resistance in cancer cells. While multiple aspects of TME have been studied using in vitro, ex vivo, and in vivo tumor models and engineering tools, the influence of matrix viscoelasticity on pancreatic cancer cells and its associated TME remained largely unexplored. In this contribution, we synthesized a new biomimetic hydrogel with tunable matrix stiffness and stress-relaxation for evaluating the effect of matrix viscoelasticity on pancreatic cancer cell (PCC) behaviors in vitro. Using three simple monomers and Reverse-Addition Fragmentation Chain-Transfer (RAFT) polymerization, we synthesized a new class of phenylboronic acid containing polymers (e.g., poly (OEGA-s-HEAA-s-APBA) or PEHA). Norbornene group was conjugated to HEAA on PEHA via carbic anhydride, affording a new NB and BA dually modified polymer - PEHNBA amenable for orthogonal thiol-norbornene photopolymerization and boronate ester diol complexation. The former provided tunable matrix elasticity, while the latter gave rise to matrix stress-relaxation (or viscoelasticity). The new PEHNBA polymers were shown to be highly cytocompatible for in situ encapsulation of PCCs and cancer-associated fibroblasts (CAFs). Furthermore, we demonstrated that hydrogels with high stress-relaxation promoted spreading of CAFs, which in turns promoted PCC proliferation and spreading in the viscoelastic matrix. Compared with elastic matrix, viscoelastic gels upregulated the secretion of soluble proteins known to promote epithelial-mesenchymal transition (EMT). This study demonstrated the crucial influence of matrix viscoelasticity on pancreatic cancer cell fate and provided an engineered viscoelastic matrix for future studies and applications related to TME.