Browsing by Author "Lin, Chien-Chi"
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Item Application of Salubrinal for Bone Fracture Healing(Office of the Vice Chancellor for Research, 2014-04-11) Yokota, Hiroki; Lin, Chien-ChiThe long-term objective of this project is to commercialize a novel synthetic chemical agent, salubrinal, for treatment of bone growth and fracture healing. Bone morphogenetic proteins (BMPs) are clinically administered as growth stimulators for bone fracture healing. However, BMPs are not only expensive, but also stimulate ectopic bone formation and potentially induce cancer. A synthetic chemical agent that permits facile storage and administration could reduce costs, and provide longer shelf-life, and better bone healing outcomes. Currently, no synthetic chemical agents as a stimulator of fracture healing are clinically available. The research team recently identified “salubrinal,” a synthetic chemical agent, as a potential therapeutic stimulator of bone growth and fracture healing. An invention disclosure and a U.S. patent were filed. In this FORCES project, we are examining efficacy of salubrinal using a mouse model of closed tibia fracture. The results strongly indicate that salubrinal can accelerate bone fracture healing.Item Assessing monocyte phenotype in poly(γ-glutamic acid) hydrogels formed by orthogonal thiol–norbornene chemistry(IOP, 2021-07) Kim, Min Hee; Lin, Chien-Chi; Biomedical Engineering, School of Engineering and TechnologyHydrogels with tunable properties are highly desirable in tissue engineering applications as they can serve as artificial extracellular matrix to control cellular fate processes, including adhesion, migration, differentiation, and other phenotypic changes via matrix induced mechanotransduction. Poly(γ-glutamic acid) (PGA) is an natural anionic polypeptide that has excellent biocompatibility, biodegradability, and water solubility. Moreover, the abundant carboxylic acids on PGA can be readily modified to introduce additional functionality or facilitate chemical crosslinking. PGA and its derivatives have been widely used in tissue engineering applications. However, no prior work has explored orthogonal crosslinking of PGA hydrogels by thiol-norbornene (NB) chemistry. In this study, we report the synthesis and orthogonal crosslinking of PGA-norbornene (PGANB) hydrogels. PGANB was synthesized by standard carbodiimide chemistry and crosslinked into hydrogels via either photopolymerization or enzymatic reaction. Moduli of PGA hydrogels were readily tuned by controlling thiol-NB crosslinking conditions or stoichiometric ratio of functional groups. Orthogonally crosslinked PGA hydrogels were used to evaluate the influence of mechanical cues of hydrogel substrate on the phenotype of naïve human monocytes and M0 macrophages in 3D culture.Item Biomimetic and enzyme-responsive dynamic hydrogels for studying cell-matrix interactions in pancreatic ductal adenocarcinoma(Elsevier, 2018-04) Liu, Hung-Yi; Korc, Murray; Lin, Chien-Chi; Biomedical and Applied Sciences, School of DentistryThe tumor microenvironment (TME) governs all aspects of cancer progression and in vitro 3D cell culture platforms are increasingly developed to emulate the interactions between components of the stromal tissues and cancer cells. However, conventional cell culture platforms are inadequate in recapitulating the TME, which has complex compositions and dynamically changing matrix mechanics. In this study, we developed a dynamic gelatin-hyaluronic acid hybrid hydrogel system through integrating modular thiol-norbornene photopolymerization and enzyme-triggered on-demand matrix stiffening. In particular, gelatin was dually modified with norbornene and 4-hydroxyphenylacetic acid to render this bioactive protein photo-crosslinkable (through thiol-norbornene gelation) and responsive to tyrosinase-triggered on-demand stiffening (through HPA dimerization). In addition to the modified gelatin that provides basic cell adhesive motifs and protease cleavable sequences, hyaluronic acid (HA), an essential tumor matrix, was modularly and covalently incorporated into the cell-laden gel network. We systematically characterized macromer modification, gel crosslinking, as well as enzyme-triggered stiffening and degradation. We also evaluated the influence of matrix composition and dynamic stiffening on pancreatic ductal adenocarcinoma (PDAC) cell fate in 3D. We found that either HA-containing matrix or a dynamically stiffened microenvironment inhibited PDAC cell growth. Interestingly, these two factors synergistically induced cell phenotypic changes that resembled cell migration and/or invasion in 3D. Additional mRNA expression array analyses revealed changes unique to the presence of HA, to a stiffened microenvironment, or to the combination of both. Finally, we presented immunostaining and mRNA expression data to demonstrate that these irregular PDAC cell phenotypes were a result of matrix-induced epithelial-mesenchymal transition (EMT).Item Biomimetic stiffening of cell-laden hydrogels via sequential thiol-ene and hydrazone click reactions(Elsevier, 2021) Chang, Chun-Yi; Johnson, Hunter C.; Babb, Olivia; Fishel, Melissa L.; Lin, Chien-Chi; Biomedical Engineering, School of Engineering and TechnologyHydrogels with dynamically tunable crosslinking are invaluable for directing stem cell fate and mimicking a stiffening matrix during fibrosis or tumor development. The increases in matrix stiffness during tissue development are often accompanied by the accumulation of extracellular matrices (e.g., collagen, hyaluronic acid (HA)), a phenomenon that has received little attention in the development of dynamic hydrogels. In this contribution, we present a gelatin-based cell-laden hydrogel system capable of being dynamically stiffened while accumulating HA, a key glycosaminoglycans (GAG) increasingly deposited by stromal cells during tumor progression. Central to this strategy is the synthesis of a dually-modified gelatin macromer – gelatin-norbornene-carbohydrazide (GelNB-CH), which is susceptible to both thiol-norbornene photopolymerization and hydrazone click chemistry. We demonstrate that the crosslinking density of cell-laden thiol-norbornene hydrogels can be dynamically tuned via simple incubation with aldehyde-bearing macromers (e.g., oxidized dextran (oDex) or oHA). The GelNB-CH hydrogel system is highly cytocompatible, as demonstrated by in situ encapsulation of pancreatic cancer cells (PCC) and cancer-associated fibroblasts (CAF). The unique dynamic stiffening scheme provides a platform to study tandem accumulation of HA and elevation in matrix stiffness in the pancreatic tumor microenvironment.Item Chemically defined and dynamic click hydrogels support hair cell differentiation in human inner ear organoids(Elsevier, 2025) Arkenberg, Matthew R.; Jafarkhani, Mahboubeh; Lin, Chien-Chi; Hashino, Eri; Otolaryngology -- Head and Neck Surgery, School of MedicineThe mechanical properties in the inner ear microenvironment play a key role in its patterning during embryonic development. To recapitulate inner ear development in vitro, three-dimensional tissue engineering strategies including the application of representative tissue models and scaffolds are of increasing interest. Human inner ear organoids are a promising model to recapitulate developmental processes; however, the current protocol requires Matrigel that contains ill-defined extracellular matrix components. Here, we implement an alternative, chemically defined, dynamic hydrogel to support the differentiation of human inner ear organoids. Specifically, thiol-norbornene and hydrazide-aldehyde click chemistries are used to fabricate inner ear organoid-laden, gelatin-based scaffolds. We identify optimal formulations to support hair cell development with comparable efficiency and fidelity to Matrigel-cultured organoids. These results suggest that the chemically defined hydrogel may serve as a viable alternative to Matrigel for inner ear tissue engineering.Item Click Hydrogels to Assess Stiffness-Induced Activation of Pancreatic Cancer-Associated Fibroblasts and Its Impact on Cancer Cell Spreading(Wiley, 2025) Chang, Chun-Yi; Lin, Chien-Chi; Medicine, School of MedicinePancreatic ductal adenocarcinoma (PDAC) is marked by significant desmoplastic reactions, or the accumulation of excessive extracellular matrices. PDAC stroma has abnormally high stiffness, which alters cancer cell behaviors and creates a barrier for effective drug delivery. Unfortunately, clinical trials using a combination of chemotherapy and matrix-degrading enzyme have led to disappointing results, as the degradation of stromal tissue likely accelerated the dissemination of cancer cells. High matrix stiffness has been shown to activate cancer-associated fibroblasts (CAFs), increasing their interaction with pancreatic cancer cells (PCCs) through promoting proliferation, migration, and resistance to chemotherapy. With the advance of biomaterials science and engineering, it is now possible to design chemically defined matrices to understand the role of stiffness in activating pancreatic CAFs and how this may alter cancer cell migration. Here, we developed a norbornene-based click hydrogel system with independently tunable stiffness and cell adhesive ligand to evaluate stiffness-induced activation of CAFs and migration of PCCs. Our results show that matrix stiffness did not alter matrix deposition from CAFs but affected nuclear localization of Yes-associated protein (YAP). Our results also verify the role of CAFs on promoting PCC migration and an elevated substrate stiffness further increased PCC motility.Item Clickable modular polysaccharide nanoparticles for selective cell-targeting(Elsevier, 2020-04-15) Peuler, Kevin; Dimmitt, Nathan; Lin, Chien-Chi; Biomedical Engineering, School of Engineering and TechnologyA therapeutic nanocarrier capable of cell targeting has the potential to reduce off-target effects of otherwise effective drugs. Nanoparticle surface modification can be tailored for specific cells, however multistep surface modification can prove slow and difficult for a variety of cell types. Here, we designed drug carrying polysaccharide based nanoparticles with a layered structure for clickable surface modification. The center of nanoparticle was composed of cationic macromer (e.g., poly-L-lysine) and anionic polysaccharide (e.g., heparin). Furthermore, a ‘clickable’ polysaccharide was installed on the surface of the nanoparticles to permit a wide range of bioconjugation via norbornene-tetrazine click chemistry. The utilities of these layered nanoparticles were demonstrated via enhanced protein sequestration, selective cell targeting (via PEGylation or altering polysaccharide coating), as well as loading and release of chemotherapeutic. The drug-loaded nanocarriers proved cytotoxic to J774A.1 monocytes and MOLM-14 leukemia cells.Item Comparative study of visible light polymerized gelatin hydrogels for 3D culture of hepatic progenitor cells(Wiley, 2017-03) Greene, Tanja; Lin, Tsai-Yu; Andrisani, Oaurania M.; Lin, Chien-Chi; Department of Biomedical Engineering, School of Engineering and TechnologyPhotopolymerization techniques have been widely used to create hydrogels for biomedical applications. Visible light-based photopolymerizations are commonly initiated by type II (i.e., noncleavage-type) photoinitiator in conjunction with a coinitiator. On the other hand, type I photoinitiators (i.e., cleavage type) are rarely compatible with visible light-based initiation due to their limited molar absorbability in the visible light wavelengths. Here, we report visible light initiated orthogonal photoclick crosslinking to fabricate gelatin-norbornene and poly(ethylene glycol)-tetra-thiol hydrogels using either cleavage-type (i.e., lithium acylphosphinate, LAP) or noncleavage-type photoinitiator (i.e., eosin-Y, EY) without the use of a coinitiator. Regardless of the initiator type, the step-growth gelatin-PEG hybrid hydrogels crosslinked and degraded similarly. While both systems exhibited similar cytocompatibility for hepatic progenitor HepaRG cells, gelation initiated by noncleavage-type initiator EY afforded slightly higher degree of hepatic gene expression.Item Correction: Sun et al. Generation of the Chondroprotective Proteomes by Activating PI3K and TNFα Signaling. Cancers 2022, 14, 3039(MDPI, 2022-09-09) Sun, Xun; Li, Ke-Xin; Figueiredo, Marxa L.; Lin, Chien-Chi; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyErratum for: Generation of the Chondroprotective Proteomes by Activating PI3K and TNFα Signaling. Sun X, Li KX, Figueiredo ML, Lin CC, Li BY, Yokota H. Cancers (Basel). 2022 Jun 21;14(13):3039. doi: 10.3390/cancers14133039. PMID: 35804814Item Degradable and Multifunctional PEG-Based Hydrogels Formed by iEDDA Click Chemistry with Stable Click-Induced Supramolecular Interactions(American Chemical Society, 2024-02-16) Dimmitt, Nathan H.; Lin, Chien-Chi; Biomedical Engineering, Purdue School of Engineering and TechnologyThe inverse electron demand Diels-Alder (iEDDA) reactions are highly efficient click chemistry increasingly utilized in bioconjugation, live cell labeling, and the synthesis and modification of biomaterials. iEDDA click reactions have also been used to cross-link tetrazine (Tz) and norbornene (NB) modified macromers [e.g., multiarm poly(ethylene glycol) or PEG]. In these hydrogels, Tz-NB adducts exhibit stable supramolecular interactions with a high hydrolytic stability. Toward engineering a new class of PEG-based click hydrogels with highly adaptable properties, we previously reported a new group of NB-derivatized PEG macromers via reacting hydroxyl-terminated PEG with carbic anhydride (CA). In this work, we show that c cross-linked by PEGNBCA or its derivatives exhibited fast and tunable hydrolytic degradation. Here, we show that PEGNBCA (either mono- or octafunctional) and its dopamine or tyramine conjugated derivatives (i.e., PEGNB-D and PEGNB-T) readily cross-link with 4-arm PEG-Tz to form a novel class of multifunctional iEDDA click hydrogels. Through modularly adjusting the macromers with unstable and stable iEDDA click-induced supramolecular interactions (iEDDA-CSI), we achieved highly tunable degradation, with full degradation in less than 2 weeks to over two months. We also show that secondary enzymatic reactions could dynamically stiffen these hydrogels. These hydrogels could also be spatiotemporally photopatterned through visible light-initiated photochemistry. Finally, the iEDDA-CSI hydrogels post ester hydrolysis displayed shear-thinning and self-healing properties, enabling injectable delivery.