Browsing by Author "Li, I-Che"

Now showing 1 - 5 of 5
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    Covalent Capture of Aligned Self-Assembling Nanofibers
    (American Chemical Society, 2017) Li, I-Che; Hartgerink, Jeffrey D.
    A great deal of effort has been invested in the design and characterization of systems which spontaneously assemble into nanofibers. These systems are interesting for their fundamental supramolecular chemistry and have also been shown to be promising materials, particularly for biomedical applications. Multidomain peptides are one such assembler, and in previous work we have demonstrated the reversibility of their assembly under mild and easily controlled conditions, along with their utility for time-controlled drug delivery, protein delivery, cell encapsulation, and cell delivery applications. Additionally, their highly compliant criteria for sequence selection allows them to be modified to incorporate protease susceptibility and biological-recognition motifs for cell adhesion and angiogenesis. However, control of their assembly has been limited to the formation of disorganized nanofibers. In this work, we expand our ability to manipulate multidomain-peptide assembly into parallel-aligned fiber bundles. Albeit this alignment is achieved by the shearing forces of syringe delivery, it is also dependent on the amino acid sequence of the multidomain peptide. The incorporation of the amino acid DOPA (3,4-dihydroxyphenylalanine) allows the self-assembled nanofibers to form an anisotropic hydrogel string under modest shear stress. The hydrogel string shows remarkable birefringence, and highly aligned nanofibers are visible in scanning electronic microscopy. Furthermore, the covalent linkage induced by DOPA oxidation allows covalent capture of the aligned nanofiber bundles, enhancing their birefringence and structural integrity.
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    Design of Multidomain Peptides and Collagen Mimetic Peptides for Biological Applications
    (2018-04-05) Li, I-Che; Hartgerink, Jeffrey D.
    Supramolecular chemistry plays an important role in designing self-assembling peptides. The goal of this work is to design, synthesize, and customize multidomain peptides (MDPs) and collagen mimetic peptides (CMPs) for biological applications. In the first part of this work, we modify the MDP nanofibers to achieve controlled drug release and macroscopic anisotropy. In the second part, we explored residue substitutions in CMPs to capture helical conformations and to target natural collagens. As a type of peptide hydrogel, MDPs respond to external shearing forces and have reversible self-assembly under mild conditions. Controlled drug release is accomplished by modifying the hydrophobic interior of the MDP to construct hollow fibers for the encapsulation of anti-cancer drugs, antibiotics, or nonsteroidal anti-inflammatory drugs. Macroscopic anisotropy was achieved by modifying the hydrophilic exterior of the MDP to achieve organized self-assembly into parallel aligned fiber bundles. With the help of shearing forces of syringe extrusion and the incorporation of the amino acid DOPA (3,4-dihydroxyphenylalanine), the self-assembled nanofibers form an anisotropic hydrogel string under modest shear stress. The anisotropic texture was further crosslinked by oxidative polymerization of DOPA residues and pushed to a new level for tissue regeneration. Collagen forms trimeric helical structures with various thermal stability, which is highly related to the residue substitutions. In our CMP design for collagen covalent capture, lysine and aspartate were employed in a trimeric helical structure to form axial salt-bridges. By utilizing carbodiimide-mediated amidation between amine and carboxylate, the crosslinked collagen helical dimers and trimers were observed on MALDI-TOF MS. Lastly, we attempted to design customized CMPs for natural collagen targeting. Based on different sequences of host natural collagens, the guest CMPs contain substitutions to maximize pairwise interactions, including charge pairs and cation-pi pairs. The CMP design was demonstrated to form destabilized collagen helical structure, but failed to hybridize with the synthetic natural collagen. Through the exploration of different host peptides, we believe this strategy would provide an advanced model once a complete understanding of substitution effect in collagen is given.
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    Drug-Triggered and Cross-Linked Self-Assembling Nanofibrous Hydrogels
    (American Chemical Society, 2015) Kumar, Vivek A.; Shi, Siyu; Wang, Benjamin K.; Li, I-Che; Jalan, Abhishek A.; Sarkar, Biplab; Wickremasinghe, Navindee C.; Hartgerink, Jeffrey D.
    Self-assembly of multidomain peptides (MDP) can be tailored to carry payloads that modulate the extracellular environment. Controlled release of growth factors, cytokines, and small-molecule drugs allows for unique control of in vitro and in vivo responses. In this study, we demonstrate this process of ionic cross-linking of peptides using multivalent drugs to create hydrogels for sustained long-term delivery of drugs. Using phosphate, heparin, clodronate, trypan, and suramin, we demonstrate the utility of this strategy. Although all multivalent anions result in good hydrogel formation, demonstrating the generality of this approach, suramin led to the formation of the best hydrogels per unit concentration and was studied in greater detail. Suramin ionically cross-linked MDP into a fibrous meshwork as determined by scanning and transmission electron microscopy. We measured material storage and loss modulus using rheometry and showed a distinct increase in G′ and G″ as a function of suramin concentration. Release of suramin from scaffolds was determined using UV spectroscopy and showed prolonged release over a 30 day period. Suramin bioavailability and function were demonstrated by attenuated M1 polarization of THP-1 cells compared to positive control. Overall, this design strategy has allowed for the development of a novel class of polymeric delivery vehicles with generally long-term release and, in the case of suramin, cross-linked hydrogels that can modulate cellular phenotype.
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    Multidomain Peptide Hydrogel Accelerates Healing of Full-Thickness Wounds in Diabetic Mice
    (American Chemical Society, 2018) Carrejo, Nicole C.; Moore, Amanda N.; Lopez Silva, Tania L.; Leach, David G.; Li, I-Che; Walker, Douglas R.; Hartgerink, Jeffrey D.
    In vivo, multidomain peptide (MDP) hydrogels undergo rapid cell infiltration and elicit a mild inflammatory response which promotes angiogenesis. Over time, the nanofibers are degraded and a natural collagen-based extracellular matrix is produced remodeling the artificial material into natural tissue. These properties make MDPs particularly well suited for applications in regeneration. In this work, we test the regenerative potential of MDP hydrogels in a diabetic wound healing model. When applied to full-thickness dermal wounds in genetically diabetic mice, the MDP hydrogel resulted in significantly accelerated wound healing compared to a clinically used hydrogel, as well as a control buffer. Treatment with the MDP hydrogel resulted in wound closure in 14 days, formation of thick granulation tissue including dense vascularization, innervation, and hair follicle regeneration. This suggests the MDP hydrogel could be an attractive choice for treatment of wounds in diabetic patients.
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    Nanofibrous peptide hydrogel elicits angiogenesis and neurogenesis without drugs, proteins, or cells
    (Elsevier, 2018) Moore, Amanda N.; Lopez Silva, Tania L.; Carrejo, Nicole C.; Origel Marmolejo, Carlos A.; Li, I-Che; Hartgerink, Jeffrey D.
    The design of materials for regenerative medicine has focused on delivery of small molecule drugs, proteins, and cells to help accelerate healing. Additionally, biomaterials have been designed with covalently attached mimics of growth factors, cytokines, or key extracellular matrix components allowing the biomaterial itself to drive biological response. While the approach may vary, the goal of biomaterial design has often centered on promoting either cellular infiltration, degradation, vascularization, or innervation of the scaffold. Numerous successful studies have utilized this complex, multicomponent approach; however, we demonstrate here that a simple nanofibrous peptide hydrogel unexpectedly and innately promotes all of these regenerative responses when subcutaneously implanted into the dorsal tissue of healthy rats. Despite containing no small molecule drugs, cells, proteins or protein mimics, the innate response to this material results in rapid cellular infiltration, production of a wide range of cytokines and growth factors by the infiltrating cells, and remodeling of the synthetic material to a natural collagen-containing ECM. During the remodeling process, a strong angiogenic response and an unprecedented degree of innervation is observed. Collectively, this simple peptide-based material provides an ideal foundational system for a variety of bioregenerative approaches.