7 research outputs found
Adsorption and Sustained Delivery of Small Molecules from Nanosilicate Hydrogel Composites
Two-dimensional nanosilicate particles (NS) have shown promise for the prolonged release of small-molecule therapeutics while minimizing burst release. When incorporated in a hydrogel, the high surface area and charge of NS enable electrostatic adsorption and/or intercalation of therapeutics, providing a lever to localize and control release. However, little is known about the physio-chemical interplay between the hydrogel, NS, and encapsulated small molecules. Here, we fabricated polyethylene glycol (PEG)-NS hydrogels for the release of model small molecules such as acridine orange (AO). We then elucidated the effect of NS concentration, NS/AO incubation time, and the ability of NS to freely associate with AO on hydrogel properties and AO release profiles. Overall, NS incorporation increased the hydrogel stiffness and decreased swelling and mesh size. When individual NS particles were embedded within the hydrogel, a 70-fold decrease in AO release was observed compared to PEG-only hydrogels, due to adsorption of AO onto NS surfaces. When NS was pre-incubated and complexed with AO prior to hydrogel encapsulation, a >9000-fold decrease in AO release was observed due to intercalation of AO between NS layers. Similar results were observed for other small molecules. Our results show the potential for use of these nanocomposite hydrogels for the tunable, long-term release of small molecules
Adsorption and Sustained Delivery of Small Molecules from Nanosilicate Hydrogel Composites
Two-dimensional nanosilicate particles (NS) have shown promise for the prolonged release of small-molecule therapeutics while minimizing burst release. When incorporated in a hydrogel, the high surface area and charge of NS enable electrostatic adsorption and/or intercalation of therapeutics, providing a lever to localize and control release. However, little is known about the physio-chemical interplay between the hydrogel, NS, and encapsulated small molecules. Here, we fabricated polyethylene glycol (PEG)-NS hydrogels for the release of model small molecules such as acridine orange (AO). We then elucidated the effect of NS concentration, NS/AO incubation time, and the ability of NS to freely associate with AO on hydrogel properties and AO release profiles. Overall, NS incorporation increased the hydrogel stiffness and decreased swelling and mesh size. When individual NS particles were embedded within the hydrogel, a 70-fold decrease in AO release was observed compared to PEG-only hydrogels, due to adsorption of AO onto NS surfaces. When NS was pre-incubated and complexed with AO prior to hydrogel encapsulation, a >9000-fold decrease in AO release was observed due to intercalation of AO between NS layers. Similar results were observed for other small molecules. Our results show the potential for use of these nanocomposite hydrogels for the tunable, long-term release of small molecules
Laponite-Based Nanocomposite Hydrogels for Drug Delivery Applications
Hydrogels are widely used for therapeutic delivery applications due to their biocompatibility, biodegradability, and ability to control release kinetics by tuning swelling and mechanical properties. However, their clinical utility is hampered by unfavorable pharmacokinetic properties, including high initial burst release and difficulty in achieving prolonged release, especially for small molecules (<500 Da). The incorporation of nanomaterials within hydrogels has emerged as viable option as a method to trap therapeutics within the hydrogel and sustain release kinetics. Specifically, two-dimensional nanosilicate particles offer a plethora of beneficial characteristics, including dually charged surfaces, degradability, and enhanced mechanical properties within hydrogels. The nanosilicate–hydrogel composite system offers benefits not obtainable by just one component, highlighting the need for detail characterization of these nanocomposite hydrogels. This review focuses on Laponite, a disc-shaped nanosilicate with diameter of 30 nm and thickness of 1 nm. The benefits of using Laponite within hydrogels are explored, as well as examples of Laponite–hydrogel composites currently being investigated for their ability to prolong the release of small molecules and macromolecules such as proteins. Future work will further characterize the interplay between nanosilicates, hydrogel polymer, and encapsulated therapeutics, and how each of these components affect release kinetics and mechanical properties
Carrageenan-Based Crowding and Confinement Combination Approach to Increase Collagen Deposition for In Vitro Tissue Development
Connective tissue models grown from cell monolayers can be instrumental in a variety of biomedical fields such as drug screening, wound healing, and regenerative engineering. However, while connective tissues contain abundant fibrillar collagen, achieving a sufficient assembly and retention of fibrillar collagen in vitro is challenging. Unlike the dilute cell culture environment, the body’s environment is characterized by a high density of soluble macromolecules (crowding) and macromolecular networks (confinement), which contribute to extracellular matrix (ECM) assembly in vivo. Consequently, macromolecular crowding (MMC) has been successfully used to enhance the processing of type I procollagen, leading to significant increases in fibrillar collagen assembly and accumulation during in vitro culture of a variety of cell types. In this study, we developed a combination approach using a carrageenan hydrogel, which released soluble macromolecules and served as a confinement barrier. We first evaluated the local carrageenan release and then confirmed the effectiveness of this combination approach on collagen accumulation by the human MG-63 bone cell line. Additionally, computational modeling of oxygen and glucose transport within the culture system showed no negative effects of the hydrogel and its releasates on cell viability
Micro-Clotting of Platelet-Rich Plasma Upon Loading in Hydrogel Microspheres Leads to Prolonged Protein Release and Slower Microsphere Degradation
Platelet-rich plasma (PRP) is an autologous blood product that contains a variety of growth factors (GFs) that are released upon platelet activation. Despite some therapeutic potential of PRP in vitro, in vivo data are not convincing. Bolus injection of PRP is cleared rapidly from the body diminishing its therapeutic efficacy. This highlights a need for a delivery vehicle for a sustained release of PRP to improve its therapeutic effect. In this study, we used microfluidics to fabricate biodegradable PRP-loaded polyethylene glycol (PEG) microspheres. PRP was incorporated into the microspheres as a lyophilized PRP powder either as is (powder PRP) or first solubilized and pre-clotted to remove clots (liquid PRP). A high PRP loading of 10% w/v was achieved for both PRP preparations. We characterized the properties of the resulting PRP-loaded PEG microspheres including swelling, modulus, degradation, and protein release as a function of PRP loading and preparation. Overall, loading powder PRP into the PEG microspheres significantly affected the properties of microspheres, with the most pronounced effect noted in degradation. We further determined that microsphere degradation in the presence of powder PRP was affected by platelet aggregation and clotting. Platelet aggregation did not prevent but prolonged sustained PRP release from the microspheres. The delivery system developed and characterized herein could be useful for the loading and releasing of PRP to promote tissue regeneration and wound healing or to suppress tissue degeneration in osteoarthritis, and intervertebral disc degeneration
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CCL21 and beta-cell antigen releasing hydrogels as tolerance-inducing therapy in Type I diabetes
Type-I Diabetes (T1D) is caused by defective immunotolerance mechanisms enabling autoreactive T cells to escape regulation in lymphoid organs and destroy insulin-producing β-cells in the pancreas, leading to insulin dependence. Strategies to promote β-cell tolerance could arrest T1D. We previously showed that secretion of secondary lymphoid chemokine CCL21 by CCL21 transgenic β-cells induced tolerance and protected non-obese diabetic (NOD) mice from T1D. T1D protection was associated with formation of lymph node-like stromal networks containing tolerogenic fibroblastic reticular cells (FRCs). Here, we developed a polyethylene glycol (PEG) hydrogel platform with hydrolytically degradable PEG-diester dithiol crosslinkers to provide controlled and sustained delivery of CCL21 and β-cell antigens for at least 28 days in vitro and recapitulate properties associated with the tolerogenic environment of CCL21 transgenic β-cells in our previous studies. CCL21 and MHC-II restricted antigens were tethered to gels via simple click-chemistry while MHC-I restricted antigens were loaded in PEG-based polymeric nanovesicles and incorporated in the gel networks. CCL21 and antigen release kinetics depended on the PEG gel tethering strategy and the linkers. Importantly, in vitro functionality, chemotaxis, and activation of antigen-specific T cells were preserved. Implantation of CCL21 and β-cell antigen gels under the kidney capsule of pre-diabetic NOD mice led to enrichment of adoptively transferred antigen-specific T cells, formation of gp38 + FRC-like stromal cell networks, and increased regulation of specific T cells with reduced accumulation within pancreatic islets. Thus, our platform for sustained release of β-cell antigens and CCL21 immunomodulatory molecule could enable the development of antigen-specific tolerance therapies for T1D.
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•Different PEG-DD linkers can form hydrogels with fast (PEG-DD1) or slow (PEG-DD2) degradation and molecule release profiles.•Tethering CCL21 on PEG-DD linkers controls and prolongs its release while maintaining its functionality as a chemoattractant.•Beta cell peptides tethered on PEG-DD or loaded in nanovesicles have controlled release and maintain their functionality.•CCL21+BDC2.5 gels in NOD mice promote FRC-like networks and antigen-specific T cell enrichment in the implant site.•CCL21+BDC2.5 gels lead to a decrease of antigen-specific T cells and reduced infiltration in pancreatic islets
Silicate Clay-Hydrogel Nanoscale Composites for Sustained Delivery of Small Molecules
Hydrogels have been widely used for therapeutic delivery
applications
due to their tunability and biocompatibility, although delivery of
small molecules is difficult due to high burst release and rapid diffusion
from the device. Nanosilicate clays (nanoclays) have shown the adsorption
potential of small molecules, offering a lever to prolong the release
kinetics of hydrogel delivery devices. However, further characterization
of small molecule–nanoclay interactions and their effect on
molecule release is needed to allow for the custom design of tunable
nanocomposite hydrogel delivery devices. Here, we have characterized
the adsorption of small molecules onto three nanoclays, Laponite,
montmorillonite, and halloysite, and monitored their release in various
conditions. The layered structures of Laponite and montmorillonite
led to cationic exchange of the small molecules into the interlayer
space, whereas the small molecules were adsorbed onto the surface
of the tubular halloysite. The addition of nanoclays to polyethylene
glycol (PEG) hydrogels significantly slowed the release of small molecules,
especially from Laponite (500-fold decrease) and montmorillonite (∼3000-fold
decrease) composite gels. Cationic small molecules were shown to be
released significantly slower from nanocomposite hydrogels than anionic
ones. The incubation time of small molecules with nanoclays prior
to hydrogel encapsulation also played a key role in determining their
release rate, with montmorillonite showing near-immediate adsorption
while halloysite exhibited a higher dependence on incubation time
due to slower adsorption kinetics. Release buffer salt concentration
and pH were shown to affect release kinetics due to modulation of
nanoclay–small molecule interactions. These results show the
potential for formation of a highly tunable nanocomposite hydrogel
delivery device for a greatly prolonged release of small molecules
compared to traditional hydrogels