Development of a PEG Derivative Containing Hydrolytically Degradable Hemiacetals.
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ABSTRACT:
SUBMITTER: Reid B
PROVIDER: S-EPMC3534955 | biostudies-literature | 2010 Dec
REPOSITORIES: biostudies-literature
Publications
Development of a PEG Derivative Containing Hydrolytically Degradable Hemiacetals.
Reid Branden B Tzeng Stephany S Warren Andrew A Kozielski Kristen K Elisseeff Jennifer J
Macromolecules 20101108 23
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Project description:Hydrogels cross-linked by inverse electron demand Diels-Alder (iEDDA) click chemistry are increasingly used in biomedical applications. With a few exceptions in naturally derived and chemically modified macromers, iEDDA click hydrogels exhibit long-term hydrolytic stability, and no synthetic iEDDA click hydrogels can undergo accelerated and tunable hydrolytic degradation. We have previously reported a novel method for synthesizing norbornene (NB)-functionalized multiarm poly(ethylene glycol) (PEG), where carbic anhydride (CA) was used to replace 5-norbornene-2-carboxylic acid. The new PEGNBCA-based thiol-norbornene hydrogels exhibited unexpected fast yet highly tunable hydrolytic degradation. In this contribution, we leveraged the new PEGNBCA macromer for forming iEDDA click hydrogels with [methyl]tetrazine ([m]Tz)-modified macromers, leading to the first group of synthetic iEDDA click hydrogels with highly tunable hydrolytic degradation kinetics. We further exploited Tz and mTz dual conjugation to achieve tunable hydrolytic degradation with an in vitro degradation time ranging from 2 weeks to 3 months. Finally, we demonstrated the excellent in vitro cytocompatibility and in vivo biocompatibility of the new injectable PEGNBCA-based iEDDA click cross-linked hydrogels.
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Project description:Zwitterionic polymers, ampholytic macromolecules containing ionic moieties of opposite sign on the same pendant groups, exhibit strong protein-repulsive properties and an inherent biological inertness. For that reason, these highly hydrated inner salt macromolecules have emerged as some of the most viable alternatives to poly(ethylene glycol) (PEG), a gold standard in enabling stealth behavior in life science applications. However, the structural diversity of polymer zwitterions remains limited, and currently available macromolecules do not possess an intrinsic ability to undergo hydrolytical degradation, an important prerequisite for use in drug delivery applications. The present paper reports on the synthesis of a zwitterionic polymer, a multimerized form (two thousand copies), of a biologically benign buffering agent, HEPES, which is covalently assembled on a polyphosphazene backbone. The polymer exhibits typical polyzwitterionic solution behavior, an environmentally dependent hydrolytic degradation pattern, and excellent in vitro compatibility, features that highlight its potential utility for life science applications.
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Project description:UnlabelledPhotopolymerizable and hydrolytically labile poly(ethylene glycol) (PEG) hydrogels formed from photo-clickable reactions were investigated as cell delivery platforms for cartilage tissue engineering (TE). PEG hydrogels were formed from thiol-norbornene PEG macromers whereby the crosslinks contained caprolactone segments with hydrolytically labile ester linkages. Juvenile bovine chondrocytes encapsulated in the hydrogels were cultured for up to four weeks and assessed biochemically and histologically, using standard destructive assays, and for mechanical and ultrasound properties, as nondestructive assays. Bulk degradation of acellular hydrogels was confirmed by a decrease in compressive modulus and an increase in mass swelling ratio over time. Chondrocytes deposited increasing amounts of sulfated glycosaminoglycans and collagens in the hydrogels with time. Spatially, collagen type II and aggrecan were present in the neotissue with formation of a territorial matrix beginning at day 21. Nondestructive measurements revealed an 8-fold increase in compressive modulus from days 7 to 28, which correlated with total collagen content. Ultrasound measurements revealed changes in the constructs over time, which differed from the mechanical properties, and appeared to correlate with ECM structure and organization shown by immunohistochemical analysis. Overall, non-destructive and destructive measurements show that this new hydrolytically degradable PEG hydrogel is promising for cartilage TE.Statement of significanceDesigning synthetic hydrogels whose degradation matches tissue growth is critical to maintaining mechanical integrity as the hydrogel degrades and new tissue forms, but is challenging due to the nature of the hydrogel crosslinks that inhibit diffusion of tissue matrix molecules. This study details a promising, new, photo-clickable and synthetic hydrogel whose degradation supports cartilaginous tissue matrix growth leading to the formation of a territorial matrix, concomitant with an increase in mechanical properties. Nondestructive assays based on mechanical and ultrasonic properties were also investigated using a novel instrument and found to correlate with matrix deposition and evolution. In sum, this study presents a new hydrogel platform combined with nondestructive assessments, which together have potential for in vitro cartilage tissue engineering.
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Project description:Biodegradable hydrogels were synthesized by the click reaction of 4-arm azido-terminated PEG differing in molecular weight (2,100 and 8,800) and two alkyne-terminated peptides: [alkyne]-GFLGK-[alkyne] and ([alkyne]-GFLG)(2)K. The physical properties of in situ formed hydrogels were examined. The hydrogels were highly elastic as determined by rheological and microrheological studies. Swelling degree and enzymatic degradation by papain were dependent on the molecular weight of the PEG, but not the peptide. For PEG8800-based hydrogels, time-course analysis of degradation showed that the molecular weight of the soluble fraction quickly reached the PEG precursor value. These findings may guide future design of hydrogels with controllable mechanical properties and enzymatic degradability.
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Project description:Hydrogel microparticles (microgels) are an attractive approach for therapeutic delivery because of their modularity, injectability, and enhanced integration with the host tissue. Multiple microgel fabrication strategies and chemistries have been implemented, yet manipulation of microgel degradability and its effect on in vivo tissue responses remains underexplored. Here, the authors report a facile method to synthesize microgels crosslinked with ester-containing junctions to afford tunable degradation kinetics. Monodisperse microgels of maleimide-functionalized poly(ethylene-glycol) are generated using droplet microfluidics crosslinked with thiol-terminated, ester-containing molecules. Tunable mechanics are achievable based on the ratio of degradable to nondegradable crosslinkers in the continuous phase. Degradation in an aqueous medium leads to microgel deformation based on swelling and a decrease in elastic modulus. Furthermore, degradation byproducts are cytocompatible and do not cause monocytic cell activation under noninflammatory conditions. These injectable microgels possess time-dependent degradation on the order of weeks in vivo. Lastly, the evaluation of tissue responses in a subcutaneous dorsal pocket shows a dynamic type-1 like immune response to the synthetic microgels, driven by interferon gamma (IFN-γ ) expression, which can be moderated by tuning the degradation properties. Collectively, this study demonstrates the development of a hydrolytic microgel platform that can be adapted to desired host tissue immune responses.
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Project description:Poly(lactic acid) choline iodide ester methacrylate, poly(PLA4ChMA), is a cationic degradable polymer that can flocculate particles and dewater oil sands from tailings ponds. This novel material has yet to be characterized in terms of environmental and human health. If ingested, this substance may become bioaccessible. The bioaccessibility (bioaccessible fraction) of an ingested contaminant is a measure of the portion of an ingested dose that solubilizes and may be available for systemic absorption. In the present study, the partially degraded flocculant and its degradation products, modelled using lactic acid and choline chloride, were subjected to a modified physiologically based extraction test (PBET). Bioaccessible fractions were estimated by proton nuclear magnetic resonance (1H-NMR) spectroscopy and by high-performance liquid chromatography (HPLC). The measured bioaccessibility of lactic acid in gastric solution containing choline chloride is ∼100% but slightly dropped to 94% in intestinal solution at a solid-to-liquid ratio of 1:200. The partially degraded poly(PLA4ChMA) did not degrade further during the PBET and is not solubilized (i.e., 0% bioaccessibility) in the gastric phase but is fully solubilized (i.e., 100% bioaccessibility) in the intestinal phase. At the end of PBET intestinal digestion, the molar ratio of lactic acid to choline chloride in the presence of degraded poly(PLA4ChMA) was 2, approximately the same as in the initial solution. Thus, lactic acid and choline chloride are solubilized to the same extents in both gastric and intestinal solutions. Results suggest that HPLC can be used to directly estimate the bioaccessibility of lactic acid, whereas 1H - NMR may be used to indirectly quantify the bioaccessibility of both lactic acid and choline chloride by determining their molar ratio in PBET extracts. In future works, these findings may be applied to the estimation of risks from exposure to poly(PLA4ChMA) as well as to the remediation of contaminants flocculated by poly(PLA4ChMA) in tailings ponds and in other wastewaters.
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Project description:The objective of this work was to create 3D hydrogel matrices with defined mechanical properties as well as tunable degradability for use in applications involving protein delivery and cell encapsulation. Therefore, we report the synthesis and characterization of a novel hydrolytically degradable poly(ethylene glycol) (PEG) hydrogel composed of PEG vinyl sulfone (PEG-VS) cross-linked with PEG-diester-dithiol. Unlike previously reported degradable PEG-based hydrogels, these materials are homogeneous in structure, fully hydrophilic, and have highly specific cross-linking chemistry. We characterized hydrogel degradation and associated trends in mechanical properties, that is, storage modulus (G'), swelling ratio (Q(M)), and mesh size (xi). Degradation time and the monitored mechanical properties of the hydrogel correlated with cross-linker molecular weight, cross-linker functionality, and total polymer density; these properties changed predictably as degradation proceeded (G' decreased, whereas Q(M) and xi increased) until the gels reached complete degradation. Balb/3T3 fibroblast adhesion and proliferation within the 3D hydrogel matrices were also verified. In sum, these unique properties indicate that the reported degradable PEG hydrogels are well poised for specific applications in protein and cell delivery to repair soft tissue.
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Project description:Healing articular cartilage remains a significant clinical challenge because of its limited self-healing capacity. While delivery of autologous chondrocytes to cartilage defects has received growing interest, combining cell-based therapies with scaffolds that capture aspects of native tissue and promote cell-mediated remodeling could improve outcomes. Currently, scaffold-based therapies with encapsulated chondrocytes permit matrix production; however, resorption of the scaffold does not match the rate of production by cells leading to generally low extracellular matrix outputs. Here, a poly (ethylene glycol) (PEG) norbornene hydrogel is functionalized with thiolated transforming growth factor (TGF-β1) and cross-linked by an MMP-degradable peptide. Chondrocytes are co-encapsulated with a smaller population of mesenchymal stem cells, with the goal of stimulating matrix production and increasing bulk mechanical properties of the scaffold. The co-encapsulated cells cleave the MMP-degradable target sequence more readily than either cell population alone. Relative to non-degradable gels, cellularly degraded materials show significantly increased glycosaminoglycan and collagen deposition over just 14 d of culture, while maintaining high levels of viability and producing a more widely-distributed matrix. These results indicate the potential of an enzymatically degradable, peptide-functionalized PEG hydrogel to locally influence and promote cartilage matrix production over a short period. Scaffolds that permit cell-mediated remodeling may be useful in designing treatment options for cartilage tissue engineering applications.
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