Biodegradable Hybrid Hydrogels Research Articles

Chitosan based hybrid hydrogels for drug delivery: Preparation, biodegradation, thermal, and mechanical properties

AbstractIn the present paper, biodegradable hybrid hydrogels were prepared by using chitosan as a natural polymer and polyurethane containing azomethine as a synthetic polymer for the drug delivery application for 5‐fluorouracil. The fabricated hydrogels were characterized via FT‐IR and SEM analysis. Besides, the thermal, mechanical, and wettability properties, water uptake, biodegradation, protein absorption, drug loading, and release behaviors of the hybrid hydrogels were studied. The obtained results indicated that the fabricated hybrid hydrogels have exhibited good mechanical, hydrophilic, water uptake, and biodegradation behaviors. The hybrid hydrogels also showed 50% drug release amounts and they could be a good candidate for the controlled delivery of 5‐FU due to these properties.

Hydrosoluble collagen based biodegradable hybrid hydrogel for biomedical scaffold

Hydrogel scaffolds are explored as efficient methods to repair damaged organs or tissues. In this study, we developed a hybrid hydrogel system based on collagen (Col) and PEG-derived polymer (PEGF) for biomedical scaffold. The Col-PEGF hybrid hydrogel, in which different materials were combined and sequential interpenetrating networks were built, achieved significantly enhanced mechanical strength and viscoelasticity compared with the corresponding Col hydrogel or PEGF hydrogel. Degradation test indicated that Col enabled the hybrid hydrogel to be broken down via enzymatic degradation while PEGF contributed to the anti-degradation of the hydrogel. This balanced biodegradability of Col-PEGF hydrogel would be advantageous to the application for tissue engineering and regenerative medicine. Moreover, the Col-PEGF hybrid hydrogel with micron-sized pores and variable moisture performed good biocompatibility to NIH-3T3 cells, and supplied a favorable environment for cell growth and proliferation. Therefore, the Col-PEGF hydrogel will provide a promising biomedical scaffold for the therapy of tissue defects.

Hybrid cross‐linked hydrogels as a technology platform forinvitrorelease of cephradine

Hydrogel‐based drug delivery systems can leverage therapeutically favorable upshots of drug release and found clinical uses. Hydrogels offer temporal and spatial control over the release of different therapeutic agents. Because of their tailor made controllable degradability, physical properties, and ability to prevent the labile drugs from degradation, hydrogels provide platform on which diverse physicochemical interactions with entrapped drugs cause to control drug release. Herein, we report the fabrication of novel vinyltrimethoxy silane (VTMS) cross‐linked chitosan/polyvinyl pyrrolidone hydrogels. Swelling in distilled water in conjunction with different buffer and electrolyte solutions was performed to assess the swellability of hydrogels. Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and X‐ray diffraction (XRD) analysis were further conducted to investigate the possible interactions between components, thermal stability, and crystallinity of as‐prepared hybrid hydrogels, respectively. In vitro time‐dependent biodegradability, antimicrobial study, and cytotoxicity were also carried out to evaluate their extensive biocompatibility and cytotoxic behavior. More interestingly, in vitro drug release study allowed for the controlled release of cephradine. Therefore, this facile strategy developed the novel biocompatible and biodegradable hybrid hydrogels, which could significantly expand the scope of these hydrogels in other biomedical applications like scaffolds, skin regeneration, tissue engineering, etc.

A single dose of thermal-sensitive biodegradable hybrid hydrogel promotes functional recovery after spinal cord injury

Sensorimotor functional recovery after spinal cord injury (SCI) is still a large challenge in the clinic. Cabazitaxel (Cab) is a microtubule inhibitor approved by the FDA in 2010 for metastatic castration-resistant prostate cancer. Interestingly, we had detected that Cab promoted neurite outgrowth of the cultured cortical neurons. To further study whether Cab facilitates locomotion repair and figure out the underlying mechanism, we designed an injectable and biodegradable hybrid hydrogel (Cab-M/H) to improve the solubility and bioavailability of Cab, and the rat lateral hemisection model was established. After local application, Cab-M/H formed a 3D cross-linked hydrogel, which served as a drug reservoir, and the hydrogel matrix degraded gradually with the sustained release of Cab. BBB scoring and electrophysiology test indicated that Cab-M/H effectively promoted motor behavioral recovery. Pathological assay suggested Cab-M/H significantly reduced fibrotic scarring and decreased deposition of the axon-growth inhibitory molecules, as well boosted nerve regeneration and prevented demyelination around the injury site. Furthermore, the Cab-M/H treatment did not initiate any relative abnormal pathologic changes. These data demonstrate that a single low-dose administration of Cab-M/H at the injury site potently facilitates functional recovery. Therefore, the study provides a new and promising candidate for the global fight against SCI.

Accelerate Healing of Severe Burn Wounds by Mouse Bone Marrow Mesenchymal Stem Cell-Seeded Biodegradable Hydrogel Scaffold Synthesized from Arginine-Based Poly(ester amide) and Chitosan.

Severe burns are some of the most challenging problems in clinics and still lack ideal modalities. Mesenchymal stem cells (MSCs) incorporated with biomaterial coverage of burn wounds may offer a viable solution. In this report, we seeded MSCs to a biodegradable hybrid hydrogel, namely ACgel, that was synthesized from unsaturated arginine-based poly(ester amide) (UArg-PEA) and chitosan derivative. MSC adhered to ACgels. ACgels maintained a high viability of MSCs in culture for 6 days. MSC seeded to ACgels presented well in third-degree burn wounds of mice at 8 days postburn (dpb) after the necrotic full-thickness skin of burn wounds was debrided and filled and covered by MSC-carrying ACgels. MSC-seeded ACgels promoted the closure, reepithelialization, granulation tissue formation, and vascularization of the burn wounds. ACgels alone can also promote vascularization but less effectively compared with MSC-seeded ACgels. The actions of MSC-seeded ACgels or ACgels alone involve the induction of reparative, anti-inflammatory interleukin-10, and M2-like macrophages, as well as the reduction of inflammatory cytokine TNFα and M1-like macrophages at the late inflammatory phase of burn wound healing, which provided the mechanistic insights associated with inflammation and macrophages in burn wounds. For the studied regimens of these treatments, no toxicity was identified to MSCs or mice. Our results indicate that MSC-seeded ACgels have potential use as a novel adjuvant therapy for severe burns to complement commonly used skin grafting and, thus, minimize the downsides of grafting.

Injectable biodegradable hybrid hydrogels based on thiolated collagen and oligo(acryloyl carbonate)–poly(ethylene glycol)–oligo(acryloyl carbonate) copolymer for functional cardiac regeneration

Injectable biodegradable hybrid hydrogels were designed and developed based on thiolated collagen (Col-SH) and multiple acrylate containing oligo(acryloyl carbonate)-b-poly(ethylene glycol)-b-oligo(acryloyl carbonate) (OAC-PEG-OAC) copolymers for functional cardiac regeneration. Hydrogels were readily formed under physiological conditions (37°C and pH 7.4) from Col-SH and OAC-PEG-OAC via a Michael-type addition reaction, with gelation times ranging from 0.4 to 8.1min and storage moduli from 11.4 to 55.6kPa, depending on the polymer concentrations, solution pH and degrees of substitution of Col-SH. The collagen component in the hybrid hydrogels retained its enzymatic degradability against collagenase, and the degradation time of the hydrogels increased with increasing polymer concentration. In vitro studies showed that bone marrow mesenchymal stem cells (BMSCs) exhibited rapid cell spreading and extensive cellular network formation on these hybrid hydrogels. In a rat infarction model, the infarcted left ventricle was injected with PBS, hybrid hydrogels, BMSCs or BMSC-encapsulating hybrid hydrogels. Echocardiography demonstrated that the hybrid hydrogels and BMSC-encapsulating hydrogels could increase the ejection fraction at 28days compared to the PBS control group, resulting in improved cardiac function. Histology revealed that the injected hybrid hydrogels significantly reduced the infarct size and increased the wall thickness, and these were further improved with the BMSC-encapsulating hybrid hydrogel treatment, probably related to the enhanced engraftment and persistence of the BMSCs when delivered within the hybrid hydrogel. Thus, these injectable hybrid hydrogels combining intrinsic bioactivity of collagen, controlled mechanical properties and enhanced stability provide a versatile platform for functional cardiac regeneration.

Development of a biocompatible and biodegradable hybrid hydrogel platform for sustained release of ionic drugs.

In this study, we reported the development of a new drug encapsulation strategy and a robust hybrid hydrogel platform for controlled and sustained release of small and large molecule ionic drugs. A biodegradable, biocompatible and temperature stimuli responsive hybrid hydrogel platform was fabricated from arginine based unsaturated poly(ester amides) (Arg-UPEAs), Pluronic diacrylate (Pluronic-DA) and alginate by the UV photo-crosslinking method, combining the favorable properties of a hydrogel and a polyelectrolyte complex. The hydrogels were systematically characterized, including the swelling mechanics, mechanical properties, biodegradation and interior morphologies. In vitro biocompatibility study showed that the hydrogels could support the cell attachment and proliferation well. Some model drugs, such as hydrochloride salts of hydralazine, insulin and interleukin-12, were encapsulated into the hydrogels and the drug release behavior was investigated using HPLC, LC-MS, BCA assay and ELISA assay. The obtained release profiles indicated that the Pluronic/Arg-UPEA/alginate hybrid hydrogels could release ionic drugs over weeks in vitro via a sustained manner. The structure-function study of hydrogels indicated that the polymer structure, hydrogel composition and environmental temperature had strong effects on the hydrogel properties and their drug release profiles.

A novel family of biodegradable hybrid hydrogels from arginine-based poly(ester amide) and hyaluronic acid precursors

A new family of biodegradable and charged hybrid hydrogels was designed and fabricated via photo-crosslinking in an aqueous medium from a hyaluronic acid (HA) precursor and a relatively new amino acid-based poly(ester amide) (AA-PEA) precursor. The HA precursor was synthesized by incorporating an unsaturated moiety (aminoethyl methacrylate, AEMA), while the AA-PEA precursor was synthesized from unsaturated arginine-based poly(ester amide)s (UArg-PEA). These two water soluble precursors were photo-crosslinked to formulate a new family of biodegradable hybrid hydrogels. The chemical structure of these hybrid hydrogels was characterized, and their swelling, mechanical, morphological, biodegradation and drug release properties were examined as a function of the feed ratio of these 2 precursors and the degree of substitution (DS) of AEMA groups in HA-AEMA. The resulting hybrid hydrogels showed a 400–600% swelling ratio, and pH dependent swelling was observed only in a pure HA-AEMA hydrogel. The hybrid hydrogels showed a distinctive sheet-like multi-layered 3D microporous structure confirmed by SEM. Upon trypsin catalyzed biodegradation, the hybrid hydrogels showed 50 to 70% weight loss within 6 days, while the same hybrid hydrogels showed less than 5% weight loss in a PBS medium. The hybrid hydrogels showed a sustained release of bovine serum albumin (BSA) over 25 h, while the pure HA-AEMA hydrogel exhibited a complete release of BSA within 5 h. When compared with a pure HA-AEMA hydrogel, the cationic Arg-PEA/HA-AEMA hybrid hydrogels significantly improved the attachment and proliferation of Hela cells on hydrogel surfaces.

Optimization of Vasculogenesis within Naturally-Derived, Biodegradable Hybrid Hydrogel Scaffolds

INTRODUCTION: Cellular ingrowth and neovascularization of acellular tissue-regeneration scaffolds represent the rate-limiting steps of permanent integration.1 In previous work, we have demonstrated that naturally-derived, biodegradable hybrid hydrogel scaffolds fabricated from a 10:1 w/w combination of alginate and type I collagen allow for maximal human umbilical vein endothelial cell (HUVEC) adherence and invasion in an in vitro wound healing model. We next sought to stimulate endothelial tubule formation within these scaffolds. METHODS: Hybrid hydrogel scaffolds were fabricated as before. Scaffolds were seeded with 3.0×105 HUVECs and maintained under standard cell culture conditions. After 3 days, culture media was supplemented with basic fibroblast growth factor (bFGF) at varying physiologic concentrations. Additional scaffolds were seeded with human aortic smooth muscle cells (HASMCs), followed by HUVECs 3 days later. After 2 weeks of HUVEC culture, all scaffolds were labeled with DiI-Ac-LDL and DAPI, and imaged using confocal microscopy. RESULTS: HUVECs were maximally confluent on hybrid scaffolds when cultured with media supplemented with bFGF 20ng/mL (372.5±37.4) compared with 0ng/mL (250.7±18.2, p=0.005), 1ng/mL (179.0±17.4, p<1.0x10-2), 5ng/mL (198.5±17.2, p<1.0x10-3), and 10ng/mL (273.3±22.9, p=0.030). However, the addition of growth factor stimulated neither an increase in HUVEC invasion nor tubule formation within the scaffold substrate. In contrast, a “dose-dependent” increase in tubule content and network-like organization was observed as the co-culture ratio of HASMCs to HUVECS from increased from 1:10 to 1:1 (Figures 1-2).Figure 1: Co-culture of human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs) in a 1:10 ratio within hybrid hydrogel scaffolds resulted in clusters of cells without an overlying structure or pattern. Scale bar = 100um.Figure 2: Co-culture of human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs) in a 1:1 ratio within hybrid hydrogel scaffolds resulted in an increase in tubule formation and network organization. Scale bar = 100um.CONCLUSION: Even at high concentrations, the presence of bFGF alone is insufficient to stimulate HUVECs to form tubules within hydrogel scaffolds. Instead, the complex chemical and possibly contextual cues offered by vascular smooth muscle cells are required to instruct endothelial cells to assemble into vasculogenic configurations. These findings provide important insights into the instruction of endothelial tubule and network formation and bring us one step closer to the fabrication of pre-vascularized artificial tissue. DISCLOSURES: This work was supported in part by the Ruth L. Kirschstein National Research Service Award (T32 HL083824-05) Institutional Research Training Grant (Dr. Reiffel), and the Weill Cornell Medical College Clinical and Translational Science Center (TL1RR024998; Dr. Fullerton).

Optimizing Endothelial Cell Adhesion and Invasion with Naturally-Derived, Biodegradable Hybrid Hydrogel Scaffolds

Reiffel, Alyssa J. MD; Perez, Justin L. BS; Sohn, Allie M. MD; Israely, Edo BA; Jimenez, Natalia BS; Spector, Jason A. MD

Novel injectable biodegradable glycol chitosan‐based hydrogels crosslinked by Michael‐type addition reaction with oligo(acryloyl carbonate)‐b‐poly(ethylene glycol)‐b‐oligo(acryloyl carbonate) copolymers

Novel injectable biodegradable glycol chitosan hydrogels were developed based on thiolated glycol chitosan (GC-SH) and water soluble oligo(acryloyl carbonate)-b-poly(ethylene glycol)-b-oligo(acryloyl carbonate) (OAC-PEG-OAC) triblock copolymers via Michael-type addition reaction. The rheology measurements showed that robust hydrogels were formed rapidly upon mixing aqueous solutions of GC-SH and OAC-PEG-OAC at remarkably low total polymer concentrations of 1.5-4.5 wt % under physiological conditions. The gelation times (varying from 10 s to 17 min) and storage moduli (100 to 4300 Pa) of hydrogels could be controlled by degrees of substitution (DS) of GC-SH, solution pH, and polymer concentration. These glycol chitosan hydrogels had microporous structures, low swelling and slow hydrolytic degradation (stable for over 6 months) under physiological conditions. Notably, these hydrogels were prone to enzymatic degradation with lysozyme. The multiple acryloyl functional groups of OAC-PEG-OAC allowed facile conjugation with thiol-containing biomolecules prior to gelation endowing hydrogels with specific bioactivity. The preliminary cell culture studies revealed that these glycol chitosan hydrogels were cell non-adhesive while Gly-Arg-Gly-Asp-Cys (GRGDC) peptide modified hydrogels could well support adhesion and growth of both MG63 osteoblast and L929 fibroblast cells. These rapidly in situ forming enzymatically biodegradable hybrid hydrogels have great potentials in the development of injectable cell-specific bioactive extracellular matrices for tissue engineering.

Synthesis, characterization and biodegradation of poly(ester amide)s based hydrogels

A series of new biodegradable hybrid hydrogels were designed and fabricated from a new family of amino acid-based functional poly(ester amide) (PEA-AG) and commercial poly(ethylene glycol) diacrylate (PEG-DA) or Pluronic diacrylate (Pluronic-DA) by UV photocrosslinking. These biodegradable hybrid hydrogels were characterized in terms of equilibrium swelling ratio (Qeq), compression modulus by dynamic mechanical analysis (DMA), and interior morphology by scanning electron microscope (SEM). Both the precursors’ chemical structures and feed ratio had significant effect on the properties of the hybrid hydrogels. All these hybrid hydrogels had a three-dimensional porous network structure. The hydrophobicity, crosslinking density and mechanical strength of the hybrid hydrogels increased with an increase in allylglycine (AG) content in the PEA-AG, but the swelling and pore size of the hybrid hydrogels decreased. The biodegradation rate of these hybrid hydrogels in an enzyme (α-chymotrypsin) solution was faster than in a pure PBS buffer control, and the biodegradation rate increased with an increase in α-chymotrypsin concentration and allylglycine content.

Synthesis, characterization and cytotoxicity of photo-crosslinked maleic chitosan–polyethylene glycol diacrylate hybrid hydrogels

Synthetic hydrogels are important biomaterials for many biomedical applications and hydrogels produced via photo-gelation have shown particular promise. In this paper, we describe a new family of biodegradable hybrid hydrogels fabricated in aqueous solution via long wavelength UV photo-crosslinking using maleic chitosan and polyethylene glycol diacrylate (PEGDA) as precursors. The maleic chitosan precursor was prepared by a simple one-step chemical modification of chitosan, with high yields, and characterized by Fourier transform infrared spectroscopy, (1)H NMR and (13)C NMR. Maleic chitosan and PEGDA precursors at a wide range of weight feed ratios were mixed in aqueous solution and directly photo-crosslinked for 10 min under a long wavelength UV light (365 nm) using 4-(2-hydroxyethoxy) phenyl-(2-hydroxy-2-propyl) ketone (Irgacure 2959) as photoinitiator. It was observed that as the weight feed ratio of maleic chitosan to PEGDA decreased the pore sizes of the hydrogel samples decreased, thereby increasing the densities of the hydrogel networks and producing a lower swelling ratio and a higher compressive modulus. The molecular weight of PEGDA had a similar effect. Preliminary cell cytotoxicity tests of both the maleic chitosan precursor and maleic chitosan/PEGDA hydrogels, based on the MTT assay and live-dead assay, respectively, showed that these new chitosan-based biodegradable biomaterials were relatively non-toxic to bovine aortic endothelial cells at low dosages.

Functional groups affect physical and biological properties of dextran‐based hydrogels

Modification of dextran backbone allows the development of a hydrogel with specific characteristics. To enhance their functionality for tissue-engineered scaffolds, a series of dextran-based macromers was synthesized by incorporating various functional groups, including allyl isocyanate (Dex-AI), ethylamine (Dex-AE), chloroacetic acid (Dex-AC), or maleic-anhydride (Dex-AM) into dextrans. The dextran-based biodegradable hybrid hydrogels are developed by integrating polyethylene glycol diacrylate (PEGDA). To explore the effect of different derivatives on hydrogel properties, three different ratios of Dex/PEGDA are examined: low (20/80), medium (40/60), and high (60/40). Differences in physical and biological properties of the hydrogels are found, including swelling, degradation rate, mechanics, crosslinking density, biocompatibility (in vitro and in vivo), and vascular endothelial growth factor release. The results also indicate that the incorporation of amine groups into dextran gives rise to hydrogels with better biocompatible and release properties. We, therefore, conclude that the incorporation of different functional groups affects the fundamental properties of a dextran-based hydrogel network, and that amine groups are preferred to generate hydrogels for biomedical use.

Biodegradable hydrophobic–hydrophilic hybrid hydrogels: swelling behavior and controlled drug release

The objective of this work was to investigate a new family of hydrophobic–hydrophilic biodegradable hybrid hydrogels as drug carriers. A series of hydrophobic–hydrophilic biodegradable hybrid hydrogels was formulated via photo means from hydrophobic three-arm poly (ε-caprolactone) maleic acid (PGCL-Ma) and hydrophilic dextran maleic acid (Dex-Ma) precursors over a wide range of the two precursors' feed ratio (PGCL-Ma/Dex-Ma at 100:0, 70:30, 50:50, 30:70 and 0:100). A low-molecular-weight and hydrophilic drug, the α-7 agonist cocaine methiodide, was used as the model drug for the release study from the hybrid hydrogels in pH 7.4 phosphate buffer solution at 37°C. The swelling data of these hybrid hydrogels depended on the hydrophobic to hydrophilic precursors' feed ratio, and there were several-fold differences in swelling ratios between a pure hydrophilic Dex-Ma and a pure hydrophobic PGCL-Ma hydrogels. The presence of the hydrophobic PGCL-Ma component significantly reduced the initial burst swelling of the hybrid hydrogels. Depending on the two precursors' feed ratios, the swelling data during the early period obeyed either Fickian diffusion (for 50:50 PGCL-Ma/Dex-Ma hydrogel), non-Fickian or anomalous transport (for 70:30 and 100:0 PGCL-Ma/Dex-Ma), or relaxation-controlled (for 30:70 and 0:100 PGCL-Ma/Dex-Ma). A wide range of cocaine methiodide release profiles was achieved by controlling hydrophobic to hydrophilic precursors' feed ratios. Initial drug burst release was significantly reduced as the concentration of the hydrophobic PGCL-Ma component increased in the hybrid hydrogels. The bulk of cocaine methiodide released during the 160-h period was via diffusion-controlled mechanism, while degradation-controlled mechanism dominated thereafter.

In vitro release behavior of insulin from biodegradable hybrid hydrogel networks of polysaccharide and synthetic biodegradable polyester.

The controlled release of insulin from a series of biodegradable hybrid hydrogel network containing dextran derivative of allyl isocyanate (dex-AI) and poly (D,L) lactide diacrylate macromer (PDLLAM) over a wide range of composition ratio was investigated. Laser confocal scanning microscope was used to understand the insulin dispersion and release mechanism in the hydrogels. We found that the dispersion of insulin in the hydrogel network appeared to become less homogeneous as the PDLLAM composition in the hydrogel increased. The increase in hydrogel degradability imparted by PDLLAM incorporation shifted the hydrogel to a more open structure at a later release time, which facilitated the release rate and extent of insulin. From the result of release kinetics study (i.e., diffusion coefficient), insulin release occurred through diffusion and degradation controlled mechanisms. In addition, a comparison of the release characteristics of indomethacin, insulin and bovine serum albumin from the hydrogel network showed that the following parameters determined the release kinetics: drug molecular weight and size, hydrogel swellability and degradability, drug solubility in water and the hydrophobic interaction between drugs and the hydrogel network.

The Effect of Molecular Weight of Biodegradable Hydrogel Components on Indomethacin Release from Dextran and Poly(DL)lactic Acid Based Hydrogels

Biodegradable hybrid hydrogels from chemically modified dextran and poly(DL)lactic acid (PDLLA) were prepared by UV photocrosslinking of different molecular weights (MWs) of these precursors. A series biodegradable hybrid hydrogels were obtained by changing the composition ratio of hydrogels and MWs of dextran and PDLLA. These hydrogels were characterized by swelling and in vitro biodegradation-induced morphological structure changes. Indomethacin (IDM) was entrapped in these hydrogels and the release kinetics were investigated in a pH 7.4 phosphate buffer solution. The relationship between hydrogel swelling and biodegradation, IDM release from the network hydrogels and the molecular weights of dextran and PDLLA were studied. It was found that the swelling and biodegradation of these hybrid hydrogels were affected by both the MWs of the polymer component and the composition ratio of the hydrogels. IDM release from the hybrid hydrogel networks depended on the structure and hydrophobicity of the hydrogels; the MW effect on IDM release profiles was smaller than on hydrogel properties.