Hydrogel Micropillar Array for Temperature Sensing in Fluid.

Localized temperature sensing and control on a micron-scale have diverse applications in biological systems. We present a micron-sized hydrogel pillar array as potential temperature probes and actuators by exploiting sensitive temperature dependence of their volume change. Soft lithography-based molding processes were presented to fabricate poly N-isopropyl acrylamide (p-NIPAAm)-based hydrogel pillar array on a glass substrate. Au nanorods as light-induced heating elements were embedded within the hydrogel pillars, and near-infrared (NIR) light was used to modulate temperature in a local area. First, static responses of the micro-pillar array were characterized as a function of its temperature. It was shown that the hydrogel had a sensitive volume transition near its low critical solution temperature (LCST). Furthermore, we showed that LCST could be readily adjusted by utilizing copolymerizing with acrylamide (AAM). To demonstrate the feasibility of spatiotemporal temperature mapping and modulation using the presented pillar array, pulsed NIR light was illuminated on a local area of the hydrogel pillar array, and its responses were recorded. Dynamic temperature change in water was mapped based on the abrupt volume change characteristics of the hydrogel pillar, and its potential actuation using NIR light was successfully demonstrated. Considering that the structure can be arrayed in a two-dimensional pixel format with high spatial resolution and high sensitive temperature characteristics, the presented method and the device structure can have diverse applications to change and sense local temperatures in liquid. This is particularly useful in biological systems, where their physiological temperature can be modulated and mapped with high spatial resolution.

Folic-Acid-Conjugated Thermoresponsive Polymeric Particles for Targeted Delivery of 5-Fluorouracil to CRC Cells.

Colorectal cancer is the fourth most common cancer worldwide and the third most frequently diagnosed form of cancer associated with high mortality rates. Recently, targeted drug delivery systems have been under increasing attention owing to advantages such as high therapeutic effectiveness with a significant depletion in adverse events. In this report, we describe the biocompatible and thermoresponsive FA-conjugated PHEA-b-PNIPAAm copolymers as nanocarriers for the delivery of 5-FU. The block copolymers were obtained using RAFT (Reversible Addition-Fragmentation chain Transfer) polymerization and were characterized by methods such as SEC (Size Exclusion Chromatography), NMR (Nuclear Magnetic Resonance), UV-Vis (Ultraviolet-Visible), FT-IR (Fourier Transform Infrared) spectroscopy, and TGA (Thermogravimetric Analysis). Nanoparticles were formed from polymers with and without the drug-5-fluorouracil, which was confirmed using DLS (Dynamic Light Scattering), zeta potential measurements, and TEM (Transmission Electron Microscopy) imaging. The cloud points of the polymers were found to be close to the temperature of the human body. Eventually, polymeric carriers were tested as drug delivery systems for the safety, compatibility, and targeting of colorectal cancer cells (CRC). The biological evaluation indicated high compatibility with the representative host cells. Furthermore, it showed that proposed nanosystems might have therapeutic potential as mitigators for 5-FU-induced monocytopenia, cardiotoxicity, and other chemotherapy-associated disorders. Moreover, results show increased cytotoxicity against cancer cells compared to the drug, including a line with a drug resistance phenotype. Additionally, the ability of synthesized carriers to induce apoptosis and necrosis in treated CRC cells has been confirmed. Undoubtedly, the presented aspects of colorectal cancer therapy promise future solutions to overcome the conventional limitations of current treatment regimens for this type of cancer and to improve the quality of life of the patients.

Dissolution and Solubility Enhancement of the Highly Lipophilic Drug Phenytoin via Interaction with Poly(N-isopropylacrylamide-co-vinylpyrrolidone) Excipients.

Excipients of natural or synthetic origin play an important role in pharmaceutical performance to enhance the solubility, bioavailability, release, and stability of insoluble drugs. Herein, a series of seven excipient models was prepared by both homopolymerization and copolymerization of 1-vinyl-2-pyrrolidone (VP) and N-isopropylacrylamide (NIPAAm) by free radical polymerization yielding two homopolymers poly(VP) and poly(NIPAAm) and five copolymers of poly(NIPAAm-co-VP) at difference compositions. While the VP monomer provided aqueous solubility at a variety of conditions to the excipient, the incorporation of NIPAAm into the copolymer offered additional hydrogen bond donating sites to optimize the drug-polymer interactions in the system. Due to the presence of NIPAAm, the copolymers were sensitive to temperature as well. It was found that as the proportion of VP was increased (from 0 to 100%), the lower critical solution temperature (LCST) and the water solubility of the polymer models increased. To examine the role of specific drug-polymer interactions during dissolution on drug solubility and bioavailability, the polymers were formulated with the anticonvulsant drug phenytoin, which is a poorly water-soluble BCS class II drug where oral absorption is limited by the drug solubility. Amorphous solid dispersions (ASD) were prepared via spray drying of phenytoin with the polymer excipient models to contain 10% and 25% by weight drug loading. Physical characterization of the ASDs by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) revealed that the polymers held the drug in a high-energy amorphous phase in all the formulations prepared. All ASDs exhibited improved in vitro dissolution rates compared to drug only and physical mixtures of the polymers and the drug. Drug solubility was the highest with the ASDs containing poly(NIPAAm-co-VP) 60:40 and 50:50, which showed a solubility enhancement of near 14-fold increase compared to pure drug, indicating the significance of copolymer composition to improve drug-polymer interactions toward increasing bioavailability.

In Vitro and Ex Vivo Evaluation of Novel Methacrylated Chitosan-PNIPAAm-Hyaluronic Acid Hydrogels Loaded with Progesterone for Applications in Vaginal Delivery.

Miscarriage is defined as the loss of a pregnancy before 24 weeks and administration of progesterone in pregnancy has considerably decreased the risk of premature birth. Progesterone (PGT) starting from the luteal phase stabilizes pregnancy, promotes differentiation of the endometrium, and facilitates the implantation of the embryo. Within the present study, novel hybrid hydrogels based on chitosan methacrylate (CHT), hyaluronic acid (HA), and poly(N-isopropylacrylamide) (PNIPAAm) for vaginal delivery of progesterone were evaluated. The hydrogels were characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) for structural identity assessment and evaluation of their morphological aspects. The ability to swell, the release capacity, enzymatic degradation, cytotoxicity, and mucoadhesion were also reported. The characterized hydrogels demonstrated mucoadhesive properties in contact with the vaginal tissue of swine and bovine origin as substrates, and biodegradability and controlled release in a simulated vaginal environment. Cytocompatibility tests confirmed the ability of the hydrogels and progesterone to support cell viability and growth. The results showed pH-dependent behavior, controlled drug release, good cytocompatibility, and mucoadhesive properties. The hydrogels with higher chitosan amounts demonstrated better bioadhesive properties. This study provides insights into the potential of these hydrogels for the controlled vaginal delivery of progesterone, with promising therapeutic effects and no cytotoxicity observed. The experimental results indicated that a composition with a moderate content of PNIPAAm was suitable for the controlled delivery of progesterone.

Temperature-Responsive Separation Membrane with High Antifouling Performance for Efficient Separation.

Temperature-responsive separation membranes can significantly change their permeability and separation properties in response to changes in their surrounding temperature, improving efficiency and reducing membrane costs. This study focuses on the modification of polyvinylidene fluoride (PVDF) membranes with amphiphilic temperature-responsive copolymer and inorganic nanoparticles. We prepared an amphiphilic temperature-responsive copolymer in which the hydrophilic poly(N-isopropyl acrylamide) (PNIPAAm) was side-linked to a hydrophobic polyvinylidene fluoride (PVDF) skeleton. Subsequently, PVDF-g-PNIPAAm polymer and graphene oxide (GO) were blended with PVDF to prepare temperature-responsive separation membranes. The results showed that temperature-responsive polymers with different NIPAAm grafting ratios were successfully prepared by adjusting the material ratio of NIPAAm to PVDF. PVDF-g-PNIPAAm was blended with PVDF with different grafting ratios to obtain separate membranes with different temperature responses. GO and PVDF-g-PNIPAAm formed a relatively stable hydrogen bond network, which improved the internal structure and antifouling performance of the membrane without affecting the temperature response, thus extending the service life of the membrane.

Empirical Law for the Magnetorheological Effect of Nanocomposite Hydrogels with Magnetite Microparticles.

Hydrogels are functional smart materials which can be tailored by modifying their chemical composition. Further functionalization can be achieved by incorporating magnetic particles into the gel matrix. In this study, a hydrogel with magnetite micro-particles is synthesized and characterized by rheological measurements. Inorganic clay is used as the crosslinking agent, which additionally prevents the sedimentation of the micro-particles during the synthesis of the gel. The mass fractions for the magnetite particles in the synthesized gels range from 10% to 60% in the initial state. Rheological measurements are performed in different degrees of swelling using temperature as a stimulus. The influence of a homogeneous magnetic field is analyzed by a step-wise activation and deactivation during dynamic mechanical analysis. For the evaluation of the magnetorheological effect in the steady states a procedure is developed, which takes occurring drift effects into account. Using the magnetic flux density, the particle volume fraction and the storage modulus as independent parameters, a general product approach is deployed for a regression analysis of the dataset. In the end, an empirical law for the magnetorheological effect in nanocomposite hydrogels can be found.

Mechanism for the Magnetorheological Effect of Nanocomposite Hydrogels with Magnetite Microparticles.

In a previous study, we presented an empirical law for the magnetorheological effect of nanocomposite hydrogels with magnetite microparticles derived from rheological data. In order to understand the underlying processes, we employ computed tomography for structure analysis. This allows the evaluation of the translational and rotational movement of the magnetic particles. Gels with 10% and 3.0% magnetic particle mass content are investigated at three degrees of swelling and at different magnetic flux densities in steady states by means of computed tomography. Since a temperature-controlled sample-chamber is difficult to implement in a tomographic setup, salt is used to deswell the gels instead. Based on the findings of the particle movement, we propose a mechanism using an energy-based approach. This leads to a theoretical law that shows the same scaling behavior as the previously found empirical law.

Thermogelling hydrogel charge and lower critical solution temperature influence cellular infiltration and tissue integration in an ex vivo cartilage explant model.

Thermogelling hydrogels based on poly(N-isopropyl acrylamide) (p[NiPAAm]) and crosslinked with a peptide-bearing macromer poly(glycolic acid)-poly(ethylene glycol)-poly(glycolic acid)-di(but-2-yne-1,4-dithiol) (PdBT) were fabricated to assess the role of hydrogel charge and lower critical solution temperature (LCST) over time in influencing cellular infiltration and tissue integration in an ex vivo cartilage explant model over 21 days. The p(NiPAAm)-based thermogelling polymer was synthesized to possess 0, 5, and 10 mol% dimethyl-γ-butyrolactone acrylate (DBA) to raise the LCST over time as the lactone rings hydrolyzed. Further, three peptides were designed to impart charge into the hydrogels via conjugation to the PdBT crosslinker. The positively, neutrally, and negatively charged peptides K4 (+), zwitterionic K2E2 (0), and E4 (-), respectively, were conjugated to the modular PdBT crosslinker and the hydrogels were evaluated for their thermogelation behavior in vitro before injection into the cartilage explant models. Samples were collected at days 0 and 21, and tissue integration and cellular infiltration were assessed via mechanical pushout testing and histology. Negatively charged hydrogels whose LCST changed over time (10 mol% DBA) were demonstrated to promote the greatest tissue integration when compared to the positive and neutral gels of the same thermogelling polymer formulation due to increased transport and diffusion across the hydrogel-tissue interface. Indeed, the negatively charged thermogelling polymer groups containing 5 and 10 mol% DBA demonstrated cellular infiltration and cartilage-like matrix deposition via histology. This study demonstrates the important role that material physicochemical properties play in dictating cell and tissue behavior and can inform future cartilage tissue engineering strategies.

Capture and Release of Cancer Cells Through Smart Bioelectronics.

Noninvasive collection of target cells such as circulating tumor cells (CTCs) is crucial for biology and medicine research. Conventional methods of cell collection are often complex, requiring either size-dependent sorting or invasive enzymatic reactions. Here, we show the development of a functional polymer film, which combines the thermoresponsive poly(N-isopropylacrylamide) and the conducting poly(3,4-ethylenedioxythiopene)/poly(styrene sulfonate), and its use for the capture and release of CTCs. When coated onto microfabricated gold electrodes, the proposed polymer films are capable of noninvasively capturing and controllably releasing cells while, at the same time, monitoring these processes with conventional electrical measurements.

Temperature-responsive electrospun nanofibers for 'on-off' switchable release of dextran.

We propose a new type of 'smart' nanofiber (NF) with dynamically and reversibly tunable properties for the 'on-off' controlled release of the polysaccharide dextran. The fibers are produced by electrospinning copolymers of N-isopropylacrylamide (NIPAAm) and N-hydroxymethylacrylamide (HMAAm). The OH groups of HMAAm are subsequently crosslinked by thermal curing. The copolymers were successfully fabricated into a well-defined nanofibrous structure with a diameter of about 600-700 nm, and the fibers preserved their morphology even after thermal curing. The resulting crosslinked NFs showed rapid and reversible volume changes in aqueous media in response to cycles of temperature alternation. The fibrous morphology was maintained for the crosslinked NFs even after the cycles of temperature alternation, while non-crosslinked NFs collapsed and dispersed quickly in the aqueous solution. Dextran-containing NFs were prepared by electrospinning the copolymers blended with fluorescein isothiocyanate (FITC)-dextran, and the 'on-off' switchable release of FITC-dextran from the crosslinked NFs was observed. Almost all the FITC-dextran was released from the NFs after six heating cycles, whereas only a negligible amount of FITC-dextran was evolved during the cooling process. The reported incorporation of smart properties into NFs takes advantage of their extremely large surface area and porosity and is expected to provide a simple platform for on-off drug delivery.

Influence of cyclodextrin on the solubility of a classically prepared 2-vinylcyclopropane macromonomer in aqueous solution.

A macromonomer 5 consisting of a polymerizable vinylcyclopropane end group and a poly(N-isopropylacrylamide) (poly(NiPAAm)) chain was obtained from amidation of 1-ethoxycarbonyl-2-vinylcyclopropane-1-carboxylic acid (4) with an amino-terminated poly(NiPAAm) 3 as an example. This macromonomer 5 showed an LCST effect after complexation of the vinyl end group with ß-cyclodextrin in water. Via radical ring-opening copolymerization of 5 and NiPAAm a graft copolymer 8 with a clouding point of 32 °C was synthesized. The branched unsaturated polymer was treated with ozone to cleave the double bonds of the main chain.

Synthetic Thermo-Responsive Terpolymers as Tunable Scaffolds for Cell Culture Applications.

The use of tailored synthetic hydrogels for in vitro tissue culture and biomanufacturing provides the advantage of mimicking the cell microenvironment without issues of batch-to-batch variability. To that end, this work focused on the design, characterization, and preliminary evaluation of thermo-responsive, transparent synthetic terpolymers based on N-isopropylacrylamide, vinylphenylboronic acid, and polyethylene glycol for cell manufacturing and in vitro culture applications. Polymer physical properties were characterized by FT-IR, 1H-NMR, DLS, rheology, and thermal-gravimetric analysis. Tested combinations provided polymers with a lower critical solution temperature (LCST) between 30 and 45 °C. Terpolymer elastic/shear modulus varied between 0.3 and 19.1 kPa at 37 °C. Cellular characterization indicated low cell cytotoxicity on NIH-3T3. Experiments with the ovarian cancer model SKOV-3 and Jurkat T cells showed the terpolymers' capacity for cell encapsulation without interfering with staining or imaging protocols. In addition, cell growth and high levels of pluripotency demonstrated the capability of terpolymer to culture iPSCs. Characterization results confirmed a promising use of terpolymers as a tunable scaffold for cell culture applications.

Osmanthus Fragrans Loaded NIPAAM Hydrogel Promotes Osteogenic Differentiation of MC3T3-E1.

There is an urgent need to find long-acting, natural osteogenesis-promoting drug systems. In this study, first the potential targets and mechanism of osmanthus fragrans (O. fragrans) extract in regulating osteogenic differentiation based on autophagy were analyzed by network pharmacology and molecular docking. Then, osmanthus fragrans was extracted using the ethanol reflux method and an osmanthus fragrans extract loaded Poly N-isopropylacrylamide (OF/NIPAAM) hydrogel was prepared by electron beam radiation. The chemical components of the osmanthus fragrans extract and the microstructure of OF/NIPAAM hydrogels were characterized by ultraviolet-visible spectrophotometry (UV-Vis) and X-ray diffraction (XRD), respectively. Mouse embryonic osteoblast precursor cells MC3T3-E1 were cultured with different concentrations of OF/NIPAAM hydrogel to discover cell proliferation activity by CCK-8 assay. Alkaline phosphatase (ALP) staining and alizarin red staining were used to observe the differentiation and calcification. Through experimental exploration, we found that a total of 11 targets were predicted, which are TP53, CASP3, SIRT1, etc., and osmanthus fragrans had good binding activity to TP53. In vitro, except for proliferation promotion, OF/NIPAAM hydrogel enhanced ALP activity and formation of mineralized nodules of MC3T3-E1 cells at a concentration equal to or less than 62.5 µg/mL (p < 0.05). The addition of autophagy inhibitor 3-methyladenine (3-MA) reduced ALP activity and mineralized nodule formation.

In vivo evaluation of temperature-responsive antimicrobial-loaded PNIPAAm hydrogels for prevention of surgical site infection.

Surgical site infections (SSIs) are a persistent clinical challenge. Local antimicrobial delivery may reduce the risk of SSI by increasing drug concentrations and distribution in vulnerable surgical sites compared to what is achieved using systemic antimicrobial prophylaxis alone. In this work, we describe a comprehensive in vivo evaluation of the safety and efficacy of poly(N-isopropylacrylamide-co-dimethylbutyrolactone acrylamide-co-Jeffamine M-1000 acrylamide) [PNDJ], an injectable temperature-responsive hydrogel carrier for antimicrobial delivery in surgical sites. Biodistribution data indicate that PNDJ is primarily cleared via the liver and kidneys following drug delivery. Antimicrobial-loaded PNDJ was generally well-tolerated locally and systemically when applied in bone, muscle, articulating joints, and intraperitoneal space, although mild renal toxicity consistent with the released antimicrobials was identified at high doses in rats. Dosing of PNDJ at bone-implant interfaces did not affect normal tissue healing and function of orthopedic implants in a transcortical plug model in rabbits and in canine total hip arthroplasty. Finally, PNDJ was effective at preventing recurrence of implant-associated MSSA and MRSA osteomyelitis in rabbits, showing a trend toward outperforming commercially available antimicrobial-loaded bone cement and systemic antimicrobial administration. These studies indicate that antimicrobial-loaded PNDJ hydrogels are well-tolerated and could reduce incidence of SSI in a variety of surgical procedures.

Smart Hydrogels: Preparation, Characterization, and Determination of Transition Points of Crosslinked N-Isopropyl Acrylamide/Acrylamide/Carboxylic Acids Polymers.

Smart hydrogels (SH) were prepared by thermal free radical polymerization of N-isopropyl acrylamide (NIPAAm), acrylamide (AAm) with acrylic acid (A) or maleic acid (M), and N,N'-methylene bisacrylamide. Spectroscopic and thermal characterizations of SHs were performed using FTIR, TGA, and DSC. To determine the effects of SHs on swelling characteristics, swelling studies were performed in different solvents, solutions, temperatures, pHs, and ionic strengths. In addition, cycle equilibrium swelling studies were carried out at different temperatures and pHs. The temperature and pH transition points of SHs are calculated using a sigmoidal equation. The pH transition points were calculated as 5.2 and 4.2 for SH-M and SH-A, respectively. The NIPAAm/AAm hydrogel exhibits a critical solution temperature (LCST) of 28.35 °C, while the SH-A and SH-M hydrogels exhibit the LCST of 34.215 °C and 28.798 °C, respectively, and the LCST of SH-A is close to the body. temperature. Commercial (CHSA) and blood human serum albumin (BHSA) were used to find the adsorption properties of biopolymers on SHs. SH-M was the most efficient SH, adsorbing 49% of CHSA while absorbing 16% of BHSA. In conclusion, the sigmoidal equation or Gaussian approach can be a useful tool for chemists, chemical engineers, polymer and plastics scientists to find the transition points of smart hydrogels.

Characterization of the phase transition mechanism of P(NiPAAm-co-AAc) copolymer hydrogel using 2D correlation IR spectroscopy.

A thermo-responsive polymer, poly(N-isopropylacrylamide) (PNiPAAm), was copolymerized with acrylic acid (AAc) in this study. Its phase transitions during the heating and cooling processes were investigated using IR spectroscopy, principal component analysis (PCA), and two-dimensional correlation spectroscopy (2D-COS). During the heating process, the hydrogen bonding between side chain in P(NiPAAm-co-AAc) copolymer hydrogel and H2O was broken first, and then the formation of the intramolecular interaction in P(NiPAAm-co-AAc) copolymer hydrogel occurred. However, unlike the heating process, intensities of bands in the CH stretching region were changed before those in the CO stretching including the NH bending region during the cooling process. The results indicate that the phase transition of P(NiPAAm-co-AAc) copolymer hydrogel is an irreversible process at the molecular levels.

Calix[4]arene-click-cyclodextrin and supramolecular structures with watersoluble NIPAAM-copolymers bearing adamantyl units: "Rings on ring on chain".

We describe the calixarene-cyclodextrin-coupling via click reaction starting from 5,11,17,23-tetra-tert-butyl-25,27-dipropargylether-26,28-hydroxy-calix[4]arene (calix[4]arene-dipropargylether) (2) onto 6I-azido-6I-deoxycyclomaltoheptaose (3) under microwave assisted conditions. The coupling was proven by MALDI-TOF mass spectrometry, ¹H NMR and IR-spectroscopy. The pH dependent supramolecular complex formation with poly(NIPAAM) bearing attached adamantyl units was investigated by dynamic light scattering (DLS) and turbidity measurements.

Poly(N-isopropylacrylamide)-based dual-crosslinking biohybrid injectable hydrogels for vascularization.

Injectable hydrogels provide a powerful and non-invasive approach for numerous applications in cell transplantation, growth factor delivery, tissue regeneration and so forth. The properties of injectable hydrogels should be well-tuned for specific applications, where their overall design should ensure biocompatibility, non-toxicity, robust mechanical properties, and most importantly the ability to promote vascularization and integration with the host tissue/organ. Among these criteria, vascularization remains a key design element in the development of functional therapeutic hydrogels for successful translation into clinical settings. To that end, there is still a critical need for the development of the next generation of injectable hydrogels with precisely tuned biophysical and biochemical properties which could simultaneously promote tissue vascularization. In this work, we developed a temperature responsive, dual-crosslinking, biohybrid hydrogels, modified with a vasculogenic peptide for applications in regenerative medicine, specifically tissue vascularization. The synthesized hydrogels consisted of poly(N-isopropylacrylamide)-based copolymer, functionalized gelation and angiogenic VEGF-mimetic QK peptide with enhanced shear-thinning and injectability properties. QK peptide is a VEGF-mimetic vasculogenic peptide which binds to VEGF receptors and activates intercellular pathway for vascularization. Apart from the presence of QK peptide, the mechanical properties of the hydrogels were precisely tuned by altering the polymer concentration, enabling successful assembly and endothelial cell network formation. Extended in vitro studies demonstrated successful encapsulation and homogeneous distribution of endothelial cells within the three-dimensional (3D) environment of the hydrogel matrix with significantly enhanced vascularization in presence of the QK peptide as early as 3 days of culture. A small, preliminary in vivo study in mice showed a trend of increased blood vessel formation in hydrogels that incorporated the QK peptide. Overall, our study presents the design and characterization of injectable, dual-crosslinking and vasculogenic hydrogels with controlled properties which could be utilized for numerous applications in regenerative medicine, minimally invasive cell and drug delivery as well as fundamental studies on tissue vascularization and angiogenesis. STATEMENT OF SIGNIFICANCE: In this work, we synthesized a new class of temperature responsive, dual-crosslinking, biohybrid injectable hydrogels with enhanced vascularization properties for broad applications in regenerative medicine and minimally invasive cell/drug delivery. The developed hydrogels properly accommodated 3D culture, assembly and network formation of endothelial cells, as evidenced by in vitro and in vivo studies.

Chitosan based thermosensitive injectable hydrogels for controlled delivery of loxoprofen: development, characterization and in-vivo evaluation.

Oral drug delivery is natural, most acceptable and desirable route for nearly all drugs, but many drugs like NSAIDs when delivered by this route cause gastrointestinal irritation, gastric bleeding, ulcers, and many undesirable effects which limits their usage by oral delivery. Moreover, it is almost impossible to control the release of a drug in a targeted location in body. We developed thermo-responsive chitosan-co-poly(N-isopropyl-acrylamide) injectable hydrogel as an alternative for the gastro-protective and controlled delivery of loxoprofen sodium as a model drug. A free radical polymerization technique was used to synthesize thermo-responsive hydrogel by cross-linking chitosan HCl with NIPAAM using glutaraldehyde as cross-linker. Confirmation of crosslinked hydrogel structure was done by Fourier transform infrared spectra (FTIR). The thermal stability of hydrogel was confirmed through thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The scanning electron microscopy (SEM) was performed to evaluate the structural morphology of cross-linked hydrogel. To evaluate the rheological behavior of hydrogel with increasing temperature, rheological study was performed. Swelling and in vitro drug release studies were carried out under various temperature and pH conditions. The swelling study revealed that maximum swelling was observed at low pH (pH 1.2) and low temperature (25 °C) compared to the high range of pH and temperature and it resulted in quick release of the drug. The high range of pH (7.4) and temperature (37 °C) however caused controlled release of the drug. The in vivo evaluation of the developed hydrogel in rabbits demonstrated the controlled release behavior of fabricated system.

Temperature-Induced Mechanomodulation of Interpenetrating Networks of Star Poly(ethylene glycol)-Heparin and Poly(N-isopropylacrylamide).

Thermoresponsive interpenetrating networks (IPNs) were prepared by sequential synthesis of a biohybrid network of star-shaped poly(ethylene glycol) [starPEG] and heparin and a poly(N-isopropylacrylamide)-polymer network. Amide bond formation was used for cross-linking of the starPEG-heparin network and photo-cross-linking with N,N'-methylenebis(acrylamide) was applied for the formation of the second polymer network. Both networks were linked by chain entanglements and hydrogen bonds only. The obtained sequential IPNs (seq-IPNs) showed temperature-dependent network properties as reflected by swelling and elasticity data as well as by the release of glycosaminoglycan-binding growth factors. The elastic modulus of the seq-IPNs was found to be amplified up to 50-fold upon temperature change from 22 to 37 °C compared to the intrinsic elastic moduli of the two combined networks. The heparin concentration (as well as the complexation of growth factors with the hydrogel-contained heparin) was demonstrated to be variably independent from the mechanical properties (elastic moduli) of the hydrogels. Illustrating the usability of the developed seq-IPN platform for cell fate control, the thermo-modulation of the release of vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP-2) is shown as well as the osteogenic differentiation of human mesenchymal stem cells exposed to stiff and BMP-2 releasing seq-IPNs.