Fabrication of ulcer-adhesive oral keratin hydrogel for gastric ulcer healing in a rat.

Hydrogel has been used for in suit gastric ulcer therapy by stopping bleeding, separating from ulcer from gastric fluids and providing extracellular matrix scaffold for tissue regeneration, however, this treatment guided with endoscopic catheter in most cases. Here, we developed an oral keratin hydrogel to accelerate the ulcer healing without endoscopic guidance, which can specially adhere to the ulcer because of the high-viscosity gel formation on the wound surface in vivo. Approximately 50% of the ulcer-adhesive keratin hydrogel can resident in ethanol-treated rat stomach within 12 h, while approximately 18% of them maintained in health rat stomach in the same amount of time. Furthermore, Keratin hydrogels accelerated the ethanol-induced gastric ulcer healing by stopping the bleeding, preventing the epithelium cells from gastric acid damage, suppressing inflammation and promoting re-epithelization. The oral administration of keratin hydrogel in gastric ulcer treatment can enhance the patient compliance and reduce the gastroscopy complications. Our research findings reveal a promising biomaterial-based approach for treating gastrointestinal ulcers.

Preparation and mechanism of hydroxyapatite hollow microspheres with different surface charge by biomimetic method.

To meet the different application requirements in various fields, hydroxyapatite (HA) hollow microspheres with different surface charge were synthesized successfully by biomimetic method using Ca(NO3)2·4H2O and (NH4)2HPO4 in the presence of polyethylene glycol (PEG). Scanning electron microscopy (SEM), High-resolution TEM (HRTEM), X-ray powder diffraction (XRD), and Zeta PALS were used to characterize the obtained samples. The results indicated that the concentration of PEG and temperature significantly affect the morphology of the obtained samples. After incubation for 5 d, the HA hollow microspheres with positive surface charge, HA spherical nanoparticles with surface charge close to zero and calcium deficiency HA (d-HA) hollow microspheres with negative surface charge were obtained respectively in the presence of 5% PEG, 6% PEG and 7% PEG at 15 °C. Brunauer-Emmett-Teller (BET) revealed that the specific surface area of HA hollow microspheres reached 98.50 m2/g, while that of HA spherical nanoparticles were only 4.12 m2/g, hollow microspheres show a better application prospect. The possible formation mechanism was also discussed. Ca/P molar ratio >1.67, the surface charge of HA hollow microspheres inclines to be positive. Ca/P molar ratio <1.67, the surface charge of d-HA hollow microspheres tends to be negative.

Rhein-PEG-nHA conjugate as a bone targeted drug delivery vehicle for enhanced cancer chemoradiotherapy.

Bone-targeted therapies have been the choice of treatments for cancer metastases in bone to minimize skeletal morbidity and preserve patients' quality of life. Rhein is of particular interest due to its high bone affinity. Here we reported a novel Rhein- polyethylene glycol (PEG)-nano hydroxyapatite (nHA) conjugate to deliver doxorubicin (DOX) and Phosphorus-32 (32P) simultaneously for enhanced cancer chemo-radiotherapy. The synthetic Rhein-PEG-nHA conjugates were sphere in shape with an average diameter of ~120 nm. Their morphology, drug release and bone affinity were confirmed in vitro. The release profiles of DOX depend on pH condition, but 32P exhibited good stability. Rhein-PEG-nHA also showed high bone affinity in vivo, and the tumor volume decreased after the DOX@Rhein-PEG-nHA and 32P@Rhein-PEG-nHA treatments. Most importantly, the DOX/32P@Rhein-PEG-nHA showed the strongest inhibition on the growth of bone metastases of breast cancer. We revealed the potential of Rhein-PEG-nHA in combined chemo-radiation treatment for bone metastases of breast cancer.

Fabrication of an expandable keratin sponge for improved hemostasis in a penetrating trauma.

Effective hemostasis improvements for penetrating traumas remain a research priority for civilian and noncivilian applications. Herein, we fabricated an expandable keratin sponge (EKS) for the hemostatic treatment of a penetrating trauma based on the excellent hemostatic ability of keratin and the expandable property of polyacrylamide (PAM). EKSs with semi-interpenetrating networks were fabricated by radical polymerization of keratin and PAM, and the EKS showed rapid expansion upon blood absorption. This sponge exhibited effective hemostasis on a rat penetrating liver hemorrhage, and the expansion of the EKS was dependent on the bleeding volume. In addition, the results of a shear wave elastography analysis showed that the elasticity of the liver tissue increased from 12.5 kPa to 21.2 kPa after the penetrating liver trauma treated by the EKS, and the mechanical strength of the liver tissue was maintained after 1 h of the EKS application. Further in vivo tests indicated the effectiveness of the EKS for hemostasis in a swine femoral artery transection hemorrhage model. This EKS is promising for hemostatic applications.

Thermo-sensitive keratin hydrogel against iron-induced brain injury after experimental intracerebral hemorrhage.

In situ keratin hydrogel offer a promising strategy to relieve the brain injury after intracerebral hemorrhage (ICH) by delivering the iron chelator directly to the stroke site. However, the injectable property of traditional keratin hydrogel is unsatisfactory, which can't provide adaptable filling of lesion defects with irregular shapes. Herein, the thermo sensitive keratin-g-PNIPAM polymers with different graft ratios were synthesized, and deferoxamine mesylate (DFO) loaded thermo sensitive keratin hydrogels (TKGs) were prepared using the oxidative crosslinking method. The lower critical solution temperature of TKGs can be tailored from 28.5 to 31.8 °C by varying the graft ratios of keratin to NIPAM, and TKG can fill up the complex shapes of lesion cavities easily due to the characteristic of sol-gel transition. In addition, TKGs exhibit stronger adsorption and clearance capacities for the Fe2+ than keratin gel. Meanwhile, in situ injection of TKG with different DFO loadings (0.1, 1.0, and 10 mg/mL) into the hematoma region after ICH surgery showed a stronger effect on the reduction of ICH-induced iron deposits, brain non-heme iron content, brain edema and ROS level compared to the DFO treatment by intraperitoneal administration. Thus, the developed TKG can be potentially exploited for iron-induced brain injury after ICH.

An enhanced charge-driven intranasal delivery of nicardipine attenuates brain injury after intracerebral hemorrhage.

Intranasal drug delivery provided an alternative and effective approach for the intervention of an intracerebral hemorrhage (ICH). However, the short retention time at the absorption site and slow drug transport in intranasal gel influence the drug bioavailability and outcome of ICH. Herein, we fabricated a novel intranasal gel with oriented drug migration utilizing a charge-driven strategy to attenuate brain injury after ICH. Nicardipine hydrochloride (NCD) was entrapped in chitosan nanoparticles (CS NPs) and dispersed in an HAMC gel. Subsequently, one side of the gel was coated with a positively charged film. The oriented migration of CS NPs in the HAMC gel was determined, and the drug bioavailability was also enhanced. Furthermore, a blood-induced ICH rat model was established to evaluate the therapeutic effect of CS NPs + HAMC composites. Intranasal administration of the CS NPs + HAMC (+) composite showed a stronger neuroprotective effect in terms of brain edema reduction and neural apoptosis inhibition compared to the CS NPs + HAMC composite. These results suggested that the oriented and rapid drug transport from nose to brain can be achieved using the charge-driven strategy, and this intranasal drug delivery system has the potential to provide a new therapeutic strategy for the treatment of ICH.

Development of keratin nanoparticles for controlled gastric mucoadhesion and drug release.

BACKGROUND: Nanotechnology-based drug delivery systems have been widely used for oral and systemic dosage forms delivery depending on the mucoadhesive interaction, and keratin has been applied for biomedical applications and drug delivery. However, few reports have focused on the keratin-based mucoadhesive drug delivery system and their mechanisms of mucoadhesion. Thus, the mucoadhesion controlled kerateine (reduced keratin, KTN)/keratose (oxidized keratin, KOS) composite nanoparticles were prepared via adjusting the proportion of KTN and KOS to achieve controlled gastric mucoadhesion and drug release based on their different mucoadhesive abilities and pH-sensitive properties. Furthermore, the mechanisms of mucoadhesion for KTN and KOS were also investigated in the present study. RESULTS: The composite keratin nanoparticles (KNPs) with different mass ratio of KTN to KOS, including 100/0 (KNP-1), 75/25 (KNP-2), 50/50 (KNP-3), and 25/75 (KNP-4), displayed different drug release rates and gastric mucoadhesion capacities, and then altered the drug pharmacokinetic performances. The stronger mucoadhesive ability of nanoparticle could supply longer gastric retention time, indicating that KTN displayed a stronger mucoadhesion than that of KOS. Furthermore, the mechanisms of mucoadhesion for KTN and KOS at different pH conditions were also investigated. The binding between KTN and porcine gastric mucin (PGM) is dominated by electrostatic attractions and hydrogen bondings at pH 4.5, and disulfide bonds also plays a key role in the interaction at pH 7.4. While, the main mechanisms of KOS and PGM interactions are hydrogen bondings and hydrophobic interactions in pH 7.4 condition and were hydrogen bondings at pH 4.5. CONCLUSIONS: The resulting knowledge offer an efficient strategy to control the gastric mucoadhesion and drug release of nano drug delivery systems, and the elaboration of mucoadhesive mechanism of keratins will enable the rational design of nanocarriers for specific mucoadhesive drug delivery.

[The effect of a simulated inflammation procedure in simulated body fluid on bone-like apatite formation on porous HA/beta-TCP bioceramics].

The formation of bone-like apatite on porous HA/beta-TCP bioceramics in dynamic simulated body fluid (SBF) undergoing a simulated inflammation procedure (pH = 6.5) was investigated in order to study the mechanism of osteoinduction and build a new method to choose biomaterials with better bioactivity. The results showed that the surface of porous HA/beta-TCP bioceramics which underwent a simulated inflammation procedure in dynamic SBF was more smooth. The light acidity in the simulated inflammation procedure would dissolve the fine grains and the parts possessing smaller curvature radius on the surface of porous HA/beta-TCP bioceramics, which would reduce the bioceramics solubility. Followed in normal SBF (pH = 7.4), the amount of bone-like apatite formed on the porous HA/beta-TCP bioceramics was less than that of porous HA/beta-TCP bioceramics incubation in normal SBF all along. The results also showed that the amount of bone-like apatite formed on the porous HA/beta-TCP bioceramics sintered by a microwave plasma was more than that of porous HA/beta-TCP bioceramics sintered by a conventional furnace.