Titanium alloy composited with dual-cytokine releasing polysaccharide hydrogel to enhance osseointegration via osteogenic and macrophage polarization signaling pathways

Titanium alloy has been widely used in orthopedic surgeries as bone defect filling. However, the regeneration of high-quality new bones is limited due to the pro-inflammatory microenvironment around implants, resulting in a high occurrence rate of implant loosening or failure in osteological therapy. In this study, extracellular matrix (ECM)-mimetic polysaccharide hydrogel co-delivering BMP-2 and IL-4 was composited with 3D printed titanium alloy to promote the osseointegration and regulate macrophage response to create a pro-healing microenvironment in bone defect. Notably, it is discovered from the bioinformatics data that IL-4 and BMP-2 could affect each other through multiple signal pathways to achieve a synergistic effect towards osteogenesis. The composite scaffold significantly promoted the osteoblast differentiation and proliferation of human bone marrow mesenchyme stem cells (hBMSCs). The repair of large-scale femur defect in rat indicated that the dual-cytokine-delivered composite scaffold could manipulate a lower inflammatory level in situ by polarizing macrophages to M2 phenotype, resulting in superior efficacy of mature new bone regeneration over the treatment of native titanium alloy or that with an individual cytokine. Collectively, this work highlights the importance of M2-type macrophages-enriched immune-environment in bone healing. The biomimetic hydrogel-metal implant composite is a versatile and advanced scaffold for accelerating in vivo bone regeneration, holding great promise in treating orthopedic diseases.

Composite Cerium Oxide Nanoparticles - Containing Polysaccharide Hydrogel as Effective Agent for Burn Wound Healing

A high risk of complications in burn injuries is associated with the development of systemic inflammatory response syndrome. Thermal injury (burn) causes the release of cytokines and prostaglandia, resulting in increased interaction between leukocytes, platelets and endothelial cells. Activation of leukocytes leads to an increase in the formation of reactive oxygen species (ROS) and nitrogen, which is normally compensated by the activation of protective antioxidant enzymes. An imbalance between the activity of the radical-producing and antioxidant systems leads to an excess of free radicals and the development of oxidative stress. Oxidative stress limits the repair of damaged tissue and also leads to localized chronic inflammation. Thus, the removal of inflammation and a decrease in the ROS level, which exceeds the physiological level in the burn zone, seems to be expedient for accelerating the healing process of burn injuries of the skin. In this study, we used a polysaccharide hydrogel modified with cerium dioxide (CeO2) nanoparticles, which have unique anti-inflammatory and antioxidant properties, as an effective agent for the treatment of thermal burns. It has been shown that modification of the hydrogel with CeO2 nanoparticles provides accelerated healing of a model burn wound in rats. Already on the 5th day after the treatment of damage to the skin with the modified hydrogel, a decrease in the area of ​​the burn wound that is different from the control is observed. The use of a hydrogel accelerates the healing process of a burn wound on the 25th day by 25.42% (p <0.05) and ensures complete healing of burn wounds on average 5 days earlier in comparison with the control group with Levomekol ointment. Treatment of burn wounds using a hydrogel leads to the formation of a small post-burn scar. Thus, a polysaccharide hydrogel modified with CeO2 nanoparticles can be considered as an effective wound healing agent in the treatment of thermal burns and skin lesions of various etiologies.

Editing the Shape Morphing of Monocomponent Natural Polysaccharide Hydrogel Films

Shape-morphing hydrogels can be widely used to develop artificial muscles, reconfigurable biodevices, and soft robotics. However, conventional approaches for developing shape-morphing hydrogels highly rely on composite materials or complex manufacturing techniques, which limit their practical applications. Herein, we develop an unprecedented strategy to edit the shape morphing of monocomponent natural polysaccharide hydrogel films via integrating gradient cross-linking density and geometry effect. Owing to the synergistic effect, the shape morphing of chitosan (CS) hydrogel films with gradient cross-linking density can be facilely edited by changing their geometries (length-to-width ratios or thicknesses). Therefore, helix, short-side rolling, and long-side rolling can be easily customized. Furthermore, various complex artificial 3D deformations such as artificial claw, horn, and flower can also be obtained by combining various flat CS hydrogel films with different geometries into one system, which can further demonstrate various shape transformations as triggered by pH. This work offers a simple strategy to construct a monocomponent hydrogel with geometry-directing programmable deformations, which provides universal insights into the design of shape-morphing polymers and will promote their applications in biodevices and soft robotics.

EMBR-31. DEVELOPMENT OF INJECTABLE POLYSACCHARIDE HYDROGEL TO ENHANCE DRUG PENETRATION IN PEDIATRIC BRAIN TUMORS

Improving unacceptable low response rates and reducing acute and long-term morbidities remain significant challenges in pediatric neuro-oncology. Chemotherapy is an effective primary or adjuvant treatment for pediatric disease, but current administration approaches hinder the pharmacological activity exerted by chemotherapy treatments. Barriers in the route of drug administration and in the tumor microenvironment limit anticancer drugs from penetrating tissue efficiently and reaching all cancer cells. Strategies have been proposed to overcome these barriers with hope of leading to sustained and elongated drug exposure in solid tumors. However, few methods have been explored to design drug delivery systems to circumvent these barriers with potential to enhance drug penetration and reduce adverse systemic side effects in treating pediatric brain tumors. In this study, we validate an injectable polysaccharide hydrogel capable of releasing drugs locally at tumor site, sustaining drug concentration, and eliciting tumor response. We synthesized a hydrogel with dimethyl sulfoxide (DMSO) incorporating amylopectin, a polysaccharide found in starch, loaded with doxorubicin. We determined the structure of doxorubicin is not altered when released from the hydrogel through characterization of drug-loaded and unloaded hydrogels, suggesting drug is encapsulated in the hydrogel network and is able to maintain structure to induce mechanism of action. We tested sustained release of drug and therapeutic efficacy in vitro with DAOY, a medulloblastoma cell line. Our approach demonstrates that local drug delivery presents potential to enhance drug penetration in pediatric brain tumors by sustaining drug concentration at tumor site for an extended period of time. Local drug delivery systems have been investigated for decades but few have been investigated for treatment of pediatric brain tumors. For researchers, physicians, and clinicians, this research can lead to a greater effort to improve current outcomes of conventional drug treatment and provide an opportunity to address current challenges in pediatric oncology.