Photocrosslinked gelatin/chondroitin sulfate/chitosan-based composites with tunable multifunctionality for bone tissue regeneration.

Novel hydrogel-based multifunctional systems prepared utilizing photocrosslinking and freeze-drying processes (PhotoCross/Freeze-dried) dedicated for bone tissue regeneration are presented. Fabricated materials, composed of methacrylated gelatin, chitosan, and chondroitin sulfate, possess interesting features including bioactivity, biocompatibility, as well as antibacterial activity. Importantly, their degradation and swellability might be easily tuned by playing with the biopolymeric content in the photocrosllinked systems. To broaden the potential application and deliver the therapeutic features, mesoporous silica particles functionalized with methacrylate moieties decorated with hydroxyapatite and loaded with the antiosteoporotic drug, alendronate, (MSP-MA-HAp-ALN) were dispersed within the biopolymeric sol and photocrosslinked. It was demonstrated that the obtained composites are characterized by a significantly extended degradation time, ensuring optimal conditions for balancing hybrids removal with the deposition of fresh bone. We have shown that attachment of MSP-MA-HAp-ALN to the polymeric matrix minimizes the initial burst effect and provides a prolonged release of ALN (up to 22 days). Moreover, the biological evaluation in vitro suggested the capability of the resulted systems to promote bone remodeling. Developed materials might potentially serve as scaffolds that after implantation will fill up bone defects of various origin (osteoporosis, tumour resection, accidents) providing the favourable conditions for bone regeneration and supporting the infections' treatment.

In vitro/ex vivo evaluation of multifunctional collagen/chitosan/hyaluronic acid hydrogel-based alendronate delivery systems.

Injectable hydrogel-based materials have emerged as promising alendronate (ALN) delivery systems for the treatment of osteoporosis. However, their intrinsic permeability limits the sustained delivery of small-molecule drugs. In response to this challenge, we present the multifunctional hybrids composed of mesoporous silica particles decorated with hydroxyapatite and loaded with alendronate (MSP-NH2-HAp-ALN), which are immobilized in collagen/chitosan/hyaluronic acid-based hydrogel. We have mainly focused on the biological in vitro/ex vivo evaluation of developed composites. It was found that the extracts released from tested systems do not exhibit hemolytic properties and are safe for blood elements and the human liver cell model. The resulting materials create an environment conducive to differentiating human bone marrow mesenchymal stem cells and reduce the viability of osteoclast precursors (RAW 264.7). Importantly, even the system with the lowest concentration of ALN caused a substantial cytotoxic effect on RAW 264.7 cells; their viability decreased to 20 % and 10 % of control on 3 and 7 day of culture. Additionally, prolonged ALN release (up to 20 days) with minimized burst release was observed, while material features (wettability, swellability, degradation, mechanical properties) depended on MSP-NH2-HAp-ALN content. The obtained data indicate that developed composites establish a high-potential formulation for safe and effective osteoporosis therapy.

Towards Controlling the Local Bone Tissue Remodeling-Multifunctional Injectable Composites for Osteoporosis Treatment.

Alendronate (ALN) is the most commonly prescribed oral nitrogen-containing bisphosphonate for osteoporosis therapy. However, its administration is associated with serious side effects. Therefore, the drug delivery systems (DDS) enabling local administration and localized action of that drug are still of great importance. Herein, a novel multifunctional DDS system based on the hydroxyapatite-decorated mesoporous silica particles (MSP-NH2-HAp-ALN) embedded into collagen/chitosan/chondroitin sulfate hydrogel for simultaneous osteoporosis treatment and bone regeneration is proposed. In such a system, the hydrogel serves as a carrier for the controlled delivery of ALN at the site of implantation, thus limiting potential adverse effects. The involvement of MSP-NH2-HAp-ALN in the crosslinking process was established, as well as the ability of hybrids to be used as injectable systems. We have shown that the attachment of MSP-NH2-HAp-ALN to the polymeric matrix provides a prolonged ALN release (up to 20 days) and minimizes the initial burst effect. It was revealed that obtained composites are effective osteoconductive materials capable of supporting the osteoblast-like cell (MG-63) functions and inhibiting osteoclast-like cell (J7741.A) proliferation in vitro. The purposely selected biomimetic composition of these materials (biopolymer hydrogel enriched with the mineral phase) allows their biointegration (in vitro study in the simulated body fluid) and delivers the desired physicochemical features (mechanical, wettability, swellability). Furthermore, the antibacterial activity of the composites in in vitro experiments was also demonstrated.

How Efficient are Alendronate-Nano/Biomaterial Combinations for Anti-Osteoporosis Therapy? An Evidence-Based Review of the Literature.

Osteoporosis is defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Because of the systemic nature of osteoporosis, the associated escalation in fracture risk affects virtually all skeletal sites. The problem is serious since it is estimated that more than 23 million men and women are at high risk of osteoporotic-like breakages in the European Union. Alendronate (ALN) is the most commonly prescribed oral nitrogen-containing bisphosphonate (BP) for the prevention and the therapy of osteoporosis. This is also one of the most intensely studied drugs in this field. However, ALN is characterized by restricted oral absorption and bioavailability and simultaneously its administration has serious side-effects (jaw osteonecrosis, irritation of the gastrointestinal system, nausea, musculoskeletal pain, and cardiovascular risks). Therefore, delivery systems enabling controlled release and local action of this drug are of great interest, being widely researched and presented in the literature. In this review, we discuss the current trends in the design of various types of alendronate carriers. Our paper is focused on the most recent developments in the field of nano/biomaterials-based systems for ALN delivery, including nano/microformulations, synthetic/natural polymeric and inorganic materials, hydrogel-based materials, scaffolds, coated-like structures, as well as organic-inorganic hybrids. Topics related to the treatment of complex bone diseases including osteoporosis have been covered in several more general reviews; however, the systems for this particular drug have not yet been discussed in detail.

Clindamycin-Loaded Halloysite Nanotubes as the Antibacterial Component of Composite Hydrogel for Bone Repair.

A new drug delivery system consisting of clindamycin phosphate entrapped in acid-etched halloysite nanotubes was successfully prepared and characterized. It was then used as an antibacterial component of the multicomponent hydrogel designed as a material for bone regeneration. First, halloysite (HNT) was etched and clindamycin phosphate (CP) was entrapped in both raw and modified nanotubes, resulting in HNT-CP and EHNT-CP systems. They were characterized using SEM, TEM, TGA and FTIR; the entrapment efficiency and release of CP from both systems were also studied. EHNT-CP was then used as an antibacterial component of the two hydrogels composed of alginate, collagen and ß-TCP. The hydrogels were prepared using different crosslinking procedures but had the same composition. The morphology, porosity, degradation rate, CP release profile, cytocompatibility, antibacterial activity and ability to induce biomineralization were studied for both materials. The hydrogel obtained by a chemical crosslinking with EDC followed by the physical crosslinking with calcium ions had better properties and was shown to have potential as a bone repair material.

Lysine-functionalized chondroitin sulfate improves the biological properties of collagen/chitosan-based injectable hydrogels.

Novel bioactive collagen/chitosan/lysine-functionalized chondroitin sulfate (CSmod) injectable hydrogels are presented. The modification of CS with amine groups introduced with lysine moieties (the degree of substitution about 21%) guarantees its covalent binding with the hydrogel network while genipin crosslinking. Both the physicochemical and biological features of developed hydrogels might be adjusted by playing with CSmod and crosslinking agent concentrations. It was revealed that materials became more hydrophobic with increased CSmod content, while crosslinking degree and enzymatic degradation studies established the influence of CSmod concentration and Ch:CSmod ratio on the crosslinking process. In situ rheological experiments verified the injectability of resulted systems. The biological in vitro evaluation demonstrated that all designed materials are biocompatible as they supported proliferation and adhesion of MG-63 cell line. In vitro biomineralization study employing simulated body fluid model revealed CSmod-content dependent bioactivity of obtained hydrogels. Importantly for pristine collagen/chitosan materials, the formation of apatite-like structures was not observed. Our findings demonstrate that developed injectable ColChCSmod hydrogels particularly system with the greatest CSmod concentration exhibits high bioactive potential, without the need of applying additional inducers what renders them promising materials within tissue engineering applications.