Synergistic bone regeneration through sequential dual-drug delivery

The clinical use of bioactive molecules in bone regeneration has been known to have side effects, which result from uncontrolled and supraphysiological doses. In this study, we demonstrated the synergistic effect of two bioactive molecules, bone morphogenic protein-2 (BMP-2) and alendronate (ALN), by releasing them in a sequential manner. Collagen-hydroxyapatite composite scaffolds functionalized using BMP-2 are loaded with biodegradable microspheres where ALN is encapsulated. The results indicate an initial release of BMP-2 for a few days, followed by the sequential release of ALN after two weeks. The composite scaffolds significantly increase osteogenic activity owing to the synergistic effect of BMP-2 and ALN. Enhanced bone regeneration was identified at eight weeks post-implantation in the rat 8-mm critical-sized defect. Our findings suggest that the sequential delivery of BMP-2 and ALN from the scaffolds results in a synergistic effect on bone regeneration, which is unprecedented. Therefore, such a system exhibits potential for the application of cell-free tissue engineering.

Sequential Dual-Drug Delivery Biomimetic Hydrogel for Temporal Orchestration of Acute Neuroprotection and Chronic Regeneration in Spinal Cord Injury.

3D-printed scaffold with halloysite nanotubes laden as a sequential drug delivery system regulates vascularized bone tissue healing

Bone healing is a complex process that requires the participation of cells and bioactive factors. Stromal derived factor-1 α (SDF-1α) and magnesium ions (Mg2+) both are significant bioactive factors for cell recruitment and osteogenesis during bone regeneration. Thus, a bifunctional hydrogel containing a sequential delivery system is fabricated to improve osteogenesis. During sequential delivery of the hydrogel, SDF-1α is predominantly released at the early stage of bone mesenchymal stem cells (BMSCs) recruitment, while Mg2+ are constantly delivered at a later stage to improve osteogenic differentiation of recruited cells. In addition, due to the early release of SDF-1α, the hydrogel showed strong BMSCs recruitment and proliferation activity. Mg2+ can not only induce up-regulation of osteogenic gene expression in vitro, but also promote bone tissue and angiogenesis in vivo. Taken together, the injection of xanthan gum-polydopamine crosslinked hydrogel co-loading SDF-1α and Mg2+ (XPMS hydrogel) provides a novel strategy to repair bone defects.

The importance of provision of growth factors in the engineering of tissues has long been shown to control the behavior of the cells within the construct and several approaches were applied toward this end. In nature, more than one type of growth factor is known to be effective during the healing of tissue defects and their peak concentrations are not always simultaneous. One of the most recent strategies includes the delivery of a combination of growth factors with the dose and timing to mimic the natural regeneration cascade. The sequential delivery of bone morphogenetic proteins BMP-2 and BMP-7 which are early and late appearing factors during bone regeneration, respectively, was shown in vitro to enhance osteoblastic differentiation of bone marrow derived mesenchymal stem cells. In the present study, the aim was to study the effectiveness of this delivery strategy in a rabbit iliac crest model. 3D plotted poly(ε-caprolactone) scaffolds were loaded with BMP carrying nanoparticles to achieve: (a) single BMP-2 or BMP-7 delivery, and (b) their combined delivery in a simultaneous or (c) sequential (biomimetic) fashion. After eight weeks of implantation, computed tomography and biomechanical tests showed better mineralized matrix formation and bone-implant union strength at the defect site in the case of sequential delivery compared to single or simultaneous delivery modes. Bone mineral density (BMD) and push-out stress were: 33.65±2.25 g cm−3 and 14.5±2.28 MPa, respectively, and almost 2.5 fold higher in comparison to those without growth factors (BMD: 14.14±1.21 g cm−3; PS: 6.59±0.65 MPa). This study, therefore, supports those obtained in vitro and emphasizes the importance of mimicking the natural timing of bioavailability of osteogenic factors in improving the regeneration of critical-sized bone defects.

Mediating bone regeneration by means of drug eluting implants: From passive to smart strategies

An all-silk-derived functional nanosphere matrix for sequential biomolecule delivery and in situ osteochondral regeneration

Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration

Dual-function hydrogels with sequential release of GSK3β inhibitor and VEGF inhibit inflammation and promote angiogenesis after stroke

Drug combination therapies employing dual-drug delivery systems offer an effective approach to reduce disadvantages of single-drug therapy, such as high dose and easy generation of drug resistance. Herein, a dual-drug delivery system based on nanogel-incorporated injectable hydrogel (NHG) was designed for sequential local delivery of combretastatin-A4 phosphate (CA4P) and doxorubicin (DOX) for antiangiogenesis and anticancer combination therapy. The injectable hydrogel was prepared for loading and quick release of hydrophilic drug CA4P, while the pH and redox stimuli-responsive nanohydrogels were incorporated into the injectable hydrogel by pH-responsive boronate ester bond for sustained long-term DOX delivery. The dual-drug-loaded NHG system released CA4P and DOX sequentially and exhibited high inhibitory activities on the cancer cell proliferation in vitro. It displayed superior therapeutic efficacy in vivo with only one single injection. Immunohistochemistry analyses suggested a synergistic therapeutic effect through tumor vascular collapse caused by CA4P and tumor cell apoptosis induced by DOX. The combination therapy of antiangiogenic and cytotoxic drugs using NHG delivery system offers a promising approach for improved cancer therapeutic efficacy. The nanogel-embedded injectable hydrogel can be employed as a universal drug carrier for local dual-drug delivery with sequential release behaviors by simple injection.

PLGA/PDLLA core–shell submicron spheres sequential release system: Preparation, characterization and promotion of bone regeneration in vitro and in vivo

Binary polymer systems provide significant advantages in the preparation of materials used in biomedical applications. To highlight the importance and need of binary polymer systems in biomedical applications; utilisations of nano-carrier and fibre are discussed in detail in terms of their use as biomaterial, and their potential for further development with focus on dual and sequential drug delivery applications. On the other hand, in fibre technology, creation of binary polymer systems have been investigated using spinning processes such as electrospinning and even more recently innovated pressurised gyration. How these methods can be used to promote the mass production of binary polymer systems with various morphologies and characteristics are elucidated. The effects of different polymer materials, including solvents, mechanical properties, and the rate of degradation of polymers, are discussed. Current polymer blending systems and manufacturing processes are analysed, and technologies for biomaterials are carefully considered with up to date details.

Author response for "Dual and sequential drug delivery systems with antimicrobial and bone regenerative therapeutic effects"

Review for "Dual and sequential drug delivery systems with antimicrobial and bone regenerative therapeutic effects"

Bone defect healing is often compromised by infections acquired during surgery, hindering regeneration. An effective solution should first prevent infection and then promote bone repair. Localised drug-delivery systems capable of dual and sequential release of antimicrobial and bone-regenerative agents represent a promising solution; however, precisely controlling this sequential release remains an unmet challenge. To address this issue, this study explores a novel approach by developing delivery systems based on either hollow or non-hollow porous bioceramics with an alginate hydrogel matrix, resulting in cutting-edge systems with a controlled, stage-specific release of antimicrobial and bone regenerative agents that meet the clinical needs. Gentamicin served as the antimicrobial agent, while raloxifene and/or alendronate represented hydrophobic and hydrophilic bone-regenerative agents. The systems were evaluated for release profiles, kinetic modelling, and the effects of lyophilisation and sterilisation (using ethylene oxide or supercritical CO2) on drug stability and release kinetics. The release followed a precise dual-sequential pattern: gentamicin was released over 2-3 weeks, followed by another 2-3 weeks of bone-regenerative agents. Kinetic model fitting showed that gentamicin release was driven mainly by diffusion (with or without hydrogel swelling), and raloxifene/alendronate release was dominated by a mixture of diffusion and polymeric matrix swelling/erosion. Lyophilisation and sterilisation preserved release profiles, though timeframes shifted slightly, with supercritical CO2 causing minimal delay. Gentamicin retained strong antimicrobial activity post-processing, confirming the system's potential for infection control and bone repair.