Sustained Release Of Growth Factors Research Articles

Growth factor-loaded ovarian extracellular matrix hydrogels promote in vivo ovarian niche regeneration and enhance fertility in premature ovarian insufficiency preclinical models

Premature ovarian insufficiency (POI) means menopause before 40 years of age affecting about 1% of women. Approaches based on cell therapy and the paracrine effects of stem cells or bioproducts such as platelet-rich plasma have been proposed, but concerns remain about undesired systemic effects, as well as the need to optimize delivery methods through bioengineering methods. This study explores the efficacy of decellularized bovine ovarian cortex extracellular matrix (OvaECM) hydrogels alone and as a growth factor (GF) carrier (OvaECM+GF) in a chemotherapy-induced POI murine model. In vitro assays showed a gradual release of GF from the OvaECM sustained for two weeks. Chemotherapy drastically reduced follicle numbers, but OvaECM+GF treatment restored pre-antral follicle development. Moreover, this treatment notably regenerated the ovarian microenvironment by increasing cell proliferation and microvessel density while reducing chemotherapy-induced apoptosis and fibrosis. Whole-ovary RNA sequencing and gene set enrichment analysis revealed an upregulation of regeneration-related genes and a downregulation of apoptotic pathways. The OvaECM+GF treatment also yielded significantly better outcomes following ovarian stimulation and in vitro fertilization. After two consecutive crossbreeding cycles, OvaECM+GF-treated mice showed normal reproductive function. This research showcases the biocompatibility and efficacy of OvaECM to reverse POI in mice, setting a foundation to explore innovative bioengineering-based POI therapies. Statement of significancePremature ovarian insufficiency (POI) affects about 1% of women worldwide, causing early menopause before 40 years old. Current treatments alleviate symptoms but do not restore ovarian function. This study explores an innovative approach using ovarian cortex extracellular matrix hydrogels to deliver growth factors into the murine ovarian niche and reverse POI. In vitro release kinetic assays demonstrated a gradual and sustained release of growth factors. In a POI-induced mouse model, intraovarian injections of the hydrogel encapsulating growth factors restored pre-antral follicle development, increased cell proliferation, reduced apoptosis and fibrosis, and improved ovarian response and in vitro fertilization outcomes. Long-term benefits included larger litter sizes. This innovative technique shows promise in regenerating the ovarian environment and improving reproductive outcomes.

Enriched advanced platelet-rich fibrin plus gold nanoparticles against Enterococcus faecalis for its potential use in revascularization for necrotic immature permanent teeth

Background: Regenerative endodontic procedures allow reinforcement of root canal wall and continuation of root development, opening new therapeutic possibilities. The root canal system of infected teeth is colonized by a variety of microorganisms, which hinder the regenerative process, leading to treatment failure if not adequately addressed, thereby requiring careful attention to microbial control. Aim and Objective: The aim of the study was to assess the antimicrobial activity of advanced platelet-rich fibrin (A-PRF) and gold nanoparticles (AuNps) against Enterococcus faecalis. Materials and Methods: Intravenous blood (5–6 ml) was drawn from four healthy individuals, and A-PRF was prepared through centrifugation at 1500 revolutions per minute (rpm) for 14 min. A-PRF was doped with 3 µl of AuNps and centrifuged at 1000 rpm for 1 min. Antimicrobial activity was assessed using disk diffusion; inhibition zones were measured. For minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), A-PRF + AuNps were added to the microbial broth at varying concentrations to determine growth inhibition and microbial death. Results: Disk diffusion assays revealed significant antibacterial effects against E. faecalis. Norfloxacin displayed the highest mean zone of inhibition (20.33 ± 1.53 mm), followed by the Test group (A-PRF + AuNPs) (19.33 ± 0.58 mm). Multiple comparisons indicated significant differences (P < 0.001). MIC of A-PRF + AuNPs against E. faecalis was 0.031 mg/ml, with MBC at 0.015 mg/ml. Conclusion: The addition of AuNPs to A-PRF offers the potential for sustained growth factor release while maintaining the sterility of the canal, leading to successful revitalization and regeneration. The combined use of A-PRF + AuNps shows promise for enhancing revascularization in necrotic immature permanent teeth.

Autologous Platelet-rich Fibrin as a Three-dimensional Structural Scaffold in the Healing of Contracted Orbital Sockets.

Evaluation of platelet-rich fibrin as an adjuvant in surface healing of contracted orbital sockets. Prospective, interventional, and comparative study of 25 patients with moderate to severe contracted sockets conducted over 2 years (February 2020-February 2022). Group 1 underwent a dermis-fat graft with fornix forming sutures supplemented by a platelet-rich fibrin membrane, while group 2 received a dermis-fat graft with fornix forming sutures only. Patients over 18 years were evaluated as per prefixed inclusion and exclusion criteria. Assessments were conducted at 1, 3, and 12 months postsurgery, focusing on wound evaluation, socket epithelialization, postoperative pain, prosthesis rehabilitation, and complications, if any. Wound evaluation and pain intensity were assessed utilizing the wound evaluation score and visual analog scale, respectively. Socket epithelization was documented clinically at every visit. The study showed a mean age of 38.8 ± 8.8 years, with a 2:1 male-to-female ratio. Group 1 consistently scored higher on wound evaluation score than group 2 at all follow-up points. In group 1, 81.8% achieved a maximum wound evaluation score at 4 weeks and 100% at 3 and 12 months, compared to group 2's 42.8%, 50%, and 57.1%, respectively (p < 0.05). Postoperative contracture occurred in 3 group 2 patients at the final follow-up, with 6 showing unsatisfactory appearance. Group 1 demonstrated significantly lower pain intensity on postoperative day 1 (p = 0.03), and greater epithelization at 4 weeks. platelet-rich fibrin appears to be an effective solution for enhancing wound healing during socket reconstruction, attributed to its sustained release of growth factors and mesenchymal stem cells.

Injectable, stable, and biodegradable hydrogel with platelet-rich plasma induced by l-serine and sodium alginate for effective treatment of intrauterine adhesions

The combination of pharmacological and physical barrier therapy is a highly promising strategy for treating intrauterine adhesions (IUAs), but there lacks a suitable scaffold that integrates good injectability, proper mechanical stability and degradability, excellent biocompatibility, and non-toxic, non-rejection therapeutic agents. To address this, a novel injectable, degradable hydrogel composed of poly(ethylene glycol) diacrylate (PEGDA), sodium alginate (SA), and l-serine, and loaded with platelet-rich plasma (PRP) (referred to as PSL-PRP) is developed for treating IUAs. l-Serine induces rapid gelation within 1 min and enhances the mechanical properties of the hydrogel, while degradable SA provides the hydrogel with strength, toughness, and appropriate degradation capabilities. As a result, the hydrogel exhibits an excellent scaffold for sustained release of growth factors in PRP and serves as an effective physical barrier. In vivo testing using a rat model of IUAs demonstrates that in situ injection of the PSL-PRP hydrogel significantly reduces fibrosis and promotes endometrial regeneration, ultimately leading to fertility restoration. The combined advantages make the PSL-PRP hydrogel very promising in IUAs therapy and in preventing adhesions in other internal tissue wounds.

Liquid‐Metal‐Loaded Hydrogel with Antibacterial Effect and Sustained Release of Growth Factor for Wound Healing

AbstractMultifunctional medical hydrogels play an important role in wound healing because of their excellent biocompatibility, convenient operation, and drug release capacity. So far, many efforts have been exploited to developing new‐generation hydrogels with distinctive capabilities in promoting wound healing. Herein, the liquid‐metal (LM)‐loaded hydrogels are reported with antibacterial effect under an 808 nm near‐infrared laser irradiation for wound healing therapeutic strategies. The addition of LM droplets enables the hydrogel to control the temperature rise and plays an antibacterial effect with the release of gallium3+ under laser irradiation. Benefiting from the porous network structure of hydrogels, the encapsulated growth factors can be released stably at the wound site. Under the synergistic effect of LM and growth factors in the wound tissue, the hydrogel displays antibacterial features and promotes the regeneration of epithelial tissue and neovascularization, thereby further accelerating wound healing. This hydrogel has proven biosafety and low toxicity in vitro and in vivo. With these advantages, such hydrogel is a promising candidate to be developed as a new medical product for future clinical medicine.

Molybdesum selenide-based platelet-rich plasma containing carboxymethyl chitosan/polyvinyl pyrrolidone composite antioxidant hydrogels dressing promotes the wound healing

Excess free radicals at the wound site can cause an inflammatory response, which is not conducive to wound healing. Hydrogels with antioxidant properties can prevent inflammatory storms by scavenging free radicals from the wound site and inhibiting the release of inflammatory factors. In this study, we prepared the carboxymethyl chitosan (CMCS)/polyvinyl pyrrolidone (PVP)/Molybdenum (IV) Selenide (MoSe2), and platelet-rich plasma (PRP) (CMCS/PVP/MoSe2/PRP) hydrogels for accelerating the repair of wounds. In the hydrogels, the MoSe2 can scavenge various free radicals to reduce oxidative stress at the site of inflammation, endowed the hydrogels with antioxidant properties. Interestingly, growth factors released by PRP assisted the tissue repair by promoting the formation of new capillaries. CMCS as a backbone not only showed good biocompatibility and biodegradability but also played a significant role in maintaining the sustained release of growth factors. In addition, incorporating PVP enhanced the tissue adhesion and mechanical properties. The multifunctional composite antioxidant hydrogels have good swelling properties and biodegradability, which is completely degraded within 28 days. Thus, the antioxidant CMCS/PVP/MoSe2/PRP hydrogels provide a new idea for designing ideal multifunctional wound dressings.

3D Printing of Succulent‐Inspired Microneedle Array for Enhanced Tissue Adhesion and Controllable Drug Release

AbstractControllable and long‐term release remains a great challenge in current drug delivery systems. Benefiting from their efficient drug loading and painless administration, microneedles (MNs) have emerged as a promising platform for transdermal drug delivery, while they often fail to achieve long‐term tissue adhesion and controllable extended drug release. Here, 3D printing of an innovative MN patch is presented with succulent‐inspired responsive microstructures and light‐controllable long‐term release capability. The MN exhibits a reversible shrink‐swell volume change behavior in response to surrounding humidity, which enables sufficient mechanical strength for skin penetration under the shrinkage conditions and efficient long‐term adhesion when swollen in skin tissues. Moreover, the MN patch introduces a controllable long‐term drug release system, achieved through the integration of thiolated heparin (Hep‐SH) for sustained growth factor release and graphene oxide (GO) nanosheets for controlled drug release via near infrared (NIR) laser irradiation. The MN patches with growth factor loading have good biocompatibility and can promote the proliferation, migration, and proangiogenesis of endothelial cells is further demonstrated. Thus, it is believed that such flexible MN patches can be promising candidates for controllable long‐term transdermal drug delivery as well as other related tissue engineering applications.

Biomimetic biphasic microsphere preparation based on the thermodynamic incompatibility of glycosaminoglycan with gelatin methacrylate for hair regeneration

Hair follicle (HF) tissue engineering is promising for hair loss treatment especially for androgenetic alopecia. Physiologically, the initiation of HF morphogenesis relies on the interactions between hair germ mesenchymal and epithelial layers. To simulate this intricate process, in this study, a co-flowing microfluidic-assisted technology was developed to produce dual aqueous microdroplets capturing growth factors and double-layer cells for subsequent use in hair regeneration. Microspheres, called G/HAD, were generated using glycosaminoglycan-based photo-crosslinkable biological macromolecule (HAD) shells and gelatin methacrylate (GelMA) cores to enclose mesenchymal cells (MSCs) and mouse epidermal cells (EPCs). The findings indicated that the glycosaminoglycan-based HAD shells display thermodynamic incompatibility with GelMA cores, resulting in the aqueous phase separation of G/HAD cell spheres. These G/HAD microspheres exhibited favorable characteristics, including sustained growth factor release and wet adhesion properties. After transplantation into the dorsal skin of BALB/c nude mice, G/HAD cell microspheres efficiently induced the regeneration of HFs. This approach enables the mass production of approximately 250 dual-layer microspheres per minute. Thus, this dual-layer microsphere fabrication method holds great potential in improving current hair regeneration techniques and can also be combined with other tissue engineering techniques for various regenerative purposes.

Development of a Nanoparticle System for Controlled Release in Bioprinted Respiratory Scaffolds.

The use of nanoparticle systems for the controlled release of growth factors is a promising approach to mimicking of the biochemical environment of native tissues in tissue engineering. However, sustaining growth factor release inside an appropriate therapeutic window is a challenge, particularly in bioprinted scaffolds. In this study, a chitosan-coated alginate-based nanoparticle system loaded with hepatocyte growth factor was developed and then incorporated into bioprinted scaffolds. The release kinetics were investigated with a focus on identifying the impact of the chitosan coating and culture conditions. Our results demonstrated that the chitosan coating decreased the release rate and lessened the initial burst release, while culturing in dynamic conditions had no significant impact compared to static conditions. The nanoparticles were then incorporated into bioinks at various concentrations, and scaffolds with a three-dimensional (3D) structure were bioprinted from the bioinks containing human pulmonary fibroblasts and bronchial epithelial cells to investigate the potential use of a controlled release system in respiratory tissue engineering. It was found that the bioink loaded with a concentration of 4 µg/mL of nanoparticles had better printability compared to other concentrations, while the mechanical stability of the scaffolds was maintained over a 14-day culture period. The examination of the incorporated cells demonstrated a high degree of viability and proliferation with visualization of the beginning of an epithelial barrier layer. Taken together, this study demonstrates that a chitosan-coated alginate-based nanoparticle system allows the sustained release of growth factors in bioprinted respiratory tissue scaffolds.

Triple-layered core-shell fiber dressings with enduring platelet conservation and sustained growth factor release abilities for chronic wound healing.

Platelet-rich plasma (PRP) is one of the most popular biomaterials in regenerative medicine. However, the difficulties encountered in its preservation, and the requirement for on-demand preparation severely limit its application. In addition, its rapid degradation in the wound microenvironment makes the sustained release of growth factors impossible and finally reduces the therapeutic effect on chronic wounds. Here, a multifunctional dressing based on triple-layered core-shell fibers for loading and enduring preservation of PRP was developed using a one-step coaxial bioprinting technique combined with freeze-drying. The platelets were effectively dispersed and immobilized in the core layer of the fiber, leading to a sustained release of growth factors from the PRP. The rate of release can be controlled by adjusting the triple-layered core-shell structure. Simultaneously, the triple-layered core-shell structure can reduce the deactivation of PRP during freezing and storage. The experimental findings suggest that PRP exhibits sustained activity, facilitating the process of wound healing even after a storage period of 180 days. Furthermore, the protective mechanism of PRP by the triple-layered core-shell fiber was investigated, and the conditions for freeze-drying and storage were optimized, further enhancing the long-term storability of PRP. As a result, the multifunctional core-shell fiber dressings developed in this study offer a novel approach for sustained growth factor release and the enduring preservation of active PRP.

Platelet-rich plasma in orthopedics: Bridging innovation and clinical applications for bone repair.

In the burgeoning domain of orthopedic therapeutic research, Platelet-Rich Plasma (PRP) has firmly established its position, transforming paradigms ranging from tissue regeneration to the management of chondral lesions. This review delves into PRP's recent integrations with cutting-edge interventions such as 3D-printed scaffolds, its role in bone and cartilage defect management, and its enhanced efficacy when combined with molecules like Kartogenin (KGN) for fibrocartilage zone repair. Significant attention is paid to tissue engineering for meniscal interventions, where a combination of KGN, PRP, and bone marrow-derived mesenchymal stem cells are under exploration. Within the sphere of osteochondral regenerative therapy, the synergy of PRP with Bone Marrow Aspirate Concentrate (BMAC) represents a noteworthy leap towards cartilage regeneration. The innovative incorporation of PRP with biomaterials like hydroxyapatite and graphene oxide further underscores its versatility in supporting structural integrity and ensuring sustained growth factor release. However, while PRP's autologous and nontoxic nature makes it an inherently safe option, concerns arising from its preparation methods, particularly with bovine thrombin, necessitate caution. As of 2023, despite the burgeoning promise of PRP in bone healing, the quest for its standardization, optimization, and substantiation through rigorous clinical trials continues. This comprehensive review elucidates the contemporary applications, challenges, and future trajectories of PRP in orthopedics, aiming to spotlight areas primed for further research and exploration.

Lyophilized platelet rich fibrin and gelatin incorporated bioadhesive bone cement composite for repair of mandibular continuity defects

Mandibular continuity defects stem from conditions such as malignancies, trauma, cysts, osteomyelitis and osteoradionecrosis, presenting significant challenges. If mandibular reconstruction fails, it can result in facial collapse, causing significant aesthetic and functional concerns for the patient. In the present study we developed a bio-adhesive Bone Cement (BC) enriched with lyophilised PRF and gelatin to enhance bone repair and induce regeneration. The developed BC consisted of a mixture of Tetracalcium Phosphate (TTCP) and O-Phospho-l-serine (OPLS) in addition to lyophilised Platelet Rich Fibrin (PRF) for sustained growth factor release and gelatin (GE) for improved cement resorption. It is primarily designed for in-situ application, conforming to the shape and size of the defect for effective bone repair and regeneration. The study evaluated four groups: (i) BC (control), (ii) BC-GE (control), (iii) BC-PRF, and (iv) BC-GE-PRF. All the four groups were characterised using FTIR, SEM and XRD. The mechanical studies of the prepared beads exhibited a significant increase in the compressive strength of the PRF loaded bone cement composites. In vitro degradation study of the beads over a 60-day period revealed a significantly higher percentage of bone cement resorption in the gelatin-incorporated groups, BC-GE (44 ± 0.5 %), and BC-GE-PRF (45 ± 2 %). The assessment of growth factor release (TGF-β and VEGF) using ELISA revealed a prolonged and sustained release of both growth factors over a 28-day period. In vitro studies were performed on human Dental Follicle Stem Cells (DFSCs) to assess cell attachment, proliferation, mineralisation and osteogenic differentiation. These studies clearly depicted that BC-PRF and BC-GE-PRF showed significantly greater proliferation of DFSCs. Furthermore, BC-PRF and BC-GE-PRF samples exhibited notably elevated expression of Runx2 and OPN (osteogenic markers), as well as a higher intensity of alizarin red stain (mineralisation). Therefore, it was concluded that PRF incorporated bioadhesive bone cement composites greatly enhance the cell attachment, proliferation, mineralisation and osteogenic differentiation of the DFSCs. Thus, the PRF and gelatin incorporated bone cement composites is expected to facilitate effective and faster bone regeneration and healing in a wide range of dental and maxillofacial defects.

ROS/pH dual responsive PRP-loaded multifunctional chitosan hydrogels with controlled release of growth factors for skin wound healing

Platelet-rich plasma (PRP) contains a variety of growth factors (GFs) and has been used in the treatment of a variety of diseases, including skin lesions. In particular, PRP with low immunogenicity will be more widely used. However, the explosive release of GFs limits its further application. In order to achieve controlled release of GFs, a multifunctional and reactive oxygen species (ROS)/pH dual responsive hydrogel was developed to load PRP derived from human cord blood for the treatment of skin wound healing. Based on the hydrogen bond and Schiff base interaction, carboxymethyl chitosan (CMCS), oxidized dextran (Odex) and oligomeric procyanidins (OPC) were crosslinked to form CMCS/Odex/OPC/PRP hydrogel with good injectability, self-healing, adhesion, ROS scavenging, antibacterial activity, controlled and sustained release of GFs. In vitro cell experiments suggested that this hydrogel possessed excellent biocompatibility and could promote the proliferation and migration of L929. In vivo healing of full-layer skin wounds further indicated that the prepared hydrogel could regulate inflammation and promote epithelialization, collagen deposition, and angiogenesis. In summary, this present study demonstrates that CMCS/Odex/OPC/PRP hydrogel may serve as a promising multifunctional dressing for skin wound healing.

Injectable phase-separated tetra-armed poly(ethylene glycol) hydrogel scaffold allows sustained release of growth factors to enhance the repair of critical bone defects

With the rising prevalence of bone-related injuries, it is crucial to improve treatments for fractures and defects. Tissue engineering offers a promising solution in the form of injectable hydrogel scaffolds that can sustain the release of growth factors like bone morphogenetic protein-2 (BMP-2) for bone repair. Recently, we discovered that tetra-PEG hydrogels (Tetra gels) undergo gel-gel phase separation (GGPS) at low polymer content, resulting in hydrophobicity and tissue affinity. In this work, we examined the potential of a newer class of gel, the oligo-tetra-PEG gel (Oligo gel), as a growth factor-releasing scaffold. We investigated the extent of GGPS occurring in the two gels and assessed their ability to sustain BMP-2 release and osteogenic potential in a mouse calvarial defect model. The Oligo gel underwent a greater degree of GGPS than the Tetra gel, exhibiting higher turbidity, hydrophobicity, and pore formation. The Oligo gel demonstrated sustained protein or growth factor release over a 21-day period from protein release kinetics and osteogenic cell differentiation studies. Finally, BMP-2-loaded Oligo gels achieved complete regeneration of critical-sized calvarial defects within 28 days, significantly outperforming Tetra gels. The easy formulation, injectability, and capacity for sustained release makes the Oligo gel a promising candidate therapeutic biomaterial.

An injectable bioactive dressing based on platelet-rich plasma and nanoclay: Sustained release of deferoxamine to accelerate chronic wound healing.

Delayed diabetic wound healing has placed an enormous burden on society. The key factors limiting wound healing include unresolved inflammation and impaired angiogenesis. Platelet-rich plasma (PRP) gel, a popular biomaterial in the field of regeneration, has limited applications due to its non-injectable properties and rapid release and degradation of growth factors. Here, we prepared an injectable hydrogel (DPLG) based on PRP and laponite by a simple one-step mixing method. Taking advantages of the non-covalent interactions, DPLG could overcome the limitations of PRP gels, which is injectable to fill irregular injures and could serve as a local drug reservoir to achieve the sustained release of growth factors in PRP and deferoxamine (an angiogenesis promoter). DPLG has an excellent ability in accelerating wound healing by promoting macrophage polarization and angiogenesis in a full-thickness skin defect model in type I diabetic rats and normal rats. Taken together, this study may provide the ingenious and simple bioactive wound dressing with a superior ability to promote wound healing.

Zn2+ incorporated composite polysaccharide microspheres for sustained growth factor release and wound healing.

The development of new wound dressings has always been an issue of great clinical importance and research promise. In this study, we designed a novel double cross-linked polysaccharide hydrogel microspheres based on alginate (ALG) and hyaluronic acid methacrylate (HAMA) from gas-assisted microfluidics for wound healing. The microspheres from gas-assisted microfluidics showed an uniform size and good microsphere morphology. Moreover, this composite polysaccharide hydrogel microspheres were constructed by harnessing the fact that zinc ions (Zn2+) can cross-link with ALG as well as histidine-tagged vascular endothelial growth (His-VEGF) to achieve long-term His-VEGF release, thus promoting angiogenesis and wound healing. Meanwhile, Zn2+, as an important trace element, can exert antibacterial and anti-inflammatory effects, reshaping the trauma microenvironment. In addition, photo cross-linked HAMA was introduced into the microspheres to further improve its mechanical properties and drug release ability. In summary, this novel Zn2+ composite polysaccharide hydrogel microspheres loaded with His-VEGF based on a dual cross-linked strategy exhibited synergistic antimicrobial and angiogenic effects in promoting wound healing.

Effects of advanced platelet-rich fibrin on deep partial-thickness burn wounds in nude mice

Effects of advanced platelet-rich fibrin on deep partial-thickness burn wounds in nude mice

Dynamically Cross-Linked Granular Hydrogels for 3D Printing and Therapeutic Delivery.

Granular hydrogels have recently emerged as promising biomaterials for tissue engineering and 3D-printing applications, addressing the limitations of bulk hydrogels while exhibiting desirable properties such as injectability and high porosity. However, their structural stability can be improved with post-injection interparticle cross-linking. In this study, we developed granular hydrogels with interparticle cross-linking through reversible and dynamic covalent bonds. We fragmented photo-cross-linked bulk hydrogels to produce aldehyde or hydrazide-functionalized microgels using chondroitin sulfate. Mixing these microgels facilitated interparticle cross-linking through reversible hydrazone bonds, providing shear-thinning and self-healing properties for injectability and 3D printing. The resulting granular hydrogels displayed high mechanical stability without the need for secondary cross-linking. Furthermore, the porosity and sustained release of growth factors from these hydrogels synergistically enhanced cell recruitment. Our study highlights the potential of reversible interparticle cross-linking for designing injectable and 3D printable therapeutic delivery scaffolds using granular hydrogels. Overall, our study highlights the potential of reversible interparticle cross-linking to improve the structural stability of granular hydrogels, making them an effective biomaterial for use in tissue engineering and 3D-printing applications.

BMP-2 releasing mineral-coated microparticle-integrated hydrogel system for enhanced bone regeneration.

Introduction: Large bone defects (LBD) caused by trauma, infection, and tumor resection remain a significant clinical challenge. Although therapeutic agents such as bone morphogenetic protein-2 (BMP-2), have shown substantial potency in various clinical scenarios, their uncontrollable release kinetics has raised considerable concern from the clinical viewpoint. Mineral-coated microparticle (MCM) has shown its excellent biologics loading and delivery potential due to its superior protein-binding capacity and controllable degradation behaviors; thus, it is conceivable that MCM can be combined with hydrogel systems to enable optimized BMP-2 delivery for LBD healing. Methods: Herein, BMP-2 was immobilized on MCMs via electrostatic interaction between its side chains with the coating surface. Subsequently, MCM@BMP-2 is anchored into a hydrogel by the crosslinking of chitosan (CS) and polyethylene glycol (PEG). Results and Discussion: This microparticle-hydrogel system exhibits good biocompatibility, excellent vascularization, and the sustained release of BMP-2 in the bone defect. Furthermore, it is observed that this microsphere-hydrogel system accelerates bone formation by promoting the expression of osteogenesis-related proteins such as RUNX2, osteopontin, and osteocalcin in bone marrow mesenchymal stem cells (BMSCs). Thus, this newly developed multifunctional microparticle-hydrogel system with vascularization, osteogenesis, and sustained release of growth factor demonstrates an effective therapeutic strategy toward LBD.

A bioactive microparticle-loaded osteogenically enhanced bioprinted scaffold that permits sustained release of BMP-2.

Extrusion-based bioprinting technology is widely used for tissue regeneration and reconstruction. However, the method that uses only hydrogel as the bioink base material exhibits limited biofunctional properties and needs improvement to achieve the desired tissue regeneration. In this study, we present a three-dimensionally printed bioactive microparticle-loaded scaffold for use in bone regeneration applications. The unique structure of the microparticles provided sustained release of growth factor for > 4 weeks without the use of toxic or harmful substances. Before and after printing, the optimal particle ratio in the bioink for cell viability demonstrated a survival rate of ≥ 85% over 7 days. Notably, osteogenic differentiation and mineralization-mediated by human periosteum-derived cells in scaffolds with bioactive microparticles-increased over a 2-week interval. Here, we present an alternative bioprinting strategy that uses the sustained release of bioactive microparticles to improve biofunctional properties in a manner that is acceptable for clinical bone regeneration applications.