Sustained Release Of Vancomycin Research Articles

3D-printed porous titanium rods equipped with vancomycin-loaded hydrogels and polycaprolactone membranes for intelligent antibacterial drug release

Implant-related infections pose significant challenges to orthopedic surgeries due to the high risk of severe complications. The widespread use of bioactive prostheses in joint replacements, featuring roughened surfaces and tight integration with the bone marrow cavity, has facilitated bacterial proliferation and complicated treatment. Developing antibacterial coatings for orthopedic implants has been a key research focus in recent years to address this critical issue. Researchers have designed coatings using various materials and antibacterial strategies. In this study, we fabricated 3D-printed porous titanium rods, incorporated vancomycin-loaded mPEG750-b-PCL2500 gel, and coated them with a PCL layer. We then evaluated the antibacterial efficacy through both in vitro and in vivo experiments. Our coating passively inhibits bacterial biofilm formation and actively controls antibiotic release in response to bacterial growth, providing a practical solution for proactive and sustained infection control. This study utilized 3D printing technology to produce porous titanium rod implants simulating bioactive joint prostheses. The porous structure of the titanium rods was used to load a thermoresponsive gel, mPEG750-b-PCL2500 (PEG: polyethylene glycol; PCL: polycaprolactone), serving as a novel drug delivery system carrying vancomycin for controlled antibiotic release. The assembly was then covered with a PCL membrane that inhibits bacterial biofilm formation early in infection and degrades when exposed to lipase solutions, mimicking enzymatic activity during bacterial infections. This setup provides infection-responsive protection and promotes drug release. We investigated the coating’s controlled release, antibacterial capability, and biocompatibility through in vitro experiments. We established a Staphylococcus aureus infection model in rabbits, implanting titanium rods in the femoral medullary cavity. We evaluated the efficacy and safety of the composite coating in preventing implant-related infections using imaging, hematology, and pathology. In vitro experiments demonstrated that the PCL membrane stably protects encapsulated vancomycin during PBS immersion. The PCL membrane rapidly degraded at a lipase concentration of 0.2 mg/mL. The mPEG750-b-PCL2500 gel ensured stable and sustained vancomycin release, inhibiting bacterial growth. We investigated the antibacterial effect of the 3D-printed titanium material, coated with PCL and loaded with mPEG750-b-PCL2500 hydrogel, using a rabbit Staphylococcus aureus infection model. Imaging, hematology, and histopathology confirmed that our composite antibacterial coating exhibited excellent antibacterial effects and infection prevention, with good safety in trials. Our results indicate that the composite antibacterial coating effectively protects vancomycin in the hydrogel from premature release in the absence of bacterial infection. The outer PCL membrane inhibits bacterial growth and prevents biofilm formation. Upon contact with bacterial lipase, the PCL membrane rapidly degrades, releasing vancomycin for antibacterial action. The mPEG750-b-PCL2500 gel provides stable and sustained vancomycin release, prolonging its antibacterial effects. Our composite antibacterial coating demonstrates promising potential for clinical application.

Vancomycin-encapsulated hydrogel loaded microarc-oxidized 3D-printed porous Ti6Al4V implant for infected bone defects: Reconstruction, anti-infection, and osseointegration

Infected bone defect is a formidable clinical challenge. Conventional approaches to prevention and treatment for infected bone defects are unsatisfactory. The key elements of the treatment are bone defect reconstruction, anti-infection, and osteogenesis. Conventional treatment methods remain unsatisfactory owing to the absence of composite integrating materials with anti-infective, and osteogenic activities as well as proper mechanical strength at the same time. In this study, we fabricated a vancomycin-encapsulated hydrogel with bacteria-responsive release properties combined with a shaved porous (submicron-micron) three-dimensional-printed Ti6Al4V implant. The implant surface, modified with submicron-sized pores through microarc oxidation (MAO), showed enhanced osteogenic activity and integrated well with the hydrogel drug release system, enabling sustained vancomycin release. In vitro experiments underscored the commendable antibacterial ability, biosafety, and osteoinductive potential. Effective antibacterial and osteogenic abilities of the implant were further demonstrated in vivo in infected rabbit bone defects. These results showed that the vancomycin-encapsulated hydrogel-loaded microarc-oxidized 3D-printed porous Ti6Al4V can repair the infected bone defects with satisfactory anti-infection and osseointegration effects.

Electrospun Chitosan-Based Nanofibrous Coating for the Local and Sustained Release of Vancomycin.

As the population ages, the number of vascular surgery procedures performed increases. Older adults often have multiple comorbidities, such as diabetes and hypertension, that increase the risk of complications from vascular surgery including vascular graft infection (VGI). VGI is a serious complication with significant morbidity, mortality, and healthcare costs. Here, we aimed to develop a nanofibrous chitosan-based coating for vascular grafts loaded with different concentrations of the vancomycin antibiotic vancomycin (VAN). Blending chitosan with poly(vinyl alcohol) or poly(ethylene oxide) copolymers improved solubility and ease of spinning. Thermal gravimetric analysis and Fourier transform infrared spectroscopy confirmed the presence of VAN in the nanofibrous membranes. Kinetics of VAN release from the nanofibrous mats were evaluated using high-performance liquid chromatography, showing a burst followed by sustained release over 24 h. To achieve longer sustained release, a poly(lactic-co-glycolic acid) coating was applied, resulting in extended release of up to 7 days. Biocompatibility assessment using human umbilical vein endothelial cells demonstrated successful attachment and viability of the nanofiber patches. Our study provides insights into the development of a drug delivery system for vascular grafts aimed at preventing infection during implantation, highlighting the potential of electrospinning as a promising technique in the field of vascular surgery.

Hydrogel delivery of DNase I and liposomal vancomycin to eradicate fracture-related methicillin-resistant staphylococcus aureus infection and support osteoporotic fracture healing.

Fracture-related infection (FRI) is a devastating complication in orthopedic surgery. A recent study showed that FRI causes more severe infection and further delays healing in osteoporotic bone. Moreover, bacterial biofilm formed on implants cannot be eradicated by systemic antibiotics, warranting novel treatments.Here, we developed a DNase I and Vancomycin hydrogel delivery vehicle to eradicate Methicillin-resistant Staphylococcus aureus (MRSA) infection in vivo. Vancomycin was encapsulated in liposomes, and DNase I and Vancomycin/liposomal-Vancomycin was loaded on thermosensitive hydrogel. In vitro drug release test showed a burst release of DNase I (77.2%) within 72h and sustained release of Vancomycin (82.6%) up to day 14. The in vivo efficacy was evaluated in a clinically relevant ovariectomy (OVX) induced osteoporotic metaphyseal fracture model with MRSA infection, and a total of 120 Sprague Dawley rats were used. In the OVX with infection group, biofilm development caused a drastic inflammatory response, trabecular bone destruction, and non-union. In the DNase I and Vancomycin co-delivery hydrogel group (OVX-Inf-DVG), bacteria on bone and implant were eradicated. X-ray and micro-CT showed preservation of trabecular bone and bone union. HE staining showed the absence of inflammatory necrosis, and fracture healing was restored. The local elevation of TNF-α and IL-6 and increased number of osteoclasts were prevented in the OVX-Inf-DVG group. Our findings suggest that dual release of DNase I and Vancomycin initially followed by Vancomycin only later up to 14 days effectively eliminates MRSA infection, prevents biofilm development and provides a sterile environment to promote fracture healing in osteoporotic bone with FRI. STATEMENT OF SIGNIFICANCE: The biofilm on implants are difficult to eradicate, causing recurrent infection and non-union in fracture-related infection (FRI). Here we developed a hydrogel therapy with high in vivo efficacy to eliminate MRSA biofilm infection in a clinically-relevant FRI model in osteoporotic bone. By loading DNase I and vancomycin/liposomal-vancomycin on thermosensitive poly-(DL-lactic acidco-glycolic acid) (PLGA)-polyethylene glycol (PEG)-PLGA hydrogel, a dual release of DNase I and Vancomycin was achieved whilst preserving enzyme activity. In this model, the progressive development of infection caused a drastic inflammatory response, osteoclastogenesis, trabecular bone destruction, and non-union of fracture. These pathological changes were successfully prevented by the dual delivery of DNase I and vancomycin. Our findings provide a promising strategy for FRI in osteoporotic bone.

Strong adhesive and drug-loaded hydrogels for enhancing bone–implant interface fixation and anti-infection properties

The bonding strength of the bone–titanium (Ti) implant interface is critical for patients undergoing joint replacement. However, current bone adhesives used in clinic have shortcomings, such as biological inertness, cytotoxicity, and lack of osteogenic ability. In this study, a simple and low-cost hydrogel-based bone adhesive was prepared to improve the osseointegration ability and anti-infection ability of the bone–implant interface. A multifunctional hydrogel was prepared by incorporating nano-hydroxyapatite (HA) on polyethyleneimine (PEI) and polyacrylic acid (PAA) (PEI/PAA–HA). It was shown that PEI/PAA–HA hydrogel exhibited good self-healing and strong adhesive ability. The adhesive strengths of bone–Ti and Ti–Ti were measured as 2.30 ± 0.15 MPa and 1.07 ± 0.07 MPa, respectively. Vancomycin (VAN) was loaded into the PEI/PAA–HA hydrogel (PEI/PAA–HA-VAN) via a simple immersion method. The PEI/PAA-HA-VAN showed excellent antibacterial effect by sustained release of VAN. In addition, the PEI/PAA-HA-VAN hydrogel exhibited excellent cytocompatibility promoting the expression of osteogenic genes and the deposition of mineralized matrix. Collectively, this strong adhesive hydrogel showed great potential in enhancing bone-implant interface fixation.

Controlled Release Mechanism of Vancomycin from Double-Layer Poly-L-Lactic Acid-Coated Implants for Prevention of Bacterial Infection.

Implantation failure due to bacterial infection incurs significant medical expenditure annually, and treatment tends to be complicated. This study proposes a method to prevent bacterial infection in implants using an antibiotic delivery system consisting of vancomycin loaded into poly-L-lactic acid (PLLA) matrices. A thin layer of this antibiotic-containing polymer was formed on stainless steel surfaces using a simple dip-coating method. SEM images of the polymeric layer revealed a honeycomb structure of the PLLA network with the entrapment of vancomycin molecules inside. In the in vitro release study, a rapid burst release was observed, followed by a sustained release of vancomycin for approximately 3 days. To extend the release time, a drug-free topcoat of PLLA was introduced to provide a diffusion resistance layer. As expected, the formulation with the drug-free topcoat exhibited a significant extension of the release time to approximately three weeks. Furthermore, the bonding strength between the double-layer polymer and the stainless steel substrate, which was an important property reflecting the quality of the coating, significantly increased compared to that of the single layer to the level that met the requirement for medical coating applications. The release profile of vancomycin from the double-layer PLLA film was best fitted with the Korsmeyer–Peppas model, indicating a combination of Fickian diffusion-controlled release and a polymer relaxation mechanism. More importantly, the double-layer vancomycin-PLLA coating exhibited antibacterial activity against S. aureus, as confirmed by the agar diffusion assay, the bacterial survival assay, and the inhibition of bacterial surface colonization without being toxic to normal cells (L929). Our results showed that the proposed antibiotic delivery system using the double-layer PLLA coating is a promising solution to prevent bacterial infection that may occur after orthopedic implantation.

Preparation and Characterization of Vancomycin-Loaded Microsphere Composite Scaffolds

Objective: To fabricate and characterize sustained release antibacterial microsphere composite scaffolds for bone tissue engineering. Methods: First, poly(lactic acid glycolic acid) (PLGA) copolymer, chitosan (CS), and hyaluronic acid (HA) were used to prepare porous microspheres by the emulsion method. Vancomycin (VA) hydrochloride was loaded onto the microspheres (VA@PLGA-CS-HA) for sustained release of drug, after which hydroxyapatite (HAP) was added (VA@PLGA-CS-HA/HAP). The detailed in vitro characterization of the antibacterial sustained-release microspheres was performed using various techniques including the Cell Counting Kit-8 assay; hemolysis, osteogenic, and antibacterial experiments; scanning electron microscopy (SEM); and mechanical testing. Results: SEM showed that the sustained-release PLGA-CS-HA microspheres had a regular spherical shape, and the composite scaffolds of VA@PLGA-CS-HA/HAP microspheres were compact in structure. The relative colony-forming unit was less than 3% after 14 d of intervention. Cytotoxicity testing revealed that the relative growth rate of MC3T3-E1 and MG-63 osteoblast cells was more than 80% when the concentration of VA did not exceed 50 mg/mL. The mechanical strength of the scaffolds was comparable to that of human cancellous bone. The composite scaffolds enhanced the alkaline phosphatase activity of MG-63 cells and promoted the mRNA expression of osteogenic genes such as runt-related transcription factor 2, osteocalcin, osteopontin, and collagen. Conclusion: VA@PLGA-CS-HA microspheres can control the slow and sustained release of VA in vitro. The VA@PLGA-CS-HA/HAP microsphere composite scaffolds has a slower degradation rate and good antibacterial and mechanical properties in vitro.

Development and pharmacological evaluation of vancomycin loaded chitosan films

Burn injuries are the most prevalent and devastating form of skin trauma. Current study aimed to fabricate novel chitosan-based composite films of vancomycin for wound healing applications. The developed vancomycin-chitosan films were evaluated for various quality attributes and were subjected to anti-bacterial activity against methicillin resistant Staphylococcus aureus (MRSA) and wound healing efficacy study in rat model. The prepared vancomycin-chitosan film 2 (VCF2) physically displayed a substantial tensile strength and swelling ratio. Pharmacologically, VCF2 exhibited sustained vancomycin release, excellent antibacterial activity and improved wound healing efficacy in rats. The superior wound healing potential was ascribed to the enhanced levels of reduced glutathione, glutathione-S-transferase, catalase and decreased lipid peroxidation. Furthermore, improved angiogenesis, granulation, epidermal regeneration and down regulation in the expressions of tumor necrosis factor, cyclooxygenase-2 and nuclear factor kappa B were the reasons of improved wound healing as confirmed by histopathological and molecular techniques. Thus, it is plausible to say that VCF2 could provide a potential therapeutic approach in burn wounds.

Supramolecular self-assembled drug delivery system (SADDs) of vancomycin and tocopherol succinate as an antibacterial agent: in vitro, in silico and in vivo evaluations

In this study self-assembled drug delivery system (SADDs) composed of a hydrophobic d-α-tocopherol succinate (TS) and a hydrophilic vancomycin (VCM) were formulated, and its potential for enhancing the antibacterial activity of VCM against Staphylococcus aureus (SA) and Methicillin-resistant Staphylococcus aureus (MRSA) were explored. The SADDs were synthesized via supramolecular complexation, then characterized for in silico, in vitro and in vivo studies. In silico studies confirmed the self-assembly of VCM/TS into NPs. The size, surface charge and drug loading of the SADDs was ˂100 nm, −27 mV and 68%, respectively. The SADDs were non-hemolytic and biosafe. A sustained release of VCM from SADDs was noted, with 52.2% release after 48 hr. The in vitro antibacterial test showed a twofold decrease in Minimum inhibitory concentration (MIC) against SA and MRSA, and a significantly higher reduction in MRSA biofilms compared to bare VCM. Further, in silico studies confirmed strong and stable binding of TS to MRSA efflux pumps. The in vivo study using mice skin infection models showed a 9.5-fold reduction in bacterial load after treatment with SADDs, in comparison with bare VCM. These findings affirmed that VCM/TS NPs as a promising novel nano-delivery for treating bacterial infections.

Sustained release of vancomycin from bacterial cellulose membrane as dural substitutes for anti-inflammatory wound closure in rabbits.

To reduce the incidence of infection after craniocerebral operation, a type of bacterial cellulose, which can be used as a promising vehicle for the sustained release of vancomycin bacterial cellul...

Sustainable release of vancomycin from micro-arc oxidised 3D-printed porous Ti6Al4V for treating methicillin-resistant Staphylococcus aureus bone infection and enhancing osteogenesis in a rabbit tibia osteomyelitis model.

Elimination of infection and enhancement of osteogenesis by orthopaedic implants are two critical factors in the treatment of complex bone infections. A prolonged and expensive procedure requiring two surgical steps and a 6-8-week period of joint immobilisation is utilised as a primary treatment for revision arthroplasty of an infected prosthesis, greatly affecting long-term patient care for the ageing population. Here, we evaluated the effects of vancomycin-loaded in micro-arc oxidised (MAO) three-dimensional (3D) printed porous Ti6Al4V scaffolds on osteogenesis. This system showed a high loading capacity and sustained vancomycin release kinetics, as demonstrated using high-performance liquid chromatography. In vivo, 0.1 mL of 108 colony forming units (CFU) methicillin-resistant Staphylococcus aureus was injected into the tibias of rabbits to induce severe osteomyelitis. Physical, haematological, radiographic, microbiological, and histopathological analyses were performed to evaluate the effects of treatment. Rabbits with vancomycin-loaded in MAO scaffolds showed the inhibition of bone infection and enhancement of osteogenesis, resulting in better outcomes than in the other groups. Overall, these findings demonstrated the potential of this 3D printed porous Ti6Al4V, with good osteogenesis and sustained vancomycin release properties, for application in the treatment of complex bone infections.

Novel two-chain fatty acid-based lipids for development of vancomycin pH-responsive liposomes against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA)

The development of bacterial resistance against antibiotics is attributed to poor localisation of lethal antibiotic dose at the infection site. This study reports on the synthesis and use of novel two-chain fatty acid-based lipids (FAL) containing amino acid head groups in the formulation of pH-responsive liposomes for the targeted delivery of vancomycin (VAN). The formulated liposomes were characterised for their size, polydispersity index (PDI), surface charge and morphology. The drug-loading capacity, drug release, cell viability, and in vitro and in vivo efficacy of the formulations were investigated. A sustained VAN release profile was observed and in vitro antibacterial studies against S. aureus and MRSA showed superior and prolonged activity over 72 h at both pH 7.4 and 6.0. Enhanced antibacterial activity at pH 6.0 was observed for the DOAPA-VAN-Lipo and DLAPA-VAN-Lipo formulations. Flow cytometry studies indicated a high killing rate of MRSA cells using DOAPA-VN-Lipo (71.98%) and DLAPA-VN-Lipo (73.32%). In vivo studies showed reduced MRSA recovered from mice treated with formulations by four- and two-folds lower than bare VN treated mice, respectively. The targeted delivery of VAN can be improved by novel pH-responsive liposomes from the two-chain (FAL) designed in this study.

Antimicrobial Activity of 3D-Printed Poly(ε-Caprolactone) (PCL) Composite Scaffolds Presenting Vancomycin-Loaded Polylactic Acid-Glycolic Acid (PLGA) Microspheres.

BackgroundThe aim of this study was to design and test a novel composite scaffold with antibacterial efficacy for treating bone infections using a three-dimensional (3D) printed poly(ɛ-caprolactone) (PCL) scaffold coated with polydopamine (PDA) for the adsorption of polylactic acid-glycolic acid (PLGA) microspheres loaded with vancomycin.Material/MethodsVancomycin-loaded PLGA microspheres were produced by the double-emulsion method, and microsphere morphology, drug-loading dosage, encapsulation efficiency, average diameter, and release characteristics were examined. Composite scaffolds were prepared by adsorption of the microspheres on PDA-coated, 3D-printed PCL scaffolds, and scaffold morphology, biocompatibility, vancomycin release, and antibacterial efficacy were evaluated.ResultsThe vancomycin-loaded microspheres were smooth, round, uniform in size, and had no adhesion phenomenon, and exhibited sustained release of vancomycin from the microspheres for more than 4 weeks. Upon modification with PDA, the PCL scaffold changed from white to black, and after microsphere adsorption, dot-like white particles were seen. On scanning electron microscopy, PDA particles were observed on the PCL/PDA composite scaffolds, and PLGA microspheres were evenly dispersed over the PDA coating on the PCL/PDA/PLGA composite scaffolds. Cell viability assays showed that the adhesion and proliferation of rabbit bone mesenchymal stem cells were greater on the PCL/PDA scaffolds than on unmodified PCL scaffolds. Microsphere adsorption had no significant effect on cell proliferation. In vitro release of vancomycin from the composite scaffolds was observed for more than 4 weeks, and observation of the inhibition zone on agar plates of Staphylococcus aureus showed that the scaffolds maintained their antibacterial effect for more than 4 weeks.ConclusionsThe 3D-printed, PDA-coated PCL scaffold carrying vancomycin-loaded PLGA microspheres exhibited good biocompatibility and a sustained antibacterial effect in vitro.

Antibiotic Elution and Mechanical Strength of PMMA Bone Cement Loaded With Borate Bioactive Glass.

Introduction: Local delivery of antibiotics using bone cement as the delivery vehicle is an established method of managing implant-associated orthopedic infections. Various fillers have been added to cement to increase antibiotic elution, but they often do so at the expense of strength. This study evaluated the effect of adding a borate bioactive glass, previously shown to promote bone formation, on vancomycin elution from PMMA bone cement.Methods: Five cement composites were made: three loaded with borate bioactive glass along with 0, 1, and 5 grams of vancomycin and two without any glass but with 1 and 5 grams vancomycin to serve as controls. The specimens were soaked in PBS. Eluate of vancomycin was collected every 24 hours and analyzed by HPLC. Orthopedic-relevant mechanical properties of each composite were tested over time.Results: The addition of borate bioactive glass provided an increase in vancomycin release at Day 1 and an increase in sustained vancomycin release throughout the treatment period. An 87.6% and 21.1% increase in cumulative vancomycin release was seen for both 1g and 5g loading groups, respectively. Compressive strength of all composites remained above the weight-bearing threshold of 70 MPa throughout the duration of the study with the glass-containing composites showing comparable strength to their respective controls.Conclusion: The incorporation of borate bioactive glass into commercial PMMA bone cement can significantly increase the elution of vancomycin. The mechanical strength of the cement-glass composites remained above 70 MPa even after soaking for 8 weeks, suggesting their suitability for orthopedic weight-bearing applications.

Chitosan nanoparticles and povidone iodine containing alginate gel for prevention and treatment of orthopedic implant associated infections

Orthopedic Implant associated infections (OIAIs) are the most serious complications in the orthopedic surgery. Such complications are of major concern unless encountered during initial stages of contamination due to the bacterial biofilm formation. Thus, our aim is to eradicate bacteria at the early stages of infection. Herein, we develop a vancomycin-loaded chitosan nanoparticles (CNPs) and povidone-iodine (PI) containing in situ alginate (CNPs-PI-Alg) gel for antibacterial and antibiofilm activity, respectively. The CNPs were synthesized by ionic gelation method and the processing parameters were optimized to attain nanoparticles of 200–250 nm size and 37.13 ± 3.18 mV charge. A PI-loaded in situ alginate (PI-Alg) gel served as a carrier wherein, the CNPs were incorporated to attain sustained release of an antibacterial agent. The CNPs-PI-Alg gel showed more stability and mechanical properties compared to the Blank-Alg gel. The CNPs-PI-Alg gel exhibited sustained release of vancomycin and PI over a period of 10–15 days. The hemolysis and cytocompatibility studies demonstrated the safety and biocompatibility of CNPs-PI-Alg gel. Furthermore, significant antibacterial and antibiofilm effect against Staphylococcus aureus showed that the CNPs-PI-Alg in situ gel has a potential for the prevention of OIAIs.

Polydopamine-assisted functionalization of heparin and vancomycin onto microarc-oxidized 3D printed porous Ti6Al4V for improved hemocompatibility, osteogenic and anti-infection potencies

Enhanced antiinfection activities, improved hemocompatibility and osteo-compatibility, and reinforced osseointegration are among the most important considerations in designing multifunctional orthopedic biomaterials. Hereby, anti-infective and osteogenic multifunctional 3D printed porous Ti6Al4V implant with excellent hemocompatibility was successfully designed and fabricated. In brief, osteogenic micro-arc oxidation (MAO) coatings with micro/nanoscale porous topography were generated in situ on 3D printed Ti6Al4V scaffolds, on which heparin and vancomycin were easily immobilized. The surface microstructure, morphology, and chemical compositions were characterized employing scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). High loading capacity and sustained vancomycin release profiles were revealed using high performance liquid chromatography (HPLC). Favorable antibacterial and antibiofilm performances against pathogenic Staphylococcus aureus ( S. aureus ) were validated in vitro through microbial viability assays, Live/Dead bacterial staining, and crystal violet staining. Human mesenchymal stem cells (hMSCs) were seeded on the scaffolds and their proliferation and viability were assessed using Cell Counting Kit and Live/Dead cell viability kit. Further, osteoblastic differentiation abilities were evaluated using alkaline phosphatase (ALP) activity as a hall marker. Additionally, the improved hemocompatibility of the heparinized scaffolds was confirmed by activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT). Overall, our results show that the surface-modified 3D printed porous Ti6Al4V possesses balanced antibacterial and osteogenic functions while exhibiting extra anticlotting effects, boding well for future application in customized functional reconstruction of intricate bone defects.

Antimicrobial Properties and Osteogenicity of Vancomycin-Loaded Synthetic Scaffolds Obtained by Supercritical Foaming.

Advanced porous synthetic scaffolds are particularly suitable for regeneration of damaged tissues, but there is the risk of infections due to the colonization of microorganisms, forming biofilms. Supercritical foaming is an attractive processing method to prepare bone scaffolds, regulating simultaneously the porosity and loading of bioactive compounds without loss of activity. In this work, scaffolds made of poly-ε-caprolactone (50 kDa), containing chitosan and an antimicrobial agent (vancomycin), were processed by supercritical CO2 foaming for bone regeneration purposes. The obtained scaffolds showed a suitable combination of morphological (porosity, pore size distribution, and interconnectivity), time-dependent in vitro vancomycin release behavior and biological properties (cell viability and proliferation, osteodifferentiation, and tissue-scaffold integration). The scaffolds sustained vancomycin release for more than 2 weeks. Finally, the antimicrobial activity of the scaffolds was tested against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria after 24 h of incubation with full growth inhibition for S. aureus.

Mesoporous silica nanoparticles/gelatin porous composite scaffolds with localized and sustained release of vancomycin for treatment of infected bone defects.

Treatment of infected bone defects still remains a formidable clinical challenge, the design of bone implants with the controlled release of antibiotics is now regarded as a powerful strategy for infection control and bone healing. In this study, we fabricated a composite scaffold based on vancomycin (Van) loaded mesoporous silica nanoparticles (Van@MSNs) and a gelatin matrix. The microscopic structure of the gelatin-based composite scaffolds was characterized as highly porous. By the addition of MSNs, an enhancement in the compression property of MSNs-incorporated composite scaffolds was observed. The Van could release from the Van@MSNs incorporated composite scaffold in a sustained-release manner with a minimal burst, and thus effectively inhibit the growth of Staphylococcus aureus in a subsequent in vitro antibacterial study. In addition, the drug-loaded composite scaffold showed no unfavorable effects on the proliferation and differentiation of bone mesenchymal stem cells (BMSCs), confirming good biocompatibility. Moreover, in vivo results demonstrated that the antibiotic-loaded composite scaffold could significantly reduce bacterial contamination while promoting bone healing. Thus, our results suggest that the fabricated Van@MSNs/Gelatin composite scaffold with a localized and sustained release of antibiotics is a promising biomaterial for treating infected bone defects.

Dual Function Injectable Hydrogel for Controlled Release of Antibiotic and Local Antibacterial Therapy.

We present vancomycin-loaded dual-function injectable hydrogel that delivers antibiotic locally suitable for treatment of infections in avascular or necrotic tissues. The syringe-deliverable gels were developed using polydextran aldehyde and an inherently antibacterial polymer N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride along with vancomycin. The antibiotic was primarily encapsulated via reversible imine bonds formed between vancomycin and polydextran aldehyde in the hydrogel which allowed sustained release of vancomycin over an extended period of time in a pH-dependent manner. Being inherently antibacterial, the gels displayed excellent efficacy against bacteria due to dual mode of action (killing bacteria upon contact as well as by releasing antibiotics into surroundings). Upon subcutaneous implantation, the gel was shown to kill methicillin-resistant Staphylococcus aureus (>99.999%) when bacteria were introduced directly into the gel as well as at distal site from the gel in a mice model. These materials thus represent as novel noninvasive drug-delivery device suitable for local antibiotic therapy.

Electrospun Nanofibrous Silk Fibroin Membranes Containing Gelatin Nanospheres for Controlled Delivery of Biomolecules.

Development of novel and effective drug delivery systems for controlled release of bioactive molecules is of critical importance in the field of regenerative medicine. Here, oppositely charged gelatin nanospheres are incorporated into silk fibroin nanofibers through a colloidal electrospinning technique. A novel fibrous nano-in-nano drug delivery system is fabricated without the use of any organic solvent. The distribution of fluorescently labeled gelatin A and B nanospheres inside the nanofibers can be fine-tuned by simple adjustment of the weight ratio between the nanospheres and the relative feeding rate of core and shell solutions containing nanospheres by using single and coaxial nozzle electrospinning, respectively. Incorporation of vancomycin-loaded gelatin B nanospheres into the silk fibroin nanofibrous membranes results in a more sustained release of vancomycin, compared to the gelatin nanospheres free membranes. In addition, these membranes exhibit excellent and prolonged antibacterial effects against Staphylococcus aureus. Moreover, these membranes support the attachment, spreading, and proliferation of periodontal ligament cells. These results suggest that the beneficial properties of gelatin nanospheres can be exploited to improve the biological functionality of electrospun nanofibrous silk fibroin membranes.