Sequential treatment of infectious bone defects with 3D-printed body temperature-responsive shape memory scaffold coated with metal-polyphenol layers

Treatment of infected lower limb bone defects using the bone transport with locking plate technique (BTLP): A retrospective case series of 90 patients.

There is no consensus for the management of critical infected bone defects. The purpose of this study was to produce a vancomycin-impregnated electrospun polycaprolactone (PCL) membrane for the treatment of infected critical bone defects, and test it in a rabbit model. Electrospinning produced a resorbable PCL fiber membrane containing vancomycin approximately 1 mm in thickness, with a pore diameter of <10 μm. Femur defects were made in the limbs of 18 rabbits and infected with Staphylococcus aureus. The rabbits were divided into three groups according to treatment: (1) Experimental group: rabbit freeze-dried allogeneic bone graft and the vancomycin-PCL membrane. (2) Control group 1: bone graft. (3) Control group 2: vancomycin-PCL membrane only. Culture showed no difference in osteoclast activity between the three groups. Transwell testing showed that almost no fibroblasts passed through the membrane during the first 24 h, but some fibroblasts were able to pass it after 72 h. At 12 weeks after surgery, there was significantly less inflammatory cell infiltration in the experimental compared to the control groups. New bone formation and fracture bone callus were greater in the experimental group than control groups. We thus conclude the resorbable electrospun vancomycin-impregnated PCL membrane was effective at controlling bone infection, and in the regeneration of bone in a critical bone defect animal model.

We fabricated a biodegradable antibiotic-eluting poly(d,l)-lactide-co-glycolide nanofiber-loaded deproteinized bone (ANDB) scaffold that provided sustained delivery of vancomycin to repair methicillin-resistant Staphylococcus aureus bone defects. To fabricate the biodegradable ANDB, poly(d,l)-lactide-co-glycolide and vancomycin were first dissolved in 1,1,1,3,3,3-hexafluoro-2-propano. The solution was then electrospun to produce biodegradable antibiotic-eluting membranes that were deposited on the surface of bovine deproteinized cancellous bone. We used scanning electron microscopy to determine the properties of the scaffold. Both elution and high-performance liquid chromatography assays were used to evaluate the invitro vancomycin release rate from the ANDB scaffold. Three types of scaffolds were co-cultured with bacteria to confirm the invitro antibacterial activity. The infected bone defect rabbit model was induced by injecting 10(7) colony forming units of a methicillin-resistant Staphylococcus aureus strain into the radial defect of rabbits. Animals were then separated into treatment groups and implanted according to the following scheme: ANDB scaffold in group A, poly(d,l)-lactide-co-glycolide nanofiber-loaded deproteinized bone (NDB) scaffold with intravenous (i.v.) vancomycin in group B, and NDB scaffold alone in group C. Treatment efficacy was evaluated after eight weeks using radiological, microbiological, and histological examinations. Invitro results revealed that biodegradable ANDB scaffolds released concentrations of vancomycin that were greater than the minimum inhibitory concentration for more than four weeks. Bacterial inhibition tests also confirmed antibacterial efficacy lasted for approximately four weeks. Radiological and histological scores obtained invivo revealed significant differences between groups A, B and C. Importantly, group A had significantly lower bacterial load and better bone regeneration when compared to either group B or C. Collectively, these results show that our fabricated ANDB scaffolds possess: (1) effective bactericidal activity against methicillin-resistant Staphylococcus aureus, (2) the ability to promote site-specific bone regeneration, and (3) the potential for use in the treatment of infected bone defects.

Background Treating infectious bone defects combined with large soft-tissue lesions poses significant clinical challenges. Herein, we introduced a modified two-stage treatment approach involving the implantation of 3D-printed prostheses and flap repair to treat large segmental infectious tibial bone defects. Method We conducted a retrospective study of 13 patients treated at our center between April 2018 and March 2022 for tibial infections owing to posttraumatic infection and chronic osteomyelitis combined with soft tissue defects. The average defect length was 14.0 cm (range, 5.7–22.9 cm). The flap area ranged from 14 × 5 to 15 × 8 + 25 × 15 cm. Sural neurocutaneous, lesser saphenous neurocutaneous, and local fasciocutaneous flaps were used to repair the skin defects. In the second stage, 3D-printed prostheses were designed and implanted. Union rate, complications, and functional outcomes were assessed at the final follow-up. Result The average follow-up period was 31.1 months (range, 17–47 months), with an average interval of 208.1 days (range, 139–359 days) between the two stages. According to our criteria, 7 of the 13 patients achieved radiographic healing without intervention. Two patients developed prosthesis-related complications and underwent revision surgery. Two patients experienced recurrent infections leading to prosthesis removal and debridement surgery, with the infection ultimately eradicated in one and the other undergoing amputation. Three patients experienced noninfectious flap-related complications, however, all eventually healed through surgical intervention. Conclusion The use of 3D-printed porous titanium prostheses combined with flap soft-tissue repair for the treatment of infectious tibial bone defects did not increase the rate of infection recurrence and provided good functional recovery, offering more options for the treatment of infectious bone defects.

Dual-functional thermosensitive hydrogel for reducing infection and enhancing bone regeneration in infected bone defects

The treatment of infected bone defects remains a challenge due to the complex biological processes involved, including antibacterial, anti-inflammatory, angiogenesis and bone regeneration. Polyetherimide (PEI) has promising applications in orthopaedics, but its biological inertness limits its clinical efficacy. In this study, a smart near-infrared (NIR) light and magnetic field responsive 3D printed scaffold was developed by combining PEI and Fe3O4nanoparticles. Gelatin methacrylate hydrogel containing aloe-emodin (AE), a natural antimicrobial and antioxidant compound, was subsequently injected into the 3D printed scaffold to create the P-Fe3O4@GM-AE composite scaffold. This composite scaffold exhibited several key functionalities: Firstly, it effectively eliminated methicillin-resistantStaphylococcus aureuswhen exposed to NIR light, achieving anin vivoantimicrobial rate of 99.97 ± 0.1%. Secondly, it effectively removed reactive oxygen species and prevented the pro-inflammatory M1 polarization of macrophages in the infected bone defect microenvironment, creating favorable conditions for bone reconstruction. Moreover, during the reconstruction stage, the magnetic composite scaffold, when combined with a static magnetic field, promoted osteogenesis-angiogenesis coupling, thereby accelerating bone repair. Thus, this study provides new insights and methods for the sequential treatment of infected bone defects.

Innervation Innervation is the initiating factor for bone regeneration and plays a key regulatory role in subsequent vascularization, ossification, and mineralization processes. A biomaterial that can induce skeletal-associated neural network reconstruction and bone regeneration with high antibacterial activity is proposed for the treatment of infected bone defects. In article 2201349, Tingfang Sun, Zhiqiang Luo, Xiaodong Guo, and co-workers load magnesium-modified black phosphorus nanosheets (BP@Mg) in GelMA for the treatment of infected bone defects. The photosensitive hydrogel has a strong antibacterial activity and improves the local microenvironment. BP@Mg promotes the secretion of Schwann cells and the outgrowth of CGRP+ sensory nerve fibers, thus enhancing the nerve–bone crosstalk and finally realizing innerved bone regeneration.

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

The clinical treatment of infectious bone defects is difficult and time-consuming due to the coexistence of infection and bone defects, and the simultaneous control of infection and repair of bone defects is considered a promising therapy. In this study, a dual-drug delivery scaffold system was fabricated by the combination of a three-dimensional (3D) printed scaffold with hydrogel for infected bone defects repair. The 3D printed polycaprolactone scaffold was incorporated with biodegradable mesoporous silica nanoparticles containing the small molecular drug fingolimod (FTY720) to provide structural support and promote angiogenesis and osteogenesis. The vancomycin (Van)-loaded hydrogel was prepared from aldehyde hyaluronic acid (AHA) and carboxymethyl chitosan (NOCC) by the Schiff base reaction, which can fill the pores of the 3D-printed scaffold to produce a bifunctional composite scaffold. The in vitro results demonstrated that the composite scaffold had Van concentration-dependent antimicrobial properties. Furthermore, the FTY720-loaded composite scaffold demonstrated excellent biocompatibility, vascularization, and osteogenic ability in vitro. In the rat femoral defect model with bacterial infection, the dual-drug composite scaffold showed a better outcome in both infection control and bone regeneration compared to other groups. Therefore, the prepared bifunctional composite scaffold has potential application in the treatment of infected bone defects.

&amp;nbsp;Treatment of large bone defects remains a clinical challenge, especially for defects compounded by infection. It is essential to develop dual functional therapeutic systems that inhibit bacterial growth and promote bone regeneration for infected bone defects treatment. However, the ideal bone substitute biomaterials to repair infected bone defects remain scarce. In this study, we fabricated a novel magnetic nanocomposite with polycaprolactone (PCL)/Fe3O4@zinc-based imidazole zeolite framework-8 (ZIF-8) through three-dimensional (3D) printing technology. The biomaterial characterization, biocompatibility, antibacterial activity, and osteogenic ability of the 3D-printed PCL/Fe3O4@ZIF-8 nanocomposite were systematically investigated in vivo and in vitro. The 3D-printed PCL/Fe3O4@ZIF-8 nanocomposite scaffolds showed a square porous grid structure with rough surface, thermal stability, superparamagnetic character, and slow release of Zn2+. The elevation of Fe3O4@ZIF-8 concentration increased surface roughness and porosity, improved the mechanical properties, and enhanced the saturation magnetization of PCL/Fe3O4@ZIF-8 scaffolds. The PCL/Fe3O4@ZIF-8 scaffolds possessed good biocompatibility and promoted the proliferation and adhesion of rat bone marrow mesenchymal stem cells (BMSCs). The PCL/Fe3O4@ZIF-8 scaffolds also upregulated the expression of osteogenic-related genes and proteins and promoted the osteogenic differentiation of BMSCs by activating the Wnt/&amp;beta;-catenin signaling pathway. Furthermore, the scaffolds showed excellent antibacterial activities, which increased with increasing Fe3O4@ ZIF-8 nanoparticle concentration. In vivo experiments proved that the scaffolds eliminated infection and promoted new bone formation in infected bone defect. Given excellent osteogenic and antibacterial activities, the 3D-printed PCL/Fe3O4@ZIF-8 nanocomposite scaffolds could serve as novel materials for the treatment of infected bone defects.

3D printing for bone repair: Coupling infection therapy and defect regeneration

Experimental study of β-TCP scaffold loaded with VAN/PLGA microspheres in the treatment of infectious bone defects

The treatment of infectious bone defects has become a troublesome issue in orthopedics. The disease requires effective anti-infective and bone-reconstruction therapeutic functionalities. In this study, we prepared a novel antibacterial material (vancomycin-impregnated periosteal extracellular matrix [Van-PEM]) by embedding vancomycin in a periosteal extracellular matrix (PEM)-derived hydrogel via physical stirring for the treatment of infectious bone defects. The microstructure, porosity, degradation, and release properties of this antibacterial hydrogel were characterized. The in vitro hemolytic reaction, cytotoxicity, osteogenic ability, and antibacterial properties were also carefully studied. The results showed that the Van-PEM hydrogel possessed a fibrous network structure with high porosity. Moreover, the hydrogel demonstrated slow degradation in vitro and could release vancomycin for at least 1 week. The hydrogel showed no cytotoxicity and possessed good biocompatibility with blood cells. It also promoted osteogenesis and exerted a significant bactericidal effect. Subsequently, the anti-infection and bone-healing abilities of the antibacterial hydrogel were investigated in a rat model of infectious calvarial defects, and the infectious skull defect was successfully cured in vivo. Therefore, Van-PEM hydrogels may represent a promising therapeutic approach for treating infectious bone defects.

Objective To investigate the effects of xenogenic bone with chitosan/norvancomycin sustained-release biomaterials in treating infectious bone defects in rabbits. Methods Xenogenic bone with chitosan/norvancomycin sustained-release biomaterials was made by electrospinning technique. Rabbit infectious bone defect models were made by Methicillin-resistant Staphylococcus aureus. A successful model was evaluated with the standard of more than three points in Norden score assessment. All models were divided into two groups by random number table method, with eight models in each. The control group was treated with surgical debridement, and the experimental group was implanted with bone particles of xenogenic bone with chitosan/norvancomycin sustained-release system after debridement. Postoperatively, general conditions, X-ray, histological results of HE staining, and bacteriological examination results of the rabbits were observed. Results X-ray showed significant bone defects, sequestration, periosteal reaction, and soft tissue swelling after one month of modeling, with Norden score of (3.84±0.52)points. The general conditions were good and the sinus tracts were healed in experimental group after two months of treatment. The control group demonstrated generally poor conditions with swollen sinus and purulent discharge. Two rabbits were died of sepsis. The pathological scores of tibial were (0.41±0.08)points in experimental group, and (3.27±0.26)points in control group by gross observation. The pathological score of experimental group was significantly lower than control group(P<0.05). The bone defects were basically repaired in experimental group. The longest diameter of bone defect in experimental group was (0.11±0.02)cm, significantly smaller than (0.48±0.06)cm in control group (P<0.05). There were no obvious signs of osteomyelitis and the bone defects were well repaired in experimental group. Periosteal reaction, soft tissue swelling, a substantial number of bone destruction, and sequestration were observed in control group. The Norden score was (1.32±0.23)points in experimental group, lower than (5.21±0.48)points in control group(P<0.05). HE staining showed a large amount of trabecular bone formation, bone cell formation, and fibrous hyperplasia in experimental group, with no obvious signs of infection. On the other hand, infiltration of inflammatory cells, necrotic tissue, and sequestration were observed in control group. The histological score was(0.61±0.10) points in experimental group, lower than (4.21±0.41) points in control group (P<0.05). The negative rate of bacterial culture in experimental group was 33%, lower than 100% in control group (P<0.05). Conclusion Xenogenic bone with chitosan/norvancomycin sustained-release biomaterials has excellent effect in infection clearance and bone defect reparation in treatment of infectious bone defects in rabbits. Key words: Osteomyelitis; Chitosan; Anti-bacterial agents; Drug delivery systems

Objective To investigate the efficacy of quick antiinfective spacer combined with Masquelet technique in the treatment of infectious bone defects. Methods From January 2006 to June 2013, we treated 52 patients with infectious bone defects. They were 46 men and 6 women, aged from 19 to 46 years (average, 31.3 years). They were treated by debridement and anti-infection therapy at the first stage when the individualized quick antiinfective spacers were prepared (a mixture of antibiotics and bone cement powder added by polymethyl methacrylate morphon). At the second stage, the bone defects were repaired using Masquelet technique before they were internally fixated. Results The 52 patients were followed up for an average time of 21 months (range, from 13 to 28 months). All the infectious bone defects were healed. X-ray examination showed that the bone mineral density at the bone grafting area increased significantly compared with pre-operation, suggesting granular bone resorption and new bone formation. All the fractures obtained bony union after 6 to 10 months (average, 7.5 months), without recurrence of infection or teratogenesis. Conclusions Quick antiinfective spacer can control local infection in the early period of bone defect by sustainable local release of effective antibiotics of high concentrations while it maintains limb length, increases the stability of fracture ends, and reduces contracture of bone and soft tissue. All these roles may create favorable conditions for late repair, reduce the infection rate and improve the efficacy of early management. Key words: Fractures, bone; Infection; Masquelet technique; Wound and injuries; Fracture fixation, internal