A resorbable, antibiotic-eluting bone void filler (AEBVF) was developed to address device-related infections. The AEBVF provides two functions: osteoconductive matrix for bone restoration, and local antibiotic delivery to treat device-related infections. In vitro evaluations of this AEBVF demonstrated antimicrobial activity to 7 weeks against Staphylococcus aureus (S. aureus).1 Subsequent rabbit studies demonstrated bactericidal capacity2 of the AEBVF against 105 CFU S. aureus and osteoconductivity.1 We hypothesized that the AEBVF would restore bone volume while eliminating 105 CFU S. aureus in a pilot sheep femoral condyle defect model. Four groups (n=2/group) were utilized to assess osteoconductivity (Group A-commercial ProOsteon & B-AEBVF) and antimicrobial activity (Group C-ProOsteon with 105 CFU S. aureus & D-AEBVF with 105 CFU S. aureus). AEBVF devices comprised degradable polymers (PCL, PEG, PLGA), ProOsteon (Biomet, USA), CaCl2, and tobramycin.3 Devices (1.5cc ProOsteon or 6 AEBVF croutons) were implanted into rectangular defects in the medial face of each sheep femoral condyle. Defects were evaluated using backscatter electron microscopy, mineral apposition rate (MAR) analysis, and light microscopy with Sanderson's Rapid Bone Stain (SRBS). All animals in Groups A, B, and D survived to the 12-week endpoint. In contrast, Group C animals were euthanized 11 days post-op. MAR and SRBS demonstrated comparable bone remodeling and defect restoration after 12 weeks in Groups A, B, and D. Notably, implant volumes of Groups A and D were greatly diminished (0.16±0.1%; 0.35%) after 12 weeks, compared to Group A (13.23±3.2%) and Time “0” (16.8%). These data show the AEBVF device's ability to: eliminate 105 CFU S. aureus, promote bone remodeling comparable to known bone void filler, and degrade at rates that do not interfere with bone remodeling

Introduction

Cerament, a bioresorbable hydroxyapatite and calcium sulfate cement, is known to be used as a bone-graft substitute in traumatic bone defect cases. However, its use in open fractures has not previously been studied.

To test the hypothesis that: CERAMENT[™]|G (C-G) would improve new bone growth and decrease infection rate after debridement as compared with 1) CERAMENT|BONE VOID FILLER (CBVF) and 2) no void filler in a rat osteomyelitis model.

72 Sprague Dawley rats were injected with 1.5 × 10∧6 CFU of S. aureus into a drill hole in the right tibia. After 3 weeks, the osteomyelitic defect was debrided, and filled with either: 1) C-G (n=32), 2) CBVF (n=20), or 3) nothing (n=20). 6 weeks after the second surgery, 20 rats from each group were sacrificed and the right tibias were harvested. A long-term group (n=12) of C-G treated rats were also sacrificed at 6 months after the second surgery. The tissues were sonicated and the colony forming units in the sonicate were quantified by serial dilutions and culture. MicroCT was used to quantify the new bone growth (BV/TV) in the debrided osteomyelitic void. Histological samples were analyzed for the presence of a neutrophil response by a blinded pathologist.

(*: p<0.05)

Positive cultures in:

○ 30% of animals treated with CBVF

Neutrophil reaction in:

○ 35% of animals treated with CBVF

The BV/TV in:

○ C-G treated rats was 24% greater than CBVF treated rats (*)

Animals sacrificed at 6 months which were treated with C-G did not have any evidence of infection by culture or histology. The bone mass of the implanted limb was higher than the contralateral (non-operated) side.

CERAMENT|G decreased the rate of infection and increased new bone growth as compared with both CBVF and no void filler in a debrided osteomyelitic environment. Animals treated with C-G at 6 months showed no evidence of infection and retained a higher bone mass relative to the contralateral (non-operated) side.

This study supports the use of CERAMENT|G as a readily available void filler which could be used in osteomyelitic environments after debridement.

Aim. There are no definitive criteria for the definition of osteomyelitis in the hand and wrist and published case series are small. It remains a relatively uncommon, but difficult to treat problem. We present a series of 30 cases from 2016 to 2021 from a tertiary referral centre. We propose that the principles of thorough surgical debridement, dead space management, skeletal stabilisation and culture driven antibiotic therapy are the key to management of osteomyelitis in the hand and wrist. In addition, we show how these basic principles can be used for both functional and aesthetic impact for the wrist and digits with illustrated cases. Methods. We conducted a retrospective chart review over a 6 year period and recorded the site of the infection, the soft tissue and bony management, whether antibiotic eluting bone filler was used, the isolated bacterial species, the number of surgical procedures undertaken to treat the infection and the success rate for clearing the infection. Results. 17/30 cases had pre-existing metalwork in-situ. There were 19 phalangeal/metacarpal infections and 11 carpal infections. 24 patients had native joint involvement. A drug eluting bone void filler was used in 23/30 cases in order to manage the dead space. In 7/30 cases had polymicrobial organisms isolated, 15/30 had only one organism cultured. The most common organism cultured was Staphylococcus aureus. Complete resolution of osteomyelitis or joint infection was achieved in 29/30 cases with follow up ranging from six months to six years. 2/30 cases required thorough debridement of the distal phalanx; bone void filler provided an aesthetically optimal result to improve fingertip contour whilst managing the dead space. Conclusion. Osteomyelitis of the hand and wrist is optimally managed with thorough surgical debridement, dead space management with a drug eluting bone void filler, skeletal stabilisation and culture directed antibiotic therapy. In addition, the bone void filler provides pulp support and improves the aesthetic contour of fingertips in which distal phalangeal osteomyelitis was successfully treated

Aim. To study the antimicrobial effect of a gentamicin loaded bio-composite bone void filler in relation to a limited or extensive debridement of osteomyelitis lesions, respectively. Methods. Nine pigs were inoculated into the right proximal tibial bone with a high virulent gentamicin sensitive strain of Staphylococcus aureus (10. 4. CFU). Seven days after inoculation, Group A pigs (n=3) were exposed to a limited debridement of the bone lesion, whereas Group B pigs (n=3) were exposed to an extensive debridement. The bone defects of Groups A and B were filled with (2–5 ml) of an absorbable gentamicin (175 mg/10 mL) loaded bio-composite. The animals of Group A and B were euthanized 12 days after revision surgery. Group C animals did not undergo revision surgery and were euthanized seven (n=1) or nineteen (n=2) days post inoculation in order to follow the development of the untreated infection. None of the animals were treated with systemic antimicrobials. All bones were exposed to a post mortem CT scan and rigours pathological examinations. The surrounding bone tissue and the bio-composite were sampled for microbiology. Results. All animals developed a substantial purulent bone infection in the inoculated leg prior to revision surgery. In the cases of limited debridement, the bone lesions surrounding the bio-composite bone void filler had clearly expanded since revision surgery, and contained extensive amounts of pus, necrotic bone tissue and oedematous fibrotic tissue. In the cases of extensive debridement, the bio-composite bone void filler was surrounded by only a few mm of fibrosis and sclerotic bone tissue i.e. the bone lesions were not expanding. However, in one pig the bio-composite bone void filler was communicating with a small purulent osteolytic lesion without a sclerotic border indicating appearance after revision surgery. In all pigs, S. aureus bacteria were post mortem cultured from the adjacent bone tissue and the bio-composite surface. Conclusions. The gentamicin concentrations within the bio-composite could not eradicate the residual infection after debridement. However, extensive debridement and filling of the bone void with gentamicin loaded bio-composite contained the lesion formed by revision surgery, which are important complementing roles as adjuvant to systemic antimicrobial therapy and the immune system in eradication of the infection. The present study emphasizes that extensive debridement is fundamental for successful treatment of bone infections and that antimicrobial loaded bone void fillers or bone substitutes should not be used as an alternative to extensive debridement

Introduction. When third body particles originating from bone cement or bone void fillers become trapped between articulating surfaces of joint replacements, contact surfaces may be damaged leading to accelerated wear and premature failure of the implant. In this study, the damage to cobalt chrome counterfaces by third body particles from PMMA bone cement (GMV, DePuy) and various bone void fillers was investigated; then wear tests of UHMWPE were carried out against these surfaces. Methods. Third body particles of polymerised GMV bone cement and the bone void fillers; OsteoSet (with tobramycin), Stimulan and Stimulan+ (with vancomycin and tobramycin) (provided by Biocomposites Ltd.) were trapped between an UHMWPE pin and a highly polished cobalt chrome plate. A load of 120N was applied to the pin and using an Instron materials testing machine, the plate was pulled beneath the pin to recreate third body damage [1]. The resulting surface topography of the plate was analysed using white light interferometry (Bruker NPFLEX). Pin on plate wear tests of GUR 1020 UHMWPE pins were carried out against the plates perpendicular to the direction of damage for 500,000 cycles in 25% bovine serum using a 6-station multi-axial reciprocating rig under conditions to replicate the kinematics in total knee replacement. Wear of the pins was determined by gravimetric analysis and results were compared to negative (highly polished) control plates and positive controls scratched with a diamond stylus (lip height 2µm). Statistical analysis was carried out using one-way ANOVA with significance taken at p<0.05. Results. Following damage simulation with Stimulan and Stimulan+, no scratches could be seen on the surface of the cobalt chrome plates using a stereomicroscope under 63× magnification (Figure 1). Table 1 shows that OsteoSet caused surface damage with the highest density of scratches, which had a greater mean lip height than those caused by the other third body materials. Stimulan+ caused significantly (p=0.002) fewer scratches than Osteoset and the surface damage caused by Stimulan was below the resolution of the surface analysis measurement technique used. The pin on plate wear test showed that under the test conditions used, the wear of UHMWPE was similar (p=0.108) for negative control plates and plates scratched with third body particles and a significant (p<0.001) increase in wear was only observed against the positive control plates [2]. Discussion. This study shows that third body particles originating from bone cement and bone void fillers can damage the surface of highly polished cobalt chrome plates and that materials of similar composition can cause varying severity of damage. Wear tests against plates damaged with third body particles did not significantly affect the wear of UHMWPE and to significantly increase wear, scratches needed to have a lip height of 2µm or above

Objective . A clinical investigation into a new bone void filler is giving first data on systemic and local exposure to the anti-infective substance after implantation. Method . A total of 20 patients with post-traumatic/post-operative bone infections were enrolled in this open-label, prospective study. After radical surgical debridement, the bone cavity was filled with this material. The 21-day hospitalisation phase included determination of gentamicin concentrations in plasma, urine and wound exudate, assessment of wound healing, infection parameters, implant resorption, laboratory parameters, and adverse event monitoring. The follow-up period was six months. . Results . Systemic exposure to gentamicin after implantation was very low as local gentamicin concentrations were measured in wound exudate after six to ten hours. There were no signs of infectious complication throughout the clinical phase. Four patients had recurrent infections several weeks to months after implantation. The outcome was deemed successful by remission of infection in 16 (80%) of these problematic long-term treated patients. Safety laboratory measurements did not indicate nephrotoxic or hepatotoxic effects. . Conclusions . Local application of calcium sulphate/carbonate bone void filler comprising gentamicin revealed sufficient active local levels of the antibiotic by simultaneous significant low systemic exposure in patients with mostly chronic osteomyelitis/osteitis. The material was safe and well tolerated. Cite this article: Bone Joint Res 2014;3:223–9

Purpose. Infections in orthopaedic surgery are costly, debilitating complications. The search for new treatments and prevention strategies has led to the use of antibiotic-filled calcium sulfate (CaS) as a bone void filler that is both safe and effective. The purpose of this study was to examine the available data on the efficacy of this technology. Methods. A literature search was performed for studies that evaluated the use of antibiotic-loaded CaS cement in orthopaedics published between inception of the databases to 2017. Selected studies included randomized controlled trials (RCTs) and observational studies published in the English language that met the following criteria: 1) patients underwent an orthopaedic procedure; 2) CaS cement with an antibiotic was used; and 3) at least one of our outcomes were mentioned. Outcomes included resolution of infection, complications related to treatment, subsequent surgeries, overall infection rate, fracture union rate, clinical outcomes, and wound complications. A total of 17 studies were included. Results. Ten studies examined the use of antibiotic-eluting CaS cement with surgical debridement to treat osteomyelitis and reported resolution rates ranging from 80–100%. Two studies examined CaS for prophylaxis of infection after open fracture, with subsequent infection rates ranging from 0–22%. Two studies examined infected non-unions with CaS used as an adjunct to surgery with an 87.5% infection clearance rate. Finally, three studies examined the use of local antibiotic release from CaS in the repair of infected TKAs or THAs, with success rates ranging from 52–93.3%. Conclusion. Initial results support the use of CaS with surgical debridement for osteomyelitis and infected non-unions. Results are mixed for CaS use in the prophylaxis of infection after open fractures and for PJIs, thereby necessitating further research. Overall the studies were small, retrospective, and lacked controls. Further research should focus on RCTs to minimize bias and investigate for non-inferiority. For any figures or tables, please contact authors directly

Aim. Antibiotic-loaded biomaterials are often used in dead space management after excision of infected bone. This study assessed the chronological progression of new bone formation in infected defects, filled only with an absorbable, osteoconductive bone void filler with Gentamicin (1). Method. 163 patients were treated for osteomyelitis or infected fractures with a single-stage excision, implantation of antibiotic carrier, stabilisation and wound closure. All had Cierny & Mader Type III (n=128) or Type IV (n=35) infection. No bone grafting was performed in any patient. Patients were followed up for a minimum of 12 months (mean 21.4 months; 12–56). Bone void filling was assessed on serial digitised, standardized radiographs taken immediately after surgery, at 6 weeks, 3, 6 and 12 months and then yearly. Data on defect size, location, degree of void filling, quality of the bone-biomaterial interface and material leakage were collected. Bone formation was calculated at final follow-up, as a percentage of initial defect volume, by determining the bone area on AP and lateral radiographs to the nearest 5%. Results. 138 patients had adequate radiographs for assessment. Infection was eradicated in 95.7%. 2.5% of patients suffered a fracture during follow-up. Overall, bone formation was good (mean 73.8% defect filling), with one quarter of patients having complete defect filling and 87% having more than 50% of the defect healed. Bone formed better in metaphyseal defects compared to diaphyseal defects (mean 79% filling vs 66%; p<0.02). Good interdigitation of the biomaterial with the host bone, seen on the initial radiograph, was associated with more bone formation (77% vs 69%; p=0.021). Leakage of the biomaterial out of the defect reduced mean bone formation from 77% to 62% (p=0.006). 38 cases had radiographs more than 2 years after implantation. In 24 (63.2%), bone formation continued to increase after the first year radiograph. Conclusion. This biomaterial was effective in allowing significant amounts of bone to form in the defect. This removed the need for bone grafting in this series, with a low risk of fracture or recurrent infection. However, bone formation is affected by the site of the lesion and the adequacy of filling at surgery. It is important to achieve good contact between the bone surface and the biomaterial at operation. Bone formation is slow and progresses for at least 2 years after implantation, in two thirds of patients

Introduction. Calcium sulfate bone void fillers (CS-BVF) are increasingly being used for dead space management in infected arthroplasty revision surgery. The use of loose beads of CS-BVF close to the articulating surfaces of an implant means there is potential for them to migrate between the articulating surfaces acting as a third body particle. The aim of this study was to investigate the influence of CS-BVF on the third body wear of total knee replacements. Methods. The influence of CS-BVF on wear was investigated using the commercially available CS-BVF ‘Stimulan’ (Biocomposites Ltd., UK) and posterior stabilised U2 total knee replacement system implants (United Orthopaedic Corp., Taiwan). The experimental wear simulation was performed using a six station ProSim electropneumatic knee simulator (Simulation Solutions, UK) running the Leeds intermediate kinematics input profile [1]. To investigate the damage that could be caused by the third body particles, 5cc of CS-BVF beads (excess) were placed on the tibial component of the implant, the simulator was run dry for 60 cycles before adding lubricant (25% bovine serum supplemented with 0.03% sodium azide) and running for an additional 115,000 cycles representative of the 6–8 weeks the CS-BVF are present in the body prior to their resorption. The surface topography of the cobalt chrome femorals was analysed using contacting profilometry to ascertain whether the third body particles of CS-BVF had damaged the surfaces. To investigate the influence of CS-BVF on the third body wear of the UHMWPE tibials, 3 million cycles (MC) of wear simulation was subsequently carried out. The wear of the UHMWPE tibials was assessed gravimetrically and the wear of implants tested with CS-BVF was compared to the wear against negative controls (initial Ra∼0.02µm) and positive controls (initial Ra ∼0.4µm) damaged with a diamond stylus. N=6 was completed for each condition, statistical analysis was carried out using ANOVA with significance taken at p<0.05. Results. Light scratching was visible on the surface of the cobalt chrome femorals after the implants were challenged with the CS-BVF, however, there was no significant difference (p>0.05) between the surface roughness of the negative controls and those challenged with CS-BVF for any of the roughness parameters of interest (Table 1 & Figure 1). 3MC of wear simulation showed no significant difference (p>0.05) between implants subjected to the third body wear protocol and the negative controls (Figure 2). To significantly increase the wear of the UHMWPE tibials, the damage to the cobalt chrome femorals had to be above a threshold as in the positive controls scratched with a diamond stylus. Conclusions. This study showed that the CS-BVF ‘Stimulan’ had no influence on the third body wear or surface topography of total knee replacements compared to negative controls. Therefore, when used close to articulating surfaces of a metal-on-polyethylene joint replacement, CS-BVF may not influence the wear of an implant or be detrimental to its longevity

Autogenous bone grafting limitations have motivated the development of Tissue-Engineered (TE) biomaterials that offer an alternative as bone void fillers. However, the lack of a blood supply within implanted constructs may result in avascular necrosis and construct failure. 1. The aim of this project was to investigate the potential of novel TE constructs to promote vascularisation and bone defect repair using two distinct approaches. In Study 1, we investigated the potential of a mesenchymal stem cell (MSC) and endothelial cell (EC) co-culture to stimulate pre-vascularisation of biomaterials prior to in vivo implantation. 2. In Study 2, we investigated the potential of TE hypertrophic cartilage to promote the release of angiogenic factors such as VEGF, vascular invasion and subsequent endochondral bone formation in an in vivo model. Collagen-only (Coll), collagen-glycosaminoglycan (CG) and collagen-hydroxyapatite (CHA) scaffolds were fabricated by freeze-drying. 3. , seeded with cells and implanted into critical-sized calvarial and femoral defects in immunocompetent rats. In Study 1, Coll and CG scaffolds were initially seeded with ECs, allowed to form capillary-like networks before the delayed addition of MSCs and continued culture prior to calvarial implantation. In Study 2, CG and CHA scaffolds were seeded with MSCs and cultured under chondrogenic and subsequent hypertrophic conditions to form a cartilage pre-cursor prior to calvarial and femoral implantation in vivo. MicroCT and histomorphometry quantification demonstrated the ability of both systems to support increased bone formation compared to controls. Moreover, the greatest levels of bone formation were observed in the CG groups, notably in those containing cartilage tissue (Study 2). Assessment of the immune response suggests the addition of MSCs promotes the polarisation of macrophages away from inflammation (M1) towards a pro-remodelling phenotype (M2). We have developed distinct collagen-based systems that promote vascularisation and ultimately enhance bone formation, confirming their potential as advanced strategies for bone repair applications

Gentamicin sulphate is a potent antibiotic, widely used by clinicians to treat Staphylococcus aureus bacterial complications in orthopaedic surgery and osteomyelitis. Antibiotics as administered are poorly localised and can accumulate with toxic effects. Achieving a better targeted release and controlled dosage has been an ongoing unmet microengineering challenge. In this study we evaluated the antibiotic release potential of beta tricalcium phosphate (β-TCP) micro and macrospheres to eradicate Staphylococcus aureus and maintain osteoblast biocompatibility. Gentamicin was absorbed onto and within the spheres at an average amount of 4.2 mg per sample. Human osteoblast cell studies at five days incubation showed attachment and growth on the spheres surface with no detrimental effect on the cell viability. A time delayed antibacterial efficacy test was designed with the bacteria introduced at predetermined time intervals from 0–60 minutes. We demonstrated that hydroxyapatite covered Foraminifera nano-, micro- macrospheres facilitated the slow release of the encapsulated pharmaceutical agent. Principally, this arises owing to their unique architecture of pores, struts and channels, which amplifies physiological degradation and calcium phosphate dissolution to release attached pharmaceuticals in a controlled manner. The Staphylococcus aureus growth response following exposure to the gentamicin incorporated microspheres at various time intervals showed the complete elimination of the bacteria within 30 minutes. Gentamicin release continued with no re-emergence of bacteria. β-TCP nano to macro size spheres show promise as potential bone void filler particles with, in this case, supplementary delivery of antibiotic agent. Owing to their unique structure, excellent drug retention and slow release properties, they could be used in reconstructive orthopaedics to treat osteomyelitis caused by Staphylococcus aureus and possibly other sensitive organisms

Introduction. The need for regeneration and repair of bone presents itself in a variety of clinical situations. The current gold standard of treatment is autograft harvested from the iliac crest or local bone. Inherent disadvantages associated with the use of autogenous bone include limited supply, increased operating time and donor site morbidity. This study utilized a challenging model of posterolateral fusion to evaluate the in vivo response of an engineered collagen carrier combined with nano-structured hydroxyapatite (NanOss Bioactive 3D, Pioneer Surgical) compared to a collagen porous beta-tricalcium phosphate bone void filler (Vitoss BA, Orthovita). Materials and Methods. A single level posterolateral fusion was performed in 72 adult rabbits at 6, 12 and 26 weeks (8 per group per time point). Group 1: nanOss Bioactive 3D + bone marrow aspirate (BMA) + autograft, Group 2: Vitoss BA + BMA and Group 3: Autograft + BMA were compared were compared using radiographic (X-ray and Micro-computed tomography (μCT), biomechanics (manual palpation and tensile testing at 12 and 26 weeks) and histology. Results. Radiographic grading and μCT demonstrated progressive increases in radiopacity at the transverse processes and at the middle of the developing fusion for Groups 1 and 3. New bone formation was noted for Group 2 only at the transverse processes (not in the middle of the fusion site). In this challenging model, manual palpation revealed comparable fusion rates in Groups 1 and 3 (43% and 38%, respectively). None of the animals from Group 2 were fused by manual palpation. Group 3 outperformed Group 2 (P<0.05) while the results were similar to Group 1. Histology on the transverse processes at 6, 12, and 26 weeks demonstrated an osteoconductive response with woven bone formation and subsequent remodeling for all groups. Histology in the middle of the fusion mass (between the transverse processes) also demonstrated an osteoconductive response with remodeling and the development of marrow spaces in the Groups 1 and 3 at 6, 12, and 26 weeks. Bone formation in the middle of the fusion was negligible at 6, 12 and 26 weeks for Group 2. Discussion. Posterolateral fusion models represent an extremely challenging biological site to evaluate bone graft materials and provide insight into clinical performance. Group 1 (nanOss Bioactive 3D + Autograft + BMA) performed well in the current model providing an osteoconductive scaffold that supported new bone formation on the transverse processes as well as in the middle of the fusion mass and that remodeled with time based on all endpoints. The graft materials had yet to completely resorb by 26 weeks in the current model. Group 2 performed well on the transverse processes in terms of new bone formation however new bone in the middle of the fusion mass was negligible at 6, 12, and 26 weeks. Group 3 (Autograft + BMA) performed well with new bone formation and remodeling on the transverse process and in the middle of the fusion mass as well as is consistently reported with this model