A population-based epidemiological and health economic analysis of fracture-related infection.

Aims: The aim of this study was to perform the first population-based description of the epidemiological and health economic burden of fracture-related infection (FRI). Methods: This is a retrospective cohort study of operatively managed orthopaedic trauma patients from 1 January 2007 to 31 December 2016, performed in Queensland, Australia. Record linkage was used to develop a person-centric, population-based dataset incorporating routinely collected administrative, clinical, and health economic information. The FRI group consisted of patients with International Classification of Disease 10th Revision diagnosis codes for deep infection associated with an implanted device within two years following surgery, while all others were deemed not infected. Demographic and clinical variables, as well as healthcare utilization costs, were compared. Results: There were 111,402 patients operatively managed for orthopaedic trauma, with 2,775 of these (2.5%) complicated by FRI. The development of FRI had a statistically significant association with older age, male sex, residing in rural/remote areas, Aboriginal or Torres Strait Islander background, lower socioeconomic status, road traffic accident, work-related injuries, open fractures, anatomical region (lower limb, spine, pelvis), high injury severity, requiring soft-tissue coverage, and medical comorbidities (univariate analysis). Patients with FRI had an eight-times longer median inpatient length of stay (24 days vs 3 days), and a 2.8-times higher mean estimated inpatient hospitalization cost (AU$56,565 vs AU$19,773) compared with uninfected patients. The total estimated inpatient cost of the FRI cohort to the healthcare system was AU$156.9 million over the ten-year period. Conclusion: The results of this study advocate for improvements in trauma care and infection management, address social determinants of health, and highlight the upside potential to improve prevention and treatment strategies.

Mortality, patient-reported outcome measures, and the health economic burden of prosthetic joint infection.

Prosthetic joint infection (PJI) is one of the most devastating complications for a patient following arthroplasty. This scoping review aims to evaluate the burden of PJI on individual patients and the healthcare system regarding the mortality rate, patient-reported quality of life, and healthcare resource utilisation. Patients with PJI have up to a five-fold higher mortality rate than those who have undergone an uninfected primary arthroplasty. There is an increased use of ambulatory aids and reduced joint function scores in patients with PJI. Global quality of life is poorer, specifically measured by the EQ-5D. Direct hospitalisation costs are two- to five-fold higher, attributed to surgery and prostheses, antibiotics, and a prolonged inpatient stay. There is an immense clinical and health economic burden secondary to PJI worldwide. This is expected to rise exponentially due to the increasing number of primary procedures and an ageing population with comorbidities Improving preventative and treatment strategies is imperative for patients and the healthcare system.

Convergence of scaffold-guided bone regeneration principles and microvascular tissue transfer surgery.

A preclinical evaluation using a regenerative medicine methodology comprising an additively manufactured medical-grade ε-polycaprolactone ß-tricalcium phosphate (mPCL-TCP) scaffold with a corticoperiosteal flap was undertaken in eight sheep with a tibial critical-size segmental bone defect (9.5 cm3, M size) using the regenerative matching axial vascularization (RMAV) approach. Biomechanical, radiological, histological, and immunohistochemical analysis confirmed functional bone regeneration comparable to a clinical gold standard control (autologous bone graft) and was superior to a scaffold control group (mPCL-TCP only). Affirmative bone regeneration results from a pilot study using an XL size defect volume (19 cm3) subsequently supported clinical translation. A 27-year-old adult male underwent reconstruction of a 36-cm near-total intercalary tibial defect secondary to osteomyelitis using the RMAV approach. Robust bone regeneration led to complete independent weight bearing within 24 months. This article demonstrates the widely advocated and seldomly accomplished concept of "bench-to-bedside" research and has weighty implications for reconstructive surgery and regenerative medicine more generally.

Scaffold-guided bone regeneration in large volume tibial segmental defects.

Large volume losses in weight bearing long bones are a major challenge in clinical practice. Despite multiple innovations over the last decades, significant limitations subsist in current clinical treatment options which is driving a strong clinical demand for clinically translatable treatment alternatives, including bone tissue engineering applications. Despite these shortcomings, preclinical large animal models of large volume segmental bone defects to investigate the regenerative capacity of bone tissue engineering strategies under clinically relevant conditions are rarely described in literature. We herein present a newly established preclinical ovine animal model for the treatment of XL volume (19 cm3) segmental tibial defects. In eight aged male Merino sheep (age > 6 years) a mid-diaphyseal tibial segmental defect was created and stabilized with a 5.6 mm Dynamic Compression Plate (DCP). We present short-term (3 months) and long-term (12-15 months) results of a pilot study using medical grade Polycaprolactone-Tricalciumphosphate (mPCL-TCP) scaffolds combined with a dose of 2 mg rhBMP-7 delivered in Platelet-Rich- Plasma (PRP). Furthermore, detailed analyses of the mechanical properties of the scaffolds as well as interfragmentary movement (IFM) and DCP-surface strain in vitro and a comprehensive description of the surgical and post-surgery protocol and post-mortem analysis is given.

Cutibacterium acnes in shoulder surgery: a scoping review of strategies for prevention, diagnosis, and treatment.

BACKGROUND: Cutibacterium acnes is a commensal, gram-positive, facultatively anaerobic bacillus that resides in the dermis. Historically thought to be a contaminant when identified on cultured specimens, recent advances in diagnostic technology have now implicated it as the most common organism responsible for postoperative shoulder infections. Despite a recognition of the role of this organism and a significant research interest in recent years, there is clear lack of consensus guideline on strategies to prevent, diagnose, and treat postoperative shoulder infection. METHOD: The electronic databases PubMed, MEDLINE, CINAHL, Scopus, and Web of Science were searched in March 2020. All experimental and nonexperimental studies that investigate C acnes in shoulder surgery were included. Inclusion was limited to articles published after 2000 and written in English; reviews, gray literature, or abstracts were excluded. A total of 70 studies were included in this review. This scoping review was performed in accordance with the Extended Preferred Reporting Items of Systematic Reviews and Meta-Analyses Statement for Scoping Reviews (PRISMA-ScR). RESULTS: Standard surgical prophylactic regimens such as intravenous antibiotics and topical chlorhexidine are ineffective at removing C acnes from the deep layer of the dermis, and there is a shift toward using topical benzoyl peroxide with significantly improved efficacy. An improved understanding of the bacteria has demonstrated that a prolonged culture time of up to 14 days is needed, especially in cases of established infection. Advances in diagnostics such as sonication and molecular-based testing are promising. Although usually thought to be susceptible to a broad range of antibiotics, resistance is emerging to clindamycin. An improved understanding of its ability to form a biofilm highlights the difficulty in treating an established infection. CONCLUSION: The role of C acnes causing postoperative infection following shoulder surgery is being increasingly recognized. Strategies for prevention, diagnosis, and treatment have been outlined from both an antimicrobial and surgical perspective. A number of these strategies are emerging and require further research to demonstrate efficacy before implementation into clinical guidelines.

The influence of biomechanical stability on bone healing and fracture-related infection: the legacy of Stephan Perren.

Bone healing is a complicated process of tissue regeneration that is influenced by multiple biological and biomechanical processes. In a minority of cases, these physiological processes are complicated by issues such as nonunion and/or fracture-related infection (FRI). Based on a select few in vivo experimental animal studies, construct stability is considered an important factor influencing both prevention and treatment of FRI. Stephan Perren played a pivotal role in the evolution of our current understanding of the critical relationship between biomechanics, fracture healing and infection. Furthermore, his concept of strain theory and the process of fracture healing is familiar to several generations of surgeons and has influenced implant development and design for the past 50 years. In this review we describe the role of biomechanical stability on fracture healing, and provide a detailed analysis of the preclinical studies addressing this in the context of FRI. Furthermore, we demonstrate how Perren's concepts of stability are still applied to current surgical techniques to aid in the prevention and treatment of FRI. Finally, we highlight the key knowledge gaps in the underlying basic research literature that need to be addressed as we continue to optimize patient care.

A preclinical large-animal model for the assessment of critical-size load-bearing bone defect reconstruction.

Critical-size bone defects, which require large-volume tissue reconstruction, remain a clinical challenge. Bone engineering has the potential to provide new treatment concepts, yet clinical translation requires anatomically and physiologically relevant preclinical models. The ovine critical-size long-bone defect model has been validated in numerous studies as a preclinical tool for evaluating both conventional and novel bone-engineering concepts. With sufficient training and experience in large-animal studies, it is a technically feasible procedure with a high level of reproducibility when appropriate preoperative and postoperative management protocols are followed. The model can be established by following a procedure that includes the following stages: (i) preoperative planning and preparation, (ii) the surgical approach, (iii) postoperative management, and (iv) postmortem analysis. Using this model, full results for peer-reviewed publication can be attained within 2 years. In this protocol, we comprehensively describe how to establish proficiency using the preclinical model for the evaluation of a range of bone defect reconstruction options.

Convergence of Scaffold-Guided Bone Reconstruction and Surgical Vascularization Strategies-A Quest for Regenerative Matching Axial Vascularization.

The prevalent challenge facing tissue engineering today is the lack of adequate vascularization to support the growth, function, and viability of tissue engineered constructs (TECs) that require blood vessel supply. The research and clinical community rely on the increasing knowledge of angiogenic and vasculogenic processes to stimulate a clinically-relevant vascular network formation within TECs. The regenerative matching axial vascularization approach presented in this manuscript incorporates the advantages of flap-based techniques for neo-vascularization yet also harnesses the in vivo bioreactor principle in a more directed "like for like" approach to further assist regeneration of the specific tissue type that is lost, such as a corticoperiosteal flap in critical sized bone defect reconstruction.

Value of PCR in sonication fluid for the diagnosis of orthopedic hardware-associated infections: Has the molecular era arrived?

INTRODUCTION: Bone healing disturbance following fracture fixation represents a continuing challenge. We evaluated a novel fully automated polymerase chain reaction (PCR) assay using sonication fluid from retrieved orthopedic hardware to diagnose infection. PATIENTS AND METHODS: In this prospective diagnostic cohort study, explanted orthopedic hardware materials from consecutive patients were investigated by sonication and the resulting sonication fluid was analyzed by culture (standard procedure) and multiplex PCR (investigational procedure). Hardware-associated infection was defined as visible purulence, presence of a sinus tract, implant on view, inflammation in peri-implant tissue or positive culture. McNemar's chi-squared test was used to compare the performance of diagnostic tests. For the clinical performance all pathogens were considered, whereas for analytical performance only microorganisms were considered for which primers are included in the PCR assay. RESULTS: Among 51 patients, hardware-associated infection was diagnosed in 38 cases (75%) and non-infectious causes in 13 patients (25%). The sensitivity for diagnosing infection was 66% for peri-implant tissue culture, 84% for sonication fluid culture, 71% (clinical performance) and 77% (analytical performance) for sonication fluid PCR, the specificity of all tests was >90%. The analytical sensitivity of PCR was higher for gram-negative bacilli (100%), coagulase-negative staphylococci (89%) and Staphylococcus aureus (75%) than for Cutibacterium (formerly Propionibacterium) acnes (57%), enterococci (50%) and Candida spp. (25%). CONCLUSION: The performance of sonication fluid PCR for diagnosis of orthopedic hardware-associated infection was comparable to culture tests. The additional advantage of PCR was short processing time (<5 h) and fully automated procedure. With further improvement of the performance, PCR has the potential to complement conventional cultures.

Hematogenous vertebral osteomyelitis associated with intravascular device-associated infections - A retrospective cohort study.

INTRODUCTION: Aim of the study was to investigate the clinical, microbiological, radiological, and treatment characteristics of hematogenous vertebral osteomyelitis originating from infected intravascular devices. PATIENTS AND METHODS: Patients with secondary hematogenous vertebral osteomyelitis caused by an infected intravascular device were included in this retrospective cohort study. Patients with prior spinal surgery were excluded. Categorical variables were compared using χ2 or Fisher's exact tests and continuous variables using the Mann-Whitney U test. RESULTS: Sixty-seven patients with hematogenous vertebral osteomyelitis were included. Intravenous catheters were the source of infection in 45 patients (67%) and cardiovascular devices in 22 (33%). Fever was present in 21 patients (45%). The main pathogens were coagulase-negative staphylococci, isolated in 42 patients (63%), which grew from blood culture in 52 patients (87%), from vertebral tissue in 29 patients (56%) and from the explanted intravascular device in 18 patients (60%), where it was sampled. Infective endocarditis was diagnosed in 14 of 45 patients (31%), more common with cardiovascular devices than with intravascular catheters (56% versus 15%; P=0.008). CONCLUSIONS: In patients with vertebral osteomyelitis, growth of coagulase-negative staphylococci in blood is highly suggestive for intravascular device-associated infection. Despite absence of systemic or local signs of inflammation at the site of the device, blood cultures should be collected and echocardiography performed in these patients.

Modulation of fixation stiffness from flexible to stiff in a rat model of bone healing.

Background and purpose - Constant fixator stiffness for the duration of healing may not provide suitable mechanical conditions for all stages of bone repair. We therefore investigated the influence of stiffening fixation on callus stiffness and morphology in a rat diaphyseal osteotomy model to determine whether healing time was shortened and callus stiffness increased through modulation of fixation from flexible to stiff. Material and methods - An external unilateral fixator was applied to the osteotomized femur and stiffened by decreasing the offset of the inner fixator bar at 3, 7, 14, and 21 days after operation. After 5 weeks, the rats were killed and healing was evaluated with mechanical, histological, and microcomputed tomography methods. Constant fixation stiffness control groups with either stiff or flexible fixation were included for comparison. Results - The callus stiffness of the stiff group and all 4 experimental groups was greater than in the flexible group. The callus of the flexible group was larger but contained a higher proportion of unmineralized tissue and cartilage. The stiff and modulated groups (3, 7, 14, and 21 days) all showed bony bridging at 5 weeks, as well as signs of callus remodeling. Stiffening fixation at 7 and 14 days after osteotomy produced the highest degree of callus bridging. Bone mineral density in the fracture gap was highest in animals in which the fixation was stiffened after 14 days. Interpretation - The predicted benefit of a large robust callus formed through early flexible fixation could not be shown, but the benefits of stabilizing a flexible construct to achieve timely healing were demonstrated at all time points.

Vascularised bone transfer: History, blood supply and contemporary problems.

BACKGROUND: Since the description of the free fibula flap by Taylor in 1975, many flaps composed of bone have been described. This review documents the history of vascularised bone transfer and reflects on the current understanding of blood supply in an effort to define all clinically described osseous flaps. METHODS: A structured review of MEDLINE and Google Scholar was performed to identify all clinically described bone flaps in humans. Data regarding patterns of vascularity were collected where available from the anatomical literature. RESULTS: Vascularised bone transfer has evolved stepwise in concert with advances in reconstructive surgery techniques. This began with local flaps of the craniofacial skeleton in the late 19th century, followed by regional flaps such as the fibula flap for tibial reconstruction in the early 20th century. Prelaminated and pedicled myo-osseous flaps predominated until the advent of microsurgery and free tissue transfer in the 1960s and 1970s. Fifty-two different bone flaps were identified from 27 different bones. These flaps can be broadly classified into three types to reflect the pedicle: nutrient vessel (NV), penetrating periosteal vessel (PPV) and non-penetrating periosteal vessel (NPPV). NPPVs can be further classified according to the anatomical structure that serves as a conduit for the pedicle which may be direct-periosteal, musculoperiosteal or fascioperiosteal. DISCUSSION: The blood supply to bone is well described and is important to the reconstructive surgeon in the design of reliable vascularised bone suitable for transfer into defects requiring osseous replacement. Further study in this field could be directed at the implications of the pattern of bone flap vascularity on reconstructive outcomes, the changes in bone vascularity after osteotomy and the existence of "true" and "choke" anastomoses in cortical bone.

Can we safely deform a plate to fit every bone? Population-based fit assessment and finite element deformation of a distal tibial plate.

Anatomically precontoured plates are commonly used to treat periarticular fractures. A well-fitting plate can be used as a tool for anatomical reduction of the fractured bone. Recent studies highlighted that some plates fit poorly for many patients due to considerable shape variations between bones of the same anatomical site. While it is impossible to design one shape that fits all, it is also burdensome for the manufacturers and hospitals to produce, store and manage multiple plate shapes without the certainty of utilization by a patient population. In this study, we investigated the number of shapes required for maximum fit within a given dataset, and if they could be obtained by manually deforming the original plate. A distal medial tibial plate was automatically positioned on 45 individual tibiae, and the optimal deformation was determined iteratively using finite element analysis simulation. Within the studied dataset, we found that: (i) 89% fit could be achieved with four shapes, (ii) 100% fit was impossible through mechanical deformation, and (iii) the deformations required to obtain the four plate shapes were safe for the stainless steel plate for further clinical use. The proposed framework is easily transferable to other orthopaedic plates.

Monitoring Healing Progression and Characterizing the Mechanical Environment in Preclinical Models for Bone Tissue Engineering.

The treatment of large segmental bone defects remains a significant clinical challenge. Due to limitations surrounding the use of bone grafts, tissue-engineered constructs for the repair of large bone defects could offer an alternative. Before translation of any newly developed tissue engineering (TE) approach to the clinic, efficacy of the treatment must be shown in a validated preclinical large animal model. Currently, biomechanical testing, histology, and microcomputed tomography are performed to assess the quality and quantity of the regenerated bone. However, in vivo monitoring of the progression of healing is seldom performed, which could reveal important information regarding time to restoration of mechanical function and acceleration of regeneration. Furthermore, since the mechanical environment is known to influence bone regeneration, and limb loading of the animals can poorly be controlled, characterizing activity and load history could provide the ability to explain variability in the acquired data sets and potentially outliers based on abnormal loading. Many approaches have been devised to monitor the progression of healing and characterize the mechanical environment in fracture healing studies. In this article, we review previous methods and share results of recent work of our group toward developing and implementing a comprehensive biomechanical monitoring system to study bone regeneration in preclinical TE studies.

Delayed minimally invasive injection of allogenic bone marrow stromal cell sheets regenerates large bone defects in an ovine preclinical animal model.

Cell-based tissue engineering approaches are promising strategies in the field of regenerative medicine. However, the mode of cell delivery is still a concern and needs to be significantly improved. Scaffolds and/or matrices loaded with cells are often transplanted into a bone defect immediately after the defect has been created. At this point, the nutrient and oxygen supply is low and the inflammatory cascade is incited, thus creating a highly unfavorable microenvironment for transplanted cells to survive and participate in the regeneration process. We therefore developed a unique treatment concept using the delayed injection of allogenic bone marrow stromal cell (BMSC) sheets to regenerate a critical-sized tibial defect in sheep to study the effect of the cells' regeneration potential when introduced at a postinflammatory stage. Minimally invasive percutaneous injection of allogenic BMSCs into biodegradable composite scaffolds 4 weeks after the defect surgery led to significantly improved bone regeneration compared with preseeded scaffold/cell constructs and scaffold-only groups. Biomechanical testing and microcomputed tomography showed comparable results to the clinical reference standard (i.e., an autologous bone graft). To our knowledge, we are the first to show in a validated preclinical large animal model that delayed allogenic cell transplantation can provide applicable clinical treatment alternatives for challenging bone defects in the future.

Effects of strain artefacts arising from a pre-defined callus domain in models of bone healing mechanobiology.

Iterative computational models have been used to investigate the regulation of bone fracture healing by local mechanical conditions. Although their predictions replicate some mechanical responses and histological features, they do not typically reproduce the predominantly radial hard callus growth pattern observed in larger mammals. We hypothesised that this discrepancy results from an artefact of the models' initial geometry. Using axisymmetric finite element models, we demonstrated that pre-defining a field of soft tissue in which callus may develop introduces high deviatoric strains in the periosteal region adjacent to the fracture. These bone-inhibiting strains are not present when the initial soft tissue is confined to a thin periosteal layer. As observed in previous healing models, tissue differentiation algorithms regulated by deviatoric strain predicted hard callus forming remotely and growing towards the fracture. While dilatational strain regulation allowed early bone formation closer to the fracture, hard callus still formed initially over a broad area, rather than expanding over time. Modelling callus growth from a thin periosteal layer successfully predicted the initiation of hard callus growth close to the fracture site. However, these models were still susceptible to elevated deviatoric strains in the soft tissues at the edge of the hard callus. Our study highlights the importance of the initial soft tissue geometry used for finite element models of fracture healing. If this cannot be defined accurately, alternative mechanisms for the prediction of early callus development should be investigated.

Automated fit quantification of tibial nail designs during the insertion using computer three-dimensional modelling.

Intramedullary nailing is the standard fixation method for displaced diaphyseal fractures of the tibia. An optimal nail design should both facilitate insertion and anatomically fit the bone geometry at its final position in order to reduce the risk of stress fractures and malalignments. Due to the nonexistence of suitable commercial software, we developed a software tool for the automated fit assessment of nail designs. Furthermore, we demonstrated that an optimised nail, which fits better at the final position, is also easier to insert. Three-dimensional models of two nail designs and 20 tibiae were used. The fitting was quantified in terms of surface area, maximum distance, sum of surface areas and sum of maximum distances by which the nail was protruding into the cortex. The software was programmed to insert the nail into the bone model and to quantify the fit at defined increment levels. On average, the misfit during the insertion in terms of the four fitting parameters was smaller for the Expert Tibial Nail Proximal bend (476.3 mm(2), 1.5 mm, 2029.8 mm(2), 6.5 mm) than the Expert Tibial Nail (736.7 mm(2), 2.2 mm, 2491.4 mm(2), 8.0 mm). The differences were statistically significant (p ≤ 0.05). The software could be used by nail implant manufacturers for the purpose of implant design validation.

Metal artifacts from titanium and steel screws in CT, 1.5T and 3T MR images of the tibial Pilon: a quantitative assessment in 3D.

Radiographs are commonly used to assess articular reduction of the distal tibia (pilon) fractures postoperatively, but may reveal malreductions inaccurately. While magnetic resonance imaging (MRI) and computed tomography (CT) are potential three-dimensional (3D) alternatives they generate metal-related artifacts. This study aims to quantify the artifact size from orthopaedic screws using CT, 1.5T and 3T MRI data. Three screws were inserted into one intact human cadaver ankle specimen proximal to and along the distal articular surface, then CT, 1.5T and 3T MRI scanned. Four types of screws were investigated: titanium alloy (TA), stainless steel (SS) (Ø =3.5 mm), cannulated TA (CTA) and cannulated SS (CSS) (Ø =4.0 mm, Ø empty core =2.6 mm). 3D artifact models were reconstructed using adaptive thresholding. The artifact size was measured by calculating the perpendicular distance from the central screw axis to the boundary of the artifact in four anatomical directions with respect to the distal tibia. The artifact sizes (in the order of TA, SS, CTA and CSS) from CT were 2.0, 2.6, 1.6 and 2.0 mm; from 1.5T MRI they were 3.7, 10.9, 2.9, and 9 mm; and 3T MRI they were 4.4, 15.3, 3.8, and 11.6 mm respectively. Therefore, CT can be used as long as the screws are at a safe distance of about 2 mm from the articular surface. MRI can be used if the screws are at least 3 mm away from the articular surface except for SS and CSS. Artifacts from steel screws were too large thus obstructed the pilon from being visualised in MRI. Significant differences (P<0.05) were found in the size of artifacts between all imaging modalities, screw types and material types, except 1.5T versus 3T MRI for the SS screws (P=0.063). CTA screws near the joint surface can improve postoperative assessment in CT and MRI. MRI presents a favourable non-ionising alternative when using titanium hardware. Since these factors may influence the quality of postoperative assessment, potential improvements in operative techniques should be considered.

Polycaprolactone scaffold and reduced rhBMP-7 dose for the regeneration of critical-sized defects in sheep tibiae.

The transplantation of autologous bone graft as a treatment for large bone defects has the limitation of harvesting co-morbidity and limited availability. This drives the orthopaedic research community to develop bone graft substitutes. Routinely, supra-physiological doses of bone morphogenetic proteins (BMPs) are applied perpetuating concerns over undesired side effects and cost of BMPs. We therefore aimed to design a composite scaffold that allows maintenance of protein bioactivity and enhances growth factor retention at the implantation site. Critical-sized defects in sheep tibiae were treated with the autograft and with two dosages of rhBMP-7, 3.5 mg and 1.75 mg, embedded in a slowly degradable medical grade poly(ε-caprolactone) (PCL) scaffold with ß-tricalcium phosphate microparticles (mPCL-TCP). Specimens were characterised by biomechanical testing, microcomputed tomography and histology. Bridging was observed within 3 months for the autograft and both rhBMP-7 treatments. No significant difference was observed between the low and high rhBMP-7 dosages or between any of the rhBMP-7 groups and autograft implantation. Scaffolds alone did not induce comparable levels of bone formation compared to the autograft and rhBMP-7 groups. In summary, the mPCL-TCP scaffold with the lower rhBMP-7 dose led to equivalent results to autograft transplantation or the high BMP dosage. Our data suggest a promising clinical future for BMP application in scaffold-based bone tissue engineering, lowering and optimising the amount of required BMP.