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Bone & Joint Open
Vol. 5, Issue 1 | Pages 9 - 19
16 Jan 2024
Dijkstra H van de Kuit A de Groot TM Canta O Groot OQ Oosterhoff JH Doornberg JN

Aims. Machine-learning (ML) prediction models in orthopaedic trauma hold great promise in assisting clinicians in various tasks, such as personalized risk stratification. However, an overview of current applications and critical appraisal to peer-reviewed guidelines is lacking. The objectives of this study are to 1) provide an overview of current ML prediction models in orthopaedic trauma; 2) evaluate the completeness of reporting following the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) statement; and 3) assess the risk of bias following the Prediction model Risk Of Bias Assessment Tool (PROBAST) tool. Methods. A systematic search screening 3,252 studies identified 45 ML-based prediction models in orthopaedic trauma up to January 2023. The TRIPOD statement assessed transparent reporting and the PROBAST tool the risk of bias. Results. A total of 40 studies reported on training and internal validation; four studies performed both development and external validation, and one study performed only external validation. The most commonly reported outcomes were mortality (33%, 15/45) and length of hospital stay (9%, 4/45), and the majority of prediction models were developed in the hip fracture population (60%, 27/45). The overall median completeness for the TRIPOD statement was 62% (interquartile range 30 to 81%). The overall risk of bias in the PROBAST tool was low in 24% (11/45), high in 69% (31/45), and unclear in 7% (3/45) of the studies. High risk of bias was mainly due to analysis domain concerns including small datasets with low number of outcomes, complete-case analysis in case of missing data, and no reporting of performance measures. Conclusion. The results of this study showed that despite a myriad of potential clinically useful applications, a substantial part of ML studies in orthopaedic trauma lack transparent reporting, and are at high risk of bias. These problems must be resolved by following established guidelines to instil confidence in ML models among patients and clinicians. Otherwise, there will remain a sizeable gap between the development of ML prediction models and their clinical application in our day-to-day orthopaedic trauma practice. Cite this article: Bone Jt Open 2024;5(1):9–19


Bone & Joint Open
Vol. 3, Issue 7 | Pages 549 - 556
1 Jul 2022
Poacher AT Bhachoo H Weston J Shergill K Poacher G Froud J

Aims. Evidence exists of a consistent decline in the value and time that medical schools place upon their undergraduate orthopaedic placements. This limited exposure to trauma and orthopaedics (T&O) during medical school will be the only experience in the speciality for the majority of doctors. This review aims to provide an overview of undergraduate orthopaedic training in the UK. Methods. This review summarizes the relevant literature from the last 20 years in the UK. Articles were selected from database searches using MEDLINE, EMBASE, ERIC, Cochrane, and Web of Science. A total of 16 papers met the inclusion criteria. Results. The length of exposure to T&O is declining; the mean total placement duration of two to three weeks is significantly less than the four- to six-week minimum advised by most relevant sources. The main teaching methods described in the literature included didactic lectures, bedside teaching, and small group case-based discussions. Students preferred interactive, blended learning teaching styles over didactic methods. This improvement in satisfaction was reflected in improvements in student assessment scores. However, studies failed to assess competencies in clinical skills and examinations, which is consistent with the opinions of UK foundation year doctors, approximately 40% of whom report a “poor” understanding of orthopaedics. Furthermore, the majority of UK doctors are not exposed to orthopaedics at the postgraduate level, which only serves to amplify the disparity between junior and generalist knowledge, and the standards expected by senior colleagues and professional bodies. Conclusion. There is a deficit in undergraduate orthopaedic training within the UK which has only worsened in the last 20 years, leaving medical students and foundation doctors with a potentially significant lack of orthopaedic knowledge. Cite this article: Bone Jt Open 2022;3(7):549–556


Bone & Joint Open
Vol. 3, Issue 7 | Pages 582 - 588
1 Jul 2022
Hodel S Selman F Mania S Maurer SM Laux CJ Farshad M

Aims. Preprint servers allow authors to publish full-text manuscripts or interim findings prior to undergoing peer review. Several preprint servers have extended their services to biological sciences, clinical research, and medicine. The purpose of this study was to systematically identify and analyze all articles related to Trauma & Orthopaedic (T&O) surgery published in five medical preprint servers, and to investigate the factors that influence the subsequent rate of publication in a peer-reviewed journal. Methods. All preprints covering T&O surgery were systematically searched in five medical preprint servers (medRxiv, OSF Preprints, Preprints.org, PeerJ, and Research Square) and subsequently identified after a minimum of 12 months by searching for the title, keywords, and corresponding author in Google Scholar, PubMed, Scopus, Embase, Cochrane, and the Web of Science. Subsequent publication of a work was defined as publication in a peer-reviewed indexed journal. The rate of publication and time to peer-reviewed publication were assessed. Differences in definitive publication rates of preprints according to geographical origin and level of evidence were analyzed. Results. The number of preprints increased from 2014 to 2020 (p < 0.001). A total of 38.6% of the identified preprints (n = 331) were published in a peer-reviewed indexed journal after a mean time of 8.7 months (SD 5.4 (1 to 27)). The highest proportion of missing subsequent publications was in the preprints originating from Africa, Asia/Middle East, and South America, or in those that covered clinical research with a lower level of evidence (p < 0.001). Conclusion. Preprints are being published in increasing numbers in T&O surgery. Depending on the geographical origin and level of evidence, almost two-thirds of preprints are not subsequently published in a peer-reviewed indexed journal after one year. This raises major concerns regarding the dissemination and persistence of potentially wrong scientific work that bypasses peer review, and the orthopaedic community should discuss appropriate preventive measures. Cite this article: Bone Jt Open 2022;3(7):582–588


Bone & Joint Research
Vol. 13, Issue 5 | Pages 201 - 213
1 May 2024
Hamoodi Z Gehringer CK Bull LM Hughes T Kearsley-Fleet L Sergeant JC Watts AC

Aims. The aims of this study were to identify and evaluate the current literature examining the prognostic factors which are associated with failure of total elbow arthroplasty (TEA). Methods. Electronic literature searches were conducted using MEDLINE, Embase, PubMed, and Cochrane. All studies reporting prognostic estimates for factors associated with the revision of a primary TEA were included. The risk of bias was assessed using the Quality In Prognosis Studies (QUIPS) tool, and the quality of evidence was assessed using the modified Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. Due to low quality of the evidence and the heterogeneous nature of the studies, a narrative synthesis was used. Results. A total of 19 studies met the inclusion criteria, investigating 28 possible prognostic factors. Most QUIPS domains (84%) were rated as moderate to high risk of bias. The quality of the evidence was low or very low for all prognostic factors. In low-quality evidence, prognostic factors with consistent associations with failure of TEA in more than one study were: the sequelae of trauma leading to TEA, either independently or combined with acute trauma, and male sex. Several other studies investigating sex reported no association. The evidence for other factors was of very low quality and mostly involved exploratory studies. Conclusion. The current evidence investigating the prognostic factors associated with failure of TEA is of low or very low quality, and studies generally have a moderate to high risk of bias. Prognostic factors are subject to uncertainty, should be interpreted with caution, and are of little clinical value. Higher-quality evidence is required to determine robust prognostic factors for failure of TEA. Cite this article: Bone Joint Res 2024;13(5):201–213


Bone & Joint Research
Vol. 12, Issue 2 | Pages 138 - 146
14 Feb 2023
Aquilina AL Claireaux H Aquilina CO Tutton E Fitzpatrick R Costa ML Griffin XL

Aims. Open lower limb fracture is a life-changing injury affecting 11.5 per 100,000 adults each year, and causes significant morbidity and resource demand on trauma infrastructures. This study aims to identify what, and how, outcomes have been reported for people following open lower limb fracture over ten years. Methods. Systematic literature searches identified all clinical studies reporting outcomes for adults following open lower limb fracture between January 2009 and July 2019. All outcomes and outcome measurement instruments were extracted verbatim. An iterative process was used to group outcome terms under standardized outcome headings categorized using an outcome taxonomy. Results. A total of 532 eligible studies were identified, reporting 1,803 outcomes with 786 unique outcome terms, which collapsed to 82 standardized outcome headings. Overall 479 individual outcome measurement instruments were identified, including 298 outcome definitions, 27 patient- and 18 clinician-reported outcome measures, and six physical performance measures. The most-reported outcome was ‘bone union/healing’ reported in over 50% of included studies, while health-related quality of life was only measured in 6% of included studies. Conclusion. Outcomes reported for people recovering from open lower limb fracture are heterogeneous, liable to outcome reporting bias, and vary widely in the definitions and the measurement tools used to collect them. Outcomes likely to be important to patients, such as quality of life and measures of physical functioning, have been neglected. This systematic review identifies the need to unify outcome measures reported on patients recovering from open lower limb fracture; this may be addressed by creating a core outcome set. Cite this article: Bone Joint Res 2023;12(2):138–146


Bone & Joint Research
Vol. 12, Issue 9 | Pages 536 - 545
8 Sep 2023
Luo P Yuan Q Yang M Wan X Xu P

Osteoarthritis (OA) is mainly caused by ageing, strain, trauma, and congenital joint abnormalities, resulting in articular cartilage degeneration. During the pathogenesis of OA, the changes in subchondral bone (SB) are not only secondary manifestations of OA, but also an active part of the disease, and are closely associated with the severity of OA. In different stages of OA, there were microstructural changes in SB. Osteocytes, osteoblasts, and osteoclasts in SB are important in the pathogenesis of OA. The signal transduction mechanism in SB is necessary to maintain the balance of a stable phenotype, extracellular matrix (ECM) synthesis, and bone remodelling between articular cartilage and SB. An imbalance in signal transduction can lead to reduced cartilage quality and SB thickening, which leads to the progression of OA. By understanding changes in SB in OA, researchers are exploring drugs that can regulate these changes, which will help to provide new ideas for the treatment of OA. Cite this article: Bone Joint Res 2023;12(9):536–545


Bone & Joint Open
Vol. 1, Issue 11 | Pages 683 - 690
1 Nov 2020
Khan SA Asokan A Handford C Logan P Moores T

Background. Due to the overwhelming demand for trauma services, resulting from increasing emergency department attendances over the past decade, virtual fracture clinics (VFCs) have become the fashion to keep up with the demand and help comply with the BOA Standards for Trauma and Orthopaedics (BOAST) guidelines. In this article, we perform a systematic review asking, “How useful are VFCs?”, and what injuries and conditions can be treated safely and effectively, to help decrease patient face to face consultations. Our primary outcomes were patient satisfaction, clinical efficiency and cost analysis, and clinical outcomes. Methods. We performed a systematic literature search of all papers pertaining to VFCs, using the search engines PubMed, MEDLINE, and the Cochrane Database, according to the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) checklist. Searches were carried out and screened by two authors, with final study eligibility confirmed by the senior author. Results. In total, 21 records were relevant to our research question. Six orthopaedic injuries were identified as suitable for VFC review, with a further four discussed in detail. A reduction of face to face appointments of up to 50% was reported with greater compliance to BOAST guidelines (46.4%) and cost saving (up to £212,000). Conclusions. This systematic review demonstrates that the VFC model can help deliver a safe, more cost-effective, and more efficient arm of the trauma service to patients. Cite this article: Bone Joint Open 2020;1-11:683–690


Bone & Joint Open
Vol. 2, Issue 5 | Pages 344 - 350
31 May 2021
Ahmad SS Hoos L Perka C Stöckle U Braun KF Konrads C

Aims. The follow-up interval of a study represents an important aspect that is frequently mentioned in the title of the manuscript. Authors arbitrarily define whether the follow-up of their study is short-, mid-, or long-term. There is no clear consensus in that regard and definitions show a large range of variation. It was therefore the aim of this study to systematically identify clinical research published in high-impact orthopaedic journals in the last five years and extract follow-up information to deduce corresponding evidence-based definitions of short-, mid-, and long-term follow-up. Methods. A systematic literature search was performed to identify papers published in the six highest ranked orthopaedic journals during the years 2015 to 2019. Follow-up intervals were analyzed. Each article was assigned to a corresponding subspecialty field: sports traumatology, knee arthroplasty and reconstruction, hip-preserving surgery, hip arthroplasty, shoulder and elbow arthroplasty, hand and wrist, foot and ankle, paediatric orthopaedics, orthopaedic trauma, spine, and tumour. Mean follow-up data were tabulated for the corresponding subspecialty fields. Comparison between means was conducted using analysis of variance. Results. Of 16,161 published articles, 590 met the inclusion criteria. Of these, 321 were of level IV evidence, 176 level III, 53 level II, and 40 level I. Considering all included articles, a long-term study published in the included high impact journals had a mean follow-up of 151.6 months, a mid-term study of 63.5 months, and a short-term study of 30.0 months. Conclusion. The results of this study provide evidence-based definitions for orthopaedic follow-up intervals that should provide a citable standard for the planning of clinical studies. A minimum mean follow-up of a short-term study should be 30 months (2.5 years), while a mid-term study should aim for a mean follow-up of 60 months (five years), and a long-term study should aim for a mean of 150 months (12.5 years). Level of Evidence: Level I. Cite this article: Bone Jt Open 2021;2(5):344–350


Bone & Joint Open
Vol. 5, Issue 3 | Pages 252 - 259
28 Mar 2024
Syziu A Aamir J Mason LW

Aims

Posterior malleolar (PM) fractures are commonly associated with ankle fractures, pilon fractures, and to a lesser extent tibial shaft fractures. The tibialis posterior (TP) tendon entrapment is a rare complication associated with PM fractures. If undiagnosed, TP entrapment is associated with complications, ranging from reduced range of ankle movement to instability and pes planus deformities, which require further surgeries including radical treatments such as arthrodesis.

Methods

The inclusion criteria applied in PubMed, Scopus, and Medline database searches were: all adult studies published between 2012 and 2022; and studies written in English. Outcome of TP entrapment in patients with ankle injuries was assessed by two reviewers independently.


Bone & Joint Open
Vol. 5, Issue 5 | Pages 374 - 384
1 May 2024
Bensa A Sangiorgio A Deabate L Illuminati A Pompa B Filardo G

Aims

Robotic-assisted unicompartmental knee arthroplasty (R-UKA) has been proposed as an approach to improve the results of the conventional manual UKA (C-UKA). The aim of this meta-analysis was to analyze the studies comparing R-UKA and C-UKA in terms of clinical outcomes, radiological results, operating time, complications, and revisions.

Methods

The literature search was conducted on three databases (PubMed, Cochrane, and Web of Science) on 20 February 2024 according to the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Inclusion criteria were comparative studies, written in the English language, with no time limitations, on the comparison of R-UKA and C-UKA. The quality of each article was assessed using the Downs and Black Checklist for Measuring Quality.


Bone & Joint Open
Vol. 5, Issue 12 | Pages 1049 - 1066
1 Dec 2024
Lister J James S Sharma HK Hewitt C Fulbright H Leggett H McDaid C

Aims

Lower limb reconstruction (LLR) has a profound impact on patients, affecting multiple areas of their lives. Many patient-reported outcome measures (PROMs) are employed to assess these impacts; however, there are concerns that they do not adequately capture all outcomes important to patients, and may lack content validity in this context. This review explored whether PROMs used with adults requiring, undergoing, or after undergoing LLR exhibited content validity and adequately captured outcomes considered relevant and important to patients.

Methods

A total of 37 PROMs were identified. Systematic searches were performed to retrieve content validity studies in the adult LLR population, and hand-searches used to find PROM development studies. Content validity assessments for each measure were performed following Consensus-based Standards for the selection of health measurement Instruments (COSMIN) guidelines. A mapping exercise compared all PROMs to a conceptual framework previously developed by the study team (‘the PROLLIT framework’) to explore whether each PROM covered important and relevant concepts.


Bone & Joint Research
Vol. 11, Issue 11 | Pages 814 - 825
14 Nov 2022
Ponkilainen V Kuitunen I Liukkonen R Vaajala M Reito A Uimonen M

Aims

The aim of this systematic review and meta-analysis was to gather epidemiological information on selected musculoskeletal injuries and to provide pooled injury-specific incidence rates.

Methods

PubMed (National Library of Medicine) and Scopus (Elsevier) databases were searched. Articles were eligible for inclusion if they reported incidence rate (or count with population at risk), contained data on adult population, and were written in English language. The number of cases and population at risk were collected, and the pooled incidence rates (per 100,000 person-years) with 95% confidence intervals (CIs) were calculated by using either a fixed or random effects model.


Bone & Joint Research
Vol. 11, Issue 10 | Pages 700 - 714
4 Oct 2022
Li J Cheung W Chow SK Ip M Leung SYS Wong RMY

Aims

Biofilm-related infection is a major complication that occurs in orthopaedic surgery. Various treatments are available but efficacy to eradicate infections varies significantly. A systematic review was performed to evaluate therapeutic interventions combating biofilm-related infections on in vivo animal models.

Methods

Literature research was performed on PubMed and Embase databases. Keywords used for search criteria were “bone AND biofilm”. Information on the species of the animal model, bacterial strain, evaluation of biofilm and bone infection, complications, key findings on observations, prevention, and treatment of biofilm were extracted.


Bone & Joint Research
Vol. 9, Issue 3 | Pages 108 - 119
1 Mar 2020
Akhbari P Karamchandani U Jaggard MKJ Graça G Bhattacharya R Lindon JC Williams HRT Gupte CM

Aims. Metabolic profiling is a top-down method of analysis looking at metabolites, which are the intermediate or end products of various cellular pathways. Our primary objective was to perform a systematic review of the published literature to identify metabolites in human synovial fluid (HSF), which have been categorized by metabolic profiling techniques. A secondary objective was to identify any metabolites that may represent potential biomarkers of orthopaedic disease processes. Methods. A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines using the MEDLINE, Embase, PubMed, and Cochrane databases. Studies included were case series, case control series, and cohort studies looking specifically at HSF. Results. The primary analysis, which pooled the results from 17 published studies and four meeting abstracts, identified over 200 metabolites. Seven of these studies (six published studies, one meeting abstract) had asymptomatic control groups and collectively suggested 26 putative biomarkers in osteoarthritis, inflammatory arthropathies, and trauma. These can broadly be categorized into amino acids plus related metabolites, fatty acids, ketones, and sugars. Conclusion. The role of metabolic profiling in orthopaedics is fast evolving with many metabolites already identified in a variety of pathologies. However, these results need to be interpreted with caution due to the presence of multiple confounding factors in many of the studies. Future research should include largescale epidemiological metabolic profiling studies incorporating various confounding factors with appropriate statistical analysis to account for multiple testing of the data. Cite this article:Bone Joint Res. 2020;9(3):108–119


Bone & Joint Open
Vol. 3, Issue 3 | Pages 245 - 251
16 Mar 2022
Lester D Barber C Sowers CB Cyrus JW Vap AR Golladay GJ Patel NK

Aims

Return to sport following undergoing total (TKA) and unicompartmental knee arthroplasty (UKA) has been researched with meta-analyses and systematic reviews of varying quality. The aim of this study is to create an umbrella review to consolidate the data into consensus guidelines for returning to sports following TKA and UKA.

Methods

Systematic reviews and meta-analyses written between 2010 and 2020 were systematically searched. Studies were independently screened by two reviewers and methodology quality was assessed. Variables for analysis included objective classification of which sports are safe to participate in postoperatively, time to return to sport, prognostic indicators of returning, and reasons patients do not.


Bone & Joint Research
Vol. 10, Issue 8 | Pages 474 - 487
2 Aug 2021
Duan M Wang Q Liu Y Xie J

Transforming growth factor-beta2 (TGF-β2) is recognized as a versatile cytokine that plays a vital role in regulation of joint development, homeostasis, and diseases, but its role as a biological mechanism is understood far less than that of its counterpart, TGF-β1. Cartilage as a load-resisting structure in vertebrates however displays a fragile performance when any tissue disturbance occurs, due to its lack of blood vessels, nerves, and lymphatics. Recent reports have indicated that TGF-β2 is involved in the physiological processes of chondrocytes such as proliferation, differentiation, migration, and apoptosis, and the pathological progress of cartilage such as osteoarthritis (OA) and rheumatoid arthritis (RA). TGF-β2 also shows its potent capacity in the repair of cartilage defects by recruiting autologous mesenchymal stem cells and promoting secretion of other growth factor clusters. In addition, some pioneering studies have already considered it as a potential target in the treatment of OA and RA. This article aims to summarize the current progress of TGF-β2 in cartilage development and diseases, which might provide new cues for remodelling of cartilage defect and intervention of cartilage diseases.


Bone & Joint Research
Vol. 10, Issue 7 | Pages 445 - 458
7 Jul 2021
Zhu S Zhang X Chen X Wang Y Li S Qian W

Aims

The value of core decompression (CD) in the treatment of osteonecrosis of the femoral head (ONFH) remains controversial. We conducted a systematic review and meta-analysis to evaluate whether CD combined with other treatments could improve the clinical and radiological outcomes of ONFH patients compared with CD alone.

Methods

We searched the PubMed, Embase, Web of Science, and Cochrane Library databases until June 2020. All randomized controlled trials (RCTs) and clinical controlled trials (CCTs) comparing CD alone and CD combined with other measures (CD + cell therapy, CD + bone grafting, CD + porous tantalum rod, etc.) for the treatment of ONFH were considered eligible for inclusion. The primary outcomes of interest were Harris Hip Score (HHS), ONFH stage progression, structural failure (collapse) of the femoral head, and conversion to total hip arthroplasty (THA). The pooled data were analyzed using Review Manager 5.3 software.


Bone & Joint Research
Vol. 9, Issue 7 | Pages 368 - 385
1 Jul 2020
Chow SK Chim Y Wang J Wong RM Choy VM Cheung W

A balanced inflammatory response is important for successful fracture healing. The response of osteoporotic fracture healing is deranged and an altered inflammatory response can be one underlying cause. The objectives of this review were to compare the inflammatory responses between normal and osteoporotic fractures and to examine the potential effects on different healing outcomes. A systematic literature search was conducted with relevant keywords in PubMed, Embase, and Web of Science independently. Original preclinical studies and clinical studies involving the investigation of inflammatory response in fracture healing in ovariectomized (OVX) animals or osteoporotic/elderly patients with available full text and written in English were included. In total, 14 articles were selected. Various inflammatory factors were reported; of those tumour necrosis factor-α (TNF-α) and interleukin (IL)-6 are two commonly studied markers. Preclinical studies showed that OVX animals generally demonstrated higher systemic inflammatory response and poorer healing outcomes compared to normal controls (SHAM). However, it is inconclusive if the local inflammatory response is higher or lower in OVX animals. As for clinical studies, they mainly examine the temporal changes of the inflammatory stage or perform comparison between osteoporotic/fragility fracture patients and normal subjects without fracture. Our review of these studies emphasizes the lack of understanding that inflammation plays in the altered fracture healing response of osteoporotic/elderly patients. Taken together, it is clear that additional studies, preclinical and clinical, are required to dissect the regulatory role of inflammatory response in osteoporotic fracture healing.

Cite this article: Bone Joint Res 2020;9(7):368–385.


Bone & Joint Open
Vol. 1, Issue 5 | Pages 121 - 130
13 May 2020
Crosby BT Behbahani A Olujohungbe O Cottam B Perry D

Objectives

This review aims to summarize the outcomes used to describe effectiveness of treatments for paediatric wrist fractures within existing literature.

Method

We searched the Cochrane Library, Scopus, and Ovid Medline for studies pertaining to paediatric wrist fractures. Three authors independently identified and reviewed eligible studies. This resulted in a list of outcome domains and outcomes measures used within clinical research. Outcomes were mapped onto domains defined by the COMET collaborative.


Bone & Joint Research
Vol. 7, Issue 3 | Pages 232 - 243
1 Mar 2018
Winkler T Sass FA Duda GN Schmidt-Bleek K

Despite its intrinsic ability to regenerate form and function after injury, bone tissue can be challenged by a multitude of pathological conditions. While innovative approaches have helped to unravel the cascades of bone healing, this knowledge has so far not improved the clinical outcomes of bone defect treatment. Recent findings have allowed us to gain in-depth knowledge about the physiological conditions and biological principles of bone regeneration. Now it is time to transfer the lessons learned from bone healing to the challenging scenarios in defects and employ innovative technologies to enable biomaterial-based strategies for bone defect healing. This review aims to provide an overview on endogenous cascades of bone material formation and how these are transferred to new perspectives in biomaterial-driven approaches in bone regeneration.

Cite this article: T. Winkler, F. A. Sass, G. N. Duda, K. Schmidt-Bleek. A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering: The unsolved challenge. Bone Joint Res 2018;7:232–243. DOI: 10.1302/2046-3758.73.BJR-2017-0270.R1.