Redefining biomaterial biocompatibility: challenges for artificial intelligence and text mining.

The surge in 'Big data' has significantly influenced biomaterials research and development, with vast data volumes emerging from clinical trials, scientific literature, electronic health records, and other sources. Biocompatibility is essential in developing safe medical devices and biomaterials to perform as intended without provoking adverse reactions. Therefore, establishing an artificial intelligence (AI)-driven biocompatibility definition has become decisive for automating data extraction and profiling safety effectiveness. This definition should both reflect the attributes related to biocompatibility and be compatible with computational data-mining methods. Here, we discuss the need for a comprehensive and contemporary definition of biocompatibility and the challenges in developing one. We also identify the key elements that comprise biocompatibility, and propose an integrated biocompatibility definition that enables data-mining approaches.

Biomaterials text mining: A hands-on comparative study of methods on polydioxanone biocompatibility.

Scientific information extraction is fundamental for research and innovation, but is currently mostly a manual, time-consuming process. Text Mining tools (TMTs) enable automated, accurate and quick information extraction from text, but there is little precedent of their use in the biomaterials field. Here, we compare the ability of various TMTs to extract useful information from biomaterials abstracts. Focusing on the biocompatibility of polydioxanone, a biodegradable polymer for which there are relatively few scientific publications, we tested several tools ranging from machine learning approaches and statistical text analysis to MeSH indexing and domain-specific semantic tools for Named Entity Recognition. We also evaluated their output alongside a manual review of systematic reviews and meta-analyses. The findings show that TMTs can be highly efficient and powerful for mapping biomaterials texts and rapidly yield up-to-date information. Here, TMTs enable one to identify dominating themes, see the evolution of specific terms and topics, and learn about key medical applications in biomaterials literature over the years. The analysis also shows that ambiguity around biomaterials nomenclature is a significant challenge in mining biomedical literature that is yet to be tackled. This research showcases the potential value of using Natural Language Processing and domain-specific tools to extract and organize biomaterials data.

DEBBIE: The Open Access Database of Experimental Scaffolds and Biomaterials Built Using an Automated Text Mining Pipeline.

Biomaterials research output has experienced an exponential increase over the last three decades. The majority of research is published in the form of scientific articles and is therefore available as unstructured text, making it a challenging input for computational processing. Computational tools are becoming essential to overcome this information overload. Among them, text mining systems present an attractive option for the automated extraction of information from text documents into structured datasets. This work presents the first automated system for biomaterial related information extraction from the National Library of Medicine's premier bibliographic database (MEDLINE) research abstracts into a searchable database. The system is a text mining pipeline that periodically retrieves abstracts from PubMed and identifies research and clinical studies of biomaterials. Thereafter, the pipeline identifies sixteen concept types of interest in the abstract using the Biomaterials Annotator, a tool for biomaterials Named Entity Recognition (NER). These concepts of interest, along with the abstract and relevant metadata are then deposited in DEBBIE, the Database of Experimental Biomaterials and their Biological Effect. DEBBIE is accessible through a web application that provides keyword searches and displays results in an intuitive and meaningful manner, aiming to facilitate an efficient mapping and organization of biomaterials information.

Characterizing the macro and micro mechanical properties of scaffolds for rotator cuff repair.

BACKGROUND: Retearing after rotator cuff surgery is a major clinical problem. Numerous scaffolds are being used to try to reduce retear rates. However, few have demonstrated clinical efficacy. We hypothesize that this lack of efficacy is due to insufficient mechanical properties. Therefore, we compared the macro and nano/micro mechanical properties of 7 commercially available scaffolds to those of the human supraspinatus tendons, whose function they seek to restore. METHODS: The clinically approved scaffolds tested were X-Repair, LARS ligament, Poly-Tape, BioFiber, GraftJacket, Permacol, and Conexa. Fresh frozen cadaveric human supraspinatus tendon samples were used. Macro mechanical properties were determined through tensile testing and rheometry. Scanning probe microscopy and scanning electron microscopy were performed to assess properties of materials at the nano/microscale (morphology, Young modulus, loss tangent). RESULTS: None of the scaffolds tested adequately approximated both the macro and micro mechanical properties of human supraspinatus tendon. Macroscale mechanical properties were insufficient to restore load-bearing function. The best-performing scaffolds on the macroscale (X-Repair, LARS ligament) had poor nano/microscale properties. Scaffolds approximating tendon properties on the nano/microscale (BioFiber, biologic scaffolds) had poor macroscale properties. CONCLUSION: Existing scaffolds failed to adequately approximate the mechanical properties of human supraspinatus tendons. Combining the macroscopic mechanical properties of a synthetic scaffold with the micro mechanical properties of biologic scaffold could better achieve this goal. Future work should focus on advancing techniques to create new scaffolds with more desirable mechanical properties. This may help improve outcomes for rotator cuff surgery patients.

A quantitative label-free analysis of the extracellular proteome of human supraspinatus tendon reveals damage to the pericellular and elastic fibre niches in torn and aged tissue.

Tears of the human supraspinatus tendon are common and often cause painful and debilitating loss of function. Progressive failure of the tendon leading to structural abnormality and tearing is accompanied by numerous cellular and extra-cellular matrix (ECM) changes in the tendon tissue. This proteomics study aimed to compare torn and aged rotator cuff tissue to young and healthy tissue, and provide the first ECM inventory of human supraspinatus tendon generated using label-free quantitative LC-MS/MS. Employing two digestion protocols (trypsin and elastase), we analysed grain-sized tendon supraspinatus biopsies from older patients with torn tendons and from healthy, young controls. Our findings confirm measurable degradation of collagen fibrils and associated proteins in old and torn tendons, suggesting a significant loss of tissue organisation. A particularly marked reduction of cartilage oligomeric matrix protein (COMP) raises the possibility of using changes in levels of this glycoprotein as a marker of abnormal tissue, as previously suggested in horse models. Surprisingly, and despite using an elastase digestion for validation, elastin was not detected, suggesting that it is not highly abundant in human supraspinatus tendon as previously thought. Finally, we identified marked changes to the elastic fibre, fibrillin-rich niche and the pericellular matrix. Further investigation of these regions may yield other potential biomarkers and help to explain detrimental cellular processes associated with tendon ageing and tendinopathy.

Identifying the optimum source of mesenchymal stem cells for use in knee surgery.

Single sitting procedures where the mononuclear cell fraction is extracted from bone marrow and implanted directly into cartilage and bone defects are becoming more popular as novel treatments for cartilage defects which have, until now had few treatment options. This is on the basis that the mesenchymal stem cells (MSCs) contained within will repair the damaged tissue. This study sought to determine if the femur and tibia could provide equivalent amounts of mesenchymal stem cells, with equivalent viability and proliferative capacity, to that obtained from the gold standard of the pelvis in order to potentially reduce the morbidity associated with these procedures. Bone marrow was extracted from the pelvis, femur, and tibia of human subjects. The mononuclear cell fraction was extracted and cultured in the laboratory. Mesenchymal stem cell populations were assessed using a colony forming unit count. Viability was assessed using a PrestoBlue viability assay. Population doubling number was calculated between the end of passage 0 and passage three to determine the proliferative abilities of the different populations. Finally, the cell surface phenotype of the cells was determined by flow cytometry. The results showed that the pelvis was superior to the femur and tibia in terms of the number of stem cells isolated. There was no statistically significant difference in the phenotype of the cells isolated from different locations. This work shows that when undertaking single sitting procedures, the pelvis remains the optimum source for obtaining MSCs, despite the morbidity associated with bone marrow collection from the pelvis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1868-1875, 2017.

Effect of Exercise on Ovulation: A Systematic Review.

BACKGROUND: Infertility has been described as a devastating life crisis for couples, and has a particularly severe effect on women, in terms of anxiety and depression. Anovulation accounts for around 30% of female infertility, and while lifestyle factors such as physical activity are known to be important, the relationship between exercise and ovulation is multi-factorial and complex, and to date there are no clear recommendations concerning exercise regimes. OBJECTIVES: The objective of this review was to systematically assess the effect of physical activity on ovulation and to discuss the possible mechanisms by which exercise acts to modulate ovulation in reproductive-age women. This was done with a view to improve existing guidelines for women wishing to conceive, as well as women suffering from anovulatory infertility. SEARCH METHODS: The published literature was searched up to April 2016 using the search terms ovulation, anovulatory, fertility, sport, physical activity and exercise. Both observational and interventional studies were considered, as well as studies that combined exercise with diet. Case studies and articles that did not report anovulation/ovulation or ovarian morphology as outcomes were excluded. Studies involving administered drugs in addition to exercise were excluded. RESULTS: In total, ten interventions and four observational cohort studies were deemed relevant. Cohort studies showed that there is an increased risk of anovulation in extremely heavy exercisers (>60 min/day), but vigorous exercise of 30-60 min/day was associated with reduced risk of anovulatory infertility. Ten interventions were identified, and of these three have studied the effect of vigorous exercise on ovulation in healthy, ovulating women, but only one showed a significant disruption of ovulation as a result. Seven studies have investigated the effect of exercise on overweight/obese women suffering from polycystic ovary syndrome (PCOS) or anovulatory infertility, showing that exercise, with or without diet, can lead to resumption of ovulation. The mechanism by which exercise affects ovulation is most probably via modulation of the hypothalamic-pituitary-gonadal (HPG) axis due to increased activity of the hypothalamic-pituitary-adrenal (HPA) axis. In heavy exercisers and/or underweight women, an energy drain, low leptin and fluctuating opioids caused by excess exercise have been implicated in HPA dysfunction. In overweight and obese women (with or without PCOS), exercise contributed to lower insulin and free androgen levels, leading to the restoration of HPA regulation of ovulation. CONCLUSIONS: Several clear gaps have been identified in the existing literature. Short-term studies of over-training have not always produced the disturbance to ovulation identified in the observational studies, bringing up the question of the roles of longer term training and chronic energy deficit. We believe this merits further investigation in specific cohorts, such as professional athletes. Another gap is the complete absence of exercise-based interventions in anovulatory women with a normal body mass index (BMI). The possibly unjustified focus on weight loss rather than the exercise programme means there is also a lack of studies comparing types of physical activity, intensity and settings. We believe that these gaps are delaying an efficient and effective use of exercise as a therapeutic modality to treat anovulatory infertility.

A comparative evaluation of the effect of polymer chemistry and fiber orientation on mesenchymal stem cell differentiation.

Bioengineered tissue scaffolds in combination with cells hold great promise for tissue regeneration. The aim of this study was to determine how the chemistry and fiber orientation of engineered scaffolds affect the differentiation of mesenchymal stem cells (MSCs). Adipogenic, chondrogenic, and osteogenic differentiation on aligned and randomly orientated electrospun scaffolds of Poly (lactic-co-glycolic) acid (PLGA) and Polydioxanone (PDO) were compared. MSCs were seeded onto scaffolds and cultured for 14 days under adipogenic-, chondrogenic-, or osteogenic-inducing conditions. Cell viability was assessed by alamarBlue metabolic activity assays and gene expression was determined by qRT-PCR. Cell-scaffold interactions were visualized using fluorescence and scanning electron microscopy. Cells grew in response to scaffold fiber orientation and cell viability, cell coverage, and gene expression analysis showed that PDO supports greater multilineage differentiation of MSCs. An aligned PDO scaffold supports highest adipogenic and osteogenic differentiation whereas fiber orientation did not have a consistent effect on chondrogenesis. Electrospun scaffolds, selected on the basis of fiber chemistry and alignment parameters could provide great therapeutic potential for restoration of fat, cartilage, and bone tissue. This study supports the continued investigation of an electrospun PDO scaffold for tissue repair and regeneration and highlights the potential of optimizing fiber orientation for improved utility. © 2016 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2843-2853, 2016.

Gene expression profiles of changes underlying different-sized human rotator cuff tendon tears.

BACKGROUND: Progressive cellular and extracellular matrix (ECM) changes related to age and disease severity have been demonstrated in rotator cuff tendon tears. Larger rotator cuff tears demonstrate structural abnormalities that potentially adversely influence healing potential. This study aimed to gain greater insight into the relationship of pathologic changes to tear size by analyzing gene expression profiles from normal rotator cuff tendons, small rotator cuff tears, and large rotator cuff tears. METHODS: We analyzed gene expression profiles of 28 human rotator cuff tendons using microarrays representing the entire genome; 11 large and 5 small torn rotator cuff tendon specimens were obtained intraoperatively from tear edges, which we compared with 12 age-matched normal controls. We performed real-time polymerase chain reaction and immunohistochemistry for validation. RESULTS: Torn rotator cuff tendons demonstrated upregulation of a number of key genes, such as matrix metalloproteinase 3, 10, 12, 13, 15, 21, and 25; a disintegrin and metalloproteinase (ADAM) 12, 15, and 22; and aggrecan. Amyloid was downregulated in all tears. Small tears displayed upregulation of bone morphogenetic protein 5. Chemokines and cytokines that may play a role in chemotaxis were altered; interleukins 3, 10, 13, and 15 were upregulated in tears, whereas interleukins 1, 8, 11, 18, and 27 were downregulated. CONCLUSIONS: The gene expression profiles of normal controls and small and large rotator cuff tear groups differ significantly. Extracellular matrix remodeling genes were found to contribute to rotator cuff tear pathogenesis. Rotator cuff tears displayed upregulation of a number of matrix metalloproteinase (3, 10, 12, 13, 15, 21, and 25), a disintegrin and metalloproteinase (ADAM 12, 15, and 22) genes, and downregulation of some interleukins (1, 8, and 27), which play important roles in chemotaxis. These gene products may potentially have a role as biomarkers of failure of healing or therapeutic targets to improve tendon healing.

Fabrication of continuous electrospun filaments with potential for use as medical fibres.

Soft tissue injuries represent a substantial and growing social and economic burden. Medical fibres are commonly used to repair these injuries during surgery. Patient's outcomes are, however, not promising with around 40% of surgical repairs failing within the first few months after surgery due to poor tissue regeneration. The application of nanofibrous filaments and yarns as medical fibres and scaffolds has been suggested to improve soft tissue regeneration and enhance the quality of the repair. However, due to a lack of robustness and reliability of the current fabrication methods, continuous nanofibrous filaments cannot be manufactured and scaled up in industrial settings and are not currently available for clinical use. We have developed a robust and automated method that enables the manufacture of continuous electrospun filaments and which has the potential to be integrated into existing textile production lines. The technology uses a wire guide to form submicrofibres in a dense, narrow mesh which can be detached as a long and continuous thread. The thread can then be stretched and used to create multifilament yarns which can imitate the hierarchical architecture of tissues such as tendons and ligaments. Electrospun polydioxanone yarns produced by this method showed improved cellular proliferation and adhesion when compared to medical monofilament fibres in current clinical use. In vivo, the electrospun yarns showed a good safety profile with mild foreign body reaction and complete degradation within 5 months after implantation. These results suggest that this filament collection method has the potential to become a useful platform for the fabrication of future medical textiles.

Distribution and expression of type VI collagen and elastic fibers in human rotator cuff tendon tears.

There is increasing evidence for a progressive extracellular matrix change in rotator cuff disease progression. Directly surrounding the cell is the pericellular matrix, where assembly of matrix aggregates typically occurs making it critical in the response of tendon cells to pathological conditions. Studies in animal models have identified type VI collagen, fibrillin-1 and elastin to be located in the pericellular matrix of tendon and contribute in maintaining the structural and biomechanical integrity of tendon. However, there have been no reports on the localization of these proteins in human tendon biopsies. This study aimed to characterize the distribution of these ECM components in human rotator cuffs and gain greater insight into the relationship of pathology to tear size by analyzing the distribution and expression profiles of these ECM components. Confocal microscopy confirmed the localization of these structural molecules in the pericellular matrix of the human rotator cuff. Tendon degeneration led to an increased visibility of these components with a significant disorganization in the distribution of type VI collagen. At the genetic level, an increase in tear size was linked to an increased transcription of type VI collagen and fibrillin-1 with no significant alteration in the elastin levels. This is the first study to confirm the localization of type VI collagen, elastin and fibrillin-1 in the pericellular region of human supraspinatus tendon and assesses the effect of tendon degeneration on these structures, thus providing a useful insight into the composition of human rotator cuff tears which can be instrumental in predicting disease prognosis.

Repairing damaged tendon and muscle: are mesenchymal stem cells and scaffolds the answer?

Mesenchymal stem cells (MSCs) have become an area of intense interest in the treatment of musculoskeletal conditions, such as muscle and tendon injury, as various animal and human trials have demonstrated that implantation with MSCs leads to improved healing and function. However, these trials have usually been relatively small scale and lacking in adequate controls. Additionally, the optimum source of these cells has yet to be determined, partly due to a lack of understanding as to how MSCs produce their beneficial effects when implanted. Scaffolds have been shown to improve tissue-engineering repairs but require further work to optimize their interactions with both native tissue and implanted MSCs. Robust, well-controlled trials are therefore required to determine the usefulness of MSCs in musculoskeletal tissue repair.

Synthetic and degradable patches: an emerging solution for rotator cuff repair.

The use of rotator cuff augmentation has increased dramatically over the last 10 years in response to the high rate of failure observed after non-augmented surgery. However, although augmentations have been shown to reduce shoulder pain, there is no consensus or clear guideline as to what is the safest or most efficacious material. Current augmentations, either available commercially or in development, can be classified into three categories: non-degradable structures, extra cellular matrix (ECM)-based patches and degradable synthetic scaffolds. Non-degradable structures have excellent mechanical properties, but can cause problems of infection and loss of integrity in the long-term. ECM-based patches usually demonstrate excellent biological properties in vitro, but studies have highlighted complications in vivo due to poor mechanical support and to infection or inflammation. Degradable synthetic scaffolds represent the new generation of implants. It is proposed that a combination of good mechanical properties, active promotion of biological healing, low infection risk and bio-absorption are the ideal characteristics of an augmentation material. Among the materials with these features, those processed by electrospinning have shown great promis. However, their clinical effectiveness has yet to be proven and well conducted clinical trials are urgently required.

Differential growth on sutures of tendon cells derived from torn human rotator cuff.

Rotator cuff tendon pathology is proposed to account for 30-70% of all shoulder pain and surgical repair with a nonabsorbable suture is the common option for painful rotator cuff tears that have failed conservative treatment. A number of studies have suggested the beneficial effect of augmenting the repair with implants constructed from polymers used for sutures. Thus, it was of interest to investigate the affinity of tendon-derived fibroblasts, often thought to be the repairing agents of torn tendons, to commonly used sutures. The aim of this comparative study was to evaluate the suitability of these sutures for the construction of a patch by measuring cell survival, proliferation, and migration of human tendon-derived fibroblasts on different sutures. To ensure relevance to the target tissue, cells used in this study were obtained from torn human supraspinatus tendons. An initial comparison of cell proliferation on suture mats showed an overall positive proliferation on polyester (Ethibond) and polydioxanone (PDSII) mats and a reduction of proliferation on vicryl (polyglactin 910) compared to day one. The results also showed that the degradation products of vicryl had a negative effect on cell growth over 10 weeks. Of the commercial sutures selected and tested, Ethibond showed the best performance in terms of cell attachment and increase in biomass. The degradable PDSII also showed good interaction with cells in vitro, but relatively poor cell adhesion. This study provides useful and clinically relevant information, which could help to guide future considerations for candidate materials from which to construct tissue repair patches.

Modulation of cell growth on exposure to silkworm and spider silk fibers.

Recent years have seen an increased interest in the use of natural and modified silks for tissue engineering. Despite longstanding concerns regarding the biocompatibility of silk sutures, only a few studies have been carried out to investigate the biocompatibility of natural silk fibers. Here, we report an in vitro assessment of the effect of nonmodified, degummed silks on cells. We describe the effects of degummed silk fibers as well as extracted sericin on cell metabolism and proliferation. Endothelial cells directly exposed to native degummed Bombyx mori and Antheraea pernyi silks showed lower rates of proliferation and metabolism than nonexposed cells. A similar but milder effect was observed for cells in direct contact with Nephila edulis egg sack fibers. Sericin and silk-conditioned medium had no negative effect on cell proliferation except in medium supplemented with 5% bovine serum prior to conditioning with A. pernyi silk. The toxicity of A. pernyi was negligible after thorough enzymatic treatment of the fibers with trypsin. It is, therefore, proposed that A. pernyi silk contain one or more cytotoxic components, which need to be removed prior to medical use.

Ultrastructure of insect and spider cocoon silks.

Despite much interest in the extraordinary mechanical properties of silks, the structure of native silk fibers is still not fully understood. In the present study, the morphology, topography, and organization of insect and spider cocoon silks were investigated using a range of imaging methods. Field emission scanning electron microscopy was used to observe transverse and longitude structures in silk fibers subjected to tensile fracturing, freeze fracturing, or polishing. In addition, ultrathin sections of silk brins embedded in resin were examined using transmission electron microscopy. Finally, dry silk brins were examined by confocal microscopy. The results confirmed the existence of well-oriented bundles of nanofibrils in all the silks examined and gave an indication of a hierarchical construction of the brin. Observed separation of the microfibrils in fractured brins suggests that the multifibrillar structure of the silk fiber contributes to toughness by allowing dissipation of energy in the controlled propagation of cracks.