Gerjon Hannink

Bioresorbability, porosity and mechanical strength of bone substitutes: what is optimal for bone regeneration?

Bone repair is a multi-dimensional process that requires osteogenic cells, an osteoconductive matrix, osteoinductive signalling, mechanical stability and vascularization. In clinical practice, bone substitute materials are being used for reconstructive purposes, bone stock augmentation, and bone repair. Over the last decade, the use of calcium phosphate (CaP) based bone substitute materials has increased exponentially. These bone substitute materials vary in composition, mechanical strength and biological mechanism of function, each having their own advantages and disadvantages. It is known that intrinsic material properties of CaP bone substitutes have a profound effect on their mechanical and biological behaviour and associated biodegradation. These material properties of bone substitutes, such as porosity, composition and geometry change the trade-off between mechanical and biological performance. The choice of the optimal bone substitutes is therefore not always an easy one, and largely depends on the clinical application and its associated biological and mechanical needs. Not all bone graft substitutes will perform the same way, and their performance in one clinical site may not necessarily predict their performance in another site. CaP bone substitutes unfortunately have yet to achieve optimal mechanical and biological performance and to date each material has its own trade-off between mechanical and biological performance. This review describes the effect of intrinsic material properties on biological performance, mechanical strength and biodegradability of CaP bone substitutes.

Sentinel node biopsy for squamous cell carcinoma of the oral cavity and oropharynx: A diagnostic meta-analysis

BACKGROUND The aim of the study was to systematically assess the accuracy of a sentinel lymph node biopsy (SLNB) in cT1/T2N0 oral cavity and oropharyngeal squamous cell carcinoma patients. METHODS We searched electronic databases, including EMBASE and MEDLINE (Pubmed) up to November 7 2012, by combining oral cancer keywords with sentinel node biopsy keywords. We included diagnostic accuracy studies which used neck dissection as a reference test for the sentinel node biopsy. Study characteristics and measures of accuracy were extracted. Diagnostic accuracy was calculated from 2 × 2 tables. RESULTS 21 Studies (847 patients) could be included. Most of these patients had oral cavity squamous cell carcinoma (OCSCC). The pooled data showed an overall sensitivity of 0.93 [95% CI 0.90-0.95]. Subgroup analysis showed no significant differences in subgroups. CONCLUSION The high sensitivity of SLNB supports a role in the diagnostic work-up of OCSCC.

Meniscus Replacement Using Synthetic Materials

The meniscus plays a critical role in load transmission, stability and energy dissipation in the knee joint. Loss of the meniscus leads to joint degeneration and osteoarthritis. An increased understanding of the degenerative changes that occur after meniscectomy made clear that it is beneficial to save as much meniscal tissue as possible. Meniscal repair has become a standard procedure, and partial resection of damaged menisci should be performed as sparingly as possible. However, not all damaged menisci can be treated by partial resection or by repair, making a total meniscectomy inevitable. In these cases, replacement of the resected meniscal tissue by an implant might avoid the articular cartilage degeneration. Different types of meniscal substitutes, such as allografts, collagen, permanent synthetic scaffolds, and biodegradable scaffolds, have been used in experimental and clinical studies. This review highlights the research on these meniscal substitutes and shows that current research is mainly focused on a biological tissue-engineering approach either with or without additional cell-seeding techniques.

Comparison of registered and published primary outcomes in randomized clinical trials of surgical interventions

Objective:To assess the proportion of registered surgical trials with results published in journals with high-impact factors; compare the primary outcomes specified in trial registries with those reported in the published papers; and determine whether primary outcome-reporting bias favored significant outcomes. Background:Outcome-reporting bias, that is, the selective reporting of a subset of the original registered outcome measures based on their results, has not yet been studied specifically for surgical trials. Methods:We searched PubMed for reports of surgical randomized controlled trials (RCTs) indexed between 2007 and 2012 in 10 general medical journals and 10 surgical journals with the highest impact factors. For each article included, we obtained the trial registration information using a standardized data extraction form. Results:Of the 327 evaluated surgical trials, registration was lacking for 109 (33%) published papers. Two (2%) of these papers were published in general medical journals and 107 (98%) in surgical journals. Twelve (6%) of the trials were still recruiting patients, and 48 (22%) were registered after completion of the study. A total of 152 trials were registered before the end of the trial with the primary outcome clearly specified. Among these papers, 49% (75 of 152) showed some evidence of discrepancies between outcomes registered and the outcomes published, most often related to omitting or introducing a primary outcome. These discrepancies favored statistically significant results in 28% of the papers. Conclusions:The quality of registration of surgical trials published in surgical journals was inferior to those published in general medical journals. Comparison of the primary outcomes of surgical RCTs registered with their subsequent publication indicated that selective outcome reporting is prevalent and appears to be higher than in general medical trials.

Injectable bone-graft substitutes: Current products, their characteristics and indications, and new developments

More than a decade has passed since the first injectable bone substitutes were introduced for use in orthopaedic trauma, and over recent years the number of commercial products has increased dramatically. Despite the fact that these bone substitutes have been on the market for many years, knowledge amongst potential users on how and when they might be useful is still fairly limited. Most injectable bone substitutes belong to one of two major groups: by far the largest group contains products based on various calcium phosphate (CP) mixtures, whilst the smaller group consists of calcium sulphate (CS) compounds. Following mixing, the CP or CS paste can be injected into--for instance--a fracture space for augmentation as an alternative to bone graft, or around a screw for augmentation if the bone is weak. Within minutes an in situ process makes the substitute hard; the mechanical strength in compression resembles that of cancellous bone, whereas the strength in bending and shear is lower. Over time, CP products undergo remodelling through a cell-mediated process that seems to mimic the normal bone remodelling, whilst CS products are dissolved through a faster process that is not cell-mediated. For CP, a number of clinical studies have shown that it can be useful for augmentation of metaphyseal fractures when a space is present. Randomised studies have verified that CP works especially well in tibial plateau fractures when compared with conventional bone grafting. So far the number of clinical studies on CS products is very low. Development at present seems to be heading towards premixed or directly mixed products as well as new compounds that contain fibres or other components to enhance bending and shear strength. Products that are based on combinations of CP and CS are also being developed to combine the fast-dissolving CS with the stronger and more slowly remodelling CP. Injectable bone substitutes, and especially CS, have also been targeted as potentially good carriers for antibiotics and growth factors.

Management of the N0 neck in early stage oral squamous cell cancer: a modeling study of the cost-effectiveness

OBJECTIVES To assess the cost-effectiveness of five strategies for diagnosing and treating cT1-2N0 oral squamous cell cancer. MATERIALS AND METHODS A Markov decision analytic model was used to evaluate the cost-effectiveness of (1) elective neck dissection (END), (2) watchful waiting (WW), (3) gene expression profiling (GEP) followed by neck dissection (ND) or WW, (4) sentinel lymph node (SLN) procedure followed by ND or WW, and (5) GEP and SLN (for positive GEP) followed by ND or WW. Uncertainty was addressed using one-way and probabilistic sensitivity analyses. RESULTS Base-case analysis showed that SLN procedure followed by ND or WW was the most effective and most cost effective strategy. Compared with direct END the incremental cost effectiveness ratio was €3356 per QALY gained. Uncertainty analysis showed that the model was sensitive to changes in assumed occult metastases incidence and utility values. SLN was found to have the highest probability (66%) of being cost-effective of the five strategies, at a willingness to pay of €80,000 per QALY. CONCLUSIONS Given the current evidence and costs the SLN procedure followed by ND or WW appears to be the most cost effective strategy for diagnosing and treating oral squamous cell cancer patients. Our model provides the foundation for future diagnostic and therapeutic research in this field and shows that further information on quality of life in this population is highly valuable.

Anisotropic Porous Biodegradable Scaffolds for Musculoskeletal Tissue Engineering

It has been generally accepted that tissue engineered constructs should closely resemble the in-vivo mechanical and structural properties of the tissues they are intended to replace. However, most scaffolds produced so far were isotropic porous scaffolds with non-characterized mechanical properties, different from those of the native healthy tissue. Tissues that are formed into these scaffolds are initially formed in the isotropic porous structure and since most tissues have significant anisotropic extracellular matrix components and concomitant mechanical properties, the formed tissues have no structural and functional relationships with the native tissues. The complete regeneration of tissues requires a second differentiation step after resorption of the isotropic scaffold. It is doubtful if the required plasticity for this remains present in already final differentiated tissue. It would be much more efficacious if the newly formed tissues in the scaffold could differentiate directly into the anisotropic organization of the native tissues. Therefore, anisotropic scaffolds that enable such a direct differentiation might be extremely helpful to realize this goal. Up to now, anisotropic scaffolds have been fabricated using modified conventional techniques, solid free-form fabrication techniques, and a few alternative methods. In this review we present the current status and discuss the procedures that are currently being used for anisotropic scaffold fabrication.

Ageing is associated with reduction of mechanically-induced activation of Smad2/3P signaling in articular cartilage

OBJECTIVE Mechanical signals control key cellular processes in articular cartilage. Previously we have shown that mechanical compression is an important ALK5/Smad2/3P activator in cartilage explants. However, age-related changes in the cartilage are known to affect tissue mechanosensitivity and also ALK5/Smad2/3P signaling. We have investigated whether ageing of cartilage is associated with an altered response to mechanical compression. DESIGN Articular cartilage explants of two different age groups (young-6-36 months old, aged-6 - 13 years old) were subjected to dynamic mechanical compression with 3 MPa (physiological) or 12 MPa (excessive) load. Subsequently, essential cartilage extracellular matrix (ECM) components and tissue growth factors gene expression was measured in young and aged cartilage by QPCR. Furthermore, the ability of young and aged cartilage, to activate the Smad2/3P signaling in response to compression was analyzed and compared. This was done by immunohistochemical (IH) Smad2P detection and Smad3-responsive gene expression analysis. RESULTS Aged cartilage showed a highly reduced capacity for mechanically-mediated activation of Smad2/3P signaling when compared to young cartilage. Compression of aged cartilage, induced collagen type II (Col2a1) and fibronectin (Fn1) expression to a far lesser extent than in young cartilage. Additionally, in aged cartilage no mechanically mediated up-regulation of bone morphogenetic protein 2 (Bmp2) and connective tissue growth factor (Ctgf) was observed. CONCLUSIONS We identified age-related changes in cellular responses to mechanical stimulation of articular cartilage. We propose that these changes might be associated with age-related alterations in cartilage functioning and can underlie mechanisms for development of age-related cartilage diseases like osteoarthritis (OA).

Tissue adhesives for meniscus tear repair: an overview of current advances and prospects for future clinical solutions

Menisci are crucial structures in the knee joint as they play important functions in load transfer, maintaining joint stability and in homeostasis of articular cartilage. Unfortunately, ones of the most frequently occurring knee injuries are meniscal tears. Particularly tears in the avascular zone of the meniscus usually do not heal spontaneously and lead to pain, swelling and locking of the knee joint. Eventually, after a (partial) meniscectomy, they will lead to osteoarthritis. Current treatment modalities to repair tears and by that restore the integrity of the native meniscus still carry their drawbacks and a new robust solution is desired. A strong tissue adhesive could provide such a solution and could potentially improve on sutures, which are the current gold standard. Moreover, a glue could serve as a carrier for biological compounds known to enhance tissue healing. Only few tissue adhesives, e.g., Dermabond® and fibrin glue, are already successfully used in clinical practice for other applications, but are not considered suitable for gluing meniscus tissue due to their sub-optimal mechanical properties or toxicity. There is a growing interest and research field focusing on the development of novel polymer-based tissue adhesives, but up to now, there is no material specially designed for the repair of meniscal tears. In this review, we discuss the current clinical gold standard treatment of meniscal tears and present an overview of new developments in this field. Moreover, we discuss the properties of different tissue adhesives for their potential use in meniscal tear repair. Finally, we formulate recommendations regarding the design criteria of material properties and adhesive strength for clinically applicable glues for meniscal tears.

Platelet-Rich Plasma Can Replace Fetal Bovine Serum in Human Meniscus Cell Cultures

Concerns over fetal bovine serum (FBS) limit the clinical application of cultured tissue-engineered constructs. Therefore, we investigated if platelet-rich plasma (PRP) can fully replace FBS for meniscus tissue engineering purposes. Human PRP and platelet-poor plasma (PPP) were isolated from three healthy adult donors. Human meniscal fibrochondrocytes (MFCs) were isolated from resected tissue after a partial meniscectomy on a young patient. Passage-4 MFCs were cultured in monolayer for 24 h, and 3 and 7 days. Six different culture media were used containing different amounts of either PRP or PPP and compared to a medium containing 10% FBS. dsDNA was quantified, and gene expression levels of collagen types I and II and aggrecan were measured at different time points with quantitative polymerase chain reaction in the cultured MFCs. After 7 days, the dsDNA quantity was significantly higher in MFCs cultured in 10% and 20% PRP compared to the other PRP and PPP conditions, but equal to 10% FBS. Collagen type I expression was lower in MFCs cultured with medium containing 5% PRP, 10% and 20% PPP compared to FBS. When medium with 10% PRP or 20% PRP was used, expressions were not significantly different from medium containing 10% FBS. Collagen type II expression was absent in all medium conditions. Aggrecan expression did not show differences between the different media used. However, after 7 days a higher aggrecan expression was measured in most culture conditions, except for 5% PRP, which was similar compared to FBS. Statistical significance was found between donors at various time points in DNA quantification and gene expression, but the same donors were not statistically different in all conditions. At 7 days cell cultured with 10% PRP and 20% PRP showed a higher density, with large areas of clusters, compared to other conditions. In an MFC culture medium, FBS can be replaced by 10% PRP or 20% PRP without altering proliferation and gene expression of human MFCs.