Scientific research and literature remain the foundation of each avenue of dentistry. Dr. Giulia Cerino, Manager of Medical Communications at Geistlich Pharma, sits down with Dr. Steven Eckert to discuss the keys to success in regard to scientific research. Dr. Steven Eckert definitely has a library of tips and experience being a researcher himself as well as the Editor-in-Chief for the International Journal of Oral and Maxillofacial Implants. Whether you are conducting your own research, or you are looking forward to an interesting read – checking out this interview is without-a-doubt worthwhile.
Collagen plays an important role in the regeneration of tissue. This is why Geistlich Pharma has devoted itself to collagen expertise.
Eleven scientists working at Geistlich Pharma have dedicated themselves exclusively to collagen research. Dr. Lothar Schlösser, Niklaus Stiefel and Daniel Suppiger have advanced the company’s 160 years of collagen expertise with their work, as they have developed innovative biomaterials for tissue regeneration.
Dr. Schlösser, collagen performs so many different functions in the body. Is it also the same for the collagen in Geistlich biomaterials?
Dr. Schlösser: It certainly is. The Geistlich Bio-Gide® collagen membrane is a good example. The dense collagen of the upper layer acts as a dividing wall between a bone graft and the soft tissue. The lower layer has a more open structure in comparison. It adheres well to the tissue, allows cells to colonize and contains fibers that serve as “guiding templates” for somatic cells. Although these are very different properties, Geistlich collagen has them all.
How can one modify a protein so that it has either this or that property?
N. Stiefel: Many people think that it has something to do with which one of the 30 different types of collagen one uses, but in fact it is a question of the original tissue and how it is processed. It’s like when you are looking for a house. You can either buy a complete, ready built detached house, or you can buy the individual bricks and assemble something completely new.
And which approach does Geistlich use?
Dr. Schlösser: Both strategies have a role to play for us. Some of our products, for example, if they should be strong to retain sutures, contain native organized collagen tissue obtained using a gentle preparation process. In other cases we have designed our collagen tissue completely from scratch using natural collagen components in order to obtain a specific effect, for example, to achieve good volume stability when healing.
How do the cells react when you alter the collagen?
D. Suppiger: That is the crucial question for our cell laboratory. We continually optimize our collagen products until the right cells do what we want them to: mucosal cells, bone cells, cartilage cells, etc. And to go back to the analogy of houses for a moment, after doing the cell tests, we can really say: here’s the nursery, there’s the living room and that’s the cellar, i.e., testing particular “rooms” to make sure they “attract” the right cells.}
How can the research department help to improve the products?
D. Suppiger: A large part of our work consists of optimizing the handling of a product without compromising its proper effect on cells. Our focus is on the clinician from the very beginning. What’s important to the dentist or orthopedic surgeon? Does the product have to create volume? Must it be easily hydrated? For the requirement analysis, we work together with many clinicians around the world, from top surgeons to less experienced dentists.
Dr. Schlösser: And we test the prototypes in the same way, of course. Finally, we always have animal cadaver models in the lab so that in-house and external specialists can test how the new products perform in use.
How do human cells respond to biomaterials? And how can the interaction be further improved? Geistlich traces these questions in its cell laboratory.
The human body, taken at a cellular level, has long ceased being the closed village community that it was once considered to be. In 1890 Themistocles Gluck fitted the first artificial knee joint in Berlin. Since then, foreign matter within the body has become almost a matter of routine.
There are now 950,000 artificial hip and knee joints implanted each year, just in Europe. To this can be added 6 million dental implants, 2 million of which are accompanied by bone replacement augmentation.
An entire arm of research is now concerned with perfectly integrating biomaterials into human tissue. How do cells respond to the impostor? How can integration be made better, faster and with fewer complications? At Geistlich Pharma’s research site in Wolhusen, a research team is dedicated to these questions. Seven biologists are currently working on investigating the precise interactions between somatic cells and Geistlich biomaterials. Research group leader Dr. Paul Buxton explains to us why this cell research is important.
Geistlich has its own laboratory for testing how cells react to our products. For what exactly are you looking?
Dr. Buxton: We test, for example, different variants of a new bone replacement biomaterial, or we vary specific parameters in the production of Geistlich Bio-Oss®. The key question then is: how does the new product affect the bone-forming cells? What variant best promotes osteogenesis?
Dr. Buxton: Precisely. Cell tests make it possible for us to compare biomaterials at a very early stage of development. Still, findings about cell behavior in a test tube alone are insufficient. Cell tests have to be so well controlled that they really allow conclusions about the situation in a patient. In a certain way this, in turn, is more chaotic, as many different cell types are involved.
Is it possible to make reliable statements with cells such as, for example, with a mechanical tear-resistance test?
Dr. Buxton: To some extent yes. Let’s take, for instance, collagen structures. For the cells these fibers are their home, and they detect the tiniest differences. Certain structures have a function for these cells, others do not, although this is nearly impossible to see “from the outside.” Neither can we calculate it from the chemical, physical and mechanical description of a product, although there are rules. For example, soft materials tend to give rise to neural cell types during cell differentiation, while stiff materials tend to give rise to bone cells, but these hypotheses always require individual tests.
Geistlich Pharma’s cell research: The researchers investigate, for example, which RNA and which proteins are being expressed in different cell types – depending on their surroundings and the biomaterials with which they interact.
Dr. Buxton: To compare which genes are transcribed in mesenchymal stem cells in various situations or on various biomaterials. This, in turn, allows conclusions about how these stem cells further differentiate, and whether they multiply. Such tests permit “objective” statements on whether a product, for instance, promotes the production of bone-forming cells.
Does your research confirm the general wisdom: the more natural the better?
Dr. Buxton: Nature is certainly a good starting point because cells accept natural biomaterials best. Therefore, Geistlich focuses on preparing its biomaterials as “gently” as possible. On the other hand it is nonsensical to only imitate nature without first understanding it. Mankind remained unsuccessful as long as they continued to design, for example, a flying machine just like a bird. Only when they let go of the natural template did “artificial birds” actually take to the sky.
What does this signify for the development of new products?
Dr. Buxton: Our cell research also puts us in a position to fully understand what happens during regeneration and why our materials work so well. We have made some very interesting discoveries in this area, mainly regarding the differentiation of mesenchymal stem cells into osteoblasts. Now we would like to use the discovered mechanisms further, so not just creating new products by trial and error, but by thoroughly understanding interactions at a cellular level.
What can ideally be achieved through such research?
Dr. Buxton: If a good biomaterial contributes to lowering the complication rate by one percent, for a million patients that at least means 10,000 better treatment results.
Collagen is an ancient building block for life that makes a broad variety of tissues. Conversation with the collagen expert Dr. Lothar Schlösser, Head of Geistlich Material Discovery Research, on the successful use of collagen in regenerating bones, cartilage and skin.
Dr. Schlösser, where would our body be without collagen?
Dr. Schlösser: Nearly one third of endogenous proteins are made from collagen. Without this building material we would be nothing. To begin with, we would be completely permeable and a cluster of cells devoid of form, because everywhere, where boundaries are required or where protected spaces need to be created, collagen is used in the body. Secondly, no bone could maintain itself without collagen. Our skeleton would be far too brittle, and we would immediately collapse. Bones possess strength and a certain flexibility because of collagen reinforcement. And thirdly, collagen is vital for providing structure. In the area between cells, collagen is the predominant protein conducting tissue formation. It provides a type of construction manual.
Collagen also seems to be a model for evolutionary success…
Dr. Schlösser: Yes, collagen is far older than bone. Collagen was found in primordial and primitive organisms, such as fresh water polyps, jellyfish and sponges. But even as evolution progressed and bone appeared, collagen continued to be an essential building material.
Nature tinkered with this material in the course of evolutionary history and tried it out in a wide range of areas and functions. This resulted in many extremely useful applications in our body, typically in conjunction with other materials, such as in the combination of collagen and bone.
You make use of this link in bone regeneration.
Dr. Schlösser: That’s right. If I want to build up bone in order to fix dental implants, I need to shield the area for a while. This requires a collagen membrane that is sufficiently impermeable to prevent soft tissue cells from growing into the bony defect. Bone cannot be formed in sites where soft tissues are found.
The membrane is permeable in spite of this barrier function. It permits, for example, nutrients to be exchanged and some communication between the spaces. We therefore have a reliable impediment to soft tissue cells such as fibroblasts, but not complete impermeability.
To what extent is it possible to influence the raw material collagen, to shape it to a required form?
Dr. Schlösser: Considerably. We want to provide the body with a processed raw material characterized by a very specific organization and architecture. To accomplish this, we partly disassemble the bundles of collagen fiber into their component parts and reassemble them, so to speak, by means of freeze-drying. Depending on how this freezing process is controlled, we end up with bigger or smaller ice crystals. Bigger ice crystals produce larger pores, and smaller crystals smaller ones. For membranes with a barrier function, the collagen is not divided but left with its natural organization and architecture.
There is a big need for skin regeneration worldwide. Do Geistlich collagens play a role?
Dr. Schlösser: We don’t have any approved products for these indications, yet. However, a clinical study has been started employing collagen matrices for maxillofacial surgery. It has to do with skin regeneration in the facial area, such as after surgically removing so-called basaliomas, which are tumors that chiefly develop in facial regions with exposure to the sun, such as the forehead, nose or ears. The prevalence has increased a lot in recent years. Many of them have to be excised.
If you leave such a wound to heal on its own, scarred and indented tissue forms, which can be disfiguring, particularly in the face. So far there has not been anything that restores the tissue without leaving a disfigurement. An ingenious collagen matrix system can fill the defects and, as our preliminary data shows, provide good skin regeneration.
Other parts of the body also need “repairing”…
Dr. Schlösser: Yes, knees, for instance. Sports can involve painful cartilage injuries. The AMIC® technique removes part of the damaged cartilage, and the bone beneath it is drilled so that it can bleed into the defect and allow new tissue to form. A suitable collagen membrane is placed over the defect, and provides a protected area in which the tissue can regenerate.
And it works?
Dr. Schlösser: It does, indeed! This operation is relatively complex – but not, for example, compared to the ACI technique, which requires chondrocytes to be cultivated – but it works.
But normally the body repairs itself…
Dr. Schlösser: That is the point. Ultimately, we are just giving nature a little leg up. A body wants to regenerate. But to do so, nature needs protected spaces and assembly instructions that it does not always have.
If we provide a matrix and a safe “zone of tranquility,” the body will have a much easier task regenerating specific structures. We are empowering the body.
Does the body ever say, “I don’t want your help” and reject the material?
Dr. Schlösser: Collagen is very old and preserved genetically across various species. That is, with just a few small exceptions, it is the same building material in all mammals. If collagen is processed well – and this is where Geistlich of course comes in with its expertise – it does not cause immunological reactions. The very rare cases of a collagen allergy are special exceptions.
What needs to be considered?
Dr. Schlösser: The raw material has to be processed very conscientiously and cleanly. It is crucial to stabilize the material.
Collagen is able to store a great deal of water. But this characteristic can destabilize the structure.
Nature helps itself by cross-linking molecules that stabilize the material. If you use processes that weaken the collagen scaffold it then has to be cross-linked to be restabilized. If you cannot control this artificial cross-linking, tissue integration and inflammation can become problems.
Geistlich has been researching and working with collagen as a company for many decades. Do you believe this material still harbors secrets?
Dr. Schlösser: Collagen is extremely versatile; there is still much that we don’t know. Although I have been involved with collagen for a very long time, the material still surprises and fascinates me on a regular Basis.
During a sinus floor elevation, various complications can arise from a perforation of the Schneiderian membrane. How can we predict and avoid complications? How should we deal with a perforated membrane?
Since the Academy of Osseointegration Sinus Consensus Conference held in 1998 the sinus lift has been deemed a highly predictable procedure and effective therapeutic modality.1 For nearly 3000 sinus graft implants with a minimum of three years in function, implant success was 90.0 % over a ten-year period. Set against this knowledge the underlying issue is that, while many studies have evaluated the efficacy of implants in sinus grafts, few have focused specifically on the success of the sinus graft itself. Sinus grafting remains one of the more technically challenging procedures due to, amongst other issues, the delicacy of the Schneiderian membrane and the risk of perforation, post-operative infection and loss of the graft.
Membrane perforation complications
In an article recently published in the Journal of Craniofacial Surgery,2 the risk of complications was described as being “quite low,” and yet one of the more common liability issues in dentistry was the failure of implants in sinus grafts due to the inadvertent partial or complete penetration of implants into the maxillary antrum, along with other sinus lift sequelae. By far the most common complication recorded in the literature is perforation of the Schneiderian membrane, which has been reported to occur in approximately 7 % to 40 % of cases.3-6 However, of greater interest are the underlying complications reported to result from membrane perforation, along with the incidence for such complications.
In a recent study of 200 consecutive sinus lift procedures, 25.7 % experienced a perforation, and of this group, 14.9 % developed further post-operative complications.3
In another study of 359 sinus augmentation procedures, perforation was reported in 41.8 % of cases.5 Of note, 11.3 % of these perforations went on to total graft failure. Conversely, if the membrane remained intact, the graft only failed in 3.4 % of the cases. Of the sinuses developing sinusitis or secondary infection requiring antibiotics, 85 % had a membrane perforation. Accordingly, while membrane perforation may not be seen as a particularly significant complication, it is a potential gateway to more serious sequelae that can result in graft failure. Therefore, membrane perforation should be taken seriously, and clinicians should understand how the risk for perforation might be assessed pre-surgically so that appropriate precautions might be taken. Also, intra-operative risk-minimizing procedures can help limit the size of membrane perforations to <5 mm or, more importantly, avoid complete membrane blow-out.
Factors that influence the complication rate of sinus floor elevation.
First and foremost, pre-operative planning must be computed tomography (CT)-based,7 providing not only three-dimensional (3-D) information on sinus morphology but also the presence or absence of additional risk factors. Septae, the thickness of the sinus membrane, the degree of sinus opacity, the thickness of the buccal cortex, residual bone height and the location of the zygomatic buttress all have the potential to increase sinus perforation risk. Using the Lund Mackay Classification sinuses can be scored for health, i.e., maxillary, frontal, ethmoidal and sphenoidal, to give an overall rating to the patient’s diagnosis, as well as a score of 0 or 2 for the ostiomeatal complex, which has a major bearing on sinus ventilation and drainage.8
A 3-D valuation is the only way to arrive at a thorough risk assessment. In addition, 3D imagery can be used to assess the risk for tearing or snagging the branch of the maxillary artery that passes through the canal buccally, which can result in significant bleeding9, impairing visibility and further increasing the risk for membrane perforation.
Limiting the size of perforations
Despite the best planning and preparation, perforations can still occur. A simple but effective method for limiting the size of sinus perforations involves using a so-called isolation protocol when a perforation first presents. Typically, a perforation will occur adjacent to the edge of the bony window, and the most important first task is to begin preparing a secondary window remote to the first so that the perforation is centralized within the expanded secondary window. It is important not to remove bone directly around the perforation, since this will typically result in a growing perforation. Prior to elevating the membrane, the perforation should be partially covered with Geistlich Bio-Gide®. There is some question as to the need for the Schneiderian membrane for de novo bone formation within the extra-sinusoidal space, however it is prudent to avoid complete coverage of the Schneiderian membrane with Geistlich Bio-Gide® so that the endosteal tissue might be in contact with the subsequent Geistlich Bio-Oss® graft and assist with native bone induction.
The membrane should be elevated remotely from and surrounding the perforation, gradually detaching it and ensuring that healthy membrane surrounds the perforation, which, again, is protected by Geistlich Bio‑Gide®.
Thickening of the membrane post-operatively
The elevated Schneiderian membrane will thicken notably post-operatively. In a recent study the mean thickness of the membrane prior to surgery was 0.73 mm and thickened up to 7.0 mm seven days’ post-surgery.10 This increase was significant, and it took many months for the membrane thickness to return to baseline. This thickening was directly correlated with the extent of sinus elevation.
Thickening has a potential two-fold effect: on the positive side, it can aid in the closure of small perforations, but on the negative side, it can force graft material back out the access window, reducing graft volume within the extra-sinusoidal space. It is imperative to cover the access window with a second collagen membrane, and there may be a valid argument for securing the membrane with pins to resist graft extrusion.
Use of antibiotics
A final tip, when patients have a history of sinus infection, is to rehydrate both Geistlich Bio-Gide® and Geistlich Bio-Oss® in a tetracycline solution of 1 g tetracycline in 20 ml of sterile saline. Tetracycline is known to chelate tenaciously to hydroxyapatite, and Geistlich Bio-Oss® can act as a slow release carrier for this broad spectrum antibiotic.11 There is also evidence that tetracycline delays the degradation of Geistlich Bio-Gide®, thereby increasing barrier function duration.12,13
- Jensen OT, et al.: Int J Oral Maxillofac Implants 1998; 13 Suppl: 11–45.
- Boffano P, Forouzanfar T: J Craniofac Surg 2014; 25(2): e210–12.
- Moreno Vazquez JC, et al.: J Oral Maxillofac Surg 2014; 72(5): 892–901.
- Lin YH, et al.: Clin Oral Implants Res 2016; 27(5): 612–17.
- Nolan PJ, et al.: J Oral Maxillofac Surg 2014; 72(1): 47–52.
- Becker ST, et al.: Clin Oral Implants Res 2008; 19(12): 1285–89.
- Torretta S, et al.: Clin Oral Implants Res 2013; 24: Suppl A100: 57–62.
- Rosano G, et al.: Clin Oral Implants Res 2011; 22(7):711-5.
- Hopkins C, et al.: Otolaryngol Head Neck Surg 2007; 137(4): 555–61.
- Makary C, et al.: Int J Oral Maxillofac Implants 2016; 31(2):331-7.
- Dashti A, et al.: J Biomed Mater Res & Appl Biomater 2010; 93(2): 394–400.
- Moses O, et al.: J Periodontol 2001; 72(11): 1588–93.
- Zohar R, et al.: J Periodontol 2004; 75(8): 1096–101.
- Wen SC, et al.: Clin Oral Implants Res 2015; 26(10): 1158–64.
- Insua A, et al.: Clin Oral Implants Res 2017 ; 28(6):654-661.
- Bornstein MM, et al.: Int J Oral Maxillofac Implants 2016; 31(2): 280–87.
For two decades Prof. Stuart Froum has been treating peri-implantitis patients. He has recently published the results of his experience.
Prof. Froum, what first got you interested in peri-implantitis?
Prof. Froum: In the 80’s dental implants were a new phenomenon, attempted by few and watched critically by many. In the 1990’s and on into the early 2000’s, thanks to intelligent research, success rates were high, and popularity grew by double digits. That’s when the problem referrals started coming into our office.
Because peri-implant disease looked like periodontal disease, even if the etiology was not identical, as a periodontist and educator, I was interested, but I could see that, just as in the early implant days, it would take time and lots of work to find predictable solutions.
However, with peri-implantitis, because it was a problem no one wanted to see, the problem would have to be acknowledged before solutions could be adopted.
You encouraged the US periodontal society (AAP) to adopt guidelines and publish a position paper.
Prof. Froum: Yes, and that was a first step. The EFP and EAO have taken similar steps, seeking consensus around disease definition, etiology and treatment. Getting the societies and, in turn, the clinicians and industry to acknowledge and clarify the problem was no easy task.
We know that peri-implantitis occurs, within the general population of patients, but perhaps not with the same prevalence at all centers – and that’s an important distinction. However, systematic reviews of prevalence report that 5–10 years after implant placement, peri-implantitis affects about 10 % of implants and 20 % of patients.1 But let’s face it, implants have been the goose that laid the golden egg, and no one wanted to upset that egg basket!
That’s why we and others started with publications describing the problem, looking at the incidence and prevalence and testing potential treatment solutions. But we had to start by defining the problem. Without that, no one could agree on how often the problem occurs or, in turn, how we should treat it. Currently peri-implant mucositis and peri-implantitis have been defined, and even more useful, a proposal for a tiered disease classification has been published.2
Your first dental implant complications conference was in NYC in 2012. You went on to run three more. What was the response to those conferences? Do you think they were helpful?
Your Manhattan practice has become known for its treatment of peri-implantitis. What impact has that had on your practice and your relationship with your referring clinicians?
Prof. Froum: We’re proud of what we can do to treat peri-implantitis, but even if we end up with happy patients, peri-implantitis is not a “happy” event – for patients or their referring clinicians. For patients who had the unrealistic expectation that their implants were permanent solutions for problem teeth, there is not only disappointment and the prospect of more treatment but also the question of how things are going to be made right and who is responsible.
Certainly saving implants, even with advanced peri-implantitis, costs significantly less than removing the implants, reconstructing the hard and soft tissue lost due to the disease and replacing the implant and restoration. Even if explantation, augmentation and placement of a new implant and restoration are successful, the cost of a lost implant is approximately three to four times the cost of saving an implant. This cost combined with pain and time delay to restoration can be the difference between keeping and losing a patient.
How do you work with your referring clinicians?
Prof. Froum: When I was a kid in Brooklyn, a new barbershop opened right across the street from an old barbershop and undercut prices by advertising haircuts for 25 cents. Haircuts at that time were 75 cents and up. Soon the old barbershop hung a sign: “We fix 25 cent haircuts for two dollars.” And the old barbershop was a lot more successful than the new one. The lesson? You get what you pay for, and if there are problems down the road, you get what you pay for again!
We are honest with our clinical referrers and our patients, telling them the best and worst that could happen, and then we treat our patients as individuals.
A dentist friend of mine sent me charts and radiographs of one of his peri-implantitis patients, who happened to be his wife. He said, “Stu, will you treat her?” “No,” I said, “but I’ll teach you how to treat her.” Every year, on their anniversary, I get a radiograph of the healthy implant along with a nice thank you note.
The answer is education. We should all be able to diagnose and treat peri-implantitis. Hands-on courses (like the ones Paul Rosen and I give) teach clinicians the techniques that have been so effective in our hands.
In my consent form for implants I include the risk of peri-implantitis as a potential complication. I also tell patients that implants, like teeth, require homecare and professional maintenance and monitoring. If disease occurs and it’s diagnosed and effectively treated in an early state, the chances of treatment being successful and the patient retaining the implant are excellent. When a dentist or a patient wait until the disease has progressed to a point where the patient has pain or an abscess or advanced bone loss due to peri-implantitis, chances of successful treatment are greatly decreased.
How did you develop your peri-implantitis treatment protocols?
Prof. Froum: No one comes up with clinical solutions on his or her own. Collaborative research teams arrive at answers through the teachings of their mentors and by working together. I’m grateful to those who helped me understand periodontal disease and the scientific approach to problem solving, like Dr. Sigmund Stahl, who inspired my clinical research. Along with my research colleagues at the NYU Department of Periodontics and Implant Dentistry, I worked with Dr. Paul Rosen and my son Scott. Together, through trial and error and over two decades of implant therapy learning, we arrived at the solutions you can read about in our most recent publication.3
Your cleaning and regeneration protocol was originally published in 2012, and you followed up with your 2015 publication on 170 implants in 100 patients. What has all this work taught you about treating peri-implantitis?
Prof. Froum: That’s a question that could fill a book, and it has!4 But if I had to sum up, there are eight essential factors for success: (1) proper case selection, (2) flap access that ensures adequate blood supply, (3) extensive implant surface decontamination, including placement of a growth factor, (4) defect debridement, (5) defect fill with proper bone grafts and biologics, (6) coverage with an absorbable membrane, or if there is a deficiency of keratinized tissue, a connective tissue graft, (7) coronal flaps to ensure complete coverage of the membrane/ graft, and (8) professional maintenance with excellent homecare. The key is matching the individual diagnosis with the proper therapy. In our 2015 publication, working in this way resulted in 168 successes out of 170 consecutively treated peri-implantitis cases, with no mucosal margin recession (0.5 mm average gain), bone gains (1.77 mm average) and maintenance with follow-up two to ten years. That tells me that with the proper case selection, results can be predictable and maintained.
Has your knowledge about peri-implantitis changed your implant practice? Do you look at patients, site development and follow-up maintenance/ hygiene differently?
Prof. Froum: Yes. Patient risk factors, implant placement and angulation, proper prostheses for maintenance, and much more… We work top down, looking at how our end outcomes will match our patients’ needs and be maintainable. We have patients who are on two to three month recalls, and we are all in this together – patient, surgeon and restorative dentist.
Interview by Todd Scantlebury
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- Mombelli A, et al.: Clin Oral Implants Res 2012; 23 Suppl 6: 67–76.
- Froum SJ, Rosen PS: Int J Periodontics Restorative Dent 2012; 32(5): 533–40.
- Froum SJ, et al.: Int J Periodontics Restorative Dent 2015; 35(6): 857–63.
- Froum, Stuart J. ed. Dental Implant Complications: Etiology, Prevention, and Treatment, 2nd Edition. Hoboken, New Jersey: Wiley Blackwell, 2016.